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Chapter 200 – Disorders of the Neuromuscular Junction

Chapter 200 – Disorders of the Neuromuscular Junction

 

DEBORAH I. FRIEDMAN

 

 

 

 

 

DEFINITION

• A disorder of the neuromuscular junction, caused by an antibody-mediated autoimmune attack on postsynaptic acetylcholine receptors or the altered presynaptic release of acetylcholine.

 

KEY FEATURE

• Ocular or generalized muscle weakness.

 

ASSOCIATED FEATURES

• Ptosis and ocular motility disturbances.

• Facial, trunk, and limb weakness.

• Speech and swallowing dysfunction.

• Respiratory compromise.

• Autonomic nervous system dysfunction.

 

 

 

MYASTHENIA GRAVIS

INTRODUCTION

Of all the disorders of the neuromuscular junction ( Table 200-1 ), myasthenia gravis is the most common.[1] It is a disorder caused by an antibody-mediated autoimmune attack on the acetylcholine (ACh) receptors at the neuromuscular junction. The hallmark of myasthenia gravis is fluctuating muscle weakness that worsens with exertion and improves with rest. Ocular manifestations, such as ptosis and diplopia, are present frequently at onset and eventually are present in most patients.

EPIDEMIOLOGY AND PATHOGENESIS

The prevalence of myasthenia gravis is rising, largely as a result of longer lifespan. An estimated 15 cases occur per million population.[2] [3] Women are affected twice as frequently as men. The incidence has one peak in the second and third decades, which includes mostly women, and another in the sixth and seventh decades, which involves mostly men. However, it can occur at any age. Myasthenia gravis rarely is familial, but heredity might

 

TABLE 200-1 — DISORDERS OF NEUROMUSCULAR TRANSMISSION

Disorder

Cause

Location

Defect

Symptoms

Treatment

Myasthenia gravis

Autoimmune

Postsynaptic

Antibodies to ACh receptor

Ptosis, diplopia

Weakness, improves with rest

Pyridostigmine (Mestinon), corticosteroids, immunosuppressants; thymectomy

Botulism

Clostridium botulinum infection

Presynaptic

Impaired ACh release

Ptosis, diplopia, tonic pupils, accommodative impairment, bulbar weakness, cholinergic blockade

Respiratory support

Antitoxin

Lambert–Eaton myasthenic syndrome

Paraneoplastic

Presynaptic

Impaired Ach release

Rarely ptosis, diplopia

Proximal muscle weakness

Autonomic dysfunction

Treat malignancy—diaminopyridine, corticosteroids, immunosuppressants

Organophosphate toxicity

Insecticides

Chemical warfare

Synaptic

Inhibits acetyl-cholinesterase

Rapid respiratory failure

Muscle twitching then paralysis

Mental status changes

Pupillary miosis

Atropine, pralidoxine

Black widow spider (Latrodectus mactans) bite

a-Larotoxin

Presynaptic

Increased

ACh release

Autonomic hyperactivity

Vasoconstriction

Painful, rigid abdomen

Calcium, magnesium, atropine, antivenin; warming

Tick paralysis

Toxic

Presynaptic

Impaired

ACh release

Irritability, pain, paralysis

Respiratory paralysis

Late signs—unreactive pupils, ophthalmoplegia

Remove tick, supportive measures

Scorpion toxin

Toxic

Presynaptic

Increased

ACh release

Agitation, respiratory failure, blurred vision, abnormal eye movements, jerking of extremities, autonomic dysfunction

Calcium, atropine, antivenin, supportive measures

ACh, Acetylcholine.

 

 

 

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Figure 200-1 Neuromuscular junctions. In myasthenia gravis, acetylcholine is released from presynaptic vesicles and diffuses across the synaptic cleft to the postsynaptic receptors. Acetylcholinesterase, located deep within the synaptic folds, hydrolyzes acetylcholine. There is also a simplification of the postsynaptic site with a reduced number of receptors. (From Drachman DB. Myasthenia gravis. N Engl J Med. 1994;330:1797–810.)

be a risk factor. Young female patients who have thymic hyperplasia often have human lymphocyte antigen (HLA)-B8 and HLA-DR3 patterns. An association exists with HLA-B7 and HLA-DR2 in patients over 40 years of age.

Knowledge of the anatomy and physiology of the normal neuromuscular junction helps to understand its disorders. The neuromuscular junction is composed of the motor axon terminal, the synaptic cleft, and the postsynaptic surface of the muscle cell ( Fig. 200-1 ), in which deep infoldings occur. Acetylcholine (ACh) is stored in vesicles in the cytoplasm of the nerve terminal and mediates neuromuscular transmission. Depolarization of the axon by an action potential causes release of ACh into the synaptic cleft by calcium-dependent, voltage-dependent exocytosis. Ordinarily, more ACh is released than is needed to produce neuromuscular transmission, which creates a safety factor. Once released, the ACh diffuses across the synaptic cleft to the postsynaptic folds.

 

The postsynaptic folds contain the ACh receptors and acetylcholinesterase, the enzyme that hydrolyzes ACh. In general, the receptors are located on the tips of the folds and acetylcholinesterase is concentrated deeper within the synaptic folds. When two ACh molecules bind to a receptor, conformational changes occur and an ion channel opens, which results in a local depolarization and subsequent muscle contraction. An additional safety factor exists at this level, because the potential generally exceeds the threshold required for depolarization of a muscle fiber (end-plate potential). Innervated receptors undergo continuous turnover, with a half-life of 8–11 days.

In myasthenia gravis, the major pathological changes are found at the postsynaptic membrane, with loss and simplification of the postjunctional folds, reduced numbers of ACh receptors, and a widened synaptic cleft. New receptors are synthesized, but they are not incorporated into the damaged postsynaptic membrane, which results in a loss of receptors at the junction. Patients who have myasthenia gravis contain about one third the number of ACh receptors found in healthy controls. The number of receptors seems to parallel the severity of weakness. With a reduced number of receptors, the end-plate potential is inadequate to generate contraction of some muscle fibers; this produces the characteristic muscle weakness. Normally, a decline (“rundown”) occurs in the amount of ACh released by successive muscle contractions. At myasthenic junctions, the rundown produces progressive failure of neuromuscular transmission, because of the reduced number of receptors. This accounts for the muscular fatigability that is the hallmark of the disease.

The muscular abnormalities in myasthenia gravis result from an antibody-mediated process that likely originates in the thymus gland. The antibodies both accelerate the rate of degradation of ACh receptors and block ACh binding sites. B-cells produce the autoantibodies, but T-cells also are important in the autoantibody response of myasthenia gravis. In myasthenia gravis, the T- and B-cells produced by the thymus gland are more responsive to the ACh receptor than are their counterparts in the peripheral blood. Of patients who have myasthenia gravis, 75% have thymic abnormalities; of these, 85% have thymic hyperplasia and 15% have thymomas. Perhaps the strongest evidence for the importance of the thymus gland in the pathogenesis of myasthenia is the effectiveness of thymectomy.

OCULAR MANIFESTATIONS

Ocular symptoms, ptosis and diplopia, are present at onset in about 70% of patients and eventually are present in 90%. Ptosis, either isolated or associated with extraocular muscle involvement, often is the first symptom. The ptosis may be unilateral or bilateral, symmetrical or asymmetrical, and often it is more pronounced as the day progresses.

Involvement of the extraocular muscles varies from single-muscle paresis to total ophthalmoplegia. Myasthenia gravis may simulate an ocular motor nerve palsy, unilateral or bilateral internuclear ophthalmoplegia, or a gaze palsy. When the levator palpebrae superioris also is involved, the disease may mimic a pupil-sparing third nerve palsy. Patients experience diplopia, which usually fluctuates throughout the day; sometimes the disease produces vertical separation of the images, at other times it causes horizontal diplopia. The diplopia may be intermittent. Other motility abnormalities include saccadic dysmetria and decreased final saccadic velocity, small “quiver” eye movements, and gaze-evoked nystagmus.[4] Nystagmus occurs because of muscle fatigue; isolated nystagmus as a sign of myasthenia gravis is rare. For practical purposes, the pupils are normal in myasthenia gravis. Although anisocoria, impaired accommodation, and sluggishly reactive pupils have been described, the abnormalities are subtle and not clinically significant.

DIAGNOSIS

The diagnosis of myasthenia gravis usually is suspected from the patient’s symptoms and the physical examination. The presence of ptosis and extraocular muscle weakness that either fluctuates or does not conform to any pattern of ocular motor nerve paresis raises the suspicion of myasthenia gravis. Many ocular signs may be present on the examination. With unilateral ptosis, the other eyelid may appear retracted, exhibiting Hering’s law of equal innervation. If the ptotic eyelid is lifted manually, the ptosis worsens on the contralateral side ( Fig. 200-2 ). This finding is not exclusive to myasthenia but frequently is present in patients who have the condition. Cogan’s lid twitch sign demonstrates the rapid recovery and easy fatigability of the levator. When the patient looks down for 10–20 seconds and then rapidly looks up to primary position, the upper eyelids often overshoot (retract) and then settle back into a stable position; a downward drift of the lids or several twitches may be observed. Prolonged upgaze produces muscle fatigue, with eyelid droop or downward drift of the eyes. As the patient attempts repeated large-amplitude saccades, slowing of the eye movements may occur with repetition. Ice placed on a ptotic lid may prolong the time for which the ACh receptor channels open and produce clinical improvement. The ice test is a sensitive and specific test for myasthenia gravis.[5] [6] [7]

 

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Figure 200-2 Myasthenia gravis. A, Right ptosis and compensatory left upper lid retraction. B, On looking right note right abduction deficit and left lid retraction to compensate for right ptosis. C, On sustained upgaze, right upper lid becomes fatigued.

 

With generalized myasthenia gravis, muscle strength testing reveals weakness, usually more prominent proximally. Individual muscles weaken with repetitive testing; the strength improves after a brief period of rest.

No specific laboratory test exists for myasthenia gravis. A combination of physical examination, pharmacological tests, blood tests, and electrodiagnostic tests often is needed to confirm the diagnosis. If a demonstrable, measurable abnormality is present on the examination, administration of an acetylcholinesterase inhibitor produces increased strength of myasthenic muscles.[8] The most commonly used agent is intravenous edrophonium (Tensilon), because of its rapid onset of action (30 seconds) and short duration of action (5 minutes). Baseline readings are taken for the pulse, blood pressure, and the physical sign to be measured. For ocular manifestations, this may include measurement of the palpebral fissures and levator function or quantitation of subtle motility deficits using a Maddox rod or Hess screen.[9] The patient should be warned of potential side effects, including diaphoresis, abdominal cramping, nausea, vomiting, salivation, and light-headedness.

Although the complication rate is very low, the most dangerous complication is heart block, and atropine sulfate should be made available immediately (0.4–0.6?mg, adult dose).[10] Alternatively, patients may be pretreated with intramuscular or subcutaneous atropine. An assistant is required to monitor the patient’s pulse and blood pressure during the test. Ten milligrams is drawn into a tuberculin syringe. After administration of an initial test dose of 2?mg intravenously, the patient is observed for 1 minute while the pulse is monitored. Some patients improve with the test dose. If no improvement and no adverse reaction occur, an additional 4?mg is administered. The remaining 4?mg can be used if no effect is seen. The presence of eyelid fasciculations indicates that an adequate dose was injected. The response to edrophonium often is dramatic (see Fig. 200-2 ). Intramuscular neostigmine (Prostigmin) is useful in children who may not cooperate with intravenous injections. Neostigmine (1.5?mg for adults or 0.04?mg/kg for children, mixed with 0.6?mg atropine sulfate) produces observable effects within 15 minutes; peak action occurs 30 minutes after injection.

A safe alternative to the edrophonium test is the sleep test. [11] After the baseline deficit has been documented, the patient rests quietly with eyes closed for 30 minutes. The measurements are repeated immediately after the patient “wakes up” and opens the eyes. Improvement after rest is characteristic of myasthenia gravis.

A serum assay for anti–ACh receptor antibodies should be obtained for all patients who have suspected myasthenia gravis. Antibody titers do not correlate with the severity of the disease. The binding antibody is obtained most commonly, being detected in approximately 90% of patients who have generalized myasthenia gravis and 70% of patients who have ocular myasthenia. Blocking antibodies are present in approximately 60% of patients who have generalized myasthenia and 50% of patients who have ocular disease, and rarely are present (1%) without binding antibodies.

Electrophysiological tests are useful for the diagnosis of myasthenia gravis if other tests are inconclusive. Repetitive supramaximal motor nerve stimulation (1–3?Hz) produces a progressive decremental response of the compound muscle action potentials during the first four or five stimuli. The amplitude of the response then either levels off or increases slightly because of post-tetanic potentiation. This technique shows abnormalities in 40–90% of patients who have myasthenia gravis and results are more likely to be positive with severe disease. Single fiber electromyography (SFEMG) demonstrates “jitter,” which indicates the variability of propagation time to individual muscle fibers supplied by the same motor neuron. Intermittent “blocking” caused by failure of conduction at the neuromuscular junction also may occur. The sensitivity of SFEMG is approximately 90%.[12] In particular, SFEMG of the superior rectus and levator palpebralis muscles is extremely sensitive for the detection of ocular myasthenia gravis.[13] Conversion from ocular to generalized disease is less likely with normal SFEMG findings of the upper extremities.[14]

Because 10–15% of patients who have myasthenia gravis have a thymic tumor, high-quality radiographic imaging of the chest (computed tomography or magnetic resonance imaging) is mandatory, even for patients with solely ocular findings ( Fig. 200-3 ). A plain chest radiograph alone is not adequate for this purpose. Fullness of the thymus gland typically is seen up to age 30 years. The persistence of a thymus gland in a patient over 40 years of age or an increase in size on serial imaging studies raises the suspicion that a thymoma is present.

Other testing is directed toward associated systemic diseases and treatment. It is not unusual for patients who have myasthenia to have another autoimmune disease. Because 5% of patients who have myasthenia gravis have co-existent thyroid disease, thyroid function tests should be obtained for all patients. Complete blood count, antinuclear antibody analysis, and erythrocyte sedimentation rates typically are drawn in patients who have confirmed myasthenia gravis. If treatment with corticosteroids is planned, diabetes and tuberculosis should be excluded. Neuroimaging of the brain is not required routinely

 

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but may be considered for atypical cases that are antibody negative and refractory to treatment ( Table 200-2 ).

SYSTEMIC ASSOCIATIONS

Generalized myasthenia gravis develops in 75% of patients. The nonocular symptoms include facial weakness, weakness of the jaw when chewing, dysarthria, and dysphagia. Nuchal muscular weakness produces inability to hold the head up. Weakness of the limbs is common. If the erector spinae muscles are involved, the patient may be unable to maintain an erect posture. Most patients feel tired with reduced stamina. In severe cases, weakness of the muscles of the chest and diaphragm produces dyspnea. A pronounced drop in the vital capacity leads to myasthenic crisis, which requires mechanical ventilation and aggressive treatment.

Approximately 12% of neonates born to myasthenic mothers develop transient neonatal myasthenia gravis, as a result of maternal

 

 

Figure 200-3 Computed tomography of the chest with contrast enhancement. Shown is a large, multilobulated thymoma in a 32-year-old man with ocular myasthenia gravis. The mass is in proximity to the aortic arch and the ascending aorta. A focal calcification is present anteriorly. The patient’s ptosis and diplopia remitted following removal of the thymoma.

 

 

TABLE 200-2 — DIFFERENTIAL DIAGNOSIS OF THE NEUROMUSCULAR JUNCTION

Disorder

Pupils

Ocular Motility

Lids

Other Ocular Findings

Other Systemic Findings

Myasthenia gravis

Normal

Fluctuating ophthalmoparesis

Ptosis

Cogan’s lid twich sign

Fluctuating weakness that improves with rest

Graves’ ophthalmopathy

Normal

Restricted EOM

Positive forced duction testing

Lid retraction

Lid lag

Conjunctival infection

Keratoconjunctivitis sicca

Exophthalmos

Optic neuropathy

Symptoms of hyperthyroidism may be present

Botulism

Dilated, poorly reactive

Light–near dissociation

Ophthalmoparesis

Ptosis

Limb weakness

Bulbar signs

Respiratory failure

Urinary retention

Constipation

Lambert–Eaton myasthenic syndrome

Usually normal

Usually normal

Usually normal

Keratoconjunctivitis sicca

Autonomic and sensory symptoms

Guillain–Barré syndrome

Normal or poorly reactive

Normal or ophthalmoparesis

Ptosis

Facial diplegia

Limb weakness

Areflexia

Respiratory failure

Progressive external ophthalmoplegia

Normal

Slowly progressive

Symmetrical ophthalmoparesis

Slowly progressive

Ptosis

May have pigmentary retinopathy

None unless coexisting mitochondrial disorder

EOM, Extraocular movement.

 

 

transmission of autoantibodies through the placenta; these trigger independent antibody production by the infant. Affected neonates have generalized weakness with difficulty eating, respiratory weakness, a poor cry, and facial weakness, which are noticed shortly after birth. The symptoms last for several weeks and then resolve without recurrence.

Thymic enlargement and thymoma frequently are present in patients who have myasthenia gravis. Other autoimmune disorders, such as thyroid disease, systemic lupus erythematosus, and pernicious anemia, are found with increased frequency in patients with myasthenia gravis. Aplastic anemia, ulcerative colitis, Sjögren’s disease, Kaposi’s sarcoma, and lymphoid tumor of the orbit are less common associations.

TREATMENT

The major therapies for myasthenia gravis follow:

• Acetylcholinesterase inhibitors

• Immunosuppression

• Symptomatic treatment of ocular abnormalities

• Avoidance of agents that worsen neuromuscular transmission

Acetylcholinesterase inhibitors raise the safety factor for neuromuscular transmission by preventing the degradation of ACh. Although these agents provide symptomatic improvement in muscle weakness, they do not treat the disease directly. However, because of their rapid effectiveness and lack of long-term side effects, they often are the first agents used in the treatment of myasthenia. Pyridostigmine (Mestinon), the most commonly used drug, has a duration of action of 2–8 hours. It is most useful for the treatment of systemic weakness of myasthenia gravis and may not improve the diplopia. The usual starting dose is 30–60?mg every 4 hours while awake. Larger doses or more frequent dosing intervals may be used as needed. Above 120?mg every 3 hours, no additional effectiveness is likely and a risk exists of cholinergic crises. A delayed release preparation taken at bedtime is useful for patients who have profound weakness upon awakening in the morning. The most common side effects from these agents are gastrointestinal disturbances (nausea, diarrhea) and muscle twitching. Overdosage results in sialorrhea, blurred vision, and worsening weakness (cholinergic crisis). It may be difficult to differentiate cholinergic crisis as a result of medication from worsening of the disease, that is myasthenic

 

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crisis. Diplopia often does not improve with pyridostigmine and may be treated with immunosuppressive agents.[15]

Thymectomy is indicated for all patients who have a thymoma and may be beneficial for some patients who do not have one.[16] Thymectomy produces improvement in almost all cases with no thymoma present and results in complete remission in 35–45% of patients. The benefits of thymectomy may not be apparent for 2–3 years, yet some patients respond almost immediately after surgery. It usually is recommended for patients under the age of 55 years who have generalized disease. The presence or absence of ACh receptor antibodies does not seem to influence the efficacy of the surgery. A trans-sternal approach is preferable, to allow adequate visualization of the thoracic cavity and total thymus removal. Ectopic rests of thymic tissue may be undiscovered if the less invasive transcervical technique is used. The morbidity and mortality rates from thymectomy are quite low. Because any surgical procedure may worsen myasthenia, some patients benefit from a short course of plasmapheresis preoperatively. Alternative methods of direct thymic suppression, such as radiation therapy, are not effective.

Immunosuppressants, mainly cytotoxic agents and corticosteroids, treat the disease directly and generally are employed in patients who do not improve satisfactorily with acetylcholinesterase inhibitors. It may be several weeks to months before these medications take effect. Prednisone is used most frequently, and various dosing strategies are employed. Daily administration of high doses (60–100?mg) may produce substantial worsening within the first 2 weeks of treatment and should be used with caution. Other regimens use increasing, daily, low doses of prednisone, or alternate-day dosing. Alternate-day dosing has the advantage of fewer side effects, and many patients who have purely ocular symptoms improve on a low dosage (20–30?mg) of alternate-day therapy. The risks of long-term prednisone administration include peptic ulcer, osteoporosis, femoral neck fracture, diabetes, skin breakdown, weight gain, and cushingoid features. Appropriate medical precautions and monitoring are required. To minimize the complication rate, the lowest dosage of prednisone possible should be used, and other immunosuppressant agents added, if needed.

Azathioprine, cyclophosphamide, and cyclosporine are effective for the long-term management of myasthenia gravis and may be used in combination with prednisone and pyridostigmine.[17] Mycophenolate mofetil was safe and effective in short-term studies.[18] These medications have fewer long-term side effects than prednisone. Blood counts must be taken, and liver and renal function must be monitored, and a small possibility exists that a neoplasm will develop after many years of treatment.

Plasmapheresis effectively reduces circulating autoantibodies. It typically is reserved for patients in myasthenic crisis or is used preoperatively for thymectomy in patients who have severe weakness. Improvement is rapid, but transient. Like plasmapheresis, intravenous immune globulin produces rapid improvement through a difficult period of myasthenic weakness (400?mg/kg per day for 5 days). [19] [20] Patients in myasthenic crisis require aggressive pulmonary treatment, often need intubation and mechanical ventilation, and are best managed in the intensive care unit.

As a rule, ptosis typically responds to treatment and diplopia may be refractory. Ocular symptoms can be treated symptomatically as other therapies are initiated, or when these are ineffective. Lid crutches may be beneficial for patients who have ptosis, but ptosis surgery should be reserved for patients who are stable and refractory to other treatments. Diplopia is managed using patching or prisms; strabismus surgery is inappropriate for patients who have myasthenia gravis.

Medications that lower the safety factor of neuromuscular transmission should be avoided in patients who have myasthenia. Penicillamine causes a myasthenic syndrome that may be associated with autoantibody production. Many antibiotics decrease the production or release of ACh, including the aminoglycoside agents (streptomycin, neomycin, kanamycin, gentamicin, tobramycin, amikacin, viomycin), bacitracin, polymyxins (polymixin A and B, colistin), and the monobasic amino acid antibiotics (lincomycin and clindamycin). Rarely, worsening of myasthenia occurs with erythromycin or following iodinated contrast dye administration. All neuromuscular blocking agents, such as curare and depolarizing agents, should be used with caution. Chloroquine, lithium, and magnesium affect both presynaptic and postsynaptic transmission. Antiarrhythmic agents, including procainamide and quinidine, can cause or worsen myasthenia gravis. Phenytoin, ß-blockers, cisplatin, phenothiazines, and tetracyclines may have similar effects.

COURSE AND OUTCOME

Despite its ominous name, myasthenia gravis is seldom fatal; most patients experience remission or good control of their symptoms with treatment. Of those patients who have only ocular symptoms and signs at onset, 10–20% undergo spontaneous remission and 50–80% develop generalized disease, almost always within 2 years of onset of the disorder.[21] Patients who have ocular myasthenia who are over the age of 50 years are more likely to progress to generalized myasthenia, while a younger age at onset carries a better prognosis.

In adults, the disease is most labile during the first 10 years; most deaths occur during the first year. After 10 years, the course becomes more stable. The long-term prognosis is poorer when a thymoma is present.[22] When death occurs from myasthenia gravis, usually it is because of respiratory failure with secondary cardiac dysfunction.

BOTULISM

INTRODUCTION

Botulism is a potentially life-threatening disorder caused by the toxin of Clostridium botulinum. Three types exist—food-borne, wound, and infantile. The clinical picture is characterized by rapidly evolving cranial nerve and respiratory weakness with autonomic dysfunction. Associated symptoms include hyposalivation, dysphagia, dysarthria, respiratory failure, muscular weakness, constipation, urinary retention, nausea, and vomiting.

EPIDEMIOLOGY AND PATHOGENESIS

Botulism, caused by the neurotoxin elaborated by Cl. botulinum, may take many forms. Its site of action is the presynaptic nerve terminal, where it prevents the release of ACh. The preformed toxin may be ingested, as in food-borne botulism, or gain access by wound infection. Alternatively, the bacterium or spore may colonize the gastrointestinal tract, as in infant botulism.

At least eight types of toxin have been described, but only three forms commonly affect humans. In the United States, about 60% of cases of botulism result from type A, 30% from type B, and 10% from type E. Type A is found in the western United States and type B in the eastern United States. Type E, found in raw fish, is most common in Alaska. Type A botulism is usually the most severe form of the disease. The most common food sources of botulism are vegetables, meat, and fish. Commercially canned foods account for only 3% of cases; 97% arise from consumption of home-preserved foods. Restaurant outbreaks are rare but represent 42% of cases. About 10 outbreaks occur yearly, with a mean of 2.2 persons affected per outbreak.

Historically, classic or food-borne botulism was caused by inadequately cleaned, smoked, salted, or dried fish or meat. Contemporary risk factors include commercial or home-prepared condiments, vegetables, nonacid foods, and preserved raw fish.[23] Plastic food storage bags and containers provide a near-perfect anaerobic environment for growth of Cl. botulinum.

 

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Home-canned vegetables and garlic (particularly when coated in oil), canned fruit, fish, and condiments (especially garlic and peppers) accounted for most outbreak reports in the 1980s. The risk increases when foods are held for long periods at ambient temperatures or are reheated inadequately before serving. Because the spores of Cl. botulinum are ubiquitous in the soil, they also contaminate foods that are harvested from the ground (e.g., onions, potatoes).

Wound botulism always has been the least common form of botulism but is increasing in incidence as a result of intravenous drug abuse and cocaine abuse associated with necrotic nasal passages.[24]

Infant botulism occurs during the age range 2–6 months in previously healthy infants. The course is subacute and may be difficult to diagnose until the child becomes severely ill. The classic source of infection is honey. Transmission of spores from adults to infants is possible from soil contamination of clothing. A similar infection can be seen in adults who have achlorhydria, following gastrointestinal operations, and who have blind loops of the bowel.

OCULAR MANIFESTATIONS

Ophthalmic manifestations are not likely to occur in isolation but are part of a systemic illness. Diplopia and ptosis occur with varying degrees of ophthalmoparesis. Internal ophthalmoplegia with accommodation paresis produces blurred vision. The pupils often are abnormal, with a poor reaction to light. Pupillary light–near dissociation may be observed during the acute infection and occasionally persists after recovery.[25] Quivering eye movements have been described. Hypolacrimation is found often.

DIAGNOSIS

The diagnosis is based on the symptoms and signs, the circumstances of infection, electrophysiological studies, and isolation of the organism or toxin.

When botulism is suspected, stool, gastric aspirate, and at least 20?ml of serum should be collected for analysis. If the source of contaminated food is available, it may be submitted to the relevant health department for evaluation. Identification of botulinum toxin in serum and stool is performed using a mouse bioassay. The organism is isolated in the stool but, rarely, it is present in the serum of patients who have infant botulism. A Tensilon test result is almost always negative. The spinal fluid findings are normal. Electrophysiological studies are very helpful and show changes similar to those seen in the Lambert–Eaton syndrome. Because ACh release is blocked, changes of denervation are detected on electromyography. Small, evoked action potentials and posttetanic facilitation following exercise or supramaximal nerve stimulation are characteristic. In contrast to the changes in the Lambert–Eaton syndrome (see below), post-tetanic facilitation persists for up to 20 minutes with botulism.

DIFFERENTIAL DIAGNOSIS

The Guillain–Barré syndrome, Miller–Fisher syndrome, and poliomyelitis resemble botulism clinically. Myasthenia gravis spares the pupils and is more gradual in onset. Tick paralysis, diphtheria, organophosphate toxicity, shellfish toxicity, and hypokalemic periodic paralysis are other diagnostic considerations.

SYSTEMIC ASSOCIATIONS

Symptoms of food-borne botulism begin 12 hours to 8 days after ingestion of the toxin. Typically, the patient is conscious and afebrile. The characteristic systemic symptoms include hyposalivation and respiratory failure, urinary retention, constipation, and vomiting. Limb weakness may resemble that of Guillain–Barré syndrome, with ascending or descending paralysis. The reflexes are often normal. Prominent bulbar symptoms and cranial nerve palsies may develop. At worst, the patient is “locked in,” unable to move or respond, but fully awake.

In wound botulism, symptoms begin 4–18 days after injury and are identical to those of food-borne botulism.

Infant botulism causes constipation and weakness, with descending paralysis.[26] The infant has a poor suck, a weak cry, and becomes hypotonic. Impairment of extraocular movement, facial weakness, and cranial nerve palsies are common. Dilated pupils, respiratory arrest, and death may follow. The course often is insidious and mistaken for failure to thrive.

TREATMENT

The most important aspect of treatment is supportive, with mechanical ventilation when necessary. If the patient is not allergic to horse serum (pretesting for hypersensitivity is required), trivalent acute bacterial endocarditis antitoxin is administered, although its efficacy is uncertain. Guanidine is no longer recommended. Recovery occurs spontaneously as new synapses develop; this may take 6–12 months.

LAMBERT–EATON MYASTHENIC SYNDROME

INTRODUCTION

First described in 1953 as a triad of muscle weakness, autonomic dysfunction, and hyporeflexia, the Lambert–Eaton myasthenic syndrome (LEMS) shares clinical features with myasthenia gravis. Unlike myasthenia gravis, LEMS is a presynaptic disorder of neuromuscular transmission affecting calcium channels. [27] This rare disorder is associated with a malignancy, such as oat cell carcinoma of the lung, in at least 50% of cases.[28] Symptoms of LEMS typically precede the diagnosis of the neoplasm.

EPIDEMIOLOGY AND PATHOGENESIS

Most patients who have the paraneoplastic form are over 40 years of age. Smoking is a risk factor because of the high association with bronchogenic carcinoma. About 3% of patients who have small cell carcinoma of the lung have LEMS.[29] The non-neoplastic form is associated with pernicious anemia, thyroid disease, Sjögren’s syndrome, and other autoimmune disorders. A personal or family history of autoimmune disease is found in 34% of patients who have primary LEMS.[30] Myasthenia gravis and LEMS may occur concurrently.

Symptoms are caused by impaired release of ACh from the nerve terminal. End-plate potentials are too small to generate an action potential. Striated muscle, glands, and smooth muscle are affected. Calcium and guanidine increase neurotransmitter release, which results in improved strength.

OCULAR MANIFESTATIONS

In contrast to myasthenia gravis, ocular manifestations are not prominent. Decreased lacrimation leads to keratoconjunctivitis sicca, which is the predominant ocular complaint. Ptosis and intermittent diplopia may occur. Sluggishly reactive pupils and tonic pupils are infrequent.[31] Slow, saccadic velocities that normalize after exercise have been described. There is one report of a patient with ophthalmoparesis and pseudoblepharospasm.[32]

DIAGNOSIS

Rapid onset and progression of symptoms over weeks to months is common in the paraneoplastic form. The non-neoplastic variety

 

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has an insidious onset with mild, stable symptoms. Patients generally have proximal muscle weakness and leg pain. Autonomic involvement is present in 50% of cases, which results in dry mouth, constipation, hypohidrosis, impotence, orthostatic hypotension, and urinary retention. Unlike myasthenia gravis, muscle strength improves following voluntary contraction or repetitive testing. Paradoxical lid elevation may occur after prolonged upgaze.[33] The deep tendon reflexes are hypoactive or absent at rest and increase with voluntary muscle contraction.

Electrophysiological studies confirm the diagnosis. Low rates of nerve stimulation (2–3?Hz) produce a decremental response, but high rates (20–50?Hz) cause a two- to tenfold incremental increase in the compound action potential. SFEMG shows changes similar to those found in myasthenia gravis. The Tensilon test is negative and anti–ACh receptor antibodies are not present, although calcium channel antibodies have been found in about 50% of patients.

DIFFERENTIAL DIAGNOSIS

Disorders that produce proximal muscle weakness may resemble the myasthenic syndrome. Myasthenia gravis usually can be excluded clinically, with its prominent ocular and facial involvement. Guillain–Barré syndrome, polymyositis, lumbosacral plexopathies, and polyradiculopathies can be excluded by electrophysiological testing and neuroimaging.

SYSTEMIC ASSOCIATIONS

More than 80% of the associated malignancies are small cell carcinomas of the lung. A computed tomography or magnetic resonance image of the chest may be supplemented by bronchoscopy or sputum analysis to diagnose the lung carcinoma. Other tumors associated with LEMS include small cell carcinoma of the cervix or the prostate, adenocarcinoma, and lymphoma. The myasthenic syndrome may precede the detection of the malignancy by up to 7 years and rarely follows detection of the tumor.[27] If no malignancy is found, repeated investigations are warranted. Other laboratory testing includes thyroid function tests, complete blood count, erythrocyte sedimentation rate, antinuclear antibodies, anti-Ro, and anti-La (SS-A, SS-B) to evaluate for the association of the non-neoplastic form with pernicious anemia, thyroid disease, Sjögren’s syndrome, and other autoimmune disorders.

TREATMENT

Guanidine is effective, but it has potentially severe side effects, including bone marrow depression, paresthesias, renal and hepatic impairment, confusion, atrial fibrillation, and hypotension. Typically, anticholinesterases are tried as first-line therapy. 3,4-Diaminopyridine is a more direct treatment; it works by blocking potassium channels and enhancing the release of ACh from the presynaptic nerve terminal. A definite and sustained response to aminopyridines occurs in most patients.[34] Treatment with plasmapheresis, intravenous immunoglobulin, corticosteroids, and azathioprine usually leads to improvement in strength.[35] Immunosuppressants may take several months to be effective. Magnesium should be avoided, because it worsens the weakness. Other medications that decrease neuromuscular transmission should be used with caution. Treatment of the underlying carcinoma may produce improved strength.

COURSE AND OUTCOMES

The presence or absence of malignancy largely determines the prognosis. Those patients who have lung cancer should be screened regularly for recurrence within the first 4 years of diagnosis and advised to stop smoking. Most patients can lead a moderately active lifestyle with treatment but should avoid vigorous exercise.

 

 

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