Downloaded from http://jnnp.bmj.com/ on May 11, 2017 - Published by group.bmj.
com
JNNP Online First, published on May 10, 2017 as 10.1136/jnnp-2017-315574
1
Department of Neurosciences
and Mental Health, Hospital
de Santa Maria-CHLN, Lisbon,
Portugal
2
Institute of Physiology-IMM,
Faculty of Medicine, University
of Lisbon, Lisbon, Portugal
3
Bushell Chair of Neurology,
Sydney Medical School,
University of Sydney, Brain
& Mind Centre, University of
Sydney, Sydney, NSW, Australia
4
Department of Neurology,,
Barts and The London School of
Medicine and Dentistry, Queen
Mary University of London,
London, UK
Correspondence to
Professor Mamede de Carvalho,
Institute of Physiology-IMM,
Faculty of Medicine,University
of Lisbon, Portugal, 1649-028,
Lisbon, Portugal; ​mamedemg@​
mail.​telepac.​pt
Received 22 February 2017
Revised 20 March 2017
Accepted 29 March 2017
To cite: de Carvalho M,
Kiernan MC, Swash M. J
Neurol Neurosurg Psychiatry
Published Online First: [please
include Day Month Year].
doi:10.1136/jnnp-2017-
315574
Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd under licence.
Neurodegeneration
REVIEW
Fasciculation in amyotrophic lateral sclerosis: origin
and pathophysiological relevance
Mamede de Carvalho,1,2 Matthew C Kiernan,3 Michael Swash2,4
ABSTRACT
This review considers the origin and significance of
fasciculations in neurological practice, with an emphasis
on fasciculations in amyotrophic lateral sclerosis (ALS),
and in benign fasciculation syndromes. Fasciculation
represents a brief spontaneous contraction that affects
a small number of muscle fibres, causing a flicker of
movement under the skin. While an understanding of
the role of fasciculation in ALS remains incomplete,
fasciculations derive from ectopic activity generated
in the motor system. A proximal origin seems likely to
contribute to the generation of fasciculation in the early
stages of ALS, while distal sites of origin become more
prominent later in the disease, associated with distal
motor axonal sprouting as part of the reinnervation
response that develops secondary to loss of motor
neurons. Fasciculations are distinct from the recurrent
trains of axonal firing described in neuromyotonia.
Fasciculation without weakness, muscle atrophy or
increased tendon reflexes suggests a benign fasciculation
syndrome, even when of sudden onset. Regardless
of origin, fasciculations often present as the initial
abnormality in ALS, an early harbinger of dysfunction and
aberrant firing of motor neurons.
INTRODUCTION
Although their origin remains a source of debate,
fasciculations are a very obvious phenomenon in
amyotrophic lateral sclerosis (ALS). These appar-
ently random, spontaneous twitching of muscle
fibres are enough to trigger anxiety in the healthiest
of people and send them scurrying to Dr Google.
But when manifested in the presence of concom-
itant muscle wasting, fasciculations take on more
complex considerations.
Fasciculations may appear irregular both in terms
of firing pattern and muscle involvement, although
intensive technological investigation and mathe-
matical modelling suggests a more ordered devel-
opment. In the case of ALS, while fasciculations
are an almost inevitable accompaniment of the
disease, the role of fasciculations in disease patho-
genesis remains to be determined. Similarly, in a
disease defined by involvement of the upper and
lower motor neuron, with or without fronto-tem-
poral dementia, determination of how, whether
and when fasciculations may arise in the upper or
lower motor neuron compartments or, indeed, arise
simultaneously in both, may prove critical in under-
standing the underlying disease process.
In the case of the motor axon, fasciculations may
arise from both proximal and distal segments and,
de Carvalho M, et al. J Neurol Neurosurg Psychiatry 2017;0:1–7. doi:10.1136/jnnp-2017-315574
separately, from within the motor neuron itself
(figure 1). Fasciculations have also been identified
as linked to cortical hyperexcitability in ALS, with
elegant descriptions of synchrony of discharges
suggestive of a common synaptic input arising
from the corticospinal tract. Perhaps, at a simple
level, the hyperexcitability that drives the devel-
opment of fasciculation may be generated periph-
erally as a result of membrane instability in motor
axons as well as in lower motor neurons that are
intrinsically hyperexcitable. There is evidence, in
addition, that fasciculations may be recruited by a
hyperexcitable corticospinal system. The apparent
contrast between these two compartments of the
human nervous system will form the crux of this
review, which will explore the origins and patho-
genic significance of fasciculations in ALS. We will
further consider that fasciculations may occur in
many disease states other than ALS, and indeed in
healthy subjects, where their origin and significance
remain somewhat mysterious.
HISTORICAL PERSPECTIVE
Involuntary ‘fibrillar twitching’ or ‘flickering’ of
limb muscles and the tongue, seen through skin
and mucous membrane, was first described in the
disorder now recognised as ALS more than 150
years ago.1 It was an early clinical observation that
fasciculation precedes other symptoms.2 Even in the
19th century ‘fibrillar twitching’ was understood as
a sign of a denervating, rather than a myopathic
disorder, and Charcot emphasised its importance in
the diagnosis of ALS.3
The modern term ‘fasciculation’ was introduced
by Denny-Brown and Pennybacker in their seminal
1938 paper4 to describe electromyographic (EMG)
evidence that these involuntary twitches were due
to spontaneous contraction of muscle fascicles,
originating from motor unit depolarisation. They
reserved the term fibrillation for small diphasic
electrical potentials originating from denervated
single muscle fibres. Nonetheless, in clinical prac-
tice, fasciculation of the tongue is sometimes still
referred to as ‘fibrillation’, a terminology that refers
to the early 19th-century descriptions. However,
even in the tongue it is improbable that fibrillating
single muscle fibre activity can be visualised, given
the small size of individual muscle fibres.
ORIGIN OF FASCICULATION
Fasciculations are characteristic of ALS.1–5 They
are important in diagnosis of the disease and have
been incorporated in formal diagnostic criteria.6
1
 Downloaded from http://jnnp.bmj.com/ on May 11, 2017 - Published by group.bmj.com
Neurodegeneration
Figure 1  Potential generators of fasciculation across compartments
of the human nervous system. Corticospinal and propriospinal drive
represent upper motor neuron activation of an anterior horn cell (AHC)
. Modulation of output from the AHC occurs via Renshaw cell collateral
inhibition, and also by input from interneurons and propriospinal neurons
and by afferents from muscle spindles and tendon organs (Group la,
Group lb and Group ll afferents). In amyotrophic lateral sclerosis (ALS),
there is functional abnormality in the upper motor neuron (UMN) and in
the AHC that develops over time, leading to axonal degeneration (and
attempted regeneration), with loss of the terminal innervation of muscle
fibres, causing weakness. Hyperexcitability of the UMN pathway may drive
surviving AHCs in the lower motor neuron (LMN) towards hyperexcitability,
leading to fasciculation; that is, spontaneous firing in the LMN pathway.
These fasciculations may arise in the AHC early in ALS, and in the terminal
arborisation when there is regeneration after muscle fibre denervation,
especially later in the disease. Spontaneous motor unit activity also
occurs at an axonal level in autoimmune and metabolic channelopathies
and states of ionic imbalance. Benign fasciculation disorder (BFS), with
or without cramp, represents a distal LMN excitability of uncertain
biochemical causation.
Real-time ultrasound imaging has revealed the dramatic extent
of fasciculation in ALS.7 Fasciculations were at first thought
always to originate in the lower motor neuron, near the soma of
motor neurons.4 However, Norris noted that fasciculations could
sometimes be recorded synchronously in muscles innervated by
the same myotome, but by different motor nerves, suggesting
that some fasciculations may have a supranuclear or perhaps
even a cortical origin.8 It should be recognised, nonetheless, that
in LMN disorders, slight contraction of a muscle in one limb can
be associated with simultaneous contraction of a muscle in the
opposite limb.9 In support for a central origin, reduction in the
frequency of fasciculation (although not complete suppression)
may develop following spinal anaesthesia, indicating a central
origin or at least influence that may promote the generation of
fasciculations.10 Furthermore, in ALS, some fasciculations can
be driven by cortical stimulation.11 These observations suggest
central modulation or, alternatively, that a distal axonal gener-
ator can be over-ridden by more proximally generated neuronal
activity. To clarify these possibilities, collision and F-wave tech-
niques have been used to determine the origin of fasciculations,
with mixed findings, leading to conclusions that fasciculations
can arise both in distal and proximal parts of the lower motor
neuron (LMN).12–15
Apart from any central influence, the origin of fasciculations is
dependent on the functional state of the LMN (figure 1). In ALS,
complex unstable fasciculations arise in abnormal, reinnervated,
surviving motor units, most likely from a generator site located
2 de Carvalho M, et al. J Neurol Neurosurg Psychiatry 2017;0:1–7. doi:10.1136/jnnp-2017-315574
Figure 2  (A) Fasciculation potentials of stable, simple morphology,
recorded from an early affected muscle in an ALS patient. The origin of such
potentials is probably in the proximal motor axon or in the anterior horn
cell. (B) A polyphasic, unstable fasciculation potential, possibly originating
from distal motor axonal spouts following reinnervation. There are eight
consecutive discharges representing firing of the same motor unit.
in distal axonal branches.16 Complex and unstable fasciculations
tend to be found predominantly in weak, wasted muscles and
have longer interdischarge intervals (IDIs), as compared with
less complex, more stable fasciculations.17 These features may in
turn suggest a more proximal origin for fasciculations recorded
in mildly denervated muscles, consistent with the observation
that 77% of all stable fasciculations could be voluntarily acti-
vated, as opposed to 12% of the more complex and unstable
fasciculations found in weak atrophic muscles, which have a
greater fibre density and jitter compared with stronger muscles.16
Studies of complex fasciculations have determined that double
fasciculations occurred in two band intervals, 4–10 ms, related to
an abnormal supernormal period in distal axonal branches, and
30–50 ms, indicating a common generator at a more proximal
origin.17 High-density surface EMG recording has confirmed
this finding of two typical IDI interval sets of fasciculations in
ALS; 4–5 ms and approximately 70 ms. Approximately 80% of
fasciculations recorded in ALS with this technique were in the
shorter IDI band, perhaps suggesting an origin in distal axon
branches,18 although others have criticised this interpretation,
suggesting that short IDIs do not rule out a more proximal
origin.19 A technique using double EMG needle recordings from
two different motor units has revealed that, early in the disease,
many fasciculations have a proximal origin.20 However, this
double recording technique technique does not allow verifica-
tion of Norris’ observations that suggested a spinal contribution
(or perhaps a relay centre) for at least some fasciculations in ALS.
In ALS, fasciculations are often the first and only abnormality
recorded in muscles as yet seemingly unaffected by the disease,
at least without evidence of dysfunction involving the lower
motor neuron. These early fasciculations are typically of simple
morphology (figure 2A). They may precede other features of
ALS by many months. In follow-up studies, both voluntarily
generated motor unit potential (MUPs)and spontaneous fascic-
ulations become more complex, showing increased jitter and
blocking of components of these complex units,2 consistent with
ongoing reinnervation as a compensatory process during motor
neurodegeneration (figure 2B). However, compensatory rein-
nervation is insufficient to keep pace with the ongoing motor
pathway destruction in the disease.
Early reduction of the motor threshold, most pronounced
in ALS patients with profuse fasciculations, preserved muscle
bulk and hyper-reflexia, has suggested a cortical origin for some
fasciculations.21 Indeed, cortical motor hyperexcitability is a
very early feature of ALS, even developing before the disease
becomes clinically and symptomatically evident.22 Fasciculations
 Downloaded from http://jnnp.bmj.com/ on May 11, 2017 - Published by group.bmj.com
that appear early in the course of the disease have the same
morphology as the first recruited motor units (figure 2A), a
finding consistent with increased excitability within LMNs, at
anterior horn cell level22, which probably also occurs in more
affected neurons. This observation is confirmed by the increased
frequency of fasciculation potentials observed following periph-
eral sensory nerve stimulation.23 Prolific fasciculation potentials
recorded during an EMG examination appear to be a poor prog-
nostic factor,24 25 implying hyperexcitability of the peripheral
motor system.26 The infrequent fasciculations found in primary
lateral sclerosis (PLS) fire at a much lower frequency.25 In PLS,
neurodegeneration is restricted to the upper motor neuron,
and survival is much longer. In progressive muscular atrophy,
a disorder that pathologically resembles classical Charcot ALS,
fasciculations are prominent although survival is variable.
Abnormal behaviour of the axonal membrane and constituent
ion channels has been identified in motor nerves in patients
with ALS by threshold tracking techniques which have revealed
changes indicative of increased persistent Na+ channel conduc-
tion and reduction in K+ currents.21 Follow-up studies show
increasing K+ channel dysfunction in motor axons, but in longi-
tudinal studies, K+ channel dysfunction was greater in patients
with ALS with relatively stable CMAP amplitudes, suggesting
that this change could be a compensatory mechanism.27 Both
decreased K+ conductance and increased persistent Na+ conduc-
tance contribute to instability of the axonal membrane, resulting
in the development of ectopic activity. Computer modelling
suggested that reducing voltage-dependent potassium conduc-
tance caused axon instability, a possible mechanism for induction
of fasciculation potentials.28 Studies in the superoxide dismutase
oxygen 1 (SOD1) animal model of ALS suggest that at an early
phase motor axons enter a state of membrane depolarisation but,
later in the disease, axonal degeneration causes more complex
changes in axonal excitability.29 In addition to suggesting further
therapeutic targets in ALS, reduction in axonal K+ conduc-
tance decreases a hyperpolarising tendency while an increase in
persistent Na+ conductance increases depolarising drive.30 In
ALS the prognosis is determined, at least in part, by the advent
of an increasing persistent axonal sodium current, as detected in
threshold tracking studies.26
Regenerating motor end plates are more sensitive to acetyl-
choline released in synaptic clefts, as shown in neurogenic
disorders by fasciculations induced by small doses of paren-
teral neostigmine.31 The efferent impulse from a motor neuron
is generated at the initial segment of the nerve fibre (the axon
hillock) where the threshold (the inverse of electrical excit-
ability) of the neuronal membrane is lowest. Neuronal firing
occurs in response to a change in membrane charge caused by
the summated, graded excitatory postsynaptic potentials (EPSPs)
at dendritic synapses with the cell body. EPSPs develop from the
opening of ligand-gated channels by glutamate, released from
presynaptic terminals, a major excitatory neurotransmitter that
leads to hypopolarisation, making spontaneous neuronal firing
more likely. Glutamate is present in increased concentration in
the neuropil in ALS. Neuronal inhibition is induced by glycine,
an inhibitory transmitter released from presynaptic terminals
that triggers a chloride current, causing transient neuronal
membrane hyperpolarisation. Inhibition also occurs by depo-
larisation of the primary afferent (Group Ia) terminal through
the action of gamma-amino butyric acid, an inhibitory trans-
mitter present in that spindle afferent system. The resultant
change in the gain of the motoneuron, a consequence of some
of these effects, can induce a persistent inward current and a
plateau potential, long outlasting the inducing neuronal activity,
de Carvalho M, et al. J Neurol Neurosurg Psychiatry 2017;0:1–7. doi:10.1136/jnnp-2017-315574
Neurodegeneration
increasing the probability that the neuron will discharge. Motor
axons innervating muscles have different properties according
to their discharge rates. Fasciculation is more likely to arise in
larger, faster conducting motor axons since these are more excit-
able and have greater hyperpolarisation-activated cyclic nucleo-
tide-gated channel (HCN) activity.32 HCN activity is associated
with a prolonged after-hyperpolarisation potential, a potential
dependent on a calcium-activated potassium channel.32
Fasciculations therefore have complex biophysical origins,
and these are different in motor neuronal cell bodies and motor
axons. In ALS, there is evidence that fasciculations are induced
in cell bodies early in the disease and in distal axons later,
when there is well-developed reinnervation with distal axonal
sprouting (figure 2B). Neuromyotonia, a form of repetitive,
spontaneous, motor axonal discharge, probably develops from
biophysical abnormalities in voltage-activated slow K+ channels
in motor axons, sometimes associated with specific antibody
blockade.33 Better understanding of the factors favouring ectopic
impulse generation would lead to more effective management,
for example, by specific sodium-channel blocking drugs, antiglu-
tamatergic drugs, or perhaps, magnesium supplements.
CLINICAL CORRELATES OF FASCICULATION
Although fasciculations occur in healthy people, in particular in
foot muscles and gastrocnemius,34 such fasciculations are infre-
quently symptomatic. Awareness of fasciculations often raises
concern about the possibility of motor neuron disease, especially
in the modern era, in which, access to the Internet reinforces this
possible association (http://www.​aboutbfs.​com). This concern
is inevitably frequent among physicians or other workers in
healthcare systems, and has been termed fasciculation anxiety
syndrome.35 It is an important disease marker only when asso-
ciated with other neurological symptoms and signs, particularly
weakness. For example, diffuse fasciculations and weak wasted
muscles suggest ALS, but fasciculations without motor system
abnormality are likely to be benign.
Distal fasciculations occur in neuropathies, especially multi-
focal motor neuropathy36 and also in chronic inflammatory
demyelinating polyneuropathy (CIDP) but only rarely in diabetic
neuropathy or Charcot-Marie-Tooth disease. Focal demyelin-
ation in peripheral motor or sensory axons can lead to increased
axonal excitability and ectopic firing, and fasciculations may
develop after peripheral compressive nerve injury or traumatic
motor root lesions.37 Sometimes focal fasciculations follow radi-
ation injury to cervical plexus38 or to the spinal cord as part of a
slowly progressive LMN syndrome.39 Fasciculations are promi-
nent in chronic lower motor neuron disorders such as postpolio
syndrome,40 spinal muscular atrophy, especially bulbo-facial
fasciculation in Kennedy’s disease.41 In the latter disorder, EMG
recordings have shown that fasciculation potentials occur at a
much slower rate than in ALS and tend not to be complex in
type.41 Fasciculations occur in partially denervated upper limb
muscles in cervical spondylotic myelopathy, and in cervical spon-
dylosis they have also been described in leg muscles, a feature
suggesting coincidental lumbar spondylosis or perhaps an asso-
ciated UMN influence.42 Acquired metabolic disorders may also
be associated with fasciculations, as in thyrotoxicosis,43 hypo-
calcaemia44 and hypomagnesaemia.45 Cholinergic hyperactivity
at motor end plates secondary to organophosphate poisoning
causes widespread fasciculations.46 Neurotoxic envenomisation,
due to certain spider, snake and scorpion bites causes fascicula-
tions as paralysis develops.47 Finally, fasciculation can also result
from high caffeine intake, unaccustomed exercise48 and drugs
3
 Downloaded from http://jnnp.bmj.com/ on May 11, 2017 - Published by group.bmj.com
Neurodegeneration
with serotoninergic49 or cholinergic activity (pyridostigmine),31
or depolarising paralytic agents, for example, succinylcholine
used in surgical anaesthesia.50 Sparse distal fasciculations were
reported in 2 of 70 patients with inclusion body myositis, but
this appears exceptionally uncommon.51
METHODS FOR DETECTING FASCICULATIONS
Fasciculations are typically identified by clinical observation
in muscles at rest, that is, superficial parts of muscles, such as
deltoids, biceps brachii, triceps and thenar eminence in the
upper limbs or in quadriceps and calf muscles in the lower limbs.
The tongue is a particularly suitable muscle for clinical detec-
tion of fasciculations since its mucous epithelium is thin; indeed,
bilateral fasciculation of the tongue is highly suspicious of a diag-
nosis of ALS.5 Patients can sometimes feel the movement of an
affected muscle during fasciculations or they or their partners
may observe the abnormal involuntary muscular movement.
Fasciculatory contraction of a muscle is a different phenomenon,
closely associated with chronic reinnervation such that contrac-
tions of large reinnervated motor units can be seen through the
mucous membrane of the tongue or the skin overlying a limb
muscle during a movement. Sometimes cramps accompany
fasciculations during voluntary movements, both in ALS and in
the benign cramp-fasciculation syndrome.52
The conventional EMG method for fasciculation detection
requires recording with a concentric needle EMG electrode from
several locations, each for at least 90 s to be sure that fascicula-
tions are or are not present.53 Fasciculation potentials should be
searched for in several upper limb and lower limb muscles and
also, when clinically relevant, in the genioglossus, although in
the latter it is difficult to achieve full relaxation during needle
EMG examination. The trapezius muscle has been recommended
as the most informative muscle for detecting fasciculations in
possible ALS.54 Surface electrodes, placed at multiple recording
sites, have also been used.25 55 High-density surface EMG, which
provides simultaneous information about many different motor
units is particularly suitable for long recordings.48 Ultrasound
imaging can directly visualise fasciculations in resting muscle7
including tongue and other muscles such as biceps brachii which
are accessible to the ultrasound probe.56 These studies reveal
near simultaneous contraction of several fascicles, suggesting
that many neighbouring motor units are often recruited into
fasciculatory activity. In contrast, concentric needle EMG elec-
trodes, which are designed for recording from a few motor units
in focal areas of muscle, do not reveal the full extent of fascicu-
lation. Ultrasound imaging may be the most sensitive method for
fasciculation potential (FP) detection,57 since the full depth of a
muscle can be examined. However, ultrasound studies do not
allow analysis of the morphology or firing characteristics of the
motor units involved. 
BENIGN FASCICULATION AND CRAMP FASCICULATION
SYNDROMES
Across a range of nerve hyperexcitability syndromes, benign
fasciculation syndrome (BFS) presents with persistent fascicula-
tion, without other neurological abnormality (box 1). Although
benign fasciculations are very common in leg muscles,34 other
muscles are also commonly affected23 48 without progression or
neurological causation (box 1). The phenomenon is often inter-
mittent but may continue for months or years. Benign fascicula-
tions are often more prominent after exercise, and less obvious
after a period of rest, and diurnal variation in frequency and firing
rate may be noted.58 Fasciculations may also be precipitated and
4 de Carvalho M, et al. J Neurol Neurosurg Psychiatry 2017;0:1–7. doi:10.1136/jnnp-2017-315574
Box 1  Causes of fasciculation
Motor neuron disease and its variants
Spinal muscular atrophy and Kennedy syndrome
SCA 3 (Machado-Joseph disease)
Postpolio syndrome
Herpes Virus one infection
Neuropathies
►► Multifocal motor neuropathy with conduction block
►► Chronic inflammatory demyelinating polyneuropathy
►► Other Immune-related neuropathies (eg, IgM1- related)
►► Charcot–Marie–Tooth syndromes
►► Nerve entrapment syndromes and nerve injuries
Motor root and plexus lesions
►► Inflammatory
►► Radiation plexopathy
Spinal cord disorders
►► Syringomyelia
►► Cervical spondylosis with cord compression
►► Radiation myelopathy
►► Viral myelitis for example, herpes zoster, rabies
Metabolic disease
►► Hypocalcaemia
►► Hyperthyroidism
►► Hypomagnesaemia
Hyperexcitability of peripheral motor axons
►► Benign fasciculation syndrome
►► Cramp-fasciculation syndrome
►► Post-exercise fasciculation
Drug-related fasciculation
►► Caffeine, cholinergic drugs, amphetamines, antihistamines,
serotonin compounds, salbutamol, benzodiazepine
withdrawal
►► Organophosphate insecticide poisoning
Envenomisation: bites by snakes, funnel-web spider, or scorpion
Pharmacological cholinergic block in anaesthetic practice
Related autoimmune disorders
►► Anti-voltage-gated potassium channels (VGKC) immune
disease (encephalopathy with peripheral axonal disorder)
►► Neuromyotonia
Inclusion body myositis
aggravated through mood-related changes, particularly anxiety,
presumably through hyperventilation and alterations in central
excitability. Electromyographic analysis (figure 2) typically
confirms that the fasciculations in BFS are simple in form without
evidence of reinnervation and without impulse blocking within
the fasciculation potential itself3 (figure 2). BFS may commence
relatively abruptly, although without any associated illness.
Axonal excitability was studied in a carefully defined group of
20 subjects with benign fasciculations, not on medication, using
the threshold tracking technique.59 The results, analysed with
mathematical modelling, were best explained by depolarisation
of the voltage dependency of HCN channels in motor axons,
causing increased inward rectification, although polarisation
parameters of the resting membrane potential were not changed.
It was suggested that HCN channels had a functional role during
the rhythmic discharge associated with a voluntary contraction.
 Downloaded from http://jnnp.bmj.com/ on May 11, 2017 - Published by group.bmj.com
It was also noted in this study that in BFS motor unit discharge
rates were higher than controls during maximal voluntary effort,
implying disturbance of the firing rate–force relationship, caused
by an abnormality in orderly recruitment.
The firing frequency of benign fasciculations has been reported
to be faster than the fasciculations observed in motor neuron
disease,60 although Mills confirmed this only in advanced ALS.17
Unlike ALS, in which fasciculations often originate from several
different, closely related motor units, benign fasciculations
generally originate from a single hyperexcitable motor unit,
without increased complexity (figure 1 and 2). The origin of this
ectopic activity is most frequently proximal to the distal axonal
branching point.2 19 An ultrasound study of benign fascicula-
tions has confirmed a predominant but not exclusive lower limb
distribution,34 with a possible slight increase in fasciculations in
lower limb muscles after exercise,48 61 not found in studies of
a hand muscle.23 Furthermore, the firing frequency of fascicu-
lations in BFS has been shown to vary at different times in the
day.58 BFS probably represents a spectrum of disordered LMN
function (figure 1). The key difference between fasciculations
associated with BFS, unlike ALS, is that in BFS muscle strength,
tone and tendon reflexes are all normal. However, fasciculation
potentials in concentric needle EMG recordings in the very early
stages of ALS may be of normal morphology, as is usual but not
invariable in BFS,17 rather than the more characteristic complex
morphology usually associated with fasciculation potentials in
established ALS.2 60 62
A variant of BFS, cramp-fasciculation syndrome, is asso-
ciated with pain, exercise intolerance, subjective fatigue and
anxiety, as well as spontaneous cramp at rest and on exertion
and fasciculation at rest.63 This condition typically occurs in
young men. In young women intermittent distal tingling may
be an associated feature (the terms ‘latent tetany’, ‘cryptotetany’
and ‘spasmophilia’ have also been used to describe this clinical
picture). In some patients, an association with mild hypomagne-
saemia has been identified.64 In these patients, fasciculations and
paraesthesiae may be induced following 10 min of cuff-induced
upper limb ischaemia followed by hyperventilation.65 After this
test, protocol myokymic discharges (figure 3) and fascicula-
tions become more prominent, as identified by EMG. Studies
of muscle twitching, cramps and paraesthesiae with ectopic
activity induced by hyperventilation or ischaemia, identified
differential behaviour between sensory and motor fibres, in that
Figure 3  Myokymic discharges recorded in an upper limb muscle after
ischaemic release following 10 min cuff inflation. There are clusters of
motor unit discharges originating from axonal sites following the ischaemic
period. This abnormality is associated with the ‘spasmophilia syndrome’,
associated with axonal hyperexcitability ascribed to hypomagnesaemia (see
text).
de Carvalho M, et al. J Neurol Neurosurg Psychiatry 2017;0:1–7. doi:10.1136/jnnp-2017-315574
Neurodegeneration
sensory fibres were more likely to develop ectopic activity. These
differences between sensory and motor nerve fibres in periph-
eral nerves appeared to relate to selective effects of hyperven-
tilation on ‘threshold channels’ in the axons. The latter were
considered analogous to persistent sodium channels active at
resting membrane potential but expressed more in sensory than
in motor axons. Separate studies in cramp identified bistability
in the motor neuronal membrane as the likely trigger.52 Specif-
ically, when the membrane was stable above threshold, that is,
hyperpolarised at rest, spontaneous depolarisation may occur
leading to motor neuronal discharges at 8–12 Hz, causing the
clinical phenomena of myokymia and fasciculation. Progres-
sion to cramp may occur from ephaptic transmission to adja-
cent muscle fibres or recruitment of additional motor neurons.
This motor neuronal activity can be suppressed by vibratory
stimulation of Ia afferents and also by electrical stimulation of
the motor axons.52 Fasciculation may occur associated with this
motor neuronal bistability when the resting membrane potential
is at a higher than normal level.
Cramps, occurring as a sole manifestation, tend to become
more frequent in older people, often in the context of statin
therapy; they are rare in upper limbs of healthy subjects without
metabolic imbalance. Cramps may also develop during high-
rate repetitive nerve stimulation.66 Benign fasciculations and
cramp-fasciculation syndrome can be regarded as part of a
larger spectrum of disease that also incorporates acquired
auto-immune neuromyotonia.67 Indeed, antibodies to the volt-
age-gated potassium channel complex have been identified in
32% of patients with cramp-fasciculation syndrome,68 including
leucine-rich glioma-inactivated-1 antibodies in a small, tested
subset of patients. In a minority of patients, fasciculations and
cramps may be associated with a non-progressive motor neuron
disease syndrome with chronic neurogenic changes on EMG and
increased creatine kinase (CK).69 These syndromes typically do
not progress to motor neuron disease.70 However, exceptionally
rarely, progression or cramp-fasciculation syndrome to ALS has
been reported.71
ALL THAT FASCICULATE ARE NOT ALS
Prominent fasciculations and muscle atrophy, with predom-
inant upper extremity involvement and brisk reflexes36 may
cause multifocal motor neuropathy (MMN) to be misdiagnosed
as ALS.72 Although focal conduction block in motor nerves
suggests the diagnosis of MMN, it is sometimes difficult to
detect, either because it is absent or very proximal. Neurophysi-
ological evidence of chronic reinnervation within distinct nerve
territories is important in differentiating MMN from slowly
progressive ALS, and ultrasound can be useful to detect focal
nerve enlargement. Systematic studies of the distribution and
frequency of fasciculations in motor neuropathies, for example,
by using ultrasound as a detection methodology, are lacking.
Axonal excitability studies have demonstrated a different
pattern of abnormality in patients with MMN as compared
with those with ALS. Distal to the site of conduction block in
MMN there are changes indicative of axonal hyperpolarisa-
tion, including increased threshold change in threshold elec-
trotonus (both depolarising and hyperpolarising) and promi-
nently increased superexcitability.73 These abnormalities were
normalised by application of depolarising current, suggesting
that there was membrane hyperpolarisation. The development
of hyperpolarisation distal to the site of conduction block
implies blockade of Na+/K+ pump activity at the lesion site,
leading to intracellular accumulation of Na+ (figure 1). As the
5
 Downloaded from http://jnnp.bmj.com/ on May 11, 2017 - Published by group.bmj.com
Neurodegeneration
excess Na+ ions diffuse along the axon, the axon pump distal to
the block tends to overcompensate in an attempt to correct the
ionic imbalance. Overactivity of the pump therefore leads to a
net hyperpolarisation in membrane potential due to the discrep-
ancy in K+ and Na+ transport ratios. Accordingly, areas of depo-
larisation and hyperpolarisation surround the site of conduction
block along the axon. This pattern of excitability change differ-
entiates MMN from ALS.
In postpolio syndrome, fasciculations have been described in
the majority of affected patients, associated with loss of endur-
ance, limited ambulation, increased weakness with functional
impairment and increased fatigue.74 Fasciculations in postpolio
syndrome are usually more prominent after exercise and consist
of large involuntary fascicular contractions, representing rein-
nervated motor units or groups of motor units.9 Fasciculations
were a well-recognised feature in acute poliomyelitis, before
onset of the paralytic phase of the illness. Ritchie Russell75
noted that in acute polio ‘the slight involuntary contractions of
muscular units closely resembled those seen in motor neuron
disease’ and that 'the appearance of this sign often indicates that
paralysis will affect the muscles showing fasciculation within
the next 24 hours’, an observation raising tempting speculations
regarding fasciculation and motor neuron death in ALS. Thus, in
acute poliomyelitis fasciculations were considered to originate
from sick, infected lower motor neurons, whereas the complex
fasciculations characteristic of postpolio syndrome probably
originate in distal regenerated axonal branches innervating
residual reinnervated motor units, sometimes associated with
action tremor.9
In syringomyelia, fasciculations occur in affected muscles,
therefore usually in a segmental distribution in upper limb
muscles.76Compressive root lesions cause pain and sensory
symptoms with weakness and fasciculations. Most fascicula-
tions in root lesions originate from distal axonal sprouts asso-
ciated with reinnervation, but some (about 25%) have a more
proximal origin, presumably at the point of compression of the
motor root.37 Fasciculation is also a feature of isolated acute or
subacute peripheral nerve compression syndromes,77 although
in chronic nerve compression disorders such as carpal tunnel
syndrome, fasciculations are rarely observed clinically.78 Because
nerve compression causes focal demyelination, these discrepan-
cies raise the probability that specific mechanisms, such as trau-
ma-induced channelopathies in the nodal structures or ephaptic
axonal activity at the site of compression–demyelination are
important in this process.
Fasciculation, especially of the tongue, is prominent in type1
and type 2 spinal muscle atrophy, disorders in which survival is
relatively short. Fasciculation in limb muscles and tongue can
also be seen in patients with type 3 spinal muscular atrophy
(SMA).
FASCICULATIONS—AN UNRESOLVED ISSUE
"When you have eliminated all which is impossible, then what-
ever remains, however improbable, must be the truth." (Arthur
Conan Doyle, The Case-Book of Sherlock Holmes).
Fasciculations in ALS are associated with hyperexcitability of
the peripheral motor axon, and the disease itself is associated
with hyperexcitability in the central nervous system. At present,
the extent of interplay between central and lower motor neuron
excitability and fasciculations remains unresolved. It seems likely
that repetitive fasciculation implies rapid progression, although
the biophysical abnormalities underlying fasciculations in ALS
remain incompletely understood. It is possible, for example, that
6 de Carvalho M, et al. J Neurol Neurosurg Psychiatry 2017;0:1–7. doi:10.1136/jnnp-2017-315574
rapid fasciculation may precipitate metabolic stress in affected
motor neurons, thus hastening cell death.
Returning then to basic principles, ALS results from neurode-
generation in several compartments or systems in the nervous
system. While there remain questions of primacy, if we simply
accept that there exist proximal and distal factors in fascic-
ulation, it remains conceivable that early in the disease, when
fasciculations may appear as a primary manifestation, in the
absence of muscle weakness, the processes linked to supraspinal
excitability are dominant. Later, with progressive dysfunction of
the lower motor neuron system, as muscles become weak and
complex highly unstable motor units develop, ectopic activity is
driven through peripheral motor axonal generators. Eventually,
as corticospinal tract and peripheral motor axons degenerate,
fasciculations (and cramp) become less prominent. Regardless of
these suppositions, fasciculations are a major and characteristic
feature of ALS, and consideration of their contribution to the
pathophysiology of the disease seems critical to unravelling the
complex jigsaw that is ALS.
Competing interests  None declared.
Provenance and peer review  Commissioned; externally peer reviewed.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2017. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
REFERENCES
1 Turner MR, Swash M, Ebers GC. Lockhart Clarke's contribution to the description of
amyotrophic lateral sclerosis. Brain 2010;133:3470–9.
2 de Carvalho M, Swash M. Fasciculation potentials and earliest changes in motor unit
physiology in ALS. J Neurol Neurosurg Psychiatry 2013;84:963–8.
3 Charcot J-M. Amyotrophies spinales deuteropathiques sclérose latérale
amyotrophique & sclérose latérale amyotrophique. Bureaux du Progrès Médical
1874;2:234–66.
4 Denny-Brown D, Pennybacker JD. Fibrillation and fasciculation in voluntary muscle.
Brain 1938;61:311–2.
5 Li T-M AE, Alberman E, Swash M. A suggested approach to the differential
diagnosis of motor neuron disease from other neurological conditions. Lancet
1986;ii:731–2.
6 de Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostis criteria for diagnosis of
amyotrophic lateral sclerosis. Clin Neurophysiol 2008;119:497–503.
7 Arts IM, van Rooij FG, Overeem S, et al. Quantitative muscle ultrasonography in
amyotrophic lateral sclerosis. Ultrasound Med Biol 2008;34:354–61.
8 Norris FH. Synchronous fasciculation in motor neuron disease. Arch Neurol
1965;13:495–500.
9 Marshall J, Walsh EG. Physiological tremor. J Neurol Neurosurg Psychiatry
1956;19:260–7.
10 Swank RL, Price JC. Fascicular muscular twitichings in myotrophic lateral sclerosis:
their origin. Archives of Neurology and Psychiatry 1943;49:22–6.
11 Kaji R, Kohara M, Kimura J. Fasciculations evoked by magnetic cortical stimulation in
patients with amyotrophic lateral sclerosis. Neurology 1993;43:A277–8.
12 Wettstein A. The origin of fasciculations in motor neuron disease. Ann Neurol
1979;5:295–300.
13 Roth G. The origin of fasciculations. Ann Neurol 1982;12:542–7.
14 Roth G. Fasciculations and their F-response. localisation of their axonal origin. J
Neurol Sci 1984;63:299–306.
15 Conradi S, Grimby L, Lundemo G. Pathophysiology of fasciculations in ALS as studied
by electromyography of single motor units. Muscle Nerve 1982;5:202–8.
16 de Carvalho M, Swash M. Fasciculation potentials: a study of amyotrophic lateral
sclerosis and other neurogenic disorders. Muscle Nerve 1998;21:336–44.
17 Mills KR. Characteristics of fasciculations in amyotrophic lateral sclerosis and the
benign fasciculation syndrome. Brain 2010;133:3458–69.
18 Janko M, Trontelj JV, Gersak K. Fasciculations in motor neuron disease: discharge
rate reflects extent and recency of collateral sprouting. J Neurol Neurosurg Psychiatry
1989;52:1375–81.
19 Kleine BU, Stegeman DF, Schelhaas HJ, et al. Firing pattern of fasciculations in ALS:
evidence for axonal and neuronal origin. Neurology 2008;70:353–9.
20 de Carvalho M, Swash M. Origin of fasciculations in amyotrophic lateral sclerosis and
benign fasciculation syndrome. JAMA Neurol 2013;70:1562–5.
21 Vucic S, Ziemann U, Eisen A, et al. Transcranial magnetic stimulation and
amyotrophic lateral sclerosis: pathophysiological insights. J Neurol Neurosurg
Psychiatry 2013;84:1161–70.
 Downloaded from http://jnnp.bmj.com/ on May 11, 2017 - Published by group.bmj.com
22 de Carvalho M, Swash M. Physiology of the fasciculation potentials in amyotrophic
lateral sclerosis: which motor units fasciculate? J Physiol Sci 2016.
23 de Carvalho M, Turkman A, Pinto S, et al. Modulation of fasciculation frequency in
amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2016;87:226–8.
24 Krarup C. Lower motor neuron involvement examined by quantitative
electromyography in amyotrophic lateral sclerosis. Clin Neurophysiol
2011;122:414–22.
25 de Carvalho M, Swash M. Fasciculation discharge frequency in amyotrophic lateral
sclerosis and related disorders. Clin Neurophysiol 2016;127:2257–62.
26 Kanai K, Shibuya K, Sato Y, et al. Motor axonal excitability properties are strong
predictors for survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry
2012;83:734–8.
27 Cheah BC, Lin CS, Park SB, et al. Progressive axonal dysfunction and clinical
impairment in ALS. Clin Neurophysiol 2012;123:2460–7.
28 Bostock H, Sharief MK, Reid G, et al. Axonal ion channel dysfunction in amyotrophic
lateral sclerosis. Brain 1995;118:217–25.
29 Vucic S, Kiernan MC. Axonal excitability properties in amyotrophic lateral sclerosis.
Clin Neurophysiol 2006;117:1458–61.
30 Kiernan MC, Lin CS, Burke D. Differences in activity-dependent hyperpolarization in
human sensory and motor axons. J Physiol 2004;558:341–9.
31 Patel AN, Swami RK. Muscle percussion and neostigmine test in the clinical
evaluation of neuromuscular disorders. N Engl J Med 1969;281:523–6.
32 Benarroch EE. HCN channels: function and clinical implications. Neurology
2013;80:304–10.
33 Santos MO, Swash M, de Carvalho M. The generator site in acquired autoimmune
neuromyotonia. Clin Neurophysiol 2017;128:643–6.
34 Mitsikostas DD, Karandreas N, Coutsopetras P, et al. Fasciculation potentials in
healthy people. Muscle Nerve 1998;21:533–5.
35 Simon NG, Kiernan MC. Fasciculation anxiety syndrome in clinicians. J Neurol
2013;260:1743–7.
36 Roth G, Rohr J, Magistris MR, et al. Motor neuropathy with proximal multifocal
persistent conduction block, fasciculations and myokymia. Evolution to tetraplegia.
Eur Neurol 1986;25:416–23.
37 de Carvalho M, Swash M. Origin of fasciculations in root lesions. Clin Neurophysiol
2016;127:870–3.
38 Esteban A, Traba A. Fasciculation-myokymic activity and prolonged nerve conduction
block. A physiopathological relationship in radiation-induced brachial plexopathy.
Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section
1993;89:382–91.
39 de Greve JL, Bruyland M, de Keyser J, et al. Lower motor neuron disease in a
patient with hodgkin's disease treated with radiotherapy. Clin Neurol Neurosurg
1984;86:43–6.
40 Miranda-Pfeilsticker B, Figarella-Branger D, Pellissier JF, et al. Post-poliomyelitis
syndrome: 29 cases. Rev Neurol 1992;148:355–61.
41 Hirota N, Eisen A, Weber M. Complex fasciculations and their origin in amyotrophic
lateral sclerosis and Kennedy's disease. Muscle Nerve 2000;23:1872–5.
42 Kasdon DL. Cervical spondylotic myelopathy with reversible fasciculations in the
lower extremities. Arch Neurol 1977;34:774–6.
43 Bernard JD, Larson MA, Norris FH. Thyrotoxic periodic paralysis in Californians of
Mexican and Filipino ancestry. Calif Med 1972;116:70–4.
44 Reber PM, Heath H. Hypocalcemic emergencies. Med Clin North Am
1995:79:93–106.
45 Villa A, Zanada P, Pellegrino A, et al. Iatrogenic hypomagnesemia: an underestimated
clinical problem. Italian Journal of Medicine 2015;9:287–9.
46 Gutmann L, Besser R. Organophosphate intoxication: pharmacologic,
Neurophysiologic, clinical, and therapeutic considerations. Semin Neurol
1990;10:46–51.
47 Karlsson E, Mbugua PM, Rodriguez-Ithurralde D. Fasciculins: anticholinesterase
toxins from the venom of the greenmamba Dendroaspis angusticeps. J
Physiol(paris) 1984;79:232–40.
48 Fermont J, Arts IM, Overeem S, et al. Prevalence and distribution of fasciculations in
healthy adults: effect of age, caffeine consumption and exercise. Amyotroph Lateral
Scler 2010;11:181–6.
de Carvalho M, et al. J Neurol Neurosurg Psychiatry 2017;0:1–7. doi:10.1136/jnnp-2017-315574
Neurodegeneration
49 Spirko BA, Wiley JF. Serotonin syndrome: a new pediatric intoxication. Pediatr Emerg
Care 1999;15:440–3.
50 Baraka A. Self-taming of succinylcholine-induced fasciculations. Anesthesiology
1977;46:292–3.
51 Dabby R, Lange DJ, Trojaborg W, et al. Inclusion body myositis mimicking
amyotrophic lateral sclerosis. Arch Neurol 2001;58:1253–6.
52 Baldissera F, Cavallari P, Dworzak F. Motor neuron 'bistability'. A pathogenetic
mechanism for cramps and myokymia. Brain 1994;117(Pt 5):929–39.
53 Mills KR. Detecting fasciculations in amyotrophic lateral sclerosis: duration of
observation required. J Neurol Neurosurg Psychiatry 2011;82:549–51.
54 Sonoo M, Kuwabara S, Shimizu T, et al. Utility of trapezius EMG for diagnosis of
amyotrophic lateral sclerosis. Muscle Nerve 2009;39:63–70.
55 Hjorth RJ, Walsh JC, Willison RG. The distribution and frequency of spontaneous
fasciculations in motor neurone disease. J Neurol Sci 1973;18:469–74.
56 Misawa S, Noto Y, Shibuya K, et al. Ultrasonographic detection of fasciculations
markedly increases diagnostic sensitivity of ALS. Neurology 2011;77:1532–7.
57 Noto YI, Shibuya K, Shahrizaila N, et al. Detection of fasciculations in amyotrophic
lateral sclerosis: the optimal ultrasound scan time. Muscle Nerve 2017.
58 Van der Heijden A, Spaans F, Reulen J. Fasciculation potentials in foot and
leg muscles of healthy young adults. Electroencephalogr Clin Neurophysiol
1994;93:163–8.
59 Czesnik D, Howells J, Negro F, et al. Increased HCN channel driven inward
rectification in benign cramp fasciculation syndrome. Brain 2015;138:3168–79.
60 Trojaborg W, Buchthal F. Malignant and benign fasciculations. Acta Neurol Scand
1965;41:251–4.
61 Czell D, Goldman B, Weber M. Distribution of fasciculations in healthy adults after
exercise: an ultrasound study. Muscle Nerve 2016;54:132–5.
62 Eisen A, Vucic S. Fasciculation potentials: a diagnostic biomarker of early ALS? J
Neurol Neurosurg Psychiatry 2013;84:948.
63 Layzer RB. The origin of muscle fasciculations and cramps. Muscle Nerve
1994;17:1243–9.
64 Durlach J, Lebrun R. La tétanie magnési privé chez l`homme. Étude Biochem
Electromyograph Path Bact 1959;7:17–18.
65 Mogyoros I, Kiernan MC, Burke D, et al. Excitability changes in human sensory and
motor axons during hyperventilation and ischaemia. Brain 1997;120:317–25.
66 Tahmoush AJ, Alonso RJ, Tahmoush GP, et al. Cramp-fasciculation syndrome: a
treatable hyperexcitable peripheral nerve disorder. Neurology 1991;41:1021–4.
67 Shimatani Y, Nodera H, Shibuta Y, et al. Abnormal gating of axonal slow potassium
current in cramp-fasciculation syndrome. Clin Neurophysiol 2015;126:1246–54.
68 Liewluck T, Klein CJ, Jones LK. Cramp-fasciculation syndrome in patients with and
without neural autoantibodies. Muscle Nerve 2014;49:351–6.
69 de Carvalho M, Swash M. Fasciculation-cramp syndrome preceding anterior
horn cell disease: an intermediate syndrome? J Neurol Neurosurg Psychiatry
2011;82:459–61.
70 Blexrud MD, Windebank AJ, Daube JR. Long-term follow-up of 121 patients with
benign fasciculations. Ann Neurol 1993;34:622–5.
71 de Carvalho M, Swash M. Cramps, muscle pain, and fasciculations: not always
benign? Neurology 2004;63:721–3.
72 Arcila-Londono X, Lewis RA. Multifocal motor neuropathy. Handb Clin Neurol
2013;115:429–92.
73 Kiernan MC, Guglielmi JM, Kaji R, et al. Evidence for axonal membrane
hyperpolarization in multifocal motor neuropathy with conduction block. Brain
2002;125:664–75.
74 Cosgrove JL, Alexander MA, Kitts EL, et al. Late effects of Poliomyelitis. Arch Phys
Med Rehabil 1987;68:4–7.
75 Ritchie Russell W. Poliomyelitis. London: Edward Arnold, 1952:1–84.
76 Glatzel W, Grünes JU. Results of electromyographical and electroneurographical
investigations concerning syringomyelia. Eur Neurol 1976;14:60–7.
77 Simpson JA, Thomaides T. Fasciculation and focal loss of nerve accommodation in
peripheral neuropathies. Acta Neurol Scand 1988;77:133–41.
78 Werner RA, Andary M. Carpal tunnel syndrome: pathophysiology and clinical
neurophysiology. Clin Neurophysiol 2002;113:1373–81.
7
 Downloaded from http://jnnp.bmj.com/ on May 11, 2017 - Published by group.bmj.com

Fasciculation in amyotrophic lateral

sclerosis: origin and pathophysiological
relevance
Mamede de Carvalho, Matthew C Kiernan and Michael Swash

J Neurol Neurosurg Psychiatry published online May 10, 2017

Updated information and services can be found at:

http://jnnp.bmj.com/content/early/2017/05/10/jnnp-2017-315574

These include:

References This article cites 75 articles, 17 of which you can access for free at:
http://jnnp.bmj.com/content/early/2017/05/10/jnnp-2017-315574#BIBL

Email alerting Receive free email alerts when new articles cite this article. Sign up in the
service box at the top right corner of the online article.

Notes

To request permissions go to:

http://group.bmj.com/group/rights-licensing/permissions

To order reprints go to:

http://journals.bmj.com/cgi/reprintform

To subscribe to BMJ go to:

http://group.bmj.com/subscribe/