Muscle Disorders

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Chapter 6 Muscle Disorders

The clinical evaluation can usually distinguish disorders of muscle from those of the central nervous system (CNS) and peripheral nervous system (PNS) (Table 6-1). It can then divide muscle disorders into those of the neuromuscular junction and those of the muscles themselves, myopathies (Box 6-1). Surprisingly, considering their physiologic distance from the brain, several muscle disorders are associated with mental retardation, cognitive decline, personality changes, or use of psychotropic medications.

TABLE 6-1 Signs of Central Nervous System (CNS), Peripheral Nervous System (PNS), and Muscle Disorders

^*Hemiparesis, paraparesis, etc.

Neuromuscular Junction Disorders

Myasthenia Gravis

Neuromuscular Transmission Impairment

Normally, the presynaptic neuron at the neuromuscular junction releases discrete amounts – packets or quanta – of acetylcholine (ACh) across the neuromuscular junction to trigger a muscle contraction (Fig. 6-1). After the muscle contraction, acetylcholinesterase (AChE) (or simply “cholinesterase”) metabolizes ACh.

FIGURE 6-1 At the neuromuscular junction, the peripheral nerve endings contain discrete packets or quanta of acetylcholine (ACh) (dark blue). In response to stimulation, presynaptic neurons release about 200 ACh packets. They cross the synaptic cleft of the neuromuscular junction to reach ACh receptor-binding sites, situated deeply in convolutions of the postsynaptic membrane. ACh–receptor interactions open cation channels, thereby inducing an end-plate potential. If this potential reaches a certain magnitude, it triggers an action potential along the muscle fiber. Action potentials open calcium storage sites, which produce muscle contractions.

In myasthenia gravis, the classic neuromuscular junction disorder, ACh receptor antibodies block, impair, or actually destroy ACh receptors (Fig. 6-2). These antibodies predominantly attack ACh receptors located in the extraocular, facial, neck and proximal limb muscles. When binding to antibody-inactivated receptors, ACh produces only weak, unsustained muscle contractions. Another characteristic of the ACh receptor antibodies is that they attack only nicotinic ACh – not muscarinic ACh – receptors. Moreover, they do not penetrate the blood–brain barrier and do not interfere with CNS function. In contrast, they readily pass through the placenta and cause transient myasthenia symptoms in neonates of mothers with myasthenia gravis.

FIGURE 6-2 In myasthenia gravis, acetylcholine (ACh) receptors become abnormally shallow and lose many of their binding sites. The synaptic cleft widens, which further impedes neuromuscular transmission.

In approximately 80% of myasthenia gravis cases, the serum contains ACh receptor antibodies. In one-half of the remainder, the serum has antibodies to antimuscle-specific kinase (MuSK).

Standard treatments for myasthenia gravis attempt either to increase ACh concentration at the neuromuscular junction or restore the integrity of ACh receptors. To increase ACh concentration by slowing its metabolism, neurologists typically prescribe cholinesterase inhibitors or simply anticholinesterases, such as pyridostigmine (Mestinon). If patients cannot swallow, neurologists usually order intravenous or intramuscular neostigmine (Prostigmin). By increasing ACh activity, cholinesterase inhibitors increase muscle strength.

In the other therapeutic strategy – restoring the integrity of ACh receptors – neurologists administer steroids, other immunosuppressive medications, plasmapheresis, or intravenous infusions of immunoglobulins (IVIG). (Neurologists also infuse IVIG in Guillain–Barré syndrome [see Chapter 5], a commonly occurring inflammatory PNS illness.)

Other illnesses and some medications may also impair ACh neuromuscular transmission and cause weakness. For example, botulinum toxin, as both a naturally occurring food poison and a medication, blocks the release of ACh packets from the presynaptic membrane and causes paresis (see later).

At the postsynaptic side of the neuromuscular junction, the muscle relaxant succinylcholine binds to the ACh receptors. With their ACh receptors inactivated, muscles weaken to the point of flaccid paralysis. Succinylcholine, which resists cholinesterases, has a paralyzing effect that last for hours. It facilitates major surgery and electroconvulsive therapy (ECT).

ACh, unlike dopamine and serotonin, serves as a transmitter at both the neuromuscular junction and the CNS. Also, metabolism instead of reuptake almost entirely terminates its action. Antibodies associated with myasthenia gravis impair neuromuscular junction but not CNS ACh transmission: One reason is that neuromuscular ACh receptors are nicotinic, but cerebral ACh receptors are mostly muscarinic (see Chapter 21).

Physicians caring for myasthenia gravis patients who have almost complete paralysis but normal cognitive status see the stark contrast between impaired neuromuscular junction activity but preserved CNS ACh activity. Similarly, most anticholinesterase medications have no effect on cognitive status or other CNS function because they do not penetrate the blood–brain barrier. One of the few exceptions, physostigmine, penetrates into the CNS where it can preserve ACh concentrations. Thus, researchers proposed physostigmine as a treatment for conditions with low CNS ACh levels, such as Alzheimer disease. However, in various experiments with Alzheimer disease, despite increasing cerebral ACh concentrations, physostigmine produced no clinical benefit (see Chapter 7).

Clinical Features

Myasthenia gravis has a signature: weakness of the ocular motility (oculomotor), facial, and bulbar muscles that is asymmetric and fluctuating. The susceptibility of those muscles and the asymmetry remain unexplained. However, the weakness, at least in the initial months of the illness, varies in almost a diurnal pattern because exertion weakens muscles and thus symptoms appear predominantly in the late afternoon or early evening as well as after vigorous activities. Rest and sleep temporarily restore strength.

As their first symptom, almost 90% of patients, who are typically young women or older men, develop diplopia and ptosis. When facial and neck muscle weakness emerges, a nasal tone suffuses patients’ speech and, when attempting to smile, they grimace (Fig. 6-3). These patients have significant trouble whistling and chewing. Neck, shoulder, and swallowing and respiratory muscles weaken as the disease progresses, i.e., myasthenia gravis causes bulbar palsy (see Chapter 4). In severe cases, patients suffer respiratory distress, quadriplegia, and an inability to speak (anarthria). Paralysis can spread and worsen so much that patients reach a “locked-in” state (see Chapter 11).

FIGURE 6-3 Left, This young woman described several weeks of intermittent double vision and nasal speech. She had left-sided ptosis and bilateral, asymmetric facial muscle weakness, evident in the loss of the contour of the right nasolabial fold and sagging lower lip. Right, Intravenous administration of the cholinesterase inhibitor edrophonium (Tensilon) 10 mg – the Tensilon test – produces a 60-second restoration of eyelid, ocular, and facial strength. This typically brief but dramatic restoration of her strength resulted from edrophonium transiently inhibiting cholinesterase to increase acetylcholine activity.

Absence of certain findings is equally important. Again, in contrast to the physical incapacity, neither the disease nor the medications directly produce changes in mentation or level of consciousness. In addition, although extraocular muscles weaken, intraocular muscles remain strong. Thus, patients may have complete ptosis and no eyeball movement, but their pupils are normal in size and reactivity to light. Another oddity is that, even though patients may be quadriparetic, bladder and bowel sphincter muscle strength will remain normal. Of course, as in muscle disorders, myasthenia does not impair sensation.

Although patients with myasthenia gravis most often have spontaneously occurring exacerbations, intercurrent illnesses, such as pneumonia, or psychologic stress may precipitate them. In addition, about 40% of pregnant women with myasthenia gravis undergo exacerbations, which occur with equal frequency during each trimester. On the other hand, about 30% of pregnant women with myasthenia gravis enjoy a remission.

Neurologists usually attempt to confirm a clinical diagnosis of myasthenia by performing a Tensilon (edrophonium) test (see Fig. 6-3). Alternatively, they perform the “ice cube test,” which presumably temporarily uncouples toxic antibodies from ACh receptors and, like the Tensilon test, briefly reverses ptosis in myasthenia. They test for serum antibodies to ACh receptors and, in certain circumstances, antibodies to MuSK. They may also perform an electromyogram (EMG). About 5% of patients have underlying hyperthyroidism and 10% have a mediastinal thymoma. If these conditions are present and respond to treatment, myasthenia gravis will usually improve.

Differential Diagnosis

Lesions of the oculomotor nerve (cranial nerve III), which may be a sign of a midbrain infarction (see Fig. 4-9) or nerve compression by a posterior communicating artery aneurysm, also cause extraocular muscle paresis. In addition to their usually having an abrupt and painful onset, these lesions are identifiable by a subtle finding: the pupil will be widely dilated and unreactive to light because of intraocular (pupillary) muscle paresis (see Fig. 4-6). In addition, many other illnesses cause facial and bulbar palsy: amyotrophic lateral sclerosis (ALS), Guillain–Barré syndrome, Lyme disease, Lambert–Eaton syndrome, and botulism.

Lambert–Eaton Syndrome

As in myasthenia, impaired ACh neuromuscular transmission causes weakness in the Lambert–Eaton syndrome and botulism. The major physiologic distinction is that myasthenia results from a disorder of postsynaptic receptors, but Lambert–Eaton and botulism result from impaired release of presynaptic ACh packets.

Lambert–Eaton and botulism also differ in their etiology and, to a certain extent, their clinical manifestations. A toxin causes botulism, but an autoimmune disorder, by directing antibodies against voltage-gated calcium channels, causes Lambert–Eaton. This autoimmune disorder, in turn, is frequently an expression of small cell carcinoma of the lung and occasionally a component of a rheumatologic illness. When associated with any cancer, neurologists consider Lambert–Eaton a paraneoplastic syndrome (see Chapter 19).

Although Lambert–Eaton and myasthenia both cause weakness, Lambert–Eaton first causes weakness of the limbs, but myasthenia first causes extraocular, head, and neck weakness. Moreover, repetitive exertion temporarily corrects Lambert–Eaton-induced weakness, presumably by provoking presynaptic ACh release, but any exertion exacerbates myasthenia-induced weakness. In addition, Lambert–Eaton, unlike myasthenia, causes autonomic nervous system dysfunction. Because of Lambert–Eaton patients’ autonomic dysfunction, they may also have a sluggish or absent pupillary light reflex, which would unequivocally set them apart from myasthenia patients.

Botulism

Unlike Lambert–Eaton, botulism is an infectious illness that usually results from eating contaminated food. Most often, improperly preserved food has allowed the growth of Clostridium botulinum spores that elaborate a toxin with a predilection for the presynaptic neuromuscular membrane. (Experts fear that terrorists might inject these spores into commercial food manufacturing processes, such as milk pasteurizing, to create mass poisonings.)

Botulism victims develop oculomotor, bulbar, and respiratory paralyses that resemble the Guillain–Barré syndrome as well as myasthenia gravis. However, in contrast to the course of these illnesses, botulism symptoms arise explosively and include dilated unreactive pupils.

A unique feature of botulism, which prompts a life-saving diagnosis, is that often several family members simultaneously develop nausea, vomiting, diarrhea, and fever, and then the distinctive weakness with fixed pupils 18–36 hours after sharing a meal. Botulism, as well as tetanus (see later), may also complicate drug abuse that involves shared, contaminated needles. It develops in infants fed unpasteurized (raw) honey or corn syrup that harbors the infective spores. By way of treatment, which often requires intubation and ventilatory support, physicians administer antibiotics and a botulism antitoxin (botulinum immunoglobulin).

Ironically, neurologists now routinely turn botulinum-induced paresis to an advantage. They inject pharmaceutically prepared botulinum toxin to alleviate focal dystonias and dyskinesias, such as blepharospasm, spasmodic torticollis, and writer’s cramp (see Chapter 18). Even more ironically, numerous physicians and nonphysicians routinely inject pharmaceutically prepared botulinum toxin into the paper-thin muscles underlying furrows to smooth patients’ skin.

Tetanus

A different Clostridium species elaborates the neurotoxin that causes tetanus. In this illness, the toxin from Clostridium tetani predominantly blocks presynaptic release – not of ACh, but of the CNS inhibitory neurotransmitters, gamma-aminobutyric acid (GABA) and glycine. The disease deprives patients of the normal inhibitory influence on their brain and spinal cord motor neurons. Uninhibited muscle contractions cause trismus (“lockjaw”), facial grimacing, an odd but characteristic smile (“risus sardonicus”), and muscle spasms in the limbs. The muscle contractions may be so violent that bursts of spasms mimic seizures, which neurologists term “tetanic convulsions.”

Drug addicts, who share infected needles, and workers in farming and scrap metal recovery contract tetanus. When abortion was illegal, tetanus as well as other often fatal infections complicated the procedure.

Although acutely developing facial, jaw, trunk, and limb spasms are indicative of tetanus, dopamine-blocking medications commonly produce similarly appearing dystonic reactions. Thus, psychiatrists must not blindly attribute all facial and jaw spasms to dystonic reactions. The differential diagnosis of such spasms includes strychnine poisoning, rabies, heatstroke, and head and neck infections as well as tetanus and dystonic reactions.

In fact, strychnine poisoning allows for an interesting comparison to tetanus. Lack of inhibitory neurotransmitter activity in both conditions underlies muscle spasms. One minor difference is that strychnine does not lead to trismus. The major difference is that tetanus results from impaired presynaptic release of the inhibitory neurotransmitters GABA and glycine, but strychnine results from its antagonizing these same inhibitory neurotransmitters at their postsynaptic receptors.

Nerve Gas and Other Wartime Issues

Most common insecticides are organophosphates that bind and inactivate AChE. With inactivation of its metabolic enzyme, ACh accumulates and irreversibly depolarizes postsynaptic neuromuscular junctions. After insecticides cause initial muscle contractions and fasciculations, they lead to paralysis of respiratory and other muscles. For example, malathion (Ovide), the common shampoo for head lice, irreversibly inhibits AChE. It is safe as a shampoo because so little penetrates through the skin.

On the other hand, people committing suicide, especially in India, often deliberately drink organophosphate pesticides. Similarly, the nerve gases that threatened soldiers from World War I through the Persian Gulf War bind and inactivate AChE. The common ones – GA, GB, GD, and VX – affect both the CNS and PNS. Some are gaseous, but others, such as sarin (GB), the Tokyo subway poison, are liquid. Several investigators postulated that pyridostigmine caused neurologic symptoms of the “Gulf War syndrome” (see Chapter 5); however, they provided no direct evidence and patients with myasthenia take pyridostigmine for decades with no such untoward effects.

Accumulation of ACh from poison gas or pyridostigmine toxicity in myasthenia patients causes a cholinergic crisis. Its initial features – tearing, pulmonary secretions, and miosis – reflect excessive cholinergic (parasympathetic) activity. If the poisons penetrate the CNS, excess ACh causes convulsions, rapidly developing unconsciousness, and respiratory depression.

Medical personnel will ideally receive a warning and be able to provide pretreatment. They might administer pyridostigmine, which is a reversible AChE inhibitor, as a prophylactic agent because it occupies the vulnerable site on AChE and thereby protects it from irreversible inhibition by the toxin. After nerve gas exposure or liquid ingestion, first aid consists of washing exposed skin with dilute bleach (hypochlorite). Also after exposure, field forces administer oximes because they reactivate AChE and detoxify organophosphates, and atropine because it is a competitive inhibitor of ACh and blocks the excessive cholinergic activity. In view of a high incidence of seizures, depending on the exposure, field forces also often administer a benzodiazepine. Other antiepileptic drugs are ineffective in this situation.

Survivors of nerve gas poisonings often report developing headaches, personality changes, and cognitive impairment, especially in memory. Their symptoms often mimic those of posttraumatic stress disorder.

Agent Orange, the herbicide sprayed extensively in Southeast Asia during the Vietnam War, allegedly produced cognitive impairment, psychiatric disturbances, and brain tumors. Although large scientific reviews found no evidence that it actually caused any of those problems, advocacy groups have prodded Congress into accepting a causal relationship.

Veterans with the more recent counterpart, Persian Gulf War syndrome, also described varied symptoms, including fatigue, weakness, and myalgias (painful muscle aches). Again, exhaustive studies have found no consistent, significant clinical sign or laboratory evidence of any neurologic disorder. One theory had been that, in anticipation of a nerve gas attack, soldiers had been ordered to take a “neurotoxic” antidote (pyridostigmine); however, numerous myasthenia gravis patients had been taking it for decades without such adverse effects.

The notion that silicone toxicity from breast implants causes a neuromuscular disorder and other neurologic illness, which is also unfounded, is discussed in the differential diagnosis of multiple sclerosis (see Chapter 15).

Chronic Fatigue Syndrome and Fibromyalgia

Myasthenia gravis and other neurologic disorders are sometimes unconvincingly invoked as an explanation of one of the most puzzling clinical problems: chronic fatigue syndrome. Individuals with this condition typically describe not only a generalized sense of weakness, sometimes preceded by myalgias and other flu-like symptoms, but also impaired memory and inability to concentrate. For physicians familiar with classic psychosomatic illnesses, chronic fatigue syndrome harkens back to asthenia, which involves chronic weakness and dyspnea but no objective findings.

Regardless of whether chronic fatigue syndrome constitutes a distinct entity, several well-established illnesses may induce unequivocal fatigue, sometimes accompanied by cognitive impairment: Lyme disease, acquired immunodeficiency syndrome (AIDS), mononucleosis, multiple sclerosis, sleep apnea and other sleep disturbances, and eosinophilia-myalgia syndrome. In addition, simple deconditioning from limited physical activity, including weightless space travel and confinement to a hospital bed, frequently causes weakness and loss of muscle bulk.

Fibromyalgia, a cousin of chronic fatigue syndrome, consists of entirely subjective symptoms: chronic, widespread pain, and multiple tender points. Despite patients having prominent myalgia, they have no objective evidence of muscle inflammation (myositis) or any other specific abnormality. Numerous individuals fulfilling the criteria for fibromyalgia also have equally amorphous disorders, such as irritable bowel syndrome, atypical chest pain, and transformed migraine.

Muscle Disease (Myopathy)

Myopathies have a predilection for the shoulder and hip girdle muscles. They strike these large, “proximal” muscles first, most severely, and often exclusively. Patients have difficulty performing tasks that require these muscles, such as standing, walking, climbing stairs, combing their hair, and reaching upward. Even with profound weakness, patients usually retain strength in their oculomotor, sphincter, and hand and feet muscles. (Hand and feet muscles are “distal” and more subject to neuropathies than myopathies.)

Acute myositis leads to myalgias and tenderness. Eventually in the course of their illnesses, both inflammatory and noninflammatory myopathies cause muscle weakness and atrophy (dystrophy). Deep tendon reflexes may remain normal but usually lose reactivity roughly in proportion to their weakness. Patients lack Babinski signs and sensory loss because the corticospinal and sensory tracts remain uninvolved. With most myopathies, serum concentrations of muscle-based enzymes, such as creatine kinase (CK), which neurologists previously called creatine phosphokinase, and aldolase rise and EMGs show abnormalities. Finally, with a few exceptions (see later), myopathies do not induce mental disorders.

Steroids are helpful and probably remain the first choice in treatment of inflammatory myopathies. Other nonspecific immunosuppressants, such as azathioprine, are the second-line therapy. However, monoclonal antibody medications, such as rituximab, promise to revolutionize the treatment of myositis and other inflammatory conditions.

Inherited Dystrophies

Duchenne Muscular Dystrophy

Better known simply as muscular dystrophy, Duchenne muscular dystrophy is the most frequently occurring childhood-onset myopathy. Beginning in childhood, the illness follows a chronic, progressively incapacitating, and ultimately fatal course. It is a sex-linked genetic illness, but about 30% of cases represent a de novo mutation. Although women who carry the abnormal gene may have some subtle findings and laboratory abnormalities, for practical purposes, Duchenne muscular dystrophy is restricted to boys.

Dystrophy typically first affects boys’ thighs and shoulders. The first symptom to emerge is their struggle to stand and walk. Subsequently, even though drastically weak, muscles paradoxically increase in size because fat cells and connective tissue infiltrate them (muscle pseudohypertrophy, Fig. 6-4, top). Instinctively learning Gowers’ maneuver (Fig. 6-4, bottom), boys with the illness arise from sitting only by pulling or pushing themselves upward on their own legs. Usually by age 12 years, when their musculature can no longer support their maturing frame, adolescent boys become wheelchair-bound and eventually develop respiratory insufficiency.

FIGURE 6-4 Top, This 10-year-old boy with typical Duchenne muscular dystrophy has a waddling gait and inability to raise his arms above his head because of weakness of his shoulder and pelvic girdle muscles, i.e., his proximal muscles. His weakened calf muscles show enlargement (pseudohypertrophy) not from exercise but from fat and connective tissue infiltration. He also has exaggeration of the normal inward curve of the lumbar spine, hyperlordosis. Bottom, Gowers’ maneuver, an early sign of Duchenne muscular dystrophy, consists of a young victim pushing his hands against his knees then thighs to reach a standing position. He must use his arms and hands because the disease primarily weakens hip and thigh muscles that normally would be sufficient to allow him to stand.

Psychomotor retardation and an average IQ approximately one standard deviation below normal typically accompany muscular dystrophy. This intellectual impairment is greater than with comparable chronic illnesses and, while stable, often overshadows the weakness. Of course, isolation, lack of education, and being afflicted with a progressively severe handicap account for psychologic and social, as well as cognitive, deficits. Depression typically begins when the boys’ illnesses first confines them to a wheelchair.

No cure is available, but proposed corrective treatments include transplantation of muscle cells (myoblast transfer) and gene therapy. Steroids may delay the illness’ progression for as long as 2 years.

Another feature, caused by facial and temple muscle atrophy, is a sunken and elongated face, ptosis, and a prominent forehead. This distortion forms the distinctive “hatchet face” (see Fig. 6-5). Additional neurologic and nonneurologic manifestations vary. Patients often develop cataracts, cardiac conduction system disturbances, and endocrine organ failure, such as testicular atrophy, diabetes, and infertility. Treatment is limited to replacement of endocrine deficiencies and, by giving phenytoin, quinine, or other medicines, to reducing myotonia.

Contrasting somewhat with the nonprogressive cognitive impairment of Duchenne dystrophy, patients with myotonic dystrophy almost uniformly show cognitive impairment that increases with age. In addition, lack of initiative and progressive blandness characterize patients’ personalities.

Genetics

The genetic basis of myotonic dystrophy, as well as several other neurologic illnesses, is an excessive repetition of a particular nucleotide base triplet (trinucleotide repeat) in a DNA gene mutation. In the case of myotonic dystrophy, the trinucleotide base CTG is excessively repeated in chromosome 19. The mutation leads to myotonic dystrophy’s transmission as an autosomal dominant genetic disorder. In addition, because the mutation alters ion channels in the membranes of muscle and other organ cells, neurologists refer to myotonic dystrophy as a channelopathy.

Other disorders that result from different excessive trinucleotide repeats include ones that are inherited in an autosomal recessive pattern (Friedreich ataxia), autosomal dominant pattern (spinocerebellar atrophies and Huntington disease), and sex-linked pattern (fragile X syndrome) (see Chapters 2, 13, and 18, and the Appendix). Whichever the particular trinucleotide base repeat and pattern of inheritance, physicians can easily and reliably diagnose these illnesses in symptomatic and asymptomatic individuals by testing DNA in their white blood cells.

Illnesses in this group have several features that stem from the expanded trinucleotide repeats. The severity of the symptoms is roughly proportional to the length of the repeats. For example, myotonic dystrophy patients with 50–100 trinucleotide repeats have mild and incomplete manifestations of the disorder; those with 100–1000 have, to a greater or lesser degree, all the manifestations; and those with more than 2000 show florid involvement that is often present in infancy.

Another characteristic of trinucleotide disorders is that sperm are more likely than eggs to increase their DNA repeats – as if sperm DNA were more genetically unstable than egg DNA. Thus, in these illnesses, children who have inherited the abnormal gene from their father, rather than from their mother, develop symptoms at a younger age and eventually in a more severe form. Similarly, fathers are more apt than mothers to pass along severe forms of the illness.

In addition, when transmitted from parent to child, trinucleotide repeat sequences tend to expand further rather than self-correcting. Neurologists term the trinucleotide sequences’ tendency toward greater genetic abnormality and more pronounced symptoms amplification.

A clinical counterpart of amplification is anticipation: successive generations of individuals who inherit the abnormal gene show signs of the illness at a progressively younger age. For example, a grandfather may not have been diagnosed with myotonic dystrophy until he was 38 years old. At that age, he already had an asymptomatic boy and girl who both carried the gene. The son and daughter typically would not show signs of the illness until they reached 26 years; however, by then, they might each have had several of their own children. Anticipation would be further apparent when affected grandchildren show signs in their teenage years. In the classic example, Huntington disease, dementia appears earlier in life and more severely in successive generations, especially when the father has transmitted the abnormal gene (see Chapter 18).

Indications of myotonic dystrophy and other trinucleotide repeat disorders appearing in progressively younger individuals in a family are due to the earlier emergence of the symptoms in successive generations. Their appearance is not due simply to a heightened vigilance for the condition. In contrast, an apparent increase in incidence resulting from closer scrutiny is an epidemiologic error, called ascertainment bias.

A less frequently occurring variety of myotonic dystrophy, myotonic dystrophy type 2 or proximal myotonic myopathy, has a phenotype that differs only slightly from the common myotonic dystrophy type 1. However, it has several unique genetic features: the mutation consists of a four-repeat nucleotide (a “quad” repeat); the genotype and phenotype do not correlate, and anticipation does not occur.

Inflammatory and Infectious Myopathies

Some infectious and inflammatory illnesses attack only muscles. These illnesses typically cause weakness and myalgias, as in the common “flu,” but rarely alter patients’ mental status.

Polymyositis is a nonspecific, generalized, inflammatory myopathy characterized by weakness, myalgias, and systemic symptoms, such as fever, and malaise. Neurologists term the disorder dermatomyositis if a rash – usually on the face and extensor surfaces of the elbows and knees – precedes or accompanies these symptoms. In children and many adults, a benign, self-limited systemic viral illness usually causes polymyositis. In other adults, polymyositis may be a manifestation of inflammatory diseases, such as polymyalgia rheumatica and polyarteritis nodosa.

A Trichinella infection of muscles, trichinosis, causes an infectious rather than a purely inflammatory myopathy. Victims usually develop this illness from eating undercooked pork or wild game. Thus, in the United States, hunters and recent immigrants from South and Central America are most liable to have ingested Trichinella and develop the characteristic muscle pains, fevers, and heliotrope rash.

The eosinophilia-myalgia syndrome, more of a toxic than an inflammatory disorder, results from ingesting tryptophan or tryptophan-containing products, which are usually taken by insomniacs and health food devotees. The eosinophilia-myalgia syndrome usually consists of several days of severe myalgias and a markedly elevated number and proportion of eosinophils in the blood. Patients often suffer from fatigue, rash, neuropathy, and cardiopulmonary impairments as well as from myalgias.

More than half the patients with eosinophilia-myalgia syndrome display mild depressive symptoms that cannot be correlated with their physical impairments, eosinophil concentration, or concurrent psychiatric disorders. Physicians may mislabel these patients as having chronic fatigue syndrome because of their variable symptoms and, except for the eosinophilia, lack of objective findings.

AIDS myopathy, associated with human immunodeficiency virus (HIV), also causes myalgia, weakness, weight loss, and fatigue. In most patients, the myopathy results from an infection with HIV. However, in some patients, moderate to large doses of zidovudine (popularly known as AZT) seem to be partly or totally responsible for the myopathy. In these cases, muscle biopsies often disclose abnormalities in mitochondria and withdrawing the offending medicine usually leads to at least partial improvement.

Metabolic Myopathies

With the major exception of mitochondrial myopathies inducing combinations of muscle and cerebral impairments (see later), muscle metabolism is usually independent of cerebral metabolism. For example, prolonged steroid treatment frequently produces proximal muscle weakness and wasting (steroid myopathy). It also causes a round face, acne, and an obese body with spindly limbs (“cushingoid” appearance). However, only in high doses can steroids routinely cause mood changes, agitation, and irrational behavior – loosely termed “steroid psychosis.” In fact, only patients with cerebral vasculitis, a brain tumor, or other disorder that compromises the CNS are particularly susceptible to steroid-induced mental changes.

Testosterone and other anabolic steroids, when taken in conjunction with exercising, can increase muscle size and strength. Athletes, most of whom are involved in organized sports, and body builders use this regimen to enhance their power and appearance. While deriving obvious benefits from the steroids, these individuals risk steroid myopathy, frequent depression, and occasionally steroid psychosis. Illicit steroid use is also associated with physical abuse of women.

An example of the delicate nature of muscle metabolism being notably independent of cerebral metabolism is that a low serum potassium concentration (hypokalemia) leads to profound weakness, hypokalemic myopathy, and cardiac arrhythmias, but no mental status changes. Hypokalemic myopathy is often an iatrogenic condition caused by administration of diuretics or steroids, which are sometimes surreptitiously self-administered. Psychiatrists are apt to encounter hypokalemia in patients with laxative abuse or alcoholic cirrhosis.

In contrast to hypokalemia, hyponatremia (sodium depletion) causes confusion, agitation, stupor, and seizures. Psychiatrists might encounter patients with hyponatremia and its complications because it results from compulsive water drinking; use of psychotropics, such as carbamazepine (Tegretol), oxcarbazepine (Trileptal), lithium, and selective serotonin reuptake inhibitors (SSRIs); traumatic brain injury; and numerous medical conditions.

A different disorder involving potassium metabolism is hypokalemic periodic paralysis, in which patients have dramatic attacks, lasting several hours to 2 days, of areflexic quadriparesis. During attacks of hypokalemia, patients remain alert and fully cognizant, breathing normally, and purposefully moving their eyes despite the widespread areflexic paralysis. Contrary to its label, periodic paralysis is irregular and not “periodic.” The attacks tend to occur spontaneously every few weeks, but exercise, sleep, or large carbohydrate meals often precipitate them. Although attacks resemble sleep paralysis and cataplexy (see Chapter 17), they are differentiated by a longer duration and hypokalemia. Hypokalemic periodic paralysis, sleep paralysis, and cataplexy all differ from psychogenic episodes by their areflexia.

Usually transmitted in an autosomal dominant pattern, hypokalemic periodic paralysis becomes apparent in adolescent boys. In most cases, it stems from a mutation in the calcium ion channel gene and represents another channelopathy. An adult-onset variety is associated with hyperthyroidism.

Other common metabolic myopathies are sometimes associated with mental status changes. For example, alcoholism leads to limb and cardiac muscle wasting (alcohol cardiomyopathy). In hyperthyroid myopathy, weakness develops as part of hyperthyroidism. Although the hyperthyroidism usually causes heat intolerance and hyperactivity, older individuals may have apathetic hyperthyroidism, in which signs of overactivity are remarkably absent. As a general rule, metabolic myopathies resolve when normal metabolism is restored.

Administration of atypical neuroleptics, particularly clozapine, as well as typical dopamine-blocking ones, causes a mostly asymptomatic elevation of CK serum concentrations. In as many as 10% of patients with acute psychosis, the CK concentration increases to fivefold or greater levels. Physicians might find that medication injections, excessive physical activity, or subclinical neuroleptic-induced parkinsonism or dystonia (see Chapter 18) are responsible for this elevation. An asymptomatic, isolated, mild to moderate CK elevation should not automatically trigger a diagnosis of neuroleptic-malignant syndrome (see below); however, physicians should assess the patient for other parameters of muscle breakdown and repeat the CK determination in 48 hours.

Antidepressants and amphetamines may also cause an innocuous increase in the serum CK concentration. Similarly, about 10% of individuals taking cholesterol-lowering statins have myalgia and modest elevations in serum CK concentrations. In a more serious adverse reaction, these medicines occasionally and unpredictably cause acute, catastrophic muscle breakdown and marked elevation in serum CK concentrations (cholesterol-lowering agent myopathy). Patients with hypercholesterolemia must take a statin for an average of 6 months before this more severe myopathy may appear.

Mitochondrial Myopathies

Mitochondria utilize cytochrome c oxidase and related enzymes for oxidative phosphorylation (respiratory, aerobic chain system). This metabolic system supplies about 90% of the body’s energy requirement, mostly in the form of adenosine triphosphate (ATP). In turn, the brain is the body’s greatest energy consumer. Other high-energy consumers are cardiac, skeletal, and extraocular muscles.

When they generate energy, mitochondria must constantly remove free radicals, which are highly toxic metabolic byproducts. Failure to remove them may lead to Parkinson disease and other illnesses (see Chapter 18).

Although vital, mitochondria’s energy-producing enzymes are delicate and easily poisoned. For example, cyanide rapidly and irreversibly inactivates the respiratory enzymes. With loss of aerobic metabolism in the brain, as well as in other organs, individuals exposed to cyanide almost immediately lose consciousness and then succumb to brain death. Cyanide has been used for executions in gas chambers and taken by individuals committing suicide, including the several hundred cultists in the murder/suicide massacre in Jonestown, Guyana, in 1978. Also, certain medications, through a side effect, damage mitochondria. For example, nucleoside analogs used to treat HIV infection interfere with the mitochondria’s enzyme chain and thus cause weakness and lactic acidosis.

In a group of illnesses, inherited abnormalities in the DNA of mitochondria disrupt their function. Mitochondrial DNA (mtDNA) differs significantly from chromosomal DNA (nuclear DNA [nDNA]). In contrast to nDNA, which is derived equally from each parent and arranged in familiar pairs, mtDNA is derived entirely from the mother, double-stranded but ring-shaped, and able to carry only 37 genes. It comprises 1% of total cellular DNA. As normal individuals age, they accumulate mutations in mtDNA that are responsible for some age-related changes in the muscles and brain.

Another difference between nDNA and mtDNA is that mtDNA is passed to daughter cells’ mitochondria in random, variable mixtures. The daughter cells’ mitochondria inherit variable proportions of normal and abnormal mtDNA. When the proportion of abnormal mtDNA reaches a certain level, the threshold effect, ATP production becomes insufficient for cellular function and symptoms ensue. The variable proportion of normal and abnormal mtDNA in single cells, heteroplasmy (Fig. 6-6), explains why organs typically have variable proportion of abnormal cells and the illnesses’ variable age of onset and clinical features.

FIGURE 6-6 Heteroplasmy. A, Sperm and egg nuclei each contain an equal complement of chromosomal DNA (nDNA). Sperm mitochondria, containing different DNA (mtDNA), power the flagella. B, After fertilizing an egg and transferring their nDNA to the egg’s nucleus, sperm drop away with their mitochondria and mtDNA intact. Thus, sperm mtDNA, whether mutant or wild (normal), does not enter the fertilized egg. The fertilized egg’s chromosomes undergo mitosis, resulting in equal distribution of nDNA into the two daughter cells. C, Chromosomes divide and distribute nDNA, with or without mutations, equally to daughter cells. In contrast, although mitochondria also duplicate, they do not segregate equally. If mtDNA contains mutations, daughter cells receive unequal distributions of mutant mtDNA. D, The nonrandom, non-Mendelian distribution of mitochondria and their mtDNA in daughter cells ultimately gives different organs variable proportions of mtDNA. Heteroplasmy is defined as the mixture of mitochondria, in a single cell, that contains mutant and normal mtDNA.

A different cause of mitochondria dysfunction is that mutations and other abnormalities in nDNA can impair mtDNA. For example, mutations in nDNA that influence mtDNA probably account for many of the problems underlying Wilson disease (see Chapter 18) and Friedreich ataxia (see Chapter 2). The influence of nDNA on mtDNA can explain why paternally inherited abnormal nDNA can cause malfunction of mtDNA. Moreover, it can explain how a father might transmit an illness characterized by mitochondrial dysfunction to his child.

When they occur, mtDNA abnormalities typically produce mitochondrial myopathies, which are inherited illnesses characterized by combinations of impaired muscle metabolism, brain damage, other organ system impairment, and abnormal lipid storage. Muscles, which are almost always included in the multisystem pathology, are filled by vastly increased number of mitochondria. With special histologic stains, many mitochondria appear as ragged-red fibers. In addition, normal respiratory enzymes, such as cytochrome c oxidase, are absent in many cells. The inheritance patterns of the mitochondrial myopathies do not follow Mendelian patterns, such as autosomal dominance, but reflect the vagaries of mitochondria’s maternal transmission, nDNA influence, heteroplasmy, and the threshold effect.

The primary mitochondrial myopathies, which result from mitochondria having deficiencies in cytochrome oxidase or other enzymes, cause weakness and exercise intolerance, short stature, epilepsy, deafness, and episodes of lactic acidosis. Another group of mitochondrial myopathies, progressive ophthalmoplegia and its related disorders, cause ptosis and other extraocular muscle palsies along with numerous nonneurologic manifestations, such as retinitis pigmentosa, short stature, cardiomyopathy, and endocrine abnormalities. One mitochondrial DNA disorder, Leber optic atrophy, causes hereditary optic atrophy in young men (see Chapter 12).

The best-known subgroup of mtDNA disorders, mitochondrial encephalopathies, typically causes progressively severe or intermittent mental status abnormalities that usually appear between infancy and 12 years. Children with one of these illnesses typically have mental retardation, progressive cognitive impairment, or episodes of confusion leading to stupor. In other words, mitochondrial disorders cause dementia or intermittent delirium in children. They can also cause paresis of extraocular muscles, psychomotor retardation or regression, migraine-like headaches, and optic atrophy.

Dysfunction of mitochondrial respiration characteristically leads to lactic acidosis either constantly or only during attacks. (Cyanide poisoning, because it poisons mitochondria, also leads to lactic acidosis.) In mitochondrial encephalopathies, muscle biopsies show ragged-red fibers, which represent accumulation of massive numbers of mitochondria, and a checkerboard pattern of cells that fail to stain for cytochrome c oxidase.

Mitochondrial encephalopathies include two important varieties known best by their colorful acronyms:

• MELAS: mitochondrial encephalomyelopathy, lactic acidosis, and strokelike episodes

• MERRF: myoclonic epilepsy and ragged-red fibers.

Potential therapies for the mitochondrial disorders include coenzyme CoQ10, bone marrow transplantation, and, for affected women who wish to conceive, cytoplasmic transfer.

Neuroleptic Malignant Syndrome (NMS)

Neurologists and psychiatrists have classically attributed NMS to dopamine-blocking antipsychotic agents (neuroleptics), but, because neuroleptics are not its sole cause, some physicians have sought to change its name to the Parkinson hyperpyrexia or the central dopaminergic syndrome. Whatever its name, this syndrome consists of three elements:

1. Delirium and decreased level of consciousness

2. Extrapyramidal signs, especially muscle rigidity, tremors, and dystonic posturing

3. Autonomic hyperactivity with prominent tachycardia and, although not the first sign, high fever.

The muscle rigidity, which affects the trunk and appendicular muscles, is so powerful that muscles crush themselves. It is the syndrome’s most prominent feature and a life-threatening one because the crushing causes muscle necrosis (rhabdomyolysis), which liberates muscle protein (myoglobin) into the blood (myoglobinemia) and allows myoglobin to appear in the urine (myoglobinuria). With pronounced myoglobinemia, especially in dehydrated patients, myoglobin precipitates in the renal tubules and the kidneys fail.

Laboratory tests reflect this series of events. Myoglobinemia and myoglobinuria, accompanied by elevated concentration of serum CK, indicate rhabdomyolysis. If present, elevated blood urea nitrogen and creatinine concentrations suggest renal insufficiency, not just dehydration.

NMS typically also causes autonomic dysfunction with tachycardia and cardiovascular instability. It typically raises body temperature, sometimes to levels that damage the cerebral cortex. The mortality rate of NMS, not surprisingly, had been as high as 15–20%. However, with use of second- rather than first-generation antipsychotic agents, judicious use of all psychotropics, and awareness of this complication, the frequency, severity, and mortality of NMS have fallen.

Classical descriptions have portrayed NMS in agitated, dehydrated young men, but the syndrome has also occurred in children. Patients have most often received large doses of conventional, powerful first-generation antipsychotic agents that block dopamine D₂ receptors. Use of second-generation antipsychotic agents has led, less frequently, to essentially the same syndrome. Case reports have linked NMS to nonpsychotropic dopamine-blocking medications, such as metoclopramide (Reglan), and medications not known primarily as dopamine-blocking agents, such as fluoxetine and lithium.

Not only does actively blocking dopamine from its receptors cause NMS, but failing to maintain dopamine treatment or depleting dopamine storage granules also causes it. All these mechanisms halt dopamine activity. For example, abruptly withholding dopamine precursors, such as L-dopa (Sinemet), has precipitated NMS in Parkinson disease patients. Similarly, treatment with tetrabenazine, which depletes dopamine, has caused it.

Recommended treatment, aimed at restoring dopamine activity, has included administering L-dopa, which is a dopamine precursor; dopamine agonists, such as bromocriptine and apomorphine; or amantadine, which enhances dopamine activity (see Chapter 18). A complementary approach has been to administer dantrolene (Dantrium), which restores a normal intracellular calcium distribution. Several articles have proposed administering ECT, but the rationale and results have been unclear. In any case, physicians must provide fluids, antipyretics, and other supportive measures.

Other Causes of Rhabdomyolysis, Hyperthermia, and Altered Mental States

Serotonin Syndrome

The serotonin syndrome and NMS are both usually medication-induced and their primary features include delirium, often with agitation, and autonomic hyperactivity. By way of contrast, the serotonin syndrome characteristically presents with myoclonus, although sometimes tremulousness and clonus. In another difference, the serotonin syndrome causes only mild elevations in body temperature and CK serum concentration. Its features tend to be protean, variable in severity, and delayed in onset or prolonged.

Physicians usually attribute the serotonin syndrome to an accidental or deliberate excess ingestion of a serotoninergic medicine. Potential causes all increase serotonin or serotonin-like substances at the synapse through various mechanisms: serotonin precursors (such as tryptophan); provokers of serotonin release (ecstasy, amphetamine, and cocaine); serotonin reuptake inhibitors and tricyclic antidepressants; and serotonin agonists (sumatriptan and other triptans). Even cough suppressants, dietary supplements, and St. John’s wort increase serotonin concentrations enough to cause it.

Although large enough doses of one of these medicines may alone cause the syndrome, their administration to someone already taking a serotonin metabolism inhibitor, particularly a monoamine oxidase inhibitor (MAOI), or the addition of a second serotoninergic medicine more frequently precipitates the syndrome. Because serotoninergic medicines are so commonplace, the serotonin syndrome might follow use of serotonin reuptake inhibitors in a variety of neurologic illnesses with comorbid depression, such as Parkinson disease, migraines, and chronic pain. In particular, use of deprenyl or rasagiline, which are MAOIs, will theoretically place a depressed Parkinson disease patient given an SSRI at risk of developing the serotonin syndrome. Similarly, use of a triptan, which is a serotonin agonist for migraine treatment, in conjunction with an SSRI or MAOI, raises that possibility. However, even though the coadministration of a triptan and SSRI potentially causing the serotonin syndrome has been the subject of a Food and Drug Administration warning and the gist of many examination questions, neurologists in practice have been prescribing triptans to patients taking an SSRI without encountering significant problems.

After removing the responsible medicines, initial treatment for the serotonin syndrome should support vital functions and reduce agitation with benzodiazepines. Physicians might reverse some of the excessive CNS serotonin activity by using the serotonin 5-HT_2A antagonist, cyproheptadine. As a last resort, some authors have recommended chlorpromazine, which is also a serotonin antagonist.

Malignant Hyperthermia (MH)

MH, the disorder most often compared and contrasted to NMS, also leads to rhabdomyolysis, hyperthermia, brain damage, and death. In contrast to NMS, MH is precipitated by inhaled general anesthesia, such as halothane or sevoflurane, or the muscle relaxant succinylcholine. Its underlying cause is excessive calcium release by calcium channels. A vulnerability to MH is inherited as an autosomal disorder carried on chromosome 19. Thus, psychiatrists should review the family history of patients before they administer succinylcholine prior to ECT. If MH were to develop, dantrolene may be an effective treatment.

Other Causes

Although its mechanism of action probably differs, the main features of phencyclidine intoxication – muscle rigidity, high fevers, and confusion – closely mimic NMS.

Physicians also often include anticholinergic poisoning, along with NMS and the serotonin syndrome, in the differential diagnosis of patients with fever and agitated delirium. In addition to those manifestations, anticholinergic poisoning from medications, such as scopolamine, usually produces signs of excessive sympathetic activity, including mydriasis, dry skin, urinary retention, and absent bowel sounds. Physicians faced with a febrile, agitated patient may eliminate anticholinergic poisoning from consideration if the patient has either increased muscle tone or bladder and bowel hyperactivity.

With the appropriate history, physicians probably would not confuse CNS or systemic infections with NMS. The distinction between NMS and meningitis is the most difficult because both conditions cause delirium, fever, and nuchal rigidity. Finally, sometimes neurologists consider catatonia as a manifestation of psychiatric illness in the differential diagnosis of NMS because of the setting and increased muscle tone; however, its course and lack of major autonomic dysfunction set it apart (see Chapter 18).

Laboratory Tests

Nerve Conduction Studies

Nerve conduction studies (NCS) (Fig. 6-7) can determine the site of nerve damage, confirm a clinical diagnosis of polyneuropathy, and distinguish polyneuropathy from myopathy. In addition, they can help separate neuropathies that have resulted from loss of myelin, such as Guillain–Barré syndrome, in which the conduction velocities slow, from those that have resulted from axon damage, such as with chemotherapy, in which the amplitude is reduced.