Harrison Neurology in Clinical Medicine Second Edition

SECTION III Diseases of the Central Nervous System532 be tapered by 5 mg every 2–4 weeks. The cytotoxic agent is usually continued for 1 year. Therapy of hyper- Treatment: sensitivity vasculitis is focused primarily upon removal of MONONEUROPATHIES the offending antigen trigger. Treatment of localized vas- culitis restricted to the peripheral nervous system can be Treatment for acute and subacute compressive neu- less aggressive than for systemic vasculitis because the ropathies consists of identifying and removing extrinsic risk of death from untreated disease is very low. contributors and the use of splints to avoid further com- Monotherapy with either oral glucocorticoids or a brief pression. In patients with chronic compressive neu- course of cyclophosphamide (3–6 months) may be suffi- ropathies, exacerbating factors should be identified and cient. A tissue diagnosis of vasculitis should be obtained treated before surgical correction is considered. The use before initiating therapy; a positive nerve biopsy helps to of splints, a change of work habits to avoid activities or justify long-term immunosuppressive treatment, and movements that precipitate the neuropathy, or anti- pathologic confirmation of the diagnosis is often difficult inflammatory medication for tenosynovitis may be help- after treatment has commenced. ful (see later). POLYNEUROPATHIES Surgical treatment may be required for management of chronic compressive neuropathies when conserva- DIABETIC NEUROPATHY tive measures have failed and the site of entrapment is clearly delineated. Studies of surgery in carpal tunnel Diabetes mellitus is associated with various neuropathy syndrome have been encouraging. syndromes that differ in their etiology, natural history, and treatment. The overall prevalence of neuropathy is MONONEUROPATHY MULTIPLEX 66% for type 1 and 59% for type 2 diabetes. Neuropathy can be broadly divided into symmetric and asymmetric Mononeuropathy multiplex refers to the multifocal types, although a great deal of overlap exists between involvement of individual peripheral nerves. Although these categories. Symmetric neuropathies may present as multiple compressive neuropathies can present in this small-fiber involvement (e.g., dysesthesias in the feet) or manner, more often an inflammatory cause is responsi- autonomic dysfunction (e.g., sexual impotence), but ble, and in such cases the disorder is referred to as often both occur together; examination usually reveals mononeuritis multiplex. Both systemic (67%) and nonsys- additional evidence of large-fiber involvement and of an temic (33%) vasculitis may present as mononeuritis mul- underlying generalized neuropathy. tiplex; less commonly, vasculitic neuropathy can present as an asymmetric or distal symmetric neuropathy. The asymmetric neuropathies are divided into those Among the systemic vasculitides, polyarteritis nodosa, with acute onset and those with gradual onset. Asym- rheumatoid arthritis, systemic lupus erythematosus metric abrupt-onset neuropathies include diabetic trun- (SLE), Churg-Strauss syndrome,Wegener’s granulomato- cal radiculoneuropathy (DTRN), diabetic lumbosacral sis, and hypersensitivity vasculitis should be considered; radiculoplexus neuropathy (DLSRPN), and oculomotor these are often associated with constitutional symptoms (third or sixth nerve) neuropathy. These monophasic such as fever and weight loss.The common fibular nerve conditions are thought to be due to vascular causes (previously called the common peroneal nerve) is such as infarction. Neuropathies of more gradual onset affected in ~75% of patients with vasculitic neuropathy; are usually caused by entrapment or compression and symptoms consist of a painful foot drop. The ulnar, include median neuropathy at the wrist, ulnar neuropa- median, and radial nerves may also be involved. thy at the elbow, peroneal neuropathy at the fibular head, and lateral cutaneous neuropathy at the thigh at Treatment: the inguinal ligament (meralgia paresthetica). MONONEURITIS MULTIPLEX Symmetric Diabetic Neuropathy Therapy of the necrotizing systemic vasculitides can sta- bilize and in some cases improve the neuropathy. Gluco- By far the most common form of diabetic neuropathy is corticoids [prednisone (1.5 mg/kg per day)] plus a cyto- a length-dependent diabetic sensorimotor polyneuropa- toxic agent (usually oral cyclophosphamide at 2 mg/kg thy (DSPN). The lifetime prevalence is ~55% for type 1 per day) is the treatment of choice. Aggressive therapy is and 45% for type 2 diabetes. DSPN is a mixed neuropa- warranted since the prognosis for survival of untreated thy with small- and large-fiber sensory, autonomic, and patients is poor. Prednisone can be changed to an alter- motor nerve involvement in various combinations, nate-day regimen after 1 month to minimize side effects. although sensory and autonomic symptoms are more Once a clinical response is documented, prednisone may

prominent than motor ones (Table 40-1). Proposed Treatment: 533 criteria for the diagnosis of DSPN are two or more of DIABETIC SENSORIMOTOR the following: symptoms or signs of neuropathy, abnor- POLYNEUROPATHY CHAPTER 40 Peripheral Neuropathy mal EDx studies, quantitative sensation test abnormali- ties, heart rate decrease with deep breathing or Valsalva Treatment consists of strict glucose control, which pre- maneuver. vents the neuropathy from worsening; established neu- ropathy does not usually reverse. Aldose reductase DSPN has an insidious, progressive course. Initial inhibitors to treat and prevent diabetic neuropathy have symptoms may consist of numbness, tingling, buzzing, been studied in >30 trials. Although controlled trials of burning, or prickling sensation affecting the toes and the aldose reductase inhibitors sorbinol and tolrestat feet. Paresthesias ascend up to the legs and then hands in were found to improve electrophysiologic or morpho- a stocking-glove distribution. Over time, gait distur- metric markers of DSPN, any clinically meaningful bance and distal weakness may occur. Painful or insensi- improvement in pain or sensation has been inconsis- tive extremities predispose to foot ulcers; amputation is tent. Treatment with recombinant nerve growth factor sometimes required. Examination shows a distal sensory was ineffective. Alpha lipoic acid (thioctic acid), an loss to pin, temperature, touch, and vibration sense. antioxidant, has been shown to improve experimental Ankle reflexes are invariably reduced or absent. Weak- diabetic neuropathy, and a meta-analysis of clinical trials ness, if present, is mild and involves toe flexors and suggested that the treatment (600 mg/d IV for 3 weeks) extensors. The length-dependent pattern of neuropathy is safe and improves symptoms and signs of neuropa- is evident in the stocking-glove sensory loss, and some thy. Pancreatic transplantation can halt progression of patients also show sensory loss in the anterior abdominal DSPN but is a realistic therapy only for patients who region in a wedge-shaped distribution. Autonomic have renal failure and are undergoing combined kidney symptoms including impotence, nocturnal diarrhea, dif- and pancreas transplantation. ficulty voiding, abnormalities of sweating, and abnormal fullness after eating and orthostatic hypotension may be Glycemic control is essential for the prevention of present. diabetic autonomic neuropathy. Once neuropathy is established, few effective treatments exist. The diagnosis of DSPN is usually straightforward, although other contributors to the neuropathy should Asymmetric Diabetic Neuropathy be excluded, including nutritional (vitamins B1 and B12 and folate deficiencies), toxic (alcohol, vitamin B6 Cranial Neuropathies toxicity), immune-mediated (paraprotein), and inherited The oculomotor nerves (in decreasing order of fre- causes. An alternative diagnosis should be sought in quency the sixth, third, and rarely fourth nerves) are patients with rapidly progressive or asymmetric weak- most often affected. In general, cranial neuropathy ness, a family history of neuropathy, exposure to toxins, occurs in patients older than 50 years who already have or prior malignancy. A glucose tolerance test is indicated evidence of DSPN. Abducens (sixth) nerve palsy mani- in all patients presenting with neuropathy. EDx studies fests as the sudden onset of painless double vision, and show mixed findings of axonal loss and demyelination in examination shows paralysis of abduction on the a length-dependent pattern. Nerve biopsy and lumbar affected side (Chap. 17). In a patient with diabetes who puncture are not necessary unless alternative diagnoses has no other clinical findings the diagnosis is straight- are being considered. forward. Spontaneous recovery typically occurs within 3–5 months and no treatment except an eye patch or Various hypotheses have been invoked to account for prism is necessary. Diabetic third nerve palsy is also DSPN. Increased neuronal concentrations of glucose abrupt in onset but is often heralded by intense retroor- induce the conversion of glucose to sorbitol by aldose bital pain that may be present for several days. Symp- reductase using NADPH as a coenzyme. Sorbitol toms include double vision, unilateral ptosis, and decreases levels of myo-inositol and phosphoinositides, restriction of medial gaze and upgaze. Unlike compres- leading to a decrease in diacylglycerol, protein kinase C, sive etiologies (e.g., aneurysms of the superior cerebel- and Na+, K+, ATPase activity. This sequence of events lar or posterior communicating arteries), which present leads to axonal loss and demyelination and is the basis of with an enlarged (“blown”) pupil, the pupil is nearly trials using aldose reductase inhibitors and high myo- always spared in diabetic third nerve palsy. This is due inositol diets. A second hypothesis proposes insufficient to the fact that pupillomotor fibers are present on the blood flow: increased aldose reductase activity results in outer layers of the third nerve fascicle, and an ischemic competitive inhibition of nitric oxide synthetase for lesion tends to involve the center of the fascicle. In NADPH, resulting in decreased nitric oxide and reduced atypical cases, such as those with pupillary involvement blood flow in the vasa nervorum. Altered metabolism of or without pain, a neuroimaging study, usually MRI or fatty acids, reduced concentrations of nerve growth fac- tor, and oxidative stress are possible additional contribut- ing factors.

SECTION III Diseases of the Central Nervous System534 MR angiography (MRA), is indicated to exclude an Diabetic amyotrophy (femoral neuropathy; proximal aneurysm. Most patients improve spontaneously in diabetic neuropathy) occurs in older patients, usually 3–6 months without any treatment. Symptomatic treat- with type 2 diabetes. Patients present with the abrupt ment with eye prisms is often helpful. Idiopathic neu- onset of severe pain affecting the anterior thigh. But- ropathy of the facial nerve (seventh; Bell’s palsy) is also tock and lower back pain may also be present.The pain more common in older diabetics than in nondiabetics. is worse at night and is described as burning. Weakness The clinical features and prognosis are similar to the and wasting in the thigh muscles leads to difficulty nondiabetic form (Chap. 29). climbing stairs and walking. Males are more likely to be affected, and weight loss, at times dramatic, is invariably Limb Mononeuropathies present. Although symptoms may be bilateral, one side Diabetics are also susceptible to entrapment neuropathies, is more severely affected than the other. Examination including median neuropathy at the wrist (carpal tunnel shows prominent wasting of the quadriceps muscle uni- syndrome), ulnar neuropathy at the elbow, fibular laterally with weakness of the knee extensor and hip (peroneal) neuropathy at the fibular head, and lateral flexor and, variably, ankle dorsiflexor, accompanied by cutaneous neuropathy at the inguinal ligament (meralgia sensory loss in the thigh and leg in the distribution of paresthetica). The special susceptibility of diabetic nerves the femoral nerve, and a reduced knee jerk on the may be related to endoneurial edema and vascular fac- affected side. The syndrome progresses over weeks to tors. Patients typically present with several weeks or months, then stabilizes and gradually improves. EDx months of pain, numbness, or weakness in the distribu- studies show findings of radiculopathy (L2-4), lumbar tion of the affected nerve.The approach to these entrap- plexopathy, or femoral neuropathy along with a distal ments is similar to that in individuals without diabetes. sensorimotor neuropathy. An MRI of the lumbosacral Decompressive surgery may be needed if there is associ- spine and plexus is indicated to exclude a compressive ated weakness, numbness, or pain in the distribution of cause. Cerebrospinal fluid (CSF) examination and nerve the affected nerves and if no reversible extrinsic source of biopsy should be considered whenever the diagnosis is compression (position/habits) can be identified. uncertain. The level of CSF protein is often elevated, and biopsy of the intermediate femoral cutaneous nerve Radiculopathies and Plexopathies may show microvasculitis. The condition may be quite Diabetic truncal radiculoneuropathy occurs in diabetics in painful and require opiates for pain control.Treatment with middle or later life, usually in association with underly- high-dose glucocorticoids or intravenous immunoglobulin ing DSPN. Patients present with an abrupt onset, typi- (IVIg) has been effective in case reports, although con- cally over days to weeks, of severe pain in the thoracic trolled trials have not shown clear benefit. Physiother- spine, flank, rib cage, or upper abdomen. The pain is apy and orthotic devices are helpful. The prognosis is described as burning, stabbing, or belt-like. Contact generally favorable; improvement occurs over several hyperesthesia is present in the area of pain. Associated, months in most patients treated with symptomatic sometimes profound, weight loss is often described; this measures only. A similar condition may also occur in can also be seen in diabetic amyotrophy (see later). nondiabetic patients. Examination may be normal or may reveal variable sen- sory loss in the distribution of one or several intercostal Uncommon Diabetic Neuropathies nerves and their branches. Anterior abdominal wall weakness may be noted as focal bulging of the weak- Diabetic neuropathic cachexia (acute painful neuropathy of ened region when the patient attempts to sit up. A diabetes) is an uncommon painful sensory neuropathy needle EMG of the affected muscles may confirm den- occurring in type 1 diabetics in the setting of poor glu- ervation in the abdominal or intercostal muscles; the cose control and weight loss. Manifestations include paraspinal muscles may be spared. This finding, and a severe pain in the feet ascending up to the legs and reduced fiber density measured by skin biopsy from trunk with associated allodynia. Examination may reveal symptomatic regions, suggests that the injury in diabetic distal sensory loss to pinprick and vibration and reduced truncal radiculoneuropathy is at, or distal to, the sensory or absent ankle jerks. Strength is preserved. EDx studies ganglion. The differential diagnosis in this elderly popu- may show a distal neuropathy. Unlike DSPN, the prog- lation should include herpes zoster infection (without nosis is favorable with glucose control. The painful rash) and an abdominal malignancy. Most patients symptoms reverse over months to a year. improve spontaneously, although the pain may persist for weeks to months. Pain management may be difficult and Insulin neuritis describes a painful neuropathy seen includes topical capsaicin and narcotics. The abrupt with initiation of insulin treatment for diabetes. The onset and spontaneous recovery suggest a vascular cause clinical presentation is similar to the acute painful neu- to this syndrome, although an inflammatory etiology can ropathy of diabetes, and most patients improve. not be excluded. A reversible sensory and motor polyneuropathy has been reported in association with diabetic ketoacidosis.

Most patients also have upper and lower motor neuron neuropathy may do so acutely when used at higher doses; 535CHAPTER 40 Peripheral Neuropathy signs, as well as a preexisting neuropathy.The etiology is examples include arsenic, thallium, and pyridoxine. The not clear; critical illness neuropathy may be the underly- combination of two toxic drugs, commonly seen with ing cause. Finally, chronic inflammatory demyelinating anticancer therapy (e.g., paclitaxel and cisplatin), may neuropathy (CIDP) occurs in diabetics; the disease produce greater nerve toxicity than either one alone. resembles that seen in nondiabetics. Patients with underlying conditions may be predisposed to neuropathy when exposed to some compounds, e.g., TOXIC INCLUDING CHEMOTHERAPY- vitamin B12–deficient patients who receive nitrous oxide INDUCED NEUROPATHIES anesthesia, or patients with porphyria who receive bar- biturates. Usually, however, toxic neuropathy is subacute Most toxic neuropathies are distal axonal degenerations in onset, developing over a period of months. Vin- that develop gradually over time. The causes are varied, cristine, amiodarone, nitrofurantoin, isoniazid, dimethy- including drugs, heavy metals, and industrial and envi- laminopropionitrile (DMAPN), inorganic mercury, and ronmental substances (Table 40-8). Novel anticancer thallium all cause a subacute neuropathy. The insidious drugs and antiretroviral agents are the most common onset of a chronic neuropathy occurs with exposure to drugs implicated, although over-the-counter medica- industrial toxins at low dosages over a prolonged period tions (especially pyridoxine) can also cause neuropathy. of time. Examples include acrylamide, allyl chloride, A temporal relationship between introduction of the hexacarbons, carbon disulfide, ethylene oxide, lead, and toxic substance and the onset of neuropathy is usually arsenic. In addition to preexisting neuropathy, other host noted, as is a dose-response relationship. In general, a factors, including diabetes, hepatic or renal impairment, lower dose over a longer period of time is less toxic than and alcohol abuse, may reduce the threshold for neuro- a higher dose for a short period, even if the eventual toxicity. The neuropathy may be predominantly motor cumulative doses are similar. Onset following introduc- with lead, inorganic mercury, organophosphates, buck- tion of the agent and reversal or at least arrest following thorn, dapsone, and vincristine; small-fiber sensory with its removal provide the best evidence of a toxic neu- DMAPN, thallium, nucleoside analogue reverse tran- ropathy, along with the symptoms and signs typically scriptase inhibitors (dideoxycytidine ddC, dideoxyino- caused by the suspected agent.The neuropathy may first sine ddI, stavudine d4T), ethionamide, metronidazole, manifest or may continue to progress after discontinuing and taxane; or large-fiber sensory with cisplatin, high the substance; this phenomenon, known as coasting, is doses of taxol, pyridoxine, or acrylamide. Autonomic seen with the platinum cancer drugs, hexacarbons, dysfunction can occur with vincristine, vacor, perhexi- nucleoside analogue reverse transcriptase inhibitors, and line, high dose-pyridoxine, and platinum. Other toxins pyridoxine. that may involve autonomic nerves include acrylamide (acral and pedal hyperhidrosis), DMAPN (urologic and Clinical evaluation includes a history focusing on sexual dysfunction), and hexacarbons (hyperhidrosis and the temporal relationship between exposure and onset impotence). Some toxic neuropathies also involve the of sensory or motor symptoms, comorbid diseases that cranial nerves. These include trichloroethylene, which may cause neuropathy, and symptoms of systemic toxi- causes acute dysfunction of the cranial nerves V,VII, III, city. Nerve biopsy occasionally demonstrates pathog- and II; thallium and acute fulminant vacor poisonings, nomonic features such as osmiophillic Schwann cell which cause facial diplegia with generalized neuropathy inclusions in amiodarone, perhexiline and chloroquine resembling Guillain-Barré syndrome; perhexiline, which neuropathies, and paranodal giant axonal swellings in causes facial diplegia and perioral numbness; vincristine hexacarbon neuropathies. Levels of some toxins can be and paclitaxel, which may be associated with numbness measured in certain tissues: heavy metals such as lead, in the trigeminal nerve distribution; and chlorampheni- arsenic, and thallium can be measured in urine; arsenic col, ethambutol, and nitrous oxide, all of which may can be measured in hair or nails. Blood levels of drugs cause optic neuropathy. Asymmetric neuropathy or are also useful. mononeuritis multiplex is rare but may be seen with lead, which may cause unilateral wrist drop; or with Table 40-8 lists some of the better-documented neu- DMAPN, which causes sacral dermatomal sensory loss. rotoxic substances. Awareness of the types of indus- Signs of toxicity to kidney, liver, or other organs can in tries in which toxic exposure can occur is important in some cases alert the clinician to the possibility that a identifying occupational exposure. Lower dosages and neuropathy could be toxic in origin. shorter durations of exposure may produce neuropathy in susceptible individuals such as those with underlying Cisplatin inherited neuropathy. An acute onset of neuropathy occurs with drugs such as paclitaxel, suramin, and vacor, Cisplatin (cis-diaminodichloroplatinum) is a heavy metal and with biologic agents such as ciguatera, puffer fish used to treat a variety of solid tumors. Cisplatin is toxic (tetrodotoxin), and buckthorn. Some toxic agents that otherwise require long-term exposure to produce chronic

536 TABLE 40-8 TOXIC NEUROPATHIES CIRCUMSTANCES OF TOXICITY NEUROPATHY COMMENTS AXONOPATHY Nonpharmaceutical toxins Acrylamide monomer Flocculators, grouting agents Sensory ataxia; large fiber Numbness, excessive sweating, exfoliative dermatitis Allyl chloride Epoxy resin, glycerin Dysesthesia and distal weakness Arsenic (inorganic) Copper/lead smelting, contaminant in S > M; painful; usually subacute Skin: hyperkeratosis, “rain-drop” pig- recreational drugs, suicide/homicide or chronic; may be acute follow- mentation of skin, Mees’ line in nails (herbicide/insecticide) ing large doses Carbon disulphide Viscose rayon, cellophane; airborne SM Slow NCS industrial exposure Dimethylaminopropi- Polyurethane foam SM Small-fiber neuropathy with prominent onitrile (DMAPN) bladder symptoms and impotence Ethylene oxide Sterilization of biomedicals Hexacarbons (paranodal Solvents, adhesives SM Neurofilament swelling of axons; CNS SECTION III Diseases of the Central Nervous System giant axonal) Substance abuse (glues and thinners) Lead Batteries, smelting metal ores, paints M > S; wrist drop Burton’s line, anemia, basophilic stippling Mercury (inorganic) Environmental/workplace CNS > PNS; neuropathy Tremor, insomnia, behavioral change uncommon Methyl bromide Fumigant, insecticide, refrigerant, fire Variable recovery Encephalitis, ataxia extinguisher Organophosphorus Insecticide, petroleum, plastics SM Acute toxicity presents as cholinergic esters crisis Thallium (rat poison) Rodenticides, insecticides Painful SM Thallium (alopecia, Mees’ line, hyperkeratosis) Vacor Rodenticide, suicide Rapid onset of severe axonopa- Diabetic ketoacidosis a feature of thy and autonomic dysfunction acute toxicity Pharmaceutical agents Chloramphenicol Mean cumulative dose 255 g, duration S > M Also optic neuropathy Colchicine Chronic dosing at 1.2 mg/d especially Distal paresthesias and Also myopathy with elevated serum CK in the presence of renal dysfunction proximal weakness Dapsone 200–400 mg/d over many months Pure motor, especially upper limbs May look like motor neuron disease Disulfiram 250–500 mg/d after several months SM Difficult to distinguish from alcohol used for alcoholism neuropathy Ethambutol >20 mg/kg per day over many months Sensory neuropathy Also optic neuropathy Ethionamide >15 mg/kg Sensory neuropathy Limited by GI, dermatologic and CNS side effects Gold Controversial, as rheumatoid arthritis S > M with myokymia Rash, pruritus can cause neuropathy Not dose dependent Isoniazid >5 mg/kg over weeks or about 6 months, Dose-dependent SM neuropathy Add pyridoxine 50 mg/d when using depending on acetylator status INH Metronidazole Cumulative dose > 30 g Sensory (small and large fiber) Misonidazole Cumulative dose > 18 g/m2 Sensory axonopathy Dose-limiting side effect Nitrofurantoin Standard dose of 200 mg/day over Mild SM neuropathy a few weeks Nitrous oxide Dental surgery, anesthesia, substance S >> M Toxic myeloneuropathy resembles abuse cobalamine deficiency Nucleoside analogues >12.5 mg/kg per day for ddI, 0.02 mg/kg Painful sensory neuropathy Difficult to distinguish from HIV neu- (ddC, ddI, 4dT) per day for ddC, and 0.5 mg/kg per ropathy day for 4dT Pyridoxine >200 mg a day over several months Length-dependent axonopathy Neuronopathy at higher doses Suramin Peak serum concentration of 350 μg/mL S > M; may be demyelinating Taxol Cumulative dose of >1500 mg/m2 S>M Higher single doses may cause neuronopathy Thalidomide 100 mg/d for 6 months. S>M Thalidomide (brittle nails, palmar erythema) Vincristine and other Almost all patients S > M but autonomic fibers also Vacuolar myopathy vinca alkaloids affected

TABLE 40-8 (CONTINUED) 537 TOXIC NEUROPATHIES CIRCUMSTANCES OF TOXICITY NEUROPATHY COMMENTS Myelinopathy 400 mg/day for 6–36 months, serum SM; dose-dependent Tremor CHAPTER 40 Peripheral Neuropathy Amiodarone concentration of 2.4 mg/L Hepatic toxicity S (large fiber) and M, facial, auto- Acne, brown nails Perhexiline Not dose-related nomic SM Limbs rarely affected Polychlorinated biphenyls Plasticizers, electrical insulators Demyelinating like subacute Suramin Not dose-related GBS Irreversible Mainly cranial nerves: trigeminal, May be irreversible Trichloroethylene Dry-cleaning, rubber, degreasing facial, oculomotor, optic May be irreversible agent Sensory Neuronopathy Large-fiber sensory Platinum compounds, Cumulative dose more than e.g., cisplatin 900 mg/m2 Sensory neuronopathy; gait High-dose pyridoxine ataxia, pseudoathetosis Massive parenteral doses in Sensory ataxia Taxol grams over days Single dose of ≥250 mg/m2 Note: S, sensory; M, motor; SM, sensorimotor; NCS, nerve conduction studies; CNS/PNS, central/peripheral nervous system; CK, creatine kinase; GI, gastrointestinal; GBS, Guillain-Barré syndrome; EDx, electrodiagnosis; CSF, cerebrospinal fluid; CMV, cytomegalovirus; DSPN, dia- betic sensory polyneuropathy. to dorsal root ganglia neurons, producing a dose-related those caused by cisplatin, oxaliplatin neuropathy is more large-fiber sensory neuropathy (neuronopathy). It also likely to be reversible. injures hair cells of the cochlea, causing hearing loss. Peripheral neuropathy is the dose-limiting toxicity of cis- Paclitaxel platin. A cumulative cisplatin dose of at least 300 mg/m2 may lead to paresthesias in the extremities and numbness. Paclitaxel, a diterpene alkaloid drug, is widely used as a Lhermitte’s sign, an electric shock–like sensation evoked chemotherapeutic agent. Peripheral neuropathy, which by flexion of the neck, may occur due to retrograde can be severe, is the dose-limiting toxicity. A symmet- degeneration of axons in the posterior columns of the ric, length-dependent neuropathy with prominent sen- spinal cord. Patients with preexisting neuropathy and sory (large more than small fiber) and minor motor those who receive combination chemotherapy may manifestations, is typically present. Preexisting neuropa- develop symptoms after lower cumulative doses. Sensory thy is a risk factor. The neuropathy is dose-dependent, ataxia may be disabling in patients who have severe neu- and both single and cumulative doses are important. ropathy. Small-fiber sensation (e.g., pain and temperature) The drug affects microtubule assembly, causing disrup- and strength are generally spared. tion of axonal transport and a “dying back” axonal neuropathy. Oxaliplatin Vincristine Oxaliplatin can cause an early acute and a late chronic neuropathy. The acute neuropathy begins during the Vincristine, an alkaloid derived from the pericuwinkle infusion, within minutes to hours, or within 1–2 days of plant, vinca rosea, causes a dose-dependent sensorimotor administration. Patients complain of paresthesias in the neuropathy. Lower cumulative doses (4–19 mg) cause hands or feet, mouth, or throat along with myalgias, only reflex changes, while higher doses progressively cramps, or stiffness. Shortness of breath or difficulty cause paresthesias, sensory loss (upper extremity more swallowing may occur. Symptoms are often triggered by than lower), weakness with footdrop, and hand weakness exposure to cold. Neuromyotonia may be seen on and clumsiness. Autonomic neuropathy can manifest as EMG. Although this acute toxicity occurs in >90% of cardiac arrhythmias, orthostasis, urinary bladder dysfunc- patients, it is often self-limited and resolves within days. tion, constipation, or paralytic ileus. Cranial neu- A channelopathy is thought to be the underlying mech- ropathies have also been described. anism. A chronic large-fiber ataxic neuropathy, similar to that caused by cisplatin, occurs with cumulative doses Suramin ≥780 mg/m2, generally after eight or nine treatment cycles. Even though the signs and symptoms (paresthe- Suramin is a polysulfonated naphthylurea that has been sias, distal sensory loss, and loss of reflexes) are similar to used as an antineoplastic agent and as a treatment for

SECTION III Diseases of the Central Nervous System538 certain parasitic diseases. Suramin causes a length- Prognosis for recovery depends on both the site of dependent distal axonal neuropathy in over half of pathology and the severity of the neuropathy. Involve- patients and a subacute inflammatory demyelinating ment of the dorsal root ganglion is associated with a neuropathy in ~15% of patients. Neuropathy occurs poor prognosis. Severe axonopathy requires years for with peak plasma concentrations >300 μg/mL. recovery. Demyelinating disorders, if detected early, generally are associated with a relatively rapid recovery. Thalidomide Most toxic neuropathies, even if advanced, will at least stabilize, and some will improve, when exposure to the Peripheral neuropathy remains the dose-limiting toxic- toxic agent is stopped. ity of thalidomide, which causes a length-dependent painful sensory axonal neuropathy; a sensory neuronopa- NUTRITIONAL NEUROPATHIES thy has also been reported. Peripheral neuropathy occurs in up to 75% of patients and is dose-dependent, Thiamine ( Vitamin B1 ) (Dry Beriberi) rarely occurring with cumulative doses <20 g, but invariably noted at cumulative doses >100 g. The risk Thiamine deficiency can be a result of inadequate of neuropathy is minimized at doses ≤150 mg/d. Serial intake, as may occur in alcoholism, anorexia, intentional sensory action potential measurements are important in dieting, starvation, or bulimia. Protracted vomiting, e.g., the early detection of the neuropathy. Symptoms often, in patients receiving chemotherapy or in pregnant though not always, improve with cessation or dose women with hyperemesis gravidarum, may also cause reduction.The neuropathy develops at a lower dose and thiamine deficiency. Neuropathy from thiamine defi- is typically more severe in patients with a preexisting ciency presents as the acute or subacute onset of pares- diabetic neuropathy. thesias, dysesthesias, and mild weakness in the legs. On examination a stocking-glove sensory loss, distal weak- Bortezomib ness in the legs, and loss of ankle jerks is typical. Nerve conduction tests and sural nerve biopsies show axonal Bortezomib (Velcade), a novel proteosome inhibitor degeneration. Erythrocyte transketolase activity is used in the treatment of multiple myeloma, induces a reduced in the blood.Treatment consists of oral thiamine length-dependent, sensory more than motor, axonal replacement, 100 mg/d. Alcohol-induced neuropathy polyneuropathy that is dose-dependent, increasing with develops in some patients without any identifiable increasing cycles of treatment. Both small- and large- nutritional deficiencies, suggesting that alcohol itself fiber sensory symptoms occur. In a few patients the may cause sensory neuropathy. It predominantly affects symptoms stabilize or improve after stopping treatment. small fibers and is painful, but there is considerable over- A toxic acquired demyelinating neuropathy has also lap with thiamine deficiency neuropathy. been reported. Pyridoxine ( Vitamin B6 ) Treatment: TOXIC NEUROPATHIES A subacute length-dependent axonal neuropathy occurs as a result of pyridoxine deficiency. Causes include Removal of the toxic substance is the most important step. dietary deficiency and drugs such as isoniazid, cycloserine, Specific treatments are available for some toxic neu- and penicillamine, which act as pyridoxine antagonists ropathies. Treatment for heavy metal toxicity includes by combining to the aldehyde moiety of the vitamin. chelation therapy: penicillamine or calcium-EDTA for Dietary deficiency of pyridoxine is uncommon, lead toxicity; penicillamine or British anti-Lewisite (BAL) although the requirement is increased in pregnancy. for arsenic toxicity; and potassium chloride or Prussian Measurement of xanthurenic acid after tryptophan load- blue for thallium toxicity. Pyridoxine (10–50 mg/d) can ing can help confirm the diagnosis.Treatment consists of be used to prevent and treat isoniazid neurotoxicity. oral pyridoxine, 30 mg/d. Pyridoxine supplements are Niacin and pyridoxine are recommended for ethion- recommended for prophylaxis during pregnancy and for amide neurotoxicity. There may be some benefit from patients taking isoniazid. Overzealous treatment with the use of neuroprotective agents. Vitamin E (toco- pyridoxine should be avoided, as high doses of pyridox- pherol) was reported to be neuroprotective in one ine cause a toxic sensory neuronopathy. small, unblinded study, but these results have not been confirmed. Org 2766, glutathione, diethyldithiocarba- Vitamin B12 (Cobalamin) mate, and amifostine have also been tried without con- clusive outcomes. Studies are under way to evaluate the Peripheral neuropathy is a minor part of the vitamin B12 possible efficacy of nerve growth factor. deficiency syndrome; subacute combined degeneration of the spinal cord is more prominent. Distal sensory loss

predominantly involving large-fiber modalities, dysequi- malnourished field workers and prisoners of war. Distal 539CHAPTER 40 Peripheral Neuropathy librium, Lhermitte’s sign, and the combination of an sensory loss with hyporeflexia at the ankles (peripheral absent ankle jerk and upgoing toe may be present. Pancy- nerve lesion), combined with hyperreflexia at the knees topenia, megaloblastic anemia, and glossitis are other and an ataxic gait (spinal cord involvement), indicate the signs. The principal dietary sources of vitamin B12 are combined peripheral and central axonal loss that is char- meat and dairy products; enteric processing and absorp- acteristic of this deficiency state. Treatment with vitamin tion typically occur in the terminal ileum. Common B complex frequently improves the symptoms. causes of vitamin B12 deficiency include inadequate intake, malabsorption (including post-gastrectomy), and Vitamin E Deficiency pernicious anemia. Borderline vitamin B12 deficiency may develop after exposure to nitrous oxide during anesthesia Vitamin E deficiency can occur from fat malabsorption or with chronic recreational use. Diagnosis of vitamin B12 or from abetalipoproteinemia. The clinical features of deficiency is made by low serum cobalamin levels and vitamin E deficiency resemble those of Friedreich’s raised levels of methylmalonic acid and homocysteine. ataxia (Chap. 26), with severe large-fiber loss and a Autoantibodies to intrinsic factor and gastric parietal cells non-length-dependent reduction of sensory nerve are present in pernicious anemia. Treatment is with par- action potentials suggestive of dorsal root ganglionopa- enteral administration of cobalamin (vitamin B12) . thy. The diagnosis is confirmed by measurement of serum α tocopherol and the ratio of vitamin E to total Riboflavin, Nicotinic Acid and Other serum lipids. Treatment consists of administration of α B-Group Vitamins tocopherol (400 mg bid), which may reverse or prevent progression of the sensory neuronopathy. Riboflavin and nicotinic acid deficiencies have been incriminated in neuropathies, usually in association with INFECTIONS AND PERIPHERAL deficiencies of other water-soluble vitamins. Peripheral NEUROPATHY neuropathy may be accompanied by dermatitis, diarrhea, and dementia (pellagra).The diagnosis is made on clinical HIV Infection grounds, and treatment consists of administration of 40–250 mg niacin daily. Strachan’s syndrome is character- (See also Chap. 37) HIV infection is associated with ized by a painful sensory neuropathy associated with oro- polyradiculopathies, distal symmetric polyneuropathies, genital dermatitis, amblyopia, and deafness. This syn- inflammatory demyelinating polyneuropathies, multifo- drome was first reported in Jamaica and later in cal mononeuropathies, cranial neuropathies, and neu- ropathies induced by antiretroviral drugs (Table 40-9). TABLE 40-9 NEUROPATHIES ASSOCIATED WITH HIV INFECTION HIV NEUROPATHY SYMPTOMS AND SIGNS TYPICAL CD4 DIAGNOSTIC TESTS Distal symmetric COUNTS, CELLS/μL polyneuropathy Painful paresthesias, <200 EDx studies distal sensory loss, Skin biopsy GBS, CIDP absent ankle jerk <500; >50 Progressive weakness, EDx studies Mononeuropathy multi- areflexia, numbness <500; >50 CSF studies: plex (cryoglobulinemia, elevated protein, hepatitis C) Footdrop, wrist drop, <50 variable pleocytosis CMV polyradiculopathy facial weakness EDx studies, nerve <50 biopsy Herpes zoster, tubercu- Flaccid paraparesis, <500 losis, lymphoma saddle anesthesia, EDx, CSF studies Toxic neuropathy urinary retention Depends on specific EDx, CSF studies etiology Nerve biopsy Similar to DSPN Eliminate drug: stavu- dine (d4T), didanosine (ddI), zalcidabine (ddC) Note: GBS, Guillain-Barré syndrome; CIDP, chronic inflammatory demyelinating polyneuropathy; EDx, electrodiag- nosis; CSF, cerebrospinal fluid; CMV, cytomegalovirus; DSPN, diabetic sensory polyneuropathy.

SECTION III Diseases of the Central Nervous System540 Lumbosacral polyradiculopathies are usually due to Serum lactate concentrations are elevated and acetylcarni- CMV infection and occur with advanced HIV/AIDS. tine levels are reduced as a result of mitochondrial dys- These present with pain, incontinence, and rapidly pro- function. Dideoxynucleosides have also been shown in gressive asymmetric lower extremity weakness leading vitro to inhibit gamma DNA polymerase, whereas to paraplegia. Saddle anesthesia is always present. Deep zidovudine, lamivudine, and abacavir (drugs that are not tendon reflexes are often preserved. EMG reveals find- associated with neuropathy) have only limited effects on ings of both peripheral neuropathy and lumbosacral this enzyme. radiculopathy. CSF analysis shows pleocytosis with polymorphonuclear cells; polymerase chain reaction Treatment: for CMV is positive. The differential diagnosis TOXIC NEUROPATHY FROM includes GBS; other infections including herpes viruses, ANTIRETROVIRAL DRUGS treponema, or tuberculosis; and carcinomatous meningo- radiculitis from lymphoma. Aggressive and rapid treat- Treatment consists of discontinuing the offending ment with ganciclovir, foscanet, or cidofovir should be dideoxynucleoside and changing the highly active anti- considered. retroviral therapy (HAART) regimen, provided that there is another regimen to offer. Failing this, a patient may Distal Symmetric Polyneuropathy Associated need to continue the regimen with the addition of pain- with HIV modifying drugs. Prescribing patterns have changed in HIV distal sensory symmetric polyneuropathy presents the developed world to limit the use of specific as a painful, predominantly small-fiber neuropathy. This dideoxynucleosides. However, in resource-limited coun- syndrome cannot be distinguished reliably from neu- tries, generic antiretroviral combinations typically con- ropathy caused by antiretroviral drugs (nucleoside tain d4T. After discontinuation of a toxic dideoxynucleo- reverse transcriptase inhibitors); its onset with respect to side, symptomatic improvement can be expected in exposure to the offending drugs may be the only clue. It most individuals within ~3 months. is estimated that ~30% of hospitalized patients with AIDS and 100% of individuals dying with AIDS have Various pain-modifying drugs have been tried with- evidence of neuropathy. The prevalence is lower in less out success, including tricyclic antidepressants and anti- advanced HIV infection, occurring in only 3% of those convulsants. Lamotrigine was reported to be efficacious with CD4 cell counts >200/μL. Older age, associated in a subgroup of patients in one class I trial, but results nutritional deficiencies, and toxic exposures are addi- of a smaller class II trial were contradictory. Some posi- tional risk factors for AIDS-related neuropathy. Most tive results have been achieved with topical capsaicin or patients present with painful burning, tingling, and topical lidocaine, especially in patients with symptoms numbness in the feet. Symptoms are typically bilateral, confined to the feet. Patients with severe neuropathies gradual in onset, and worse at night (features common may require narcotic analgesics for pain relief, and long- to all painful neuropathies). Examination usually shows acting narcotics such as transdermal fentanyl, mor- distal loss to pin and temperature sensation and absent phine, or oxycodone preparations are particularly or decreased ankle jerk. Weakness is either not detected useful. Specific prescribing guidelines should be used, or is confined to the intrinsic foot muscles. Asymmetric particularly if there is any history of substance abuse. presentations suggest the possibility of vasculitis (nerve Regenerative strategies, including trials of recombinant biopsy indicated) or an entrapment neuropathy. The human nerve growth factor, have been attempted. possibility of a confounding neuropathy from diabetes, alcohol, nutritional causes, or toxin exposure should Neuropathies with Lyme Disease always be considered. A focal or multifocal radiculoneuropathy may occur Nerve biopsy shows a length-dependent axonal with Borrelia burgdorferi infection. Subacute cranial neu- degeneration of sensory fibers, with little evidence of ropathy (especially VII) or painful radiculopathy may nerve-fiber regeneration. Both large myelinated and occur in the acute phase of Lyme disease, with or unmyelinated nerve fibers are lost. Inflammatory infil- without associated meningitis. The radiculitis is dyses- trates of lymphocytes and activated macrophages and thetic or painful and is variable in distribution. CSF reduced numbers of DRG neurons may be seen. pleocytosis with intrathecal production of B. burgdorferi antibodies is typical. Most patients improve either Toxic Neuropathy from Antiretroviral Drugs spontaneously or after IV ceftriaxone treatment. In the A toxic neuropathy follows exposure to specific chronic phase, a mild, chronic distal polyneuropathy dideoxynucleosides (d4T, ddI, and especially ddC), partic- (sensory more than motor) has been described; however, ularly in advanced HIV disease. Sural nerve biopsy shows severe axonal destruction, most prominently in unmyeli- nated fibers, along with mitochondrial abnormalities.

the CSF is normal and the association may be auricular nerve in the neck, median and ulnar nerves, 541 CHAPTER 40 Peripheral Neuropathy coincidental. and peroneal nerves can all be involved. Over the long term, untreated leprosy leads to claw hand deformity Herpes Zoster (from ulnar and median nerve weakness), footdrop, and inability to close the eyelids due to orbicularis oculi Reactivation of varicella zoster virus (VZV) in dorsal weakness. root ganglia produces lancinating pain and hyperalgesia in a dermatomal distribution. The pain is followed INHERITED NEUROPATHIES 3–4 days later by the appearance of a blistering skin rash. The inflammation may at times involve the adja- CHARCOT-MARIE-TOOTH DISEASE cent motor nerve roots, causing weakness and wasting. Ophthalmoplegic zoster causes weakness in the divi- Clinical Features sion of one or more oculomotor nerves; facial zoster causes facial palsy (Ramsay Hunt syndrome); thora- CMT neuropathy is the most common heritable neu- columbar zoster causes rash and sensory loss in a tho- romuscular disorder with an estimated incidence of racic or lumbar nerve root. Although pain usually 17–40 cases per 100,000 (Table 40-10). It is a chronic subsides after a few days to a week, it sometimes persists distal sensory and motor neuropathy presenting as long- (postherpetic neuralgia). Herpes zoster and posther- standing gait difficulty with frequent tripping, followed petic neuralgia both occur more commonly in the elderly by difficulty with buttoning, handling keys, turning and in immunosuppressed individuals. In the acute set- door knobs, and opening jars. There is often a history ting acyclovir, famciclovir, or valacyclovir are equally of clumsiness, frequent ankle injuries, inability to jump effective, although acyclovir must be given five times a well or to keep up with other children in races, and day as opposed to three times a day for the other being unathletic. In some patients the history suggests a two drugs. Glucocorticoids are of unproven benefit. more recent onset. If carefully sought, a family history Treatment of postherpetic neuralgia includes tricyclic can often be obtained.Wasting and weakness of the dis- antidepressants, duloxetin, gabapentin, pregabalin, oxy- tal muscles of the legs (inverted champagne bottle codone, morphine sulfate, tramodol, lidocaine patch, appearance) with hammer toes and high arched feet and topical capsaicin. A zoster vaccine (Zostavax) has (pes cavus) are commonly present, along with steppage been approved to prevent VZV in elderly patients; the gait, distal sensory loss, and distal loss of reflexes. Pes incidence of shingles is reduced by 50% and posther- cavus and hammer toes indicate that the neuropathy petic neuralgia by 67%. dates from early life. An inability to walk on the heels or perform tandem gait is often present.The differential Leprous Neuritis diagnosis is limited if there is an early age of onset, a positive family history, and longstanding symptoms. If Mycobacterium leprae causes mononeuropathy multiplex the EDx findings indicate a demyelinating process, the affecting peripheral nerves in cooler regions of the body, diagnosis of CMT can be made with confidence, reflecting the predilection for this bacterium to thrive at although genetic testing may be needed to confirm the cooler temperatures. The deformities caused by precise genotype. If the EDx findings are axonal, or if untreated leprous neuritis have led to the fear and the family history is uncertain or negative, CMT stigma attached to this disease. Although the incidence becomes a diagnosis of exclusion. Diabetes, as well as of leprous neuritis has declined, it remains a leading nutritional, toxic, endocrine, inflammatory, paraprotein- cause of neuropathy worldwide. Leprosy is classified into associated, and infectious causes, may all need to be tuberculoid, lepromatous, and borderline types; periph- excluded. Physical examination and EDx studies of at- eral nerves may be affected in all three types, and risk family members can be more useful diagnostically involved nerves are often palpably thickened. In tuber- than additional laboratory testing of the patient. Treat- culoid leprosy, a single patch of hypesthetic or anesthetic ment is supportive; patients often need foot braces but skin may occur in any location. The area is generally rarely, if ever, become wheelchair dependent. CMT hypopigmented, thickened, or red. A mononeuropathy does not reduce the life span and only rarely involves involving a nearby superficial nerve may occur. Lepro- respiratory muscles. matous leprosy produces more widespread skin thicken- ing, hypesthesia, and anhidrosis affecting the pinnae of Classification ears, dorsum of hands or feet, dorsomedial surfaces of the forearm, and anteromedial aspects of the legs. The Demyelinating forms of CMT are classified as CMT1, sensory loss spares the midline of the trunk anteriorly, and axonal forms as CMT2. Patients with nerve con- the groin, axilla, and scalp; these are the warmer regions duction velocities (NCVs) intermediate between CMT1 of the body.The fifth and seventh cranial nerves, greater and CMT2 are classified as having “intermediate CMT,” and most of these cases are X-linked. CMT is usually

542 TABLE 40-10 Charcot-Marie-Tooth 1 (CMT1) Demyelinating Neuropathies FORMS OF CHARCOT-MARIE-TOOTH DISEASE (HEREDITARY MOTOR AND SENSORY NEUROPATHY) CMT1 is the most common of the heritable neu- AND RELATED DISORDERS ropathies; inheritance is autosomal dominant. Distal weakness, wasting, and sensory loss with distal reduction DISORDER LOCUS GENE INHERITANCE of tendon reflexes and foot deformities occur as with other forms of CMT. The onset is in the first or second Charcot-Marie-Tooth Type 1 decade of life, although patients may not come to atten- tion until much later in life. EDx studies show a pattern SECTION III Diseases of the Central Nervous System (HMSNI) 17p11.2-p12 PMP22 AD of generalized demyelination with NCVs that are uni- CMT1A 1q22-q23 P0 AD formly and proportionately slowed in distal, intermedi- CMT1B 16p12-p13 SIMPLE AD ate, and proximal segments of the same nerve on the CMT1C 10q21-q22 EGR2 AD/AR opposite side, and in adjacent nerves. Findings suggestive CMT1D Xq13.1 GJB1 X-linked of heterogeneous demyelination, such as conduction CMT1X Xq21.32-24 PRPS1 X-linked block or dispersion, are not seen. Electrophysiologic evi- CMT5X 8q13-q21 GDAP1 AR dence of demyelination may be prominent even in CMT4A 11q22 MTMR2 AR patients who are clinically asymptomatic. Nerve biopsies CMT4B1 11p15 SBF2 AR show evidence of repeated bouts of demyelination and CMT4B2 8q24 NDRG1 AR remyelination. Proliferation of Schwann cells occurs in CMT4D an attempt to remyelinate; the supernumerary Schwann 10q21.1-q22.1 EGR2 AR cells are concentrically arranged around demyelinated (HMSN-Lom) 19q13 PRX AR and remyelinated axons, giving a characteristic “onion CMT4E 6q21 FIG4 AR bulb” appearance. There is also increased collagen CMT4F between the layers of Schwann cells leading to palpably CMT4J thickened nerves. Charcot-Marie-Tooth Type 2 CMT1 is classified into several genetically distinct subtypes (Table 40-10), all of which are clinically simi- (HMSNII) 1p35-p36 KIF1B AD lar. In addition, distinct phenotypes with overlapping CMT2A 3q13-q22 RAB7 AD genotypes are identified. These include HNPP; infan- CMT2B 12q23-q24 Unknown AD tile-onset or severe childhood forms, which include CMT2C 7p14 GARS AD Déjerine-Sottas syndrome (DSS) and congenital CMT2D 8p21 NEF-L AD hypomyelinating neuropathies (CHN); and Roussy- CMT2E 11q21 LMNA AR Lévy syndrome. CMT2B1 CMT1A Déjerine-Sottas This is the most common form; it is associated with the 17p11.2-p12 duplication in the PMP22 gene expressed (HMSNIII) 17p11.2-p12 PMP22 AD by Schwann cells. The duplication involves a large seg- DSS 1q22-p23 P0 AD ment of DNA (~1.4 Mb) encoding a 160-amino-acid 10q21-q22 EGR2 AD/AR protein localized to compact myelin in peripheral 19q13 PRX AD nerves. CMT1A accounts for up to 90% of CMT1 and 50% of all CMT. Deletion of the PMP22 gene produces Congenital Hypomyelination a different phenotype—HNPP (see later). Commercial testing for PMP22 duplication/deletion is widely avail- CHN 1q22-23 P0 AD able. PMP22 appears to be important in the initiation of 10q21-q22 EGR2 AR/AD myelin spirals; regulation and growth of Schwann cells; and control of thickness, stability, and maintenance of Hereditary Neuropathy with Pressure Palsies myelin sheaths. HNPP 17p11.2-p12 PMP22 AD CMT1B CMT1B accounts for <5% of CMT1 cases. It is due to Note: HMSN, hereditary motor and sensory neuropathies; PMP22, a mutation in the myelin protein zero (MPZ, or P0) peripheral myelin protein 22; P0, myelin protein zero; SIMPLE, small gene. Different mutations in the same gene can produce integral membrane protein of late endosome; Cx32, connexin32; a wide spectrum of phenotypes including DSS, CHN, EGR2 (Krox-20) early growth response 2 gene; GDAP1, ganglioside- or CMT2. P0 is quantitatively the major structural induced differentiation-associated protein-1; MTMR2, myotubularin- related protein-2; SBF2, SET binding factor 2; NDRG1, N-myc downstream regulated gene1; PRX, periaxin; KIF1B, kinesin family member 1B; RAB7, ras-associated protein 7; GARS, Glycyl-tRNA synthetase; NEFL, neurofilament, light polypeptide; LMNA, lamin A. transmitted as an autosomal dominant trait, but X-linked- dominant CMT is responsible for ~10% of CMT cases. Rare autosomal recessive forms, designated CMT4, tend to have an early onset and are more severe than the dominant types. In total, ~35 different loci and >24 genes have been identified in CMT.

protein of peripheral nerve myelin and is important in entrapment sites is preferred over surgical release or 543CHAPTER 40 Peripheral Neuropathy myelin compaction. CMT1B is clinically indistinguish- transposition. able from CMT1A; a late adult-onset form with foot- drop can occur. Genetic testing is available. Déjerine-Sottas Syndrome and Congenital Hypomyelinating Neuropathy CMT1X These are severe childhood forms of CMT1. DSS and This is an X-linked dominant form of CMT that can CHN both present with muscle weakness at birth or also affect heterozygote females. It is responsible for up infancy, with absent or very slow NCVs. Delayed motor to 10% of CMT. Males are more often affected, and milestones are noted in early childhood. Patients either female carriers are usually mildly affected or asympto- never ambulate or lose their ability to ambulate in matic. Male-to-male transmission does not occur. Onset infancy or childhood. NCVs are markedly slow (typi- in males is between 5 and 20 years of age; symptoms cally 10 m/s); CSF protein is elevated. Clinically DSS include difficulty running, sprained ankles, footdrop, and CHN are indistinguishable. DSS can be either auto- distal wasting, weakness, sensory loss, and reduced somal dominant or recessive; CHN is autosomal reces- reflexes. These features do not distinguish CMT1X sive. Nerve biopsy can distinguish the two, with DSS from other forms of CMT1. Signs of central nervous showing a thin myelin sheath surrounded by onion system (CNS) involvement, including ataxia, dysarthria, bulbs composed of concentric layers of basal lamina weakness, aphasia, disorientation, and hearing loss, may (Schwann cells are degenerated leaving the basal lam- be present, especially in males. Spontaneously resolving ina), while CHN shows lack of onion bulbs and absent confluent white matter changes may be seen on MRI. myelin sheaths. DSS may be caused by mutations of NCVs are in an intermediate range, although males PMP22, myelin protein zero (MPZ), or early growth have slower conduction velocities (25–45 m/s), which response gene (ERG2); EGR2 or MPZ mutations may be nonuniform with conduction block and disper- underlie CHN. sion. This nonuniform pattern may mimic findings of an acquired disorder such as CIDP. The mutated gene, Roussy-Lévy Syndrome GJB1, encodes the gap junction protein connexin-32, This describes a combination of demyelinating CMT which is expressed at the paranodal regions and at the with postural and action tremor. The original family Schmidt-Lanterman incisures of noncompact myelin. members had the MPZ mutation, but mutations in PMP22 (CMT1A), MPZ (CMT1B), or GJB1 (CMT1X) Hereditary Neuropathy with Liability to Pres- genes may also cause this syndrome. sure Palsies This is also called tomaculous neuropathy. It is an autoso- Charcot-Marie-Tooth 2 (CMT2) Axonal mal dominant disorder that presents as recurrent Neuropathies episodes of focal entrapment neuropathy with attacks of numbness and weakness in peroneal, ulnar, radial, and CMT2, an autosomal dominant neuropathy, is responsi- median nerves (in descending order) or in a brachial ble for one-third of CMT disease, although the number plexus distribution. Malposition of a limb or trauma of patients is increasing as more genetic abnormalities may provoke episodes of neuropathy. Some patients pre- are being identified. CMT2 has a later age of onset than sent with a progressive length-dependent polyneuropa- CMT1; family members may be affected subclinically. thy rather than with recurrent mononeuropathies, and Although typical length-dependent sensory and motor others remain entirely asymptomatic. Increased distal loss develops over the years, intrinsic hand weakness and latencies in median and peroneal nerves and reduced atrophy, present in CMT1, do not develop. velocities across the elbow of the ulnar and fibular head segment of the peroneal nerves may be found. Tomacu- CMT2A (classic CMT2) is caused by mutations in lae are sausage-shaped bodies that indicate segmental MFN2 and represents 10% of dominant CMT2; demyelination. CMT1A and HNPP are both associated CMT2B is caused by mutations in RAB7, a member of with copy number changes in the PMP22 gene—a the Rab family of ras-related GTPases that function in duplication causing CMT1A and deletion causing intracellular membrane trafficking; it presents with HNPP. Hence, CMT1A and HNPP are the reciprocal severe sensory involvement and limb ulcerations. products of unequal crossing-over during meiosis.When CMT2B overlaps with hereditary sensory neuropathy HNPP presents as a painless brachial plexus neuropathy, (HSN) type I with prominent sensory loss and severe it should be distinguished from brachial plexus neuritis sensory loss to touch and pain (see later). CMT2C is and from hereditary neuralgic amyotrophy, a familial dis- associated with vocal cord and respiratory (diaphragm) order with painful weakness and sensory loss in the involvement; the genetic defects have not been identi- brachial plexus distribution.Treatment for HNPP is sup- fied. CMT2D is an axonal CMT with upper limb pre- portive. Avoiding further compression or trauma to the dominance associated with mutations in the glycyl-tRNA synthetase gene; predominant hand involvement with

SECTION III Diseases of the Central Nervous System544 atrophy of distal hand muscles in a patient with a posi- duplication. Most CMT1 and CMT2 pedigrees are tive family history suggests CMT2D. autosomal dominant. X-linked inheritance should be suspected if males are more often affected, there is no Autosomal Recessive Forms of CMT male-to-male transmission, and EDx studies show het- erogeneous findings. Sporadic cases are difficult to eval- Autosomal recessive CMTs account for <10% of inher- uate since family members may not be available. Testing ited neuropathy cases in the Western world but may be for the CMT1A duplication/deletion and for GJB1 more common in regions of the world where consan- mutation can diagnose ~80% of all cases of CMT. guinity is common. Several genes have been identified, especially in inbred families. Demyelinating autosomal OTHER INHERITED NEUROPATHIES recessive forms, designated CMT4, are usually character- ized by early onset and more severe involvement, with Hereditary Motor Neuropathies (HMN) congenital or delayed motor milestones, facial weakness, bulbar weakness, sensorineural deafness, diaphragm The distal HMNs present with distal motor weakness weakness, and vocal cord paralysis. with sparing of sensory fibers. Seven subtypes have been described based on the age of onset and mode of inheri- Molecular Testing tance, which is usually autosomal dominant or recessive. The common HMNs present as footdrop with severe The phenotype, the inheritance pattern, and electro- wasting and weakness distally. Some variants may mani- physiologic data guide the approach to the diagnosis of fest with predominantly upper limb involvement, vocal an inherited neuropathy. Figure 40-2 summarizes an cord paralysis, or with upper motor neuron signs mimic- approach to genetic testing for CMT. If the proband has king amyotrophic lateral sclerosis (Chap. 27); the prog- CMT1, a single nerve study (median motor forearm nosis is relatively good. conduction velocity) in family members is a quick screening tool. However, if the proband has axonal Hereditary Sensory Neuropathies (HSN) CMT (CMT2), more detailed evaluation of family members may be required. Evaluation for HNPP HSNs, also called hereditary sensory and autonomic employs the same molecular test as for the CMT1A neuropathies (HSANs), are a heterogeneous group of dis- orders affecting the sensory and/or autonomic neurons. Suspected CMT HNPP Distal wasting, Infancy/early childhood (multiple entrapments) weakness, sensory (DSS or CHN) < 10 m/s PMP22 deletion Demyelinating Intermediate Axonal PMP22 mutation (CMT1) 10–38 m/s 25–45 m/s (CMT2) > 38 m/s • PMP22 duplication GJB1 (CMT1X) • MFN2 (CMT2) • MPZ mutation (CMT1A) • GJB1 (CMT1X) • EGR2 • PRX • GJB1 (CMT1X) • MPZ (CMT1B) MPZ (CMT1B) MPZ (CMT1B) • Sequence PMP22 (CMT1A) • Upper limb > lower limb: CMT2D • Severe sensory loss and ataxia: CMT4F (periaxin) • Sensory > motor: axonal CMT2 (MPZ or RAB7) • Vocal cord/diaphragm: CMT2C • Proximal weakness (wheelchair: DI CMT1B) • Deafness: CMT1E • Pyramidal features: HMSN V • CMT with optic atrophy: MFN2 gene (HMSN VI) • Tonic pupil: CMT2J (MPZ) • Scoliosis: CMT4C FIGURE 40-2 Déjerine-Sottas syndrome; CHN, congenital hypomyelinating Diagnostic approach to Charcot-Marie-Tooth disease (CMT). neuropathy; HMSN, hereditary motor and sensory neuropathy. HNPP, hereditary neuropathy with pressure palsies; DSS,

The predominant clinical presentation is of progressive peripheral neuropathy. Nearly 100 different mutations 545 CHAPTER 40 Peripheral Neuropathy distal sensory loss, although some weakness and wasting have been identified in the TTR gene, the most com- is also observed. The classification of HSN and HSAN mon being the Val30Met mutation. Liver transplanta- is based on the age of onset and mode of inheritance. tion halts disease progression. Five subtypes are described. The most common is HSN 1 (also called HSAN 1), an autosomal dominant Tangier Disease (TD) neuropathy presenting with predominant small-fiber sensory involvement with lancinating pain, loss of pain This is a rare syndrome caused by a severe deficiency and temperature sensation, and foot ulceration. Of of high-density lipoproteins (HDL) in plasma. Peripheral note, CMT2B (see earlier) also presents with predomi- neuropathy is the most disabling feature of TD and nantly sensory loss to all modalities and foot ulcera- affects ~50% of patients. Three patterns are recognized: tions. HSN 2–5 are all autosomal recessive. HSN 2 pre- a transient or relapsing, often asymmetric neuropathy sents in the first two decades of life with prominent (including isolated cranial nerve deficits); a slowly sensory loss and mutilation in hands and feet. HSN 3 progressive symmetric neuropathy most marked in the (HSAN 3), also called Riley-Day syndrome, has promi- distal upper limbs (syringomyelia-like); and a slowly nent dysautonomia. HSN 4 (HSAN 4) presents with progressive symmetric sensory motor neuropathy episodic fever, anhidrosis, and reduced response to most marked in the lower limbs. Mononeuropathies painful stimuli. HSAN 5 presents with congenital involving the oculomotor nerve, long thoracic nerve, insensitivity to pain; mutations in a sodium channel or any of the limb nerves may occur.The syringomyelic (SCN1.7) are causative. presentation includes wasting of hand muscles, loss of pain and temperature sensation, and facial diplegia. Refsum Disease The length-dependent sensorimotor neuropathy pat- tern is the least common variant. Deposits of choles- This is an autosomal recessive hypertrophic neuropathy terol esters in tonsils, liver, spleen, rectal mucosa, and caused by defective oxidation of phytanic acid, a cornea lead to the other non-neurologic manifestations branched-chain fatty acid found in dairy products, beef, of TD.There is no treatment available; a low-cholesterol lamb, and fish. The onset is in late childhood or adoles- diet or other dietary changes do not modify the cence, with a slowly progressive course of a sensorimo- natural history. Gene therapy may be possible in the tor demyelinating neuropathy with sensorineural deaf- future. ness, cerebellar ataxia, and anosmia. Retinitis pigmentosa presenting as night blindness often precedes the onset of Porphyric Neuropathy neuropathy. Thickened skin (ichthyosis), syndactyly and shortening of the fourth toe, cardiomyopathy, and Peripheral neuropathy accompanies the inherited cataracts are other features. CSF protein is typically ele- hepatic porphyrias. The triad of acute neuropathy, psy- vated. Abnormally high plasma and urinary levels of chiatric symptoms, and abdominal involvement are simi- phytanic acid are diagnostic. Although a diet low in phy- lar in all hepatic porphyrias. Variegate porphyria and tanic acid may prevent the onset of some of the compli- hereditary coproporphyria are characterized by addi- cations, compliance with this diet is usually poor. Plasma tional skin lesions (blisters and bullae) in ~50% of exchange and dialysis may be helpful for episodes of patients. Most patients with porphyria are asymptomatic worsening. between attacks. Attacks can occur spontaneously or be precipitated by certain drugs, stress, hormonal factors, Familial Amyloid Neuropathy and reduced caloric intake. Abdominal pain, constipa- tion, vomiting, and mental changes frequently herald the This is an autosomal dominant disorder in which there attacks. Peripheral neuropathy has an acute onset and is extracellular deposition of amyloid in peripheral may be preceded or accompanied by autonomic mani- nerves and other organs. A painful sensory neuropathy festations such as tachycardia, hypertension, and postural with early involvement of autonomic nerves and car- hypotension. The neuropathy is usually subacutely pro- diomyopathy is typically present. Age of onset can vary gressive (over 2–4 weeks) with diffuse weakness (often from 18–83 years. Small fibers (pain and temperature) proximal more than distal) and areflexia. Sensory loss is are more affected than large fibers (vibration and pro- generally mild and may be more prominent proximally prioception); anhidrosis, gastrointestinal disturbances in a “bathing trunk” distribution. Porphyric neuropathy (diarrhea alternating with constipation), impotence, should be considered in the differential diagnosis of orthostatic intolerance, visual changes, and arrhythmias GBS, the most common cause of rapidly progressive are additional features. Mutations in transthyretin (FAP ascending paralysis. 1 and 2), apolipoprotein A1 (FAP 3) or gelosin (FAP 4) are responsible.Transthyretin is most often implicated in CSF is acellular but the protein level is elevated, similar to that in GBS. Acute attacks are invariably

SECTION III Diseases of the Central Nervous System546 associated with increased urinary excretion of neuromuscular blockade) are purely motor and can be aminolevulinic acid and/or porphobilinogen. Measur- recognized and localized electrodiagnostically (Chap. 42). ing 24-h urinary excretion of porphobilinogen and aminolevulinic acid and 24-h fecal excretion of proto- PURE SENSORY NEUROPATHY porphyrin and coproporphyrin during a symptomatic period is the most helpful method of determining Causes include Friedreich’s ataxia, idiopathic sensory whether symptoms are due to acute porphyria. Since neuropathy, sensory neuropathy associated with Sjögren porphyrins are light sensitive, specimens must be stored syndrome, vitamin B12 neuropathy (dorsal column in the dark and tested as soon as possible. involvement is the major factor), pyridoxine toxicity, Treatment is largely supportive during the acute cri- and cisplatin neuropathy. The most severe and wide- sis and includes fluid management, ventilatory support, spread of these pure sensory syndromes exhibit poor or management of heart rate and blood pressure (auto- no recovery, suggesting irreversible lesions of nerve cell nomic dysfunction), and avoidance of medications that bodies in dorsal root and trigeminal ganglia (neu- are known to precipitate an acute attack. Oral and IV ronopathy). A painful sensory neuropathy is an early glucose and heme arginate are the mainstays of treat- feature of hereditary sensory neuropathies, lepromatous ment. Recovery from an acute attack may take several leprosy, diabetic small-fiber neuropathy, amyloidosis, months. TD, Fabry’s disease, and dysautonomia. Global sensory loss can occur with carcinomatous sensory neuropathy, Critical Illness Neuropathy hereditary sensory neuropathies, diabetic sensory neu- ropathy, vacor intoxication, and xanthomatous neuropa- See Chap. 22. thy of primary biliary cirrhosis. SPECIAL PERIPHERAL PLEXOPATHY NEUROPATHY PRESENTATIONS This refers to disorders of either the brachial or the AUTONOMIC NEUROPATHY lumbosacral plexus. Brachial plexopathy is a broad term used to define any injury, traumatic or otherwise, to the Symptoms may include orthostatic hypotension (syncope, brachial plexus. Causes include birth injury, trauma, light headedness, dizziness, fatigue, and lethargy), heat neoplasm, radiation, and familial and immune-mediated intolerance, abnormal (reduced or increased) sweating, processes (Fig. 40-3; Table 40-11). Trauma to the constipation, diarrhea, incontinence, sexual dysfunction, plexus is responsible for up to 70% of brachial plexus dry eyes, dry mouth, or visual blurriness. Autonomic lesions; the upper plexus is the most vulnerable. Brachial neuropathy is usually a manifestation of a more general- neuritis (neuralgic amyotrophy; Chap. 7), characterized ized polyneuropathy, as in diabetes, GBS, and alcoholic by sudden onset of pain in the shoulder region followed polyneuropathy, but occasionally syndromes of pure by weakness and atrophy, is the second most common pandysautonomia are encountered. Other causes include cause. In this disorder, the shoulder girdle muscles are amyloidosis and multiple drugs and toxins. Autonomic most frequently affected, and individual peripheral neuropathies are discussed in detail in Chap. 28. nerves tend to be more commonly involved. Other causes include a cervical rib or band, infiltration by PURE MOTOR NEUROPATHY malignant tumor, or prior radiation therapy. Examples of predominantly motor neuropathies include Brachial plexus lesions demonstrate characteristic acute inflammatory neuropathies such as GBS; chronic motor and sensory signs. When the upper parts of the neuropathies such as CIDP and multifocal motor neu- brachial plexus (cervical roots 5–7) are affected, weak- ropathy (MMN) (Chap. 41); some inherited neu- ness and atrophy of shoulder girdle and upper arm mus- ropathies; brachial neuropathy; diabetic lumbosacral cles occurs. Injuries to the lower brachial plexus (C8-T1 radiculoplexus neuropathy (diabetic amyotrophy); and roots) produce distal arm weakness, atrophy, and focal neuropathy due to spinal muscular atrophy, acute inter- sensory deficits in the forearm and hand. In general, mittent porphyria, diphtheria, lead, and dapsone. Motor idiopathic brachial neuritis, irradiation with >60 Gy neuronopathies include the lower-motor form of amy- (6000 rad), and specific types of trauma (arm jerked otrophic lateral sclerosis, poliomyelitis, hereditary spinal downward) result in damage to the upper portions of muscular atrophies, and an adult variant of hex- the brachial plexus. In contrast, infiltration by malignant osaminidase A deficiency (Chap. 27). Neuromuscular tumor, a cervical rib or band, and specific types of junction disorders (e.g., Lambert-Eaton myasthenic syn- trauma (arm jerked upward) cause damage to the lower drome, tick bite paralysis, and other types of toxic brachial plexus. The lumbosacral plexus is formed by the ventral pri- mary rami of L1-S4. Although often considered as a

Dorsal scapular 547 Upper Lateral Suprascapular C5 subscapular anterior Subclavius C6 thoracic C7 L C8 Axillary Medial anterior Musculocutaneous thoracic Radial P Median M T1 Long thoracic Ulnar Thoracodorsal Lower Medial subscapular antibrachial cutaneous Medial brachial cutaneous PERIPHERAL NERVES CORDS DIVISIONS TRUNKS ROOTS Anterior Posterior CHAPTER 40 Peripheral Neuropathy FIGURE 40-3 Electromyography. Baltimore, Williams and Wilkins, 1974, Brachial plexus anatomy. L, lateral; M, medial; P, poste- p. 126; with permission.) rior. (From J Goodgold: Anatomical Correlates of Clinical TABLE 40-11 BRACHIAL PLEXUS LESIONS SITE OF NERVES/NERVE MUSCLES SENSORY LOSS COMMON CAUSES INJURY ROOTS AFFECTED Small patch of skin overlying the deltoid Birth injury during difficult Upper trunk C-5 and C-6 Weakness of shoulder delivery (Erb-Duchenne abduction (supraspinatus Ulnar border of the palsy); brachial neuritis, Lower trunk C-8 and T-1 & deltoid), external rota- hand and inner also called neuralgica tion (infraspinatus) and forearm myotrophy (Parsonage- elbow flexion (biceps) Turner syndrome) Radial border of Birth injury, especially Weakness and wasting forearm and hand breech delivery (Déjerine- of small muscles of Klumpke paralysis), com- the hand (claw-hand Ulnar border of the pression by cervical rib or deformity) hand and inner band (thoracic outlet syn- forearm drome), tumor infiltration Lateral cord Musculocutaneous Weakness of flexion and Outer aspect of Trauma, stretch Medial cord nerve and lateral pronation of forearm upper arm Posterior cord part of median Trauma nerve Weakness and wasting Medial part of of small muscles of Trauma, shoulder median nerve the hand (claw hand dislocation and ulnar nerve deformity) Deltoid, extensors of Axillary and radial elbow, wrist, and fingers nerves single entity, it can be divided into a lumbar plexus the main nerves formed by the sacral plexus. The lum- (ventral rami of L1–L4) and a sacral plexus (lum- bosacral plexus courses near the paravertebral psoas bosacral trunk L4 and L5 and ventral rami of S1–S4) muscle and the sacroiliac notch and sacral ala, where it (Figs. 40-4 and 40-5). The femoral and obturator is relatively well protected from injury, unlike its upper nerves are the main nerves formed from the lumbar extremity counterpart. Disorders affecting the lum- plexus, and the sciatic, gluteal, and pudendal nerves are bosacral plexus include: trauma, intraoperative damage,

548 T12 degrees of pain, sensory deficits, and weakness in the T12 lower limbs, generally in an asymmetric distribution. Lateral femoral The onset may be acute, subacute, or insidious depend- cutaneous n. L1 ing on the etiology; the course may vary from being Iliohypogastric n. monophasic, stepwise, or progressive. EDx studies are invaluable aids for diagnosis and localization. L2 Ilioinguinal n. PERIPHERAL NERVE INJURY L3 Physical damage to peripheral nerves may result from sudden compression, crush, transection, or stretching of L4 Genito-femoral n. a nerve. The mildest form of nerve injury results when a stretch or pressure injury distorts the myelin overly- L5 ing the nodes of Ranvier and produces focal conduc- tion block. This type of injury, with conduction block Femoral n. Obturator n. but without Wallerian degeneration, is referred to as neurapraxia, or class 1 injury. This results in a transient SECTION III Diseases of the Central Nervous System Lumbosacral trunk sensation of numbness in an extremity, as occurs after FIGURE 40-4 lying or sitting in a certain position. Nerve injury that Lumbar plexus. Posterior divisions are in orange, anterior divi- interrupts the axon’s continuity and results in Wallerian sions are in yellow. (From J Goodgold: Anatomical Correlates degeneration of the nerve distal to the lesion is consid- of Clinical Electromyography. Baltimore, Williams and Wilkins, ered moderate or severe. If the endoneurium is pre- 1974, p. 126; with permission.) served, the lesion is considered moderate and is called axonotmesis, or class 2 injury. If the endoneurium is L4 destroyed, the lesion is considered severe and is called neurotmesis. Peripheral nerve lesions are often mixed; L5 neurapraxia and axonotmesis may coexist. Similarly, one fascicle may be completely disrupted while Superior gluteal S1 another is only partially affected. If the clinical and Inferior gluteal S2 electrophysiologic examinations show that the lesion is S3 complete, and if the mechanism of injury is known to be a clean laceration, then surgical repair should be S4 considered within 24 h of the injury. If the mechanism of injury is contusion, stretch, traction, or compression, Common nerve conduction studies to determine whether the Sciatic peroneal lesion is neurapraxic or axonotmesic should be delayed for 3 weeks. If neurapraxic, a return of function can be Tibial To sphincter expected, provided care is taken to ensure that there is ani externus no ongoing compressive injury. If clinical and electro- Pudendal physiologic examinations (no motor units seen by EMG) fail to reveal evidence of return of function FIGURE 40-5 after 3 months, the lesion was most likely neurotmesic, and exploration and surgical repair may need to be Lumbosacral plexus. Posterior divisions are in orange, ante- undertaken. If the lesion is incomplete, follow-up evalua- tions should be performed monthly; if no improvement rior divisions are in yellow. (From J Goodgold: Anatomical is seen, then surgery may be required. Approximately 80% of closed injuries resolve spontaneously, because Correlates of Clinical Electromyography. Baltimore, Williams these lesions are in continuity. The appearance of an advancing Tinel’s sign in the distribution of the injured and Wilkins, 1974, p. 126; with permission.) nerve indicates that the nerve is in continuity and jus- tifies postponement of surgery. The growth rate of retroperitoneal hemorrhage, radiotherapy, neoplastic regenerating axons is about 2.5 cm/month. The time invasion, diabetes mellitus, pregnancy and labor, required for regeneration is dependent on the distance retroperitoneal abscess or hemorrhage, abdominal aor- from the site of injury to the first muscle innervated tic aneurysm, and idiopathic lumbosacral plexopathy below the lesion. Since this distance is greater for (Table 40-12). Most patients present with varying proximal nerve lesions, severe proximal injuries are

TABLE 40-12 549 LUMBOSACRAL PLEXUS LESIONS SITE NERVE ROOTS MUSCLES SENSORY LOSS COMMON CAUSES Upper plexus L-2, L-3, L4 Weakness of thigh flexion Anterior thigh and Diabetic amyotrophy; (psoas), thigh adduction, medial leg; absent abdominal surgery—either and knee extension knee jerk directly/retraction, or due (quadriceps) to positioning; lum- bosacral plexitis Lower plexus L-4, L-5, S-1, and S-2 Weakness of thigh extension Posterior thigh, lateral Lumbosacral plexitis, (glutei), knee flexion leg, and entire foot; perioperative, cancer (hamstrings), foot dorsiflex- absent ankle jerk infiltration, radiation ion and plantar flexion associated with poor recovery. Brachial plexus injuries FURTHER READINGS CHAPTER 40 Peripheral Neuropathy during birth carry a better prognosis for spontaneous recovery than do those in adults. BROMBERG MB, SMITH AG (eds): Handbook of Peripheral Neuropathy. Taylor & Francis Group, FL, 2005 PERIPHERAL NERVE TUMORS DYCK PJ et al (eds): Peripheral Neuropathy. Saunders, Philadelphia, 2005 Peripheral nerve tumors, which can present as periph- ENGLAND JD et al: Practice parameter: Evaluation of distal symmetric eral neuropathy, are mostly benign and can arise in any nerve trunk or nerve twig. Although peripheral nerve polyneuropathy: Role of autonomic testing, nerve biopsy, and tumors can occur anywhere in the body, including the skin biopsy (an evidence-based review): Report of the American spinal roots and cauda equina, many are subcutaneous Academy of Neurology, American Association of Neuromuscular in location and present as a soft swelling, sometimes and Electrodiagnostic Medicine, and American Academy of with a purplish discoloration of the skin. Symptoms Physical Medicine and Rehabilitation. Neurology 72:177, 2009 can include tingling or pain when the lesion is _________ et al: Practice parameter: Evaluation of distal symmetric touched. Diagnostic studies may include imaging polyneuropathy: Role of laboratory and genetic testing (an (CT/MRI), EMG and nerve conduction studies, and evidence-based review): Report of the American Academy of tumor biopsy.Two major categories of peripheral nerve Neurology, American Association of Neuromuscular and tumors are recognized: neurilemmoma (schwannoma) Electrodiagnostic Medicine, and American Academy of Physical and neurofibroma. Neurilemmomas are usually solitary Medicine and Rehabilitation. Neurology 72:185, 2009 and grow in the nerve sheath, rendering the tumor rel- HARATI Y (ed): Neurologic Clinics. Peripheral Neuropathies. Elsevier atively easy to dissect free. In contrast, neurofibromas Saunders, Philadelphia, 2007, pp 1–330 tend to be multiple and grow in the endoneurial sub- JANI-ACSADI A et al: Charcot-Marie-Tooth neuropathies: diagnosis stance, which renders them difficult to dissect. They and management. Semin Neurol 28:185, 2008 may undergo malignant changes. Neurofibromas are JARVIK JG et al: Surgery versus non-surgical therapy for carpal tunnel the hallmark of von Recklinghausen’s neurofibromato- syndrome:A randomised parallel-group trial. Lancet 374:1074, 2009 sis (NF1) (Chap. 32). MYGLAND A: Approach to the patient with chronic polyneuropathy. Acta Neurol Scand Suppl 187:15, 2007 PRESTON DC, SHAPIRO BE (eds): Electromyography and Neuromuscular Disorders, Clinical Electrophysiological Correlations, 2d ed. Elsevier, Butterworth Heinemann, Philadelphia, 2005 SAID G: Diabetic neuropathy—a review. Nat Clin Pract Neurol 3:331, 2007

CHAPTER 41 GUILLAIN-BARRÉ SYNDROME AND OTHER IMMUNE-MEDIATED NEUROPATHIES Stephen L. Hauser I Arthur K. Asbury I Guillain-Barré Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 550 I Chronic Inflammatory Demyelinating Polyneuropathy . . . . . . 555 I Multifocal Motor Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . 556 I Neuropathies with Monoclonal Gammopathy . . . . . . . . . . . . 557 Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557 Monoclonal Gammopathy of Undetermined Significance . . . 557 I Vasculitic Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557 I Anti-Hu Paraneoplastic Neuropathy . . . . . . . . . . . . . . . . . . . 558 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558 GUILLAIN-BARRÉ SYNDROME occurring in ~50% of patients. Most patients require hos- pitalization, and almost 30% require ventilatory assistance Guillain-Barré syndrome (GBS) is an acute, frequently at some time during the illness. Fever and constitutional severe, and fulminant polyradiculoneuropathy that is symptoms are absent at the onset and, if present, cast doubt autoimmune in nature. It occurs year-round at a rate of on the diagnosis. Deep tendon reflexes attenuate or disap- about one case per million per month, or ~3500 cases pear within the first few days of onset. Cutaneous sensory per year in the United States and Canada. Men are at deficits (e.g., loss of pain and temperature sensation) are 1.5-fold higher risk for GBS than women, and in west- usually relatively mild, but functions subserved by large ern countries adults are more frequently affected than sensory fibers, such as deep tendon reflexes and proprio- children. ception, are more severely affected. Bladder dysfunction may occur in severe cases but is usually transient. If bladder Clinical Manifestations dysfunction is a prominent feature and comes early in the course, diagnostic possibilities other than GBS should be GBS manifests as rapidly evolving areflexic motor paralysis considered, particularly spinal cord disease. Once clinical with or without sensory disturbance. The usual pattern is worsening stops and the patient reaches a plateau (almost an ascending paralysis that may be first noticed as rubbery always within 4 weeks of onset), further progression is legs. Weakness typically evolves over hours to a few days unlikely. and is frequently accompanied by tingling dysesthesias in the extremities.The legs are usually more affected than the Autonomic involvement is common and may occur arms, and facial diparesis is present in 50% of affected indi- even in patients whose GBS is otherwise mild. The usual viduals. The lower cranial nerves are also frequently manifestations are loss of vasomotor control with wide fluc- involved, causing bulbar weakness with difficulty handling tuation in blood pressure, postural hypotension, and cardiac secretions and maintaining an airway; the diagnosis in dysrhythmias. These features require close monitoring and these patients may initially be mistaken for brainstem management and can be fatal. Pain is another common fea- ischemia. Pain in the neck, shoulder, back, or diffusely over ture of GBS; in addition to the acute pain described above, a the spine is also common in the early stages of GBS, deep aching pain may be present in weakened muscles that patients liken to having overexercised the previous day. 550

TABLE 41-1 551 SUBTYPES OF GUILLAIN-BARRÉ SYNDROME (GBS) PATHOLOGY SUBTYPE FEATURES ELECTRODIAGNOSIS Demyelinating First attack on Schwann myelin Acute inflammatory Adults affected more than cell surface; widespread demyelinating children; 90% of cases in Axonal damage, macrophage polyneuropathy western world; recovery activation, and lymphocytic (AIDP) rapid; anti-GM1 antibodies Axonal infiltration; variable secondary (<50%) Demyelinating axonal damage First attack at motor nodes of Acute motor axonal Children and young adults; Ranvier; macrophage activation, CHAPTER 41 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies neuropathy (AMAN) prevalent in China and few lymphocytes, frequent Mexico; may be seasonal; periaxonal macrophages; extent Acute motor sensory recovery rapid; anti-GD1a of axonal damage highly variable axonal neuropathy antibodies Same as AMAN, but also affects (AMSAN) Mostly adults; uncommon; sensory nerves and roots; recovery slow, often axonal damage usually severe M. Fisher syndrome incomplete; closely (MFS) related to AMAN Few cases examined; resembles Adults and children; AIDP uncommon; ophthalmoplegia, ataxia, and areflexia; anti-GQ1b antibodies (90%) Other pains in GBS include dysesthetic pain in the that 20–30% of all cases occurring in North America, extremities as a manifestation of sensory nerve fiber Europe, and Australia are preceded by infection or reinfec- involvement. These pains are self-limited and often tion with Campylobacter jejuni. A similar proportion is pre- respond to standard analgesics (Chap. 5). ceded by a human herpes virus infection, often CMV or Epstein-Barr virus. Other viruses and also Mycoplasma Several subtypes of GBS are recognized, as determined pneumoniae have been identified as agents involved in primarily by electrodiagnostic and pathologic distinctions antecedent infections, as have recent immunizations. The (Table 41-1). These include the axonal variants, which swine influenza vaccine, administered widely in the are often clinically severe—either acute motor axonal United States in 1976, is the most notable example; neuropathy (AMAN) or acute motor sensory axonal influenza vaccines in use from 1992–1994, however, neuropathy (AMSAN). In addition, a range of limited or resulted in only one additional case of GBS per million regional GBS syndromes are also encountered. Notable persons vaccinated. Older-type rabies vaccine, prepared in among these is the Miller Fisher syndrome (MFS; nervous system tissue, is implicated as a trigger of GBS in Table 41-1), which presents as rapidly evolving ataxia and developing countries where it is still used; the mechanism areflexia of limbs without weakness, and ophthalmoplegia, is presumably immunization against neural antigens. GBS often with pupillary paralysis. The MFS variant accounts also occurs more frequently than can be attributed to for ~5% of all cases and is strongly associated with anti- chance alone in patients with lymphoma (including bodies to the ganglioside GQ1b (see Immunopathogene- Hodgkin’s disease), in HIV-seropositive individuals, and in sis, below). Other regional variants of GBS include (1) patients with systemic lupus erythematosus (SLE). C. jejuni pure sensory forms; (2) ophthalmoplegia with anti-GQ1b has also been implicated in summer outbreaks of AMAN antibodies as part of severe motor-sensory GBS; (3) GBS among children and young adults exposed to chickens in with severe bulbar and facial paralysis, sometimes associ- rural China. ated with antecedent cytomegalovirus (CMV) infection and anti-GM2 antibodies; and (4) acute pandysautonomia Immunopathogenesis (Chap. 28). Several lines of evidence support an autoimmune basis Antecedent Events for acute inflammatory demyelinating polyneuropathy (AIDP), the most common and best-studied type of Approximately 70% of cases of GBS occur 1–3 weeks after GBS; the concept extends to all of the subtypes of GBS an acute infectious process, usually respiratory or gastroin- (Table 41-1). testinal. Culture and seroepidemiologic techniques show

SECTION III Diseases of the Central Nervous System552 It is likely that both cellular and humoral immune agents, vaccines) that misdirect to host nerve tissue mechanisms contribute to tissue damage in AIDP. T cell through a resemblance-of-epitope (molecular mimicry) activation is suggested by the finding that elevated levels of mechanism (Fig. 41-1). The neural targets are likely to cytokines and cytokine receptors are present in serum be glycoconjugates, specifically gangliosides (Table 41-2; [interleukin (IL) 2, soluble IL-2 receptor] and in cere- Fig. 41-2). Gangliosides are complex glycosphingolipids brospinal fluid (CSF) (IL-6, tumor necrosis factor α, inter- that contain one or more sialic acid residues; various gan- feron-γ ).AIDP is also closely analogous to an experimental gliosides participate in cell-cell interactions (including T cell–mediated immunopathy designated experimental those between axons and glia), modulation of receptors, allergic neuritis (EAN); EAN is induced in laboratory ani- and regulation of growth. They are typically exposed on mals by immune sensitization against protein fragments the plasma membrane of cells, rendering them suscepti- derived from peripheral nerve proteins, and in particular ble to an antibody-mediated attack. Gangliosides and against the P2 protein. Based on analogy to EAN, it was other glycoconjugates are present in large quantity in initially thought that AIDP was likely to be primarily a human nervous tissues and in key sites, such as nodes of T cell–mediated disorder; however, abundant data now Ranvier. Antiganglioside antibodies, most frequently to suggest that autoantibodies directed against nonprotein GM1, are common in GBS (20–50% of cases), particularly determinants may be central to many cases. in those preceded by C. jejuni infection. Furthermore, iso- Circumstantial evidence suggests that all GBS results lates of C. jejuni from stool cultures of patients with GBS from immune responses to nonself antigens (infectious have surface glycolipid structures that antigenically cross Gut/Peyer's Patches Regional Nodes/ Peripheral Nerves/ IL 3,4,5,10 Circulation Roots/Ganglia CD4 B cell B cell Ganglioside TCR lgG (GM-1 and others) O A MHC II Cj Schwann cell Myelin Cj plasmalemma sheath Cj Cj Cj Antigen Plasma cell presenting cell Blood/Nerve Barrier FIGURE 41-1 regional lymph nodes. Activated T cells probably also func- Postulated immunopathogenesis of GBS associated with tion to assist in opening of the blood-nerve barrier, facilitating C. jejuni infection. B cells recognize glycoconjugates on penetration of pathogenic autoantibodies. The earliest C. jejuni (Cj) (triangles) that cross-react with ganglioside pre- changes in myelin (right) consist of edema between myelin sent on Schwann cell surface and subjacent peripheral nerve lamellae and vesicular disruption (shown as circular blebs) of myelin. Some B cells, activated via a T cell–independent the outermost myelin layers. These effects are associated mechanism, secrete primarily IgM (not shown). Other B cells with activation of the C5b-C9 membrane attack complex and (upper left side) are activated via a partially T cell–dependent probably mediated by calcium entry; it is possible that the route and secrete primarily IgG; T cell help is provided by macrophage cytokine tumor necrosis factor (TNF) also par- CD4 cells activated locally by fragments of Cj proteins that ticipates in myelin damage. B, B cell; MHC II, class II major are presented on the surface of antigen-presenting cells histocompatibility complex molecule; TCR, T cell receptor; A, (APC). A critical event in the development of GBS is the axon; O, oligodendrocyte. escape of activated B cells from Peyer’s patches into

TABLE 41-2 553 PRINCIPAL ANTI-GLYCOLIPID ANTIBODIES IMPLICATED IN IMMUNE NEUROPATHIES CLINICAL PRESENTATION ANTIBODY TARGET USUAL ISOTYPE Acute Immune Neuropathies (Guillain-Barré Syndrome) IgG (polyclonal) IgG (polyclonal) Acute inflammatory demyelinating No clear patterns GM1 most common IgG (polyclonal) polyneuropathy (AIDP) IgG (polyclonal) GD1a, GM1, GM1b, GalNAc–GD1a Acute motor axonal neuropathy (AMAN) (<50% for any) GQ1b (>90%) Miller Fisher syndrome (MFS) GT1a (Most) Acute pharyngeal cervicobrachial neuropathy (APCBN) Chronic Immune Neuropathies Chronic inflammatory demyelinating Po in some No clear pattern CHAPTER 41 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies polyneuropathy (CIDP) (75%) Neural binding sites IgG, IgA (monoclonal) CIDPa (MGUS associated) (25%) SPGP, SGLPG (on MAG) (50%) IgM (monoclonal) Chronic sensory > motor neuropathy Uncertain (50%) IgM (monoclonal) GM1, GalNAc–GD1a, others IgM (polyclonal, monoclonal) Multifocal motor neuropathy (MMN) (25–50%) GD1b, GQ1b, and other b-series IgM (monoclonal) Chronic sensory ataxic neuropathy gangliosides Note: MGUS, monoclonal gammopathy of undetermined significance; MAG, myelin-associated glycoprotein. Source: Modified from HJ Willison, N Yuki: Brain 125:2591, 2002. GM1 GM1b disorders. Between 5 and 15 days after injection some GD1a GD1b recipients developed acute motor axonal GBS with high titers of anti-GM1 antibodies that recognized epitopes GaINAc-GD1a GQ1b at nodes of Ranvier and motor endplates. Experimen- tally, anti-GM1 antibodies can trigger complement- GT1a SO3 SGPG mediated injury at paranodal axon-glial junctions, dis- LM1 SO3 SGLPG rupting the clustering of sodium channels and likely contributing to conduction block (see Pathophysiology, N-acetylneuraminic acid N-acetylgalactosamine Glucose below). N-acetylglucosamine Glucuronic acid Galactose Ceramide Anti-GQ1b IgG antibodies are found in >90% of patients with MFS (Table 41-2; Fig. 41-2), and titers of FIGURE 41-2 IgG are highest early in the course. Anti-GQ1b antibod- Glycolipids implicated as antigens in immune-mediated ies are not found in other forms of GBS unless there is neuropathies. (Modified from HJ Willison, N Yuki: Brain 125: extraocular motor nerve involvement. A possible expla- 2591, 2002.) nation for this association is that extraocular motor nerves are enriched in GQ1b gangliosides in compari- react with gangliosides, including GM1, concentrated in son to limb nerves. In addition, a monoclonal anti- human nerves. Another line of evidence is derived from GQ1b antibody raised against C. jejuni isolated from a experience in Europe with parenteral use of purified bovine patient with MFS blocked neuromuscular transmission brain gangliosides for treatment of various neuropathic experimentally. Taken together, these observations provide strong but still inconclusive evidence that autoantibodies play an important pathogenic role in GBS. Although anti-gan- glioside antibodies have been studied most intensively, other antigenic targets may also be important. One report identified IgG antibodies against Schwann cells and neurons (nerve growth cone region) in some GBS cases. Proof that these antibodies are pathogenic requires that they be capable of mediating disease following direct passive transfer to naïve hosts; this has not yet

SECTION III Diseases of the Central Nervous System554 been demonstrated, although one case of apparent axonal pathology, the principal electrodiagnostic finding is maternal-fetal transplacental transfer of GBS has been reduced amplitude of compound action potentials without described. conduction slowing or prolongation of distal latencies. In ADEM, an early step in the induction of tissue damage appears to be complement deposition along the Diagnosis outer surface of the Schwann cell. Activation of comple- ment initiates a characteristic vesicular disintegration of GBS is a descriptive entity. The diagnosis is made by the myelin sheath, and also leads to recruitment of acti- recognizing the pattern of rapidly evolving paralysis vated macrophages, which participate in damage to with areflexia, absence of fever or other systemic symp- myelin and axons. In AMAN, the pattern is different in toms, and characteristic antecedent events (Table 41-3). that complement is deposited along with IgG at the Other disorders that may enter into the differential diag- nodes of Ranvier along large motor axons. nosis include acute myelopathies (especially with pro- longed back pain and sphincter disturbances); botulism Pathophysiology (pupillary reactivity lost early); diphtheria (early oropha- ryngeal disturbances); Lyme polyradiculitis and other In the demyelinating forms of GBS, the basis for flaccid tick-borne paralyses; porphyria (abdominal pain, seizures, paralysis and sensory disturbance is conduction block. psychosis); vasculitic neuropathy (check erythrocyte sedi- This finding, demonstrable electrophysiologically, implies mentation rate, described below); poliomyelitis (fever and that the axonal connections remain intact. Hence, recov- meningismus common); CMV polyradiculitis (in imm- ery can take place rapidly as remyelination occurs. In unocompromised patients); critical illness neuropathy; severe cases of demyelinating GBS, secondary axonal neuromuscular disorders such as myasthenia gravis; poi- degeneration usually occurs; its extent can be estimated sonings with organophosphates, thallium, or arsenic; tick electrophysiologically. More secondary axonal degenera- paralysis; paralytic shellfish poisoning; or severe hypophos- tion correlates with a slower rate of recovery and a phatemia (rare). Laboratory tests are helpful primarily to greater degree of residual disability. When a severe pri- exclude mimics of GBS. Electrodiagnostic features may mary axonal pattern is encountered electrophysiologi- be minimal, and the CSF protein level may not rise until cally, the implication is that axons have degenerated and the end of the first week. If the diagnosis is strongly sus- become disconnected from their targets, specifically the pected, treatment should be initiated without waiting neuromuscular junctions, and must therefore regenerate for evolution of the characteristic electrodiagnostic and for recovery to take place. In motor axonal cases in CSF findings to occur. Both tau and 14-3-3 protein levels which recovery is rapid, the lesion is thought to be local- ized to preterminal motor branches, allowing regenera- TABLE 41-3 tion and reinnervation to take place quickly. Alternatively, in mild cases, collateral sprouting and reinnervation from DIAGNOSTIC CRITERIA FOR GUILLAIN-BARRÉ surviving motor axons near the neuromuscular junction SYNDROME may begin to reestablish physiologic continuity with muscle cells over a period of several months. Required Laboratory Features 1. Progressive weakness of 2 or more limbs due to neu- ropathya CSF findings are distinctive, consisting of an elevated CSF protein level [1–10 g/L (100–1000 mg/dL)] without 2. Areflexia accompanying pleocytosis. The CSF is often normal 3. Disease course <4 weeks when symptoms have been present for ≤48 h; by the end 4. Exclusion of other causes [e.g., vasculitis (polyarteritis of the first week the level of protein is usually elevated. A transient increase in the CSF white cell count nodosa, systemic lupus erythematosus, Churg-Strauss (10–100/μL) occurs on occasion in otherwise typical syndrome), toxins (organophosphates, lead), botulism, GBS; however, a sustained CSF pleocytosis suggests an diphtheria, porphyria, localized spinal cord or cauda alternative diagnosis (viral myelitis) or a concurrent diag- equina syndrome] nosis such as unrecognized HIV infection. Electrodiag- Supportive nostic features are mild or absent in the early stages of GBS and lag behind the clinical evolution. In cases with 1. Relatively symmetric weakness demyelination (Table 41-1), prolonged distal latencies, 2. Mild sensory involvement conduction velocity slowing, evidence of conduction 3. Facial nerve or other cranial nerve involvement block, and temporal dispersion of compound action 4. Absence of fever potential are the usual features. In cases with primary 5. Typical CSF profile (acellular, increase in protein level) 6. Electrophysiologic evidence of demyelination aExcluding M. Fisher and other variant syndromes. Source: Modified from AK Asbury, DR Cornblath: Ann Neurol 27:S21, 1990.

are reported to be elevated early (during the first few although minor findings on examination (such as are- 555 CHAPTER 41 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies days of symptoms) in some cases of GBS. Tau increases flexia) may persist.The mortality rate is <5% in optimal in CSF may reflect axonal damage and predict a residual settings; death usually results from secondary pulmonary deficit. GBS patients with risk factors for HIV or with complications. The outlook is worst in patients with CSF pleocytosis should have a serologic test for HIV. severe proximal motor and sensory axonal damage. Such axonal damage may be either primary or secondary in Treatment: nature (see Pathophysiology, above), but in either case GUILLAIN-BARRÉ SYNDROME successful regeneration cannot occur. Other factors that worsen the outlook for recovery are advanced age, a ful- In the vast majority of patients with GBS, treatment minant or severe attack, and a delay in the onset of treat- should be initiated as soon after diagnosis as possible. ment. Between 5 and 10% of patients with typical GBS Each day counts; ~2 weeks after the first motor symp- have one or more late relapses; such cases are then classi- toms, immunotherapy is no longer effective. Either fied as chronic inflammatory demyelinating polyneu- high-dose intravenous immune globulin (IVIg) or ropathy (CIDP). plasmapheresis can be initiated, as they are equally effective. A combination of the two therapies is not sig- CHRONIC INFLAMMATORY nificantly better than either alone. IVIg is often the initial DEMYELINATING POLYNEUROPATHY therapy chosen because of its ease of administration and good safety record. IVIg is administered as five daily CIDP is distinguished from GBS by its chronic course. infusions for a total dose of 2 g/kg body weight. There is In other respects, this neuropathy shares many features some evidence that GBS autoantibodies are neutralized with the common demyelinating form of GBS, includ- by anti-idiotypic antibodies present in IVIg preparations, ing elevated CSF protein levels and the electrodiagnostic perhaps accounting for the therapeutic effect. A course findings of acquired demyelination. Most cases occur in of plasmapheresis usually consists of ~40–50 mL/kg adults, and men are affected slightly more often than plasma exchange (PE) four times over a week. Meta- women. The incidence of CIDP is lower than that of analysis of randomized clinical trials indicates that treat- GBS, but due to the protracted course the prevalence is ment reduces the need for mechanical ventilation by greater. nearly half (from 27% to 14% with PE), and increases the likelihood of full recovery at 1 year (from 55% to 68%). In Clinical Manifestations patients who are treated early in the course of GBS and improve, relapse may occur in the second or third week. Onset is usually gradual, sometimes subacute; in a few, the Brief retreatment with the original therapy is usually initial attack is indistinguishable from that of GBS. An effective. Glucocorticoids have not been found to be acute-onset form of CIDP should be considered when effective in GBS. Occasional patients with very mild GBS deteriorates >9 weeks after onset or relapses at least forms of GBS, especially those who appear to have three times. Symptoms are both motor and sensory in already reached a plateau when initially seen, may be most cases.Weakness of the limbs is usually symmetric but managed conservatively without IVIg or PE. can be strikingly asymmetric. There is considerable vari- ability from case to case. Some patients experience a In the worsening phase of GBS, most patients require chronic progressive course, whereas others, usually monitoring in a critical care setting, with particular younger patients, have a relapsing and remitting course. attention to vital capacity, heart rhythm, blood pressure, Some have only motor findings, and a small proportion nutrition, deep vein thrombosis prophylaxis, cardiovas- present with a relatively pure syndrome of sensory ataxia. cular status, early consideration (after 2 weeks of intuba- Tremor occurs in ~10% and may become more promi- tion) of tracheotomy, and chest physiotherapy. As noted, nent during periods of subacute worsening or improve- ~30% of patients with GBS require ventilatory assis- ment. A small proportion have cranial nerve findings, tance, sometimes for prolonged periods of time (several including external ophthalmoplegia. CIDP tends to ame- weeks or longer). Frequent turning and assiduous skin liorate over time with treatment; the result is that many care are important, as are daily range-of-motion exer- years after onset nearly 75% of patients have reasonable cises to avoid joint contractures and daily reassurance functional status. Death from CIDP is uncommon. as to the generally good outlook for recovery. Diagnosis Prognosis and Recovery The diagnosis rests on characteristic clinical, CSF, and elec- Approximately 85% of patients with GBS achieve a full trophysiologic findings.The CSF is usually acellular with an functional recovery within several months to a year, elevated protein level, sometimes several times normal. Elec- trodiagnostically, variable degrees of conduction slowing,

SECTION III Diseases of the Central Nervous System556 prolonged distal latencies, temporal dispersion of com- spontaneous remission. Controlled studies have shown pound action potentials, and conduction block are that high-dose IVIg, PE, and glucocorticoids are all more the principal features. In particular, the presence of effective than placebo. Initial therapy is usually with IVIg, conduction block is a certain sign of an acquired demyeli- administered as 0.4 g/kg body weight daily for 5 days; nating process. Evidence of axonal loss, presumably sec- most patients require periodic re-treatment at ~6-week ondary to demyelination, is present in >50% of patients. intervals. PE, which appears to be as effective as IVIg, is Serum protein electrophoresis with immunofixation is initiated at two to three treatments per week for 6 indicated to search for monoclonal gammopathy and weeks; periodic re-treatment may also be required. associated conditions (see Monoclonal Gammopathy of Treatment with glucocorticoids is another option Undetermined Significance, below). In all patients with (60–80 mg prednisone PO daily for 1–2 months, fol- presumptive CIDP, it is also reasonable to exclude vas- lowed by a gradual dose reduction of 10 mg per month culitis, collagen vascular disease (especially SLE), chronic as tolerated), but long-term adverse effects including hepatitis, HIV infection, and diabetes mellitus. Other bone demineralization, gastrointestinal bleeding, and associated conditions include inflammatory bowel disease cushingoid changes are problematic. Anecdotal experi- and Hodgkin’s lymphoma. ence suggested that glucocorticoids might be harmful to some patients with a purely motor form of CIDP, thus Pathogenesis glucocorticoids should probably be avoided when sen- sory findings are absent. Approximately one-half of Although there is evidence of immune activation in CIDP, patients with CIDP fail to respond adequately to the ini- the precise mechanisms of pathogenesis are unknown. tial therapy chosen; a different treatment should then Biopsy typically reveals little inflammation and onion-bulb be tried. Patients who fail therapy with IVIg, PE, and glu- changes (imbricated layers of attenuated Schwann cell cocorticoids may benefit from treatment with immuno- processes surrounding an axon) that result from recurrent suppressive agents such as azathioprine, methotrexate, demyelination and remyelination (Fig. 41-1).The response cyclosporine, and cyclophosphamide, either alone or as to therapy suggests that CIDP is immune-mediated; CIDP adjunctive therapy. Early experience with anti-CD20 responds to glucocorticoids, whereas GBS does not. Pas- (rituximab) has also shown promise. Use of these thera- sive transfer of demyelination into experimental animals pies requires periodic reassessment of their risks and has been accomplished using IgG purified from the serum benefits. of some patients with CIDP, lending support for a humoral autoimmune pathogenesis. Although the target MULTIFOCAL MOTOR NEUROPATHY antigen or antigens in CIDP have not yet been identified, the myelin protein Po has been implicated as a potential Multifocal motor neuropathy (MMN) is a distinctive autoantigen in some patients. It is also of interest that a but uncommon neuropathy that presents as slowly pro- CIDP-like illness developed spontaneously in the gressive motor weakness and atrophy evolving over years nonobese diabetic (NOD) mouse when the immune co- in the distribution of selected nerve trunks, associated stimulatory molecule B7-2 (CD86) was genetically with sites of persistent focal motor conduction block in deleted; this suggests that CIDP can result from altered the same nerve trunks. Sensory fibers are relatively triggering of T cells by antigen-presenting cells. spared. The arms are affected more frequently than the legs, and >75% of all patients are men. Some cases have Approximately 25% of patients with clinical features been confused with lower motor neuron forms of amy- of CIDP also have a monoclonal gammopathy of unde- otrophic lateral sclerosis (Chap. 27). Approximately 50% termined significance (MGUS). Cases associated with of patients present with high titers of polyclonal IgM monoclonal IgA or IgG usually respond to treatment as antibody to the ganglioside GM1. It is uncertain how favorably as cases without a monoclonal gammopathy. this finding relates to the discrete foci of persistent motor Patients with IgM monoclonal gammopathy tend to conduction block, but high concentrations of GM1 gan- have more sensory findings, a more protracted course, gliosides are normal constituents of nodes of Ranvier in and may have a less satisfactory response to treatment, peripheral nerve fibers. Pathology reveals demyelination although this is an area of controversy. and mild inflammatory changes at the sites of conduc- tion block. Treatment: CHRONIC INFLAMMATORY Most patients with MMN respond to high-dose IVIg DEMYELINATING POLYNEUROPATHY (dosages as for CIDP, above); periodic re-treatment is required in more than half of responders to maintain the Most authorities initiate treatment for CIDP when pro- benefit. Some refractory patients have responded to cyclo- gression is rapid or walking is compromised. If the disor- phosphamide. Glucocorticoids and PE are not effective. der is mild, management can be expectant, awaiting

NEUROPATHIES WITH MONOCLONAL monoclonal IgM immunoglobulin binds to a normal 557 CHAPTER 41 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies GAMMOPATHY peripheral nerve constituent, myelin-associated glycopro- tein (MAG), found in the paranodal regions of Schwann MULTIPLE MYELOMA cells. Binding appears to be specific for a polysaccharide epitope that is also found in other normal peripheral Clinically overt polyneuropathy occurs in ~5% of patients nerve myelin glycoproteins, P0 and PMP22, and also in with the commonly encountered type of multiple other normal nerve-related glycosphingolipids (Fig. 41-1). myeloma, which exhibits either lytic or diffuse osteo- In the MAG-positive cases, IgM paraprotein is incorpo- porotic bone lesions. These neuropathies are sensorimo- rated into the myelin sheaths of affected patients and tor, are usually mild and slowly progressive but may be widens the spacing of the myelin lamellae, thus produc- severe, and generally do not reverse with successful sup- ing a distinctive ultrastructural pattern. Demyelination pression of the myeloma. In most cases, electrodiagnostic and remyelination are the hallmarks of the lesions. The and pathologic features are consistent with a process of chronic demyelinating neuropathy appears to result from axonal degeneration. a destabilization of myelin metabolism rather than activa- tion of an immune response.Therapy with chlorambucil, In contrast, myeloma with osteosclerotic features, or cyclophosphamide combined with glucocorticoids or although representing only 3% of all myelomas, is associ- PE, often results in improvement of the neuropathy asso- ated with polyneuropathy in one-half of cases. These ciated with a prolonged reduction in the levels in the neuropathies, which may also occur with solitary plas- circulating paraprotein; chronic use of these alkylating macytoma, are distinct because they (1) are usually agents is associated with significant risks. Recent prelimi- demyelinating in nature; (2) often respond to radiation nary data also suggest that anti-CD20 (rituximab) ther- therapy or removal of the primary lesion; (3) are associ- apy may be effective. In a small proportion of patients ated with different monoclonal proteins and light chains (30% at 10 years), MGUS will in time evolve into frankly (almost always lambda as opposed to primarily kappa in malignant conditions such as multiple myeloma or the lytic type of multiple myeloma); and (4) may occur lymphoma. in association with other systemic findings including thickening of the skin, hyperpigmentation, hypertri- VASCULITIC NEUROPATHY chosis, organomegaly, endocrinopathy, anasarca, and clubbing of fingers. These are features of the POEMS Peripheral nerve involvement is common in polyarteritis syndrome (polyneuropathy, organomegaly, endocrinopa- nodosa (PAN), appearing in half of all cases clinically thy, M protein, and skin changes). The pathogenesis of and in 100% of cases at postmortem studies. The this uncommon syndrome and the explanation for its asso- most common pattern is multifocal (asymmetric) motor- ciation with lambda light chains are unknown. Treatment sensory neuropathy (mononeuropathy multiplex) due to of the neuropathy is best directed at the osteosclerotic ischemic lesions of nerve trunks and roots; however, myeloma using surgery, radiotherapy, or chemotherapy, as some cases of vasculitic neuropathy present as a distal, indicated. symmetric sensorimotor polyneuropathy. Symptoms of neuropathy are a common presenting complaint in Neuropathies are also encountered in other systemic patients with PAN. The electrodiagnostic findings are conditions with gammopathy including Waldenström’s those of an axonal process. Small- to medium-sized macroglobulinemia, primary systemic amyloidosis, and arteries of the vasa nervorum, particularly the epineural cryoglobulinemic states (mixed essential cryoglobuline- vessels, are affected in PAN, resulting in a widespread mia, some cases of hepatitis C). ischemic neuropathy. A high frequency of neuropathy occurs in allergic angiitis and granulomatosis (Churg- MONOCLONAL GAMMOPATHY Strauss syndrome). OF UNDETERMINED SIGNIFICANCE Systemic vasculitis should always be considered when a Chronic polyneuropathies occurring in association with subacute or chronically evolving mononeuropathy multi- MGUS are usually associated with the immunoglobulin plex occurs in conjunction with constitutional symptoms isotypes IgG, IgA, and IgM. From a clinical standpoint, (fever, anorexia, weight loss, loss of energy, malaise, and many of these patients are indistinguishable from patients nonspecific pains). Diagnosis of suspected vasculitic neu- with CIDP without monoclonal gammopathy (see ropathy is made by a combined nerve and muscle biopsy, Chronic Inflammatory Demyelinating Polyneuropathy, with serial section or skip-serial techniques. above), and their response to immunosuppressive agents is also similar. An exception is the syndrome of IgM Approximately one-third of biopsy-proven cases of kappa monoclonal gammopathy associated with an indo- vasculitic neuropathy are “nonsystemic” in that the vas- lent, longstanding, sometimes static sensory neuropathy, culitis appears to affect only peripheral nerves. Constitu- frequently with tremor and sensory ataxia. Most patients tional symptoms are absent, and the course is more are men and older than 50 years. In the majority, the

SECTION III Diseases of the Central Nervous System558 indolent than that of PAN. The erythrocyte sedimenta- binding proteins (HuD, HuC, and Hel-N1) that in nor- tion rate may be elevated, but other tests for systemic mal tissues are only expressed by neurons. The same disease are negative. Nevertheless, clinically silent proteins are usually expressed by SCLC, triggering in involvement of other organs is likely, and vasculitis is fre- some patients an immune response characterized by quently found in muscle biopsied at the same time as antibodies and cytotoxic T cells that cross-react with nerve. the Hu proteins of the dorsal root ganglion neurons, Vasculitic neuropathy may also be seen as part of the resulting in immune-mediated neuronal destruction. An vasculitis syndrome occurring in the course of other con- encephalomyelitis may accompany the sensory neu- nective tissue disorders. The most frequent is rheumatoid ronopathy and presumably has the same pathogenesis. arthritis, but ischemic neuropathy due to involvement of Neurologic symptoms usually precede, by ≤ 6 months, vasa nervorum may also occur in mixed cryoglobulinemia, the identification of SCLC. The sensory neuronopathy Sjögren’s syndrome, Wegener’s granulomatosis, hypersensi- runs its course in a few weeks or months and stabilizes, tivity angiitis, and progressive systemic sclerosis. Manage- leaving the patient disabled. Most cases are unresponsive ment of these neuropathies, including the “nonsystemic” to treatment with glucocorticoids, IVIg, PE, or vasculitic neuropathy, consists of treatment of the underlying immunosuppressant drugs. condition as well as the aggressive use of glucocorticoids and other immunosuppressant drugs. One reasonable start- FURTHER READINGS ing regimen is daily prednisone (initial dose 1 mg/kg per day PO with a gradual taper after 1 month) plus IV pulse BURNS TM et al: Vasculitic neuropathies. Neurol Clin 25:89, 2007 (or daily oral) cyclophosphamide for 3–6 months. HADDEN RDM et al: European Federation of Neurological Soci- ANTI-HU PARANEOPLASTIC eties/Peripheral Nerve Society guideline on management of NEUROPATHY paraproteinemic demyelinating neuropathies: Report of a joint task force of the European Federation of Neurological Societies This uncommon immune-mediated disorder manifests and the Peripheral Nerve Society. Eur J Neurol 13:809, 2006 as a sensory neuronopathy (i.e., selective damage to HUGHES RAC et al: European Federation of Neurological Societies/ sensory nerve bodies in dorsal root ganglia). The onset Peripheral Nerve Society guideline on management of chronic is often asymmetric with dysesthesias and sensory loss inflammatory demyelinating polyradiculoneuropathy: Report of in the limbs that soon progress to affect all limbs, the a joint task force of the European Federation of Neurological torso, and face. Marked sensory ataxia, pseudoathetosis, Societies and the Peripheral Nerve Society. Eur J Neurol 13:326, and inability to walk, stand, or even sit unsupported are 2006 frequent features and are secondary to the extensive __________ et al: Immunotherapy for Guillain-Barre Syndrome: A deafferentation. Subacute sensory neuronopathy may be systematic review. Brain 130:2245, 2007 idiopathic, but more than half of cases are paraneoplastic, LUNN MP, WILLISON HJ: Diagnosis and treatment in inflammatory primarily related to lung cancer, and most of those are neuropathies. J Neurol Neurosurg Psychiatry 80:249, 2009 small cell lung cancer (SCLC). Diagnosis of the under- MULEY SA, PARRY GJ: Inflammatory demyelinating neuropathies. lying SCLC requires awareness of the association, para- Curr Treat Options Neurol 11:221, 2009 neoplastic testing, and often PET scanning for the SUSUKI K et al: Anti-GM1 antibodies cause complement-mediated tumor. The target antigens are a family of RNA disruption of sodium channel clusters in peripheral motor nerve fibers. J Neurosci 27:3956, 2007 VAN SCHAIK IN et al: European Federation of Neurological Societies/ Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Eur J Neurol 13:802, 2006

CHAPTER 42 MYASTHENIA GRAVIS AND OTHER DISEASES OF THE NEUROMUSCULAR JUNCTION Daniel B. Drachman Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560 Diagnosis and Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . 560 Patient Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 Myasthenia gravis (MG) is a neuromuscular disorder synaptic folds, and by diffusion of ACh away from the characterized by weakness and fatigability of skeletal mus- receptor. cles.The underlying defect is a decrease in the number of available acetylcholine receptors (AChRs) at neuromus- In MG, the fundamental defect is a decrease in the cular junctions due to an antibody-mediated autoim- number of available AChRs at the postsynaptic muscle mune attack. Treatment now available for MG is highly membrane. In addition, the postsynaptic folds are flat- effective, although a specific cure has remained elusive. tened, or “simplified.” These changes result in decreased efficiency of neuromuscular transmission. Therefore, PATHOPHYSIOLOGY although ACh is released normally, it produces small end- plate potentials that may fail to trigger muscle action In the neuromuscular junction (Fig. 42-1), acetylcholine potentials. Failure of transmission at many neuromuscular (ACh) is synthesized in the motor nerve terminal and junctions results in weakness of muscle contraction. stored in vesicles (quanta). When an action potential travels down a motor nerve and reaches the nerve ter- The amount of ACh released per impulse normally minal, ACh from 150–200 vesicles is released and com- declines on repeated activity (termed presynaptic rundown). bines with AChRs that are densely packed at the peaks In the myasthenic patient, the decreased efficiency of of postsynaptic folds. The structure of the AChR has neuromuscular transmission combined with the normal been fully elucidated; it consists of five subunits (2α, 1β, rundown results in the activation of fewer and fewer mus- 1δ, and 1γ or ε) arranged around a central pore. When cle fibers by successive nerve impulses and hence increas- ACh combines with the binding sites on the α subunits ing weakness, or myasthenic fatigue. This mechanism also of the AChR, the channel in the AChR opens, permit- accounts for the decremental response to repetitive nerve ting the rapid entry of cations, chiefly sodium, which stimulation seen on electrodiagnostic testing. produces depolarization at the end-plate region of the muscle fiber. If the depolarization is sufficiently large, it The neuromuscular abnormalities in MG are brought initiates an action potential that is propagated along the about by an autoimmune response mediated by specific muscle fiber, triggering muscle contraction. This process anti-AChR antibodies. The anti-AChR antibodies is rapidly terminated by hydrolysis of ACh by acetyl- reduce the number of available AChRs at neuromuscu- cholinesterase (AChE), which is present within the lar junctions by three distinct mechanisms: (1) acceler- ated turnover of AChRs by a mechanism involving cross-linking and rapid endocytosis of the receptors; (2) blockade of the active site of the AChR, i.e., the site that 559

560 Axon Mitochondria Vesicle Release site Nerve terminal Muscle AChR AChE SECTION III Diseases of the Central Nervous System A Normal B MG FIGURE 42-1 AChRs (stippling); flattened, simplified postsynaptic folds; and Diagrams of (A) normal and (B) myasthenic neuromuscular a widened synaptic space. (Modified from DB Drachman: N junctions. AChE, acetylcholinesterase. See text for descrip- Engl J Med 330:1797, 1994; with permission.) tion of normal neuromuscular transmission. The MG junction demonstrates a normal nerve terminal; a reduced number of normally binds ACh; and (3) damage to the postsynaptic increased myasthenic weakness and may precipitate muscle membrane by the antibody in collaboration with “crisis” (see later). complement. An immune response to muscle-specific kinase (MuSK) can also result in myasthenia gravis, pos- The distribution of muscle weakness often has a sibly by interfering with AChR clustering. The patho- characteristic pattern. The cranial muscles, particularly genic antibodies are IgG and are T cell dependent.Thus, the lids and extraocular muscles, are often involved immunotherapeutic strategies directed against T cells are early in the course of MG, and diplopia and ptosis are effective in this antibody-mediated disease. common initial complaints. Facial weakness produces a “snarling” expression when the patient attempts to How the autoimmune response is initiated and main- smile. Weakness in chewing is most noticeable after tained in MG is not completely understood. However, prolonged effort, as in chewing meat. Speech may have the thymus appears to play a role in this process. The a nasal timbre caused by weakness of the palate or a thymus is abnormal in ~75% of patients with MG; in dysarthric “mushy” quality due to tongue weakness. ~65% the thymus is “hyperplastic,” with the presence of Difficulty in swallowing may occur as a result of weak- active germinal centers detected histologically, though ness of the palate, tongue, or pharynx, giving rise to the hyperplastic thymus is not necessarily enlarged. An nasal regurgitation or aspiration of liquids or food. additional 10% of patients have thymic tumors (thymo- Bulbar weakness is especially prominent in MuSK mas). Muscle-like cells within the thymus (myoid cells), antibody–positive MG. In ~85% of patients, the weak- which bear AChRs on their surface, may serve as a ness becomes generalized, affecting the limb muscles as source of autoantigen and trigger the autoimmune reac- well. If weakness remains restricted to the extraocular tion within the thymus gland. muscles for 3 years, it is likely that it will not become generalized, and these patients are said to have ocular CLINICAL FEATURES MG. The limb weakness in MG is often proximal and may be asymmetric. Despite the muscle weakness, deep MG is not rare, having a prevalence of 1–7 in 10,000. tendon reflexes are preserved. If weakness of respiration It affects individuals in all age groups, but peaks of becomes so severe as to require respiratory assistance, incidence occur in women in their twenties and thir- the patient is said to be in crisis. ties and in men in their fifties and sixties. Overall, women are affected more frequently than men, in a DIAGNOSIS AND EVALUATION ratio of ~3:2. The cardinal features are weakness and fatigability of muscles. The weakness increases during (Table 42-1) The diagnosis is suspected on the basis of repeated use (fatigue) and may improve following rest weakness and fatigability in the typical distribution or sleep. The course of MG is often variable. Exacer- described above, without loss of reflexes or impairment bations and remissions may occur, particularly during of sensation or other neurologic function.The suspected the first few years after the onset of the disease. diagnosis should always be confirmed definitively before Remissions are rarely complete or permanent. Unre- treatment is undertaken; this is essential because (1) lated infections or systemic disorders often lead to other treatable conditions may closely resemble MG,

TABLE 42-1 to do during early development. There is also evidence 561 CHAPTER 42 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction that MG patients without demonstrable antibodies to DIAGNOSIS OF MYASTHENIA GRAVIS (MG) either AChR or MuSK have other—as yet undefined— antibodies that impair neuromuscular transmission. History Diplopia, ptosis, weakness Electrodiagnostic Testing Weakness in characteristic distribution Fluctuation and fatigue: worse with repeated activity, Repetitive nerve stimulation often provides helpful improved by rest diagnostic evidence of MG. Anti-AChE medication is Effects of previous treatments stopped 6–24 h before testing. It is best to test weak muscles or proximal muscle groups. Electric shocks are Physical examination delivered at a rate of two or three per second to the Ptosis, diplopia appropriate nerves, and action potentials are recorded Motor power survey: quantitative testing of muscle from the muscles. In normal individuals, the amplitude strength of the evoked muscle action potentials does not change Forward arm abduction time (5 min) at these rates of stimulation. However, in myasthenic Vital capacity patients there is a rapid reduction of >10–15% in the Absence of other neurologic signs amplitude of the evoked responses. As a further test, a single dose of edrophonium may be given to prevent or Laboratory testing diminish this decremental response. Anti-AChR radioimmunoassay: ~85% positive in generalized MG; 50% in ocular MG; definite diagnosis Anticholinesterase Test if positive; negative result does not exclude MG. ~40% of AChR antibody-negative patients with Drugs that inhibit the enzyme AChE allow ACh to interact generalized MG have anti-MuSK antibodies. repeatedly with the limited number of AChRs, producing Repetitive nerve stimulation; decrement of >15% at improvement in the strength of myasthenic muscles. 3 Hz: highly probable Edrophonium is used most commonly for diagnostic test- Single-fiber electromyography: blocking and jitter, with ing because of the rapid onset (30 s) and short duration normal fiber density; confirmatory, but not specific (~5 min) of its effect. An objective end-point must be Edrophonium chloride (Tensilon) 2 mg + 8 mg IV; highly selected to evaluate the effect of edrophonium, such as probable diagnosis if unequivocally positive weakness of extraocular muscles, impairment of speech, For ocular or cranial MG: exclude intracranial lesions or the length of time that the patient can maintain the by CT or MRI arms in forward abduction. An initial IV dose of 2 mg of edrophonium is given. If definite improvement occurs, Note: AChR, acetylcholine receptor; MuSK, muscle-specific tyrosine the test is considered positive and is terminated. If there kinase. is no change, the patient is given an additional 8 mg IV. Source: From RT Johnson, JW Griffin (eds): Current Therapy in The dose is administered in two parts because some Neurologic Disease, 4th ed. St. Louis, Mosby Year Book, 1994; with patients react to edrophonium with side effects such as permission. nausea, diarrhea, salivation, fasciculations, and rarely with severe symptoms of syncope or bradycardia. Atropine and (2) the treatment of MG may involve surgery and (0.6 mg) should be drawn up in a syringe, ready for IV the prolonged use of drugs with adverse side effects. administration if these symptoms become troublesome. Antibodies to AChR or MuSK False-positive tests occur in occasional patients with other neurologic disorders, such as amyotrophic lateral As noted above, anti-AChR antibodies are detectable in sclerosis, and in placebo-reactors. False-negative or equivo- the serum of ~85% of all myasthenic patients but in only cal tests may also occur. In some cases it is helpful to use a about 50% of patients with weakness confined to the longer-acting drug such as neostigmine (15 mg PO), since ocular muscles. The presence of anti-AChR antibodies is this permits more time for detailed evaluation of strength. virtually diagnostic of MG, but a negative test does not The edrophonium test is now reserved for patients with exclude the disease. The measured level of anti-AChR clinical findings that are suggestive of MG but who have antibody does not correspond well with the severity of negative antibody and electrodiagnostic test results. MG in different patients. However, in an individual patient, a treatment-induced fall in the antibody level Inherited Myasthenic Syndromes often correlates with clinical improvement. Antibodies to MuSK have been found to be present in ~40% of AChR The congenital myasthenic syndromes (CMS) com- antibody-negative patients with generalized MG, and prise a heterogeneous group of disorders of the neuro- their presence is a useful diagnostic test in these patients. muscular junction that are not autoimmune but rather MuSK antibodies are rarely present in AChR antibody- positive patients or in patients with MG limited to ocular muscles.These antibodies may interfere with clustering of AChRs at neuromuscular junctions, as MuSK is known

562 TABLE 42-2 THE CONGENITAL MYASTHENIC SYNDROMES TYPE CLINICAL ELECTROPHYSIOLOGY GENETICS END-PLATE TREATMENT FEATURES EFFECTS Slow channel Most common; Repetitive muscle Autosomal Excitotoxic Quinidine: weak forearm response on nerve dominant; α, β, ε end-plate decreases extensors; onset stimulation; prolonged AChR mutations myopathy; end-plate 2d to 3d decade; channel opening and decreased damage; made variable severity MEPP duration Autosomal AChRs; worse by recessive; may postsynaptic anti-AChE Low-affinity Onset early; Brief and infrequent be heteroallelic damage fast channel moderately severe; channel openings; Normal end-plate 3,4-DAP; ptosis, EOM opposite of slow Autosomal structure anti-AChE Severe AChR involvement; channel syndrome recessive; SECTION III Diseases of the Central Nervous System deficiencies weakness and ε mutations most Increased length Anti-AChE; fatigue Decremental common; many Early onset; response to different mutations of end plates; 3,4-DAP variable severity; repetitive nerve fatigue; typical stimulation; Mutant gene for variable synaptic MG features decreased AChE’s collagen MEPP amplitudes anchor folds junctional folds AChE deficiency Early onset; Decremental response Small nerve Worse with variable severity; to repetitive nerve terminals; anti-AChE scoliosis; may have stimulation degenerated drugs normal EOM, absent pupillary responses Note: AChR, acetylcholine receptor; AChE, acetylcholinesterase; EOM, extraocular muscles; MEPP, miniature end-plate potentials; 3,4-DAP, 3-4-diaminopyridine. are due to genetic mutations in which virtually any Differential Diagnosis component of the neuromuscular junction may be affected. Alterations in function of the presynaptic Other conditions that cause weakness of the cranial nerve terminal or in the various subunits of the AChR and/or somatic musculature include the nonautoimmune or AChE have been identified in the various forms of CMS discussed above, drug-induced myasthenia, Lambert- CMS. These disorders share many of the clinical fea- Eaton myasthenic syndrome (LEMS), neurasthenia, hyper- tures of autoimmune MG, including weakness and fati- thyroidism, botulism, intracranial mass lesions, and gability of skeletal muscles, in some cases involving progressive external ophthalmoplegia. Treatment with extraocular muscles (EOMs), lids, and proximal mus- penicillamine (used for scleroderma or rheumatoid arthri- cles, similar to the distribution in autoimmune MG. tis) may result in true autoimmune MG, but the weakness CMS should be suspected when symptoms of myasthe- is usually mild, and recovery occurs within weeks or nia have begun in infancy or childhood and AChR months after discontinuing its use.Aminoglycoside antibi- antibody tests are consistently negative. Features of four otics or procainamide can cause exacerbation of weakness of the most common forms of CMS are summarized in myasthenic patients; very large doses can cause neuro- in Table 42-2. Although clinical features and electrodi- muscular weakness in normal individuals. agnostic and pharmacologic tests may suggest the cor- rect diagnosis, molecular analysis is required for precise LEMS is a presynaptic disorder of the neuromuscular elucidation of the defect; this may lead to helpful treat- junction that can cause weakness similar to that of MG. ment as well as genetic counseling. In the forms that The proximal muscles of the lower limbs are most com- involve the AChR, a wide variety of mutations have monly affected, but other muscles may be involved as been identified in each of the subunits, but the ε sub- well. Cranial nerve findings, including ptosis of the eye- unit is affected in ~75% of these cases. In most of the lids and diplopia, occur in up to 70% of patients and recessively inherited forms of CMS, the mutations are resemble features of MG. However, the two conditions heteroallelic; that is, different mutations affecting each are readily distinguished, since patients with LEMS have of the two alleles are present. depressed or absent reflexes, experience autonomic changes such as dry mouth and impotence, and have

incremental rather than decremental responses on repet- power on repeated effort. Hyperthyroidism is readily 563 CHAPTER 42 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction itive nerve stimulation. LEMS is caused by autoantibodies diagnosed or excluded by tests of thyroid function, which directed against P/Q type calcium channels at the should be carried out routinely in patients with sus- motor nerve terminals, which can be detected in ~85% pected MG.Abnormalities of thyroid function (hyper- or of LEMS patients by radioimmunoassay. These autoan- hypothyroidism) may increase myasthenic weakness. Bot- tibodies result in impaired release of ACh from nerve ulism can cause myasthenic-like weakness, but the pupils terminals. Most patients with LEMS have an associated are often dilated, and repetitive nerve stimulation gives malignancy, most commonly small cell carcinoma of the an incremental response. Diplopia resembling that in MG lung, which may express calcium channels that stimulate may occasionally be due to an intracranial mass lesion the autoimmune response. The diagnosis may signal that compresses nerves to the EOMs (e.g., sphenoid the presence of a tumor long before it would otherwise ridge meningioma), but MRI of the head and orbits usu- be detected, permitting early removal. Treatment of ally reveals the lesion. LEMS involves plasmapheresis and immunosuppression, as for MG. 3,4-Diaminopyridine (3,4-DAP) and pyri- Progressive external ophthalmoplegia is a rare condi- dostigmine may also be symptomatically helpful. 3,4- tion resulting in weakness of the EOMs, which may be DAP acts by blocking potassium channels, which results accompanied by weakness of the proximal muscles of in prolonged depolarization of the motor nerve termi- the limbs and other systemic features. Most patients with nals and thus enhances ACh release. Pyridostigmine pro- this condition have mitochondrial disorders that can be longs the action of ACh, allowing repeated interactions detected on muscle biopsy (Chap. 43). with AChRs. Search for Associated Conditions Botulism is due to a potent bacterial toxin produced by Clostridium botulinum. The toxin interferes with the (Table 42-3) Myasthenic patients have an increased inci- release of acetylcholine from the presynaptic neuromus- dence of several associated disorders.Thymic abnormali- cular junction, thereby interfering with neuromuscular ties occur in ~75% of patients, as noted above. Neoplas- transmission. The most common form is food-borne tic change (thymoma) may produce enlargement of the botulism from ingestion of food containing toxin; in thymus, which is detected by CT or MRI scanning of wound and intestinal botulism spores germinate and give rise to organisms that produce toxin. Patients pre- TABLE 42-3 sent with bulbar weakness (e.g., diplopia, dysarthria, dysphagia), but lack sensory symptoms and signs; deep DISORDERS ASSOCIATED WITH MYASTHENIA tendon reflexes are preserved early in the disease course. GRAVIS AND RECOMMENDED LABORATORY TESTS Weakness generalizes to the limbs and may result in res- piratory failure; reflexes may be diminished as the disease Associated disorders progresses. Mentation is normal. Autonomic findings Disorders of the thymus: thymoma, hyperplasia include paralytic ileus, constipation, urinary retention, Other autoimmune disorders: Hashimoto’s thyroiditis, dilated or poorly reactive pupils, and dry mouth. The Graves’ disease, rheumatoid arthritis, lupus erythe- demonstration of toxin in serum by bioassay is defini- matosus, skin disorders, family history of autoimmune tive, but may be negative. Nerve conduction studies disorder reveal findings of presynaptic neuromuscular blockade Disorders or circumstances that may exacerbate with reduced compound muscle action potentials myasthenia gravis: hyperthyroidism or hypothy- (CMAPs) that increase in amplitude following high fre- roidism, occult infection, medical treatment for other quency repetitive stimulation. Treatment may include conditions (see Table 42-4) intubation for airway protection, ventilatory support, or Disorders that may interfere with therapy: tuberculosis, aggressive inpatient supportive care (e.g., nutrition, DVT diabetes, peptic ulcer, gastrointestinal bleeding, renal prophylaxis). Equine antitoxin is given rapidly before the disease, hypertension, asthma, osteoporosis, obesity results of laboratory studies are available. The prognosis is better among patients with type B infection who are Recommended laboratory tests or procedures under the age of 60 years. A vaccine is available for CT or MRI of mediastinum highly exposed individuals. Tests for lupus erythematosus, antinuclear antibody, rheumatoid factor, antithyroid antibodies Neurasthenia is the historic term for a myasthenia-like Thyroid-function tests fatigue syndrome without an organic basis.These patients PPD skin test may present with subjective symptoms of weakness and Chest radiography fatigue, but muscle testing usually reveals the “jerky Fasting blood glucose measurement, hemoglobin A1c release” or “give-away weakness” characteristic of nonor- Pulmonary-function tests ganic disorders; the complaint of fatigue in these patients Bone densitometry in older patients means tiredness or apathy rather than decreasing muscle Note: PPD, purified protein derivative. Source: From RT Johnson, JW Griffin (eds): Current Therapy in Neurologic Disease, 4th ed. St. Louis, Mosby Year Book, 1993, p 379; with permission.

564 the anterior mediastinum. A thymic shadow on CT scan MANAGEMENT OF MG may normally be present through young adulthood, but enlargement of the thymus in a patient >40 years old is Establish diagnosis unequivocally (see Table 42-1) highly suspicious of thymoma. Hyperthyroidism occurs in 3–8% of patients and may aggravate the myasthenic Search for associated conditions (see Table 42-3) weakness. Thyroid function tests should be obtained in all patients with suspected MG. Because of the associa- Ocular only Generalized Crisis tion of MG with other autoimmune disorders, blood tests for rheumatoid factor and antinuclear antibodies MRI of brain Anticholinesterase Intensive care should also be carried out. Chronic infection of any (if positive, (pyridostigmine) (respiratory kind can exacerbate MG and should be sought carefully. reassess) infection, fluids) Finally, measurements of ventilatory function are valu- SECTION III Diseases of the Central Nervous System able because of the frequency and seriousness of respira- Anticholinesterase tory impairment in myasthenic patients. (pyridostigmine) Because of the side effects of glucocorticoids and other immunosuppressive agents used in the treatment of MG, a Evaluate for thymectomy thorough medical investigation should be undertaken, (indications: thymoma or searching specifically for evidence of chronic or latent generalized MG); infection (such as tuberculosis or hepatitis), hypertension, evaluate surgical risk, FVC diabetes, renal disease, and glaucoma. Good risk Poor risk Plasmapheresis Treatment: or intravenous Ig MYASTHENIA GRAVIS (good FVC) (low FVC) The prognosis has improved strikingly as a result of If unsatisfactory then advances in treatment; virtually all myasthenic patients Thymectomy can be returned to full productive lives with proper Improved If not therapy. The most useful treatments for MG include anti- improved cholinesterase medications, immunosuppressive agents, thymectomy, and plasmapheresis or intravenous Evaluate clinical status; if indicated, immunoglobulin (IVIg) (Fig. 42-2). go to immunosuppression ANTICHOLINESTERASE MEDICATIONS Immunosuppression Anticholinesterase medication produces at least partial improvement in most myasthenic patients, although See text for short-term, intermediate, improvement is complete in only a few. Pyridostigmine and long-term treatments is the most widely used anticholinesterase drug. As a rule, the beneficial action of oral pyridostigmine begins FIGURE 42-2 within 15–30 min and lasts for 3–4 h, but individual Algorithm for the management of myasthenia gravis. responses vary. Treatment is begun with a moderate FVC, forced vital capacity. dose, e.g., 30–60 mg 3–4 times daily. The frequency and amount of the dose should be tailored to the patient’s may limit the dose tolerated. Atropine/diphenoxylate or individual requirements throughout the day. For exam- loperamide is useful for the treatment of gastrointestinal ple, patients with weakness in chewing and swallowing symptoms. may benefit by taking the medication before meals so that peak strength coincides with mealtimes. Long-acting THYMECTOMY Two separate issues should be dis- pyridostigmine may occasionally be useful to get the tinguished: (1) surgical removal of thymoma, and (2) patient through the night but should never be used for thymectomy as a treatment for MG. Surgical removal of daytime medication because of variable absorption. a thymoma is necessary because of the possibility of The maximum useful dose of pyridostigmine rarely local tumor spread, although most thymomas are histo- exceeds 120 mg every 3–6 h during daytime. Overdosage logically benign. In the absence of a tumor, the available with anticholinesterase medication may cause increased evidence suggests that up to 85% of patients experi- weakness and other side effects. In some patients, ence improvement after thymectomy; of these, ~35% muscarinic side effects of the anticholinesterase med- achieve drug-free remission. However, the improvement ication (diarrhea, abdominal cramps, salivation, nausea) is typically delayed for months to years. The advantage of thymectomy is that it offers the possibility of long- term benefit, in some cases diminishing or eliminating the need for continuing medical treatment. In view of these potential benefits and of the negligible risk in skilled hands, thymectomy has gained widespread

acceptance in the treatment of MG. It is the consensus 2- to 3-day intervals), until there is marked clinical 565 that thymectomy should be carried out in all patients improvement or a dose of 50–60 mg/d is reached. This with generalized MG who are between puberty and at dose is maintained for 1–3 months and then is gradually CHAPTER 42 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction least 55 years of age. Whether thymectomy should be modified to an alternate-day regimen over the course of recommended in children, in adults >55 years, and in an additional 1–3 months; the goal is to reduce the dose patients with weakness limited to the ocular muscles is on the “off day” to zero or to a minimal level. Generally, still a matter of debate. There is also evidence that patients begin to improve within a few weeks after patients with MuSK antibody–positive MG may not reaching the maximum dose, and improvement contin- respond to thymectomy. Thymectomy must be carried ues to progress for months or years. The prednisone out in a hospital where it is performed regularly and dosage may gradually be reduced, but usually months where the staff is experienced in the pre- and postoper- or years may be needed to determine the minimum ative management, anesthesia, and surgical techniques effective dose, and close monitoring is required. Few of total thymectomy. patients are able to do without immunosuppressive agents entirely. Patients on long-term glucocorticoid IMMUNOSUPPRESSION Immunosuppression therapy must be followed carefully to prevent or treat using glucocorticoids, azathioprine, and other drugs is adverse side effects. The most common errors in gluco- effective in nearly all patients with MG. The choice of corticoid treatment of myasthenic patients include (1) drugs or other immunomodulatory treatments should insufficient persistence—improvement may be delayed be guided by the relative benefits and risks for the indi- and gradual; (2) too early, too rapid, or excessive taper- vidual patient and the urgency of treatment. It is helpful ing of dosage; and (3) lack of attention to prevention to develop a treatment plan based on short-term, inter- and treatment of side effects. mediate-term, and long-term objectives. For example, if immediate improvement is essential either because of Other Immunosuppressive Drugs Mycophe- the severity of weakness or because of the patient’s nolate mofetil, azathioprine, cyclosporine, tacrolimus, need to return to activity as soon as possible, IVIg and occasionally cyclophosphamide are effective in should be administered or plasmapheresis should be many patients, either alone or in various combinations. undertaken. For the intermediate term, glucocorticoids and cyclosporine or tacrolimus generally produce clini- Mycophenolate mofetil has become one of the most cal improvement within a period of 1–3 months. The widely used drugs in the treatment of MG because of its beneficial effects of azathioprine and mycophenolate effectiveness and relative lack of side effects. A dose of mofetil usually begin after many months (up to a year), 1–1.5 g bid is recommended. Its mechanism of action but these drugs have advantages for the long-term involves inhibition of purine synthesis by the de novo treatment of patients with MG. For the occasional pathway. Since lymphocytes lack the alternative salvage patient with MG that is genuinely refractory to optimal pathway that is present in all other cells, mycophenolate treatment with conventional immunosuppressive inhibits proliferation of lymphocytes but not proliferation agents, a course of high-dose cyclophosphamide may of other cells. It does not kill or eliminate preexisting induce long-lasting (possibly permanent) benefit by autoreactive lymphocytes, and therefore clinical improve- “rebooting” the immune system. At high doses, ment may be delayed for many months to a year, until the cyclophosphamide eliminates mature lymphocytes, but preexisting autoreactive lymphocytes die spontaneously. hematopoietic precursors (stem cells) are spared, The advantage of mycophenolate lies in its relative lack of because they express the enzyme aldehyde dehydroge- adverse side effects, with only occasional production of nase, which hydrolyzes cyclophosphamide. At present, diarrhea and rare development of leukopenia. This drug this procedure is reserved for refractory patients and has become the choice for long-term treatment of myas- should be administered only in a facility fully familiar thenic patients. Unfortunately, the cost of mycophenolate with this approach. is still very high (~$6400 U.S. annually for 1g bid). Glucocorticoid Therapy Glucocorticoids, when Until recently, azathioprine has been the most widely used properly, produce improvement in myasthenic used of these drugs because of its relative safety in weakness in the great majority of patients. To minimize most patients and long track record. Its therapeutic adverse side effects, prednisone should be given in a effect may add to that of glucocorticoids and/or allow single dose rather than in divided doses throughout the glucocorticoid dose to be reduced. However, up to the day. The initial dose should be relatively low 10% of patients are unable to tolerate azathioprine (15–25 mg/d) to avoid the early weakening that because of idiosyncratic reactions consisting of flulike occurs in about one-third of patients treated initially symptoms of fever and malaise, bone marrow depres- with a high-dose regimen. The dose is increased step- sion, or abnormalities of liver function. An initial dose of wise, as tolerated by the patient (usually by 5 mg/d at 50 mg/d should be used to test for adverse side effects. If this dose is tolerated, it is increased gradually until the

SECTION III Diseases of the Central Nervous System566 white blood count falls to ~3000–4000/μL. In patients during treatment, or within a week, and continuing for weeks to months. The mechanism of action of IVIg is not who are receiving glucocorticoids concurrently, leuko- known; the treatment has no consistent effect on the cytosis precludes the use of this measure. A reduction of measurable amount of circulating AChR antibody. the lymphocyte count to <1000/μL and/or an increase Adverse reactions are generally not serious but include of the mean corpuscular volume of red blood cells may headache, fluid overload, and rarely aseptic meningitis be used as indications of adequacy of azathioprine or renal failure. IVIg should rarely be used as a long-term dosage. The typical dosage range is 2–3 mg/kg total treatment in place of rationally managed immunosup- body weight. The beneficial effect of azathioprine takes pressive therapy. Unfortunately, there is a tendency for at least 3–6 months to begin and even longer to peak. In physicians unfamiliar with immunosuppressive treat- patients taking azathioprine, allopurinol should never ments to rely on repeated IVIg infusions, which are be used to treat hyperuricemia, because the two drugs inconvenient, usually produce only intermittent benefit, share a common degradation pathway; the result may and are costly. The intermediate and long-term treat- be severe bone marrow depression due to increased ment of myasthenic patients requires other methods of effects of the azathioprine. therapy outlined earlier in this chapter. The calcineurin inhibitors cyclosporine and tacrolimus MANAGEMENT OF MYASTHENIC CRISIS (FK506) are approximately as effective as azathioprine Myasthenic crisis is defined as an exacerbation of weak- and are being used increasingly in the management of ness sufficient to endanger life; it usually consists of res- MG.Their beneficial effect appears more rapidly than that piratory failure caused by diaphragmatic and intercostal of azathioprine. Either drug may be used alone, but they muscle weakness. Crisis rarely occurs in properly man- are usually used as an adjunct to glucocorticoids to per- aged patients. Treatment should be carried out in inten- mit reduction of the glucocorticoid dose. The usual dose sive care units staffed with teams experienced in the of cyclosporine is 4–5 mg/kg per day, and the average management of MG, respiratory insufficiency, infectious dose of tacrolimus is 0.1 mg/kg per day, given in two disease, and fluid and electrolyte therapy. The possibility equally divided doses (to minimize side effects). Side that deterioration could be due to excessive anti- effects of these drugs include hypertension and nephro- cholinesterase medication (“cholinergic crisis”) is best toxicity, which must be closely monitored.“Trough” blood excluded by temporarily stopping anticholinesterase levels are measured 12 h after the evening dose.The ther- drugs. The most common cause of crisis is intercurrent apeutic range for cyclosporine is 150–200 ng/L, and for infection. This should be treated immediately, because tacrolimus it is 5–15 ng/L. the mechanical and immunologic defenses of the patient can be assumed to be compromised. The myas- Cyclophosphamide is reserved for occasional thenic patient with fever and early infection should be patients refractory to the other drugs (see earlier for dis- treated like other immunocompromised patients. Early cussion of high-dose cyclophosphamide treatment). and effective antibiotic therapy, respiratory assistance, and pulmonary physiotherapy are essentials of the PLASMAPHERESIS AND INTRAVENOUS treatment program. As discussed above, plasmapheresis IMMUNOGLOBULIN Plasmapheresis has been or IVIg is frequently helpful in hastening recovery. used therapeutically in MG. Plasma, which contains the pathogenic antibodies, is mechanically separated from DRUGS TO AVOID IN MYASTHENIC the blood cells, which are returned to the patient. A PATIENTS Many drugs have been reported to have course of five exchanges (3–4 L per exchange) is gener- adverse effects in patients with MG (Table 42-4). How- ally administered over a 10- to 14-day period. Plasma- ever, not all patients react adversely to all these drugs. pheresis produces a short-term reduction in anti-AChR Conversely, not all “safe” drugs can be used with antibodies, with clinical improvement in many patients. impunity in patients with MG. As a rule, the listed drugs It is useful as a temporary expedient in seriously affected patients or to improve the patient’s condition should be avoided whenever possible, and myasthenic prior to surgery (e.g., thymectomy). patients should be followed closely when any new drug is introduced. The indications for the use of IVIg are the same as those for plasma exchange: to produce rapid improve- PATIENT ASSESSMENT ment to help the patient through a difficult period of myasthenic weakness or prior to surgery. This treatment In order to evaluate the effectiveness of treatment as has the advantages of not requiring special equipment well as drug-induced side effects, it is important to assess or large-bore venous access. The usual dose is 2 g/kg, the patient’s clinical status systematically at baseline and which is typically administered over 5 days (400 mg/kg per day). If tolerated, the course of IVIg can be short- ened to administer the entire dose over a 3-day period. Improvement occurs in ~70% of patients, beginning

TABLE 42-4 History Myasthenia Gravis Worksheet 567 General DRUGS WITH INTERACTIONS IN MYASTHENIA Normal Good Fair Poor GRAVIS (MG) Diplopia None Rare Occasional Constant Drugs that May Exacerbate mg Ptosis None Rare Occasional Constant Antibiotics Arms Aminoglycosides: e.g., streptomycin, tobramycin, Legs Normal Slightly Some ADL Definitely kanamycin Speech limited impairment limited Quinolones: e.g., ciprofloxacin, levofloxacin, ofloxacin, Voice gatifloxacin Normal Walks/runs Can walk limited Minimal Macrolides: e.g., erythromycin, azithromycin, Normal fatigues distances walking telithromycin Dysarthric Severely Unintelligible Nondepolarizing muscle relaxants for surgery dysarthric D-Tubocurarine (curare), pancuronium, vecuronium, atracurium Normal Fades Impaired Severely impaired Beta-blocking agents Chew Normal Fatigue on Fatigue on Feeding tube Propranalol, atenolol, metoprolol Swallow Feeding tube normal foods soft foods Local anesthetics and related agents Procaine, xylocaine in large amounts Normal Normal foods Soft foods only Procainamide (for arrhythmias) Respiration Normal Dyspnea on Dyspnea on Dyspnea CHAPTER 42 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction Botulinum toxin unusual effort any effort at rest Botox exacerbates weakness Examination Wt Arm abduction time R L Quinine derivatives L L Quinine, quinidine, chloroquine, mefloquine (Lariam) BP Pulse Deltoids R L Edema L Magnesium Vital capacity Biceps R L Decreases ACh release Cataracts? R L EOMS Triceps R L Penicillamine Ptosis time L May cause MG Face Grip R L Drugs with Important Interactions in mg Iliopsoas R Cyclosporine Quadriceps R Broad range of drug interactions, which may raise or lower cyclosporine levels. Hamstrings R Azathioprine Other R Avoid allopurinol—combination may result in myelo suppression. FIGURE 42-3 Abbreviated interval assessment form for use in evaluating on repeated interval examinations. Because of the vari- treatment for myasthenia gravis. ability of symptoms of MG, the interval history and phys- ical findings on examination must be taken into account. reliable quantitative measurement of AChR antibody lev- The most useful clinical tests include forward arm abduc- els, it is best to compare antibody levels from prior frozen tion time (up to a full 5 min), forced vital capacity, range serum aliquots with current serum samples in simultane- of eye movements, and time to development of ptosis on ously run assays. upward gaze. Manual muscle testing or, preferably, quanti- tative dynamometry of limb muscles, especially proximal FURTHER READINGS muscles, is also important. An interval form can provide a succinct summary of the patient’s status and a guide to HART IK et al: Immunosuppressant drugs for myasthenia gravis. J treatment results; an abbreviated form is shown in Neurol Neurosurg Psychiatry 80:5, 2009 Fig. 42-3. A progressive reduction in the patient’s AChR antibody level also provides clinically valuable confirma- MERIGGIOLI MN, SANDERS DB: Autoimmune myasthenia gravis: tion of the effectiveness of treatment; conversely, a rise in emerging clinical and biological heterogeneity. Lancet Neurol AChR antibody levels during tapering of immunosup- 8:475, 2009 pressive medication may predict clinical exacerbation. For SANDERS DB et al: An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 71:400, 2008 SCHNEIDER-GOLD C et al: Mycophenolate mofetil and tacrolimus: New therapeutic options in neuroimmunological diseases. Mus- cle Nerve 34:284, 2006 THE MUSCLE STUDY GROUP: A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neu- rology 71:394, 2008 ZINMAN L et al: IV immunoglobulin in patients with myasthenia gravis:A randomized controlled trial. Neurology 68:837, 2007

CHAPTER 43 MUSCULAR DYSTROPHIES AND OTHER MUSCLE DISEASES Robert H. Brown, Jr. ■ Anthony A. Amato ■ Jerry R. Mendell Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568 MTDNA Skeletal Muscle–Central Nervous Laboratory Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573 System Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588 ■ Hereditary Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574 Pure Myopathy Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . 589 Duchenne Muscular Dystrophy . . . . . . . . . . . . . . . . . . . . . . . 574 ■ Disorders of Muscle Membrane Excitability . . . . . . . . . . . . . . 589 Becker Muscular Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . 577 Calcium Channel Disorders Of Muscle . . . . . . . . . . . . . . . . . 589 Limb-Girdle Muscular Dystrophy . . . . . . . . . . . . . . . . . . . . . . 578 Sodium Channel Disorders of Muscle . . . . . . . . . . . . . . . . . . 591 Emery-Dreifuss Muscular Dystrophy . . . . . . . . . . . . . . . . . . . 578 Potassium Channel Disorders . . . . . . . . . . . . . . . . . . . . . . . . 592 Congenital Muscular Dystrophy (CMD) . . . . . . . . . . . . . . . . . 579 Chloride Channel Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 592 Myotonic Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579 ■ Endocrine and Metabolic Myopathies . . . . . . . . . . . . . . . . . . 592 Facioscapulohumeral (FSH) Muscular Dystrophy . . . . . . . . . . 581 Thyroid Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592 Oculopharyngeal Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . 582 Parathyroid Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592 Distal Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582 Adrenal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593 ■ Congenital Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584 Pituitary Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593 Central Core Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593 Nemaline Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584 Vitamin Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593 Centronuclear (Myotubular) Myopathy . . . . . . . . . . . . . . . . . . 585 ■ Myopathies of Systemic Illness . . . . . . . . . . . . . . . . . . . . . . . 593 ■ Disorders of Muscle Energy Metabolism . . . . . . . . . . . . . . . . 585 ■ Drug-Induced Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . 594 Glycogen Storage and Glycolytic Defects . . . . . . . . . . . . . . . 585 Myopathy from Lipid-Lowering Agents . . . . . . . . . . . . . . . . . 594 Lipid as an Energy Source and Associated Defects . . . . . . . 586 Glucocorticoid-Related Myopathies . . . . . . . . . . . . . . . . . . . 594 ■ Mitochondrial Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . 587 Myopathy of Nondepolarizing Neuromuscular Progressive External Ophthalmoplegia Syndromes Blocking Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595 Drug-Induced Mitochondrial Myopathy . . . . . . . . . . . . . . . . . 595 with Ragged Red Fibers . . . . . . . . . . . . . . . . . . . . . . . . . . . 587 Drugs of Abuse and Related Myopathies . . . . . . . . . . . . . . . 595 Kearns-Sayre Syndrome (KSS) . . . . . . . . . . . . . . . . . . . . . . . 587 Drug-Induced Autoimmune Myopathies . . . . . . . . . . . . . . . . 595 Progressive External Ophthalmoplegia (PEO) . . . . . . . . . . . . 588 Other Drug-Induced Myopathies . . . . . . . . . . . . . . . . . . . . . . 596 Autosomal Recessive Cardiomyopathy ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596 and Ophthalmoplegia (ARCO) . . . . . . . . . . . . . . . . . . . . . . . 588 Skeletal muscle diseases, or myopathies, are disorders with preserved reflexes and sensation. An associated sensory loss structural changes or functional impairment of muscle. suggests injury to peripheral nerve or the central nervous These conditions can be differentiated from other dis- system (CNS) rather than myopathy. On occasion, disorders eases of the motor unit (e.g., lower motor neuron or affecting the motor nerve cell bodies in the spinal cord neuromuscular junction pathologies) by characteristic (anterior horn cell disease), the neuromuscular junction, clinical and laboratory findings. Myasthenia gravis and or peripheral nerves can mimic findings of myopathy. related disorders are discussed in Chap. 42; dermato- myositis, polymyositis, and inclusion body myositis are Muscle Weakness discussed in Chap. 44. Symptoms of muscle weakness can be either intermit- CLINICAL FEATURES tent or persistent. Disorders causing intermittent weakness (Fig. 43-1) include myasthenia gravis, periodic paralyses The most common clinical findings of a myopathy are (hypokalemic, hyperkalemic, and paramyotonia congenita), proximal, symmetric limb weakness (arms or legs) with and metabolic energy deficiencies of glycolysis (especially 568

Intermittent weakness 569 Myoglobinuria No Yes Variable weakness includes Exam normal between attacks Exam usually normal between attacks Proximal > distal weakness during attacks EOMs, ptosis, bulbar and limb muscles Proximal > distal weakness during attacks Repetitive nerve Paradoxical myotonia on exam stimulation decrement Forearm exercise Low potassium level Normal or elevated Reduced lactic acid: Normal lactic acid: potassium level Consider glycolytic defect Consider CPT deficiency Hypokalemic PP Hyperkalemic PP (myotonia confined Paramyotonia congenita to eyelids) AChR AB positive AChR AB negative CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases Acquired MG Congenital MG Muscle biopsy defines specific defect Acquired MG DNA test confirms diagnosis FIGURE 43-1 antibody; PP, periodic paralysis; CPT, carnitine palmitoyl- Diagnostic evaluation of intermittent weakness. EOMs, transferase; MG, myasthenia gravis. extraocular muscles; AChR AB, acetylcholine receptor myophosphorylase deficiency) and fatty acid utilization pattern of weakness include myasthenia gravis, amy- (carnitine palmitoyltransferase deficiency and some mito- otrophic lateral sclerosis, late-onset nemaline myopathy, chondrial myopathies). The states of energy deficiency hyperparathyroidism, focal myositis, and some forms of cause activity-related muscle breakdown accompanied by inclusion body myopathy. A final pattern, recognized myoglobinuria, appearing as light-brown- to dark-brown- because of preferential distal extremity weakness, is typi- colored urine. cal of a unique category of muscular dystrophy, the distal myopathies. Most muscle disorders cause persistent weakness (Fig. 43-2). In the majority of these, including most types It is important to examine functional capabilities to help of muscular dystrophy, polymyositis, and dermatomyositis, disclose certain patterns of weakness (Table 43-2). The the proximal muscles are weaker than the distal and are Gowers’ sign (Fig. 43-4) is particularly useful. Observing symmetrically affected, and the facial muscles are spared, the gait of an individual may disclose a lordotic posture a pattern referred to as limb-girdle. The differential diag- caused by combined trunk and hip weakness, frequently nosis is more restricted for other patterns of weakness. exaggerated by toe walking (Fig. 43-5). A waddling gait Facial weakness (difficulty with eye closure and impaired is caused by the inability of weak hip muscles to prevent smile) and scapular winging (Fig. 43-3) are characteristic hip drop or hip dip. Hyperextension of the knee (genu of facioscapulohumeral dystrophy. Facial and distal limb recurvatum or backkneeing) is characteristic of quadriceps weakness associated with hand grip myotonia is virtually muscle weakness; and a steppage gait, due to footdrop, diagnostic of myotonic dystrophy. When other cranial accompanies distal weakness. nerve muscles are weak, causing ptosis or extraocular muscle weakness, the most important disorders to consider Any disorder causing muscle weakness may be accom- include neuromuscular junction disorders, oculopharyngeal panied by fatigue, referring to an inability to maintain or muscular dystrophy, mitochondrial myopathies, or some sustain a force (pathologic fatigability).This condition must of the congenital myopathies (Table 43-1). A pathogno- be differentiated from asthenia, a type of fatigue caused by monic pattern characteristic of inclusion body myositis excess tiredness or lack of energy. Associated symptoms is atrophy and weakness of the flexor forearm (e.g., wrist may help differentiate asthenia and pathologic fatigability. and finger flexors) and quadriceps muscles that is often Asthenia is often accompanied by a tendency to avoid asymmetric. Less frequently, but important diagnostically, physical activities, complaints of daytime sleepiness, neces- is the presence of a dropped head syndrome indicative sity for frequent naps, and difficulty concentrating on of selective neck extensor muscle weakness. The most activities such as reading.There may be feelings of over- important neuromuscular diseases associated with this whelming stress and depression. Thus, asthenia is not a myopathy. In contrast, pathologic fatigability occurs in

570 Persistent Weakness Patterns of Weakness on Neurologic Exam Proximal > distal Ptosis, EOMs Facial and Facial, distal, Proximal & distal Distal Dropped head PM; DM; muscular OPMD; scapular winging quadriceps; (hand grip), & Distal myopathy MG; PM; ALS dystrophies mitochondrial handgrip myotonia quadriceps myopathy; FSHD Myotonic muscular myotubular dystrophy IBM myopathy Myopathic EMG confirms muscle disease and excludes ALS Repetitive nerve stimulation indicates MG CK elevation supports myopathy May need DNA testing for further distinction of inherited myopathies SECTION III Diseases of the Central Nervous System Muscle biopsy will help distinguish many disorders FIGURE 43-2 oculopharyngeal muscular dystrophy; FSHD, facioscapulo- Diagnostic evaluation of persistent weakness. Examina- humeral dystrophy; IBM, inclusion body myositis; DM, der- tion reveals one of seven patterns of weakness. The pattern matomyositis; PM, polymyositis; MG, myasthenia gravis; ALS, of weakness in combination with the laboratory evaluation amyotrophic lateral sclerosis; CK, creatine kinase. leads to a diagnosis. EOM, extraocular muscles; OPMD, disorders of neuromuscular transmission and in disor- Muscle Pain (Myalgias), Cramps, and Stiffness ders altering energy production, including defects in glycolysis, lipid metabolism, or mitochondrial energy Muscle pain can be associated with cramps, spasms, production. Pathologic fatigability also occurs in chronic contractures, and stiff or rigid muscles. In distinction, myopathies because of difficulty accomplishing a task true myalgia (muscle aching), which can be localized or with less muscle. Pathologic fatigability is accompanied by abnormal clinical or laboratory findings. Fatigue TABLE 43-1 without those supportive features almost never indi- cates a primary muscle disease. NEUROMUSCULAR CAUSES OF PTOSIS OR OPHTHALMOPLEGIA FIGURE 43-3 Facioscapulohumeral dystrophy with prominent scapular Peripheral neuropathy winging. Guillain-Barré syndrome Miller-Fisher syndrome Neuromuscular junction Botulism Lambert-Eaton syndrome Myasthenia gravis Congenital myasthenia Myopathy Mitochondrial myopathies Kearns-Sayre syndrome Progressive external ophthalmoplegia Oculopharyngeal and oculopharyngodistal muscular dystrophy Myotonic dystrophy (ptosis only) Congenital myopathy Myotubular Nemaline (ptosis only) Hyperthyroidism/Graves disease (ophthalmoplegia without ptosis)

TABLE 43-2 571 OBSERVATIONS ON EXAMINATION THAT DISCLOSE MUSCLE WEAKNESS FUNCTIONAL IMPAIRMENT MUSCLE WEAKNESS Inability to forcibly close eyes Upper facial muscles Impaired pucker Lower facial muscles Inability to raise head from prone position Neck extensor muscles Inability to raise head from supine position Neck flexor muscles Inability to raise arms above head Proximal arm muscles (may be only scapular stabilizing muscles) Inability to walk without hyperextending knee (backkneeing Knee extensor muscles or genu recurvatum) Shortening of the Achilles tendon Inability to walk with heels touching the floor (toe walking) Anterior compartment of leg Inability to lift foot while walking (steppage gait or footdrop) Hip muscles Inability to walk without a waddling gait Hip muscles Inability to get up from the floor without climbing up the Hip muscles extremities (Gowers’ sign) Inability to get up from a chair without using arms generalized, may be accompanied by weakness, tender- CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases ness to palpation, or swelling. Certain drugs cause true myalgia (Table 43-3). There are two painful muscle conditions of particu- lar importance, neither of which is associated with muscle weakness. Fibromyalgia is a common, yet poorly understood type of myofascial pain syndrome. Patients complain of severe muscle pain and tenderness and have specific painful trigger points, sleep disturbances, FIGURE 43-4 FIGURE 43-5 Gowers’ sign showing a patient using arms to climb up the Lordotic posture, exaggerated by standing on toes, associ- legs in attempting to get up from the floor. ated with trunk and hip weakness.

SECTION III Diseases of the Central Nervous System572 TABLE 43-3 disorders. The muscle is unable to relax after an active muscle contraction. The EMG shows electrical silence. DRUGS THAT CAUSE TRUE MYALGIA Confusion is created because contracture also refers to a muscle that cannot be passively stretched to its Cimetidine proper length (fixed contracture) because of fibrosis. In Cocaine some muscle disorders, especially in Emery-Dreifuss Cyclosporine muscular dystrophy and Bethlem myopathy, fixed con- Danazol tractures occur early and represent distinctive features Emetine of the disease. Epsilon aminocaproic acid Gold Muscle stiffness can refer to different phenomena. Some Heroin patients with inflammation of joints and periarticular sur- Labetalol faces feel stiff.This condition is different from the disorders Methadone of hyperexcitable motor nerves causing stiff or rigid D-Penicillamine muscles. In stiff-person syndrome spontaneous discharges of Statins and other cholesterol-lowering agents the motor neurons of the spinal cord cause involuntary L-Tryptophan muscle contractions mainly involving the axial (trunk) and Zidovudine proximal lower extremity muscles.The gait becomes stiff and labored, with hyperlordosis of the lumbar spine. and easy fatigability. Serum creatine kinase (CK), erythro- Superimposed episodic muscle spasms are precipitated by cyte sedimentation rate (ESR), electromyography (EMG), sudden movements, unexpected noises, and emotional and muscle biopsy are normal. Polymyalgia rheumatica upset. The muscles relax during sleep. Serum antibodies occurs mainly in patients >50 years and is characterized against glutamic acid decarboxylase are present in approx- by stiffness and pain in the shoulders, lower back, hips, imately two-thirds of cases. In neuromyotonia (Isaacs’ and thighs. The ESR is elevated, while serum CK, syndrome) there is hyperexcitability of the peripheral EMG, and muscle biopsy are normal. Temporal arteritis, nerves manifesting as continuous muscle fiber activity. an inflammatory disorder of medium- and large-sized Myokymia (groups of fasciculations associated with con- arteries, usually involving one or more branches of the tinuous undulations of muscle) and impaired muscle carotid artery, may accompany polymyalgia rheumatica. relaxation are the result. Muscles of the leg are stiff, and Vision is threatened by ischemic optic neuritis. Gluco- the constant contractions of the muscle cause increased corticoids can relieve the myalgias and protect against sweating of the extremities. This peripheral nerve visual loss. hyperexcitability is antibody-mediated, targeted against voltage-gated potassium channels. The site of origin of Localized muscle pain is most often traumatic. A the spontaneous nerve discharges is principally in the common cause of sudden abrupt-onset pain is a rup- distal portion of the motor nerves. tured tendon, which leaves the muscle belly appearing rounded and shorter in appearance compared to the Myotonia is a condition of prolonged muscle contrac- normal side.The biceps brachii and Achilles tendons are tion followed by slow muscle relaxation. It always follows particularly vulnerable to rupture. Infection or neoplas- muscle activation (action myotonia), usually voluntary, tic infiltration of the muscle is a rare cause of localized but may be elicited by mechanical stimulation (percus- muscle pain. sion myotonia) of the muscle. Myotonia typically causes difficulty in releasing objects after a firm grasp. In A muscle cramp or spasm is a painful, involuntary, local- myotonic muscular dystrophy type 1 (DM1), distal weak- ized, muscle contraction with a visible or palpable hard- ness usually accompanies myotonia, whereas in DM2 ening of the muscle. Cramps are abrupt in onset, short proximal muscles are more affected; thus the related in duration, and may cause abnormal posturing of the term proximal myotonic myopathy (PROMM) is used to joint. The EMG shows firing of motor units, reflecting describe this condition. Myotonia also occurs with an origin from spontaneous neural discharge. Muscle myotonia congenita (a chloride channel disorder), but in cramps often occur in neurogenic disorders, especially this condition muscle weakness is not prominent. Myoto- motor neuron disease (Chap. 27), radiculopathies, and nia may also be seen in individuals with sodium channel polyneuropathies (Chap. 40), but are not a feature of mutations (hyperkalemic periodic paralysis or potassium- most primary muscle diseases. Duchenne muscular dys- sensitive myotonia). Another sodium channelopathy, trophy is an exception since calf muscle complaints are a paramyotonia congenita, also is associated with muscle common complaint. Muscle cramps are also common stiffness. In contrast to other disorders associated with during pregnancy. myotonia in which the myotonia is eased by repetitive activity, paramyotonia congenita is named for a para- A muscle contracture is different from a muscle cramp. doxical phenomenon whereby the myotonia worsens In both conditions, the muscle becomes hard, but a con- with repetitive activity. tracture is associated with energy failure in glycolytic

Muscle Enlargement and Atrophy TABLE 43-4 573 In most myopathies muscle tissue is replaced by fat and MYOTONIC DISORDERS CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases connective tissue, but the size of the muscle is usually not affected. However, in many limb-girdle muscular Myotonic dystrophy type 1 dystrophies (and particularly the dystrophinopathies) Myotonic dystrophy type 2/Proximal myotonic myopathy enlarged calf muscles are typical.The enlargement repre- Myotonia congenita sents true muscle hypertrophy, thus the term “pseudohy- Paramyotonia congenita pertrophy” should be avoided when referring to these Hyperkalemic periodic paralysis patients.The calf muscles remain very strong even late in Chondrodystrophic myotonia (Schwartz-Jampel the course of these disorders. Muscle enlargement can also result from infiltration by sarcoid granulomas, amy- syndrome) loid deposits, bacterial and parasitic infections, and focal Centronuclear/myotubular myopathya myositis. In contrast, muscle atrophy is characteristic of Drug-induced other myopathies. In dysferlinopathies (LGMD2B) there is a predilection for early atrophy of the gastrocnemius Cholesterol-lowering agents (statin muscles. Atrophy of the humeral muscles is characteristic medications, fibrates) of facioscapulohumeral muscular dystrophy. Cyclosporine LABORATORY EVALUATION Chloroquine Glycogen storage disordersa (Pompe disease, debrancher A limited battery of tests can be used to evaluate a sus- deficiency, branching enzyme deficiency) pected myopathy. Nearly all patients require serum enzyme Myofibrillar myopathiesa level measurements and electrodiagnostic studies as screen- ing tools to differentiate muscle disorders from other motor aAssociated with myotonic discharges on EMG but no clinical unit diseases.The other tests described—DNA studies, the myotonia. forearm exercise test, and muscle biopsy—are used to diag- nose specific types of myopathies. junction diseases. Routine nerve conduction studies are typically normal in myopathies but reduced amplitudes Serum Enzymes of compound muscle action potentials may be seen in atrophied muscles.The needle EMG may reveal irritability CK is the preferred muscle enzyme to measure in the on needle placement suggestive of a necrotizing myopathy evaluation of myopathies. Damage to muscle causes the (inflammatory myopathies, dystrophies, toxic myopathies, CK to leak from the muscle fiber to the serum.The MM myotonic myopathies), whereas a lack of irritability is char- isoenzyme predominates in skeletal muscle, while CK-MB acteristic of long-standing myopathic disorders (muscular is the marker for cardiac muscle. Serum CK can be ele- dystrophies, endocrine myopathies, disuse atrophy, and vated in normal individuals without provocation, presum- many of the metabolic myopathies). In addition, the EMG ably on a genetic basis or after strenuous activity, minor may demonstrate myotonic discharges that will narrow the trauma (including the EMG needle), a prolonged muscle differential diagnosis (Table 43-4). Another important cramp, or a generalized seizure. Aspartate aminotrans- EMG finding is the presence of short-duration, small- ferase (AST), alanine aminotransferase (ALT), aldolase, amplitude, polyphasic motor unit action potentials and lactic dehydrogenase (LDH) are enzymes sharing an (MUAPs). Such MUAPs can be seen in both myopathic origin in both muscle and liver. Problems arise when the and neuropathic disorders; however, the recruitment or levels of these enzymes are found to be elevated in a firing pattern is different. In myopathies, the MUAPs fire routine screening battery, leading to the erroneous assump- early but at a normal rate to compensate for the loss of tion that liver disease is present when in fact muscle could individual muscle fibers, whereas in neurogenic disorders be the cause. An elevated γ-glutamyl transferase (GGT) the MUAPs fire faster. The EMG is usually normal in helps to establish a liver origin since this enzyme is not steroid or disuse myopathy, both of which are associated found in muscle. with type 2 fiber atrophy; this is because the EMG prefer- entially assesses the physiologic function of type 1 fibers. Electrodiagnostic Studies The EMG can also be invaluable in helping to choose an appropriately affected muscle to sample for biopsy. EMG, repetitive nerve stimulation, and nerve conduction studies (Chap. 3) are essential methods for evaluation of DNA Analysis the patient with suspected muscle disease. In combina- tion they provide the information necessary to differenti- This now serves as an important tool for the definitive ate myopathies from neuropathies and neuromuscular diagnosis of many muscle disorders. Nevertheless, there are a number of limitations in currently available molecular diagnostics. For example, in Duchenne and Becker dystro- phies, two-thirds of patients have deletion or duplication mutations that are easy to detect, while the remainder have point mutations that are much more difficult to find.

SECTION III Diseases of the Central Nervous System574 For patients without identifiable gene defects, the muscle HEREDITARY MYOPATHIES biopsy remains the main diagnostic tool. Muscular dystrophy refers to a group of hereditary pro- Forearm Exercise Test gressive diseases each with unique phenotypic and genetic features (Tables 43-5, 43-6, and 43-7). In myopathies with intermittent symptoms, and especially those associated with myoglobinuria, there may be a defect DUCHENNE MUSCULAR DYSTROPHY in glycolysis. Many variations of the forearm exercise test exist. For safety, the test should not be performed under This X-linked recessive disorder, sometimes also called ischemic conditions to avoid an unnecessary insult to the pseudohypertrophic muscular dystrophy, has an incidence of muscle, causing rhabdomyolysis. The test is performed by ~30 per 100,000 live-born males. placing a small indwelling catheter into an antecubital vein.A baseline blood sample is obtained for lactic acid and ammo- Clinical Features nia.The forearm muscles are exercised by asking the patient to vigorously open and close the hand for 1 min. Blood is Duchenne dystrophy is present at birth, but the disorder then obtained at intervals of 1, 2, 4, 6, and 10 min for com- usually becomes apparent between 3 and 5 years of age. parison with the baseline sample.A three- to fourfold rise of The boys fall frequently and have difficulty keeping up lactic acid is typical. The simultaneous measurement of with friends when playing. Running, jumping, and hop- ammonia serves as a control, since it should also rise with ping are invariably abnormal. By 5 years, muscle weakness exercise. In patients with myophosphorylase deficiency or is obvious by muscle testing. On getting up from the floor, other glycolytic defects, the lactic acid rise will be absent or the patient uses his hands to climb up himself [Gowers’ below normal, while the rise in ammonia will reach con- maneuver (Fig. 43-4)]. Contractures of the heel cords and trol values. If there is lack of effort, neither lactic acid nor iliotibial bands become apparent by 6 years, when toe ammonia will rise. Patients with selective failure to increase walking is associated with a lordotic posture. Loss of muscle ammonia may have myoadenylate deaminase deficiency. strength is progressive, with predilection for proximal limb This condition has been reported to be a cause of myoglo- muscles and the neck flexors; leg involvement is more binuria, but deficiency of this enzyme in asymptomatic severe than arm involvement. Between 8 and 10 years, individuals makes interpretation controversial. walking may require the use of braces; joint contractures and limitations of hip flexion, knee, elbow, and wrist exten- Muscle Biopsy sion are made worse by prolonged sitting. By 12 years, most patients are wheelchair dependent. Contractures Muscle biopsy is an important step in establishing the become fixed, and a progressive scoliosis often develops diagnosis of a suspected myopathy. The biopsy is usually that may be associated with pain.The chest deformity with obtained from a quadriceps or biceps brachii muscle, less scoliosis impairs pulmonary function, which is already commonly from a deltoid muscle. Evaluation includes a diminished by muscle weakness. By 16 to 18 years, patients combination of techniques—light microscopy, histochem- are predisposed to serious, sometimes fatal pulmonary istry, immunocytochemistry with a battery of antibodies, infections. Other causes of death include aspiration of and electron microscopy. Not all techniques are needed food and acute gastric dilation. for every case. A specific diagnosis can be established in many disorders. A combination of stains to identify A cardiac cause of death is uncommon despite the mononuclear cells (polymyositis), complement (dermato- presence of a cardiomyopathy in almost all patients. myositis), and amyloid (inclusion body myositis) helps to Congestive heart failure seldom occurs except with distinguish the inflammatory myopathies. In addition, the severe stress such as pneumonia. Cardiac arrhythmias are congenital myopathies have distinctive light and electron rare. The typical electrocardiogram (ECG) shows an microscopy features essential for diagnosis. Mitochondrial increase net RS in lead V1; deep, narrow Q waves in the and metabolic (e.g., myophosphorylase and acid maltase precordial leads; and tall right precordial R waves in V1. deficiencies) myopathies also demonstrate distinctive his- Intellectual impairment in Duchenne dystrophy is com- tochemical and electron-microscopic profiles. Biopsied mon; the average intelligence quotient (IQ) is ~1 SD muscle tissue can be sent for metabolic enzyme or mito- below the mean. Impairment of intellectual function chondrial DNA analyses. A battery of antibodies is avail- appears to be nonprogressive and affects verbal ability able for the identification of missing components of the more than performance. dystrophin-glycoprotein complex and related proteins to help diagnose specific types of muscular dystrophies. Laboratory Features Western blot analysis on muscle specimens can be per- formed to determine whether specific muscle proteins are Serum CK levels are invariably elevated to between 20 reduced in quantity or are of abnormal size. and 100 times normal. The levels are abnormal at birth but decline late in the disease because of inactivity and

TABLE 43-5 575 PROGRESSIVE MUSCULAR DYSTROPHIES TYPE INHERITANCE DEFECTIVE ONSET AGE CLINICAL FEATURES OTHER ORGAN GENE/PROTEIN SYSTEMS INVOLVED Duchenne XR Dystrophin <5 years Progressive weakness Cardiomyopathy of girdle muscles Mental impairment Becker XR Dystrophin Early childhood to adult Unable to walk >12 years Cardiomyopathy Limb-girdle AD/AR Several (Tables 43-6, Progressive kyphoscoliosis 43-7) Early childhood Respiratory failure in 2d or ± Cardiomyopathy Emery- XR/AD Emerin/Lamins A/C to early adult CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases Dreifuss AR Several 3d decade Cardiomyopathy Congenital Childhood to Progressive weakness DM1: Expansion CTG adult CNS abnormalities Myotonica AD repeat of girdle muscles (hypomyelination, DM2: Expansion At birth or Able to walk >15 years malformation) (DM1, DM2) CCTG repeat within first few Respiratory failure may Eye abnormalities months Deletion, distal 4q develop by 4th decade Cardiac conduction Usually 2d Slow progressive weakness defects Expansion, poly-A decade of shoulder and hip girdle Mental impairment RNA binding May be infancy if muscles Cataracts protein mother affected Elbow contractures, humeral Frontal baldness (DM1 only) Gonadal atrophy and peroneal weakness Deafness Hypotonia, contractures, Coats’ (eye) disease delayed milestones — Progression to respiratory failure in some; static course in others Slowly progressive weakness of face, shoulder girdle, and foot dorsiflexion Preferential proximal weak- ness in DM2 Facioscapulo- AD <20 years Slowly progressive weakness humeral of face, shoulder girdle, and 5th to 6th foot dorsiflexion Oculopharyn- AD decade Slowly progressive weakness geal of extraocular, pharyngeal, and limb muscles aTwo forms of myotonic dystrophy, DM1 and DM2, have been identified. Many features overlap (see text). Note: XR, X-linked recessive; AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system. loss of muscle mass. EMG demonstrates features typical not uniformly distributed over the gene but rather are of myopathy. The muscle biopsy shows muscle fibers of most common near the beginning (5′ end) and middle of varying size as well as small groups of necrotic and the gene. Less often, Duchenne dystrophy is caused by a regenerating fibers. Connective tissue and fat replace lost gene duplication or point mutation. Identification of a muscle fibers. A definitive diagnosis of Duchenne dystro- specific mutation allows for an unequivocal diagnosis, phy can be established on the basis of dystrophin defi- makes possible accurate testing of potential carriers, and is ciency in a biopsy of muscle tissue or mutation analysis useful for prenatal diagnosis. on peripheral blood leukocytes, as discussed below. A diagnosis of Duchenne dystrophy can also be made by Duchenne dystrophy is caused by a mutation of the Western blot analysis of muscle biopsy specimens, revealing gene that encodes dystrophin, a 427-kDa protein local- abnormalities on the quantity and molecular weight of dys- ized to the inner surface of the sarcolemma of the muscle trophin protein. In addition, immunocytochemical staining fiber.The dystrophin gene is >2000 kb in size and thus is of muscle with dystrophin antibodies can be used to one of the largest identified human genes. It is localized demonstrate absence or deficiency of dystrophin localizing to the short arm of the X chromosome at Xp21. The to the sarcolemmal membrane. Carriers of the disease may most common gene mutation is a deletion.The size varies demonstrate a mosaic pattern, but dystrophin analysis of but does not correlate with disease severity. Deletions are muscle biopsy specimens for carrier detection is not reliable.

576 TABLE 43-6 AUTOSOMAL DOMINANT LIMB-GIRDLE MUSCULAR DYSTROPHIES (LGMDS) SECTION III Diseases of the Central Nervous System DISEASE CLINICAL FEATURES LABORATORY FEATURES LOCUS OR GENE LGMD1A Myotilin LGMD1B Onset 3d to 4th decade Serum CK 2 × normal Muscle weakness affects distal limb muscles, EMG mixed myopathy/neuropathy Lamin A/C LGMD1C vocal cords, and pharyngeal muscles NCS normal Onset 1st or 2d decade Serum CK 3–5 × normal Caveolin-3 LGMD1D Proximal lower limb weakness and NCS normal LGMD1E cardiomyopathy with conduction defects EMG myopathic Linked to chromosome 7q Some cases indistinguishable from Emery-Dreifuss Gene unidentified muscular dystrophy with joint contractures Serum CK 4–25 × normal Linked to chromosome 6q23 Onset in early childhood NCS normal Gene unidentified Proximal weakness EMG myopathic Gowers’ sign, calf hypertrophy Exercise-related muscle cramps Serum CK 2–4 × normal Onset 3d to 5th decade NCS normal Proximal muscle weakness EMG myopathic Cardiomyopathy and arrhythmias Serum CK usually normal Childhood onset NCS normal Proximal muscle weakness EMG myopathic Note: CK, creatine kinase; NCS, nerve conduction studies; EMG, electromyography. TABLE 43-7 AUTOSOMAL RECESSIVE LIMB-GIRDLE MUSCULAR DYSTROPHIES (LGMDS) DISEASE CLINICAL FEATURES LABORATORY FEATURES LOCUS OR GENE LGMD2A Calpain-3 Onset 1st or 2d decade Serum CK 3–15 × normal LGMD2B Tight heel cords NCS normal Dysferlin Contractures at elbows, wrists, and EMG myopathic LGMD2C–F fingers; rigid spine in some γ, α, β, δ sarcoglycans Proximal and distal weakness Serum CK 3–100 × normal LGMD2G Onset 2d or 3d decade NCS normal Telethonin LGMD2H Proximal muscle weakness at onset, EMG myopathic TRIM32 gene LGMD2I later distal (calf) muscles affected Inflammation on muscle biopsy Fukutin-related protein Miyoshi myopathy is variant of LGMD2B may simulate polymyositis LGMD2Ja with calf muscles affected at onset Serum CK 5–100 × normal Titin Onset in childhood to teenage yrs NCS normal Clinical condition similar to Duchenne EMG myopathic and Becker muscular dystrophies Cardiomyopathy uncommon Serum CK 3–17 × normal Cognitive function normal NCS normal Onset age 10 to 15 EMG myopathic Proximal and distal muscle weakness Serum CK 2–25 × normal NCS normal Onset 1st to 3d decade EMG myopathic Proximal muscle weakness Serum CK 10–30 × normal NCS normal Onset 1st to 3d decade EMG myopathic Clinical condition similar to Duchenne or Becker dystrophies Serum CK 1.5–2 × normal Cardiomyopathy (some not all) NCS normal Cognitive function normal EMG myopathic Onset 1st to 3d decade Proximal lower limb weakness Mild distal weakness Progressive weakness causes loss of ambulation aTibial muscular dystrophy is a form of titin deficiency with only distal muscle weakness (see Table 43-9). Note: CK, creatine kinase; NCS, nerve conduction studies; EMG, electromyography.

Extracellular The dystrophin-glycoprotein complex appears to con- 577 fer stability to the sarcolemma, although the function of Merosin Collagen VI each individual component of the complex is incompletely understood. Deficiency of one member of the complex Dystoglycan may cause abnormalities in other components. For example, a primary deficiency of dystrophin (Duchenne dystrophy) complex Sarcoglycan may lead to secondary loss of the sarcoglycans and dys- troglycan. The primary loss of a single sarcoglycan (see complex Limb-Girdle Muscular Dystrophy, below) results in a secondary loss of other sarcoglycans in the membrane α δβ α without uniformly affecting dystrophin. In either instance, β γ disruption of the dystrophin-glycoprotein complexes weakens the sarcolemma, causing membrane tears and a β1 α7 cascade of events leading to muscle fiber necrosis. This sequence of events occurs repeatedly during the life of a nNOS patient with muscular dystrophy. Dystrophin Calpain Caveolin-3 Integrin Treatment: F-Actin Dysferlin complex DUCHENNE MUSCULAR DYSTROPHY Golgi Glucocorticoids, administered as prednisone in a dose of 0.75 mg/kg per day, significantly slow progression of Intracelluar POMT1 Duchenne dystrophy for up to 3 years. Some patients cannot tolerate glucocorticoid therapy; weight gain and POMGnT1 increased risk of fractures in particular represent a sig- CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases Fukutin nificant deterrent for some boys. As in other recessively inherited dystrophies presumed to arise from loss of Fukutin-related function of a critical muscle gene, there is optimism that protein Duchenne disease may benefit from novel therapies that either replace the defective gene or missing protein FIGURE 43-6 or implement downstream corrections (e.g., skipping Selected muscular dystrophy–associated proteins in the mutated exons or reading through mutations that intro- cell membrane and Golgi complex. duce stop codons). Pathogenesis BECKER MUSCULAR DYSTROPHY Dystrophin is part of a large complex of sarcolemmal This less severe form of X-linked recessive muscular dys- proteins and glycoproteins (Fig. 43-6). Dystrophin binds trophy results from allelic defects of the same gene to F-actin at its amino terminus and to β-dystroglycan responsible for Duchenne dystrophy. Becker muscular at the carboxyl terminus. β-dystroglycan complexes to dystrophy is ~10 times less frequent than Duchenne, with α-dystroglycan, which binds to laminin in the extracellular an incidence of about 3 per 100,000 live-born males. matrix (ECM). Laminin has a heterotrimeric molecular structure arranged in the shape of a cross with one heavy Clinical Features chain and two light chains, β1 and γ1.The laminin heavy chain of skeletal muscle is designated laminin α2. Colla- The pattern of muscle wasting in Becker muscular dystro- gen proteins IV and VI are also found in the ECM. Like phy closely resembles that seen in Duchenne. Proximal β-dystroglycan, the transmembrane sarcoglycan proteins muscles, especially of the lower extremities, are prominently also bind to dystrophin; these five proteins (designated involved.As the disease progresses, weakness becomes more α- through ε-sarcoglycan) complex tightly with each other. generalized. Significant facial muscle weakness is not a More recently, other membrane proteins implicated in feature. Hypertrophy of muscles, particularly in the calves, muscular dystrophy have been found to be loosely affili- is an early and prominent finding. ated with constituents of the dystrophin complex. These include caveolin-3, α7 integrin, and collagenVI. Most patients with Becker dystrophy first experience difficulties between ages 5 and 15 years, although onset Dystrophin localizes to the cytoplasmic face of the in the third or fourth decade or even later can occur. muscle cell membrane. It complexes with two transmem- brane protein complexes, the dystroglycans and the sarco- glycans.The dystroglycans bind to the extracellular matrix protein merosin, which is also complexed with β1 and α7 integrins (Tables 43-5, 43-6, and 43-7). Dysferlin com- plexes with caveolin-3 (which binds to neuronal nitric oxide synthase, or nNOS) but not with the dystrophin- associated proteins or the integrins. In each of four con- genital dystrophies, there is loss of function of different Golgi-associated proteins: POMT1, POMGnT1, Fukutin, and Fukutin-related protein.

SECTION III Diseases of the Central Nervous System578 By definition, patients with Becker dystrophy walk beyond LGMD2A, etc.). Disorders receive letters in the order 15 years of age, whereas patients with Duchenne dystrophy in which they are found to have chromosomal linkage. are typically in a wheelchair by 12 years. Patients with This results in an ever-expanding list of conditions. Becker dystrophy have a reduced life expectancy, but most Presently there are 5 autosomal dominant and 10 auto- survive into the fourth or fifth decade. somal recessive disorders, summarized in Tables 43-6 and Mental retardation may occur in Becker dystrophy, 43-7. None of the conditions is as common as the dys- but it is not as common as in Duchenne. Cardiac trophinopathies; however, prevalence data for the LGMDs involvement occurs in Becker dystrophy and may result have not been systematically gathered for any large hetero- in heart failure; some patients manifest with only heart geneous population. In referral-based clinical populations, failure. Other less common presentations are asympto- Fukutin-related protein (FKRP) deficiency (LGMD2I), matic hyper-CK-emia, myalgias without weakness, and calpainopathies (LGMD2A), and to a lesser extent dys- myoglobinuria. ferlinopathies (LGMD2B) have emerged as the most common disorders. Laboratory Features EMERY-DREIFUSS MUSCULAR Serum CK levels, results of EMG, and muscle biopsy find- DYSTROPHY ings closely resemble those in Duchenne dystrophy. The diagnosis of Becker muscular dystrophy requires Western There are two genetically distinct forms of Emery- blot analysis of muscle biopsy samples demonstrating a Dreifuss muscular dystrophy (EDMD). One is inherited as reduced amount or abnormal size of dystrophin or muta- an X-linked disorder, while the other is autosomal domi- tion analysis of DNA from peripheral blood leukocytes. nant.The latter is classified under the rubric of LGMD1B, Genetic testing reveals deletions or duplications of the but clinically the conditions are closely related. dystrophin gene in 65% of patients with Becker dystrophy, approximately the same percentage as in Duchenne dys- Clinical Features trophy. In both Becker and Duchenne dystrophies, the size of the DNA deletion does not predict clinical severity; Prominent contractures can be recognized in early child- however, in ~95% of patients with Becker dystrophy, the hood and teenage years, often preceding muscle weak- DNA deletion does not alter the translational reading ness. The contractures persist throughout the course of frame of messenger RNA. These “in-frame” mutations the disease and are present at the elbows, ankles, and neck. allow for production of some dystrophin, which accounts Muscle weakness affects humeral and peroneal muscles at for the presence of altered rather than absent dystrophin first and later spreads to a limb-girdle distribution. The on western blot analysis. cardiomyopathy is potentially life threatening and may result in sudden death. A spectrum of atrial rhythm and Treatment: conduction defects includes atrial fibrillation and paralysis BECKER MUSCULAR DYSTROPHY and atrioventricular heart block. Some patients have a dilated cardiomyopathy. Female carriers of the X-linked The use of glucocorticoids has not been adequately variant may have cardiac manifestations that become clin- studied in Becker dystrophy. ically significant. LIMB-GIRDLE MUSCULAR DYSTROPHY Laboratory Features The syndrome of limb-girdle muscular dystrophy (LGMD) Serum CK may be elevated two- to tenfold. EMG is represents more than one disorder. Both males and females myopathic. Muscle biopsy shows nonspecific dystrophic are affected, with onset ranging from late in the first features. Immunohistochemistry reveals absent emerin decade to the fourth decade.The LGMDs typically mani- staining of myonuclei in X-lined EDMD. ECGs demon- fest with progressive weakness of pelvic and shoulder girdle strate atrial and atrioventricular rhythm disturbances. musculature. Respiratory insufficiency from weakness of the diaphragm may occur, as may cardiomyopathy. X-linked EDMD arises from defects in the emerin gene encoding a nuclear envelope protein.The autosomal A systematic classification of LGMD is based on auto- dominant disease is caused by mutations of the LMNA somal dominant (LGMD1) and autosomal recessive gene on chromosome 1q21.2 encoding the lamin proteins (LGMD2) inheritance. Superimposed on the backbone A and C. These proteins are alternatively spliced products of LGMD1 and LGMD2, the classification employs a of the LMNA gene that are essential components of the sequential alphabetical lettering system (LGMD1A, filamentous network underlying the inner nuclear mem- brane. Loss of structural integrity of the nuclear envelope from defects in emerin or lamin A/C accounts for over- lapping phenotypes (Fig. 43-7).

α Dystroglycans Extracellular muscles are normal). Most patients have joint contractures 579 of varying degrees at elbows, hips, knees, and ankles. Con- β tractures present at birth are referred to as arthrogryposis. Respiratory failure may be seen in some cases. Dystrophin Myotilin Intracellular Nucleus Nebulin Actin The CNS is affected in some forms of CMD. In α-Actinin merosin and FKRP deficiency, cerebral hypomyelination Telothonin may be seen by MRI, though only a small number of patients have mental retardation and seizures.Three forms Emerin Myosin of congenital muscular dystrophy have severe brain impair- CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases Nuclear Titin ment.These include Fukuyama congenital muscular dys- pore trophy (FCMD), muscle-eye-brain (MEB) disease, and Z-band Walker-Warburg syndrome (WWS). Patients are severely Lamin A/C Contractile proteins disabled in all three of these conditions. In MEB disease in sarcomere and WWS, but not in FCMD, ocular abnormalities impair vision.WWS is the most severe congenital muscular dys- FIGURE 43-7 trophy, causing death by 1 year of age. Selected muscular dystrophy–associated proteins in the nuclear membrane and sarcomere. As shown in the exploded Laboratory Features view, emerin and lamin A/C are constituents of the inner nuclear membrane. Several dystrophy-associated proteins are Serum CK is markedly elevated in all of these conditions. represented in the sarcomere including titin, nebulin, calpain, The EMG is myopathic and muscle biopsies show non- telethonin, actinin, and myotilin. The position of the dystrophin- specific dystrophic features. Merosin, or laminin α2 chain dystroglycan complex is also illustrated. (a basal lamina protein), is deficient surrounding muscle fibers in merosin deficiency. Skin biopsies can also demon- Treatment: strate defects in laminin α2 chain. In the other disorders EMERY-DREIFUSS MUSCULAR (FKRP deficiency, FCMD, MEB disease, WWS) there DYSTROPHY is abnormal alpha-dystroglycan staining in muscle. In merosin deficiency, cerebral hypomyelination is common, Supportive care should be offered for neuromuscular and a host of brain malformations are seen in FCMD, disability, including ambulatory aids, if necessary. MEB disease, and WWS. Stretching of contractures is difficult. Management of cardiomyopathy and arrhythmias (e.g., early use of a All forms of CMD are inherited as autosomal recessive cardiac pacemaker) may be life saving. disorders. Chromosomal linkage and specific gene defects are presented in Table 43-8.With the exception of merosin, the other gene defects affect posttranslational glycosylation of alpha-dystroglycan. This abnormality is thought to impair binding with merosin and leads to weakening of the dystrophin-glycoprotein complex, instability of the muscle membrane, and/or abnormalities in muscle contraction. CMDs with brain and eye phenotypes probably involve defective glycosylation of additional proteins, accounting for the more extensive phenotypes. CONGENITAL MUSCULAR Treatment: DYSTROPHY (CMD) CONGENITAL MUSCULAR DYSTROPHY There is no specific treatment for CMD. Proper wheel- This is not one entity but rather a group of disorders with chair seating is important. Management of epilepsy and varying degrees of muscle weakness, central nervous sys- cardiac manifestations is necessary for some patients. tem impairment, and eye abnormalities (Table 43-8). MYOTONIC DYSTROPHY Clinical Features Myotonic dystrophy is also known as dystrophia myotonica (DM).The condition is composed of at least two clinical dis- As a group, CMDs present at birth or in the first few orders with overlapping phenotypes and distinct molecular months of life with hypotonia and proximal or general- ized muscle weakness. Calf muscle hypertrophy is seen in some patients. Facial muscles may be weak, but other cra- nial nerve–innervated muscles are spared (e.g., extraocular

580 TABLE 43-8 CONGENITAL MUSCULAR DYSTROPHIESa DISEASE CLINICAL FEATURES LABORATORY FEATURES LOCUS OR GENE Laminin α2 chain SECTION III Diseases of the Central Nervous System Merosin Onset at birth with hypotonia, joint contractures, Serum CK 5–35 × normal deficiency delayed milestones, generalized muscle weakness EMG myopathic Fukutin-related protein Cerebral hypomyelination, less often cortical dysplasia NCS abnormal in some cases Fukitin-related Normal intelligence usually, some with MR (~6%) Fukutin protein and seizures (~8%) Serum CK 10–50 × normal deficiencyb Partial deficiency leads to milder phenotype EMG myopathic N-acetyl-glucosaminyl (LGMD picture) NCS normal transferase Fukuyama Onset at birth or shortly after (POMGnT1) congenital Hypotonia and feeding problems Serum CK 10–50 × normal muscular Weakness of proximal muscles, especially EMG myopathic O-mannoxyl- dystrophyb shoulder girdles NCS normal transferase-1 Hypertrophy of leg muscles MRI shows hydrocephalus (POMT1) Muscle-eye- Joint contractures and periventricular and brain disease Cognition normal frontal hypomyelination Onset at birth Serum CK 5–20 × normal Walker-Warburg Hypotonia, joint contractures MRI shows hydrocephalus, syndromeb Generalized muscle weakness cobblestone lissencephaly, Hypertrophy of calf muscles corpus callosum and Seizures, mental retardation cerebellar hypoplasia, cerebral Cardiomyopathy hypomyelination Onset at birth, hypotonia Eye abnormalities include: progressive myopia, Serum CK 5–20 × normal cataracts, and optic nerve, glaucoma, retinal MRI shows cobblestone pigmentary changes lissencephaly, hydrocephalus, Progressive muscle weakness encephalocele, absent corpus Joint contractures callosum Seizures, mental retardation Onset at birth, hypotonia Generalized muscle weakness Joint contractures Microphthalmos, retinal dysplasia, buphthalmos, glaucoma, cataracts Seizures, MR aAll are inherited as recessive traits. bThere is phenotypic overlap between disorders related to defective glycosylation. In muscle this is a consequence of altered glycosylation of dystroglycans; in brain/eye, other glycosylated proteins are involved. Clinically, Walker-Warburg syndrome is more severe, with death by 1 year. Note: CK, creatine kinase; EMG, electromyography; NCS, nerve conduction studies; MR, mental retardation; LGMD, limb-girdle muscular dystrophy. genetic defects: myotonic dystrophy type 1 (DM1), the the course, although preferential atrophy and weakness classic disease originally described by Steinert, and myotonic of quadriceps muscles occur in many patients. Palatal, dystrophy type 2 (DM2), also called proximal myotonic pharyngeal, and tongue involvement produce a dysarthric myopathy (PROMM). speech, nasal voice, and swallowing problems. Some patients have diaphragm and intercostal muscle weakness, resulting Clinical Features in respiratory insufficiency. The clinical expression of myotonic dystrophy varies widely Myotonia, which usually appears by age 5 years, is and involves many systems other than muscle. Affected demonstrable by percussion of the thenar eminence, the patients have a typical “hatchet-faced” appearance due to tongue, and wrist extensor muscles. Myotonia causes a slow temporalis, masseter, and facial muscle atrophy and weak- relaxation of hand grip after a forced voluntary closure. ness. Frontal baldness is also characteristic of the disease. Advanced muscle wasting makes myotonia more diffi- Neck muscles, including flexors and sternocleidomastoids, cult to detect. and distal limb muscles are involved early.Weakness of wrist extensors, finger extensors, and intrinsic hand muscles Cardiac disturbances occur commonly in patients with impairs function. Ankle dorsiflexor weakness may cause DM1. ECG abnormalities include first-degree heart block footdrop. Proximal muscles remain stronger throughout and more extensive conduction system involvement. Com- plete heart block and sudden death can occur; recently, risk factors for sudden death in these patients have been

identified, but whether pacemaker or defibrillator implan- The DNA expansions in DM1 and DM2 almost cer- 581 CHAPTER 43 Muscular Dystrophies and Other Muscle Diseases tation can mitigate this risk remains to be determined. tainly impair muscle function by a toxic gain of function Congestive heart failure occurs infrequently but may result of the mutant mRNA. In both DM1 and DM2, the from cor pulmonale secondary to respiratory failure. Mitral mutant RNA appears to form intranuclear inclusions valve prolapse also occurs commonly. Other associated composed of aberrant RNA. These RNA inclusions features include intellectual impairment, hypersomnia, sequester RNA binding proteins essential for proper posterior subcapsular cataracts, gonadal atrophy, insulin splicing of a variety of other mRNAs. This leads to resistance, and decreased esophageal and colonic motility. abnormal transcription of multiple proteins in a variety of tissues/organ systems, in turn causing the systemic Congenital myotonic dystrophy is a more severe form of manifestations of DM1 and DM2. DM1 and occurs in ~25% of infants of affected mothers. It is characterized by severe facial and bulbar weakness, Treatment: transient neonatal respiratory insufficiency, and mental MYOTONIC DYSTROPHY retardation. The myotonia in DM1 rarely warrants treatment, though DM2, or PROMM, has a distinct pattern of muscle some patients with DM2 are significantly bothered by the weakness affecting mainly proximal muscles. Other features discomfort related to the associated muscle stiffness. of the disease overlap with DM1, including cataracts, testic- Phenytoin and mexiletine are the preferred agents for the ular atrophy, insulin resistance, constipation, hypersomnia, occasional patient who requires an antimyotonia drug; and cognitive defects. Cardiac conduction defects occur other agents, particularly quinine and procainamide, may but are less common, and the hatchet face and frontal bald- worsen cardiac conduction. A cardiac pacemaker should ness are less consistent features.A very striking difference is be considered for patients with unexplained syncope, the failure to clearly identify a congenital form of DM2. advanced conduction system abnormalities with evi- dence of second-degree heart block, or trifascicular con- Laboratory Features duction disturbances with marked prolongation of the PR interval. Molded ankle-foot orthoses help prevent foot- The diagnosis of myotonic dystrophy can usually be made drop in patients with distal lower extremity weakness. on the basis of clinical findings. Serum CK levels may be Excessive daytime somnolence with or without sleep normal or mildly elevated. EMG evidence of myotonia is apnea is not uncommon. Sleep studies, noninvasive respi- present in most cases of DM1 but may be more patchy in ratory support (BiPAP), and treatment with modafinil may DM2. Muscle biopsy shows muscle atrophy, which selec- be beneficial. tively involves type 1 fibers in 50% of cases, and ringed fibers in DM1 but not in DM2. Typically, numerous FACIOSCAPULOHUMERAL (FSH) internalized nuclei can be seen in individual muscle fibers MUSCULAR DYSTROPHY as well as atrophic fibers with pyknotic nuclear clumps in both DM1 and DM2. Necrosis of muscle fibers and This form of muscular dystrophy has a prevalence of ~1 increased connective tissue, common in other muscular in 20,000. It is distinct from a similar disorder known as dystrophies, are less apparent in myotonic dystrophy. scapuloperoneal dystrophy. DM1 and DM2 are both autosomal dominant disor- Clinical Features ders. New mutations do not appear to contribute to the pool of affected individuals. DM1 is transmitted by an The condition typically has an onset in childhood or intronic mutation consisting of an unstable expansion of young adulthood. In most cases, facial weakness is the a CTG trinucleotide repeat in a serine-threonine protein initial manifestation, appearing as an inability to smile, kinase gene (named DMPK) on chromosome 19q13.3. whistle, or fully close the eyes.Weakness of the shoulder An increase in the severity of the disease phenotype in girdles, rather than the facial muscles, usually brings the successive generations (genetic anticipation) is accompa- patient to medical attention. Loss of scapular stabilizer nied by an increase in the number of trinucleotide repeats. muscles makes arm elevation difficult. Scapular winging A similar type of mutation has been identified in fragile (Fig. 43-3) becomes apparent with attempts at abduction X syndrome.The unstable triplet repeat in myotonic dys- and forward movement of the arms. Biceps and triceps trophy can be used for prenatal diagnosis. Congenital dis- muscles may be severely affected, with relative sparing of ease occurs almost exclusively in infants born to affected the deltoid muscles. Weakness is invariably worse for mothers; it is possible that sperm with greatly expanded wrist extension than for wrist flexion, and weakness of triplet repeats do not function well. the anterior compartment muscles of the legs may lead to footdrop. DM2 is caused by a DNA expansion mutation con- sisting of a CCTG repeat in intron 1 of the ZNF9 gene located at chromosome 3q13.3-q24.The gene is believed to encode an RNA binding protein expressed in many different tissues, including skeletal and cardiac muscle.