Overview
In humans, all nerve-to-nerve, nerve-to-muscle, and peripheral sensory receptor-to-nerve commu-nication occurs via synapses. An electrical signal traveling along a nerve axon is converted at a spe-cialized nerve ending called a synapse. At the synapse the electrical signal triggers release of a neurotransmitter into the synaptic cleft. The neu-rotransmitter then crosses the synaptic cleft to attach to a specialized receptor that is part of an ionic channel, resulting in either local depolariza-tion or hyperpolarizadepolariza-tion of the postsynaptic cell.
When sufficient ionic channels have been stimu-lated by neurotransmitters, the postsynaptic cell either completely depolarizes or becomes inhib-ited from depolarizing. In summary, all neural communication results from electrical-to-chemi-cal-to-electrical transmission.
There are at least 30 different types of neuro-transmitters, with the greatest number occurring in the CNS. In simple terms, neurotransmitters are classified into simple chemicals (acetylcholine, norepinephrine, and dopamine), amino acids (GABA, glycine, and glutamine), or peptides (sub-stance P and endorphins). The duration of the neurotransmitter effect may be milliseconds, as in a brief opening and closing of an ionic channel, to
hours or days, as when a receptor stimulates intra-cellular second messengers that enzymatically affect intracellular pathways.
Synaptic disorders may occur from chemical or biologic toxins, antibodies directed against synaptic receptor molecules, or genetic mutations in the synaptic receptor or membrane channel. Synaptic disorders due to mutations in calcium, potassium, and sodium ion channels (called channelopathies) are responsible for such episodic disorders as seizures, migraine-type headaches, ataxia, myoto-nia, and weakness from Lambert–Eaton syndrome.
Synaptic disorders often have several suggestive clinical features: (1) excessive inhibition or excita-tion of one transmitter pathway, (2) signs and symptoms that are episodic or fluctuate consider-ably, and (3) signs that increase with continuing firing of the synapse.
This chapter focuses on diseases that result from toxins and antibodies affecting the neuro-muscular junction to produce weakness.
not from a toxin; it originates from autoantibodies directed against the acetylcholine receptor (AchR).
There are over 30,000 individuals with MG in the United States, with a prevalence of 10/100,000 adults. The epidemiology of MG demonstrates 2 peaks. The first peak, mainly in women, occurs between ages 10 and 40 years. The second peak has a male predominance and occurs from ages 50 to 75 years.
MG is considered the classic humoral autoim-mune disease, based on well-characterized autoan-tibodies and the observation that these patients frequently develop other autoimmune diseases such as thyrotoxicosis, rheumatoid arthritis, and systemic lupus erythematosus.
Pathophysiology
The etiology or initial event that begins the onset of MG remains unknown. However, the weakness results from 3 factors. The most important one is circulating antibodies directed against the AchR on the postsynaptic membrane of the neuromus-cular junction. Some of these antibodies attach to the AchR located on key parts of the sodium/
potassium channel, thereby interfering with open-ing the sodium/potassium channel (Figure 5-1).
When sufficient AchRs are blocked by antibodies, the muscle will not depolarize sufficiently to trig-ger contraction of the muscle fiber. A second fac-tor contributing to the weakness is that AchR molecules have a faster rate of degeneration. When AchR antibodies simultaneous attach to two adja-cent AchRs, a cell signal initiates internalization of both receptors and degrades them. The turnover rate is faster than replacement of new membrane AchRs, resulting in a net loss of available AchRs at the synapse. The third factor develops because the antibody attached to the AchR triggers serum com-plement activation, producing secondary damage to the synaptic membrane. As a consequence of years of complement damage, the postsynaptic mem-brane loses its rich invaginations and becomes sim-plified in structure (Figures 5-2a and 5-2b). In severe chronic cases, the postsynaptic membrane may have a 2/3 reduction in the normal number of AchR molecules, a number insufficient to initiate depolarization and contraction of the muscle fiber even if no acetylcholine antibodies were present. In these patients, pyridostigmine usage does not improve the probability of muscle fiber contraction.
Of these patients, 75% have an associated abnormality of the thymus gland. About 85% of these patients have thymic hyperplasia with germi-nal center lymphocyte proliferation, and 15% have a thymoma. The role of the thymus gland in pro-ducing the abnormal antibodies is poorly under-stood. The current hypothesis is that the AchR antibody is a T-cell–mediated antibody response.
Surgical removal of the thymus gland often results in clinical improvement and a reduction of the number of circulating antibodies.
MG can occur in infants. Infants born to moth-ers with MG may have sufficient circulating anti-bodies to cause the infant to become floppy, weak, and have a poor suck. This transient syndrome lasts for several weeks until the maternal antibody disappears. Other infants have congenital MG that is due to genetic mutations in the AchR. These infants remain persistently weak and do not respond to immunosuppressive drugs.
Major Clinical Features
Clinical features result from blockade at the neu-romuscular junction and affect skeletal muscles in a fluctuating and fatigable manner (Table 5-1).
The disease usually has a subacute onset. Earliest symptoms are ptosis and diplopia. Patients com-plain of droopy eyelids and double vision that 50 FUNDAMENTALS OF NEUROLOGIC DISEASE
Anti-Acetylcholine Receptor Antibody
Acetylcholine
Acetylcholine Binding Site
Receptor Molecule Postsynaptic
Membrane
Figure 5-1 In myasthenia gravis, acetylcholine recep-tor antibody blocks the acetylcholine-binding site.
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varies during the day and worsens as the day pro-gresses. In 15% of patients, the disease does not progress beyond ocular problems. For most other patients, other signs of bulbar muscle weakness appear, with trouble chewing, swallowing, and speaking loudly. Some patients find they eat their big “dinner” meal for breakfast as they have trou-ble chewing meat by the end of the day. Limb weakness is common and affects proximal muscles
to a greater extent than distal muscles. Although brief maximal muscle testing may appear normal, patients often cannot hold their arms outstretched for even a minute without fatigue. In severe cases, patients cannot walk and develop respiratory weakness. Sensation, mentation, and deep tendon reflexes are not affected.
Maximal weakness appears within the first 3 years of clinical onset. About 10% of patients
CHAPTER 5—Disorders of the Neuromuscular Junction 51
Endplate
Vesicle Axon of motor neuron
Acetylcholine (ACh)
Acetylcholinesterase (AChE) ACh Receptors
Muscle
Endplate
Vesicle Axon of motor neuron
Acetylcholine (ACh)
Acetylcholinesterase (AChE) ACh Receptors
Muscle
Figure 5-2 Neuromuscular junction. (a) Normal. (b) Myasthenia gravis with simplified postsynaptic membranes.
A
B
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experience a spontaneous remission, which occurs within the first 2 years. However, the remainder of patients have a life-long chronic illness that fluctu-ates in severity.
Major Laboratory Findings
Serum antibodies directed against the AchR are found in over 85% of patients. A few additional MG patients have a blocking antibody. The level of antibody titer does not always reflect disease severity, as the test detects all AchR antibodies, including those that do not interfere with the functioning of the channel. However, for a given patient, a falling titer does reflect clinical improvement.
X-ray or CT of the chest may demonstrate a thy-moma. Elevated thyroxin blood levels indicating thyrotoxicosis are found in up to 5% of patients.
Repetitive nerve stimulation (at rate of 3/s) of proximal muscles (often the trapezius muscle) usually demonstrates a decremental fall of greater than 15% in the compound muscle action potential (see Chapter 3, “Common Neu-rologic Tests”).
The tensilon test, which can be performed in the office, is helpful for establishing the diagnosis of MG when there are clear ocular signs. Edropho-nium (Tensilon®) is a brief-acting anticholinergic drug that is slowly given intravenously to a patient.
For the next 5 to 10 minutes, an untreated MG patient should have a clear objective improvement in ptosis. Often a saline injection precedes the administration of edrophonium to evaluate for a placebo effect.
Principles of Management and Prognosis The goal of treatment is to improve strength and to reduce or eliminate circulating antibodies against the AchR. Symptomatic treatment aimed at improving strength is accomplished with anti-cholinesterase drugs. These drugs do not reduce circulating antibody titers, but are the first line to improve the patient’s strength. Pyridostigmine (Mestinon®) is the main oral drug; it is given to the patient several times a day. Anticholinergic med-ications act by interfering with acetylcholine esterase, the enzyme that cleaves acetylcholine in the synaptic cleft. Partial inhibition of this enzyme results in a longer time period that acetylcholine molecules can remain in the synaptic cleft to find unblocked AchR and increase the probability that sufficient AchR channels will open to fully depo-larize and contract the muscle fiber. Too much pyridostigmine, however, can block all the acetyl-choline esterase such that acetylacetyl-choline cannot be cleaved and removed once it attaches to an AchR.
The inability to remove acetylcholine from the receptor causes a depolarizing muscle weakness that is called a “cholinergic crisis.”
A number of treatments are aimed at reducing the amount of circulation antibody. Thymec-tomy, the surgical removal of the thymus gland, in a moderately severe patient often results in clinical improvement and a fall in antibody titer.
Corticosteroids and other immunosuppressive drugs (azathioprine and cyclosporine) are com-monly given to lower the antibody titer and improve strength. IVIg and plasma exchange by plasmaphoresis will temporarily reduce circulat-ing antibody and improve strength for several weeks. These temporary methods can be used for patients requiring prompt clinical improvement such as for elective surgery, pneumonia, or a
“myasthenic crisis.”
Patients with MG should avoid drugs such as aminoglycoside antibiotics, chloroquine, and anesthetic neuromuscular–blocking drugs (pan-curonium and D-tubocurarine), which affect the neuromuscular junction.
Using various combinations of pyridostigmine and immunosuppresants to lower circulating anti-body levels, most patients lead fairly normal lives.
Death is now uncommon and generally develops from pneumonia or acute respiratory failure.
52 FUNDAMENTALS OF NEUROLOGIC DISEASE
Table 5-1 Cardinal Features of Myasthenia Gravis
Weakness
• Bulbar muscles: ptosis, diplopia, dysarthria, dysphagia, and chewing difficulty
• Limb muscles: proximal greater than distal weakness
Fatigability of skeletal muscles
• Increased weakness in afternoon or after exercise
Normal mentation, sensation, and deep tendon reflexes
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