Case 24

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Case 24

HISTORY AND PHYSICAL EXAMINATION

A 36-year-old white man awoke with binocular diplopia; later that day, he noted blurred vision and lid ptosis. The next morning, he had nausea and vomited twice, and then he had slurred speech and difficulty swallowing. He was admitted to the hospital where magnetic resonance imaging (MRI) of the brain and cerebral angiography were normal. By the third day, he had developed complete ophthalmoplegia, severe dysarthria and dysphagia, and upper extremity weakness. Respiratory failure followed; the patient had to be intubated and required assisted ventilation. The Tensilon test was equivocal.

On examination on day 4, the patient was alert and intubated, and followed commands well. He had bilateral complete ophthalmoplegia to all gaze directions with bilateral ptosis (Figure C24-1). Pupils were dilated and unreactive to light or attempted accommodation. Corneal reflexes were depressed. The patient had bilateral peripheral facial weakness. His tongue was extremely weak, with no fasciculations. His palate did not move volitionally or to gagging. Neck flexors and extensors were weak (Medical Research Council [MRC] 3/5), as were proximal pelvic and shoulder girdle muscles (4/5). However, distal muscles were normal. Deep tendon reflexes were depressed (1/4). Sensation was normal. Cerebellar function also was normal.

Figure C24-1 Pupillary dilatation and ptosis in this patient at the time of diagnosis. The patient also had a complete ophthalmoplegia (not shown).

An electrodiagnostic (EDX) examination was requested.

Please now review the Nerve Conduction Studies and Needle EMG tables.

QUESTIONS

1. All of the following clinical manifestations are compatible with myasthenia gravis except:

A. Ophthalmoplegia.

B. Proximal muscle weakness.

C. Pupillary dilatation.

D. Neck flexor weakness.

E. Bulbar palsy.

2. The most common type of botulism in the United States is:

A. Food-borne botulism.

B. Wound botulism.

C. Infantile botulism.

4. The EDX findings in botulism include all of the following except:

A. Low-amplitude compound muscle action potentials (CMAPs).

B. Normal sensory nerve action potential (SNAP).

C. Slowing of motor conduction velocities.

D. Decrement of CMAP amplitude with slow repetitive stimulation.

E. Increment of CMAP amplitude with rapid repetitive stimulation.

F. Increment of CMAP amplitude after a brief period of exercise.

5. The following are correct statements regarding botulism and Lambert-Eaton myasthenic syndrome (LEMS), except:

A. Ocular manifestations are prominent in botulism but subtle in Lambert-Eaton Myasthenic syndrome.

B. After 50 Hz stimulation of motor nerves, the increment of CMAP amplitude generally is more prominent in botulism than in LEMS.

C. The CMAP increment is present in all motor nerves in LEMS but may be restricted to the affected muscles in botulism.

D. In both disorders, there is impairment of ACH release from the presynaptic terminal.

EDX FINDINGS AND INTERPRETATION OF DATA

The relevant EDX findings in this case are:

1. Normal sensory nerve action potentials (SNAPs).

2. Borderline or low-amplitude CMAPs.

3. Increment of the median CMAP recording abductor pollicis brevis, after a short period (10 seconds) of exercise measuring 90% (Figure C24-2).

4. Decrement of the median and spinal accessory CMAP after slow repetitive stimulation at rest (13%), with significant postexercise (post-tetanic) facilitation (Figure C24-3).

5. Increment of the CMAP amplitude after rapid, repetitive stimulation (50 Hz) measuring 100% (Figure C24-4).

Figure C24-2 Median compound muscle action potential (CMAP) at rest (waveform 1), and after a brief (10 seconds) period of exercise (waveform 2). Note the significant (90%) facilitation following exercise. Sensitivity = 2 mV/division.

Figure C24-3 Slow repetitive stimulation (2 Hz) of the median nerve. Train 1 is at rest, and Trains 2 through 5 are after 1 minute of exercise. The upper tracing shows all five stimulations. Although a decrement of the compound muscle action potential (CMAP) was evident at rest (13%), there is a dramatic facilitation of CMAP immediately after exercise (compare Train 1 to Train 2), with a subsequent return to baseline.

Figure C24-4 Increment of compound muscle action potential (CMAP) (100%) after rapid (50 Hz) repetitive stimulation of the spinal accessory nerve (sensitivity = 1 mV).

The EDX findings are consistent with a neuromuscular junction disorder of the presynaptic type, as supported by the borderline or low-amplitude baseline CMAPs, and the significant increment (>50%) of the CMAP amplitude after brief exercise and rapid repetitive stimulation of motor nerves. This case is consistent with botulism based on subacute progression of a descending muscle paralysis (ocular to bulbar to limbs), the muscarinic involvement (pupillary dilatation), and the EDX findings (presynaptic blockade). It is not consistent with Lambert-Eaton myasthenic syndrome because of the rapid evolution of symptoms, the prominent oculobulbar muscle weakness, and the relatively modest increment on rapid repetitive stimulation and after brief exercise (see electrodiagnosis).

DISCUSSION

Physiology and Pathophysiology

Botulinum toxin is produced by the anaerobic bacterium Clostridium botulinum. Eight immunologically distinct subtypes of the toxin have been identified (A, B, C1, C2, D, E, F, and G). Five serotypes are associated with human disease, with types A and B being the most common. Botulinum toxin type A is the most common in the United States, accounting for 60% of reported cases; it is the predominant type west of the Mississippi and is the most toxic of all subtypes. Type B serotype causes 30% of US cases and is the most common in Europe. It is the major type east of the Mississippi and tends to cause a milder illness.

Botulinum toxin is an extremely potent toxin with doses as small as 0.05 to 0.1 μg causing death in humans. The toxin has significant affinity to both muscarinic and nicotinic cholinergic nerve terminals resulting in autonomic failure and skeletal muscle paralysis. The toxin results in failure of ACH release from the presynaptic terminal and ultimately leads to destruction of the presynaptic terminal. Botulinum toxin first attaches irreversibly to the axonal terminal, and enters via endocytosis without interfering with the calcium channel (calcium entry is not blocked by botulinum toxin). The toxin then interferes with the calcium-dependent intracellular cascade that is responsible for ACH release, by cleaving proteins essential for docking and fusion of the presynaptic vesicles at the presynaptic active zones. Electron microscopy of nerve endings exposed to the toxin reveal a “log jam” of vesicles in the presynaptic terminals. It is now known that various serotypes bind to different presynaptic proteins: botulinum toxin A and E hydrolyze synaptosomal-associated protein-25 (SNAP-25), a protein of the presynaptic membrane; botulinum toxins B, D, F, and G specifically cleave synaptobrevin, a membrane protein of the neurotransmitter-containing vesicles; botulinum toxin C cleaves both SNAP-25 and syntaxin, a nerve plasmalemma protein (Figure C24-5). Because the ultimate result of this intoxication is interference with neurotransmitter release (exocytosis of synaptic vesicles) and destruction of the nerve terminals, recovery of neurologic function is protracted since it is dependent on the regrowth of sprouts from the injured nerve terminal.

Figure C24-5 Neuromuscular junction demonstrating the action of botulinum toxin. After entering the axon terminal by means of the botulinum toxin and endocytosis, the protease action of the toxin cleaves synaptic proteins leading to the compromise of synaptic vesicle release. Botulinum toxins A, C, and E cleave synaptosomal-associated protein (SNAP-25), shown in this illustration. Types B, D, F, and G cleave a synaptobrevin vesicle-associated membrane protein (VAMP), and type C cleaves syntaxin.

(Reprinted from Hallet M. One man’s poison: clinical applications of botulinum toxin. N Engl J Med 1999;341:118–120, with permission. Copyright © 1999 Massachusetts Medical Society.)

Clinical Features

Botulism is a rare but serious and potentially fatal illness. The clinical picture and severity of botulism are variable since they are dependent on the type of toxin, the dose ingested, and the mode of entry. Although both skeletal muscle weakness and autonomic dysfunction occur in most cases, neuromuscular symptoms tend to overshadow type A intoxication, while dysautonomia dominates disease caused by types B and E. Depending on the mode of entry of the toxin into the bloodstream, botulism is classified into four clinically distinct forms.

1. Food-borne (classic) botulism. This is the most severe and debilitating form. It is caused by ingestion of food contaminated by the preformed toxin, which is then absorbed from the gut and distributed by the blood. Home canned foods (fish, vegetables, potatoes, garlic in oil, sautéed onions, etc.) are common vehicles for food-borne botulism. Factors that enhance spore germination and toxin production are low oxygen, low acidity, and high water content, while foods with high acid content, such as vinegar and tomato, are rarely associated with botulism. Classic botulism may manifest as an outbreak (such as restaurant-associated outbreaks), although two-thirds of reported cases have affected single individuals. Boiling food thoroughly should destroy the toxin.

The presentation of food-borne botulism is stereotypical. The onset of symptoms is within 2 to 36 hours after ingestion and their peak is at 4 to 5 days. Muscle weakness become often generalized and evolves in a distinctive way. Symptoms begin in the ocular and bulbar musculature with blurred vision, double vision, ptosis, dysarthria, and dysphagia. Weakness then descends, usually symmetrically, to involve muscles of the trunk and limbs, and in severe cases, the respiratory muscles. Proximal muscles are weaker than distal ones, and the upper extremities usually are more involved than lower ones. Autonomic manifestations include diarrhea, nausea, and vomiting early in the illness and later dry mouth, blurred vision, constipation, ileus, and urinary retention. Dilated, fixed, or poorly reactive pupils are common but may be delayed.

2. Infant botulism. First described in 1976, this is the most common form of botulism in the United States. It occurs in infants, younger than 1 year of age, with a peak incidence at 2 to 4 months. Infant botulism is caused by ingestion of Clostridium botulinum spores that colonize the intestinal tract, leading to in vivo production of toxin and its absorption into the bloodstream. The infant gut is hospitable to the growth of the bacterium because it often lacks both the protective bacterial flora and the clostridium-inhibiting bile acids found in normal adult intestinal tract. Honey consumption as a significant risk factor for infant botulism and, hence, should not be fed to infants under the age of 1 year. Breast-feeding as a risk factor or a protective variable is a controversial issue.

Constipation is often the first symptom in infantile botulism, followed by poor feeding, weak cry, and loss of head control. This may be followed, in 1–3 days, by a symmetrical descending paralysis that involves the cranial muscles, the proximal limb muscles, and, rarely, the diaphragm.

Adult variations of infant botulism have been described. This form usually occurs in patients with gastrointestinal disorders, such as Crohn’s disease, achlorhydria, prior gut surgery, or antibiotic treatment, who may allow the bacteria to germinate in their intestinal tract. The diagnosis is confirmed by culturing Clostridium botulinum in feces of these adult patients.

3. Wound botulism. This form is extremely rare. It is caused by anaerobic wound infection by Clostridium botulinum, with in vivo production of toxin and absorption into the bloodstream. Usually, the site of infection is a traumatic or surgical wound. Subcutaneous abscesses at injection sites of intravenous drug abusers or sinusitis of intranasal cocaine abusers may also be the source of Clostridium botulinum infection. Neurologic manifestations of wound botulism are similar to those of food-borne botulism; fever from wound infection might occur. In up to a half of patients with wound botulism, the toxin is not detected in the serum and the bacteria cannot be isolated from the wound.

4. Iatrogenic (inadvertent) botulism. Botulinum toxin has had an increasing role in treating several neurological disorders including dystonias, spasticity, migraine, and back pain. It has also become a popular agent in the field of cosmetics and plastic surgery. A common adverse effect of the injected toxin using therapeutic doses is its spread from an injected muscle to adjacent muscles. For example, patients with cervical dystonia may develop transient dysphagia when the sternocleidomastoid muscle is injected, and diplopia is a common adverse effect of orbicularis oculi injection in patients with blepharospasm. In addition, the toxin circulates in the blood and produces asymptomatic blockade of transmitter release at distant neuromuscular junctions and in the autonomic nervous system. This has been confirmed by finding prolonged jitter with blocking on single fiber EMG and morphologic abnormalities from muscles distant from the injection. Cases of inadvertent injection of systemically toxic doses of toxin are increasingly being reported. This has resulted in generalized weakness and a disorder that is very similar to classic food-born botulism.

The diagnosis of botulism may be difficult and requires a high index of suspicion. Many cases go unrecognized and are diagnosed with various neuromuscular, medical, and even psychiatric diagnoses (Table C24-1). The diagnosis is relatively easy in epidemics, or if two or more cases are identified simultaneously. Botulism should be suspected when there is:

• Rapid, usually descending, muscular weakness (ocular to bulbar to extremities).

• Subacute bilateral ophthalmoplegia, particularly when it is associated with pupillary dilatation.

• Generalized weakness associated with autonomic symptoms (constipation, dry mouth, urinary retention).

• A history of ingestion of possibly contaminated food (canned food, restaurant food, etc.), the presence of a wound, or subacute poor feeding and constipation in infants.

Table C24-1 Diagnosis of 31 Previously Unrecognized Canadian Patients With Botulism After the Identification of Two Teenaged Sisters With Type B Botulism ^*

Discharge Diagnosis	Number of Patients
Myasthenia gravis	7
Psychiatric illness^†	4
Viral syndrome	4
Botulism^‡	3
Stroke	3
Guillain-Barré syndrome	3
Inflammatory myopathy	2
Diabetic complications	1
Hyperemesis gravidarum	1
Hypothyroidism	1
Laryngeal trauma	1
Overexertion	1

* The outbreak was subsequently identified as spoiled commercial chopped garlic in soybean oil.

† Includes hysteria, agitated depression, separation reaction, and factitious weakness.

‡ All three patients were family members whose diagnosis represented the initial recognition of the outbreak.

Data from St. Louis ME et al. Botulism from chopped garlic: delayed recognition of a major outbreak. Ann Intern Med 1988;108:363–368.

The diagnosis of botulism is confirmed by:

• Electrodiagnostic testing (see following section). This is a rapid, readily available method of identification because the findings are pathognomonic.

• Identification of the toxin in serum, using mouse bioassay studies with antitoxin neutralization. This is usually performed by injecting mice with serum, with or without antitoxin, and observing for death due to paralysis. The sensitivity of serum testing declines if there is a delay in the collection of the specimens; Only one-third of serum samples collected more than 2 days after toxin ingestion are positive.

• Identification of the organism in stool cultures (especially in infantile cases) or wound culture (in wound botulism). Clostridium botulinum is found in the stool of 60% of patients with botulism, but this also depends on the timing of samples collection; only one-third of stool cultures are positive after 3 days of acute exposure.

Treatment of botulism should be initiated as soon as the diagnosis is suspected and confirmed by electrophysiologic findings. Specific treatment for botulism is limited, and therapy is primarily supportive.

• Supportive treatment is an essential component in survival. This includes prolonged, artificial ventilation, feeding, prophylaxis for deep vein thrombosis, and physical therapy for prevention of muscle and tendon contractures.

• Efforts to neutralize the toxin should be made. Antitoxin administration is controversial because of the lack of definite efficacy in many cases and the danger of allergic reactions (20% of patients with 2% rate of anaphylaxis). A trivalent antitoxin (A, B, and E) should be administered early, since it is most effective early in the disease while the toxin is still in the blood and before it is bound at the nerve terminals. The antitoxin is unlikely to be effective 3 days or more after toxic exposure. Cleansing the gastrointestinal tract by enema or lactulose and neomycin also is useful, particularly in infantile botulism.

• Agents that enhance the release of ACH can be used as adjuncts. Drugs that potentially help include guanidine and 3,4-diaminopyridine.

The prognosis for botulism has been influenced by great advances in critical care and respiratory support. Mortality from botulism in the United States has declined from about 50% before 1950 to 7.5% between 1976 and 1984. Heightened awareness, better recognition, and earlier administration of antitoxin might have played a role in this dramatic improvement in outcome. Recovery of neurologic function is usually protracted because it is dependent on regeneration of new endplates, which may continue for as long as 5 years.

Electrodiagnosis

The EDX studies provide a rapid evidence of botulism awaiting the bioassay and stool cultures. The latter two tests may also be negative. The EDX findings in botulism are compatible with a presynaptic defect of the neuromuscular junction (see electrodiagnosis in Cases 17 and 21). The findings are as follows:

1. Normal sensory nerve conduction studies.

2. Low CMAP amplitudes in 85% of cases, particularly when recording from clinically affected (weak) muscles (usually proximal), since many muscle fibers do not reach threshold after a single stimulus because of the inadequate release of quanta (vesicles). This is the most consistent EDX finding in botulism. Motor distal latencies and conduction velocities are, however, normal.

3. Decrement of CMAP after slow repetitive stimulation (2 to 3 Hz). This finding is uncommon and is usually mild, not exceeding 8 to 15% of baseline. It is explained by the progressive depletion of the immediately available ACH stores.

4. Increment of CMAP after rapid repetitive stimulation (30 to 50 Hz), or after a brief (10 seconds) of exercise CMAP. With tetanic stimulation, Ca²⁺ influx is greatly enhanced resulting in larger releases of quanta. This leads to increasing number of muscle fibers reaching the threshold required for the generation of muscle action potentials. The CMAP increment in botulism is modest, between 30 and 100%, when compared to the increment in LEMS, which usually is greater than 200% (Table C24-2). This increment may be absent, especially in severely affected muscles particularly when botulism is due to type A toxin.

5. Normal needle EMG or evidence of increased number of short-duration, low-amplitude, and polyphasic motor unit action potentials on needle EMG, with fibrillation potentials in severely weakened muscles. This is best explained by the physiologic blocking of neuromuscular transmission and denervation of many muscle fibers.

6. Increased jitter with blocking on single-fiber EMG. Jitter improves following rapid stimulation owing to enhancement of ACH release by the influx of Ca²⁺ into the presynaptic terminal.

Table C24-2 Electrophysiological Differences Between Two Common Presynaptic Neuromuscular Disorders (Botulism and Lambert-Eaton Myasthenic Syndrome)

Electrophysiology	Botulism	Lambert-Eaton Myasthenic Syndrome
Baseline CMAPs	Low in amplitudes, particularly in proximal and weak muscles	Low in amplitudes in all muscles
CMAP increment	Present in clinically affected muscles	Present in all muscles
Degree of CMAP increment	Moderate (30–100%)	Marked (>200%)

Although the clinical presentations of LEMS and botulism are quite different, their EDX findings are similar, but with certain distinctions, since both are due to a presynaptic defect of ACH release (see Table C24-2).

FOLLOW-UP

After EDX confirmation, the patient’s family recalled that the patient had lunch with a friend at a local restaurant the day before the onset of symptoms. Both had a “homemade” soup. The friend became ill that night with severe nausea and vomiting, but subsequent neurologic symptoms did not develop.

The patient was given trivalent antitoxin within 24 hours of diagnosis. However, he continued to worsen over the ensuing days to complete paralysis of all voluntary muscles on days 5 to 7 (except for flicker movements of the hands and feet). Deep tendon reflexes became unelicited. On days 8 to 10, paralytic ileus developed, and the patient lost sphincteric control. Repeated EDX examinations showed a decline in baseline CMAP amplitudes. Bioassay of serum and stool cultures at the Centers for Disease Control (CDC) confirmed the diagnosis of botulism due to Clostridium botulinum type A.

Recovery was protracted. The patient was completely paralyzed, except for finger flickers, until day 15. Between days 15 and 30, he showed gradual improvement: strength returned, first in the distal muscles and then proximally. Later, he regained his ability to write and started communicating this way. Paralytic ileus resolved, but ventilation dependency was unchanged, with vital capacity ranging between 500 and 700 mL. Between months 2 and 3, his strength improved such that he could sit and feed himself. Extraocular movements returned gradually to full range. Pupils were still large but started reacting to light. Swallowing and speech improved gradually. During month 4, ventilation improved to allow extubation and then discharge for physical rehabilitation.

When the patient was seen 6 months after the onset of illness, he complained of easy fatigability and poor endurance. He had no appreciable muscle atrophy and minimal weakness of proximal and neck muscles (MRC 5-/5), and he had regained all deep tendon reflexes. Pupils were normal. The patient returned to work 1 month later. Examination 1 year later revealed no abnormality. Baseline CMAPs returned to normal, with absence of increment after rapid repetitive stimulation or postexercise facilitation (Figure C24-6).

Figure C24-6 Median compound muscle action potential (CMAP) at rest (waveform 1) and after exercise (waveform 2), during acute illness (A) and after recovery (B). Sensitivity in (A) is 2 mV/division, and in (B) it is 5 mV/division. Note the significant increment of CMAP on the first study (90%) and the lack of increment on the second. Note also that the baseline CMAP has improved significantly from 4.2 mV to 9 mV (compare waveforms 1 in (A) and (B)).

Food-borne botulism.

ANSWERS

1. C; 2. C; 3. D; 4. C; 5. B

SUGGESTED READINGS

Cherrington M. Botulism. Ten-year experience. Arch Neurol. 1974;30:432-437.

Cherrington M. Electrophysiologic methods as an aid in diagnosis of botulism: a review. Muscle Nerve. 1982;5:528-529.

Cherington M. Botulism: update and review. Semin Neurol. 2004;24:155-163.

Cornblath DR, Sladky JT, Sumner AJ. Clinical electrophysiology of infantile botulism. Muscle Nerve. 1983;6:448-652.

Hallet M. One man’s poison: clinical applications of botulinum toxin. N Engl J Med. 1999;341:118-120.

Hunter WB. Snappy exocytoxins. Nature. 1993;365:104-105.

Katirji B, Kaminski HJ. Electrodiagnostic approach to the patient with suspected neuromuscular junction disorder. Neurol Clin. 2002;20:557-586.

Pickett JB. Infant botulism: the first five years. Muscle Nerve. 1982;5:S26-S27.

Pickett J, et al. Syndrome of botulism in infancy: clinical and electrophysiologic study. N Engl J Med. 1976;295:770-772.

Robinson RF. Management of botulism. Ann Pharmacother. 2003;37:127-131.

Shapiro RL, Hatheway C, Swerdlow DL. Botulism in the United States: a clinical and epidemiologic review. Ann Intern Med. 1998;129:221-228.

St. Louis ME, et al. Botulism from chopped garlic: delayed recognition of a major outbreak. Ann Intern Med. 1988;108:363-368.

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