Muscle Disorders

Neuromuscular Transmission Impairment

Normally, the presynaptic neuron at the neuromuscular junction releases discrete amounts—packets or quanta —of acetylcholine (ACh) into the neuromuscular junction. The neurotransmitter engages receptors on the muscle membrane to trigger a contraction ( Fig. 6.1 ). After the muscle contraction, acetylcholinesterase (AChE) (or simply “cholinesterase”) metabolizes ACh.

In myasthenia gravis (MG) , the classic neuromuscular junction disorder, antibodies against the ACh receptor block binding of ACh to the receptor, leading to development of weakness and respiratory difficulty. Other illnesses and some medications may also impair ACh transmission at the neuromuscular junction, although through different mechanisms, and cause the same problems. 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 lasts for hours. It facilitates major surgery and electroconvulsive therapy (ECT).

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

MG patients with almost complete paralysis but normal cognitive status illustrate the stark contrast between impaired neuromuscular junction ACh activity and preserved CNS ACh activity. Similarly, most anticholinesterase medications used to treat MG 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 preserves 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

MG has a signature: weakness of the ocular motility (oculomotor), facial, and bulbar muscles that is asymmetric and fluctuating. Neurologists always suspect neuromuscular junction disease when they elicit a history of this “fatiguing” weakness, and they frequently find it on physical examination. 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.

Almost 90% of patients, typically young women or older men, develop diplopia and ptosis as their first symptoms. When facial and neck muscle weakness emerges, a nasal tone suffuses patients’ speech, and they grimace when attempting to smile ( Fig. 6.3 ). These patients have significant trouble whistling and chewing. Neck, shoulder, swallowing, and respiratory muscles weaken as the disease progresses, that is, MG causes bulbar palsy (see Chapter 4 ). In severe cases, patients suffer respiratory distress, quadriplegia, and inability to speak (anarthria) . Paralysis can spread and worsen so much that patients reach a “locked-in” state (see Chapter 11 ).

Absence of certain findings is equally important. Again, compared 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 develop quadriparesis, their bladder and bowel sphincters’ strength remain normal. Of course, as in muscle disorders, MG does not impair sensation.

Although exacerbations of MG often occur spontaneously, about 40% of pregnant women with MG undergo exacerbations, which occur with equal frequency during each trimester. On the other hand, about 30% of pregnant women with MG enjoy a remission. Intercurrent illnesses, such as pneumonia, or psychologic stress may also precipitate a flare-up.

Notably, the SARS-CoV-2 (COVID-19) pandemic, which quickly spread across the globe beginning in 2020, caused severe MG exacerbations. The underlying pathophysiology was likely a combination of baseline patient immunosuppression, predilection of the virus to cause pneumonia, and an overwhelming inflammatory response to the infection. Additionally, initial medications used for treatment of COVID-19, particularly azithromycin and hydroxychloroquine, worsen MG symptoms, even in the absence of infection.

There are no known risks of COVID-19 vaccination specific to patients with MG or other neuromuscular disorders. However, patients who receive immunosuppressive therapy may have to adjust the timing of their vaccinations because treatments may transiently impair the efficacy of vaccinations. Neurologists have otherwise encouraged their patients to obtain the vaccine without delay.

Another newly described cause of myasthenia is an occasionally occurring adverse reaction to immune checkpoint inhibitor treatment for certain cancers (see Chapter 19 ). This iatrogenic disorder causes the same clinical features as common MG; however, it is often accompanied by inflammatory myocarditis. In a minority of these cases, the serum shows antibodies to ACh receptors (see later).

For decades, neurologists confirmed a clinical diagnosis of myasthenia by performing a “Tensilon Test” (see Fig. 6.3 ), which entailed an intravenous injection of the cholinesterase inhibitor edrophonium (Tensilon). However, because edrophonium often produces a sudden increase in systemic cholinergic activity, it caused bradycardia and other adverse effects. Neurologists sometimes perform the less risky ice pack test that presumably slows the kinetics of AChE and thereby improves neuromuscular transmission (see Fig. 6.3 , bottom ). Although both tests may produce dramatic improvements in facial or ocular mobility, the changes are brief, and the tests produce a substantial number of false-positive and false-negative results.

For a firm diagnosis, neurologists now rely on serum tests to detect antibodies to ACh receptors or, in certain circumstances, antibodies to MuSK. They may also perform repetitive nerve stimulation testing at low frequency. In this test, affected muscles characteristically show a decremental response by contracting less and less to the stimulation.

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 due to intraocular (pupillary) muscle paresis (see Fig. 4.6 ). In addition, many other neurologic illnesses cause facial and bulbar palsy: amyotrophic lateral sclerosis (ALS), botulism, Guillain-Barré syndrome, Lambert-Eaton syndrome, and Lyme disease, among others. Rarely, a patient will report the sudden onset of dysarthria, dysphagia, and diplopia and ultimately receive the diagnosis of conversion disorder.

Treatment

Standard treatments for MG attempt to either 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 long-acting 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, these medicines increase muscle strength.

In the other therapeutic strategy, restoring the integrity of ACh receptors, neurologists administer steroids, other immunosuppressive medications, plasmapheresis (plasma exchange), or intravenous infusions of immunoglobulins (IVIG). In refractory cases of MG, neurologists also use the synthetic monoclonal antibody rituximab (Rituxan), which binds to the CD20 antigen on B-cells. Rituximab depletes these cells and thereby suppresses the hyperimmune response that had caused the patient’s symptoms. Neurologists also infuse IVIG in Guillain-Barré syndrome and rituximab in refractory forms of chronic inflammatory demyelinating polyneuropathy (CIDP) [see Chapter 5 ]. For patients who have symptoms resistant to or intolerant of older therapies, the monoclonal antibody complement inhibitor eculizumab has been approved more recently for the treatment of AChR antibody-positive MG. This expensive infusion must be given every 2 weeks but has been shown to reduce disease severity. Additionally, patients receiving this newer medication must be vaccinated against meningococcal diseases as the immune response to this infection requires the complement cascade.

About 5% of MG patients have underlying hyperthyroidism, and 10% have a mediastinal thymoma. If these conditions are present and respond to treatment, MG will usually improve.