Neuro Estudio de Casos Del Dolor Neurologico 2021

Case studies in neurological pain
Downloaded from Cambridge Books Online by IP 128.122.149.145 on Fri Feb 01 15:50:33 WET 2013.
http://ebooks.cambridge.org/ebook.jsf?bid=CBO9781139194099
Cambridge Books Online © Cambridge University Press, 2013
Case Studies in Neurological
Pain
Claudia Sommer
Professor of Neurology at the University of Würzburg, Würzburg, Germany
Douglas W. Zochodne
Professor of Clinical Neurosciences at the Hotchkiss Brain Institute and the University of Calgary, Calgary, Alberta, Canada
CAMBRID GE UNIVERSIT Y PRESS
Cambridge, New York, Melbourne, Madrid, Cape Town,
Singapore, São Paulo, Delhi, Mexico City
Cambridge University Press

he Edinburgh Building, Cambridge CB2 8RU, UK
Published in the United States of America by Cambridge

University Press, New York
www.cambridge.org
Information on this title: www.cambridge.org/9780521695268
c Claudia Sommer and Douglas W. Zochodne 2012

his publication is in copyright. Subject to statutory

exception and to the provisions of relevant collective
licensing agreements, no reproduction of any part may
take place without the written permission of Cambridge
University Press.
First published 2012
Printed and bound in the United Kingdom by the MPG Books

Group
A catalog record for this publication is available from the British

Library
Library of Congress Cataloging in Publication data

Sommer, C. (Claudia)
Case studies in neurological pain / Claudia Sommer, Douglas
Zochodne.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-521-69526-8 (pbk.)
I. Zochodne, Douglas W. II. Title.
[DNLM: 1. Neuralgia. 2. Nervous System Diseases –
complications. WL 544]
616.8 – dc23 2012020248
ISBN 978-0-521-69526-8 Paperback
Cambridge University Press has no responsibility for the

persistence or accuracy of URLs for external or third-party
internet websites referred to in this publication and does not
guarantee that any content on such websites is, or will remain,
accurate or appropriate.
Every efort has been made in preparing this book to provide

accurate and up-to-date information which is in accord with
accepted standards and practice at the time of publication.
Although case histories are drawn from actual cases, every efort
has been made to disguise the identities of the individuals
involved. Nevertheless, the authors, editors and publishers can
make no warranties that the information contained herein is
totally free from error, not least because clinical standards are
constantly changing through research and regulation. he
authors, editors and publishers therefore disclaim all liability for
direct or consequential damages resulting from the use of
material contained in this book. Readers are strongly advised to
pay careful attention to information provided by the
manufacturer of any drugs or equipment that they plan to use.
Contents
Acknowledgments vii
Introduction 1 12 Pain in vasculitic neuropathy 54

13 Painful polyneuropathy associated
with anti-MAG autoantibodies 59
Section A – The biology of
neuropathic pain 14 Painful polyneuropathy associated
with inherited amyloidosis 62
1 Mechanisms of neuropathic pain 2
15 Small iber neuropathy in
sarcoidosis 66
Section B – Focal, or localized 16 Pain and small iber polyneuropathy
neuropathies in Fabry disease 70
2 Pain and carpal tunnel syndrome 16

3 Pain and cervical radiculopathy 19 Section D – Other neuromuscular
4 Pain and diabetic lumbosacral and neurological disorders
plexopathy 23 17 Pain and proximal myotonic
5 Pain and meralgia paresthetica 27 myopathy (DM2) 74
6 Pain and Lyme radiculopathy 18 Complex regional pain syndrome 77

(borrelia-associated radiculitis) 30 19 Pain and polymyalgia rheumatica 82
7 Neuralgic amyotrophy 34 20 Phantom pain 84
8 Painful radiculopathy associated with
herpes zoster infection 37
Section E – CNS disorders
21 Pain in Parkinson’s disease 89
Section C – Generalized
22 Pain associated with amyotrophic
neuropathies or polyneuropathies lateral sclerosis (ALS) 93
9 Pain and chronic inlammatory
23 Pain in Brown-Séquard syndrome 96
demyelinating polyneuropathy 41
24 Pain in syringomyelia 99
10 Pain and diabetic polyneuropathy
(DPN) 45 25 Central pain with thalamic infarct 104
11 Painful idiopathic polyneuropathy 50 26 Pain in multiple sclerosis 108
Contents
Section F – Headache disorders Section G – Treatment

27 Chronic migraine 113 32 Therapeutics in neuropathic pain 135
28 Cluster headache 118
29 Paroxysmal hemicrania 122
30 Trigeminal neuralgia 126 Index 138
31 Headache and acute cerebral ischemia 130
vi
Acknowledgments
Dr. Sommer acknowledges the help of Professor Lazlo Zochodne provided expert and detailed editorial assis-
Solymosi in providing radiological images and of tance for drats of the text. Sally Yakiwchuk pro-
Dr. José Perez for intraoperative photographs. Dr. vided citation prooing assistance. Jane Seakins of
Zochodne acknowledges the support of the Hotchkiss Cambridge Press provided ongoing publishing sup-
Brain Institute, University of Calgary and external port and encouragement.
funding from CIHR, CDA and AHFMR. Barbara
vii
Introduction
Among all patients with neurological disorders, pain clinical indings, investigations, diagnosis, and treat-
is probably the most common symptom experienced. ment. Some vignettes indicate highly complex health
Identifying, understanding, and treating pain is a care trajectories, another important lesson for non-
responsibility of health care providers in all branches clinicians. Despite the vignettes arising from widely
of neurology. separated health care environments in Canada and
his text is about pain in neurological diseases, Germany, the similarities in these health care chal-
both “neuropathic” pain that is recognized in sensory lenges are remarkable. Approximately half of the
neuron disorders but also other types of pain less com- vignettes arise from each clinic. Keeping in mind that
monly considered. hese latter disorders include for the literature is evolving and that some types of neu-
example, pain in Parkinson’s disease, ALS, and muscle rological pain have had limited attention, we review
diseases. he text includes speciic chapters on mecha- key literature points in each vignette and provide cita-
nisms of neuropathic pain, updated with new ideas on tions where possible. As might be expected, the cita-
its pathogenesis, and a summary of recent therapeutic tion density varies widely among these disorders indi-
guidelines. Most of the text however centers on actual cating an uneven literature available to guide clinicians
patient encounters at the Neurology clinics of the Uni- or instruct others. In many instances, illustrations are
versities of Wurzburg and Calgary. his emphasis is taken directly from the patients presented but other
to make the vignettes relevant to clinical practitioners illustrations are also provided as general examples.
but also to introduce researchers and workers in indus- Medicine is a complex specialty that requires
try to the complex and challenging issues faced dur- a tailored approach to care for individuals. While
ing direct patient encounters. herapeutic failures are large cohorts of patients studied in clinical trials
common among our vignettes, highlighting the fact provide essential evidence on which to base prac-
that current therapeutic advances remain inadequate – tice, the reality is much more complex. We have
a challenge for researchers to ind better approaches. hoped to convey these challenges, and some current
In each section, we highlight a clinic patient insights into the associated neurological pain in this
case in a “vignette” emphasizing the patient’s history, text.
http://dx.doi.org/10.1017/CBO9781139194099.001
Section A The biology of neuropathic pain
Chapter
Mechanisms of neuropathic pain
1
he clinical cases presented in this text highlight the a disorder of the peripheral nervous system. Using
variety of clinical neurological disorders associated this qualiication, its characteristics share common
with pain. As should be evident from the range of con- descriptive features: burning, prickling, tingling
ditions presented and the parts of the nervous sys- (paresthesiae), electrical sensations, and pain gen-
tem they impact, pain can arise from any level of erated by otherwise innocuous stimuli (allodynia).
the neuraxis: sensory receptor to cortex. Similarly the More recently, neuropathic pain has also been used
disease processes that generate it are extensive from to describe pain arising anywhere along the neuraxis.
sensory neuropathies to thalamic cerebral infarction. his broader usage has generated more descriptors, as
he experience of pain is subjective, inluenced by the demonstrated in the cases presented in this text.
context in which it occurs and the person in whom his introductory chapter presents a brief overview
it develops. It may be painful to one person while of the mechanisms and mediators of pain in neurologi-
it brings on a heightened, reduced or even absent cal conditions. It is a body of knowledge that is rapidly
response in another. he degree of pain is heavily inlu- expanding beyond ideas that can be conveyed at the
enced by the circumstances in which it occurs and time of writing. Much of this knowledge has evolved
the underlying psychological status of the suferer. For from investigations of speciic peripheral neuropathic
example, patients with depression may have greater pain mechanisms. he pain process involves the ner-
diiculty coping with pain and its intensity may be vous system widely; even pain of exclusive peripheral
magniied by the concurrent problems they face. For origin may lead to secondary changes within the sen-
these reasons, it is best described as a “pain experi- sory ganglia, dorsal horn of spinal cord, brainstem,
ence,” as distinguished from nociception, the trans- thalamus, and cortex. Major aspects are illustrated in a
mission of potentially harmful stimuli through neu- summary scheme [Figure 1.1]. We begin by discussing
roanatomical “wiring” and neurochemical mediators. mechanisms that generate pain in the periphery at
“Neuropathic pain” is a subset of the pain experi- either damaged or intact distal axons and nerve ter-
ence speciic to damage incurred in the nervous sys- minals, and then proceed to analyze its development
tem. A current deinition of neuropathic pain is pro- higher along the neuraxis.
vided by Treede and colleagues who describe it as
“pain arising as a direct consequence of a lesion or dis-
ease afecting the somatosensory system” (1). In this Ectopic impulses
description, neuropathic pain was graded on the fol- he development of the pain experience from distal
lowing criteria: 1. pain with a distinct neuroanatom- injuries begins with ectopic, or unexpected sponta-
ically plausible distribution; 2. a history suggestive of neous discharges from peripheral axons and their ter-
a relevent lesion or disease involving the peripheral or minals. he terminals of axons that normally subserve
central somatosensory system; 3. demonstration of the nociception are found in the epidermis of the skin but
distinct neuroanatomically plausible distribution by at also in many other tissues such as the meninges, liver
least one conirmatory test; 4. demonstration of the rel- capsule, joint capsule, periosteum, mesentery, and
evant lesion or disease by at least one conirmatory test. muscle. A large complement of aferent axons, usually
With the above criteria, deinite neuropathic pain met unmyelinated “C” ibers, are normally found in nerves
all 4, probable 1, 2 and 3 or 4, possible 1 and 2. to muscles and serve to transmit painful stimuli. his
Strictly speaking, neuropathic pain has been used explains why muscles can become painful ater pro-
2 to refer to symptoms associated with neuropathy, longed exercise or during needle electromyography.
Chapter 1: Mechanisms of neuropathic pain
MECHANISMS OF NEUROPATHIC PAIN Figure 1.1. Simplified scheme

identifying major events involving the
neuraxis in the generation of neuropathic
Change in neuron phenotype pain. These include (from right to left),
Ion channel remodeling activation of nociceptors with neurogenic
Central sensitization Intraganglionic sprouting inflammation, a cascade of molecular
including windup events associated with Wallerian (WD)
Remodelling and Wallerian-like degeneration (WLD) in
Microglial activation Damage to axons the nerve trunk, alterations in neuronal
phenotypes in the dorsal root ganglia
Nociceptive with WD and WLD with ion channel remodeling and
neurons Activation of nervi nervorum
intraganglionic sprouting, and changes in
the dorsal horn of the spinal cord
including remodeling, windup, and
Activation of nociceptors microglial activation.
Dorsal root ganglion Neurogenic inflammation
Peripheral nerve
Lumbar spinal cord Skin
At one time, it was also deliberately evoked by neurol- potentials is uncertain but the process likely involves
ogists who tested patients for tabes dorsalis by iden- a redistribution or alteration in their ion channels.
tifying lack of sensation to deep pain while squeez- Devor and colleagues demonstrated that injured axons
ing major proximal muscles. Tabes dorsalis, a tertiary swell to form axonal endbulbs, enlarged proximal por-
complication of syphilis (neurosyphilis), inlames and tions of severed axons where axoplasmic material can
damages the dorsal root entry zone of aferent ibers accumulate (2). Within these endbulbs, accumulations
resulting in loss of deep pain sensitivity. of sodium channels, some inserted into the mem-
Normally nociception is transmitted by unmyelin- brane, may be capable of generating ectopic activity.
ated C axons and small myelinated A␦ axons with Speciic blockers of these channels, such as phenytoin
conduction velocities of 0.5–2.0 m/s and 12–30 m/s, or lidocaine, interrupt spontaneous discharges. Sev-
respectively. It is not known whether specialized struc- eral mechanisms are capable of changing the electri-
tures within these ibers are found at their terminals, cal properties of sodium channel subtypes Nav 1.1 to
but it is generally thought that they transmit nocicep- 1.9 and thus the sensitivity of the respective nerve iber
tion through “bare” or “free” nerve endings. hey are (3, 4) [see below]. Genetic alterations in the sodium
stimulated by noxious mechanical, chemical, or ther- channel subtype Nav 1.7 may lead to hyperactive chan-
mal stimuli through specialized channels or receptors. nels. his is the pathophysiological basis of disorders
A large complement of “silent” nociceptors, those only such as erythromelalgia and paroxysmal extreme pain
recruited during tissue damage and more signiicant disorder (5). On the other hand, mutations that silence
injuries, may also exist. the channel lead to congenital insensitivity to pain (6).
In discussing neuropathic pain, our emphasis is In addition to structural alterations of individ-
on how damaged or diseased axons or neurons gen- ual damaged axons, pain may also arise from aferent
erate pain. Ectopic action potential discharges can be ibers that self-innervate the peripheral nerve trunk.
recorded from single axons proximal to a nerve trunk Nervi nervorum are unmyelinated axons found within
injury and their frequency has a strong direct correla- the epineurial nerve sheath (7–9). his fascinating
tion with the perceived intensity of pain. Ectopic dis- mechanism is considered in more detail later.
charges may be continuous or tonic, in phasic bursts, he activation or sensitization of peripheral axons,
or completely irregular. How quiescent transmitting especially ater injury, involves the participation of
axons develop the capacity for generating ectopic a range of pain-generating and pain-attenuating 3
Section A: The biology of neuropathic pain
molecules, considered below. he sheer numbers of macological inhibitors to either bradykinin receptor
players involved has prompted diverse thoughts on that dampen neuropathic pain in rats (10).
therapy and intervention to treat neuropathic pain. ATP acts as an algesic molecule through spe-
ciic purinergic receptors that include P2X3, P2X2/3,
P2X4, P2X7, and P2Y. Alternatively, P2X3 antagonists
Algesic molecules are analgesic. P2X receptors are nonselective cation
Within the vicinity of an injured peripheral nerve channels permeable to calcium, sodium, and potas-
axon, a range of newly expressed molecules are capa- sium with downstream actions on the MAPK path-
ble of facilitating ectopic discharges that result in way. Whereas P2X3, P2X2/3, and P2Y activate neurons
pain. hese molecules are termed algesic. Extracellular directly, P2X4 and P2Y may activate neurons indi-
potassium, released from dead and dying cells, helps to rectly through the activation of nearby microglia (11).
depolarize nearby axons. Similarly, there may be accu- P2Y may also modulate TRPV1 receptors and increase
mulation of hydrogen ions in ischemic acidotic injured their sensitivity (see below). In a related pathway, P1
tissues that activate acid-sensitive ion channels and receptors activated by adenosine inhibit nociception.
TRP channels (see below). Several algesic molecules During peripheral nerve injury, there is rapid
likely inluence the excitability of damaged axons by expression of inlammatory mediators produced by
synergistic interactions, or by changing the proper- intrinsic cells such as Schwann cells, endothelial cells,
ties of the inal common pathway mediated by ion and ibroblasts in the early phase, within hours. hese
channels expressed on axons. Speciic ion channels are mediators are also expressed by invading macrophages
described below. and T-lymphocytes at later phases over several days.
Combinations of algesic molecules released from One interesting scenario involves a sequence of events
local macrophages and leukocytes comprise an that follows initial primary axon damage: activation of
“inlammatory soup” that generates neuropathic pain: Schwann cells occurs as a result of calcium released
these include tumour necrosis factor ␣ (TNF␣), nitric from damaged axons (12), the activation of Toll-
oxide (NO), interleukin-1␤ (IL-1␤), proteases that act like receptors (13), and the subsequent production of
on PAR2 receptors, and others. Algesic molecules are pro-inlammatory cytokines, chemokines. Additional
linked with generating pain behavior in experimental molecules involved in this process include calpain
animal models. Histamine is associated with the (14, 15) and later glutamate (16). Chemokines such
development of closely related sensory symptoms as CCL-2, in addition to their release by inlamma-
including both pain and itch. Nerve growth factor tory cells, may be packed into neuronal synaptic vesi-
(NGF) is a potent algesic substance causing sensations cles and serve as neurotransmitters in the spinal cord
of deep aching pain when injected subcutaneously (17, 18). Ater injury, Schwann cells and hematogenous
or intramuscularly. NGF may act through its high macrophages newly express iNOS (inducible nitric
ainity TrkA receptors, known to be expressed in oxide synthase), a potent generator of NO, an addi-
small caliber sensory axons that subserve nociception. tional inlammatory mediator (19).
Neuropeptides, such as substance P (SP) and cal- Prostaglandins synthesized by cyclooxygenases
citonin gene-related peptide (CGRP), are released by (COX1 and COX2), especially PGE2, are also medi-
sensory axons in tissues during injury. It is possi- ators of pain during inlammation. COX2 may be the
ble that they auto-reactivate the sensory axons that more important of the two cyclooxygenase enzymes
originally released them to amplify pain sensations. during neuropathic pain and it is mainly expressed
Better described however, is a pathway in which SP by Schwann cells and inlammatory cells such as
and CGRP act on mast cells to release histamine and macrophages ater nerve injury (20–22). PGE2 acting
serotonin as direct algesic molecules. Bradykinin is through its EP1 receptors activates sodium and potas-
an algesic molecule that arises from the proteolytic sium channels in neurons, inhibits potassium chan-
cleavage product of kininogen during inlammation. nels, releases SP and CGRP, and sensitizes neurons to
Bradykinin acts on B1 and B2 receptors, both of which bradykinin and capsaicin (23).
are upregulated in sensory ganglia ater a peripheral Proteinase-activated receptors (PARs) are a spe-
injury. B2 receptors rise early, within 48 h of injury, cial class of cell surface receptors activated by pro-
4 whereas B1 receptors rise later, by 14 days. Both con- teinases such as thrombin, trypsin, mast cell tryptase,
tribute toward pain behavior as demonstrated by phar- and others (24). Cleavage at their extracellular amino
terminus exposes a tethered ligand that in turn acti- attenuate neuropathic pain but CB1 inhibition may
vates the receptor. PAR1 and PAR2 are expressed on cause undesirable side-efects because of its unrelated
sensory aferents, and PAR2 agonists can induce the actions on neurons (31).
release of SP and CGRP by sensory neurons to pro- Anti-inlammatory cytokines such as IL-4 and IL-
mote hyperalgesia (25). In contrast, PAR1 agonists are 10 not only counteract pro-inlammatory cytokines
associated with analgesia (26). but also appear to have an intrinsic analgesic action
Taken together, it is highly likely that the neuro- (34). Overall, these molecules are coordinated within
pathic phenotype arises from a combination of algesic an anti-inlammatory systemic cytokine proile that
molecules, in turn overcoming endogenous forms of attenuates neuropathic pain in humans with periph-
analgesia, considered next. eral neuropathy (35).
Galanin is a neuropeptide that can inluence pain
behavior. Activation of its GALR1 receptors inhibits
Analgesic molecules nociception, whereas its GALR2 receptors are excita-
Injured peripheral nerves also express analgesic medi- tory. By blocking SP and CGRP action and increasing
ators that dampen pain sensations. he endogenous the actions of morphine, its predominant action dur-
opioids are the most prominent. For example, ␤ endor- ing peripheral nerve injury or inlammation is anal-
phin and met-enkephalin are expressed by inlamma- gesic (36). Finally, the neurotrophic molecule NT-3
tory cells at injury sites (27, 28). his form of expres- acts to reduce thermal hyperalgesia by downregulating
sion may attenuate pain by altering the release of the expression of TRPV1 channels (see below) (37).
algesic molecules from inlammatory cells that inil- We next consider how speciic anatomical sites of
trate the injured nerve. In addition however, endoge- the peripheral nervous system and spinal cord partici-
nous opioids can act directly on local ␮ opioid recep- pate in the generation of neuropathic pain. We start
tors expressed by axons, including axonal endbulbs. by considering how axons participate in peripheral
For example, ligation of ␮ opioid receptors by small inlammation.
near nerve doses of agonists reversed features of exper-
imental neuropathic pain including thermal hyperal- Neurogenic inlammation and nervi
gesia and mechanical allodynia (29).
Nociceptin (orphanin FQ) is an analgesic molecule nervorum
that acts on opioid receptor-like 1 (ORL1) receptors. Tissue damage that generates pain is closely associated
Both the ligand and receptor are expressed by DRG with neurogenic inlammation. Neurogenic inlamma-
sensory neurons and their expression increases follow- tion refers to the active participation of terminal sen-
ing peripheral inlammatory stimuli (30). Part of their sory axons in expanding and intensifying an inlam-
analgesic action arises from suppression of inlamma- matory reaction associated with tissue damage. Classi-
tory pain mediators. cally, activated sensory axons within inlamed tissues
Cannabinoids are analogs of ⌬ 9 -tetrahydro- send discharges back toward the central nervous sys-
cannabinol (THC), the active ingredient of marijuana. tem. At branch points along the activated sensory axon
hey operate as analgesics by acting on two separate tree, axons arising send backired antidromic (the
receptors, labeled CB1 and CB2 (31–33). CB1 recep- reverse direction of physiological axon activation) dis-
tors are found in the central and peripheral nervous charges down axons where they release neuropeptides
system where they inhibit calcium inlux and enhance (38, 39). Because these territories are adjacent to those
inward-rectifying potassium channels. In contrast, originally associated with sensory terminal activation
CB2 receptors are largely localized to immune cells (branch territories), the release of these neuropeptides
(mast cells, T cells, B cells, NK cells, microglial cells, can thereby enlarge the inlammatory response. SP
and macrophages in addition to monocytes and and CGRP are potent vasodilators, whereas SP also
PMNs) and keratinocytes. Expression may also be causes plasma extravasation from vessels. Both may
found on microglial cells in the dorsal horn of the act on mast cells, causing their degranulation and
spinal cord that are activated following nerve injury. release of histamine, serotonin, and proteases (39).
Ater nerve injury CB2 receptor expression is dramat- hrough neurogenic inlammation, local neu-
ically upregulated on primary sensory neurons. hus, ropeptides contribute to the cardinal signs of inlam- 5
inhibition of CB1 receptors, CB2 receptors or both mation in tissues, as elegantly described by Lewis
(38, 40): dolor (pain), rubor (redness from rises in nerve that is accompanied by cytokines, chemokines,
blood low), and tumor (swelling from plasma extrava- NGF, NO, and other molecules. Previous studies have
sation). Peripheral nerve trunks, self-innervated by SP outlined the timetable of cytokine and chemokine
and CGRP nervi nervorum axons in their epineurial expression during WD with both early rises in some
sheaths, also undergo this type of enhanced inlamma- mediators and later rises in others. One working
tion (7). It is possible that inlammatory neuropathies hypothesis suggests that neuropathic pain may be
may generate neuropathic pain through this mech- triggered and maintained as a function of the intensity
anism without the presence of overt axon damage of the nearby inlammatory milieu. In conditions
(8, 9). such as diabetes, where the onset and clearance of
Overactive neurogenic inlammation may also inlammation is delayed, neuropathic pain may be
contribute to pain syndromes such as complex regional prolonged (44). During regeneration and clearance of
pain syndromes I and II (CRPS I and II). CRPS I the products of WD, neuropathic pain diminishes. he
by deinition does not include actual nerve damage, only caveat to this concept is that regenerating sprouts
whereas CRPS II does. Relex sympathetic dystrophy can exhibit mechanosensitivity and may promote
(RSD) is a term previously applied to CRPS; adren- some types of neuropathic pain during recovery.
ergic overactivity was thought to be involved in its Next we discuss how DRG sensory neurons par-
pathogenesis. he evidence for prominent adrener- ticipate in pain generation.
gic involvement however, has been limited and other
mechanisms may account for its features. For exam- Changes within sensory dorsal root
ple, chronic activation of SP and CGRP containing C
nociceptors may better account for the redness and ganglia and their terminals
swelling that accompany CRPS (41, 42). Next we dis- Sensory dorsal root ganglia (DRGs) that house the cell
cuss how axon degeneration may generate inlamma- bodies, or perikarya, of sensory neurons, participate in
tion and pain. the development of neuropathic pain. Normally, DRG
neurons can be segregated into various types depend-
ing on their size, peptide content, and other proper-
Inlammation, Wallerian ties (45). Small sensory neurons are classically asso-
degeneration, Wallerian-like ciated with nociception, express SP, CGRP, and also
express TrkA receptors that are ligated by NGF. A sec-
degeneration ond population of small sensory neurons are known as
Following nerve injury, axons and neurons are exposed non-peptidergic, are responsive to GDNF, express the
to inlammatory pain mediators, or algesic molecules GDNF and neurturin receptors GFR␣1 and GFR␣2,
as discussed above. Speciic inlammatory disorders of respectively, and have a binding site for the Grifonia
peripheral nerves, such as vasculitis, CIDP or GBS, simplicifolia IB4 plant lectin. hese neurons project
may be expected to attract large numbers of lym- to lamina IIi (inner portion of lamina II) and are
phocytes and macrophages to the endoneurium. Ater referred to as NGF unresponsive small aferents. hus,
simple axon injuries however, such as transection or these neurons difer from TrkA neurons that project to
crush, an inlammatory cascade also occurs. Augustus laminae I and IIo. Ater axon injuries, DRG neurons
Waller described a sequence of pathological changes change their phenotype in numerous ways, facilitat-
that develop distal to sharp nerve transections since ing pain discharges and allowing them to act as inde-
referred to as Wallerian degeneration (WD) (43). pendent generators of ectopic discharges. hus, ater
Wallerian-like degeneration (WLD) refers to a near a peripheral axon lesion, ectopic discharges can arise
identical sequence of events in distal axons that may not only from damaged axons at the injury site, but
follow a crush or occur in other neuropathies. also from their parent DRG neurons. DRG neurons
Within 1–2 days following injury, axonal swellings assume pacemaker-like properties, generating spon-
or endbulbs develop in proximal stump axons. heir taneous ectopic discharges that correlate with pain
potential role in elaborating neuropeptides and intensity (2).
expressing sodium channels was considered above. he alterations in DRG neurons associated with
6 Later, by days 3–5 following nerve injury, there is an axon injury and neuropathic pain involve expres-
inlux of macrophages into the injured peripheral sion of speciic ion channel subtypes. Both rises and
declines in speciic channels have been described: here are changes in calcium channel expression
declines in Nav 1.9 (NaN/SNS2; TTX resistant, found and function, including their interaction with adren-
in small to medium sized neurons), Nav 1.8 (SNS/PN3; ergic receptors (52, 53) ater axon injury. A notable
TTX resistant; found in small neurons), IKIR (inwardly example is the ␣2␦-1 calcium channel subunit, upreg-
rectifying), and Kv 1.4 (fast transient potassium chan- ulated ater axon injury, and now known to be the
nel, small neurons) and rises in Nav 1.3 (sodium chan- target of the analgesic compounds pregabalin and
nel, Na␤3 subunit in small neurons) and KCNQ2,3,5 gabapentin (54–56). N-type calcium channels (Cav 2.2)
(related to potassium channels and associated with M may be particularly important in the generation of
currents). Still other changes are described in large neuropathic and chronic pain. Widely distributed in
DRG sensory neurons but their association with neu- the nervous system, these channels exhibit high den-
ropathic pain is uncertain, e.g., declines in Kv 1.1,1.2, T sity expression in DRG neurons and in the synaptic
Ca2+ , Kv ␤2.1, and IKIR . Some ion channel changes in terminals of the dorsal horn, laminae I and II. In the
both large and small neurons difer when the ganglia dorsal horn of the spinal cord, N-type channels con-
are inlamed or exposed to NGF (see review by Law- trol glutamate and SP release (57). Peptides isolated
son (46)). from cone snails, such as ␻-conotoxin-MVIIA and
Alterations in Nav 1.7 (PN1 or hNE9), also ␻-conotoxin-GVIA that block N-type calcium chan-
expressed in DRG sensory neurons, are of consid- nels, are potent analgesic molecules (58, 59). More-
erable interest (47). For example, lack of functional over, there are two calcium channel splice isoforms of
Nav 1.7 is associated with insensitivity to pain but N-type calcium channels labeled e37a and e37b that
paradoxically a pain syndrome known as erythrome- have difering properties (60). E37a is expressed in 55%
lalgia can arise from mutations of Nav 1.7. he mutated of nociceptive capsaicin-sensitive neurons, and con-
channel has altered properties that promote hyper- tributes to SP release. E37a knockdown blocks basal
excitability of neurons. Patients with erythromelalgia thermal and mechanical nociception, thermal and
describe the cardinal features of neuropathic pain mechanical inlammatory hyperalgesia tested using
including chronic burning sensations of the limbs. the formalin paw test, and thermal hyperalgesia in the
An additional pain syndrome known as paroxysmal chronic constriction (CCI) neuropathic pain model.
extreme pain disorder (PEPD) is associated with E37b has fewer efects overall but alters tactile allo-
a separate distinct mutation of Nav 1.7. Unexpected dynia. Inhibition of the binding of collapsin response
expression of Nav 1.7 has been identiied in the axons of mediator protein 2 (CRMP-2) to Cav 2.2 decreased
chronic human neuromas where they may contribute neuropeptide release from DRG neurons and reduced
toward ectopic discharges and neuropathic pain (48). excitatory synaptic transmission in the spinal cord
Recently, Faber et al. (49) identiied missense gain of dorsal horn (61).
function mutations of Nav 1.7 that result in neuronal In addition to ion channels, there is a wide reper-
hyperexcitability in 8 of 28 patients with idiopathic toire of molecular changes in DRG sensory neu-
painful small iber neuropathy. he collaboration with rons that have sustained an injury to their axons.
Nav 1.8, nearly exclusively expressed in DRG sensory Some are associated with the development of pain,
neurons, is also involved in the pain syndromes linked whereas others prepare neurons for regenerative activ-
to mutant Nav 1.7 channels. Nav 1.8 may also be a ity (RAGs, or regeneration associated genes). Morpho-
critical player in other types of neuropathic pain (47). logical changes accompany alterations of RAGs, ret-
he hyperpolarization-activated, cyclic nucleotide- rograde changes known as the “cell body reaction”
gated cation channel (HCN2) in Nav 1.8 expressing (or the “axon reaction”: central chromatolysis and dis-
nociceptors appears to be critical for the iring of these placement of nuclei to the periphery of the cell (62)).
neurons ater nerve injury and in inlammation (50). Medium diameter sensory aferents, newly expressing
he roles of Nav 1.9 and Nav 1.3 are less clear. SP, initiate the transmission of pain information. Ater
Sensory neurons also express A-type K+ chan- axotomy, small neurons upregulate galanin, a poten-
nels that attenuate pain. Two subtypes known as Kv3.4 tial analgesic peptide, downregulate ␮ opioid recep-
and Kv4.3 have distinguished themselves; when these tors, and downregulate the peptides SP and CGRP, the
subtypes are suppressed by antisense oligodeoxynu- TrkA NGF receptor, and P2X3 purinergic receptors.
cleotides, rats develop mechanical hyperalgesia with- P2X3 receptors are prominent on IB4 non-peptidergic 7
out thermal hyperalgesia (51). neurons. Ater injury, large neurons upregulate BDNF,
TNF␣, NPY, and ␣2 adrenergic receptors. In contrast melastatin 8), the cold- and menthol-sensitive recep-
to the downregulation of opioid receptors ater injury tor neurons comprise 5–10% of the DRG neuron pop-
described above, a partial nerve injury model showed ulation; this proportion increased ipsilateral to an
increases in ␮-opioid receptors (MORs) expressed by experimental neuropathic lesion (chronic constriction
sensory neurons ipsilateral to the injury (29). Periph- injury) along with a rise in their sensitivity (68). his
eral inlammation also generates rises in CGRP, SP, and may be a mechanism for the process of cold allodynia,
BDNF in DRG neurons that contrast to the declines the perception of innocuous cold stimuli as painful.
observed ater injury (63). Acid-sensing ion channels (ASICs) also partici-
DRG neurons express ␬ and ␦ opioid receptors, pate in the generation of pain, with functions and
sometimes colocalized, that inluence pain transmis- expression patterns that overlap with TRPs (69). hese
sion and that may change during inlammation (64). are voltage-independent depolarizing cation channels
Small DRG neurons express ␦-opioid receptors (DOR) largely used by sodium ions. he PNS expresses ASIC
that, like MORs, are analgesic (63). Nociceptin and 1a,b, 2a,b, and ASIC3. ASIC3 are the most well charac-
its receptor ORL1 are expressed in larger numbers of terized and serve as mediators of acid-induced cuta-
DRG neurons ater peripheral inlammatory lesions neous pain, integrators of thermal hypersensitivity
(30). during inlammation, and mediators of muscle pain.
Sensory neurons that are not primarily injured Bohlen et al. (70) examined the toxin from the venom
but housed in the same DRG as injured neighbors of the Texus coral snake (Micrurus tener tener) and
may change their phenotype in ways that promote puriied a toxin responsible for the intense pain gener-
neuropathic pain. his interesting phenomenon may ated by this venom. he toxin, MitTx, was highly selec-
arise from interactions of intact “en passant” axons tive for ASIC1a and 1b channels.
with inlammatory mediators associated with dam- In addition to morphological and molecular
aged neighbours, or through interactions within the changes in parent neuron perikarya ater injury, there
DRG itself. Examples of neurons that change their are also changes in the behavior of their neighbouring
DRG phenotype when not directly injured are those glial cells. Sensory neurons in DRG are closely sur-
containing CGRP (65) and P2X3 (66). P2X3 recep- rounded by perineuronal satellite cells, cytoplasmic
tors, discussed above, are cation channels activated by poor relatives of SCs that closely wrap them. Remark-
ATP, exclusively localized to DRG and trigeminal sen- ably, these cells enlarge and proliferate ater injury
sory neurons. hey may facilitate pain neurotransmis- indicating a sensitivity to events involving the neuron
sion. CGRP, as discussed above, arises from small and some distance away. While it is known that satellite
medium sized sensory neurons. It has a role in neuro- cells can elaborate growth factors, it is also possible
genic inlammation as a vasodilator and potentiates SP that they participate in the neuronal remodeling that
nociceptive signaling in the dorsal horn of the spinal leads to neuropathic pain. his hypothesis remains
cord. unexplored. Macrophages inlux into DRG ater distal
Another important family of molecules expressed axotomy and can elaborate IL-6, and likely other
by sensory neurons are the transient receptor potential inlammatory mediators (71–74). hus, both changes
proteins (TRPs), ion channels permeable to cations. in perikaryal properties and involvement in neigh-
he classical TRP channels include the capsaicin boring cells may allow DRGs to act as pacemakers as
receptor (TRPV1) that mediates heat and acid stim- neuropathic pain develops.
uli and the TRPM8 or menthol channel that mediates Injuries to peripheral nerves also induce retro-
cold sensations. Other TRPs include TRPV2,3,4 and grade sprouting of sympathetic adrenergic axons from
TRPA1 (mild warming for TRPV4; moderate warm- nearby perivascular innervation into ganglia (75–77).
ing to 31◦ C for TRPV3, heat for TRPV1 and noxious he axons form pericellular basket-like structures in
heat for TRPV2 with mild cooling by TRPM8 and nox- which tyrosine hydroxylase (TH) varicosities contact
ious cooling by TRPA1). Ipsilateral to a partial nerve sensory neuron perikarya. his interesting property
injury (CCI, chronic constriction injury), increases in depends on NGF availability in the ganglia as a result
TRPA1, TRPV1, TRPV2, and TRPM8 were observed of retrograde transport of the growth factor from
(37, 67). Rises in TRPV1 occur in small to medium target tissues. Noradrenergic sympathetic sprouting
8 sized neurons in the DRG and could be suppressed varies in its latency of onset in experimental nerve
by NT-3 (37). TRPM8 (transient receptor potential injury and pain models. his intriguing phenomenon
may be related to “sympathetically mediated pain” as aspartate) receptors. Predictably, infusion of NMDA
described in CRPS I and II (Chapter 18). intrathecally in rats generates a regional pain syn-
he possibility that neuropathic pain might also be drome (79). Recently, zinc has been discovered to be
generated by direct damage to DRGs is also a consid- an endogenous modulator of excitatory neurotrans-
eration. Relatively little work has examined the con- mission in the spinal cord through NMDA receptors
sequences of direct traumatic DRG injury. he possi- containing a particular subunit named NR2A (80).
bility that common pain syndromes such as cervical he adipocytokine leptin is a molecule that enhances
or lumbar spondylosis may involve compression and NMDA receptor function in neuropathic pain (81, 82).
damage of DRG neurons is addressed in Chapter 3 Mapping the activation of the proto-oncogene c-
(cervical radiculopathy). fos protein Fos has allowed analysis of the neu-
Alterations in DRG neuronal behavior “feed for- roanatomic basis of pain pathway participation ater
ward” into altered processing of pain discharges in the injury or inlammation, and its modulation (e.g., by
central nervous system, considered next. analgesics) (see review by Coggeshall (83)). Fos rapidly
rises in neurons during activation of the nociceptive
or pain pathways and its behavior is speciic, induced
Role of the dorsal horn of spinal cord by few stimuli beyond pain. Although its expression
he dorsal horn of the spinal cord (and the nucleus of can persist in chronic pain states, its expression is typ-
the spinal trigeminal tract) is the irst central aferent ically short-term in a maximum range of 30 min to 2 h.
center to receive nociceptive discharges. heir com- his facilitates its analysis in acute pain studies. Lam-
plex circuitry predictably inluences the information inae I and II develop intense expression of Fos ater
that ascends to other CNS centers. Similarly, their noxious stimuli followed by upregulation in lamina V
output can be modiied by descending systems that and others. Higher centers that express Fos include the
are largely anti-nociceptive but also pro-nociceptive. reticular formation, the nucleus of the solitary tract,
As one might expect, their connections also undergo the parabrachial nucleus, the periaqueductal gray, the
important changes in the setting of peripheral nerve locus coeruleus, the hypothalamus, the thalamus, and
injury or inlammation. the cortex. Fos upregulation follows peripheral nerve
he dorsal horn is divided into Rexed laminae, the lesions, spinal cord damage, dorsal root avulsion, and
outermost of which by deinition is layer I. Unmyelin- DRG irritation. Interestingly, simple dorsal root injury
ated C aferents largely synapse in layer II (IB4 neu- does not activate Fos. As expected from the earlier dis-
rons may also synapse in layer I), also known as the cussion, Fos expression can be attenuated by a range
substantia gelatinosa. Small myelinated A␦ nociceptive of analgesics including: opioids, NMDA antagonists,
aferents synapse in layers I and V. he most impor- GABAB agonists, NK1 antagonists, cannabinoids, and
tant neurotransmitter released by aferents is gluta- nonsteroidal anti-inlammatory agents (83).
mate, in turn acting on NMDA and AMPA receptors he remodeling of architecture in the dorsal horn
of second order sensory ibers or interneurons (63). of the spinal cord following nerve injury is not con-
Other neurotransmitters that act in concert with gluta- ined to neurons. Microglia, described as the resident
mate include the neuropeptides SP and CGRP. Dorsal inlammatory cells of the CNS, are activated in the
horn neurons can be classiied as projection neurons dorsal horn within 24 h of a peripheral nerve injury.
with axons travelling to higher centers or interneu- here are morphological changes, proliferation, and
rons that are capable of inluencing pain transmission. rises in expression of several critical molecules includ-
he projection neurons are more likely to be found in ing CR3, toll-like receptor-4, CD14, CD4, and MC
lamina I and they cross the midline to ascend in the class II protein (84). Key microglial proteins such as
spinothalamic tract (78). Interneurons are classiied P2X4 receptors and the second messenger p38 MAP
as nociceptive-speciic (majority), polymodal, or wide kinase are likely critical in mediating pain signals.
dynamic range, coding both innocuous and injuri- Microglia may facilitate pain signaling by dampening
ous stimuli and they synapse, among others, with pro- dorsal horn inhibitory mechanisms or facilitating exci-
jection neurons. Many interneurons also demonstrate tation. BDNF released from microglia appears to be
the property of windup referring to an increase in an important participant in central sensitization (85).
their sensitivity with repeated stimuli. his property is Beggs and Salter (86) suggest that enhanced BDNF 9
mediated by glutamate through NMDA (N-methyl-D- release acts on lamina I neurons of the doral horn
Figure 1.2. Hypothesis linking events in microglia with projection neurons in the dorsal horn of the spinal cord as proposed by Beggs and
Salter (86). In this scheme, activation of P2X4 receptors increases BDNF synthesis and release through a p38MAPK-dependent mechanism.
BDNF downregulates KCC2 channels in the membranes of dorsal horn lamina I neurons, reducing GABA inhibition and increasing neuronal
excitability in response to NMDA receptor agonists. The overall result is to change neurons that are normally nociceptive-specific to become
wide dynamic range in phenotype, increasing hyperalgesia, allodynia, and spontaneous pain. Reproduced with permission from Beggs and
Salter (86).
through TrkB receptors to suppress KCC2 chloride enhancement of central sensitivity through NMDA
transporters. his increases intraneuronal Cl− levels, (89, 90), and loss of GABAergic inhibition (91).
leading to a role of GABA receptors in rendering neu-
ron hyperexcitability. Both diminished GABA inhibi-
tion and facilitated glutamatergic input contribute to a
Brainstem relays and the descending
change in neurons from a nociceptive speciic to wide modulation of pain
dynamic range phenotype, contributing to hyperalge- here are two main brainstem pain centers: the
sia, allodynia, and spontaneous pain [Figure 1.2]. parabrachial area found in the midbrain and rostral
Diminished synaptic inhibition may also be caused pons and the periaqueductal gray area of the mid-
by spinal endocannabinoids using CB1 receptors, brain. Parabrachial neurons project to the amygdala
which are activated upon strong nociceptive simu- and ventrolateral and medial hypothalamus (78). he
lation and reduce the release of GABA and glycine periaqueductal gray area projects descending axons to
(87). Overall, changes in the excitability of the dor- the spinal cord. Closely associated with the periaque-
10 sal horn involve several mechanisms that include spe- ductal gray neurons are those of the rostral ventro-
ciic changes in spontaneous excitability (88), windup medial medulla.
Descending input into the dorsal horn of the rostral anterior cingulate gyrus (including Brodmann
spinal cord arises from several neuroanatomical loci area 24) likely contributes to emotional responses dur-
(92). Monosynaptic inputs into the dorsal horn arise ing pain. he anterior cingulate has close recipro-
from the hypothalamus, the parabrachial nucleus, cal connections to its posterior counterpart which, in
the nucleus tractus solitarius, the brainstem nucleus turn, connects to the parietal cortex, occipital cor-
raphe magnus, the rostroventromedial medulla, the tex, striatal nuclei, and thalamic nuclei. Other corti-
dorsal reticular nucleus, the cerebral cortex, and cal areas that participate in pain responses include the
the periaqueductal gray area in the midbrain. Sev- parietal somatosensory areas (S1, and S2 or Brodmann
eral neurotransmitters are involved. Norepinephrine areas 3, 1, 2) and the insula which in turn is closely
inhibits primary aferents and projection neurons connected to the somatosensory cortex and the amyg-
directly and inhibits projection neurons indirectly dala. he insula is also thought to participate in afec-
through enkephalin and GABA interneurons. Sim- tive components of the pain experience.
ilar inhibitory pathways use dopamine and sero- he prefrontal cortex (especially area 10) may
tonin. Serotonin acts on 5HT3 receptors expressed on integrate inputs through reciprocal connections to
interneurons, but probably also on 5-HT2 receptors on the somatosensory cortex and the anterior cingulate
interneurons, 5-HT1A receptors on projection neurons gyrus. Patients who previously underwent prefrontal
and 5-HT1B/D receptors on primary aferents. Both leucotomy for intractable pain reported loss of the
serotonin and norepinephrine, the latter released from unpleasant aspect of their pain experience. All of these
axons arising in the locus coeruleus, dampen nocicep- cortical areas naturally have widespread connections
tive aferent discharges. elsewhere including the motor cortices and basal gan-
Treatment of pain using spinal cord stimulation is glia. hese may become activated (as detected on PET
based on activation of the descending analgesic sys- and fMRI studies) during painful states. Furthermore,
tem. Descending pathways can include facilitatory cir- these sites in turn may elicit motor responses through
cuits, also mediated by norepinephrine, dopamine, their connections to the motor outputs. Surprisingly,
and serotonin (92). the amygdala, associated with emotional behavior, and
the hippocampus, associated with memory forma-
tion, may be inactive during pain states. Nonetheless,
Thalamic participation in pain the amygdala is connected to the periaqueductal grey
Nociceptive input into the thalamus is divided nucleus of the brainstem that in turn, is very much
into the lateral sensory-discriminative and medial activated during pain. he amygdala is also connected
motivational-afective systems (93). he lateral input to the hypothalamus that is involved in the autonomic
constitutes the ventral posterior nucleus of the tha- responses to painful stimuli.
lamus. he medial nuclei include the intralaminar Recent insights into the participation and plasti-
(centromedian, centrolateral, and parafascicular) city of the anterior cingulate cortex (gyrus; ACC) are
and midline nuclei. he lateral nuclei have better provided by Zhuo (94). Painful inputs into the ACC as
facility to identify the location and intensity of well as forebrain and insular cortex trigger unpleasant
pain and they project to the somatosensory cortex. sensations and experiences. he somatosensory cor-
he medial nuclei project to the anterior cingulate tex, in contrast, is thought to help determine the loca-
gyrus. tion and quality of pain, whereas the hippocampus
may contribute to pain-related spatial memory. Elec-
trophysiological recordings from ACC neurons have
Cortical pain centers identiied responses to injury and speciic nocicep-
he participation of the CNS in pain perception was tor neurons. Plastic properties observed within ACC
comprehensively reviewed by Hudson (93). Several neurons have included long-term potentiation and
parts of the human cerebrum participate in pain per- depression, mediated through alterations in glutamate
ception. One of the most important is the cingulate receptor signaling, NMDA (N-methyl-D-aspartate)
gyrus, a part of the limbic system found above and receptors, and calcium-calmodulin activated adeny-
along the corpus callosum. he cingulate cortex con- lyl cyclases (94). All of these properties have high-
tains opioid receptors, and receives projections from lighted parallel forms of neuronal behavior in pain and 11
midline and intralaminar nuclei of the thalamus. he memory.
Summary (9) Asbury AK, Fields HL. Pain due to peripheral nerve
damage: an hypothesis. Neurology 1984;34:1587–
Neuropathic pain involves a complex and redundant 1590.
system of wiring and molecules that is only slowly
(10) Levy D, Zochodne DW. Increased mRNA expression
being unraveled. While initial pain generators are of the B1 and B2 bradykinin receptors and
found in target tissues and in the primary aferent antinociceptive efects of their antagonists in an
sensory axons that innervate them, the “pain experi- animal model of neuropathic pain. Pain 2000;86:
ence,” if prolonged, involves multiple levels of the 265–271.
neuraxis. When the “wiring” is primarily damaged (11) Donnelly-Roberts D, McGaraughty S, Shieh CC,
in neurological disease, a level of further complex- Honore P, Jarvis MF. Painful purinergic receptors.
ity is added that contributes toward the ampliica- J Pharmacol Exp her 2008;324:409–415.
tion and persistence of pain. he neuroanatomical (12) George EB, Glass JD, Griin JW. Axotomy-induced
changes involve a combination of dorsal and higher axonal degeneration is mediated by calcium inlux
circuit remodeling, recruitment of microglia, inappro- through ion-speciic channels. J Neurosci
priate sprouting of axons within DRGs, and repara- 1995;15:6445–6452.
tive changes in the distal axons. he molecular changes (13) Boivin A, Pineau I, Barrette B, et al. Toll-like receptor
are diverse and include changes in both pro- and anti- signaling is critical for Wallerian degeneration and
functional recovery ater peripheral nerve injury.
nociceptive systems. Prominent among these are alter-
J Neurosci 2007;27:12565–12576.
ations in ion channel properties of neurons; upreg-
(14) Üçeyler N, Sommer C. Cytokine regulation in animal
ulation of cytokines, chemokines, and inlammatory
models of neuropathic pain and in human diseases.
peptides; changes in the expression of opioids and Neurosci Lett 2008;437:194–198.
cannabinoids; altered TRP channels; and changes in
(15) Üçeyler N, Tscharke A, Sommer C. Early cytokine
NMDA receptors. expression in mouse sciatic nerve ater chronic
constriction nerve injury depends on calpain. Brain
Behav Immun 2007;21:553–560.
(16) Kleinschnitz C, Brinkhof J, Zelenka M, Sommer C,
References Stoll G. he extent of cytokine induction in
(1) Treede RD, Jensen TS, Campbell JN, et al. peripheral nerve lesions depends on the mode of
Neuropathic pain: redeinition and a grading system injury and NMDA receptor signaling. J
for clinical and research purposes. Neurology Neuroimmunol 2004;149:77–83.
2008;70:1630–1635.
(17) Jung H, Toth PT, White FA, Miller RJ. Monocyte
(2) Devor M. Neuropathic pain and injured nerve: chemoattractant protein-1 functions as a
peripheral mechanisms. Br Med Bull 1991;47: neuromodulator in dorsal root ganglia neurons.
619–630. J Neurochem 2008;104:254–263.
(3) Benarroch EE. Sodium channels and pain. Neurology (18) White FA, Jung H, Miller RJ. Chemokines and the
2007;68:233–236. pathophysiology of neuropathic pain. Proc Natl Acad
(4) Lai J, Porreca F, Hunter JC, Gold MS. Voltage-gated Sci U S A 2007;104:20151–20158.
sodium channels and hyperalgesia. Annu Rev (19) Levy D, Hoke A, Zochodne DW. Local expression
Pharmacol Toxicol 2004;44:371–397. of inducible nitric oxide synthase in an animal
(5) Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. model of neuropathic pain. Neurosci Lett 1999;260:
Sodium channels in normal and pathological pain. 207–209.
Annu Rev Neurosci 2010;33:325–347. (20) Durrenberger PF, Facer P, Casula MA, et al.
(6) Cox JJ, Sheynin J, Shorer Z, et al. Congenital Prostanoid receptor EP1 and Cox-2 in injured human
insensitivity to pain: novel SCN9A missense and nerves and a rat model of nerve injury: a time-course
in-frame deletion mutations. Hum Mutat study. BMC Neurol 2006;6:1.
2010;31:E1670–E1686. (21) Ma W, Eisenach JC. Morphological and
(7) Zochodne DW. Epineurial peptides: a role in pharmacological evidence for the role of peripheral
neuropathic pain? Can J Neurol Sci 1993;20:69–72. prostaglandins in the pathogenesis of neuropathic
(8) Bove GM, Light AR. he nervi nervorum, missing pain. Eur J Neurosci 2002;15:1037–1047.
link for neuropathic pain? Pain Forum (22) Ma W, Eisenach JC. Cyclooxygenase 2 in
12 1997;6:181–190. iniltrating inlammatory cells in injured nerve is
universally up-regulated following various types of (36) Wiesenfeld-Hallin Z, Xu XJ, Crawley JN, Hokfelt T.
peripheral nerve injury. Neuroscience 2003;121: Galanin and spinal nociceptive mechanisms: recent
691–704. results from transgenic and knock-out models.
(23) Vanegas H, Schaible HG. Prostaglandins and Neuropeptides 2005;39:207–210.
cyclooxygenases [correction of cycloxygenases] in the (37) Wilson-Gerwing TD, Dmyterko MV, Zochodne DW,
spinal cord. Prog Neurobiol 2001;64:327–363. Johnston JM, Verge VM. Neurotrophin-3 suppresses
(24) Vergnolle N, Ferazzini M, D’Andrea MR, thermal hyperalgesia associated with neuropathic
Buddenkotte J, Steinhof M. Proteinase-activated pain and attenuates transient receptor potential
receptors: novel signals for peripheral nerves. Trends vanilloid receptor-1 expression in adult sensory
Neurosci 2003;26:496–500. neurons. J Neurosci 2005;25:758–767.
(25) Vergnolle N, Bunnett NW, Sharkey KA, et al. (38) Lewis T. he nocifensor system of nerves and its
Proteinase-activated receptor-2 and hyperalgesia: A reactions. Br Med J 1937;27:431–494.
novel pain pathway. Nat Med 2001;7:821–826. (39) Holzer P. Local efector functions of
(26) Asfaha S, Brussee V, Chapman K, Zochodne DW, capsaicin-sensitive sensory nerve endings:
Vergnolle N. Proteinase-activated receptor-1 agonists involvement of tachykinins, calcitonin gene-related
attenuate nociception in response to noxious stimuli. peptide and other neuropeptides. Neuroscience
Br J Pharmacol 2002;135:1101–1106. 1988;24:739–768.
(27) Przewlocki R, Hassan AHS, Lason W, Epplen C, Herz (40) Lewis T, Harris KE, Grant RT. Observations relating
A, Stein C. Gene expression and localization of opioid to the inluence of the cutaneous nerves on various
peptides in immune cells of inlamed tissue: reactions of the cutaneous vessels. Heart
functional role in antinociception. Neuroscience 1927;14:1–17.
1992;48:491–500. (41) Cline MA, Ochoa J, Torebjork HE. Chronic
(28) Stein C, Hassan AH, Przewlocki R, Gramsch C, Peter hyperalgesia and skin warming caused by sensitized
K, Herz A. Opioids from immunocytes interact with C nociceptors. Brain 1989;112:621–647.
receptors on sensory nerves to inhibit nociception (42) Lax H, Zochodne DW. Causalgic median
in inlammation. Proc Natl Acad Sci USA 1990;87: mononeuropathies: segmental rubror and edema.
5935–5939. Muscle Nerve 1995;18:245–247.
(29) Truong W, Cheng C, Xu QG, Li XQ, Zochodne DW. (43) Waller A. Experiments on the section of the
Mu opioid receptors and analgesia at the site of a glossopharyngeal and hypoglossal nerves of the frog
peripheral nerve injury. Ann Neurol 2003;53:366–375. and observations of the alterations produced thereby
(30) Chen Y, Sommer C. Activation of the nociceptin in the structure of their primitive ibers. Philos Trans
opioid system in rat sensory neurons produces R Soc Lond B Biol Sci 1850;140:423–429.
antinociceptive efects in inlammatory pain: (44) Kennedy JM, Zochodne DW. he regenerative deicit
involvement of inlammatory mediators. J Neurosci of peripheral nerves in experimental diabetes: its
Res 2007;85:1478–1488. extent, timing and possible mechanisms. Brain
(31) Guindon J, Hohmann AG. Cannabinoid CB2 2000;123:2118–2129.
receptors: a therapeutic target for the treatment of (45) Verge VMK, Gratto KA, Karchewski LA, Richardson
inlammatory and neuropathic pain. Br J Pharmacol PM. Neurotrophins and nerve injury in the adult.
2008;153:319–334. Philos Trans R Soc Lond B Biol Sci 1996;351:423–430.
(32) Guindon J, Hohmann AG. he endocannabinoid (46) Lawson SN. he peripheral sensory nervous system:
system and pain. CNS Neurol Disord Drug Targets dorsal root ganglion neurons. In: Dyck PJ, homas
2009;8:403–421. PK, eds. Peripheral Neuropathy. 4th edition.
(33) Dray A. Neuropathic pain: emerging treatments. Br J Philadelphia: Elsevier Saunders, 2005:163–202.
Anaesth 2008;101:48–58. (47) Cummins TR, Sheets PL, Waxman SG. he roles of
(34) Vale ML, Marques JB, Moreira CA, et al. sodium channels in nociception: Implications for
Antinociceptive efects of interleukin-4, -10, and -13 mechanisms of pain. Pain 2007;131:243–257.
on the writhing response in mice and (48) England JD, Gamboni F, Ferguson MA, Levinson SR.
zymosan-induced knee joint incapacitation in rats. Sodium channels accumulate at the tips of injured
J Pharmacol Exp her 2003;304:102–108. axons. Muscle Nerve 1994;17:593–598.
(35) Üçeyler N, Rogausch JP, Toyka KV, Sommer C. (49) Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of
Diferential expression of cytokines in painful and function Nav1.7 mutations in idiopathic small iber
painless neuropathies. Neurology 2007;69:42–49. neuropathy. Ann Neurol 2012;71:26–39. 13
(50) Emery EC, Young GT, Berrocoso EM, Chen L, (64) Ji RR, Zhang Q, Law PY, Low HH, Elde R, Hokfelt T.
McNaughton PA. HCN2 ion channels play a central Expression of m, d, and k-opioid receptor-like
role in inlammatory and neuropathic pain. Science immunoreactivities in rat dorsal root ganglia ater
2011;333:1462–1466. carrageenan-induced inlammation. J Neurosci
(51) Chien LY, Cheng JK, Chu D, Cheng CF, Tsaur ML. 1995;15:8156–8166.
Reduced expression of A-type potassium channels in (65) Li X-Q, Verge VMK, Johnston JM, Zochodne DW.
primary sensory neurons induces mechanical CGRP peptide and regenerating sensory axons.
hypersensitivity. J Neurosci 2007;27:9855–9865. J Neuropathol Exp Neurol 2004;63:1092–1103.
(52) Abdulla FA, Smith PA. Ectopic alpha2-adrenoceptors (66) Tsuzuki K, Kondo E, Fukuoka T, et al. Diferential
couple to N-type Ca2+ channels in axotomized rat regulation of P2X(3) mRNA expression by peripheral
sensory neurons. J Neurosci 1997;17:1633–1641. nerve injury in intact and injured neurons in the rat
(53) Abdulla FA, Moran TD, Balasubramanyan S, Smith sensory ganglia. Pain 2001;91:351–360.
PA. Efects and consequences of nerve injury on the (67) Frederick J, Buck ME, Matson DJ, Cortright DN.
electrical properties of sensory neurons. Can J Physiol Increased TRPA1, TRPM8, and TRPV2 expression in
Pharmacol 2003;81:663–682. dorsal root ganglia by nerve injury. Biochem Biophys
(54) Luo ZD, Chaplan SR, Higuera ES, et al. Upregulation Res Commun 2007;358:1058–1064.
of dorsal root ganglion (alpha)2(delta) calcium (68) Xing H, Chen M, Ling J, Tan W, Gu JG. TRPM8
channel subunit and its correlation with allodynia mechanism of cold allodynia ater chronic nerve
in spinal nerve-injured rats. J Neurosci 2001;21: injury. J Neurosci 2007;27:13680–13690.
1868–1875. (69) Deval E, Gasull X, Noel J, et al. Acid-sensing ion
(55) Newton RA, Bingham S, Case PC, Sanger GJ, Lawson channels (ASICs): pharmacology and implication in
SN. Dorsal root ganglion neurons show increased pain. Pharmacol her 2010;128:549–558.
expression of the calcium channel alpha2delta-1 (70) Bohlen CJ, Chesler AT, Sharif-Naeini R, et al. A
subunit following partial sciatic nerve injury. Brain heteromeric Texas coral snake toxin targets
Res Mol Brain Res 2001;95:1–8. acid-sensing ion channels to produce pain. Nature
(56) Sills GJ. he mechanisms of action of gabapentin 2011;479:410–414.
and pregabalin. Curr Opin Pharmacol 2006;6: (71) Ramer MS, Murphy PG, Richardson PM, Bisby MA.
108–113. Spinal nerve lesion-induced mechanoallodynia and
(57) Smith MT, Cabot PJ, Ross FB, Robertson AD, Lewis adrenergic sprouting in sensory ganglia are
RJ. he novel N-type calcium channel blocker, attenuated in interleukin-6 knockout mice. Pain
AM336, produces potent dose-dependent 1998;78:115–121.
antinociception ater intrathecal dosing in rats and (72) Murphy PG, Borthwick LA, Altares M, Gauldie J,
inhibits substance P release in rat spinal cord slices. Kaplan D, Richardson PM. Reciprocal actions of
Pain 2002;96:119–127. interleukin-6 and brain-derived neurotrophic factor
(58) Snutch TP. Targeting chronic and neuropathic pain: on rat and mouse primary sensory neurons. Eur J
the N-type calcium channel comes of age. NeuroRx Neurosci 2000;12:1891–1899.
2005;2:662–670. (73) Murphy PG, Borthwick LS, Johnston RS, Kuchel G,
(59) Yaksh TL. Calcium channels as therapeutic targets in Richardson PM. Nature of the retrograde signal from
neuropathic pain. J Pain 2006;7:S13–S30. injured nerves that induces interleukin-6 mRNA in
(60) Altier C, Dale CS, Kisilevsky AE, et al. Diferential neurons. J Neurosci 1999;19:3791–3800.
role of N-type calcium channel splice isoforms in (74) Murphy PG, Grondin J, Altares M, Richardson PM.
pain. J Neurosci 2007;27:6363–6373. Induction of interleukin-6 in axotomized sensory
(61) Brittain JM, Duarte DB, Wilson SM, et al. neurons. J Neurosci 1995;15:5130–5138.
Suppression of inlammatory and neuropathic pain (75) Ramer MS, Bisby MA. Adrenergic innervation of rat
by uncoupling CRMP-2 from the presynaptic Ca(2) sensory ganglia following proximal or distal painful
channel complex. Nat Med 2011;17:822–829. sciatic neuropathy: distinct mechanisms revealed by
(62) Lieberman AR. he axon reaction: a review of the anti-NGF treatment. Eur J Neurosci 1999;11:
principal features of perikaryal responses to axon 837–846.
injury. Int Rev Neurobiol 1971;14:49–124. (76) McLachlan EM, Janig W, Devor M, Michaelis M.
(63) Zhang X, Bao L. he development and modulation of Peripheral nerve injury triggers noradrenergic
nociceptive circuitry. Curr Opin Neurobiol 2006;16: sprouting within dorsal root ganglia. Nature
14 460–466. 1993;363:543–546.
(77) Chung K, Yoon YW, Chung JM. Sprouting (87) Pernia-Andrade AJ, Kato A, Witschi R, et al. Spinal
sympathetic ibers form synaptic varicosities in the endocannabinoids and CB1 receptors mediate
dorsal root ganglion of the rat with neuropathic C-iber-induced heterosynaptic pain sensitization.
injury. Brain Res 1997;751:275–280. Science 2009;325:760–764.
(78) Suzuki R, Dickenson A. Spinal and supraspinal (88) Dalal A, Tata M, Allegre G, Gekiere F, Bons N,
contributions to central sensitization in peripheral Albe-Fessard D. Spontaneous activity of rat dorsal
neuropathy. Neurosignals 2005;14:175–181. horn cells in spinal segments of sciatic projection
(79) Zochodne DW, Murray M, Nag S, Riopelle RJ. A following transection of sciatic nerve or of
segmental chronic pain syndrome in rats associated corresponding dorsal roots. Neuroscience
with intrathecal infusion of NMDA: evidence for 1999;94:217–228.
selective action in the dorsal horn. Can J Neurol Sci (89) Woolf CJ, hompson SW. he induction and
1994;21:24–28. maintenance of central sensitization is dependent on
(80) Nozaki C, Vergnano AM, Filliol D, et al. Zinc N-methyl-D-aspartic acid receptor activation;
alleviates pain through high-ainity binding to the implications for the treatment of post-injury
NMDA receptor NR2A subunit. Nat Neurosci pain hypersensitivity states. Pain 1991;44:
2011;14:1017–1022. 293–299.
(81) Lim G, Wang S, Zhang Y, Tian Y, Mao J. Spinal leptin (90) Kohno T, Moore KA, Baba H, Woolf CJ. Peripheral
contributes to the pathogenesis of neuropathic pain nerve injury alters excitatory synaptic transmission in
in rodents. J Clin Invest 2009;119:295–304. lamina II of the rat dorsal horn. J Physiol 2003;548:
131–138.
(82) Tian Y, Wang S, Ma Y, Lim G, Kim H, Mao J. Leptin
enhances NMDA-induced spinal excitation in rats: A (91) Sivilotti L, Woolf CJ. he contribution of GABAA
functional link between adipocytokine and and glycine receptors to central sensitization:
neuropathic pain. Pain 2011;152:1263–1271. disinhibition and touch-evoked allodynia in the
spinal cord. J Neurophysiol 1994;72:169–179.
(83) Coggeshall RE. Fos, nociception and the dorsal horn.
Prog Neurobiol 2005;77:299–352. (92) Millan MJ. Descending control of pain. Prog
Neurobiol 2002;66:355–474.
(84) Tsuda M, Inoue K, Salter MW. Neuropathic pain and
spinal microglia: a big problem from molecules in (93) Hudson AJ. Pain perception and response: central
“small” glia. Trends Neurosci 2005;28:101–107. nervous system mechanisms. Can J Neurol Sci
2000;27:2–16.
(85) Coull JA, Beggs S, Boudreau D, et al. BDNF from
microglia causes the shit in neuronal anion gradient (94) Zhuo M. Canadian Association of Neuroscience
underlying neuropathic pain. Nature 2005;438: review: cellular and synaptic insights into
1017–1021. physiological and pathological pain. EJLB-CIHR
Michael Smith Chair in Neurosciences and Mental
(86) Beggs S, Salter MW. Microglia-neuronal signalling in Health lecture. Can J Neurol Sci 2005;32:
neuropathic pain hypersensitivity 2.0. Curr Opin 27–36.
Neurobiol 2010;20:474–480.
15
Section B Focal, or localized neuropathies
Chapter
Pain and carpal tunnel syndrome
2
Carpal tunnel syndrome is one of the most com- he neurological examination of the upper limbs
mon acquired neuropathies and accounts for substan- was normal. In particular, there was no Horner’s sign
tial disability with loss of time from work. Neuro- and no weakness or sensory loss in either median
pathic pain is a prominent feature. In this vignette, we nerve territory. he upper limb deep tendon relexes
describe a patient with chronic symptoms of carpal were intact and symmetrical. here was no Tinel or
tunnel syndrome in both hands and discuss the pain Phalen sign.
associated with this focal neuropathy. Electrophysiological studies were completed in the
upper limbs. In let median ibers, motor conduction
was intact and the amplitude of the compound muscle
Clinical case vignette action potential (CMAP) was normal. here was mild
A 53-year-old right-handed female, working as a slowing of antidromic sensory conduction from the
teacher, had experienced a 10-year history of symp- wrist to the index inger on the let with greater slowing
toms in her hands. he symptoms initially involved from the wrist to the middle digit. Palmar conduction,
the right hand but following a right carpal tunnel with stimulation in the palm and recording over the
release, she began experiencing prominent let hand wrist, was normal in the ulnar nerve distribution but
symptoms. hese had been present for approximately there was signiicant slowing in the median territory.
18 months and resembled her prior diiculties on Let radial sensory and let ulnar motor and sensory
the right. She described discomfort on the let at the conduction were normal. he let median and ulnar
severity level of 7/10 with tingling in the ingers, and F wave latencies were within the normal range. On
burning, “pins and needles” at night, and electric-like the right, median and ulnar motor and sensory con-
shocks in the wrist and forearm. he electric shocks duction studies were essentially normal beyond bor-
were provoked by grasping or picking up objects. derline, likely residual slowing of right median palmar
Marking term papers of her pupils or using a computer conduction. Overall the studies conirmed evidence of
exacerbated her discomfort. he symptoms might mild let-sided carpal tunnel syndrome involving sen-
awaken her at night and in the morning. She noticed sory ibers.
diiculty with her grip on the let. Her hand felt weak he patient was scheduled for consideration of pos-
to lit, grasp, or carry bags but she had not noted paral- sible let carpal tunnel release by a plastic surgeon.
ysis of speciic muscles. Her let hand felt cold and
numb but she denied persistent loss of sensation. he Pain description
patient had not tried using a wrist splint on the let. he let hand pain involved the middle of the hand and
here was no history of diabetes or thyroid disease. radiated to the thumb and wrist. It also involved the
he patient reported chronic neck and lumbar discom- ingers and forearm. he patient described the sensa-
fort. She could not generate sensory symptoms in her tion as uncomfortable at 7/10; the tingling, burning,
hands by moving or turning her neck. Her medica- and electic shock sensations were exacerbated at night
tions included celecoxib, cetirizine/pseudoephedrine, or with use of her hands.
vitamins, and minerals. She had undergone bilateral
mastectomies 1 year prior for carcinoma of the breast.
Neither chemotherapy nor radiation had been admin- Discussion
16 istered. She had prior lower limb varicose vein surgery his patient’s case description illustrates many key
and right de Quervain’s tenosynovitis. features of carpal tunnel syndrome (CTS). CTS is a
Chapter 2: Pain and carpal tunnel syndrome
focal neuropathy of the median nerve at the wrist. he its beneit in CTS with either very mild symptoms
carpal tunnel is a narrow passageway for the median or severe symptoms is uncertain (2). Approximately
nerve into the hand and is bounded dorsally (deep) by 75% of patients respond to carpal tunnel surgery (3).
the concave surfaces of the carpal bones (hamate, cap- Surgery can identify other causes of median nerve
itate, trapezoid, and trapezium) and ventrally (under compression at this level including anomalous muscles
the skin) by the lexor retinaculum. he carpal liga- or vessels. Exposed median nerves that have been com-
ment that roofs the tunnel is connected to the trapez- pressed may appear swollen, lattened, or inlamed (1).
ium and scaphoid on the radial side and pisiform and Corticosteroid injection relieves symptoms better than
hook of hamate on the ulnar side of the wrist. he placebo (4) but it is argued that the beneit may only
median nerve shares the carpal tunnel with the long be short-term (3). Pre-operative electrophysiological
inger lexors of the hand, likely explaining why, as in studies improve the likelihood that the diagnosis is
our patient, wrist and inger movements can exacer- accurate and that the patient will beneit from decom-
bate the pain. pression. Carpal tunnel release has been inadvertently
Risk factors for the development of CTS include carried out in patients with radiculopathy, motor neu-
pregnancy, repetitive hand work, diabetes mellitus, ron disease, syringomyelia, MS, and polyneuropathy
hypothyroidism, rheumatoid arthritis, local fractures (3). hus, a careful diagnostic evaluation using electro-
and their associated deformities, amyloidosis, and physiological studies is important.
anomalous muscles or blood vessels (1). In patients
with a family history of bilateral CTS or other entrap-
ment neuropathies, inherited sensitivity to pressure Pain in carpal tunnel syndrome
palsy (HNPP) should be considered. he pain in CTS can be severe; some patients rank
In our patient, the condition was painful and inter- it as 10/10, it frequently reoccurs at night, and it can
fered with her ability to work. he pain was cen- substantially limit their ability to work. he pain oten
tered over the wrist but radiated into her ingers appears to involve the whole hand as well as the wrist,
and forearm. She experienced a sensation of hand forearm, and more proximal areas. Because axon dam-
weakness although no objective weakness could be age may not necessarily complicate CTS, it is inter-
demonstrated on her neurological examination. Many esting to consider what generates the pain in this
patients report that the symptoms involve the whole disorder. he pain does appear to be position- and
of the hand without localizing to speciic ingers. Clas- use-dependent, suggesting a mechanosensitive local
sically however, the sensory symptoms involve the trigger. Mechanosensitivity is the basis for the Tinel’s
median nerve territory, that is, the thumb, index, sign, the reproduction of characteristic clinical symp-
middle, and radial half of the ring inger. In the toms by mild tapping over the carpal tunnel. hat
patient described here, clinical sensory examination many patients experience immediate pain relief and
was intact. Not all patients with CTS are noted to paresthesiae on decompression (1) is also remarkable,
have a Tinel’s or Phalen’s sign and many patients suggesting the presence of an ongoing peripheral nerve
with mild CTS do not have objective sensory deicits generator of the pain syndrome.
on examination. Many patients also report clumsi- Atroshi et al. (5) examined 2466 people from the
ness and loss of hand dexterity. An important clini- general population in Sweden who responded to a ran-
cal inding in CTS is sparing of the territory of the domized survey. Approximately 14% reported pain,
palmar cutaneous branch that innervates the skin of numbness or tingling in the median nerve distribution.
the base of the thenar eminence and does not course Of these, approximately 5% of the original respon-
through the carpal tunnel. Sensory loss in presumed ders to the survey (approximately one third of those
CTS should, therefore, not include this territory. Bilat- with symptoms) had electrophysiological evidence of
eral CTS is common and should be routinely sought median neuropathy and 2.7% had clinically and elec-
even in patients with unilateral symptoms. Because trophysiologically conirmed CTS. In 125 control sub-
diabetes mellitus and hypothyroidism are important jects without symptoms, electrophysiological studies
predisposing factors, these should be screened for in identiied asymptomatic CTS in 18%.
patients with CTS. In some instances, painful mononeuropathy
Decompressive surgery relieves symptoms of CTS may be associated with segmental rubor (redness) 17
more efectively than simple splinting but evidence for and edema (swelling) strictly conined to the nerve
Section B: Focal, or localized neuropathies
“RSD” or relex sympathetic dystrophy at one time but

has more recently been classiied as CRPS II (complex
regional pain syndrome II); also known as “causalgia”
in which a pain syndrome with sot tissue changes is
associated with a local nerve injury. Ochoa and col-
leagues have described “angry” backiring nociceptors
that once activated by injury, cause antidromic release
of peptides into the territory of the injury (7, 8). hese
peptides, including substance P (SP) and calcitonin
gene-related peptide (CGRP), can be released locally
by unmyelinated axon terminals and cause pain,
edema from plasma extravasation, and vasodilatation.
“Failed” carpal tunnel release, with ongoing pain
Figure 2.1. Rubor and swelling in a patient with CTS who had and disability, is an important complication. he
undergone decompressive surgery. Note the recently healed most important cause is pre-surgical misdiagnosis, but
surgical scar (arrow). The patient had a complex pain syndrome
(CRPS II) associated with his median mononeuropathy that was incomplete release, adhesive neuritis, or intraoperative
associated with severe pain, swelling, and localized color change. injury to the median nerve or the cutaneous sensory
While the etiology for the localized changes is uncertain, branch may also contribute to ongoing postoperative
recruitment of activity from peptidergic axons (expressing SP and
CGRP) may contribute. This patient is described in reference (6). pain (9).
territory in question. We described two patients References

with these tissue changes in association with “acute” (1) Singh SK, Midha R. Carpal tunnel syndrome. In:
median nerve injury at the level of the wrist in a Midha R, Zager EL, eds. Surgery of Peripheral Nerves.
previous report (6). he irst patient had acute or New York: hieme, 2008:94–99.
chronic symptoms of CTS exacerbated by repairing (2) Verdugo RJ, Salinas RA, Castillo JL, Cea JG. Surgical
her windows in her house. She described bilateral versus non-surgical treatment for carpal tunnel
volar wrist pain, radiating proximally, rated as 10/10, syndrome. Cochrane Database Syst Rev 2008;
followed by right median sensory loss, paresthesiae, CD001552.
and loss of hand power. She had a Tinel’s sign, mild (3) Bland JD. Treatment of carpal tunnel syndrome.
APB weakness without wasting, and loss of light Muscle Nerve 2007;36:167–171.
touch and pinprick sensation in the median territory. (4) Marshall S, Tardif G, Ashworth N. Local
here was striking hand and digital edema conined corticosteroid injection for carpal tunnel syndrome.
to the median territory. She had marked slowing and Cochrane Database Syst Rev 2007;CD001554.
dispersion strictly across the carpal tunnel segment (5) Atroshi I, Gummesson C, Johnsson R, Ornstein E,
but no denervation to suggest axonal interruption. Ranstam J, Rosen I. Prevalence of carpal tunnel
syndrome in a general population. JAMA 1999;282:
he symptoms largely improved with splinting and
153–158.
anti-inlammatory medication but she eventually did
require carpal tunnel release over the next 2 years. he (6) Lax H, Zochodne DW. Causalgic median
mononeuropathies: segmental rubror and edema.
unusual facet of this patient was that the pain syn- Muscle Nerve 1995;18:245–247.
drome and edema changes resolved concurrently with
(7) Ochoa JL. Essence, investigation, and management of
improvement of demyelination (only) at the carpal
“neuropathic” pains: hopes from acknowledgment of
tunnel. he second patient had sensory and motor chaos. Muscle Nerve 1993;16:997–1008.
abnormalities in the median nerve territory ater a fall
(8) Ochoa JL. he human sensory unit and pain: new
from a ladder onto his outstretched hand. Despite early concepts, syndromes, and tests. Muscle Nerve 1993;
carpal tunnel release, a pain syndrome ensued with 16:1009–1016.
cold sensation, color change, and swelling that was (9) Graham B. Recurrent or persistent symptoms
strictly conined to the median territory [Figure 2.1]. following carpal tunnel release. In: Midha R, Zager
18 He improved spontaneously over time. his kind of EL, eds. Surgery of Peripheral Nerves. New York:
syndrome might have been inappropriately termed hieme, 2008:105–108.
Chapter
Pain and cervical radiculopathy
3
Cervical radiculopathy is one of the most common He had downgoing plantar relexes. here was alter-
causes of neuropathic pain. Our clinical vignette ation to sensation to light touch and pinprick involv-
describes a patient with cervical radiculopathy sec- ing the right index, lateral middle, and thumb ingers
ondary to intervertebral disc protrusion associated partly into the forearm and a patchy change in the lat-
with focal neuropathic pain. eral arm above the elbow.
Overall, the clinical indings were highly sugges-
tive of a right C7 radiculopathy with possible minor
Clinical case vignette involvement of C6. Electrophysiological studies identi-
A 38-year-old right-handed man turned his neck to ied normal right and let median and ulnar motor and
hear a sound while descending some stairs and devel- sensory conduction. Let and right median and ulnar
oped an immediate pain in his neck and right shoul- F wave latencies were within the normal range. Nee-
der. He rated its severity as 8/10, describing the pain dle electromyography of the right triceps, biceps, and
as unlike anything he had experienced before. It had extensor digitorum communis muscles were normal.
persisted for 3 weeks by the time of presentation to Paraspinal muscle testing was deferred because of the
the Neurology service. he pain radiated into his right patient’s pain. MR imaging of the cervical intraspinal
arm into the dorsal forearm, thumb, and index and space [Figure 3.1] identiied a right disc extrusion at
middle ingers. hese ingers also went numb, and C6–7 producing severe right neural foraminal steno-
he described a swollen, burning pufy sensation asso- sis. here was no signiicant spinal cord compression.
ciated with them. He also described aching sensa- he patient was referred for a spinal neurosurgical
tions, made worse with movement or straightening of opinion regarding the possibility of a C6–7 discectomy.
his arm and further aggravated at night. Turning his
head to the let increased the pain. A small dose of Pain description
gabapentin (300 mg twice daily) was unhelpful. He he patient described a swollen, burning, and pufy
denied symptoms in the let arm or in the legs, and discomfort in the neck and right shoulder with aching
there was no sphincter disturbance. into his forearm, thumb, and middle and index ingers.
he patient had sufered a fall 8 years earlier with Movement, such as turning to the let or extension of
a diagnosis of let (opposite side from the current the head, increased the pain. It was prominent at night.
problems) brachial plexus injury but with no associ- he pain was initially rated as 8/10 in severity but later
ated paralysis or sensory loss. He had otherwise been diminished to 5–6/10. he regional localization of his
healthy and there was no prior history of neurologi- pain, the association with neck discomfort and neck
cal disease, neck surgery or injury. here was no family movement, and prominent involvement in a nerve
history of neurological disease. root territory indicated radiculopathy with nerve root
On neurological examination, the patient had neck damage.
discomfort with reduced neck lexion and extension.
here was no Horner’s sign. he cranial nerves were
intact. here was mild weakness of right elbow, wrist, Discussion
and inger extension (Grade 4+/5 MRC). Other mus- Radiculopathies involving the C7 nerve root are the
cle groups had normal bulk, power, tone, and coordi- most common of the cervical radiculopathies (1).
nation. he right triceps relex was absent but other Radiculopathies can also develop in patients with mul- 19
deep tendon relexes were present and symmetrical. tilevel cervical spondylosis that unfortunately are less
Figure 3.1. MR images of the cervical spine from the patient described in this chapter. Image A is a sagittal T2-weighted image showing a
C67 disc protrusion impinging the cervical subarachnoid space. Images B and C show the disc protrusion at higher magnification on T1-(B)
and T2-(C) weighted images. There was mild spinal cord indentation but no significant compression. Image D is a coronal view of the
herniated disk showing loss of the foraminal subarachnoid space on the right side (arrow).
amenable to surgical therapy. One of the irst and Clinic in 1957 (2). C7 radiculopathy was associated
most comprehensive analyses of neurological symp- with neck pain in 55% of the patients, scapular or inter-
20 toms from radiculopathy was provided by Yoss and scapular pain in 37%, shoulder pain in 83%, lateral arm
colleagues who examined 100 patients at the Mayo pain in 53%, and posterior arm pain in 34% of patients.
Chapter 3: Pain and cervical radiculopathy
Our patient’s descriptions of prominent shoulder and Progressive neurological dysfunction and intract-
lateral/posterior arm pain mirrored these indings. In able pain are the usual indications for possible sur-
the Mayo series, 65% of patients had lost their triceps gical decompression (3), although high quality evi-
relex and 65% had triceps weakness, indings identi- dence of long-term beneits is limited, as addressed by
cal to our patient. Finally, Yoss reported that only 24% a Cochrane review (4).
of their overall series of patients had objective indings
of sensory loss in the ingers, hand or arm associated
with C7 radiculopathy. he same pattern of changes, Pain in radiculopathy
including thumb involvement, was observed in our Pain from cervical root damage occurs in 83/100,000
patient. adults annually (5). As in our patient, it typically has a
In all patients with radiculopathy, it is important radiating or shooting quality oten with an electric sen-
to note whether there are symptoms or signs of spinal sation. here are two main types of compression that
cord compression. his can occur from discs that her- oten overlap. he nerve root and its associated dor-
niate centrally into the spinal canal, from more chronic sal root ganglia may be compressed by an osteophyte,
degenerative changes or from other causes. Spinal a degenerative bony outgrowth in the foramina that
cord compression may be associated with sensory and causes narrowing. his problem, known as spondy-
motor symptoms in the lower limbs, diiculty with losis, may account for up to 70% of cervical radicu-
bowel or bladder sensation, and control and loss of lopathies, especially in older patients. In younger peo-
balance. Lower (or upper) limb spasticity, weakness, ple especially but overall in 20% of radiculopathies,
hyperrelexia, upgoing plantar relexes, and a sensory intervertebral disc herniation may be responsible for
level may be identiied on examination. nerve root and ganglia compression (3). Less common
Electrophysiological studies are helpful in localiz- causes of cervical radiculopathy can occur and include
ing the level of radiculopathy as well as characteriz- tumors, cysts or infection.
ing the presence and degree of axonal degeneration Radicular pain may arise from one of several mech-
in the involved territory. It may also exclude con- anisms: stretching of nerve sheaths or meninges as
founding conditions such as carpal tunnel syndrome the root enters the spinal canal, ischemia, local root
or ulnar neuropathy at the elbow. Depending on the demyelination, local inlammation causing abnormal
duration and degree of axonal involvement and the axonal excitability, or from changes in the intrinsic
root involved, there may be loss of the amplitude of properties of nearby sensory neurons within dorsal
the compound muscle action potential (e.g., abductor root ganglia (DRG) due to compression.
pollicus brevis and abductor digiti minimi in C8 and here is evidence that DRG sensory neurons can
T1 radiculopathies), preserved sensory nerve action develop abnormal excitability and generate sponta-
potentials, and evidence of denervation in the involved neous ectopic discharges associated with neuropathic
muscles, including paraspinal muscles. hese studies pain (6). An experimental model of chronic compres-
were normal in our patient, indicating that axonal sion of the DRG from foraminal stenosis was pro-
damage had not occurred or was too early to detect. duced by insertion of stainless steel rods into the L4
Given the 3-week duration of weakness, the absence and L5 intervertebral foramina of rats (7). At 5–10 days
of denervation in the weak triceps muscle may indi- later, electrophysiological recordings from these neu-
cate that there was conduction block from demyelina- rons identiied abnormal ectopic spontaneous activity
tion in the proximal compressed C7 nerve root. his in 10% of compressed neurons compared with only
is because axonal damage and degeneration of the C7 1% of control uninjured neurons. Spontaneous activ-
nerve root within this time-frame should “normally” ity was identiied in large, medium, and small neu-
be associated with signs of denervation including ib- rons and could be classiied as type I activity, asso-
rillations and positive sharp waves. heir absence, ciated with subthreshold membrane potential oscil-
despite weakness, suggests demyelination of C7 with- lations and arising from the neuron soma, or less
out signiicant disruption of the nerve root axons. excitable type II activity without subthreshold oscil-
In other instances, frank denervation may be absent lations and arising from the proximal axons within
either because the interval between injury and sam- the ganglion. Abnormal spontaneous activity arising
pling is too short (e.g., less that 10–14 days) or too long from compressed neurons was thought to produce 21
because reinnervation has already begun. “spurious” sensory information (e.g., paresthesiae).
Abnormal discharges could also be triggered by dis- that predispose neurons to increased ectopic iring,
tal “physiological” stimuli (e.g., normal sensory stim- generating pain.
ulus), and these discharges could also block normal
transmission. his may be analogous to descriptions References
in the clinical setting where patients with paresthesiae (1) Wilbourn AJ, Aminof MJ. he electrophysiologic
sometimes complain that normal sensitivity is altered examination in patients with radiculopathies. Muscle
by the presence of concurrent tingling sensations. In Nerve 1988;11:1099–1114.
the model, ectopic discharges were tonic, bursting, or (2) Yoss RE, Corbin KB, MacCarty CS, Love JG.
irregular. Type I activity was more commonly asso- Signiicance of symptoms and signs in localization of
ciated with bursting and type II with irregular dis- involved root in cervical disk protrusion. Neurology
charges. All of these data indicate that at least two 1957;7:673–683.
(soma, proximal axon) sites within the DRG can gen- (3) Polston DW. Cervical radiculopathy. Neurol Clin
erate abnormal ectopic activity associated with neuro- 2007;25:373–385.
pathic pain. (4) Fouyas IP, Statham PF, Sandercock PA. Cochrane
Inlammation in the area of the DRG may also review on the role of surgery in cervical spondylotic
promote abnormal spontaneous discharges of sensory radiculomyelopathy. Spine (Phila Pa 1976) 2002;27:
neurons. For example, arachidonic acid is released 736–747.
from cell membranes by phospholipases present in (5) Van ZJ, Harney D, Joosten EA, et al. he role of the
the nucleus pulposus from a herniated disc. Arachi- dorsal root ganglion in cervical radicular pain:
donic acid, in turn, is the precursor for prostaglandins diagnosis, pathophysiology, and rationale for
treatment. Reg Anesth Pain Med 2006;31:152–167.
(especially PGE2) synthesized by cyclo-oxygenase-
2 (COX-2) that is expressed by inlammatory cells. (6) Wall PD, Devor M. Sensory aferent impulses
originate from dorsal root ganglia as well as from the
Other algesic (pain generating molecules) that might
periphery in normal and nerve injured rats. Pain
generate inappropriate excitability of sensory neu- 1983;17:321–339.
rons near a disc protrusion may include NGF, BDNF,
(7) Ma C, LaMotte RH. Multiple sites for generation
interleukin 1 and 6, nitric oxide, TNF, and oth- of ectopic spontaneous activity in neurons of the
ers (see review by Van Zundert et al. (5)). In a model chronically compressed dorsal root ganglion.
of noncompressive disc herniation in rats, altered J Neurosci 2007;27:14059–14068.
gait accompanied mechanical allodynia, local inlam- (8) Shamji MF, Allen KD, So S, et al. Gait abnormalities
mation, and autoreactive immune activation (8). In and inlammatory cytokines in an autologous nucleus
human herniated intervertebral discs, Shamji et al. pulposus model of radiculopathy. Spine (Phila Pa
noted greater interleukin-17 positivity, macrophage 1976) 2009;34:648–654.
presence, and cellularity (9). In work using cultured (9) Shamji MF, Setton LA, Jarvis W, et al.
human intervertebral disc cells obtained from patients Proinlammatory cytokine expression proile in
scheduled for surgical disc therapy, exposure to IL-17, degenerated and herniated human intervertebral disc
IFN , or TNF showed an increase in their produc- tissues. Arthritis Rheum 2010;62:1974–1982.
tion of inlammatory mediators, nitric oxide (NOx), (10) Gabr MA, Jing L, Helbling AR, et al. Interleukin-17
prostaglandin E2 (PGE2), interleukin-6 (IL-6), and synergizes with IFNgamma or TNFalpha to promote
inlammatory mediator release and intercellular
intercellular adhesion molecule (ICAM-1); the ind-
adhesion molecule-1 (ICAM-1) expression in human
ings identiied an immunogenic phenotype (10). hus, intervertebral disc cells. J Orthop Res 2011;29:
the intervertebral disc is described as immunogenic 1–7.
but both the DRG and the nerve root appear to require (11) Mulleman D, Mammou S, Grifoul I, Watier H,
an additional mechanical insult to generate pain (11). Goupille P. Pathophysiology of disk-related sciatica.
In response to local inlammation, there may be sec- I.–Evidence supporting a chemical component. Joint
ondary changes in sodium channel subunit expression Bone Spine 2006;73:151–158.
22
Chapter
Pain and diabetic lumbosacral plexopathy
4
Lumbosacral plexopathy, also known as diabetic On neurological examination, he had mild inten-
amyotrophy, is a less common complication of dia- tion tremor but the upper limbs were otherwise nor-
betes than polyneuropathy and it can lead to devastat- mal. He had wasting of the thighs, especially on the
ing disability. his vignette describes a patient who had right, but normal bulk of extensor digitorum brevis
a relatively mild but recurrent version of this condition muscles. here was weakness of hip lexors on the right
and exhibited spontaneous recovery. Some patients (4+/5) and quadriceps (4/5), whereas other muscle
may be bedridden for several months with incomplete groups in the right lower limb and all of the muscles
recovery. in the let lower limb had normal power. Fascicula-
tions were noted in the right thigh, and he had dii-
culty performing heel-shin testing on the right. All of
Clinical case vignette the deep tendon relexes, including ankle relexes, were
A 70-year-old man developed the sudden onset of intact except an absent right quadriceps relex. Sensa-
severe sharp aching discomfort in his thighs. He had tion to light touch and pinprick was diminished in the
been diagnosed with type 2 diabetes mellitus 1 year right anterior thigh and medial leg below the knee in
earlier but had known glucose intolerance before that the saphenous nerve distribution. Sensation to vibra-
for 15 years. here was no history of retinopathy tion was diminished in the right toe. Sensory examina-
or nephropathy, and his glucose control had been tion in other areas, including position testing, was nor-
good with fasting morning measurements in the 6–7 mal. He had some diiculty walking tandem but could
mmol/L range. he pain was predominantly limited to stand on his toes and heels. here was no Romberg
the right thigh with lesser symptoms on the let thigh. sign. His blood pressure was 150/85 with a pulse of 88
Ater the onset of pain, he experienced gradual loss of supine and fell to 95/60, without a change in pulse, on
strength in his legs and eventually required the use of standing.
a cane. Neurological consultation was requested sev- An MRI of his lumbar spine and lumbosacral
eral months later. At 9 months following the onset of plexus identiied mild central canal stenosis at L34
his diiculties, he reported that the pain had dimin- with ligamentum lavum and facet joint hypertrophy.
ished to half of its former severity and his strength here were no pelvic abnormalities. he right vas-
was slowly improving. Overall, he had also lost 23 tus lateralis had a mild increase in signal intensity on
lbs in weight. He had not experienced sensory loss the inversion recovery sequences. Normal laboratory
but had noticed paresthesiae in both thighs. here blood work included: hemogram, ESR, electrolytes,
were no upper limb symptoms. He also described calcium, CK, serum protein electrophoresis, PSA, B12,
erectile dysfunction, occasional postural lightheaded- and TSH. He had an elevated GGT level (502; nor-
ness, and constipation. here were no other sphincter mal,
50 U/L) but did admit to regular ethanol use.
diiculties. Barium enema, upper GI series, and abdominal ultra-
His medications included nifedipine, gabapentin sound were normal.
(600 mg divided in three doses), acetaminophen with he patient’s use of gabapentin was associated with
codeine, and gliclazide. here was no prior history of unacceptable dizziness, and he stopped the medication
hypertension, cardiac disease, or other systemic dis- in favor of long-acting codeine and eventually long-
orders. He had a previous hemorrhoidectomy, hernia acting morphine (MS contin 60 mg twice daily).
repairs, varicocele, and let carpal tunnel release (15 Electrophysiogical studies (10 months from onset)
years earlier). here was no relevant family history. identiied asymmetric CMAPs recorded over the
23
vastus medialis (3.2 mV on the right; 7.2 mV on the

let). Bilateral peroneal motor, bilateral tibial motor,
right supericial peroneal sensory, and right sural sen-
sory (amplitude 9.4 V [normal, 6.0]; CV 41 m/s
[normal, 39]) conduction studies were normal. Nee-
dle electromyography identiied enlarged motor units
in the right rectus femoris and tibialis anterior but no
abnormal spontaneous activity (ibrillations or posi-
tive sharp waves). Right iliopsoas and L3/L4 paraspinal
muscles were normal.
Seven months ater his original presentation (16
months from onset), he developed bilateral ankle pain,
a let foot drop, weakness of right foot plantar lex-
ion, stocking and inger sensory loss, and had lost
both knee relexes and his right ankle relex. He had
maintained strict control of his glucose levels before
these new symptoms. Repeat electrophysiology identi-
ied patchy but active denervation with ibrillations in
the let tibialis anterior, right medial head of gastroc-
nemius, and enlarged motor units in the right tibialis
anterior and let medial head of gastrocnemius with-
Figure 4.1. Proximal lower limb muscles of a patient with diabetic
out abnormal spontaneous activity. Rectus femoris was lumbosacral plexopathy. Note the wasting of the right (left side of
unchanged and there was no paraspinal denervation. image) thigh, particularly involving the vastus medialis.
Repeat imaging of the lumbar spine and lumbosacral
plexus was unchanged. An ankle/foot orthosis was pre-
scribed. Over the next few months, his new symptoms, tralateral peroneal nerve and ipsilateral tibial nerve.
including pain, improved, and he began to gain weight. Only ater the latter problem improved did he begin to
Five years ater his original presentation, he had regain his substantial weight loss. Imaging studies did
some persistent pain below his knees but his strength identify mild lumbar canal stenosis but the indings
had largely recovered and bilateral ankle and knee were not suicient to explain his prolonged progres-
relexes had reappeared. He had distal foot sensory sive, then resolving course. He had no evidence of a
loss. He remained on a low dose of morphine (15 mg connective tissue disease or vasculitis. When irst seen,
twice daily) and retained excellent control of his glu- his pain and disability had slowly been improving.
cose levels. he clinical features and course of this patient’s
condition are indicative of diabetic lumbosacral plex-
Pain description opathy (also called diabetic radiculoplexus neuropa-
thy, asymmetric motor neuropathy, Bruns-Garland
he patient described severe (10/10) sharp aching deep
syndrome, or diabetic amyotrophy) (1). It is an uncom-
discomfort in his thigh that radiated into the tibial area
mon but severe complication of diabetes mellitus and
and ankle. He also described the discomfort as burn-
may develop despite optimal control of hyperglycemia,
ing. he initial symptoms were predominantly right
as observed in the present patient. Some instances may
sided.
begin ater initiation of insulin therapy. he condition
is slowly progressive with prominent and intense deep
Discussion aching thigh pain followed by atrophy and weakness of
his patient developed an asymmetrical painful neu- proximal lower limb muscles [Figure 4.1]. Severe lower
ropathy largely involving the femoral nerve territory limb weakness oten conines patients to a wheelchair.
associated with mild type 2 diabetes mellitus. He also Over the course of several months, the pain and then
had sensory loss in the femoral and saphenous nerve the weakness may resolve but symptoms may recur
24 territories. He had a prolonged biphasic neurological on the contralateral side or in other territories as
condition with a later exacerbation involving the con- with this patient. Weight loss, or cachexia, may be
Chapter 4: Pain and diabetic lumbosacral plexopathy
prominent and the course may be very prolonged,

requiring hospitalization for pain control. Sponta-
neous recovery ater many months is the typical out-
come. Gabapentin was not helpful in our patient
and, like many patients with this condition, opioid
therapy was eventually required. Electrophysiologi-
cal studies may identify denervation in the weak
and wasted muscles including prominent paraspinal
muscle ibrillations and positive sharp waves. here
may also be widespread features of generalized dia-
betic polyneuropathy. he irst electrophysiological
studies for this patient were done 10 months into
the course of his disease; at this time, ibrillations
and positive waves had disappeared. He did have
enlarged motor unit potentials indicative of prior
denervation and reinnervation as well as loss of the
amplitude of the CMAP recorded over the right vas-
tus medialis. Acute patchy denervation was identi-
ied in other motor nerve territories during a later
exacerbation.
he etiology of diabetic lumbosacral plexopathy
is uncertain. Original descriptions, including a serial
section pathological study through the lumbosacral
plexus, emphasized infarction of nerve roots with
occlusion of vasa nervorum (2). Several recent stud-
ies that have examined biopsies of the intermediolat-
eral cutaneous nerves of the thigh described inlam-
matory vasculitis-like changes in nerve microvessels
(3–6) [Figure 4.2]. Because clinical trial evidence is
limited, optimal treatment plans are unclear; one series
advocates the beneits of intravenous immunoglobu-
lin while the experience of one of the authors (D.Z.)
suggests the opposite (7, 8). A recent report has sug-
gested that the use of corticosteroids facilitates rapid Figure 4.2. Transverse paraffin sections of sural nerves from
pain control but unfortunately, without an improve- patients with diabetic lumbosacral plexopathy as reported in Dyck
et al. (6). In the top image (hematoxylin and eosin stain), an
ment in disability (9). epineurial arteriole shows mononuclear cell infiltration within its
wall. In the bottom image (Turnbull blue stain), another epineurial
arteriole shows intimal thickening and proliferation (arrowhead),
Pain in diabetic lumbosacral adventitial scarring, recanalization, and perivascular hemosiderin
plexopathy (arrow, blue). The asterix indicates fresh blood. The changes have
suggested microvasculitis. Reproduced with permission from
he pain experienced by patients with diabetic lum- Neurology (6).
bosacral plexopathy is intense, prolonged, and diicult
to treat. Opioid therapy may be required and hospital- inlammation on nerve biopsy, cachexia, and response
ization is frequent. he cognitive and gastrointestinal to corticosteroids all suggest a role for inlamma-
complications of chronic opioid therapy are problem- tory cytokines. What repertoire of cytokines and
atic. he pain is typically reported to be deep within chemokines may participate and why this inlamma-
the thigh and precedes muscle weakness. tory condition develops in the irst place are unknown.
Several mechanisms may account for this unique Kawamura, Dyck, and colleagues (10) analyzed sural
pain syndrome. Its development early in the course nerves from 19 patients with diabetic lumbosacral 25
of the neurological impairment, association with plexopathy and compared the indings with disease
controls and biopsies from patients with nondiabetic (4) Said G, Goulon-Goeau C, Lacroix C, Moulonguet A.
lumbosacral plexopathy, an uncommon but simi- Nerve biopsy indings in diferent patterns of
lar condition. Nerve blood vessels had increases in proximal diabetic neuropathy. Ann Neurol
ICAM-1 (intracellular adhesion molecule-1), whereas 1994;35:559–569.
Schwann cells and macrophages had increased expres- (5) Said G, Elgrably F, Lacroix C, et al. Painful proximal
sion of TNF. Both ICAM and TNF are inlam- diabetic neuropathy: inlammatory nerve lesions and
spontaneous favorable outcome. Ann Neurol 1997;41:
matory mediators that may contribute to neuropathic 762–770.
pain. Infarction of the plexus alone might also lead
(6) Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and
to pain in this condition by generating ectopic dis-
ischemia in diabetic lumbosacral radiculoplexus
charges from injured nerves or activation of nervi neuropathy. Neurology 1999;53:2113–2121.
nervorum, the unmyelinated axons that innervate the
(7) Zochodne DW, Isaac D, Jones C. Failure of
nerve trunk. immunotherapy to prevent, arrest or reverse diabetic
lumbosacral plexopathy. Acta Neurol Scand 2013;
107:299–301.
References (8) Krendel DA, Costigan DA, Hopkins LC. Successful
(1) Barohn RJ, Sahenk Z, Warmolts JR, Mendell JR. he treatment of neuropathies in patients with diabetes
Bruns-Garland syndrome (diabetic amyotrophy). mellitus. Arch Neurol 1995;52:1053–1061.
Revisited 100 years later. Arch Neurol 1991;48: (9) Dyck JB, O’Brien PC, Bosch EP, et al. Results of a
1130–1135. controlled trial of IV methylprednisolone in diabetic
(2) Raf MC, Sangalang V, Asbury AK. Ischemic lumbosacral radiculoplexus neuropathy (DLRPN): a
mononeuropathy multiplex associated with diabetes preliminary indication of eicacy. J Peripher Nerv Syst
mellitus. Arch Neurol 1968;18:487–499. 2005;10 (Suppl 1):21.
(3) Dyck PJ, Windebank AJ. Diabetic and nondiabetic (10) Kawamura N, Dyck PJ, Schmeichel AM, Engelstad
lumbosacral radiculoplexus neuropathies: new JK, Low PA, Dyck PJ. Inlammatory mediators in
insights into pathophysiology and treatment. Muscle diabetic and non-diabetic lumbosacral radiculoplexus
Nerve 2002;25:477–491. neuropathy. Acta Neuropathol 2008;115:231–239.
26
Chapter
Pain and meralgia paresthetica
5
Meralgia paresthetica is a common focal neuropathy central abdominal obesity. Other diiculties included
of the lateral cutaneous nerve of the thigh in the upper depression and chronic abdominal pain.
lateral leg. Unfortunately, it is diicult to treat, partic-
ularly if it is associated with chronic neuropathic pain.
his vignette describes a patient with painful bilateral
Pain description
meralgia paresthetica superimposed on chronic pain his patient described a pain syndrome rated as 10/10
from osteoarthritis. in severity. He experienced joint pain unrelated to
the neuropathy that accompanied burning pain in his
legs along both thighs. His walking was very limited
because of pain from both areas. Overall, his pain syn-
Clinical case vignette drome developed in the context of several other forms
A 49-year-old right-handed man experienced a 3-year of somatic pain and disability including osteoarthritis
history of burning pain in his legs, starting on the out- and chronic abdominal discomfort.
side of the let thigh and associated with numbness.
Two years ater the onset, he noted similar burning
pain involving the right lateral thigh with loss of sen- Discussion
sation. He denied signiicant loss of sensation or pain Meralgia paresthetica was diagnosed in this patient
in his feet. on the basis of clinical assessment without additional
His history was complicated by early onset and imaging or electrophysiological testing. he diagno-
accelerated familial osteoarthritis that had interrupted sis was established by the distribution of the sensory
his job as an oil ield worker. He was unable to walk alteration in the lateral side of the thigh with preser-
more than two blocks because of ankle and knee pain. vation of quadriceps motor power and the quadriceps
here was no history of diabetes. He had undergone a relexes. He did not have diabetes, a common predis-
cervical laminectomy at level C5/6 14 years earlier but posing condition to this neuropathy, but he did have
no other lumbar surgery. A previous lumbar myelo- abdominal obesity, thought to compress the nerve at
gram 6 years earlier identiied multilevel degenerative the level of the inguinal ligament. Other local causes
changes and multilevel mild disc bulging without def- of nerve entrapment were not identiied.
inite spinal stenosis. Although the patient had experi- Meralgia paresthetica arises from local compres-
enced several limb fractures in the past, he did not link sion of the lateral femoral cutaneous nerve of the
any of these events to his ongoing pain problem. thigh. he nerve is a branch of the lumbar plexus
Neurological examination identiied changes to arising from the L2 and L3 nerve roots and travels
light touch and pinprick in the distributions of both from the lateral side of the psoas major muscle over
lateral cutaneous nerves of the thigh; there was the iliacus muscle deep to its fascia. It passes into
hypersensitivity to pinprick but loss of sensation to the thigh medial to the anterior superior iliac spine
light touch. here was no analgesia or anesthesia. through a space beneath the lateral attachment of the
he remaining neurological examination, including inguinal ligament. It enters into the thigh anterior
quadriceps relexes, was normal. here was no evi- over the sartorius muscle with anterior and posterior
dence of an inguinal lesion such as a lymph node branches that pierce the fascia lata to innervate the lat-
or scar that might compress the lateral cutaneous eral thigh. here are variations in its course, however,
nerves of the thigh. Notably, the patient did not have described in other references (1, 2). hese sources also 27
evidence of radiculopathy. He was overweight with list causes of the neuropathy that include compression
Figure 5.1. femoral territory motor power and a preserved quadri-

Distribution of ceps relex clinically excludes most of these lesions.
sensory loss,
paresthiae, or pain Relying exclusively on changes from imaging stud-
in a patient with left ies can be problematic because lumbar spondylosis
meralgia is common in the general population. Moreover, an
paresthetica. The
area of involvement understanding of whether individual axons have been
can be highly damaged as detected by imaging signal changes can
variable among only be guessed at. In our patient, there was concur-
patients. Key
features include the rent lumbar spondylosis unrelated to his neurologi-
preservation of cal problem. In instances where radiculopathy, plex-
quadriceps motor opathy, or femoral neuropathy are suspected how-
power and an intact
ipsilateral ever, needle electromyography can be helpful; ibrilla-
quadriceps (knee) tions and positive sharp waves in the involved territory
reflex. may be identiied. Paraspinal muscles may also show
denervation in radiculopathies. here is no denerva-
tion of proximal lower limbs or paraspinal muscles in
meralgia paresthetica. Although conduction studies of
the lateral cutaneous nerve of the thigh are described
and are possibly helpful in making a diagnosis, in the
author’s experience, these studies are less technically
reliable than those of other nerve territories, particu-
from obesity, pregnancy, ascites, local tumors, wear- larly in obese subjects.
ing heavy belts (such as toolbelts) or tight clothing, here is no high-quality clinical trial evidence to
local hip pathology, inherited sensitivity to pressure indicate that surgical decompression of the lateral
palsy, diabetes mellitus, prolonged recumbency, injec- femoral cutaneous nerve at the thigh is of greater ben-
tions, trauma, local surgery (hernia repair, appendec- eit than conservative management. In some cases,
tomy, iliac crest bone grat harvesting, others). Pelvic the condition can resolve spontaneously over time.
tumours and other lesions can target this nerve proxi- Despite these uncertainties (1), patients may choose to
mal to the inguinal ligament and injuries or injections undergo decompression if weight loss, local anesthetic
can injure the nerve in the thigh. he nerve is not com- injections, or steroid injections are unhelpful and if
monly targeted by vasculitis or other polyneuropathies pain is intractable.
beyond diabetes, in the author’s experience. Occasion-
ally, patients such as the one described in this vignette
can have bilateral involvement if a predisposing cause, Pain in meralgia paresthetica and
such as obesity, is present. he characteristic features
are sensory loss, pain, paresthesiae, or a combination other focal neuropathies
of these, involving the lateral thigh above the knee and As in many focal neuropathies, the pain from mer-
below the hip [Figure 5.1]. he actual size of the area algia paresthetica is typically more widespread than
of involvement can be quite variable. the actual sensory deicit. Pain may radiate proxi-
high numbness and pain can also arise from L2– mally up the leg and below the knee. Because most
L4 radiculopathies; this patient had a known history instances of meralgia paresthetica arise from compres-
of lumbar degenerative spondylosis. Radicular pain sion at and around the inguinal ligament, the symp-
and associated radicular neurological deicits difer toms are impacted by leg posture or walking. Pain is
from those of meralgia paresthetica in that they oten sometimes relieved by sitting to reduce the stretch or
radiate from the back and are associated with loss of tension on the nerve. here may be painful paresthe-
the quadriceps relex (L3, L4 radiculopathies), muscle siae that is roughly localized to the lateral thigh, with
wasting, or weakness. Imaging studies of the lumbar allodynia and accompanying lancinating or aching
intraspinal space or pelvis may be important to rule pains. A Tinel’s sign over the nerve at the inguinal lig-
28 out other compressive lesions that involve the nerve ament may be present, also indicating mechanosensi-
roots or plexus. Oten however, the preservation of tivity.
Chapter 5: Pain and meralgia paresthetica
he development of mechanosensitivity in focal Over the course of the next few days, the underlying
areas of peripheral nerve damage is not fully under- nerve segment develops swelling, ischemia from stran-
stood. One important possibility is that impaired gulation, and preferential damage to large myelin-
axoplasmic transport at sites of injury promotes the ated axons. Rats (or mice) with CCI develop a short-
accumulation of mechanosensitive ion channels that ened latency to withdrawal from a noninjurious ther-
generate ectopic activity. Dilley and Bove (3) gen- mal plantar paw stimulus and increased withdrawal
erated mechanical sensitivity in unmyelinated axons and paw licking to stimulation with hairs of graded
by local blockade of axoplasmic transport without bending force (von Frey hairs). Despite extensive work
overt inlammation or axon damage. he authors pos- using this model, analogous to many types of focal
tulated that speciic accumulation of mechanosensi- injuries in humans including meralgia paresthetica,
tive channels proximal to the blockade was respon- the exact source of the pain generators is controver-
sible for sensitivity. In additional work, they demon- sial. Axonal degeneration does not immediately ensue
strated that axoplasmic blockade proximal to a site as in a crush or transection injury and spared small
of nerve inlammation prevented the development of unmyelinated axons preserve sensation beyond the site
mechanosensitivity. of injury. Over time, regenerating axons may grow
Speciic ion channels may be associated with beyond and around the sutures and the pain syn-
the development of mechanosensitivity. Lewin and drome disappears. Ectopic discharges can be recorded
Moshourab (4) reviewed mechanisms of mechanosen- proximal to CCI, possibly due to contributions from
sation and describe roles for both C unmyelin- both injured large myelinated axons and nearby unin-
ated axons (C-mechanoheat, C-mechanocold, jured C umyelinated axons. Nearby damaged axons
C-mechanosensitive, C-mechanoheatcold [poly- may generate inlammation that promotes ectopic dis-
modal] and C-silent, or mechanoinsensitive and charges either in C ibers en passant or from the intact
thermal insensitive) and A␦ small myelinated axons ends of damaged large axons.
(A-mechanosensitive with or without additional
thermal sensitivity). Speciic channels associated with
mechanociceptor sensitivity may include the ASIC References
family (acid-sensitive ion channels; BNC1, BNaC1) (1) Cook D, Midha R. Meralgia paresthetica. In: Midha
comprising ASIC members 1–4. Mechanosensitiv- R, Zager EL, eds. Surgery of Peripheral Nerves. New
York: hieme, 2008:167–170.
ity in ASIC3 knockout mice is impaired (5). he
involvement of TRP (transient receptor potential) (2) Stewart JD. Focal Peripheral Neuropathies. 3rd edition.
Philadelphia: Lippincott Williams and Wilkins, 2000.
channels in mechanosensitivity is also implicated.
While the TRPV1, also known as VR1 or vanilloid, (3) Dilley A, Bove GM. Disruption of axoplasmic
transport induces mechanical sensitivity in intact
capsaicin-sensitive channel is the best known among
rat C-ibre nociceptor axons. J Physiol 2008;586:
this group, there are at least 33 TRP channel genes 593–604.
in mammals (6). TRPA1 channels, expressed in
(4) Lewin GR, Moshourab R. Mechanosensation and
small-diameter nociceptive neurons, may be involved pain. J Neurobiol 2004;61:30–44.
in the sensitivity to painful mechanical simuli. TRPV4
(5) Price MP, McIlwrath SL, Xie J, et al. he DRASIC
is yet another among this family of channels that may
cation channel contributes to the detection of
be similarly implicated. cutaneous touch and acid stimuli in mice. Neuron
Pain from focal neuropathies is well demonstrated 2001;32:1071–1083.
in rodent models. hermal hyperalgesia and mechan- (6) Christensen AP, Corey DP. TRP channels in
ical allodynia in speciic and standardized nerve mechanosensation: direct or indirect activation? Nat
injuries is extensively documented. he best known is Rev Neurosci 2007;8:510–521.
the chronic constriction injury (CCI) model described (7) Bennett GJ, Xie YK. A peripheral mononeuropathy in
by Bennett and Xie (7) that involves the placement of rat that produces disorders of pain sensation like
four loose ligatures around the sciatic nerve of the rat. those seen in man. Pain 1988;33:87–107.
29
Chapter
Pain and Lyme radiculopathy
6 (borrelia-associated radiculitis)
Several types of painful neurological problems may

occur in Lyme disease, or borreliosis. his clini-
cal vignette describes a patient with painful truncal
radiculopathy that resulted from borrelia infection.
Clinical case vignette

A 66-year-old man developed pain of the let abdom-
inal wall. He also complained of constipation. Ater
consultation with his physician, a tentative diagno-
sis of diverticulitis was made and the patient was
treated with the antibiotic ciproloxacin. No improve-
ment was observed ater 2 weeks of treatment.
Gastroscopy, colonoscopy, and colon barium x-ray
studies were normal. His pain progressed and he
developed numbness of the let abdomen. Tramadol,
200 mg per day in divided doses, was prescribed and
provided moderate pain relief. MRI scans of the tho-
a
racic and lumbar spinal cord were normal. he patient
was referred to the Neurology service because of his
persisting numbness.
he patient’s past history revealed a motorcycle
accident with injury of the let brachial plexus and frac-
tures of the let thigh and knee. He had no individual
or family history of diabetes. Upon speciic question-
ing, the patient remembered a tick bite approximately
4 months earlier but there was no history of rash that
might suggest erythema migrans.
On general examination, there was no fever; the
patient was obese but otherwise in good general
health. On neurological examination, the patient had
an abdominal wall paresis with bulging on the let b
side easily overlooked because of abdominal obesity
[Figure 6.1a]. he cranial nerves were intact. here was Figure 6.1. (a) Patient with left abdominal wall palsy due to
borrelia infection. (b) Area of pain, patient drawing.
mild weakness of shoulder abduction and elbow lex-
ion and abduction (MRC grade 4/5) as residuum of
the motorcycle accident. All other muscles had nor- tion to light touch and pinprick was reduced in an
mal bulk, power, and tone. Coordination, stance, and area comprising the dermatomes T7 to T11 on the let
30 gait were normal. Tendon relexes were normal and [Figure 6.1b]. his was also the area where the
symmetrical, plantar relexes were downward. Sensa- pain sensation occurred. Light touch and pinprick
Chapter 6: Pain and Lyme radiculopathy (borrelia-associated radiculitis)
Tibial nerve SEP Figure 6.2. Original recordings of the

patient’s neurophysiological findings: (a)
Tibial sensory evoked potentials (SEP) with
prolonged latencies on the left. (b) Tibial
motor evoked potentials (MEP) showed
prolonged peripheral latencies bilaterally.
R: 47.2 ms L: 48.0 ms
a
Tibial nerve MEP
Cortical stimulation R
35.2 ms (n 33.2)
Cortical stimulation L
Lumbar stimulation R
Lumbar stimulation L
17.6 ms (n 15.8)
sensation were also reduced in an area over the let total protein were normal, and there were three iden-
shoulder following the motorcycle accident. tical oligoclonal bands in the CSF and serum. Borrelia
Neurophysiological testing revealed prolonged ELISA was positive for IgG and Western blot showed
latencies of tibial evoked sensory potentials on the two IgG bands. he CSF:Serum anti-B. burgdorferi
let. Median nerve evoked sensory potentials were antibody index was elevated with a value of 8.2 (nor-
normal. Motor evoked potentials showed prolonged mal,
1.4). A diagnosis of borrelia radiculitis (Lyme
peripheral latencies bilaterally [Figure 6.2]. radiculitis) was made. he patient was treated with
Routine laboratory tests were unremarkable. C- cetriaxone 2 g/day for 3 weeks. A combination of sus-
reactive protein was slightly elevated to 0.87 mg/dl tained release tramadol 100 mg twice daily and pre-
(normal, 0–0.5). Glycosylated hemoglobin was normal gabalin 150 mg twice daily provided pain relief. Com-
as was an oral glucose tolerance test. Borrelia serol- plete recovery occurred over the next 3 months.
ogy revealed a positive enzyme-linked immunosor-
bent assay (ELISA) for IgG and positive Western blots
with several strong bands for IgG and IgM. Assum- Pain description
ing radiculitis, lumbar puncture was performed, which he patient’s overall pain intensity at initial presen-
revealed pleocytosis with 45 WBCs/l, mostly lym- tation was rated as 6/10, despite treatment with tra- 31
phocytes. Cerebrospinal luid glucose, albumin, and madol. he patient described the pain as a constant
burning with intermittent stabbing; it also had a deep glucose. Cranial neuritis, oten presenting as bilateral
aching component. Movement did not impact the facial palsy, is another manifestation (3). Less com-
severity of the pain. he pain was localized to the mon neurological manifestations include mononeuri-
upper let abdomen. On the Neuropathic Pain Symp- tis multiplex, distal symmetric peripheral neuropathy,
tom Inventory (NPSI) (1), the patient characterized his brachial or lumbosacral plexopathies, myelitis with
pain as burning (6/10), squeezing (4/10), pressure-like severe ataxia, and encephalomyelitis mimicking mul-
(4/10), and stabbing (4/10). Overall pain intensity was tiple sclerosis.
reduced to 2–3/10 under combined treatment with tra- Given the typical history, clinical indings, and bor-
madol and pregabalin. relia serology, the inal diagnosis was unequivocal in
this patient. he neurophysiological results also may
have indicated a subclinical bilateral involvement. Par-
Discussion enteral cetriaxone (2 g once daily) or cefotaxime (2 g
Painful paralysis of the abdominal wall muscles is a every 8 h) for 14–28 days are established regimens for
very uncommon clinical manifestation of Lyme neu- the treatment of neuroborreliosis. In European adults
roborreliosis. In a group of 90 patients sufering from with Lyme neuroborreliosis, oral doxycycline 200 mg
early stage Lyme neuroborreliosis however, abdominal per day proved to be as efective as intravenous cetri-
wall weakness was found in 11 cases (2). he lower axone (5).
thoracic segments (T7–12) are most oten involved. It is still controversial whether infection with bor-
Bilateral occurrence is not uncommon. Electromyo- relia may lead to a syndrome encompassing chronic
graphy may show ibrillation potentials and positive widespread pain and chronic fatigue (6, 7). Most
sharp waves in paraspinal and abdominal wall mus- experts argue that the assumption that chronic, subjec-
cles. Diagnostic errors are frequent, resembling the tive symptoms are caused by persistent infection with
well-known descriptions of misdiagnosis that occurs B. burgdorferi is not supported by adequate laboratory
in diabetic thoracoabdominal radiculopathy (2). Our studies or controlled clinical trials, and that the use
patient was not diabetic. If the patient had been a dia- of prolonged, antibiotic treatments is not warranted
betic, it is possible that lumbar puncture would not (8).
have been performed and the diagnosis missed or at
least further delayed. Pain was the leading symptom,
and the abdominal wall palsy was not evident to the
irst physician examining the patient, possibly due to Pain in radiculitis
the patient’s obesity and to the relatively mild extent of Lyme radiculitis is typically painful, which does not
the paresis. Furthermore, the patient complained help in diferentiating it from compressive radiculopa-
of constipation. his constellation led to the con- thy or diabetic radiculopathy. he pain is oten burn-
sideration of diverticulitis that resulted in several ing, lancinating and strictly conined to the afected
unnecessary and partially invasive diagnostic mea- dermatomes. Paresthesias, allodynia, and hyperalgesia
sures, and delayed speciic treatment. Elsewhere, cases may occur in the involved region.
mistaken for an acute abdominal crisis have been In terms of its pathophysiology, radiculitis pain
described (3). he diferential diagnosis may also is likely to consist of a combination of inlammatory
include post-herpetic neuralgia, and spinal disorders, and neuropathic pain. Unlike acute herpes zoster,
as in fractured vertebrae due to malignancy; these were another infection commonly leading to radiculitis,
excluded by imaging in the present case. there are no experimental models of borrelia-
Lyme neuroborreliosis develops in 15–20% of associated radicular pain. Consequently, detailed
untreated individuals with borreliosis. he typical pre- knowledge of its pathophysiology is lacking. In
sentation is the combination of lymphocytic menin- the nonhuman primate model of Lyme borreliosis,
gitis, cranial neuritis, and radiculoneuritis, as orig- inlammation localized to nerve roots, dorsal root
inally described (4). If meningitis is the leading ganglia, and leptomeninges was established (9).
syndrome, patients typically have headache and pho- Iniltrating cells were mostly lymphocytes and B
tosensitivity, are febrile, and CSF shows mild lym- cells. Analogous to other types of nerve or root
phocytic pleocytosis (mostly
100 WBCs/l), mildly inlammation, spontaneous activity and sensitization
32
elevated protein, and normal or minimally decreased of nociceptors can be inferred.
Chapter 6: Pain and Lyme radiculopathy (borrelia-associated radiculitis)
References European Lyme neuroborreliosis: a multicentre,

non-inferiority, double-blind, randomised trial.
(1) Bouhassira D, Attal N, Fermanian J, et al. Lancet Neurol 2008;7:690–695.
Development and validation of the Neuropathic Pain (6) Cairns V, Godwin J. Post-Lyme borreliosis syndrome:
Symptom Inventory. Pain 2004;108:248–257. a meta-analysis of reported symptoms. Int J Epidemiol
(2) Pfadenhauer K, Schonsteiner T, Stohr M. 2005;34:1340–1345.
[horaco-abdominal manifestation of stage II Lyme (7) Weissmann G. “Chronic Lyme” and other medically
neuroborreliosis]. Nervenarzt 1998;69:296–299. unexplained syndromes. Faseb J 2007;21:299–301.
(3) Halperin JJ. Is neuroborreliosis a medical emergency? (8) Feder HM Jr, Johnson BJ, O’Connell S, et al. A critical
Neurocrit Care 2006;4:260–266. appraisal of “chronic Lyme disease”. N Engl J Med
(4) Garin C, Bujadoux A. Paralysie par les tiques. J Med 2007;357:1422–1430.
Lyon 1922;71:765–767. (9) Bai Y, Narayan K, Dail D, et al. Spinal cord
(5) Ljostad U, Skogvoll E, Eikeland R, et al. Oral involvement in the nonhuman primate model of
doxycycline versus intravenous cetriaxone for Lyme disease. Lab Invest 2004;84:160–172.
33
Chapter
Neuralgic amyotrophy
7
Neuralgic amyotrophy, or brachial neuritis, is an were normal. he EMG of the involved muscles did
intense inlammatory disorder involving the brachial not show abnormal spontaneous activity and motor
plexus. Neuropathic pain at its outset can be very dif- unit recruitment showed a mild neurogenic pattern.
icult to treat. In this vignette a patient with idio- he patient was treated with oral prednisolone at 1
pathic neuralgic amyotrophy is presented, highlight- mg/kg for 10 days. he steroid was tapered over 4
ing its typical course. weeks and then stopped. Pain did not recur. Regular
physiotherapy was initiated. One year later, right arm
strength had recovered, and the periscapular atrophy
Clinical case vignette had largely recovered.
A 25-year-old mechanic developed the abrupt onset of
severe right shoulder pain. he pain was prominent at Pain description
night and interfered with sleep. Ibuprofen ofered little he patient described his shoulder pain as very severe,
beneit. he pain disappeared a few days later, and unusual, and “like never before.” An active sports-
the patient thought his problem had resolved. During man, he had experienced previous injuries including
the following weeks, he noted increasing weakness of an acromioclavicular joint injury on the let which
his right arm prompting him to see a neurologist 2 resulted from a past skiing accident. He described his
months later. On examination, he had mild atrophy current pain as much more severe, equivalent to 8–
of all shoulder muscles and a winged scapula on the 9 out of 10. It was localized around the shoulder gir-
right [Figure 7.1]. here was weakness of all shoulder dle, had started one night in the early morning hours
muscles on the right with an MRC score of 4-5. he and had reached its maximum within a few hours. he
right hand and inger extensors had mild weakness patient described the pain as deep, aching, and unlike
graded as 4+/5. Tendon jerks were brisk and sym- anything he had previously experienced. Due to its
metrical; pathological relexes were absent. Sensation severity, he could not sleep and spent most of the time
was completely normal for all modalities. Laboratory sitting on the sofa. Ibuprofen and other NSAIDS did
investigations, including cerebrospinal luid analysis, not alleviate the pain.
34
Figure 7.1 Winging of the right scapula in a patient with idiopathic variant of neuralgic amyotrophy.
Chapter 7: Neuralgic amyotrophy
Discussion cases however, it has a very low sensitivity for the

diagnosis of INA. In contrast, MRI of the shoulder
Neuralgic amyotrophy was described in 1948 by Par-
musculature may delineate the pattern of wasted
sonage and Turner, who identiied 136 cases between
involved muscles. Imaging may also help determine
1941 and 1945. Synonyms for this disorder include
prognosis (2).
Parsonage-Turner syndrome, plexus neuritis, sporadic
Laboratory testing is unhelpful. he presence of
brachial plexus neuropathy, and neuralgic amyotro-
anti-ganglioside antibodies has been described. CSF
phy (NA). Both idiopathic (INA) and hereditary vari-
rarely reveals increased protein levels or oligoclonal
ant (HNA) forms occur. INA has an incidence of 1–
bands. EMG shows signs of denervation and re-
4/100,000, comparable to Guillain-Barré syndrome.
innervation in the involved muscles. In nerve conduc-
HNA is rare and has been described in approximately
tion studies, CMAP amplitudes are only reduced when
200 families worldwide. Men are more alicted than
muscles are signiicantly weak although asymmetri-
women, in a ratio of 3:2. INA occurs most oten in the
cally reduced CMAP responses may accompany ib-
second to fourth decade of life, HNA in the second
rillation potentials and positive sharp waves. he dif-
decade. Onset at any age is possible, particularly in the
ferential diagnosis of brachial plexus lesion includes
case of INA. he clinical picture typically consists of
trauma, radiation, Pancoast tumor, thoracic outlet
acute and very severe shoulder–arm pain that remits
syndrome, and infectious causes such as neuroborre-
over days or weeks followed by multifocal atrophic
liosis and HIV.
pareses in the same region. he interval between the
onset of pain and the development of weakness varies
between under 24 h to over 2 weeks. Rare forms with- Pain in neuralgic amyotrophy
out pain (1) have also been reported. Apart from speciic tests that eliminate alternative dif-
he weakness of INA may involve all parts of the ferential diagnoses in patients with INA, speciic pain
brachial plexus. In 70% of cases, the upper plexus is characteristics are very helpful in distinguishing it
involved. Sensory deicits may be present and may not from other manifestations of shoulder disease (1). If
correspond to the anatomical distribution of the motor the pain is acute, very severe, and unlike anything the
deicits. his patchy pattern is a helpful diagnostic sign. patient has previously experienced, a diagnosis of INA
he contralateral arm has mild involvement in a third is very likely. If not, NA is possible but alternative
of all patients. herefore, a full neurological exami- pathologies should be considered. With limited pas-
nation with testing of muscle strength in apparently sive arm external rotation or abduction, shoulder joint
unafected muscles is necessary. he typical motor pat- pathology such as bursitis or tendinitis is more likely. If
tern is that of an upper brachial plexus lesion. he the pain is in the same root distribution as the symp-
periscapular and perihumeral muscles are involved in toms (paresis, sensory disturbances), cervical radicu-
70% of men. he long thoracic nerve is involved in lopathy should be considered. In 90% of patients, the
two thirds of patients, oten leading to winging of the disorder starts with an unusual, very severe pain in
scapula (Figure 1). he lower plexus is involved in the shoulder–arm area that reaches maximum sever-
approximately 25% of women and 10% of men. ity within a few hours. he duration of severe or mod-
While the brachial plexus is predominantly erate pain can range from less than 24 h to persisting
afected in INA, 60% of HNA patients have involve- for several months. Standard analgesics have no efect.
ment of the lumbosacral plexus, involved in only 17% Patients describe the pain as unusually severe, radiat-
of INA patients. Rarely, the phrenic nerve, the facial ing from the shoulder to the neck and to the arm. In
nerve, and abdominal nerves may be involved. he 60%, the onset occurs when the patient is at rest or
medial and lateral antebrachial cutaneous nerves, sleeping, and remains severe at night interfering with
which innervate the volar forearm, may also be sleep. When asked to quantify the pain, patients usu-
impacted because they emerge directly from the ally mark scores between 7 and 10 out of 10. Up to
brachial plexus. his causes pain and a sensory 80% of patients report some pain, although milder, at
deicit of the volar forearm. SNAP amplitudes may be the onset of the weakness. On examination, the pain is
reduced. Hyperintense areas of the brachial plexus in increased by elevating and abducting the arm; this has
T2-weighted MRI scans have been reported. Because been termed, “the Lasègue sign of the arm.” he pain
this inding is only present in approximately 10% of usually remits within weeks to months. In the acute 35
phase, the inlammatory aspect of the pain predom- and recovery in strength (6). Other immune treat-
inates. Within days to weeks, this leads to a second ments appear to have no efect (7).
phase which is considered mostly neuropathic and is During the third, musculoskeletal phase of pain
characterized by spontaneous or movement-induced which can vary in duration, pharmacological treat-
shooting pain and tingling sensations in the anatom- ment has little efect. A combination of physical
ical distribution of the plexus. Once the acute pain therapy and adaptation to activities of daily life is
has subsided, a diferent, musculoskeletal type of pain, recommended (1). It is important that involved mus-
caused by muscular instability at the shoulder joint cles are not overused and further damaged. Secondary
may develop. Patients with instability of the scapula joint pathology, such as irritation of the rotator cuf,
due to paresis of the serratus anterior, rhomboid, or bursitis or cuf tendon rupture, requires orthopedic
trapezius muscle and with instability of the rotator cuf intervention.
have a higher risk for developing this musculoskeletal
pain. References
INA is regarded as an auto-immune disorder (1) van Alfen N. he neuralgic amyotrophy consultation.
(1). As observed in Guillain-Barré syndrome, spe- J Neurol 2007;254:695–704.
ciic events appear to trigger an immune response in (2) Scalf RE, Wenger DE, Frick MA, Mandrekar JN,
approximately 50% of cases. hese include infections, Adkins MC. MRI indings of 26 patients with
surgery, pregnancy, mental and physical stress, immu- Parsonage-Turner syndrome. AJR Am J Roentgenol
2007;189:W39–W44.
nizations, and immunodulating therapies. Mechan-
ical factors may also be a risk factor. Because (3) Pellegrino JE, Rebbeck TR, Brown MJ, Bird TD,
Chance PF. Mapping of hereditary neuralgic
approximately 50% of patients do not report a preced-
amyotrophy (familial brachial plexus neuropathy)
ing event, other factors must also be considered. In to distal chromosome 17q. Neurology 1996;46:
HNA, this requires review of the genetic background. 1128–1132.
In approximately 55% of families, the gene for HNA (4) Hannibal MC, Ruzzo EK, Miller LR, et al. SEPT9 gene
has been localized to the SEPT9 gene on human chro- sequencing analysis reveals recurrent mutations in
mosome 17q25.3 (3, 4). Septins are highly conserved hereditary neuralgic amyotrophy. Neurology 2009;
ilamentous proteins. he SEPT9 mutation may regu- 72:1755–1759.
late interactions of septin-9 with other septins or other (5) Nagata K, Asano T, Nozawa Y, Inagaki M.
cellular proteins (5), but the mechanism by which it Biochemical and cell biological analyses of a
leads to HNA is unknown. mammalian septin complex, Sept7/9b/11. J Biol Chem
In the acute phase, a combination of a long-acting 2004;279:55895–55904.
NSAID and an opiate, such as diclofenac 100 mg bid (6) van Eijk JJ, van Alfen N, Berrevoets M, van der Wilt
and 10–30 mg of a slow release morphine, is recom- GJ, Pillen S, van Engelen BG. Evaluation of
mended. An NSAID alone is oten not suicient. In prednisolone treatment in the acute phase of
neuralgic amyotrophy: an observational study.
the second phase when the neuropathic component is
J Neurol Neurosurg Psychiatry 2009;80:1120–1124.
predominant, drugs prescribed for neuropathic pain
may be helpful. hey include pregabalin, gabapentin, (7) van Alfen N, van Engelen BG, Hughes RA. Treatment
for idiopathic and hereditary neuralgic amyotrophy
amitriptyline, or carbamazepine. Case reports have (brachial neuritis). Cochrane Database Syst Rev
linked the use of oral prednisolone to faster pain relief 2009:CD006976.
36
Chapter
Painful radiculopathy associated with
8 herpes zoster infection
Herpes zoster is associated with one of the most area. She had weakness of the right deltoid (2/5), right
intense neuropathic pain syndromes. he virus is asso- biceps (3–/5) with an intact brachioradialis, triceps,
ciated with pain in the territory of one or more adja- and other right upper limb muscles. he let arm and
cent nerve roots, most commonly on the trunk but lower limbs were intact. he right biceps and brachio-
occasionally involving cervical and lumbar root distri- radialis relexes were absent. On sensory examination,
butions. Pain and a vesicular rash may be associated there was loss to light touch and pinprick over the ante-
with motor weakness and denervation in the territory rior forearm, medial arm, and lateral shoulder. here
involved. Zoster-related neuropathic pain has igured were no other neurological indings.
prominently in clinical trials but oten is refractory to Electrophysiological studies identiied a reduction
treatment. in the amplitude of the compound muscle action
potential recorded over the right deltoid muscle on
stimulation of the axillary nerve. Needle electromyo-
Clinical case vignette graphy identiied abnormal spontaneous activity with
A 72-year-old right-handed female developed neck ibrillations and positive sharp waves in the right
and shoulder discomfort ater attending a wedding. deltoid, biceps, and right C6 paraspinal muscles.
Chiropractic “cupping” failed to alleviate the pain, and here were reduced numbers of motor unit potentials
she developed a vesicular rash involving the lateral side recorded from the right deltoid muscle and to a lesser
of her right neck, right posterior shoulder, posterior extent in the right biceps. Overall, the indings were
arm, and volar forearm. She was treated with valcy- indicative of a right C5–6 radiculopathy secondary to
clovir. he rash persisted for approximately 6 weeks herpes zoster radiculitis.
before healing. he skin lesions were associated with MR imaging identiied a signal abnormality involv-
both supericial and deep pain rated as 8–9/10 in ing the cervical spinal cord from C2–3 to C6–7 involv-
severity. ing the central gray matter including the anterior
As the vesicles presented, the patient developed and posterior horns with sparing of peripheral white
weakness liting her arm up or bending at the elbow. matter [Figure 8.1A]. he changes primarily involved
She had diiculty combing her hair, feeding herself, the right hemicord where mild enhancement was
and raising her arm. She noted tingling from her right observed. here was no cord edema. Osteophytes and
shoulder radiating down her arm and into her thumb foraminal stenosis were also identiied at several lev-
with sensory loss in a similar distribution. els and on both sides of the cervical spine (C34, C45,
here had been no prior episodes of herpes zoster. C56).
She had been in good health and there was no his- he weakness persisted over the next 6 weeks with
tory of diabetes mellitus, malignancy, or immunosup- the onset of slow and gradual improvement ater that.
pression. Medications included synthroid, gabapentin, Burning supericial discomfort persisted for 6 months
vitamins, acetaminophen with codeine, and losartan. ater the onset of the rash. By 9 months ater the
On examination at 3 months following her initial rash, she could comb her hair, and by 10 months, she
symptoms, she had healed scars characteristic of her- reported only 75% of her baseline strength. Recovery
pes zoster involving the right lateral neck, anterome- was complicated by a pre-existing diagnosis of painless
dial arm, and volar forearm including the antebrachial rotator cuf impingement in the same arm.
37
Figure 8.1. The upper panel (A) is a coronal MR image of the cervical spine at approximately the level C4 (T2 weighted) showing a signal
change involving the right side of the spinal cord extending from the dorsal horn into the anterior gray matter (arrow). The photographs in (B)
and (C) illustrate examples of healed scars from herpes zoster in a separate patient that had involvement of the C8 and T1 nerve root
distributions with associated motor weakness in the hand and forearm.
Pain description her neck into her shoulder, upper arm, and fore-
he patient had no previous history of arm pain. She arm. By 10 months ater the onset of the rash, this
reported supericial burning discomfort that she rated pain was persistent and was exacerbated by use and
as 9/10 in severity and that was distributed over the movement. At this time, it was rated as 2–3/10 in
same area as the rash. he pain outlasted the rash severity.
however, persisting for 6 months in total. It was exac- Analgesic medications had been helpful, but their
erbated by contact with clothing or the bed covers actions were incomplete. An initial trial of gabapentin
and by movement. he pain was present day and up to 2400 mg daily was associated with cognitive
night without remit and interfered with her ability to side efects. Pregabalin was more efective but induced
sleep; she was unable to lie on her side with her head lower limb edema. Acetaminophen/oxycodone was
38 propped up. A second type of pain was described as helpful. By 10 months, she was still using codeine con-
deep and aching, of similar severity radiating from tin and acetaminophen with codeine.
Chapter 8: Painful radiculopathy associated with herpes zoster infection
Discussion extend into the posterior horn of the spinal cord,

and less commonly into the anterior horn rendering
he patient presented with features of herpes zoster
“poliomyelitis” (inlammation of gray matter). In acute
radiculitis of the C5–C6 distribution with the initial
zoster, pain usually lasts for 1–6 weeks with resolution
onset of severe pain followed by the outbreak of a
of the rash (small cutaneous scars may remain) (2).
characteristic rash. he rash was described as clusters
Ater the lesions have healed, scars may be evident in
of papules that developed into vesicles on an erythe-
the nerve root territory involved [Figure 8.1B,C].
matous base. Although some instances of zoster radi-
Painful herpes zoster radiculitis or cranial neuri-
culitis occur in the absence of rash (“zoster sine her-
tis is only one of several complications of zoster infec-
pete”), the characteristic rash, sensory symptoms, and
tion of the nervous system which includes vasculopa-
pain follow a segmental distribution involving one or
thy, myelopathy, and retinal necrosis. Vasculopathy
more adjacent root territories. Pain from early truncal
may be associated with focal ischemic neurological
herpes zoster may incorrectly suggest an abdominal
deicits and cerebral hemorrhage. Facial nerve zoster
or thoracic emergency. In this patient, the diagnostic
is associated with facial paralysis (Ramsay Hunt syn-
features involved the C5 and C6 skin sensory territo-
drome) and trigeminal zoster is a medical emergency
ries over the shoulder and upper arm with some sen-
(herpes zoster ophthalmicus). Zoster sine herpete
sory symptoms radiating into the thumb. he patient’s
exhibits segmental or radicular pain in the absence of a
description of neuropathic pain with zoster was char-
rash. While the existence of this syndrome has been in
acteristic and included supericial burning with allo-
some doubt historically, several recent cases have con-
dynia, but also deep discomfort. In addition to the
irmed infection in the clinical syndrome without rash
exquisite pain syndrome associated with zoster, seg-
(2, 3). Acute zoster is treated with antiviral agents and
mental involvement of motor neurons can also develop
analgesics. Childhood varicella vaccination may lead
with denervation, as identiied in this patient, in the
to a reduction in the prevalence of herpes zoster and in
territory of sensory symptoms and rash. he patient
2006, a new zoster vaccine was approved by the FDA
had relatively mild motor involvement but denerva-
for healthy adults over 60 years of age who are seropos-
tion in other territories can be severe rendering foot
itive for the virus (2).
drop, hand paralysis, and other deicits depending on
the level of involvement. Needle electromyography is
helpful in mapping out the distribution of the de-
nervation. In this case, paraspinal muscle involvement
Pain associated with herpes zoster
indicated a proximal level of involvement at the root infection
or segmental gray matter. Imaging studies conirmed Post-herpetic neuralgia occurs in 40% of zoster
segmental signal change in the spinal cord on the side patients over the age of 60 (4) and is deined as pain
of involvement. Given the persistent nature of the dis- that persists for at least 3 months ater the disap-
comfort over many months, she later fulilled the diag- pearance of the rash. he exact mechanisms through
nosis of post-herpetic neuralgia. Our patient did not which zoster generates pain is uncertain, but a role
have diabetes mellitus or immunosuppression, but her for local ganglion virus reactivation and ganglioni-
older age was a risk factor. tis has been considered. For example, up to 7% of
Herpes zoster arises from human infection with a DRG neurons may contain latent virus (2). Associated
neurotropic alpha-herpesvirus. It is a common disor- mechanisms likely involve altered properties of sur-
der with an incidence at 5–6.5 per 1000 but its inci- viving neuron subpopulations that may predispose a
dence increases with age and may occur in up to pain phenotype. hese include a shit in the excitabil-
11 per 1000 persons by the age of 70 (1). he pain ity characteristics of residual neurons, long-term plas-
associated with herpes zoster arises from an acute tic changes of neuronal sodium or calcium chan-
inlammatory reaction that involves one or more adja- nels, persistent DRG iniltration of inlammatory cells
cent segmental sensory dorsal root ganglia (or sen- with inlammatory cytokines, TNF␣ or free-radicals,
sory cranial nerves) with extension into nerve roots. or inally, alterations in the behavior of perineuronal
Segmental mild leptomeningeal inlammation is com- glial cells. Because the inlammation of herpes zoster
mon and acutely infected ganglia have direct evidence oten involves leptomeninges and the dorsal horn of
of herpes zoster virus invasion. Inlammation can also the spinal cord, altered dorsal horn circuitry, as occurs 39
ater simple axotomy injuries or peripheral inlam- (2) Mueller NH, Gilden DH, Cohrs RJ, Mahalingam R,
atory lesions, may also play an important role. he Nagel MA. Varicella zoster virus infection: clinical
burning phenotype combined with striking allodynia features, molecular pathogenesis of disease, and
argues for mechanisms that involve smaller caliber latency. Neurol Clin 2008;26:675–697, viii.
nociceptive neurons, but also remodeling of normally (3) Blumenthal DT, Shacham-Shmueli E, Bokstein F,
non-nociceptive pathways that usually involve light et al. Zoster sine herpete: virologic veriication by
detection of anti-VZV IgG antibody in CSF.
touch to mediate allodynia. Neurology 2011;76:484–485.
(4) Rogers RS, III, Tindall JP. Herpes zoster in the
References elderly. Postgrad Med 1971;50:153–157.
(1) Donahue JG, Choo PW, Manson JE, Platt R. he
incidence of herpes zoster. Arch Intern Med
1995;155:1605–1609.
40
Section C Generalized neuropathies or polyneuropathies
Chapter
Pain and chronic inlammatory
9 demyelinating polyneuropathy
Chronic inlammatory demyelinating polyneuropathy and heels but had an unusual lurching gait, improved
(CIDP) is a progressive or relapsing disorder of periph- with using a cane.
eral nerves associated with prominent motor involve- Ater his initial visit, the patient was followed inter-
ment. his vignette describes a patient with CIDP who mittently for 14 years in clinic. His ongoing neurologi-
experienced severe neuropathic pain. he diagnosis at cal care was signiicantly complicated by long absences
outset was challenging and his condition (and pain) out of the country, depression, and very limited com-
progressed because he declined ongoing therapy. pliance with treatment regimens. His overall course
was that of gradual deterioration and increasing neu-
ropathic pain, despite some periods of improvement
Clinical case vignette while on immunosuppressive medication. Four years
A 51-year-old right-handed construction worker had ater initial evaluation, he required a cane to ambulate.
a 6-year history of burning tingling sensations that His irst set of electrophysiological studies in our clinic
began in his feet from the ankle down and then pro- identiied patchy slowing of motor conduction veloc-
gressed to involve the posterior calf. He experienced ity in his ulnar and peroneal nerves and difuse loss of
cramping in his feet or legs and developed loss of sen- sensory nerve action potentials (SNAPs); the indings
sation with paresthesiae of his legs. During the year were not diagnostic of demyelinating neuropathy. Two
before his assessment, he had noted a decline in bal- years later however, more prominent indings of pri-
ance, diiculty liting his feet, numbness in his inger- mary demyelination appeared on repeat studies. here
tips, and burning in his forearms. was evidence of clinical deterioration with a decline in
he patient had undergone two prior lumbar walking, mild weakness of his interosseous muscles,
laminectomies, the irst 25 years earlier and the sec- and weakness of toe dorsilexors. His sensory loss had
ond, 1 year later. he second procedure did not advanced. He had temporal dispersion in his ulnar
improve his symptoms. He had been treated out of the motor territory, a lengthening of his peroneal distal
country with prednisone and cyclophosphamide for motor latency with a fall in the peroneal motor con-
a possible inlammatory neuropathy, although a irm duction velocity [Table 9.1 and Figure 9.1]. Dener-
diagnosis had not been established. He had remote vation was identiied in the tibialis anterior (ibril-
removal of an abdominal paraganglioma. He was tak- lations, positive sharp waves, and fasciculations). A
ing diazepam but no other medications. here was course of intravenous gamma globulin (IVIG) was
no history of diabetes, hypertension, or signiicant associated with improved electrophysiological results
systemic disease, and there was no family history of but produced relatively little symptomatic improve-
polyneuropathy. A brother was later diagnosed with ment. Upon returning to the country and clinic ater a
ALS. 2-year absence, he showed further deterioration. Trials
On neurological examination, he had loss of mus- of prednisone, intravenous methylprednisolone, and
cle bulk below his knees, efort-limited voluntary mus- azathioprine were associated with uncertain beneit
cle recruitment but otherwise normal muscle power and were complicated by out of country absences from
throughout. He was arrelexic. On sensory examina- follow-up and by the patient’s intermittent decisions to
tion, there was loss of sensation to light touch, pin- stop treatments. Overall treatment was sporadic. Over
prick, cold sensation, and vibration perception in his the years of follow-up, IVIG was associated with at
feet to the mid-tibia and in his ingers. His toes were least two documented episodes of clinical and elec-
anesthetic and analgesic. He could stand on his toes trophysiological improvement but the patient declined
41
Section C: Generalized neuropathies or polyneuropathies
Table 9.1. Serial electrophysiological studies (selected)

Ulnar∗ Peroneal†
Date CMAPd CMAPp CV CMAPd CMAPp CV Comment
1994 8.7 5.8 44 3.2 3.3 39
1996 5.2 3.8 49 0.89 0.71 33
1996 10.6 7.7 46 1.7 1.4 30 Post-IVIG
1998 9.2 6.1 44 1.7 1.2 28 IVIG, prednisone
2000 7.1 5.0 45 0.12 0.07 29 No therapy
2001 8.7 7.3 41 0.31 0.24 29 Azathioprine,IVIG
2006 7.7 5.6 34 0.02 No therapy
2007 5.3 3.4 33 abs abs Refused therapy
∗ Studies were done at wrist, below and above elbow (and higher), but above elbow results not shown.
† Studies were done at ankle, fibular head, and knee but knee results not shown; absent SNAPs were noted in all studies in the median,
ulnar, sural, and superficial peroneal territories; median and tibial studies not shown.
CVs: conduction velocity [m/s] in the forearm segment (ulnar) or below the knee (peroneal) (normal, 50 in ulnar, 40 in peroneal); CMAP:
compound muscle action potential (d = distal; p = proximal (mV); normal, 5.0 ulnar, 2.0 peroneal).
was wheelchair bound. Sphincter function remained

intact. His electrophysiological studies showed loss or
absence of motor potentials with dispersion, slowing of
conduction velocity, and difuse loss of SNAPs. Com-
pared with his original studies, his upper limb CMAPs
1 mV S1 had declined by over 50% and his lower limb CMAPs
5 ms had disappeared [Table 9.1]. hroughout his course,
CIDP: Peroneal motor conduction neuropathic pain was a signiicant and unrelenting
problem. He was admitted twice to the Neurology Unit
but became noncompliant and refused rehabilitation,
immunomodulatory therapy, psychiatric input, or an
assessment by the pain service.
CSF identiied an elevated protein (0.87 g/L), nor-
mal glucose, and no white cells. A gastrocnemius mus-
cle biopsy early in his course showed scattered atrophic
S2
ibers and rare grouped ibers. A sural nerve biopsy
performed before his evaluation in our clinic iden-
tiied loss of large myelinated axons, axonal degen-
S3 eration, macrophage iniltration, and thin ibers with
some evidence of segmental demyelination. Inlam-
Figure 9.1 Examples of peroneal motor waveforms in the patient
described in this vignette. The CMAPs (compound muscle action
mation or onion bulbs were not identiied. Amyloid
potentials) illustrated were recorded from the extensor digitorum was not present. he overall pathological diagnosis was
brevis with stimulation at the ankle (S1), fibular head (S2), and knee that of CIDP. He declined further nerve biopsies to
(S3). Note that the CMAP amplitudes are reduced (normal, 2.0 mV)
and dispersed on more proximal stimulation.
help substantiate the diagnosis, given his diiculties
with treatment regimens. he evolution of his course
and his electrophysiology results however, clariied the
further treatment. Fourteen years ater his original diagnosis.
presentation to our clinic, he exhibited substantial Other investigations were either normal or nega-
deterioration with difuse limb weakness especially tive and included: complete blood count, glucose, elec-
42 distally (bilateral foot drop), distal wasting, arrelexia, trolytes, creatinine, uric acid, calcium, albumin, phos-
and loss of sensation distal to his knees and elbows. He phorus, CK, LDH, bilirubin, alkaline phosphatase,
Chapter 9: Pain and chronic inflammatory demyelinating polyneuropathy
ALT, GGT, ESR, TSH, B12 level, red cell folate, RPR untreated and severe CIDP rendering him near bed
(syphilis serology), HIV serology, serum protein elec- bound with encephalopathic complications of opioid
trophoresis (repeated assays), ANA, SS-A/Ro, anti- use.
DNA, rheumatoid factor, antibodies to GM1, MAG he diagnosis of CIDP is conirmed by the clinical
(courtesy of Pestronk lab, Washington University), indings of a progressive or recurrent motor and sen-
anti-Yo, anti-Hu, anti-MPP-1 and antibodies to Purk- sory polyneuropathy, electrophysiological indings of
inje cells, 24-h Holter monitor, CT head scan, CT primary demyelination (prolonged distal motor laten-
angiogram of brain, CT abdomen and pelvis, brain cies, conduction slowing, conduction block, temporal
MRI. His cholesterol level was mildly elevated (7.33 dispersion, and prolonged F wave latencies), features
mmol/L; normal,
6.2). An ECG suggested mild of primary demyelination on nerve biopsy (segmental
right ventricular hypertrophy. An MRI of the cervical or paranodal demyelination with or without inlam-
intraspinal space showed multilevel degenerative disc mation), and rises in CSF protein without a pleocyto-
disease without root or cord compression. sis. Although they were not evident during early eval-
uations, our patient eventually displayed all of these
Pain description indings. He fulilled strict diagnostic criteria for CIDP
as originally delineated by the American Academy of
In his initial clinic visit, the patient described cramps
Neurology (1) and more recent criteria by the Euro-
in his limbs and prickling, burning sensations below
pean Federation of Neurological Societies/Peripheral
his knees particularly in the feet and posterior calves,
Nerve Society (2). CIDP is described as relapsing in
and in his forearms. Over his course, he used a large
approximately 65% of patients and as progressive in
number of medications for pain including diazepam,
35% of patients (3). Our patient was typical of the latter
acetaminophen with codeine, gabapentin (up to 2700
group.
mg/day was unhelpful), cesamet, oxycontin, capsaicin
Other features of CIDP that suggest axon loss
cream, amitriptyline, meperidine, morphine, hydro-
include loss of motor and sensory potentials and de-
morphone, and nortriptyline. heir beneits were
nervation (ibrillations and positive sharp waves) on
uncertain because of highly variable follow-up and
electrophysiological testing. Similarly nerve biopsies
compliance. Several regimens were stopped on his own
may show prominent axon loss. Our patient exhibited
without a clear report of the reasons or results of their
these indings.
use. He had noticed partial beneit with amitripty-
Prednisone, azathioprine, plasma exchange, and
line (50–75 mg qhs) but discontinued the medica-
IVIG all have an evidence basis for their use in CIDP.
tion. Long-acting morphine sulfate (MS contin 30 mg
Randomized trials however, have largely been limited
twice daily) provided some relief but unfortunately,
to short-term management of CIDP patients and con-
the patient also developed opioid-related confusion
sequently, long-term descriptions of the fate of these
and somnolence. He continued to report intense and
patients are rare. hey include instances of rapid neu-
unremitting pain in his legs below the knees and
rological deterioration. Some patients do not respond
forearms. It was unclear whether immunomodulatory
to therapy (up to a third in some trials) despite a
therapy (IVIG, prednisone), given intermittently dur-
irm diagnosis of CIDP. Two important neuropathies
ing his course, helped with pain relief.
to consider in the diferential diagnosis of CIDP
are inherited sensitivity to pressure palsy (HNPP),
Discussion an autosomal dominant disorder with a mutation in
his patient had a progressive, eventually severe motor myelin protein PMP22, and sporadic or inherited amy-
and sensory polyneuropathy with prominent neuro- loidosis with late onset. A family history of entrapment
pathic pain. He had at least two remissions in his clini- neuropathies in HNPPP may not always be forthcom-
cal condition when successful sustained immunother- ing. Amyloidosis is usually progressive as an exclusive
apy (IVIG, prednisone and IVIG) was administered. axonal disorder, but some cases may have features of
Unfortunately depression, noncompliance, and long primary demyelination (4). Our patient did not have
absences from clinic made it diicult to optimize either a family history of neuropathy, entrapment at sites of
his immunotherapy or his neuropathic pain medica- compression, a monoclonal protein, or neuropathic
tion. By the time of his inal hospitalization when ulcers. Amyloid was not identiied in his muscle or 43
he refused all treatment, he manifested essentially nerve biopsy.
Pain in CIDP mission. Our patient highlighted the intensive pain

and immunomodulatory care required for some CIDP
Neuropathic pain as a complication of CIDP is thought
patients, made particularly problematic when compli-
less common than in other forms of neuropathy.
ance and follow-up are compromised.
McCombe et al. (3) reported pain, ranging from burn-
ing feet to aching muscle pain, as a chief complaint
in 20% of patients; our patient experienced these
symptoms as well. Toth and Au (5) reported neuro- References
pathic pain in 41% of patients with immune medi- (1) Ad Hoc Subcommittee of the American Academy of
ated polyneuropathy. In previous work, we described Neurology AIDS Taskforce. Research criteria for
two patients with prominent upper limb neuropathic diagnosis of chronic inlammatory demyelinating
polyneuropathy (CIDP). Neurology 1991;41:617–618.
pain complicating CIDP (6). Clinical and electrophys-
iological worsening was associated with deep and dis- (2) European Federation of Neurological Societies/
Peripheral Nerve Society Guideline on management
tressing upper limb aching. In one patient, discomfort
of chronic inlammatory demyelinating
regularly predicted electrophysiological relapse of his polyradiculoneuropathy. Report of a joint task force
neuropathy before the onset of more obvious clinical of the European Federation of Neurological Societies
signs. Resolution of the pain also predicted improve- and the Peripheral Nerve Society. J Peripher Nerv Syst
ment. Boukhris et al. (7) examined 5 of 27 patients with 2005;10:220–228.
CIDP that had chronic progressive disease and promi- (3) McCombe PA, Pollard JD, McLeod JG. Chronic
nent pain, similar to our cases. Bilateral radicular-like inlammatory demyelinating polyradiculoneuropathy.
pain in three patients, paresthesiae in four patients, A clinical and electrophysiological study of 92 cases.
and lower limb involvement in three patients were Brain 1987;110:1617–1630.
described. As in other CIDP patients without pain, (4) Benson MD, Kincaid JC. he molecular biology and
these patients had clinical, electrophysiological, and clinical features of amyloid neuropathy. Muscle Nerve
biopsy features of demyelinating neuropathy. Using a 2007;36:411–423.
visual analog scale, the pain intensity was rated as 9/10 (5) Toth C, Au S. A prospective identiication of
pretreatment and 4/10 ater treatment combining anal- neuropathic pain in speciic chronic polyneuropathy
syndromes and response to pharmacological therapy.
gesic agents with immunomodulatory therapy.
Pain 2008;138:657–666.
It is interesting to speculate why pain may be a fea-
(6) Zochodne DW, Brunet DG. Upper limb pain
ture of CIDP. Compression secondary to nerve root
in chronic demyelinating polyneuropathy:
hypertrophy is a possible explanation. Another is the electrophysiological correlates. Acta Neurol Scand
generation of ectopic axonal discharges from axons 1994;90:270–275.
exposed to low grade chronic inlammation, the medi- (7) Boukhris S, Magy L, Khalil M, Sindou P, Vallat JM.
ators described in other chapters of this text. Finally, Pain as the presenting symptom of chronic
loss of large iber input at the level of the dorsal inlammatory demyelinating polyradiculoneuropathy
horn may contribute to undampened pain neurotrans- (CIDP). J Neurol Sci 2007;254:33–38.
44
Chapter
Pain and diabetic polyneuropathy (DPN)
10
Diabetic polyneuropathy (DPN) is one of the most wasting of ulnar innervated hand muscles and exten-
common causes of neuropathic pain. Pain may be the sor digitorum brevis muscles with weakness in his
presenting feature of DPN, and it may be severe despite ulnar hand muscles (Grade 4/5 MRC) and toe dor-
relatively modest evidence of peripheral nerve dam- silexors (4+/5). He had difuse loss of deep tendon
age. Diabetes mellitus (DM) can be associated with relexes. Sensation to pinprick and light touch was
several forms of neuropathy, or nerve damage, includ- impaired in the distal legs and feet, and there was anal-
ing focal neuropathies such as carpal tunnel syndrome gesia and anesthesia in his toes. Vibration perception
and lumbosacral plexopathy. In this case we empha- was absent in his toes and position sensitivity was nor-
size DPN, a generalized form of neuropathy that can be mal. He had diiculty walking tandem or standing on
diagnosed in up to 50% of diabetic patients, but we also his heels. here was no Romberg’s sign. here were no
highlight how it can accompany focal neuropathies foot ulcers. here was a 25 mm Hg drop in his sys-
in the same patient. We describe a type 2 diabetic tolic blood pressure with standing. His overall ind-
patient who developed severe and painful DPN associ- ings indicated moderately severe DPN with autonomic
ated with poor compliance with his diabetes treatment involvement and superimposed bilateral focal ulnar
regimen. neuropathies.
Electrophysiological studies identiied prolonged
upper limb distal motor latencies, slowing of motor
Clinical case vignette conduction velocities, and low amplitude CMAPs in
A 58-year-old right-handed man had a 3-year his- the median and ulnar nerves. here was temporal dis-
tory of type 2 DM, on treatment with glyburide, with persion in the ulnar motor territory. Only very small
poor compliance of blood glucose monitoring and amplitude distal tibial CMAPs over abductor hallu-
reluctance to attend speciic diabetes education clin- cis could be recorded with prolonged distal latencies.
ics. Randomly sampled blood glucose levels taken by he peroneal CMAPs recorded over extensor digitor-
his daughter ranged from 16 to 31 mmol/L. here was um brevis muscles were absent. He had complete
no history of nephropathy or retinopathy when he pre- absence of upper and lower limb sensory potentials
sented with neuropathic symptoms. in the median, ulnar, radial, supericial peroneal, and
He described a feeling of “pads” on the soles of sural nerves. Needle electromyography identiied ib-
his feet for approximately 1 year that sometimes inter- rillation potentials and positive sharp waves in the
fered with his balance. He denied pain, loss of sen- tibialis anterior and irst dorsal interosseous muscles
sation, or paresthesiae on initial visits to the neurol- with a reduced number of enlarged, rapidly iring vol-
ogy clinic. He also denied weakness of his muscles untary motor unit potentials. Overall, the indings
or loss of balance otherwise. Erectile dysfunction had indicated a severe motor and sensory polyneuropa-
been present for 1 year, but he had no other autonomic thy with prominent features of axonal degeneration
nervous system symptoms beyond rare dizziness with and superimposed features of primary demyelination.
standing. He had previously been healthy. here was hese electrophysiological abnormalities were more
a family history of DM involving his father and two severe than the clinical indings or the history had
brothers. suggested.
On initial neurological examination, he had intact Other laboratory investigations were normal (neg-
mental functioning beyond denial of his medical prob- ative), including complete blood count, alkaline phos-
lems, with normal speech and cranial nerves. He had phatase, ALT, creatinine, urinalysis, serum protein
45
electrophoresis, ESR, and TSH. His cholesterol was Pain in DPN

elevated at 5.34 mmol/L (normal,
5.20) with nor-
Pain can develop at any stage of DPN. Symptoms may
mal triglycerides and HDL, and elevated LDL at 3.75
include nocturnal burning discomfort, allodynia, elec-
mmol/L (normal,
3.40). Fasting glucose was 13.2
trical jolts, but also deep aching pain, as described by
mmol/L and hemoglobin A1C was 0.091 (normal,
our patient. In some patients, there is prominent pain

0.061). His CK level was mildly elevated at 490 (nor-
before signs of polyneuropathy develop. In the absence
mal,
195 U/L).
of frank axon loss, this indicates that altered excitabil-
Over the next 1–2 years, there was marginal
ity, associated with early molecular changes of axons
improvement in his compliance and a consultation
and sensory neurons in ganglia, may be responsible.
with a diabetologist was arranged. Signs of his DPN
Several mechanisms have been considered in the
continued to progress with bilateral foot drop, sensory
pathogenesis of neuropathic pain in DPN. he liter-
loss in his hands and distal to his knees, and a Romberg
ature addressing neuropathic pain in animal models
sign. He would stumble on rough terrain at work. By
of disease has rapidly expanded over the past decade.
year 2 ater diagnosis, he had developed prominent
Abnormalities that develop in diabetic peripheral neu-
lower limb pain. Gabapentin and ankle/foot orthoses
rons include changes in the distributions of sodium or
were prescribed. Four years ater his original visit to
calcium channels that favor the generation of abnor-
the Neurology clinic he required treatment for a small
mal ectopic discharges and initiate the pain cascade. In
preulcerative lesion on the skin in the second right PIP
particular, the speciic channels linked to experimental
joint and ith metatarsal head area.
DPN include Cav 3.2 T-type calcium channels (upreg-
ulation) (1), sodium channels Nav 1.3 (upregulation),
Nav 1.7 (upregulation, increased tyrosine phosphory-
Pain description lation), Nav 1.6 and Nav 1.8 (both downregulated but
At 6 years ater his initial visit (9 years from diagno- with increased serine/threonine phosphorylation; Nav
sis of DM), he described pain in his calves and thighs 1.6 also had increased tyrosine phosphorylation) (2);
worse with resting ater activity. Pain interfered with Nav 1.9 (upregulated) and 3 (upregulated) (3, 4).
his ability to sleep. It was aggravated by cold con- here is however, considerable variability amid
tact and included a tingling component but its most the results and conclusions in the experimental work.
common descriptor was aching discomfort rather than hree major test paradigms are routinely used to eval-
burning or squeezing. His pain was continuous and uate pain in experimental DPN models. hese include
he ranked it as severe as 8/10. He experienced some the latency of withdrawal to a thermal stimulus applied
beneit from gabapentin, did not tolerate pregabalin to the hindpaw (Hargreaves test) (5), the response to
or amitriptyline, and was also treated with low-dose, mechanical stimulation of the hindpaw with either a
long-acting morphine (15 mg q12h). von-Frey hair of graded bending strength or an elec-
tronically controlled probe of deined force (Randall-
Selitto test) and the latency to taillick withdrawal
Discussion to a heat stimulus applied to the tail. Yet another
his patient developed a relentlessly progressive form approach is to superimpose the hindpaw formalin
of DPN in the setting of very poor control of his type 2 injection paradigm on diabetic models. his model
DM. Prominent early features were loss of sensation generates two phases of pain behavior, with the sec-
and focal ulnar neuropathies, later pain, skin ulcer- ond exaggerated in diabetic models (6). Calcutt (7) has
ation, and inally, progressive distal motor weakness reviewed some of the diiculties in analyzing mod-
in the legs. he electrophysiological features identi- els of neuropathic pain, citing various technical vari-
ied prominent axonal loss but also features of pri- ations and inconsistencies. For example, a thermal
mary demyelination, both well recognized in advanced stimulus applied to a rat paw may penetrate more
DPN. In the setting of uncontrolled hyperglycemia, his deeply and trigger aferent responses from deeper
DPN progressed over 6 years of follow-up. Gabapentin sensory axons than discrete mechanical stimuli. An
provided only partial pain control and eventually, the important consideration in DPN pain models is the
patient required a low-dose opioid. Progresssive sen- duration of diabetes. In outbred Swiss-Webster mice
46 sory alterations in DPN are illustrated in Figure 10.1. studied serially over several months of diabetes, initial
Chapter 10: Pain and diabetic polyneuropathy (DPN)
Figure 10.1. Progressive stocking then stocking and glove sensory changes in a patient with diabetic polyneuropathy. The shaded areas
can represent pain, paresthesiae, or loss of sensation. Reproduced with permission from Diabetic Neurology (23).
thermal hyperalgesia and mechanical allodynia were further argued that a high concentration of glucose
later followed by loss of thermal and mechanical sensa- (45 mmol/L) could itself induce rises in the Nav 1.7 in
tion, consistent with eventual loss of distal skin inner- neonatal rat sensory neurons through the actions of
vation as neuropathy progressed (8). phosphorylated PKC and p38. Dobretsov et al. (14)
Changes of speciic ion channel molecular sub- argue instead that impaired insulin signaling before
classes may develop in DPN and account for diferent frank diabetes, instead of hyperglycemia, is responsi-
types of pain syndromes. For example, in some models ble for the dysfunction of sensory axons.
including analysis of ZDF diabetic rats, a model of type Other mechanisms of neuropathic pain speciically
2 diabetes mellitus, mechanical allodynia was more in the setting of diabetes have been investigated. A
prominent than thermal hyperalgesia (9–11). While bradykinin B1 receptor (BKB1-R) antagonist reversed
the technical factors discussed above may account for thermal hyperalgesia in two type 1 diabetic models
these diferences, recent literature indicates for exam- in rats: STZ diabetic and BB/Wor-DP rats (15). Hong
ple that N-type calcium channel splice variant iso- and Wiley demonstrated that painful experimental
forms labelled e37a and 337b (12) mediate diferent diabetic neuropathy was associated with changes in
forms of pain. Similarly, A-type potassium channels the expression of the VR1 (vanilloid, TRPV1) recep-
attenuate mechanical but not thermal hyperalgesia tor (rises in large neurons, declines in small neurons).
(see Chapter 1). Rises in the tetrameric membrane-expressed version
Recent work by Chattopadhyay et al. (13) demon- of the TRPV1 receptor during experimental diabetes
strated that rats with STZ-induced diabetes of dura- were also linked to rises in its sensitivity through PKC-
tion 6 weeks upregulate Nav 1.7 channels in DRGs and mediated phosphorylation. PKC has been linked to the
that a subcutaneous inoculation of a herpes simplex- development of pain in models of DPN. For example,
based vector expressing proenkephalin reversed these inhibition of PKC also attenuated hyperalgesia in STZ
changes. At the same time, heat and cold hyperalgesia diabetic rats (16), whereas activation of PKC increased
and mechanical allodynia were reversed. he authors thermal hyperalgesia (17). Finally, changes at the level 47
of the dorsal horn of the spinal cord or higher may (4) Shah BS, Gonzalez MI, Bramwell S, Pinnock RD, Lee
also be implicated in the development of neuropathic K, Dixon AK. Beta3, a novel auxiliary subunit for the
pain (18, 19). Speciically Ramos et al. (19) show that voltage gated sodium channel is upregulated in
rats with early STZ-induced diabetes had rises in spinal sensory neurones following streptozocin induced
diabetic neuropathy in rat. Neurosci Lett 2001;309:
COX-2 protein and activity that accompanied abnor- 1–4.
malities in pain behavior with formalin testing. Hyper-
(5) Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A
algesia to formalin and rises in COX-2 were prevented new and sensitive method for measuring thermal
by insulin treatment or by using an aldose reductase nociception in cutaneous hyperalgesia. Pain 1988;
inhibitor capable of crossing the blood–brain barrier 32:77–88.
to act on the dorsal horn of the spinal cord. Over- (6) Calcutt NA, Jorge MC, Yaksh TL, Chaplan SR.
all, these indings indicate that DPN is associated with Tactile allodynia and formalin hyperalgesia in
multilevel changes in the neuraxis that promote pain, streptozotocin-diabetic rats: efects of insulin, aldose
including alterations of primary sensory neurons and reductase inhibition and lidocaine. Pain 1996;68:
abnormal signaling through the dorsal horn of the 293–299.
spinal cord. (7) Calcutt NA. Experimental models of painful diabetic
he current state of the literature evaluating anal- neuropathy. J Neurol Sci 2004;220:137–139.
gesic therapy for human diabetic polyneuropathy has (8) Toth C, Rong LL, Yang C, et al. RAGE and
been reviewed elsewhere and is considered in Chap- experimental diabetic neuropathy. Diabetes
ter 32 (20, 21). Briely, there is evidence for the use 2008;57:1002–1017.
of tricyclic antidepressants, gabapentin, pregabalin, (9) Brussee V, Guo GF, Dong YY, et al. Distal
opioids (including tramadol), and duloxetine. Opi- degenerative sensory neuropathy in a long term
oids and gabapentin may have synergistic actions (22). type 2 diabetes rat model. Diabetes 2008;57:
1664–1673.
In complex diabetic patients with renal disease and
involvement of other organ systems, gabapentin or (10) Fox A, Eastwood C, Gentry C, Manning D, Urban L.
Critical evaluation of the streptozotocin model of
opioids may be the safest agents of choice. Gabapentin
painful diabetic neuropathy in the rat. Pain 1999;
dosage requires downward revision in renal failure 81:307–316.
patients but it remains efective. Initial therapy with
(11) Romanovsky D, Cruz NF, Dienel GA, Dobretsov M.
gabapentin is one of the authors’ (DZ) treatment of Mechanical hyperalgesia correlates with insulin
irst choice, perhaps beginning with a low evening dose deiciency in normoglycemic streptozotocin-treated
(e.g., 300 mg). Side-efects include cognitive dysfunc- rats. Neurobiol Dis 2006;24:384–394.
tion and dizziness particularly with the highest doses (12) Altier C, Dale CS, Kisilevsky AE, et al. Diferential
used (4000 mg). Opioids also cause cognitive dysfunc- role of N-type calcium channel splice isoforms in
tion and constipation. pain. J Neurosci 2007;27:6363–6373.
(13) Chattopadhyay M, Mata M, Fink DJ. Continuous
delta-opioid receptor activation reduces neuronal
References voltage-gated sodium channel (NaV1.7) levels
(1) Jagodic MM, Pathirathna S, Nelson MT, et al. through activation of protein kinase C in painful
Cell-speciic alterations of T-type calcium current diabetic neuropathy. J Neurosci 2008;28:6652–
in painful diabetic neuropathy enhance excitability 6658.
of sensory neurons. J Neurosci 2007;27:3305– (14) Dobretsov M, Ghaleb AH, Romanovsky D, Pablo CS,
3316. Stimers JR. Impaired insulin signaling as a potential
(2) Hong S, Morrow TJ, Paulson PE, Isom LL, Wiley JW. trigger of pain in diabetes and prediabetes. Int
Early painful diabetic neuropathy is associated with Anesthesiol Clin 2007;45:95–105.
diferential changes in tetrodotoxin-sensitive and (15) Gabra BH, Benrezzak O, Pheng LH, et al. Inhibition
-resistant sodium channels in dorsal root ganglion of type 1 diabetic hyperalgesia in streptozotocin-
neurons in the rat. J Biol Chem 2004;279:29341– induced Wistar versus spontaneous gene-prone
29350. BB/Worchester rats: eicacy of a selective bradykinin
(3) Craner MJ, Klein JP, Renganathan M, Black JA, B1 receptor antagonist. J Neuropathol Exp Neurol
Waxman SG. Changes of sodium channel expression 2005;64:782–789.
48 in experimental painful diabetic neuropathy. Ann (16) Ahlgren SC, Levine JD. Protein kinase C inhibitors
Neurol 2002;52:786–792. decrease hyperalgesia and C-iber hyperexcitability in
Chapter 10: Pain and diabetic polyneuropathy (DPN)
the streptozotocin-diabetic rat. J Neurophysiol (20) Zochodne DW. Diabetes mellitus and the peripheral
1994;72:684–692. nervous system: manifestations and mechanisms.
(17) Ohsawa M, Kamei J. Possible involvement of spinal Muscle Nerve 2007;36:144–166.
protein kinase C in thermal allodynia and (21) Vinik A. Clinical review: use of antiepileptic drugs in
hyperalgesia in diabetic mice. Eur J Pharmacol the treatment of chronic painful diabetic neuropathy.
1999;372:221–228. J Clin Endocrinol Metab 2005;90:4936–4945.
(18) Calcutt NA. Potential mechanisms of neuropathic (22) Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF,
pain in diabetes. Int Rev Neurobiol 2002;50: Houlden RL. Morphine, gabapentin, or their
205–228. combination for neuropathic pain. N Engl J Med
(19) Ramos KM, Jiang Y, Svensson CI, Calcutt NA. 2005;352:1324–1334.
Pathogenesis of spinally mediated hyperalgesia in (23) Zochodne DW, Kline GA, Smith E, Hill MD. Diabetic
diabetes. Diabetes 2007;56:1569–1576. Neurology. New York: Informa, 2010.
49
Chapter
Painful idiopathic polyneuropathy
11
A large proportion of polyneuropathies, especially purinol, gabapentin, trazodone, and quinine sulfate.
sensory polyneuropathies, are classiied as idiopathic He used 2 ounces of ethanol weekly and was a non-
because their speciic etiologies have not been iden- smoker. here was no family history of neurological
tiied. Although additional causes of polyneuropa- disease.
thy have emerged within this group, the proportion On his initial neurological examination, he had
with an unknown cause remains substantial. Some are stocking loss of sensation to his knees and loss in
associated with glucose intolerance. In this case, we his volar ingers involving light touch and pinprick.
describe a patient with a painful idiopathic sensory here was analgesia in his toes without anesthesia. He
polyneuropathy followed over 7 years. Pharmacother- had absent vibration sensation in one large toe and
apy was challenging because of associated side-efects. reduced vibration sensation in the other. Position sen-
Whereas several comorbid conditions were present, sation was normal. Motor power and tone were normal
none were identiied as causing the condition. throughout and there was no wasting excepting the
extensor digitorum brevis muscles. Ankle relexes were
absent. His gait was antalgic. He had a mild intention
Clinical case vignette tremor. here was no Romberg sign. General examina-
A 70-year-old right-handed retired professor was eval- tion identiied obesity, distal foot swelling, and changes
uated for a 10-year history of sensory symptoms in of osteoarthritis in his knees.
his legs. he onset was gradual, and the symptoms Investigations included the following normal stud-
had been progressive. He described loss of balance ies: complete blood count, ESR, calcium, serum and
and symmetrical burning pain in his legs, soles of his urine protein electrophoresis, electrolytes, creatinine,
feet, and toes. His legs felt heavy and “leaden.” here TSH, B12, fasting and 2-h PC glucose, hemoglobin
were sensations of tingling and numbness in his in- A1C, ANA, and GGT. A methylmalonic acid level
gers. here was loss of sensation in his legs distal to was borderline elevated (0.20 M; normal, 0.02–0.15).
the knees, but he denied speciic muscle weakness. As Imaging studies of the lumbar spine identiied changes
a result, he was no longer able to walk his dogs and of spondylosis, L45 foraminal stenosis, but no spinal
had gained 30 lbs from inactivity. here was no his- stenosis. Cervical MRI identiied spondylosis and mild
tory of foot ulcer. He noticed constipation and blad- spinal stenosis. Electrophysiological testing identi-
der urgency. While gabapentin provided some relief, ied low amplitude distal peroneal CMAPs, border-
he was unable to increase the dose beyond 1200 mg line reductions in motor conduction velocities in his
daily because of lower limb swelling. legs, an absent supericial peroneal sensory poten-
His prior medical history was complex with tial, and a low amplitude sural potential. In the upper
osteoarthritis requiring a previous let knee and right limbs, motor conduction was normal, but sensory
hip replacement. Other problems included chronic potentials were reduced in amplitude or absent. Nee-
neck and back discomfort, hypertension, dyslipidemia, dle electromyography identiied occasional ibrilla-
sleep apnea, benign prostatic hypertrophy, gastro- tion potentials in his tibialis anterior muscle with
esophageal relux, chronic hearing loss attributed to reduced numbers of enlarged motor unit potentials.
military service and working in a mine, and a previ- Gastrocnemius had enlarged motor unit potentials.
ous TIA. He had prior diverticulitis surgery, tonsil- Right irst dorsal interosseous and deltoid muscles
lectomy, and a breast reduction. Medications included were normal. A second set of studies 2 years later
50 candesartan, amiloride, omeprazole, celecoxib, allo- identiied further declines in his lower limb CMAPs,
Chapter 11: Painful idiopathic polyneuropathy
Topiramate was associated with nausea and dizziness.

He continued taking gabapentin in varying doses (up
to 3900 mg) but was uncertain of its beneit. He noticed
some beneit from hydromorphone and dimenhydri-
nate combined and from the use of TENS (transcu-
taneous electrical nerve stimulation). Venlafaxine had
uncertain beneit. By age 81, he had ongoing loss of
sensation to light touch and pinprick below his knees,
absent vibration sensation in his toes, and loss of all
deep tendon relexes excepting the let triceps. Motor
function was preserved. He had stopped his opioid
medication and had decided against further speciic
neuropathic pain medications.
Pain description
he patient experienced continuous burning lower
limb pain below the knees involving his soles and
toes. He had a sensation “like sandpaper” over his feet.
Other descriptors included squeezing, pressure, tin-
gling, “pins and needles,” and stabbing, but he denied
allodynia from touching or cold. He generally rated the
pain intensity as 4/10 on average, and in a range of 3–
5/10; his ability to sleep was impacted. On some visits,
he rated the pain intensity somewhat higher at 8/10.
he pain had a major impact on his ability to enjoy life.
He rated his health state as 2/10, with 10 representing
the best imaginable health state.
Discussion
(Figure 11.1. Transverse sections of sural nerve biopsy from the he largest category of painful small iber periph-
patient described in this vignette. The sample is epon-embedded eral neuropathies are idiopathic, or of uncertain cause
and stained with toluidine blue at lower power (A) and higher
power (B) [Bar = 50 m for A and 100 m for B]. Note the severe (1–3). his overlaps with patients classiied as hav-
and widespread diffuse loss of large and small myelinated axons. ing chronic idiopathic axonal polyneuropathy, thought
Occasional myelinated fibers are clustered indicating regenerative to constitute approximately 10–18% of patients with
sprouts.
chronic axonal polyneuropathy (4–7). hese series
and his sural potential had disappeared. A right describe the mean age of onset as 57, not unlike the
sural nerve biopsy identiied severe loss of myelinated onset at age 60 in our patient. Our patient’s neu-
axons (90%), mild signs of active axonal degenera- ropathy was not strictly small iber given his symp-
tion without inlammation, vascular changes, or amy- tom of imbalance and the detection of reduced vibra-
loid deposition. Occasional regenerative clusters and tion perception and loss of deep tendon relexes. In
occasional thinly myelinated axons were identiied addition, his lower limb sensory nerve action poten-
[Figure 11.1]. tials gradually declined over time. His diagnosis was
he patient was followed intermittently for 7 years. likely best classiied as mixed iber neuropathy. In
Pregabalin caused unacceptable lower limb swelling. patients without signs of large iber involvement and
At the age of 74 and following a trial of nabilone pre- normal nerve conduction studies, skin biopsy may
scribed by the pain clinic, he developed tachycardia identify loss of epidermal axons, indicating small iber
and at the same time sufered a let parietal cerebral involvement. An extensive investigation in our patient,
infarct from which he made a near complete recovery. including nerve biopsy, failed to identify the cause, and 51
Long-acting codeine and oxycontin caused nausea. his condition slowly progressed over time. Repeated
tests for impaired glucose metabolism or diabetes Bednarik et al. (11) evaluated 84 patients with
mellitus were negative, and he did not use signii- painful sensory neuropathy and predominant small
cant amounts of ethanol. A skin biopsy was not per- iber involvement. In this study, individuals with signs
formed. Our patient resembles those described by of large iber involvement were excluded, although
Notermans et al. (8) who followed 75 patients with they were included if they had abnormal sensory
chronic idiopathic axonal polyneuropathy over 5 years nerve conduction results. hus, this group of patients
and only discovered a deinite cause in four patients difered from the patient reported here in our case
(two inherited, one CIDP, and one secondary to vignette. Patients with motor involvement were also
alcohol). not included. In comparison to 47 asymptomatic
Hughes et al. (6) studied 50 consecutive patients age- and sex-matched control subjects, a multivari-
with chronic idiopathic axonal polyneuropathy and ate regression model indicated that diabetes melli-
compared them to 50 control persons from the same tus, chronic alcoholism, and serum cholesterol lev-
region. Twenty-two patients (44%) had pain and 26 els independently were associated with small iber
(52%) had evidence of only sensory involvement. neuropathy. No etiology was identiied in 22.6% of
here was no increased risk of ethanol use, impaired patients. Interestingly, the presence of sensory conduc-
glucose tolerance, or fasting hyperglycemia in the tion changes, indicative of a more widespread spec-
patients with polyneuropathy. Elevated triglyceride trum of iber involvement, did not inluence the ind-
levels had a signiicant association with polyneuropa- ings. Although not rigorously examined in this or
thy. Patients with chronic idiopathic axonal polyneu- other studies, we suspect that many strictly small
ropathy were more likely to be older men, and the iber sensory neuropathies later develop involvement
features were gradually progressive and symmetric. of larger ibers, as in our patient. Indeed, a signii-
Autonomic symptoms were not prominent. cant proportion of patients initially diagnosed with
Despite the failure of Hughes et al. to link chronic exclusive sensory polyneuropathies may have subclin-
idiopathic axonal polyneuropathy to impaired glu- ical motor abnormalities on electrophysiological test-
cose metabolism, other series have identiied a linking (12). Our patient had wasted EDB muscles and low
age. Singleton et al. (9) reported on the records of 89 amplitude peroneal CMAPs without weakness.
patients with idiopathic polyneuropathy and identiied Erdmann et al. (5) identiied pain in 77% of the
28 (31%) with frank diabetes mellitus. Of the remain- 56 patients they studied, among several other dis-
ing 61 patients, 25% had impaired glucose tolerance, abilities in patients with chronic idiopathic axonal
a prevalence of twice that expected in an unselected polyneuropathy. Fatigue, loss of autonomy outdoors,
population. Approximately one third had neuropathic and poor balance were also common among their
pain. group. Predictably, lower limbs had greater involve-
Nebuchennykh et al. (10) examined 70 patients ment, as might be expected, than the upper limbs.
from Norway with idiopathic sensory polyneuropa-
thy. Sixteen patients (23%) had impaired glucose Pain in chronic idiopathic axonal
metabolism; 3% had frank diabetes mellitus, 4% had
impaired fasting glucose, 3% had impaired fasting glu- polyneuropathies
cose and glucose tolerance and 13% had impaired Despite diferences among the series described above,
glucose tolerance. Neuropathic pain was described in neuropathic pain is a common and constant feature.
69% of patients with impaired glucose metabolism and Because the etiologies of many of these polyneu-
68% of the remaining patients, indicating no signif- ropathies remain unknown, the mechanisms of pain
icant diference in the predisposition to pain. Pure are unclear. In patients with impaired glucose toler-
sensory involvement was present in 35% of those ance, abnormalities of sensory neurons that gener-
with impaired glucose metabolism and 48% of the ate pain may be similar to those secondary to frank
remainder. Sural potentials were abnormal in 25% of diabetes (see Chapter 10). Recently, Faber et al. (13)
those with impaired glucose metabolism and 13% of identiied mutations in the function of the sodium
the remainder. Overall, the authors believed that the channel Nav 1.7 in a signiicant proportion of patients
prevalence of impaired glucose metabolism was lower with idiopathic small iber neuropathy. he SCN9A
52 in the Norwegian population with neuropathy than in gene encodes for Nav 1.7, and the mutations resulted
other reported series. in a gain of function. As discussed in Chapter 1, pain
Chapter 11: Painful idiopathic polyneuropathy
syndromes including erythromelalgia and paroxysmal (3) Hoitsma E, Reulen JP, de BM, Drent M, Spaans F,
extreme pain disorder (PEPD) can arise from muta- Faber CG. Small iber neuropathy: a common and
tions of Nav 1.7 (14). Faber et al. studied 28 patients important clinical disorder. J Neurol Sci 2004;227:
who met the strict criteria for idiopathic small iber 119–130.
neuropathy: no underlying etiology, normal strength, (4) McLeod JG, Tuck RR, Pollard JD, Cameron J, Walsh
normal tendon relexes, normal vibration perception, JC. Chronic polyneuropathy of undetermined cause.
J Neurol Neurosurg Psychiatry 1984;47:530–535.
and normal nerve conduction studies. he patients had
reduced intraepidermal nerve iber density plus abnor- (5) Erdmann PG, Teunissen LL, van Genderen FR, et al.
Functioning of patients with chronic idiopathic
mal quantitative sensory testing (QST) with at least
axonal polyneuropathy (CIAP). J Neurol 2007;254:
two appropriate symptoms. Symptoms were burn- 1204–1211.
ing feet, allodynia, diminished pain and/or tempera-
(6) Hughes RA, Umapathi T, Gray IA, et al. A controlled
ture sensation, dry eyes or mouth, orthostatic dizzi- investigation of the cause of chronic idiopathic axonal
ness, bowel and urinary disturbances, sweating abnor- polyneuropathy. Brain 2004;127:1723–1730.
malities, visual accommodation problems or blurred (7) Dyck PJ, Oviatt KF, Lambert EH. Intensive
vision, impotence, diminished ejaculation or lubri- evaluation of referred unclassiied neuropathies yields
cation, hot lashes, and palpitations. SCN9A analysis improved diagnosis. Ann Neurol 1981;10:222–226.
identiied missense mutations in 8 of the 28 patients (8) Notermans NC, Wokke JH, van der Graaf Y, Franssen
screened, rendering Nav 1.7 channels hyperexcitable. H, van Dijk GW, Jennekens FG. Chronic idiopathic
Overall, the group of patients with mutations was on axonal polyneuropathy: a ive year follow up. J Neurol
average a younger population with a mean age of 32.4, Neurosurg Psychiatry 1994;57:1525–1527.
making the suspicion of an inherited cause more likely. (9) Singleton JR, Smith AG, Bromberg MB. Painful
Pain was of distal onset and its intensity varied but it sensory polyneuropathy associated with impaired
did not share the characteristics of temperature sen- glucose tolerance. Muscle Nerve 2001;24:1225–
sitivity observed in erythromelalgia. Seven of the 8 1228.
patients also had autonomic complaints. he authors (10) Nebuchennykh M, Loseth S, Jorde R, Mellgren SI.
suggested that abnormal sodium channel activation of Idiopathic polyneuropathy and impaired glucose
metabolism in a Norwegian patient series. Eur J
small primary aferent ibers might lead to secondary
Neurol 2008;15:810–816.
degeneration and neuropathy.
Overall, the majority of patients with painful idio- (11) Bednarik J, Vlckova-Moravcova E, Bursova S,
Belobradkova J, Dusek L, Sommer C. Etiology of
pathic polyneuropathies do not have an explanation small-iber neuropathy. J Peripher Nerv Syst
for their symptoms. However, it may be that a range 2009;14:177–183.
of additional ion channel changes, either primary or
(12) Chhibber S, Toth C. Lack of motor progression in
secondary, may eventually be linked to this condition. isolated sensory peripheral neuropathy. Can J Neurol
Sci 2010;37:517–520.
References (13) Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of
(1) Periquet MI, Novak V, Collins MP, et al. Painful function Nav1.7 mutations in idiopathic small iber
sensory neuropathy: prospective evaluation using neuropathy. Ann Neurol 2012;71:26–39.
skin biopsy. Neurology 1999;53:1641–1647. (14) Cummins TR, Sheets PL, Waxman SG. he roles of
(2) Lacomis D. Small-iber neuropathy. Muscle Nerve sodium channels in nociception: Implications for
2002;26:173–188. mechanisms of pain. Pain 2007;131:243–257.
53
Chapter
Pain in vasculitic neuropathy
12
Neuropathy secondary to vasculitis, either systemic rheumatoid factor, cryoglobulins, and serum comple-
or conined to the peripheral nervous system, usu- ment were normal. Atypical anti-neutrophil cytoplas-
ally begins asymmetrically, classically as mononeu- mic antibody (xANCA) was positive at 1:320. Cere-
ritis multiplex. Acute mononeuropathies from vas- brospinal luid showed mildly increased protein with
culitis may be very painful. A signiicant proportion 0.63 g/dl (normal,
0.45) and positive oligoclonal
of patients however, also present with a more sym- bands. Magnetic resonance tomography of the brain
metrical bilateral polyneuropathy secondary to under- and spinal cord showed no indication of multiple
lying vasculitis. A patient with bilateral symmetric sclerosis and no spinal stenosis. Sural nerve biopsy
chronic neuropathy secondary to nonsystemic vasculi- revealed a moderate axonal neuropathy with active
tis is described. axonal degeneration and perivascular inlammatory
iniltrates, some of which iniltrated the vessel walls
[Figure 12.1]. A tentative diagnosis of non-systemic
Clinical case vignette vasculitic neuropathy (NSVN) was made and intra-
A 62-year-old recently widowed man presented with venous corticosteroids were given at a dose of 1 g/day
a 2-year history of burning pain and numbness of for 3 consecutive days. he patient experienced rapid
both lower legs, more pronounced on the let. Ater relief from the shooting pain, but painful nightly mus-
walking distances of more than 800 meters, both legs cle cramps persisted. Magnesium substitution was not
became painful. For longer walks, he used a cane efective, and carbamazepine was initiated to reduce
because of a feeling of instability. He complained of nerve hyperexcitability. Azathioprine, a steroid spar-
brief episodes of spontaneous shooting pain in both ing agent, was added to the patient’s medications;
legs that occurred approximately 10 times per day. steroids were slowly tapered. It was discontinued 3
At night, he sufered from frequent cramps in his months later because of abdominal pain and vomiting.
calf muscles. Amitriptyline, taken as a nightly dose of A second attempt to give azathioprine ater the gas-
75 mg, provided no relief; higher doses were not toler- trointestinal symptoms had remitted led to rapid onset
ated because of micturition problems. of the same symptoms. he drug was inally stopped
Examination revealed fasciculations in both calves, ater gastroscopy excluded other causes for his symp-
loss of achilles tendon relexes, mild pareses of toe dor- toms.
silexion, a stocking pattern of loss to all sensory qual- Four months later, the patient returned to the Neu-
ities on both lower legs, and mild ataxia on stand- rology clinic with complaints of increased pain and
ing. Nerve conduction studies gave normal results at reduced walking ability. He had bilateral foot drop
the arms and showed moderate reduction of com- and a markedly ataxic gait. His mood was subdued
pound muscle action potential (CMAP) and sensory and he said that he did not enjoy life any more.
(SNAP) amplitudes in the tibial and sural nerves, Repeated high-dose steroids induced a second remis-
respectively. Electromyography (EMG) of the lower sion but symptoms returned once the steroids were
leg muscles showed occasional ibrillations and fasci- tapered. Although carbamazepine provided suicient
culations. Laboratory investigations including serum relief from the nocturnal cramps, it was discontinued
chemistry, complete blood count, erythrocyte sed- because of hyponatremia. Gabapentin was adminis-
imentation rate, serum vitamin B12 concentration, tered for neuropathic pain, and when required, an opi-
serum protein electrophoresis, antinuclear antibodies, oid (oxycodone) was added. his combination resulted
54 anti-SSA/SSB antibodies, paraneoplastic antibodies, in some relief and the patient rated his pain as bearable.
Chapter 12: Pain in vasculitic neuropathy
e
e
A B
Figure 12.1 Photomicrographs of the patient’s sural nerve biopsy. (A) Paraffin-embedded section immunoreacted for T lymphocytes with
antibodies to CD3. Note perivascular T cells with occasional lymphocytes infiltrating the vessel wall. e = endoneurium, p = perineurium,
v = vessels. (B) Semi-thin plastic-embedded section illustrating the enlarged and heavily vascularized perineurium (p), patchy nerve fiber
loss in the endoneurium (e) and acute axonal degeneration (arrow). Bar = 10 m.
he patient’s symptoms were slowly progressive one occasion soon ater admission, the patient became
and eventually spread to the forearms. Over the next somnolent due to opioid intoxication and was trans-
few years, several immunosuppressive treatment reg- ferred to the intensive care unit. Drug toxicity was
imens were attempted. Cyclosporin A was given for a the result of self-medication with fentanyl patches for
total of 9 months with gaps because of problems with pain. he analgesic treatment was changed to a combi-
the patient’s health care provider. Several months ater nation of pregabalin and amitriptyline. Muscle cramps
cyclosporine A was paused, the patient complained were treated with quinidine. As before, the patient
about progressive weakness of his ingers. On exami- appeared to respond initially but experienced no long-
nation, mild weakness (MRC grade 4/5) of the inger term beneit. A course of intravenous immunoglob-
extensors and abductors were seen bilaterally. Nerve ulin at a dose of 2 g/kg bodyweight was not efec-
conduction studies showed a deterioration of the tibial tive. Finally, cyclophosphamide was initiated. Use of
nerve territory CMAP. he patient required 10 mg of this drug had been avoided because systemic vasculi-
long-acting morphine daily for pain control. Over the tis had not been diagnosed and peripheral nerve vas-
next 2 years, the patient received additional courses of culitis had not been fully conirmed despite the sug-
high-dose corticosteroids with identical results: abate- gestive histological indings. he patient tolerated the
ment of symptoms that returned following tapering. drug well and received 12 cycles over the next year. For-
Despite prophylaxis with calcium, vitamin D, and a tunately, the patient’s condition stabilized under this
bisphosphonate, osteoporosis had developed and back treatment. Pain control was attained through a com-
pain was an additional complaint. During a rehabili- bination of pregabalin and tramadol. Muscle cramps
tation treatment, back pain worsened and the patient were reduced with phenytoin, which was also toler-
was admitted to hospital. X-ray of the lumbar spine ated well. On one occasion however, the patient devel-
showed a T12 compression fracture, which was con- oped an intercurrent infection and presented with
irmed on MRI and considered osteoporotic. Verte- blurred vision, nystagmus, and pronounced gait ataxia.
broplasty was performed, resulting in almost complete Phenytoin blood levels had increased to 34.4 mg/L
relief of the back pain. (therapeutic laboratory range, 5–10 mg/L). Symptoms
Gait ataxia was progressive. Repeated electrophys- rapidly settled ater the drug was stopped and inlam-
iological examinations showed a slow decline in motor matory parameters normalized. Oxcarbazepine, which
nerve compound potential amplitudes [Figure 12.2]. was subsequently administered, also reduced the mus-
Because the patient still complained of excruciating cle cramps, but as with carbamazepine, led to severe
pain, the pain medication was changed to pregabalin hyponatremia; at a later stage, phenytoin was again 55
and a fentanyl patch which inally brought relief. On prescribed and tolerated well by the patient. Ater
Figure 12.2 Evaluation of tibial nerve compound muscle action potential (CMAP) over time. Note slowly progressive reduction of CMAP
amplitude, with the first signs of recovery in the last panel.
the 12th course of cyclophosphamide, the patient neuropathy. Alternatively, a spinal lesion might have
appeared stable and immunosuppression was stopped. been responsible for these symptoms but this was not
Conversion to azathioprine was attempted, but as evident in the initial spinal MRI scans. Muscle cramps,
before, the patient experienced gastrointestinal side- mostly in the gastrocnemius and soleus muscle, were
efects. Six-month follow-up checks conirmed that the an early symptom and related to muscle denervation
patient remained stable without the use of immuno- caused by the neuropathy. Back pain, which developed
suppressive medication. When the patient was last during the disease course, was caused by an osteo-
seen, he had returned from a short vacation with his porotic fracture. he patient had considerable dii-
new partner. His mood was substantially improved, culty describing the character or severity of his pain.
and he commented that his pain and his ataxia were Over the many years of his treatment, he refused to
alleviated “on the arm of his new love.” provide quantitative measures of pain. Instead, he used
verbal descriptors for his pain, including “excruciat-
ing,” “unbearable,” or “torturing.”
Pain description
his patient complained of diferent types of pain
caused by at least three sets of pathological processes. Discussion
56 Burning pain, numbness, and intermittent shooting his patient’s course was complicated by several fea-
pain in the lower legs were suggestive of a peripheral tures. he patient had various types and causes of
Chapter 12: Pain in vasculitic neuropathy
pain due to several, ongoing pathological processes. prophylaxis. Azathioprine was prescribed on several
He had typical neuropathic pain, with a combination occasions by diferent physicians, and gastrointesti-
of distally accentuated burning pain and numbness as nal side-efects occurred each time. he sodium chan-
well as intermittent shooting pain. he clinical and nel antiepileptics carbamazepine and oxcarbazepine,
neurophysiological manifestations as described above which eiciently reduced his muscle cramps, also
conirmed this diagnosis (1). he patient also suf- induced severe hyponatremia. he attempt to change
fered from severe muscle cramps, which tended to per- from an oral slow-release opioid to transdermal fen-
sist even if the neuropathic pain was well controlled. tanyl led to opioid intoxication. Phenytoin, which also
Finally, he had a treatment-related complication; an reduced the cramps and was well tolerated, led to
osteoporotic fracture of the 12th thoracic vertebra also intoxication when an intercurrent infection occurred.
induced pain. Fortunately, all of these adverse efects were reversible.
Several evidence-based guidelines for the treat- A further striking aspect was the marked improve-
ment of neuropathic pain are currently available as dis- ment in both pain and gait when the previously griev-
cussed and reviewed in Chapter 32 (2, 3). Over the ing widower developed a relationship with a new
course of his illness, the patient received several irst- companion.
line drugs for his condition including amitriptyline, Given the asymmetric onset of a sensorimotor neu-
gabapentin, pregabalin, and opioids when required. ropathy with pronounced pain, the suggestive mor-
Combining drugs with diferent mechanisms of action phology in the sural nerve and some signs of an inlam-
is a long-standing practice in the clinical setting. Ran- matory constellation (xANCA positive, oligoclonal
domized controlled trials have only recently investi- bands in the CSF), a diagnosis of NSVN was made in
gated combination therapies involving gabapentin and this patient. here are no randomized controlled trials
morphine (4), oxycodone (5), or nortriptyline (6), or involving drug therapy for NSVN (9). Corticosteroid
pregabalin and oxycodone (7). he evidence that com- monotherapy for at least 6 months is considered irst-
bination therapy may be more eicient and induce line (10). Combination therapy is considered neces-
fewer side-efects than higher doses of a single drug is sary for rapidly progressive NSVN and patients who
inconclusive. Monotherapy should be attempted irst. have success with corticosteroid monotherapy. Once
Muscle cramps are involuntary, generally painful remission is induced, cyclophosphamide should be
contractions of a muscle or muscle group. here is replaced with azathioprine or methotrexate. Although
a high frequency of occasional muscle cramps in the long-term outcome is reasonably positive for most
the general population. In many cases, these mus- patients, more than one third relapse and a few may die
cle cramps are idiopathic or induced by exercise or from the disease or treatment complications (11).
transient electrolyte disturbances. Several neuromus-
cular disorders, including peripheral neuropathies,
neuromyotonia, and metabolic myopathies, lead to Pain in vasculitic neuropathy
episodes of muscle cramp. he best evidence for treat- Eighty to ninety percent of patients with vasculitic
ment eicacy is available for quinine, which is associ- neuropathy experience pain (12). he pain itself is not
ated with uncommon, but serious side-efects such as diferent from that in other peripheral neuropathies
pancytopenia, cardiac arrhythmia, or visual loss [and except that it can be focally or multifocally accentu-
has been withdrawn in the USA by the FDA] (8). ated. Although the multiplex distribution is consid-
here is equivocal evidence from class II studies that ered typical for vasculitic neuropathy however, the
magnesium may be helpful. Other class II studies neuropathy (and consequently the pain) has a dis-
involving diltiazem hydrochloride, natidrofuryl, and tal symmetric distribution in approximately 70% of
vitamin B complex conirmed some degree of efec- patients. Immunosuppressive treatment may alleviate
tiveness. here are no data from clinical trials for fre- pain in some patients. However, a study that examined
quently used drugs such as baclofen, carbamazepine, a large cohort of patients reported that 41% still expe-
and oxcarbazepine. rienced pain ater combination therapy (12).
Our patient with vasculitic neuropathy was prone Vasculitic neuropathy is a classic example of pain
to adverse drug efects, experiencing several in a pre- induced by a combination of nerve injury and inlam-
dictable manner. Corticosteroids led to severe osteo- mation. he nerve ibers sufer axonal damage through 57
porosis and an osteoporotic fracture despite regular the vasculitis, either by direct ischemic injury or
through inlammatory injury. C-ibers are involved in (7) Gatti A, Sabato AF, Occhioni R, Colini Baldeschi G,
most cases (11). Pro-inlammatory cytokines, which Reale C. Controlled-release oxycodone and
are strong mediators of pain (13), are increased in sural pregabalin in the treatment of neuropathic pain:
nerve biopsies of vasculitic neuropathy (14). Further- results of a multicenter Italian study. Eur Neurol
2009;61:129–137.
more, patients with painful neuropathy have higher
systemic levels of pro-inlammatory cytokines (15). (8) Katzberg HD, Khan AH, So YT. Assessment:
symptomatic treatment for muscle cramps (an
Combining anti-inlammatory with anti-neuropathic evidence-based review): report of the therapeutics
treatment may be an efective strategy for pain con- and technology assessment subcommittee of the
trol in vasculitic neuropathy although this has not been American Academy of Neurology. Neurology
formally investigated. 2010;74:691–696.
(9) Vrancken AF, Hughes RA, Said G, Wokke JH,
Notermans NC. Immunosuppressive treatment for
References non-systemic vasculitic neuropathy. Cochrane
(1) Treede RD, Jensen TS, Campbell JN, et al. Database Syst Rev 2007:CD006050.
Neuropathic pain: redeinition and a grading system (10) Collins MP, Dyck PJB, Gronseth GS, et al. Peripheral
for clinical and research purposes. Neurology Nerve Society Guideline on the classiication,
2008;70:1630–1635. diagnosis, investigation, and immunosuppressive
(2) Dworkin RH, O’Connor AB, Audette J, et al. therapy of nonsystemic vasculitic neuropathy:
Recommendations for the pharmacological executive summary. J Peripher Nerv Syst
management of neuropathic pain: an overview and 2010;15:176–184.
literature update. Mayo Clin Proc 2010;85:S3–S14. (11) Collins MP, Periquet-Collins I. Nonsystemic
(3) Attal N, Cruccu G, Baron R, et al. EFNS guidelines on vasculitic neuropathy: update on diagnosis,
the pharmacological treatment of neuropathic pain: classiication, pathogenesis, and treatment. Front
2010 revision. Eur J Neurol 2010;17:1113-e88. Neurol Neurosci 2009;26:26–66.
(4) Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, (12) Collins MP, Periquet MI, Mendell JR, Sahenk Z,
Houlden RL. Morphine, gabapentin, or their Nagaraja HN, Kissel JT. Nonsystemic vasculitic
combination for neuropathic pain. N Engl J Med neuropathy: insights from a clinical cohort. Neurology
2005;352:1324–1334. 2003;61:623–630.
(5) Hanna M, O’Brien C, Wilson MC. Prolonged-release (13) Üçeyler N, Schäfers M, Sommer C. Mode of action of
oxycodone enhances the efects of existing gabapentin cytokines on nociceptive neurons. Exp Brain Res
therapy in painful diabetic neuropathy patients. Eur J 2009;196:67–78.
Pain 2008;12:804–813. (14) Lindenlaub T, Sommer C. Cytokines in sural nerve
(6) Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, biopsies from inlammatory and non-inlammatory
Houlden RL. Nortriptyline and gabapentin, alone and neuropathies. Acta Neuropathol 2003;105:593–602.
in combination for neuropathic pain: a double-blind, (15) Üçeyler N, Rogausch JP, Toyka KV, Sommer C.
randomised controlled crossover trial. Lancet Diferential expression of cytokines in painful and
2009;374:1252–1261. painless neuropathies. Neurology 2007;69:42–49.
58
Chapter
Painful polyneuropathy associated with
13 anti-MAG autoantibodies
Neuropathic pain may be the presenting feature in

patients with polyneuropathy, and may progress in
tandem with the disease. While painful polyneu-
ropathies are oten erroneously classiied as “small
iber” in type, several types may actually be associated
with intractable pain. We discuss pain in a patient with
an autoimmune, sensory predominant polyneuropa-
thy, particularly involving “large ibers” and originat-
ing as an autoimmune attack against myelin, not axons.

A 67-year-old right-handed female retired medical
secretary presented with a 1-year history of sensory Figure 13.1. Electrophysiological studies from the patient
described in this vignette. The tracings are CMAPs recorded from
alteration in the let foot that began in the let large toe. the abductor pollicus brevis on stimulation at the wrist. The top
he symptoms progressed to the right foot 2 months tracing is from the patient and the lower tracing from a control
later. he patient described the sensation as “some- subject. Note the prolonged distal motor latency and dispersed
appearance of the CMAP from the patient. Patients with anti-MAG
thing under my feet” with an insensitivity to cold. polyneuropathy have pronounced demyelination in distal
She experienced “prickling” as well and her walk- segments, as illustrated.
ing balance declined. She denied speciic weakness of
muscles, sphincter dysfunction, or symptoms in her
upper limbs. he patient had a history of mild type of motor conduction velocities (e.g., ulnar 30 m/s,
2 diabetes mellitus, pernicious anemia, hypercholes- N 50 m/s; peroneal 35 m/s; N 39 m/s), mild
terolemia, and ulcerative colitis. here was no family reductions in the amplitudes of the CMAPs, and
history of polyneuropathy. temporal dispersion of CMAPs with more proximal
Neurological examination disclosed intact mental stimulation. Median and ulnar sensory nerve action
function, cranial nerves, motor power, muscle bulk, potentials (SNAPs) were absent and the sural poten-
and upper limb coordination. Ankle relexes were tials were reduced in amplitude with mild conduction
absent but other deep tendon relexes were intact. velocity slowing (2.4 V, 36 m/s; N 6 V, 39
here was partial loss of sensation to light touch, pin- m/s). Needle electrode examination of the tibialis
prick, and temperature in the distal foot and there was anterior and extensor digitorum brevis was normal.
complete loss of vibration perception in her large toes. Overall, the studies identiied a widespread senso-
Sensory examination in the upper limbs was normal. rimotor polyneuropathy with features of primary
Position testing of the toes was also normal. She was demyelination.
mildly unsteady on her feet, but there was no Romberg Serum protein electrophoresis identiied a mono-
sign. clonal gammopathy (1.3 g/L) characterized as IgM.
Electrophysiological studies identiied several Bone marrow and lymph node biopsies and skeletal
abnormalities. he distal motor latencies of the survey were normal. Other blood work including com-
median, ulnar, peroneal, and tibial nerves were plete blood count, sedimentation rate, fasting glucose, 59
prolonged [Figure 13.1]. here was difuse slowing CK, ALT, cholesterol, triglycerides, HDL, LDL, B12
ably cold, encased in concrete or that “someone was

pulling” her toes upward. She felt cramping in her foot
muscles and red hot itchy sensations in her hands. Her
most prominent symptom was uncomfortable pares-
thesiae (tingling) in her feet throughout the day and
night. She ranked the pain as 5–6/10 during the day
and 10/10 at night. Aching, burning, and electrical-
like shocks were additional descriptors. Her pain was
associated with frustration, anger, and loneliness and
contributed to her balance diiculties. She experienced
some beneit from gabapentin but was reluctant to use
more than 300 mg at night because of cognitive side-
efects.
Discussion
Figure 13.2. Transverse section of a sural nerve immunoreacted his patient developed an autoimmune peripheral
with serum from a separate patient with anti-MAG polyneuropathy.
Note the selective immunoreactivity of the myelin sheaths
neuropathy associated with antibodies directed against
indicating immunoreactivity of IgM antibodies in this serum with a myelin-associated glycoprotein (MAG), a constituent
myelin antigen. Bar = 20 m. of normal myelin. Her progressive sensory loss, loss
of balance, and uncomfortable positive sensory symp-
level, folate, TSH, and autoantibodies to Yo, Hu, and toms were classic features of this condition. In addi-
SS-A/Ro were normal. ANA was positive at 1:160 tion, her descriptors of paresthesiae (tingling), burn-
but anti-DNA was negative. IgM to MAG (myelin- ing, and electrical-like sensations conirmed the diag-
associated glycoprotein) at a titer of 80,000 (Wash- nosis of neuropathic pain. Anti-MAG polyneuropa-
ington University, St. Louis; N
1500) was positive. thy is particularly directed toward myelin in large
A right sural nerve biopsy identiied loss of axons, axons and the patient’s electrophysiological features
myelin thinning, occasional endoneurial lymphocytes, identiied prominent demyelination, especially in very
and on teased analysis, both segmental and paranodal distal nerves (prolonged distal motor latencies). Her
demyelination. Immunohistochemistry demonstrated biopsy conirmed demyelination but also identiied
IgM localized to the myelin sheaths (illustrated in a loss of axons, an additional feature of the disease.
separate patient in Figure 13.2). Although she had mild type 2 diabetes mellitus, she
he patient noted increased numbness and more was not thought to have superimposed diabetic neu-
prominent discomfort over the next 2 years. Exami- ropathy. Although IVIG and gabapentin provided
nation identiied a gradual progression in her sensory some relief, their efects were incomplete and signii-
loss. IVIG therapy was initiated and was associated cantly interfered with her quality of life. Such incom-
with a subjective improvement in balance, discomfort, plete responses typically decrease patient interest to
and sensory loss. Despite regular monthly IVIG treat- currently available forms of therapy. Otherwise high
ments over the next 5 years, however, there was over- functioning individuals oten prefer not to use opioids
all clinical and electrophysiological evidence of grad- or other agents because of their cognitive side-efects.
ual deterioration of her polyneuropathy. Sensory loss
progressed to the thigh level and involved the hands Pain in anti-MAG polyneuropathy
and distal forearms. She developed mild toe extension
Because multiple mechanisms can potentially gen-
weakness and sufered several falls because of a decline
erate neuropathic pain, understanding how it arises
in her balance. Her neuropathic pain became more
in an individual patient may be diicult. First, it
prominent.
seems diicult to reconcile prominent pain in a
patient in whom an autoimmune attack is directed at
Pain description myelin, and not the axon itself. Neuropathic pain how-
60 he patient described several types of discomfort ever, is common in demyelinating polyneuropathies
including a sensation that her feet were uncomfort- including Guillain-Barré syndrome (1) and chronic
Chapter 13: Painful polyneuropathy associated with anti-MAG autoantibodies
inlammatory demyelinating polyneuropathy (CIDP) References

(2). In the two patients described in (2), severe and (1) Moulin DE, Hagen N, Feasby TE, Amireh R, Hahn A.
deep boring upper limb pain predicted early relapses Pain in Guillain-Barré syndrome. Neurology 1997;48:
of CIDP that eventually required further therapy (2). 328–331.
It may be that the inlammatory response associated (2) Zochodne DW, Brunet DG. Upper limb pain
with demyelinating neuropathies triggers ectopic dis- in chronic demyelinating polyneuropathy:
charges of nearby “bystander” axons: mediators might electrophysiological correlates. Acta Neurol
include TNF, nitric oxide, bradykinin, interleukins, Scand 1994;90:270–275.
or others (3–6). he critical role of Schwann cells, the (3) Sommer C, Lindenlaub T, Teuteberg P, Schafers M,
chief supporting cells of the peripheral nervous sys- Hartung T, Toyka KV. Anti-TNF-neutralizing
tem for axons and neurons, must also be considered. antibodies reduce pain-related behavior in two
Without such support, axons may become dysfunc- diferent mouse models of painful mononeuropathy.
Brain Res 2001;913:86–89.
tional and degenerate, a process in itself that might
trigger ectopic painful discharges through abnor- (4) Levy D, Zochodne DW. Local nitric oxide synthase
activity in a model of neuropathic pain. Eur J Neurosci
mal sodium channel distributions or kinetics. Alter-
1998;10:1846–1855.
ations in the peptide content of the parent axon
or cell body in the sensory ganglion is an addi- (5) Levy D, Zochodne DW. Increased mRNA expression
of the B1 and B2 bradykinin receptors and
tional source of painful ectopic discharges in neuro- antinociceptive efects of their antagonists in an
pathic pain (7, 8). In our patient, lymphocytes capa- animal model of neuropathic pain. Pain 2000;86:
ble of releasing inlammatory mediators had indeed 265–271.
entered the nerve and axons had also been destroyed. (6) Rowbotham MC, Petersen KL, Davies PS, Friedman
Finally, some have postulated that internodes denuded EK, Fields HL. Recent developments in the treatment
of myelin are capable of generating ectopic activity of neuropathic pain. In: Devor M, Rowbotham MC,
through recruitment of neighbor axons, or ephactic Wiesenfeld-Hallin Z, eds. Proceedings of the 9th
transmission (9). World Congress of Pain. Seattle: IASP Press, 2000:
Initial treatment for neuropathic pain from 833–855.
polyneuropathy probably should begin with better (7) Cummins TR, Dib-Hajj S, Black JA, Waxman SG.
tolerated agents such as gabapentin, other antiepilep- Sodium channels as molecular targets in pain. In:
Devor M, Rowbotham MC, Wiesenfeld-Hallin Z, eds.
tics, followed by tricyclic antidepressants (such as
Proceedings of the 9th World Congress on Pain. Seattle:
amitriptyline) and inally opioids. Evidence-based IASP Press, 2000:77–91.
guidelines for the priority in initiating these agents
(8) Devor M. he pathophysiology of damaged
has been debated and consensus statements are peripheral nerves. In: Wall PD, Melzack R, eds.
summarized in Chapter 32. Low-dose opioid therapy Textbook of Pain. 4th edition. London: Churchill
(oxycontin, fentanyl patches, slow-release morphine) Livingston, 1994:79–100.
can be a safe and efective approach in patients (9) Amir R, Devor M. Axonal cross-excitation in
with signiicant cardiac or renal comorbidity but nerve-end neuromas: comparison of A- and C-ibers.
constipation and cognitive side-efects are frequent. J Neurophysiol 1992;68:1160–1166.
61
Chapter
Painful polyneuropathy associated with
14 inherited amyloidosis
he polyneuropathy associated with amyloidosis clas- walked with an unsteady steppage gait. An inability to
sically involves small caliber sensory and autonomic stand on his toes or his heels accompanied a Romberg
axons early, and is oten associated with promi- sign. here was no signiicant postural blood pressure
nent neuropathic pain. his chapter describes a drop with standing.
patient with late-onset inherited amyloidosis-related Electrophysiological studies identiied widespread
polyneuropathy. severe reductions or loss of CMAP amplitudes. Distal
motor latencies were prolonged in the median and
ulnar nerves at the wrists and there was slowing of
Clinical case vignette forearm ulnar motor and leg peroneal motor con-
his 72-year-old right-handed male of Danish extrac- duction velocity. SNAPs were markedly reduced in
tion developed symptoms approximately 5 years amplitude with patchy slowing of conduction veloci-
before evaluation. He described “cold” feet that ties in the upper limbs. SNAPs were absent in the lower
evolved into painful, burning sensations in a stock- limbs. Needle electrode study of tibialis anterior and
ing distribution also associated with paresthesiae. he vastus lateralis identiied ibrillation potentials, pos-
symptoms gradually progressed proximally up his legs itive sharp waves, and a reduced number of enlarged
and involved his inger tips 2 years before presenta- motor unit potentials with an increased iring rate.
tion. Six months before his visit, he noticed a decline Normal (negative) laboratory studies included:
in balance with falls in the shower, clumsiness in his complete blood count, ESR, INR, electrolytes, fast-
ine inger movements, and allodynia. Other symp- ing glucose, calcium, magnesium, urinalysis, venous
toms included a decline in grip strength, diiculty aris- lactate, alkaline phosphatase, ALT, AST, bilirubin
ing from chairs, and erectile dysfunction. Bowel and (total and direct), ferritin, GGT, LDH, total pro-
bladder dysfunction or postural lightheadedness were tein, albumin, B12, TSH, HbA1C, lipid proile,
denied although diarrhea had developed just before cryoglobulin, serum protein electrophoresis, urine
the visit. protein electrophoresis, immunoixation, quantitative
A prior lumbar laminectomy, cholecystectomy, and immunoglobulins, antibodies to sulfatide and MAG,
borderline diabetes mellitus were reported. here was RF, and skeletal survey. A CK level was mildly elevated
no deinite history of polyneuropathy involving his at 263 U/L (normal,
195). he ANA screen was pos-
parents, a sister, or three sons, although his father died itive at 1:320 and showed a nucleolar pattern. Bone
at a young age for unrelated reasons. density scores in the spine and femoral neck were in
On neurological examination, mental status, the osteoporotic range. A CT scan of the chest (and
speech, and cranial nerves were intact. He had wasting plain chest ilm) and abdomen identiied atelectasis
of his intrinsic hand muscles and lower limb pitting in the let costophrenic angle and right middle lobe
edema. here was weakness of his hand muscles (4/5) and hypertrophy of the let ventricle, but the studies
and in foot dorsilexion, plantar lexion, inversion, were otherwise normal. An electrocardiogram showed
and eversion (3/5). Lower limb relexes were absent, normal sinus rhythm, nonspeciic T wave abnormali-
and there was loss of sensation distal to the knees and ties inferolaterally and low voltage QRS limb leads. A
proximal ingers. here was loss of sensitivity to light two-dimensional echocardiogram identiied increased
touch distal to his knees and analgesia and anesthesia thickness of the right and let ventricles with normal
in his toes. He had loss of vibration sensation in his function, biatrial enlargement, and mild mitral and tri-
62 toes, made errors with position sensation testing, and cuspid regurgitation.
Chapter 14: Painful polyneuropathy associated with inherited amyloidosis
Figure 14.1 Images illustrating amyloid polyneuropathy in patients other than described in the clinical vignette. Images A and B show
examples of self-injury and ulceration in the finger tips and feet of a patient who had amputations of his large toes because of ulceration and
infection. This patient had acquired amyloidosis with severe amyloid polyneuropathy and insensitivity to injury. Images C and D illustrate
histological examples of amyloid deposition in a transverse section of a sural nerve illuminated by polarized light and stained with Congo red.
The arrow points to apple-green birefringence surrounding an endoneurial vessel. In D, illustrated is a teased myelinated axon with a large
amyloid deposit (arrow) adjacent to and partly compressing it.
A right sural nerve biopsy showed severe loss of nia, and spasms. It was aggravated by walking, long
myelinated axons, hyalinized endoneurial and peri- standing, or sitting. Partial relief was achieved with
neurial blood vessels that were birefringent green gabapentin, amitriptyline, and oxycontin. High doses
on Congo red staining with polarized light, rare of gabapentin were associated with diarrhea, whereas
macrophages without an inlammatory iniltrate, and opioids induced severe constipation and nausea. He
other endoneurial amyloid deposits. he indings described progressive daily pain extending from his
identiied a severe neuropathy with evidence of amy- feet to his hips.
loidosis. Amyloidosis was conirmed and was linked
to a V30M mutation of the TTR (transthyretin)
gene [courtesy of Amyloid Treatment and Research Discussion
Program, Boston Medical University, Dr. Martha his patient had a severe and progressive sensory and
Skinner]. motor polyneuropathy associated with familial amy-
Two years following his visit, the patient required loidotic polyneuropathy (FAP). Amyloidosis refers
admission to hospital with urinary retention, pneu- to a spectrum of systemic and neurological disor-
monia, weight loss, and right-sided cardiac failure. He ders associated with the deposition of protein that
died 3 months later at home. exhibits apple-green birefringent luorescence under
a luorescence microscope when the tissue is stained
with Congo red dye (see review (1))[Figure 14.1C,D].
Pain description Amyloidosis involving the peripheral nervous system
During 2 years of follow-up, this patient’s pri- can be primary acquired, associated with deposits of
mary diiculty was his severe and intractable neuro- immunoglobulin light chains, or familial as described
pathic pain that routinely interrupted his sleep. He in this case. Familial amyloidosis was originally clas- 63
described burning hyperalgesia, paresthesiae, allody- siied as FAP Types I–IV, but is currently associated
with transthyretin mutations (Type I, Portuguese toms were reported. At autopsy in three patients, amy-
or Andrade; Type II Indiana-Swiss, or Rukavina), loid deposits were noted in the sympathetic ganglia,
apolipoprotein A-I mutations (Type III Iowa or Van dorsal root ganglia, and peripheral nerve trunks, and
Allen), and gelsolin mutations (Type IV Finnish or were associated with axonal degeneration. Unmyeli-
Meretoja). nated axons were relatively spared, a possible rea-
V30M (valine is substituted with methionine), the son for the prominent symptoms of pain described
mutation in our patient, is the most common of the in other series of patients with late onset V30M FAP.
transthyretin mutations, is autosomal dominant and Overall the changes were thought less severe than
linked to FAP Type I and II. his was also the muta- those of early onset amyloidosis. Autonomic diicul-
tion discovered in the original Portuguese or Andrade ties included postural hypotension, occasional syn-
kindred. While V30M transthyretin amyloidosis was cope, alternating diarrhea and constipation, urinary
originally described as FAPI and identiied in patients retention, male sexual impotence, and distal loss of
from Portugal, Japan, Sweden, and the USA, it is 1 of sweating. Patients most oten had panmodal loss of
over 100 mutations identiied in the primary struc- sensation, greater lower limb than upper limb weak-
ture of transthyretin, a plasma transport protein for ness and in the heart, cardiac conduction abnormali-
thyroid hormone and retinol-binding protein (2). he ties or hypertrophy.
onset has been described as late in Sweden, as in Our patient’s disease course was relentless and pro-
our patient, but early in Portugal. V30M is associated gressive with evidence of gastrointestinal (diarrhea
with peripheral neuropathy, carpal tunnel syndrome, alternating with constipation) and cardiac (ventricular
autonomic neuropathy, and vitreous opacities. Painful wall thickening and later right heart failure) involve-
burning feet may be an initial symptom of periph- ment. Beyond orthotopic liver transplantation, not
eral neuropathy. Loss of small iber sensory modali- considered for our patient because of his advanced age,
ties is prominent (pain and temperature sensation) in a efective treatment for FAP is limited.
stocking and glove distribution. Self-injury and ulcer-
ation may develop from loss of protective sensation Pain in amyloid-associated
[Figure 14.1A,B]. Distal lower limb weakness is
common and autonomic symptoms include postu- polyneuropathy
ral lightheadedness from postural hypotension, bowel While the prevalence of pain in FAP patients is
and bladder emptying abnormalities, impotence, and thought to be high, exact igures are diicult to
sweating loss (1). Electrophysiological studies show ascertain. In a series of ten patients selected for liver
evidence of a progressive axonal sensory and motor transplantation in Boston, ive had lancinating pain
polyneuropathy, as observed in our patient, with that improved ater the transplant (4). It is uncertain
superimposed carpal tunnel syndrome. Ocular abnor- whether deposits of amyloid proteins in nerve trunks
malities include scalloped pupils, vitreous opacities or ganglia might signal speciic pain receptors or
mentioned above, keratoconjunctivitis sicca, and glau- channels. Painful amyloid polyneuropathy has been
coma. It remains unclear how the variant protein gen- identiied as an example of “small iber” neuropathy.
erates axonal damage in FAP, but it is thought to be Why loss of small ibers should generate pain rather
neurotoxic. Despite his late onset, our patient had no than analgesia is problematic. Targeting of small axons
clear family history of the condition, normally dis- and their ganglia perikarya before frank drop out may
played in an autosomal dominant inheritance pattern. be a reasonable explanation for this clinical syndrome.
Some instances are secondary to spontaneous de novo While polyneuropathy in amyloidosis is oten associ-
mutations and penetrance may be as low as 50%. ated with selective small axon loss, our patient’s nerve
he clinical, electrophysiological and biopsy results biopsy identiied widespread loss of both myelinated
of probands from 35 families in Japan with V30M and unmyelinated axons in addition to amyloid depo-
FAP were reviewed by Misu et al. (3). While neu- sition. His pain descriptors indicated neuropathic
ropathic pain was not speciically mentioned in this pain with burning, uncomfortable paresthesiae and
group, initial paresthesiae were the most common ini- allodynia. he diiculties of current pharmacological
tial complaint. he patients were late-onset (from age therapy for severe neuropathic pain were illustrated
64 50), predominantly male, and had a family history by the patient’s severe gastrointestinal side-efects
in only one third of instances. Few autonomic symp- that ensued in attempting to titrate his analgesics.
Chapter 14: Painful polyneuropathy associated with inherited amyloidosis
Despite the use of higher doses, his symptoms were (3) Misu K, Hattori N, Nagamatsu M, et al. Late-onset
only partially relieved. familial amyloid polyneuropathy type I (transthyretin
Met30-associated familial amyloid polyneuropathy)
unrelated to endemic focus in Japan. Clinicopatho-
References logical and genetic features. Brain 1999;122(Pt 10):
(1) Mendell JR. Familial amyloid polyneuropathies. 1951–1962.
In: Mendell JR, Kissel JT, Cornblath DR, eds. (4) Pomfret EA, Lewis WD, Jenkins RL, et al. Efect of
Diagnosis and Management of Peripheral Nerve orthotopic liver transplantation on the progression of
Disorders. Oxford: Oxford University Press, familial amyloidotic polyneuropathy. Transplantation
2001:477–491. 1998;65:918–925.
(2) Benson MD, Kincaid JC. he molecular biology and
clinical features of amyloid neuropathy. Muscle Nerve
2007;36:411–423.
65
Chapter
Small iber neuropathy in sarcoidosis
15
his patient vignette illustrates how a neuropathic pain
syndrome may lead to an unexpected underlying diag-
nosis. Unexplained pain in sarcoidosis may guide the
way toward a diagnosis of small iber neuropathy.

A 50-year-old female physician presented with burn-
ing pain in the soles of her feet and the palms of
her hands. She had been taking nonsteroidal anti- A
inlammatory drugs without efect. Her medical his-
tory was unremarkable except for arterial hyperten-
sion and obesity. Neurological examination was nor-
mal. Nerve conduction studies gave normal results
in the motor nerves and showed moderate reduction
of sensory nerve action potential amplitudes in the
let sural nerve. he sympathetic skin response in the
arms and legs was normal. Quantitative sensory testing
revealed a moderately increased detection threshold
for warm temperatures in the feet, with normal thresh-
olds for all other sensory qualities, and normal thresh- B
olds in the hands. Laboratory investigations including
serum chemistry, complete blood count, erythrocyte
sedimentation rate, serum vitamin B12 concentration,
serum protein electrophoresis, antinuclear antibodies,
and angiotensin-converting enzyme (ACE) were all
normal. Cerebrospinal luid, including the ACE level,
was also normal.
An initial and tentative diagnosis of small iber
b
neuropathy (SFN) was made; a skin punch biopsy
was performed and processed for analysis of skin C
innervation and inlammatory cells. In a sample taken
from the lower leg, intraepidermal nerve iber den- Figure 15.1 Skin biopsy from the lower (A) and upper (B) leg of
the patient. (A, B) Immunofluorescent staining with antibodies to
sity (IENFD) was reduced to 3.3 ibers/mm (nor- PGP 9.5 to visualize intra- and subepidermal nerve fibers (arrows).
mal, 9.5 ± 3), and IENFD from the upper thigh, at Note reduction of nerve fibers in (A). (C) Immunohistochemical
9 ibers/mm, was in the lower range of normal. stains for macrophages and T lymphocytes (arrows) in the
subepidermal skin. The presence of granulomas is notably absent.
he results conirmed a length-dependent small iber
neuropathy [Figure 15.1A,B]. Dermal macrophages
and T-lymphocytes were also moderately increased
66 [Figure 15.1C,D].
Chapter 15: Small fiber neuropathy in sarcoidosis
monary function was almost normalized, the medi-

astinal lymph nodes had become smaller, and the
patient did not complain of pain. Prednisolone was
further tapered. One year later, now under 6 mg
daily of prednisolone, the patient reported intermit-
tent increases of the burning acral pain, which spon-
taneously resolved ater several days. She did not wish
symptomatic treatment for neuropathic pain.
Pain description
In the initial phase of her disease, the patient described
burning pain and a tingling in the soles of her feet
while at rest as well as in the palms of her hands. She
Figure 15.2 Computerized tomography scan of the patient’s lung ranked her pain at 4–5/10 when at rest. When touched
showing bihilar mediastinal lymph node enlargement (arrows). by clothing or ater prolonged standing, her pain sever-
Images: courtesy of Prof. Hahn, Inst. for Radiology, University ity could increase to 8/10. Ater the initiation of treat-
Hospital of Würzburg.
ment, the pain was markedly reduced, but the patient
noticed a sensation of numbness in the areas that had
Because the patient also complained of weight loss
previously been painful.
of 4 kg in the last 3 months as well as increased
sweating, a chest x-ray and subsequently a CT scan
of the thorax were done; bihilar mediastinal lymph Discussion
node enlargement was found [Figure 15.2]. Pulmonary Sarcoidosis is a disseminated granulomatous disease of
function testing showed a moderate restrictive venti- presumed auto-immune origin. here may be a genetic
latory impairment. Lymphoma and sarcoidosis were disposition (1, 2). Exogenous causative factors rang-
considered as diferential diagnoses. Bronchial lavage ing from drugs to pollen and viruses are also suspect.
revealed 15% of lymphocytic cells in low cytometry, he Mycobacterium tuberculosis catalase-peroxidase
mostly T-lymphocytes, with an increased CD4/CD8 (mKatG) protein is a potential antigen (3). he preva-
ratio of 3.3 (normal: 1.1–2.5). Transbronchial biopsy lence of sarcoidosis ranges from 1–40 per 100,000
of the lymph nodes revealed non-caseating epithe- among various ethnic and racial groups. Almost all
lioid granulomas, typical of sarcoidosis. Granuloma- organs may be impacted, most oten lung, liver, skin,
tous iniltrates were also found in a skin biopsy of and eyes. he disease is chronic and progressive in
the chin. A diagnosis of sarcoidosis with multi-organ approximately 25% of cases. Neurosarcoidosis with
involvement was made and treatment with cortico- CNS involvement has been estimated at 10% of all
steroids, complemented by osteoporosis prophylaxis, cases (4), but this statistic may be underestimated
was initiated. Prednisolone was initiated at a dose of 1 (5). Neurosarcoidosis mimics most CNS diseases and
mg/kg, then slowly tapered to a maintenance dose of 20 consequently, a list of diferential diagnoses can be
mg daily and later supplemented by azathioprine 150 long (6). Treatment options include corticosteroids,
mg/day for steroid sparing. Under this treatment regi- azathioprine and methotrexate. Anti-tumor necrosis
men, the pain was markedly reduced and symptomatic factor-alpha (TNF) therapy has also been used (7).
treatment for neuropathic pain was not required. Sarcoid peripheral neuropathy has long been rec-
Approximately 6 months ater the diagnosis had been ognized, oten described as a vasculitis-like neuropa-
made, the prednisolone dose was reduced to 10 mg, thy with typical granulomas in the nerve (8– 10). In
and shortly ater that, pain resumed. A complete inter- a Dutch treatment center for this disease, almost 50%
nal medical and neurological check-up revealed no of all patients complained of pain and paresthesias in
major changes, except that sural nerve conduction the distal extremities (11). he suspicion that these
studies were now normal. he prednisolone dose was patients might be sufering from small iber neuropa-
increased to 15 mg daily for several weeks and later thy (SFN) was subsequently conirmed by QST and
again reduced to 10 mg. When the patient was seen by quantiication of skin innervation. Many patients 67
again 1 year later, she was generally improved, pul- also had symptoms of autonomic dysfunction. Other
potential causes of SFN were excluded. Sarcoidosis nerve ibers or in their environment may be respon-
therapy, such as corticosteroids or TNF inhibitors, may sible for inducing sensations of pain. Because small
help alleviate SFN symptoms (12). Patients respon- iber neuropathy is characterized by localized pain,
sive to intravenous immunoglobulins have also been local increases in inlammatory mediators, which then
described (13). When suicient immunosuppressive activate and sensitize nociceptors, may play a role.
treatment of sarcoidosis is given and pain persists, Dysregulated cytokine inlammatory mediators in the
medications for neuropathic pain may be prescribed skin may be a factor explaining pain in sarcoidosis
(14); data for the most efective treatment regimen are (1). In idiopathic length-dependent SFN, local skin
unavailable (14). cytokine proiles are shited to a proinlammatory sta-
Small iber neuropathies are a subtype of sensory tus within involved body areas (19). In the subgroup of
neuropathies exclusively or predominately afecting patients with small iber neuropathy, cytokine expres-
small diameter nerve ibers, and are discussed in more sion in the painful skin was greatly increased com-
detail in Chapter 11. hese include small diameter pared with uninvolved skin. hus, local increases in
myelinated ibers (A∂) and unmyelinated (C) ibers. pro-inlammatory cytokines like TNF may be involved
Both sensory and autonomic ibers may be involved. in the pathophysiology of pain in small iber neuropa-
he typical and most common presentation is a com- thy. Whether this is true in sarcoid SFN, or whether
plaint of burning feet (15). In the patient described other inlammatory mediators are more important in
above, SFN was the irst manifestation of sarcoidosis. this disorder, requires clariication.
he history of weight loss and increased sweating trig- Treatment in sarcoidosis is dependent on the extent
gered a more extensive diagnostic workup, including of organ involvement. Most patients with sarcoido-
chest x-ray, which eventually led to the diagnosis. sis require no speciic treatment (1). When treatment
is necessary, patients usually improve with moderate
doses of corticosteroids. However, long-standing cor-
Pain in sarcoidosis ticosteroid treatment leads to unwanted side-efects.
Patients with sarcoidosis experience several types of TNF inhibitors have been investigated for the treat-
pain; the SFN-related pain represents one of several. In ment of sarcoidosis, but are not yet recommended
a Dutch survey of over 800 patients, 72% complained for use. Immunosuppressants including azathioprine,
of pain. Arthralgia was the most frequent (53.8%), fol- methotrexate, cyclosporine, and cyclophosphamide
lowed by muscle pain (40.2%), headache (28.0%), and are used, particularly in cases involving neurosar-
chest pain (26.9%). Patients with more types of pain coidosis (6), but evidence-based data from trials are
had impaired indices of their quality of life. he typical unavailable. he pain in sarcoid SFN is frequently alle-
and most common presentation of SFN is a complaint viated by immunosuppressive treatment. If this is not
of burning feet. Approximately 50% of patients have suicient, symptomatic treatment may be attempted
paresthesias, lancinating pain, and negative symptoms with medications used for other types of neuropathic
including numbness (15, 16). he initial presentation pain including amitriptyline, gabapentin, pregabalin,
is in the feet; the hands may become involved over and others (14). One small controlled trial has given
time. he persistent pain is variously described as some indication that pain in idiopathic small iber
burning, prickling, or deep and aching. Lancinating neuropathy may respond to drugs generally given for
pains are described as brief, stabbing, or like electric neuropathic pain (20). Local treatment options like
shocks. he feet may feel cold, or feel as if the skin is too lidocaine or capsaicin patches may potentially be help-
tight. Patients may also complain of thermal hypersen- ful but there are no controlled data yet on their use in
sitivity. Pain is oten worse at rest, particularly at night, either sarcoid-related or idiopathic SFN.
and may interfere with sleep. Allodynia may make bed-
sheets intolerable and prevent patients from wearing
certain footwear. References
he mere loss of skin innervation is not necessar- (1) Morgenthau AS, Iannuzzi MC. Recent advances in
ily associated with pain (17). For example, patients sarcoidosis. Chest 2011;139:174–182.
with motor neuron disease and no pain may have (2) Hofmann S, Fischer A, Till A, et al. A genome-wide
68 considerable loss of small ibers in the skin (18). In association study reveals evidence of association with
these instances, additional factors in the damaged sarcoidosis at 6p12.1. Eur Respir J 2011;38:1127–1135.
Chapter 15: Small fiber neuropathy in sarcoidosis
(3) Song Z, Marzilli L, Greenlee BM, et al. Mycobacterial (12) Hoitsma E, Faber CG, van Santen-Hoeut M, De
catalase-peroxidase is a tissue antigen and target of Vries J, Reulen JP, Drent M. Improvement of small
the adaptive immune response in systemic iber neuropathy in a sarcoidosis patient ater
sarcoidosis. J Exp Med 2005;201:755–767. treatment with inliximab. Sarcoidosis Vasc Difuse
(4) Terushkin V, Stern BJ, Judson MA, et al. Lung Dis 2006;23:73–77.
Neurosarcoidosis: presentations and management. (13) Parambil JG, Tavee JO, Zhou L, Pearson KS, Culver
Neurologist 2010;16:2–15. DA. Eicacy of intravenous immunoglobulin for
(5) Joseph FG, Scolding NJ. Neurosarcoidosis: a study of small iber neuropathy associated with sarcoidosis.
30 new cases. J Neurol Neurosurg Psychiatry 2009;80: Respir Med 2011;105:101–105.
297–304. (14) Attal N, Cruccu G, Baron R, et al. EFNS guidelines on
(6) Hoitsma E, Drent M, Sharma OP. A pragmatic the pharmacological treatment of neuropathic pain:
approach to diagnosing and treating neurosarcoidosis 2010 revision. Eur J Neurol 2010;17:1113–e88.
in the 21st century. Curr Opin Pulm Med 2010;16: (15) Lacomis D. Small-iber neuropathy. Muscle Nerve
472–479. 2002;26:173–188.
(7) Baughman RP, Drent M, Kavuru M, et al. Inliximab (16) Sommer C, Lauria G. Chapter 41 Painful small-iber
therapy in patients with chronic sarcoidosis and neuropathies. Handb Clin Neurol 2006;81:621–633.
pulmonary involvement. Am J Respir Crit Care Med (17) Vlckova-Moravcova E, Bednarik J, Belobradkova J,
2006;174:795–802. Sommer C. Small-ibre involvement in diabetic
(8) Galassi G, Gibertoni M, Mancini A, et al. Sarcoidosis patients with neuropathic foot pain. Diabet Med
of the peripheral nerve: clinical, electrophysiological 2008;25:692–699.
and histological study of two cases. Eur Neurol (18) Weis J, Katona I, Muller-Newen G, et al. Small-iber
1984;23:459–465. neuropathy in patients with ALS. Neurology 2011;
(9) Zuniga G, Ropper AH, Frank J. Sarcoid peripheral 76:2024–2029.
neuropathy. Neurology 1991;41:1558–1561. (19) Üçeyler N, Kake W, Riediger N, et al. Elevated
(10) Said G, Lacroix C, Plante-Bordeneuve V, et al. Nerve proinlammatory cytokine expression in afected skin
granulomas and vasculitis in sarcoid peripheral in small iber neuropathy. Neurology 2010;74:1806–
neuropathy: a clinicopathological study of 11 1813.
patients. Brain 2002;125:264–275. (20) Ho TW, Backonja M, Ma J, Leibensperger H, Froman
(11) Hoitsma E, Marziniak M, Faber CG, et al. Small ibre S, Polydekis M. Eicient assessment of neuropathic
neuropathy in sarcoidosis. Lancet 2002;359:2085– pain drugs in patients with small iber sensory
2086. neuropathies. Pain 2009;141:19–24.
69
Chapter
Pain and small iber polyneuropathy in
16 Fabry disease
Fabry disease (FD) is an inherited, X-linked lyso- fever. He had sufered many similar episodes during
somal storage disorder caused by deiciency of the childhood and into adulthood, with some improve-
enzyme -galactosidase A (-GAL) (1). he disease ment ater initiation of symptomatic treatment with
is characterized by intracellular deposition of glyco- phenytoin. he patient further reported that, under
sphingolipids (mostly globotriaosylceramide, GL-3) ERT, painful episodes occurred less frequently and
that may involve various organs including the central were less severe. Heat tolerance was likewise improved.
and peripheral nervous systems. Pain is an early symp- Neurological examination was normal except for evi-
tom that can facilitate recognition of the disease and dence of carpal tunnel syndrome (CTS) involving the
in turn, prevent major organ failure through adequate right hand. Electrodiagnostic studies showed reduc-
and timely treatment. tions in median nerve SNAP amplitude and nerve con-
duction velocity (NCV) in combination with a pro-
longed distal motor latency of the right motor median
Clinical case vignette nerve, conirming CTS. Nerve conduction studies of
A 41-year-old man was diagnosed with FD in April the let median and the right sural nerve were normal
2004 through the process of family screening ater as was the sympathetic skin response at the right foot.
conirmation of FD in his brother. A splicing defect Quantitative sensory testing (QST) at the right foot
of IVS3 + 1 G A on the GLA-gene and loss of revealed increased cold detection threshold (CDT),
-GAL activity were discovered. His medical history warm detection threshold (WDT), and thermal sensi-
included a deep femoral vein thrombosis in 1993 and tivity threshold (limen) (TSL), indicating loss of func-
a myocardial infarction in 1996. Typical Fabry-related tion of A- and C-ibers (Table 16.1). A skin punch
symptoms included repeated acute hearing loss, biopsy was taken from the right lower leg 10 cm
periumbilical angioektasia, and heat intolerance with above the lateral malleolus [Figure 16.1]. Intraepider-
hypohidrosis. he patient also reported pain in his mal nerve iber density was reduced to 1.1 ibers/mm
hands and feet triggered by fever. Kidney function, (normal, 10±3 ibers/mm), conirming small-iber
measured by clearance of technetium-99m-labeled neuropathy.
diethylenetriamine pentaacetate (99mTc-DTPA), A follow-up examination was done in April 2008.
revealed a glomerular iltration rate (GFR) of 140 he patient was in a stable clinical condition, renal
mL/min per 1.73 m2 (normal range, 90–150 mL), and cardiac parameters were within normal ranges. He
without evidence of proteinuria. Echocardiography reported less severe pain and fewer pain attacks dur-
showed a borderline hypertrophy of the let ventricle ing the last year; evaluated with the Graded Chronic
with a septum wall thickness of 12 mm (normal Pain Scale (GCPS) (2), he also had lower pain scores
range,
12 mm). Enzyme replacement therapy (ERT) (total score of the 1–3 items of GCPS) and pain-related
was initiated shortly ater the diagnosis of FD was disability (total score of the 5–7 items of GCPS) com-
conirmed in April 2004. pared with 2007. he grade of pain severity ame-
he irst neurological examination of the patient liorated from grade III in 2007 to grade I in 2008
was performed in April 2007. At that time, cardiac and (Table 16.1). Nerve conduction of the right median
renal status were within the normal range. he patient nerve improved following carpal tunnel surgery in
reported typical Fabry crises in which he had attacks June 2007. In QST of the right foot, thermal thresh-
of severe burning pain in his hands and feet induced olds were improved when compared with the previous
70 by exercise, stress, and temperature changes, including examination [Table 16.1].
Chapter 16: Pain and small fiber polyneuropathy in Fabry disease
Table 16.1. Neurophysiological findings, quantitative sensory testing, and pain rating
Right sural Right median nerve NCS
nerve NCS Sensory Motor QST GCPS scores
SNAP NCV SNAP NCV DL CMAP NCV DML CDT WDT TSL Pain Pain Grade of pain
(␮V) (m/s) (␮V) (m/s) (ms) (mV) (m/s) (ms) (◦ C) (◦ C) (◦ C) intensity∗ disability† severity‡
2007 18.4 50.0 18.0 34.5 4.6 9.1 n.d. 5.8 –22 18 32.7 40 3 III
2008 17.8 47.0 24.0 46.0 3.6 11.7 52.0 4.8 –9.1 11 18.4 30 0 I
Scores derived from ∗ items 1–3; † items 5–7, and ‡ items 1–7 of the GCPS questionnaire, related to the 4 weeks previous to examination.
CDT: cold detection threshold; CMAP: compound muscle action potential; DML: distal motor latency; GCPS: Graded Clinical Pain Scale; GFR:
glomerular filtration rate; IENFD: intraepidermal nerve fiber density; NCS: nerve conduction studies; NCV: nerve conduction velocity; n.d.;
not done; QST: quantitative sensory testing; SNAP: sensory nerve action potential; TSL: thermal sensory limen (temperature change needed
to detect difference).
WDT: Warm detection threshold
could also bring on pain crises. he patient char-

acterized the pain as mostly burning although deep
aching pain could also occur. In addition, he com-
plained of nightly pain in the right hand which could
be attributed to the CTS and was no longer present at
the follow-up visit. he patient had learned over the
years that standard analgesics were not helpful and that
a a daily intake of 300 mg phenytoin in divided doses
reduced the pain intensity. He took the medication
mostly in summer and when he anticipated physical
exertion.
Discussion
his patient had experienced typical acral pains
related to Fabry disease throughout his life-time. Pain
occurred with febrile episodes in his childhood and
b also with febrile infections in adulthood. Hot ambi-
ent temperature and increases of body core temper-
Figure 16.1. (A) Photomicrograph of a section from the patient’s
skin biopsy from the lower calf. Immunofluorescence with ature through physical exercise also induced pain.
antibodies to the pan-axonal marker protein gene product (PGP) Although the patient had further typical Fabry-related
9.5. Note only subepidermal nerve fibers (open arrows) as symptoms such as hypohidrosis, repeated acute hear-
compared to that in a section from a control person (B) with
numerous intraepidermal nerve fibers (arrows) and subepidermal ing loss, and periumbilical angioektasia, the diagno-
nerve fibers (open arrows). Bar = 20 m. Dotted line: sis was not made until the patient’s more severely
Dermal–epidermal junction. afected brother was diagnosed with Fabry’s disease.
Despite the long duration of disease, the patient was
relatively mildly involved; renal function and cardiac
Pain description function were normal and borderline normal, respec-
Although pain intensity was rated as 4/10 in the weeks tively. In other patients with a similar history, the diag-
preceding the irst visit, the patient described intermit- nosis is sometimes made when renal failure has already
tent peaks of pain that reached an intensity of 8/10. occurred.
hese peaks were associated with physical exercise, Apart from cardiac and renal involvement, one rea-
stress, and hot temperatures, including fever. Abrupt son for the limited life expectancy of Fabry patients
temperature changes, no matter in which direction, is central nervous system involvement mainly due to 71
ischemic strokes (3). Along with macroangiopathic Pain in Fabry disease

changes, Fabry patients frequently develop cerebral
In children, pain is oten the earliest sign of Fabry dis-
microangiopathy that causes progressive white matter
ease. he typical manifestation is burning acral pain
lesions (WMLs) (4, 5). his may lead to deterioration
associated with febrile illnesses. he burning pain in
of cognitive function.
the hands and feet is classically referred to as acro-
In the peripheral nervous system, Fabry patients
paresthesia although this term is technically incorrect
develop a neuropathy primarily involving C-ibers
because paresthesia is deined as a non-painful abnor-
and A-ibers (small-iber neuropathy) (6–8). Large-
mal skin sensation (17). he diagnosis is oten missed
iber involvement is mainly limited to patients in
because the pain is attributed to the infectious illness
advanced disease stages already sufering from renal
itself. Later in life, patients may sufer from pain of
impairment. Routine neurophysiological tests selec-
similar characteristics ater physical exertion which
tively evaluate faster conducting myelinated A- and
can be debilitating. Recurrent, very severe attacks of
A-ibers. To test the function of small nerve ibers,
pain (“pain crises”) oten begin in the distal extremities
other diagnostic tools are necessary. A bedside test
and may radiate proximally. hey can be so intense that
of small-iber function and quantitative sensory test-
the patient is conined to bed and prescribed opioids.
ing (QST) are useful approaches (9–11). Quantitative
hese pain crises may be triggered by a rapidly chang-
thermotesting is a psychophysical method of evalu-
ing core body temperature, sudden exposure to cold,
ating temperature perception and pain thresholds in
rapid changes in humidity, and fatigue. As patients
various skin areas (9–11). Fabry patients usually show
age, pain attacks can become less frequent and less
raised thresholds of cold more than warm perception
intense. Given the lack of clinical trials speciically test-
(9, 12, 13). With these indings, and ater more com-
ing analgesics in Fabry disease, general guidelines for
mon causes of small-iber neuropathy (such as diabetes
the treatment of neuropathic pain are recommended.
mellitus or alcohol abuse) are excluded, the diagnosis
Open trials and case histories report successful treat-
of Fabry disease should be considered and an enzyme
ment with phenytoin, carbamazepine, and gabapentin
test performed. It is assumed that small-iber neuropa-
(18–20). he detection of neuropathic pain in Fabry
thy is mainly due to GL-3 deposits in the dorsal root
disease is, therefore, important for the following rea-
ganglion (DRG) neurons which may also be a cause
sons: 1. In children, neuropathic pain may be the irst
for the pain. he vulnerability of small DRG neurons
clue to suggest the diagnosis. 2. An early diagnosis can
in this condition and the triggering of pain to temper-
prevent irreversible damage and limit organ involve-
ature changes is not yet understood.
ment (21). 3. he correct diagnosis of neuropathic pain
ERT may reduce neuropathic pain, but larger trials
is required to initiate adequate symptomatic therapy
are needed to conirm this (14, 15). Some patients may
and to improve the patient’s quality of life.
substantially reduce their pain medication when under
ERT. Others ind that ERT provokes pain, particularly
in the early stages of treatment, and symptomatic treat- References
ment is required. Improvement of small iber function (1) Zarate YA, Hopkin RJ. Fabry’s disease. Lancet 2008;
under ERT has been established in previous investiga- 372:1427–1435.
tions as assessed by QST (14, 15). In this patient, small (2) Von Korf M, Ormel J, Keefe FJ, Dworkin SF. Grading
iber function had also considerably improved (Table the severity of chronic pain. Pain 1992;40:133–149.
16.1) ater 1 year of follow-up. (3) Fellgiebel A. Stroke and brain structural alterations in
A very common manifestation of Fabry disease Fabry disease. Clin her 2007;29(Suppl A):S9–S10.
is hypohidrosis, which may lead to heat intolerance. (4) Fellgiebel A, Müller MJ, Ginsberg L. CNS
Hypohidrosis is presumably the consequence of both manifestations of Fabry’s disease. Lancet Neurol
direct damage to sweat glands caused by GL-3 deposits 2006;5:791–795.
and reduced sweat gland innervation (16). he sym- (5) Crutchield KE, Patronas NJ, Dambrosia JM, et al.
pathetic skin response may be used to test for sweat Quantitative analysis of cerebral vasculopathy in
gland function but it has a low sensitivity and can patients with Fabry disease. Neurology 1998;50:
appear normal even when sudomotor function is 1746–1749.
72 substantially disrupted. his was the case with our (6) Lacomis D. Small-iber neuropathy. Muscle Nerve
patient. 2002;26:173–188.
Chapter 16: Pain and small fiber polyneuropathy in Fabry disease
(7) Moller AT, Jensen TS. Neurological manifestations in C-, Adelta-, and Abeta-nerve ibers in Fabry
Fabry’s disease. Nat Clin Pract Neurol 2007;3:95–106. neuropathy. Neurology 2004;62:1066–1072.
(8) Torvin Møller A, Winther Bach F, Feldt-Rasmussen (16) Yamamoto K, Sobue G, Iwase S, Kumazawa K,
U, et al. Functional and structural nerve iber indings Mitsuma T, Mano T. Possible mechanism of
in heterozygote patients with Fabry disease. Pain anhidrosis in a symptomatic female carrier of Fabry’s
2009;145:237–245. disease: an assessment by skin sympathetic nerve
(9) Maag R, Binder A, Maier C, et al. Detection of a activity and sympathetic skin response. Clin Auton
characteristic painful neuropathy in Fabry disease: a Res 1996;6:107–110.
pilot study. Pain Med 2008;9:1217–1223. (17) Weidemann F, Strotmann JM, Breunig F, et al.
(10) Rolke R, Baron R, Maier C, et al. Quantitative sensory Misleading terms in Anderson-Fabry disease. Eur J
testing in the German Research Network on Clin Invest 2008;38:191–196.
Neuropathic Pain (DFNS): standardized protocol and (18) Duperrat B, Puissant A, Saurat JH, Delanoe MJ,
reference values. Pain 2006;123:231–243. Doyard PA, Grunfeld JP. [Proceedings: Fabry’s
(11) Hilz MJ. Evaluation of peripheral and autonomic disease, angiokeratomas present at birth. Efect of
nerve function in Fabry disease. Acta Paediatr Suppl diphenylhydantoin on painful attacks]. Ann Dermatol
2002;91:38–42. Syphiligr (Paris) 1975;102:392–393.
(12) Dutsch M, Marthol H, Stemper B, Brys M, Haendl T, (19) Ries M, Mengel E, Kutschke G, et al. Use of
Hilz MJ. Small iber dysfunction predominates in gabapentin to reduce chronic neuropathic pain in
Fabry neuropathy. J Clin Neurophysiol 2002;19:575– Fabry disease. J Inherit Metab Dis 2003;26:413–414.
586. (20) Filling-Katz MR, Merrick HF, Fink JK, Miles RB,
(13) Luciano CA, Russell JW, Banerjee TK, et al. Sokol J, Barton NW. Carbamazepine in Fabry’s
Physiological characterization of neuropathy in disease: efective analgesia with dose-dependent
Fabry’s disease. Muscle Nerve 2002;26:622–629. exacerbation of autonomic dysfunction. Neurology
1989;39:598–600.
(14) Schifmann R, Floeter MK, Dambrosia JM, et al.
Enzyme replacement therapy improves peripheral (21) Desnick RJ, Brady R, Barranger J, et al. Fabry disease,
nerve and sweat function in Fabry disease. Muscle an under-recognized multisystemic disorder: expert
Nerve 2003;28:703–710. recommendations for diagnosis, management, and
enzyme replacement therapy. Ann Intern Med
(15) Hilz MJ, Brys M, Marthol H, Stemper B, Dutsch M. 2003;138:338–346.
Enzyme replacement therapy improves function of
73
Section D Other neuromuscular and neurological disorders
Chapter
Pain and proximal myotonic
17 myopathy (DM2)
Many types of muscle disease can be associated with included cyclobenzaprine, quinine, amitriptyline,
chronic pain. While these do not classically involve marijuana, baclofen, mexilitene, and gabapentin all
sensory systems, muscles include a large complement with limited beneits or side-efects.
of C unmyelinated nociceptive aferents. his vignette he patient’s sister, age 42, had a 20-year history
describes a patient with myotonic dystrophy Type 2, of difuse limb pain, muscle spasms, and fatigue. She
an autosomal muscular dystrophy with a peculiar described painful spasms at her hips and knees that
predilection for muscle pain. would awaken her from sleep. She smoked marijuana
and took opioid medications for her pain. She had
weakness of proximal muscles without clinical myoto-
Clinical case vignette nia. Her diiculties progressed over 3 years of follow-
A 50-year-old man presented with a 24-year history of up and she developed difuse wasting, increased proxi-
diiculties with his muscles. Despite a career of pro- mal limb weakness, neck extensor weakness, and clini-
fessional dancing, he noted diiculty going up stairs cal myotonia. She also developed cardiomyopathy and
and stifness and slowness of his muscles to “warm up.” sufered a ventricular thrombus.
Five years ater the onset of his complaints (19 years On neurological examination of the index patient,
earlier, age 31) he could run up a light of stairs, but he had mild hand incoordination, minimal weakness
at the time of evaluation he was barely able to climb on arising from a squatting position, and absent ankle
stairs. He had diiculty releasing his grip ater holding relexes. Muscle strength in both axial and truncal
onto things. He also had prominent pain in the legs, muscles was otherwise intact. He did not exhibit typi-
hands, and arms and rated its severity as 6–9/10. he cal percussion myotonia of his thenar muscles.
pain was brought on almost immediately ater exertion Electrophysiological studies indicated borderline
and he could only walk a maximum of two blocks. He distal slowing of motor and sensory conduction. Nee-
also noted some slurring of speech, impaired swallow- dle electromyography identiied myotonic discharges
ing of luids, and diiculty chewing. He had noticed a that were recorded in tibialis anterior, vastus medialis,
decline in his balance. triceps, irst dorsal interosseous, biceps, and deltoid
Neurological review was otherwise negative. He muscles. Some of the voluntarily recruited motor unit
had used intravenous street drugs once 30 years ear- potentials were decreased in duration and polypha-
lier and smoked occasional marijuana. He was unable sic, suggestive of a myopathic process. His CK level
to tolerate mexiletine, phenytoin, or quinine. was mildly elevated at 575 U/L (normal,
195).
He had a family history of neuromuscular dis- Hemogram, sedimentation rate, electrolytes (includ-
ease involving his sister and his son. Other details ing calcium and magnesium levels), hepatic func-
of the family history were uncertain. His son, aged tion, ANA, and TSH level were all normal. A right
28, had a life-long history of “shaky” hands, diiculty quadriceps muscle biopsy showed mild nondiagnostic
releasing things with his hands, and muscle pain changes: increased central nuclei, excess variation in
on exertion. he son had temporalis and masseter iber size with some atrophic muscle ibers, and occa-
atrophy with atypical clinical percussion myotonia but sional pyknotic nuclear clumps.
no muscle weakness. A muscle biopsy in this family An initial diagnosis of myotonic muscular dystro-
member identiied only nonspeciic changes with phy was considered but testing for the DM (DM1)
rare thin muscle ibers and molecular testing for the gene variable length polymorphism region was nega-
74 DM gene was negative. Medications for his son’s pain tive. Ater the family history was established, a clinical
Chapter 17: Pain and proximal myotonic myopathy (DM2)
diagnosis of autosomal dominant proximal myotonic Table 17.1 Pain localization in type 2 diabetes mellitus (DM2)∗
myopathy, or Myotonic Dystrophy Type 2 (DM2), was Patients with Patients
made. his was conirmed by identifying a CCTG Pain variable† DM2/PROMM with OMD
repeat expansion in the ZNF9 gene. At 7 years fol- Limb muscles: Proximal 22/24 13/24
lowing the original evaluation, he had noted a decline Distal 20/24 13/24
in balance and speech and was using a motorized Arms 17/24‡ 7/24
Forearms 12/24 6/24
wheelchair outside of the home. He could walk up Hands/fingers 4/24 6/24
to 3–4 blocks but usually was exhausted ater half a Thighs 19/24‡ 9/24
block. He reported continued spasms and pain, rated Lower legs 17/24 12/24
Calf 13/24 11/24
as 4/10 on average but as severe as 8/10. For his pain, he Anterior tibial muscle 11/24§ 0/24
was using long-acting morphine (130 mg twice daily), Peroneal 3/24 1/24
extra short-acting morphine for breakthrough pain, Feet 5/24 6/24
and baclofen. On examination he had mild proximal Limb girdles: 15/24 8/24
(4+/5 MRC) weakness of deltoids, hip lexors, and Low back: 17/24 10/24
quadriceps, intact power otherwise, no myotonia, and Others: Knee 8/24 2/24
mild dysarthria. Jaw 3/24 2/24
Unilateral: 4/24 3/24
Pain description Bilateral: Asymmetrical 1/24 5/24
Symmetrical 20/24 16/24
he pain was described as muscular aching and cramp-
ing involving the hands, arms, and legs. he pain Radiating pain 14/24§ 0/24
∗ Radiating, pain radiating from the pelvic limb girdle to the thighs
was typically worsened from exertion. It was perhaps
aggravated by the cold but its onset was unrelated to or lower legs. Details of pain description from George et al. (2)
in DM2, including its localization, site, and radiation (a) and its
meals. he intensity of the discomfort could vary. He descriptors (b) using the McGill pain questionnaire.
† Data were obtained with MPQ. Data indicate the number of
also experienced chronic neck and lower back discom-
fort. His son described similar soreness and aching in patients with this variable out of the total number of patients
examined.
his legs. His sister also described muscle pains requir- ‡ Significantly different from OMD (P
0.05; Fisher’s exact test).
§ Significantly different from OMD (P
0.001; Fisher’s exact test).
ing long-term marijuana and opioid use.
Discussion
DM2 is an autosomal dominant disorder of muscles speciic alterations. Unlike DM1, pain is a prominent
caused by an unstable expansion of a CCTG tetraplet feature of DM2.
repeat in intron 1 of the zinc inger 9 (ZFN9) gene
on chromosome 3q21.3 (1). It is uncertain how the
genetic abnormality accounts for the clinical pheno- Pain in DM2
type of the disorder. his patient, his son, and sister Pain is a common feature of DM2, reported to occur in
(and possibly his father) were similarly involved. Like 46% of patients (1, 2). Its presence is unrelated to the
the better known disorder myotonic dystrophy Type 1 presence or severity of myotonia and it may render dis-
(DM1 or DM), patients with DM2 may develop mus- comfort to touch or muscle palpation. Some patients
cle weakness, stifness from abnormal excitability of may have chest pain that is mistaken for cardiac dis-
muscles (myotonia), and have abnormalities of other ease. Nonetheless, DM2 is also associated with cardiac
organs such as the brain (e.g., cognitive dysfunction), conduction abnormalities, but less frequently than in
eyes (cataracts), and the endocrine system (insulin DM1. While our patient had pain brought on by exer-
resistance). DM2 is associated with less weakness than cise, the pain in DM2 may not necessarily be exercise
DM1, and it predominantly involves proximal muscles related.
(it has also been called PROMM-proximal myotonic George et al. (2) identiied musculoskeletal pain in
myopathy). As in our patient, clinical myotonia is less 23 of 24 patients with DM2 in their clinic. heir mean
readily demonstrated but electrical myotonia on nee- age was 57 and symptoms of muscle disease had been
dle electromyography may be prominent. CK levels present for a mean of 15 years. he pain was localized 75
can be mildly elevated and muscle biopsy shows non- to muscles and several types of pain were described
Section D: Other neuromuscular and neurological disorders
(mean of 5 and a maximum of 12 pain types/patient). is interesting that both in our patient and his sister,
he pain rating index using the McGill pain ques- several analgesics were tried with mixed results. Our
tionnaire and the numbers of pain types were greater patient found some mild beneit from mexilitene. Both
in DM2 patients than those with other muscular dis- brother and sister found smoking marijuana helped
orders. Descriptors included “tugging,” “dull,” “stab- their symptoms. Ischemic and overcontracted muscles
bing,” “sore,” “tender,” and “exhausting.” Pain was can generate intense pain in patients likely through
proximal and distal involving arms, forearms, thighs, the participation of a rich unmyelinated nociceptor
and lower legs most oten. Feet and hands were less population that innervates muscles. A separate genetic
involved and the pain was oten described as asymmet- alteration of sensory axon function in DM2 cannot
rical. In 8 patients, musculoskeletal pain was the most be excluded. DM2 pain is chronic and not associated
disabling feature of their condition compared with 3 with muscle iber necrosis, yet it localizes to both limb
of 24 patients with other muscular disorders. Pain was and truncal muscles suggesting an interaction between
frequently exacerbated by exercise (17/24 patients), by deep aferents and abnormal muscle molecular archi-
cold (10/24), or by palpation (11/24). Pain also usually tecture. No speciic forms of treatment have been iden-
persisted for 6 months or more. he indings did not tiied for DM2.
support the use of massage for treatment, an approach
that worsened symptoms. Overall the indings iden- References
tiied a unique pain phenotype difering from that of (1) Meola G, Moxley RT, III. Myotonic dystrophy type 2
patients with other muscle disorders. Summary infor- and related myotonic disorders. J Neurol 2004;251:
mation from this source is illustrated in Table 17.1. 1173–1182.
he mechanism of pain in DM2 is unknown. It (2) George A, Schneider-Gold C, Zier S, Reiners K,
is described as deep and cramping despite the ind- Sommer C. Musculoskeletal pain in patients with
ing that myotonia and cramps in DM2 are much less myotonic dystrophy type 2. Arch Neurol 2004;61:
common than in DM1 where pain is infrequent. It 1938–1942.
76
Chapter
Complex regional pain syndrome
18
Complex regional pain syndromes (CRPS), encom-
passing previous terms such as causalgia, relex sym-
pathetic dystrophy, Sudeck’s atrophy, and others, com-
plicate sot tissue or peripheral nerve damage to an
extremity. It is a challenging pain syndrome both for
the patient and the clinician.

A 52-year-old, right-handed truck driver fell from his
truck while unloading some goods. He noticed pain
and swelling of his let hand and pain at his let hip
and let ankle. Despite his injuries, he drove approxi-
mately 500 km to his home. He visited the local hospi-
tal 2 days ater the accident. he examining physician
Figure 18.1. Mild CRPS of the left hand with discoloration (red),
found a grossly swollen let hand but an x-ray revealed edema, and prominent veins.
no fracture. Two days later, the pain and swelling had
not subsided and the patient visited a second physi-
cian. A distal radius fracture was diagnosed. An open
cast was applied to the let lower arm. he patient was restricted, a repeat radiograph was performed which
re-examined 5 days later. Blood supply and sensory showed spotty osteoporotic changes at the trapezius
and motor function in the arm were found to be nor- and the base of the irst metacarpal bone. he patient
mal and a circular cast was applied. he patient rated was referred to a specialist for hand surgery at which
his pain as 2 on a scale of 0–10. point a diagnosis of CRPS I was established.
he cast was removed 6 weeks later. Shortly there- Approximately 6 months following the initial
ater, the patient reported a massive increase in pain, injury, the patient obtained appointments at a pain
up to 8/10. He felt mild pain at rest (3/10) but the clinic. Swelling of the let hand with disturbed vaso-
slightest hand movement, such as during physiother- and sudomotor function were noted. he let hand
apy, exacerbated the pain. His physician noted swelling felt warmer to touch, and sweating was increased
and a slight bluish discoloration of the let hand. [Figure 18.1]. Motor strength was reduced due to pain.
here was a decreased range of motion of the ingers Repeated sympathetic blocks of the stellate ganglion
and wrist. Range of motion at the wrist was reduced were performed twice weekly for 5 weeks. Under this
to extension of 40◦ and lexion of 70◦ . he patient treatment, pain at rest resolved and pain with move-
reported that the swelling was variable, and that the ments was reduced to 4–5/10. he range of motion
color of the hand could change from bluish to deep increased. An attempt to further improve the situation
red. He was treated with acupuncture and transcu- by combining the treatment with 25 mg of amitripty-
taneous electrotherapy for 3 months by his ortho- line at bedtime was unsuccessful because of anti-
pedic surgeon, but his condition did not improve. cholinergic side-efects. A selective serotonin reuptake
When the patient tried to move his hand, his pain rat- inhibitor, citalopram, was then prescribed but discon- 77
ings increased to 8/10. Because movement was still tinued because of nervous agitation.
During the following months, the patient received in the middle of the 19th century as the irst descrip-
regular physiotherapy. His condition was stable but tion of CRPS. It was then termed causalgia due to
he was not pain free, particularly when moving the the burning character of the pain. At the beginning
let hand. Approximately 1 year ater the initial injury, of the 20th century, Paul Sudeck, a surgeon from
the patient underwent hip replacement surgery on Hamburg, Germany, published a study about post-
the right. In this context, he received a course of bis- traumatic bone atrophy (2) describing a pain syn-
phosphonates ater which he reported his let hand drome associated with edema and trophic changes of
to be pain free. Notably, within 1 month of using the skin. Later, the term sympathetic relex dystro-
crutches for mobility, pain in the let hand recurred phy was coined because clinical investigations revealed
with strength of 6/10. Sympathetic blocks and intra- that the disorder appeared to be caused by overactivity
venous application of bisphosphonates were repeated. of the sympathetic nervous system; sympathetic blocks
Follow-up examinations revealed that the patient was were believed efective analgesic agents (3). When later
pain-free most of the time. He felt intermittent exa- studies raised doubts about the relexive activation
cerbations of pain ater exertion or sometimes spon- of the sympathetic nervous system, the International
taneously that usually resolved within several days. Association for the Study of Pain (IASP) introduced
Except for evidence of a reduced callus on the let, no a purely descriptive term, complex regional pain syn-
diference between the hands were noted on inspec- drome (CRPS). his remains the oicial term for this
tion, and skin temperature was equal on both sides. syndrome (4).
he range of movement was normal. Let grip strength Traditionally, CRPS is classiied as CRPS I and
was still reduced compared with the right. Nerve con- CRPS II. In CRPS I, there is no overt nerve injury, in
duction studies of the ulnar, median, and radial nerve CRPS II, there is injury of a major nerve trunk. Because
were normal. injury of small nerves and nerve endings occurs in all
trauma, the distinction has recently been debated (5),
Pain description in particular because reduced skin innervation has also
been shown in CRPS I (6, 7).
During the acute phase of his CRPS, the patient
As with many disorders involving pain, CRPS is
described pain at rest and upon moving the hand. His
conirmed by speciic diagnostic criteria (8). hese
pain at rest had a severity of 3–4/10 and upon move-
“Budapest criteria” are reproduced in Table 18.1. Pain,
ment its severity could increase to 8/10. Ater using the
disproportionate to the inciting event, is obligatory.
let hand, pain at rest worsened for periods of several
Edema, discoloration, and other vasomotor abnormal-
hours to days. Also, swelling and discoloration of the
ities may vary in intensity as described in Figure 18.1.
hand also increased following exertion. As a result, the
Trophic changes may occur in approximately 50% of
patient tended to restrict use of his let hand. When
patients. hese include increased hair- and nail growth
describing the pain, the patient used descriptors like
in the acute stage, but reduced hair- and nail growth
aching, stabbing, sharp, and sometimes burning.
and skin atrophy in chronic stages. Severely afected
patients may also develop muscle atrophy and contrac-
Discussion tures.
his patient had a typical, moderately severe course Approximately 75% of patients have weakness of
of CRPS I. His pain increased when it should have the involved site (9). In acute stages, this may be
abated. Swelling, discoloration, temperature changes, pain-dependent and guarding may result. Range of
sweating disturbances, and motor dysfunction were motion may be reduced due to edema. In chronic
present (see Figure 18.1 for an example from a dif- stages, contractions and ibrosis on palmar and plantar
ferent patient). he course was protracted, symptoms sides of hands or feet may impede movement. Tremor,
improved with treatment and with time, and exacerba- myoclonus, and dystonia may occur, increasing in fre-
tions occurred upon increased use of the hand. Finally, quency in chronic cases (9, 10).
the patient reached a stable, almost pain-free state.
Treatment in this patient was challenging and alterna-
tive approaches may have been more efective. Pain in CRPS
78 Most physicians cite the publication, “Gunshot Apart from the clinical distinction between CRPS I
wounds and other injuries of nerves” by Mitchell (1) (without major nerve trunk injury) and CRPS II (with
Chapter 18: Complex regional pain syndrome
Table 18.1 Clinical diagnostic criteria for CRPS according to Harden et al. (27)
1. Persisting pain, which is disproportionate to any inciting event
2. At least one symptom in three of the four following categories:
Sensory symptoms: reports of hyperesthesia and/or allodynia
Vasomotor symptoms: reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry
Sudomotor/edema symptoms: reports of edema and/or sweating changes and/or sweating asymmetry
Motor/trophic symptoms: reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or
trophic changes (hair, nail, skin)
3. At least one sign demonstrated in two or more of the following categories at time of evaluation:
Sensory signs: evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint
movement)
Vasomotor signs: evidence of temperature asymmetry and/or skin color changes and/or asymmetry
Sudomotor/edema signs: evidence of edema and/or sweating changes and/or sweating asymmetry
Motor/trophic signs: evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or
trophic changes (hair, nail, skin)
4. There is no other diagnosis that better explains the signs and symptoms
nerve injury), patients may also be described as having polymorphisms related to CRPS have been identiied,
“warm” or “cold” CRPS. he warm type usually devel- i.e., the HLA system in patients with CRPS and dys-
ops post-traumatically, the skin is red and skin tem- tonia (15). Associations with other candidate genes
perature is increased on the afected side. If the dis- are inconclusive. During the process of injury and
order becomes chronic, the skin may acquire bluish inlammation, cutaneous innervation is damaged (6)
overtones and become cold. he cold phenotype is rare with deicits in cutaneous sensitivity (12). his may
(20%) and oten develops following minor trauma or contribute to trophic skin changes. he sympathetic
even spontaneously (5). innervation can be equally involved. Similar processes
Most patients with CRPS have pain at rest (11). It is likely occur in the deep tissues but this has not been
oten perceived as deep pain although it may also con- conirmed. Continuous aferent input from damaged
sist of a supericial sensation on the skin. It is described and sensitized nociceptors may then lead to plasti-
as tearing, burning, or stinging. Numbness, paresthe- city in the central pain pathways as conirmed by func-
sias, or a feeling of foreignness of the afected limb tional imaging studies of the brain, electrophysiolog-
occurs in up to 30% of patients. Nearly all patients ical brain mapping, and receptor-ligand studies (13,
report increased pain under certain circumstances, for 16). All changes appear reversible whether due to natu-
example when lowering the limb, upon joint move- ral healing processes or following treatment of the con-
ment, or upon light touch. Brush-evoked pain (cuta- dition (17).
neous dynamic mechanical allodynia) is present in Systemic corticosteroids can be efective if pre-
approximately 30% of CRPS patients and is more com- scribed early in the disease process (18, 19). he usual
mon in the chronic phase. dose is 30–40 mg/day of prednisolone-equivalent
Quantitative sensory testing reveals hyperalgesia to for 4 weeks, or 1 mg/kg for 1 week with taper-
pressure, but somewhat paradoxically, deicits in the ing over 3 weeks. Bisphosphonates have been suc-
perception of cold and warm as well as vibratory stim- cessful as demonstrated in four controlled trials
uli (12) [Figure 18.2]. (alendronate (20, 21), clodronate (22), pamidronate
he pathophysiology of CRPS is incompletely (23)). hey reduce pain, improve function, and block
understood (13). Several contributing factors however, osteoclast activity. Data on calcitonin are discrepant.
have been identiied. Following injury, peripheral neu- Case reports conirm some success with intravenous
rogenic inlammation occurs with release of inlam- immunoglobulin and TNF blockers. Topical dimethyl-
matory mediators like neuropeptides-cytokines, and sulfoxide (DMSO 50%), a free-radical scavenger, may
growth factors (5, 12, 14). his process is reversed also have beneit (24). Physiotherapy and ergother-
during normal healing, but persists in CRPS. Con- apy are recommended, but should be performed by
sequently, some researchers regard CRPS as a dei- a therapist with special knowledge of CRPS to pre-
ciency in resolution of inlammation. A genetic com- vent complications. Motor imagery (mirror therapy) 79
ponent may also be involved, although only a few gene may be eicient (25). It is important that the patients
Figure 18.2. Example of results of quantitative sensory testing in a cohort of CRPS patients. Reproduced with permission from Üçeyler et al.
(12). Z-score sensory profile of 31 CRPS patients on the affected limb. The Z-score profile of CRPS patients was compared with healthy control
subjects as represented by a Z-score “zero.” The sensory profile of the affected limbs shows a predominant loss of sensory function in terms of
cold hypoesthesia (CDT), warm hypoesthesia (WDT), an increased threshold for the detection of temperature differences (thermal sensory
limen, TSL), an increased number of paradoxical heat sensations (PHS), and vibratory hypoesthesia (VDT). In contrast to a decreased cutaneous
sensitivity across C-fiber, A-delta- and A-beta-fiber mediated stimuli, deep pain sensitivity to blunt pressure (PPT) was increased. This sensory
profile is consistent with deafferentation in combination with peripheral sensitization of the nociceptive system in this subgroup of CRPS
patients. Z-score: Numbers of standard deviations between patient data and group-specific mean values of healthy control subjects. MPT:
mechanical pain threshold; MPS: mechanical pain sensitivity; WUR: wind-up ratio; MDT: mechanical detection threshold; VDT: vibration
detection threshold; DMA: dynamic mechanical allodynia. Shown data represent mean Z-scores ± SEM. For DMA and PHS raw data are
shown (mean ± SEM). ∗ P
0.05; ∗∗ P
0.01; ∗∗∗ P
0.001 (one-way analysis of variance).
practice these therapies independently between regu- (4) Merskey H, Bogduk N. Classiication of Chronic Pain.
lar guided sessions. Sympathetic blocks can be used Descriptions of Chronic Pain Syndromes and
when less invasive measures prove insuicient. Spinal Deinition of Pain Terms. Seattle: IASP Press, 1994.
cord stimulation or intrathecal baclofen may be an (5) Birklein F. Complex regional pain syndrome. In:
option for patients with otherwise refractory pain (26). Aminof MJ, Boller F, Swaab DF, eds. Handbook of
Psychotherapy is indicated if there are psychological Clinical Neurology. Edinburgh: Elsevier, 2006:529–
546.
comorbidities such as depression and anxiety.
(6) Albrecht PJ, Hines S, Eisenberg E, et al. Pathologic
alterations of cutaneous innervation and vasculature
References in afected limbs from patients with complex regional
(1) Mitchell SW, Morehouse GR, Keen WW. Gunshot pain syndrome. Pain 2006;120:244–266.
Wounds and Other Injuries of Nerves. Philadelphia: JB (7) Oaklander AL, Fields HL. Is relex sympathetic
Lippincott & Co., 1864. dystrophy/complex regional pain syndrome type I a
(2) Sudeck P. Über die akute (relektorische) small-iber neuropathy? Ann Neurol 2009;65:629–638.
Knochenatrophie nach Entzündungen und (8) Harden RN, Bruehl S, Perez RS, et al. Validation of
Verletzungen in den Extremitäten und ihre klinischen proposed diagnostic criteria (the “Budapest Criteria”)
Erscheinungen. Fortschr Röntgenstr 1901;5:227–293. for Complex Regional Pain Syndrome. Pain 2010;
(3) Bonica JJ. Causalgia and other relex sympathetic 150:268–274.
dystrophies. In: Bonica JJ, ed. Advances in Pain (9) de Boer RD, Marinus J, van Hilten JJ, et al.
80 Research and herapy. New York: Raven Press, Distribution of signs and symptoms of complex
1979:141–166. regional pain syndrome type I in patients meeting the
Chapter 18: Complex regional pain syndrome
diagnostic criteria of the International Association for pain syndrome following stroke: a randomized
the Study of Pain. Eur J Pain 2011;15:830.e1-8. controlled trial. QJM 2006;99:89–95.
(10) van Hilten JJ. Movement disorders in complex (20) Adami S, Fossaluzza V, Gatti D, Fracassi E, Braga V.
regional pain syndrome. Pain Med 2010;11: Bisphosphonate therapy of relex sympathetic
1274–1277. dystrophy syndrome. Ann Rheum Dis 1997;56:
(11) Birklein F, Riedl B, Sieweke N, Weber M, Neundorfer 201–204.
B. Neurological indings in complex regional pain (21) Manicourt DH, Brasseur JP, Boutsen Y, Depreseux G,
syndromes–analysis of 145 cases. Acta Neurol Scand Devogelaer JP. Role of alendronate in therapy for
2000;101:262–269. posttraumatic complex regional pain syndrome type I
(12) Üçeyler N, Eberle T, Rolke R, Birklein F, Sommer C. of the lower extremity. Arthritis Rheum 2004;50:
Diferential expression patterns of cytokines in 3690–3697.
complex regional pain syndrome. Pain 2007;132: (22) Varenna M, Zucchi F, Ghiringhelli D, et al.
195–205. Intravenous clodronate in the treatment of relex
(13) Bruehl S. An update on the pathophysiology of sympathetic dystrophy syndrome. A randomized,
complex regional pain syndrome. Anesthesiology double blind, placebo controlled study. J Rheumatol
2010;113:713–725. 2000;27:1477–1483.
(14) Krämer HH, Eberle T, Üçeyler N, et al. TNF-alpha in (23) Robinson JN, Sandom J, Chapman PT. Eicacy of
CRPS and “normal” trauma – signiicant diferences pamidronate in complex regional pain syndrome type
between tissue and serum. Pain 2011;152:285–290. I. Pain Med 2004;5:276–280.
(15) de Rooij AM, Florencia Gosso M, Haasnoot GW, (24) Zuurmond WW, Langendijk PN, Bezemer PD, Brink
et al. HLA-B62 and HLA-DQ8 are associated with HE, de Lange JJ, van Loenen AC. Treatment of acute
Complex Regional Pain Syndrome with ixed relex sympathetic dystrophy with DMSO 50% in a
dystonia. Pain 2009;145:82–85. fatty cream. Acta Anaesthesiol Scand 1996;40:364–
367.
(16) Klega A, Eberle T, Buchholz HG, et al. Central
opioidergic neurotransmission in complex regional (25) Moseley GL, Zalucki N, Birklein F, Marinus J, van
pain syndrome. Neurology 2010;75:129–136. Hilten JJ, Luomajoki H. hinking about movement
hurts: the efect of motor imagery on pain and
(17) Maihofner C, Handwerker HO, Neundorfer B, swelling in people with chronic arm pain. Arthritis
Birklein F. Cortical reorganization during recovery Rheum 2008;59:623–631.
from complex regional pain syndrome. Neurology
2004;63:693–701. (26) Tran de QH, Duong S, Bertini P, Finlayson RJ.
Treatment of complex regional pain syndrome: a
(18) Christensen K, Jensen EM, Noer I. he relex review of the evidence. Can J Anaesth 2010;57:
dystrophy syndrome response to treatment with 149–166.
systemic corticosteroids. Acta Chir Scand 1982;
148:653–655. (27) Harden RN, Bruehl S, Stanton-Hicks M, Wilson PR.
Proposed new diagnostic criteria for complex
(19) Kalita J, Vajpayee A, Misra UK. Comparison of regional pain syndrome. Pain Med 2007;8:
prednisolone with piroxicam in complex regional 326–331.
81
Chapter
Pain and polymyalgia rheumatica
19
Polymyalgia rheumatica is a subacute disorder that conduction studies. Needle electromyography identi-
may be associated with deep aching proximal mus- ied minor changes in motor unit coniguration (small
cle weakness. We describe a patient with this disorder amplitude and duration MUPs) in right deltoid and
who was initially considered to have an inlammatory triceps, but there was no abnormal spontaneous activ-
myopathy. ity. Iliopsoas was normal. A let deltoid muscle biopsy
was normal and a diagnosis of polymyalgia rheumat-
ica (PMR) was made. He resumed prednisone ater
Clinical case vignette the muscle biopsy with a gradual tapering course from
A 75-year-old man was evaluated ater a 5- to 6- 50 mg daily over the next 3 months. At that time, he
month history of pain and limb weakness. He had dif- reported dramatic improvement in his pain and mus-
iculty arising from a toilet or low chair and required cle function. Neurological examination indicated that
hand support to ascend stairs. Muscle pain was promi- he had normal muscle power throughout and no dii-
nent in his thighs and hips, limiting his ability to culty arising from a chair without use of his arms. He
use farm machinery. He noticed some improvement had regained weight.
when he took doses of his wife’s non-steroidal anti-
inlammatory medication. He also noticed some mild Pain description
right temporomandibular joint discomfort with chew- he patient described deep aching proximal muscle
ing but denied rash, dysphagia, neck weakness, diplo- pain largely centered around his “hips” and thighs.
plia, or change in speech. here were no headaches or he pain interfered with his ability to work and climb
visual changes. He had lost 10 kg in weight and thought stairs, and it responded dramatically to the use of glu-
there was atrophy of his thighs. In the past, he had cocorticoid therapy.
sufered knee osteoarthritis, coronary artery disease,
and hyperlipidemia. He had a brother with polymyal-
gia rheumatica and a nephew with amyotrophic lateral Discussion
sclerosis (ALS). PMR is an auto-immune inlammatory disorder that
On neurological examination, he had normal presents in older patients with proximal muscle pain
extraocular movements and neck muscle power. here and weakness. Although patients describe weakness,
was mild and questionable proximal upper limb weak- formal neurological examination is either normal or,
ness, and mild deltoid and quadriceps loss of bulk. He as in the patient described here, demonstrates equivo-
could not arise from a squat or chair without using his cal weakness. Apparent weakness may be secondary to
arms. Deep tendon relexes and sensation were intact. pain and limited voluntary efort. Morning “stifness”
He had been started on two doses of prednisone is frequently described. Important negatives are the
50 mg 6 days before evaluation which was then absence of ophthalmoparesis, neck lexor weakness, or
discontinued until the time of neurological evalu- extensor weakness. he patients have intact relexes
ation. His ESR was borderline elevated at 14 (normal, and sensation. PMR is associated with temporal arteri-

10 mm/h), C-reactive protein elevated at 20.8 (nor- tis, not diagnosed in the patient described here despite
mal,
8.0 mg/L), and CK normal. Other blood work some very mild temporomandibular joint discomfort.
was normal, including electrolytes, quantitative RF, A high index of suspicion however, is required in
82 ANA screen, SSA/Ro, and TSH. Electrophysiologi- patients with PMR to identify temporal arteritis given
cal studies were largely normal, including repetitive the serious risks of visual loss. Rarely patients may
Chapter 19: Pain and polymyalgia rheumatica
sufer cerebral infarction from giant cell arterial dam- matory cytokines or limited ischemic damage from
age. Additional clinical features accompanying PMR arteritis are possibilities. Kreiner and Galbo described
include weight loss, occasional fever, and anemia. Our elevated cytokines in PMR that included interleukin-
patient had weight loss but did not develop anemia. 1 (IL-1), IL-1 receptor antagonist, IL-6, IL-8, and
Key laboratory diagnostic features are elevation of the monocyte chemoattractant protein 1. In a separate
ESR (40 mm/h) and CRP. Whereas only the CRP was report, these authors also noted elevated glutamate
signiicantly elevated in our patient, he had received and PGE (2) within muscle in PMR patients compared
two doses of oral prednisone before his evaluation that with control or patient plasma levels (2, 3). Shintani
may have partly treated his PMR. Electrophysiological et al. (4) observed elevated IgG, IgA, and ibrinogen
studies are characteristically normal or may show bor- deposits in the perifascicular area of the perimysium
derline changes in motor unit coniguration. Muscle in patients with PMR. How these rises in cytokines
biopsy may be normal or occasionally shows nonspe- and other molecules are generated and their impact on
ciic changes such as “moth-eaten” ibers. he biopsy local pain aferents is uncertain.
in PMR does not identify inlammation. Finally, the
clinical response to steroid is a key feature; dramatic
improvement, as in the patient described here, is References
expected. Most instances of PMR are sporadic, and the (1) Hernandez-Rodriguez J, Cid MC, Lopez-Soto A,
description of PMR in his brother is unusual. Espigol-Frigole G, Bosch X. Treatment of
While our patient initially received high doses polymyalgia rheumatica: a systematic review. Arch
of prednisone, recent evidence-based reviews suggest Intern Med 2009;169:1839–1850.
that a dose of 15 mg is appropriate and reduces the (2) Kreiner F, Galbo H. Elevated muscle interstitial levels
risks of long-term prednisone-related side-efects (1). of pain-inducing substances in symptomatic muscles
Methotrexate (e.g., 10 mg/wk) can be ofered as a in patients with polymyalgia rheumatica. Pain
steroid sparing agent. Because relapses can occur, ther- 2011;152:1127–1132.
apy for up to 2 years may be required. (3) Kreiner F, Langberg H, Galbo H. Increased muscle
interstitial levels of inlammatory cytokines in
polymyalgia rheumatica. Arthritis Rheum 2010;62:
Pain in polymyalgia rheumatica 3768–3775.
he mechanisms of proximal muscle pain that develop (4) Shintani S, Shiigai T, Matsui Y. Polymyalgia
in PMR patients are uncertain, given the nonspeciic rheumatica (PMR): clinical, laboratory, and
muscle biopsy indings. Activation of deep muscle or immunoluorescence studies in 13 patients. Clin
connective tissue unmyelinated C-ibers by inlam- Neurol Neurosurg 2002;104:20–29.
83
Chapter
Phantom pain
20
he enigmatic phenomenon of phantom pain, i.e., pain
perceived in a body part that is no longer present, has
intrigued physicians and scientists for centuries. his is
relected in the descriptions of numerous case reports
in the older literature and more recently, by a series of
studies using sophisticated functional brain imaging.
he following case report illustrates the challenge but
also the possibilities for success when phantom pain is
treated in the acute stage.

A 31-year-old engineer presented 4 weeks ater ampu-
tation of the right leg at the thigh and asked for an
invasive procedure to alleviate pain. He described the
pain as intermittent, sharp, shooting, and cramp-like.
He had developed severe electrifying pain perceived
to be in the amputated right foot within days of his
surgery. A stump revision 2 weeks later yielded an
improvement that lasted for 3 days. Carbamazepine
and tilidine/naloxone had been given without suc-
cess. Iniltration of the stump with the local anesthetic
mepivacaine provided pain relief for approximately an
hour. Current therapy consisted of diclofenac 50 mg Figure 20.1. A drawing of the patient’s deformed lower limb
before amputation, based on his description.
tid, amitriptyline 50 mg tid, and tramadol 75 mg tid.
On examination, the stump was bland but painful to
touch. sonal note, he wanted to hold his daughter in his arms
Further history-taking revealed that the patient’s while standing upright.
right leg had been deformed from birth with a ixed he patient was advised about the use of a trans-
lexion in the knee. he atrophic lower leg extended cutaneous electrical nerve stimulator (TENS). He was
laterally at an angle of approximately 90◦ [Figure 20.1]. prescribed sustained-release morphine (20 mg bid)
Despite this malformation, the patient had led a nor- under comedication with sodium picosulfate as a lax-
mal life. He was fully integrated in society having ative, and fast-acting morphine for breakthrough pain
completed an engineering degree and he had recently (morphine hydrochloride oral solution 2%, up to 20
embarked on his career. He had married and had mg every 6 h). Amitriptyline was increased to 125
become the father of a healthy daughter. He was active mg/day. One week later, the patient reported that
in sports. His motivation for the amputation was TENS had no efect. He had good pain relief for 2–3 h
84 twofold; he wanted to wear a prosthesis in his profes- ater taking the opiate medication. However, he com-
sional environment to avoid attention and on a per- plained about side-efects, including fatigue, sweating,
Chapter 20: Phantom pain
Table 20.1. Reported incidence of phantom limb pain in the [Table 20.1] due to several factors. It may be diicult to
literature∗
distinguish phantom pain from residual limb pain or
% Phantom from phantom sensation, which is benign in nature. In
Reference N pain earlier studies, frequencies were calculated from med-
Ewalt et al., 1947 (22) 2284 2 ical records of patients seeking pain treatment and
Henderson and Smyth, 1948 (23) ∼300 ∼1.5 perhaps underestimated when compared with more
recent and objective studies (1). Time ater amputation
Abramson and Feibel, 1981 (24) 2000 ∼2
is an important factor determining the prevalence of
Sherman and Sherman, 1983 (25) 764 85
phantom pain. Most studies show a decrease of phan-
Sherman et al., 1984 (26) 2750 78 tom pain prevalence over a longer time-frame (2, 3). A
Pohjolainen, 1991 (27) 124 59 study involving 42 patients with amputations for can-
Houghton et al., 1994 (2) 176 78 cer conirmed that 60% had phantom pain at 1 month
Wartan et al., 1997 (28) 526 55 and 32% at 2 years (4). he severity of phantom pain
also appears to decline over time (5, 6).
Kooijman et al., 2000 (29) 124 51
Seventy-ive percent of patients complain of pain
Ephraim et al., 2005 (30) 914 80
onset within the irst week ater surgery (7). Addi-
Taghipour et al., 2009 (31) 141 89 tionally, there are individual case reports of onset
Kern et al., 2009 (32) 537 75 years ater amputation. Constant daily pain appears
∗
Only large case series with 100 patients were considered. rare in the chronic phase; occurrences between several
times per day and less than once a month have been
reported (8). he pain oten occurs intermittently, and
constipation, and hypotension. He was given dihy- the duration of each attack varies between seconds and
droergotamine as prolonged-release tablets bid, and a hours, rarely days. he pain is mostly localized distally,
more potent laxative. he patient returned 3 months regardless of the level of amputation. Patients use a
later and reported of his ability to return to work wide range of pain descriptors. he pain is variously
shortly ater the previous visit. He had experienced described as shooting, burning, stabbing, or cramp-
good pain relief with tolerable side-efects. He had ing. Patients may experience electrical shocks, itching,
managed to taper his medication to the point of being throbbing, and tingling. Phantom pain is occasionally
pain-free without analgesia for 4 weeks. He reported a similar to preamputation pain (1).
phantom sensation but it was benign or painless and Many predisposing factors toward the develop-
did not impact his activities. ment of phantom pain have been studied. Possible pre-
dictors include preamputation pain and acute postop-
Pain description erative pain (9). In a group of patients with lower limb
he onset of pain began within days following the amputation due to peripheral vascular disease, the use
amputation. he pain was not constant but intermit- of passive coping strategies, especially catastrophiz-
tent. he sensation was most intense in the missing ing before amputation, was associated with phantom
foot, the patient describing it as electric-shock–like, pain (10).
stabbing, shooting, and sometimes throbbing and bor-
ing. Pain attacks could be provoked by pressure to the
stump, but also occurred spontaneously. In the acute
Phantom pain
phase, the patient rated the pain intensity as 10/10. Understanding of the pathophysiology of phantom
When he was irst treated with opioids, the intensity pain is still incomplete. Several studies demonstrate
decreased to 5/10 when the drugs achieved their max- neuroplastic changes in somatosensory and motor cor-
imum efect. tices following limb amputation (11, 12) [Figure 20.2].
A relationship between the reorganization in the sen-
sory cortex and the intensity of phantom pain has been
Discussion observed (11). Peripheral causes likely also contribute.
Phantom pain may occur in almost any body part Because amputees with chronic residual limb pain
but is most frequently reported ater limb ampu- have phantom pain more frequently, it has been sug- 85
tation. he reported incidence varies considerably gested that neuromas in the stump exhibit abnormal
A B C
Figure 20.2. Reorganization of the cortex related to phantom pain. (A) Functional MRI data during a lip pursing task. Activation in primary
somatosensory and motor cortices in amputees without pain (B) is similar to that of healthy controls (C). In patients with phantom limb pain
(A), the cortical representation of the mouth extends into the region of the hand and arm. Reproduced with permission from Oxford
University Press (33).
controlled analgesia, initiated 48 h pre-operatively and

continuing for 48 h postoperatively, was shown to
decrease phantom pain at 6 months in a study with 65
patients (14). Use of a prolonged postoperative peri-
neural infusion of ropivacaine 0.5% yielded a similar
efect at 1 year (15). Intense pre-emptive analgesia is
consequently recommended before amputation (16).
Once phantom pain occurs, pharmacological and
non-pharmacological treatment should be initiated.
Many case reports show some improvement with
TENS, but a recent meta-analysis could not iden-
tify high quality evidence of its eicacy (17). Cur-
Figure 20.3. Setup for mirror therapy used for a lower limb rently, mirror therapy is regarded as the most promis-
amputee. Reproduced with permission from Neurologist [1].
ing non-pharmacological therapy for phantom pain
(1). Patients see their intact limb relected in a mirror
activity, triggering the pain. Ramachandran and placed parasagittally between the arms or legs. hey
Hirstein propose at least ive diferent sources of phan- are instructed to move the intact limb and the phantom
tom pain: residual limb neuromas, cortical remapping, limb simultaneously (18)[Figure 20.1]. Patients have
corollary discharge, body image, and somatic memo- reported a relief of spasm-like phantom pain follow-
ries, thus linking phantom pain to both cortical and ing a single session (18). A small randomized, sham-
peripheral mechanisms (1). controlled, cross-over study conducted in lower limb
It has long been debated whether any preventive amputees conirmed a signiicant impact of mirror
treatment might be eicacious in phantom pain. A therapy (19).
systematic review published in 2010 could not ind Several drugs have been tested for their eicacy
robust evidence that pre-emptive analgesia minimized in relieving phantom limb pain. Positive results from
the risk of chronic pain ater amputation for critical randomized controlled trials are available for mor-
86 ischemia of peripheral vascular disease (13). Recently, phine, amitriptyline and other tricyclic antidepres-
optimized epidural analgesia or intravenous patient- sants (1). Deep brain stimulation (20) and spinal cord
Chapter 20: Phantom pain
stimulation have been used with success in case series vascular disease: a systematic review. Ann Vasc Surg
of otherwise refractory patients (21). 2010;24:1139–1146.
(14) Karanikolas M, Aretha D, Tsolakis I, et al. Optimized
References perioperative analgesia reduces chronic phantom
limb pain intensity, prevalence, and frequency: a
(1) Weeks SR, Anderson-Barnes VC, Tsao JW. Phantom prospective, randomized, clinical trial. Anesthesiology
limb pain: theories and therapies. Neurologist 2011;114:1144–1154.
2010;16:277–286.
(15) Borghi B, D’Addabbo M, White PF, et al. he use of
(2) Houghton AD, Nicholls G, Houghton AL, Saadah E, prolonged peripheral neural blockade ater lower
McColl L. Phantom pain: natural history and extremity amputation: the efect on symptoms
association with rehabilitation. Ann R Coll Surg Engl associated with phantom limb syndrome. Anesth
1994;76:22–25. Analg 2010;111:1308–1315.
(3) Jensen TS, Krebs B, Nielsen J, Rasmussen P. (16) Rathmell JP, Kehlet H. Do we have the tools to
Immediate and long-term phantom limb pain in prevent phantom limb pain? Anesthesiology
amputees: incidence, clinical characteristics and 2011;114:1021–1024.
relationship to pre-amputation limb pain. Pain
1985;21:267–278. (17) Mulvey MR, Bagnall AM, Johnson MI, Marchant PR.
Transcutaneous electrical nerve stimulation (TENS)
(4) Mishra S, Bhatnagar S, Gupta D, Diwedi A. Incidence for phantom pain and stump pain following
and management of phantom limb pain according to amputation in adults. Cochrane Database Syst Rev
World Health Organization analgesic ladder in 2010:CD007264.
amputees of malignant origin. Am J Hosp Palliat Care
2007;24:455–462. (18) Ramachandran VS, Altschuler EL. he use of visual
feedback, in particular mirror visual feedback, in
(5) Hunter JP, Katz J, Davis KD. Stability of phantom restoring brain function. Brain 2009;132:1693–1710.
limb phenomena ater upper limb amputation: a
longitudinal study. Neuroscience 2008;156:939–949. (19) Chan BL, Witt R, Charrow AP, et al. Mirror therapy
for phantom limb pain. N Engl J Med 2007;357:
(6) Bosmans JC, Geertzen JH, Post WJ, van der Schans 2206–2207.
CP, Dijkstra PU. Factors associated with phantom
limb pain: a 31/2-year prospective study. Clin Rehabil (20) Bittar RG, Otero S, Carter H, Aziz TZ. Deep brain
2010;24:444–453. stimulation for phantom limb pain. J Clin Neurosci
2005;12:399–404.
(7) Nikolajsen L, Jensen TS. Phantom limb pain.
Br J Anaesth 2001;87:107–116. (21) Viswanathan A, Phan PC, Burton AW. Use of spinal
cord stimulation in the treatment of phantom limb
(8) Schley MT, Wilms P, Toepfner S, et al. Painful and pain: case series and review of the literature. Pain
nonpainful phantom and stump sensations in acute Pract 2010;10:479–484.
traumatic amputees. J Trauma 2008;65:858–864.
(22) Ewalt JR, Randall GC, Morris H. he phantom limb.
(9) Hanley MA, Jensen MP, Smith DG, Ehde DM, Psychosom Med 1947;9:118–123.
Edwards WT, Robinson LR. Preamputation pain and
acute pain predict chronic pain ater lower extremity (23) Henderson WR, Smyth GE. Phantom limbs. J Neurol
amputation. J Pain 2007;8:102–109. Neurosurg Psychiatry 1948;11:88–112.
(10) Richardson C, Glenn S, Horgan M, Nurmikko T. A (24) Abramson AS, Feibel A. he phantom phenomenon:
prospective study of factors associated with the its use and disuse. Bull N Y Acad Med 1981;57:99–112.
presence of phantom limb pain six months ater (25) Sherman RA, Sherman CJ. Prevalence and
major lower limb amputation in patients with characteristics of chronic phantom limb pain among
peripheral vascular disease. J Pain 2007;8:793– American veterans. Results of a trial survey. Am J
801. Phys Med 1983;62:227–238.
(11) Flor H, Nikolajsen L, Staehelin Jensen T. Phantom (26) Sherman RA, Sherman CJ, Parker L. Chronic
limb pain: a case of maladaptive CNS plasticity? Nat phantom and stump pain among American veterans:
Rev Neurosci 2006;7:873–881. results of a survey. Pain 1984;18:83–95.
(12) MacIver K, Lloyd DM, Kelly S, Roberts N, Nurmikko (27) Pohjolainen T. A clinical evaluation of stumps in
T. Phantom limb pain, cortical reorganization and lower limb amputees. Prosthet Orthot Int 1991;15:
the therapeutic efect of mental imagery. Brain 178–184.
2008;131:2181–2191. (28) Wartan SW, Hamann W, Wedley JR, McColl I.
(13) Ypsilantis E, Tang TY. Pre-emptive analgesia for Phantom pain and sensation among British veteran 87
chronic limb pain ater amputation for peripheral amputees. Br J Anaesth 1997;78:652–659.
(29) Kooijman CM, Dijkstra PU, Geertzen JH, Elzinga A, prosthesis center in Iran. J Orthop Trauma
van der Schans CP. Phantom pain and phantom 2009;23:525–530.
sensations in upper limb amputees: an (32) Kern U, Busch V, Rockland M, Kohl M, Birklein F.
epidemiological study. Pain 2000;87:33–41. [Prevalence and risk factors of phantom limb pain
(30) Ephraim PL, Wegener ST, MacKenzie EJ, Dillingham and phantom limb sensations in Germany. A
TR, Pezzin LE. Phantom pain, residual limb pain, and nationwide ield survey]. Schmerz 2009;23:479–
back pain in amputees: results of a national survey. 488.
Arch Phys Med Rehabil 2005;86:1910–1919. (33) Lotze M, Flor H, Grodd W, Larbig W, Birbaumer N.
(31) Taghipour H, Moharamzad Y, Mai AR, et al. Quality Phantom movements and pain. An fMRI study in
of life among veterans with war-related unilateral upper limb amputees. Brain 2001;124:2268–
lower extremity amputation: a long-term survey in a 2277.
88
Section E CNS disorders
Chapter
Pain in Parkinson’s disease
21
Patients with Parkinson’s disease (PD) predominantly scan of the brain showed mild periventricular white
sufer from motor disturbances. hese patients how- matter lesions, compatible with a history of arterial
ever, may also be alicted with several non-motor hypertension, but no other abnormalities. A spinal
symptoms, including pain. he non-motor symptoms MRI scan conirmed no new indings when compared
are common, occur in all stages of PD, and are prob- with a scan taken the previous year. A neurophysi-
ably under-reported and under-treated (1). Because ological examination was performed. Somatosensory
pain is a key determinant of quality of life, pain in evoked potentials with stimulation of the tibial nerve
PD should be recognized, appropriately classiied, and were normal, excluding major conduction failure of
treated. the spinal cord. Nerve conduction studies of the sural
and tibial nerves on both sides showed mild reduc-
tions in amplitudes and normal conduction velocities.
Clinical case vignette A peripheral neuropathy was diagnosed and labora-
A 59-year-old male schoolteacher with a history of tory tests to clarify the etiology of the neuropathy were
arterial hypertension presented with pain in his right ordered. Serum chemistry, complete blood count, ery-
leg which had started 3 years ago. he pain was located throcyte sedimentation rate, serum vitamin B12 con-
in the right thigh, and from there it radiated down centration, serum protein electrophoresis, antinuclear
to the lower leg and also up to the lumbar spinal antibodies, and a glucose tolerance test were all nor-
region. he pain was constant and was aggravated by mal. A diagnosis of “asymmetric idiopathic painful
standing for several hours or ater vigorous walking. peripheral neuropathy” was made. Because the clini-
he patient felt increasingly challenged, because as a cal and electrophysiological indings were only mildly
schoolteacher, he spent most of his time standing in abnormal, the neurologist opted against more invasive
front of his class. His general practitioner irst referred tests (i.e., lumbar puncture and sural nerve biopsy) and
him to an orthopedic surgeon who ordered an MRI prescribed symptomatic treatment with pregabalin
scan of the lumbar spinal cord. Spondylosis of sev- 75 mg bid. he patient experienced some relief, down-
eral lumbar segments was diagnosed. A non-steroidal grading his pain intensity from 5 to 3 on a numeric
anti-inlammatory drug (NSAID) was prescribed and rating scale (NRS) of 0–10. He remained satisied with
the patient was administered several courses of phys- this regimen until 6 months later when his ambula-
ical therapy. he therapist emphasized strengthening tion was further impaired by a feeling of stifness in the
of the spinal muscles and for a time, the patient expe- right leg. He started using a walking stick and sensed
rienced some pain relief. When the pain recurred, the that he was dragging his right leg. here were occa-
patient consulted a second orthopedic surgeon who sional falls due to tripping over the right foot. When
performed anesthetic blocks of several lumbar roots the patient consulted the neurologist again, a rigid–
with lidocaine. he patient observed no efect and the akinetic syndrome involving the right side of the body
pain intensiied. Approximately 1 year ater the onset was noted on examination. His handwriting displayed
of the pain, the patient additionally observed some micrography. When walking, he displayed a slightly
numbness in the right leg. He was referred to a neu- stooped posture, short shuling steps, and a reduced
rologist who considered the diferential diagnoses of arm swing on the right. Upon passive movement of
let hemisphere lesion of the brain such as a stroke or the arms, mild rigidity accentuated on the right side
tumor, of a lumbar radicular lesion, and of polyneu- was evident. A diagnosis of Parkinson’s disease (PD)
ropathy of the mononeuritis multiplex type. An MRI was made, and the patient received a combination of
89
Section E: CNS disorders
levodopa/benserazide and a dopamine agonist. When example, central pain is regarded as a direct con-
the patient was seen again 4 weeks later, the motor sequence of the neurotransmitter disequilibrium of
symptoms had markedly improved and the leg pain PD. Dyskinesia-related pain is also regarded as direct
had diminished in intensity to 2/10. PD-associated pain. In contrast, a musculoskeletal
problem due to poor posture is classiied as sec-
ondary. Orofacial pain, caused by bruxism, is consid-
Discussion ered secondary, but because of its potential response to
he recent attention to non-motor symptoms in PD dopaminergic treatment it may also be directly linked
(1, 2) is attributable to two factors. Together, motor and to PD.
non-motor symptoms signiicantly impact quality of
life and must be addressed (3). Non-motor symptoms
in isolation may also be indicative of a presymptomatic Pain in Parkinson’s disease
or pre-motor stage in PD. Reduction in the sense of Dopamine can modulate pain at several levels within
smell, rapid eye movement disorder, constipation, and the nervous system, including the spinal cord, thala-
depression are recognized pre-motor symptoms while mus, periaqueductal grey area, basal ganglia, and cin-
apathy, fatigue, and pain are considered possible pre- gulate cortex (1). he cortical–basal ganglia–thalamic
motor symptoms (2). circuit is involved in modulating the motor, emo-
Pain in PD may occur in the early stages of the dis- tional, autonomic, and cognitive responses to pain
ease. With other signs and symptoms yet subtle, the (7). Several indings point to abnormal pain pro-
presence of pain in isolation may be misleading and cessing in PD patients. For example, PD patients
result in a delayed diagnosis. In a report of a 65-year- with central pain had lower heat pain and laser pin-
old patient with arm pain for 2 years, PD was inally prick thresholds, higher laser-evoked potential (LEP)
diagnosed with the development of tremor in her right amplitudes, and less habituation of sympathetic sudo-
leg (4). Yet another case presented in the literature motor responses to repetitive pain stimuli than PD
involved a patient who presented with leg pain, as in patients without pain and control subjects. Further-
this vignette. Securing a diagnosis was further compli- more, these responses were signiicantly attenuated
cated by the young age of the patient (5). A inal con- ater the administration of levodopa (8). A possible
sideration is that PD tends to impact the upper limbs explanation for this occurrence is the dysfunction of
irst, and a presentation with lower limb symptoms dopamine-dependent autonomic centers which regu-
may be unexpected, resulting in inappropriate diag- late autonomic function and inhibitory control of pain.
nostic procedures. Other studies found lower thresholds to heat pain on
Non-motor symptoms may be present throughout the involved side of PD patients (9).
the course of PD, and pain is a major component of In one study involving six patients with noctur-
the non-motor symptom complex. In three prevalence nal pain and restless legs syndrome, there was marked
studies, pain was present in 21 to 46% of PD patients improvement of pain ater overnight apomorphine
(2). he results of a French cross-sectional study found infusion (10). Also, the use of deep brain stimulation
prevalence as high as 62% (6); pain had an average of the subthalamic nucleus and bilateral pallidal stim-
60 mm of 100 mm on a visual analog scale, twice that ulation improved pain during levodopa of-periods
of control patients. (11, 12). Finally, patients given subthalamic stimula-
Pain in PD is classiied according to six distinct cat- tion believed that their pain had subsided even if other
egories: 1. a musculoskeletal problem related to poor types of pain, mostly musculoskeletal, were induced by
posture, awkward mechanical function, or physical the treatment itself (13).
wear and tear; 2. PD-related central or visceral pain; 3. Imaging studies also support the concept of abnor-
pain due to luctuations (dyskinesia and dystonia pain, mal pain processing in this disease. PD patients in the
pain in of-periods); 4. nocturnal pain (linked to rest- of state had increased pain-induced cortical activa-
less legs, to nocturnal akinesia); 5. orofacial pain; 6. tion in a PET study; conversely, cortical activation was
peripheral limb pain due to edema or limb pain that reduced during the on state (14). Of interest, this was
is drug-induced (2). not altered by apomorphine, a strong stimulator of the
90 Direct PD-associated pain and secondary pain due dopaminergic system (15). Manipulations of the pal-
to the sequelae of PD are also diferentiated (1). For lidum, either surgically or by electrical stimulation,
Chapter 21: Pain in Parkinson’s disease
have alleviated pain in PD patients, indicating a role of (5) Sekef-Sallem FA, Barbosa ER. Diagnostic pitfalls in
this structure in pain modulation (7). Muscular pain Parkinson’s disease: case report. Arq Neuropsiquiatr
is also thought to involve central as well as peripheral 2007;65:348–351.
mechanisms (16). Impulses from the peripheral ner- (6) Negre-Pages L, Regragui W, Bouhassira D,
vous system may also be inluential. Skin biopsy analy- Grandjean H, Rascol O. Chronic pain in Parkinson’s
ses show loss of intraepidermal nerve ibers (17), and a disease: the cross-sectional French DoPaMiP survey.
Mov Disord 2008;23:1361–1369.
disproportionally high percentage of PD patients have
peripheral neuropathy; the use of levodopa is asso- (7) Ha AD, Jankovic J. Pain in Parkinson’s disease. Mov
Disord 2012;27:485–491.
ciated with polyneuropathy linked to B12 deiciency
(18, 19). (8) Schestatsky P, Kumru H, Valls-Sole J, et al.
Neurophysiologic study of central pain in patients
A signiicant association between pain and depres-
with Parkinson disease. Neurology 2007;69:
sion scores is evident in PD patients. his associa- 2162–2169.
tion, together with the inconstant response of pain
(9) Djaldetti R, Shifrin A, Rogowski Z, Sprecher E,
symptoms to dopaminergic drugs, gives credence to Melamed E, Yarnitsky D. Quantitative measurement
the concept that serotonin and norepinephrin, play a of pain sensation in patients with Parkinson disease.
role in pain in PD patients. Indeed, the selective sero- Neurology 2004;62:2171–2175.
tonin and norepinephrine reuptake inhibitor duloxe- (10) Reuter I, Ellis CM, Ray Chaudhuri K. Nocturnal
tine improved pain in a small study that examined PD subcutaneous apomorphine infusion in Parkinson’s
patients (20). disease and restless legs syndrome. Acta Neurol Scand
Most authors suggest a multidisciplinary approach 1999;100:163–167.
(7). Physical therapy is warranted to maintain mobility (11) Loher TJ, Burgunder JM, Weber S, Sommerhalder R,
and to prevent contractures. Conventional analgesics Krauss JK. Efect of chronic pallidal deep brain
like NSAIDs may provide some symptomatic relief if stimulation on of period dystonia and sensory
pain is due to comorbid rheumatologic and orthope- symptoms in advanced Parkinson’s disease. J Neurol
Neurosurg Psychiatry 2002;73:395–399.
dic complications. Dopaminergic treatment may help
to improve musculoskeletal pain by reducing akinesia (12) Witjas T, Kaphan E, Regis J, et al. Efects of chronic
subthalamic stimulation on nonmotor luctuations in
and rigidity. he efect of dopaminergic agents on pain
Parkinson’s disease. Mov Disord 2007;22:1729–
however, remains controversial because studies have 1734.
yielded conlicting results (7). An analgesic antidepres-
(13) Kim HJ, Jeon BS, Lee JY, Paek SH, Kim DG. he
sant may be prescribed as described above. Deep brain beneit of subthalamic deep brain stimulation on pain
stimulation of the subthalamic nucleus and globus pal- in Parkinson disease: a 2-year follow-up study.
lidus, as with dopaminergic therapy, appears to pro- Neurosurgery 2011;70:18–23.
vide some pain relief. his is conirmed by some stud- (14) Brefel-Courbon C, Payoux P, halamas C, et al. Efect
ies but not in others (13, 21, 22). of levodopa on pain threshold in Parkinson’s disease:
a clinical and positron emission tomography study.
References Mov Disord 2005;20:1557–1563.
(1) Chaudhuri KR, Schapira AH. Non-motor symptoms (15) Dellapina E, Gerdelat-Mas A, Ory-Magne F, et al.
of Parkinson’s disease: dopaminergic pathophysiology Apomorphine efect on pain threshold in Parkinson’s
and treatment. Lancet Neurol 2009;8:464–474. disease: a clinical and positron emission tomography
study. Mov Disord 2011;26:153–157.
(2) Chaudhuri KR, Odin P, Antonini A, Martinez-Martin
P. Parkinson’s disease: the non-motor issues. (16) Tinazzi M, Recchia S, Simonetto S, et al. Muscular
Parkinsonism Relat Disord 2011;17:717–723. pain in Parkinson’s disease and nociceptive
processing assessed with CO2 laser-evoked
(3) Martinez-Martin P, Rodriguez-Blazquez C, Kurtis
potentials. Mov Disord 2010;25:213–220.
MM, Chaudhuri KR. he impact of non-motor
symptoms on health-related quality of life of patients (17) Nolano M, Provitera V, Estraneo A, et al. Sensory
with Parkinson’s disease. Mov Disord 2011;26:399– deicit in Parkinson’s disease: evidence of a cutaneous
406. denervation. Brain 2008;131:1903–1911.
(4) Gilbert GJ. Biceps pain as the presenting symptom of (18) Rajabally YA, Martey J. Neuropathy in Parkinson
Parkinson disease: efective treatment with L-dopa. disease: Prevalence and determinants. Neurology
South Med J 2004;97:776–777. 2011;77:1947–1950. 91
(19) Toth C, Breithaupt K, Ge S, et al. Levodopa, (21) Kim HJ, Jeon BS, Paek SH. Efect of deep brain
methylmalonic acid, and neuropathy in idiopathic stimulation on pain in Parkinson disease. J Neurol Sci
Parkinson disease. Ann Neurol 2010;68:28–36. 2011;310:251–255.
(20) Djaldetti R, Yust-Katz S, Kolianov V, Melamed E, (22) Maruo T, Saitoh Y, Hosomi K, et al. Deep brain
Dabby R. he efect of duloxetine on primary pain stimulation of the subthalamic nucleus improves
symptoms in Parkinson disease. Clin Neuropharmacol temperature sensation in patients with Parkinson’s
2007;30:201–205. disease. Pain 2011;152:860–865.
92
Chapter
Pain associated with amyotrophic lateral
22 sclerosis (ALS)
Pain can be associated with neurological conditions By 2 years ater the onset of his neurological symp-
not normally linked to damage or disruption of spe- toms, the patient was anarthric, had developed more
ciic pain or sensory pathways. Whether these forms of extensive wasting, and had more severe weakness of
pain should be described as “neuropathic” is debatable, both his hands and legs. He had severe dysphagia with
yet they are prominent problems faced by patients. secondary weight loss and there was a fall in his vital
he loss of normal muscle control in a patient with capacity to 61% of the predicted value (112% 5 months
a motor disorder, such as progressive ALS, can gen- earlier). He declined a percutaneous gastroscopy tube
erate several forms of pain because of impaired limb for enteral feeding.
and spine architecture and the inability to move limbs Electrophysiological studies identiied low ampli-
promptly when they are poorly aligned. In conditions tude lower limb motor CMAPs without dispersion,
with disease of lower motor neurons, abnormal cramp block or conduction slowing. Sensory potentials were
discharges can also arise. normal. Needle electromyography identiied ibrilla-
tions and positive sharp waves in the following mus-
cles: let irst dorsal interosseous, let deltoid, let and
Clinical case vignette right tibialis anterior, let gastrocnemius, let vastus
A 54-year-old right-handed man developed slurring of medialis, right abductor pollicus brevis, C6 and L5
speech followed by diiculty swallowing and walking paraspinal muscles, and the tongue.
over a 1-year period. Dysphagia was noted for solids, Normal (negative) laboratory studies included:
liquids, and tablets. Although he had previously run up genetic analysis for SOD1 mutation, genetic analy-
to 10 km daily, his walking became slow and diicult sis for androgen receptor triplet (Kennedy’s disease),
and he could barely complete 2 km. He noted weakness complete blood count, ESR, electrolytes, urea, crea-
and wasting of his calf muscles and generalized mus- tinine, calcium, aluminum, ferritin, iron, TIBC, lipid
cle twitching. He denied sensory, sphincter, or cogni- proile (borderline elevated cholesterol), TSH, B12,
tive problems. Hyperlipidemia, psoriasis, hepatitis as SPEP (serum protein electrophoresis), ALT, GGT, AST,
a child, and a benign neck lymph node biopsy were ANA, RF, glucose, urinalysis, HIV 1 and 2 serol-
features of his previous medical history. His medica- ogy, syphilis serology, AchR antibody, urinary cop-
tions included numerous vitamins and supplements, per excretion, ceruloplasmin, CT chest, abdomen and
long-acting niacin for hyperlipidemia, and aspirin. His pelvis, MR brain, thoracic spine, and lumbar spine.
father had died of ALS at age 61. Creatine kinase was elevated at 833 (normal,
195
Neurological examination identiied dysarthria. U/L). MRI of C spine showed multilevel degenerative
He had tongue fasciculations but no deinite tongue changes with mild cervical spinal stenosis.
atrophy or weakness, and otherwise normal cranial
nerves. He had spasticity of his arms and legs, scattered
limb muscle fasciculations, and weakness of intrin- Pain description
sic hand muscles, ankle dorsilexors, and ankle plan- At 2 years following the onset of his ALS symptoms, the
tar lexors. here was atrophy in his hand muscles. patient noted painful cramps and spasms in his hands
He had brisk deep tendon relexes (+3/4) through- and forearms, sometimes related to position. He had
out, a jaw jerk, Hofman signs, and downgoing plantar experienced similar intermittent symptoms over the
responses. Sensory examination was normal. His gait past 2 years but they became more prominent later as 93
was slowed and spastic. He was prescribed riluzole. he developed severe weakness of his hands. Although
he also described fasciculations, he did not categorize

them as painful. Earlier in his course, he also described
painful tingling sensations radiating from his neck
down into his arms, a symptom suggestive of Lher-
mitte’s phenomenon. hese issues prompted his inves-
tigation with cervical spine MR imaging; the degener-
ative changes identiied however did not account for
the progressive weakness and atrophy involving all of
his limbs.
Discussion
his patient presented with classical symptoms and
signs of bulbar and limb amyotrophic lateral sclero-
sis (ALS). His irst symptoms were dysarthria and
dysphagia, then limb spasticity and weakness. Elec-
trophysiological studies conirmed widespread limb
(and tongue) denervation indicating lower motor neu-
ron dropout. Other investigations failed to identify
an alternative explanation for his severe, progressive
course. As his condition progressed, he developed new
symptoms that included pain and cramping in the Figure 22.1 Wasted shoulder girdle muscles in a patient (not the
hands. he pain did not have typical descriptive quali- patient in this vignette) with ALS. Note the loss of deltoid muscle on
the right and of the supraspinatus muscle on the left. Weakness of
ties of neuropathic pain because there was an absence axial muscles with loss of their normal supportive function may
of burning, tingling, or electrical sensations. Earlier contribute toward musculoskeletal pain in ALS patients.
shooting sensations of pain may have been due to con-
current cervical spinal degenerative disc disease.
their limbs from injury can account for pain. Falls may
be frequent in patients with footdrop or limb spasti-
Pain in ALS city from ALS. Spinal pain can be especially problem-
Although ALS primarily targets motor units, patients atic in patients that cannot adjust their position in beds
with this disorder can experience pain (1). As is appar- or wheelchairs. here may be denervation of truncal
ent from this case description, symptoms of pain in spinal muscles that maintain proper alignment of the
ALS typically difer from neuropathic pain symptoms neck and lower back [Figure 22.1]. Finally, spasticity
such as burning, electrical, tingling, prickling, and may be severe in patients with more upper motor neu-
hypersensitivity that are associated with disease of the ron involvement. Patients with primary lateral scle-
sensory system. Rather the patient noted cramping rosis, a cousin of ALS, can have very prominent and
and spasms. Diseased motor units in ALS develop painful spasticity.
spontaneous activity that accounts for both fascicu- he prevalence of pain in ALS has had limited
lations as well as painful cramping of major muscle attention. Chio et al. (2) reported pain in 56.9% of 160
groups. he molecular trigger for this activity is not patients, a higher prevalence than in controls (33.1%).
fully understood. he patients had ALS for a mean of 31 months and
Another important quality of pain experienced described their pain as largely involving the extrem-
by patients with ALS is an exaggeration of pre-ALS ities. here were no signiicant diferences in the fre-
musculoskeletal damage. his patient also presented quency of pain in relationship with the type of ALS
with a pre-existing cervical spondylosis and as early onset. Pain increased in frequency and intensity with
muscle weakness developed, he developed radicular- progression of the disease and interfered with activ-
like shooting discomfort. Patients with paralysis from ities of daily living. In a separate study, 19% of ALS
ALS have diiculty moving limbs that are placed in patients rated pain as 4 or greater on a six-point scale.
94 awkward and uncomfortable positions. Because most Pain correlated with feelings of hopelessness, sufering,
patients have intact sensation, their failure to protect and depression (3).
Chapter 22: Pain associated with amyotrophic lateral sclerosis (ALS)
Treatment of pain from ALS may include sim- References

ple measures such as repositioning, appropriate (1) Wicks P. Reassessing received wisdom in ALS–pain is
padding, and physiotherapy of impaired limbs. common when studied systematically. Eur J Neurol
Patients may require neck support, particularly 2012;19:531–532.
when in a wheelchair. Cramps may be treated with (2) Chiò A, Canosa A, Gallo S, et al. Pain in amyotrophic
levetiracetam, physiotherapy, physical exercise, or lateral sclerosis: a population-based controlled study.
hydrotherapy (see the recent EFNS guideline on the Eur J Neurol 2012;19:551–555.
clinical management of ALS (4)). Painful spasticity (3) Ganzini L, Johnston WS, Hofman WF. Correlates of
may be treated with baclofen, dantrolene, tizanidine, sufering in amyotrophic lateral sclerosis. Neurology
or botulinum toxin injections. Simple analgesics or 1999;52:1434–1440.
low-dose opioid preparations may be used in ALS (4) Andersen PM, Abrahams S, Borasio GD, et al. EFNS
patients, although respiratory depression and consti- guidelines on the Clinical Management of
pation are diicult side-efects in advanced disease. Amyotrophic Lateral Sclerosis (MALS) – revised
he author has noted some anecdotal beneit from the report of an EFNS task force. Eur J Neurol
2012;19:360–375.
use of gabapentin or pregabalin.
95
Chapter
Pain in Brown-Séquard syndrome
23
Brown-Séquard syndrome is classically encountered
in acute traumatic spine injuries with hemisection
of the spinal cord. Rarely, it can also be encoun-
tered in cervical spondylosis. his vignette illus-
trates central pain of spinal origin in a patient with
cervical myelopathy and incomplete Brown-Séquard
syndrome.

A 61-year-old man with a history of cervical pain
attributed to spondylosis had an acute episode of pain
radiating into the right arm with numbness of the
3rd to 5th ingers. Spinal MRI conirmed degenerative
spondylosis without root compression. Cerebrospinal
luid analyzed ater lumbar tap, to exclude infectious
radiculitis, was normal. Ater symptomatic treatment
with NSAIDs and muscle relaxants over 5 days, the
symptoms resolved. During the week ater discharge
from hospital, the patient developed burning pain and
loss of temperature sense of the right half of his body. Figure 23.1. T2-weighted spinal MRI of the patient. A left
He noticed the loss of temperature sensation when the ventrolateral lesion is visible at the level of C3 (oval). The inset shows
the lesion at the horizontal plane (arrow). Courtesy of Prof. Solymosi,
use of heat pads for pain relief resulted in burns to the Department of Neuroradiology, University Hospital of Würzburg.
skin. he face and neck were not involved. he patient
was readmitted to hospital. On examination, a mild
central hemiparesis on the let, reduction of vibration drome was present on examination. Very mild hemi-
and position sense on the let, and loss of pain and tem- paresis on the let was manifested by reduced strength
perature sense on the right were observed below C3. A of inger extension and abnormal one-legged hopping.
second spinal MRI conirmed a lesion at the level of Sensory indings were as described above, and the
C3 on T2-weighted images with a ventrolateral accen- dissociation of sensory modalities was conirmed by
tuation [Figure 23.1]. Cerebrospinal luid was again quantitative sensory testing [Figure 23.2]. he patient’s
normal, and spinal ischemia, possibly related to spinal pain drawing is shown in Figure 23.3. Neurophysio-
stenosis, was diagnosed. he patient was started on logical studies revealed pathological magnetic evoked
secondary prevention of ischemic events with ASA 100 potentials recorded from the right lower leg, but nor-
mg, and gabapentin, 600 mg tid, was administered for mal somatosensory evoked potentials when stimu-
central pain. his led to a moderate reduction of the lating the tibial nerve. he lesion on T2-weighted
pain for the irst 6 weeks although the efect abated MRI was smaller in size than previously assessed. he
from this time onward. One year later, the patient’s gabapentin was changed to pregabalin 150 mg tid,
96 symptoms still had not improved and he was seen for which reduced the pain intensity to 3/10 with luctu-
a second opinion. An incomplete Brown-Séquard syn- ations.
Chapter 23: Pain in Brown-Séquard syndrome
Discussion
Brown-Séquard syndrome was irst described
in 1850 by the neurologist Dr. Charles Edouard
Brown-Séquard. Brown-Séquard syndrome is deined
as an ipsilateral loss of motor function and propri-
oception combined with contralateral loss of pain
and temperature sensation due to spinothalamic tract
dysfunction. he clinical picture relects hemisection
or hemicompression of the spinal cord with ipsilateral
loss of function of the tracts crossing above the lesion
Figure 23.2. Quantitative sensory testing of the dorsal foot
revealed increased temperature perception thresholds and loss of (corticospinal tract, dorsal column), contralateral
pain perception (red circles) at the contralateral side and an loss of function of the tract axons crossing below
ipsilateral increase in tactile detection thresholds (blue circle) the level (spinothalamic tract), and only mild loss of
compared with controls (black line). Calculation according to (7).
CDT: cold detection threshold; WDT: warm detection threshold; TSL: function of such qualities that are represented in more
thermal sensory limen (ability to detect temperature differences); than one tract, like epicritic sensation (dorsal column
CPT: cold pain threshold; HPT: heat pain threshold; MDT; mechanical and spinothalamic tract). Herniated cervical discs or
pain detection threshold; MPT: mechanical pain threshold; MPS:
mechanical pain sensitivity; WUR: wind-up ratio of ten painful cervical spinal stenosis may also cause Brown-Séquard
stimuli; VDT: vibration detection threshold; PPT: pressure pain syndrome (1, 2). Pain may be part of this syndrome
threshold. but is rarely described in detail. Pain as occurs in
Brown-Séquard syndrome is comparable to other
forms of spinal cord damage.
Pain in spinal cord injury

Central neuropathic pain is a well-known sequel of
spinal cord injury. In a follow-up study of 100 patients,
pain was present in 64% at 6 months ater the injury,
and 21% of these described it as severe (3). In spinal
cord injury, pain has been well studied and described
in several publications (for review see Siddall and
Finnerup (4)), in contrast to Brown-Séquard syn-
drome. Patients with spinal cord injury pain sufer
from various types of pain including musculoskeletal,
at the injured cord level, and pain below the injured
cord level. Aspects of “below level” pain are most
related to the case described above. Patients describe
Fig. 23.3. Pain drawing as depicted by the patient. Note sparing of a constant throbbing, burning, and stabbing pain that
face and upper cervical segments.
is difusely located caudal to the level of the injury. he
pain may be associated with hyperalgesia.
he pathophysiology of pain caused by a spinal
cord lesion is assumed to include neuronal hyper-
Pain description excitability, reduced inhibition, and neuronal reorgan-
he patient’s pain was described as burning with a ization or plasticity. Increased neuronal excitability
maximal intensity of 8/10 and a mean intensity of 5/10. may be the consequence of the dramatic increase in
he patient could not identify aggravating factors, but excitatory amino acids resulting from a major lesion
there were spontaneous luctuations. Warming allevi- of nervous structures. In addition, there is activation
ated the pain but had to be used with care because of glial cells, which in turn release pro-inlammatory
of the risk of burns. he patient admitted to suicidal cytokines and chemokines that act on neurons (5). An
ideation when the pain was intense. Standard anal- important mechanism is the probable loss of descend- 97
gesics had no efect. ing and local inhibition. Damage to the ascending and
descending pathways in the spinal cord results in dis- the literature. Spine (Phila Pa 1976) 2008;33:
ruption of local inhibitory interneurons and loss or E279–E282.
decreased inluence of supraspinal and propriospinal (3) Siddall PJ, McClelland JM, Rutkowski SB, Cousins
inhibitory pathways. Recently, spinal and supraspinal MJ. A longitudinal study of the prevalence and
reorganization have been linked to spinal cord injury characteristics of pain in the irst 5 years following
pain. For example, difusion tensor imaging showed spinal cord injury. Pain 2003;103:249–257.
anatomical changes in pain-related regions as well (4) Siddall PJ, Finnerup NB. Chapter 46 Pain following
as regions of the classic reward circuitry, speciically spinal cord injury. Handb Clin Neurol 2006;81:689–
703.
the nucleus accumbens and orbitofrontal, dorsolateral
prefrontal, and posterior parietal cortex (6). (5) McMahon SB, Malcangio M. Current challenges in
glia-pain biology. Neuron 2009;64:46–54.
(6) Gustin SM, Wrigley PJ, Siddall PJ, Henderson LA.
References Brain anatomy changes associated with persistent
(1) Sani S, Boco T, Deutsch H. Cervical stenosis neuropathic pain following spinal cord injury. Cereb
presenting with acute Brown-Sequard syndrome: case Cortex 2010;20:1409–1419.
report. Spine (Phila Pa 1976) 2005;30:E481–E483.
(7) Rolke R, Baron R, Maier C, et al. Quantitative sensory
(2) Sayer FT, Vitali AM, Low HL, Paquette S, Honey CR. testing in the German Research Network on
Brown-Sequard syndrome produced by C3-C4 Neuropathic Pain (DFNS): standardized protocol and
cervical disc herniation: a case report and review of reference values. Pain 2006;123:231–243.
98
Chapter
Pain in syringomyelia
24
Syringomyelia is a disorder in which a cavity forms
within the spinal cord, leading to a speciic com-
bination of symptoms. Some authors use the term
syringomyelia exclusively for cavities outside of the
central canal, and hydromyelia for cavities that develop
from central canal dilatation lined with ependymal
cells. his chapter uses the term syringomyelia for both
conditions.

A 23-year-old male experienced a severe accident
while hiking in the mountains. He had polytrauma,
including a brain contusion and multiple bone frac-
tures. Hospitalized for several months, he recovered
well, leading a normal professional and private life
until the age of 70. He then presented with a 9-month
history of pain and paresthesiae in his right hand. Six
months prior, he had also noted weakness of the right
hand. His walking ability had declined. Having no pre-
vious impairments, he became exhausted ater 1 h of
walking at a normal pace. In particular, his let leg grew
tired and needed to be pulled along. He denied having
any relevant pain or weakness until 3 years prior when
Figure 24.1. Sketch depicting patient’s sensory loss.
he noticed mild, intermittent pain and paresthesiae in
the let lower arm, including the entire hand.
On examination, the patient was fully conscious
and cooperative. His gait was ataxic and tandem gait let side. Laboratory tests were unremarkable. EMG
was not possible. One-legged hopping was normal studies revealed ibrillations from the let irst dorsal
on the right, but impaired on the let. here was interosseus muscle, mild prolongation of somatosen-
mild muscle atrophy of the let arm and leg muscles, sory evoked potentials from the tibial nerve, and
more pronounced than on the right. He had bilateral normal motor and sensory nerve conduction studies
weakness and wasting of the intrinsic hand muscles. of the ulnar and median nerves on both sides. Ampli-
Tendon jerks were present and brisker on the let. tudes of magnetic evoked potentials were reduced
he Babinski sign was present bilaterally. Sensory ater let cortical stimulation, with normal latencies.
testing revealed loss of sensation for touch, pinprick, Spinal MRI showed an extensive cavity in the upper
and loss of temperature sense on the let below the spinal cord that ranged from the 2nd cervical to the
level of T4 and reduced pain and temperature of the 2nd thoracic vertebral body [Figure 24.2]. Finally,
right arm [Figure 24.1]. here was loss of vibration degenerative spondylosis with segmental spinal 99
perception at the right malleolus but normal on the stenosis accentuated at C3/4 to C4/5 was identiied.
Figure 24.2. T2-weighted spinal MRI of the patient: (left and middle) sagittal, (right, upper and lower) axial reconstruction. Note the
extended syrinx, spanning over more than seven segments (a). At its widest diameter at the level of Th 1/2, the syrinx has more than doubled
the diameter of the cord and the remaining myelin is compressed. Courtesy of Prof. Solymosi, Department of Neuroradiology, University
Hospital of Würzburg.
he patient consulted with a neurosurgeon but are also cases of syringomyelia in the lumbar region.
decided against surgical intervention. Pain treatment Most cases of syringomyelia are associated with devel-
was initiated with pregabalin, which provided beneit. opmental disorders, usually a Chiari I malformation.
Acquired syringomyelia is thought to be caused by sev-
Pain description eral factors. Trauma is likely the most common, the
syrinx is then situated above the level of the spinal
he patient described his pain in the right arm as
injury. A CSF leak ater brachial plexus avulsion has
alternating in quality: burning, aching, and pressing.
also been described as a causative factor (2). Others
He had intermittent electric-shock–like pain radiating
include spinal arachnoiditis and spinal or infratento-
into the right hand. Allodynia was absent although the
rial tumors.
patient reported a tingling sensation that was essen-
Pain, segmental dissociated sensory loss, and
tially continuous (paresthesiae) in the right arm. Gen-
atrophic paresis, generally of the hands, are typi-
erally, the pain in the let arm was milder, intermittent,
cal clinical symptoms. he onset is usually insidi-
and although present for several years, it had not moti-
ous in both developmental and acquired cases. he
vated the patient to see a doctor. In addition to spon-
quality and distribution of symptoms and signs are
taneous luctuations, there were also changes in pain
determined by the centromedullary localization of the
intensity evoked by certain factors. Coughing, strain-
lesion. his localization interrupts incoming lateral
ing, bodily exertion, as well as psychological stress
spinothalamic crossing tract ibers causing impair-
aggravated his symptoms.
ment of pain and temperature sensation bilaterally
or ipsilateral to the paracentral extension of the
Discussion syrinx (3) and thus leads to “dissociated” sensory loss.
he term syringomyelia is ascribed to d’Angers in 1824 “Dissociated” refers to the selective involvement of
(1). he cystic cavity is typically found in the cervi- pain and temperature sensibility with sparing of light
100 cal spinal cord; if it extends upward into the medulla touch, position, and vibration sensation. Quantita-
oblongata, the condition is called syringobulbia. here tive sensory testing can aid in the diagnosis through
Chapter 24: Pain in syringomyelia
detection of increased warm and cold thresholds and deformity, and stenosis. CSF low in post-traumatic
to a lesser degree, increased pain thresholds (4). syringomyelia patients may be turbulent, and inlu-
Because the cervical cord is the most common local- enced by a locally tethered cord and blockage of the
ization, the ulnar border of the hand and forearm subarachnoid space by arachnoid scarring (7).
are oten initially afected by dissociated sensory loss.
In syringobulbia, the area may extend to the upper
arm, the upper part of the chest and back and the Pain in syringomyelia
face. he distribution may be uni- or bilateral. If the Pain is a major complaint in a signiicant propor-
syrinx extends and involves the dorsal root entry zone, tion of syringomyelia patients and is likely due to dis-
all sensory qualities are involved. Additional involve- ordered neuronal processing in the damaged dorsal
ment may include anterior spinothalamic tracts, pos- horn. Symptomatic syringomyelia is reported in only
terior columns, or corticospinal tracts. Loss of pro- 1–9% of patients with spinal injury. Approximately
prioceptive and tactile sensation may follow as well 50% of patients with traumatic, and most patients
as increased vibration detection thresholds. Extension with developmental syringomyelia sufer from pain.
of the syrinx to the ventral horn induces wasting and he pain quality in syringomyelia has been variously
weakness with fasciculations. he very large, irregu- described as dull, aching, or burning (7). Paroxysmal
lar syrinx of the patient described above explains the shooting pain may also be present. Diferent types
combination of these symptoms. hus, depending on of pain may coexist in one patient (4). he pain is
the localization of the syrinx, there can be combined oten perceived at or above the level of injury and may
upper and lower motor signs in the arms or in the legs. expand over time. Its intensity may be mild or severe.
here may be trophic changes in the hands including Constant or intermittent pain may occur. Coughing,
hyperkeratosis and edema. Horner’s syndrome is fre- sneezing, straining, or sitting can exacerbate the pain.
quently found (5). Syringobulbia may induce further Evoked pain is common, manifesting as allodynia or
cranial nerve symptoms including nystagmus, palatal hyperalgesia (9). Some patients report persistent pain
weakness, and tongue atrophy with fasciculations (6). ater evoked pain, i.e., ater sensations or delayed sen-
Post-traumatic syringomyelia may manifest with sations. Tingling and pins-and-needles sensations may
symptoms in a time-frame anywhere from 3 months also occur, as well as numbness.
to 35 years ater the trauma. Consequently, patients Neuropathic arthropathy of the shoulder is another
with a late motor and sensory deterioration or a pain syndrome associated with post-traumatic
newly developed pain syndrome ater spinal cord syringomyelia (10). Neuropathic arthropathy is seen
injury should be evaluated for the presence of a post- in 25% of patients with syringomyelia and occurs at
traumatic syrinx. Typically, the patients develop an the upper extremity in 80%. Patients present with
ascending sensory level, pain in the neck or arms, shoulder pain, swelling of the shoulder or elbow, and
muscle weakness, and later spasticity. Syringomyelia decreased range of motion. Active forward lexion
symptoms develop in 1 to 9% of patients ater and abduction are most impaired, passive movements
spinal injury. Radiologically deined syringomyelia, are painful. Loss of sensation in the shoulder area
in contrast, develops in up to 30% of spinal injury may be found. Diagnostic work-up includes radio-
patients within 30 years ater the injury (7). Traumatic graphs of the shoulder which may show osteolysis
syringomyelia is of the non-communicating variety of the humeral head and the glenoid process. he
without continuity to the fourth ventricle (3). he diagnosis of syringomyelia may be delayed if the
post-traumatic syrinx is usually localized next to the patient initially presents for orthopedic evaluation.
injury site and extends rostrally in 81%, caudally in 4%, he pathophysiology of neuropathic arthropathy
and in both directions in 15% of cases. It may extend is assumed to include trophic disturbances due to
for more than ten vertebral levels (7). lack of innervation and repetitive microtrauma
he pathogenesis of post-traumatic syringomyelia because of reduced or lost pain sensation. Treatment
is not entirely understood. Predisposing factors consists in treating the underlying syrinx. Surgical
include increasing age, uncorrected kyphosis, cervical manipulations at the shoulder alone may aggravate
and thoracic level displaced fractures, and spinal the situation, causing further deterioration (10). Pain
instrumentation without decompression (8). here is in syringomyelia is classiied as central neuropathic 101
an association with subarachnoid adhesions, spinal pain. he presence of thermal sensory deicits may
be linked to the disinhibition theory of pain (11) and imately 10% of the patients had surgical procedures
spinothalamic neurons are thought hyperexcitable. for progressively worsening neuropathic pain, their
Alternatively, the thermosensory disinhibition theory only symptom. In 47% of this group, surgery provided
proposes that central pain results from disruption pain relief and enhanced quality of life (17). Finally,
of the normal inhibition of the pathways mediating spinal cordectomy is a potential therapy for paraplegic
thermal sensation in the nociceptive system (12). patients with intractable symptoms. It ofers reduced
here is no simple direct relationship between the pain and improved quality of life in select patients (18).
magnitude of extent of sensory loss and the presence,
quality, or intensity of neuropathic pain (9). In a recent References
study where 37 patients with syringomyelia were (1) Nogues MA. Syringomyelia. In: Gilman, ed.
examined, the 27 patients with neuropathic pain were MedLink Neurology. San Diego: MedLink
indistinguishable from those without pain in quantita- Corporation.
tive sensory testing, laser-evoked and somatosensory- (2) Scholsem M, Scholtes F, Belachew S, Martin D.
evoked potentials, and three-dimensional MRI iber Acquired tonsillar herniation and syringomyelia ater
tracking analyses (13). Among patients with neuro- pleural efusion aspiration: case report. Neurosurgery
pathic pain, those with greater structural damage as 2008;62:E1172–E1173; discussion E1173.
assessed by MR fractional anisotropy, had higher aver- (3) Milhorat TH. Classiication of syringomyelia.
age daily pain intensity. his correlation was stronger Neurosurg Focus 2000;8:E1.
in patients with spontaneous pain than in patients with (4) Attal N, Bouhassira D. Pain in syringomyelia/bulbia.
both spontaneous and evoked pain. Patients with both Handb Clin Neurol 2006;81:705–713.
spontaneous and evoked pain had less structural spinal (5) Kerrison JB, Biousse V, Newman NJ. Isolated
cord damage and better preserved spinothalamic and Horner’s syndrome and syringomyelia. J Neurol
lemniscal tract function. Pathophysiological mecha- Neurosurg Psychiatry 2000;69:131–132.
nisms responsible for the various components of pain (6) Delpirou C, Heroum C, Blard JM, Pages M. [Acute
in syringomyelia are current topics of discussion (4). onset syringomyelia: two cases]. Rev Neurol (Paris)
hey also include supraspinal involvement. 2001;157:692–694.
Several surgical treatment options are available, (7) Brodbelt AR, Stoodley MA. Post-traumatic
including shunting of the syrinx to the subarachnoid syringomyelia: a review. J Clin Neurosci 2003;10:
space or to either the pleural or peritoneal cavities, 401–408.
spinal cord untethering with or without duraplasty, (8) Vannemreddy SS, Rowed DW, Bharatwal N.
and cordectomy. An expert panel recently agreed that Posttraumatic syringomyelia: predisposing factors.
a surgical intervention is indicated in the setting of Br J Neurosurg 2002;16:276–283.
motor deterioration, but could not ind suicient evi- (9) Ducreux D, Attal N, Parker F, Bouhassira D.
dence to recommend surgery in patients with asymp- Mechanisms of central neuropathic pain: a combined
psychophysical and fMRI study in syringomyelia.
tomatic syrinx or with sensory loss and pain as the Brain 2006;129:963–976.
only symptoms (14). here was no strong evidence to
(10) Atalar AC, Sungur M, Demirhan M, Ozger H.
support the superiority of one surgical technique over
Neuropathic arthropathy of the shoulder associated
the others, but some evidence appeared to conirm with syringomyelia: a report of six cases. Acta Orthop
that spinal cord untethering with expansile duraplasty Traumatol Turc 2010;44:328–336.
might be preferable. his method has not consistently (11) Boivie J, Leijon G, Johansson I. Central post-stroke
beneitted patients although shunting and reducing the pain–a study of the mechanisms through analyses of
cyst volume in a large post-traumatic syrinx would the sensory abnormalities. Pain 1989;37:173–185.
seem to be a logical approach (14, 15). Arachnoidol- (12) Craig AD, Chen K, Bandy D, Reiman EM.
ysis, i.e., surgical loosening of arachnoid adhesion at hermosensory activation of insular cortex. Nat
the level of injury, seems to provide some beneit. It Neurosci 2000;3:184–190.
aims to restore normal CSF low around the injured (13) Hatem SM, Attal N, Ducreux D, et al. Clinical,
segment. In a small series of patients, the procedure functional and structural determinants of central
led to reduction of cyst length in over 50% of cases as pain in syringomyelia. Brain 2010;133:3409–3422.
102 well as a decrease in pain (16). In a follow-up study that (14) Bonield CM, Levi AD, Arnold PM, Okonkwo DO.
included 362 patients 12 years ater surgery, approx- Surgical management of post-traumatic
Chapter 24: Pain in syringomyelia
syringomyelia. Spine (Phila Pa 1976) 2010;35:S245– (17) Falci SP, Indeck C, Lammertse DP. Posttraumatic
S258. spinal cord tethering and syringomyelia: surgical
(15) Attal N, Parker F, Tadie M, Aghakani N, Bouhassira treatment and long-term outcome. J Neurosurg Spine
D. Efects of surgery on the sensory deicits of 2009;11:445–460.
syringomyelia and predictors of outcome: a long term (18) Gautschi OP, Seule MA, Cadosch D, et al.
prospective study. J Neurol Neurosurg Psychiatry Health-related quality of life following spinal
2004;75:1025–1030. cordectomy for syringomyelia. Acta Neurochir (Wien)
(16) Aghakhani N, Baussart B, David P, et al. Surgical 2011;153:575–579.
treatment of posttraumatic syringomyelia.
Neurosurgery 2010;66:1120–1127; discussion 1127.
103
Chapter
Central pain with thalamic infarct
25
Although central pain can originate from diverse areas brisker on the right. Strength of inger adduction and
of the brain, lesions in the thalamus, in particular in its abduction of the right hand was slightly reduced (4+/5
ventroposterior part, are particularly associated with MRC grade). Grip strength with a medium-sized rub-
chronic pain. Among the patients with post-stroke ber bulb was 48 kPA on the let (normal) and 20 kPA
pain, approximately 60% have lesions in the thalamus on the right (reduced); otherwise motor power was
(1). he importance of the ventroposterior part of the normal. he inger–nose test was mildly dysmetric on
thalamus is illustrated in the vignette that follows. the right, and rapid alternating movements of the right
hand were slowed. Light touch of the palmar aspect of
the ingers on the right was perceived as uncomfortable
Clinical case vignette pins and needles (allodynia). he perception threshold
A 69-year-old right-handed woman presented with for von Frey hairs was 4 mg on the let index inger,
an 18-month history of pain in the right hand. She 28 mg on the right, indicating hypoesthesia. Moder-
described the pain as continuous with an intensity of ate pressure was perceived as extremely painful, indi-
7/10 and not aggravated by movement. he onset of cating hyperalgesia. Temperature and vibration sense
the pain had been acute, accompanied by slight weak- were normal, and sensation was normal in the rest of
ness of the right hand, and paresthesias of the right the body.
palm and the upper right lip. he patient had been he patient had seen several pain specialists and
investigated for carpal tunnel syndrome, and when various pharmaceutical treatment regimens had been
this was negative, a CT head scan was performed attempted. NSAIDs, lupirtine, and metamizole were
which revealed a let thalamic infarct [Figure 25.1]. without efect. Weak and strong opioids were used in
he patient had sufered from a right thalamic infarct low doses (e.g., oxycodone 10 mg), but were rapidly
5 years earlier. his older infarct was also evident on discontinued because of side-efects. Tricyclic anti-
the CT but the patient did not have residual deicits. A depressants yielded the same results. Gabapentin was
cardiac embolism likely was responsible for the lesions; given at a dose of up to 1200 mg and in combi-
the patient had received an aortic valve replacement 10 nation with desipramine. he patient only reported
years earlier and was on anticoagulation. Concomitant a maximal reduction of 1/10. Long-term side-efects
disorders included arterial hypertension, compensated included nausea, confusion, loss of appetite, constipa-
renal insuiciency, and relux esophagitis. In addition, headache, ankle edema, and itching. herapeutic
tion to previous neurological examinations, medical, anticoagulation levels were rendered unstable by the
orthopedic, and rheumatological examinations had above treatments.
been performed which yielded no alternative causes of At the time of consultation, the patient had dis-
pain. continued all pain medication and was asking for new
he patient described the pain in the right hand options. Pregabalin was started at a dose of 75 mg bid.
as deep and sore, like needles, but also numb. It was Because the patient experienced an unstable gait and
most intense on the palmar side of the irst four ingers. a sense of confusion, she discontinued the medica-
Touch was perceived as unpleasant. Passive and active tion ater 4 days. Physical therapy and cold water baths
movement did not inluence the pain. Cooling reduced for the right hand were also prescribed. hree months
the pain intensity which was 7/10 on most days. later, she reported a moderate pain reduction to 6/10.
Neurological examination revealed intact mental he neurological indings were unchanged except for
104 function and cranial nerves. Deep tendon relexes were an increase in grip strength to 30 kPa on the right.
Chapter 25: Central pain with thalamic infarct
Figure 25.1 (A) Original MRI scan of the

patient, showing a large thalamic infarct
on the right (arrow) and a small thalamic
infarct (arrowhead) on the left. Courtesy of
Prof. Solymosi, Department of
Neuroradiology, University Hospital of
Würzburg. (B) Schematic diagram of the
main thalamic nuclei (modified after
Schmahmann (2)). The patient’s infarcts are
shown as dark structures. Nuclei involved
in the patient’s strokes: MD: mediodorsal
nucleus; VPM: ventral posterior medial
nucleus; VPL: ventral posterior medial
lateral nucleus; a: anterior; p: posterior.
R L
VA VA
R MTT MTT R
VAmc VAmc
VLa VLa
VLp MD MD VLp
Infarct 2
VPLa VPLa
VPM VPM
Infarct 1 3rd
ventricle
VPLp VPLp
PLm PLm
LP LP
PII PII
B
Discussion and medial nuclei. Infarcts in this area may lead to the
classical features of thalamic syndrome that include
Two aspects of this case history are signiicant: 1. the sensory loss, impaired extremity movement and pain.
presence of bilateral thalamic infarcts, of which one led Eighteen months ater her stroke, our patient exhibited
to central pain; 2. the patient’s relative lack of response mild sensory loss and motor dysfunction but her pain
to pharmacological treatment. remained severe.
he patient’s irst infarct occurred in the para- he treatment of central neuropathic pain is dii-
median artery territory (2) [Figure 25.1Aa] which cult (3, 4). Randomized controlled trials are scarce, and
perfuses the posteromedial thalamus [Figure 25.1Bb]. although most give negative results, some progress has
hese lesions usually lead to decreased level of been made. Amitriptyline was of therapeutic beneit in
consciousness, neuropsychologial disturbances, and a small trial (5). Lamotrigine showed a modest efect
abnormalities of vertical gaze. he patient did not in one study (6). Success with gabapentin and prega-
remember any symptoms from the irst stroke, likely balin were reported in single case reports, but in a ran-
because of her decreased level of consciousness at the domized controlled trial pregabalin did not result in
time. he second stroke occurred in the territory of more pain reduction than placebo (7). Opioids, in par-
the inferolateral artery which supplies the ventrolat- ticular slow-release formulations like fentanyl patches, 105
eral thalamus including the ventral posterior lateral appear to beneit some patients (8). Given these limited
results, stimulation procedures and ablative surgery loss of normal inhibition of cold pain. In this hypothe-
have also been attempted. he latter had no efect on sis, there is an imbalance between a lateral spinothala-
chronic pain (9). Deep brain stimulation, in partic- mic tract involved in signaling the feeling of cold and
ular of the periventricular grey regions and of the a medial spinothalamic tract signaling pain (4). A dis-
motor cortex, successfully alleviated pain in individual turbance of GABAergic neurotransmission between
patients (10, 11). the sensory thalamus and sensory cortical areas has
Despite the high scores given on the NRS pain also been suggested (17).
rating scale out of 10, our patient’s distress was not
severe enough to justify such treatment. Simpler phys-
ical measures proved adequate. References
(1) Bowsher D, Leijon G, huomas KA. Central
poststroke pain: correlation of MRI with clinical pain
Central post-stroke pain characteristics and sensory abnormalities. Neurology
1998;51:1352–1358.
Chronic pain ater stroke has been described in up to
55% of patients, but most of this pain is central and not (2) Schmahmann JD. Vascular syndromes of the
directly linked to the cerebral ischemia (4). Pain ater thalamus. Stroke 2003;34:2264–2278.
stroke may be associated with pre-existing chronic (3) Boivie J. Central pain. In: McMahon SB, Koltzenburg
pain disorders. he most common chronic post-stroke M, eds. Textbook of Pain. Edinburgh: Churchill
Livingstone, 2006:1057–1074.
pain that is indirectly related to the stroke is shoul-
der pain, which occurs in 30–40% of patients with (4) Klit H, Finnerup NB, Jensen TS. Central post-stroke
pain: clinical characteristics, pathophysiology, and
stroke (4). It is related to sensory and motor deicits
management. Lancet Neurol 2009;8:857–868.
on the involved side, subluxation, and a limited range
(5) Leijon G, Boivie J. Central post-stroke pain–a
of movement.
controlled trial of amitriptyline and carbamazepine.
In a population-based study in Denmark, the Pain 1989;36:27–36.
prevalence of deinite or probable central post-stroke
(6) Vestergaard K, Andersen G, Gottrup H, Kristensen
pain was 7.3% (12). Pinprick hyperalgesia was present BT, Jensen TS. Lamotrigine for central poststroke
in 57%, cold allodynia in 40%, and brush-evoked pain: a randomized controlled trial. Neurology
dysesthesia in 51% of afected patients. 2001;56:184–190.
he thalamic syndrome was irst described by (7) Kim JS, Bashford G, Murphy TK, Martin A, Dror V,
Dejerine and Roussy (13). he onset of pain is usu- Cheung R. Safety and eicacy of pregabalin in
ally delayed (1–3 months ater the stoke), but can also patients with central post-stroke pain. Pain 2011;
be a sign of acute stroke (14) as in this patient where 152:1018–1023.
pain was among the acute symptoms. he hand is most (8) Eisenberg E, McNicol ED, Carr DB. Eicacy and
frequently alicted in thalamic pain. All pain quali- safety of opioid agonists in the treatment of
ties may be involved (1). here are no pathognomonic neuropathic pain of nonmalignant origin: systematic
features. Descriptors used for spontaneous pain are review and meta-analysis of randomized controlled
trials. JAMA 2005;293:3043–3052.
burning, aching, pricking, freezing, and squeezing;
intermittent pain is oten described as lancinating or (9) Tasker RR. History of lesioning for pain. Stereotact
Funct Neurosurg 2001;77:163–165.
shooting (4). Central pain resulting from posterior
parasylvian lesions has been suggested as a separate (10) Nandi D, Smith H, Owen S, Joint C, Stein J, Aziz T.
entity characterized by burning or aching pain with Peri-ventricular grey stimulation versus motor cortex
stimulation for post stroke neuropathic pain. J Clin
allodynia (15). Neurosci 2002;9:557–561.
he pathophysiology of central pain is contro-
(11) Yamamoto T, Katayama Y, Hirayama T, Tsubokawa
versial. Partial injury to the spinothalamic pathway
T. Pharmacological classiication of central
seems to involve a greater risk for central pain than post-stroke pain: comparison with the results of
complete injury (16). Mechanisms discussed have chronic motor cortex stimulation therapy. Pain
included abnormal hypersensitivity of central neurons 1997;72:5–12.
and ibers, alterations in impulse patterns, and activa- (12) Klit H, Finnerup NB, Andersen G, Jensen TS. Central
106 tion of silent synapses. he thermosensory disinhibi- poststroke pain: a population-based study. Pain
tion theory states that central post-stroke pain is due to 2011;152:818–824.
Chapter 25: Central pain with thalamic infarct
(13) Dejerine J, Roussy G. Le syndrome thalamique. Rev (16) Hong JH, Choi BY, Chang CH, et al. he prevalence
Neurol 1906;14:521–532. of central poststroke pain according to the integrity of
(14) Paciaroni M, Bogousslavsky J. Pure sensory the spino-thalamo-cortical pathway. Eur Neurol
syndromes in thalamic stroke. Eur Neurol 2012;67:12–17.
1998;39:211–217. (17) Canavero S, Bonicalzi V. Central pain syndrome:
(15) Garcia-Larrea L, Perchet C, Creac’h C, et al. elucidation of genesis and treatment. Expert Rev
Operculo-insular pain (parasylvian pain): a distinct Neurother 2007;7:1485–1497.
central pain syndrome. Brain 2010;133:2528–2539.
107
Chapter
Pain in multiple sclerosis
26
Whether pain is more frequent in patients with mul- continuous burning pain in both legs which was worse
tiple sclerosis (MS) than in the general population has at night. While she could cope with most of these
been debated. Independent of this question, it is worth symptoms, she regularly saw a neurologist for the pain
knowing the special characteristics of pain in MS and associated with her trigeminal neuralgia. When car-
the available treatment options. bamazepine appeared to lose its efect, treatment was
changed to lamotrigine, which was slowly increased to
100 mg bid. With her MS being conirmed as being sec-
Clinical case vignette ondary chronic progressive, the patient’s basic therapy
A 30-year-old female experienced her irst symptoms was changed to mitoxantrone at 3-monthly applica-
of MS when she noticed numbness of her palms. No tions. his was stopped ater three applications because
neurological diagnosis was made, but the patient of toxic cardiomyopathy. he trigeminal pain wors-
was found to sufer from bipolar afective disorder. ened again, and the patient was hardly able to speak,
Her history included one suicide attempt with the eat, or drink without provoking pain attacks. Lamo-
use of antidepressant drugs. Her family history was trigine was stopped and carbamazepine was initiated
positive for depression. Five years later, a diagnosis again, this time up to 1200 mg/day. his dose provided
of relapsing-remitting MS was conirmed when the some pain relief, but the patient sufered from severe
patient presented with hemiparesis on the right that fatigue and believed that her ataxia had become
improved while she received a course of corticosteroid even worse. She was referred to the Department of
treatment. Treatment with Interferon-ß1b was initi- Neurosurgery for evaluation. Cranial MRI showed
ated. She developed slowly progressive weakness and multiple MS lesions [Figure 26.1] although none
spasticity of both legs 2 years later and a secondary were speciic to the area of the trigeminal nucleus.
progressive disease course was diagnosed. In the same Vascular compression of the trigeminal nerve entry
year, the patient also reported an intermittent electric- zone into the pons was not detected. Despite this
shock–like pain in the let jaw. here were weeks when inding and supported by case reports in the literature
she experienced this pain with almost every movement (1), a trigeminovascular decompression (Jannetta
of the facial muscles, and other periods when she was operation) was performed. here were no periopera-
almost pain free. A diagnosis of trigeminal neuralgia tive complications. Immediately post-operatively the
was made, and carbamazepine, administered up to a patient reported that the pain attacks had stopped.
dose of 800 mg/day, provided some pain relief. Addi- While convalescing on the neurosurgical ward, no
tional MS symptoms developed in the next 2 years, further attacks occurred. Carbamazepine was slowly
including bladder disturbance and ataxia. he patient tapered to 150 mg bid over the next 2 months. While
underwent repeated pulse therapies with high-dose there were no further episodes of pain, the patient,
methylprednisolone, but these did not noticeably fearful of recurrence, did not wish to have the dose
improve her motor symptoms and had no efect on reduced any further.
the pain. Over time, the patient developed other Nine months later, she came to the Emergency
types of intermittent pain that could last for months, Department with complaints of increasing facial pain
followed by some degree of remission. One prominent attacks on the let. he pain attacks had changed in
complaint was Lhermitte’s sign which the patient did character. Still in the same location, they currently
not classify as painful but as very disturbing. She lasted up to 30 min in duration and produced a burn-
108 sometimes presented with back pain, headache, or a ing sensation. She reported that attempts to increase
Chapter 26: Pain in multiple sclerosis
Figure 26.1. (left) MRI scan at the height of the lateral ventricles showing multiple periventrical lesions (arrows), typical in MS. (right) Pontine
lesion (arrow), potentially responsible for trigeminal neuralgia in this patient. Courtesy of Prof. Solymosi, Department of Neuroradiology,
University Hospital of Würzburg.
the carbamazepine dose had aggravated her condition. or two branches of the trigeminal nerve are character-
Low-dose pregabalin was added to her drug therapy istic of trigeminal neuralgia. he attacks could be brief,
but this also increased her pain. She was very anxious lasting only for a few seconds, or they could persist for
and oten agitated. When asked about her pain level, up to 30 min in duration. Pain attacks were induced
she could not precisely describe it and believed that she by touching the skin, talking, eating, and brushing the
was more handicapped by the fear of pain than by the teeth. Ater the pain-free period following the Jannetta
pain itself. She requested further neurosurgical input operation, the quality of the pain changed. Attacks
but further intervention was declined. he patient sub- were no longer brief but generally lasted up to 30 min
sequently admitted herself to a psychiatric hospital and produced a burning sensation. hey were less
where she was stabilized and experienced reasonable dependent upon touch or facial movement and
health in the following months. When she reported appeared related to the patient’s emotional or psycho-
again to our outpatient department, she clearly stated logical state.
that the facial pain attacks were related to stress or anx- he other, less severe pains and dysesthesias the
iety and that her use of relaxation techniques was help- patient sufered from were Lhermitte’s sign, a tingling
ful. She had stopped all medication related to trigemi- feeling running down her spine when she bent her
nal neuralgia. She was able to walk with an ambulator head, and painful leg spasms that were dependent on
in her home and used a wheelchair out-of-doors. She the degree of spasticity at a certain time point. Fur-
still had intermittent painful spasms in her legs, Lher- thermore, she had a variable leg pain that sometimes
mitte’s sign on bending the head, and dysesthesias of manifested as a continuous burning pain, sometimes
the legs. hese symptoms annoyed her but she did not as dysesthesia with a tingling and mildly burning sen-
want any speciic treatment for them. sation.
Pain description Pain in multiple sclerosis

he patient’s original pain attacks of stabbing and he epidemiology and the characteristics of pain in 109
electric-shock–like character in the distribution of one patients with MS have been described in several large
cohorts. he resulting estimates of pain prevalence and peripheral neuropathic pain and psychiatric dis-
have ranged between 29 and 86% of MS patients. A ease is negative (6). he most common pain qualities
systematic review identiied a point prevalence of pain in a series of 100 patients with MS and central pain
of nearly 50% (2). he presence of pain was associ- were burning and aching. he most common central
ated with increased age, duration of illness, depres- neuropathic pain conditions in patients with MS are
sion, degree of functional impairment, and fatigue. extremity pain, trigeminal neuralgia, and Lhermitte’s
Pain reporting by MS patients may be similar to that sign. Extremity pain is usually chronic and described
reported by the general population but MS patients as a continuous burning pain which is oten bilateral,
are more likely to have severe pain, to use analgesics, worse at night, and exacerbated during physical activ-
or to sufer from interference with activities of daily ity. It is thought to derive from lesions in the spinal
living (3). Pain is associated with poorer quality of cord leading to dysfunction of inhibitory GABAergic
life in MS patients and most prominently afects phys- interneurons.
ical and emotional functioning (2). Older patients, Trigeminal neuralgia, with a prevalence of 1–2%, is
those with longer disease duration and greater dis- 20 times more common in MS patients than in the gen-
ease severity have a higher likelihood to sufer from eral population. his condition has also been labeled
pain. here seems to be no gender diference in the “atypical facial pain” associated with MS. MS patients,
prevalence of pain, but women report a greater sever- on average, are much younger than patients with clas-
ity. here is a higher risk of developing pain in chronic sical trigeminal neuralgia. Also, approximately 20%
progressive types than in relapsing-remitting MS (4). of cases with trigeminal neuralgia are bilateral in MS
Clinical data suggest that only patients with lesions patients, which is much more than in the general pop-
in the spinothalamo-cortical pathways run the risk of ulation. It may be the presenting symptom of MS (10).
developing central pain (5, 6). In contrast, localization Lesions at the trigeminal nerve entry zone are present
of the inlammatory/demyelinating lesions speciically in some patients, although similar lesions have been
within the pain pathway on MRI scans was not associ- reported in patients without trigeminal pain (11, 12).
ated with increased pain (7). Even lesions in the trigeminal root itself have been
In a cross-sectional study involving 1672 Italian described, but only in a few case series (13, 14). his
patients (4), the most frequent pain complaint was has also been conirmed in autopsy cases.
dysesthetic pain with 18%, followed by back pain, Lhermitte’s sign is caused by demyelinating lesions
painful spams, and Lhermitte’s sign. Trigeminal neur- in the posterior columns of the cervical spinal cord
algia occurred only in 2% of patients. In Portuguese (15), which lead to hypersensitivity of cervical sen-
MS patients, the prevalence of pain was 34%, with sory axons to stretching. In prospective studies, Lher-
headache and back pain being the most common sites mitte’s sign has been present at some point during the
(8). It has been hypothesized that, like in other chronic disease course in 40% of patients (2). Patients usually
pain, a biopsychosocial perspective should be taken in report that they can elicit the symptom by neck lex-
MS (9). In the patient cohort studied by these authors, ion and describe its character as electric-shock – like
pain was present in 82%. Interestingly, pain intensity or tingling. he duration is short, lasting only a few
correlated only with physical aspects, whereas qual- seconds. Lhermitte’ sign, once it appears, may remit
ity of pain was additionally associated with increased within 4–6 weeks but it may also recur or become
avoidance, resignation, and fatigue. chronic.
Patients with MS may sufer from several difer- Many MS patients sufer from spasticity, but this
ent types of pain, including central pain, extremity is not necessarily painful. Some patients have painful
pain, trigeminal neuralgia, Lhermitte’s sign, painful tonic spasms lasting a few minutes, which may occur
tonic spasms, back pain, and headache (2). he fol- several times per day. hey can be triggered by touch,
lowing classiication of pain in MS has been suggested: movement, or strong emotions. In the past, these
1. continuous central neuropathic pain, 2. intermit- spasms have also been called “brainstem seizures,” but
tent central neuropathic pain, 3. musculoskeletal pain, there are no data conirming the epileptic character of
4. mixed neuropathic and non-neuropathic pain (2). these spasms.
Central pain is assumed if the distribution of pain is he frequency of headache, in particular migraine,
110 consistent with a central nervous system lesion, and seems to be increased in MS patients. his has been
if a thorough evaluation for alternative nociceptive associated with lesions in the midbrain (16). Sec-
Chapter 26: Pain in multiple sclerosis
ondary musculoskeletal pain may also develop in MS or lamotrigine; there are insuicient data however to
patients, possibly due to weakness, muscle spasms, deinitely prove eicacy or the preference of one drug
spasticity, and reduced mobility. Secondary muscu- over another (19, 20). In summary, pain treatment
loskeletal pain can manifest in the form of back pain in MS remains an individual decision. he potential
or extremity pain. Chronic steroid use can cause osteo- side-efects of therapeutic regimes and their impact on
porosis with a risk of compression fractures. quality of life must be carefully weighed.
It is unclear whether disease-modifying treatment
improves the pain. Pain is not a primary outcome in References
most clinical trials involving MS. here are transient (1) Broggi G, Ferroli P, Franzini A, et al. Operative
increases of pain in the irst month of treatment with indings and outcomes of microvascular
interferon beta (17). Interferon beta and glatiramer decompression for trigeminal neuralgia in 35 patients
acetate treatment may be associated with an increased afected by multiple sclerosis. Neurosurgery
incidence of headaches, especially in patients with a 2004;55:830–838; discussion 838–839.
history of headaches (18). (2) O’Connor AB, Schwid SR, Herrmann DN, Markman
Few trials have explicitly tested the efects of drugs JD, Dworkin RH. Pain associated with multiple
to treat pain in MS (19). Of those, ive have tested sclerosis: systematic review and proposed
the efect of cannabinoids. he results of these tri- classiication. Pain 2008;137:96–111.
als suggest that cannabinoids may be efective in (3) Svendsen KB, Jensen TS, Overvad K, Hansen HJ,
some patients with MS pain, but conirmatory trials Koch-Henriksen N, Bach FW. Pain in patients with
multiple sclerosis: a population-based study. Arch
are needed. Furthermore, there are concerns about Neurol 2003;60:1089–1094.
the long-term safety of these drugs, including the
(4) Solaro C, Brichetto G, Amato MP, et al. he
risk of precipitating psychosis or schizophrenia, espe-
prevalence of pain in multiple sclerosis: a multicenter
cially in individuals with environmental or genetic risk cross-sectional study. Neurology 2004;63:919–921.
factors (2).
(5) Osterberg A, Boivie J. Central pain in multiple
Gabapentin has been suggested as irst-line treat- sclerosis – sensory abnormalities. Eur J Pain
ment for patients with spasticity-related pain because 2010;14:104–110.
of its good safety proile (20). Oral baclofen and (6) Osterberg A, Boivie J, huomas KA. Central pain in
cannabinoids are regarded as second-line drugs. multiple sclerosis – prevalence and clinical
Intrathecal baclofen can be used for patients with characteristics. Eur J Pain 2005;9:531–542.
severe spasticity resistant to oral drugs. In painful tonic (7) Svendsen KB, Sorensen L, Jensen TS, Hansen HJ,
spasms, gabapentin and pregabalin produced pain Bach FW. MRI of the central nervous system in MS
relief in open-label studies. Lamotrigine was efec- patients with and without pain. Eur J Pain 2011;
tive in improving pain in ive of eight patients with 15:395–401.
painful tonic spasms. Orally administered sodium (8) Seixas D, Sa MJ, Galhardo V, Guimaraes J, Lima D.
channel blockers such as carbamazepine are also rec- Pain in Portuguese patients with multiple sclerosis.
ommended. Trigeminal neuropathy can be treated Front Neurol 2011;2:20.
with carbamazepine, oxcarbazepine, or lamotrigine. (9) Michalski D, Liebig S, homae E, Hinz A, Bergh FT.
he response rate to sodium channel blockers seems Pain in patients with multiple sclerosis: a complex
to be lower than in classical trigeminal neuralgia. assessment including quantitative and qualitative
measurements provides for a disease-related
Gabapentin and topiramate may be alternatives. Miso-
biopsychosocial pain model. J Pain Res 2011;4:
prostol, a prostaglandin-E1-analog that targets the 219–225.
MS-related inlammatory mechanisms, was efective
(10) Hooge JP, Redekop WK. Trigeminal neuralgia in
in two small studies. Experts recommend treatment multiple sclerosis. Neurology 1995;45:1294–1296.
of MS-related trigeminal neuralgia along the guide-
(11) da Silva CJ, da Rocha AJ, Mendes MF, et al.
lines for classical trigeminal neuralgia (19–21). Lher-
Trigeminal involvement in multiple sclerosis:
mitte’s sign is not oten speciically treated. Should magnetic resonance imaging indings with clinical
treatment be required, orally administered sodium- correlation in a series of patients. Mult Scler
channel blockers such as carbamazepine or oxcar- 2005;11:282–285.
bazepine may be ofered. Central neuropathic pain can 111
be treated with tricyclic antidepressants, gabapentin,
(12) Gass A, Kitchen N, MacManus DG, Moseley IF, (17) Arnoldus JH, Killestein J, Pfennings LE, Jelles B,
Hennerici MG, Miller DH. Trigeminal neuralgia in Uitdehaag BM, Polman CH. Quality of life during the
patients with multiple sclerosis: lesion localization irst 6 months of interferon-beta treatment in patients
with magnetic resonance imaging. Neurology with MS. Mult Scler 2000;6:338–342.
1997;49:1142–1144. (18) Pöllmann W, Erasmus LP, Feneberg W, Straube A.
(13) Ferroli P, Farina L, Franzini A, Milanese C, Broggi G. he efect of glatiramer acetate treatment on
Linear pontine and trigeminal root lesions and pre-existing headaches in patients with MS.
trigeminal neuralgia. Arch Neurol 2001;58:1311–1312. Neurology 2006;66:275–277.
(14) Nakashima I, Fujihara K, Kimpara T, Okita N, Takase (19) Solaro C, Uccelli MM. Management of pain in
S, Itoyama Y. Linear pontine trigeminal root lesions multiple sclerosis: a pharmacological approach.
in multiple sclerosis: clinical and magnetic resonance Nat Rev Neurol 2011;7:519–527.
imaging studies in 5 cases. Arch Neurol 2001;58: (20) Truini A, Galeotti F, Cruccu G. Treating pain in
101–104. multiple sclerosis. Expert Opin Pharmacother
(15) Gutrecht JA, Zamani AA, Slagado ED. 2011;12:2355–2368.
Anatomic-radiologic basis of Lhermitte’s sign in (21) Cruccu G, Gronseth G, Alksne J, et al. AAN-EFNS
multiple sclerosis. Arch Neurol 1993;50:849–851. guidelines on trigeminal neuralgia management. Eur
(16) Gee JR, Chang J, Dublin AB, Vijayan N. he J Neurol 2008;15:1013–1028.
association of brainstem lesions with migraine-like
headache: an imaging study of multiple sclerosis.
Headache 2005;45:670–677.
112
Section F Headache disorders
Chapter
Chronic migraine
27
he prevalence of migraine is approximately 6% in imately 20 tablets of sumatriptan per month, and hav-
men and 15% in women. While episodic migraine ing very few headache-free days. She was still able to
is adequately treated with analgesics or triptans that abort the attacks by medicating herself quickly and as
stop a migraine attack, the therapeutic management of a result had good work attendance with few sick days.
chronic migraine can be challenging. Increasingly, she had noticed a background headache
between migraine attacks. She had always been athletic
and until the onset of this second headache, had man-
Clinical case vignette aged to run three times a week, inding that regular
A 49-year-old female reported that she had sufered exercise reduced the frequency of her migraines. Due
migraine attacks since age 25. Her family history to the ongoing nature of the headache, she was forced
included a brother and son with the same aliction. to reduce her physical activity and had gained 20 kg
For many years, the migraine occurred approximately over 2 years.
once per week. he patient was able to abort the At the time of consultation, the patient sufered
attacks with aspirin or a combination of aspirin and from a headache of intermediate severity. On exami-
paracetamol. Attacks were described as one sided but nation, her head was sensitive to percussion and the
the side varied. he headache was pulsating, became pericranial musculature was hyperalgesic to pressure.
more severe upon movement, and reached a severity Her neurological examination was otherwise normal.
of 8/10. Most attacks were accompanied by nausea. If he patient was advised to use a headache diary
the attacks were severe, and in particular if the patient (Table 27.1) and given options for migraine prophy-
were unable to take her analgesic within a speciic laxis. She opted against ß-blockers because of their past
time-frame, vomiting occurred. hese attacks were inefectiveness. Ater informed consent, she agreed to
also accompanied by severe sensitivity to light, noise, try topiramate, a second drug designed and licensed
and also smells. During severe attacks, the patient felt for migraine prophylaxis. She was made aware of fre-
compelled to lie down. If she managed to fall asleep, quently encountered side-efects including tingling of
the attacks were usually gone the next morning. Five the hands, changes in taste of carbonated drinks, irri-
years previously with attacks occurring at a rate of tability, depression, and weight loss. he initial dose of
4 per month, the patient had been prescribed a beta- topiramate was 25 mg with a weekly increase of 25 mg
blocker for prophylaxis. She experienced no improve- to a maintenance dose of 50 mg bid. he patient was
ment and terminated the drug ater 8 weeks. Acupunc- reassessed 3 months later. She had noticed a marked
ture with an accredited physician was attempted with decline in headache days and triptan intake since being
no beneicial results. Ater 3 months, this was also ter- on the maintenance dose of topiramate. For the irst
minated. he patient resolved to live with her once time in years, she had headache-free stretches lasting
weekly migraine attack by taking an analgesic in the up to 10 days [Table 27.1].
early stages of an attack and hopefully, becoming pain
free within a few hours.
In the past 2 years, the patient began to experi- Pain description
ence more frequent, even daily migraine attacks. Sim- he IHC criteria for migraine are pulsating headaches
ple analgesics were no longer efective, and the patient accompanied by two of the following: nausea, vomit-
began using a triptan (sumatriptan). Upon examina- ing, and sensitivity to noise and light. Our patient ful- 113
tion at the migraine clinic, she reported taking approx- illed these criteria. Her additional complaint of a more
Section F: Headache disorders
Table 27.1. Headache diary recorded from the patient described in this vignette
Jan Feb March April May June July
1 MTT H H MTT
2 MT H MTT H MT
3 H MTT MTT H H H
4 H MTT MTT H H
5 H MT M H
6 MTT H MT M
7 MTT H H H
8 M H M H
9 MTT MTT M H
10 MTT MTT MTT H M
11 MTT MTT H MT H
12 H MTT H MT MTT H
13 H MT H H MT
14 MTT MT H MT M M
15 MTT H MT H M H
16 MTT H MT H H
17 H
18 MTT MTT H H H
19 H MTT H H H
20 M H M M MT
21 MT M MTT H
22 MT MT M M H MT
23 H M MTT H H M
24 H H MTT H H
25 H H MTT H H
26 MT MTT H H H H
27 MT MTT H H H H H
28 M H H H H
29 H H H
30 H H H H
31 H H
No sumatriptan tablets 23 21 20 4 4 1 4
Start topiramate
M: migraine attack; T: one sumatriptan tablet; H: headache.
continuous headache interspersed with headaches that Discussion

increased in severity and which the patient believed to
be migraines was of interest. She described the former he condition of chronic migraine was initially
as being of intermediate severity, pressure-like, and termed “transformed migraine” (1). It denoted
114 involving the entire skull. In addition, the diference patients with medication overuse as well as patients
in severity between the two types had become smaller. whose ailment had completely changed (transformed)
Chapter 27: Chronic migraine
to resemble a tension headache. he second edition new daily persistent headache. Here, the headache is
of the International Classiication of Headache Disor- unremitting from onset or within 3 days of onset (2).
ders (2) adopted the term chronic migraine. Chronic he presence of more than one migrainous feature
migraine was initially deined as migraine without (photophobia, phonophobia, nausea) precludes this
aura for 15 or more days per month for longer than diagnosis. he other primary chronic headache,
3 months and in the absence of medication overuse. hemicrania continua, manifests with unilateral pain
For several reasons, this deinition was unhelpful in like most migraine attacks. he pain is continuous,
clinical practice. Many patients with chronic migraine but there may be phases of moderate intensity and
can use considerable amounts of medication. he exacerbations of high intensity, which may resemble
headache character changes when migraine becomes an attack. Because nausea and photophobia may
chronic, and inally, migraine headaches do not occur in hemicrania continua, it may be mistaken for
share the same characteristics. hus, the deinition of migraine. It does not respond to either acute or pro-
chronic migraine has changed over time. he revised phylactic migraine drugs but notably, indomethacin is
deinition requires 15 or more headache days per efective. hus, the hallmark of hemicrania continua,
month, of which 8 or more fulill the migraine criteria the presence of ipsilateral autonomic symptoms
(3). Of note, a change in headache character is an indi- including lacrimation, conjunctival injection, ptosis,
cation for brain imaging so that causes of secondary and rhinorrhea, must be carefully assessed.
headache can be excluded (4). he current deinition Chronic migraine is a dynamic entity. In a recent
of chronic migraine includes cases with medication study on the evolution of chronic migraine, 26% of
overuse, but this should be separately noted because patients re-experienced episodic migraine and 34%
it changes the treatment approach (5). Patients are had persistent chronic migraine (10). Age of onset
required to experience typical migraine headache or depression status were not related factors. More
during at least 8 of their 15 or more headache days per patients without prophylactic medication began expe-
month. Migraine can be diagnosed if the headache is riencing episodic migraine again. Also, more patients
unilateral, of moderate to severe intensity, pulsating, with severe allodynia had persistent chronic migraine.
and aggravated by physical activity. At least two of A further negative predictor of remission was a high
these characteristics must be present. Combined frequency rate, i.e., attacks occurring 25–31 days per
associated symptoms (nausea and/or vomiting, month. Finally, another study demonstrates that com-
photophobia, and phonophobia) are required. pliance to preventive medication is a factor in favor of
he reported prevalence of chronic migraine is reversion to episodic migraine (11).
1.4–2.2% in the overall population (6). Patients with Like other chronic pain disorders, chronic
episodic migraine have an annual risk of 2.5% of devel- migraine is associated with several comorbidities
oping chronic migraine (7). An intermediate headache such as depression, anxiety, disorders of the heart and
frequency of 6 to 9 days per month and in particu- of the respiratory system (5). Most of these are also
lar, a critical frequency of 10 to 14 headache days per associated with episodic migraine, but the incidence is
month, increase the risk for chronicity (8). Additional much higher in chronic migraine. his relationship is
risk factors include obesity, stressful life events, snor- also supported by the migraine disability assessment
ing, and overuse of certain classes of medication. he scale (MIDAS) which assesses the level of patient
use of barbiturates and opiates is associated with an disability. Here, patients with episodic migraine reach
increased risk of developing chronic migraine (9). a score of 10, those with chronic migraine in contrast
he diferential diagnosis of chronic migraine have a score of 63 (5).
includes other primary headache disorders with
attacks of long duration. Chronic tension-type
headache can be diferentiated from chronic migraine Pain in chronic migraine
by its character. It is usually bilateral, not pulsating, Structural, functional, and pharmacologic changes
and of mild to moderate intensity. It is not aggravated have been implicated in the pathophysiology of
by physical activity. he associated symptoms of chronic migraine (12). As in other chronic pain dis-
migraine like photophobia, phonophobia, nausea, and orders, decreased areas of gray matter in several
vomiting are not present, or, if so, only mildly and not brain regions involved in pain processing have been 115
in combination (2). Another diferential diagnosis is found. Iron deposition in the basal ganglia and thus
an increased accumulation of iron in the antinoci- References

ceptive network appear to have a role in migraine (1) Mathew NT, Stubits E, Nigam MP. Transformation of
chroniication or possibly physiological response to episodic migraine into daily headache: analysis of
repeated activation of brain areas involved in cen- factors. Headache 1982;22:66–68.
tral pain processing (13). Increased cortical excitability (2) Headache Classiication Subcommittee of the
was demonstrated in patients with chronic migraine International Headache Society. he International
using transcranial magnetic stimulation combined Classiication of Headache Disorders. 2nd edition.
with positron emission tomography (PET) (12). he Cephalalgia 2004;24(Suppl 1):9–160.
allodynia oten observed in patients with chronic (3) Katsarava Z, Manack A, Yoon MS, et al. Chronic
migraine is interpreted as an indication of central sen- migraine: classiication and comparisons. Cephalalgia
sitization, i.e., CNS involvement is stronger in chronic 2011;31:520–529.
as opposed to episodic migraine. (4) Silberstein SD. Practice parameter: evidence-based
As in episodic migraine, individual attacks can guidelines for migraine headache (an evidence-based
be treated with triptans. However, triptans should review): report of the Quality Standards
Subcommittee of the American Academy of
not be taken for more than 9 days per month. he
Neurology. Neurology 2000;55:754–762.
risk for chronic misuse of triptans becomes signif-
icant with its use of 12 days or more per month (5) Lipton RB. Chronic migraine, classiication,
diferential diagnosis, and epidemiology. Headache
(7). Non-pharmacologic measures to reduce headache 2011;51(Suppl 2):77–83.
frequency include regular exercise, relaxation tech-
(6) Natoli JL, Manack A, Dean B, et al. Global prevalence
niques such as progressive muscular relaxation, and of chronic migraine: a systematic review. Cephalalgia
acupuncture. Regular exercise (exercise for more than 2010;30:599–609.
3 times a week for more than 30 min at a time)
(7) Bigal ME, Serrano D, Buse D, Scher A, Stewart WF,
is one of the factors favoring remission of chronic Lipton RB. Acute migraine medications and
migraine (11). evolution from episodic to chronic migraine: a
he drugs available for prophylactic treatment of longitudinal population-based study. Headache
migraine are derived from very diferent substance 2008;48:1157–1168.
groups but have one point in common. All of them (8) Lipton RB. Tracing transformation: chronic migraine
experimentally reduce cortical spreading depression, classiication, progression, and epidemiology.
a factor thought to be central to migraine patho- Neurology 2009;72:S3–S7.
genesis. his was shown for propranolol, topiramate, (9) Bigal ME, Lipton RB. Concepts and mechanisms of
valproate, amitriptyline, and methysergide (14). Of migraine chroniication. Headache 2008;48:7–15.
these, topiramate in particular was used in a trial (10) Manack A, Buse DC, Serrano D, Turkel CC, Lipton
with chronic migraine (15). Subcutaneous botulinum RB. Rates, predictors, and consequences of remission
toxin, which also reduced headache days in patients from chronic migraine to episodic migraine.
with chronic migraine (16), is assumed to reduce Neurology 2011;76:711–718.
peripheral sensitization. Prophylactic medication is (11) Seok JI, Cho HI, Chung CS. From transformed
recommended in all patients with chronic migraine migraine to episodic migraine: reversion factors.
Headache 2006;46:1186–1190.
to reduce sufering and to avoid potential long-term
sequelae (17). (12) Mathew NT. Pathophysiology of chronic migraine
and mode of action of preventive medications.
he impact of prophylactic medication observed in
Headache 2011;51(Suppl 2):84–92.
the patient described above is among the most favor-
able ones in the author’s experience. It is unlikely (13) Kruit MC, Launer LJ, Overbosch J, van Buchem MA,
Ferrari MD. Iron accumulation in deep brain nuclei
that the rapid decline in triptan use was caused by in migraine: a population-based magnetic resonance
the prophylactic medication alone. he successful res- imaging study. Cephalalgia 2009;29:351–359.
olution to this case may also be attributed to edu-
(14) Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA.
cating the patient about the problems of chronic Suppression of cortical spreading depression in
migraine and medication overuse. he combination of migraine prophylaxis. Ann Neurol 2006;59:652–
patient information, attention to her needs, and care 661.
116 plus the preventive medication may all have been of (15) Diener HC, Bussone G, Van Oene JC, Lahaye M,
beneit. Schwalen S, Goadsby PJ. Topiramate reduces
Chapter 27: Chronic migraine
headache days in chronic migraine: a randomized, placebo-controlled phase of the PREEMPT 2 trial.
double-blind, placebo-controlled study. Cephalalgia Cephalalgia 2010;30:804–814.
2007;27:814–823. (17) Evers S, Afra J, Frese A, et al. EFNS guideline
(16) Diener HC, Dodick DW, Aurora SK, et al. on the drug treatment of migraine – revised report of
OnabotulinumtoxinA for treatment of chronic an EFNS task force. Eur J Neurol 2009;16:
migraine: results from the double-blind, randomized, 968–981.
117
Chapter
Cluster headache
28
Cluster headache is one of several primary headache Figure 28.1. Drawing
conditions. In contrast to most other headaches, it including the main
symptoms of a cluster
primarily targets men. Patients sufer from attacks of headache attack: Very
excruciating pain, which present in a speciic tem- severe pain in the region
poral pattern. of the orbit, conjunctival
injection, lacrimation, and
rhinorrhea.

A 41-year-old man was seen at the headache clinic in
October 2011 complaining of pain attacks which had
woken him with uncanny punctuality at 2 a.m for the
past 15 nights. His descriptions localized the attacks
to the right orbit and were of such extreme severity
that he felt compelled to leave his bed and pace in his
room. Asked about the quality of his pain, the patient
stated it was as if someone had pushed his eyeball to stress at work or alcohol consumption, which readily
out from behind or someone had stabbed a hot dag- responded to ibuprofen. hey occurred during the day,
ger through his eye [Figure 28.1]. He spoke of suici- were holocephalic and of dull quality, and had no other
dal ideation during these attacks. Upon questioning, associated symptoms. hey did not impact his activi-
he also reported reddening and tearing in his right eye ties, whether work related or otherwise. hey usually
as well as “runniness” in the right nostril. he attacks lasted for several hours and were alleviated by either
always occurred on the same side and usually lasted ibuprofen or by vigorous walking in fresh air. here
between 30 and 60 min. Aterward, he still experienced was no family history of migraine or other headache
a dull pain on the right side of his head, but was able disorders. As an accountant, he had a sedentary occu-
to resume sleeping. Other than feeling fatigued, he had pation but exercised in his free time and felt reason-
no other symptoms on the following mornings. His use ably it. He was a cigarette smoker and drank moderate
of over-the-counter analgesics included ibuprofen and amounts of wine and beer.
paracetamol but neither relieved the pain. Because the he patient was informed that his headache ful-
durations of the attacks were limited to approximately illed the criteria for cluster headache and the treat-
1 h, he wondered if the analgesics might have had some ment options were discussed. He remained in the hos-
efect. pital overnight for a trial of oxygen treatment which
When asked for previous headache experiences, resulted in abortion of his attack within 10 min. He
the patient reported that he had sufered from a sim- was discharged with a prescription of subcutaneous
ilar episode approximately 2 years previously. At that sumatriptan for self-application should further attacks
time, the attacks had also been very severe, although occur. he patient’s attacks did return, and the suma-
not as excruciating as his current attacks. he episode triptan alleviated his symptoms within 15 min. In
had lasted approximately 10 or 12 days, and he had not addition, a dose of 1 mg/kg of oral prednisolone was
consulted a physician. he patient’s history was other- initiated and the patient was instructed to reduce
118 wise unremarkable. He had never been seriously ill. He the dose once the nightly attacks ended. Ater a few
occasionally sufered from mild headaches, likely due nights with milder attacks, the attacks ceased and the
Chapter 28: Cluster headache
prednisolone was tapered over 3 weeks. At a follow-up Table 28.1. Criteria for cluster headache according to the
International Headache Society (IHS) (22)
visit 3 months later, the patient was free of headache
complaints. At least 5 attacks fulfilling the following criteria:
Severe or very severe unilateral orbital, supraorbital, or temporal
pain lasting 15 to 180 min if untreated.
Pain description Headache accompanied by one of the following:
– ipsilateral conjunctival infection or lacrimation
he patient described his pain as very severe, excru- – ipsilateral nasal congestion or rhinorrhea
ciating, and worse than anything he had experienced – ipsilateral eyelid edema
before. Asked to rate the pain on a scale of 0 to 10, – ipsilateral forehead and facial sweating
– ipsilateral miosis or ptosis
he chose “12.” He could not attribute any of the stan- – a sense of restlessness or agitation
dard pain qualities (burning, pulsating, dull, etc.) to Attacks have a frequency from one every other day to 8 per day
his experience, but instead used very vivid descrip- Attacks are not attributed to another disorder
tions and analogies. For example, the pain felt as if Episodic cluster headache: at least two cluster periods lasting
7 days to 1 year and separated by pain-free remission periods of
someone was pushing the eyeball out from behind or 1 month or more; chronic cluster headache: attacks that recur for
splitting his skull at the site of his orbit with a burn- more than 1 year, without remission periods or with remission
ing dagger. He admitted to suicidal ideations during periods lasting less than 1 month.
the attacks. Standard analgesics had no efect. he pain
attacks woke him up from sleep, and he felt compelled
ponent, but speciic genes have not been identiied.
to get up and walk about, although this by no means
Lifestyle plays an important role (4). Patients with clus-
reduced the pain intensity. he patient also reported
ter headache are typically smokers and have frequent
associated symptoms such as reddening and lacrima-
alcohol intake.
tion of the ipsilateral eye and rhinorrhea.
Cluster headache must be diferentiated from the
other trigemino-autonomic syndromes. All exhibit
Discussion short-lasting, unilateral, severe headache attacks with
Cluster headache is a distinct clinical syndrome ipsilateral autonomic symptoms. he main difer-
already described in detail by Nicolas Tulp in the 17th ences are those of duration and frequency of attacks.
century (1). Following the observations of Bayard T. In paroxysmal hemicrania, women are more oten
Horton, a neurologist in North America, the syndrome afected; attacks last from 2 to 45 min and may occur
became known as Horton headache (1). It is currently up to 40 times per day. he syndrome responds to
classiied among the trigeminal autonomic cephalal- preventive treatment with indomethacin. SUNCT syn-
gias. he term cluster headache is derived from the drome (shortlasting unilateral neuralgiform headache
periodicity of the attacks which occur in “clusters” and with conjunctival injection and tearing) targets mainly
then remit for various time spans. men; attacks have a duration of seconds to minutes
he International Headache Society (IHS) has and may occur up to 30 times per hour. he preven-
deined this syndrome as severe or very severe uni- tive treatment of choice is lamotrigine. Importantly,
lateral orbital, supraorbital and/or temporal pain last- other conditions, including carotid artery dissection,
ing 15–180 min if untreated, accompanied either by tumors, and inlammatory infectious diseases, may
ipsilateral conjunctival injection or lacrimation, ipsi- mimic cluster headache (5). hese so-called symp-
lateral nasal congestion or rhinorrhea, ipsilateral eye- tomatic cluster headache conditions exhibit red lags,
lid edema, ipsilateral miosis, or ptosis or a sense of i.e., late onset, prolonged attacks, and abnormal ind-
restlessness or agitation [Table 28.1]. Most patients ings on neurological examination which must be fur-
experience combinations of these symptoms. Addi- ther investigated. A cranial MRI with arteriogram and
tional mandatory criteria are a frequency of attacks of venogram sequences should be performed in these
one in 2 days to eight per day and the exclusion of other instances.
causative disorders. Treatment goals are twofold and include abortion
Cluster headache has an estimated prevalence of of the individual attacks and shortening of the clus-
0.1% in the general population (2). Men are afected ter period. Cluster headache attacks do not respond
more than women in a ratio of approximately 4 to 1. to standard analgesics. Inhalation of pure oxygen, low
he mean age of initial presentation is 30 years. Onset rate of 7–10 l/min by a facial mask, provides relief 119
in childhood is possible (3). here is a familial com- in approximately 60% of cases. Attacks usually stop
within 15 min (6, 7). here are no side-efects but the onset of a headache that reaches its maximum inten-
patient requires access to an oxygen supply. Before sity within 10 min and lasts for 30 to 180 min. he
the availability of triptans, ergotamines were the most pain is almost always unilateral and rarely switches
efective treatment. Most patients are currently pre- sides. he most common sites of maximal pain are
scribed sumatriptan or other triptans. Sumatriptan can the orbital, retro-orbital, temporal, supraorbital, and
be injected subcutaneously and leads to a pain-free infraorbital areas. Cranial autonomic symptoms or the
state within 20 min in approximately 75% of patients. typical restlessness must be present to conirm the
he contraindications to its use include cardiovas- diagnosis. Patients usually experience 1 to 3 attacks per
cular and cerebrovascular disorders, and untreated 24 h. Symptoms in cluster may be similar to those of
arterial hypertension. Intranasal zolmitriptan can also migraine including nausea, photophobia, and phono-
provide relief (8), as do other orally ingested trip- phobia (14).
tans. Pre-emptive use with triptans may prevent clus- Apart from the extreme pain intensity and patients’
ter attacks but the data have not been conclusive. vivid descriptions of the attack, temporal periodicity
he mainstay of treatment is prevention of further is the most salient characteristic of cluster headache.
attacks. First-line drugs are glucocorticosteroids and Attacks oten occur at the same time every night as the
verapamil. Open studies and case series conirm the 2 am awakening described in this vignette. here may
clinically well-known eicacy of steroids such as pred- be a mirror-like, sometimes milder attack in the early
nisone or dexamethasone. Approximately 70–80% of aternoon. hese attacks occur in clusters or bouts
all cluster headache patients respond to the standard that may persist for weeks to months until the attacks
dosage of 1 mg/kg of steroid. Patients typically experi- become milder and eventually cease. Patients may be
ence some relief of their symptoms within 3 days. he pain free for several months to years until the onset
initial dose is maintained for 5–7 days, then depend- of the next cluster, a condition referred to as episodic
ing on the response, the steroid is slowly tapered over cluster headache. Rarely, the attacks may persist for
2–3 weeks (9). If relapses occur during tapering, the several years in which case the diagnosis is chronic
steroid can be increased again or verapamil may be cluster headache. he IHS deines this condition as the
added. In some patients, a maintenance dose over the absence of remission for 1 year or by short remissions
estimated time period of the cluster, i.e., 2 months, may of less than 1 month.
be required. In refractory cases, pulse therapy with A pathophysiological model for cluster headache
500–1000 g of methylprednisolone for 3 days is rec- must somehow account for the unilateral localization
ommended. Verapamil is also eicient in reducing the of the pain, the ipsilateral autonomic symptoms, the
cluster duration, although full eicacy may require 2– typical circadian occurrence of individual attacks, and
3 weeks of use. here is no consensus on a standard the seasonal recurrence of the cluster periods (15).
dose and the range of prescribed strengths is from 240 he proposal that pathology in the cavernous sinus
to 960 mg/day. An increase of 80 mg every 14 days is such as inlammation is responsible for this condition
recommended. Regular echocardiographs are neces- has been recently challenged (16). Symptomatic clus-
sary to monitor the development of a prolonged PR ter headache secondary to venous thrombosis or to
interval (9). Further treatment options in refractory other pathologies involving the cavernous sinus may
cases are topiramate and lithium, the latter in particu- be relevant considerations (17, 18). he severe unilat-
lar in chronic cluster headache (10). In the more com- eral pain is likely mediated by activation of the irst
mon episodic type, it is important that the preventive division of the trigeminal nerve. Trigemino-vascular
treatment is tapered and discontinued when the clus- activation, as in the case of migraine, is considered the
ter period has passed. For patients who do not respond common inal pathway of pain generation, supported
satisfactorily to drug treatment, other options include by the rapid actions of triptans in the attacks.
suboccipital injection of steroids (11), occipital nerve Due to the intriguing temporal characteristics of
stimulation (12), or even deep brain stimulation (13). the attacks, cluster headache has also been viewed as a
disturbance of the biological clock caused by hypotha-
lamic dysfunction. Hormonal alterations are described
Pain in cluster headache in men with cluster headache (19). Similarly, the auto-
120 he typical attack has been described above. Attacks nomic symptoms are regarded as a consequence of
oten occur when the patient is asleep. here is rapid hypothalamic disturbance with trigeminal discharge
Chapter 28: Cluster headache
(15). Parasympathetic hyperactivity with increased (10) Ashkenazi A, Schwedt T. Cluster headache–acute
outlow from the seventh cranial nerve may lead to and prophylactic therapy. Headache 2011;51:
vasodilation and perivascular edema, which results in 272–286.
compression of sympathetic ibers around the carotid (11) Leroux E, Valade D, Taifas I, et al. Suboccipital steroid
artery (20). he posterior hypothalamus is activated injections for transitional treatment of patients with
during an attack as demonstrated by positron emis- more than two cluster headache attacks per day: a
randomised, double-blind, placebo-controlled trial.
sion tomography (PET) (21). his has also led to the Lancet Neurol 2011;10:891–897.
use of hypothalamic stimulation as a treatment option
(12) Magis D, Gerardy PY, Remacle JM, Schoenen J.
in severe cases. In summary, most experts regard clus-
Sustained efectiveness of occipital nerve stimulation
ter headache as a syndrome involving peripheral and in drug-resistant chronic cluster headache. Headache
central pain generators. he pathophysiology may also 2011;51:1191–1201.
involve deicits of pain inhibition or alterations in (13) May A. Hypothalamic deep-brain stimulation: target
hypothalamic function. and potential mechanism for the treatment of cluster
headache. Cephalalgia 2008;28:799–803.
References (14) Bahra A, Goadsby PJ. Diagnostic delays and
(1) Horton BT, MacLean AR, Craig WM. A new mis-management in cluster headache. Acta Neurol
syndrome of vascular headache; results of treatment Scand 2004;109:175–179.
with histamine: a preliminary report. Mayo Clin Proc (15) Leone M, Bussone G. Pathophysiology of trigeminal
1939;14:250–257. autonomic cephalalgias. Lancet Neurol
(2) Fischera M, Marziniak M, Gralow I, Evers S. he 2009;8:755–764.
incidence and prevalence of cluster headache: a (16) Schuh-Hofer S, Richter M, Israel H, et al. he use of
meta-analysis of population-based studies. radiolabelled human serum albumin and
Cephalalgia 2008;28:614–618. SPECT/MRI co-registration to study inlammation in
(3) Lampl C. Childhood-onset cluster headache. Pediatr the cavernous sinus of cluster headache patients.
Neurol 2002;27:138–140. Cephalalgia 2006;26:1115–1122.
(4) Sjostrand C, Russell MB, Ekbom K, Waldenlind E. (17) Park KI, Chu K, Park JM, Kim M. Cluster-like
Familial cluster headache: demographic patterns in headache secondary to cerebral venous thrombosis. J
afected and nonafected. Headache 2010;50:374–382. Clin Neurol 2006;2:70–73.
(5) Mainardi F, Trucco M, Maggioni F, Palestini C, (18) Palmieri A, Mainardi F, Maggioni F, Dainese F,
Dainese F, Zanchin G. Cluster-like headache. A Zanchin G. Cluster-like headache secondary to
comprehensive reappraisal. Cephalalgia cavernous sinus metastasis. Cephalalgia
2010;30:399–412. 2005;25:743–745.
(6) Fogan L. Treatment of cluster headache. A (19) May A. Cluster headache: pathogenesis, diagnosis,
double-blind comparison of oxygen v air inhalation. and management. Lancet 2005;366:843–855.
Arch Neurol 1985;42:362–363. (20) Hardebo JE. How cluster headache is explained
(7) Cohen AS, Burns B, Goadsby PJ. High-low oxygen as an intracavernous inlammatory process lesioning
for treatment of cluster headache: a randomized trial. sympathetic ibers. Headache 1994;34:
JAMA 2009;302:2451–2457. 125–131.
(8) Law S, Derry S, Moore RA. Triptans for acute cluster (21) May A, Bahra A, Buchel C, Frackowiak RS, Goadsby
headache. Cochrane Database Syst Rev PJ. Hypothalamic activation in cluster headache
2010:CD008042. attacks. Lancet 1998;352:275–278.
(9) May A, Leone M, Afra J, et al. EFNS guidelines on (22) Headache Classiication Subcommittee of the
the treatment of cluster headache and other International Headache Society. he International
trigeminal-autonomic cephalalgias. Eur J Neurol Classiication of Headache Disorders: 2nd edition.
2006;13:1066–1077. Cephalalgia 2004;24(Suppl 1):9–160.
121
Chapter
Paroxysmal hemicrania
29
Paroxysmal hemicrania is a rare primary headache
syndrome characterized by repeated attacks of strictly
unilateral, severe, short-lasting pain associated with
cranial autonomic symptoms. Recognition of the syn-
drome is important because it responds speciically to
indomethacin.

A 38-year-old woman presented with a 3-year history
of facial pain. he pain was localized to the let upper
jaw and radiated to the let temple and to the back of
her head [Figure 29.1]. Pain attacks of 5- to 15-min
duration were experienced at a rate of 10–20 per day.
he severity of the attacks was such that the patient was
forced to stop her activities. In the intervals between
attacks, she was completely pain free. he patient had
a long history of specialist consultations. She had irst
seen a dentist, whom she had instructed to extract a let
upper molar, although the dentist was unconvinced of Figure 29.1. Reproduction of pain drawing based on the patient’s
original sketch.
any existing pathology. he pain persisted despite the
extraction. Her family physician diagnosed trigeminal
neuralgia and performed acupuncture for 2 months to see an orthopedic surgeon. his specialist diagnosed
without success. he patient then went to see a neurol- neuralgia of the let occipitalis major and auricularis
ogist who diagnosed a “vascular facial pain,” prescrib- magnus nerve. He prescribed the analgesic lupirtine
ing a sympathomimetic and a benzodiazepine. he and additionally attempted chiropraxy to the temporo-
drug combination reduced neither pain severity nor mandibular joint. he outcome remained unsuccess-
frequency of attacks. She then consulted a further neu- ful, and the patient next consulted an anesthesiolog-
rological specialist in an outpatient clinic. he diagno- ical pain specialist from whom she received three
sis was “atypical facial pain” and amitriptyline was pre- diagnoses: atypical facial pain, cluster headache, and
scribed. he patient tried using this drug in ascending spondylosis of the cervical spine. Treatment was mul-
doses up to 125 mg/day for 6 months with no success. timodal. For the irst time in the course of her long
Side-efects included dry mouth, constipation, and history, the patient was advised to keep a pain diary.
orthostatic hypotension. She stopped using amitripty- Pharmacological treatment with a combination of car-
line and consulted a second dentist. his dentist diag- bamazepine and doxepine was started. A local anes-
nosed craniomandibular dysfunction, gave injections thetic was injected at regular intervals into trigger
with a local anesthetic, and prescribed a splint. he points of the cervical musculature. he patient fur-
122 patient wore the splint for 3 months but experienced ther received lymph drainage, relaxation therapy, and
no improvement. he dentist then advised the patient conlict-centered psychotherapy. Several months later
Chapter 29: Paroxysmal hemicrania
and still seeking relief, the patient consulted a fur- Table 29.1. IHS criteria of paroxysmal hemicrania (summarized
from Headache Classification Committee (3))
ther neurologist. his neurologist suspected pathol-
ogy in the temporomandibular joint and referred Paroxysmal hemicrania
the patient to an orthodontic surgeon. However, the Description Attacks with similar characteristics of
patient decided to see a second anesthesiologist and pain and associated symptoms and
signs to those of cluster headache, but
visited a clinic specializing in radiofrequency ther- shorter-lasting, more frequent and
apy. Radiofrequency facet denervation was performed commonly in females, that exclusively
at several levels of the cervical spinal cord. With no respond to indomethacin.
therapeutic relief ater several treatment sessions, the Diagnostic criteria: A. At least 20 attacks fulfilling criteria
patient appeared at our Neurology outpatient clinic. B–D
B. Attacks of severe unilateral orbital,
At the time of consultation, the patient was pain supraorbital or temporal pain lasting
free. Neurologic and psychological examination were 2–30 min
completely normal. here was no tenderness of peri- C. Headache is accompanied by at
least one of the following:
cranial or cervical muscles. Upon detailed history tak-
1. ipsilateral conjunctival injection
ing, the patient reported that sometimes during the and/or lacrimation
pain attacks, her let eye became red and she noticed 2. ipsilateral nasal congestion
lacrimation. Based on the temporal characteristics of and/or rhinorrhoea
the pain attacks, the localization, and the associated 3. ipsilateral eyelid oedema
4. ipsilateral forehead and facial
symptoms, a diagnosis of chronic paroxysmal hemi- sweating
crania was made. An initial dose of indomethacin 5. ipsilateral miosis and/or ptosis
50 mg/day was prescribed with gradual increases to D. Attacks have a greater frequency
a maximum of 250 mg. he patient’s attacks ceased than 5 per day for more than 50% of
entirely with a dose of 150 mg. Indomethacin was the time, although periods with
lower frequency may occur
tapered to 12.5 mg/day, and the patient remained sta-
E. Attacks are completely prevented
ble and tolerated the drug well. by therapeutic doses of
indomethacin (at least 150 mg p.o.
must be prescribed to confirm a
Pain description response)
he patient gave a precise description of her pain. F. Not attributed to another disorder
She described attacks of 10 to 15 min in duration. In
the intervals between attacks, she was completely pain
providers. here is a considerable risk that unneces-
free. he pain was localized to the let upper jaw and
sary, sometimes irreversible, procedures, i.e., tooth
radiated to the let temple and back of the head. It
extraction, are attempted (2).
was strictly unilateral and never changed sides. he
he term trigeminal autonomic cephalalgias refers
attacks occurred 10 to 20 times per day. During most
to a group of headaches characterized by unilateral
attacks, the let eye became red with tears. here were
head or face pain with accompanying autonomic
no precipitating factors, and the onset of the attacks
features. he International Headache Society’s (IHS)
was unpredictable. Severity was gauged at 6–8/10, and
criteria for PH are given in Table 29.1 (3). he hall-
there was very little if anything the patient could do to
mark feature of PH is cessation of the pain attacks
reduce pain severity. She sometimes took novamin sul-
upon treatment with indomethacin, a distinguish-
fone drops and had the impression that these ofered
ing feature that diferentiates PH from the other
some relief. During the attacks, the patient stopped her
trigemino-autonomic headaches. Episodic PH may
activities when possible and waited for the attack to
be diagnosed if there are pain-free periods of one
subside.
month or longer. In all other cases, the diagnosis is
chronic paroxysmal hemicrania (CPH). PH was irst
Discussion described by Sjaastand and Dale as a new treatable
PH is classiied among the trigemino-autonomic headache entity in 1974 (4). PH is characterized by
cephalalgias (1). It is important to recognize trigemino intense, strictly unilateral pain attacks localized to
autonomic headaches, and in particular PH, because the temporal region, the orbita, the forehead or the 123
patients oten consult dentists or other oral health care ear, or a combination of those areas. he localization
is similar to that in cluster headache. Associated he etiology and pathophysiology of PH are

symptoms, including ipsilateral conjunctival injection unknown. A primary CNS disorder with disturbance
and lacrimation, are also described lasting 2–30 min of the central control of sympathetic and parasym-
(5) and are thus shorter than those of cluster headache, pathetic systems is assumed. Some clue to a pos-
which last 30–90 min, and are considerably longer sible mechanism may lie in its exclusive response
than those in SUNCT, another trigemino-autonomic to indomethacin. Indomethacin, in contrast to other
cephalalgia (Short-lasting, Unilateral, Neuralgiform NSAIDS, reduces nitric oxide–induced dural vasodi-
headache attacks with Conjunctival injection and lation (10). hus, the efect on prostaglandin synthe-
Tearing), which last for mere seconds. Attacks are sis may not be relevant for the treatment efect in PH
also more frequent than those experienced in cluster because other NSAIDS are not efective in PH.
headache. he attacks typically last 10–15 min. While Cases of secondary PH with an underlying pathol-
cluster headache usually occurs 1–2 times per 24 h, PH ogy (11) are possible. Among the diferential diag-
attacks may occur 10–20 times per day. Furthermore, noses are intracranial tumors (12), collagenoses (13)
more women than men sufer from PH while approx- and arteriovenous malformations (14). In patients
imately 80% of cluster headache patients are men. with a poor response to indomethacin or with addi-
During PH attacks, patients usually sit quietly or lie tional neurologic symptoms or signs, a brain MRI scan
down in bed, activity that contrasts with that during and blood tests for inlammation markers should be
cluster headache, where patients feel compelled to performed.
walk around (2). Attacks are more frequent during the No agents have proven eicacious in aborting
day but may also occur during the night. Nighttime an acute PH attack. here is anecdotal evidence of
attacks are sometimes longer and more severe (6). some pain alleviation by sumatriptan (15) or by
In addition to lacrimation and conjunctival injec- novamine sulfone. Standard treatment is prophylaxis
tion, some patients have ipsilateral eyelid edema and with indomethacin. Drug doses should be initiated
miosis. Photophobia and phonophobia, oten ipsilat- at 50 mg and increased to at least 150 mg/day for
eral to the pain, may occur and may bring to mind the 3–4 days, with a maximum dose of 250 mg/day. Pain
diferential diagnosis of migraine, although individual relief should occur within a few hours to days. he
migraine attacks are of much longer duration. drug may then be tapered to a maintenance dose
of between 25 to 100 mg/day although this varies
between patients. Unfortunately when indomethacin
Pain in paroxysmal hemicrania is stopped, the headache returns. Common side-efects
PH pain is unilateral and always afects the same side. are gastritis, gastric ulcers, and bleeding, therefore,
Patients describe an excruciating, throbbing, boring, a gastric protective agent should be prescribed. If
or pulsating pain. Triggers are observed by a minor- indomethacin cannot be tolerated, a COX-2 inhibitor
ity of patients and may include exercise or stress (6). (celecoxib) may be prescribed. A response to 150
Between attacks, most patients are entirely pain free. mg/day of topiramate has also been described in some
Some have intermittent tenderness in the symptomatic case reports (16, 17). Occipital nerve stimulation is
area. In the presence of severe pain between attacks, another option for patients who are unresponsive to or
the diferential diagnosis of hemicrania continua must cannot tolerate indomethacin (18). Deep brain stimu-
be considered (7). Hemicrania continua is described lation has been suggested for patients who are unre-
as persistent strictly unilateral headache responsive sponsive to other treatments (19).
to indomethacin. As in PH, there are also autonomic
symptoms but these are less consistent.
he exact prevalence of PH is not known but it is References
rare, attributing to the long delay between onset and
(1) May A. Update on the diagnosis and management of
diagnosis. PH was irst reported in women only. Later trigemino-autonomic headaches. J Neurol
studies found a female/male ratio of 2.4/1 (8) or even 2006;253:1525–1532.
of 1/1 (6), although the latter contradicts the authors’ (2) Klasser GD, Balasubramaniam R. Trigeminal
clinical experience. he onset is usually in the third autonomic cephalalgias. Part 2: Paroxysmal
124 decade (mid-range) of adulthood. PH has also been hemicrania. Oral Surg Oral Med Oral Pathol Oral
reported in children (9). Radiol Endod 2007;104:640–646.
Chapter 29: Paroxysmal hemicrania
(3) Headache Classiication Committee of the association with other pathologies: a review.
International Headache Society. he International Cephalalgia 2004;24:173–184.
Classiication of Headache Disorders. 2nd edition. (12) Dafer RM, Hocker S, Kumar R, McGee J, Jay WM.
Cephalalgia 2004;24(Suppl 1):1–160. Resolution of paroxysmal hemicrania ater resection
(4) Sjaastad O, Dale I. Evidence for a new (?), treatable of intracranial meningioma. Semin Ophthalmol
headache entity. Headache 1974;14:105–108. 2010;25:34–35.
(5) Russell D. Chronic paroxysmal hemicrania: severity, (13) Medina JL. Organic headaches mimicking chronic
duration and time of occurrence of attacks. paroxysmal hemicrania. Headache 1992;32:73–74.
Cephalalgia 1984;4:53–56. (14) Newman LC, Herskovitz S, Lipton RB, Solomon S.
(6) Cittadini E, Matharu MS, Goadsby PJ. Paroxysmal Chronic paroxysmal headache: two cases with
hemicrania: a prospective clinical study of 31 cases. cerebrovascular disease. Headache 1992;32:
Brain 2008;131:1142–1155. 75–76.
(7) Goadsby PJ, Cittadini E, Cohen AS. Trigeminal (15) Pascual J, Quijano J. A case of chronic paroxysmal
autonomic cephalalgias: paroxysmal hemicrania, hemicrania responding to subcutaneous sumatriptan.
SUNCT/SUNA, and hemicrania continua. Semin J Neurol Neurosurg Psychiatry 1998;65:407.
Neurol 2010;30:186–191. (16) Cohen AS, Goadsby PJ. Paroxysmal hemicrania
(8) Sjaastad O, Bakketeig LS. he rare, unilateral responding to topiramate. J Neurol Neurosurg
headaches. Vaga study of headache epidemiology. Psychiatry 2007;78:96–97.
J Headache Pain 2007;8:19–27. (17) Camarda C, Camarda R, Monastero R. Chronic
(9) Blankenburg M, Hechler T, Dubbel G, Wamsler C, paroxysmal hemicrania and hemicrania continua
Zernikow B. Paroxysmal hemicrania in children – responding to topiramate: two case reports. Clin
symptoms, diagnostic criteria, therapy and outcome. Neurol Neurosurg 2008;110:88–91.
Cephalalgia 2009;29:873–882. (18) Burns B, Watkins L, Goadsby PJ. Treatment of
(10) Summ O, Andreou AP, Akerman S, Goadsby PJ. A hemicrania continua by occipital nerve stimulation
potential nitrergic mechanism of action for with a bion device: long-term follow-up of a crossover
indomethacin, but not of other COX inhibitors: study. Lancet Neurol 2008;7:1001–1012.
relevance to indomethacin-sensitive headaches. (19) Franzini A, Messina G, Cordella R, Marras C, Broggi
J Headache Pain 2010;11:477–483. G. Deep brain stimulation of the posteromedial
(11) Trucco M, Mainardi F, Maggioni F, Badino R, hypothalamus: indications, long-term results, and
Zanchin G. Chronic paroxysmal hemicrania, neurophysiological considerations. Neurosurg Focus
hemicrania continua and SUNCT syndrome in 2010;29:E13.
125
Chapter
Trigeminal neuralgia
30
Trigeminal neuralgia is a very characteristic facial pain
of the elderly, and is usually caused by neurovascular
compression adjacent in the brainstem. In this older
age group, it is important that the diagnosis of trigem-
inal neuralgia be diferentiated from trigeminal neu-
ropathy. If it occurs in a young patient, investigations
into an underlying disorder must be considered.

A 75-year-old male presented with an 8-week history
of severe pain attacks in the area of the let upper jaw.
He had experienced a similar episode approximately
12 months previously but the pain had spontaneously
resolved ater 6 weeks. he individual attacks only
lasted for a few seconds, but they were extremely severe
and could occur frequently on a daily basis. During
the last 2 weeks, the pain had progressively intensiied Figure 30.1. Intraoperative photograph showing the trigeminal
and the number of attacks had increased. he attacks nerve (TN) and the superior cerebellar artery, which is compressing
the nerve. The neurosurgeon is mobilizing the artery with a small
were usually precipitated by the patient washing his spatula. Courtesy Dr. José Perez, Department of Neurosurgery,
face, brushing his teeth, shaving, eating, and talking. University Würzburg, Germany.
To avoid the onset of new attacks, he refused to eat and
drink. His wife became worried and convinced him to ongoing treatment, the patient experienced a return of
see a doctor. On examination, the patient was dehy- his pain 6 months later. he dose of carbamazepine was
drated, mildly slowed, but fully oriented. He refused to increased to 600 mg bid but the resulting side-efects
have his let face touched and spoke minimally, indi- of dizziness and unsteady gait were intolerable. Cranial
cating to his wife to speak for him. His neurologi- MRI showed contact between the trigeminal nerve and
cal examination was otherwise normal. A diagnosis of a vascular loop. Ater a neurosurgical consultation, a
trigeminal neuralgia involving its second branch, the Janetta nerve decompression operation was success-
maxillary nerve, was made. he patient was admit- fully performed [Figure 30.1]. At his 2-year follow-up
ted to the ward, and given intravenous luids and a visit, the patient continued to experience full remis-
long-acting opioid with rapid onset. Ater an EKG con- sion.
irmed the absence of heart block, 250 mg of intra-
venous phenytoin was slowly administered followed
by 100 mg of oral phenytoin tid. Carbamazepine was Pain description
started at a dose of 200 mg bid, and increased to 400 mg he patient described the pain attacks as stabbing and
bid over the next 2 days at which time the phenytoin electric-shock–like. he pain was felt in the skin and
was tapered. he patient reported relief of pain almost deep tissues in the area of the let lower face and radi-
126 immediately ater the infusion and experienced very ated to the corner of the mouth [Figure 30.2]. hese
few attacks with full doses of carbamazepine. Despite very brief attacks sometimes came in episodes lasting
Chapter 30: Trigeminal neuralgia
Table 30.1. International Headache Society (IHS) diagnostic in elderly patients, more oten in women than in men.
criteria of trigeminal neuralgia (1)
Younger patients with trigeminal neuralgia likely have
Paroxysmal attacks of pain lasting from a fraction of a second an additional underlying disease; see below.
to 2 min, affecting one or more divisions of the trigeminal he pathogenesis of what is now called “typical”
nerve and
Pain has at least one of the following characteristics: trigeminal neuralgia was initially suspected by the
1. intense, sharp, superficial or stabbing neurosurgeon Dandy approximately 80 years ago (see
2. precipitated from trigger areas or by trigger factors Prasad and Galetta (2)). Compression of the trigem-
Attacks are stereotyped in the individual patient
There is no clinically evident neurological deficit inal nerve at the entry zone into the pons was later
The pain cannot be attributed to another disorder conirmed to be present in 80–90% of patients with
typical trigeminal neuralgia. he superior cerebellar
artery is usually involved. In the trigeminal nerve root,
ibers of the second trigeminal branch, V2, are located
medially. Because compression typically occurs at this
point, pain in the distribution of the maxillary nerve
is the most common manifestation of typical trigemi-
nal neuralgia. An MRI scan, using speciic sequences,
can conirm the compression of the nerve by a vas-
cular loop with a sensitivity of almost 100% (3, 4)
(Figure 30.1). Speciicity is lower, because a neurovas-
cular contact can also be found in approximately 50%
on the contralateral side (5) and in up to 20% of asymp-
tomatic controls; this inding is only relevant in the
presence of clinical symptoms.
he pathological process is assumed to mainly
occur in the transition zone between central myelin
and peripheral myelin at the entry zone of the trigem-
inal root into the pons. CNS myelin, synthesized
by oligodendrocytes, is more vulnerable to compres-
sion than peripheral nerve myelin. Focal demyelin-
Figure 30.2. Pain drawing by the patient. The area of most severe, ation, close to the vascular indentation, has been
stabbing pain is depicted in red. observed (6). hinly myelinated A-delta nociceptive
ibers seem particularly vulnerable to these changes.
he demyelination leads to direct membrane-to-
up to 10 min. Aterward, there was a short period membrane contact of axons, to spontaneous activ-
during which the patient was pain free, even if he ity, and to mechanosensitization from pressure by
touched his facial skin. Otherwise, pain attacks could the overlying artery. Ephaptic impulse propagation
be induced by touching the skin, talking, eating, brush- between ibers mediating tactile impulses and noci-
ing the teeth, and shaving. he patient consequently ceptors is a possible explanation for the triggering of
avoided these activities as much as possible. Standard pain sensations. Furthermore, partially injured sen-
analgesics (acetaminophen, aspirin) neither reduced sory neurons may develop bursts of “ater discharge.”
the pain nor diminished the number of attacks. his means that discharges extend beyond the dura-
tion of a stimulus. Neighboring neurons may be
recruited, which leads to a further increase of the elec-
Discussion trical activity and thus of the pain. he electrical activ-
Trigeminal neuralgia is characterized by brief attacks ity is terminated by hyperpolarization due to the inlux
of unilateral pain in the territory of one or more of potassium ions (7).
branches of the trigeminal nerve; the diagnostic cri- When the compression is relieved operatively, pain
teria for this condition, as deined by the International usually ceases immediately. his is explained by the
Headache Society (IHS), are listed in Table 30.1 (1). It reduction in ectopic impulse generation (6). Progres- 127
has an overall prevalence of 1:30000 and occurs mostly sive demyelination may also be associated with axonal
damage, such that trigeminal neuralgia can induce recur, the same drug may be used again and is likely to
spontaneous continuous pain in the long-term or on be therapeutic for a second course.
a chronic basis. At this stage, the success rate of neu- Interventional treatment procedures may be indi-
rovascular decompression is considerably reduced (8). cated if drug therapy is unsuccessful (9). hese include
Young patients in an age range of 15–45 years microvascular decompression in the cerebello-pontine
who are alicted with trigeminal neuralgia must be angle, percutaneous procedures at the Gasserian gan-
investigated for an underlying disease. Multiple scle- glion, and radiosurgical treatment. Based on the
rosis presents with symptoms resembling trigemi- pathomechanism of neurovascular compression,
nal neuralgia in 1–5% of cases. Other symptomatic the surgical procedure named ater Janetta (10) may
causes include tumors of the cerebellar pontine angle, successfully abolish the underlying cause of trigeminal
aneurysms, or ischemic brain infarction. In these con- neuralgia. Healthy patients capable of undergoing
ditions, a cranial MRI scan can exclude a tumor, general anesthesia are eligible. he trigeminal root is
an aneurysm, a cerebral infarct, or an inlammatory decompressed by a retrosigmoidal approach through
demyelinating lesion diagnostic of multiple sclerosis. the occipital fossa, the trigeminal root is identiied,
Neurophysiologic tests including the blink relex, the and if a compressing artery can be seen, it is separated
masseter relex, and evoked potentials of the trigem- from the nerve (Figure 30.2). Short- and long-term
inal nerve may also substantiate a trigeminal nerve success rates are good with acute improvement in
lesion. If multiple sclerosis is suspected, cerebrospinal 87–98% of patients and long-term results at 8 years
luid and neurophysiologic investigation are helpful. in 60% of patients. he rate of complications is 1–2%
Because the pain attacks or sensations induced by with rare serious complications (2, 11).
trigeminal neuralgia are brief, medical treatment is Older patients in poor general health can be treated
best directed toward reducing the number of attacks. with selective percutaneous high frequency thermo-
Drugs acting at voltage-gated sodium channels appear lesions of the Gasserian ganglion. Under radiographic
most therapeutic. Carbamazepine remains the drug of control, a needle is introduced into the foramen
choice and is the only drug tested in several placebo- ovale. Radiofrequency stimulation is used to selec-
controlled randomized controlled trials. he therapeu- tively destroy the nociceptive trigeminal ibers. he
tic dose is between 800 and 1600 mg/day; the ini- relapse rate is 20% in 10 years but the procedure can be
tial dose of 200 mg bid should be gradually and care- repeated. his method can also be helpful in patients
fully incremented. Sustained-release formulations are with multiple sclerosis. Percutaneous balloon com-
preferable. he initial response rate to carbamazepine pression is an alternate procedure (12). Because both
is almost 90%. Increases in dosage strength may are essentially destructive procedures, numbness and
be necessary throughout the duration of the disease. dysesthesias may occur as side-efects, more rarely ker-
Side-efects include sedation, dizziness, and unsteady atitis, anesthesia dolorosa, and dysfunction of mastica-
gait; these issues must be addressed while achieving tory muscles. Stereotactic gamma knife radiosurgery
a therapeutic dose. If rapid onset of action is needed, is a third procedure considerably less destructive than
phenytoin can be given intravenously (of label use) the above. It has an initial success rate of 86% and 75%
at 250 mg bid ater exclusion of conduction block by at 33 months (13). Complications are mild and occur
EKG, or orally using 100 mg tid. Second-line drugs in approximately 10% of cases. his method has shown
are lamotrigine, which has been used as an add-on eicacy in patients with trigeminal neuralgia caused by
medication in one small trial, and gabapentin, which multiple sclerosis (14).
has been eicient in open-label trials. Case reports
describe successful pain control with valproic acid,
oxcarbazepine, pregabalin, and topiramate; data from Pain in trigeminal neuralgia
randomized controlled trials are unavailable. Miso- he pain attacks in trigeminal neuralgia are typically
prostol was useful in a small case series of patients with described as lancinating, stabbing, or electric-shock–
multiple sclerosis. like. hey may occur spontaneously or be triggered by
Spontaneous remissions may occur in the natural trivial stimuli such as touching the skin, chewing, talk-
history of trigeminal neuralgia. he weaning of pain ing, brushing the teeth, shaving, or even a breeze of
128 medication may be considered in a patient who has air. he second or third branch of the trigeminal nerve
been asymptomatic for at least 2 months. If symptoms is most commonly involved. An individual attack may
Chapter 30: Trigeminal neuralgia
last a mere second but because they usually occur in (6) Love S, Coakham HB. Trigeminal neuralgia:
clusters, patients may report that they last for longer pathology and pathogenesis. Brain 2001;124:
durations of time. Fearing the onset of new attacks, 2347–2360.
elderly patients may avoid luid and food intake, and (7) Zakrzewska JM, McMillan R. Trigeminal neuralgia:
may present in the clinic in a dehydrated, oten con- the diagnosis and management of this excruciating
fused state. Some patients become suicidal. he patho- and poorly understood facial pain. Postgrad Med J
2011;87:410–416.
physiology is assumed to entail demyelination of noci-
ceptive A-delta ibers at the entrance into the pons. (8) Tyler-Kabara EC, Kassam AB, Horowitz MH, et al.
Predictors of outcome in surgically managed patients
his is believed to lead to a faster spread of excitation,
with typical and atypical trigeminal neuralgia:
for example through ephaptic connections between comparison of results following microvascular
nerve ibers. he explanation is plausible considering decompression. J Neurosurg 2002;96:527–531.
the therapeutic actions of the sodium channel blocker (9) Zakrzewska JM, Akram H. Neurosurgical
carbamazepine in this disease. interventions for the treatment of classical trigeminal
neuralgia. Cochrane Database Syst Rev 2011;9:
References CD007312.
(1) Headache Classiication Committee of the (10) Jannetta PJ. Outcome ater microvascular
International Headache Society. he International decompression for typical trigeminal neuralgia,
Classiication of Headache Disorders. 2nd edition. hemifacial spasm, tinnitus, disabling positional
Cephalalgia 2004;24(Suppl 1):1–160. vertigo, and glossopharyngeal neuralgia (honored
guest lecture). Clin Neurosurg 1997;44:331–
(2) Prasad S, Galetta S. Trigeminal neuralgia: historical
383.
notes and current concepts. Neurologist 2009;15:
87–94. (11) Sekula RF, Marchan EM, Fletcher LH, Casey KF,
Jannetta PJ. Microvascular decompression for
(3) Meaney JF, Eldridge PR, Dunn LT, Nixon TE,
trigeminal neuralgia in elderly patients. J Neurosurg
Whitehouse GH, Miles JB. Demonstration of
2008;108:689–691.
neurovascular compression in trigeminal neuralgia
with magnetic resonance imaging. Comparison with (12) Skirving DJ, Dan NG. A 20-year review of
surgical indings in 52 consecutive operative cases. percutaneous balloon compression of the trigeminal
J Neurosurg 1995;83:799–805. ganglion. J Neurosurg 2001;94:913–917.
(4) Patel A, Kassam A, Horowitz M, Chang YF. (13) Kondziolka D, Lunsford LD, Flickinger JC.
Microvascular decompression in the management of Stereotactic radiosurgery for the treatment of
glossopharyngeal neuralgia: analysis of 217 cases. trigeminal neuralgia. Clin J Pain 2002;18:
Neurosurgery 2002;50:705–710; discussion 710–711. 42–47.
(5) Lorenzoni J, David P, Devriendt D. Patterns of (14) Regis J, Metellus P, Hayashi M, Roussel P, Donnet A,
neurovascular compression in patients with classic Bille-Turc F. Prospective controlled trial of gamma
trigeminal neuralgia: a high-resolution MRI-based knife surgery for essential trigeminal neuralgia.
study. Eur J Radiol 2009 [Epub ahead of print]. J Neurosurg 2006;104:913–924.
129
Chapter
Headache and acute cerebral ischemia
31
Patients with an acute headache are oten fearful of infarct of the right posterior inferior cerebellar artery
having experienced a stroke. When presented with [Figure 31.1b]. he patient meanwhile had only mild
cases of acute and severe headache however, neurol- headache, increased vertigo, and no other neurologi-
ogists are inclined to consider subarachnoid hemor- cal symptoms or signs for the next 2 days. On the third
rhage as the classic emergency diagnosis, requiring day however, he awoke with nausea and vomited, and
immediate action. Cerebral ischemia is less oten con- his headache again increased in severity. On examina-
sidered in the context of acute headache. Headache at tion, he had developed nystagmus on let gaze but no
the onset of cerebral ischemia associated with stroke is other neurological deicits. Head CT revealed swelling
illustrated in the following case study. of the infarct with compression of the 4th ventricle, lat-
eral shit of the 3rd ventricle, and visible lower horns of
the lateral ventricles, indicating increased intracranial
Clinical case vignette pressure due to edema in the peri-infarct area [Figure
A 24-year-old law student experienced a sudden attack 31.1c]. he patient was transferred to the intensive
of vertigo on a Sunday while at rest, without any care unit. A posterior fossa craniectomy was con-
prior exertion. Soon aterward, he noticed a headache sidered but postponed because the patient remained
that began at the back of his skull and gradually stable. He received osmotherapy and was closely mon-
increased in intensity. On Monday, the headache inten- itored. Two days later, both the headache and nystag-
sity increased yet again, and the patient saw his gen- mus had resolved, and a control CT revealed normal-
eral practitioner. Due to the severity of the headache ization of the ventricles [Figure 31.1d]. he patient
in a young man who did not usually sufer from was subsequently discharged from the intensive care
head pains, a diagnosis of subarachnoid hemorrhage unit and investigated for a potential embolus that
was suspected. he patient was referred to the hos- may have caused the stroke. Doppler sonography, 24-h
pital emergency department that same night. He was EKG, laboratory tests for a coagulation disorder, and
found to have mild neck stifness (meningismus), cerebral angiography were all normal. Finally, trans-
but was awake, alert, and had an otherwise nor- esophageal echocardiography detected a patent fora-
mal neurological examination. An emergency cranial men ovale with a hypermobile atrial septum. Antico-
computed tomography (CT) did not detect intracra- agulation with warfarin was considered the treatment
nial blood and was considered normal. A spinal tap of choice but was initiated only 2 weeks later to reduce
was performed in the expectation of inding hemor- the risk of hemorrhagic transformation of the infarct.
rhagic cerebrospinal luid (CSF), conirming a diag-
nosis of subarachnoid hemorrhage. he CSF however,
was clear and contained 50 cells/␮l of mostly lym-
phocytes. A putative diagnosis of viral meningitis was Pain description
made and CSF samples were sent for analysis. he he patient described a novel posterior headache that
patient received intravenous paracetamol for symp- developed subacutely at the time of presentation then
tomatic treatment and headache intensity decreased worsened on day 3, coincident with evidence for cere-
from 6/10 to 3/10. he CT was re-evaluated, and a bellar edema. It was associated with nausea, vom-
130 right cerebellar infarct was diagnosed [Figure 31.1a]. iting, neck stifness, and other symptoms and signs
Magnetic resonance imaging (MRI) conirmed a large of cerebral ischemia. While the association has been
Chapter 31: Headache and acute cerebral ischemia
Figure 31.1. Cranial images from the

patient presented in this vignette. A head
CT scan in (a) showed mild hypointensity
of the right cerebellum (circled), identified
as an extensive infarction on a FLAIR
sequence MR (b). Later on day 3 during his
hospitalization, significant edema of the
right cerebellar hemisphere with shift
(large arrow) was identified with
enlargement of the temporal horns of the
lateral ventricles (small arrows). Two days
later the ventricular enlargement had
resolved, along with the headache
(d). Courtesy of Prof. Solymosi, Department
of Neuroradiology, University Hospital of
Würzburg.
a b
c d
previously recognized, presentation of stroke with a detecting early infarction in the posterior fossa, an
new onset headache in a young patient is unusual. MRI with difusion-weighted imaging (DWI) is gener-
ally accepted as the investigation of choice (1). It must
be noted however, that MRI also has low sensitivity in
Discussion the cerebellum. While the overall sensitivity of DWI
Two aspects of this case history are important: 1. he is 80–95% in the irst 24 h, false-negative studies may
occurrence of headache at the onset of stroke without occur, especially in the posterior circulation (2).
accompanying neurological deicits. 2. he renewed Our patient had no obvious risk factors. Risk
increase in headache intensity concurrent with the rise factors for cerebellar infarcts are generally identi-
in intracranial pressure. cal to those for ischemic stroke and include: hyper-
Upon initial presentation, our patient underwent tension, diabetes, cigarette smoking, hyperlipidaemia,
a CT scan to rule out a subarachnoid bleed. Because and atrial ibrillation. Vertebral artery dissection ater
CT is typically negative in the irst hours ater acute preceding trauma might have induced his stroke but a 131
ischemic stroke and also has a low sensitivity for dissection was not visualized using duplex sonography
or MRI. he patient had no history of trauma; how- experience double vision, disturbances of pupillary
ever, a history of major or minor head or neck reaction and a progressive decline in level of con-
trauma, including chiropractic manipulations, is iden- sciousness. Corticosteroids have no efect and osmotic
tiied in fewer than half of cases of dissection (3). diuretics have only transient beneits. If craniectomy
Patent foramen ovale is yet another potential cause is attempted on patients who become comatose, the
of embolism in young patients. In a study involving outcome is favorable in 50% of cases. Without surgery,
patients younger than 40 years of age who sufered there is an 85% risk of death (3).
a cerebellar stroke, approximately 50% were found to Surgical intervention remains contentious. Exter-
have a patent foramen ovale (4). Less common causes nal ventricular drainage is considered the irst meas-
include hypercoagulable states, vasculitis, and acute ure. Suboccipital craniectomy with removal of the
marijuana or cocaine use. In our patient, the presence infarcted tissue is usually attempted next because
of a patent foramen ovale with a hypermobile atrial craniectomy in itself carries an increased risk of mor-
septum was conirmed and the likely cause of his cere- bidity and mortality (3).
bellar stroke.
Infarcts of the cerebellum oten result in gen-
eral symptoms including dizziness, nausea, vomiting, Pain in acute cerebral ischemia
unsteady gait, and headache, all of which can be caused Headache is not usually considered a hallmark of
by common and benign disorders. Neurological signs, ischemic stroke; the frequency of headache is higher
like dysarthria, ataxia, and nystagmus, may be absent in intracerebral hemorrhage than in ischemia (7, 8).
or very mild (3). Of the three vascular areas in the cere- However, headache at the onset of cerebral ischemia
bellum, the posterior inferior cerebellar artery (PICA), may occur and its frequency, characteristics, and rela-
anterior inferior cerebellar artery (AICA), and super- tion to stroke localization are well documented (9).
ior cerebellar artery (SCA), the PICA appears most he incidence of headache is slightly higher in strokes
associated with headache and vertigo (5). of the posterior than the anterior circulation (15–65
In our patient, the inding of CSF pleocytosis with vs. 8–46%). Also, headache intensity tends to be higher
50 cells/␮l could have been diagnostic of a viral menin- in posterior circulation ischemia. On average, 40% of
gitis. He had no fever and general malaise, which patients with cerebellar stroke experience headache
can also be typical of this condition. Furthermore, (10). Because patients typically manifest neurological
enteroviruses are known to cause syndromes with deicits like hemiparesis or aphasia during an ischemic
headache and gastrointestinal disturbance. Cerebral attack, headache is infrequently described. Physicians
vasculitis, which can also cause stroke associated with may fail to question patients regarding the presence
headache, was considered but angiography of the cere- of headache while patients may either be too anxious
bral arteries was normal. CSF analysis is not useful about their other neurological deicits or incapable of
or even recommended in patients with stroke (and expressing themselves. his case, which highlights the
is contraindicated if a cerebellar stroke with swelling constellation of headache as essentially the singular
is suspected); there may be CSF pleocytosis of up to symptom in a large ischemic stroke, is striking. Data
60 cells/␮l if a spinal tap is performed early in cerebral for this scenario are currently unavailable. It should
ischemia, particularly if the infarct is close to the sub- be noted that headache may also be a symptom of
arachnoid surface (6). a transient ischemic attack (TIA); several prospective
he secondary increase in headache intensity asso- studies suggest that this occurs in 16 to 36 of cases
ciated with vomiting on day 4 of our patient’s admis- (11, 12). he frequency of headache in cardioembolic
sion was likely due to increased intracranial pres- stroke is not diferent from that in large vessel dis-
sure. Infarcts in the posterior fossa lead to edema ease. One exception however, may occur in the case
formation resulting in compression of adjacent tis- of lacunar stroke where headache frequency is low,
sue in approximately 10–20% of patients. On aver- i.e., 1–23% (9). Headache quality in stroke does not
age, edema peaks on the third day post-infarction appear to have any deining features and may mimic
but can occur at any time within the irst 7 days tension-type headache, migraine, or others. he pain
(3). Approximately 50% of patients with radiograph- is oten pressure-like, or sometimes pulsating. Patients
132 ical evidence of a mass efect also deteriorate clini- have also described stabbing or burning sensations.
cally due to increased intracranial pressure. hey may he localization of the pain is not strictly related to
Chapter 31: Headache and acute cerebral ischemia
the site of the ischemia. Prospective studies have been been a second possibility on his diferential diagnosis.
unable to conirm past observations that patients with Vestibular migraine presents at any age and is known
ischemia in the territory of the basilar artery may ex- to peak in men in their fourth decade. It is character-
perience a severe throbbing occipital headache that is ized by repeated attacks of vertigo lasting seconds to
aggravated by stooping and straining (see Evans and hours and rarely days, as well as a mild to moderate
Mitsias (9)). Similarly, the headache site is not help- headache.
ful in predicting stroke localization. he onset of the In summary, occipital headache with vertigo
headache may be acute or gradually increase in sever- may be indicative of cerebellar infarct. A secondary
ity. he severity is greatest at presentation. A headache increase in headache character in a patient with cere-
that is considered to be stroke-related must persist for a bellar infarct is highly suspicious of increased intracra-
minimum of one day. he mean duration is 3.8 days. As nial pressure.
with subarachnoid hemorrhage, a sentinel headache
which occurs hours to days before the ischemic
event may occur in approximately 10–43% of patients References
(13, 14). (1) Olivot JM, Albers GW. Difusion-perfusion MRI for
Because headache is a common occurrence, it may triaging transient ischemic attack and acute
be diicult to decide which patients require further cerebrovascular syndromes. Curr Opin Neurol
investigations. Young patients with a headache asso- 2011;24:44–49.
ciated with dizziness or vertigo should be monitored (2) Oppenheim C, Stanescu R, Dormont D, et al.
because these symptoms may be warning signs of cere- False-negative difusion-weighted MR indings in
bellar infarction or vertebral artery dissection (14). acute ischemic stroke. AJNR Am J Neuroradiol
Most guidelines concur that physicians should be 2000;21:1434–1440.
vigilant about and investigate all patients with new, (3) Edlow JA, Newman-Toker DE, Savitz SI. Diagnosis
abrupt-onset, persistent, or unusual headaches, par- and initial management of cerebellar infarction.
Lancet Neurol 2008;7:951–964.
ticularly if located posteriorly or in the neck (15, 16).
“hunderclap” headaches may similarly herald cere- (4) Barinagarrementeria F, Amaya LE, Cantu C. Causes
and mechanisms of cerebellar infarction in young
bellar infarction (17).
patients. Stroke 1997;28:2400–2404.
he pathophysiology of stroke-related headache
(5) Kase CS, Norrving B, Levine SR, et al. Cerebellar
is unclear. Because there are no nociceptors in the
infarction. Clinical and anatomic observations in 66
brain parenchyma, pain signals come from meningeal cases. Stroke 1993;24:76–83.
aferents and the innervation of the large cerebral
(6) Carhuapoma JR, Welch KMA. Cerebral spinal luid in
arteries. hese are likely activated by stretching due stroke. In: Welch KMA, Caplan LR, Reis DJ, Siesjö
to the edema associated with large infarcts. In cases BK, Weir B, eds. Primer on Cerebrovascular Diseases.
of small to medium infarcts, other mechanisms of San Diego: Academic Press, 1997:597–599.
headache generation are presumed. hese include (7) Vestergaard K, Andersen G, Nielsen MI, Jensen TS.
direct ischemia of these structures or the release of Headache in stroke. Stroke 1993;24:1621–1624.
algogenic substances, for example vasoactive neu- (8) Jorgensen HS, Jespersen HF, Nakayama H, Raaschou
ropeptides or nitric oxide, from vessels related to the HO, Olsen TS. Headache in stroke: the Copenhagen
ischemic area (9). Stimulation of the trigeminovascu- Stroke Study. Neurology 1994;44:1793–1797.
lar system by large vessel aferent ibers around the (9) Evans RW, Mitsias PD. Headache at onset of acute
large arteries is assumed to be the inal pathway. he cerebral ischemia. Headache 2009;49:902–908.
density of perivascular innervation may be higher in (10) Tentschert S, Wimmer R, Greisenegger S, Lang W,
the posterior circulation, a likely explanation for the Lalouschek W. Headache at stroke onset in 2196
higher prevalence of headache in this area. patients with ischemic stroke or transient ischemic
he average age of patients diagnosed with cerebel- attack. Stroke 2005;36:e1–e3.
lar infarct is 65 years (3). his occurrence in our young (11) Edmeads J. he headache of ischemic cerebrovascular
patient is unusual. He had no family history of neuro- disease. Headache 1979;19:345–349.
logical disease. His complaints of vertigo and headache (12) Ferro JM, Costa I, Melo TP, et al. Headache
were initially diagnosed as a possible gastrointesti- associated with transient ischemic attacks. Headache 133
nal disorder although vestibular migraine might have 1995;35:544–548.
(13) Gorelick PB, Hier DB, Caplan LR, Langenberg P. (16) Kim BM, Kim SH, Kim DI, et al. Outcomes and
Headache in acute cerebrovascular disease. Neurology prognostic factors of intracranial unruptured
1986;36:1445–1450. vertebrobasilar artery dissection. Neurology
(14) Williams D, Wilson TG. he diagnosis of the major 2011;76:1735–1741.
and minor syndromes of basilar insuiciency. Brain (17) Sutton Brown M, Morrish W, Zochodne DW.
1962;85:741–774. Recurrent coital “hunderclap” headache associated
(15) Jordan JE. Headache. AJNR Am J Neuroradiol with ischaemic stroke. Cephalalgia 2006;26:1028–
2007;28:1824–1826. 1030.
134
Section G Treatment
Chapter
Therapeutics in neuropathic pain
32
he speciic mechanisms responsible for generating Overall approaches are to exclude other causes
neuropathic pain continue to be unravelled. he hope of pain, as well as evaluating and treating concur-
is that novel and targeted approaches will ofer bet- rent depression, underlying medical disorders (uncon-
ter eicacy than current approaches. At the time of trolled glycemic control in diabetes, hypertension,
writing, these approaches are well dissected by guide- obesity, hyperlipidemia, smoking), and adjacent sot
lines and literature reviews, some recently published. tissue injury, including ulcers. For allodynia, use of a
None of the agents highlighted by these publications blanket cradle to lit bedclothes from the feet is help-
have ofered dramatic pain relief and all therapeu- ful. Abnormalities of gait may predispose patients to
tic regimens sufer from potential side-efects. he pain from hip, knee, and ankle injury. Some patients
guidelines and agents described in this chapter, there- with more severe lower limb weakness may develop
fore, are likely to be outdated soon as newer trials carpal tunnel syndrome from overuse of the upper
are completed and published. It is also important to limbs.
emphasize that the recommendations, dosing sched- For pharmacological pain therapy, the major
ules, and potential side-efects are only summarized classes of agents used are antidepressants, includ-
here. hey do not substitute for a detailed appraisal ing serotonin and norepinephrine uptake inhibitors,
of proposed therapy in a given patient, and it is anti-epileptics (“anti-convulsants”), and opioids. Pub-
imperative for the clinician to consult primary litera- lished guidelines also include other pharmacological
ture and detailed drug monographs when considering approaches but uniformly admit that their evidence
therapy. basis is lower tiered.
Overall considerations Guidelines

herapy for neuropathic pain should begin with con-
sideration of nonpharmacological approaches such as EFNS guidelines 2010 (1)
the use of comfortable, properly itting footware, treat- he most recent 2010 version of the EFNS guide-
ment of associated foot ulcers, exclusion of other lines for the treatment of neuropathic pain used a
causes of pain, and simple self-limited use of anal- search of the Cochrane library from 2005 expanded
gesics. If possible, reversal of the underlying neuro- to MEDLINE and other electronic databases includ-
logical cause for pain should be undertaken, a direc- ing unpublished industry trials. Sixty-four RCTs (ran-
tion that may obviate the need for ongoing speciic domized controlled trials) using placebo or active drug
pain therapy. In many chronic neurological disor- comparators were identiied. Level A evidence was
ders with irreversible disability and damage however, presented for: duloxetine, gabapentin-morphine, tri-
this option is not available. Treatment needs to take cylcic antidepressants, gabapentin, oxycodone, pre-
into account the needs and preferences of patients gabalin, tramadol, and venlafaxine ER. Level B rat-
and patients should have the opportunity to make ings for eicacy were described for botulinum toxin,
informed decisions. Good communication is essential dextromethorphan, gabapentin/venlafaxine, and levo-
and should be supported by evidence-based written dopa. Carbamazepine and phenytoin achieved level
information. his material should also be culturally C ratings for eicacy overall but carbamazepine had
appropriate. a speciic level A rating in trigeminal neuralgia. 135
Section G: Treatment
Recommendations were duloxetine, gabapentin, pre- improving quality of life and sleep. Gabapentin and
gabalin, tricyclic antidepressants, and venlafaxine ER sodium valproate were classiied as probably efective
as irst-line therapy and opioids, including tramadol, and given a Level B Recommendation. A lag concern-
as second or third line. ing the risk of birth defects was placed for sodium
valproate. Other agents deemed probably efective
(Level B) were: amitriptyline, venlafaxine, duloxetine,
Recommendations of IASP (International dextromethorphan, morphine sulfate, tramadol, oxy-
Association for the Study of Pain), codone, capsaicin, isorbide dinitrate, and percuta-
neous electrical stimulation. Topiramate, desipramine,
NEUPSIG (Neuropathic Pain Special Interest imipramine, luoxetine or the combination of nor-
Group)(2) 2010 triptyline and luphenazine, and alpha lipoic acid had
his working group suggested symptomatic treatment insuicient evidence for or against their use. Oxcar-
of neuropathic pain with one of the following: 1. nor- bazepine, lamotrigine, lacosamide, clonidine, pentoxi-
triptyline, desipramine, or an SNRI (serotonin and fylline, and mexiletine had evidence against their efec-
norepinephrine reuptake inhibitors speciically dulox- tiveness (negative Level B Recommendation).
etine or venlafaxine); 2. gabapentin or pregabalin;
3. topical lidocaine for localized pain; 4. opioids or
tramadol alone or in combination for acute exac-
erbations. his group had a stepwise approach to
pain management: Step 1 - assessment of patient and
National Institute of Health and Clinical
investigate causes, comorbidities, including detailed Excellence (NICE, United Kingdom; from:
discussion with patient; Step 2 - therapy as above; www.nice.org.uk/guidance/cg96)
Step 3 - reassess pain and health-related quality of
his analysis considered 34 forms of pharmacolog-
life, continue therapy if pain is 3/10 or less, con-
ical treatment for neuropathic pain and examined
sider second- or third-line therapy if unsuccessful
23,207 studies including 90 randomized controlled
and if needed, referral to pain specialist or pain
clinical trials including economic evidence. he guide-
clinic.
lines recommended duloxetine for painful diabetic
neuropathy as irst-line therapy. If this agent was
Evidence-based guidelines for the contraindicated, amitriptyline then pregabalin were
the next choices. hird-line treatment considered tra-
treatment of diabetic neuropathic pain, AAN madol alone or in combination with second-line ther-
(American Academy of Neurology), AANEM apies. Topical lidocaine was suggested for localized
pain. Duloxetine was thought to be the most cost efec-
(American Association of Neuromuscular tive treatment followed by amitriptyline and prega-
and Electrodiagnostic Medicine), and balin.
AAPMR (American Academy of Physical
Medicine and Rehabilitation) (3)
his group based their recommendations for the
treatment of diabetic neuropathic pain on a litera- Commentary on guidelines
ture search of MEDLINE and EMBASE of fully pub- Taken together, these guidelines for the treatment
lished peer-reviewed articles between 1960 and August of neuropathic pain provide relatively similar rec-
2008. Both pharmacological and nonpharmacological ommendations. he AAN guidelines focus on dia-
approaches were considered. Among 2234 abstracts betic neuropathic pain, unlike the others listed. First-
used to identify full-length papers, 79 articles were line recommendations (or Level A Recommendations)
included, excluding case reports and review articles. vary because of diferences in diabetic and nondiabetic
Based on Class I evidence, pregabalin was established neuropathic pain trials as well as difering criteria for
136 as a Level A Recommendation as efective in lessen- weighting of the evidence (e.g., % study population
ing the pain of peripheral diabetic neuropathy and retention).
Chapter 32: Therapeutics in neuropathic pain
Speciic agents1 Opioids

Tramadol can be initiated at 37.5 mg po q3–6h, and is
Calcium channel ␣2-␦ ligands, gabapentin, oten combined with 325 mg of acetaminophen [long-
and pregabalin acting preparations starting at a single dose of 100–150
mg daily to a maximum of 300–400 mg daily]; long-
Gabapentin can be initiated in low doses (e.g., 300
acting (controlled-release) oxycodone 10–100 mg can
mg qhs) and increased to 300 mg tid to a maxi-
be given divided into twice daily administration [ratio
mum of 3600–4000 mg daily. It does not interfere
of eicacy to morphine is 1.5 mg oxycodone/1.0 mg
with the metabolism of other drugs and is nominally
morphine]; morphine sulfate is given as 30–60 mg
nonsedative and nonaddictive. Side-efects are: dizzi-
bid of a long-acting preparation (e.g., MS contin) and
ness, fatigue, and cognitive complaints with initial
may be the treatment of choice with severe unremit-
usage or higher doses, and lower limb edema. hese
tant pain and severe underlying systemic disease (e.g.,
agents are excreted by the kidney (dose reduction in
renal failure, cardiac disease); side-efects from opioids
renal failure). Pregabalin can be started at 75 mg qhs,
are as follows: cognitive dysfunction, somnolence, res-
titrated up to 75 mg bid to a maximum of 600 mg daily.
piratory depression, constipation, pruritus, dizziness,
he side-efect proile is similar to gabapentin.
nausea, vomiting, and rebound headache syndrome;
risk of addiction, dose escalation, and withdrawal syn-
Serotonin and norepinephrine reuptake drome; questionable risk of suicidal ideation from oxy-
codone.
inhibitors (SSRIs and SSNRIs;
antidepressants) Local agents
Venlafaxine can be initiated at 37.5 mg/day and he 5% lidocaine patch can be used in post-herpetic
increased weekly by 37.5 mg/day to a maximum of 225 neuralgia. It is applied to the area of painful skin for
mg/day. Side-efects are: nausea, dizziness, drowsiness, 12 h and then removed for the next 12 h. he eicacy
hyperhidrosis, hypertension, and constipation. Dulox- may not be potent enough in monotherapy but it can
etine can be started at 30 mg daily titrated up to a max- be a useful supplement to systemic treatment and has
imum of 120 mg daily. Side-efects are: risk of hepato- few side-efects. he 8% capsaicin patch is licensed in
toxicity, nausea, dry mouth, constipation, somnolence, Europe for peripheral neuropathic pain excepting that
hyperhidrosis, and decreased appetite. Amitriptyline from diabetic neuropathy. It is applied to the painful
can be started at 10–25 mg qhs once daily then skin for 30 min ater local anesthesia and may provide
titrated up to 100–150 mg. Side-efects include next pain relief for up to 12 weeks. Side-efects may be local
day drowsiness, lethargy, dry mouth, constipation, reactions and an initial increased burning pain.
and bladder retention; amitriptyline may help with
prominent nocturnal pain; exert caution in patients
with cardiac conduction abnormalities or prostatic
References
(1) Attal N, Cruccu G, Haanpaa M, et al. EFNS guidelines
hypertrophy. on pharmacological treatment of neuropathic pain.
Eur J Neurol 2006;13:1153–1169.
(2) Dworkin RH, O’Connor AB, Audette J, et al.
Recommendations for the pharmacological
1
herapeutic agents are only briely described here and management of neuropathic pain: an overview and
recommendations are listed as suggestions only. Clinicians literature update. Mayo Clin Proc 2010;85:S3–S14.
should be aware that recommended therapy for pain or (3) Bril V, England J, Franklin GM, et al. Evidence-based
other disorders may change with time and the regimens and guideline: treatment of painful diabetic neuropathy:
approvals vary with the jurisdiction. All therapeutics should report of the American Academy of Neurology, the
be used only with complete reference to indications, con- American Association of Neuromuscular and
traindications, adverse efects, and dosage. hese suggestions Electrodiagnostic Medicine, and the American
are also not based on speciic FDA approval in the United Academy of Physical Medicine and Rehabilitation.
States. Neurology 2011;76:1758–1765.
137
Index
acetaminophen anti-neutrophil cytoplasmic antibodies capsaicin 68, 137

CIDP 43 54 CIDP 43
herpes zoster 37, 38 arachidonic acid 22 carbamazepine
lumbosacral plexopathy 23 Fabry disease 72
arrelexia 42
acid-sensing ion channels 8 neuralgic amyotrophy 36
arthralgia 68 paroxysmal hemicrania 122
acroparesthesia 72
ASIC channels 29 phantom pain 84
alendronate 79 trigeminal neuralgia 108, 126, 128
ATP 4 vasculitic neuropathy 54, 55, 57
algesic molecules 4–5, 22
axonal endbulbs 3 carpal tunnel release 17, 18
allodynia 2, 5, 28
amyloid-associated polyneuropathy azathioprine carpal tunnel syndrome 16–18, 45, 70,
63 CIDP 41, 43 104
central post-stroke pain 104, 106 vasculitic neuropathy 54, 56 pain characteristics 17–18
chronic migraine 115 risk factors 17
CRPS 79 baclofen
diabetic polyneuropathy 46 amyotrophic lateral sclerosis 95 causalgia 18, 77
herpes zoster 39 multiple sclerosis 111 celecoxib 50
sarcoidosis 68 vasculitic neuropathy 57 paroxysmal hemicrania 124
syringomyelia 101 balance, loss of 50 central post-stroke pain 104–106
allopurinol 50 benserazide 90 cerebral ischemia, acute 130–133
amiloride 50 beta-endorphin 5 pain characteristics 132–133
amitriptyline 137 bisphosphonates in CRPS 78, 79 cervical radiculopathy 19–22
amyloid-associated polyneuropathy pain characteristics 21–22
63 borrelia-associated radiculitis 30–32
cesamet 43
anti-MAG polyneuropathy 61 botulinum toxin in amyotrophic lateral
central post-stroke pain 105 sclerosis 95 chemokines 4, 25
CIDP 43 brachial neuritis 34–36 chronic constriction injury 29
CRPS 77
diabetic polyneuropathy 46 brachial plexus 35 chronic inlammatory demyelinating
migraine 116 injury 19 polyneuropathy. See CIDP
neuralgic amyotrophy 36 bradykinin 4, 61 CIDP 41–44, 61
phantom pain 84 pain characteristics 44
sarcoidosis 68 brainstem relays 10–11
citalopram 77
vasculitic neuropathy 54, 55, 57 Brown-Séquard syndrome 96–98
clodronate 79
amputations, phantom pain 84–87 Bruns-Garland syndrome. See
lumbosacral plexopathy cluster headache 118–121
amyloid-associated polyneuropathy diferential diagnosis 119
62–65 burning feet 44, 64, 68 pain characteristics 120–121
pain characteristics 64 prevalence 119
amyloidosis 43 calcitonin 79
CMAPs
amyotrophic lateral sclerosis 93–95 calcitonin gene-related peptide 4, 18 amyloid-associated polyneuropathy
pain characteristics 94–95 calcium channel ␣2-␦ ligands 137 62
analgesic molecules 5 candesartan 50 CIDP 42
diabetic polyneuropathy 45
anti-MAG polyneuropathy 59–61 cannabinoids 5 painful idiopathic polyneuropathy
138 pain characteristics 60–61 multiple sclerosis pain 111 50
Index
polyneuropathy 59 dorsal root ganglia 6–9, 21 galanin 5

vasculitic neuropathy 54 doxepine 122 gliclazide 23
codeine duloxetine 137 glucocorticosteroids 120
CIDP 43 diabetic polyneuropathy 48
herpes zoster 37 Guillain-Barré syndrome 35, 36, 60
lumbosacral plexopathy 23 dysarthria 93
painful idiopathic polyneuropathy dysesthesia 109 Hargreaves test 46
51
headache
complex regional pain syndromes 6, ectopic impulses 4 cerebral ischemia 130–133
18, 77–80 edema 62 cluster 118–121
pain characteristics 78–80 migraine 113–116
electromyography 54
compound motor action potentials. See multiple sclerosis 110
needle. See needle electromyography
CMAPs paroxysmal hemicrania 122–124
enzyme replacement therapy in Fabry thunderclap 133
constipation 23, 30, 32 disease 70, 72
hearing loss 70, 71
cortical pain centers 11 erectile dysfunction 23, 45, 62
heat intolerance 70
corticosteroids erythromelalgia 3, 53
carpal tunnel syndrome 17 herpes zoster 37–40
CRPS 79 pain characteristics 39
Fabry disease 70–72
sarcoidosis 68 pain characteristics 72 herpes zoster ophthalmicus 39
cranial neuritis 39 familial amyloidotic polyneuropathy histamine 4
CRPS. See complex regional pain 63 Hofman sign 93
syndrome fentanyl 61 Horner’s sign 16, 19
cyclooxygenases 4, 22 central post-stroke pain 105
vasculitic neuropathy 55 Horner’s syndrome 101
cyclophosphamide
lupirtine hydromorphone
CIDP 41
central post-stroke pain 104 CIDP 43
sarcoidosis 68
paroxysmal hemicrania 122 painful idiopathic polyneuropathy
vasculitic neuropathy 55
51
cyclosporine A foot drop 42, 46, 54
hydromyelia 99
sarcoidosis 68
vasculitic neuropathy 55 gabapentin 50, 137 hyperalgesia 5, 7, 48, 63
amyloid-associated polyneuropathy central post-stroke pain 104,
cytokines 25 63 106
anti-inlammatory 5 amyotrophic lateral sclerosis 95 pressure 79
anti-MAG polyneuropathy 60, 61 syringomyelia 101
dantrolene 95 Brown-Séquard syndrome 96 thermal 29
decompressive surgery 17 central post-stroke pain 104,
hypoesthesia 104
deep brain stimulation 91 105
cervical radiculopathy 19 hypohidrosis 70, 71, 72
dexamethasone 120 CIDP 43 hyponatremia 54, 55
diabetes mellitus 45 diabetic polyneuropathy 46, 48
Fabry disease 72
diabetic amyotrophy 23–26 herpes zoster 37, 38 ICAM-1 22, 26
diabetic polyneuropathy 45–48 lumbosacral plexopathy 23, 25 indomethacin
experimental studies 46–48 multiple sclerosis 111 mode of action 124
pain characteristics 46–48 neuralgic amyotrophy 36 paroxysmal hemicrania 122, 123
diabetic thoracoabdominal painful idiopathic polyneuropathy inlammation 6
radiculopathy 32 51
sarcoidosis 68 inlammatory mediators 4
diazepam in CIDP 41, 43 side-efects 48 inherited sensitivity to pressure palsy
diclofenac 36 vasculitic neuropathy 54, 57 43
phantom pain 84 gait abnormalities interleukin-1␤ 4
diltiazem 57 antalgic gait 50
ataxic gait 54, 55 interleukin-6 22
dimenhydrinate 51 lurching gait 41 intracellular adhesion molecule-1. See 139
dimethylsulfoxide 79 steppage gait 62 ICAM-1
Index
intracranial pressure 132 morphine 61, 137 non-steroidal anti-inlammatory

intravenous gamma globulin 41, 43 CIDP 43 drugs. See NSAIDs
diabetic polyneuropathy 46 norepinephrine reuptake inhibitors
Jannetta operation 108 phantom pain 84 137
vasculitic neuropathy 57
nortriptyline
Kennedy’s disease 93 motor neuron disease 68 CIDP 43
multiple sclerosis 108–111 vasculitic neuropathy 57
lamotrigine pain characteristics 109–111
central post-stroke pain 105 novamine sulfone 124
multiple sclerosis 111 muscle cramps 55, 56, 57 NSAIDs
lateral femoral cutaneous nerve of the muscle weakness Brown-Séquard syndrome 96
thigh 27 CIDP 41 central post-stroke pain 104
herpes zoster 37 Parkinson’s disease 89, 91
levodopa 90
myelin-associated glycoprotein
Lhermitte’s sign 94, 108, 109, 110 60 obesity 27, 30
causes 110 omeprazole 50
myotonic dystrophy type 2 74–76
lidocaine 68, 137 pain characteristics 75–76 opioids 48, 137
losartan 37 See also speciic drugs
lumbar spondylosis 28 nabilone 51 osteoarthritis 27, 50
lumbosacral plexopathy 23–26, 45 natidrofuryl 57 osteoporosis 55
etiology 25 needle electromyography oxcarbazepine
pain characteristics 25 amyotrophic lateral sclerosis 93 trigeminal neuralgia 128
Lyme radiculopathy 30–32 diabetic polyneuropathy 45 vasculitic neuropathy 55, 57
pain characteristics 32 herpes zoster 39
myotonic dystrophy type 2 74 oxycodone 54, 137
polymyalgia rheumatica 82 central post-stroke pain 104
MAG. See myelin-associated herpes zoster 38
glycoprotein nerve conduction velocity 70 vasculitic neuropathy 57
mechanosensitivity 28 nerve growth factor 4 oxycontin 61
ion channels involved in 29 nervi nervorum 3, 5–6 amyloid-associated polyneuropathy
meningismus 130 neuralgic amyotrophy 34–36 63
meperidine 43 pain characteristics 35–36 CIDP 43
painful idiopathic polyneuropathy
meralgia paraesthetica 27–29 neurogenic inlammation 5–6 51
pain characteristics 28–29 neuromyotonia 57 oxygen therapy in cluster headache 119
metamizole 104 neuropathic pain 2
met-enkephalin 5 pain experience 2
neuropathic pain mechanisms 12
methotrexate 68 algesic molecules 4–5 painful idiopathic polyneuropathy
polymyalgia rheumatica 83 analgesic molecules 5 50–53
brainstem relays 10–11 pain characteristics 52–53
methylprednisolone
CIDP 41 cortical pain centers 11 pamidronate 79
cluster headache 120 dorsal horn of spinal cord 9–10
ectopic impulses 4 paresthesiae 2
trigeminal neuralgia 108 amyloid-associated polyneuropathy
nervi nervorum 5–6
methysergide 116 sensory dorsal root ganglia 6–9 62, 63
thalamic 11 anti-MAG polyneuropathy 60
migraine disability assessment scale CIDP 41
(MIDAS) 115 Wallerian degeneration 6
lumbosacral plexopathy 23
migraine, chronic 113–116 Neuropathic Pain Symptom Inventory syringomyelia 100
diferential diagnosis 115 (NPSI) 32
Parkinson’s disease 89–91
pain characteristics 115–116 neuropathy 2 pain characteristics 90–91
prevalence 115
nifedipine 23 paroxysmal extreme pain disorder 3, 7,
mirror therapy in phantom pain 86 53
nitric oxide 4, 22, 61
misoprostol 111, 128 paroxysmal hemicrania 119, 122–124
nociceptin 5
140 monoclonal gammopathy 59 pain characteristics 124
nociception 3
Index
Parsonage-Turner syndrome. See proteinase-activated receptors 4 sumatriptan

neuralgic amyotrophy cluster headache 118, 120
patent foramen ovale 132 quantitative sensory testing 53, 70, 72 migraine 113
quinidine 55 paroxysmal hemicrania 124
periumbilical angioektasia 70, 71
quinine 50, 57 SUNCT 124
Phalen’s sign 16, 17
sural nerve biopsy 51, 63
phantom pain 84–87 Ramsay Hunt syndrome 39 synthroid 37
phenytoin Randall-Selitto test 46
Fabry disease 70, 72 syringobulbia 100
vasculitic neuropathy 55 relex sympathetic dystrophy 6, 18, 77 syringomyelia 99–102
phonophobia 115, 120, 124 relexes 16, 30, 62, 104 pain characteristics 101–102
ankle 23, 24, 50, 59
photophobia 115, 120, 124 biceps 37 tabes dorsalis 3
pins and needles 16 brachioradialis 37 thalamic syndrome 105, 106
plantar 19, 30
plasma exchange 43 quadriceps 23, 24, 27, 28 thalamus 11
polymyalgia rheumatica 82–83 triceps 19, 21 thunderclap headache 133
pain characteristics 83 riluzole 93 Tinel’s sign 16, 17, 18, 28
polyneuropathy Romberg sign 23, 45, 46, 50, 59, 62
amyloid-associated 62–65 tizanidine 95
anti-MAG 59–61 ropivacaine 86 topiramate
CIDP 41–44 migraine 113, 116
Fabry disease 70–72 sarcoid peripheral neuropathy 66–68 multiple sclerosis 111
painful idiopathic 50–53 pain characteristics 68 painful idiopathic polyneuropathy
postherpetic neuralgia 39 Schwann cells 4, 61 51
trigeminal neuralgia 128
postural hypotension 62 sensory loss
anti-MAG polyneuropathy 59 tramadol 31, 137
prednisolone 34 carpal tunnel syndrome 16, 18 diabetic polyneuropathy 48
cluster headache 118 CIDP 41 phantom pain 84
CRPS 79 lumbosacral plexopathy 23 vasculitic neuropathy 55
prednisone 43 Lyme radiculopathy 30 transcutaneous electrical nerve
CIDP 41 meralgia paresthetica 27 stimulation (TENS)
cluster headache 120 sensory nerve action potentials. See painful idiopathic polyneuropathy
polymyalgia rheumatica 82, 83 SNAPs 51
pregabalin 137 phantom pain 84
SEPT9 gene mutation 36
amyotrophic lateral sclerosis 95 transient ischemic attacks 132
Brown-Séquard syndrome 96 serotonin re-uptake inhibitors 137
central post-stroke pain 104, 105 transient receptor potential channels
shoulder pain in neuralgic amyotrophy 29
diabetic polyneuropathy 46, 48 34–36
herpes zoster 38 transient receptor potential proteins 8
Lyme radiculopathy 32 small iber neuropathy 66, 67
trazodone 50
multiple sclerosis 109, 111 SNAPs
neuralgic amyotrophy 36 amyloid-associated polyneuropathy treatment 135–137
painful idiopathic polyneuropathy 62 EFNS guidelines 135
51 CIDP 41 evidence-based 136
Parkinson’s disease 89 Fabry disease 70 IASP recommendations 136
sarcoidosis 68 polyneuropathy 59 NICE guidelines 136
syringomyelia 100 See also speciic drugs
spasticity 94
trigeminal neuralgia 128 tremor 50
vasculitic neuropathy 55, 57 spinal cord
compression 21 tricyclic antidepressants 48
pressure palsy, inherited sensitivity to dorsal horn 9–10 central post-stroke pain 104
17 injury 97 trigeminal neuralgia 108, 109, 110,
propranolol 116 spondylosis 21 126–129
prostaglandin E2 22 pain characteristics 128
substance P 4, 18
prostaglandins 4 Sudeck’s atrophy 77
trigemino-autonomic cephalalgias 123 141
Index
trigeminovascular decompression migraine 116 vertigo 130

108 trigeminal neuralgia vitamin B complex 57
TRPA1 channel 29 128
TRPV1 channel 29 vasculitic neuropathy Wallerian degeneration 6
54–58 Wallerian-like degeneration 6
TRPV4 channel 29 pain characteristics 57
tumor necrosis factor ␣ 4, 26, weight loss 23
venlafaxine 137
61 painful idiopathic polyneuropathy white matter lesions 72
51
V30M mutation 64 zoster radiculitis 37–40
verapamil 120
valproate zoster sine herpete 39
142

Neuro Estudio de Casos Del Dolor Neurologico 2021

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Neuro Estudio de Casos Del Dolor Neurologico 2021

Uploaded by

Copyright:

Available Formats

Case studies in neurological pain

Cambridge University Press

Published in the United States of America by Cambridge

c Claudia Sommer and Douglas W. Zochodne 2012

his publication is in copyright. Subject to statutory

First published 2012

Printed and bound in the United Kingdom by the MPG Books

A catalog record for this publication is available from the British

Library of Congress Cataloging in Publication data

ISBN 978-0-521-69526-8 Paperback

Cambridge University Press has no responsibility for the

Every efort has been made in preparing this book to provide

Introduction 1 12 Pain in vasculitic neuropathy 54

2 Pain and carpal tunnel syndrome 16

6 Pain and Lyme radiculopathy 18 Complex regional pain syndrome 77

Section F – Headache disorders Section G – Treatment

31 Headache and acute cerebral ischemia 130

MECHANISMS OF NEUROPATHIC PAIN Figure 1.1. Simplified scheme

Lumbar spinal cord Skin

“RSD” or relex sympathetic dystrophy at one time but

territory in question. We described two patients References

vastus medialis (3.2 mV on the right; 7.2 mV on the

prominent and the course may be very prolonged,

Figure 5.1. femoral territory motor power and a preserved quadri-

Several types of painful neurological problems may

Clinical case vignette

Tibial nerve SEP Figure 6.2. Original recordings of the

Tibial nerve MEP

References European Lyme neuroborreliosis: a multicentre,

Discussion cases however, it has a very low sensitivity for the

8 herpes zoster infection

Discussion extend into the posterior horn of the spinal cord,

Table 9.1. Serial electrophysiological studies (selected)

was wheelchair bound. Sphincter function remained

Pain in CIDP mission. Our patient highlighted the intensive pain

electrophoresis, ESR, and TSH. His cholesterol was Pain in DPN

Topiramate was associated with nausea and dizziness.

Neuropathic pain may be the presenting feature in

Clinical case vignette

ably cold, encased in concrete or that “someone was

inlammatory demyelinating polyneuropathy (CIDP) References

Clinical case vignette

monary function was almost normalized, the medi-

could also bring on pain crises. he patient char-

ischemic strokes (3). Along with macroangiopathic Pain in Fabry disease

Clinical case vignette

Clinical case vignette

controlled analgesia, initiated 48 h pre-operatively and

he also described fasciculations, he did not categorize

Treatment of pain from ALS may include sim- References

Clinical case vignette

Pain in spinal cord injury

Clinical case vignette

Figure 25.1 (A) Original MRI scan of the

Pain description Pain in multiple sclerosis

continuous headache interspersed with headaches that Discussion

an increased accumulation of iron in the antinoci- References

Clinical case vignette

Clinical case vignette

is similar to that in cluster headache. Associated he etiology and pathophysiology of PH are

Clinical case vignette

Figure 31.1. Cranial images from the

Overall considerations Guidelines

Speciic agents1 Opioids