Other Metabolic Disorders
Polyneuropathy develops in up to 60% of patients with chronic renal failure. The risk of uremic neuropathy is related to the duration and severity of renal failure. Slowing of motor conduction velocity is seen when the creatinine clearance falls below 10% of normal, although conduction slowing is only roughly correlated with symptoms. Uremic neuropathy is sensorimo-tor in nature, with distal predominance of symptoms and signs. Once established, uremic neuropathy tends to worsen slowly, the main troublesome symptom being unpleasant dysesthesia in the feet. Disabling motor weakness is rare. The chief pathologic finding in uremic neuropathy is axonal degeneration, which is most abundant in the most distal parts of the PNS. Etio-logically, impairment of neuronal soma or axon function probably results from the buildup of a neurotoxic substance or substances normally excreted by the kidneys, but the details are not known. Both dialysis and renal transplantation generally have a beneficial effect. Dialysis can prevent, stabilize, or often decrease the severity of neuropathy. The effects of renal transplantation may be striking, and even severe uremic neuropathy can be expected to improve in the months after transplantation. The widespread availability of these treatments has made symptomatic uremic neuropathy relatively uncommon.
Mild distal axonal polyneuropathy sometimes occurs in patients with hypothyroidism, acromegaly, or polycythemia. These neuropathies are not disabling, but sensory symptoms may be troublesome. Patients in intensive care units with multiple organ dysfunction syndrome and sepsis sometimes experience a severe axonal polyneuropathy. The pathogenesis of this condition, known as critical illness polyneuropathy, is unknown.23 Critical illness polyneuropathy is usually suspected either when a patient in an intensive care unit cannot be weaned from the ventilator despite adequate cardiopulmonary function or when limb weakness occurs in an alert ICU patient. Because it is difficult to examine the PNS properly in critically ill patients and because critical illness polyneuropathy is a diagnosis of exclusion, clearly establishing the diagnosis can be difficult. A similar clinical picture can also be caused by a critical illness myopathy, particularly in patients treated with high-dose glucocorticoids and long-acting neuromuscular blockers (e.g., vecuronium). Limited data suggest that critical illness neuropathy improves in patients who survive the illness.24
Inherited Polyneuropathies
Inherited polyneuropathies are common and frequently overlooked, especially in adults.12 Patients often remain relatively asymptomatic for many years and, therefore, may not seek medical advice until middle age or later. A very slow progression of symptoms over years is suggestive of an inherited cause. Patients with inherited polyneuropathies may complain of numbness, by which they usually mean decreased sensation. Symptoms of prickling or pins-and-needles paresthesia in a patient with polyneuropathy favors an acquired cause. However, the complaint of burning feet is nonspecific, occurring in both inherited and acquired polyneuropathies. As a rule, inherited neuropathies begin and progress symmetrically; asymmetrical progression suggests an acquired polyneuropathy.
Once inherited polyneuropathy is suspected, proving the diagnosis may require considerable effort. Simply asking the patient about a family history of neuropathy is seldom productive. Questioning should be more general, such as whether anyone in the family has foot complaints, has a foot deformity (especially high arches), or requires special shoes, canes, or braces. A negative family history does not exclude a diagnosis of inherited neuropathy. Because of its chronicity or mildness, or both, the condition often goes unrecognized in a family. In recessive cases, by definition, neither parent is affected, and siblings may be spared. Paternity may be less well established than it appears. The most effective next step is to examine first-degree relatives, particularly those with any history of foot or walking troubles. Although this procedure is time-consuming, it has a good yield and is more cost-effective than a barrage of laboratory tests that may all prove negative.
Knowledge about the specific genetic defects related to various inherited neuropathies is expanding rapidly,25 but clinical classification remains important. Traditionally, the inherited neuropathies are divided into three main categories according to clinical features: (1) hereditary motor and sensory neuropathy, (2) hereditary sensory and autonomic neuropathy, and (3) hereditary motor neuropathy (also called spinal muscular atrophy) [see Table 4]. Genetic testing for some inherited neuropathies is now available (e.g., PMP22 gene [Charcot-Marie-Tooth disease type 1], connexin-32 gene [X-linked Charcot-Marie-Tooth disease]). Although there are still no specific therapies for inherited neuropathies, correct diagnosis remains important for prognosis, education, and genetic counseling. In general, the deficits in inherited neuropathies progress very slowly, life expectancy is normal, and most patients remain ambulatory all their lives.
Immune-Inflammatory Polyneuropathies
Guillain-Barre syndrome Guillain-Barre syndrome (GBS), or acute inflammatory demyelinating polyradiculoneuropathy, is the most common cause of acute generalized paralysis in the Western world. Most large general hospitals care for several patients with GBS every year, and the management of these patients often falls to general physicians. The natural history of GBS is favorable in most cases, but a good outcome depends on meticulous medical and nursing care during the peak of neurologic disability.
The diagnosis of GBS is not difficult once the signs are fullblown. However, in the first few days, symptoms can be vague and the signs equivocal. It is common for a patient to be discharged from the emergency room with a diagnosis of anxiety, only to return a day or two later with obvious progressive limb weakness. Most often, the first symptom is prickling paresthesia, beginning in the feet and spreading proximally hour by hour. Weakness is noticed some hours to a few days later. Some patients have only motor symptoms without sensory symptoms. Classically, symptoms begin symmetrically in the distal limbs and proceed proximally (so-called ascending paralysis), and nerve conduction studies provide evidence of a demyelinating process affecting spinal roots and peripheral nerves (a demyelinating polyradiculoneuropathy). Variations on this classic presentation are common and include syndromes in which cranial nerve (e.g., Miller Fisher syndrome) or autonomic involvement predominate, as well as syndromes that are primarily axonal rather than demyelinating.26 It is evident that Guillain-Barre syndrome must be regarded as a rather elastic category, although all clinical variants share the key features of being acute-onset, immune-mediated disorders of the PNS, with a self-limited monophasic course. In addition to motor, sensory, or autonomic symptoms, many patients have pain, most often manifested as a deep ache in the back or limbs or as dysesthetic limb pain.27
Autonomic dysfunction may be a significant problem in some patients with GBS, particularly those with severe weakness. Marked blood pressure fluctuation and refractory hypotension are the major problems, although hyperthermia, pupillary paralysis, and cardiac dysrhythmias may occur.
Muscle weakness can be expected to increase during the first few days and then remain stable for days to weeks. Weakness may range from mild (e.g., slight weakness of ankle dorsiflexion) to severe; flaccid quadriparesis with respiratory muscle paralysis occurs in as many as 30% of patients. It is impossible to predict within the first 2 days how much weakness will develop in a given patient. Therefore, it is advisable to observe any patient with GBS in the hospital until the severity is apparent. As a general rule, weakness reaches its maximum within 14 days. The ensuing period of stable weakness, before recovery begins, lasts days to months, with a median duration of 4 weeks. A rough correlation exists between the severity of weakness and the interval before the onset of recovery. Once recovery begins, the patient usually makes noticeable gains on a weekly basis. A year after onset, most patients have made a complete or substantial recovery, but as many as 15% remain bedridden or wheelchair bound. Recurrent episodes of GBS, sometimes spread out over many years, occur in about 3% of patients.
The fundamental pathologic event in GBS is the stripping of myelin from axons by macrophages, which occurs in a patchy fashion throughout the PNS. A cascade of events involving cell-mediated and humoral immune mechanisms is assumed to be activated, and lymphocytic inflammatory infiltrates are often found in nerve and nerve roots examined by biopsy or at autopsy. The triggers and specific molecular targets of the immune attack are unknown. There is a lingering concern about influenza vaccination as a precipitant of GBS; retrospective epidemiologic studies have found a small relative risk of GBS among vaccine recipients in the 1992 through 1994 influenza seasons.28 Studies of the pathogenesis of GBS have focused on the potential roles of antecedent Campylobacter jejuni infection and the production of antiganglioside autoantibodies, both of which occur in a large number of patients with GBS.29
The differential diagnosis of an acute sensorimotor polyneu-ropathy is short [see Table 2]. Before the development of the polio vaccine, the major differential diagnosis was between GBS and poliomyelitis, but poliomyelitis is now rare. If signs of systemic illness accompany an acute polyneuropathy, consideration should be given to vasculitic neuropathy, lymphomatous infiltration of the nerve roots, acute intermittent porphyria, diphtheria, and arsenic poisoning. An ischemic lesion of the pons may initially produce acute flaccid quadriparesis and mimic GBS before clear upper motor neuron signs develop. With cranial nerve variants of GBS (e.g., Miller Fisher syndrome), myasthenia gravis and botulism must be excluded.
GBS is diagnosed primarily from the clinical features, but laboratory tests can help support the diagnosis and exclude other causes of acute polyneuropathy. The cerebrospinal fluid in GBS characteristically shows elevated protein levels, normal glucose levels, and no pleocytosis. If a mononuclear pleocytosis is found, meningeal infiltration by lymphoma or carcinoma must be seriously considered. An acute polyradiculopathy similar to GBS but with CSF pleocytosis may occur at the time of HIV serocon-version [see Polyneuropathies Caused by Infectious Diseases, below]. Nerve conduction studies in GBS usually demonstrate widespread slowing of conduction velocities or, more commonly, proximal conduction block and can provide some prognostic information. Neither the CSF nor the nerve conduction abnormalities are diagnostic of GBS, and both tests may be normal, particularly during the first few days of the disease.
Once a diagnosis of GBS is made, the first priority is to monitor respiratory muscle function closely and be prepared to intervene if ventilatory failure develops. Frequent bedside measurements of vital capacity or maximum inspiratory force, or both, and clinical evaluation for signs of respiratory muscle fatigue are important. A patient with a vital capacity of less than 20 ml/kg is likely to experience frank ventilatory failure, and elective intubation should be strongly considered.
Several large clinical trials have shown that two therapies— plasma exchange and intravenous immunoglobulin (IVIg)—im-prove the rate of recovery in patients with moderate to severe GBS (e.g., patients who are unable to walk).30-32 Both treatments appear to modulate the inflammatory process that produces nerve injury, but they are not thought to promote remyelination or nerve regeneration. A beneficial effect can be shown only if plasma exchange or IVIg is begun within 2 weeks after onset of neuropathic symptoms. It is probably wise to begin treatment as soon as the diagnosis has been made, if the weakness is sufficiently severe, or if the signs progress while the patient is under observation. Usually, five treatments are given over 5 to 10 days; some patients may relapse and require further treatments (e.g., twice weekly for 3 weeks). Combined treatment (plasma exchange followed by IVIg) offers no clear advantage over either treatment alone,30 and glucocorticoids conferred no additional benefit when added to plasma exchange in a large controlled tri-al33 and have no benefit when used alone.34 Plasma exchange and IVIg appear to be equally effective and have similar costs and relapse rates, but many clinicians believe IVIg is the treatment of choice because it is considerably easier to administer than plasma exchange. Because IVIg is made from pooled blood, it is difficult to completely eliminate concerns about infectious risk, even though multiple purification procedures are now used, and there have been no proven cases of IVIg-transmitted infection for over a decade. There is also uncertainty about whether the supply of IVIg is adequate to meet the demand. A new therapeutic strategy is CSF filtration; a small controlled trial found this modality to be at least as effective as plasma exchange, with fewer complications.35
Because many patients remain bedridden for months, meticulous nursing care is essential. Measures to prevent pressure sores and venous thrombosis are necessary, and the patient is also in constant danger of urinary and pulmonary infections. Pain is a major problem for some patients and seems to be related partly to immobility and partly to nerve inflammation and dysfunction. Regular range-of-motion physiotherapy exercises and judicious use of analgesics and agents such as amitriptyline are beneficial. A particular challenge for all staff members is psychological support of the patient; there are several eloquent accounts of the patient’s perspective in GBS.36
Chronic inflammatory demyelinating polyradiculoneu-ropathy Like GBS, chronic inflammatory demyelinating poly-radiculoneuropathy (CIDP) is an immune-mediated neuropathy. The fundamental pathologic event is the stripping of myelin from axons by macrophages, which slows or blocks nerve impulse conduction, causing weakness and sensory loss. Clinically, CIDP differs from GBS in several important respects. The onset of CIDP is insidious, with symptoms and signs developing over weeks to months, compared with the rapid initial course of GBS. Unlike the monophasic, self-limited course of GBS, the natural history of CIDP is variable. The usual pattern of CIDP is slow worsening over months, producing chronic moderate disability. Some patients have a relapsing and remitting course, and a few experience gradual spontaneous remission. Major autonomic or respiratory involvement, which is common in GBS, is unusual in CIDP.
No single clinical or laboratory finding is pathognomonic for CIDP, and the diagnosis is made from a combination of an appropriate history, signs of neuropathy, electrophysiologic evidence of demyelination, and an acellular CSF with an increased protein level. Nerve biopsy can support the diagnosis but is usually unnecessary. A similar type of chronic neuropathy can occur in patients with monoclonal gammopathy, osteosclerotic myeloma, and HIV infection.
The efficacy of a number of treatments for CIDP has been demonstrated in controlled trials. Plasma exchange37 and IVIg38 produce improvement in 2 to 3 weeks in most patients, but the improvement is short-lived, and patients need either repeated treatments or alternative long-term therapies. High-dose pred-nisone is also effective,39 but the response is usually less impressive and slower, and the patient faces the potential complications associated with long-term glucocorticoid use. A double-blind crossover trial of interferon beta in treatment-resistant CIDP showed no benefit,40 but there is anecdotal support for other im-munomodulating drugs, including cyclosporine, azathioprine, interferon alfa, cyclophosphamide, and mycophenolate mofetil. Careful monitoring of neurologic impairment and treatment by neurologists experienced with CIDP are important.
Monoclonal protein-associated polyneuropathy Polyneu-ropathy and a monoclonal gammopathy may occur in some patients who have amyloidosis, multiple myeloma, osteosclerotic myeloma, Waldenstrom macroglobulinemia, or lymphoma. If none of these hematologic conditions is found, then the patient is considered to have monoclonal gammopathy of undetermined significance (MGUS). The relation between MGUS and neuropathy is unsettled, but epidemiologic and pathologic evidence suggests that MGUS causes the neuropathy.
MGUS neuropathy has variable clinical and electrophysiolog-ic features. There is often electrophysiologic and pathologic evidence of prominent demyelination, and the clinical picture closely resembles that of CIDP. Some patients have a painful, ax-onal neuropathy with mild deficits. IgM-associated neuropathy tends to be more severe, with more ataxia and more evidence of nerve conduction slowing and dispersion, which indicates that some relation exists between the class of immunoglobulins and the features of the neuropathy.
MGUS neuropathy is generally slowly progressive, though the degree of disability is variable. Therapeutic approaches aim either to suppress production of the monoclonal protein or to remove it from the circulation. Anecdotal reports exist of responses to chlorambucil, melphalan, and prednisone. A controlled trial showed plasma exchange to be beneficial in patients with IgG and IgA gammopathies but not in those with IgM gammopa-thy.42 IVIg appears to be beneficial in IgG MGUS neuropathy, but a controlled trial has not been conducted.43
Amyloid neuropathy Polyneuropathy characterized by amyloid deposition in nerve occurs in two settings: (1) as a feature in about 15% of patients with systemic amyloidosis, in whom the amyloidogenic protein is immunoglobulin, and (2) as an autosomal dominant disorder, familial amyloid polyneu-ropathy (FAP), in which the amyloid most commonly consists of mutated forms of transthyretin, a normal serum protein.44 Both types feature a symmetrical sensorimotor polyneuropathy distinguished by the frequent presence of important or predominant autonomic features. Amyloidosis is also a rare cause of carpal tunnel syndrome.
The diagnosis of amyloid neuropathy is made by nerve biopsy. Acquired amyloid neuropathy and inherited amyloid neuropathy are histopathologically similar but can be distinguished by immunohistochemical analysis. Trials of melphalan, gluco-corticoids, and colchicine have had little impact on the outcome of patients with primary amyloidosis, including any improvement of the neuropathy. Unlike in primary amyloidosis, neuropathy is usually the major cause of disability in FAP, and most patients survive for a decade or more after diagnosis. Liver transplantation may halt progression of the neuropathy in FAP.
Osteosclerotic myeloma Osteosclerotic myeloma is a variant of myeloma in which patients have one or sometimes several osteosclerotic bony lesions. Biopsy reveals malignant plasma cell proliferation. Commonly, these bony lesions occur within a constellation that includes polyneuropathy, organomegaly, endocrine abnormalities, monoclonal gammopathy, and skin changes (POEMS syndrome). The polyneuropathy is typically demyelinating and resembles CIDP. POEMS syndrome is important to recognize because there may be significant clinical improvement with irradiation of the bony lesion.
Paraneoplastic neuropathy Several distinctive nonmetastat-ic neurologic syndromes that develop in cancer patients have been described since the 1950s. Paraneoplastic syndromes are believed to have an immunologic basis, developing as a consequence of the host’s attempt to mount an immune response to the cancer [see 11:VINeoplastic Disorders].
Vasculitic neuropathy Neuropathy is a frequent manifestation of certain systemic vasculitides. Vasculitic neuropathy is is-chemic, a consequence of involvement of nutrient vessels of nerve by the inflammatory process. Because of the robust blood supply of nerve and its relative resistance to ischemic injury, the development of neuropathy in vasculitis implies extensive vessel involvement. The vasculitis tends to be patchy, and asymmetry of nerve involvement is common, so individual nerves are often affected while neighboring nerves are spared; this is the classic syndrome of multiple mononeuropathies. However, as the involvement of nerve blood supply advances and more nerves become involved, a pattern of multiple mononeu-ropathies may become more difficult to identify. About 30% of cases of vasculitic neuropathy are symmetrical polyneu-ropathies at initial diagnosis, 30% are asymmetrical polyneu-ropathies, and 40% are multiple mononeuropathies.
Among patients with vasculitic neuropathy, the main associated systemic vasculitides are polyarteritis nodosa, rheumatoid vasculitis, Sjogren syndrome, Wegener granulomatosis, and allergic granulomatous angiitis (Churg-Strauss syndrome). Neuropathy is particularly common in polyarteritis nodosa, occurring in at least half of all cases. The clinical and neuropathologic features of the neuropathy in these disorders are similar, and a specific diagnosis depends on the systemic, nonneurologic features. Vasculitic neuropathy can often be suspected from the clinical setting alone, but definitive diagnosis depends on nerve biopsy. Antineutrophil cytoplasmic antibodies are often found in vasculitic neuropathy, but false positive test results limit their diagnostic usefulness.
Vasculitic neuropathy is managed by treating the underlying systemic vasculitis. This therapy generally requires high-dose prednisone, cyclophosphamide, or both. In vasculitis, neuropathy is seldom a cause of death, although it may produce significant disability. If life-threatening events, such as renal or car-diorespiratory failure, can be successfully treated, the prospects for neurologic improvement are good, although improvement may take many months.48
Patients with clinical and neuropathologic features of vas-culitic neuropathy sometimes have no evidence of systemic vas-culitis. This syndrome, termed nonsystemic vasculitic neuropathy, appears to have a more benign natural history than does systemic vasculitis. Corticosteroids are often used if the patient has significant or progressive neurologic disability, although there are no controlled trials. The largest retrospective series of patients with nonsystemic vasculitic neuropathy suggested that combination immunotherapy (corticosteroids plus cyclophos-phamide) was more effective than corticosteroids alone in inducing remission and improving disability.
Neuropathies related to other connective tissue diseases
Peripheral neuropathy may occur in other connective tissue diseases, such as systemic lupus erythematosus [see 15:IV Systemic Lupus Erythematosus], although it can be difficult to ascertain whether the neuropathy is a direct complication of the connective tissue disease or a secondary effect of another complication (e.g., secondary to renal failure). It is usually assumed that neuropathy in such cases has an inflammatory basis, but few pathologic studies exist to support this belief. An ataxic sensory neu-ronopathy, clinically very similar to the paraneoplastic syndrome [see 11:VI Neoplastic Disorders], has been described in patients with Sjogren syndrome and is caused by an inflammatory infiltration of dorsal root ganglia.50 Inflammatory sensory neuropathies also occur in patients with sicca syndrome who lack extraglandular features of Sjogren syndrome.
Neuropathies Caused by Toxins and Nutritional Deficiencies
Substances toxic to peripheral nerves include a variety of industrial chemicals, naturally occurring compounds, and drugs. Most toxic neuropathies begin distally, progress insidiously over weeks to months, and have electrophysiologic features of an axonal neuropathy. With some exceptions, nonspecific axon-al degeneration is the main histologic feature, and nerve biopsy is seldom helpful in making the diagnosis.
Drugs Drug-induced neuropathy is a common problem, particularly in a hospital-based practice. A careful drug history is an important part of the investigation of any polyneuropathy. Peripheral neuropathy is a well-established adverse effect of many drugs [see Table 5]. In ideal circumstances, before a drug is labeled as potentially neurotoxic, the affected patient should be found to be free of other potential causes of neuropathy, and cessation of the drug should lead to some clinical improvement. It is important to realize that recovery may take many months. In some toxic neuropathies, the patient experiences the phenomenon known as coasting, in which the neuropathy continues to worsen for some weeks after exposure has ceased. For most well-established peripheral nerve toxins, there is experimental evidence of toxicity in animals and neuronal cell culture. With some antineoplastics (e.g., cisplatin), neuropathy may be the dose-limiting side effect. In animal models, cisplatin neuropathy may be prevented or alleviated by coadministration of neurotrophins, such as NT-3, a strategy that may prove applicable to humans.
Industrial chemicals A patient’s occupational history may be important because a number of industrial chemicals are known to be neurotoxic [see Table 6]. Most of these compounds were found to be neurotoxic after clusters of cases appeared in workers in specific industries, and subsequent awareness of the dangers of these compounds has reduced the incidence of cases. Most of these chemicals produce axonal neuropathies with nonspecific pathologic changes. Proving that a neuropathy is caused by exposure to a chemical requires careful epidemiologic work supported by animal or tissue culture studies.
Metals In addition to drugs containing gold and platinum, poisoning by other metals may produce neuropathy. Exposure is often the result of homicidal or suicidal intent, so the history may be of dubious value. Diagnosis must be made from the associated clinical features. For example, lead neuropathy is predominantly motor, with a predilection for the upper limbs, and is associated with abdominal pain, constipation, and anemia. In addition to causing neuropathy, arsenic poisoning produces abdominal pain, vomiting, diarrhea, skin and nail changes, and pancytopenia. Thallium neuropathy is distinguished by alopecia and abdominal pain. Organic and inorganic mercury compounds can produce neuropathy, but CNS effects usually predominate [see 8:IManagement of Poisoning and Drug Overdose].
|
Table 6 Industrial Chemicals That May Cause Polyneuropathy |
|
|
Acrylamide |
Methyl bromide |
|
Allyl chloride |
Methyl butyl ketone* |
|
Carbon disulfide |
Organophosphorus esters |
|
Dimethylaminopropionitrile |
Polychlorinated biphenyls |
|
Ethylene oxide |
Trichloroethylene |
|
Hexane* |
Vacor |
*Exposure to these compounds also occurs as a result of glue sniffing and other solvent abuse.
The diagnosis of metal neuropathy hinges on demonstrating increased urinary excretion of the metal or increased levels in the hair or nails. Requests for such assays should be prompted by clinical suspicion and are not part of the routine investigation of polyneuropathy.
Ethanol A distal, often painful neuropathy is common in chronic alcoholics. The main symptoms are burning, stabbing pains and numbness in the feet and sometimes in the hands. Sensory loss or painful hypersensitivity in the feet, loss of the ankle reflexes, and mild distal weakness form the typical picture. Whether the neuropathy is caused by a direct toxic effect of ethanol, malnutrition, or both remains unresolved.
Attempts to produce neuropathy with ethanol in well-fed animals have been unsuccessful, although in neuronal cell cultures, growth inhibition can be produced with moderately high concentrations of ethanol. A Danish study that carefully examined a cohort of alcoholic beer drinkers with neuropathy found no clinical, electrophysiologic, or histologic differences between those who were well nourished and those who were malnour-ished.53 Danish beer is supplemented with thiamine and pyri-doxine, so it is unlikely that deficiency of these vitamins was the cause of neuropathy in these patients.
Although the pathogenesis of neuropathy in alcoholics is debated, the clinical setting is characteristic in that other signs and symptoms of alcoholism are generally present, including chronic liver disease, memory impairment, and ataxia of gait. Estimates of ethanol intake are notoriously unreliable, but in the Danish study, neuropathy developed only in patients who consumed 3 L of beer or 300 ml of spirits daily for at least 3 years. An important corollary of these observations is that in a patient with neuropathy who drinks moderately, is well nourished, and is free of signs of chronic liver disease, alcoholic neuropathy is unlikely; therefore, in such a patient, other causes of neuropathy should be sought.
Treatment of alcoholic neuropathy is simple in principle but difficult in practice. Ethanol ingestion must be stopped and adequate nutrition ensured. If such measures can be achieved, gradual improvement can be expected, although it may take months and be incomplete.
Nutritional deficiencies Polyneuropathy can be a manifestation of starvation, as seen in famine victims or in prisoners of war. The precise dietary components responsible for neuropathy in starvation are unclear, although one or more B vitamins are assumed to be critical. Certain vitamin deficiencies can cause neuropathy in specific situations, but there is no physiologic basis for routinely prescribing multivitamins for neuropathy in patients with normal diets.
Thiamine (vitamin B1) deficiency produces beriberi, the main features of which are polyneuropathy and cardiac failure. The neuropathy is distal and axonal, with painful sensory symptoms. With progression, distal weakness may develop. Cranial nerve involvement was described in older accounts of beriberi.
Pyridoxine (vitamin B6) deficiency is responsible for the neuropathy caused by isoniazid, which increases excretion of pyri-doxine. Administration of pyridoxine with isoniazid prevents the neuropathy. However, excessive doses of pyridoxine (a fad in the 1970s) produce a severe sensory neuronopathy.
A mild polyneuropathy may be part of the neurologic syndrome produced by cobalamin (vitamin B12) deficiency. However, vitamin B12 deficiency probably does not present as poly- neuropathy alone; the main clinical features are the result of myelopathy (subacute combined degeneration).
Vitamin E deficiency from malabsorption may result in an ataxic syndrome caused by degeneration of the peripheral and central processes of dorsal root ganglia neurons. Cerebellar involvement may be present in some patients.
Polyneuropathies Caused by Infectious Diseases
Leprosy Leprosy, a mycobacterial infectious disease of peripheral nerves, is probably the most common cause of polyneu-ropathy in the world [see 7:II Infections Due to Mycobacteria]. Most cases occur in tropical and subtropical regions, although there are endemic foci along the Gulf Coast of Florida and Louisiana. Most patients with leprosy in North America and Europe are immigrants from countries where leprosy is common.
Sensory loss is the cardinal symptom of leprosy. It is often discovered because of a painless injury. Because of the temperature requirements of Mycobacterium leprae, cutaneous sensory and mixed nerves in parts of the body with low ambient temperature are most likely to be affected. The result is a distribution of signs unlike those of any other polyneuropathy, with sensory loss over the external ears, the zygomatic arches, and extensor surfaces of joints. Major nerves are most likely to be affected where they travel close to the surface (e.g., the ulnar nerve at the elbow). Involvement of cutaneous nerves is generally sharply demarcated, especially in the tuberculoid form of leprosy, and the overlying dermis and epidermis are affected, producing the classic anesthetic macule. Motor weakness does not occur until sensory loss is well established. Weakness is usually patchy and asymmetrical and may suggest other causes of multiple mononeuropathies. The diagnosis of leprosy is made by nerve or skin biopsy, using the Fite method to stain and identify M. leprae.
Leprosy is a curable disease. The degree of recovery in advanced cases may be limited, so it is important that the disease be diagnosed and treated before major neuropathic deficits develop [see 7:II Infections Due to Mycobacteria].
HIV infection Several PNS disorders occur in patients with HIV infection, some in the early stages of infection and some only after progression to AIDS [see 7:XXXIII HIV and AIDS]. Distal, painful neuropathy is very common in patients with AIDS. The main symptom is continuous burning discomfort, mostly in the feet, where some degree of sensory loss is apparent. Motor involvement is usually minor, although the patients are often debilitated by concomitant infections and weight loss. The cause is sometimes identifiable—for example, vitamin B12 deficiency or treatment with a retroviral agent known to be neu-rotoxic (e.g., 2,3-dideoxycytidine or zalcitabine)54—but the cause in some patients remains unclear. The HIV genome has been detected in dorsal root ganglia neurons and satellite cells in patients with AIDS and neuropathy,55 and expression of the HIV genome in transgenic mice produces peripheral nerve disease.56 Whether neuropathy in humans with HIV is actually caused by direct infection of nerves by HIV remains to be proved.
Neuropathy is a frequent dose-limiting side effect of nucleo-side analogue antiretrovirals (e.g., zalcitabine), but fortunately, neither zidovudine (AZT) nor the protease inhibitors appear to cause neuropathy. In a phase II trial, nerve growth factor, compared with placebo, reduced neuropathic pain in HIV-infected patients who had distal sensory neuropathy, although injection-site pain produced impaired masking in a substantial portion of treated patients.57
GBS and CIDP typically occur early in the course of HIV infection. They may be the presenting features of HIV infection, and HIV testing should be considered in patients with GBS or CIDP. The neurologic picture and response to treatment in patients with HIV are similar to those in non-HIV-infected patients, except that there is usually a lymphocytic pleocytosis in the CSF.
A syndrome of multiple mononeuropathies may occur in HIV-positive patients. Nerve biopsy may show perivascular inflammatory infiltrates, necrotizing vasculitis, or cytomegalovirus (CMV) inclusions. Patients with evidence of CMV infection may respond to ganciclovir58 [see 7:XXVI Herpesvirus Infections]. Patients with HIV infection that is complicated by the diffuse in-filtrative lymphocytosis syndrome may experience a subacute axonal neuropathy; nerve biopsies in these patients have shown striking perivascular CD8+ lymphocyte infiltrates, and the neuropathy seems to abate with corticosteroids or zidovudine.
Acute lumbosacral polyradiculopathy is a devastating syndrome of leg weakness, leg and perineal sensory loss, and urinary retention that develops over 1 to 2 weeks, usually in patients with advanced AIDS. The CSF shows a distinctive poly-morphonuclear pleocytosis. In most cases, there is evidence of concomitant CMV infection, and the neurologic picture is caused by invasion of lumbosacral nerve roots by CMV. Prompt diagnosis and treatment with ganciclovir may produce improvement [see 7:XXVI Herpesvirus Infections]. A similar picture may be produced by lymphoma.60
Lyme disease Lyme disease is caused by the spirochete Bor-relia burgdorferi, which is transmitted to humans by ixodid ticks. The disease occurs worldwide but is most common in the northeastern United States and northern Europe [see 7:VII Leptospirosis, Relapsing Fever, Rat-Bite Fever, and Lyme Disease]. Peripheral neuropathy may occur in early or late disseminated Lyme disease. It is unclear whether the neurologic manifestations are caused directly by spirochetal invasion of nerve tissue or by the host’s immune response to the organism.
The main early neurologic features are cranial neuropathies, spinal radiculopathies, or both.61 Headache and neck stiffness may accompany the peripheral nerve symptoms, reflecting meningeal inflammation. Facial neuropathy is the most common cranial neuropathy, and a misdiagnosis of Bell palsy is often made. However, unlike in idiopathic Bell palsy, bilateral facial neuropathy is common in Lyme disease. Other cranial neuropathies occur less often.
Spinal nerve root involvement typically begins with pain in a radicular distribution, followed by weakness in 1 to 4 weeks. The weakness is often asymmetrical and patchy, resembling multiple mononeuropathies. In addition to the predominant radicular signs, there is frequently electrophysiologic evidence of a mild widespread polyneuropathy. Both cranial and spinal neuropathies in early-stage Lyme disease have a favorable natural history, with recovery in weeks to months. Treatment with antibiotics may hasten recovery.
In late-stage Lyme disease, patients may experience either a mild distal polyneuropathy or radicular pain with sensory signs. Many of these patients will have had previous symptoms of localized or early disseminated disease. Unlike cranial neuropathy and radiculoneuropathy of early-stage disease, the peripheral neuropathy of late-stage disease tends not to resolve without treatment.
The diagnosis of Lyme neuropathy rests on a history of possible tick exposure, compatible symptoms and signs, and positive serologic testing for B. burgdorferi. In early-stage disease, neurologic involvement is almost always accompanied by a lympho-cytic CSF pleocytosis, but in late-stage disease, pleocytosis is exceptional and the CSF may be normal. Sural nerve biopsy in early- or late-stage disease shows axonal degeneration and perivas-cular inflammatory infiltrates, but these findings are nonspecific. Particularly in late-stage disease, response to a course of antibiotics may provide the most convincing evidence of the diagnosis [see 7:VII Leptospirosis, Relapsing Fever, Rat-Bite Fever, and Lyme Disease].
Varicella-zoster virus infection Varicella-zoster virus (VZV), a member of the human herpesvirus family, is the most common viral pathogen in the PNS [see 7:XXVI Herpesvirus Infections]. After initial VZV infection, which usually occurs during childhood in the form of varicella (chickenpox), some VZV virions may enter cutaneous sensory axons and are carried by retrograde axon-al transport to sensory neuron cell bodies in the dorsal root or cranial ganglia, where they remain in an inactive form.
Years later, the virus can return to an active, proliferative state because of alterations in immune function that are incompletely understood. The cytopathic effects of VZV replication and the ensuing immune response produce an intense inflammatory necrot-ic ganglionitis, resulting in dermatomal sensory alteration, pain, and the dermatomal vesicular skin rash known as herpes zoster.
Herpes zoster is most common in persons older than 60 years, although it also occurs in younger persons. The incidence is much higher in immunocompromised patients, in whom there is also a risk of disseminated VZV infection, which has considerable mortality. Herpes zoster is usually unilateral, involving one to three adjacent dermatomes. Thoracic and trigeminal (especially ophthalmic) dermatomes are most often affected.
The initial symptom is dermatomal pain, followed in 3 to 7 days by the vesicular eruption. Sensory loss is difficult to demonstrate until the skin lesions begin to heal. Motor weakness is reported in as many as 30% of patients but may not be noticed by a patient distracted by pain. The cutaneous lesions persist for 7 to 10 days and then resolve, often leaving depigmented areas and scarring. Motor weakness can be expected to improve spontaneously in most patients. Pain also improves slowly, except in patients who experience postherpetic neuralgia (PHN).
PHN is usually defined as pain persisting more than 4 to 8 weeks after healing of the skin lesions. The risk of PHN after an episode of herpes zoster increases with age, reaching as high as 45% in patients older than 65 years. Patients with PHN experience a continuous burning dermatomal pain, on which brief, lancinating pains may be superimposed. Often, there is also allo-dynia in the affected dermatome, so that the touch of clothes or even hair may cause excruciating pain. Some patients with PHN experience gradual improvement over weeks to months, but persistence of symptoms for years is not unusual. Prevention of PHN is probably the main rationale for using antiviral agents in an immunocompetent patient. A large placebo-controlled trial of famciclovir showed a clear reduction in the incidence of PHN, especially in the elderly.62 It is assumed that acyclovir offers a similar benefit, but this assumption is unproved. In one study, the addition of prednisolone to 7- or 21-day courses of acyclovir did not alter the frequency of PHN,63 although glucocorticoids may reduce acute-phase pain.
PHN presents a formidable therapeutic challenge. Amitripty-line or other tricyclic medications have been the usual first-line agents, but gabapentin is being increasingly used and was shown to be superior to placebo in a controlled trial.64 Lancinating pain may be reduced by carbamazepine or other anticonvul-sants. Topical application of local anesthetics and long-term use of opioids are advocated by some clinicians.
