Diagnosing and Managing Peripheral Neuropathy

DIAGNOSING AND MANAGING PERIPHERAL NEUROPATHY

Rebecca Storment Garcia

A manuscript submitted in partial fulfillment of The requirements for the degree of

Master of Nursing

Washington State University College of Nursing

May 2003 11

To the Faculty of Washington State University:

The members ofthe committee appointed to examine the dissertation/thesis of REBECCA STORMENT GARCIA find it satisfactory and recommend that it be accepted.

Chair iii

DIAGNOSING AND MANAGING PERIPHERAL NEUROPATHY

Abstract

By Rebecca Storment Garcia, Washington State University May 2003

Chair: Lorna Schumann

The successful management of neuropathic pain is measured by the degree of relief and functional improvement experienced by the patient. Neuropathy can be divided into two major types: focal mononeuritis and diffuse polyneuropathy.

Symptoms of neuropathy present in many different ways depending on the types of nerve fibers affected. Large nerve fiber neuropathies present with symptoms such as weakness, muscle wasting, deficits in proprioception, deep tendon reflexes and vibratory sense.

Small nerve fiber neuropathies present with alterations to heat, cold and pain sensations.

Neuropathic pain has been described as intolerable burning, crushing, searing, stabbing, stinging, pins and needles, aching, and electrical shocks. Peripheral neuropathy has a variety of causes such as entrapment, ischemia, hereditary disorders, systemic and metabolic disease, vitamin deficiency, and toxic exposure making an accurate diagnosis difficult. Therefore, a thorough detailed medical history combined with a physical and neurologic exam is the first step in reaching a definitive diagnosis leading to the effective management of neuropathic pain. IV

TABLE OF CONTENTS

Page

SIGNATURE PAGE ii

ABSTRACT iii

LIST OF TABLES vi

DEDICATION vii

MANUSCRIPT

Epidemiology 1

Pain theories 2

Neuropathic pain 4

Types of pain 5

Stages of neuropathy 5

Types of peripheral neuropathy 6

Ischemic neuropathies 6

Entrapment neuropathies 7

Diffuse polyneuropathies 8

Hereditary neuropathies 9

Neuropathy associated with systemic and metabolic disorders 10

Nutritional deficiencies 11

Toxic disorders 13

Idiopathic inflammatory polyneuropathy 13

Infection 14

Diagnosis 16 v

Treatment options 19

Research 24

Ineffective Treatments 25

Summary 26 vi

LIST OF TABLES

Page 1. Various causes of peripheral neuropathy 29

2. Examples of Small and Large Nerve Fiber Function 30

3. Treatment Options for Dysthesia, Paresthesia, and Muscular Pain 31

4. Differentiate between Mononeuritis and Entrapment 32

5. Toxic Neuropathies: Clinical & Pathological Features 33

6. Occupations leading to Neuromuscular Disorders 34

7. Treatment options for Distal symmetrical Polyneuropathy 35 vii

Dedication

This paper is dedicated to my husband, Jose, and children, Joseph and Gabriel, with heartfelt gratitude for their support and forbearance during this endeavor. I would also like to thank Theresa, Libby and Francisco for their patience and support. 1

The successful management of neuropathic pain is measured by the degree of relief

and functional improvement experienced by the patient. Successful management is

achieved by first obtaining an accurate diagnosis, which may be difficult since neuropathic

pain encompasses a diverse number of syndron1es. The first step to reaching a definitive

diagnosis is to obtain a detailed medical history combined with a physical and neurologic

exam (Talarico, Sudarshan, Marcus & Caudill, 1998).

Epidemiology

Approximately 1% of the population, or 2.5 million people in the United States

suffer from moderate to severe neuropathic pain. More than 15 different mechanisms

causing neuropathic pain have been identified by research. There are more than 30 drugs that are currently being developed for the treatment of neuropathic pain. (Novel compounds to drive the neuropathic pain market, 2003). "Neuropathic Pain", a report from

Enhanced Perspective Publications, states that the current U.S. neuropathic pain market is worth an estimated 430 million dollars. The United States Food and Drug Administration has approved more products, some completely new in the treatment of neuropathic pain, are expected on the market by the end of 2003. It is predicted that the neuropathic pain market will double to $800 million by 2007 (Novel compounds to drive the neuropathic pain market, 2003).

There are numerous causes of neuropathic pain. Toxic substances, various drugs, and many infectious diseases can cause neuropathy (Mosby, 1998). Other causes of neuropathic pain are infiltrating surgery, ischemia (thalamic syndrome) radiotherapy, chemotherapy, endocrine disorders, and vitamin deficiencies (Sykes, Johnson, & Hanks,

1997). Refer to Table 1 for various causes of peripheral neuropathy. 2

Pain Theories

In the 16th century, a French philosopher and mathematician, Rene Descartes, proposed one of the earlier pain theories. He theorized that the intensity of pain is directly related to the amount of associated tissue injury. The Specificity Theory is generally accurate when applied to certain types of injuries such as a pinprick or cutting one's hand with a knife. However, during World War II, Beecher observed that one out of three soldiers wounded in combat required morphine. Upon returning to his practice after the war, Beecher noted that trauma patients with similar injuries required different amounts of morphine for pain from their wounds. He believed that the meaning attached to the injuries in the two groups explained the different levels of pain; for the soldier it meant going home, for the civilian patient it meant loss of income, activities and other negative consequences. Patients following limb amputation experience phantom pain. The patient may report sensations as though the limb is still there. The Specificity Theory does not account for pain experience when there is no ongoing tissue injury (Modem theories of chronic pain, 2003).

The Gate Control theory proposes that "gates" located on nerve fibers in the spinal cord, between the peripheral nerves and the brain, control the flow of pain messages from the peripheral nerves to the brain. Factors that determine how the spinal nerve gates will manage the pain signal are intensity of the pain message, and competition from other incoming nerve messages (touch, vibration, heat, etc). Signals from the brain also tell the spinal cord to increase or decrease the priority of the pain signal. The message can be handled in the following ways, depending on how the gate processes the signal: allowed to 3 pass directly to the brain; altered prior to being forwarded to the brain; or prevented from reaching the brain (Modem theories of chronic pain, 2003).

Endorphins produced by the brain stem, which acts as a morphine-like substances, can inhibit or blunt incoming pain signals. Vigorous exercise, stress and excitement may stimulate the production of endorphins. The inhibition of pain signals is why athletes may not notice pain of a fairly serious injury until after the competition is over or why exercise helps control chronic back pain (Modem theories of chronic pain, 2003).

Stress and anxiety can amplify pain signals at the nerve gate as it moves up the spinal cord. Impulses from the brain can "close" the nerve gate, preventing the signal from reaching the brain. Events and conditions can cause pain gates to open, causing more suffering. Sensory factors that include injury, inactivity, long-term narcotic use, poor body mechanics, and poor pacing of activities intensify pain. Cognitive factors, such as focusing on the pain, having no outside interests or distractions, worrying about the pain, and other negative thoughts open pain gates intensifying pain. Factors such as depression, anger, anxiety, stress, frustration, hopelessness and helplessness also add to the pain level.

Sensory factors, such as increasing activities, short-term use of pain medications, relaxation training and meditation can close the pain gates. Cognitive factors including outside interest, distraction and thoughts that help a patient cope, can close the pain gates. Having a positive attitude, overcoming depression, taking control of one's pain, and stress management can reduce suffering (Modem theories of chronic pain, 2003). 4

Neuropathic Pain

Symptoms of neuropathy present in many different ways depending on the types of

nerve fibers affected. An accurate diagnosis is made difficult, when more than one fiber

type is involved. Large-fiber nerves are myelinated transmitting impulses quickly.

Neuropathies present with symptoms such as weakness, muscle wasting, and deficits in

proprioception, deep tendon reflexes and vibratory sense. When A-delta fibers are affected

the patient will experience deep-seated pain, numbness, and impaired cold perception

(Vinik, 2000).

C fibers are unmyelinated nerves that transmit impulses more slowly. When C

fibers are affected, spontaneous pain (often described as burning sensation), allodynia

(nonpainful stimuli interpreted as painful), and hyperalgesia (minimally painful stimuli

interpreted as excruciatingly painful) occur. Pain is poorly localized with a dull ache that

lingers after the initial pain (Banasik, 2000, p. 1082). Decreased sensitivity to light touch,

pinprick and heat are symptoms that follow with C fiber impairment. Snlall-fiber

neuropathies usually precede large-nerve-fiber damage and are manifested initially in the

lower peripheral nerves.

Small-nerve fibers of the autonomic nervous system can be affected causing

delayed gastric emptying, orthostatic hypotension, resting tachycardia, and cutaneous blood

flow dysregulation. Other abnormalities that may be present are impotence in males,

unawareness of hypoglycemic states, impaired sweating and decreased bladder tone.

.Approximately 50% of patients with peripheral neuropathy will have asymptomatic

autonomic peripheral neuropathy. Patients with autonomic peripheral neuropathy have an

increased mortality rate, as high as 50%, within 3 years of diagnosis. Neuropathy may be 5

reversible or at least controlled, if diagnosed early (Vinik, 2002). Table 2 lists differences

between small and large nerve fiber function.

Types of Pain

Neuropathic pain can be categorized into three types: dysethesia pain, paresthesias

pain and muscular pain. Dysethesia pain is characterized by a burning sensation.

Dysethesia pain is attributed to cutaneous or subcutaneous distribution and is caused by an

increased firing of damaged fibers or abnormally excitable nociceptive fibers. Parasthesia

pain is characterized as pins and needles, electrical shocks, numbness, aching, "knife-like",

"shooting pain" or "lancinating" pain. There are a number of possible etiologies of

paresthesic pain: spontaneous activity and increased mechanosensitivity near the cell body

of damaged afferent axons in the dorsal root ganglion; loss of segmental inhibition of large

myelinated fibers on small unmyelinated fibers; demyelinated patches of myelinated axons

generating ectopic impulses; or physiologic stimulation of endings of nociceptive afferents

that innervate the nerve sheaths themselves causing increased firings. Muscular pain may be caused by demyelinated patches in motor nerves that cause ectopic neural impulses to

the muscle. Ectopic impulses result in muscle spasms and pain. Muscular pain is described as a dull ache, night cramps, band-like sensation, drawing sensation, spasms and toothache-like pain (Tanenberg et aI., 2001). Patients often suffer serious disability as a result of the intense pain. Suicide although unusual, is a well-described complication of neuropathic pain (Presley, 1992). Refer to Table 3 for medications to treat pain.

Stages of Neuropathy

There are three proposed stages of neuropathy, which are functional neuropathy,

structural neuropathy and nerve death. Functional neuropathy occurs when there is a 6

biochemical alteration in nerve function without pathology. Functional neuropathy is

reversible. Structural neuropathy occurs when there is loss or structural change in the

nerve fibers. Structural neuropathy type may also be reversible. Nerve death occurs when

there is a critical decrease in nerve fiber density and neuronal death takes place. At this

stage, symptoms are no longer reversible. In diabetic neuropathy, for example, there is a

distal-to-proximal gradient in nerve fiber loss. The pattern of nerve fiber loss reflects the

differences and the stages of nerve damage, proximal nerve fibers are the least affected and

distal nerve fibers are more likely to have the greatest structural damage. Therefore, the

potential for reversibility will likely be in a proximal-to-distal manner (Vinik, 2002).

Types of Peripheral Neuropathy

There are two major types of neuropathy, focal mononeuropathy and diffuse

polyneuropathy. Focal mononeuropathies are restricted to the territory of the affected

nerve leading to sensory, motor or mixed deficits. Focal mononeuropathies can be divided

into two categories: mononeuritis (ischemic) and entrapment neuropathies. Mononeuritis is

a vascular lesion that resolves spontaneously. Entrapment neuropathy results from

repeated minor trauma and is progressive. Multiple mononeuropathies suggest a patchy

multifocal disease process (Tanenberg et aI., 2001; Vinik, 2002). Table 4 lists differences

between mononeuropathies and entrapment neuropathies.

Ischemic Neuropathies

Ischemic mononeuropathies are due to entrapment or compression of a nerve, a plexus of nerves or a nerve root causing an acute ischemic event. Ischemic n10noneuropathies are sudden in onset, asymmetric in distribution and have a self-limiting course. Examples include femoral neuropathies, radiculopathies, plexopathies, and cranial 7

neuropathies. Diagnosis of focal ischemic neuropathy is made by clinical examination and

presenting symptoms (Aminoff, 2000; Tanerlberg et aI., 2001).

Entrapment Neuropathies

Entrapment mononeuropathies happen when a nerve is compressed. Entrapment

mononeuropathies occur at innumerable anatomic locations of the body. The American

society of Anesthesiologist organized a task force to reduce the frequency of occurrence or

minimize the severity of peripheral neuropathies related to peri-operative positioning

(Practice advisory, 2000). Entrapment mononeuropathies have a gradual onset, are either

asymmetric or symmetric in distribution and have a progressive course (Tanenberg et aI.,

2001). Therapy includes rest, splints, diuretics, injections of steroids plus local anesthetic

or surgery for relief (Vinik, 2002).

The more common entrapment neuropathies are carpal tunnel syndrome, ulnar entrapment and tarsal tunnel syndrome. Carpal tunnel syndrome can be differentiated from a mononeuritis of the median nerve by an electromyogram. If the patient does not have a diagnosis of diabetes, testing should be done, since one third of those with entrapment neuropathies have diabetes (Tanenberg et aI., 2001; Vinik, 2002).

Tarsal tunnel syndrome is caused by the entrapment of the tibial nerve in the tibial tunnel. Tarsal tunnel entrapment causes symptoms of paresthesias or numbness in the distal foot with the heel spared or involved. Pain generally worsens as the day progresses and increases with activity. Pain is improved with the resting of the foot. Abnormal two point discrimination test, abnormal vibratory sensation, and weakness and wasting of the foot muscles are signs of tarsal tunnel syndrome. Occasionally, a gait disturbance will be noted. The diagnosis is made from presenting signs and symptoms, which are confirmed 8

by electrodiagnostic measures. Symptoms are treated with steroid injections or surgery

(Tanenberg et aI., 2001).

Diffuse Polyneuropathies

Diffuse polyneuropathies are symmetric with sensory, motor or mixed deficits.

Diffuse polyneuropathies are caused by hereditary, infection, structural, vascular,

metabolic, toxic disorders and idiopathic inflammatory polyneuropathy (Aminoff, 2000;

Tanenberg et aI., 2001). Diffuse polyneuropathies have an insidious onset with a

symmetric distribution and progressive course. Variants of distal symmetric polyneuropathy are small fiber and large fiber neuropathy. Small nerve fiber neuropathy presents with a normal neurologic exam, but may have severe dysesthetic pain. Large nerve fiber neuropathy presents with an abnormal neurologic exam such as weakness, muscle wasting and deficits in proprioception, deep tendon reflexes and vibratory sense

(Tanenberg et aI., 2001; Vanik, 2002).

Distal neuropathy may involve sensory, motor, autonomic nerves or mixed presentation. Sensory nellropathy results in pain, numbness, and decreased position sense, resulting in gait changes. Motor neuropathy presents with muscle wasting and foot deformities leading to abnormal pressure points. Autonomic neuropathy can cause arterial blood flow shunting away from the surface of the skin resulting in arterialization of the venous blood from the foot. The decrease in transcutaneous oxygen on the plantar surface where the arteriovenous shunt exists is dependent upon the severity of the neuropathy.

Autonomic neuropathy can also result in decreased pseudomotor function and/or loss of sweating which causes the foot to become dry and cracked (Tanenberg et aI., 2001). 9

Hereditary Neuropathies

Autosomal-Dominant neuropathies are the most easily missed inherited

abnormalities. Pes cavus or highly arched foot and thin legs are hallmarks of autosomal

dominant motor and sensory neuropathies. Patients will present with symptoms of

weakness of the legs and complain of cramps, clumsiness and tripping (Lamb, 1985).

Charcot-Marie-Tooth disease is usually an autosomal dominant genetic disorder.

Clinical presentation includes distal weakness and wasting in the legs, distal sensory loss and depressed or absent tendon reflexes. Foot deformities or gait disturbances may be seen in early childhood or adolescence. Segmental demyelination and remyelination of peripheral nerves, increased transverse fascicular area and Schwann cell hyperplasia are pathological changes. Electrodiagnostic studies reveal a marked reduction in motor and sensory nerve conduction velocity (Aminoff, 2000).

Fabry disease, an X-chromosome-linked genetic metabolic disorder, affects an estimated 2,000 to 4,000 people, mostly males, in the United States. It is caused by a deficiency of alpha-galactosidase-A enzyme that normally assists in the breaking down of a lipid called globotriaosylceramide (Gb3). Gb3 accumulates in many of the cells, tissues and organs of the affected patient, when there is not enough alpha-galactosidase. Children or adolescents will present with severe neuropathic pain that causes burning sensations in the hands and feet, as these are the years the earliest symptoms appear. Symptoms are exacerbated by exercise and during hot weather. Other symptoms are small, raised, reddish-purple blemishes on the skin. Impaired arterial circulation leading to early heart attacks, strokes and other medical problems develop, as the patient grows older (Enzyme therapy reduces neuropathic pain effectively and safely, 2001). 10

Acute attacks of both variegate porphyria and acute intermittent porphyria can

affect peripheral nerves. Initially, motor nerves are affected in the upper limbs rather than

the lower. Sensory neuropathy may be either proximal or distal. Autonomic symptoms

may be pronounced. Rapid improvement of symptoms nlay be noted by intravenous

infusion of Hematin 4 mg/kg over 15 minutes once to twice daily. A diet high in

carbohydrates, may also be helpful (Aminoff, 2000).

Neuropathy Associated with Systemic and Metabolic Disorders

One complication of diabetes is peripheral neuropathy. Diabetes may lead to

symmetric sensory or mixed polyneuropathy, asymmetric motor neuropathy, thoracoabdominal radiculopathy, autonomic neuropathy or isolated lesions of individual nerves (Aminoff, 2000). Initially, symptoms of peripheral neuropathy begin with a pins and needles sensation in the hands and/or feet. The loss of sensation and burning pain has a glove- and/or stocking- type distribution caused by the dying back of distal and proximal nerves. If neuropathy is detected early and glucose levels are normalized, symptoms can be relieved. However, the duration and type of diabetes appears to correspond to the severity of diabetic neuropathy (Talarico et aI., 1998). Diabetic amytrophy is characterized by asymmetric weakness and wasting involving predominantly the proximal muscles of the legs, accompanied by local pain. Thoracoabdominal radiculopathy is characterized by pain over the trunk. Autonomic neuropathy may cause postural hypotension, impaired thermoregulatory sweating, postgustatory hyperhidrosis, constipation, flatulence, diarrhea, impotence, urinary retention and incontinence. Compression or entrapment of individual peripheral nerves are common and treatment is symptomatic, although surgery may be necessary for decompression (Aminoff, 2000). 11

Uremic neuropathy is a complication of renal disease. These patients present with loss of proprioception, and sensorimotor loss. The first symptoms reported are burning, prickling, nllmbness of toes and feet and unawareness of foot position. Patients usually present with neuropathic symptoms that progress distally to proximally, are symmetric and affect the feet more than the hands. Moderate reduction in sensory conduction velocity will be confirmed electrophysiologically. The treatment and cure of uremic neuropathy is transplant. However, dialysis can help improve symptoms (Aminoff, 2000).

Alcoholics may present with sensorimotor polyneuropathy. Symptoms include painful cramps, muscle tenderness, and painful paresthesias more mirked in the legs than arms. Nerve conduction velocity studies may only show a slight reduction. A similar presentation occurs in thiamine deficiency or beriberi (Aminoff, 2000).

Multiple myeloma may cause a segmented demyelination that presents as a symmetric sensorimotor polyneuropathy of gradual onset, progressive in course, and accompanied by pain and dysesthesias in the limbs. Neuropathy associated with multiple myeloma responds poorly to treatment (Aminoff, 2000).

Nutritional Deficiencies

Thiamine (vitamin Bl) or beriberi is described in three forms. One of which is termed the "dry form". Thiamine is involved in the glycolytic and pentose phosphate pathways of carbohydrate metabolism. The dry form of beriberi is chacterized by nerve damage with degeneration of myelin sheaths, peripheral neuritis, paralysis, and atrophy of muscles (Sacher, McPherson, & Campos, 2000). Thiamine deficiency affects sensory, motor and autonomic nerves symmetrically. Symptoms include symmetric motor and sensory neuropathy with pain, muscle cramps, burning feet, lancinating pain and calf 12

tenderness, sensory loss and loss of reflexes. Causative disorders are alcoholism, malnutrition fron1 primarily eating only polished rice; HIV infection; systemic malignancy;

anorexia nervosa, dialysis, malabsorption and repeated vomiting from gastric resection or

pregnancy, and a diet of raw fish (carp). Therapeutic response to treatment of thiamine 50 mg p.o. daily confirms diagnosis (Vitamin & nutrition related syndromes, 2003).

Pyridoxine (vitamin B6) is a cofactor for decarboxylase, deaminase, and transaminase enzymes. Pyridoxine is also involved in converting tryptophan to nicotinic acid. Since pyridoxine is readily available in foods, primary deficiency is unusual.

However, since only the phosphorylated form of pyridoxine (pyridoxal-5-phosphate) is active, certain drugs can block phosphorylation leading to deficiency. These drugs include hydralazine, oral contraceptives, penicillamine, and isoniazid. Other symptoms include cheilosis, stomatitis, glossitis, dermatitis and polyneuritis (Sacher et aI., 2000). Diagnosis is confirmed by the results of an erythrocyte glutamic pyruvate transaminase, measurement of tryptophan metabolites after tryptophan loading, and high serum and CSF pyruvate

(Vitamin & nutrition related syndromes, 2003).

Cobalamin (vitamin B12) deficiency presents as a polyneuropathy affecting sensory, motor and autonomic nerve pathways. Vitamin B12 is present in all food of animal origin, therefore strict vegetarians who exclude dairy products, meat and fish are at risk. Surgical procedures that eliminate the site of intrinsic factor production in the stomach also lead to vitamin B12 deficiency. Early symptoms include distal paresthesias, with later complaints of difficulty with balance, reduced or absent reflexes at the ankles, and postural hypotension. Other symptoms of megaloblastic anemia are glossitis and hyperpigmented fingernails. Diagnotic testing results include B12 levels < 100 pg/ml, and 13

levels of high homocysteine and methymalonic acid (Linker, 2000). High elevations of

homocysteine are found in individuals with low levels of vitamin B6, vitamin B12 or folic

acid. An elevated homocysteine level is clinically significant because it is a risk factor for

progression of atherosclerosis and occurrence of myocardial infarction (Sacher et aI.,

2000). Treatment consists of vitamin B12, 1 mg intramuscular injection every three

months. Paresthesias will resolve within a few weeks (Linker, 2000).

Toxic Disorders

Damage to peripheral nerves have shown to be a dose limiting side effect of the

many cancer chemotherapy treatments (Grant awarded for drug discovery to treat peripheral nerve dysfunction, 2001). Paclitaxel therapy causes debilitating myalgias and

arthralgias that resolve after the dose is reduced or drug is discontinued (Management of side effects of cancer and chemotherapy, 2002). Xeloda also causes neuropathy.

Neuropathy may be a delayed adverse side effect of statin drugs. A study conducted in Denmark, revealed that those taking statin drugs had a 16.1-fold risk of definite idiopathic neuropathy. People who used statins for 2 years or more had an increased neuropathy risk that was 26.4 times the control groups risk (Statin drugs increase risk of peripheral neuropathy, 2002). Tables 5 and 6 list other toxins and occupations that cause peripheral neuropathy.

Idiopathic Inflammatory Polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is thought to be caused by an immune disorder of the nerves, because the disorder responds to corticosteroids and plasma exchange (Aminoff, 2000; van Doom, Vermeulen, Mulder, &

Busch, 1991). eIDP is the destruction of myelin sheaths around the axons of the peripheral 14 nerves by an attack of the immune system. A long-term alternate day steroid therapy can yield substantial improvement. However, plasma exchange produces temporary improvement in 80% of patients and is recommended for slow responders, severe initial disability relapse reversal or if steroids are contraindicated (Donaghy, 2001). CIDP also responds to azathioprine (Imuran), cyclophosphamide (Cytoxan) and cyclosporin A.

Immunoglobulin therapy (IVIG) has been used to treat patients over an extended period, yielding favorable results. The advantage to immunoglobulin therapy is that it does not have the side-effect profile of corticosteroids (van Doom et aI., 1991). Improvement from

IVIG is noted in about 65% of CICP patients after 4 to 10 weeks of treatment (Donaghy,

2001).

Multifocal motor neuropathy (MFMN) with conduction block is another idiopathic polyneuropathy. MFMN responds promptly to IVIG with responses lasting 6 to 12 weeks.

MFMN deteriorates with the use of steroids. A maintenance regimen of IVIG is suggested to avoid relapse and prevent background deterioration. IVIG may be administered in the home, except for patients with Medicare. Cyclophosphamide is also effective in the treatment of MFMN, but has an undesirable side-effect profile. CIDP and MFMN patients usually relapse when therapy is stopped (Donaghy, 2001).

Infection

Demyelinating polyradiculoneuropathy can occur in HIV-seropositive patients with

AIDS. Symptoms include distal weakness, and depressed or absent tendon reflexes, pain and dysthesias. Treatment includes antidepressants, nonnarcotic and narcotic analgesics, anticonvulsants and acupuncture (Shlay et aI., 1998). 15

Guillain-Barre' is a rapidly progressive syndrome that presents with muscle

weakness, w11ich begins shortly after an infectious disorder or surgery. An association with

Campylobacter jejuni enteritis preceeding illness has been noted. The presentation begins

with weakness to the extremities that ascends to the face. Sensory symptoms are usually

less conspicuous than motor symptoms. Distal paresthesias and dysesthesias are con1mon,

and neuropathic or radicular pain is also present in many patients. Diagnostic testing

should exclude porphyric, diphtheritic, or toxic (heavy metal hexacarbon, organophosphate) neuropathies. Other considerations are poliomyelitis, botulism, and tick paralysis. Prednisone is ineffective and may actually affect the outcome adversely by prolonging recovery time. Plasmapheresis is best performed within the first few days of illness and for clinically severe or rapidly progressive cases or those with ventilatory impairment. Intravenous immunoglobulin 400 mglkg/d for 5 days is beneficial and less stressful on the cardiovascular system than plasmapheresis (Aminoff, 2000).

Postherpetic neuralgia (PHN) is the most common disorder associated with herpes zoster. PHN is a chronic neuropathic pain disorder characterized by burning and paroxysmal pain, exquisite skin sensitivity, abnormal pain perception, sensory loss, allodynia and hyperalgesia. The pain occurs in a unilateral distribution along the affected nerve root in which the virus has settled. The most common areas affected are the chest wall and face. Symptoms may last for three to six months or may persist for years, if generalized nerve demyelination has taken place (Talarico et aI., 1998). Simple analgesics or non-steroidal anti-inflammatory drugs are used to treat mild to moderate neuropathic pain, however, most patients will need other centrally acting drugs (Martin, 2003). The use 16

of lidocaine patch (5%) has been confirmed in recent studies to be safe and efficacious for

the relief of postherpetic neuralgia (PHN) (Gammaitoni, Alvarez & Galer, 2002).

Leprosy, although not common in the United States, is the third most common cause of neuropathy world wide. Leprosy is caused by the acid-fast rod, Mycobacterium leprae. Consider leprosy in individuals who have a history of residence in endemic areas, especially in early childhood. Suspect disease in immigrants arriving from tropical and subtropical Asia, Africa, Central and South America, Pacific regions and individuals in the southern USA. Symptoms include anesthesia, neuritis, and paresthesias resulting from nerve infiltration and thickening. Bilateral ulnar neuropathy is highly suggestive of leprosy. Diagnosis is confirmed by the presence of acid-fast bacilli in a skin or a thickened nerve biopsy. When a patient presents with pale, macular or nodular erythematous skin lesions, with anesthesia and history of residence in an area where leprosy is endemic, consider leprosy. Leprosy is treatable using a combination therapy of Dapsone 50-100 mg/d, clofazimine 50 mg/d and rifampin 10 mg/kg/d orally for a minimum of 2 -3 years or until all biopsies are negative for acid-fast bacilli (Chambers, 2003).

Diagnosis

A thorough medical history should include history of recent traumas, injuries, infections or accidents. Obtain a personal and family medical history to include obesity, diabetes, or nutritional disorders secondary to chronic diarrhea. Ask the patient to describe the pain, (dull ache or lancinating flashes) body partes) affected, waxing and waning, if physical or emotional stress exacerbates the symptoms. Ask about additional symptoms and how the pain affected ability to work, perform other activities and sleep. Review medications currently or previously taken, past or present exposures to toxins, and social 17 habits including alcohol consumption (Talarico et aI., 1998). A history and physical exam helps narrow the cause, thus offering a more appropriate treatment plan (Senneff, 1999).

Basic laboratory tests to be considered in the diagnosis of peripheral neuropathy include electrolyte panel, complete blood count, glycosylated hemoglobin, TSH, ESR,

Rheumatoid factor, ANA, vitamin B12, serum/urine protein, urine toxicology for heavy metals, liver function test, immunoelectrophoresis and serologic test for syphilis. A radiograph of spine and/or chest should be ordered to rule out malignancy or pathologic fracture, and a nerve conduction study should be performed (Aminoff, 2000).

To test the integrity of C fibers and predict the level of function and recovery, a quantitative sensory test (QST), skin blood flow, and skin biopsies measuring nerve fibers positive for protein gene product 9.5 are performed (Vinik, 2002).

Pin-Prick sensation is used to test large nerve fiber function. Using a Wartenberg pinwheel, roll it slowly across the skin using the weight of the tool as the force of pressure.

Roll the pinwheel from the tip of the middle finger to the elbow on the volar surface of both arms. Next, roll the pinwheel from the tip of the middle toe to the knee on the anterior surface of both legs. Use a metric rule from tip of digit approximately 150 millimeters up the limb. Document the level the sensation goes from numb to dull or dull to sharp. Look for patterns that show abnormalities: proximal or distal, asymmetric or symmetric, and compare upper to lower extremities (Tanenberg et aI., 2001).

Tendon reflex examination tests the reflex arc and a number of suprasegmental systems that alter the quality of the reflex. This test evaluates function of large motor nerves. An absent tendon reflex can be caused by diseases of muscle, afferent nerve, efferent nerve, spinal nerve root, or spinal cord. Look for patterns that show abnormalities 18 proximal or distal, asymmetric or symmetric, or upper compared to lower extremity

(Tanenberg et aI., 2001).

Muscle strength, although difficult to quantitate, should be obtained for an overall sense of large nerve fiber function and muscle group action. Assess muscle strength of the lower extremity with dorsiflexion of the foot; deep peroneal nerve, plantar flexion; tibial nerve, leg flexion and extension at the knee; sciatic nerve. Assess muscle strength of the upper extremity with flexion of the wrist; median nerve, extension of the wrist; radial nerve, flexion of the forearm; radial nerve, extension of the forearm; radial nerve. Compare sensory function to muscle strength and note the differences (Tanenberg et aI., 2001).

Position sense is affected by diseases of the posterior spinal roots, posterior spinal columns and the parietal lobe. This test assesses large nerve fiber function. The digit is firmly grasped and is pointed up or down while the patient's eyes are closed. The patient should respond by giving the correct position of the digit. The process is repeated several times to both great toes and both thumbs (Tanenberg et aI., 2001).

The sense of touch is evaluated using monofilament testing. A 5.07 monofilament is placed in contact with skin until the monofilament buckles. Callused skin should be avoided. The patient with intact sensation will be able to feel the sensation by the time the monofilament buckles. When a patient is unable to detect a 5.07 monofilament, protective sensation is lost and severe sensory neuropathy is present (Tanenberg et aI., 2001).

Vibratory sense is assessed by using a 128-Hz tuning fork to check large nerve fiber function. The vibrating tuning fork is placed at the base of both thumbnails and great toenails for at least 10 seconds. Results are recorded as either present or absent (Tanenberg et aI., 2001). 19

Gait is evaluated by watching the patient walk a straight line, heel to toe. Watch for the heel to strike before the toes. Note, if the heel and toes strike at the same time or the foot slaps the floors as in foot drop. Balance can be evaluated by having the patient walk on both heels (Tanenberg et aI., 2001).

Common methods to quantitatively test nerve function of large and small nerve fibers are electrophysiology testing (nerve conduction velocity) and vibratory perception threshold. Nerve conduction velocity tests the transmission of electrical impulses through the largest myelinated fibers (Tanenberg et aI., 2001).

Treatment Options

Treatment for neuropathy is complicated by the fact that there are so many causes.

Routine analgesics may be ineffective in treating neuropathic pain. If a patient is not receiving adequate pain relief from nonsteroidal anti-inflammatory drugs or from standard doses of opiates, consider a diagnosis of neuropathic pain. Drug classes that are effective for neuropathic pain are the tricyclic antidepressants, anticonvulsants, and alpha-adrenergic antagonists, as well as topical anesthetics (Presley, 1992).

In order for a nerve impulse to travel from one nerve to another, the sending cell releases a tiny amount of neurotransmitter. This chemical carries the nerve impulse across the synapse, a microscopic gap between nerves. Abnormally low levels of neurotransmitters are associated with depression. Tricyclic antidepressants relieve neuropathic pain by selectively inhibiting the reuptake of the neurotransmitter, norepinephrine, thus elevating the brain's threshold to pain (Gibbons, 2000; Senneff,

1999). One of the most extensively studied and most widely used drugs in this class is amytriptyline hydrochloride (Elavil). Nortriptyline hydrochloride (Pamelor), imipramine 20 hydrochloride (Tofranil) and desipramine hydrochloride (Norpramin) are other tricyclics that have proved to be effective. The suggested starting dose of Amytriptyline is 10-25 mg at night, starting low and titrating upwards on a weekly basis, until pain control improves or until side effects become intolerable. Amitriptyline within the range of 25-75 mg has been found to cause an analgesic effect. Tricyclic antidepressants rarely produce toxicity and do not produce euphoria or tolerance, so potential for abuse is low. However, as the dose is increased, so is the frequency of unwanted side effects. Tricyclic antidepressants are thought to inhibit the uptake of biogenic amines, such as serotonin and norepinephrine, neurotransmitters that inhibit pain-transmitting neurons (Presley, 1992; Sykes et aI., 1997).

Refer to Table 7 for additional options for treating distal symmetrical polynellropathy.

Anticonvulsant drugs may be useful for the treatment of the "electric shock" component of pain. Studies suggest that injured nerves may develop hyperexcitability and spontaneous ectopic activity. Paroxysmal neuralgic pain resembles epilepsy in certain respects, therefore antiepileptic drugs may provide pain relief. The refractory period is prolonged relative to the action potential duration. Hydantoins stabilize the threshold against hyperexcitability (Edmunds, 2000). Trigeminal neuralgia is treated with

Carbamazepine (Tegretol). Carbamazepine is an iminostilbene derivative chemically related to the Tricyclic antidepressants. The mechanism of action is believed to reduce summation of temporal stimulation leading to neural discharge by limiting influx of sodium ions across cell membrane, thus modulating the pain signal (Turkoski, Lance, & Bonfiglio,

2001). Clonazepam (Anafranil) and sodium valproate (Depakote) are also useful for the treatment of various lancinating pains, such as postherpetic neuralgia, tabes dorsalis, phantom limb pain, diabetic neuropathy and the thalamic syndrome (Presley, 1992). 21

Intravenous infusion of lidocaine has been successful in treating spontaneous

activity in neuromas and reduces pain in diabetic neuropathy and other neuropathic

conditions. Because intravenous lidocaine has been shown to be successful in suppressing

neuropathic pain, it may eventually prove to be a successful test to identify a neuropathic

component to a chronic pain syndrome. The use of the oral antiarrhythmic and lidocaine cogener mexiletine hydrochloride (Mexitil) has been used successfully to relieve neuropathic pain in those where other regimens have failed. Oral mexiletine, 50-200 mg three times a day, has been shown effective in treating "burning" pain. Although the mechanism of action is unclear, it is thought to involve alterations in spinal cord processing, rather than by peripheral axonal or receptor blockade (Presley, 1992).

Regional anesthetic blocks of the appropriate sympathetic ganglia have traditionally treated reflex sympathetic dystrophy syndrome. Regional anesthetic blocks are affective because neuropathic pains are maintained or augmented by efferent activity in the sympathetic nervous system. Sympathetically maintained pains are now thought to be mediated largely through alpha-adrenergic mechanisms. A simple diagnostic test for sympathetically maintained pain is to administer an intravenous infusion of phentolamine mesylate (Regitine). If a patient responds to phentolan1ine infusion, a daily treatn1ent with oral phenoxybenzamine hydrochloride or other alpha-adrenergic antagonist, which may permanently eliminate sympathetically mediated components of pain. However, side effects of hypotension may limit therapy (Presley, 1992).

Enzyme replacement therapy has been shown to decrease plasma levels of Gb3 by

50% resulting in improved kidney pathology and function, heart function and decreased or alleviated neuropathic pain. Enzyme replacement products from Transkaryotic Therapies, 22

Inc used in clinical trials by the National Institute of Health (NIH) and a product by

Genzyme Corporation used in clinical trials at Mt. Sinai School of Medicine in New York.

Both companies have filed for FDA marketing approval of their enzyme replacement

products (Enzyme therapy reduces neuropathic pain effectively and safely, 2001).

Patients with chronic limb ischemic neuropathy may benefit from injections of

human plasmid in muscles. Human plasmid causes therapeutic angiogenesis in the affected

limb. Treated patients had an increased ankle-brachial index, sensory score, peroneal

motor amplitude and quantitative vibration. Therefore, ischemic neuropathy may be a

reversible condition with the use of therapeutic angiogenesis (Simovic, 2001).

Counter-irritation is used by some for pain relief. This is a systematic rubbing of

the affected part, through an application of heat, cold, or chemicals to acupuncture or

transcutaneous electrical nerve stimulation (Sykes et aI., 1997). Acupuncture is the

insertion of stainless steel needles at specific sites to stimulate nerves causing endorphins to

be released into the muscles, spinal cord and brain to decrease pain. A study performed at

the Department of Medicine, University of Manchester, United Kingdom, evaluated the effectiveness of acupuncture for the treatment of chronic peripheral diabetic neuropathy.

Participants experienced a 77% reduction in symptoms with 67% of the participants able to

stop or reduce medications during the following 18 to 52 weeks. Seven participants reported that their symptoms had completely resolved (Senneff, 1999)

Success of transcutaneous electrical nerves stimulation (TENS) depends upon correct positioning of the electrodes and optimal adjustment of the electrical output, which

differ from person to person. Surface electrodes are connected to a small portable battery to stimulate large diameter nerves in the skin and subcutaneous tissue. TENS is relatively 23 free of side effects however, efficacy often declines over a few weeks, and it is difficult to predict which patient will benefit (Sykes et aI., 1997).

Physical therapy for gait and balance problems related to peripheral neuropathy should be recommended. Results from a clinical trial designed to determine if a specific exercise regimen had an effect on postural stability and confidence concluded that exercise improved balance. The participants performed three daily exercises over three weeks: range-of-motion of the ankle, heel raises and wall slides. Patients noted a rapid increase in available distal lower-extremity strength. Increased muscle strength may help to decrease fall risk in those with postural instability (Shoemaker, 2001).

Psychotherapies have become increasingly popular as a technique for pain relief. If anxiety can intensify pain, relaxation should help relieve or reduce pain. Biofeedback picks up signals from muscles where electrodes have been attached to the skin. The device emits an audible or visual signal when muscles tense. The relaxing of the muscles minimizes the signal. In theory, biofeedback permits one to regulate heart rate, blood pressure, muscle tension and emotions (Senneff, 2001).

Hypnosis works by giving suggestions to the subconscious. A study of 241 patients undergoing invasive medical procedures had pronounced reduction on pain and anxiety and improved hemodynamics after self-hypnosis. Patients report a heightened sense of well being, deep relaxation and reduction in pain with hypnosis (Senneff, 2001,).

Meditation and relaxation techniques are additional ways of controlling anxiety.

Dr. Bushnell, at McGill University, states that relaxation techniques can change the way the brain responds to painful stimuli. Meditation may change neural pathways that control 24 physical pain sensations by stimulating the inhibitory nerves that extend from the brain to the spinal cord blocking the sensation of pain (Senneff, 2001).

The use of music as a healing influence is an ancient practice found in the writings of Aristotle and Plato. During World War I and World War II, Veteran Hospitals played music to veterans suffering from both physical and emotional trauma from the war with a notable response. A study conducted in Norway used the combination of music with guided imagery, and deep relaxation to reduce symptoms of chronic pain syndromes. The body releases endorphins as music is heard thereby reducing the sensation of pain (Senneff,

2001).

Research

Therapeutic angiogenesis is showing favorable results in the reversal of ischemic neuropathy. The effects of vascular endothelial growth factor gene therapy showed improvements in the vascular ankle-brachial index and improvement in neuropathy in the treated leg (Simovic, 2001).

The effects of recombinant adeno-associated viral (rAAV)-mediated over expression of brain-derived neurotrophic factor (BDNF) in the spinal cord of chronic neuropathic pain after unilateral chronic constriction injury (CCI) of the sciatic nerve is being investigated at the University of Miami School of Medicine, Miami, Florida. The investigations involve rats with allodynia and hyperalgesia induced by CCI in the hindpaws. Results demonstrated permanent reversal in the first week after vector injection.

Data suggests that rAAV-mediated gene transfer could potentially be used to reverse chronic pain after nervous system injuries in humans (Neurotrophic factor, 2002). 25

Amyloid polyneuropathy is a nerve disorder caused by abnormal deposits of

amyloid protein. The study published by Ikeda et aI., in 1997 demonstrated that although

amyloid deposits in the biopsy specimen remained, the number of myelinated fibers were markedly increased. Myelinated fibers per millimeter square increased after transplantation from 1,326 to 4,740 nerves per millimeter square. Peripheral nerves regenerated in patients with familial amyloid polyneuropathy after liver transplantation with marked clinical improvement three years after surgery (Ravits, 1998).

Topical amitriptyline (Elavil) and ketamine (Ketalar) for relief of neuropathic pain is currently being studied in a controlled clinical trial with initial results to be reported in

2003. This topical combination drug formulation is for chronic neuropathic pain resulting from diabetes, traumatic and herpetic neuropathies (Clinical progress, 2002).

Prostaglandin 12 (small 2) analog (beraprost sodium), theoretically induces relaxation of vascular smooth muscle, reducing nerve ischemia resulting in increased nerve function (Tanenberg et aI., 2001).

Ineffective Treatments

A randomized controlled trial comparing Acupuncture, amitriptyline and placebo for pain due to HIV-related peripheral neuropathy found that neither was more effective than placebo in relieving pain (Shlay et aI., 1998).

Riluzole (Rilutek) blocks sodium channels and depresses glutamate transmission which in theory would alleviate neuropathic pain. Two prospective, randomized, double blind, placebo controlled crossover trials were conducted comparing Riluzole 50 mg twice daily or 100 mg twice daily to a placebo in patients with chronic painful neuropathy.

Riluzole failed to provide significant improvement in neuropathic pain (Rubin, 2000). 26

Summary

Approximately, 1% of the population, or 2.5 million people in the United States suffer from moderate to severe neuropathic pain. There are numerous causes of neuropathic pain. The successful management of symptoms is measured by the degree of relief and functional improvement experienced by the patient. Successful management is achieved by first obtaining an accurate diagnosis which may be difficult since neuropathic pain encompasses a diverse number of syndromes. The Gate Control theory proposes that

"gates" located on nerve fibers in the spinal cord, between the peripheral nerves and the brain, control the flow of pain messages from the peripheral nerves to the brain.

Endorphins produced by the brain stem, which acts as a morphine-like substance, can inhibit or muffle incoming pain signals. Stress and anxiety can amplify pain signals at the nerve gate as it moves up the spinal cord. Impulses from the brain can "close" the nerve gate, preventing the signal from reaching the brain. Events and conditions can cause pain gates to open causing more suffering.

Symptoms of neuropathy present in many different ways depending on the types of nerve fibers affected. Focal mononeuropathies are restricted to the territory of the affected nerve leading to sensory, motor or mixed deficits. Diffuse polyneuropathy are symmetric with sensory, motor or mixed deficits and are caused by hereditary, nletabolic, and toxic disorders and idiopathic inflammatory polyneuropathy.

Treatment for neuropathy is complicated by the fact that t~ere are so many causes.

Routine analgesics may be ineffective in treating neuropathic pain. Drug classes that are effective for neuropathic pain are the tricyclic antidepressants, anticonvulsants, and alpha 27 adrenergic antagonists, as well as topical anesthetics. Counter-irritation, acupuncture, meditation and music therapy may reduce pain and anxiety.

Patients with peripheral neuropathy, regardless of the cause, suffer from unrelenting symptoms, unless effective therapy can by prescribed. Therefore, the practitioner must perform an extensive medical history and physical exam to help narrow the cause, thus offering a more appropriate treatment plan to reduce symptoms. 28

Table 1

Various causes of peripheral neuropathy.

Toxic substances Drugs Diseases Other Antimony Diphenylhydantoin Alcoholism Infiltrating tumors Arsenic Isoniazid Arteriosclerosis Surgery Carbon monoxide Nitrofurantoin Beriberi Ischemia (thalan1ic Copper Thalidomide Chronic GI disease syndrome) Lead Vincristine Diabetes Radiotherapy Mercury Hypothyroidism Chemotherapy Nitrobenzol Leprosy Endocrine disorders Organophosphates Pellagra Vitamin deficiencies Thallium Porphyria Infections Rheumatoid arthritis Postherpetic Systemic lupus neuralgia, HIV, erythematous tabes dorsalis. , Mosby s MedIcal, NurSIng, & AllIed Health DIctIonary (5 th ed). (1998) p5A45 Retrieved March 9, 2003, from http://web3.infotrac.galegroup.com/itw/infomark/163/821/58639964w3/purl=rcl HRCA 0 J!,

Sykes, J., Johnson, R., & Hanks, G. (1997). Difficult pain problems. British Medical Journal, 315(7112),867. Retrieved February 21,2003, from Galegroup database. 29

Table 2

Examples of Small and Large Nerve Fiber Function Small Nerve Fiber functions Large nerve fiber functions Heat sensation Vibration Cold sensation Pinwheel sensation Pain sensation Deep tendon reflexes Autonomic nervous system Position sense functions Sense of light touch Sudomotor functions Motor nerves Vascular AV shunt control

Tanenberg,R., Schumer, M., Greene, D., Pfeifer, M. (2001). The diabetic foot. J. Bowker & M. Pfeifer (Ed.), Neuropathic problems ofthe lower extremities in diabetic patients (6th ed.). (p. 50). St. Louis, Missouri: Mosby, Inc. Printed with permission. 30

Table 3

Treatment Options for Dysthesia, Paresthesia and Muscular Pain

Dysethesia Pain Paresthesia Pain Muscular Pain Capsaicin cream 0.25% and Imipramine 50 mg PO q Metaxalone 800 mg TID or 0.075% apply topically HS, may increse up to QID for 2 weeks. three to four times a day. 150mg. NSAIDS are also effective. Gabapentin up to 3600 mg Mexiletine initial dose of in divided doses daily. 150 mg po x 3 days, increase to 300 mg x 3 days, then increase to 10 mglkg in divided doses. ECG before administration, after 3 day intervals x 3, if no arrhythmias, obtain a 24 hour holter monitor. Monior periodically for arrhythmias. Take after evening meal to prevent nausea.

Carbamazapine initial dose 100 mg BID; increase to maximum dose of 400mg TID over a 6-weeks. CBC testing for aplastic anemia. LFT for elevated enzymes.

Phenytoin. Initial dose of 100 mg TID and increase over 6 weeks to max dose of 200mg TID. Tanenberg,R., Schumer, M., Greene, D., Pfeifer, M. (2001). The diabetic foot. J. Bowker & M. Pfeifer (Ed.), Neuropathic problems ofthe lower extremities in diabetic patients (6th ed.). (pp.53-54). St. Louis, Missouri: Mosby, Inc. 31

Table 4

Differentiate between Mononeuritis and Entrapment Mononeuritis Entrapment 0 Sudden onset 0 Gradual onset 0 Usually single nerve, may 0 Single nerves exposed to be multiple trauma 0 Common nerves involved: 0 Common nerves involved: cranial nerves III, VI, VII, median, ulnar, peroneal Illnar, median, peroneal medial, and lateral plantar 0 Not progressive and 0 Progressive resolves spontaneously 0 Treatment with rest, splints, 0 Symptomatic treatment diuretics, steroid injections, and surgery for paralysis

Vinik, A. (2002). Neuropathy: new concepts in evaluation and treatment. Southern Medical Journal, 95,(1),21. Printed with permission. 32

Table 5

Toxic Neuropathies: Clinical & Pathological Features

Axonal Demyelinating I Mixed Sensory SensorylMotor Motor

Almitrine Acrylamide B-bungarotoxin Buckhorn Amiodarone Chloramphenicol Alcohol (ethanol) Botulism Chloroquine Ethylene Dioxin Allyl chloride Gangliosides Diphtheria glycol Doxorubicin Arsenic Latrotoxin FK506 Tryptophan Theambutol Cadmium Black widow Hexachlorophene Gold Theionamide Carbon disulfide Lead Muzolimine Hexacarbons Etoposide (VP- Chlorphenoxy Mercury Perhexiline n-Hexane 16) Ciguatoxin Misoprostol Procainamide Sodium Gemcitabine Cochicine Tetanus Tellurium Cyanate Glutehimide Cyanide Tick paralysis Zimeldine Suramin Hydralazine Dapsone Ifosfamide Disulfiram Interferon-alpha DMAPN Isoniazid Ethylene oxide Lead Lithium Metronidazole Methyl bromide Misonidazole Nitrofurantoin Nitrous oxide Organo- Nucleosides phosphates ddC;ddI;d4T Podophyllin Phenytoin PCBs Platinum analogs Saxitoxin Propafenone Spanish toxic oil Pyridoxine Taxol Statins Tetradotoxin Thalidomide Thallium Trichloroethylene TOCP Vacor (PNU) Vinca alkaloids

Toxic neuropathies retrieved from http://www.neuro.wustl.edu/neuromuscular/nother/toxic.htm.Printed with permission. 33

Table 6

Occupations leading to Neuromuscular Disorders: Batteries: Lead Cabinet maker: Hexacarbon Copper smelting: Arsenic Demolition: Lead Dentist: Nitrous oxide Dry cleaner: Trichloroethylene Epoxy resin: Allyl chloride Farmers: Organophosphates Glass & Ceramics: Tellurium Mining: Arsenic Painter: Hexacarbon Plastic industry: Acrylamide Rayon industry: Carbon disulfide Rubber industry: Trichloroethylene Tool use: Vibration syndrome Toxic neuropathies retrieved from http://www.neuro.wustl.edu/neuromuscular/nother/toxic.htm.Printed with permission. 34

Table 7

Treatment options for Distal symmetrical Polyneuropathy

Drug Dose Comments Gabapentin 100 mg tablets 0 Titrate upwards until pain Day 1-3: 1 tablet 2 times a day resolves, maximum dose is Day 4-6: 2 tablets 2 times a day reached or symptoms are too great. 300 mg tablets 0 If symptoms too great, continue Day 7-9: 1 tablet 2 times a day for 6 days the last dose tolerated Day 10-12: 1 tablet 3 times a day and then try to increase again. Day 13-15: 2 tablets 3 times a day 0 If unable to tolerate maximum Day 16-on: 2 tablets 4 times a day dose continue at last dose tolerated. 0 Side effects: drowsiness, lethargy, fatigue, depression.

Capsaicin 0.025%-0.075% 0 Use 4 times a day in order to desensitize 0 Warn about increased burning during early part of treatment. Mexiletine Day 1: ECG Side effects: nausea, ectopic beats. Day 1-3: Mexiletine 150 mg pc supper for 3 days. Day 4: rhythm strip (5min) Day 4-6: Mexiletine 300 mg pc supper for 3 days. Day 7: Rhythm strip (5min) Days 7-9: Mexiletine 10 mg/kg divided daily pc meals and snacks for 3 days. Day 10: Holter (24hrs) After day 10: con't. at last dose Tricyclic Day 1: 50 mg po q hs Side effects: postural hypotension, antidepressants Increase to max. dose of 150mg po q dry mouth, urinary retention (men), e.g., Imipramine hs somnolence. Carbamazepine Day 1: 100 mg PO bid Side effects: aplastic anemia, nausea, e.g., Tegretol Increase to max. dose 400 mg PO tid increased LFfs. Phenytoin Day 1: 100 mg PO tid, Side effects: multiple, GI, CNS, e.g., Dilantin Increase to max. dose of 200 mg po increased LFf, rhythm disturbance. tid. Skeletal muscle 400 mg tablets; 2 PO pc tid-qid Side effects: lethargy, nausea. relaxant e.g., Metaxalone Tanenberg,R., Schumer, M., Greene, D., Pfeifer, M. (2001). The diabetic foot. J. Bowker & M. Pfeifer (Ed.), Neuropathic problems ofthe lower extremities in diabetic patients (6th ed.). (p.58). St. Louis, Missouri: Mosby, Inc. Printed with permission. 35

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