This is the final part in a 3-part series on a practical approach to the diagnosis

Transcription

1 DIAGNOSIS UPDATE Evaluation of Peripheral Neuropathy. Part III: Vasculitic, Infectious, Inherited, and Idiopathic Neuropathies John J. Kelly, MD Department of Neurology, The George Washington University Medical Center, Washington, DC In this, the third of a 3-part series on peripheral neuropathy, the syndromes of vasculitic, infectious, inherited, and idiopathic neuropathy are discussed. Vasculitis is a frequent cause of neuropathy in the setting of a connective tissue disease. The infectious neuropathies most likely to be encountered in the United States are those due to varicella-zoster virus, human immunodeficiency virus, Lyme disease, hepatitis C virus, and, most recently, West Nile virus. Inherited neuropathies are divided into 2 main types: predominant motor or predominant sensory. The former are generally classed as the Charcot-Marie-Tooth diseases and the latter as the hereditary sensory neuropathies. Each category has a number of different subtypes. If the results of routine screening tests are negative, the clinician must consider special testing for unusual disorders, including evaluations for underlying autoimmune or malignant disorders, genetic tests for inherited neuropathies, and other unusual or selectively ordered tests. These tests are very expensive and should be ordered only after the common causes of neuropathy are excluded. Unless the neuropathy can be substantially alleviated or cured, symptomatic treatment (most often for pain) plays a significant role for these patients. [Rev Neurol Dis. 2005;2(2):70-79] 2005 MedReviews, LLC Key words: Cytomegalovirus Hepatitis C Herpes zoster HIV Idiopathic neuropathy Inherited neuropathy Lyme disease Neuropathy Peripheral neuropathy Treatment Vasculitis This is the final part in a 3-part series on a practical approach to the diagnosis of peripheral neuropathy. In this article, I discuss the syndromes of vasculitic, infectious, inherited, and idiopathic neuropathy. I also discuss the utility of special immunologic and genetic tests that I find most useful in diagnosing neuropathies. Finally, I discuss symptomatic treatment, which frequently is all that can be offered to patients. 70 VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES

2 Peripheral Neuropathy, Part III Vasculitic and Connective Tissue Disease Associated Neuropathies Vasculitis is a frequent cause of neuropathy in the setting of a connective tissue disease. Vasculitis affects vasa nervorum and feeder vessels, with resultant fascicular infarction. 1 The most common areas of nerve infarction are the thigh or upper arm, which are the watershed areas for nerve perfusion. 1 Thus, foot drop, mimicking a peroneal lesion at the fibula head, is usually due to a sciatic nerve lesion in the thigh, where the peroneal division is more vulnerable than the tibial. Because of the randomness of these lesions, patients usually develop an asymmetrical, regional neuropathy syndrome termed mononeuritis multiplex. However, some patients might develop a relatively symmetrical neuropathy resembling conventional neuropathies, owing to the coalescence of many lesions. 2-5 Therefore, vasculitis should be considered in any recent and rapidly progressive axonal neuropathy. Much less commonly, vasculitis is restricted to peripheral nerves and lacks systemic manifestations and is called nonsystemic vasculitis. 6 In these patients, the only clues to the diagnosis are the regional pattern of nerve involvement and the electrophysiologic findings, which do not differ from those of systemic vasculitis. Whether this syndrome is truly a different disorder or represents only a milder form of systemic vasculitis is unknown. Patients with systemic vasculitis might present with a primary vasculitic neuropathy, or vasculitis might be part of an underlying collagen vascular disease, such as Wegener s granulomatosis, Churg-Strauss syndrome, polyarteritis nodosa, rheumatoid vasculitis, microscopic polyangiitis, or mixed cryoglobulinemia associated with hepatitis C infection. 2,7 With the systemic variants of vasculitis, diagnosis is much easier, and the collaboration of an internist or rheumatologist is important. Vasculitic neuropathy patients typically present with the sudden onset of a painful mononeuropathy. Pain typically occurs at the site of Vasculitis should be considered in any recent and rapidly progressive axonal neuropathy. nerve infarct, most commonly in the thigh or upper arm. Patients develop distal weakness, loss of reflexes, and dysesthesias, which are usually painful. The deficit is usually at its maximum within a few days and might improve somewhat with time unless further infarcts occur or the nerve is totally destroyed. Most patients begin to accumulate further lesions and deficits within weeks to months. These deficits generally remain somewhat asymmetric but might evolve into a generalized neuropathy pattern resembling diabetic neuropathy or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In these patients, a careful history of a sudden, painful onset of asymmetric symptoms should suggest the diagnosis. If the syndrome is systemic in origin, other symptoms, such as fever, weight loss, and those clinical and laboratory findings that are specific to the underlying disease, typically occur. If the patient has nonsystemic vasculitis, however, there are no other symptoms or laboratory findings to suggest an inflammatory or autoimmune disorder, and only the history and pattern of involvement might suggest a vasculitic process. Neurophysiologic testing is extremely helpful. Nearly all patients have the electrophysiologic findings of axonal degeneration, which is asymmetric and might be restricted to individual peripheral nerves. The clinical presentation and the findings from electromyography (EMG) are very suggestive of vasculitis in most cases and warrant biopsy of an affected nerve (Figure 1). In general, the sensitivity of nerve biopsy in an affected nerve, such as the sural or superficial peroneal, is quite high, in the range of 60% to 80%. 2 Some investigators have advocated muscle and nerve biopsy, and in some cases distal muscle biopsy is more informative than nerve. 6 For patients for Figure 1. Nerve biopsy in vasculitic neuropathy. (A) Low-power hematoxylin-eosin preparation showing vasculitis of a medium-sized epineurial artery. (B) Intermediate-power view of the same biopsy, showing chronic inflammation of the blood vessel wall and luminal thrombosis. Figure courtesy of Robert Jones, MD, Department of Pathology, The George Washington University Medical Center, Washington, DC. A B VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES 71

3 Peripheral Neuropathy, Part III continued whom suspicion is high but with negative biopsy results, a second biopsy of another involved nerve is indicated. Patients usually require treatment with steroids and cytotoxic agents, such as cyclophosphamide. Unless the clinician is experienced in treating these disorders, referral to an appropriate specialist is advised. Nonsystemic vasculitic syndromes restricted to the peripheral nervous system are generally not as severe as systemic vasculitis and are often initially treated with glucocorticoids. 2 However, if the patient relapses or fails to respond, cytotoxic agents are usually added. 8 The prognosis is generally good if the patient is diagnosed early and treated aggressively before severe axonal damage occurs. Neuropathies Due to Infectious Diseases Infectious diseases can cause peripheral neuropathy. 9,10 Worldwide, leprosy is the most common disease, but it is rarely seen in the United States. Thus, I will focus on a few of the most common infectious neuropathies likely to be encountered by the US clinician. Varicella-Zoster Virus The most common infectious neuropathy in the western hemisphere is herpes zoster radiculoneuropathy. 9,11-13 Because this disorder is well known to neurologists, I will not describe it in detail. However, several subcategories of varicella-zoster virus infection warrant mention. The first is called zoster sine herpete or zoster without rash. These patients develop the symptoms of a typical herpes zoster infection of the face, trunk, or limb without the typical rash. Owing to the lack of telltale rash, the clinician must recognize the clinical pattern and have a high index of suspicion to make this diagnosis. The diagnosis is sometimes made clinically, and patients are treated with antivirals. Diagnosis can be confirmed by cerebrospinal fluid (CSF) examination, which shows lymphocytic pleocytosis, elevated viral titer indexes compared with serum, and/or positive results on polymerase chain reaction (PCR). 14 The second disorder is so-called segmental zoster paresis or zoster radiculopathy. Patients with this rare condition develop limb zoster associated with areflexia, sensory loss, and weakness, which can be profound. In the absence of the typical rash, vasculitis needs to be considered. Electromyography usually shows involvement of nerve roots and sometimes peripheral nerves, in a specific root or multiple root distribution. These patients generally make a good recovery unless axonal damage is quite severe. The diagnosis should be considered in the setting of acute or subacute onset of a painful, severe apparent radiculopathy, especially if there is involvement of multiple roots and no imaging abnormalities to support radiculopathy. The third disorder is postherpetic neuralgia. Recent evidence has showed persistent varicella-zoster virus infection in these patients, and treatment with antivirals has lessened the pain and hastened remission in small numbers of patients. These preliminary findings need to be confirmed by large, prospective, double-blind series. 14 Human Immunodeficiency Virus Human immunodeficiency virus (HIV) infection can be associated with peripheral neuropathy For practical clinical purposes, HIV infection can be divided into 2 categories: early HIV infection, with low viral loads and immunostimulation, and late HIV infection, with very high viral loads and severe immunosuppression. In early HIV infection, immunostimulation can lead to secondary autoimmune syndromes. These patients might present with typical, autoimmune Guillain-Barré syndrome (GBS), CIDP, or vasculitic neuropathy. On occasion, these disorders are the heralding events indicating an underlying HIV infection. One of our patients, an intravenous drug abuser, presented with typical GBS. His CSF showed a very high protein level but also a cellular pleocytosis of 50 to 60 lymphocytes. Because this is unusual in typical GBS, we checked his HIV status. His HIV titer was initially negative but, on repetition 1 month later, he had seroconverted, In zoster sine herpete, patients develop the symptoms of a typical herpes zoster infection of the face, trunk, or limb without the typical rash. suggesting GBS in the setting of acute HIV infection. These patients respond to plasmapheresis and intravenous immunoglobulin, as do patients without HIV infection. Intravenous immunoglobulin and plasmapheresis are the treatments of choice in these patients, especially for GBS, which requires only short-term treatment. Patients with autoimmune neuropathy late in HIV infection are difficult to treat, owing to profound immunosuppression. However, most of the late neuropathies are not autoimmune in etiology. The most common of the HIV neuropathies is a painful, bland, distal, sensorypredominant neuropathy of axonal type, similar to that seen in many other conditions. 10,11,19 The etiology of this syndrome is unclear but might be related to toxic and 72 VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES

4 Peripheral Neuropathy, Part III metabolic factors of late HIV infection or to the use of antiviral drugs. 20 Cytomegalovirus can present with 2 syndromes in patients with late HIV infection. The first and most common is polyradiculopathy that starts in the sacral regions. 21 These patients present with numbness and pain in the sacral area with loss of bowel, bladder, and sexual function. The symptoms rapidly ascend over days to weeks through the lumbar, the thoracic, and the cervical roots, with paralysis and death. Cerebrospinal fluid protein levels are very high, there is a marked cellular pleocytosis, consisting mostly of granulocytes, and CSF glucose levels are low. These findings suggest an inflammatory process and are distinct from the CSF findings of GBS or vasculitis. Cerebrospinal fluid PCR has a high rate of positivity, but this patient should be treated promptly on the basis of the clinical presentation and CSF findings, without delay for laboratory confirmation. If cytomegalovirus is recognized early, the initiation of treatment with antiviral drugs can halt or reverse the process. Cytomegalovirus can also present, in patients less severely immunosuppressed, with a more indolent, progressive mononeuritis multiplex or generalized neuropathy syndrome with pathologic changes similar to those in vasculitis. This syndrome occurs in late HIV infection and might require nerve biopsy. These patients generally also respond to antivirals. Lyme Disease Lyme disease can cause peripheral neuropathy. 10,22 The most common Cytomegalovirus can present with 2 syndromes in patients with late HIV infection: the first and most common is polyradiculopathy that starts in the sacral regions. of these is facial neuropathy. This can be bilateral or part of a more widespread polyneuritis cranialis occurring during the first stages of Lyme infection. Rarely, patients manifest with GBS. Lumbosacral radiculopathies or plexopathies can also present early in Lyme disease. Extraneurologic manifestations and CSF examination might help establish the diagnosis. The presence of a CSF cellular pleocytosis in this setting can suggest viral infection with Lyme or HIV. These disorders tend to occur during the first or second stage of Lyme disease, generally within the first 6 months of infection. Diffuse polyneuropathy, on the other hand, tends to be more characteristic of stage III disease. These patients might develop a distal, symmetrical, sensory-dominant neuropathy with pain, but significant objective findings are minimal. The neuropathy responds to appropriate antibiotic treatment if diagnosed early, but late cases are difficult to treat. Electromyography is helpful, generally demonstrating a distal axonal neuropathy with predominantly axonal changes. Definitive diagnosis is based on recognition of the clinical syndrome and positive serology. Hepatitis C Virus Hepatitis C virus is now relatively common in certain populations in the United States. This virus can be associated with a mixed cryoglobulinemia, which causes a vasculitic neuropathy. 7 Biopsy of the affected nerve shows vasculitis. Serum tests demonstrate cryoglobulinemia and hepatitis C viral infection. West Nile Virus The most recently described infectious neuropathy syndrome is the West Nile virus, which causes an acute, asymmetric, flaccid paralysis resembling polio. 10 As in polio, the target of the West Nile virus is the anterior horn cell. Patients presenting with a polio-like illness should be tested for West Nile virus. Neurophysiologic findings are consistent with anterior horn cell disease with regional denervation, preserved sensory potentials, and relatively preserved conduction velocities until the motor responses are very low. Unless symptoms are severe and extensive, these patients generally make some degree of recovery, but they are often left with residual weakness and atrophy, similar to that of polio patients. Inherited Neuropathies Some studies have shown that up to 20% or more of undiagnosed peripheral neuropathies, when studied Patients presenting with a polio-like illness should be tested for West Nile virus. thoroughly, are inherited. 23 The family history is often unreliable, however, because the phenotype of these patients is highly variable Despite dominant inheritance in many of these syndromes, patients who carry the defective gene might show few or no signs of the neuropathy, whereas siblings or offspring might be more severely involved and symptomatic early in life. Subtle VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES 73

5 Peripheral Neuropathy, Part III continued involvement can be passed off as a family trait, such as bad feet or an unusual gait. Because of the very slow progression of these disorders over many years, patients learn to adapt to their limitations and might not consider their symptoms abnormal. A negative family history in a patient with the clinical manifestations of an inherited neuropathy is not unusual. Thus, families should be brought in and examined both clinically and even electrophysiologically to establish a reliable family tree. 26 At present, in some syndromes, this can be accomplished with genetic testing. Inherited neuropathies are divided into 2 main types: predominant motor or predominant sensory. 25 The former are generally classed as the Charcot-Marie-Tooth (CMT) diseases and the latter as the hereditary sensory neuropathies. Each category has a number of different subtypes, and each subtype might have several distinct genetic defects, which makes a working knowledge of these neuropathies difficult for those who do not see these patients regularly. Thus, for simplicity, I will focus on the main types likely to be seen by the average neurologist rather than discussing all the variants. Charcot-Marie-Tooth Disease These patients tend to segregate into 2 main types on the basis of neurophysiologic and morphologic studies. Despite lifelong, progressive disease, they initially present throughout life with distal leg symptoms and difficulty walking. 26 The deterioration is slow and insidious and might go on for decades before being recognized. Functional changes, however, are stepwise, and a sudden worsening, such as the onset of tripping and falling, might lead them to seek medical attention. This might suggest a sudden onset and raise the possibility of an acquired neuropathy, such as CIDP. Careful history, however, can often establish that the patient never could walk well and always had difficulty with certain motor activities, such as running. Poor balance, leg cramps, difficulty fitting shoes, and trouble opening jars are often characteristic of these patients, their siblings, and a parent. Clinical clues to the diagnosis of CMT disease should be sought in the appearance of the feet. Thus, the peripheral neuropathy specialist must become familiar with the appearance of normal and abnormal feet. Common features include high arches, cocked-up toes, tight heel (Achilles) cords that limit dorsiflexion to 90 or less, and thin, atrophic muscles in the feet and distal legs (Figure 2). The hands might also show subtle atrophy, often most noticeable as guttering in the intermetacarpal In Charcot-Marie-Tooth disease, the deterioration is slow and insidious and might go on for decades before being recognized. spaces, secondary to atrophy of the interosseus muscles. The classic inverted champagne bottle or stork-leg appearance of the legs featured in most textbooks is seen only in advanced cases. Most patients have sensory loss by clinical testing, but some do not. Reflexes are generally absent in the legs, especially at the ankles, and are often diminished in the arms. Palpation of nerves can reveal thickening and firmness in some syndromes, especially those with myelin defects. Nerves are best felt in the upper arm, Figure 2. This is the typical appearance of the legs and feet in a patient with Charcot-Marie-Tooth disease. The patient has wasting of the calf muscles, high arches, slight cocking of lateral toes, and atrophy of the intrinsic foot muscles. On examination, in addition to this, the heel cords are often tight, with dorsiflexion less than 90. Reprinted with permission from Dyck et al. 26 just below the axilla, where the neurovascular bundle can be rolled against the humerus. 26 Here, they are accessible and generally unaffected by trauma. Neurophysiologic testing is useful in diagnosis and had been the mainstay of classification until genetic studies became available. Patients are generally segregated clinically and by EMG testing into 2 main groups, CMT disease types 1 and 2, both of which comprise a number of subcategories based on genetic abnormalities. 27,28 Both of these conditions are most commonly dominantly inherited, although recessively inherited and X-linked recessive variants have been described. 24,27,28 Patients with CMT1 have a demyelinating neuropathy with secondary axon loss. 24 Nerve conduction studies show slowing of conduction velocities (CVs) in the 20 to 30 m/s range, especially those with CMT1a. Rarely, patients might have a CV above 40 m/s and might mistakenly be thought to have CMT2. Most of these patients have genetic abnormalities different from type 1a VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES

6 Peripheral Neuropathy, Part III Charcot-Marie-Tooth disease type 2 is seen in approximately one third of CMT patients and has a primary axonal neuropathy. 27,28 Slowing in these patients is minimal but rarely below 40 m/s and is often close to normal, especially in nerves with relatively preserved motor responses. 25 Any slowing is generally correlated with loss of the fastest conducting fibers and low-amplitude motor responses. Some rare types of CMT are associated with extraneurologic features, such as cataracts and presumably separate genetic defects. Occasionally, patients present with pure motor findings on examination, EMG, and biopsy. Some call this CMT3. These patients seem to have a localized form of motor neuron disease or spinal muscular atrophy affecting the distal limbs and are referred to as having hereditary motor neuropathy. 24 The prototype of CMT disease is CMT1a, the most common genetic abnormality, which accounts for up to 60% of cases of CMT1. Charcot- Marie-Tooth disease type 1a is caused by an expanded trinucleotide repeat in a segment of the myelin PMP-22 gene on chromosome Patients with trinucleotide-repeat diseases are known to have great phenotypic variability, depending on the size of the repeat. Owing to the demyelinating nature of the EMG findings, this condition can be mistaken for CIDP if there is no obvious family history and if the long history and skeletal abnormalities are not recognized, as discussed above. Aside from the clinical history and findings, another key feature of CMT1 is the relative uniformity of the nerve CVs in adjacent nerves and in proximal and distal segments of the same nerve (EH Lambert, personal communication, 1967). As opposed to CIDP, there is a lack of conduction block or marked dispersion with proximal stimulation. However, other genetic forms of CMT1 have been reported to show such characteristics, which can lead to confusion with CIDP. Although genetic testing is available for most of the CMT1 neuropathies, fewer tests exist for the CMT2 and other variants at present. Commercial laboratories provide a menu of choices, based on clinical characteristics and electrophysiologic study results. Because these tests are expensive, the clinician should limit choices to the most likely etiologies, on the basis of the clinical and electrophysiologic characteristics. Another important category of inherited motor neuropathy is the syndrome of hereditary neuropathy with pressure palsies. 24,33,34 This dominantly inherited disorder is due to a deletion in the PMP-22 gene, the same gene on chromosome 17 affected in CMT1a. 35 These patients are prone to mononeuropathies due to relatively trivial trauma, such as crossing the legs or leaning on the elbows. Symptoms generally start in the late teens or early 20s. Occasionally, patients can develop a generalized neuropathy later in life. Diagnosis requires recognition of a mononeuropathy, usually after trivial trauma, in an otherwise healthy young person with no risk factors. Neurophysiology shows subtle signs of widespread neuropathy, such as prolonged distal latencies, slowing across common compression sites like the elbow, wrist, and fibula head, and mild distal latency prolongation, suggesting a subtle disorder of the myelin sheath. The diagnosis can be made by nerve biopsy, which shows a peculiar, sausage-like swelling of the myelin sheath, but is now usually made by commercially available genetic testing. Once diagnosis is made, treatment consists of lifestyle changes, but patients can do well if they are careful. Hereditary Sensory Neuropathies These patients might develop symptoms of small- and large-fiber sensory dysfunction, with pain and distal sensory loss in limbs, hands, and feet. 24 Some develop finger and foot ulceration and other lesions, with infection and subsequent loss of digits or appendages. Some types might have autonomic involvement. Motor symptoms are mild or absent in most. Sensory amplitudes are reduced, but motor nerve conduction studies are generally normal, suggesting an axonal or neuronal process. Diagnosis usually rests on Idiopathic, painful distal sensory motor neuropathies are the bane of most neuropathy specialists. recognition of the clinical syndrome, the family history and, in some cases, genetic testing. Idiopathic Neuropathy Idiopathic, painful distal sensory motor neuropathies are the bane of most neuropathy specialists. I call it the forgotten neuropathy because there is little written about it, and it is not the subject of significant research. These disorders account for approximately 20% of all neuropathies in general 23 but might account for 50% or more in neuropathy clinics, where patients are sent for second opinions and management of pain. This syndrome generally occurs in elderly patients. Idiopathic neuropathy in otherwise healthy, young patients suggests the possibility of a genetic disorder, VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES 75

7 Peripheral Neuropathy, Part III continued presuming a complete workup. Typical patients are usually in their 70s or 80s and might be otherwise healthy. They develop a painful, predominantly sensory axonal neuropathy that is symmetrical, affects the distal limbs, and is length dependent. Sensory loss usually affects small more than large sensory fibers, with loss of pain and temperature sensation to a greater extent than discriminative sensation. Patients complain of neuropathic pain and have trouble sleeping. There is often evidence of foot muscle atrophy, but as a rule, weakness is not prominent. Ankle jerks are usually absent or reduced, but proximal reflexes might be unaffected. Functional limitation is relatively mild. Patients, however, might become depressed owing to chronic pain and lack of sleep. These patients should be evaluated for all the usual causes unless the family history is positive. Recent studies suggest that a sizable proportion of these patients might have neuropathy due to the so-called metabolic syndrome or the glucose intolerance syndrome, despite normal or borderline fasting plasma glucose levels or normal hemoglobin A12C levels. 36 A 2-hour glucose tolerance test should be conducted if there is suspicion of this disorder. Associated mononeuropathies suggest the possibility of diabetes or vasculitis. Carpal tunnel syndrome and autonomic involvement can suggest diabetes or amyloidosis. Because even elderly patients can present with symptoms of inherited neuropathy, a careful family history and examination for skeletal changes mentioned above can help. We rarely biopsy these patients unless we think there is a reasonable chance that they have a condition that can be identified by biopsy, can be treated, or that has significant prognostic implications, such as amyloidosis (see part II of this series 37 ). These patients usually require medications to control pain and promote sleep at night (see the section on symptomatic treatment, below). Idiopathic neuropathy is always a presumptive diagnosis, and I generally follow these patients for several years to make sure they are not developing a more serious neuropathy. If the patient suddenly and significantly worsens, then reevaluation and biopsy should be considered. Generally these patients do quite well in terms of functional limitations and remain ambulatory during their lives, but they might require ankle/foot orthosis and other devices to help with ambulation after years of progression. Special Tests In part I of this series, 38 I indicated the routine screening tests suitable for the first round of investigation of a peripheral neuropathy patient after EMG. If this first round is negative, most causes have been excluded, and the clinician must consider special testing for unusual disorders. These tests include evaluations for underlying autoimmune or malignant disorders, genetic tests for inherited neuropathies, and other unusual or selectively ordered tests (Table 1). It is impossible to cover all tests in a review such as this, but Table 1 indicates the tests that I find most helpful on a day-to-day basis. It bears reemphasis that these tests are very expensive and, unless ordered when clearly indicated, are usually negative. Thus, they should be ordered only after the common causes of neuropathy are excluded and if a disorder that the test identifies is consistent with the clinical syndrome and results from basic studies, especially neurophysiology. For example, it would be a waste of resources to order a CMT1a screen in a patient with an axonal pattern on nerve conduction studies. Often, the testing laboratories group multiple tests Table 1 Most Helpful Special Tests for Neuropathy Type of Disorder Specific Tests Syndrome Neurophysiology Autoimmune GM1 (IgG) and GBS variants Axonal pattern other ganglioside (AMAN, AMSAN) antibodies GQ1b Fisher variant of GBS Axonal GM1 (IgM) Multifocal motor Demyelinating neuropathy with CB IgM MAG Anti-MAG Demyelinating monoclonal neuropathy with very long antibodies DLs Inherited Genetic tests for: Inherited Demyelinating neuropathies CMT1, CMT2, neuropathy or axonal CMTX, and HNPP+ Paraneoplastic Anti-Hu, Anti-CV2 Ig, immunoglobulin; GBS, Guillain-Barré syndrome; AMAN, acute motor axonal neuropathy; AMSAN, acute motor and sensory axonal neuropathy; CB, conduction block on nerve conduction studies; DL, distal latency on nerve conduction studies; CMT, Charcot-Marie-Tooth disease; HNPP, hereditary neuropathy with pressure palsies. 76 VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES

8 Peripheral Neuropathy, Part III in a package, which increases cost and results in many negative studies. These tests should ideally be ordered individually to fit the syndrome. Symptomatic Treatment of Neuropathy Unless the neuropathy can be substantially alleviated or cured, symptomatic treatment plays a significant role in these patients. Most of the symptomatic treatments are for pain. Because pain can be debilitating and lead to insomnia, depression, and even suicide, familiarity with these treatments is important. Nocturnal exacerbation in particular is a diagnostic feature of neuropathy and often the primary target of treatment. For mild pain, nonnarcotic analgesics, such as nonsteroidal antiinflammatory drugs, are sometimes effective, if patients can tolerate them. The most effective of these in my experience is tramadol, which also can be taken during the day on an as-needed basis. The main side effects of tramadol are a mild degree of sedation in occasional patients and a potential to provoke epileptic seizures, especially at high doses and in patients who have a lowered seizure threshold. Tramadol can also be used with the other drugs discussed below or as a rescue drug for breakthrough pain during the day or night. The old tricyclic antidepressants are still a mainstay of many drug regimens, because they dull pain and improve sleep. If patients can get a good night s sleep, pain is much easier to manage the next day. Unfortunately, however, tricyclics have many side effects and either cannot be tolerated or are If patients can get a good night s sleep, pain is much easier to manage the next day. found to be ineffective by approximately half of neuropathy patients, in my experience. Also, they generally cannot be taken during the day, which limits their usefulness. The most troublesome side effects are somnolence, confusion, and memory loss. They also cause dry mouth, constipation, and urinary retention in some and are capable of causing cardiac arrhythmia at high doses. If used, they must be started very slowly and the dose gradually increased over several weeks. If used in elderly or frail patients, for whom the risk of side effects is greater, an extremely slow escalation is recommended. In these patients, I generally increase amitriptyline or nortriptyline by 10 mg per week until the desired effect is achieved or side effects become intolerable. The patient is told to return weekly or call in to report side effects. Generally, increasing beyond 75 to 100 mg per night is not helpful and can be potentially dangerous, especially in frail or elderly patients. The newer antidepressants are much less useful, in my experience, unless there is a concomitant depression that needs to be treated. Another helpful class of medications is the newer antiepileptic drugs, such as gabapentin and topiramate. I find gabapentin to be the most helpful and best tolerated drug in this group. It works to some extent in approximately 70% of patients in my experience and is particularly useful during the day because patients generally can tolerate it well and are able to work and drive. This drug needs to be taken several times during the day and at night if necessary for sleep. The dose can be titrated up to very high levels of several thousand milligrams per day in divided doses, with minimal side effects in most patients. In my experience, if it helps at all in relatively low doses of 300 to 600 mg q.i.d., then it works even better with successively higher doses. I generally start with 300 mg t.i.d. in most patients (or 100 t.i.d. in old or frail patients) and titrate up every week or 2, usually over the phone. It is a very safe drug, with few side effects and few drug interactions. The most common complaints, true of most antiepileptics, are confusion, somnolence, dizziness, and forgetfulness. It is now available in generic form. Topiramate is less helpful and has more side effects, in my experience. However, one of its side effects, weight loss, is generally considered beneficial by most patients. In general, if gabapentin does not work, I have had little luck with trying topiramate or the other newer anticonvulsants. Often, these drugs are combined. For example, some of my patients take a tricyclic at night and gabapentin during the day. Some use tramadol for daytime breakthrough pain or in anticipation of an activity that will provoke pain. As an adjunct, some patients use anesthetic patches for areas of intense localized pain. These are often helpful in postherpetic neuralgia or localized neuropathy pain syndromes, such as mononeuropathies. Capsaicin cream has a limited utility but does work for some patients. It is inconvenient to use, causes local burning when first used, has to be applied several times per day, and takes several weeks to take effect. Most patients abandon it before this, but I have treated a few who stuck it out and had good results. Others have advocated nerve or spinal cord stimulation for neuropathy pain VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES 77

9 Peripheral Neuropathy, Part III continued control. I have avoided this in general, but I have inherited a few patients who have tried it. In my experience, it is rarely helpful for generalized neuropathy, although it can have a role as a last-ditch treatment in neuropathy pain localized to one leg. When none of these work, narcotics can be very helpful. This treatment has to be approached with great care, owing to regulatory issues, after the other treatments listed above are exhausted. However, most patients with no history of substance abuse or addictive behavior are very reliable and respond well to narcotics. I generally prescribe them at night to promote sleep. Usually, a long-acting narcotic is preferred because pain relief endures for the entire sleep period and the drug is less likely to be abused. I generally enlist the help of the spouse, if available, to help monitor the situation, and I ask the patient to sign a treatment contract if I have any doubts. I see the patients every few months and monitor their drug use. I have had a number of patients whose lives have been made bearable by careful use of chronic narcotics and have had only a rare patient who abused the medications. Conclusion The diagnostic approach to peripheral neuropathy is logical and stepwise. The patient s history, as in all of neurology, is often the cornerstone in establishing a neuropathy diagnosis. The history can be suggestive enough that, on occasion, a diagnosis of neuropathy can be made even without physical signs or laboratory confirmation. The examination helps to categorize and quantitate the neuropathy. Associated findings, such as skeletal or skin changes, should be sought and can be very helpful diagnostically. Testing should be approached in a logical fashion, keeping in mind the nature of the clinical syndrome. The results of neurophysiologic testing can be very helpful for categorizing the disorder and planning the diagnostic attack. The first round of testing, unless the clinical evaluation and electrophysiologic testing suggest a specific diagnosis, should be aimed at the most common etiologies, such as those caused by metabolic disorders, medications, toxins, underlying diseases, and heredity. If these tests are negative, special tests for genetic, autoimmune, and paraneoplastic disorders should be considered on a selective basis if the clinical and laboratory attributes of the neuropathy are suggestive. Nerve biopsy should be delayed to the last and should only be done if the laboratory and pathologist can properly evaluate the tissue and if the differential diagnosis includes a disorder that can be diagnosed by biopsy. Curative treatments are unfortunately only Main Points Vasculitis is a frequent cause of neuropathy in the setting of a connective tissue disease. These patients typically present with the sudden onset of a painful mononeuropathy; nearly all have electrophysiologic findings of asymmetric axonal degeneration, and they usually require treatment with steroids and cytotoxic agents, such as cyclophosphamide. Infectious diseases can cause peripheral neuropathy. The infectious neuropathies most likely to be encountered in the United States are those due to varicella-zoster virus, human immunodeficiency virus, Lyme disease, hepatitis C virus and, most recently, West Nile virus. Inherited neuropathies are divided into 2 main types: predominant motor or predominant sensory. The former are generally classed as the Charcot-Marie-Tooth diseases and the latter as the hereditary sensory neuropathies. Idiopathic, painful distal sensory motor neuropathies account for approximately 20% of all neuropathies in general and occur mostly in elderly patients. Typical patients develop a painful, predominantly sensory axonal neuropathy that is symmetrical, affects the distal limbs, and is length dependent; they usually require medications to control pain and promote sleep. Tests for underlying autoimmune or malignant disorders, genetic tests for inherited neuropathies, and other unusual or selectively ordered tests are very expensive and, unless ordered when clearly indicated, are usually negative. Thus, they should be ordered only after the common causes of neuropathy are excluded. Most symptomatic treatment for peripheral neuropathy is for pain. Pain can be managed with nonnarcotic analgesics, such as tramadol; tricyclic antidepressants, which dull pain and improve sleep (but which have many adverse effects); newer antiepileptic drugs, such as gabapentin; and, as an adjunct, anesthetic patches. Narcotic treatment has to be approached with great care, owing to regulatory issues, and only after other treatments have been exhausted. 78 VOL. 2 NO REVIEWS IN NEUROLOGICAL DISEASES

10 Peripheral Neuropathy, Part III available and effective in a minority of patients, usually those with autoimmune disease. Autoimmune treatments should be used only if the evidence is highly suggestive of inflammation and autoimmunity. Although the diagnostic rate for cases of unselected neuropathy has improved from approximately 50% when I entered neurology in 1973 to approximately 70% now, approximately 20% are still undiagnosed. For these, we have symptomatic treatments, which consist of medications for pain and aids, bracing, and other support modalities for negative symptoms. References 1. Dyck PJ, Conn DL, Okazaki H. Necrotizing angiopathic neuropathy. Three-dimensional morphology of fiber degeneration related to sites of occluded vessels. Mayo Clin Proc. 1972;47: Burns TM. Vasculitic neuropathy. Continuum. 2003;9: Kissel JT, Slivka AP, Warmolts JR, et al. The clinical spectrum of necrotizing angiopathy of the peripheral nervous system. 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