3513 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction CHAPTER 448

the two conditions are usually readily distinguished because patients

with LEMS have depressed or absent reflexes and experience autonomic changes such as dry mouth and impotence. Nerve stimulation

produces an initial low-amplitude compound muscle action potential

and, at low rates of repetitive stimulation (2–3 Hz), a decremental

responses as seen in MG; however, at high rates (20–50 Hz) or following brief exercise, incremental responses occur. LEMS is caused

by autoantibodies directed against P/Q-type calcium channels at the

motor nerve terminals detected in ~85% of LEMS patients. These

autoantibodies impair the release of ACh from nerve terminals. In

young adults, particularly women, LEMS is not associated with an

underlying cancer. However, in older adults, most LEMS is associated

with malignancy, most commonly small-cell lung cancer (SCLC). The

tumor cells may express calcium channels that stimulate the autoimmune response. Treatment of LEMS involves plasmapheresis and

immunotherapy, as for MG. 3,4-DAP and pyridostigmine can also help

with symptoms. 3,4-DAP acts by blocking potassium channels, which

results in prolonged depolarization of the motor nerve terminals and

thus enhances ACh release. Pyridostigmine prolongs the action of

ACh, allowing repeated interactions with AChRs.

Botulism (Chap. 153) is due to potent bacterial toxins produced

by any of eight different strains of Clostridium botulinum. The toxins enzymatically cleave specific proteins essential for the release of

ACh from the motor nerve terminal, thereby interfering with neuromuscular transmission. Most commonly, botulism is caused by

ingestion of improperly prepared food containing toxin. Rarely, the

nearly ubiquitous spores of C. botulinum may germinate in wounds.

In infants, the spores may germinate in the gastrointestinal (GI) tract

and release toxin, causing muscle weakness. Patients present with

myasthenia-like bulbar weakness (e.g., diplopia, dysarthria, dysphagia)

and lack sensory symptoms and signs. Weakness may generalize to

the limbs and may result in respiratory failure. Reflexes are present

early, but they may be diminished as the disease progresses. Mentation

is normal. Autonomic findings include paralytic ileus, constipation,

urinary retention, dilated or poorly reactive pupils, and dry mouth.

The demonstration of toxin in serum by bioassay is definitive, but the

results usually take a relatively long time to be completed and may be

negative. Nerve stimulation studies reveal reduced compound muscle

action potential (CMAP) amplitudes that increase following highfrequency repetitive stimulation. Treatment includes ventilatory support and aggressive inpatient supportive care (e.g., nutrition, deep-vein

thrombosis prophylaxis) as needed. Antitoxin should be given as early

as possible to be effective and can be obtained through the Centers for

Disease Control and Prevention. A preventive vaccine is available for

laboratory workers or other highly exposed individuals.

Neurasthenia is the historic term for a myasthenia-like fatigue

syndrome without an organic basis. These patients may present with

subjective symptoms of weakness and fatigue, but muscle testing

usually reveals the “give-away weakness” characteristic of nonorganic

disorders; the complaint of fatigue in these patients means tiredness or

apathy rather than decreasing muscle power on repeated effort. Hyperthyroidism is readily diagnosed or excluded by tests of thyroid function,

which should be carried out routinely in patients with suspected MG.

Abnormalities of thyroid function (hyper- or hypothyroidism) may

increase myasthenic weakness. Diplopia resembling that in MG may

occasionally be due to an intracranial mass lesion that compresses

nerves to the EOMs (e.g., sphenoid ridge meningioma), but magnetic

resonance imaging (MRI) of the head and orbits usually reveals the

lesion.

Progressive external ophthalmoplegia is a rare condition resulting in

weakness of the EOMs, which may be accompanied by weakness of

the proximal muscles of the limbs and other systemic features. Most

patients with this condition have mitochondrial disorders that can be

detected by genetic testing or with muscle biopsy (Chap. 449).

Search for Associated Conditions (Table 448-3) Myasthenic

patients have an increased incidence of several associated disorders.

Thymic abnormalities occur in ~75% of AChR antibody–positive

patients, as noted above. Neoplastic change (thymoma) may produce

enlargement of the thymus, which is detected by chest computed

tomography (CT). A thymic shadow on CT scan may normally be

present through young adulthood, but enlargement of the thymus in

a patient age >40 years is highly suspicious of thymoma. Hyperthyroidism occurs in 3–8% of patients and may aggravate the myasthenic

weakness. Thyroid function tests should be obtained in all patients

with suspected MG. Other autoimmune disorders, most commonly

systemic lupus erythematosus and rheumatoid arthritis, can coexist

with MG; associations also occur with neuromyelitis optica, neuromyotonia, Morvan’s syndrome (encephalitis, insomnia, confusion,

hallucinations, autonomic dysfunction, and neuromyotonia), rippling

muscle disease, granulomatous myositis/myocarditis, and chronic

inflammatory demyelinating polyneuropathy.

An infection of any kind can exacerbate typical MG and should be

sought carefully in patients with relapses. Because of the side effects of

glucocorticoids and other immunotherapies used in the treatment of

MG, a thorough medical investigation should be undertaken, searching

specifically for evidence of chronic or latent infection (such as tuberculosis or hepatitis), hypertension, diabetes, renal disease, and glaucoma.

TREATMENT

Myasthenia Gravis

The prognosis has improved strikingly as a result of advances in

treatment. Nearly all myasthenic patients can be returned to full

productive lives with proper therapy. The most useful treatments

for MG include anticholinesterase medications, glucocorticoids

and other immunosuppressive agents, thymectomy, plasmapheresis, IVIg, rituximab, and complement inhibitors (eculizumab)

(Fig. 448-2).

ANTICHOLINESTERASE MEDICATIONS

Anticholinesterase medication produces at least partial improvement in most myasthenic patients, although improvement is complete in only a few. Patients with anti-MuSK MG generally obtain

less benefit from anticholinesterase agents than those with AChR

antibodies and may actually worsen. Pyridostigmine is the most

widely used anticholinesterase drug and is initiated at a dosage

of 30–60 mg three to four times daily. The beneficial action of

oral pyridostigmine begins within 15–30 min and lasts for 3–4 h,

but individual responses vary. The frequency and amount of the

dose should be tailored to the patient’s individual requirements

TABLE 448-3 Disorders Associated with Myasthenia Gravis and

Recommended Laboratory Tests

Associated disorders

Disorders of the thymus: thymoma, hyperplasia

 Other autoimmune neurologic disorders: chronic inflammatory demyelinating

polyneuropathy, neuromyelitis optica

 Other autoimmune disorders: Hashimoto’s thyroiditis, Graves’ disease,

rheumatoid arthritis, systemic lupus erythematosus, skin disorders, family

history of autoimmune disorder

 Disorders or circumstances that may exacerbate myasthenia gravis:

hyperthyroidism or hypothyroidism, occult infection, medical treatment for

other conditions (see Table 448-4)

 Disorders that may interfere with therapy: tuberculosis, diabetes, peptic ulcer,

gastrointestinal bleeding, renal disease, hypertension, asthma, osteoporosis,

obesity

Recommended laboratory tests or procedures

CT or MRI of chest

Tests for antinuclear antibodies, rheumatoid factor

Thyroid function tests

Testing for tuberculosis

Fasting blood glucose, hemoglobin A1c

Pulmonary function tests

Bone densitometry

Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging.

3514 PART 13 Neurologic Disorders

throughout the day. For example, patients with weakness in chewing

and swallowing may benefit by taking the medication before meals

so that peak strength coincides with mealtimes. Long-acting pyridostigmine may occasionally be useful to get the patient through

the night but should not be used for daytime medication because of

variable absorption. The maximum useful dose of pyridostigmine

rarely exceeds 300 mg daily. Overdosage with anticholinesterase

medication may cause increased weakness and other side effects.

In some patients, muscarinic side effects of the anticholinesterase

medication (diarrhea, abdominal cramps, salivation, nausea) may

limit the dose tolerated. Atropine/diphenoxylate or loperamide is

useful for the treatment of GI symptoms.

THYMECTOMY

Two separate issues should be distinguished: (1) surgical removal

of thymoma, and (2) thymectomy as a treatment for MG. Surgical

removal of a thymoma is necessary because of the possibility of

local tumor spread, although most thymomas are histologically

benign. A large international trial of extended transternal thymectomy in nonthymomatous, AChR antibody–positive, generalized

MG demonstrated that participants who underwent thymectomy

had improved strength and function, required less prednisone

and fewer additions of second-line agents (e.g., azathioprine), and

fewer hospitalizations for exacerbations lasting at least 5 years.

Whether or not less invasive thymectomy may be beneficial is

unknown. Also, patients with ocular myasthenia, MuSK-positive,

and seronegative MG were excluded from the study; retrospective

and anecdotal evidence suggests that these patients may not benefit

from thymectomy. Thymectomy should never be carried out as an

emergency procedure, but only when the patient is adequately prepared. If necessary, treatment with IVIg or plasmapheresis may be

used before surgery to maximize strength in weak patients.

IMMUNOTHERAPY

The choice of immunotherapy should be guided by the relative

benefits and risks for the individual patient and the urgency of

treatment. It is helpful to develop a treatment plan based on shortterm, intermediate-term, and long-term objectives. For example, if

immediate improvement is essential either because of the severity

of weakness or because of the patient’s need to return to activity as

soon as possible, IVIg should be administered or plasmapheresis

should be undertaken. For the intermediate term, glucocorticoids

and cyclosporine or tacrolimus generally produce clinical improvement within a period of 1–3 months. The beneficial effects of

azathioprine and mycophenolate mofetil usually begin after many

months (as long as a year), but these drugs have advantages for

the long-term treatment of patients with MG. There is a growing

body of evidence that rituximab is effective in patients with MuSK

antibody. Complement inhibition with intravenous eculizumab can

improve MG within 1–3 months but is expensive and requires a

loading dose of 4 weekly infusions followed by every-other-week

infusions for maintenance.

Glucocorticoid Therapy Glucocorticoids, when used properly,

produce improvement in myasthenic weakness in the great majority

of patients. To minimize adverse side effects, prednisone should

be given in a single dose rather than in divided doses throughout

the day. In patients with only mild or moderate weakness, the initial dose should be relatively low (15–25 mg/d) to avoid the early

weakening that occurs in 10–15% of patients treated initially with

a high-dose regimen. The dose is increased stepwise, as tolerated

by the patient (usually by 5 mg/d at 2- to 3-day intervals), until

there is marked clinical improvement or a dose of 50–60 mg/d is

reached. In patients with more severe weakness and those already

in the hospital, starting at a high dose is reasonable. Patients are

maintained on the dose that controls their symptoms for about

a month, and then the dosage is slowly tapered (no faster than

10 mg a month until on 20 mg daily and then by 2.5–5 mg a month)

to determine the minimum effective dose, and close monitoring

is required. Some patients can be managed without the addition

of other immunotherapies. Patients on long-term glucocorticoid

therapy must be followed carefully to prevent or treat adverse

side effects. The most common errors in glucocorticoid treatment of myasthenic patients include (1) insufficient persistence—

improvement may be delayed and gradual; (2) tapering the dosage

too early, too rapidly, or excessively; and (3) lack of attention to

prevention and treatment of side effects.

The management of patients treated with glucocorticoids is

discussed in Chap. 386.

Other Immunotherapies Mycophenolate mofetil, azathioprine,

cyclosporine, tacrolimus, rituximab, eculizumab, and occasionally

cyclophosphamide are effective in many patients, either alone or in

various combinations.

Mycophenolate mofetil is widely used because of its presumed

effectiveness and relative lack of side effects. A dose of 1–1.5 g bid

is recommended. Its mechanism of action involves inhibition of

purine synthesis by the de novo pathway. Since lymphocytes have

only the de novo pathway, but lack the alternative salvage pathway

that is present in all other cells, mycophenolate inhibits proliferation

of lymphocytes but not proliferation of other cells. It does not kill

or eliminate preexisting autoreactive lymphocytes, and therefore,

clinical improvement may be delayed for many months to a year,

until the preexisting autoreactive lymphocytes die spontaneously.

The advantage of mycophenolate lies in its relative lack of adverse

side effects, with only occasional production of GI symptoms, rare

development of leukopenia, and very small risks of malignancy or

Establish diagnosis unequivocally (see Table 448-1)

Search for associated conditions (see Table 448-3)

Ocular only

MRI of brain

 (if positive,

 reassess)

Anticholinesterase

 (pyridostigmine)

Anticholinesterase

 (pyridostigmine)

Evaluate for thymectomy

 (indications: thymoma or

 generalized MG with

 anti-AChR antibodies);

evaluate surgical risk, FVC

Crisis

Intensive care

 (tx respiratory

 infection; fluids)

Generalized

If unsatisfactory

Thymectomy

Good risk

 (good FVC)

Poor risk

 (low FVC)

If not

 improved

Immunosuppression

Evaluate clinical status; if indicated,

 go to immunosuppression

Improved

See text for short-term, intermediate,

and long-term treatments

Plasmapheresis

 or intravenous Ig

then

FIGURE 448-2 Algorithm for the management of myasthenia gravis. FVC, forced

vital capacity; MRI, magnetic resonance imaging.

3515 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction CHAPTER 448

progressive multifocal leukoencephalopathy inherent in nearly all

immunosuppressive treatments. Although two published studies

did not show positive outcomes, most experts attribute the negative

results to flaws in the trial designs, and mycophenolate is widely

used for long-term treatment of myasthenic patients.

Azathioprine has long been used for MG, and a randomized,

clinical trial demonstrated that it was effective in reducing the

dosage of prednisone necessary to control symptoms. However, the

beneficial effect can take a year or more to become evident. Approximately 10–15% of patients are unable to tolerate azathioprine

because of idiosyncratic reactions consisting of flulike symptoms

of fever and malaise, bone marrow suppression, or abnormalities

of liver function. An initial dose of 50 mg/d is given for about

a week to test for these side effects. If this dose is tolerated, it is

increased gradually to ~2–3 mg/kg of total body weight or until the

white blood count falls to 3000–4000/μL. Allopurinol should never

be used in combination with azathioprine because the two drugs

share a common degradation pathway; the result may be severe bone

marrow suppression due to increased effects of the azathioprine.

The calcineurin inhibitors cyclosporine and tacrolimus seem to

be effective in MG and appear to work more rapidly than azathioprine and mycophenolate. However, they are associated with more

frequent severe side effects including hypertension and nephrotoxicity. The usual dose of cyclosporine is 4–5 mg/kg per d, and the

average dose of tacrolimus is 0.07–0.1 mg/kg per d, given in two

equally divided doses. “Trough” blood levels are measured 12 h

after the evening dose. The therapeutic range for the trough level

of cyclosporine is 150–200 ng/L, and for tacrolimus, it is 5–15 ng/L.

Rituximab (Rituxan) is a monoclonal antibody that binds to

the CD20 molecule on B lymphocytes. It is widely used for the

treatment of B-cell lymphomas and has also proven successful in

the treatment of several autoimmune diseases including rheumatoid arthritis, pemphigus, and some IgM-related neuropathies.

There is a growing literature on the benefit of rituximab in MuSK

antibody–positive MG, which was previously more difficult to treat

than anti-AChR–positive MG. A large, randomized trial of AChR

antibody–positive generalized MG failed to demonstrate efficacy.

The usual dose is 1 g IV on two occasions 2 weeks apart. Periodically, a repeat course needs to be administered; some MuSK

patients go 2–3 years between infusions.

Eculizumab, a monoclonal antibody that binds to the terminal

complement component 5 (C5), demonstrated efficacy in a large

phase 3 clinical trial. The drug is administered intravenously every

2 weeks. Complement inhibition increases the risk of meningococcal infection, so ideally, a first series of vaccinations is given prior to

initiation, and many recommend antibiotic prophylaxis (penicillin)

while patients receive therapy. A benefit of eculizumab is that it

works within 1–3 months and patients can often wean down on

other immunotherapies. There are promising early results from

other complement inhibitors, including subcutaneously administered drugs. For the rare refractory MG patient, a course of

high-dose cyclophosphamide may induce long-lasting benefit. At

high doses, cyclophosphamide eliminates mature lymphocytes but

spares hematopoietic precursors (stem cells), because they express

the enzyme aldehyde dehydrogenase, which hydrolyzes cyclophosphamide. This procedure is reserved for refractory patients and

should be administered only in a facility fully familiar with this

approach. Maintenance immunotherapy after treatment is usually

required to sustain the beneficial effect.

PLASMAPHERESIS AND INTRAVENOUS

IMMUNOGLOBULIN

Plasmapheresis has been used therapeutically in MG. Plasma, which

contains the pathogenic antibodies, is mechanically separated from

the blood cells, which are returned to the patient. A course of five

exchanges (3–4 L per exchange) is generally administered over a

10- to 14-day period. Plasmapheresis produces a short-term reduction in anti-AChR antibodies, with clinical improvement in many

patients. It is useful as a temporary expedient in seriously affected

patients or to improve the patient’s condition prior to surgery (e.g.,

thymectomy).

The indications for the use of IVIg are the same as those for

plasma exchange: to produce rapid improvement to help the patient

through a difficult period of myasthenic weakness or prior to surgery. This treatment has the advantages of not requiring special

equipment or large-bore venous access. The usual dose is 2 g/kg,

which is typically administered over 2–5 days. Improvement occurs

in ~70% of patients, beginning during treatment or within a week

and continuing for weeks to months. The mechanism of action of

IVIg is not known; the treatment has no consistent long-term effect

on the measurable amount of circulating AChR antibody. Adverse

reactions are generally not serious but may include headache, fluid

overload, and rarely aseptic meningitis or renal failure. IVIg or

plasma exchange is occasionally used in combination with other

immunosuppressive therapy for maintenance treatment of difficult

MG.

INVESTIGATIONAL TREATMENTS

Early results of fragment crystalized neonatal receptor (FcRn) blockers

also appear promising. FcRn bind immunoglobulins, thereby rescuing them from lysosomal destruction. Blocking this receptor allows

for degradation of anti-AChR, anti-MuSK, anti-LR4, and other

antibodies, reducing their levels to 60–85% within 1–2 months.

Several trials of different FcRn blockers are underway.

MANAGEMENT OF MYASTHENIC CRISIS

Myasthenic crisis is defined as an exacerbation of weakness sufficient to endanger life; it usually includes ventilatory failure caused by

diaphragmatic and intercostal muscle weakness. Treatment should

be carried out in intensive care units staffed with teams experienced

in the management of MG. The possibility that deterioration could

be due to excessive anticholinesterase medication (“cholinergic

crisis”) is best excluded by temporarily stopping anticholinesterase

drugs. The most common cause of crisis is intercurrent infection.

This should be treated immediately because the mechanical and

immunologic defenses of the patient can be assumed to be compromised. The myasthenic patient with fever and early infection

should be treated like other immunocompromised patients. Early

and effective antibiotic therapy, ventilatory assistance, and pulmonary physiotherapy are essentials of the treatment program. As

discussed above, plasmapheresis or IVIg is frequently helpful in

hastening recovery.

DRUGS TO AVOID IN MYASTHENIC PATIENTS

Many drugs can potentially exacerbate weakness in patients with

MG (Table 448-4). As a rule, the listed drugs should be avoided

whenever possible.

■ PATIENT ASSESSMENT

To evaluate the effectiveness of treatment as well as drug-induced side

effects, it is important to assess the patient’s clinical status systematically at baseline and on repeated interval examinations. Following the

patient with spirometry with determination of forced vital capacity and

mean inspiratory and expiratory pressures is important.

PROGNOSIS

Approximately 20% of patients with MG achieve a sustained remission

and can be tapered off all immunotherapies. There does not appear

to be a correlation between disease severity and likelihood of remission. Thymectomy may increase the chance of achieving remission

in anti-AChR MG, but the large randomized trial was too short in

duration to examine this endpoint; rather, the results revealed only

that thymectomy was efficacious and led to less use of glucocorticoids

and second-line agents. Mortality from MG diminished greatly during

the twentieth century, changing from a “grave” illness with mortality of

nearly 70% a century ago, to 2–30% by the 1950s, with contemporary

estimates in the 1–2% range. Anti-MuSK patients generally were more

difficult to treat than anti-AChR MG in the past. However, recent series

3516 PART 13 Neurologic Disorders

TABLE 448-4 Drugs with Interactions in Myasthenia Gravis (MG)

Drugs That May Exacerbate MG

Antibiotics

Aminoglycosides: e.g., streptomycin, tobramycin, kanamycin

Quinolones: e.g., ciprofloxacin, levofloxacin, ofloxacin, gatifloxacin

Macrolides: e.g., erythromycin, azithromycin

Nondepolarizing muscle relaxants for surgery

d-Tubocurarine (curare), pancuronium, vecuronium, atracurium

Beta-blocking agents

Propranolol, atenolol, metoprolol

Local anesthetics and related agents

Procaine, Xylocaine in large amounts

Procainamide (for arrhythmias)

Botulinum toxin

Botox exacerbates weakness

Quinine derivatives

Quinine, quinidine, chloroquine, mefloquine (Lariam)

Magnesium

Decreases acetylcholine release

Penicillamine

May cause MG

Check point inhibitors

May cause MG and other autoimmune neuromuscular disorders (e.g., myositis,

inflammatory neuropathy)

Drugs with Important Interactions in MG

Cyclosporine and tacrolimus

Broad range of drug interactions, which may raise or lower levels.

Azathioprine

Avoid allopurinol—combination may result in myelosuppression.

VIDEO 448-1 Myasthenia gravis and other diseases of the neuromuscular junction.

suggest that rituximab is effective in this subgroup, thereby reducing

these risks and improving the prognosis. Nonparaneoplastic LEMS

is usually responsive to immunotherapy and symptomatic treatment

with pyridostigmine and 3,4-DAP. In older adults, LEMS is most

often paraneoplastic, and screening for an underlying tumor is indicated (Chap. 94). Recent studies suggest that survival in patients with

LEMS has improved, for uncertain reasons and likely not due to earlier

diagnosis and treatment of the tumor. There is wide variability in age of

onset, severity, and prognosis of the many types of CMS.

GLOBAL ISSUES

The incidence of MG and its subtypes varies in different populations,

for example, occurring in ~2–10/106

 individuals in the United States

and the Netherlands and up to 20/106

 individuals in Spain. Estimates of

prevalence in different parts of the world range widely from 2–200/106

.

The age of onset may also be influenced by geographic and/or ethnic

differences. Juvenile-onset MG is uncommon in Western populations

but may represent more than half of cases in Asians. MuSK MG

appears to be more common in the Mediterranean area of Europe

than in northern Europe and is also more common in the northern

regions of East Asia than in the southern regions. A concern during the

COVID-19 pandemic is whether MG patients on immunosuppressive

therapies might be at increased risk of infection or developing a more

severe course. Furthermore, flares of MG can be triggered by infection,

and contracting COVID-19 may lead to an exacerbation, including

MG crisis. I have not reduced the dosage of immunosuppressive medications in MG patients who are doing well but have been more likely to

manage worsening disease by treating with IVIg rather than increasing

the dosage of, or adding new, immunosuppressive agents. Patients are

strongly advised to wear masks and maintain social distancing. An

international panel has published guidelines for management of MG

patients during this crisis.

■ FURTHER READING

Amato AA, Russell JA: Neuromuscular Disorders, 2nd ed. New York,

McGraw-Hill, 2016, pp. 581–655.

Ciafaloni E: Myasthenia gravis and congenital myasthenic syndromes. Continuum (Mineap Minn) 25:1767, 2009.

Evoli A et al: Myasthenia gravis with antibodies to MuSK: An update.

Ann NY Acad Sci 1412:82, 2018.

Garg N et al: Late presentations of congenital myasthenic syndromes:

How many do we miss? Muscle Nerve 54:721, 2016.

Gilhus NE: Myasthenia gravis. N Engl J Med 375:2570, 2016.

Guidon AC: Lambert-Eaton myasthenic syndrome, botulism, and

immune checkpoint inhibitor-related myasthenia gravis. Continuum

(Minneap Minn) 25:1785, 2019.

Howard JF Jr et al: Safety and efficacy of eculizumab in antiacetylcholine receptor antibody-positive refractory generalised

myasthenia gravis (REGAIN): A phase 3, randomised, double-blind,

placebo-controlled, multicentre study. Lancet Neurol 16:976, 2017.

Howard JF Jr et al: Randomized phase 2 study of FcRn antagonist

efgartigimod in generalized myasthenia gravis. Neurology 92:e2661,

2019.

International MG/COVID-19 Working Group et al: Guidance

for the management of myasthenia gravis (MG) and Lambert-Eaton

myasthenic syndrome (LEMS) during the COVID-19 pandemic.

J Neurol Sci 412:116803, 2020.

Tandan R et al: Rituximab treatment of myasthenia gravis: A systematic review. Muscle Nerve 56:185, 2017.

Wolfe GI et al: Randomized trial of thymectomy in myasthenia gravis.

N Engl J Med 375:511, 2016.

Wolfe GI et al: Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia

gravis: 2-year extension of the MGTX randomised trial. Lancet

Neurol 18:259, 2019.

Myopathies are disorders with structural changes or functional impairment of muscle and can be differentiated from other diseases of the

motor unit (e.g., lower motor neuron or neuromuscular junction

pathologies) by characteristic clinical and laboratory findings. Myasthenia gravis and related disorders are discussed in Chap. 448;

inflammatory myopathies are discussed in Chap. 365.

■ CLINICAL FEATURES

The most important aspect of assessing individuals with neuromuscular disorders is taking a thorough history of the patient’s symptoms, disease progression, and past medical and family history, as

well as performing a detailed neurologic examination. Based on this

and additional laboratory workup (e.g., serum creatine kinase [CK],

electromyography [EMG]), one can usually localize the site of the

lesion to muscle (as opposed to motor neurons, peripheral nerves, or

neuromuscular junction) and the pattern of muscle involvement. It is

this pattern of muscle involvement that is most useful in narrowing

the differential diagnosis (Table 449-1). Most myopathies present

with proximal, symmetric limb weakness with preserved reflexes and

sensation. However, asymmetric and predominantly distal weakness

can be seen in some myopathies. An associated sensory loss suggests a

peripheral neuropathy or a central nervous system (CNS) abnormality

449 Muscular Dystrophies and

Other Muscle Diseases

Anthony A. Amato, Robert H. Brown, Jr.

3517 Muscular Dystrophies and Other Muscle Diseases CHAPTER 449

TABLE 449-1 Myopathies by Pattern of Weakness/Muscle Involvement

Proximal (Limb-Girdle) Weakness Late-onset central core (RYR1 mutations)

Sporadic late-onset nemaline rod with or without a monoclonal gammopathy

Metabolic (late-onset Pompe, McArdle disease, lipid storage, mitochondrial)

Hyperparathyroidism/osteomalacia/vitamin D deficiency

Myasthenia gravis

Eye Muscle Weakness (Ptosis/Ophthalmoparesis)

Ptosis without ophthalmoparesis

Myotonic dystrophy

Congenital myopathies

Neuromuscular junction disorders

Ptosis with ophthalmoparesis

Oculopharyngeal dystrophy

Mitochondrial myopathy

hIBM type 3

Neuromuscular junction disorders

Episodic Weakness or Myoglobinuria

Related to exercise

Glycogenoses (e.g., McArdle disease, etc.)

Lipid disorders (e.g., CPT2 deficiency)

Mitochondrial myopathies (e.g., cytochrome B deficiency)

Not related to exercise

 RYR1 mutations can cause malignant hyperthermia, episodic rhabdomyolysis/

myoglobinuria, and atypical periodic paralysis

Other causes of malignant hyperthermia

Drugs/toxins (e.g., statins)

Prolonged/intensive eccentric exercise

Inflammatory (e.g., PM/DM—rare, viral/bacterial infections)

Delayed or unrelated to exercise

 Periodic paralysis (e.g., hereditary hyper- or hypokalemic, thyrotoxic,

associated renal tubular acidosis, acquired electrolyte imbalance)

NMJ disorders

Muscle Stiffness/Decreased Ability to Relax

Myotonic dystrophy 1 and 2

Myotonia congenita

Paramyotonia congenita

Hyperkalemic periodic paralysis with myotonia

Potassium aggravated myotonia

Schwartz-Jampel syndrome

Other: rippling muscle disease (acquired and hereditary), acquired

neuromyotonia (Isaacs’ syndrome), stiff-person syndrome, Brody’s disease

Most dystrophies (e.g., dystrophinophies, limb-girdle, myofibrillar myopathy,

myotonic dystrophy type 2, rare FSHD)

Congenital myopathies (e.g., central core, multiminicore, centronuclear,

nemaline rod)

Metabolic myopathies (e.g., glycogen and lipid storage diseases)

Mitochondrial myopathies

Inflammatory myopathies (DM, PM, IMNM, anti-synthetase syndrome)

Toxic myopathies (see Table 449-6)

Endocrine myopathies

Neuromuscular junction disorders (myasthenia gravis, LEMS, congenital

myasthenia, botulism, see Chap. 448)

Distal Weakness

Distal muscular dystrophies/myofibrillar myopathy (see Table 449-5)

Congenital myopathies (e.g., late-onset centronuclear and nemaline rod

myopathies)

Metabolic

 Glycogen storage disease (e.g., brancher and debrancher deficiency, rarely

McArdle disease)

 Lipid storage disease (e.g., neutral lipid storage myopathy,

multiacyldehydrogenase deficiency)

NMJ disorders (e.g., rare myasthenia gravis and congenital myasthenia)

Proximal Arm/Distal Leg Weakness (Scapuloperoneal or

Humeroperonal) Weakness

Facioscapulohumeral muscular dystrophy (FSHD)

Scapuloperoneal myopathy and neuropathy

Myofibrillar myopathies

Emery-Dreifuss muscular dystrophy (EDMD)

Bethlem myopathy

Distal Arm/Proximal Leg Weakness

Inclusion body myositis (usually wrist and finger flexors in arms, hip flexors and

knee extensors in legs, and asymmetric)

Myotonic dystrophy (uncommon presentation)

Axial Muscle Weakness

Inflammatory (cervicobrachial myositis)

sIBM and hIBM

Myotonic dystrophy 2

Isolated neck extensor myopathy/bent spine syndrome

FSHD

Abbreviations: DM, dermatomyositis; hIBM, hereditary inclusion body myopathy; IMNM, immune-mediated necrotizing myopathy; LEMS, Lambert-Eaton myasthenic

syndrome; NMJ, neuromuscular junction; PM, polymyositis; sIBM, sporadic inclusion body myositis.

(e.g., myelopathy) rather than a myopathy. On occasion, disorders

affecting the motor nerve cell bodies in the spinal cord (anterior horn

cell disease), the neuromuscular junction, or peripheral nerves can

mimic findings of myopathy.

Muscle Weakness Symptoms of muscle weakness can be either

intermittent or persistent. Disorders causing intermittent weakness

(Table 449-1 and Fig. 449-1) include myasthenia gravis, periodic paralyses (hypokalemic or hyperkalemic), and metabolic energy deficiencies

of glycolysis (especially myophosphorylase deficiency), fatty acid utilization (carnitine palmitoyltransferase [CPT] deficiency), and some

mitochondrial myopathies. The states of energy deficiency cause activityrelated muscle breakdown accompanied by myoglobinuria.

Most muscle disorders cause persistent weakness (Table 449-1 and

Fig. 449-2). In the majority of these, including most types of muscular

dystrophy and inflammatory myopathies, the proximal muscles are

weaker than the distal and are symmetrically affected, and the facial

muscles are spared, a pattern referred to as limb-girdle weakness. The

differential diagnosis is more restricted for other patterns of weakness.

Facial weakness (difficulty with eye closure and impaired smile) and

scapular winging (Fig. 449-3) are characteristic of facioscapulohumeral dystrophy (FSHD). Facial and distal limb weakness associated

with hand grip myotonia is virtually diagnostic of myotonic dystrophy

type 1. When other cranial nerve muscles are weak, causing ptosis or

extraocular muscle weakness, the most important disorders to consider

include neuromuscular junction disorders, oculopharyngeal muscular dystrophy, mitochondrial myopathies, or some of the congenital

myopathies (Table 449-1). A pathognomonic pattern characteristic of

inclusion body myositis is atrophy and weakness of the flexor forearm

(e.g., wrist and finger flexors) and quadriceps muscles that is often

asymmetric. Less frequently seen, but important diagnostically, are the

axial myopathies that predominantly affect the paraspinal muscles and

include dropped head syndrome indicative of selective neck extensor

muscle weakness. The most important neuromuscular diseases associated with this axial muscle weakness include myasthenia gravis, amyotrophic lateral sclerosis, late-onset core or nemaline rod myopathy,

3518 PART 13 Neurologic Disorders

Intermittent weakness

Myoglobinuria

Variable weakness includes

 EOMs, ptosis, bulbar and limb muscles

No Yes

Exam normal between attacks

Proximal > distal weakness during attacks

Exam usually normal between attacks

Proximal > distal weakness during attacks

Forearm exercise

DNA test confirms diagnosis

Low potassium

level Normal or elevated

 potassium level

Hypokalemic PP Hyperkalemic PP

Paramyotonia congenita

Reduced lactic acid rise

Consider glycolytic defect

Normal lactic acid rise

Consider CPT deficiency

or other fatty acid

metabolism disorders No Yes

AChR or Musk AB positive

Acquired seropositive

MG

Check chest CT

for thymoma

Lambert-Eaton

myasthenic syndrome

Check:

Voltage gated Ca

 channel Abs

 Chest CT for lung Ca

Yes No

Yes No

Decrement on 2–3 Hz repetitive

nerve stimulation (RNS) or

increased jitter on single fiber

EMG (SFEMG)

Consider:

 Seronegative MG

 Congenital

myasthenia*

 Psychosomatic

 weakness**

*Genetic testing

 (Chap. 448)

**If Abs, RNS, SFEMG

 are all normal or negative

EKG

Abnormal

Check for dysmorphic

features

Genetic testing for

Anderson-Tawil syndrome

Normal

Myotonia on exam

Genetic testing

No diagnosis

Muscle biopsy

FIGURE 449-1 Diagnostic evaluation of intermittent weakness. AChR AB, acetylcholine receptor antibody; CPT, carnitine palmitoyltransferase; EKG, electrocardiogram;

EMG, electromyogram; EOMs, extraocular muscles; MG, myasthenia gravis; PP, periodic paralysis.

Persistent Weakness

Patterns of Weakness on Neurologic Exam

Myopathic EMG confirms muscle disease and excludes ALS

Repetitive nerve stimulation abnormalities suggest a neuromuscular

junction disorder (e.g., MG, LEMS, botulism)

CK elevation supports myopathy

May need DNA testing for further distinction of inherited myopathies

Muscle biopsy will help distinguish many disorders

Proximal > distal

 IMNM; PM; DM;

 anti-synthetase

 syndrome;

 muscular

 dystrophies;

 mitochondrial

 and metabolic

myopathies;

toxic, endocrine

myopathies

Facial, distal,

 quadriceps;

 handgrip myotonia

 Myotonic muscular

 dystrophy

Proximal & distal

(hand grip), and

quadriceps

 IBM

Ptosis, EOMs

 OPMD;

 mitochondrial

 myopathy;

 myotubular

 myopathy

Facial weakness

and scapular

winging

 (FSHD)

Dropped head/

Axial

 MG; PM; ALS;

 hyperpara-

 thyroid;

 Axial myopathy

Distal

 Distal myopathy

 (see Table

 449-1)

FIGURE 449-2 Diagnostic evaluation of persistent weakness. Examination reveals one of seven patterns of weakness. The pattern of weakness in combination with the

laboratory evaluation leads to a diagnosis. ALS, amyotrophic lateral sclerosis; CK, creatine kinase; DM, dermatomyositis; EMG, electromyography; EOMs, extraocular

muscles; FSHD, facioscapulohumeral dystrophy; IBM, inclusion body myositis; IMNM, immune-mediated necrotizing myopathy; MG, myasthenia gravis; OPMD,

oculopharyngeal muscular dystrophy; PM, polymyositis.

hyperparathyroidism, focal myositis, and some forms of inclusion body

myopathy. A final pattern, recognized because of preferential distal

extremity weakness, is seen in the distal myopathies.

It is important to examine functional capabilities to help disclose

certain patterns of weakness (Table 449-1 and Table 449-2). The

Gower sign (Fig. 449-4) is particularly useful. Observing the gait of

an individual may disclose a lordotic posture caused by combined

trunk and hip weakness, frequently exaggerated by toe walking

(Fig. 449-5). A waddling gait is caused by the inability of weak hip

muscles to prevent hip drop or hip dip. Hyperextension of the knee

(genu recurvatum or back-kneeing) is characteristic of quadriceps

muscle weakness; and a steppage gait, due to foot drop, accompanies

distal weakness.

Any disorder causing muscle weakness may be accompanied by

fatigue, referring to an inability to maintain or sustain a force (pathologic fatigability). This condition must be differentiated from asthenia,

a type of fatigue caused by excess tiredness or lack of energy. Associated

symptoms may help differentiate asthenia and pathologic fatigability.

Asthenia is often accompanied by a tendency to avoid physical activities, complaints of daytime sleepiness, necessity for frequent naps, and

3519 Muscular Dystrophies and Other Muscle Diseases CHAPTER 449

difficulty concentrating on activities such as reading. There may be

feelings of overwhelming stress and depression. In contrast, pathologic

fatigability occurs in disorders of neuromuscular transmission and in

disorders altering energy production, including defects in glycolysis,

lipid metabolism, or mitochondrial energy production. Pathologic fatigability also occurs in chronic myopathies because of difficulty accomplishing a task with less muscle. Pathologic fatigability is accompanied

by abnormal clinical or laboratory findings. Fatigue without those

supportive features almost never indicates a primary muscle disease.

Muscle Pain (Myalgias), Cramps, and Stiffness Some myopathies can be associated with muscle pain, cramps, contractures, stiff or

rigid muscles, or inability to relax the muscles (e.g., myotonia) (Table

449-1). Muscle cramps are abrupt in onset, short in duration, triggered

by voluntary muscle contraction, and may cause abnormal posturing of the joint. Muscle cramps often occur in neurogenic disorders,

especially motor neuron disease (Chap. 437), radiculopathies, and

polyneuropathies (Chap. 446), but are not a feature of most primary

muscle diseases.

A muscle contracture is different from a muscle cramp. In both

conditions, the muscle becomes hard, but a contracture is associated

with energy failure in glycolytic disorders. The muscle is unable to

FIGURE 449-3 Facioscapulohumeral dystrophy with prominent scapular winging.

TABLE 449-2 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 (back-kneeing or

genu recurvatum)

Knee extensor muscles

Inability to walk with heels touching

the floor (toe walking)

Shortening of the Achilles tendon

Inability to lift foot while walking

(steppage gait or foot drop)

Anterior compartment of leg

Inability to walk without a waddling

gait

Hip muscles

Inability to get up from the floor without

climbing up the extremities (Gowers’

sign)

Hip, thigh, and trunk muscles

Inability to get up from a chair without

using arms

Hip muscles

relax after an active muscle contraction. The EMG shows electrical

silence. Confusion is created because contracture also refers to a

muscle that cannot be passively stretched to its proper length (fixed

contracture) because of fibrosis. In some muscle disorders, especially in

Emery-Dreifuss muscular dystrophy (EDMD) and Bethlem myopathy,

fixed contractures occur early and represent distinctive features of the

disease.

Myotonia is a condition of prolonged muscle contraction followed

by slow muscle relaxation. It always follows muscle activation (action

myotonia), usually voluntary, but may be elicited by mechanical stimulation (percussion myotonia) of the muscle. Myotonia typically causes

difficulty in releasing objects after a firm grasp. In myotonic muscular

dystrophy type 1 (DM1), distal weakness usually accompanies myotonia, whereas in DM2, proximal muscles are more affected. Myotonia

also occurs with myotonia congenita (a chloride channel disorder), but

in this condition, muscle weakness is not prominent. Myotonia may

also be seen in individuals with sodium channel mutations (hyperkalemic periodic paralysis or potassium-sensitive myotonia). Another

sodium channelopathy, paramyotonia congenita (PC), also is associated

with muscle stiffness. In contrast to other disorders associated with

myotonia in which the myotonia is eased by repetitive activity, PC is

named for a paradoxical phenomenon whereby the myotonia worsens

with repetitive activity. Potassium-aggravated myotonia is an allelic

FIGURE 449-4 Gower sign showing a patient using his arms to climb up the legs in

attempting to get up from the floor.