Diabetic Neuropathy : Clinical Manifestations and Management AK Daif, MD Consultant and Professor of Neurology KKUH, college of Medicine

Diabetic 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 Damage

Myelinated Neuron

Incidence of Diabetic Neuropathy as a proportion of all diabetics 20 years after diagnosis

Risk Factors Glucose control Duration of diabetes Damage to blood vessels Mechanical injury to nerves Autoimmune factors Genetic susceptibility Lifestyle factors –Smoking –Diet

Underlying 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 manifestations Nerve fibres degenerate Blood vessels supplying the nerves are ‘grossly diseased’ Any theory needs to account for both

Pathways of action Polyol pathway Triose phosphate effects Failure of nerve growth & repair mechanism Fatty acid metabolism

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

Triose 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 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 PGE 1 –Required for microvascular system DLMG - Prostaglandin E 1 AA - Prostacyclin

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. 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. 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 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 Symmetric polyneuropathy Autonomic neuropathy Polyradiculopathy Mononeuropathy

Symmetric 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 Ulceration (painless) Neuropathic edema Charcot arthropathy Callosities

Treatment of Symmetric Polyneuropathy Glucose control Pain control –Tricyclic antidepressants –Topical creams –Anticonvulsants Foot care

Essentials 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 Neuropathy Symptomatic 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 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 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. Treatment –Foot care/elevate feet when sitting –Eliminate aggravating drugs –Reduce edema midodrine diuretics –Support stockings –Screen for CVD

Genitourinary 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 Symptoms/Signs –Exercise intolerance –Postural hypotension Treatment –Discontinue aggravating drugs –Change posture (make postural changes slowly, elevate bed) –Increase plasma volume

Polyradiculopathy 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. Polyradiculopathies are diagnosed by electromyographic (EMG) studies Treatment –Foot care –Glucose control –Pain control

Mononeuropathy 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.

Treatment –Foot care –Glucose control –Pain control

Other Treatment Options Aldose reductase inhibitors ACE inhibitors Weight control Exercise

Anticonvulsant 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 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 Fewest AEs Most AEs AEs = adverse effects.

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

References 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 of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), DHHS; 2002 National Diabetes Information Clearinghouse. Prevent Diabetes Problems: Keep Your Feet and Skin Healthy. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), DHHS; 2003

References, cont. Feldman, EL: Pathogenesis and prevention of diabetic polyneuropathy. In UpToDate. Wellesley, MA, UpToDate, Feldman, EL, McCulloch, DK: Treatment of diabetic neuropathy. In UpToDate. Wellesley, MA, UpToDate, Stevens, MJ: Diabetic autonomic neuropathy. In UpToDate. Wellesley, MA, UpToDate, Feldman, EL: Clinical manifestations and diagnosis of diabetic polyneuropathy. In UpToDate. Wellesley, MA, UpToDate, 2003.