(BQ) Part 2 book “Neuromuscular disorders” has contents: Toxic neuropathies, neuropathies associated with endocrinopathies, idiopathic polyneuropathy, autoimmune myasthenia gravis, muscular dystrophies, congenital myopathies, metabolic myopathies, mitochondrial disorders,… and other contents.
CHAPTER 20 Toxic Neuropathies This chapter reviews neuropathies associated with various drugs and other environmental exposures (Table 20-1) Toxic neuropathies due to chemotherapeutic agents are discussed in Chapter 19 The associated neuropathy for most of these is an axonal, length-dependent predominantly sensory neuropathy The history of exposure and sometimes the involvement of other organ systems help to suggest the correct diagnosis Although we mention features that have been reported on nerve biopsy, this is not typically part of the workup as in most cases the abnormalities are nonspecific ►► TOXIC NEUROPATHIES ASSOCIATED WITH MEDICATIONS Pathogenesis The pathogenic basis of the neuropathy is not known Some have found that metronidazole binds to DNA and/or RNA, which could lead to breaks and impair transcription or translation to normal proteins.7,8 Others have speculated that toxicity may arise from the production of nitro radical anions that bind and disrupt normal protein/enzyme function.8 Furthermore, the histological abnormalities in metronidazole-treated rodents and abnormalities on brain MRI scans in patients with metronidazole-associated encephalopathy resemble thiamine (vitamin B1) deficiency It has been postulated that there may be enzymatic conversion of metronidazole to an analog of thiamine, which may act as a B1 antagonist.9 METRONIDAZOLE MISONIDAZOLE Clinical Features Clinical Features Metronidazole is used to treat a variety of protozoan infections and Crohn disease.1–8 Metronidazole is a member of the nitroimidazole group and has been associated with hyperalgesia and hypesthesia in a length-dependent pattern Autonomic dysfunction may develop as well Motor strength is typically normal The cumulative dose at which neuropathy occurs is wide, ranging from 3.6 to 228 g Although there is no clear dose effect, neuropathy appears to occur more frequently in patients receiving greater than 1.5 g daily of metronidazole for 30 or more days The neuropathic symptoms usually improve upon discontinuation of the drug, but there can be a coasting effect such that the symptoms may continue to worsen for several weeks Some patients are left with residual sensory symptoms Misonidazole is used as an adjuvant agent in the treatment of various malignancies.10–13 As with metronidazole, misonidazole is a member of the nitroimidazole group Some patients have developed painful paresthesias and sometimes distal weakness in a length-dependent pattern after approximately 3–5 weeks of therapeutic drug administration (total dose greater than 18 g) Vibratory and temperature perception are usually reduced, but muscle stretch reflexes are preserved The neuropathy usually improves following discontinuation of the drug Laboratory Features Histopathology Nerve conduction studies (NCS) may be normal, as typical of a small fiber neuropathy, or reveal reduced amplitudes or absent sensory nerve action potentials (SNAPs) in the legs worse than in the arms Motor conduction studies are usually normal A reduction in the large myelinated fibers with axonal degeneration and segmental demyelination and remyelination has been found on sural nerve biopsies Accumulation of neurofilaments with axonal swellings can be found on electron microscopy (EM) Histopathology Pathogenesis Nerve biopsies are not routinely performed for this but have demonstrated loss of myelinated nerve fibers The pathogenic basis of the neuropathy is not known, but may be similar to metronidazole Laboratory Features Sensory NCS reveal reduced amplitudes or unobtainable responses in the legs more than the arms Motor conduction studies are typically normal Chapter 20 Toxic Neuropathies 449 ►► TABLE 20-1. TOXIC NEUROPATHIES Drug Mechanism of Neurotoxicity Misonidazole Unknown Metronidazole Unknown Chloroquine and hydroxychloroquine Amphiphilic properties may lead to drug–lipid complexes that are indigestible and result in accumulation of autophagic vacuoles Amphiphilic Paresthesia and pain with properties may loss of large and small lead to drug–lipid fiber sensory modalities complexes that and distal weakness in are indigestible length-dependent pattern; and result in superimposed myopathy accumulation may lead to proximal of autophagic weakness vacuoles Amiodarone Colchicine Inhibits polymerization of tubulin in microtubules and impairs axoplasmic flow Podophyllin Binds to microtubules and impairs axoplasmic flow Thalidomide Unknown Disulfiram Dapsone Accumulation of neurofilaments and impaired axoplasmic flow Unknown Leflunomide Unknown Clinical Features Painful paresthesias, loss of large and small fiber sensory modalities, and sometimes distal weakness in lengthdependent pattern Painful paresthesias, loss of large and small fiber sensory modalities, and sometimes distal weakness in lengthdependent pattern Loss of large and small fiber sensory modalities and distal weakness in length-dependent pattern; superimposed myopathy may lead to proximal weakness Numbness and paresthesia with loss of large fiber modalities in a lengthdependent fashion; superimposed myopathy may lead to proximal in addition to distal weakness Sensory loss, tingling, muscle weakness, and diminished muscle stretch reflexes in length-dependent pattern; autonomic neuropathy Numbness, tingling, burning pain, and weakness in a lengthdependent pattern Numbness, tingling, and burning pain in a lengthdependent pattern Distal weakness that may progress to proximal muscles; sensory loss Paresthesia and numbness in a length-dependent pattern Nerve Histopathology EMG/NCS Axonal degeneration of large myelinated fibers; axonal swellings; segmental demyelination Axonal degeneration Low-amplitude or unobtainable SNAPs with normal or only slightly reduced CMAP amplitudes Axonal degeneration with autophagic vacuoles in nerves as well as muscle fibers Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes; distal denervation on EMG; irritability and myopathic-appearing MUAPs proximally in patients with superimposed toxic myopathy Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes; can also have prominent slowing of CVs; distal denervation on EMG; irritability and myopathicappearing MUAPs proximally in patients with superimposed toxic myopathy Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes; irritability and myopathicappearing MUAPs proximally in patients with superimposed toxic myopathy Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Axonal degeneration and segmental demyelination with myeloid inclusions in nerves and muscle fibers Nerve biopsies demonstrate axonal degeneration; muscle biopsies reveal fibers with vacuoles Axonal degeneration Axonal degeneration; Autopsy studies reveal degeneration of dorsal root ganglia Axonal degeneration with accumulation of neurofilaments in the axons Axonal degeneration and segmental demyelination Unknown Low-amplitude or unobtainable SNAPs with normal CMAP Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Low-amplitude or unobtainable CMAPs with normal or reduced SNAP amplitudes Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes (continued) 450 SECTION II SPECIFIC DISORDERS ►► TABLE 20-1. (CONTINUED) Drug Mechanism of Neurotoxicity Nitrofurantoin Unknown Numbness, painful paresthesia, and severe weakness that may resemble GBS Pyridoxine (vitamin B6) Unknown Isoniazid Ethambutol Inhibit pyridoxal phosphokinase leading to pyridoxine deficiency Unknown Dysesthesia and sensory ataxia; impaired large fiber sensory modalities on examination Dysesthesia and sensory ataxia; impaired large fiber sensory modalities on examination Antinucleosides Unknown Phenytoin Unknown Lithium Unknown Acrylamide Unknown; may be caused by impaired axonal transport Carbon disulfide Unknown Ethylene oxide Unknown; may act as alkylating agent and bind DNA Binds and inhibits neuropathy target esterase Organophosphates Hexacarbons Unknown; may lead to covalent cross-linking between neurofilaments Lead Unknown; may interfere with mitochondria Clinical Features Numbness with loss of large fiber modalities on examination Dysesthesia and sensory ataxia; impaired large fiber sensory modalities on examination Numbness with loss of large fiber modalities on examination Numbness with loss of large fiber modalities on examination Numbness with loss of large fiber modalities on examination; sensory ataxia; mild distal weakness Length-dependent numbness and tingling with mild distal weakness Length-dependent numbness and tingling; may have mild distal weakness Early features are those of neuromuscular blockade with generalized weakness; later axonal sensorimotor PN ensues Acute, severe sensorimotor PN that may resemble GBS Encephalopathy; motor neuropathy (often resembles radial neuropathy with wrist and finger drop); autonomic neuropathy; bluish-black discoloration of gums Nerve Histopathology EMG/NCS Axonal degeneration; autopsy studies reveal degeneration of dorsal root ganglia and anterior horn cells Marked loss of sensory axons and cell bodies in dorsal root ganglia Marked loss of sensory axons and cell bodies in dorsal root ganglia and degeneration of the dorsal columns Axonal degeneration Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Axonal degeneration Reduced amplitudes or absent SNAPs Axonal degeneration and segmental demyelination Axonal degeneration Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Degeneration of sensory axons in peripheral nerves and posterior columns, spinocerebellar tracts, mamillary bodies, optic tracts, and corticospinal tracts in the CNS Axonal swellings with accumulation of neurofilaments Axonal degeneration Axonal degeneration along with degeneration of gracile fasciculus and corticospinal tracts Axonal degeneration and giant axons swollen with neurofilaments Axonal degeneration of motor axons Reduced amplitudes or absent SNAPs Reduced amplitudes or absent SNAPs and to a lesser extent CMAPs Reduced amplitudes or absent SNAPs Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Early: repetitive firing of CMAPs and decrement with repetitive nerve stimulation Late: axonal sensorimotor PN Features of a mixed axonal and/ or demyelinating sensorimotor axonal PN-reduced amplitudes, prolonged distal latencies, conduction block, and slowing of CVs Reduction of CMAP amplitudes with active denervation on EMG Chapter 20 Toxic Neuropathies 451 ►► TABLE 20-1. (CONTINUED) Drug Mechanism of Neurotoxicity Mercury Unknown; may combine with sulfhydryl groups Thallium Unknown Arsenic Unknown; may combine with sulfhydryl groups Gold Unknown Nerve Histopathology Clinical Features Abdominal pain and nephrotic syndrome; encephalopathy; ataxia; paresthesia Encephalopathy; painful sensory symptoms; mild loss of vibration; distal or generalized weakness may also develop; autonomic neuropathy; alopecia Abdominal discomfort, burning pain, and paresthesia; generalized weakness; autonomic insufficiency; can resemble GBS Distal paresthesia and reduction of all sensory modalities EMG/NCS Axonal degeneration; degeneration of dorsal root ganglia, calcarine, and cerebellar cortex Axonal degeneration Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Axonal degeneration Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes may have demyelinating features: prolonged distal latencies and slowing of CVs Low-amplitude or unobtainable SNAPs Axonal degeneration PN, polyneuropathy; EMG, electromyography; MUAPs, motor unit action potentials; NCS, nerve conduction studies; GBS, Guillain–Barré syndrome; CMAP, compound muscle action potential; SNAP, sensory nerve action potential; CV, conduction velocity CHLOROQUINE Clinical Features Chloroquine is used in the treatment of malaria, sarcoidosis, systemic lupus erythematosus, scleroderma, and rheumatoid arthritis (RA) Chloroquine is associated with a toxic myopathy characterized by slowly progressive, painless, proximal weakness and atrophy, which is worse in the legs than in the arms (discussed in Chapter 35).14–16 A neuropathy can also develop with or without the myopathy, leading to sensory loss, distal weakness, and reduced muscle stretch reflexes The “neuromyopathy” usually appears in patients taking 500 mg/d for a year or more but has been reported with doses as low as 200 mg/d The signs and symptoms of the neuropathy and myopathy are usually reversible following discontinuation of chloroquine Laboratory Features Serum creatine kinase (CK) levels are usually elevated due to the superimposed myopathy NCS reveal mild slowing of motor and sensory nerve conduction velocities (NCVs) with a mild to moderate reduction in the amplitudes NCS may be normal in patients with only the myopathy Electromyography (EMG) demonstrates myopathic motor unit action potentials (MUAPs), increased insertional activity in the form of positive sharp waves, fibrillation potentials, and occasionally myotonic potentials, particularly in the proximal muscles Neurogenic MUAPs and reduced recruitment are found in more distal muscles Histopathology Nerve biopsies demonstrate autophagic vacuoles and inclusions within Schwann cells (Fig 20-1) Vacuoles may also be evident in muscle biopsies Pathogenesis The pathogenic basis of the neuropathy is not known but may be related to the amphiphilic properties of the drug Chloroquine contains both hydrophobic and hydrophilic regions that allow chloroquine to interact with the anionic phospholipids of cell membranes and organelles This drug– lipid complex may be resistant to digestion by lysosomal enzymes, leading to the formation of autophagic vacuoles filled with myeloid debris that may, in turn, cause degeneration of nerves and muscle fibers HYDROXYCHLOROQUINE Hydroxychloroquine is structurally similar to chloroquine and, not surprisingly, has also been associated with a toxic neuromyopathy.17 Weakness and histological abnormalities are usually not as severe as seen in chloroquine myopathy Vacuoles are typically absent on biopsy, but EM still may 452 SECTION II SPECIFIC DISORDERS A B Figure 20-1. Chloroquine neuropathy Ultrastructural examination confirmed the presence of cytoplasmic lamellar inclusions in the Schwann cell cytoplasm (A) Close examination shows the dimorphism of the inclusions made up of both curvilinear bodies and laminated (myeloid) osmophilic material in smooth muscle cell (B) (Reproduced with permission from Bilbao JM: November 1998–70 year old woman with SLE, paraproteinemia and polyneuropathy Brain Pathol 1999;9(2):423–424.) demonstrate abnormal accumulation of myeloid and curvilinear bodies studies EMG demonstrates fibrillation potentials, positive sharp waves, and occasionally myotonic discharges with a mixture of myopathic and neurogenic-appearing MUAPs AMIODARONE Histopathology Clinical Features Muscle biopsies demonstrate neurogenic atrophy, particularly in distal muscles, and autophagic vacuoles with myeloid and dense inclusions on EM Sural nerve biopsies demonstrate a combination of segmental demyelination and axonal loss EM reveals lamellar or dense inclusions in Schwann cells, pericytes, and endothelial cells The inclusions in muscle and nerve biopsies have persisted as long as years following discontinuation of the medication Amiodarone is an antiarrhythmic medication that is also associated with a neuromyopathy similar to chloroquine18–23 Severe proximal and distal weakness can develop in the legs worse than in the arms, combined with distal sensory loss, tingling, and burning pain In addition, amiodarone is also associated with tremor, thyroid dysfunction, keratitis, pigmentary skin changes, hepatitis, pulmonary fibrosis, and parotid gland hypertrophy The neuromyopathy typically appears after patients have taken the medication for 2–3 years Physical examination demonstrates arm and leg weakness, reduced sensation to all modalities, and diminished muscle stretch reflexes The neuromyopathy usually improves following discontinuation of the drug Pathogenesis The pathogenesis is presumably similar to other amphiphilic medications (e.g., chloroquine) COLCHICINE Laboratory Features Clinical Features Sensory NCS reveal markedly reduced amplitudes and, when obtainable, mild to moderately slow conduction velocities and prolonged distal latencies.19,21,22 Motor NCS may also be abnormal, but usually not to the same degree as seen in sensory Colchicine is used primarily to treat patients with gout and is also associated with a toxic neuropathy and myopathy.24–26 Affected individuals usually present with proximal weakness along with numbness and tingling in the distal extremities Chapter 20 Toxic Neuropathies Reduced sensation to touch, vibration, position sense, and diminished muscle stretch reflexes are found on examination Laboratory Features Motor and sensory NCS demonstrate reduced amplitudes.24–26 The distal motor and sensory latencies can be normal or slightly prolonged and conduction velocities are normal or mildly slow EMG demonstrates fibrillation potentials and positive sharp waves along with short-duration, low-amplitude MUAPs in the proximal limb muscles and long-duration, large-amplitude MUAPs distally Histopathology Muscle biopsies reveal a vacuolar myopathy, while sensory nerve biopsies demonstrate axonal degeneration Pathogenesis Colchicine inhibits the polymerization of tubulin into microtubules The disruption of the microtubules probably leads to defective intracellular movement of important proteins, nutrients, and waste products in muscles and nerves.25 PODOPHYLLIN Clinical Features Podophyllin is a topical agent used to treat condylomata acuminata Systemic side effects include pancytopenia and liver and renal dysfunction Podophyllin is also potentially toxic to both the central and the peripheral nervous systems (PNS), leading to psychosis, altered consciousness, and polyneuropathy.27,28 The neuropathy is characterized by slowly progressive sensory loss, paresthesias, muscle weakness, and diminished muscle stretch reflexes in a length-dependent pattern Autonomic neuropathy with nausea, vomiting, gastrointestinal paresis, urinary retention, orthostatic hypotension, and tachycardia may also occur The signs and symptoms of this toxic neuropathy can progress for a couple of months even after stopping the medication The neuropathy gradually improves with discontinuation of the podophyllin, but it can take several months to over a year and residual deficits may remain Laboratory Features Cerebrospinal fluid (CSF) protein levels can be elevated Laboratory evaluation may also demonstrate pancytopenia, liver function abnormalities, and renal insufficiency Sensory NCS reveal absent SNAPs or their reduced amplitudes Motor NCS are less affected but can demonstrate reduced amplitudes Histopathology Nerve biopsies demonstrate axonal degeneration 453 Pathogenesis Podophyllin binds to microtubules similar to colchicine and probably inhibits axoplasmic flow leading to axonal degeneration.29 THALIDOMIDE Clinical Features Thalidomide is an immunomodulating agent used to treat multiple myeloma, graft-versus-host disease, leprosy, and other autoimmune disorders.30–36 Thalidomide is associated with severe teratogenic effects as well as peripheral neuropathy, which can be dose limiting Most patients who develop the neuropathy have received a cumulative dose of at least 20 g of thalidomide.34 Less than 10% of patients receiving less than 20 g of thalidomide develop polyneuropathy Patients complain of numbness, painful tingling, burning discomfort in the feet and hands, and less commonly muscle weakness and atrophy Even after stopping the drug for 4–6 years, as many as 50% of patients continue to have significant symptoms Physical examination demonstrates a reduction in vibration and position sense, hypo- or areflexia, and occasionally proximal and distal weakness Laboratory Features NCS demonstrate reduced amplitudes or complete absence of the SNAPs with preserved conduction velocities when obtainable.30–36 Motor NCS are usually normal Histopathology Nerve biopsies reveal a loss of large-diameter myelinated fibers and axonal degeneration.35 Degeneration of dorsal root ganglion cells has been appreciated on autopsies Pathogenesis The pathogenic basis of the neuropathy is not known DISULFIRAM Clinical Features Disulfiram (antabuse) is used to treat alcoholism It is metabolized to carbon disulfide, which is a neurotoxin and can have adverse effects on both the PNS and the central nervous system (CNS).37–44 A neuropathy with distal weakness (e.g., foot drop) and sensory loss may develop as early as 10 days to as long as 18 months after starting the drug Laboratory Features NCS are suggestive of an axonal sensorimotor polyneuropathy with reduced amplitudes or absent SNAPs and CMAPs with normal or only moderately slow conduction 454 SECTION II SPECIFIC DISORDERS velocities.37,40,41 Needle EMG reveals fibrillation potentials and positive sharp waves in distal muscles along with decreased recruitment of neurogenic-appearing MUAPs Histopathology Sural nerve biopsy has demonstrated axonal degeneration and segmental demyelination with a loss of predominately large-diameter fibers, although small-diameter fibers can be affected as well.37–40 On EM, swollen axonal due to the accumulation of neurofilamentous debris within the myelinated and unmyelinated axons may be appreciated Pathogenesis The neuropathy may be secondary to carbon disulfide, which is a metabolite of disulfiram A similar axonal neuropathy characterized by accumulation of neurofilaments occurs with carbon disulfide toxicity dehydrogenase This enzyme catalyzes the rate-limiting step in the de novo synthesis of pyrimidines that are necessary for lymphocyte production There have been several reports of patients treated with leflunomide who developed distal numbness and paresthesia.50–55 The median duration of treatment at the onset of neuropathy was 7.5 months (range weeks to 29 months) in one large study.52 Laboratory Features NCS may demonstrate features of a primarily axonal, sensorimotor polyneuropathy.50–55 More commonly, the NCS are normal and not correlate with symptoms, which suggests that leflunomide may cause a small fiber neuropathy.54 In this regard, a study of leflunomide treatment in patients with RA revealed abnormal cold detection on quantitative sensory testing compared to controls; vibratory thresholds were normal.55 Histopathology There are no reports of nerve biopsies DAPSONE Clinical Features Dapsone is used primarily for the treatment of leprosy and for various dermatologic conditions A primarily motor neuropathy can develop as early as days to as long as years after starting the drug.45–49 Weakness initially involves the hands and feet and over time progresses to affect more proximal muscles Occasionally, patients complain of sensory symptoms without weakness Pathogenesis The pathogenic basis for the neuropathy is not known Treatment The neuropathy usually improves after withdrawal of the medication NITROFURANTOIN Laboratory Features Clinical Features Motor and sensory NCS usually demonstrate reduced amplitudes with normal or only slightly slow conduction velocities.45–49 The NCS usually improve after the dapsone is discontinued Biopsy of the motor nerve terminal at the extensor brevis muscle has demonstrated axonal atrophy and Wallerian degeneration of the distal motor nerve terminals.49 Sural nerve biopsy may reveal a loss of myelinated nerve fibers Nitrofurantoin is an antibiotic most often used to treat urinary tract infections and may cause an acute and severe sensorimotor polyneuropathy 56–60 or a non–length-dependent small fiber neuropathy/ganglionopathy.61 Patients may develop numbness, painful paresthesia, and sometimes quadriparesis Elderly and those with baseline renal insufficiency are most at risk Physical examination most often reveals decrease of all sensory modalities (except in cases of small fiber neuronopathy) in the distal regions of the upper and lower limbs Muscle stretch reflexes are reduced or absent Most patients slowly improve following discontinuation of the drug Pathogenesis Laboratory Features The pathogenic basis of the neuropathy is not known NCS may demonstrate reduced amplitudes or absent SNAPs and CMAPs suggestive of an axonopathy58,59 or may be normal in cases of a small fiber neuropathy/ganglionopathy.61 Histopathology LEFLUNOMIDE Clinical Features Leflunomide is used for the treatment of RA It is a prodrug for an active metabolite that reversibly inhibits dihydroorotate Histopathology Sural nerve biopsy may reveal loss of large myelinated fibers with signs of active Wallerian degeneration.58 An autopsy study has shown degeneration of the spinal roots, dorsal Chapter 20 Toxic Neuropathies more severely affected than ventral roots, and chromatolysis of the anterior horn cells.57 Skin biopsies in patients with small fiber sensory neuropathy/ganglionopathy have shown distinctive morphologic changes with clustered terminal nerve swellings without a reduction in density.61 Pathogenesis The pathogenic basis of the neuropathy is not known PYRIDOXINE (VITAMIN B6) TOXICITY Clinical Features Pyridoxine is an essential vitamin that serves as a coenzyme for transamination and decarboxylation The recommended daily allowance in adults is 2–4 mg However, at high doses (116 mg/d) patients can develop a severe sensory neuropathy with dysesthesia and sensory ataxia.62–66 Some patients also complain of a Lhermitte’s sign There is one report of a patient taking 9.6 g pyridoxine per day who developed weakness as well.67 Neurological examination reveals marked impaired vibratory perception and proprioception Sensory loss can begin and be more severe in the upper than in the lower limbs Muscle strength is usually normal, although there may be loss of fine motor control Gait is wide based and unsteady secondary to the sensory ataxia Muscle stretch reflexes are reduced or absent Laboratory Features NCS usually reveal absent or markedly reduced SNAP amplitudes with relatively preserved CMAPs,62–66 although one case with severe weakness reported reduced CMAP amplitudes and moderately slowing of CVs.67 455 develops in at least 17% of patients taking in excess of mg/ kg/d of INH The elderly, malnourished, and “slow acetylators” are at increased risk of developing the neuropathy Patients present with numbness and tingling in their hands and feet The neuropathy usually develops after months in patients receiving smaller doses but can begin within a few weeks in patients on large doses The neuropathic symptoms resolve after a few days or weeks upon stopping the INH, if done early However, if the medication is continued, the neuropathy may evolve with more proximal numbness as well as distal weakness Recovery at this stage can take months and may be incomplete Examination reveals loss of all sensory modalities, distal muscle atrophy and weakness, reduced muscle stretch reflexes, and occasionally sensory ataxia Prophylactic administration of pyridoxine 100 mg/d can prevent the neuropathy from developing Laboratory Features NCS reveal decreased amplitudes of the SNAPs Histopathology Sural nerve biopsies reveal axonal degeneration and loss of both myelinated and unmyelinated nerve fibers.69 Autopsy studies have demonstrated degeneration of the dorsal columns Pathogenesis INH inhibits pyridoxal phosphokinase resulting in pyridoxine deficiency Because INH is metabolized by acetylation, individuals who are slow acetylators (an autosomal-recessive trait) maintain a higher serum concentration of INH and are more at risk of developing the neuropathy than people with rapid acetylation Acetylation can also slow with age Histopathology Nerve biopsies have shown loss of axons of all fiber diameters.65,66 Reduced numbers of dorsal root ganglion cells and subsequent degeneration of both the peripheral and the central sensory tracts have been appreciated in animal models Pathogenesis The pathogenic basis for the neuropathy associated with pyridoxine toxicity is not known ISONIAZID Clinical Features Isoniazid (INH) is used for the treatment of tuberculosis One of the most common side effects of INH is peripheral neuropathy.68–70 Standard doses of INH (3–5 mg/kg/d) are associated with a 2% incidence of neuropathy, while neuropathy ETHAMBUTOL Clinical Features Ethambutol is also used to treat tuberculosis and has been associated with a sensory neuropathy and a severe optic neuropathy in patients receiving prolonged doses in excess of 20 mg/kg/d.71,72 Patients develop numbness in the hands and feet without significant weakness Examination reveals a loss of large fiber modalities and reduced muscle stretch reflexes distally The peripheral neuropathy gradually improves after stopping of the medication; however, recovery of the optic neuropathy is more variable Laboratory Features NCS reveal decreased amplitudes of the SNAPs with normal sensory distal latencies and conduction velocities Motor conduction studies are usually normal 456 SECTION II SPECIFIC DISORDERS Histopathology Pathogenesis A decreased number of myelinated nerve fibers due to axonal degeneration has been noted in human and animal studies.73 These nucleoside analogs inhibit mitochondrial DNA polymerase, which is the suspected pathogenic basis for the neuropathy Acetyl-carnitine deficiency may contribute to the neurotoxicity of these nucleoside analogs Pathogenesis The pathogenic basis of the neuropathy is not known PHENYTOIN FLUOROQUINOLONES The fluoroquinolones are wide-spectrum antibiotics that have been associated with a sensory polyneuropathy and optic neuropathy.74,75 In a review, onset of adverse events was described as usually being rapid, with 33% of patients developing symptoms within 24 hours of initiating treatment, 58% within 72 hours, and 84% within one week.74 There also has been a report that fluoroquinolones might unmask previously unrecognized hereditary neuropathy.75 NUCLEOSIDE NEUROPATHIES Clinical Features The nucleoside analogs zalcitabine (dideoxycytidine or ddC), didanosine (dideoxyinosine or ddI), stavudine (d4T), and lamivudine (3TC) are antiretroviral nucleoside reverse transcriptase inhibitor used to treat HIV infection One of the major dose-limiting side effects of these medications is a predominantly sensory, length-dependent, symmetrically painful neuropathy.76–79 ddC is the most extensively studied nucleoside analog and at doses greater than 0.18 mg/kg/d, is associated with a subacute onset of severe burning and lancinating pains in the feet and hands One-third of patients on lower doses of ddC (0.03 mg/kg/d) develop a neuropathy within week to a year (mean of 16 weeks) after starting the medication On examination, hyperpathia, reduced pinprick, and temperature sensation, and to a lesser degree impaired touch and vibratory perception are found Muscle stretch reflexes are diminished, particularly at the ankles Occasionally, mild weakness of the ankles and of foot intrinsics is appreciated Because of a “coasting effect,” patients can continue to worsen even 2–3 weeks after stopping the medication However, improvement in the neuropathy is seen in most patients following dose reduction after several months (mean time about 10 weeks) Laboratory Features Sensory NCS reveal decreased amplitudes or absent responses with normal distal latencies and CVs.76–79 Motor NCS are usually normal Impaired temperature and vibratory thresholds have been noted on QST.76 The QST abnormalities, particularly vibratory perception precede clinical symptoms or standard nerve conduction abnormalities Clinical Features Phenytoin is a commonly used antiepileptic medication A rare side effect of phenytoin is a mild, primarily sensory neuropathy associated with reduced light touch, proprioception, and vibration as well as diminished or absent muscle stretch reflexes at the ankles.80–84 Mild distal weakness may be seen The neuropathy improves on discontinuation of the medication Laboratory Features NCS reveal decreased amplitudes of the SNAPs with normal sensory distal latencies and conduction velocities NCS demonstrate slightly reduced amplitudes and slow CVs in about 20% of patients taking only phenytoin Motor NCS are usually normal Histopathology Sural nerve biopsy has reportedly demonstrated a loss of the large myelinated axons along with segmental demyelination and remyelination.84 Pathogenesis The pathogenic basis of the neuropathy is not known LITHIUM Clinical Features Lithium is more often associated with CNS toxicity (tremor, dysarthria, confusion, obtundation, sweating, and seizures), but some patients have developed sensorimotor peripheral neuropathies (distal motor and sensory loss and reduced muscle stretch reflexes).85–87 Laboratory Features NCS reveal decreased amplitudes of the SNAPs with normal sensory distal latencies and conduction velocities NCS demonstrate reduced amplitudes or absent SNAPs and CMAPs Histopathology Nerve biopsies have demonstrated a loss of large myelinated fibers Chapter 20 Toxic Neuropathies Pathogenesis The pathogenic basis of the neuropathy is not known STATINS Several case reports and epidemiologic series suggest that statin use may be associated with a small risk of peripheral neuropathy.88–91 However, we must emphasize that these reports not establish that statins cause peripheral neuropathy Many patients on statins have other neuropathic comorbidities which confounds assignment of causal status The neuropathy that has been associated with statin usage is predominantly sensory and typical of “idiopathic sensory polyneuropathy.” Some, but not all patients, report improved symptoms following discontinuation of the statin Because of the well-known benefits to statins, particularly in high-risk patients, and the unproven causal nature of statin use and neuropathies we not typically advise our patients to discontinue statin use ►► TOXIC NEUROPATHIES ASSOCIATED WITH INDUSTRIAL AGENTS 457 NCS reveal absent or markedly reduced amplitude in the SNAPs.92–96 The CMAP amplitudes are normal or only slightly reduced, but temporal dispersion of the CMAPs may be observed in patients exposed to high levels of the substance Histopathology Sural nerve biopsies reveal axonal degeneration with loss of the large myelinated fibers The earliest histological abnormality in animals exposed to acrylamide is paranodal accumulation of 10-nm neurofilaments at the distal ends of the peripheral nerves Subsequently, the distal axons enlarge and degenerate as can the posterior columns, spinocerebellar tracts, optic tracts, mammillary bodies, and the corticospinal tracts Pathogenesis The exact pathogenic basis for the toxic neuropathy is unknown but is felt that acrylamide impairs fast bidirectional axonal transport as well as slow antegrade transport ACRYLAMIDE CARBON DISULFIDE Clinical Features Clinical Features Acrylamide, a vinyl monomer, is an important industrial agent used as a flocculating and grouting agent It can be absorbed through the skin, ingested (following exposure to contaminated well water due to acrylamide grouting of the wells) or inhaled into the lungs Following exposure, affected individuals may develop a distal sensorimotor polyneuropathy characterized by a loss of large fiber function.92–96 Pain and paresthesia are uncommon Some patients have ataxia and dysarthria; increasing irritability may also be seen Chronic low-level exposure may cause mental confusion and hallucinations in addition to weakness, gait difficulties, and occasionally urinary incontinence Exposure to the skin is associated with contact dermatitis On examination, there is a loss of vibration and proprioception with relatively good preservation of touch, pain, and temperature sensation Patients may be ataxic and demonstrate a positive Romberg sign Muscle stretch reflexes are reduced Mild distal muscle atrophy and weakness may be appreciated Patients with only low levels of exposure usually make a good recovery; however, those exposed to large amounts can take a year or more for significant improvement to occur and may not completely recover Carbon disulfide is used to make rayon and cellophane and can be inhaled or absorbed through the skin Acute exposure to high levels of carbon disulfide may lead to CNS abnormalities (e.g., psychosis), which resolve with elimination of exposure Chronic low-level exposure to carbon disulfide has also been associated with a toxic peripheral neuropathy characterized by length-dependent numbness and tingling.97 Examination reveals a loss of all sensory modalities and diminished muscle stretch reflexes Mild muscle atrophy and weakness may be evident distally Laboratory Features NCS reveal decreased amplitudes of the SNAPs with normal sensory distal latencies and conduction velocities Laboratory Features NCS reveal slowing of sensory and perhaps motor CVs Histopathology Detailed descriptions of the histopathology in humans are lacking However, experimental studies in animals have shown accumulation of 10-nm neurofilaments and axonal swellings similar to that seen in acrylamide and hexacarbon toxicity Pathogenesis The pathogenic basis for the neuropathy is not known 934 Index Fast channel syndromes, 633 Fazio Londe syndrome, 213 FCMD See Fukuyama congenital muscular dystrophy (FCMD) FDC See Functional dual coating (FDC) Femoral nerve, 541f, 542, 544, 546f, 548f Femoral neuropathy, 570–571 Fiberoptic endoscopic evaluation of swallowing (FEES), 143, 166 Fibric acid derivatives, myopathies by, 890 Fibrofatty replacement, 669 Fibromyalgia, 882–883 Fibular (peroneal) nerve, 542f, 546, 549f Filamin-C, 703 Finasteride myopathy, 898–899 Finger–nose test, 14 Fingerprint body myopathy, 732 clinical features, 732 histopathology, 732 laboratory features, 732 molecular genetics and pathogenesis, 732 treatment, 732 Finkelstein test, 915, 916f Flavin adenine dinucleotide (FAD), 759 Flexibility training, 145, 145t Flick sign, 526 Floor reaction orthoses (FROs), 152, 152f Floppy infant, 629 Fluoroquinolones, neuropathy by, 456 Focal mitochondrial depletion, 790–791 clinical features, 790 histopathology, 790–791 laboratory features, 790 molecular genetics and pathogenesis, 791 treatment, 791 Focal myositis, 853–854 clinical features, 853 histopathology, 853 laboratory features, 853, 854f pathogenesis, 854 Folate deficiency, 421 Foodborne botulism, 637 Foot abnormalities, rehabilitation approach for, 163–164 Foot drop, rehabilitation of, 162–163 Forearm crutch, 154, 154f Forearm exercise test, 19, 779 Freeze-fracture analysis, 624 Friedreich ataxia (FA), 203, 306 clinical features, 306 histopathology, 306 laboratory features, 306 molecular genetics and pathogenesis, 306 treatment, 306 Frontotemporal lobar degeneration (FTLD), 174, 177, 189 See also Amyotrophic lateral sclerosis (ALS) FROs See Floor reaction orthoses (FROs) FSHD See Facioscapulohumeral muscular dystrophy (FSHD) FTLD See Frontotemporal lobar degeneration (FTLD) Fukutin, 661, 678, 683 Fukutin-related protein (FKRP), 661 Fukuyama congenital muscular dystrophy (FCMD), 661, 683 clinical features, 683 laboratory features, 683 molecular genetics and pathogenesis, 683 Functional dual coating (FDC), 639 Fungal myositis, 857 F-wave, 30–32, 31f, 506 G Gastric/bariatric surgery, peripheral neuropathy with, 422 Gastrocnemius muscles, 688 GBS See Guillain–Barré syndrome (GBS) Gelsolin-related amyloidosis, 397 clinical features, 397, 398f histopathology, 397 molecular genetics and pathogenesis, 397 treatment, 397 Gene therapy, in dystrophinopathies treatment, 666–667 Genetic counseling, in hereditary spastic paraparesis, 205 Genitofemoral nerve, 541–542, 541f, 546f Genitofemoral neuropathy, 569 GFPT1 See Glutamine-Fructose-6-Phosphate Transaminase (GFPT1) Giant axonal neuropathy, 309–310 clinical features, 309 histopathology, 309, 310f laboratory features, 309 molecular genetics and pathogenesis, 310 Giant cell arteritis, 373 See also Vasculitic meuropathies Gitelman syndrome, 817 Gleevec See Imatinib mesylate Globoid cell leukodystrophy See Krabbe disease Glue sniffer’s neuropathy, 458–459, 459f l-Glutamic acid decarboxylase (GAD), 257 Glutamine-Fructose-6-Phosphate Transaminase (GFPT1), 629, 633 Glutaric aciduria type II See Multi-acyl-CoA dehydrogenase deficiency (MADD) Gluten-induced enteropathy See Celiac disease Glyceraldehyde 3-phosphate, 755 Glycerol kinase, 667 Glycerol kinase deficiency (GKD), 667–668 Glyceroluria, 667 Glycogen branching enzyme (GBE1), 750 Glycogenin deficiency See Glycogenosis type XV Glycogenoses, 742 Glycogenosis type 0, 742–743 clinical features, 742–743 histopathology, 743 laboratory features, 743 molecular genetics and pathogenesis, 743 treatment, 743 Glycogenosis type II, 743–747 clinical features, 745 histopathology, 745–746, 746f laboratory features, 745 molecular genetics and pathogenesis, 746–747 treatment, 747 Glycogenosis type III, 747–748 cause, 747 clinical features, 747 histopathology, 747–748 laboratory features, 747 molecular genetics and pathogenesis, 748 treatment, 748 Glycogenosis type IV, 748–750 cause, 748 clinical features, 748 histopathology, 748, 749f laboratory features, 748 molecular genetics and pathogenesis, 750 treatment, 750 Glycogenosis type V, 750–751 clinical features, 750 histopathology, 750 laboratory features, 750 molecular genetics and pathogenesis, 750–751 treatment, 751 Glycogenosis type VII, 751–752 clinical features, 751 histopathology, 752 laboratory features, 752 molecular genetics and pathogenesis, 752 treatment, 752 Glycogenosis type VIII/IX, 752 clinical features, 752 histopathology, 752 laboratory features, 752 molecular genetics and pathogenesis, 752 treatment, 752 Glycogenosis type X, 753 clinical features, 753 histopathology, 753 laboratory features, 753 molecular genetics and pathogenesis, 753 treatment, 753 Glycogenosis type XI, 753 clinical features, 753 histopathology, 753 laboratory features, 753 molecular genetics and pathogenesis, 753 treatment, 753 Glycogenosis type XII, 753–754 clinical features, 753 histopathology, 753 laboratory features, 753 molecular genetics and pathogenesis, 753 treatment, 754 Glycogenosis type XIII, 754 clinical features, 754 histopathology, 754 laboratory features, 754 molecular genetics and pathogenesis, 754 treatment, 754 Glycogenosis type XIV, 754 clinical features, 754 histopathology, 754 laboratory features, 754 molecular genetics and pathogenesis, 754 treatment, 754 Glycogenosis type XV, 754 clinical features, 754 histopathology, 754 laboratory features, 754 molecular genetics and pathogenesis, 754 treatment, 754 Glycogen storage diseases (GSD), 19–20, 742 Glycolytic pathways, 744f See also Glycogenosis type Index 935 GNE myopathy, 699, 704 See also Nonaka distal myopathy Gold therapy, neuropathy by, 461 Gomori trichrome stain, 702, 726, 780 Gout syndrome, 392, 757 Gower maneuver, 745 Gowers sign, 719 Graft-versus-host disease (GVHD), 438 Granulomatosis with polyangiitis, 376 See also Vasculitic meuropathies Granulomatous myositis, 852, 852f Greater trochanteric bursitis, 918–919 diagnosis, 918–919, 918f symptoms, 918 treatment, 919 GSD See Glycogen storage diseases (GSD) Guanidine in botulism treatment, 641 in LEMS treatment, 626, 647 Guillain–Barre syndrome (GBS), 320–334, 639 acute inflammatory demyelinating polyradiculoneuropathy, 320–327 axonal GBS acute motor axonal neuropathy (AMAN), 328–330 acute motor–sensory axonal neuropathy (AMSAN), 327–328 immune mechanisms in, 326f and related disoders, 320, 321t autoimmune autonomic neuropathy, 333–334 idiopathic sensory neuronopathy, 331–332 Miller Fisher syndrome, 330–331 small fiber neuropathies, 332–333 Guyon’s canal, 502 H Hand splints, 151, 151f Hand weakness, rehabilitation approach for, 161–162 Hansen disease See Leprosy Hawkins test, 911, 912f HBAT See Heptavalent botulinum antitoxin (HBAT) Head ptosis, rehabilitation approach in, 160 HELLP See Hemolysis, elevated liver enzymes, low platelets (HELLP) Hemolysis, elevated liver enzymes, low platelets (HELLP), 764 Heptavalent botulinum antitoxin (HBAT), 640 Hereditary ataxias, 299t, 306 abetalipoproteinemia, 307–308 ataxia-telangiectasia, 308 ataxia with oculomotor apraxia type 1, 308 ataxia with oculomotor apraxia type 2, 308–309 Cockayne syndrome, 309 Friedreich ataxia, 306 vitamin E deficiency, 306–307 Hereditary IBM Type 3, 704–705 clinical features, 704 histopathology, 705 laboratory features, 705 molecular genetics and pathogenesis, 705 Hereditary inclusion body myopathies (H-IBM), 704 with cerebral hypomyelination, 705 with Paget disease and frontotemporal dementia, 705 causes, 705 Hereditary inclusion body myopathies with Paget disease and frontotemporal dementia (h-IBMPFD) clinical features, 705 histopathology, 705 laboratory features, 705 molecular genetics and pathogenesis, 705 Hereditary inclusion body myopathy (h-IBM2), 704 clinical features, 704 histopathology, 704 laboratory features, 704 molecular genetics and pathogenesis, 704 treatment, 704 Hereditary myopathy with early respiratory failure, 677–678 clinical features, 677–678 histopathology, 678 laboratory features, 678 molecular genetics and pathogenesis, 678 Hereditary myopathy with early respiratory failure (HMERF), 676 Hereditary neuralgic amyotrophy (HNA), 281–282, 519 clinical features, 281 histopathology, 282 laboratory features, 282 molecular genetics and pathogenesis, 282 Hereditary neuropathy with liability to pressure palsies (HNPP), 269, 270f, 271–272 clinical features, 271–272 histopatholgy, 272, 272f laboratory features, 272 molecular genetics and pathogenesis, 272 Hereditary neuropathy with neuromyotonia, 282 Hereditary sensory and autonomic neuropathies (HSANs), 282–284, 283t HSAN1 clinical features, 284 histopathology, 284, 285f laboratory features, 284 molecular genetics and pathogenesis, 284 HSAN2 clinical features, 284, 286f histopathology, 285, 286f laboratory features, 284 molecular genetics and pathogenesis, 285–286 HSAN3 clinical features, 285–286 histopathology, 286 laboratory features, 286 molecular genetics and pathogenesis, 286–287 HSAN4 clinical features, 287 histopathology, 287 laboratory features, 287 molecular genetics and pathogenesis, 287 HSAN5 clinical features, 287 histopathology, 287 molecular genetics and pathogenesis, 287 Hereditary spastic paraparesis (HSP), 184, 199–206, 200t–201t clinical features, 199, 202 circumducting leg with equinovarus foot posturing, 199, 201f hammer toes and cavus deformity, 199, 201f complicated, 199 differential diagnosis, 202–203 histopathology, 204 laboratory features, 203 management, 204–206, 205t pathogenesis, 204 uncomplicated, 199 Herpes varicella-zoster (HVZ) infection, neuropathy with, 414–415 clinical features, 414 histopathology, 414 laboratory features, 414 pathogenesis, 414 treatment, 415 Hexacarbon toxicity, 458–459 Hexosaminidase A deficiency, 185 h-IBM2 See Hereditary inclusion body myopathy (h-IBM2) Hidden botulism, 638 Highly active antiretroviral therapy (HAART), 895 Hip joint osteoarthritis, 917–918 diagnosis, 917–918, 917f symptoms, 917 treatment, 918 Hirayama disease, 183, 216 clinical features, 216 asymmetric forearm and hand atrophy, 216, 216f tremor and cold paresis, 216 differential diagnosis, 216–21 electrodiagnosis, 217 histopathology, 217 laboratory features, 217 management, 217–218 pathophysiology, 217 History taking, 3–10 See also Neuromuscular disorders ankle weakness, autonomic system function impairment, symptoms of, 9–10 elbow flexion and extension weakness, extraocular muscle involvement, facial weakness, 7, 8t hip flexion, weakness of, hypoventilation symptom, 8–9 jaw weakness, knee extensor weakness, lower motor neuron disorders, 6–7 motor symptoms, 3, muscle weakness, 4t–6t, neck muscles, weakness of, 8, 8t pain history, 10 ptosis, 7, 7t questioning in, scapula, weakness of, 8, 8t sensory symptoms, 3–4, shoulder girdle weakness, symptoms identification, system review, 936 Index History taking (Continued ) tongue weakness, 7–8 UMN involvement, ventilatory muscle weakness, 8, 8t wrist and digit weakness, HIV See Human immunodeficiency virus (HIV) HMERF See Hereditary myopathy with early respiratory failure (HMERF) HMG-CoA reductase inhibitors, myopathies by, 887, 889–890, 889f HMSN IV See Refsum disease HMSN-Lom, 279–280 HNA See Hereditary neuralgic amyotrophy (HNA) HNPP See Hereditary neuropathy with liability to pressure palsies (HNPP) Holocyclotoxin, 643 Holter monitoring, 667 Horner syndrome, 491 H reflex, 30–32, 32f, 506, 622 HSP See Hereditary spastic paraparesis (HSP) Hu antigens, 428 Human Genome Organization, 680 Human immunodeficiency virus (HIV), 854–855 peripheral neuropathy with, 411–414, 411t autonomic neuropathy, 413 distal symmetric polyneuropathy, 411–412 inflammatory demyelinating polyneuropathy, 412 multiple mononeuropathies, 413 progressive polyradiculopathy, 412–413 sensory neuronopathy/ganglionopathy, 413–414 Human T-leukemia virus (HTLV-1), 414, 855 Humeral cuff slings, 150 Hutchinson–Gilford progeria syndrome, 670 Hyaline body myopathy, 732–734 clinical features, 732 histopathology, 733, 733f laboratory features, 733 molecular genetics and pathogenesis, 733–734 treatment, 734 Hydroxychloroquine myopathy, 892 Hydroxychloroquine neuropathy, 451–452 Hypercalcemia, 880 Hyperekplexia, 258–259 clinical features, 258 diagnosis and differential diagnosis, 258 histopathology, 259 laboratory features, 258–259 pathogenesis, 259 treatment, 259 Hypereosinophilic syndrome (HES), 390, 850 Hyperglycerolemia, 667 Hyperkalemia, 879–880 Hypermagnesemia, 648, 880 Hyperparathyroidism and motor neuron disease, 875 and osteomalacia, 874–875 Hypersensitivity vasculitis, 377, 377f See also Vasculitic meuropathies Hypertension and tick paralysis, 642 Hyperuricemic syndromes, 757 Hypoglycemia/hyperinsulinemia, 473–474 clinical features, 473 histopathology, 474 laboratory features, 473–474 pathogenesis, 474 treatment, 474 Hypokalemia, 879 HYPOKPP1 See Primary hypokalemic periodic paralysis type (HYPOKPP1) Hypomagnesemia, 880 Hypoparathyroidism, 875–876 clinical features, 875–876 histopathology, 876 laboratory features, 876 pathogenesis, 876 treatment, 876 Hypophosphatemia, 423, 880 Hypothyroidism, 474–475 clinical features, 474 histopathology, 474 laboratory features, 474 pathogenesis, 474 treatment, 474 Hypothyroid myopathy, 873–874 clinical features, 873 histopathology, 874 laboratory features, 873–874 pathogenesis, 874 treatment, 874 Hypotonia, 638 I IBM See Inclusion body myositis (IBM) Ice therapy, 914, 914f, 919 Idiopathic polyneuropathies, 478–488 chronic, idiopathic, length-dependent sensory or sensorimotor polyneuropathy, 478–485 facial onset sensory and motor neuronopathy, 487–488 idiopathic sensory neuronopathy/ ganglionopathy, 485–487 idiopathic small fiber sensory neuronopathy, 487 Idiopathic sensory neuronopathy, 485–487 clinical features, 485–486 histopathology, 486 laboratory features, 486 pathogenesis, 486 treatment, 486–487 Idiopathic sensory neuronopathy/ ganglionopathy, 331–332 clinical features, 331 histopathology, 332 laboratory features, 332 pathogenesis, 332 treatment, 332 Idiopathic sensory/sensorimotor polyneuropathy with cancer, 430–431 clinical features, 430 histopathology, 430 laboratory features, 430 pathogenesis, 430–431 treatment, 431 Idiopathic small fiber sensory neuronopathy, 487 clinical features, 487 histopathology, 487 laboratory features, 487 pathogenesis, 487 treatment, 487 Ifosfamide, 442 IGRA See Interferon (IFN) gamma release assay (IGRA) Iliohypogastric nerve, 541, 546f Iliohypogastric neuropathy, 569 Ilioinguinal nerve, 541, 546f Ilioinguinal neuropathy, 568–569 Imaging, nerve and muscle, 75–78 Imatinib mesylate, 897 Immune-mediated brachial plexus neuropathy (IBPN), 514–515 Immune-mediated necrotizing myopathy (IMNM), 848–849 See also Inflammatory myopathies clinical features, 848–849 histopathology, 849, 849f laboratory features, 849 pathogenesis, 849 treatment, 849 Immunohistochemistry, 92–93, 94f Immunomodulating therapy, 114–131 drugs used, 115–116t general considerations, 114, 116, 118 immunosuppressive therapy, 117t individual treatments modalities, 120 alemtuzumab, 120–121 azathioprine, 121–122 corticosteroids, 122–123 cyclophosphamide, 124 cyclosporine, 124–125 eculizumab, 125 etanercept, 125–126 infliximab, 126 interferon α and β, 126 intravenous immunoglobulin, 126–128 methotrexate, 128–129 mycophenolate mofetil, 129–130 plasma exchange, 130 rituximab, 130–131 tacrolimus, 131 in MG, 605–608 risk considerations with, 118–120 cancer, 120 infectious disease, 118–120 Pneumocystis jirovecii, 118–119 pregnancy and children, 120 progressive multifocal leukoencephalopathy, 119 stongyloidiasis, 119–120 tuberculosis, 119 vaccines, 120 Immunomodulation, definition of, 114 See also Immunomodulating therapy Immunosuppression, definition of, 114 See also Immunomodulating therapy Immunosuppressive therapy, 859t See also Immunomodulating therapy for vasculitic neuropathy, 378–379 IMNM See Immune-mediated necrotizing myopathy (IMNM) Impaired glucose tolerance (IGT), 466–467, 478 Index 937 Inborn errors of metabolism, biochemical testing for, 64, 68, 69t Inclusion body myositis (IBM), 18, 663, 843– 848 See also Inflammatory myopathies associated manifestations, 844 clinical features, 843–844, 843f differential diagnosis, 848 electrophysiological studies, 845 histopathology, 845–847, 845f–847f laboratory features, 844, 844f, 845f pathogenesis, 847–848 prognosis, 848 role of exercise in, 147 Infantile botulism, 637 Infantile neuroaxonal dystrophy, 310 Infantile spinal muscular atrophies, non-SMN, 212–213 Infection, neuropathies associated with, 404–415, 405t cytomegalovirus infection, 414 diphtheritic neuropathy, 410–411 Epstein–Barr virus infection, 414 hepatitis viruses, 414 herpes varicella-zoster (HVZ) infection, 414–415 HIV infection, 411, 411t autonomic neuropathy, 413 distal symmetric polyneuropathy, 411–412 inflammatory demyelinating polyneuropathy, 412 multiple mononeuropathies, 413 progressive polyradiculopathy, 412–413 sensory neuronopathy/ganglionopathy, 413–414 human T-lymphocyte type (HTLV-1) infection, 414 leprosy, 404–409 Lyme disease, 409–410 Infection-related vasculitis, 376 See also Vasculitic meuropathies Infiltrating tumors, 431, 432f, 433f Inflammatory bowel disease, 389 Inflammatory demyelinating polyneuropathy, HIV-related, 412 Inflammatory myopathies, 827–863 bacterial infections, 856 Behcet’s disease, 853 Bohan and Peter criteria, 827, 832t clinical and laboratory features, 828t dermatomyositis, 827–838 diagnostic criteria, 829–831t diffuse fasciitis with eosinophilia, 851–852 eosinophilic myopathy, 850–851 European neuromuscular center 2011 workshop criteria, 831t exercise studies in, 147 focal myositis, 853–854 fungal myositis, 857 granulomatous and giant cell myositis, 852 immune-mediated necrotizing myopathy, 848–849 incidence, 827 inclusion body myositis, 843–848 myositis associated with Lyme disease, 856 overlap syndrome, 841–843 parasitic infections cysticercosis, 857–858 toxoplasmosis, 858 trichinosis, 857, 857f polymyositis, 838–841 sarcoid myopathy, 852–853 treatment, 858–863 azathioprine, 861–862 chlorambucil, 862 concurrent management, 860 corticosteroids, 858–860 cyclophosphamide, 862 cyclosporine, 862–863 etanercept, 863 infliximab, 863 intravenous immunoglobulin, 861 methotrexate, 861 mycophenylate mofetil, 862 plasmapheresis or leukapheresis, 863 rituximab, 862 second-line therapies, 860 tacrolimus, 863 thymectomy, 863 total body irradiation, 863 viral infections human immunodeficiency virus, 854–855 human T-cell leukemia virus type 1, 855 influenza viruses, 855–856 other viral-related myositis, 856 Infliximab, 115t, 126 for inflammatory myopathies, 863 Influenza viruses, 855–856 Integrins, 657f, 659 Interferon α and β, 115t, 126 Interferon (IFN) gamma release assay (IGRA), 119 International Classification of Functioning, Disability and Health (ICF) model, on impairments, 143 Interstitial lung disease (ILD), 832 Intrathecal baclofen, in hereditary spastic paraparesis, 204, 205t Intravenous β, for cardioprotection, 645 Intravenous immunoglobulin (IVIg), 115t, 117t, 126–128, 227, 229 adverse effects, 127–128 for CIDP, 350t, 351–352 for inflammatory myopathies, 861 management considerations, 128 mechanism of action, 126–127 for MG, 607 uses, 127 Ipecac, 899 Isaacs syndrome (IS), 243–248, 245t clinical features, 243–245 diagnosis and differential diagnosis, 245–246 histopathology, 247 laboratory features, 246–247, 247f myokymic discharges, 246–247, 247f neuromyotonic discharges, 246, 247f pathogenesis, 247–248 treatment, 248 Isoniazid (INH), neuropathy by, 455 Isotretinoin, 902 IVIg See Intravenous immunoglobulin (IVIg) Ixodes scapularis, 641 Ixodid tick, 641 J Jerking stiff-man syndrome, 255 Jimmo vs Kathleen Sebelius, 144 Jitter values, 623 Jo-1 antibodies, 832 John Cunningham (JC) virus, 119 Jordan’s anomaly, 761, 761f K KAFOs See Knee-ankle-foot-orthoses (KAFOs) Kearns-Sayre syndrome (KSS), 775, 784–785 clinical features, 784–785 histopathology, 785 laboratory features, 785 molecular genetics and pathogenesis, 785 treatment, 785 Kelch-like homologue (KLHL9), 700 Kennedy disease, 15, 183, 213–215, 622 clinical features, 213–214 differential diagnosis, 214 electrodiagnosis, 214–215 gynecomastia in, 214, 214f histopathology, 215 laboratory features, 214 management, 215 pathogenesis, 215 prevalence, 213 King–Denborough syndrome, 724 KLHL9 See Kelch-like homologue (KLHL9) Klumpke paralysis, 515 Knee-ankle-foot-orthoses (KAFOs), 152, 153f, 162 Komuragaeri (calf-spasm) disease, 253 See also Satoyoshi syndrome Krabbe disease, 299–301 clinical features, 299 histopathology, 300 laboratory features, 299–300 molecular genetics and pathogenesis, 300–301 treatment, 301 Kraits, 645 KSS See Kearns-Sayre syndrome (KSS) Kugelberg–Welander disease, 208–212 See also Survival motor neuron-related SMAs Kyphoscoliosis, 662, 663, 723 L Labetalol, necrotizing myopathy by, 891 Lactate dehydrogenase deficiency See Glycogenosis type XI Laing distal myopathy, 700 causes, 700 clinical features, 700 histopathology, 700 laboratory features, 700 molecular genetics and pathogenesis, 700 LAMB2 See Laminin β2 deficiency (LAMB2) LAMB2 deficiency, 635 Lambert–Eaton myasthenic syndrome (LEMS), 18 clinical features, 620–622 diagnosis and differential diagnosis, 622–624 edrophonium testing, 624 electrodiagnostic testing, 622–623, 622f histopathology, 624 imaging, 624 938 Index Lambert–Eaton myasthenic syndrome (Continued ) nonneoplastic, 620 overlap syndrome, 622 paraneoplastic, 620 pathogenesis, 624–625 serological testing, 623–624 symptoms, 621 treatment, 625–626 Lamina-associated protein (LAP), 661 Lamin A/C gene (LMNA), 669–670 causes, 670 clinical features, 669, 669f histopathology, 670 laboratory features, 669 molecular genetics and pathogenesis, 670 Laminin, 656–659 Laminin β2 deficiency (LAMB2), 631 Lamotrigine, 897 LAMP-2 See Lysosome-associated membrane protein-2 (LAMP-2) Late-onset nemaline myopathy, 728 clinical features, 728 histopathology, 728 laboratory features, 728 molecular genetics and pathogenesis, 728 treatment, 728 Lateral cutaneous nerve of thigh, 541f, 544, 547f Lateral epicondylitis, 914–915 diagnosis, 914, 915f symptoms, 914 treatment, 914–915 Lateral pectoral nerve, 496 LCAD deficiency, 763 clinical features, 763 histopathology, 763 laboratory features, 763 molecular genetics and pathogenesis, 763 treatment, 763 LDB3 See LIM domain binding gene (LDB3) l-Dopa, 897 Lead neuropathy, 459 Leber hereditary optic neuropathy, 791 Leflunomide, neuropathy by, 454 Leigh syndrome, 789–790 clinical features, 789–790 histopathology, 790 laboratory features, 790 molecular genetics and pathogenesis, 790 Leisure activities, devices for, 159 LEMS See Lambert–Eaton myasthenic syndrome (LEMS) Length-dependent polyneuropathy, 16–17 Leprosy, 404–409 bacteriological index (BI), 406 borderline, 404, 405t, 407f clinical features, 404, 406f, 407f histopathology, 406, 408f laboratory features, 405, 408f lepromatous, 404, 405t morphological index (MI), 406 pathogenesis, 406 prevention, 409 reversal reaction, 409 Ridley–Joplin classification, 404, 405t treatment, 406, 409 tuberculoid, 404, 405t, 406f Lesch-Nyhan syndrome, 757 Leukemia, 431 Leukoencephalopathy, of MNGIE, 787 Lewis Sumner syndrome See Multifocal acquired demyelinating and sensory motor neuropathy (MADSAM) LGMD H See Limb-girdle muscular dystrophy H (LGMD H) Limb-girdle muscular dystrophy (LGMD), 656, 668 autosomal-dominant, 668 caveolin-3, 670 desmin, 670–671 DNAJB6, 670 lamin A/C gene, 669–670 myotilin, 668–669 transportin-3, 671 autosomal-recessive anoctamin-5, 678 calpain-3, 671–673 desmin, 679 dysferlin, 673–675 α-dystroglycan, 679 E3-ubiquitine ligase, 675–676 FKRP, 676 fukutin, 678 hereditary myopathy with early respiratory failure, 677–678 plectin-1, 679 POMGnT1, 678 POMT1, 678 POMT2, 678 sarcoglycanopathies, 675 telethonin, 675 titin, 676–677 titinopathy, 676 TRAPPC11, 679 diagnosis and treatment, 679–680, 680f Limb-girdle muscular dystrophy H (LGMD H), 719 LIM domain binding gene (LDB3), 699 Lipid metabolism disorders, 758–766, 759f, 760f Lipid storage disorders, 761 Lipoprotein receptor-related protein (LRP4), 631, 632 Lithium toxicity, 456–457 Liver transplantation and GSD IV, 750 See also Glycogenosis type IV LMNA See Lamin A/C gene (LMNA) LMN syndromes associated with malignancy, 234–235 Lofstrand crutches, 154, 154f Long thoracic nerve, 495 Long thoracic neuropathy, 520–521, 521f, 521t Lou Gehrig disease See Amyotrophic lateral sclerosis (ALS) Lower extremities, focal neuropathies of, 537–574 anatomy related to lumbosacral nerve roots, 537–540, 538f, 539f lumbosacral plexus, 540, 541f, 542f, 543–544t peripheral nerves, 540–548, 541f, 542f, 543–544t, 545t, 546f–550f electrodiagnostic studies, 549–551 imaging, 551–552 mononeuropathies, 565–571 monoradiculopathies, 552–558, 552t, 553f, 554f, 554t pathophysiology, 548–549 plexopathies and radiculoplexus neuropathies, 562–565 polyradiculopathies, 558–562 sciatic neuropathies, 571–574 Lower extremity amyotrophic diplegia (LAD), 180 Lower limb orthoses, 151–152, 152f LRP4 See Lipoprotein receptor-related protein (LRP4) LSOs See Lumbosacral orthoses (LSOs) L-tryptophan, 895–896 Lumbosacral monoradiculopathies See Monoradiculopathies, lumbosacral Lumbosacral nerve roots, 537–540, 538f, 539f Lumbosacral orthoses (LSOs), 150 Lumbosacral plexopathies and radiculoplexus neuropathies, 562–565, 563t differential diagnosis, 563 etiologies, 563–564 evaluation, 564 management, 564–565 Lumbosacral plexopathy, 433 Lumbosacral plexus, 540, 541f, 542f Lumbosacral polyradiculopathy See Polyradiculopathies, lumbosacral Lyme disease, 409–410, 561 causative organism, 409 clinical features, 409 histopathology, 410 laboratory features, 409–410 myositis with, 856 neurological complications with, 409, 409t pathogenesis, 410 stages of, 409 treatment, 410 Lymphoma, 434–435 clinical features, 434 histopathology, 434, 434f laboratory features, 434 pathogenesis, 435 treatment, 435 Lymphomatoid granulomatosis, 431 Lyon hypothesis, 665 Lysosomal storage disorders, neuropathies associated with, 298, 299t Fabry disease, 301 Krabbe disease, 299–301 metachromatic leukodystrophy, 298–299 Lysosome-associated membrane protein-2 (LAMP-2), 756 M Machado–Joseph disease, 203 MAD See Myoadenylate deaminase (MAD) MADD See Multi-acyl-CoA dehydrogenase deficiency (MADD) MAD deficiency See Myoadenylate deaminase deficiency (MAD deficiency) Magnesium, disorders of, 880 Magnetic resonance imaging (MRI), 75–77, 76f–78f, 507 of brachial plexus, 508f, 509f of cervical spine, 510f in dermatomyositis, 835 Index 939 Magnetic resonance spectroscopy (MRS), 780 Malignancy, neuropathies associated with, 427–443, 428t bone marrow transplantation and, 438 chemotherapy agents, and toxic neuropathy, 438, 439t bortezomib, 442–443 carfilzomib, 443 cisplatin, 438–440, 439t cytosine arabinoside, 442 docetaxel, 441 etoposide, 440 ifosfamide, 442 oxaliplatin, 440 paclitaxel, 441 suramin, 441–442 vincristine, 440 vinorelbine, 440 cranial neuropathies and radiculopathies brachial plexopathy, 431–433 infiltrating tumors, 431, 432f, 433f lumbosacral plexopathy, 433 MGUS neuropathy, 437–438 neuropathy related to tumor infiltration, 431 angiotrophic large-cell lymphoma, 431 leukemia, 431 lymphomatoid granulomatosis, 431 noninfiltrative peripheral neuropathies, 433–434 Castleman disease, 436 lymphoma, 434–435 multiple myeloma, 435 osteosclerotic myeloma, 435–436 Waldenstrom macroglobulinemia, 436–437 paraneoplastic neuropathies, 427 autonomic neuropathy, 430 idiopathic sensory or sensorimotor polyneuropathy, 430–431 sensorimotor polyneuropathy, 430 sensory neuronopathy/ganglionopathy, 427–430 Malignancy-related vasculitis, 376 See also Vasculitic meuropathies Malignant hyperthermia (MH), 240, 820–821, 902–903 clinical features, 820–821, 902–903 histopathology, 821, 903 laboratory features, 821, 903 pathogenesis and molecular genetics, 821, 903 treatment, 821, 903 Mamba envenomation, 646 Man-in-the-barrel syndrome, 180 Manual wheelchairs, 155 Marine envenomations, 647 Markesbery–Griggs distal myopathy, 699, 702 clinical features, 699 histopathology, 699 laboratory features, 699 molecular genetics and pathogenesis, 699 MC See Myotonia congenita (MC) MCAD deficiency, 763 clinical features, 763 histopathology, 763 laboratory features, 763 molecular genetics and pathogenesis, 763 treatment, 763 McArdle disease, aerobic training in, 147–148 MDC See Congenital muscular dystrophy (MDC) MDDGA5, 684 causes, 684 clinical features, 684 laboratory features, 684 molecular genetics and pathogenesis, 684 MDS See mtDNA depletion syndromes (MDS) Mean consecutive difference (MCD), 48 Mean sorted difference (MSD), 48 Medial cutaneous nerve of arm, 497 Medial pectoral nerve, 494f, 496 damage to, 521 Median nerve, 499, 501f, 502, 524–528 anterior interosseous syndrome, 526, 526t carpal tunnel syndrome, 526–528, 526t, 527f proximal median neuropathy, 525–526, 525f, 525t Median sternotomy, and brachial plexopathies, 519 Medical Research Council (MRC) scale, 13 MELAS See Mitochondrial myopathy lactic acidosis and strokes (MELAS) Meningoencephalitis, due to WNV, 228–229 MEPP See Miniature end-plate potential (MEPP) Meralgia paresthetica, 569–570 Mercury toxicity, 460 Merosin, 656–659, 657 Merosin deficiency, 681–682 clinical features, 681 histopathology, 681 laboratory features, 681, 681f molecular genetics and pathogenesis, 681–682 MERRF See Myoclonic epilepsy and ragged red fibers (MERRF) Metabolic myopathies, 742–766 Metachromatic leukodystrophy (MLD), 298–299 adult-onset, 298 clinical features, 298 histopathology, 298, 299f, 300f juvenile form of, 298 laboratory features, 298, 299f late infantile–onset, 298 molecular genetics and pathogenesis, 298 treatment, 299 Methotrexate, 116t, 117t, 128–129 for inflammatory myopathies, 861 Methylprednisolone, 117t Methylprednisone, in CIDP, 350t, 351 Metronidazole, neuropathy by, 448 Mexilitine in acetazolamide-responsive myotonia, 814 in myotonia fluctuans, 814 in myotonia permanens, 814 in potassium-sensitive periodic paralysis, 812 MFM See Myofibrillar myopathy (MFM) MG See Myasthenia gravis (MG) MGUS neuropathy, 437–438 clinical features, 437 histopathology, 437 laboratory features, 437 pathogenesis, 437–438 treatment, 438 MH See Malignant hyperthermia (MH) Mi-2 antibodies, 835 Microscopic polyangiitis (MPA), 376 See also Vasculitic meuropathies Miller Fisher syndrome (MFS), 330–331, 639, 642 clinical features, 330 histopathology, 330 laboratory features, 330 pathogenesis, 331 treatment, 331 Miniature end-plate potential (MEPP), 635 6-minute walk test (6MWT), 667, 747 See also Glycogenosis type II MIRAS See Mitochondria recessive ataxic syndrome (MIRAS) Misonidazole, neuropathy by, 448 Missense mutations, 702, 733 Mitochondrial disorders, 773–792 classification of, 774t genetics of, 773–777 histopathology, 780, 781f, 782f laboratory features, 777–780 molecular genetic analysis, 780 Mitochondrial DNA (mtDNA), 773 depletion myopathy, 786–787 clinical features, 786–787 histopathology, 787 laboratory features, 787 molecular genetics and pathogenesis, 787 treatment, 787 and proteins, composition of, 773 Mitochondrial function, biochemical analysis of, 780 Mitochondrial muscle disease, 783f Mitochondrial myopathies associated with exercise intolerance, 791 Charcot–Marie tooth disease, 791 clinical features, 791 histopathology, 791 laboratory features, 791 molecular genetics and pathogenesis, 791 treatment, 791 Mitochondrial myopathies, exercise studies in, 147 Mitochondrial myopathy lactic acidosis and strokes (MELAS), 782–784 clinical features, 782–783 histopathology, 784 laboratory features, 783–784 molecular genetics and pathogenesis, 784 MRI, 784f treatment, 784 Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), 775, 787–788 clinical features, 787 histopathology, 788 laboratory features, 787–788 molecular genetics and pathogenesis, 788 treatment, 788 Mitochondrial peripheral neuropathies, 778f–779f Mitochondrial respiratory chain, composition and genetic control, 777t 940 Index Mitochondrial trifunctional protein (MTP) deficiency, 764 clinical features, 764 histopathology, 764 laboratory features, 764 molecular genetics and pathogenesis, 764 treatment, 764 Mitochondria recessive ataxic syndrome (MIRAS), 787, 788 Mixed connective tissue disease (MCTD), 387, 843 Miyoshi myopathy, 673 Miyoshi myopathy like distal myopathy (MM3), 662 MLD See Metachromatic leukodystrophy (MLD) MmD See Multi/minicore myopathy (MmD) MMN See Multifocal motor neuropathy (MMN) MNDs See Motor neuron diseases (MNDs) MNGIE See Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) Mobility aids, 152–153, 154f canes, 153, 154f crutches, 154, 154f walkers, 154, 154f wheelchairs, 154–155 Modafinil, for DM1 treatment, 799 Modified barium swallow (MBS) study, 143, 166 Monoclonal proteins (MCPs), 62 Monomelic polyneuropathy, 573–574 Mononeuritis multiplex, 17 Mononeuropathies, 565–571 causes, 566t evaluation, 565–568, 567f femoral neuropathy, 570–571 genitofemoral neuropathy, 569 iliohypogastric neuropathy, 569 ilioinguinal neuropathy, 568–569 management, 568 meralgia paresthetica, 569–570 obturator neuropathy, 571 saphenous neuropathy, 571 superior and inferior gluteal neuropathies, 569 Monoradiculopathies, 15–16 Monoradiculopathies, lumbosacral, 552–558, 552t, 553f, 554f, 554t dermatomal maps, 554f differential diagnosis, 556 etiologies, 554t, 556 evaluation, 556–557 L1–2, 555, 555f L3–4, 555 L5, 556 management, 557–558 pain in, 553 S1, 556 weakness in, 554 Montréal cognitive assessment (MOCA), 182 Morvan syndrome, 245 Motor nerve hyperactivity disorders, 238–259 cramp–fasciculation syndrome (CFS), 238–243 cramps, 238–243 fasciculations, 238–243 hyperekplexia, 258–259 Isaacs syndrome (IS), 243–248 Satoyoshi syndrome, 253–254 Stiff-Person syndrome (SPS), 254–258 tetanus, 248–252 tetany, 252–253 Motor neuron diseases (MNDs), 15, 174, 622 See also specific diseases cramps in, 238 and malignancy, 232–235 Motor unit action potential (MUAP), 41, 46–47, 506–507, 623, 663, 719, 745, 779, 808 See also Electrodiagnosis (EDX) Motor unit number estimation (MUNE), 41 Mouse bioassay, in botulinum toxin detection, 639 MPS See Myofacial pain syndrome (MPS) MRS See Magnetic resonance spectroscopy (MRS) mtDNA depletion syndromes (MDS), 786 MTP deficiency See Mitochondrial trifunctional protein (MTP) deficiency MUAP See Motor unit action potential (MUAP) Multi-acyl-CoA dehydrogenase deficiency (MADD), 760, 760f, 764–765 clinical features, 764 histopathology, 765 laboratory features, 765 molecular genetics and pathogenesis, 765 treatment, 765 Multifocal acquired demyelinating and sensory motor neuropathy (MADSAM), 340, 352–353 clinical features, 341t, 352–353 histopathology, 353 laboratory features, 353 treatment, 353 Multifocal acquired motor axonopathy (MAMA), 357 Multifocal motor neuropathy (MMN), 183, 340, 341t, 354–357 clinical features, 354–355 differential diagnosis, 355 histopathology, 356 laboratory features, 355–356 pathogenesis, 356–357 treatment, 357 Multifocal neuropathy, 17 See also Mononeuritis multiplex Multi/minicore myopathy (MmD), 723–724 clinical features, 723 histopathology, 723, 723f laboratory features, 723 molecular genetics and pathogenesis, 723–724 treatment, 724 Multiple mononeuropathies, HIV-related, 413 Multiple myeloma, 435 histopathology, 435 laboratory features, 435 pathogenesis, 435 treatment, 435 Muscle atrophy, 719 Muscle biopsies, 86 indications for, 86 muscle abnormalities and, 96–100, 97f–101f in post-polio progressive muscular atrophy, 231–232, 232f skeletal muscle, structure of, 94–96, 95f techniques, 86–94 acid phosphatase stains, 90, 92, 92f Congo red stain, 92, 93f electron microscopy, 93, 95f Gomori-trichrome stains, 87, 88f, 89f hematoxylin and eosin (H&E) stain, 87, 88f immunoperoxidase stains, 92–93, 94f muscle fibere characteristics, 88t myofibrillar adenosine triphosphatase (ATPase), 90, 90f myofibrillar myopathy, 87, 89f, 90 myophosphorylase stain, 91f NADH-TR stain, 92, 93f needle biopsy, 86 oil red O stain, 92, 92f open surgery, 86 oxidative enzyme stains, 92, 92f paraffin sections, 87, 87f periodic acid–Schiff (PAS) stain, 90, 91f SDH and COX stains, 92, 93f site selection, 86 specimen collection and handling, 87 Muscle end-plate potentials (EPPs), 32 Muscle-eye-brain disease (MEB), 661 disease, 684 clinical features, 684 laboratory features, 684 MDC 1D, 684–685 MDDGA5, 684 molecular genetics and pathogenesis, 684 Muscle fiber splitting, 691 Muscle-specific kinase (MuSK), 631 activated, 631 deficiency, 632 Muscle-specific kinase (MuSK) autoantibodies, 581, 596 Muscle stretch reflexes, 719 Muscular dystrophy, 656–705, 698f molecular defects of, 658t–659t Musculocutaneous nerve, 498, 498f Musculocutaneous neuropathy, 522, 522t MuSK See Muscle-specific kinase (MuSK) Myasthenia gravis (MG), 581–609, 620 associated disorders, 585–586 clinical features, 582–583 bulbar symptoms, 582–585 facial weakness, 583 jaw weakness, 583 limb weakness, 583 ptosis or diplopia, 582 diagnosis and differential diagnosis, 586–587, 587t electrophysiological testing, 596–600 histopathology, 602–603, 603f imaging, 602 incidence and prevalence, 581 juvenile, 585 laboratory features, 594–595, 595t MuSK MG, 583 natural history, 582 neuromuscular transmission (NMT) in, 587–588 oculobulbar signs, 622 Index 941 pathophysiology, 587–594 LPR4 MG, 594 MuSK MG, 594 transient neonatal MG, 594 pharmacological testing, 600–602 serological testing, 595–596 seronegative, 583–585, 584f in specific populations, 585 transient neonatal autoimmune, 585 treatment, 603–609 in children and adolescents, 608 considerations in, 603–604 immunomodulating, 605–608 monitoring response, 608–609 symptomatic, 604 thymectomy, 605 Myasthenic muscle score (MMS), 609 Mycobacterium leprae, 404 See also Leprosy Mycophenolate mofetil (MMF), 116t, 117t, 129–130 for CIDP, 352 for inflammatory myopathies, 862 MyHC See Myosin heavy chain (MyHC) Myoadenylate deaminase (MAD), 742 Myoadenylate deaminase deficiency (MAD deficiency), 758 clinical features, 758 histopathology, 758 laboratory features, 758 molecular genetics and pathogenesis, 758 treatment, 758 Myocarditis, 646 Myoclonic epilepsy and ragged red fibers (MERRF), 781–782 clinical features, 781–782 histopathology, 782 laboratory features, 782 molecular genetics and pathogenesis, 782 treatment, 782 Myofacial pain syndrome (MPS), 882–883 Myofibrillar myopathy (MFM), 669, 701–704, 737 clinical features, 701 histopathology, 702, 703f laboratory features, 701–702 molecular genetics and pathogenesis, 702–704 treatment, 704 Myofibrillar proteins, 660 Myoglobin, 18 Myoglobinuria, 18 See also Rhabdomyolysis/ myoglobinuria (RHB/MGU) Myokymic discharges, 43, 43f Myopathic disorders, 97, 99–100, 99f, 100f Myophosphorylase deficiency See Glycogenosis type V Myosin heavy chain (MyHC), 660, 733 types, 660 Myositis-specific antibodies (MSAs), 834, 835t MYOT gene, 669 Myotilin, 702 causes, 669 clinical features, 668–669, 668f histopathology, 669 laboratory features, 669 molecular genetics and pathogenesis, 669 Myotonia, 239 Myotonia congenita (MC), 804–809 clinical features, 804–807 laboratory features, 807–808 molecular genetics and pathogenesis, 808, 808f treatment, 809 Myotonia fluctuans, 813–814 clinical features, 813 histopathology, 813 laboratory features, 813 molecular genetics and pathogenesis, 814 treatment, 814 Myotonia permanens, 814 clinical features, 814 histopathology, 814 laboratory features, 814 molecular genetics and pathogenesis, 814 treatment, 814 Myotonic discharges, 43–44, 43f Myotonic disorders, 798t Myotonic dystrophy, 147, 797–801 Myotubularin, 730 Myotubular myopathy, 728 N NARP See Neuropathy ataxia and retinitis pigmentosa (NARP) Navajo neurohepatopathy, 789 clinical features, 789 histopathology, 789 laboratory features, 789 molecular genetics and pathogenesis, 789 treatment, 789 NCS See Nerve conduction studies (NCS) Nebulin gene (NEB), 660, 700 Neck flexor weakness, 646 Necrosis, 99–100, 99f Necrotizing myopathies, 887–893 amiodarone and, 892 amphiphilic drug myopathy, 892 chloroquine and, 892, 892f cholesterol-lowering drugs and, 887–890 cyclosporine and, 891 ezetimibe and, 890 fibric acid derivatives and, 890 HMG-CoA reductase inhibitors and, 887, 889–890, 889f hydroxychloroquine and, 892 labetalol and, 891 niacin and, 890 propofol and, 891 tacrolimus and, 891 Nemaline myopathy, 724–728 clinical features, 724–725 histopathology, 726, 726f–727f laboratory features, 725–726 molecular genetics and pathogenesis, 726–728 treatment, 728 Nemaline rod myopathy, 724 See also Core-rod myopathy Neonatal tetanus, 249 Neostigmine, 604 Nerve biopsies, 100 in CIDP, 347, 348f in CMT2, 274 in CMT3, 275 in DADS neuropathy, 354 in Fabry disease, 301, 302f in giant axonal neuropathy, 309, 310f in hereditary neuropathy with liability to pressure palsies, 272, 272f indications for, 102 in perineuritis, 360 reactions to injury, 109–111 axonal degeneration, 109–110, 110f nerve vasculitis, 110, 110f onion bulb formation, 109, 109f structure of normal nerve, 107–109 techniques, 102–107 familial amyloid polyneuropathy, 105f immunoperoxidase stain, 106, 106f leprosy, borderline, 106f local anesthesia, 104 neurofibroma, 106, 107f paraffin sections, 104–105f PAS stain, 104, 106f Semithin section, 107, 107f superficial peroneal nerve, 103, 103f sural nerve, 102–103, 102f teased nerve fibers, 107, 108f in vasculitis, 371–373, 373f, 374f Nerve conduction studies (NCS), 22, 719, 745, 779 See also Electrodiagnosis (EDX) Nerve injury, mechanisms of, 502 axonotmesis, 504 neuropraxia, 502 neurotmesis, 504 Neurogenic atrophy, 96–97, 97f Neurogenic thoracic outlet syndrome, 515–516, 517f Neuroleptic malignant syndrome, 240 Neuromuscular disorders, with acute/subacute proximal or generalized weakness, 4t chronic distal weakness causing bilateral foot/heel drop, 5t chronic progressive proximal weakness, differential diagnosis of, 5t definition, diagnostic accuracy, differential diagnosis, 2, 3t, 4t in childhood/early adulthood, 3t in infants, 3t in middle to late adulthood, 4t dorsal root ganglionopathies, 15 examination in, 10–14 (see also Neuromuscular examination) with facial weakness, 8t with head drop, 8t hereditary nature, history taking, 3–10 (see also History taking) with joint contractures, 12t length-dependent polyneuropathy, 16–17 mononeuropathy, 16 monoradiculopathies, 15–16 motor neuron disorders, 15 multifocal neuropathy, 17 muscle weakness, patterns of, 6t myopathies, 18 neuromuscular transmission disorders, 17–18 plexopathy, 16 942 Index Neuromuscular disorders (Continued ) polyradiculoneuropathy, 17 polyradiculopathy, 16 ptosis/ophthalmoplegia, causes of, 7t rhabdomyolysis/myoglobinuria, 18–20, 19t with scapular winging, 8t with ventilatory muscle weakness, 9t Neuromuscular examination, 10–14 blood pressure and pulse measurements, 14 cavus foot deformities, 12 dermal or epidermal changes, 12 eyebrow position, observation of, 11 eyelid myotonia or paramyotonia, 11 eyelids and the globe, anatomic relationship between, 11 facial weakness, 10 infants examination, 14 jaw strength, 10 limb and trunk muscles examination, 11 manual muscle testing in cranial innervated muscle, 10 motor examination of cranial nerves, 10 MRC grading, 13 muscle contractures, 11–12, 12t muscles, observation of, 11 muscle weakness, tests for, 12–13 neck flexion and extension strength, 11 provocative muscle testing, 12 pupil examination, 11 scapular winging, identification of, 12 sensory examination, 14 tongue strength, 10–11 UMN signs, 13–14 ventilation, assessment of, 13 Neuromuscular mimics, 911–921, 912t biceps tendinopathy, 912–914 carpometacarpal joint osteoarthritis, 916–917 De Quervain syndrome, 915–916 greater trochanteric bursitis, 918–919 hip joint osteoarthritis, 917–918 lateral epicondylitis, 914–915 pes anserine bursitis, 919–920 plantar fasciitis, 920–921 supraspinatus tendinopathy, 911–912 Neuromuscular scoliosis, rehabilitation approach in, 160 Neuromuscular transmission disorders, 17–18 Neuromyotonia See Isaacs syndrome (IS) Neuromyotonic discharges, 44f, 45–46, 45t Neuropathies with systemic disorders, 384–398, 385t amyloid polyneuropathy, 393–397, 393t, 394f celiac disease, 389 chronic liver disease, 391 connective tissue diseases mixed connective tissue disease, 387 rheumatoid arthritis, 386 scleroderma, 387 Sjogren syndrome, 384–386 systemic lupus erythematosus, 386–387 critical illness polyneuropathy, 392–393 familial amyloid polyneuropathy (FAP), 395–397 apolipoprotein A1-related amyloidosis, 397 TTR-related amyloidosis, 395–397 gout, 392 hypereosinophilic syndrome, 390 inflammatory bowel disease, 389 primary (AL) amyloidosis, 393–395 primary biliary cirrhosis, 390 sarcoidosis, 387–389, 388f uremic neuropathy, 390–391 Whipple disease, 391–392 Neuropathy ataxia and retinitis pigmentosa (NARP), 779, 789 clinical features, 789 histopathology, 789 laboratory features, 789 molecular genetics and pathogenesis, 789 treatment, 789 Neuropraxia, 502 Neurotmesis, 504 Neutral lipid storage disease, 765–766 characteristics, 765 clinical features, 765 histopathology, 766 laboratory features, 765 molecular genetics and pathogenesis, 766 treatment, 766 Niacin, myopathies by, 890 Nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR), 719 Nighttime AFOs, 152, 153f Nitrofurantoin, neuropathy by, 454–455 Nonaka distal myopathy, 699, 704 clinical features, 699 histopathology, 699 laboratory features, 699 molecular genetics and pathogenesis, 699 Nonambulatory AFO, 152, 153f Nondystrophic myotonias and hereditary periodic paralysis, 805t Noninvasive positive pressure ventilation (NIPPV) in amyotrophic lateral sclerosis, 192–193 Nonsystemic/isolated PNS vasculitis, 377–378 See also Vasculitic meuropathies Nontropical sprue See Celiac disease Nucleoside neuropathies, 456 Numb chin syndrome, 431 Numbness, Nutritional neuropathies, 418–424, 419t alcoholic neuropathy, 423–424 cobalamin deficiency, 419–420 copper deficiency, 422–423 folate deficiency, 421 hypophosphatemia, 423 postgastrectomy/bariatric surgery deficiencies, 422 pyridoxine deficiency, 419 thiamine deficiency, 418–419 vitamin B12 deficiency secondary to nitrous oxide inhalation, 420–421 vitamin E deficiency, 421–422 Occupational therapists (OTs), 142 See also Rehabilitation Ocular neuromyotonia, 245 Oculobulbar muscles, 629 Oculopharyngeal muscular dystrophy (OPMD), 661, 696–697 causes, 696 clinical features, 696 histopathology, 696 laboratory features, 696 molecular genetics and pathogenesis, 696 treatment, 696–697 variants of, 697 Offset canes, 153 Omeprazole, 902 Onion bulbs, 109, 109f, 269, 269f Ophthalmoparesis, 621, 631 OPMD See Oculopharyngeal muscular dystrophy (OPMD) Opponens splint, 151, 151f Optic atrophy (OA1) syndrome, 789 clinical features, 789 histopathology, 789 laboratory features, 789 molecular genetics and pathogenesis, 789 treatment, 789 Optic neuritis, 646 Oral glucose tolerance test (GTT), 478, 479t Organophosphate-induced delayed polyneuropathy (OPIDP), 458 Organophosphate poisoning, 458 Organophosphates, 644 Orthoses, 149 cervical, 149–150 lower limb, 151–152, 152f thoracolumbosacral, 150 upper limb, 150–151, 151f Orthotists, 142 See also Rehabilitation Osserman scale, 609 Osteitis fibrosa, 874 Osteosclerotic myeloma, 435–436 clinical features, 435 histopathology, 436 laboratory features, 436, 436f pathogenesis, 436 treatment, 436 Outliers, 665 See also Dystrophinopathies Out-of-wind phenomena, 752 See also Glycogenosis type VII Overlap syndromes, 841–843 See also Inflammatory myopathies mixed connective tissue disease, 843 rheumatoid arthritis, 843 scleroderma, 841–842, 842f Sjögren’s syndrome, 842 systemic lupus erythematosus, 842–843 Oxaliplatin, sensory neuropathy with, 440 Oxandrolone, 666 O P OA1 syndrome See Optic atrophy (OA1) syndrome Obstetrically related plexopathies, 515 Obturator nerve, 541f, 542, 546f–548f Obturator neuropathy, 571 Occipital polymicrogyria, 681 PABPN1 protein, 696 Paclitaxel, 441 clinical features, 441 histopathology, 441 laboratory features, 441 pathogenesis, 441 Index 943 Paget disease of the bone (PDB), 705 Pain, and rehabilitation plan, 165 Palmaris brevis syndrome, 240 PAM See Potassium-aggravated myotonias (PAM) Pancoast tumors, 516 Pancreatic transplantation, 468, 469 Panhypopituitarism, 878 Paramyotonia congenita (PMC), 804, 812–813 clinical features, 812 histopathology, 813 laboratory features, 812–813, 812f molecular genetics and pathogenesis, 813 treatment, 813 Paraneoplastic encephalomyelitis (PEM)/ sensory neuronopathy (SN), 427–430 clinical features, 427–428 histopathology, 428, 429f laboratory features, 428 pathogenesis, 428–429 treatment, 429–430 Paraneoplastic MNDs, 233–234 Paraneoplastic neuropathies, 427 autonomic neuropathy, 430 idiopathic sensory or sensorimotor polyneuropathy, 430–431 sensorimotor polyneuropathy, 430 sensory neuronopathy/ganglionopathy, 427–430, 428t, 429f Paraneoplastic syndrome, 621 Parasitic infections, 857–858 cysticercosis, 857–858 toxoplasmosis, 858 trichinosis, 857, 857f Parathyroid hormone (PTH), 874 Paresthesias, Paroxysmal extreme pain disorder, 288 Parsonage–Turner syndrome, 281 PDB See Paget disease of the bone (PDB) PEMPs See Post-exercise myotonic potentials (PEMPs) PEO See Progressive external ophthalmoplegia (PEO) Percussion-induced rapid contractions (PIRC), 670 Perineuritis, 359–360 clinical features, 359–360 histopathology, 360 laboratory features, 360 pathogenesis, 360 treatment, 360 Periodic acid Schiff (PAS), 733, 746 Peripheral nerves, of lower extremity, 540–548, 541f, 542f, 543–544t, 545t, 546f–550f femoral nerve, 541f, 542, 544, 546f, 548f fibular (peroneal) nerve, 542f, 546, 549f genitofemoral nerve, 541–542, 541f, 546f iliohypogastric nerve, 541, 546f ilioinguinal nerve, 541, 546f lateral cutaneous nerve of thigh, 541f, 544, 547f obturator nerve, 541f, 542, 546f–548f posterior cutaneous nerve of thigh, 546 pudendal nerve, 541f, 542f, 546f, 547–548 sciatic nerve, 541f, 542f, 544, 546 sural nerve, 547 tibial nerve, 542f, 547, 550f Peroneal nerve, 542f, 546, 549f Peroxisomal disorders, 301 adrenoleukodystrophy/ adrenomyeloneuropathy, 301–303 cerebrotendinous xanthomatosis, 305–306 Refsum disease, 303–304 Tangier disease, 304–305 Pes anserine bursitis, 919–920 diagnosis, 919, 919f symptoms, 919 treatment, 919–920 Pes cavus deformities, 691 PFK deficiency See Glycogenosis type VII PGAM See Phosphoglycerate mutase (PGAM) PGAM deficiency See Glycogenosis type X PGK deficiency See Phosphoglycerate kinase deficiency (PGK deficiency) Phalen sign, 527 Phenytoin, 897 neuropathy by, 456 Phosphate, disorders of, 880 Phosphatidic acid phosphatase (lipin) deficiency, 766 clinical features, 766 histopathology, 766 laboratory features, 766 molecular genetics and pathogenesis, 766 treatment, 766 Phosphoglucomutase 1, 754 Phosphoglucomutase deficiency See Glycogenosis type XIV Phosphoglycerate kinase deficiency (PGK deficiency), 755 cause, 755 clinical features, 755 histopathology, 755 laboratory features, 755 molecular genetics and pathogenesis, 755 treatment, 755 Phosphoglycerate mutase (PGAM), 742 Phospholipase domain–containing protein (PNPLA2), 766 Phosphorodiamidate morpholino oligomer (PMO), 667 Phosphorylase B kinase deficiency See Glycogenosis type VIII/IX Phrenic nerve, 493, 494f Physical therapists (PTs), 142 See also Rehabilitation Pierson syndrome, 631 Piriformis syndrome, 571 Pituitary disorders, 877–879 acromegaly, 877–878 diabetes mellitus, 878 diabetic muscle infarction, 878–879 panhypopituitarism, 878 Plantar fasciitis, 920–921 diagnosis, 920, 920f, 921f symptoms, 920 treatment, 920–921 Plasma cholinesterase See Pseudocholinesterase Plasma exchange (PLEX), 116t, 130 in CIDP, 350t, 351 in inflammatory myopathies, 863 in MG, 607 Plastic posterior leaf spring (PLS) AFO, 151, 152f Platform crutches, 154 Plectin, 636 Plectin-1, 679 causes, 679 clinical features, 679 histopathology, 679 laboratory features, 679 molecular genetics and pathogenesis, 679 Plectin deficiency, 632–633 Plexopathy, 16 PM See Polymyositis (PM) PMC See Paramyotonia congenita (PMC) PML See Progressive multifocal leukoencephalopathy (PML) PMP22 protein, 270 Pneumocystis jirovecii, 118–119 PNPLA2 See Phospholipase domain– containing protein (PNPLA2) Podophyllin neuropathy, 453 POEMS syndrome See Osteosclerotic myeloma Poliomyelitis, 224–225 See also Acute flaccid paralysis (AFP) from polio virus POLIP syndrome See Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) Poly(A) binding protein nuclear (PABN1), 661 Polyarteritis nodosa (PAN), 373, 375 See also Vasculitic meuropathies Polyglucosan disease, 185 Polyhydramnios, 728 Polymerase chain reaction (PCR), 226, 639 Polymyalgia rheumatica, 882 Polymyositis (PM), 674, 838–841 See also Inflammatory myopathies associated manifestations, 839 Bohan and Peter criteria, 827, 832t clinical features, 839 differential diagnosis, 841, 841t electrophysiological features, 839 histopathology, 839–840, 840f laboratory features, 839, 840f pathogenesis, 840–841 prognosis, 841 Polyradiculoneuropathy, 17 Polyradiculopathies, lumbosacral, 558–562 etiologies, 557t, 559–561, 559f, 560f evaluation, 561–562 management, 562 Polyradiculoplexus neuropathy, 470–471 asymmetric, painful, 471–472 (See also Diabetic amyotrophy) symmetric, painless, 472–473 POMGnT1, 678 Pompe disease, 745, 756 Popeye arms, 688 Porphyria clinical features, 311, 313f histopathology, 311 laboratory features, 311 molecular genetics and pathogenesis, 311, 313, 313f treatment, 313 Posterior cutaneous nerve of thigh, 546 Posterior interosseous neuropathy, 523–524, 524f, 524t Post-exercise myotonic potentials (PEMPs), 27 944 Index Post-polio progressive muscular atrophy (PPMA), 229–232 clinical features, 229–231, 230f diagnosis and differential diagnosis, 231 histopathology, 231–232 laboratory features, 231 management, 232 pathogenesis, 232 Post-polio syndrome (PPS), 229 See also Post-polio progressive muscular atrophy (PPMA) Postsurgical inflammatory neuropathy, 378 See also Vasculitic meuropathies Potassium-aggravated myotonias (PAM), 813 Potassium, disorders of, 879–880 Potassium-sensitive periodic paralysis, 810–812 clinical features, 810 histopathology, 811 laboratory features, 810–811, 810t, 811f molecular genetics and pathogenesis, 811 treatment, 812 Power-assist wheelchairs, 155, 156f Power scooters, 155 PPMA See Post-polio progressive muscular atrophy (PPMA) Pralidoxime, in organophosphate toxicity, 645 Prednisone, 117t, 666 in CIDP, 350t, 351 in LEMS treatment, 626 Prenatal testing, in hereditary spastic paraparesis, 206 Primary (AL) amyloidosis, 393–395 clinical features, 393–394 histopathology, 394f, 395 laboratory features, 394–395 pathogenesis, 395 treatment, 395 Primary biliary cirrhosis (PBC), 390 clinical features, 390 histopathology, 390 laboratory features, 390 pathogenesis, 390 treatment, 390 Primary hypokalemic periodic paralysis type (HYPOKPP1), 815–819 clinical features, 815–817 histopathology, 817, 817f laboratory features, 817 molecular genetics and pathogenesis, 817–818, 818f treatment, 818–819 Primary lateral sclerosis (PLS), 174, 179 Procainamide, 896 Progressive bulbar palsy (PBP), 174 Progressive encephalomyelitis with rigidity and myoclonus (PERM), 255 Progressive external ophthalmoplegia (PEO), 775, 785–786, 785f clinical features, 785 histopathology, 786 laboratory features, 785–786 molecular genetics and pathogenesis, 786 treatment, 786 Progressive multifocal leukoencephalopathy (PML), 119 Progressive muscular atrophy (PMA), 174, 179–180 PROMM See Proximal myotonic myopathy (PROMM) Pronator teres syndrome, 526 Propofol, necrotizing myopathy by, 891 Proximal diabetic neuropathy See Diabetic amyotrophy Proximal hereditary motor and sensory neuropathy/neuronopathy (HMSN-P), 281 Proximal lower limb weakness, rehabilitation approach for, 162 Proximal median neuropathy, 525–526, 525f, 525t Proximal myotonic myopathy (PROMM), 797 Proximal radial neuropathy, 523, 523t Proximal ulnar neuropathy, 528–529, 528t Proximal upper limb weakness, rehabilitation approach for, 160–161 Pseudocholinesterase, 644 Pseudomyotonia, 243–245 Ptosis, 621, 630f Ptosis, and rehabilitation plan, 165–166 Ptosis surgery, 696 Pudendal nerve, 541f, 542f, 546f, 547–548 Pudendal neuropathy, 573 Purine nucleotide metabolism, disorders of, 757–758 Purkinje cell, 624, 625 Pyomyositis, 856 Pyridostigmine, 604–605, 626 in botulism treatment, 641 Pyridoxine deficiency, 419 Pyridoxine toxicity, 455 Pyruvate decarboxylase (PDC), 790 Pyruvate dehydrogenase (PDH), 790 Q QSART See Quantitative sudomotor axon reflex test (QSART) QST See Quantitative sensory testing (QST) Quad canes, 153, 154f Quantified MG score (QMS), 609 Quantitative sensory testing (QST), 56–57 Quantitative sudomotor axon reflex test (QSART), 57, 61, 479, 480f R Radial nerve, 498–499, 500f, 523–524 posterior interosseous neuropathy, 523–524, 524f, 524t proximal radial neuropathy, 523, 523t superficial radial neuropathy, 524, 524t Radiation-induced lumbosacral plexopathy, 433 Radiation-induced motor neuron disease (RIMND), 233 Radicular pain, in lower extremity, 553 Radiculopathies causes, 505t cervical, 505t, 507, 510–511 thoracic, 511 treatment, 512 Range-of-motion (ROM) exercises, 145, 145t Rapsyn deficiency, 626, 632 Recurrent myoglobinuria, 761 Red cell cholinesterase levels, 644 Reducing body myopathy, 735–737 clinical features, 735 histopathology, 735–736 laboratory features, 735 molecular genetics and pathogenesis, 736 treatment, 737 Refsum disease, 303–304 clinical features, 303–304 histopathology, 304 laboratory features, 304 molecular genetics and pathogenesis, 304 treatment, 304 Rehabilitation, 142–168 activity limitations and, 143 approach to common clinical problems, 160 axial weakness, 160 dysarthria, 167–168 dysphagia, 166–167 falls, 163 foot abnormalities, 163–164 foot drop, 162–163 hand weakness, 161–162 joint contractures, 164 pain, 165 proximal lower limb weakness, 162 proximal upper limb weakness, 160–161 ptosis, 165–166 spasticity, 164–165 spinal deformities, 160 beginning of, 143 environmental modifications, 159–160 equipments/devices for daily living, 155–156 dressing, 157, 158f driving, 159 leisure activities, 159 self-care, bathing, and toileting, 157–158 self-feeding and meal preparation, 156–157, 157f transfers, 158–159 family and support systems and, 143 impairments and, 143 Improvement Standard lawsuit, settlement in, 144 multidisciplinary team, efforts of, 142–143 occupational therapists (OTs), role of, 142 orthotists, role of, 142 participation restriction and, 143 person’s environment and, 143 physical therapists (PTs), role of, 142 reassessment and change in strategies, 144 rehabilitation A&P, development of, 143–144 speech and language pathologists (SLPs), role of, 142–143 tools for, 144 exercise, 144–148 mobility aids, 152–155 orthoses, 148–152 Rehabilitation assessment and plan (rehabilitation A&P), 143–144 Repetitive nerve stimulation (RNS), 634 Resting hand splints, 151, 151f Reverse straight leg raising, 553 Reye-like syndrome, 764 Reye syndrome, 761, 763 Rhabdomyolysis/myoglobinuria (RHB/MGU), 18–20, 646, 761 causes, 18, 19t diagnosis, 19–20 Index 945 hydration in, 20 muscle biopsy in, 20 pathophysiology, 18–19 symptoms, 18 Rheumatoid arthritis (RA), 386, 843 clinical features, 386 histopathology, 386, 386f laboratory features, 386 treatment, 386 Rigid spine muscular dystrophy (RSMD), 685 Rigid spine syndrome, 685, 691 clinical features, 685 histopathology, 685 laboratory features, 685 molecular genetics and pathogenesis, 685 Riley–Day syndrome, 285–286 Rilutek, 191 RIMND See Radiation-induced motor neuron disease (RIMND) Rippling muscle disease (RMD), 239 Rituximab, 116t, 130–131 for CIDP, 350t for inflammatory myopathies, 862 Rituximab, in LEMS treatment, 626 RMD See Rippling muscle disease (RMD) RNS See Repetitive nerve stimulation (RNS) Romberg test, 14 Roussy–Levy syndrome, 266, 273 RSMD See Rigid spine muscular dystrophy (RSMD) Ryanodine receptor gene (RYR1), 722 S Salk vaccine, 224 SANDO See Sensory ataxia neuropathy dysarthria/dysphagia ophthalmoplegia (SANDO) Saphenous neuropathy, 571 Sarcoglycan complex, 656 Sarcoglycanopathies, 675 See also Limb-girdle muscular dystrophy (LGMD) clinical features, 675 histopathology, 675 laboratory features, 675 molecular genetics and pathogenesis, 675 Sarcoid myopathy, 852–853 clinical features, 852 histopathology, 853 laboratory features, 853 pathogenesis, 853 prognosis and treatment, 853 Sarcoidosis, 387–389, 561 clinical features, 387–388 histopathology, 388–389, 388f laboratory features, 388, 388f pathogenesis, 389 treatment, 389 Sarcolemmal proteins, 656 Sarcomere, 660 Sarcomeric proteins, 657f, 660–661 Sarcoplasm, 661 Sarcoplasmic reticulum calcium-ATPase (SERCA1), 661 Sarcospan protein, 656 Sarcotubular myopathy, 731 clinical features, 731 histopathology, 731 laboratory features, 731 molecular genetics and pathogenesis, 731 treatment, 731 Satoyoshi syndrome, 253–254 clinical features, 253 diagnosis and differential diagnosis, 253 histopathology, 254 laboratory features, 253 pathogenesis, 254 treatment, 254 SCAD deficiency, 764 clinical features, 764 histopathology, 764 laboratory features, 764 molecular genetics and pathogenesis, 764 treatment, 764 Scapular–humeral–pelvic muscles, 669 Scapular winging, 8t, 12, 633 Scapular winging and calpain-3, 671 See also Calpain-3 Scapula-stabilizer muscles, 688 Scapuloperoneal muscular dystrophy, 690–691 clinical features, 690 histopathology, 690 laboratory features, 690 molecular genetics and pathogenesis, 691 treatment, 691 Scapuloperoneal neuropathy, 282 Scapuloperoneal SMA See Davidenkow syndrome SCCL See Small-cell carcinoma of the lung (SCCL) Schwann cells, 635, 657, 788 Schwartz–Jampel syndrome (SJS), 822 Sciatic nerve, 541f, 542f, 544, 546 Sciatic neuropathies, 571–574 Scleroderma, 387, 841–842, 842f Scoliosis, 667 Scorpion intoxication, 647 SDH See Succinate dehydrogenase (SDH) Sea snakes antivenom, 647 bite and effects, 647 Secondary hypokalemic paralysis, 819 Segmental necrosis, 100 Selenoprotein N gene (SEPN1), 703–704, 724 Sensorimotor polyneuropathy, paraneoplastic, 430 Sensory ataxia, 15 Sensory ataxia neuropathy dysarthria/ dysphagia ophthalmoplegia (SANDO), 777, 788 clinical features, 788 histopathology, 788 laboratory features, 788 molecular genetics and pathogenesis, 788 treatment, 788 Sensory nerve action potential (SNAP), 22, 27–30, 505 See also Electrodiagnosis (EDX) Sensory neuronopathies See Dorsal root ganglionopathies SEPN1 See Selenoprotein N gene (SEPN1) Serial casting, in contractures, 164 Serologic testing, 68 antibodies against glycolipid and glycoprotein, 70–71 antibody testing for DNMT, 71–73 for infectious causes of neuromuscular disease, 73–74 for muscle disease, 73 other tests, 74–75 paraneoplastic antibodies, 68, 70 SFEMG See Single fiber electromyography (SFEMG) Short- and long-exercise tests, 34–40, 35f, 36f, 37t, 38f–41f Shoulder support systems, 150 Shulman’s syndrome See Diffuse fasciitis with eosinophilia Sicca complex, 384 See also Sjögren syndrome Single fiber electromyography (SFEMG), 623 Sjögren syndrome, 384–386, 842 clinical features, 384 histopathology, 385, 385f laboratory features, 384–385 pathogenesis, 385–386 treatment, 386 SJS See Schwartz–Jampel syndrome (SJS) Skeletal muscle imaging, 671 in dysferlin, 674 Skeletal muscle, structure of, 94–96, 95f Skin biopsies, 111–112 in lepromatous neuropathy, 111, 111f in small fiber neuropathy, 112f Slow-channel syndrome, 630, 633 SLPs See Speech and language pathologists (SLPs) Small-cell carcinoma of the lung (SCCL), 620 Small fiber neuropathies, 56–57, 332–333 clinical features, 332 histopathology, 333 laboratory features, 333 pathogenesis, 333 treatment, 333 SMAs See Spinal muscular atrophies (SMAs) SMN See Subacute motor neuronopathy (SMN) Snail envenomation, 647 Snakes, venom and effects, 645–646 SNAP See Sensory nerve action potential (SNAP); Soluble NSF attachment proteins (SNAP) SNARE (SNAP receptor) protein, 625 Sodium channel CMS, 632 Sodium channelopathies, 809–810, 809f molecular genetics and pathogenesis/ pathophysiology, 815, 816f Sodium-dependent carnitine transporter protein, 761 Soluble NSF attachment proteins (SNAP), 622 SOX1 antigen, 624 Spasticity, 164–165 Spastic paraplegia gene (SPG), 199, 200t–201t Speech and language pathologists (SLPs), 142–143 See also Rehabilitation Speed test, 913, 913f SPG See Spastic paraplegia gene (SPG) Spinal accessory nerve, 493 Spinal accessory neuropathy, 519–520, 520f Spinal deformities, rehabilitation approach for, 160 Spinal dural arteriovenous fistulas, 562 Spinal epidural abscess, 560 Spinal fluid analysis, in tick paralysis, 642 946 Index Spinal muscular atrophies (SMAs), 207, 208t–210t benign focal amyotrophies, 216–218 childhood bulbar SMA, 213 distal spinal muscular atrophy, 218–219 non-SMN infantile forms, 212–213 scapuloperoneal, 219–220 survival motor neuron–related, 207–212 X-linked bulbospinal muscular atrophy, 213–215 Spinal muscular atrophy with respiratory distress type (SMARD1), 209, 213 Spinal nerves, 491, 492f–495f Spinal stenosis, 558, 559 Spine, anatomy of, 539, 539f Splints, 151, 151f Split hand syndrome, 280 Spondylotic disease, 556 Sporadic inclusion body myositis (s-IBM), 699 SPS See Stiff-Person syndrome (SPS) Statins, neuropathy by, 457 Steroid myopathy, 876–877, 897–898 clinical features, 876, 897–898 histopathology, 877, 877f, 898, 898f laboratory features, 876, 898 pathogenesis, 877, 898 treatment, 877, 898 Stiff-limb syndrome, 254 Stiff-Person syndrome (SPS), 185, 254–258 clinical features, 254–255 diagnosis and differential diagnosis, 255–256 histopathology, 257 laboratory features, 256–257 pathogenesis, 257 treatment, 257–258 Stongyloidiasis, 119–120 Stool culture, 639 Straight leg raising, 553 Strength training, 145–146 See also Aerobic and strengthening exercise Stretching, 145, 145t Striated muscle antibodies, 596 Strychnos toxifera, 647 Styrene See Vinyl benzene Subacute motor neuronopathy (SMN), 234 Subscapular nerve, 496–497 damage to, 521–522 Succinate dehydrogenase (SDH), 773 Succinylcholine, 647 Superficial peroneal nerve biopsy, 103, 103f Superficial radial neuropathy, 524, 524t Supramaximal stimulus, 26 Suprascapular nerve, 494f, 495–496, 497f damage to, 521 Supraspinatus tendinopathy, 911–912 diagnosis, 911, 912f symptoms, 911 treatment, 911–912 Sural nerve, 547 Sural nerve biopsy, 102–103, 102f Sural neuropathy, 573 Suramin, toxic neuropathy with, 441–442 clinical features, 441 histopathology, 442 laboratory features, 442 pathogenesis, 442 Survival motor neuron-related SMAs, 207–212 clinical features, 207–209 SMA I, 207 SMA II, 208 SMA III, 208 SMA IV, 208–209 differential diagnosis, 209–210, 210t electrodiagnosis, 211 histopathology, 211–212 laboratory features, 210–211 management, 212 mutations of survival motor neuron (SMN) gene, 207 pathogenesis, 212 types, 207 Synaptobrevin, 625 Synaptotagmin, 625 Syncoilin, 660 Syntrophin complex, 656 Systemic lupus erythematosus (SLE), 386–387, 842–843 clinical features, 386–387 histopathology, 387 laboratory features, 387 pathogenesis, 387 treatment, 387 Systemic sclerosis See Scleroderma T Tachycardia, 638 Tacrolimus, 116t, 117t, 131 for inflammatory myopathies, 863 Tacrolimus, necrotizing myopathy by, 891 TAMV See Tracheostomy-assisted mechanical ventilation (TAMV) Tangier disease, 304 clinical features, 304 histopathology, 304, 305f laboratory features, 304 molecular genetics and pathogenesis, 304 Target fibers, in neurogenic disorders, 97, 98f Tarsal tunnel syndrome, 572 Tarsorraphy, for Kearns-Sayre syndrome, 785 Tarui disease See Glycogenosis type VII Taxol See Paclitaxel Taxotere See Docetaxel TDP-43, 188–189, 188f Telethonin, 661, 675 clinical features, 675 histopathology, 675 laboratory features, 675 molecular genetics and pathogenesis, 675 Tennis elbow test, 914, 915f Tenodesis orthosis, 151 Tensilon testing, in botulism, 639 Terminal cisternae, 661 Terminal latency index (TLS), 354 Terminal nerve lesions, 519 See also Terminal nerves axillary nerve, 522–523, 522t dorsal scapular nerve, 520 long thoracic nerve, 520–521, 521f, 521t medial and lateral pectoral nerves, 521 median nerve, 524–528 anterior interosseous syndrome, 526, 526t carpal tunnel syndrome, 526–528, 526t, 527f proximal median neuropathy, 525–526, 525f, 525t musculocutaneous nerve, 522, 522t radial nerve, 523–524 posterior interosseous neuropathy, 523–524, 524f, 524t proximal radial neuropathy, 523, 523t superficial radial neuropathy, 524, 524t spinal accessory, 519–520, 520f subscapular nerve, 521–522 suprascapular nerve, 521 thoracodorsal nerve, 522 ulnar nerve, 528 proximal ulnar neuropathy, 528–529, 528t ulnar neuropathy at elbow, 529–530, 529t, 530f ulnar neuropathy at wrist/hand, 530–531, 530t, 531f, 532f Terminal nerves, 492–493, 494f from cervical roots dorsal scapular nerve, 493, 497f long thoracic nerve, 495 phrenic nerve, 493, 494f from cords axillary nerve, 498, 499f lateral pectoral nerve, 496 medial cutaneous nerve of arm, 497 medial cutaneous nerve of forearm, 497–498 medial pectoral nerve, 494f, 496 median nerve, 499, 501f, 502 musculocutaneous nerve, 498, 498f radial nerve, 498–499, 500f subscapular nerves, 496–497 thoracodorsal nerve, 497 ulnar nerve, 502, 503f spinal accessory nerve, 493 from trunks nerve to subclavius, 496 suprascapular nerve, 494f, 495–496, 497f Testing, in neuromuscular disease, 22–79 autonomic nervous system testing (ANST), 57–61 biochemical testing for inborn errors of metabolism, 64, 68, 69t blood testing, 61–63 CSF analysis, 75 DNA mutational analysis, 63–64, 65–68t electrodiagnosis (EDX), 22–56 nerve and muscle imaging, 75–78 quantitative sensory testing (QST), 56–57 serologic testing, 68–75 Tetanus, 248–252 clinical features, 248–249, 249f diagnosis and differential diagnosis, 249–250 laboratory features, 250 opisthotonus, 249f pathogenesis, 250–251 risus sardonicus in infantile tetanus, 249f treatment, 252–252 Tetany, 252–253 clinical features, 252 diagnosis and differential diagnosis, 252 laboratory features, 252 pathogenesis, 252–253 treatment, 253 Index 947 Thalidomide neuropathy, 453 Thallium toxicity, 460–461 Thiamine deficiency, 418–419 clinical features, 418 histopathology, 418 laboratory features, 418 pathogenesis, 418 treatment, 418–419 Thiopurine methyltransferase (TPMT) deficiency, 861 Thomsen disease, 804 Thoracic outlet syndrome, 515–516 Thoracic radiculopathies, 511 Thoracodorsal nerve, 497 damage to, 522 Thoracolumbosacral orthoses (TLSOs), 150 Thumb osteoarthritis, 916–917, 916f Thymectomy, in MG patients, 605 Thyrotoxic myopathy, 872–873 clinical features, 872–873 histopathology, 873 laboratory features, 873 pathogenesis, 873 treatment, 873 Thyrotoxic periodic paralysis (TPP), 819, 873–874 Tibial nerve, 542f, 547, 550f Tibial neuropathy, 572 Tick paralysis, 641–643 acute myelopathies, 642 causes, 641 clinical features, 641–642 diagnosis and differential diagnosis, 642 histopathology, 642 laboratory features, 642 pathogenesis, 643 treatment, 643 Tilt table testing, 60 Tinel sign, 527 Titin (TTN), 660–661, 676–677, 722 clinical features, 676–677 histopathology, 677 laboratory features, 677 molecular genetics and pathogenesis, 677 Titinopathy, 676 Tizanidine, in hereditary spastic paraparesis, 204–205, 205t TLSOs See Thoracolumbosacral orthoses (TLSOs) Tomaculous neuropathy See Hereditary neuropathy with liability to pressure palsies (HNPP) Toxic myopathies, 887–904, 888t with anesthetic agents and centrally acting medications, 902–903 antimicrotubular myopathies, 893–894 drug-induced inflammatory myopathies, 895–897 drug-induced mitochondrial myopathy, 894–895 drugs of abuse and, 903–904 illicit drugs and, 904 impaired protein synthesis/increased catabolism, 897–899 with multifactorial/unknown pathogenic mechanisms, 899–902 necrotizing myopathies, 887–893 Toxic neuropathies, 448–462, 449t–451t with alcohol abuse, 462 due to chemotherapeutic agents, 438–443, 439t bortezomib, 442–443 carfilzomib, 443 cisplatin, 438–440, 439t cytosine arabinoside, 442 docetaxel, 441 etoposide, 440 ifosfamide, 442 oxaliplatin, 440 paclitaxel, 441 suramin, 441–442 vincristine, 440 vinorelbine, 440 with heavy metal intoxication, 459 arsenic, 461 gold, 461 lead, 459 mercury, 460 thallium, 460–461 with industrial agents acrylamide, 457 carbon disulfide, 457 ethylene oxide, 458 hexacarbons, 458–459 organophosphate poisoning, 458 vinyl benzene, 459 with medications amiodarone, 452 chloroquine, 451 colchicine, 452–453 dapsone, 454 disulfiram, 453–454 ethambutol, 455–456 fluoroquinolones, 456 hydroxychloroquine, 451–452 isoniazid, 455 leflunomide, 454 lithium, 456–457 metronidazole, 448 misonidazole, 448 nitrofurantoin, 454–455 nucleoside neuropathies, 456 phenytoin, 456 podophyllin, 453 pyridoxine toxicity, 455 statins, 457 thalidomide, 453 Toxic oil syndrome, 896 Toxoplasmosis, 858 TPP See Thyrotoxic periodic paralysis (TPP) Tracheostomy-assisted mechanical ventilation (TAMV), 177, 193 Transfer training and aids, 158–159 Transportin-3, 671 clinical features, 671 histopathology, 671 laboratory features, 671 molecular genetics and pathogenesis, 671 Transthyretin-related amyloidosis (TTR)related amyloidosis, 395–397 clinical features, 395–396 molecular genetics and pathogenesis, 396–397 treatment, 397 TRAPPC11, 679 Trichinosis, 857, 857f Trilaminar myopathy, 732 clinical features, 732 histopathology, 732 laboratory features, 732 molecular genetics and pathogenesis, 732 treatment, 732 TRIM 32 See E3-ubiquitine ligase Triosephosphate isomerase deficiency, 755 clinical features, 755 histopathology, 755 laboratory features, 755 molecular genetics and pathogenesis, 755 treatment, 755 Tripartite motif-containing protein 32 (TRIM 32), 661 Trojan horse effect, 640 Tropomyosin, 660 Troponin, 660 Trousseau sign, 252, 876 TTN See Titin (TTN) Tuberculin skin testing (TST), 119 Tuberculosis, 119 Tubular aggregate myopathy, 735 clinical features, 735 histopathology, 735, 736f laboratory features, 735 molecular genetics and pathogenesis, 735 treatment, 735 Tumor necrosis factor alpha blockers, 897 U Ubiquilin 2, 190 Ubiquitinated inclusions (UI), 188 Ubiquitin ligase (RBCK1) deficiency, 755 cause, 755 clinical features, 755 histopathology, 755 laboratory features, 755 molecular genetics and pathogenesis, 755 treatment, 755 UCMD See Ullrich congenital muscular dystrophy (UCMD) Udd distal myopathy, 697–699 causes, 699 clinical features, 697–698 histopathology, 699 laboratory features, 698–699 molecular genetics and pathogenesis, 699 Ulcerative colitis, 389 Ullrich congenital muscular dystrophy (UCMD), 682 Ullrich disease, 682 clinical features, 682 histopathology, 682 laboratory features, 682 molecular genetics and pathogenesis, 682 Ulnar nerve, 502, 503f, 528 proximal ulnar neuropathy, 528–529, 528t ulnar neuropathy at elbow, 529–530, 529t, 530f ulnar neuropathy at wrist/hand, 530–531, 530t, 531f, 532f Ultrasonography, 77 Upper limb orthoses, 150–151, 151f 948 Index Uremic neuropathy, 390–391 clinical features, 390–391 histopathology, 391 pathogenesis, 391 treatment, 391 Utrophin, 660, 663 V Vacuolar ATPases (V-ATPases), 757 Vacuolar myopathies, 756–757 Valosin-containing protein (VCP), 661 Vasculitic meuropathies, 371–379, 372t clinical features, 371, 372f, 372t histopathology, 371–373, 373f–375f laboratory findings, 371 large-and medium-sized vessel vasculitis giant cell arteritis, 373 medium and small vessel vasculitis Behỗet syndrome, 376 ChurgStrauss syndrome, 375, 375 granulomatosis with polyangiitis, 376 microscopic polyangiitis, 376 polyarteritis nodosa, 373, 375 patterns of involvement in, 372f secondary connective tissue diseases, vasculitis with, 376 cryoglobulinemia, vasculitis associated with, 377 drug-induced hypersensitivity vasculitis, 377, 377f infection-related vasculitis, 376 malignancy-related vasculitis, 376 nonsystemic /isolated PNS vasculitis, 377–378 postsurgical inflammatory neuropathy, 378 treatment, 378–379 ANCA-associated vasculitis, 378 mixed cryoglobulinemia, 378 non-ANCA vasculitis, 378–379 V-ATPases See Vacuolar ATPases (V-ATPases) VCPDM See Vocal cord and pharyngeal distal myopathy (VCPDM) VGCC See Voltage-gated calcium channels (VGCC) Vincristine myopathy, 893–894 Vincristine, toxic neuropathy with, 440 clinical features, 440 laboratory features, 440 pathogenesis, 440 Vinyl benzene, 459 Viral infections, inflammatory myopathy associated with, 854–856, 854t human immunodeficiency virus, 854–855 human T-cell leukemia virus type 1, 855 influenza viruses, 855–856 other viral-related myositis, 856 Vitamin B1 deficiency See Thiamine deficiency Vitamin B6 deficiency See Pyridoxine deficiency Vitamin B12 deficiency, 203 See Cobalamin deficiency Vitamin E deficiency, 421–422 clinical features, 306–307, 421 histopathology, 307, 421 laboratory features, 307, 421 molecular genetics and pathogenesis, 307 pathogenesis, 421–422 treatment, 307, 422 VLCAD deficiency, 762–763 clinical features, 762–763 histopathology, 763 laboratory features, 763 molecular genetics and pathogenesis, 763 treatment, 763 Vocal cord and pharyngeal distal myopathy (VCPDM), 700 Voltage-gated calcium channels (VGCC), 620 W Waldenström macroglobulinemia, 436–437 histopathology, 437 laboratory findings, 437 pathogenesis, 437 treatment, 437 Walkers, 154, 154f Walker-Warburg syndrome (WWS), 661, 683–684 causes, 661–662, 684 clinical features, 683–684 laboratory features, 684 molecular genetics and pathogenesis, 684 Welander distal myopathy, 697 clinical features, 697 histopathology, 697 laboratory features, 697 molecular genetics and pathogenesis, 697 Werdnig–Hoffman disease, 207–212 See also Survival motor neuron-related SMAs Western blot analysis and calpain-3 reduced, 672 See also Calpain-3 West Nile virus (WNV), 227–229 and acute flaccid paralysis (AFP), 227, 228 clinical features, 227–228 diagnosis and differential diagnosis, 228 histopathology, 229 laboratory features, 228 and meningoencephalitis, 228 pathogenesis, 229 treatment, 229 Wheelchairs, 154–155, 156f Whipple disease, 391–392 clinical features, 391 histopathology, 391 laboratory features, 391 pathogenesis, 391–392 treatment, 392 William distal myopathy, 700, 703 clinical features, 700 histopathology, 700 laboratory features, 700 molecular genetics and pathogenesis, 700 Wolff–Parkinson–White syndrome, 745, 756 Wolfram syndrome, 791 Women carriers, 665–666, 665f See also Dystrophinopathies Wound botulism, 638 Wrist extensor stretch, 915, 915f Writer’s cramp, 240 WWS See Walker-Warburg syndrome (WWS) X Xerostomia, 621 X-linked bulbospinal muscular atrophy See Kennedy disease X-linked disorder, 755 X-linked EDMD, 691–692, 692f clinical features, 691 histopathology, 691 laboratory features, 691 molecular genetics and pathogenesis, 691–692 treatment, 692 X-linked infantile SMA with arthrogryposis, 209, 212–213 X-linked myopathy with excessive autophagy (XMEA), 756–757 cause, 757 clinical features, 756 histopathology, 756–757, 757f laboratory features, 756 molecular genetics and pathogenesis, 757 treatment, 757 X-linked vacuolar cardiomyopathy and myopathy See Danon disease XMEA See X-linked myopathy with excessive autophagy (XMEA) Y Yergason test, 913, 913f Z Z-band alternatively spliced PDZ motifcontaining protein (ZASP), 660 Zebra body myopathy, 734 clinical features, 734 histopathology, 734 laboratory features, 734 molecular genetics and pathogenesis, 734 treatment, 734 Zidovudine myopathy, 894–895 Zoster motor paresis, 556 ... neuropathy with 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