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 MELLITUSMicrovascular Eye disease Retinopathy

(nonproliferative/proliferative) Macular edema Neuropathy Sensory and motor (mono- and

polyneuropathy) Autonomic Nephropathy

Macrovascular Coronary heart disease Peripheral arterial disease Cerebrovascular disease Other Gastrointestinal (gastroparesis,

diarrhea) Genitourinary (uropathy/sexual

dysfunction) 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 Poor glycemic control

(Elevated HbA1c) Alcohol Hypertension Cigarette Smoking Hypertriglyceridemia

Non-modifiable Risk Factors Obesity Older age Male sex Height Family h/o neuropathic

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 anddiabetic 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 interventionSharma 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 OFPAINFUL 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.

FROM BOULTON A, VINIK, A, AREZZO J, ET AL. AMERICAN DIABETES ASSOCIATION: POSITION STATEMENT: DIABETIC NEUROPATHIES. 2005.

TREATMENT OF DIABETIC NEUROPATHY BASED ON PATHOGENETIC MECHANISMS

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 clinicaldevelopment 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 neuropathyPKC 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. 5th Edition. Harrison’s Principles of Internal Medicine. 18th 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.

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