DIABETIC

NEUROPATHY

Dr. Tushar Patil , M.D.

Senior Resident, Dept of Neurology,
King George’s Medical University, Lucknow
India
DEFINITION
An internationally agreed simple definition of Diabetic neuropathy for
clinical practice is

“the presence of symptoms and/or signs of peripheral

nerve dysfunction in people with diabetes after the
exclusion of other causes”

Boulton AJ et al. Diabetic neuropathies: a statement by

the American Diabetes Association. Diabetes Care. 2005 Apr;28(4):956-62.
A more detailed definition of neuropathy was previously agreed upon at the San
Antonio Consensus Conference:

“diabetic neuropathy is a descriptive term meaning a

demonstrable disorder, either clinically evident or
subclinical, that occurs in the setting of diabetes mellitus
without other causes for peripheral neuropathy. The
neuropathic disorder includes manifestations in the somatic
and/or autonomic parts of the peripheral nervous system”

American Diabetes Association, American Academy of Neurology: Report and

recommendations of the San Antonio Conference on Diabetic Neuropathy
(Consensus Statement). Diabetes Care 11:592–597, 1988
CHRONIC COMPLICATIONS OF
DIABETES MELLITUS
Microvascular Macrovascular
 Eye disease  Coronary heart disease

Retinopathy  Peripheral arterial disease

(nonproliferative/proliferative)  Cerebrovascular disease
Macular edema Other
 Neuropathy  Gastrointestinal (gastroparesis,
Sensory and motor (mono- and diarrhea)
polyneuropathy)  Genitourinary (uropathy/sexual
Autonomic dysfunction)
 Nephropathy  Dermatologic Infectious
 Cataracts
 Glaucoma
 Periodontal disease
 Hearing loss
DIABETIC NEUROPATHY:
PROBLEM STATEMENT
 DM risen over past two decades, 30 million in 1985 to 285 million in
2010.
 IDF projects 438 million in 2030.
 All forms of diabetes of sufficient duration are vulnerable
 May coincide with CIDP, v B12 deficiency, alcoholic neuropathy, endocrine
neuropathies.
 Additional causes in 10% to 55% of patients with DM.
 Prevalence estimates from 5% to 100%.
 Pirart’s cohort of 4400 diabetics - prevalence 45% after 25 years.
 Can occur with IGT and metabolic syndrome without hyperglycemia.
 Most common form of neuropathy in the developed countries.
 More hospitalizations than all diabetic complications
 50% to 75% of nontrauma amputations.
 Weakness and ataxia, likelihood of falling 15 times unaffected.
 25% had symptoms, 50% had neuropathy after ankle reflex or
vibration test.
 90% positive on sophisticated tests of autonomic function or
peripheral sensation.
 Major morbidity is foot ulceration, gangrene ,limb loss.
 Amputation risk 1.7-fold , 12-fold if deformity (consequence of
neuropathy), 36-fold if h/ o ulceration.
 RISK FACTORS FOR THE DEVELOPMENT OF
DIABETIC NEUROPATHY
Modifiable Risk Factors Non-modifiable Risk Factors
 Poor glycemic control  Obesity
(Elevated HbA1c)  Older age
 Alcohol  Male sex
 Hypertension  Height
 Cigarette Smoking  Family h/o neuropathic
 Hypertriglyceridemia disease
 Longer duration of diabetes
 APOE genotype
 Aldose reductase gene
hyperactivity
 Angiotensin-converting
enzyme genotype
1.Harati Y. Diabetic Neuropathies: Unanswered Questions. Neurol Clin 25 (2007) 303–317

2.Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and

diabetic neuropathy. N Engl J Med 2005;352(4):341.
 PATHOGENESIS OF DN
Hyperglycemia
 Rheological changes - increase endoneurial vascular resistance and reduce
nerve blood flow.
 Depletion of nerve myoinositol by competitive uptake & activates protein
kinase C
 Activates polyol pathway in nerve tissue through aldose reductase
 Accumulation of sorbitol and fructose in nerve
 Nonenzymatic glycosylation of structural nerve proteins .
 Glucose auto-oxidation- toxic reactive oxygen intermediates .
PATHOGENESIS OF DIABETIC
NEUROPATHY

Unger J. Pathogenesis, diagnosis, and treatment of painful

diabetic peripheral neuropathy. Applied Neurology 2007;(Suppl 1)
OTHER PATHOGENETIC
MECHANISMS
 Polyol pathway
 Myoinositol
 Glycation
 Oxidative stress
 Vascular factors
 Growth factors
 Insulin-like growth factors
 C-peptide
 VEGF
 Immune mechanisms

Boulton AJ, Malik RA, Arezzo JC, Sosenko JM.

Diabetic somatic neuropathies. Diabetes Care. 2004 Jun;27(6):1458-86.
PATHOPHYSIOLOGIC TYPES
SURAL NERVE BIOPSY FROM PATIENT WITH DIABETIC LUMBAR
RADICULOPLEXOPATHY.
Perivascular lymphocytic inflammation involves two epineurial
arterioles. (Hematoxylin and eosin, ×25.) B, In the same patient, semi-
thin transverse section illustrates selective involvement of one fascicle,
with marked loss of myelinated fibers, a pattern highly suggestive of
nerve ischemia.
 CLASSIFICATION OF DIABETIC
NEUROPATHIES
 Generalized Symmetrical Polyneuropathies
Distal sensory or sensorimotor polyneuropathy
Small-fiber neuropathy
Autonomic neuropathy
Large-fiber sensory neuropathy
 Focal and Asymmetrical Neuropathies

Cranial neuropathy (single or multiple)

Truncal neuropathy (thoracic radiculopathy)
Limb mononeuropathy (single or multiple)
Proximal motor neuropathy (lumbosacral radiculoplexopathy, amyotrophy)
 Combinations

Polyradiculoneuropathy
Diabetic neuropathic cachexia
 DISTAL SYMMETRICAL POLYNEUROPATHY

A. Acute sensory neuropathy

 Burning discomfort in feet, hyperesthesiae, deep aching pain
 Sharp, stabbing or “electric shock” like sensations in lower limbs.
 Weight loss, depression, erectile dysfunction
 Nocturnal exacerbation,Clothes irritating hyperesthetic skin.
 Allodynia on sensory testing, a normal motor exam,reduced ankle reflexes.
 Poor glycemic control , may follow an episode of ketoacidosis
 Associated with weight losss & eating disorders .
 May develop after sudden improvement of glycemic control(? Insulin
neuritis)
 Blood glucose flux in genesis of neuropathic pain .
 Degeneration of myelinated & unmyelinated fibers
 More common in DM with mitochondrial tRNA mutation at 3243
(Suzuki , 1997)
 Neural ischemia by sudden improvement of glycemic control, “steal”
effect with arteriovenous shunting
 In management, stable blood glucose control is most important.
 Onset acute or subacute, severe symptoms resolve in less than a year
 CHRONIC SENSORIMOTOR
NEUROPATHY
(DPN)

 Most common DN,3/4TH of all DN.

 Sensory predominant, autonomic correlate with severity
 Minor involvement of distal muscles of lower extremities.
 Sensory stocking-glove distribution
 Length-dependent pattern.
 Advanced- sensation impaired over chest & abdomen - wedge-shaped
area.
Large-fiber neuropathy
 Painless paresthesias beginning at the toes and feet,
 Impaired vibration & JPS
 Diminished reflexes.
 Ataxia secondary to sensory deafferentation.
 Often asymptomatic, sensory deficit on examination.

Small-fiber neuropathy
 Deep, burning, stinging, aching pain ;allodynia to light touch.
 Pain & temp impaired, relative preservation of vibration & JPS & DTR
 Often accompanied by autonomic neuropathy
 May develop soon after onset of IDDM.
 Distal joint destruction (acrodystrophic neuropathy).
 Chronic foot ulceration (4% to 10%) due to unnoticed tissue damage, vascular
insufficiency, secondary infection
 Neuropathic arthropathy(Charcot joint ) in patients with foot ulcers &
autonomic impairment,
 Small joints of feet.
 Diabetic pseudotabes - lancinating pains, loss of JPS , diabetic pupillary
abnormalities (pseudo-Argyll Robertson pupils).
EDX studies
 Absent or decreased amplitudes of sural SNAPs
 Low amplitude or absent tibial H-reflexes .
 Active denervation in intrinsic foot muscles or decreased amplitudes of
CMAPs
 Slowing of motor conduction velocities, in 2/3 rd patients.
 DIABETIC NEUROPATHY & CIDP
 CIDP, MGUS, circulating GM1 antibodies and antibodies to
neuronal cells, and inflammatory vasculitis .
 Vinik et al - half of patients with proximal neuropathies have a
vasculitis,
 9% have CIDP, MGUS, ganglioside antibody syndrome
 Sharma et al- CIDP 11 times more frequent among diabetics
 If demyelinating, CIDP should be considered.
 CIDP responds to intervention
Sharma K, Cross J, Farronay O, et al. Demyelinating neuropathy in diabetes mellitus. Arch Neurol
2002;59:758–65
 EDX and nerve biopsy suggest diabetes contributes to an
axonal damage, with demyelination in CIDP.
 Difficulties in distinguishing between diabetic
polyneuropathy and CIDP
1) Overlap of the clinical features
2) CSF protein often elevated in DM
3) EDX may show demyelination in DM
4) Nerve biopsies show varying axonal and demyelinating
changes in both conditions. 
 DIABETIC AUTONOMIC
NEUROPATHY

 Correlates with severity of somatic neuropathy.

 Subclinical impairment CVS , GI , GU dysfunction
 Orthostatic hypotension, resting tachycardia, diminished heart-rate response
to respiration
 Vagal denervation of heart- high resting pulse & loss of sinus arrhythmia.
 Painless or silent myocardial infarction.
 GI motility abnormalities of esophagus, stomach, gallbladder,bowel, fecal
incontinence.
 Delayed gastric emptying - nausea, early satiety, postprandial bloating.
 Diabetic diarrhea due to small-intestinal involvement , at night,
paroxysmal.
 Constipation due to colonic hypomotility is more common than diarrhea.
 Bacterial overgrowth may occur.
 Impaired bladder sensation - first symptom of GU dysfunction.
 Bladder atony - prolonged intervals between voiding, urinary retention,
overflow incontinence.
 Void every few hours to prevent urinary retention.
 Impotence is often first manifestation in men , occurring in more than 60%.
 Both erectile failure and retrograde ejaculation.
 Impotence usually associated with distal symmetrical polyneuropathy.
 Sudomotor abnormalities - distal anhidrosis, facial and truncal sweating, heat
intolerance.
 Gustatory sweating - profuse sweating in face following food .
 Pupillary abnormalities - constricted pupils with sluggish light reaction, in
20% .
 Blunted response to hypoglycemia - inadequate sympathetic & adrenal
response - unawareness of hypoglycemia –complicates intensive insulin
treatment
 PROXIMAL DIABETIC NEUROPATHY
(DIABETIC AMYOTROPHY OR LUMBOSACRAL
RADICULOPLEXOPATHY)

 Diabetic proximal neuropathy,. Diabetic amyotrophy, thoracic radiculopathy,

and proximal or diffuse lower extremity weakness -different presentations of
involvement of roots or proximal nerve segments.

 Asymmetrical weakness and wasting of pelvifemoral muscles may occur

abruptly or stepwise in individuals with diabetes older than 50 .

 May develop with long-standing NIDDM during poor metabolic control and
weight loss, but can occur in mild and well-controlled diabetics or be
presenting feature.
 Unilateral severe pain in the lower back, hip, and anterior thigh heralds onset

 Within days to weeks, weakness of proximal and, to a lesser extent, distal

lower-extremity muscles (iliopsoas, gluteus, thigh adductor, quadriceps,
hamstring, and anterior tibialis).
 Opposite leg affected after days to months.
 Reduced or absent knee and ankle jerks.
 Weight loss in more than half & more than nondiabetic lumbosacral
radiculoplexopathy
 Pain recedes before power improves.

 Recovery takes up to 24 months due to slow axonal regeneration, mild to moderate

weakness may persist.

 EMG - low-amplitude femoral nerve motor responses, fibrillation potentials in

thoracic and lumbar paraspinal muscles, active denervation in affected muscles.

 Neuroimaging should be considered when lumbar root, cauda lesions, or

structural lumbosacral plexopathy suspected .

 No effect of corticosteroids in recovery of motor deficit.

TRUNCAL NEUROPATHY

 T4 -T12 radiculopathy - pain or dysesthesias in distribution.

 Bulging of abdominal wall due to weakness of abdominal muscles

 In isolation or with lumbosacral radiculoplexopathy.

 Can mimic intraabdominal, intrathoracic, or intraspinal disease, zoster .

 May persist for several months before resolution within 4 to 6 months.

 EDX - active denervation in paraspinal and abdominal muscles,

 Focal anhidrosis in area of pain with thermoregulatory sweat test.

 LIMB MONONEUROPATHY

 Nerve infarction or entrapment.

 Infarction- abrupt onset of pain , variable weakness and atrophy. Median, ulnar,
fibular n. commonly affected.
 Entrapment more common than infarction.
 EDX - axonal loss in nerve infarction ; conduction block or slowing in
entrapment.
 DM in 8% to 12% of patients with CTS.
 Aggravation of ischemia in nerves with chronic endoneurial hypoxia.
MULTIPLE MONONEUROPATHIES

 Mononeuritis multiplex- replaced as rarely due to inflammation

 Involvement of two or more nerves
 Onset abrupt in one nerve, other nerves are involved sequentially
 Multiple mononeuropathies involving proximal nerves considered cause of
amyotrophy.
 Infarction results occlusion of vasa nervorum.
 Systemic vasculitis be considered in D/D
CRANIAL MONONEUROPATHIES

 3 rd nerve palsy is most common

 Pupillary sparing, from ischemic infarction of the centrifascicular
oculomotor axons
 Peripheral pupillary motor fibers spared due to collateral circulation
 4th , 6th, 7th nerves also affected.
 Bell palsy- higher frequency of diabetes.
 Rhinocerebral mucormycosis and “malignant” external otitis
 COMPARISON OF FEATURES OF MONONEUROPATHIES,
ENTRAPMENT SYNDROMES AND DISTAL SYMMETRIC
POLYNEUROPATHY

Vinik et al , Diabetic Neuropathy in Older Adults. Clin Geriatr Med 24 (2008) 407–
435
IS IT ‘‘DIABETIC NEUROPATHY’’ OR
‘‘NEUROPATHY IN A DIABETIC
PATIENT’’?
Think if-
 Rapidly progressive
 Prominent motor abnormality or cranial nerve involvement
 Disproportionate large fiber abnormalities.
 Involvement of the entire lower limbs without neuropathy of the
distal upper limb.
 More often sensory symptoms and findings in the hands
SIGNS
 Scores to assess clinical signs pioneered by Dyck , who first
described the NDS and later the Neuropathy Impairment Score
(NIS).
 A modified NDS used in several studies , can be used in
community
 Shown to be best predictor of foot ulceration and best neuropathic
end point in a large prospective community study
 The maximum NDS is 10, with a score of 6 or more being
predictive of foot ulcer risk.
THE MODIFIED NEUROPATHIC
DISABILITY SCORE.
 DEVICES FOR CLINICAL
SCREENING.
Semmes-Weinstein monofilament
 Assesses pressure perception when gentle pressure is applied to the handle
sufficient to buckle the nylon filament.
 One that exerts 10 g pressure, is most commonly used

 Also referred as 5.07 monofilament .

Graduated Rydel-Seiffer tuning fork

 Visual optical illusion to determine intensity of residual vibration on a 0–8
scale at the point of threshold (disappearance of sensation).

Tactile circumferential discriminator

 Assesses perception of calibrated change in the circumference of a probe (a
variation of two-point discrimination).
 Also demonstrated good agreement with other measures of QST.
Neuropen
 Assesses pain using both a Neurotip at one end of the “pen” and a
10-g monofilament at other end.
 Was shown to be sensitive device for assessing nerve function
when compared with the simplified NDS
ELECTROPHYSIOLOGY
 NCV is only gradually diminished by DPN, with estimates of a loss
of 0.5m/ s/ year.
 Sensitive but nonspecific index on onset
 Detecting subclinical deficits.
 Trace the progression.
 Changes related to glycemic control.
 Can reflect pathology in large axons (Atrophy, demyelination,loss of
density)
 Can improve with effective therapy
Amplitudes, area, and duration. Peak
 Strong correlation (r 0.74; P 0.001) between myelinated
fiber density and whole-nerve sural amplitude in DPN
 Loss of SNAP amplitude at a rate of 5% per year in DPN
over 10-year period
 Total area of the SNAP and CMAP suggested as means of assessing
contribution of slower conducting fibers,
 Area alone, or with peak amplitude, can be used to estimate
temporal dispersion and conduction block.
DIAGNOSTIC TESTS OF
AUTONOMIC NEUROPATHY
 Resting heart rate
>100 bpm is abnormal.
 Beat-to-beat HRV
 At rest and supine heart rate by ECG while patient breathes at 6/m
 Difference of >15 bpm - normal, <10 bpm - abnormal.
 Lowest normal value for the expiration-to-inspiration ratio of the R-R
interval is 1.17 in 20–24 years of age.
 Heart rate response to standing
 R-R interval measured at beats 15 and 30 after standing.
 Normally, tachy F.B. reflex brady. The 30:15 ratio is 1.03.
 Heart rate response to the Valsalva maneuver
 Exhales into manometer to 40 mmHg for 15 s
 Healthy subjects develop tachy & peripheral vasoconstriction during
strain & overshoot brady, rise in BP with release.
 The ratio of longest R-R to shortest R-R should be 1.2.
 Systolic blood pressure response to standing
 Sys BP measured supine. Patient stands, BP aft 2 m.
 Normal response- fall of <10 mmHg,
 Borderline - fall of 10–29 mmHg
 Abnormal - fall of >30 mmHg with symptoms
 Diastolic blood pressure response to isometric exercise
 Squeeze handgrip dynamometer to a max . Then squeezed at 30% max for 5
min.
 N response for diastolic BP is a rise of >16 mmHg in the other arm.
 ECG QT/QTc intervals

The QTc should be 440 ms.

 Neurovascular flow
 Using noninvasive laser Doppler measures of peripheral sympathetic responses to
nociception.
 Radionuclide Cardiac Imaging
 123-I-metaiodobenzylguanidine (MIBG)
 11-C-hydroxyephedrine
MANAGEMENT OF DIABETIC
NEUROPATHY
Symptomatic management
1) Exclude nondiabetic causes
● Malignant disease (e.g., bronchogenic carcinoma)
● Metabolic
● Toxic (e.g., alcohol)
● Infective (e.g., HIV infection)
● Iatrogenic (e.g., isoniazid, vinca alkaloids)
● Medication related (chemotherapy, HIV treatment)
2) Explanation, support, and practical measures (e.g., bed cradle to lift bed,
clothes off hyperesthetic skin)
3) Assess level of blood glucose control profiles
4) Aim for optimal stable control
5) Consider pharmacological therapy
CONTROL OF HYPERGLYCEMIA.
 Open-label uncontrolled studies suggested near normoglycmia
helpful in painful neuropathic symptoms.
 Stability of glycemic control equally important to level of achieved
control.
 Lack of appropriately designed controlled studies
 Generally accepted that intensive diabetes therapy aimed at near
normoglycemia should be first step in the treatment of any form of
DN.
 Duckworth et al.(2009)( 6y) no benefit for new neuropathy
 Action to Control Cardiovascular Risk in Diabetes
(ACCORD) trial- (10,000 patients) -new cases of neuropathy
significantly reduced intensive group
 ADVANCE trial –( 11,000 patients)- (5y) not significantly
affected by intensive control
 Diabetes Control and Complication Trial (DCCT; 1995) –
(5y) intensive management reduces neuropathy by 64%
 Benefit persisted for 8 years after DCCT
PHARMACOTHERAPY
 No evidence to support NSAIDs.

Tricyclic drugs
 Several RCTs supported these agents in neuropathic pains.

Mechanisms
 Inhibition of NE &/or 5-HT reuptake at synapses of central descending pain
control systems
 Antagonism of NMDA rec mediating hyperalgesia & allodynia .
 Rapid onset, suggests a mode of action not primarily relief of depression.
 use is restricted because of the frequency and severity of side effects.
 Most experience with amitriptyline and imipramine.
 Can be taken once a day in the evening.
 Desipramine also useful drug ,better tolerated than amitriptyline
 Side effects
 Drowsiness and lethargy
 Anticholinergic side effects, particularly dry mouth
 In cases of painful neuropathy resistant to tricyclic drugs, combination with
major tranquilizers
 Amitriptyline and transcutaneous electrotherapy described in failed
monotherapy.
 Superior to that of tricyclic monotherapy plus sham electrotherapy
SSRIs
 inhibit presynaptic reuptake of 5HT, not NE.
 Paroxetine but not fluoxetine associated with significant pain relief.
 Citalopram 40 mg/day was confirmed to be efficacious in relieving
neuropathic pain, but less effective than imipramine
 Side effects are less common with SSRIs.
Anticonvulsants.
 Used for many years
 Limited evidence for phenytoin and carbamazepine in DN
 Gabapentin now widely used
 In a large controlled trial, significant pain relief with reduced sleep
disturbance was reported using dosages of 900–3,600 mg daily.
 In a recent review of all the trials of gabapentin for neuropathic pain, it was
concluded that dosages of 1,800–3,600 mg per day of this agent were
effective
 Lamotrigine - antiepileptic agent with at least two antinociceptive properties.
 In a randomized placebo controlled study, Eisenberg et al confirmed

the efficacy of this agent in patients with neuropathic pain.

Antiarrhythmics.
 Mexilitine is a class 1B antiarrhythmic , structural analog of
lignocaine.
 Efficacy in neuropathic pain confirmed in controlled trials and
reviewed by Dejgard et al. and Jarvis and Coukell.
 The dosage used in trials (up to 450 mg daily) is lower than that
used for arrhythmias;
 Regular ECG monitoring necessary
 Long-term use of mexilitine cannot be recommended.
Other agents

 Tramadol - opioidlike, centrally acting, nonnarcotic analgesic.

 Although first trial was 6 weeks’ duration, subsequent follow-up study
suggested symptomatic relief could be maintained for at least 6 months
 Side effects common , similar to other opioid-like drugs.
 Similarly, two randomized trials have confirmed the efficacy of controlled-
release oxycodone for neuropathic pain in diabetes
 Opioids such as oxycodone may be considered as add-on therapies for patients
failing to respond to nonopioid medications.
TOPICAL AND PHYSICAL
TREATMENT
Topical nitrate
 A recent study suggested local application feet of isosorbide
dinitrate spray was effective in relieving overall pain & burning
discomfort

Capsaicin
 Alkaloid, in red pepper, depletes substance P and reduces
chemically induced pain.
 Several controlled studies combined in meta-analyses seem to
provide some evidence of efficacy in diabetic neuropathic pain
 Only recommended for up to 8 weeks of treatment
 Useful in localized discomfort.
Acupuncture.
 Unmasked studies support its use .
 In recent report, benefits lasted 6 months, reduced use of other analgesics
 Conduct of potential blinded studies of acupuncture is problematic; although a
placebo response is possible with acupuncture
Other physical therapies.
 Percutaneous nerve stimulation
 Static magnetic field therapy .
 Electrical spinal cord stimulation.
 A case series of patients with severe painful neuropathy unresponsive to
conventional therapy suggested efficacy of using an implanted spinal cord
stimulator.
 EVIDENCE-BASED GUIDELINE:
TREATMENT OF
PAINFUL DIABETIC
NEUROPATHY

Anticonvulsants
 If clinically appropriate, pregabalin should be offered for the treatment of PDN
(Level A).

 Gabapentin and sodium valproate should be considered for the treatment of PDN
(Level B).

 There is insufficient evidence to support or refute the use of topiramate for the
treatment of PDN (Level U).

 Oxcarbazepine, lamotrigine, and lacosamide should probably not be considered

for the treatment of PDN (Level B).

Valproate may is potentially teratogenic, be avoided in women of childbearing age. Due to weight gain and
potential worsening of glycemic control, this drug is unlikely to be the first treatment choice for PDN.
Antidepressants.

 Amitriptyline, venlafaxine, and duloxetine should be considered for the

treatment of PDN (Level B). Data are insufficient to recommend one of
these agents over the others.

 Venlafaxine may be added to gabapentin for a better response (Level C).

 There is insufficient evidence to support or refute the use of desipramine,

imipramine, fluoxetine, or the combination of nortriptyline and
fluphenazine in the treatment of PDN (Level U).
Opioids.
 Dextromethorphan, morphine sulfate, tramadol, an
oxycodone should be considered for the treatment of PDN
(Level B). Data are insufficient to recommend one agent
over the other

 The use of opioids for chronic nonmalignant pain has gained

credence over the last. Both tramadol and dextromethorphan
were associated with substantial adverse events (e.g., sedation,
nausea, and constipation).
 The use of opioids can be associated with the development of
novel pain syndromes such as rebound headache.
 Chronic use of opioids leads to tolerance and frequent escalation
of dose.
Other pharmacologic agents.

 Capsaicin and isosorbide dinitrate spray should be considered for the

treatment of PDN (Level B).

 Clonidine, pentoxifylline, and mexiletine should probably not be considered

for the treatment of PDN (Level B).

 The Lidoderm patch may be considered for the treatment of PDN (Level C).

 There is insufficient evidence to support or refute the usefulness of vitamins

and -lipoic acid in the treatment of PDN (Level U).

Although capsaicin has been effective in reducing pain in PDN clinical trials,
many patients are intolerant of the side effects, mainly burning pain on contact
with warm/hot water or in hot weather.
NONPHARMACOLOGIC
MODALITIES ?

 Percutaneous electrical nerve stimulation should be considered for

the treatment of PDN (Level B).

 Electromagnetic field treatment, low-intensity laser treatment, and

Reiki therapy should probably not be considered for the treatment of
PDN (Level B).

 Evidence is insufficient to support or refute the use of amitriptyline

plus electrotherapy for treatment of PDN (Level U).
 SUMMARY OF RECOMMENDATIONS

V. Bril, J. England, G.M. Franklin, et al. Evidence-based guideline: Treatment of painful diabeticneuropathy : Report of
the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine,
and the American Academy of Physical Medicine and Rehabilitation .Neurology 76 May 17, 2011
 AUTONOMIC NEUROPATHY
 Head of bed elevated 6 to 10 inches.
 Prevents salt & water losses during night and combat supine hypertension.
 Two cups of strong coffee or tea with meals
 Frequent small meals
 Daily fluid intake (>20 oz/day) and salt ingestion (10-20 g/day).
 Elastic body stockings may be beneficial by reducing the venous capacitance in
bed but poorly tolerated.
 Plasma volume expansion can by fludrocortisone (0.1-0.6 mg/day).
 NSAlDs, which inhibit prostaglandin synthesis, ibuprofen, 400 mg QID
 Phenylpropanolamine (25-50 mg TDS), once used to manage OH
 Midodrine, an α1-adrenergic agonist,causes vasoconstriction, also effective.
 Subcutaneous recombinant human erythropoietin effective in some patients
with OH & anemia.
 Octreotide may improve OH by splanchnic vasoconstriction.
 Delayed gastric emptying relieved with metoclopramide
 Diabetic diarrhea treated with short courses of tetracycline or erythromycin
 Clonidine reported to reduce troublesome diarrhea.
PATHOGENETIC TREATMENTS AND
PREVENTION
Aldose Reductase Inhibitors.
 The first clinical trials of ARIs in DN took place 25 years ago, and
currently only one agent is available in one country (Epalrestat in
Japan) .
 Most of the early trials can be summarized as:

● Too small. ● Too few ● Too short. ● Too late.

TREATMENT OF DIABETIC NEUROPATHY BASED ON
PATHOGENETIC MECHANISMS

FROM BOULTON A, VINIK, A, AREZZO J, ET AL. AMERICAN DIABETES

ASSOCIATION: POSITION STATEMENT: DIABETIC NEUROPATHIES. 2005.
Antioxidants
 α -LA - potential efficacy for both symptoms & modifying natural
history . (ALADIN II, ALADIN III, SYDNEY)
 Two large North American/European clinical trials of of α -LA are
in progress
 γ-LA (GLA) , component of evening primrose oil, can prevent
abnormalities in diabetes and in essential fatty acid and prostanoid
metabolism
 GLA treatment for 1 year in a randomized trial resulted in
improvement in electrophysiology and deficits
Neutrophins.
 As a result of contradictory results from clinical trials, the clinical

development of NGF was halted,

Inhibitors of glycation
 Studies of aminoguanidine, which inhibits the formation of AGEs,
mainly focused on nephropathy
 Few data are available on aminoguanidine or other inhibitors of
AGE formation in clinical neuropathy
PKC inhibition.
 Intracellular hyperglycemia increases DAG levels, which activates
PKC formation
 Preliminary data suggest that treatment with a PKC- inhibitor might
ameliorate measures of nerve function in DPN . Multicenter trials
are currently in progress
Vasodilators.
 Treatment with ACE inhibitors has been shown to improve
electophysiological measures of nerve function in mild neuropathy .
 The short-acting vasodilator isosorbide dinitrate has been shown to
improve painful symptoms, but its effect on deficits and
electrophysiology are unknown
TAKE HOME MESSAGE
 Diabetic neuropathy occurs in about 45% patients with Diabetes
Mellitus
 Metabolic and Vascular factors are implicated in pathogenesis.
 Most common type is distal symmetrical sensorimotor
polyneuropathy
 Exclude nondiabetic etiologies
 Stabilize glycemic control
 Tricyclic drugs (eg, amitriptyline 25 to 150 mg before bed)
 Anticonvulsants (eg, gabapentin, typical dose 1.8 g/day)
 Opioid or opioid-like drugs (eg, tramadol or controlled
release oxycodone)
 Drugs targeting pathogenic process are in development and may be
available in near future.
REFERENCES
 Katirji B, Koontz D. Disorders of Peripheral Nerves. In:
Bradley’s Neurology in Clinical Practice. 5 th Edition.
 Harrison’s Principles of Internal Medicine. 18 th Edition.
 Harati Y. Diabetic Neuropathies: Unanswered Questions.
Neurol Clin 25 (2007) 303–317.
 Vinik A I et al. Diabetic Autonomic Neuropathy. Diabetes Care,
Volume 26, Number 5, May 2003
 Boulton AJM. Diabetic Neuropathies:A statement by the American
Diabetes Association. Diabetes Care, Volume 28, Number 4,
April 2005.
 Vinik AI et al. Diabetic Neuropathy in Older Adults. Clin
Geriatr Med 24 (2008) 407–435.
THANK YOU