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InternalMed_Harrison. PPMS No therapies have been convincingly shown to modify the course of PPMS. A phase 3 clinical trial of glatiramer acetate in PPMS was stopped because of lack of efficacy. A phase 2/3 trial of the monoclonal antibody rituximab (anti-CD20) in PPMS was 2672 also negative, but in a preplanned secondary analysis, treatment appeared to modestly slow disability progression in patients with Gd-enhancing lesions at entry; the results of a follow-up trial with a fully humanized monoclonal anti-CD20 therapy (ocrelizumab) will soon be available. Azathioprine (2–3 mg/kg per day) has been used primarily in SPMS. Meta-analysis of published trials suggests that azathioprine is marginally effective at lowering relapse rates, although a benefit on disability progression has not been demonstrated.


InternalMed_Harrison

InternalMed_Harrison. Methotrexate (7.5–20 mg/week) was shown in one study to slow the progression of upper extremity dysfunction in SPMS. Because of the possibility of developing irreversible liver damage, some experts recommend a blind liver biopsy after 2 years of therapy. Cyclophosphamide (700 mg/m2, every other month) may be helpful for treatment-refractory patients who are (1) otherwise in good health, (2) ambulatory, and (3) <40 years of age. Because cyclophosphamide can be used for periods in excess of 3 years, it may be preferable to mitoxantrone in these circumstances. Intravenous immunoglobulin (IVIg), administered in monthly pulses (up to 1 g/kg) for up to 2 years, appears to reduce annual exacerbation rates. However, its use is limited because of its high cost, questions about optimal dose, and uncertainty about its having any impact on long-term disability. Methylprednisolone, administered in one study as monthly high-dose intravenous pulses, reduced disability progression (see above).


InternalMed_Harrison

InternalMed_Harrison. Methylprednisolone, administered in one study as monthly high-dose intravenous pulses, reduced disability progression (see above). Many purported treatments for MS have never been subjected to scientific scrutiny. These include dietary therapies (e.g., the Swank diet, in addition to others), megadose vitamins, calcium orotate, bee stings, cow colostrum, hyperbaric oxygen, procarin (a combination of histamine and caffeine), chelation, acupuncture, acupressure, various Chinese herbal remedies, and removal of mercury-amalgam tooth fillings, among many others. Patients should avoid costly or potentially hazardous unproven treatments. Many such treatments lack biologic plausibility. For example, no reliable case of mercury poisoning resembling typical MS has ever been described. Although potential roles for EBV, human herpesvirus (HHV) 6, or chlamydia have been suggested for MS, these reports are unconfirmed, and treatment with antiviral agents or antibiotics is not recommended.


InternalMed_Harrison

InternalMed_Harrison. Most recently, chronic cerebrospinal insufficiency (CCSVI) has been proposed as a cause of MS, and vascular-surgical intervention is recommended. However, the failure of independent investigators to even approximate the initial claims of 100% sensitivity and 100% specificity for the diagnostic procedure have raised considerable doubt that CCSVI is a real entity. Certainly, any potentially dangerous surgery should be avoided until more rigorous science is available.


InternalMed_Harrison

InternalMed_Harrison. For all patients, it is useful to encourage attention to a healthy lifestyle, including maintaining an optimistic outlook, a healthy diet, and regular exercise as tolerated (swimming is often well-tolerated because of the cooling effect of cold water). It is reasonable also to correct vitamin D deficiency with oral vitamin D and to recommend dietary supplementation with long-chain (omega-3) unsaturated fatty acids (present in oily fish such as salmon), because of their biologic plausibility for MS pathogenesis, safety, and general health benefits. Ataxia/tremor is often intractable. Clonazepam, 1.5–20 mg/d; primidone, 50–250 mg/d; propranolol, 40–200 mg/d; or ondansetron, 8–16 mg/d, may help. Wrist weights occasionally reduce tremor in the arm or hand. Thalamotomy or deep-brain stimulation has been tried with mixed success.


InternalMed_Harrison

InternalMed_Harrison. Spasticity and spasms may improve with physical therapy, regular exercise, and stretching. Avoidance of triggers (e.g., infections, fecal impactions, bed sores) is extremely important. Effective medications include baclofen (20–120 mg/d), diazepam (2–40 mg/d), tizanidine (8–32 mg/d), dantrolene (25–400 mg/d), and cyclobenzaprine hydrochloride (10–60 mg/d). For severe spasticity, a baclofen pump (delivering medication directly into the CSF) can provide substantial relief.


InternalMed_Harrison

InternalMed_Harrison. Weakness can sometimes be improved with the use of potassium channel blockers such as 4-aminopyridine (10–40 mg/d) and 3,4-diaminopyridine (40–80 mg/d), particularly in the setting where lower extremity weakness interferes with the patient’s ability to ambulate. The FDA has approved 4-aminopyridine (at 20 mg/d), and this can be obtained either as dalfampridine (Ampyra) or, more cheaply, through a compounding pharmacy. The principle concern with the use of these agents is the possibility of inducing seizures at high doses. Pain is treated with anticonvulsants (carbamazepine, 100–1000 mg/d; phenytoin, 300–600 mg/d; gabapentin, 300–3600 mg/d; or pregabalin, 50–300 mg/d), antidepressants (amitriptyline, 25–150 mg/d; nortriptyline, 25–150 mg/d; desipramine, 100–300 mg/d; or venlafaxine, 75–225 mg/d), or antiarrhythmics (mexiletine, 300–900 mg/d). If these approaches fail, patients should be referred to a comprehensive pain management program.


InternalMed_Harrison

InternalMed_Harrison. Bladder dysfunction management is best guided by urodynamic testing. Evening fluid restriction or frequent voluntary voiding may help detrusor hyperreflexia. If these methods fail, propantheline bromide (10–15 mg/d), oxybutynin (5–15 mg/d), hyoscyamine sulfate (0.5–0.75 mg/d), tolterodine tartrate (2–4 mg/d), or solifenacin (5–10 mg/d) may help. Coadministration of pseudoephedrine (30–60 mg) is sometimes beneficial. Detrusor/sphincter dyssynergia may respond to phenoxybenzamine (10–20 mg/d) or terazosin hydrochloride (1–20 mg/d). Loss of reflex bladder wall contraction may respond to bethanechol (30– 150 mg/d). However, both conditions often require catheterization.


InternalMed_Harrison

InternalMed_Harrison. Urinary tract infections should be treated promptly. Patients with large postvoid residual urine volumes are predisposed to infections. Prevention by urine acidification (with cranberry juice or vitamin C) inhibits some bacteria. Prophylactic administration of antibiotics is sometimes necessary but may lead to colonization by resistant organisms. Intermittent catheterization may help to prevent recurrent infections. Treatment of constipation includes high-fiber diets and fluids. Natural or other laxatives may help. Fecal incontinence may respond to a reduction in dietary fiber. Depression should be treated. Useful drugs include the selective serotonin reuptake inhibitors (fluoxetine, 20–80 mg/d, or sertraline, 50–200 mg/d), the tricyclic antidepressants (amitriptyline, 25–150 mg/d; nortriptyline, 25–150 mg/d; or desipramine, 100–300 mg/d), and the nontricyclic antidepressants (venlafaxine, 75–225 mg/d).


InternalMed_Harrison

InternalMed_Harrison. Fatigue may improve with assistive devices, help in the home, or successful management of spasticity. Patients with frequent nocturia may benefit from anticholinergic medication at bedtime. Primary MS fatigue may respond to amantadine (200 mg/d), methylphenidate (5–25 mg/d), or modafinil (100–400 mg/d). Cognitive problems may respond to the cholinesterase inhibitor donepezil hydrochloride (10 mg/d). Paroxysmal symptoms respond dramatically to low-dose anticonvulsants (acetazolamide, 200–600 mg/d; carbamazepine, 50–400 mg/d; phenytoin, 50–300 mg/d; or gabapentin, 600–1800 mg/d). Heat sensitivity may respond to heat avoidance, air-conditioning, or cooling garments.


InternalMed_Harrison

InternalMed_Harrison. Heat sensitivity may respond to heat avoidance, air-conditioning, or cooling garments. Sexual dysfunction may be helped by lubricants to aid in genital stimulation and sexual arousal. Management of pain, spasticity, fatigue, and bladder/bowel dysfunction may also help. Sildenafil (50–100 mg), tadalafil (5–20 mg), or vardenafil (5–20 mg), taken 1–2 h before sex, is now the standard treatment for maintaining erections. Numerous clinical trials are currently under way. These include studies on (1) monoclonal antibodies against CD20 to deplete B cells and against the IL-2 receptor; (2) selective oral sphingosine-1-phosphate receptor antagonists to sequester lymphocytes in secondary lymphoid organs; (3) estriol to induce a pregnancy-like state; (4) molecules to promote remyelination; and (4) bone marrow transplantation.


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InternalMed_Harrison. Acute MS (Marburg’s variant) is a fulminant demyelinating process that in some cases progresses inexorably to death within 1–2 years. Typically, there are no remissions. When acute MS presents as a solitary, usually cavitary, lesion, a brain tumor is often suspected. In such cases, a brain biopsy is usually required to establish the diagnosis. An antibody-mediated process appears to be responsible for most cases. Marburg’s variant does not seem to follow infection or vaccination, and it is unclear whether this syndrome represents an extreme form of MS or another disease altogether. No controlled trials of therapy exist; high-dose glucocorticoids, plasma exchange, and cyclophosphamide have been tried, with uncertain benefit.


InternalMed_Harrison

InternalMed_Harrison. Neuromyelitis optica (NMO; Devic’s disease) is an aggressive inflammatory disorder characterized by recurrent attacks of ON and myelitis (Table 458-7). NMO is more frequent in women than men (>3:1), typically begins in childhood or early adulthood but can arise at any age, and is uncommon in whites compared with individuals of Asian and African ancestry. Attacks of ON can be bilateral (rare in MS) or unilateral; myelitis can be severe and transverse (rare in MS) and is typically longitudinally extensive, involving three or more contiguous vertebral segments. Also in contrast to MS, progressive symptoms do not occur in NMO. The brain MRI was earlier thought to be normal in NMO, but it is now recognized that in approximately half of cases, there are lesions involving the hypothalamus causing an endocrinopathy; the lower brainstem presenting as intractable hiccoughs or vomiting from involvement of the area postrema in the lower medulla; or the cerebral hemispheres producing focal


InternalMed_Harrison

InternalMed_Harrison. causing an endocrinopathy; the lower brainstem presenting as intractable hiccoughs or vomiting from involvement of the area postrema in the lower medulla; or the cerebral hemispheres producing focal symptoms, encephalopathy, or seizures. Large MRI lesions in the cerebral hemispheres can be asymptomatic, sometimes have a “cloud-like” appearance and, unlike MS lesions, are often not destructive, and can resolve completely. Spinal cord MRI lesions typically consist of focal enhancing areas of swelling and tissue destruction, extending over three or more spinal cord segments, and on axial sequences, these are centered on the gray matter of the cord. CSF findings include pleocytosis greater than that observed in MS, with neutrophils and eosinophils present in some cases; OCBs are uncommon, occurring in fewer than 30% of NMO patients. The pathology of NMO is a distinctive astrocytopathy with inflammation, a loss of astrocytes, and an absence of staining of the water channel protein


InternalMed_Harrison

InternalMed_Harrison. occurring in fewer than 30% of NMO patients. The pathology of NMO is a distinctive astrocytopathy with inflammation, a loss of astrocytes, and an absence of staining of the water channel protein aquaporin-4 by immunohistochemistry, plus thickened blood vessel walls, demyelination, and deposition of antibody and complement.


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InternalMed_Harrison. NMO is best understood as a syndrome with diverse causes. Up to 40% of patients have a systemic autoimmune disorder, often systemic lupus erythematosus, Sjögren’s syndrome, perinuclear antineutrophil cytoplasmic antibody (p-ANCA)–associated vasculitis, myasthenia gravis, Hashimoto’s thyroiditis, or mixed connective tissue disease. In others, onset may be associated with acute infection with VZV, EBV, HIV, or tuberculosis. Rare cases appear to be paraneoplastic and Required: 1. 2. Supportive (2 of 3 criteria required): 1. 2. 3. Aquaporin-4 seropositivity Source: Adapted from DM Wingerchuk et al: Neurology 66:1485, 2006.


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InternalMed_Harrison. associated with breast, lung, or other cancers. NMO is often idio-2673 pathic, however. NMO is usually disabling over time; in one series, respiratory failure from cervical myelitis was present in one-third of patients, and 8 years after onset, 60% of patients were blind and more than half had permanent paralysis of one or more limbs. A highly specific autoantibody directed against aquaporin-4 is present in the sera of approximately two-thirds of patients with a clinical diagnosis of NMO. Seropositive patients have a very high risk for future relapses; more than half will relapse within 1 year if untreated. Aquaporin-4 is localized to the foot processes of astrocytes in close apposition to endothelial surfaces, as well as at paranodal regions near nodes of Ranvier. It is likely that aquaporin-4 antibodies are pathogenic, as passive transfer of antibodies from NMO patients into laboratory animals reproduce histologic features of the disease.


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InternalMed_Harrison. When MS affects individuals of African or Asian ancestry, there is a propensity for demyelinating lesions to involve predominantly the optic nerve and spinal cord, an MS subtype termed opticospinal MS. Interestingly, some individuals with opticospinal MS are seropositive for aquaporin-4 antibodies, suggesting that such cases represent an NMO spectrum disorder.


InternalMed_Harrison

InternalMed_Harrison. Disease-modifying therapies have not been rigorously studied in NMO. Acute attacks of NMO are usually treated with high-dose glucocorticoids (solumedrol 1–2 g/d for 5–10 days followed by a prednisone taper). Plasma exchange (typically 7 qod exchanges of 1.5 plasma volumes) has also been used empirically for acute episodes that fail to respond to glucocorticoids. Given the unfavorable natural history of untreated NMO, prophylaxis against relapses is recommended for most patients using one of the following regimens: mycophenylate mofetil (250 mg bid gradually increasing to 1000 mg bid); B cell depletion with anti-CD20 monoclonal antibody (rituximab); or a combination of glucocorticoids (500 mg IV methylprednisolone daily for 5 days; then oral prednisone 1 mg/kg per day for 2 months, followed by slow taper) plus azathioprine (2 mg/kg per day started on week 3). Available evidence suggests that use of IFN-β is ineffective and paradoxically may increase the risk of NMO relapses.


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InternalMed_Harrison. Acute disseminated encephalomyelitis (ADEM) has a monophasic course and is most frequently associated with an antecedent infection (postinfectious encephalomyelitis); approximately 5% of ADEM cases follow immunization (postvaccinal encephalomyelitis). ADEM is far more common in children than adults, and many adult cases initially thought to represent ADEM subsequently experience late relapses qualifying as either MS or another chronic inflammatory disorder such as vasculitis, sarcoid, or lymphoma. The hallmark of ADEM is the presence of widely scattered small foci of perivenular inflammation and demyelination, in contrast to larger confluent demyelinating lesions typical of MS. In the most explosive form of ADEM, acute hemorrhagic leukoencephalitis, the lesions are vasculitic and hemorrhagic, and the clinical course is devastating.


InternalMed_Harrison

InternalMed_Harrison. Postinfectious encephalomyelitis is most frequently associated with the viral exanthems of childhood. Infection with measles virus is the most common antecedent (1 in 1000 cases). Worldwide, measles encephalomyelitis is still common, although use of the live measles vaccine has dramatically reduced its incidence in developed countries. An ADEM-like illness rarely follows vaccination with live measles vaccine (1–2 in 106 immunizations). ADEM is now most frequently associated with varicella (chickenpox) infections (1 in 4000–10,000 cases). It may also follow infection with rubella, mumps, influenza, parainfluenza, EBV, HHV-6, HIV, other viruses, and Mycoplasma pneumoniae. Some patients may have a nonspecific upper respiratory infection or no known antecedent illness. In addition to measles, postvaccinal encephalomyelitis may also follow the administration 2674 of vaccines for smallpox (5 cases per million), the Semple rabies, and with predominantly cerebral involvement, acute


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InternalMed_Harrison. measles, postvaccinal encephalomyelitis may also follow the administration 2674 of vaccines for smallpox (5 cases per million), the Semple rabies, and with predominantly cerebral involvement, acute encephalitis due to Japanese encephalitis. Modern vaccines that do not require viral cul-infection with herpes simplex or other viruses including HIV may beture in CNS tissue have reduced the ADEM risk. difficult to exclude (Chap. 164); other considerations include hyper-All forms of ADEM presumably result from a cross-reactive coagulable states including the antiphospholipid antibody syndrome,immune response to the infectious agent or vaccine that then triggers vasculitis, neurosarcoid, primary CNS lymphoma, or metastatic can-an inflammatory demyelinating response. Autoantibodies to MBP and cer. An explosive presentation of MS can mimic ADEM, and especially to other myelin antigens have been detected in the CSF from some in adults, it may not be possible to distinguish these conditions


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InternalMed_Harrison. cer. An explosive presentation of MS can mimic ADEM, and especially to other myelin antigens have been detected in the CSF from some in adults, it may not be possible to distinguish these conditions atpatients with ADEM. Attempts to demonstrate direct viral invasion of onset. The simultaneous onset of disseminated symptoms and signs isthe CNS have been unsuccessful. common in ADEM and rare in MS. Similarly, meningismus, drowsi ness, coma, and seizures suggest ADEM rather than MS. Unlike MS, CLINICAL MANIFESTATIONS in ADEM, optic nerve involvement is generally bilateral and transverse In severe cases, onset is abrupt and progression rapid (hours to days). myelopathy complete. MRI findings that favor ADEM include exten-In postinfectious ADEM, the neurologic syndrome generally begins sive and relatively symmetric white matter abnormalities, basal ganglialate in the course of the viral illness as the exanthem is fading. Fever or cortical gray matter lesions, and Gd enhancement of all


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InternalMed_Harrison. and relatively symmetric white matter abnormalities, basal ganglialate in the course of the viral illness as the exanthem is fading. Fever or cortical gray matter lesions, and Gd enhancement of all abnormalreappears, and headache, meningismus, and lethargy progressing to areas. By contrast, OCBs in the CSF are more common in MS. In onecoma may develop. Seizures are common. Signs of disseminated study of adult patients initially thought to have ADEM, 30% experineurologic disease are consistently present (e.g., hemiparesis or enced additional relapses over a follow-up period of 3 years, and they quadriparesis, extensor plantar responses, lost or hyperactive ten-were reclassified as having MS. Occasional patients with “recurrent don reflexes, sensory loss, and brainstem involvement). In ADEM ADEM” have also been reported, especially children; however, it is not due to chickenpox, cerebellar involvement is often conspicuous. possible to distinguish this entity from atypical MS. CSF


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InternalMed_Harrison. ADEM ADEM” have also been reported, especially children; however, it is not due to chickenpox, cerebellar involvement is often conspicuous. possible to distinguish this entity from atypical MS. CSF protein is modestly elevated (0.5–1.5 g/L [50–150 mg/dL]). Lymphocytic pleocytosis, generally 200 cells/μL or greater, occurs in 80% of patients. Occasional patients have higher counts or a mixed polymorphonuclear-lymphocytic pattern during the initial days of the


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InternalMed_Harrison. Initial treatment is with high-dose glucocorticoids as for exacerba illness. Transient CSF oligoclonal banding has been reported. MRI usu tions of NMO (see above); depending on the response, treatment ally reveals extensive changes in the brain and spinal cord, consisting may need to be continued for 8 weeks. Patients who fail to respond within a few days may benefit from a course of plasma exchange recovery sequences with Gd enhancement on T1-weighted sequences. or intravenous immunoglobulin. The prognosis reflects the severity of the underlying acute illness. In recent case series of presumptive ADEM in adults, mortality rates of 5–20% are reported, and many The diagnosis is most reliably established when there is a history of survivors have permanent neurologic sequelae. recent vaccination or viral exanthematous illness. In severe cases In approaching a patient with a neuropathy, the clinician has three main


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InternalMed_Harrison. Anthony A. Amato, Richard J. Barohn goals: (1) identify where the lesion is, (2) identify the cause, and (3) deter mine the proper treatment. The first goal is accomplished by obtaining a thorough history, neurologic examination, and electrodiagnostic and Peripheral nerves are composed of sensory, motor, and autonomic other laboratory studies (Fig. 459-1). While gathering this information, elements. Diseases can affect the cell body of a neuron or its periph-seven key questions are asked (Table 459-1), the answers to which can eral processes, namely the axons or the encasing myelin sheaths. usually identify the category of pathology that is present (Table 459-2). Most peripheral nerves are mixed and contain sensory and motor as Despite an extensive evaluation, in approximately half of patients, no well as autonomic fibers. Nerves can be subdivided into three major etiology is ever found; these patients typically have a predominately classes: large myelinated, small myelinated, and


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InternalMed_Harrison. patients, no well as autonomic fibers. Nerves can be subdivided into three major etiology is ever found; these patients typically have a predominately classes: large myelinated, small myelinated, and small unmyelinated. sensory polyneuropathy and have been labeled as having idiopathic or Motor axons are usually large myelinated fibers that conduct rapidly cryptogenic sensory polyneuropathy (CSPN). (approximately 50 m/s). Sensory fibers may be any of the three types. Large-diameter sensory fibers conduct proprioception and vibratory sensation to the brain, while the smaller-diameter myelinated INFORMATION FROM THE HISTORY AND PHYSICAL EXAMINATION: SEVEN KEY and unmyelinated fibers transmit pain and temperature sensation. QUESTIONS (TABLE 459-1) Autonomic nerves are also small in diameter. Thus, peripheral neu-1. What Systems are Involved? It is important to determine if the ropathies can impair sensory, motor, or autonomic function, either patient’s symptoms and signs are motor,


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InternalMed_Harrison. Thus, peripheral neu-1. What Systems are Involved? It is important to determine if the ropathies can impair sensory, motor, or autonomic function, either patient’s symptoms and signs are motor, sensory, autonomic, or a com-singly or in combination. Peripheral neuropathies are further classi-bination of these. If the patient has only weakness without any evidence fied into those that primarily affect the cell body (e.g., neuronopathy of sensory or autonomic dysfunction, a motor neuropathy, neuromusor ganglionopathy), myelin (myelinopathy), and the axon (axonopathy). cular junction abnormality, or myopathy should be considered. Some These different classes of peripheral neuropathies have distinct clinical peripheral neuropathies are associated with significant autonomic nerand electrophysiologic features. This chapter discusses the clinical vous system dysfunction. Symptoms of autonomic involvement include approach to a patient suspected of having a peripheral neuropathy, fainting


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InternalMed_Harrison. features. This chapter discusses the clinical vous system dysfunction. Symptoms of autonomic involvement include approach to a patient suspected of having a peripheral neuropathy, fainting spells or orthostatic lightheadedness; heat intolerance; or any as well as specific neuropathies, including hereditary and acquired bowel, bladder, or sexual dysfunction (Chap. 454). There will typically neuropathies. The inflammatory neuropathies are discussed in be an orthostatic fall in blood pressure without an appropriate increase Chap. 460. in heart rate. Autonomic dysfunction in the absence of diabetes should


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InternalMed_Harrison. Peripheral NeuropathyChapter 459Patient Complaint: ? Neuropathy History and examination compatible with neuropathy? Mononeuropathy Mononeuropathy multiplex Polyneuropathy Evaluation of other ˜disorder or ˜reassurance and follow-up EDx Is the lesion axonal ˜or demyelinating? Is entrapment or ˜compression present? Is a contributing systemic disorder present? Axonal Demyelinating ˜with focal ˜conduction block Axonal Demyelinating Consider ˜vasculitis or other multifocal ˜process Consider ˜multifocal ˜form of ˜CIDP Subacute ˜course (months) Chronic ˜course (years) Uniform slowing, ˜chronic Nonuniform slowing, conduction block Decision on need ˜for surgery (nerve repair, ˜transposition, or release ˜procedure) Possible ˜nerve ˜biopsy Test for paraprotein, ˜HIV, Lyme disease Review history for toxins; test for associated systemic disease or intoxication Test for paraprotein, if negative Review family history; examine family members; genetic testing If chronic or ˜subacute: CIDP If


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InternalMed_Harrison. for toxins; test for associated systemic disease or intoxication Test for paraprotein, if negative Review family history; examine family members; genetic testing If chronic or ˜subacute: CIDP If acute: GBS Treatment appropriate ˜for specific diagnosis If tests are ˜negative, consider treatment for CIDP Treatment appropriate ˜for specific diagnosis Genetic counseling if appropriate Treatment for CIDP; see Ch. 460 IVIg or ˜plasmapheresis; ˜supportive ˜care including ˜respiratory assistance EDx EDx NoYes FIGURE 459-1 Approach to the evaluation of peripheral neuropathies. CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; EDx, electrodiagnostic; GBS, Guillain-Barré syndrome; IVIg, intravenous immunoglobulin.


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InternalMed_Harrison. alert the clinician to the possibility of amyloid polyneuropathy. Rarely, a pandysautonomic syndrome can be the only manifestation of a peripheral neuropathy without other motor or sensory findings. The majority of neuropathies are predominantly sensory in nature. approaCh to NeuropathiC DisorDers: seveN key questioNs 1. What systems are involved? Motor, sensory, autonomic, or combinations 2. What is the distribution of weakness? 3. What is the nature of the sensory involvement? -Temperature loss or burning or stabbing pain (e.g., small fiber) -Vibratory or proprioceptive loss (e.g., large fiber) 4. Is there evidence of upper motor neuron involvement? 5. What is the temporal evolution? Acute (days to 4 weeks) Monophasic, progressive, or relapsing-remitting 6. Is there evidence for a hereditary neuropathy? Family history of neuropathy Lack of sensory symptoms despite sensory signs 7. Are there any associated medical conditions?


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InternalMed_Harrison. Family history of neuropathy Lack of sensory symptoms despite sensory signs 7. Are there any associated medical conditions? -Cancer, diabetes mellitus, connective tissue disease or other autoimmune diseases, infection (e.g., HIV, Lyme disease, leprosy) Preceding events, drugs, toxins 2.


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InternalMed_Harrison. Preceding events, drugs, toxins 2. What is the Distribution of Weakness? Delineating the pattern of weakness, if present, is essential for diagnosis, and in this regard two additional questions should be answered: (1) Does the weakness only involve the distal extremity, or is it both proximal and distal? and (2) Is the weakness focal and asymmetric, or is it symmetric? Symmetric proximal and distal weakness is the hallmark of acquired immune demyelinating polyneuropathies, both the acute form (acute inflammatory demyelinating polyneuropathy [AIDP], also known as Guillain-Barré syndrome [GBS]) and the chronic form (chronic inflammatory demyelinating polyneuropathy [CIDP]). The importance of finding symmetric proximal and distal weakness in a patient who presents with both motor and sensory symptoms cannot be overemphasized because this identifies the important subset of patients who may have a treatable acquired demyelinating neuropathic disorder (i.e., AIDP or CIDP).


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InternalMed_Harrison. Findings of an asymmetric or multifocal pattern of weakness narrow the differential diagnosis. Some neuropathic disorders may present with unilateral extremity weakness. In the absence of sensory symptoms and signs, such weakness evolving over weeks or months would be worrisome for motor neuron disease (e.g., amyotrophic lateral sclerosis [ALS]), but it would be important to exclude multifocal motor neuropathy that may be treatable (Chap. 452). In a patient presenting with asymmetric subacute or acute sensory and motor symptoms and signs, radiculopathies, plexopathies, compressive mononeuropathies, or multiple mononeuropathies (e.g., mononeuropathy multiplex) must be considered. 3.


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InternalMed_Harrison. 3. What is the Nature of the Sensory Involvement? The patient may have loss of sensation (numbness), altered sensation to touch (hyperpathia or allodynia), or uncomfortable spontaneous sensations (tingling, burning, or aching) (Chap. 31). Neuropathic pain can be burning, dull, and poorly localized (protopathic pain), presumably transmitted by polymodal C nociceptor fibers, or sharp and lancinating (epicritic pain), relayed by A-delta fibers. If pain and temperature perception are lost, while vibratory and position sense are preserved along with patterNs of NeuropathiC DisorDers Pattern 1: Symmetric proximal and distal weakness with sensory loss Consider: inflammatory demyelinating polyneuropathy (GBS and CIDP) Pattern 2: Symmetric distal sensory loss with or without distal weakness Consider: cryptogenic or idiopathic sensory polyneuropathy (CSPN), diabetes mellitus and other metabolic disorders, drugs, toxins, familial (HSAN), CMT, amyloidosis, and others


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InternalMed_Harrison. Consider: cryptogenic or idiopathic sensory polyneuropathy (CSPN), diabetes mellitus and other metabolic disorders, drugs, toxins, familial (HSAN), CMT, amyloidosis, and others Pattern 3: Asymmetric distal weakness with sensory loss With involvement of multiple nerves Consider: multifocal CIDP, vasculitis, cryoglobulinemia, amyloidosis, sarcoid, infectious (leprosy, Lyme, hepatitis B, C, or E, HIV, CMV), HNPP, tumor infiltration With involvement of single nerves/regions Consider: may be any of the above but also could be compressive mononeuropathy, plexopathy, or radiculopathy Pattern 4: Asymmetric proximal and distal weakness with sensory loss Consider: polyradiculopathy or plexopathy due to diabetes mellitus, meningeal carcinomatosis or lymphomatosis, hereditary plexopathy (HNPP, HNA), idiopathic Pattern 5: Asymmetric distal weakness without sensory loss


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InternalMed_Harrison. Pattern 5: Asymmetric distal weakness without sensory loss With upper motor neuron findings Consider: motor neuron disease Without upper motor neuron findings Consider: progressive muscular atrophy, juvenile monomelic amyotrophy (Hirayama’s disease), multifocal motor neuropathy, multifocal acquired motor axonopathy Pattern 6: Symmetric sensory loss and distal areflexia with upper motor neuron findings Consider: Vitamin B12, vitamin E, and copper deficiency with combined system degeneration with peripheral neuropathy, hereditary leukodystrophies (e.g., adrenomyeloneuropathy) Pattern 7: Symmetric weakness without sensory loss With proximal and distal weakness Consider: SMA With distal weakness Consider: hereditary motor neuropathy (“distal” SMA) or atypical CMT Pattern 8: Asymmetric proprioceptive sensory loss without weakness


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InternalMed_Harrison. Pattern 8: Asymmetric proprioceptive sensory loss without weakness Consider causes of a sensory neuronopathy (ganglionopathy): Cancer (paraneoplastic) Sjögren’s syndrome Idiopathic sensory neuronopathy (possible GBS variant) Cisplatin and other chemotherapeutic agents Vitamin B6 toxicity HIV-related sensory neuronopathy Pattern 9: Autonomic symptoms and signs Consider neuropathies associated with prominent autonomic dysfunction: Hereditary sensory and autonomic neuropathy Amyloidosis (familial and acquired) Diabetes mellitus Idiopathic pandysautonomia (may be a variant of Guillain-Barré syndrome) Porphyria HIV-related autonomic neuropathy Vincristine and other chemotherapeutic agents


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InternalMed_Harrison. Abbreviations: CIDP, chronic inflammatory demyelinating polyneuropathy; CMT, Charcot-Marie-Tooth disease; CMV, cytomegalovirus; GBS, Guillain-Barré syndrome; HIV, human immunodeficiency virus; HNA, hereditary neuralgic amyotrophy; HNPP, hereditary neuropathy with liability to pressure palsies; HSAN, hereditary sensory and autonomic neuropathy; SMA, spinal muscular atrophy. muscle strength, deep tendon reflexes, and normal nerve conduction studies, a small-fiber neuropathy is likely. This is important, because the most likely cause of small-fiber neuropathies, when one is identified, is diabetes mellitus or glucose intolerance. Amyloid neuropathy should be considered as well in such cases, but most of these small-fiber neuropathies remain idiopathic in nature despite extensive evaluation.


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InternalMed_Harrison. Severe proprioceptive loss also narrows the differential diagnosis. Affected patients will note imbalance, especially in the dark. A neurologic examination revealing a dramatic loss of proprioception with vibration loss and normal strength should alert the clinician to consider a sensory neuronopathy/ganglionopathy (Table 459-2, Pattern 8). In particular, if this loss is asymmetric or affects the arms more than the legs, this pattern suggests a non-length-dependent process as seen in sensory neuronopathies.


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InternalMed_Harrison. 4. Is There Evidence of Upper Motor Neuron Involvement? If the patient presents with symmetric distal sensory symptoms and signs suggestive of a distal sensory neuropathy, but there is additional evidence of symmetric upper motor neuron involvement (Chap. 30), the physician should consider a disorder such as combined system degeneration with neuropathy. The most common cause for this pattern is vitamin deficiency, but other causes of combined system degeneration with neuropathy should be considered (e.g., copper deficiency, HIV infection, severe hepatic disease, adrenomyeloneuropathy). 5.


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InternalMed_Harrison. 5. What is the Temporal Evolution? It is important to determine the onset, duration, and evolution of symptoms and signs. Does the disease have an acute (days to 4 weeks), subacute (4–8 weeks), or chronic (>8 weeks) course? Is the course monophasic, progressive, or relapsing? Most neuropathies are insidious and slowly progressive in nature. Neuropathies with acute and subacute presentations include GBS, vasculitis, and radiculopathies related to diabetes or Lyme disease. A relapsing course can be present in CIDP and porphyria. 6.


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InternalMed_Harrison. 6. Is There Evidence for a Hereditary Neuropathy? In patients with slowly progressive distal weakness over many years with very little in the way of sensory symptoms yet with significant sensory deficits on clinical examination, the clinician should consider a hereditary neuropathy (e.g., Charcot-Marie-Tooth disease [CMT]). On examination, the feet may show arch and toe abnormalities (high or flat arches, hammertoes); scoliosis may be present. In suspected cases, it may be necessary to perform both neurologic and electrophysiologic studies on family members in addition to the patient. 7.


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InternalMed_Harrison. 7. Does the Patient Have Any Other Medical Conditions? It is important to inquire about associated medical conditions (e.g., diabetes mellitus, systemic lupus erythematosus); preceding or concurrent infections (e.g. diarrheal illness preceding GBS); surgeries (e.g., gastric bypass and nutritional neuropathies); medications (toxic neuropathy), including over-the-counter vitamin preparations (B6); alcohol; dietary habits; and use of dentures (e.g., fixatives contain zinc that can lead to copper deficiency). Based on the answers to the seven key questions, neuropathic disorders can be classified into several patterns based on the distribution or pattern of sensory, motor, and autonomic involvement (Table 459-2). Each pattern has a limited differential diagnosis. A final diagnosis is established by using other clues such as the temporal course, presence of other disease states, family history, and information from laboratory studies.


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InternalMed_Harrison. The electrodiagnostic (EDx) evaluation of patients with a suspected peripheral neuropathy consists of nerve conduction studies (NCS) and needle electromyography (EMG). In addition, studies of autonomic function can be valuable. The electrophysiologic data provide additional information about the distribution of the neuropathy that will support or refute the findings from the history and physical examination; they can confirm whether the neuropathic disorder is a mononeuropathy, multiple mononeuropathy (mononeuropathy multiplex), radiculopathy, plexopathy, or generalized polyneuropathy. Similarly, EDx evaluation can ascertain whether the process involves only sensory fibers, motor fibers, autonomic fibers, or a combination of these. Finally, the electrophysiologic data can help distinguish axonopathies from myelinopathies as well as axonal degeneration secondary to ganglionopathies from the more common length-dependent axonopathies.


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InternalMed_Harrison. Abbreviations: CB, conduction block; CMAP, compound motor action potential; EMG, electromyography; SNAP, sensory nerve action potential. NCS are most helpful in classifying a neuropathy as being due to axonal degeneration or segmental demyelination (Table 459-3). In general, low-amplitude potentials with relatively preserved distal latencies, conduction velocities, and late potentials, along with fibrillations on needle EMG, suggest an axonal neuropathy. On the other hand, slow conduction velocities, prolonged distal latencies and late potentials, relatively preserved amplitudes, and the absence of fibrillations on needle EMG imply a primary demyelinating neuropathy. The presence of nonuniform slowing of conduction velocity, conduction block, or temporal dispersion further suggests an acquired demyelinating neuropathy (e.g., GBS or CIDP) as opposed to a hereditary demyelinating neuropathy (e.g., CMT type 1).


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InternalMed_Harrison. Autonomic studies are used to assess small myelinated (A-delta) or unmyelinated (C) nerve fiber involvement. Such testing includes heart rate response to deep breathing, heart rate, and blood pressure response to both the Valsalva maneuver and tilt-table testing and quantitative sudomotor axon reflex testing (Chap. 454). These studies are particularly useful in patients who have pure small-fiber neuropathy or autonomic neuropathy in which routine NCS are normal.


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InternalMed_Harrison. In patients with generalized symmetric peripheral neuropathy, a standard laboratory evaluation should include a complete blood count, basic chemistries including serum electrolytes and tests of renal and hepatic function, fasting blood glucose (FBS), HbA1c, urinalysis, thyroid function tests, B12, folate, erythrocyte sedimentation rate (ESR), rheumatoid factor, antinuclear antibodies (ANA), serum protein electrophoresis (SPEP) and immunoelectrophoresis or immunofixation, and urine for Bence Jones protein. Quantification of the concentration of serum free light chains and the kappa/lambda ratio is more sensitive than SPEP, immunoelectrophoresis, or immunofixation in looking for a monoclonal gammopathy and therefore should be done if one suspects amyloidosis. A skeletal survey should be performed in patients with acquired demyelinating neuropathies and M-spikes to look for osteosclerotic or lytic lesions. Patients with monoclonal gammopathy should also be referred to a hematologist for


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InternalMed_Harrison. in patients with acquired demyelinating neuropathies and M-spikes to look for osteosclerotic or lytic lesions. Patients with monoclonal gammopathy should also be referred to a hematologist for consideration of a bone marrow biopsy. An oral glucose tolerance test is indicated in patients with painful sensory neuropathies even if FBS and HbA1c are normal, 2677 as the test is abnormal in about one-third of such patients. In addition to the above tests, patients with a mononeuropathy multiplex pattern of involvement should have a vasculitis workup, including antineutrophil cytoplasmic antibodies (ANCA), cryoglobulins, hepatitis serology, Western blot for Lyme disease, HIV, and occasionally a cytomegalovirus (CMV) titer.


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InternalMed_Harrison. There are many autoantibody panels (various antiganglioside antibodies) marketed for screening routine neuropathy patients for a treatable condition. These autoantibodies have no proven clinical util ity or added benefit beyond the information obtained from a complete clinical examination and detailed EDx. A heavy metal screen is also not necessary as a screening procedure, unless there is a history of possible exposure or suggestive features on examination (e.g., severe painful sensorimotor and autonomic neuropathy and alopecia—thallium; severe painful sensorimotor neuropathy with or without gastrointestinal [GI] disturbance and Mee’s lines—arsenic; wrist or finger extensor weakness and anemia with basophilic stippling of red blood cells—lead).


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InternalMed_Harrison. In patients with suspected GBS or CIDP, a lumbar puncture is indicated to look for an elevated cerebral spinal fluid (CSF) protein. In idiopathic cases of GBS and CIDP, there should not be pleocytosis in the CSF. If cells are present, one should consider HIV infection, Lyme disease, sarcoidosis, or lymphomatous or leukemic infiltration of nerve roots. Some patients with GBS and CIDP have abnormal liver function tests. In these cases, it is important to also check for hepatitis B and C, HIV, CMV, and Epstein-Barr virus (EBV) infection. In patients with an axonal GBS (by EMG/NCS) or those with a suspicious coinciding history (e.g., unexplained abdominal pain, psychiatric illness, significant autonomic dysfunction), it is reasonable to screen for porphyria.


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InternalMed_Harrison. In patients with a severe sensory ataxia, a sensory ganglionopathy or neuronopathy should be considered. The most common causes of sensory ganglionopathies are Sjögren’s syndrome and a paraneoplastic neuropathy. Neuropathy can be the initial manifestation of Sjögren’s syndrome. Thus, one should always inquire about dry eyes and mouth in patients with sensory signs and symptoms. Further, some patients can manifest sicca complex without full-blown Sjögren’s syndrome. Thus, patients with sensory ataxia should have a senile systemic amyloidosis (SSA) and single strand binding (SSB) in addition to the routine ANA. To work up a possible paraneoplastic sensory ganglionopathy, antineuronal nuclear antibodies (e.g., anti-Hu antibodies) should be obtained (Chap. 122). These antibodies are most commonly seen in patients with small-cell carcinoma of the lung but are seen also in breast, ovarian, lymphoma, and other cancers. Importantly, the paraneoplastic neuropathy can precede the detection of


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InternalMed_Harrison. seen in patients with small-cell carcinoma of the lung but are seen also in breast, ovarian, lymphoma, and other cancers. Importantly, the paraneoplastic neuropathy can precede the detection of the cancer, and detection of these autoantibodies should lead to a search for malignancy.


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InternalMed_Harrison. Nerve biopsies are now rarely indicated for evaluation of neuropathies. The primary indication for nerve biopsy is suspicion for amyloid neuropathy or vasculitis. In most instances, the abnormalities present on biopsies do not help distinguish one form of peripheral neuropathy from another (beyond what is already apparent by clinical examination and the NCS). Nerve biopsies should only be done if the NCS are abnormal. The sural nerve is most commonly biopsied because it is a pure sensory nerve and biopsy will not result in loss of motor function. In suspected vasculitis, a combination biopsy of a superficial peroneal nerve (pure sensory) and the underlying peroneus brevis muscle obtained from a single small incision increases the diagnostic yield. Tissue can be analyzed by frozen section and paraffin section to assess the supporting structures for evidence of inflammation, vasculitis, or amyloid deposition. Semithin plastic sections, teased fiber preparations, and electron microscopy


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InternalMed_Harrison. and paraffin section to assess the supporting structures for evidence of inflammation, vasculitis, or amyloid deposition. Semithin plastic sections, teased fiber preparations, and electron microscopy are used to assess the morphology of the nerve fibers and to distinguish axonopathies from myelinopathies.


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InternalMed_Harrison. Skin biopsies are sometimes used to diagnose a small-fiber neuropathy. Following a punch biopsy of the skin in the distal lower extremity, immunologic staining can be used to measure the density of small 2678 unmyelinated fibers. The density of these nerve fibers is reduced in patients with small-fiber neuropathies in whom NCS and routine nerve biopsies are often normal. This technique may allow for an objective measurement in patients with mainly subjective symptoms. However, it adds little to what one already knows from the clinical examination and EDx.


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InternalMed_Harrison. Charcot-Marie-Tooth (CMT) disease is the most common type of hereditary neuropathy. Rather than one disease, CMT is a syndrome of several genetically distinct disorders (Table 459-4). The various subtypes of CMT are classified according to the nerve conduction velocities and predominant pathology (e.g., demyelination or axonal degeneration), inheritance pattern (autosomal dominant, recessive, or X-linked), and the specific mutated genes. Type 1 CMT (or CMT1) refers to inherited demyelinating sensorimotor neuropathies, whereas the axonal sensory neuropathies are classified as CMT2. By definition, motor conduction velocities in the arms are slowed to less than 38 m/s in CMT1 and are greater than 38 m/s in CMT2. However, most cases of CMT1 actually have motor nerve conduction velocities (NCVs) between 20 and 25 m/s. CMT1 and CMT2 usually begin in childhood or early adult life; however, onset later in life can occur, particularly in CMT2. Both are associated with autosomal dominant


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InternalMed_Harrison. (NCVs) between 20 and 25 m/s. CMT1 and CMT2 usually begin in childhood or early adult life; however, onset later in life can occur, particularly in CMT2. Both are associated with autosomal dominant inheritance, with a few exceptions. CMT3 is an autosomal dominant neuropathy that appears in infancy and is associated with severe demyelination or hypomyelination. CMT4 is an autosomal recessive neuropathy that typically begins in childhood or early adult life. There are no medical therapies for any of the CMTs, but physical and occupational therapy can be beneficial, as can bracing (e.g., ankle-foot orthotics for foot-drop) and other orthotic devices.


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InternalMed_Harrison. CMT1 CMT1 is the most common form of hereditary neuropathy, with the ratio of CMT1:CMT2 being approximately 2:1. Affected individuals usually present in the first to third decade of life with distal leg weakness (e.g., footdrop), although patients may remain asymptomatic even late in life. People with CMT generally do not complain of numbness or tingling, which can be helpful in distinguishing CMT from acquired forms of neuropathy in which sensory symptoms usually predominate. Although usually asymptomatic in this regard, reduced sensation to all modalities is apparent on examination. Muscle stretch reflexes are unobtainable or reduced throughout. There is often atrophy of the muscles below the knee (particularly the anterior compartment), leading to so-called inverted champagne bottle legs.


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InternalMed_Harrison. Motor NCVs are usually in the 20–25 m/s range. Nerve biopsies usually are not performed on patients suspected of having CMT1, because the diagnosis usually can be made by less invasive testing (e.g., NCS and genetic studies). However, when done, the biopsies reveal reduction of myelinated nerve fibers with a predilection for the loss of the large-diameter fibers and Schwann cell proliferation around thinly or demyelinated fibers, forming so-called onion bulbs.


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InternalMed_Harrison. CMT1A is the most common subtype of CMT1, representing 70% of cases, and is caused by a 1.5-megabase (Mb) duplication within chromosome 17p11.2-12 wherein the gene for peripheral myelin protein-22 (PMP-22) lies. This results in patients having three copies of the PMP-22 gene rather than two. This protein accounts for 2–5% of myelin protein and is expressed in compact portions of the peripheral myelin sheath. Approximately 20% of patients with CMT1 have CMT1B, which is caused by mutations in the myelin protein zero (MPZ). CMT1B is for the most part clinically, electrophysiologically, and histologically indistinguishable from CMT1A. MPZ is an integral myelin protein and accounts for more than half of the myelin protein in peripheral nerves. Other forms of CMT1 are much less common and again indistinguishable from one another clinically and electrophysiologically.


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InternalMed_Harrison. CMT2 CMT2 tends to present later in life compared to CMT1. Affected individuals usually become symptomatic in the second decade of life; some cases present earlier in childhood, whereas others remain asymptomatic into late adult life. Clinically, CMT2 is for the most part indistinguishable from CMT1. NCS are helpful in this regard; in contrast to CMT1, the velocities are normal or only slightly slowed. The most common cause of CMT2 is a mutation in the gene for mitofusin 2 (MFN2), which accounts for one-third of CMT2 cases overall. MFN2 localizes to the outer mitochondrial membrane, where it regulates the mitochondrial network architecture by fusion of mitochondria. The other genes associated with CMT2 are much less common. CMTDI In dominant-intermediate CMTs (CMTDIs), the NCVs are faster than usually seen in CMT1 (e.g., >38 m/s) but slower than in CMT2.


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InternalMed_Harrison. CMTDI In dominant-intermediate CMTs (CMTDIs), the NCVs are faster than usually seen in CMT1 (e.g., >38 m/s) but slower than in CMT2. CMT3 CMT3 was originally described by Dejerine and Sottas as a hereditary demyelinating sensorimotor polyneuropathy presenting in infancy or early childhood. Affected children are severely weak. Motor NCVs are markedly slowed, typically 5–10 m/s or less. Most cases of CMT3 are caused by point mutations in the genes for PMP-22, MPZ, or ERG-2, which are also the genes responsible for CMT1. CMT4 CMT4 is extremely rare and is characterized by a severe, childhood-onset sensorimotor polyneuropathy that is usually inherited in an autosomal recessive fashion. Electrophysiologic and histologic evaluations can show demyelinating or axonal features. CMT4 is genetically heterogenic (Table 459-4).


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InternalMed_Harrison. CMT1X CMT1X is an X-linked dominant disorder with clinical features similar to CMT1 and CMT2, except that the neuropathy is much more severe in men than in women. CMT1X accounts for approximately 10–15% of CMT overall. Men usually present in the first two decades of life with atrophy and weakness of the distal arms and legs, areflexia, pes cavus, and hammertoes. Obligate women carriers are frequently asymptomatic, but can develop signs and symptoms. Onset in women is usually after the second decade of life, and the neuropathy is milder in severity.


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InternalMed_Harrison. NCS reveal features of both demyelination and axonal degeneration that are more severe in men compared to women. In men, motor NCVs in the arms and legs are moderately slowed (in the low to mid 30-m/s range). About 50% of men with CMT1X have motor NCVs between 15 and 35 m/s with about 80% of these falling between 25 and 35 m/s (intermediate slowing). In contrast, about 80% of women with CMT1X have NCVs in the normal range and 20% have NCVs in the intermediate range. CMT1X is caused by mutations in the connexin 32 gene. Connexins are gap junction structural proteins that are important in cell-to-cell communication.


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InternalMed_Harrison. Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) HNPP is an autosomal dominant disorder related to CMT1A. Although CMT1A is usually associated with a 1.5-Mb duplication in chromosome 17p11.2 that results in an extra copy of PMP-22 gene, HNPP is caused by inheritance of the chromosome with the corresponding 1.5-Mb deletion of this segment, and thus affected individuals have only one copy of the PMP-22 gene. Patients usually manifest in the second or third decade of life with painless numbness and weakness in the distribution of single peripheral nerves, although multiple mononeuropathies can occur. Symptomatic mononeuropathy or multiple mononeuropathies are often precipitated by trivial compression of nerve(s) as can occur with wearing a backpack, leaning on the elbows, or crossing one’s legs for even a short period of time. These pressure-related mononeuropathies may take weeks or months to resolve. In addition, some affected individuals manifest with a progressive or


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InternalMed_Harrison. crossing one’s legs for even a short period of time. These pressure-related mononeuropathies may take weeks or months to resolve. In addition, some affected individuals manifest with a progressive or relapsing, generalized and symmetric, sensorimotor peripheral neuropathy that resembles CMT.


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InternalMed_Harrison. Hereditary Neuralgic Amyotrophy (HNA) HNA is an autosomal dominant disorder characterized by recurrent attacks of pain, weakness, and sensory loss in the distribution of the brachial plexus often beginning in childhood. These attacks are similar to those seen with idiopathic brachial plexitis (see below). Attacks may occur in the postpartum period, following surgery, or at other times of stress. Most patients recover over several weeks or months. Slightly dysmorphic features, including hypotelorism, epicanthal folds, cleft palate, syndactyly, micrognathia, and facial asymmetry, are evident in some individuals. EDx demonstrate an axonal process. HNA is caused by mutations in septin 9 (SEPT9). Septins may be important in formation of the


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InternalMed_Harrison. CMT1 CMT1A AD 17p11.2 PMP-22 (usually duplication of gene) CMT1B AD 1q21-23 MPZ CMT1C AD 16p13.1-p12.3 LITAF CMT1D AD 10q21.1-22.1 ERG2 CMT1E (with deafness) AD 17p11.2 Point mutations in PMP 22 gene CMT1F AD 8p13-21 Neurofilament light chain CMT1G AD 14q32.33 INF2 CMT1X X-linked dominant Xq13 Connexin-32 HNPP AD 17p11.2 PMP-22 1q21-23 MPZ CMT dominant-intermediate (CMTD1) CMTD1A AD 10q24.1-25.1 ? CMTD1B AD 19.p12-13.2 Dynamin 2 CMTD1C AD 1p35 YARS CMTD1D AD 1q22 MPZ


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InternalMed_Harrison. HNPP AD 17p11.2 PMP-22 1q21-23 MPZ CMT dominant-intermediate (CMTD1) CMTD1A AD 10q24.1-25.1 ? CMTD1B AD 19.p12-13.2 Dynamin 2 CMTD1C AD 1p35 YARS CMTD1D AD 1q22 MPZ CMT2 CMT2A2 (allelic to HMSN VI with optic atrophy) AD 1p36.2 MFN2 CMT2B AD 3q13-q22 RAB7 CMT2B1 (allelic to LGMD 1B) AR 1q21.2 Lamin A/C CMT2B2 AR and AD 19q13 MED25 for AR Unknown for AD CMT2C (with vocal cord and diaphragm paralysis) AD 12q23-24 TRPV4 CMT2D (allelic to distal SMA5) AD 7p14 Glycine tRNA synthetase CMT2E (allelic to CMT 1F) AD 8p21 Neurofilament light chain CMT2F AD 7q11-q21 Heat-shock 27-kDa protein-1 CMT2G AD 12q23 Unknown CMT2I (allelic to CMT1B) AD 1q22 MPZ CMT2J AD 1q22 MPZ CMT2H, CMT2K (allelic to CMT4A) AD 8q13-q21 GDAP1 CMT2L (allelic to distal hereditary motor neuropathy type 2) AD 12q24 Heat-shock protein 8 CMT2M AD 16q22 Dynamin-2 CMT2N AD 16q22.1 AARS CMT2O AD 14q32.31 DYNC1H1 CMT2P AD 9q34.13 LRSAM1 CMT2P-Okinawa (HSMN2P) AD 3q13-q14 TFG CMT2X X-linked Xq22-24 PRPS1


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InternalMed_Harrison. CMT3 AD 17p11.2 PMP-22 (Dejerine-Sottas disease, congenital hypomyelinating neuropathy) AD 1q21-23 MPZ AR 10q21.1-22.1 ERG2 AR 19q13 Periaxon CMT4 CMT4A AR 8q13-21.1 GDAP1 CMT4B1 AR 11q23 MTMR2 CMT4B2 AR 11p15 MTMR13 CMT4C AR 5q23-33 SH3TC2 CMT4D (HMSN-Lom) AR 8q24 NDRG1 CMT4E (congenital hypomyelinating neuropathy) AR Multiple Includes PMP22, MPZ, and ERG-2 CMT4F AR 19q13.1-13.3 Periaxin CMT4G AR 10q23.2 HKI CMT4H AR 12q12-q13 Frabin CMT4J AR 6q21 FIG4 HNA AD 17q24 SEPT9 HSAN1A AD 9q22 SPTLC1 HSAN1B AD 3q21 RAB7 HSAN1C AD 14q24.3 SPTLC2 HSAN1D AD 14q21.3 ATL1 HSAN1E AD 19p13.2 DNMT1


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InternalMed_Harrison. Abbreviations: AARS, alanyl-tRNA synthetase; AD, autosomal dominant; AR, autosomal recessive; ATL, atlastin; CMT, Charcot-Marie-Tooth; DNMT1, DNA methyltransferase 1; DYNC1HI, cytoplasmic dynein 1 heavy chain 1; ERG2, early growth response-2 protein; FAM134B, family with sequence similarity 134, member B; FIG4, FDG1-related F actin-binding protein; GDAP1, ganglioside-induced differentiation-associated protein-1; HK1, hexokinase 1; HMSN-P, hereditary motor and sensory neuropathyproximal; HNA, hereditary neuralgic amyotrophy; HNPP, hereditary neuropathy with liability to pressure palsies; HSAN; hereditary sensory and autonomic neuropathy; IFN2, inverted formin-2; IKAP, kB kinase complex-associated protein; LGMD, limb girdle muscular dystrophy; LITAF, lipopolysaccharide-induced tumor necrosis factor α factor; LRSAM1, E3 ubiquitin-protein ligase; MED25, mediator 25; MFN2, mitochondrial fusion protein mitofusin 2 gene; MPZ, myelin protein zero protein; MTMR2, myotubularin-related


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InternalMed_Harrison. necrosis factor α factor; LRSAM1, E3 ubiquitin-protein ligase; MED25, mediator 25; MFN2, mitochondrial fusion protein mitofusin 2 gene; MPZ, myelin protein zero protein; MTMR2, myotubularin-related protein-2; NDRG1, N-myc downstream regulated 1; PMP-22, peripheral myelin protein-22; PRKWNK1, protein kinase, lysine deficient 1; PRPS1, phosphoribosylpyrophosphate synthetase 1; RAB7, Ras-related protein 7; SEPT9, Septin 9; SH3TC2, SH3 domain and tetratricopeptide repeats 2; SMA, spinal muscular atrophy; SPTLC, serine palmitoyltransferase long-chain base; TFG, TRK-fused gene; TrkA/NGF, tyrosine kinase A/nerve growth factor; tRNA, transfer ribonucleic acid; TRPV4, transient receptor potential cation channel, subfamily V, member 4; WNK1, WNK lysine deficient; YARS, tyrosyl-tRNA synthetase.


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InternalMed_Harrison. Source: Modified from AA Amato, J Russell: Neuromuscular Disease. New York, McGraw-Hill, 2008. neuronal cytoskeleton and have a role in cell division, but the mechanism of causing HNA is unclear. Hereditary Sensory and Autonomic Neuropathy (HSAN) The HSANs are a very rare group of hereditary neuropathies in which sensory and autonomic dysfunction predominates over muscle weakness, unlike CMT, in which motor findings are most prominent (Table 459-4). Nevertheless, affected individuals can develop motor weakness and there can be overlap with CMT. There are no medical therapies available to treat these neuropathies, other than prevention and treatment of mutilating skin and bone lesions.


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InternalMed_Harrison. Of the HSANs, only HSAN1 typically presents in adults. HSAN1 is the most common of the HSANs and is inherited in an autosomal dominant fashion. Affected individuals with HSAN1 usually manifest in the second through fourth decades of life. HSAN1 is associated with the degeneration of small myelinated and unmyelinated nerve fibers leading to severe loss of pain and temperature sensation, deep dermal ulcerations, recurrent osteomyelitis, Charcot joints, bone loss, gross foot and hand deformities, and amputated digits. Although most people with HSAN1 do not complain of numbness, they often describe burning, aching, or lancinating pains. Autonomic neuropathy is not a prominent feature, but bladder dysfunction and reduced sweating in the feet may occur. HSAN1A, which is most common, is caused by mutations in the serine palmitoyltransferase long-chain base 1 (SPTLC1) gene.


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InternalMed_Harrison. Fabry’s disease (angiokeratoma corporis diffusum) is an X-linked dominant disorder. Although men are more commonly and severely affected, women can also show severe signs of the disease. Angiokeratomas are reddish-purple maculopapular lesions that are usually found around the umbilicus, scrotum, inguinal region, and perineum. Burning or lancinating pain in the hands and feet often develops in males in late childhood or early adult life. However, the neuropathy is usually overshadowed by complications arising from the associated premature atherosclerosis (e.g., hypertension, renal failure, cardiac disease, and stroke) that often lead to death by the fifth decade of life. Some patients also manifest primarily with a dilated cardiomyopathy.


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InternalMed_Harrison. Fabry’s disease is caused by mutations in the a-galactosidase gene that leads to the accumulation of ceramide trihexoside in nerves and blood vessels. A decrease in a-galactosidase activity is evident in leukocytes and cultured fibroblasts. Glycolipid granules may be appreciated in ganglion cells of the peripheral and sympathetic nervous systems and in perineurial cells. Enzyme replacement therapy with a-galactosidase B can improve the neuropathy if patients are treated early, before irreversible nerve fiber loss.


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InternalMed_Harrison. Adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are allelic X-linked dominant disorders caused by mutations in the peroxisomal transmembrane adenosine triphosphate-binding cassette (ABC) transporter gene. Patients with ALD manifest with central nervous system (CNS) abnormalities. However, 30% with mutations in this gene present with the AMN phenotype that typically manifests in the third to fifth decade of life with mild to moderate peripheral neuropathy combined with progressive spastic paraplegia (Chap. 456). Rare patients present with an adult-onset spinocerebellar ataxia or only with adrenal insufficiency.


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InternalMed_Harrison. EDx is suggestive of a primary axonopathy with secondary demyelination. Nerve biopsies demonstrate a loss of myelinated and unmyelinated nerve fibers with lamellar inclusions in the cytoplasm of Schwann cells. Very long chain fatty acid (VLCFA) levels (C24, C25, and C26) are increased in the urine. Laboratory evidence of adrenal insufficiency is evident in approximately two-thirds of patients. The diagnosis can be confirmed by genetic testing. Adrenal insufficiency is managed by replacement therapy; however, there is no proven effective therapy for the neurologic manifestations Hereditary Disorders of Lipid Metabolism Hereditary Ataxias with Neuropathy Disorders of Defective DNA Repair of ALD/AMN. Diets low in VLCFAs and supplemented with Lorenzo’s oil (erucic and oleic acids) reduce the levels of VLCFAs and increase the levels of C22 in serum, fibroblasts, and liver; however, several large, open-label trials of Lorenzo’s oil failed to demonstrate efficacy.


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InternalMed_Harrison. Refsum’s disease can manifest in infancy to early adulthood with the classic tetrad of (1) peripheral neuropathy, (2) retinitis pigmentosa, (3) cerebellar ataxia, and (4) elevated CSF protein concentration. Most affected individuals develop progressive distal sensory loss and weakness in the legs leading to footdrop by their 20s. Subsequently, the proximal leg and arm muscles may become weak. Patients may also develop sensorineural hearing loss, cardiac conduction abnormalities, ichthyosis, and anosmia. Serum phytanic acid levels are elevated. Sensory and motor NCS reveal reduced amplitudes, prolonged latencies, and slowed conduction velocities. Nerve biopsy demonstrates a loss of myelinated nerve fibers, with remaining axons often thinly myelinated and associated with onion bulb formation.


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InternalMed_Harrison. Refsum disease is genetically heterogeneous but autosomal recessive in nature. Classical Refsum disease with childhood or early adult onset is caused by mutations in the gene that encodes for phytanoyl-CoA α-hydroxylase (PAHX). Less commonly, mutations in the gene encoding peroxin 7 receptor protein (PRX7) are responsible. These mutations lead to the accumulation of phytanic acid in the central and peripheral nervous systems. Refsum’s disease is treated by removing phytanic precursors (phytols: fish oils, dairy products, and ruminant fats) from the diet.


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InternalMed_Harrison. Tangier disease is a rare autosomal recessive disorder that can present as (1) asymmetric multiple mononeuropathies, (2) a slowly progressive symmetric polyneuropathy predominantly in the legs, or (3) a pseudo-syringomyelia pattern with dissociated sensory loss (i.e., abnormal pain/temperature perception but preserved position/vibration in the arms [Chap. 456]). The tonsils may appear swollen and yellowish-orange in color, and there may also be splenomegaly and lymphadenopathy. Tangier disease is caused by mutations in the ATP-binding cassette transporter 1 (ABC1) gene, which leads to markedly reduced levels of high-density lipoprotein (HDL) cholesterol levels, whereas triacylglycerol levels are increased. Nerve biopsies reveal axonal degeneration with demyelination and remyelination. Electron microscopy demonstrates abnormal accumulation of lipid in Schwann cells, particularly those encompassing umyelinated and small myelinated nerves. There is no specific treatment.


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InternalMed_Harrison. Porphyria is a group of inherited disorders caused by defects in heme biosynthesis (Chap. 430). Three forms of porphyria are associated with peripheral neuropathy: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). The acute neurologic manifestations are similar in each, with the exception that a photosensitive rash is seen with HCP and VP but not in AIP. Attacks of porphyria can be precipitated by certain drugs (usually those metabolized by the P450 system), hormonal changes (e.g., pregnancy, menstrual cycle), and dietary restrictions.


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InternalMed_Harrison. An acute attack of porphyria may begin with sharp abdominal pain. Subsequently, patients may develop agitation, hallucinations, or seizures. Several days later, back and extremity pain followed by weakness ensues, mimicking GBS. Weakness can involve the arms or the legs and can be asymmetric, proximal, or distal in distribution, as well as affecting the face and bulbar musculature. Dysautonomia and signs of sympathetic overactivity are common (e.g., pupillary dilation, tachycardia, and hypertension). Constipation, urinary retention, and incontinence can also be seen.


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InternalMed_Harrison. The CSF protein is typically normal or mildly elevated. Liver function tests and hematologic parameters are usually normal. Some patients are hyponatremic due to inappropriate secretion of antidiuretic hormone (Chap. 401e). The urine may appear brownish in color secondary to 2681 the high concentration of porphyrin metabolites. Accumulation of intermediary precursors of heme (i.e., d-aminolevulinic acid, porphobilinogen, uroporphobilinogen, coproporphyrinogen, and protoporphyrinogen) is found in urine. Specific enzyme activities can also be measured in erythrocytes and leukocytes. The primary abnormalities on EDx are marked reductions in compound motor action potential (CMAP) amplitudes and signs of active axonal degeneration on needle EMG. The porphyrias are inherited in an autosomal dominant fashion.


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InternalMed_Harrison. The porphyrias are inherited in an autosomal dominant fashion. AIP is associated with porphobilinogen deaminase deficiency, HCP is caused by defects in coproporphyrin oxidase, and VP is associated with protoporphyrinogen oxidase deficiency. The pathogenesis of the neuropathy is not completely understood. Treatment with glucose and hematin may reduce the accumulation of heme precursors. Intravenous glucose is started at a rate of 10–20 g/h. If there is no improvement within 24 h, intravenous hematin 2–5 mg/kg per day for 3–14 days should be given.


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InternalMed_Harrison. Familial amyloid polyneuropathy (FAP) is phenotypically and genetically heterogeneous and is caused by mutations in the genes for transthyretin (TTR), apolipoprotein A1, or gelsolin (Chap. 137). The majority of patients with FAP have mutations in the TTR gene. Amyloid deposition may be evident in abdominal fat pad, rectal, or nerve biopsies. The clinical features, histopathology, and EDx reveal abnormalities consistent with a generalized or multifocal, predominantly axonal but occasionally demyelinating, sensorimotor polyneuropathy.


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InternalMed_Harrison. Patients with TTR-related FAP usually develop insidious onset of numbness and painful paresthesias in the distal lower limbs in the third to fourth decade of life, although some patients develop the disorder later in life. Carpal tunnel syndrome (CTS) is common. Autonomic involvement can be severe, leading to postural hypotension, constipation or persistent diarrhea, erectile dysfunction, and impaired sweating. Amyloid deposition also occurs in the heart, kidneys, liver, and corneas. Patients usually die 10–15 years after the onset of symptoms from cardiac failure or complications from malnutrition. Because the liver produces much of the body’s TTR, liver transplantation has been used to treat FAP related to TTR mutations. Serum TTR levels decrease after transplantation, and improvement in clinical and EDx features has been reported.


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InternalMed_Harrison. Patients with apolipoprotein A1-related FAP (Van Allen type) usually present in the fourth decade with numbness and painful dysesthesias in the distal limbs. Gradually, the symptoms progress, leading to proximal and distal weakness and atrophy. Although autonomic neuropathy is not severe, some patients develop diarrhea, constipation, or gastroparesis. Most patients die from systemic complications of amyloidosis (e.g., renal failure) 12–15 years after the onset of the neuropathy. Gelsolin-related amyloidosis (Finnish type) is characterized by the combination of lattice corneal dystrophy and multiple cranial neuropathies that usually begin in the third decade of life. Over time, a mild generalized sensorimotor polyneuropathy develops. Autonomic dysfunction does not occur. PRIMARY OR AL AMYLOIDOSIS (SEE CHAP. 137)


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InternalMed_Harrison. PRIMARY OR AL AMYLOIDOSIS (SEE CHAP. 137) Besides FAP, amyloidosis can also be acquired. In primary or AL amyloidosis, the abnormal protein deposition is composed of immunoglobulin light chains. AL amyloidosis occurs in the setting of multiple myeloma, Waldenström’s macroglobulinemia, lymphoma, other plasmacytomas, or lymphoproliferative disorders, or without any other identifiable disease.


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InternalMed_Harrison. Approximately 30% of patients with AL primary amyloidosis present with a polyneuropathy, most typically painful dysesthesias and burning sensations in the feet. However, the trunk can be involved, and some patients manifest with a mononeuropathy multiplex pattern. CTS occurs in 25% of patients and may be the initial manifestation. The neuropathy is slowly progressive, and eventually weakness 2682 develops along with large-fiber sensory loss. Most patients develop autonomic involvement with postural hypertension, syncope, bowel and bladder incontinence, constipation, impotence, and impaired sweating. Patients generally die from their systemic illness (renal failure, cardiac disease). The monoclonal protein may be composed of IgG, IgA, IgM, or only free light chain. Lambda (λ) is more common than κ light chain (>2:1) in AL amyloidosis. The CSF protein is often increased (with normal cell count), and thus the neuropathy may be mistaken for CIDP (Chap. 460). Nerve biopsies reveal axonal


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InternalMed_Harrison. than κ light chain (>2:1) in AL amyloidosis. The CSF protein is often increased (with normal cell count), and thus the neuropathy may be mistaken for CIDP (Chap. 460). Nerve biopsies reveal axonal degeneration and amyloid deposition in either a globular or diffuse pattern infiltrating the perineurial, epineurial, and endoneurial connected tissue and in blood vessel walls. The median survival of patients with primary amyloidosis is less than 2 years, with death usually from progressive congestive heart failure or renal failure. Chemotherapy with melphalan, prednisone, and colchicine, to reduce the concentration of monoclonal proteins, and autologous stem cell transplantation may prolong survival, but whether the neuropathy improves is controversial.


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InternalMed_Harrison. Diabetes mellitus (DM) is the most common cause of peripheral neuropathy in developed countries. DM is associated with several types of polyneuropathy: distal symmetric sensory or sensorimotor polyneuropathy, autonomic neuropathy, diabetic neuropathic cachexia, polyradiculoneuropathies, cranial neuropathies, and other mononeuropathies. Risk factors for the development of neuropathy include long-standing, poorly controlled DM and the presence of retinopathy and nephropathy.


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InternalMed_Harrison. DSPN is the most common form of diabetic neuropathy and manifests as sensory loss beginning in the toes that gradually progresses over time up the legs and into the fingers and arms. When severe, a patient may develop sensory loss in the trunk (chest and abdomen), initially in the midline anteriorly and later extending laterally. Tingling, burning, deep aching pains may also be apparent. NCS usually show reduced amplitudes and mild to moderate slowing of conduction velocities (CVs). Nerve biopsy reveals axonal degeneration, endothelial hyperplasia, and, occasionally, perivascular inflammation. Tight control of glucose can reduce the risk of developing neuropathy or improve the underlying neuropathy. A variety of medications have been used with variable success to treat painful symptoms associated with DSPN, including antiepileptic medications, antidepressants, sodium channel blockers, and other analgesics (Table 459-6).


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InternalMed_Harrison. Diabetic Autonomic Neuropathy Autonomic neuropathy is typically seen in combination with DSPN. The autonomic neuropathy can manifest as abnormal sweating, dysfunctional thermoregulation, dry eyes and mouth, pupillary abnormalities, cardiac arrhythmias, postural hypotension, GI abnormalities (e.g., gastroparesis, postprandial bloating, chronic diarrhea or constipation), and genitourinary dysfunction (e.g., impotence, retrograde ejaculation, incontinence). Tests of autonomic function are generally abnormal, including sympathetic skin responses and quantitative sudomotor axon reflex testing. Sensory and motor NCS generally demonstrate features described above with DSPN.


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InternalMed_Harrison. Diabetic Radiculoplexus Neuropathy (Diabetic Amyotrophy or Bruns-Garland Syndrome) Diabetic radiculoplexus neuropathy is the presenting manifestation of DM in approximately one-third of patients. Typically, patients present with severe pain in the low back, hip, and thigh in one leg. Rarely, the diabetic polyradiculoneuropathy begins in both legs at the same time. Atrophy and weakness of proximal and distal muscles in the affected leg become apparent within a few days or weeks. The neuropathy is often accompanied or heralded by severe weight loss. Weakness usually progresses over several weeks or months, but can continue to progress for 18 months or more. Subsequently, there is slow recovery but many are left with residual weakness, sensory loss, and pain. In contrast to the more typical lumbosacral radiculoplexus neuropathy, some patients develop thoracic radiculopathy or, even less commonly, a cervical polyradiculoneuropathy. CSF protein is usually elevated, while the cell count is


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InternalMed_Harrison. lumbosacral radiculoplexus neuropathy, some patients develop thoracic radiculopathy or, even less commonly, a cervical polyradiculoneuropathy. CSF protein is usually elevated, while the cell count is normal. ESR is often increased. EDx reveals evidence of active denervation in affected proximal and distal muscles in the affected limbs and in paraspinal muscles. Nerve biopsies may demonstrate axonal degeneration along with perivascular inflammation. Patients with severe pain are sometimes treated in the acute period with glucocorticoids, although a randomized controlled trial has yet to be performed, and the natural history of this neuropathy is gradual improvement.


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InternalMed_Harrison. Diabetic Mononeuropathies or Multiple Mononeuropathies The most common mononeuropathies are median neuropathy at the wrist and ulnar neuropathy at the elbow, but peroneal neuropathy at the fibular head, and sciatic, lateral femoral, cutaneous, or cranial neuropathies also occur. In regard to cranial mononeuropathies, seventh nerve palsies are relatively common but may have other, nondiabetic etiologies. In diabetics, a third nerve palsy is most common, followed by sixth nerve, and, less frequently, fourth nerve palsies. Diabetic third nerve palsies are characteristically pupil-sparing (Chap. 39). Hypothyroidism is more commonly associated with a proximal myopathy, but some patients develop a neuropathy, most typically CTS. Rarely, a generalized sensory polyneuropathy characterized by painful paresthesias and numbness in both the legs and hands can occur. Treatment is correction of the hypothyroidism.


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InternalMed_Harrison. Sjögren’s syndrome, characterized by the sicca complex of xerophthalmia, xerostomia, and dryness of other mucous membranes, can be complicated by neuropathy (Chap. 383). Most common is a length-dependent axonal sensorimotor neuropathy characterized mainly by sensory loss in the distal extremities. A pure small-fiber neuropathy or a cranial neuropathy, particularly involving the trigeminal nerve, can also be seen. Sjögren’s syndrome is also associated with sensory neuronopathy/ganglionopathy. Patients with sensory ganglionopathies develop progressive numbness and tingling of the limbs, trunk, and face in a non-length-dependent manner such that symptoms can involve the face or arms more than the legs. The onset can be acute or insidious. Sensory examination demonstrates severe vibratory and proprioceptive loss leading to sensory ataxia.


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InternalMed_Harrison. Patients with neuropathy due to Sjögren’s syndrome may have ANAs, SS-A/Ro, and SS-B/La antibodies in the serum, but most do not. NCS demonstrate reduced amplitudes of sensory studies in the affected limbs. Nerve biopsy demonstrates axonal degeneration. Nonspecific perivascular inflammation may be present, but only rarely is there necrotizing vasculitis. There is no specific treatment for neuropathies related to Sjögren’s syndrome. When vasculitis is suspected, immunosuppressive agents may be beneficial. Occasionally, the sensory neuronopathy/ganglionopathy stabilizes or improves with immunotherapy, such as IVIg.


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InternalMed_Harrison. Peripheral neuropathy occurs in at least 50% of patients with rheumatoid arthritis (RA) and may be vasculitic in nature (Chap. 380). Vasculitic neuropathy can present with a mononeuropathy multiplex, a generalized symmetric pattern of involvement, or a combination of these patterns (Chap. 385). Neuropathies may also be due to drugs used to treat the RA (e.g., tumor necrosis blockers, leflunomide). Nerve biopsy often reveals thickening of the epineurial and endoneurial blood vessels as well as perivascular inflammation or vasculitis, with transmural inflammatory cell infiltration and fibrinoid necrosis of vessel walls. The neuropathy often is responsive to immunomodulating therapies.


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InternalMed_Harrison. Between 2 and 27% of individuals with SLE develop a peripheral neuropathy (Chap. 378). Affected patients typically present with a slowly progressive sensory loss beginning in the feet. Some patients develop burning pain and paresthesias with normal reflexes, and NCS suggest a pure small-fiber neuropathy. Less common are multiple mononeuropathies presumably secondary to necrotizing vasculitis. Rarely, a generalized sensorimotor polyneuropathy meeting clinical, laboratory, electrophysiologic, and histologic criteria for either GBS or CIDP may occur. Immunosuppressive therapy is beneficial in SLE patients with neuropathy due to vasculitis. Immunosuppressive agents are less likely to be effective in patients with a generalized sensory or sensorimotor 2683 polyneuropathy without evidence of vasculitis. Patients with a GBS or CIDP-like neuropathy should be treated accordingly (Chap. 385).


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InternalMed_Harrison. A distal symmetric, mainly sensory, polyneuropathy complicates 5–67% of scleroderma cases (Chap. 382). Cranial mononeuropathies can also develop, most commonly of the trigeminal nerve, producing numbness and dysesthesias in the face. Multiple mononeuropathies also occur. The EDx and histologic features of nerve biopsy are those of an axonal sensory greater than motor polyneuropathy. A mild distal axonal sensorimotor polyneuropathy occurs in approximately 10% of patients with MCTD.


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InternalMed_Harrison. A mild distal axonal sensorimotor polyneuropathy occurs in approximately 10% of patients with MCTD. The peripheral or central nervous system is involved in about 5% of patients with sarcoidosis (Chap. 390). The most common cranial nerve involved is the seventh nerve, which can be affected bilaterally. Some patients develop radiculopathy or polyradiculopathy. With a generalized root involvement, the clinical presentation can mimic GBS or CIDP. Patients can also present with multiple mononeuropathies or a generalized, slowly progressive, sensory greater than motor polyneuropathy. Some have features of a pure small-fiber neuropathy. EDx reveals an axonal neuropathy. Nerve biopsy can reveal noncaseating granulomas infiltrating the endoneurium, perineurium, and epineurium along with lymphocytic necrotizing angiitis. Neurosarcoidosis may respond to treatment with glucocorticoids or other immunosuppressive agents.


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InternalMed_Harrison. Hypereosinophilic syndrome is characterized by eosinophilia associated with various skin, cardiac, hematologic, and neurologic abnormalities. A generalized peripheral neuropathy or a mononeuropathy multiplex occurs in 6–14% of patients. Neurologic complications, particularly ataxia and peripheral neuropathy, are estimated to occur in 10% of patients with celiac disease (Chap. 349). A generalized sensorimotor polyneuropathy, pure motor neuropathy, multiple mononeuropathies, autonomic neuropathy, small-fiber neuropathy, and neuromyotonia have all been reported in association with celiac disease or antigliadin/antiendomysial antibodies. Nerve biopsy may reveal a loss of large myelinated fibers. The neuropathy may be secondary to malabsorption of vitamins B12 and


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InternalMed_Harrison. E. However, some patients have no appreciable vitamin deficiencies. The pathogenic basis for the neuropathy in these patients is unclear but may be autoimmune in etiology. The neuropathy does not appear to respond to a gluten-free diet. In patients with vitamin B12 or vitamin E deficiency, replacement therapy may improve or stabilize the neuropathy. Ulcerative colitis and Crohn’s disease may be complicated by GBS, CIDP, generalized axonal sensory or sensorimotor polyneuropathy, small-fiber neuropathy, or mononeuropathy (Chap. 351). These neuropathies may be autoimmune, nutritional (e.g., vitamin B12 deficiency), treatment related (e.g., metronidazole), or idiopathic in nature. An acute neuropathy with demyelination resembling GBS, CIDP, or multifocal motor neuropathy may occur in patients treated with tumor necrosis factor α blockers.


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InternalMed_Harrison. Approximately 60% of patients with renal failure develop a polyneuropathy characterized by length-dependent numbness, tingling, allodynia, and mild distal weakness. Rarely, a rapidly progressive weakness and sensory loss very similar to GBS can occur that improves with an increase in the intensity of renal dialysis or with transplantation. Mononeuropathies can also occur, the most common of which is CTS. 2684 Ischemic monomelic neuropathy (see below) can complicate arteriovenous shunts created in the arm for dialysis. EDx in uremic patients reveals features of a length-dependent, primarily axonal, sensorimotor polyneuropathy. Sural nerve biopsies demonstrate a loss of nerve fibers (particularly large myelinated nerve fibers), active axonal degeneration, and segmental and paranodal demyelination. The sensorimotor polyneuropathy can be stabilized by hemodialysis and improved with successful renal transplantation.


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InternalMed_Harrison. A generalized sensorimotor neuropathy characterized by numbness, tingling, and minor weakness in the distal aspects of primarily the lower limbs commonly occurs in patients with chronic liver failure. EDx studies are consistent with a sensory greater than motor axonopathy. Sural nerve biopsy reveals both segmental demyelination and axonal loss. It is not known if hepatic failure in isolation can cause peripheral neuropathy, as the majority of patients have liver disease secondary to other disorders, such as alcoholism or viral hepatitis, which can also cause neuropathy.


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InternalMed_Harrison. The most common causes of acute generalized weakness leading to admission to a medical intensive care unit (ICU) are GBS and myasthenia gravis (Chap. 461). However, weakness developing in critically ill patients while in the ICU is usually caused by critical illness polyneuropathy (CIP) or critical illness myopathy (CIM) or, much less commonly, by prolonged neuromuscular blockade. From a clinical and EDx standpoint, it can be quite difficult to distinguish these disorders. Most specialists suggest that CIM is more common. Both CIM and CIP develop as a complication of sepsis and multiple organ failure. They usually present as an inability to wean a patient from a ventilator. A coexisting encephalopathy may limit the neurologic exam, in particular the sensory examination. Muscle stretch reflexes are absent or reduced.


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InternalMed_Harrison. Serum creatine kinase (CK) is usually normal; an elevated serum CK would point to CIM as opposed to CIP. NCS reveal absent or markedly reduced amplitudes of motor and sensory studies in CIP, whereas sensory studies are relatively preserved in CIM. Needle EMG usually reveals profuse positive sharp waves and fibrillation potentials, and it is not unusual in patients with severe weakness to be unable to recruit motor unit action potentials. The pathogenic basis of CIP is not known. Perhaps circulating toxins and metabolic abnormalities associated with sepsis and multiorgan failure impair axonal transport or mitochondrial function, leading to axonal degeneration.


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InternalMed_Harrison. Leprosy, caused by the acid-fast bacteria Mycobacterium leprae, is the most common cause of peripheral neuropathy in Southeast Asia, Africa, and South America (Chap. 203). Clinical manifestations range from tuberculoid leprosy at one end to lepromatous leprosy at the other end of the spectrum, with borderline leprosy in between. Neuropathies are most common in patients with borderline leprosy. Superficial cutaneous nerves of the ears and distal limbs are commonly affected. Mononeuropathies, multiple mononeuropathies, or a slowly progressive symmetric sensorimotor polyneuropathy may develop. Sensory NCS are usually absent in the lower limb and are reduced in amplitude in the arms. Motor NCS may demonstrate reduced amplitudes in affected nerves but occasionally can reveal demyelinating features. Leprosy is usually diagnosed by skin lesion biopsy. Nerve biopsy can also be diagnostic, particularly when there are no apparent skin lesions. The tuberculoid form is characterized by


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InternalMed_Harrison. features. Leprosy is usually diagnosed by skin lesion biopsy. Nerve biopsy can also be diagnostic, particularly when there are no apparent skin lesions. The tuberculoid form is characterized by granulomas, and bacilli are not seen. In contrast, with lepromatous leprosy, large numbers of infiltrating bacilli, TH2 lymphocytes, and organism-laden, foamy macrophages with minimal granulomatous infiltration are evident. The bacilli are best appreciated using the Fite stain, where they can be seen as red-staining rods often in clusters free in the endoneurium, within macrophages, or within Schwann cells.


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InternalMed_Harrison. Patients are generally treated with multiple drugs: dapsone, rifampin, and clofazimine. Other medications that are used include thalidomide, pefloxacin, ofloxacin, sparfloxacin, minocycline, and clarithromycin. Patients are generally treated for 2 years. Treatment is sometimes complicated by the so-called reversal reaction, particularly in borderline leprosy. The reversal reaction can occur at any time during treatment and develops because of a shift to the tuberculoid end of the spectrum, with an increase in cellular immunity during treatment. The cellular response is upregulated as evidenced by an increased release of tumor necrosis factor α, interferon γ, and interleukin 2, with new granuloma formation. This can result in an exacerbation of the rash and the neuropathy as well as in appearance of new lesions. High-dose glucocorticoids blunt this adverse reaction and may be used prophylactically at treatment onset in high-risk patients. Erythema nodosum leprosum (ENL) is also treated


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InternalMed_Harrison. of new lesions. High-dose glucocorticoids blunt this adverse reaction and may be used prophylactically at treatment onset in high-risk patients. Erythema nodosum leprosum (ENL) is also treated with glucocorticoids or thalidomide.


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InternalMed_Harrison. Lyme disease is caused by infection with Borrelia burgdorferi, a spirochete usually transmitted by the deer tick Ixodes dammini (Chap. 210). Neurologic complications may develop during the second and third stages of infection. Facial neuropathy is most common and is bilateral in about half of cases, which is rare for idiopathic Bell’s palsy. Involvement of nerves is frequently asymmetric. Some patients present with a polyradiculoneuropathy or multiple mononeuropathies. EDx is suggestive of a primary axonopathy. Nerve biopsies can reveal axonal degeneration with perivascular inflammation. Treatment is with antibiotics (Chap. 210).


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InternalMed_Harrison. Diphtheria is caused by the bacteria Corynebacterium diphtheriae (Chap. 175). Infected individuals present with flulike symptoms of generalized myalgias, headache, fatigue, low-grade fever, and irritability within a week to 10 days of the exposure. About 20–70% of patients develop a peripheral neuropathy caused by a toxin released by the bacteria. Three to 4 weeks after infection, patients may note decreased sensation in their throat and begin to develop dysphagia, dysarthria, hoarseness, and blurred vision due to impaired accommodation. A generalized polyneuropathy may manifest 2 or 3 months following the initial infection, characterized by numbness, paresthesias, and weakness of the arms and legs and occasionally ventilatory failure. CSF protein can be elevated with or without lymphocytic pleocytosis. EDx suggests a diffuse axonal sensorimotor polyneuropathy. Antitoxin and antibiotics should be given within 48 h of symptom onset. Although early treatment reduces the incidence and


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InternalMed_Harrison. pleocytosis. EDx suggests a diffuse axonal sensorimotor polyneuropathy. Antitoxin and antibiotics should be given within 48 h of symptom onset. Although early treatment reduces the incidence and severity of some complications (i.e., cardiomyopathy), it does not appear to alter the natural history of the associated peripheral neuropathy. The neuropathy usually resolves after several months.


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InternalMed_Harrison. HIV infection can result in a variety of neurologic complications, including peripheral neuropathies (Chap. 226). Approximately 20% of HIV-infected individuals develop a neuropathy either as a direct result of the virus itself, other associated viral infections (e.g., CMV), or neurotoxicity secondary to antiviral medications (see below). The major presentations of peripheral neuropathy associated with HIV infection include (1) distal symmetric polyneuropathy, (2) inflammatory demyelinating polyneuropathy (including both GBS and CIDP), (3) multiple mononeuropathies (e.g., vasculitis, CMV-related), (4) polyradiculopathy (usually CMV-related), (5) autonomic neuropathy, and (6) sensory ganglionitis.


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InternalMed_Harrison. HIV-Related Distal Symmetric Polyneuropathy (DSP) DSP is the most common form of peripheral neuropathy associated with HIV infection and usually is seen in patients with AIDS. It is characterized by numbness and painful paresthesias involving the distal extremities. The pathogenic basis for DSP is unknown but is not due to actual infection of the peripheral nerves. The neuropathy may be immune mediated, perhaps caused by the release of cytokines from surrounding inflammatory cells. Vitamin B12 deficiency may contribute in some instances but is not a major cause of most cases of DSP. Some antiretroviral agents (e.g., dideoxycytidine, dideoxyinosine, stavudine) are also neurotoxic and can cause a painful sensory neuropathy.


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InternalMed_Harrison. HIV-Related Inflammatory Demyelinating Polyradiculoneuropathy Both AIDP and CIDP can occur as a complication of HIV infection. AIDP usually develops at the time of seroconversion, whereas CIDP can occur any time in the course of the infection. Clinical and EDx features are indistinguishable from idiopathic AIDP or CIDP (discussed in Chap. 460). In addition to elevated protein levels, lymphocytic pleocytosis is evident in the CSF, a finding that helps distinguish this HIV-associated polyradiculoneuropathy from idiopathic AIDP/CIDP.


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InternalMed_Harrison. HIV-Related Progressive Polyradiculopathy An acute, progressive lumbosacral polyradiculoneuropathy usually secondary to CMV infection can develop in patients with AIDS. Patients present with severe radicular pain, numbness, and weakness in the legs, which is usually asymmetric. CSF is abnormal, demonstrating an increased protein along with reduced glucose concentration and notably a neutrophilic pleocytosis. EDx studies reveal features of active axonal degeneration. The polyradiculoneuropathy may improve with antiviral therapy. HIV-Related Multiple Mononeuropathies Multiple mononeuropathies can also develop in patients with HIV infection, usually in the context of AIDS. Weakness, numbness, paresthesias, and pain occur in the distribution of affected nerves. Nerve biopsies can reveal axonal degeneration with necrotizing vasculitis or perivascular inflammation. Glucocorticoid treatment is indicated for vasculitis directly due to HIV infection.


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InternalMed_Harrison. HIV-Related Sensory Neuronopathy/Ganglionopathy Dorsal root ganglionitis is a very rare complication of HIV infection, and neuronopathy can be the presenting manifestation. Patients develop sensory ataxia similar to idiopathic sensory neuronopathy/ganglionopathy. NCS reveal reduced amplitudes or absence of sensory nerve action potentials (SNAPs).


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InternalMed_Harrison. Peripheral neuropathy from herpes varicella-zoster (HVZ) infection results from reactivation of latent virus or from a primary infection (Chap. 217). Two-thirds of infections in adults are characterized by dermal zoster in which severe pain and paresthesias develop in a dermatomal region followed within a week or two by a vesicular rash in the same distribution. Weakness in muscles innervated by roots corresponding to the dermatomal distribution of skin lesions occurs in 5–30% of patients. Approximately 25% of affected patients have continued pain (postherpetic neuralgia [PHN]). A large clinical trial demonstrated that vaccination against zoster reduces the incidence of HVZ among vaccine recipients by 51% and reduces the incidence of PHN by 67%. Treatment of PHN is symptomatic (Table 459-6). CMV can cause an acute lumbosacral polyradiculopathy and multiple mononeuropathies in patients with HIV infection and in other immune deficiency conditions (Chap. 219).