Diabetic Neuropathy : Clinical Manifestations and Management

Diabetic Neuropathy : Clinical Manifestations and Management

AK Daif, MD

Consultant and Professor of Neurology

KKUH, college of Medicine

Diabetic NeuropathyDiabetic Neuropathy About 60-70% of people with

diabetes have mild to severe forms of nervous system damage, including: Impaired sensation or pain in the feet

or hands

Slowed digestion of food in the stomach

Carpal tunnel syndrome

Other nerve problems

More than 60% of nontraumatic lower-limb amputations in the United States occur among people with diabetes.

Diabetic Peripheral Nerve DamageDiabetic Peripheral Nerve Damage

Myelinated NeuronMyelinated Neuron

Incidence of Diabetic Neuropathyas a proportion of all diabetics 20 years after

diagnosis

Incidence of Diabetic Neuropathyas a proportion of all diabetics 20 years after

diagnosis

No neuropathy 10%

Asymptomatic 40%

Symptomatic 50%

Risk FactorsRisk Factors

• Glucose control• Duration of diabetes• Damage to blood vessels• Mechanical injury to nerves• Autoimmune factors• Genetic susceptibility• Lifestyle factors

– Smoking– Diet

Underlying MechanismsUnderlying Mechanisms

Agreement not yet reached on exact causal relationship between insulin

imbalance and nerve damage.

The relative importance and inter-relationship of the various mechanisms is the subject of ongoing research and

debate.

Physical manifestationsPhysical manifestations

• Nerve fibres degenerate

• Blood vessels supplying the nerves are ‘grossly diseased’

Any theory needs to account for both

Pathways of actionPathways of action

• Polyol pathway

• Triose phosphate effects

• Failure of nerve growth & repair mechanism

• Fatty acid metabolism

Polyol PathwayPolyol Pathway

• Polyol = Polyhydroxy alcohols• High blood glucose

– Nerve cell and capillary membranes have insulin-independent glucose transport.

– High intra-cellular glucose levels– Conversion of glucose to sorbitol in nerve

cells by aldose reductase enzyme– Sorbitol cannot cross membranes and

therefore accumulates

Polyol PathwayPolyol Pathway

• Consequences of high sorbitol concentration:

– Osmotic damage to nerve cells

– reduction in nerve myoinositol

– Inhibition of nitric oxide (NO) production• Aldose reductase competes for NADPH• NO is vasodilator

– Increased production of free radicals• Superoxide, hydrogen peroxide, hydroxyl• Formed during mitochondrial respiration• Increased oxidative stress (proteins, lipids, DNA)

Polyol PathwayPolyol Pathway

• Treatment possibilities– Aldose reductase inhibitors– Supplemental myoinositol– Nitric oxide stimulation/sensitisation– Vasodilators– Antioxidants

Triose phosphatesTriose phosphates

• High intracellular glucose leads increased production of triose phosphates– Activation of protein kinase C (PKC) via DAG

• Damages capillaries (permeability, contractility)

• Damages nerve function

– Non-enzymic reaction with proteins & DNA• Advanced Glycation End-products (AGEs)

• Damage to capillaries and nerve fibres

• Specific cellular AGE receptors

• Protein cross-linking

Fatty acid metabolismFatty acid metabolism

• Functions of DGLA and AA in nerves– Incorporated into membranes

• required for normal nerve structure, which is required for normal nerve conduction

– Required for regulation of nerve conduction• via inositol/calcium cycle and PGE1

– Required for microvascular system• DLMG - Prostaglandin E1

• AA - Prostacyclin

Pathogenesis of Diabetic Neuropathy

Pathogenesis of Diabetic Neuropathy

• Metabolic factors– High blood glucose– Advanced glycation end products– Sorbitol – Abnormal blood fat levels

• Ischemia

• Nerve fiber repair mechanisms

Natural history of diabetic neuropathy and clinical signs and symptoms with pathological background.

Natural history of diabetic neuropathy and clinical signs and symptoms with pathological background.

• With increasing stage of neuropathy,

there is a progressive loss of nerve fibers that convey sensation.

• When the fibers undergo degeneration or impaired remyelination, they release impulse of positive symptoms.

• With progression of disease, negative symptoms of sensory loss are increased

Multifactorial etiology of diabetic neuropathy. Hyperglycemia exerts increased polyol pathway, enhanced AGE formation, increased

oxidative stress as well as cytokine release. These factors are complicatedly interactive or independently operate for the cause and development of

diabetic neuropathy directly affecting nerve tissues or through nutrient vascular tissues

Mechanisms of how polyol pathway causes neuropathy.

Increased polyol pathway affects differently nerve fibers and supplying vascular tissues. In nerve tissues, polyol yperactivity causes suppression of PKC activity by the inhibition of membranous PKC-a expression while it causes increased PKC activity by elevation of membranous PKC-b expression in vascular wall.

These dichotomous processes eventually elicit decreased Na,K-ATPase activity of nerve tissues and delay of nerve conduction

Pathological findings of sural nerve obtained from diabetic patients with clinically overt neuropathy.

Pathological findings of sural nerve obtained from diabetic patients with clinically overt neuropathy.

There is a marked loss of myelinated

nerve fibers of both large and small caliber. Endoneurial vessels show typical microangiopathic changes exemplified by thickened wall (arrow) (A).

There is also a marked loss of unmyelinated fibers at EM level (B).

Diagnostic TestsDiagnostic Tests

• Assess symptoms - muscle weakness, muscle cramps, prickling, numbness or pain, vomiting, diarrhea, poor bladder control and sexual dysfunction

• Comprehensive foot exam – Skin sensation and skin integrity– Quantitative Sensory Testing (QST)– X-ray

• Nerve conduction studies• Electromyographic examination (EMG)• Ultrasound

Classification of Diabetic Neuropathy

Classification of Diabetic Neuropathy

• Symmetric polyneuropathy

• Autonomic neuropathy

• Polyradiculopathy

• Mononeuropathy

Symmetric PolyneuropathySymmetric Polyneuropathy

• Most common form of diabetic neuropathy

• Affects distal lower extremities and hands (“stocking-glove” sensory loss)

• Symptoms/Signs– Pain– Paresthesia/dysesthesia– Loss of vibratory sensation

Complications of Sensorimotor neuropathy

Complications of Sensorimotor neuropathy

• Ulceration (painless)• Neuropathic edema• Charcot arthropathy• Callosities

Treatment of Symmetric Polyneuropathy

Treatment of Symmetric Polyneuropathy

• Glucose control

• Pain control– Tricyclic antidepressants

– Topical creams

– Anticonvulsants

• Foot care

Essentials of Foot CareEssentials of Foot Care• Examination

– Annually for all patients

– Patients with neuropathy - visual inspection of feet at every visit with a health care professional

• Advise patients to:– Use lotion to prevent dryness and cracking

– File calluses with a pumice stone

– Cut toenails weekly or as needed

– Always wear socks and well-fitting shoes

– Notify their health care provider immediately if any foot problems occur

Autonomic NeuropathyAutonomic NeuropathySymptomatic

Postural hypotension

Gastroparesis

Diabetic diarrhea

Neuropathic bladder

Erectile dysfunction

Neuropathic edema

Charcot arthropathy

Gustatatory sweating

Subclinical abnormalities

Abnormal pupillary reflexes

Esophageal dysfunction

Abnormal cardiovascular reflexes

Blunted counter-regulatory responses to hypoglycemia

Increased peripheral blood flow

Autonomic neuropathyAutonomic neuropathy

• Affects the autonomic nerves controlling internal organs – Peripheral– Genitourinary– Gastrointestinal– Cardiovascular

• Is classified as clinical or subclinical based on the presence or absence of symptoms

Peripheral Autonomic Dysfunction

Peripheral Autonomic Dysfunction

• Contributes to the following symptoms/signs:– Neuropathic arthropathy (Charcot foot)– Aching, pulsation, tightness, cramping, dry skin,

pruritus, edema, sweating abnormalities– Weakening of the bones in the foot leading to

fractures

• Testing– Direct microelectrode recording of

postglanglionic C fibers– Galvanic skin responses– Measurement of vascular responses

Peripheral Autonomic Dysfunction, cont.

Peripheral Autonomic Dysfunction, cont.

• Treatment– Foot care/elevate feet when sitting– Eliminate aggravating drugs – Reduce edema

• midodrine• diuretics

– Support stockings– Screen for CVD

Genitourinary Autonomic Neuropathy

Genitourinary Autonomic Neuropathy

Sign/Symptom TreatmentBladder dysfunction Voluntary urination;

catheterization

Retrograde ejaculation Antihistamine

Erectile dysfunction Sildenafil, tadalafil

Dyspareunia Lubricants; estrogencreams

Gastrointestinal Autonomic Neuropathy

Gastrointestinal Autonomic Neuropathy

• Symptoms/Signs– Gastroparesis resulting in anorexia, nausea,

vomiting, and early satiety– Diabetic enteropathy resulting in diarrhea and

constipation

• Treatment– Other causes of gastroparesis or enteropathy

should first be ruled out– Gastroparesis - Small, frequent meals,

metoclopramide, erythromycin– Enteropathy - loperamide, antibiotics, stool

softeners or dietary fiber

Cardiovascular Autonomic Neuropathy

Cardiovascular Autonomic Neuropathy

• Symptoms/Signs– Exercise intolerance– Postural hypotension

• Treatment– Discontinue aggravating drugs– Change posture (make postural

changes slowly, elevate bed)– Increase plasma volume

PolyradiculopathyPolyradiculopathy• Lumbar polyradiculopathy (diabetic

amyotrophy) – Thigh pain followed by muscle weakness

and atrophy

• Thoracic polyradiculopathy – Severe pain on one or both sides of the

abdomen, possibly in a band-like pattern

• Diabetic neuropathic cachexia– Polyradiculopathy + peripheral neuropathy– Associated with weight loss and

depression

Polyradiculopathy, cont.Polyradiculopathy, cont.

• Polyradiculopathies are diagnosed by electromyographic (EMG) studies

• Treatment– Foot care– Glucose control– Pain control

MononeuropathyMononeuropathy• Peripheral mononeuropathy

– Single nerve damage due to compression or ischemia

– Occurs in wrist (carpal tunnel syndrome), elbow, or foot (unilateral foot drop)

– Symptoms/Signs• numbness• edema• pain• prickling

• Cranial mononeuropathy– Affects the 12 pairs of nerves that are

connected with the brain and control sight, eye movement, hearing, and taste

– Symptoms/Signs• unilateral pain near the affected eye• paralysis of the eye muscle • double vision

• Mononeuropathy multiplex

Mononeuropathy, cont.Mononeuropathy, cont.

Mononeuropathy, cont.Mononeuropathy, cont.

• Treatment– Foot care– Glucose control– Pain control

Other Treatment OptionsOther Treatment Options

• Aldose reductase inhibitors

• ACE inhibitors

• Weight control

• Exercise

Anticonvulsant Drugs for Neuropathic Pain DisordersAnticonvulsant Drugs for

Neuropathic Pain Disorders

• Postherpetic neuralgia

– gabapentin*

– pregabalin *

• Diabetic neuropathy

– carbamazepine

– phenytoin

– gabapentin

– lamotrigine

– pregabalin *

• HIV-associated neuropathy

– lamotrigine

• Trigeminal neuralgia

– carbamazepine*

– lamotrigine

– oxcarbazepine

• Central poststroke pain

– lamotrigine

*Approved by FDA for this use.HIV = human immunodeficiency virus.

Tricyclic Antidepressants: Adverse Effects

Tricyclic Antidepressants: Adverse Effects

• Commonly reported AEs (generally anticholinergic):

– blurred vision

– cognitive changes

– constipation

– dry mouth

– orthostatic hypotension

– sedation

– sexual dysfunction

– tachycardia

– urinary retention

• Desipramine

• Nortriptyline

• Imipramine

• Doxepin

• Amitriptyline

FewestAEs

Most AEs

AEs = adverse effects.

Principles of Opioid Therapy for Neuropathic Pain

Principles of Opioid Therapy for Neuropathic Pain

• Opioids should be titrated for therapeutic efficacy versus AEs

• Fixed-dose regimens generally preferred over prn regimens• Document treatment plan and outcomes• Consider use of opioid written care agreement• Opioids can be effective in neuropathic pain• Most opioid AEs controlled with appropriate specific

management (eg, prophylactic bowel regimen, use of stimulants)

• Understand distinction between addiction, tolerance, physical dependence, and pseudoaddiction

ReferencesReferences

American Diabetes Association: Preventive Foot Care in Diabetes(Position Statement). Diabetes Care 27 (Suppl.1): S63-S64, 2004

Feldman, EL: Classification of diabetic neuropathy. In UpToDate.Wellesley, MA, UpToDate, 2003

National Diabetes Information Clearinghouse. Diabetic Neuropathies:The Nerve Damage of Diabetes. Bethesda, MD: National Institute ofDiabetes and Digestive and Kidney Diseases, National Institutes ofHealth (NIH), DHHS; 2002

National Diabetes Information Clearinghouse. Prevent DiabetesProblems: Keep Your Feet and Skin Healthy. Bethesda, MD: NationalInstitute of Diabetes and Digestive and Kidney Diseases, NationalInstitutes of Health (NIH), DHHS; 2003

References, cont.References, cont.

Feldman, EL: Pathogenesis and prevention of diabeticpolyneuropathy. In UpToDate. Wellesley, MA, UpToDate, 2003.

Feldman, EL, McCulloch, DK: Treatment of diabetic neuropathy. InUpToDate. Wellesley, MA, UpToDate, 2003.

Stevens, MJ: Diabetic autonomic neuropathy. In UpToDate.Wellesley, MA, UpToDate, 2003.

Feldman, EL: Clinical manifestations and diagnosis of diabeticpolyneuropathy. In UpToDate. Wellesley, MA, UpToDate, 2003.