+++
IDIOPATHIC INFLAMMATORY NEUROPATHIES
+++
ACUTE IDIOPATHIC POLYNEUROPATHY (GUILLAIN–BARRÉ SYNDROME)
++
Guillain–Barré syndrome is an acute or subacute polyneuropathy that can follow minor infective illnesses, inoculations, or surgical procedures or may occur without obvious precipitants. Clinical and epidemiologic evidence suggests an association with preceding Campylobacter jejuni infection. It may also occur in association with Zika virus infection. Its precise cause is unclear, but an immunologic basis is likely. Both demyelinating and axonal forms occur, with distinctive clinical and electrophysiologic features. The demyelinative form is more common in the United States, but an axonal variant is encountered occasionally (acute motor sensory axonal neuropathy). In northern China, a related axonal form occurs frequently (acute motor axonal neuropathy or AMAN). The axonal variants are caused by antibodies to gangliosides on the axon membrane, including anti-GM1, anti-GM1b, anti-GD1a, anti-GD1b, and (in AMAN) anti-GalNAC-GD1a antibodies. The Miller Fisher syndrome, another subtype, is characterized by ophthalmoplegia, ataxia, and areflexia, and is associated with anti-GQ1b antibodies (see Chapter 8, Disorders of Equilibrium); it is sometimes associated with a brainstem encephalitis (Bickerstaff encephalitis).
++
Diagnostic features are summarized in Table 10-3. Patients commonly present with ascending weakness that is symmetric, usually begins in the legs, is often more marked proximally than distally, and may be life-threatening, especially if the muscles of respiration or swallowing are involved. Some patients present instead with weakness about the bulbar, neck, and shoulder muscles, or with an acute pandysautonomia. Muscle wasting develops if axonal degeneration has occurred. Sensory complaints, although usually less marked than motor symptoms, are also frequent. The deep tendon reflexes are typically absent. There may be marked autonomic dysfunction, with tachycardia, cardiac irregularities, labile blood pressure, disturbed sweating, impaired pulmonary function, sphincter disturbances, paralytic ileus, and other abnormalities.
++
+++
Investigative Studies
++
The cerebrospinal fluid (CSF) often shows an increased protein concentration but normal cell count (cytoalbuminologic dissociation), but abnormalities may not occur in the first week. Electrophysiologic studies may reveal marked slowing of motor and sensory conduction velocity or evidence of denervation and axonal loss. The time course of the electrophysiologic changes does not necessarily parallel any clinical developments. When HIV-1 infection is suspected because of the clinical context in which the neuropathy has developed, the presence of high-risk factors, or a CSF pleocytosis, appropriate serologic studies should be performed.
++
Plasmapheresis reduces the time required for recovery and may decrease the likelihood of residual neurologic deficits. It is best instituted early, and it is indicated especially in patients with a severe or rapidly progressive deficit or respiratory compromise. Intravenous immunoglobulin (400 mg/kg/d for 5 days) is equally effective and should be used in preference to plasmapheresis in adults with cardiovascular instability and in children; the two therapies are not additive.
++
Therapy is otherwise symptomatic, the aim being to prevent such complications as respiratory failure or vascular collapse. For this reason, patients who are severely affected are best managed in intensive care units, where facilities are available for monitoring and assisted respiration if necessary (eg, if the forced vital capacity reaches 15 mL/kg, the mean inspiratory force reaches –40 mm Hg, the patient is short of breath, or the blood oxygen saturation declines). Paroxysmal hypertension may necessitate treatment with labetalol or nitroprusside. Volume replacement or treatment with pressor agents is sometimes required to counter hypotension, and low-dose heparin may help to prevent pulmonary embolism. Cardiac arrhythmias are common and—depending on their nature—may require treatment. Corticosteroids may affect the outcome adversely or delay recovery, and are not indicated. Physical therapy and rehabilitation are important aspects of treatment.
++
Symptoms and signs cease to progress by approximately 4 weeks into the illness. The disorder is self-limiting, and improvement occurs over the weeks or months after onset. Approximately 70% of patients recover completely, 25% are left with mild neurologic deficits, and 5% die, usually as a result of respiratory failure. The prognosis is poorer when there is evidence of preceding Campylobacter jejuni infection, and a more protracted course and less complete recovery are also likely when axonal degeneration is the primary pathology. Advanced age, the need for ventilatory support, or more rapid onset of symptoms may also predict a poorer prognosis.
+++
CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY
++
Chronic inflammatory demyelinating polyneuropathy is clinically similar to Guillain–Barré syndrome except that it follows a chronic progressive course, or a course characterized by relapses, and no improvement is apparent within the 6 months after onset. Its cause is not known. Its clinical features are summarized in Table 10-4. It must be distinguished from certain hereditary demyelinating neuropathies, discussed later in this chapter.
++
++
Examination of the CSF reveals findings resembling those in Guillain–Barré syndrome: the protein is elevated while the white cell count is normal. The electrophysiologic findings indicate a demyelinative neuropathy with superimposed axonal degeneration. Laboratory studies may help to identify disorders causing neuropathy, such as diabetes.
++
The disorder is often responsive to treatment with corticosteroids (prednisone 60-100 mg/d for 2-4 weeks, then gradually tapered to 5-20 mg every other day), which may be required on a long-term basis. Treatment with intravenous immunoglobulin (1 g/kg daily for 2 days with a single additional infusion at 3 weeks, or 400 mg/kg/d for 5 consecutive days for a total of 2 g, with subsequent courses as needed to maintain benefit) is also effective as initial or later therapy. When used as initial therapy, it has the advantage of fewer side effects (but greater expense) than prednisone. Its precise mode of action is unknown. Plasma exchange is another effective immunomodulator therapy, but is more difficult to administer. In nonresponsive patients, treatment with methotrexate, azathioprine, or cyclophosphamide may be helpful, but claims of benefit from these agents or from cyclosporine, interferon-β, or interferon-α require confirmation by randomized trials.
+++
METABOLIC & NUTRITIONAL NEUROPATHIES
++
Peripheral nerve involvement in diabetes is common and may take several forms (Table 10-5), which can occur in isolation or in any combination. The incidence of peripheral nerve involvement may be influenced by the adequacy of diabetes control, which should, in any event, be optimized.
++
++
Distal polyneuropathy is the most common manifestation and may be mixed (sensory, motor, and autonomic; 70% of cases) or predominantly sensory (30%). Symptoms are generally more common in the legs than arms and consist of numbness, pain, or paresthesias. It may be diagnosed presymptomatically by the presence of depressed tendon reflexes and impaired appreciation of vibration in the legs. In severe cases, there is distal sensory loss in all limbs and some accompanying motor disturbance.
++
Diabetic dysautonomia leads to many symptoms, including postural hypotension, disturbances of cardiac rhythm, impaired thermoregulatory sweating, and disturbances of bladder, bowel, gastric, and sexual function.
++
Diabetic mononeuropathy multiplex is usually characterized by pain and weakness and often has a vascular basis. The clinical deficit depends on the nerves that are affected.
++
Diabetic amyotrophy is due to radiculoplexopathy, polyradiculopathy, or polyradiculoneuropathy. Pain, weakness, and atrophy of pelvic girdle and thigh muscles are typical, with absent quadriceps reflexes and little sensory loss.
++
Diabetic mononeuropathy simplex is typically abrupt in onset and often painful.
++
CSF protein concentration is typically increased in diabetic polyneuropathy and mononeuropathy multiplex.
+++
Treatment & Prognosis
++
No specific treatment exists for the peripheral nerve complications of diabetes except when the patient has an entrapment neuropathy and may benefit from a decompressive procedure. The treatment of pain or autonomic disturbances was outlined earlier. Diabetic amyotrophy usually improves spontaneously. It is important that the control of diabetes is optimized.
+++
OTHER ENDOCRINOPATHIES
++
Hypothyroidism is associated with entrapment neuropathy, especially carpal tunnel syndrome (median nerve entrapment; see later), but rarely causes a polyneuropathy. Polyneuropathy may be mistakenly diagnosed in patients with proximal limb weakness caused by hypothyroid myopathy or in patients with delayed relaxation of tendon reflexes, a classic manifestation of hypothyroidism that is independent of neuropathy. Other neurologic manifestations of hypothyroidism include an acute confusional state (see Chapter 4, Confusional States), dementia (see Chapter 5, Dementia & Amnestic Disorders), and cerebellar ataxia (see Chapter 8, Disorders of Equilibrium).
++
This also frequently produces carpal tunnel syndrome and, less often, polyneuropathy. Because many acromegalic patients are also diabetic, it may be difficult to determine which disorder is primarily responsible for polyneuropathy in a given patient.
++
A symmetric sensorimotor polyneuropathy, predominantly axonal in type, may occur in uremia. It affects the legs more than the arms, is more marked distally than proximally, and relates to the severity of impaired renal function. Restless legs, muscle cramps, and burning feet may be associated. The neuropathy may improve markedly with renal transplantation. Carpal tunnel syndrome (see later) may also occur with renal disease and may develop distal to the arteriovenous fistulas placed in the forearm for access during hemodialysis. In patients on chronic hemodialysis, it often relates to amyloidosis and the accumulation of β2-microglobulin.
++
Primary biliary cirrhosis may lead to a sensory neuropathy that is probably of the axonal type. A predominantly demyelinative polyneuropathy can occur with chronic liver disease. There does not appear to be any correlation between the neurologic findings and the severity of the hepatic dysfunction.
+++
VITAMIN B12 DEFICIENCY
++
Vitamin B12 deficiency is associated with symmetric distal sensory and mild motor impairment and loss of tendon reflexes. Because controversy exists about the relative importance of polyneuropathy and myelopathy in producing this syndrome, vitamin B12 deficiency is considered in more detail later, in the section on myelopathies. Polyradiculoneuropathy, polyneuropathy, and myelopathy may follow bariatric surgery and relate to nutritional deficiencies, including but not limited to vitamin B12.
+++
INFECTIVE & GRANULOMATOUS NEUROPATHIES
++
Neuropathy is a common complication of HIV-1 infection (Table 10-6); involvement of peripheral nerves is seen at autopsy in approximately 40% of patients with AIDS. It may be a consequence of HIV infection or of secondary infection with other organisms (eg, cytomegalovirus, varicella-zoster virus, Treponema pallidum), have an immunologic basis, or relate to nutritional deficiency or medication.
++
++
Distal symmetric sensorimotor or predominantly sensory polyneuropathy is the most common neuropathy associated with HIV-1 infection. Axons, rather than myelin, are primarily affected. The cause is unknown, but in some patients, vitamin B12 deficiency or exposure to neurotoxic drugs (which should be discontinued if possible) may be responsible in part. Other causes of neuropathy should be excluded. HIV-1 is rarely identified in the affected nerves. Sensory symptoms predominate and include pain and paresthesias affecting especially the feet. Weakness is a minor or late feature. Ankle and sometimes knee reflexes are absent. The course is typically progressive. Combination antiretroviral therapy (cART) may help in improving sensory function. Pain may be controlled pharmacologically, as described earlier. Plasmapheresis is of no benefit.
++
Inflammatory demyelinating polyneuropathy may occur early in HIV-1 infection and follow an acute course (symptoms reaching their nadir within 4 weeks) or, in patients with severe infection, a chronic course (progression for longer than 4 weeks). The neuropathy may be immune mediated, but sometimes results from direct, secondary viral infection, as from cytomegalovirus. It is characterized by proximal, and sometimes distal, weakness with less pronounced sensory disturbances, and areflexia or hyporeflexia. The CSF is abnormal, with an elevated protein concentration and often a lymphocytic pleocytosis (unlike the findings in Guillain–Barré syndrome or chronic inflammatory demyelinating polyneuropathy in patients without HIV-1 infection). Some patients improve spontaneously or stabilize, and others may respond to corticosteroids, plasmapheresis, or intravenous immunoglobulin.
++
Lumbosacral polyradiculopathy occurs late in the course of HIV-1 infection, usually in patients with prior opportunistic infections. Cytomegalovirus infection is the cause, at least in some instances. Clinical features usually develop over several weeks and include diffuse, progressive leg weakness, back pain, painful paresthesias of the feet and perineum, lower extremity areflexia, and early urinary retention. The course may be fulminant, with ascending paralysis leading to respiratory failure, but is sometimes more benign, especially when the etiology is unclear. CSF findings include mononuclear or polymorphonuclear pleocytosis, elevated protein concentration, and decreased glucose level; a positive test for cytomegalovirus by polymerase chain reaction provides further support. It is always important to exclude meningeal lymphomatosis, cord compression, or syphilis as the underlying cause, as these require specific treatment and affect the prognosis. Patients with cytomegalovirus infection may respond to ganciclovir 2.5 mg/kg intravenously every 8 hours for 10 days, then 7.5 mg/kg/d 5 d/wk. An alternative approach is with foscarnet; in severe cases, both drugs are given. Some worsening in the first 2 weeks of ganciclovir therapy does not indicate treatment failure. The CSF should be re-examined after 3 weeks to determine whether the polymorphonuclear cell count has declined; if it has not, foscarnet should replace ganciclovir.
++
Mononeuropathy multiplex affects multiple cranial and peripheral nerves, resulting in focal weakness and sensory loss. This may have an autoimmune basis or neoplastic or infectious causes (eg, cytomegalovirus infection), or result from vasculopathy. In early HIV-1 infection, mononeuropathy multiplex may be a self-limited disorder restricted to a single limb, with spontaneous stabilization or improvement. Late in AIDS, several limbs may be affected in a progressive fashion.
++
Mononeuropathy simplex tends to occur acutely in early HIV-1 infection and improve spontaneously. It may present as unilateral or bilateral facial palsy. A vascular cause is probable.
++
Autonomic neuropathy tends to occur late in HIV-1 infections and may lead to syncopal episodes, orthostatic hypotension, disturbances of sphincter or sexual function, impaired thermoregulatory sweating, and diarrhea. The dysautonomia may relate to central or peripheral pathology. Treatment is symptomatic (as discussed in an earlier section).
++
Medication-related neuropathy may result from treatment with the antiretroviral drugs zalcitabine (ddC), didanosine (ddI), and stavudine (d4T), after approximately 4 months unless other coexisting conditions make the patient more susceptible. It is an axonal sensory neuropathy, characterized by distal tingling, numbness, and pain. Other drugs that may be associated with a neuropathy in AIDS patients include isoniazid, ethambutol, vincristine, vinblastine, Taxol, thalidomide, and the statins.
++
Leprosy is one of the most frequent causes of peripheral neuropathy worldwide. In turn, neuropathy is the most disabling manifestation of leprosy. Mycobacterium leprae affects the skin and peripheral nerves because its growth is facilitated by the cooler temperatures present at the body surface.
++
In tuberculoid leprosy, the immune response is adequate to confine the infection to one or more small patches of skin and their associated cutaneous and subcutaneous nerves. This produces a hypopigmented macule or papule over which sensation is impaired; pain and temperature appreciation are most affected. Anhidrosis occurs with involvement of autonomic fibers. Sensory deficits occur most often in the distribution of the digital, sural, radial, and posterior auricular nerves, whereas motor findings usually relate to involvement of the ulnar or fibular (peroneal) nerve. Involved nerves are often enlarged.
++
Lepromatous leprosy is a more widespread disorder that results in a symmetric, primarily sensory polyneuropathy that disproportionately affects pain and temperature sense. Its distribution is distinctive in that exposed areas of the body—especially the ears; nose; cheeks; dorsal surfaces of the hands, forearms, and feet; and lateral aspects of the legs—are preferentially involved. Unlike most polyneuropathies, that caused by leprosy tends to spare the tendon reflexes. Associated findings include resorption of the digits, trophic ulcers, and cyanosis and anhidrosis of the hands and feet.
++
Treatment depends on the type of leprosy, but typically involves dapsone, rifampicin, and clofazimine. The most recent guidelines of the World Health Organization (http://www.who.int/lep/mdt/regimens/en/index.html) should be followed. In the United States, further information can be obtained from the National Hansen’s Disease Program of the US Department of Health and Human Services (http://www.hrsa.gov/hansensdisease/).
++
Corynebacterium diphtheriae infects tissues of the upper respiratory tract and produces a toxin that causes demyelination of peripheral nerves. Within approximately 1 month after infection, patients may develop a cranial motor neuropathy with prominent impairment of ocular accommodation. Blurred vision is the usual presenting complaint. Extraocular muscles and the face, palate, pharynx, and diaphragm may also be affected, but the pupillary light reflex is preserved. Recovery typically occurs after several weeks. A more delayed syndrome that commonly has its onset 2 to 3 months after the primary infection takes the form of a symmetric distal sensorimotor polyneuropathy. Most patients recover completely. Diphtheritic neuropathy is discussed in more detail in Chapter 9, Motor Disorders.
++
Sarcoidosis can produce mononeuropathy or, rarely, polyneuropathy. The mononeuropathy commonly involves cranial nerves, especially the facial nerve. In some instances, a small-fiber neuropathy leads to pain, dysesthesias, and autonomic involvement. Clinical evaluation for extraneural disease, x-rays of the lungs and bones, examination of the CSF, and determination of serum levels of angiotensin-converting enzyme are helpful in establishing the diagnosis of sarcoidosis. Treatment with prednisone, 60 mg/d orally followed by tapering doses, may speed recovery.
+++
SEPSIS & MULTIORGAN FAILURE
++
Patients with sepsis and multiorgan failure may develop a critical illness polyneuropathy. This manifests primarily by weakness and is therefore discussed in Chapter 9, Motor Disorders.
+++
NEUROPATHIES IN VASCULITIS & COLLAGEN VASCULAR DISEASE
++
Systemic vasculitides and collagen vascular diseases can produce polyneuropathy, mononeuropathy simplex, mononeuropathy multiplex, or entrapment neuropathy (Table 10-7).
++
+++
SYSTEMIC NECROTIZING VASCULITIS
++
This includes polyarteritis nodosa and allergic angiitis and granulomatosis (Churg–Strauss syndrome). Neuropathy occurs in approximately 50% of patients, most often as mononeuropathy multiplex, which may manifest with pain of acute onset in one or more cranial or peripheral nerves. Distal symmetric sensorimotor polyneuropathy is less common. Treatment should begin as soon as the diagnosis is made; it includes prednisone 60 to 100 mg/d orally and cyclophosphamide 2 to 3 mg/d orally.
+++
GRANULOMATOSIS WITH POLYANGIITIS (WEGENER GRANULOMATOSIS)
++
Mononeuropathy multiplex or polyneuropathy occurs in up to 30% of cases. Treatment is the same as for systemic necrotizing vasculitis.
++
This disorder is considered in detail in Chapter 6, Headache & Facial Pain. Mononeuropathy affecting cranial nerves innervating the extraocular muscles can occur.
++
Rheumatoid arthritis produces entrapment neuropathy (most commonly involving the median nerve) in approximately 45% of patients and distal symmetric sensorimotor polyneuropathy in about 30%. Mononeuropathy multiplex is a frequent feature in cases complicated by necrotizing vasculitis.
+++
SYSTEMIC LUPUS ERYTHEMATOSUS
++
This is discussed in Chapter 4, Confusional States, as a cause of acute confusional states. Neuropathy occurs in up to 20% of patients. The most common pattern is a distal, symmetric sensorimotor polyneuropathy. An ascending, predominantly motor polyneuropathy (Guillain–Barré syndrome, see earlier) can also occur, as may mononeuropathy simplex or multiplex, which often affects the ulnar, radial, sciatic, or fibular (peroneal) nerve.
++
Sjögren syndrome involves the peripheral nerves in approximately 20% of cases. Distal symmetric sensorimotor polyneuropathy is most common, entrapment neuropathy (affecting especially the median nerve) is also frequent, and mononeuropathy multiplex can occur.
+++
SCLERODERMA & MIXED CONNECTIVE-TISSUE DISEASE
++
Progressive systemic sclerosis (scleroderma) and mixed connective-tissue disease may produce cranial mononeuropathy, which most often involves the trigeminal (V) nerve.
+++
NEOPLASTIC & PARAPROTEINEMIC NEUROPATHIES
+++
COMPRESSION & INFILTRATION BY TUMOR
++
Nerve compression is a common complication of multiple myeloma, lymphoma, and carcinoma. Tumorous invasion of the epineurium may occur with leukemia, lymphoma, and various cancers, particularly carcinoma of the breast or pancreas.
+++
PARANEOPLASTIC SYNDROMES
++
Carcinoma (especially small-cell cancer of the lung) and lymphoma may be associated with neuropathies that are thought to be immunologically mediated, based on the detection of autoantibodies to neuronal antigens in several cases.
+++
Sensory or Sensorimotor Polyneuropathy
++
This occurs with both carcinoma and lymphoma. It can be either an acute or chronic disorder, is sometimes asymmetric, and may be accompanied by prominent pain. The CSF is typically acellular but protein concentration may be mildly elevated. Among patients with a chronic sensorimotor polyneuropathy of uncertain cause, approximately 10% have a monoclonal gammopathy; many such patients eventually develop a hematologic malignancy, as discussed later. Treatment of the malignancy may improve the neuropathy.
++
Carcinoma can also cause sensory neuronopathy, which primarily affects the cell bodies of sensory neurons in the dorsal root ganglion and is associated with the presence of anti-Hu (or ANNA-1) antibodies (see Chapter 8, Disorders of Equilibrium). This rare condition may be the presenting manifestation of cancer. Initial symptoms of pain and numbness usually begin distally but sometimes begin proximally or in the face. The disorders often progress over days or several weeks, leading to marked sensory ataxia and impairment of all sensory modalities. Motor involvement is late, and autonomic dysfunction is uncommon. The CSF may have an inflammatory formula. Treatment of the underlying tumor is usually unrewarding.
+++
Motor Neuronopathy, Guillain–Barré Syndrome, & Other Motor Disorders
++
Lymphoma may be complicated by motor neuronopathy, a disorder of anterior horn cells. Hodgkin disease and angioimmunoblastic lymphadenopathy are sometimes associated with Guillain–Barré syndrome, which responds to treatment as in patients without malignancy. These and other paraneoplastic motor disorders (including the Lambert–Eaton myasthenic syndrome, neuromyotonia, and stiff-person syndrome) are discussed in Chapter 9, Motor Disorders.
++
An autonomic neuropathy may occur as a paraneoplastic disorder, especially in patients with small-cell lung cancer. It relates most often to anti-Hu antibodies but may also occur with an antibody against ganglionic acetylcholine receptors (anti-nAChR). It is underdiagnosed, often develops in the setting of other paraneoplastic syndromes, and has a poor prognosis. Symptoms may include hypotension, orthostatic hypotension, hypoventilation, abnormal thermoregulatory sweating, sleep apnea, gastroparesis, intestinal pseudo-obstruction, and cardiac arrhythmias, sometimes leading to sudden death. Affected patients do not improve with immunotherapy even after treatment of the underlying tumor.
++
Patients with paraproteinemic demyelinating neuropathy, especially a chronic distal sensory neuropathy, may have a malignant plasma cell dyscrasia. The paraprotein is likely to underlie the neuropathy when it is an immunoglobulin (Ig)M. When it is IgG or IgA, the neuropathy may be clinically and electrophysiologically indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy and similar in its response to treatment.
++
Polyneuropathy is a common complication of multiple myeloma. Patients affected by lytic myeloma are usually men. The clinical picture is of a distal symmetric sensorimotor polyneuropathy. All sensory modalities are affected, pain is a frequent feature, and the reflexes are depressed. The disorder is usually progressive and leads to death within 2 years.
++
Sclerotic myeloma may be accompanied by a chronic demyelinating polyneuropathy. Motor involvement predominates, but vibration and position sense may also be impaired, and the reflexes are depressed. Pain is less common than in the neuropathy of lytic myeloma, and symptoms may improve with treatment of the underlying cancer or by plasmapheresis.
++
The POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) may complicate plasma cell dyscrasias, especially osteosclerotic myeloma. The sensorimotor polyneuropathy may show certain distinctive electrophysiologic features, such as conduction slowing that is more marked in intermediate than distal nerve segments, and often responds to treatment. Local irradiation or resection of an isolated plasmacytoma should be considered, as should melphalan with or without corticosteroids.
++
A sensorimotor polyneuropathy similar to that observed with lytic myeloma may also occur in Waldenström macroglobulinemia or benign monoclonal gammopathy. Treatment with immunosuppressant drugs and plasmapheresis is sometimes helpful.
++
Nonhereditary amyloidosis occurs as an isolated disorder (primary generalized amyloidosis) or in patients with multiple myeloma and may be associated with polyneuropathy. Polyneuropathy is also a feature of hereditary amyloidosis. Amyloid neuropathies are considered later in the section on hereditary neuropathies.
+++
DRUG-INDUCED & TOXIC NEUROPATHIES
++
Polyneuropathy is one of the most common neurologic complications of chronic alcoholism; it can occur alone or in combination with other alcohol-related neurologic disorders, such as Wernicke encephalopathy (see Chapter 4, Confusional States) or the Korsakoff amnestic syndrome (see Chapter 5, Dementia & Amnestic Disorders). Controversy exists concerning the relative contributions of direct neurotoxicity of alcohol and associated nutritional (especially thiamine) deficiency in producing polyneuropathy.
++
Alcoholic polyneuropathy is typically a symmetric distal sensorimotor neuropathy. The legs are most affected, resulting in defective perception of vibration and touch and depressed or absent ankle reflexes. In some cases, distal weakness is pronounced, and autonomic dysfunction may occur. When pain occurs, it may respond to the treatment described earlier for painful neuropathy.
++
Abstinence from alcohol and thiamine repletion can halt the progression of symptoms.
++
As indicated in Table 10-2, a large number of drugs may cause neuropathies and most merit no additional comment here. With regard to isoniazid, a widely used antituberculous agent that interferes with pyridoxine metabolism, the polyneuropathy principally affects the sensory neurons. High doses, hereditary variations in drug metabolism, and malnutrition predispose to this complication. Spontaneous improvement occurs when administration of the drug is halted. Isoniazid-induced neuropathy can be prevented by concurrent administration of pyridoxine 100 mg/d orally.
++
Pyridoxine (vitamin B6) toxicity may cause a sensory neuronopathy that disproportionately impairs vibration and position sense. This disorder usually occurs in patients taking at least 200 mg of pyridoxine daily—approximately 100 times the minimum daily requirement. Sensory ataxia, Romberg sign, Lhermitte sign, and ankle areflexia are common findings. Pain is less common, and motor involvement is unusual. Symptoms are usually reversible over months to years if the abuse ceases, but an irreversible syndrome has also been reported after intravenous administration of high doses of pyridoxine.
++
Organic compounds implicated as causes of polyneuropathy include hexacarbons present in solvents and glues (eg, n-hexane, methyl n-butyl ketone) and organophosphates used as plasticizers or insecticides (eg, triorthocresyl phosphate). Sensory involvement is most striking in n-hexane neuropathy, whereas neuropathy caused by triorthocresyl phosphate primarily affects motor nerves. Organophosphate neuropathy is discussed in more detail in Chapter 9, Motor Disorders.
++
Heavy metals may also be responsible for polyneuropathy. Neuropathy caused by lead, arsenic, and thallium is discussed in Chapter 9, Motor Disorders. Gold, which is used to treat rheumatoid arthritis, may cause a symmetric polyneuropathy, and cisplatin (a platinum analogue with anticancer activity) may produce a sensory neuropathy.
+++
HEREDITARY NEUROPATHIES
+++
HEREDITARY MOTOR & SENSORY NEUROPATHIES
++
These are designated Charcot–Marie–Tooth (CMT) hereditary neuropathies. They constitute a genetically heterogeneous group of disorders having a similar clinical phenotype. There is weakness and wasting of distal muscles in the limbs, with or without sensory loss; pes cavus and reduced or absent tendon reflexes also occur. They are divided into demyelinating (CMT-1) and neuronal (CMT-2) types, the latter sparing sensory neurons and resembling progressive spinal muscular atrophy (see Chapter 9, Motor Disorders). Both types have an autosomal dominant pattern of inheritance, although apparently sporadic cases occur.
++
CMT-1 has its onset in the first decade, follows a slowly progressive course, and is of variable severity. The nerves are often palpably thickened. Nerve conduction velocities are markedly reduced. CMT-1 is subdivided on the basis of the genetic findings, but the most common forms result from duplication of or mutations in the gene for peripheral myelin protein-22 (PMP22) in CMT1A or for myelin protein zero (MPZ) in CMT1B.
++
CMT-2 is generally less severe than CMT-1, is associated with normal or near-normal nerve conduction velocities, and does not cause nerve enlargement. The most common mutations are in the gene for mitofusin 2 (MFN2), but mutations in various other genes, including MPZ, have also been reported. X-linked dominant (CMT-X) and autosomal recessive (CMT-4) variants have been described.
++
Dejerine–Sottas disease (HMSN3; CMT-3) has its onset by 2 years of age with delayed motor milestones, is characterized by a severe sensorimotor neuropathy that frequently extends to the proximal muscles, and is associated with skeletal abnormalities such as scoliosis. There is severe demyelination of the nerves. It has autosomal recessive or dominant inheritance, and the responsible mutations involve the same genes associated with CMT-1.
+++
HEREDITARY SENSORY & AUTONOMIC NEUROPATHIES
++
These neuropathies also take a variety of forms. In hereditary sensory and autonomic neuropathy (HSAN) type I, there is dominant inheritance, a gradually progressive course from onset in early adulthood, and symmetric loss of distal pain and temperature perception, with relative preservation of light touch. Perforating ulcers over pressure points and painless infections of the extremities are common. The tendon reflexes are depressed, but there is little, if any, motor disturbance. This phenotype is associated with mutations in the genes coding for serine palmitoyltransferase long-chain subunits (SPTLC1 and SPTLC2), the GTPase atlastin family (ATL1 and ATL3), or DNA methyltransferase 1 (DNMT1).
++
In HSAN type II, inheritance is recessive, onset is in infancy or early childhood, progression is slow, all sensory modalities are affected, autonomic involvement is variable, and tendon reflexes are lost. Four subtypes are recognized. The affected genes are lysine-deficient protein kinase 1 (WNK1); family with sequence similarity 134, member B (FAM134B); kinesin family member 1A (KIF1A); and voltage-gated sodium channel type IX, alpha subunit (SCN9A).
++
HSAN type III (Riley–Day syndrome, familial dysautonomia) is a progressive recessive disorder that commences in infancy. It is characterized by conspicuous autonomic dysfunction (absent tearing, and labile temperature and blood pressure), absent taste sensation, impaired pain and temperature sensation, and areflexia. The disorder, which has an increased prevalence in persons of Ashkenazi Jewish origin, is linked to mutations in the gene for inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP).
++
HSAN type IV is associated with congenital insensitivity to pain and absent sweating and has been related to recessive mutations in the gene encoding a receptor tyrosine kinase for nerve growth factor (NTRK1). Many of these patients have cognitive dysfunction. Death from hyperpyrexia may occur.
++
HSAN type V resembles type IV, but cognitive abnormalities do not occur. The mutation is in the nerve growth factor β-subunit gene (NGFB).
++
Other, less common forms have also been described.
++
Polyneuropathy can occur in both hereditary and nonhereditary forms of amyloidosis. Because small-diameter sensory and autonomic nerve fibers are especially likely to be involved, pain and temperature sensation and autonomic functions are prominently affected. Clinical presentation is commonly with distal paresthesias, dysesthesias, and numbness; postural hypotension; impaired thermoregulatory sweating; and disturbances of bladder, bowel, or sexual function. Distal weakness and wasting eventually occur. The tendon reflexes are often preserved until a relatively late stage. Entrapment neuropathy, especially carpal tunnel syndrome, may develop as a consequence of amyloid deposits.
++
In primary amyloidosis, the diagnosis is made by identifying amyloid deposits in the tissues; examination of abdominal fat aspirate is usually the initial step. Treatment has included alkylating agents or autologous peripheral blood stem-cell transplantation. In hereditary (familial) amyloidosis, genetic testing for transthyretin (TTR) mutations is more useful for establishing the diagnosis than analysis of tissues for amyloid deposition. Treatment by orthotopic liver transplantation is effective.
++
Friedreich ataxia usually has an autosomal recessive mode of inheritance but occasionally occurs with dominant inheritance. It is usually caused by an expanded GAA trinucleotide repeat in a noncoding region of the gene for frataxin (FXN), a mitochondrial protein. An ataxic gait develops, followed by clumsiness of the hands and other signs of cerebellar dysfunction. Involvement of peripheral sensory fibers leads to sensory deficits of the limbs, with depressed or absent tendon reflexes. There may also be leg weakness and extensor plantar responses from central motor involvement. This condition is considered in detail in Chapter 8, Disorders of Equilibrium.
+++
HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES
++
This is a genetically heterogeneous disorder that relates most commonly to deletion in the peripheral myelin protein 22 (PMP22) gene. Inheritance is as an autosomal dominant trait with variable expression. Patients present with simple or multiple mononeuropathies that occur after mild pressure or stretch of nerves, and electrophysiologic studies reveal that abnormalities are more widespread than is evident clinically. Patients should be advised to avoid prolonged sitting with legs crossed or leaning on the elbows, and not to engage in activities involving repetitive movements of the wrist. Protective pads worn at the elbows or knees are sometimes worthwhile.
++
In acute intermittent porphyria, which is transmitted by recessive inheritance, the initial neurologic manifestation is often a polyneuropathy that usually involves motor more than sensory fibers. Sensory symptoms and signs may be predominantly proximal or distal. The peripheral nerves may also be affected in variegate porphyria. Neuropathy caused by porphyria is considered further in Chapter 9, Motor Disorders.
++
Two autosomal recessive lipidoses are associated with polyneuropathy with a typical onset in infancy or childhood. These are metachromatic leukodystrophy, which results from deficiency of the enzyme arylsulfatase A, and Krabbe disease, due to galactocerebroside β-galactosidase deficiency.
++
Lipoprotein deficiencies that cause polyneuropathy include abetalipoproteinemia, which is associated with acanthocytosis, malabsorption, retinitis pigmentosa, and cerebellar ataxia, and Tangier disease, which produces cataract, orange discoloration of the tonsils, and hepatosplenomegaly. These are autosomal recessive conditions.
++
Refsum disease (previously HMSN IV) is an autosomal recessive disorder related to impaired metabolism of phytanic acid, resulting from mutations in the PHYH gene (encoding phytanoyl-CoA hydroxylase) in 90% of cases and from mutations in the PEX7 gene (encoding the PTS2 receptor) in 10% or less of cases. The disorder is characterized by polyneuropathy, cerebellar ataxia, retinitis pigmentosa, and ichthyosis. Sensorineural deafness, anosmia, and cardiac arrhythmias may also occur. Treatment is by restricting dietary intake of phytol. Plasmapheresis to reduce body stores of phytanic acid may also help at the initiation of treatment, especially if there is acute weakness or a cardiac arrhythmia.
++
Fabry disease is an X-linked recessive disease caused by deficiency of the enzyme α-galactosidase-A, which leads to the accumulation of α-D-galactosyl moieties in different cells and tissues. This results in a painful sensory and autonomic (ie, a small-fiber) neuropathy, angiokeratomas, renal and cardiac disease, and an increased incidence of stroke. White matter lesions may be present on brain MRI. Multiple mutations of the α-galactosidase-A (GLA) gene have been found. The diagnosis can be confirmed in males by a low α-galactosidase-A activity in leukocytes or plasma. Mutation analysis is required for the diagnosis of female carriers.
++
Pharmacologic measures (discussed earlier) may be helpful in treating pain, especially treatment with gabapentin or amitriptyline. Enzyme replacement therapy with agalsidase β or α, a recombinant human α-galactosidase A enzyme, also merits consideration. It should probably be given to all hemizygous males with low or undetectable levels of α-galactosidase-A, regardless of whether clinical features of the disease are present, but there is no agreement about this. Enzyme replacement therapy is important in reducing pain and, once started, should be continued indefinitely; it may help to stabilize or improve cardiac and renal function, although this remains unclear. Antiplatelet agents help to prevent ischemic stroke, as discussed in Chapter 13, Stroke.