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.

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.

Genetics

Because the absence or dysfunction of a crucial muscle cell membrane protein, dystrophin, causes Duchenne dystrophy, neurologists refer to this illness as a dystrophinopathy. About 75% of patients carry a mutation in the dystrophin gene – one of the largest genes in the human genome – located on the short arm of the X chromosome. In many cases, the illness arises from a new mutation rather than from an inherited one. Unlike the excessive trinucleotide repeat mutation underlying myotonic dystrophy and several other neurologic disorders (see later), the Duchenne dystrophy mutation usually consists of a DNA deletion. Genetic testing of blood samples for mutations in the dystrophin gene can diagnose not only individuals with signs of the illness but affected fetuses, females who carry the mutation (carriers), and young male carriers destined to develop the illness.

A diagnosis of Duchenne dystrophy can also be based on a muscle biopsy that shows little or no staining for dystrophin (the dystrophin test). With modern technology, needle biopsies rather than open surgical procedures provide sufficient tissue, but the procedure still involves injections, pain, and anxiety – especially in a child.

Becker Dystrophy

A relatively benign variant of Duchenne dystrophy, Becker dystrophy, results from a different mutation in the same gene. This mutation causes the production of dystrophin that is abnormal but retains some function. Individuals with Becker dystrophy, which is also a dystrophinopathy, have weakness that begins in their second decade and follows a slowly progressive course that is uncomplicated by cognitive impairment.

Myotonic Dystrophy

The most frequently occurring myopathy of adults is myotonic dystrophy. Although also an inherited muscle disorder, myotonic dystrophy differs in several respects from Duchenne dystrophy. The symptoms usually appear when individuals are young adults – 20–25 years – and both sexes are equally affected. Also, rather than having proximal muscle weakness and pseudohypertrophy, myotonic dystrophy patients develop facial and distal limb muscle weakness and atrophy. This pattern of dystrophy, while characteristic, is not unique.

Myotonic dystrophy is named for its clinical signature, myotonia, which is involuntary prolonged muscle contraction. Myotonia inhibits the release of patients’ grip for several seconds after shaking hands or grasping and turning a doorknob. Neurologists elicit this phenomenon by asking patients to make a fist and then rapidly release it. In addition, if the physician lightly taps a patient’s thenar (thumb base) muscles with a reflex hammer, myotonia causes a prolonged, visible contraction that moves the thumb medially (Fig. 6-5).

FIGURE 6-5 This 25-year-old man with myotonic dystrophy has the typically elongated, “hatchet” face caused by temporal and facial muscle wasting, frontal baldness, and ptosis. Because of myotonia, a percussion hammer striking his thenar eminence muscles precipitates a forceful, sustained contraction that draws in the thumb for 3–10 seconds. Myotonia also prevents him from rapidly releasing his grasp.

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.