D, F, and G;
tetanospasmin
Botulinum toxin C
Synaptotagmin (calcium sensor)
Plasma membrane
Botulinum toxin A, C, E
Calcium channel
Ca2+
tips and tricks
• Botulism differs from other fl accid paralyses in that it always manifests initially with prominent cranial paralysis, it invariably has a descending progression, neurological signs and symptoms are referable to extraocular and bulbar weakness and include blurring of vision, ptosis, diplopia, ophthalmo- plegia, dysarthria, and dysphagia. This is fol- lowed by a characteristic bilateral, symmetric, descending paralysis with weakness of the upper limbs followed by truncal and lower extremity weakness and autonomic dysfunction. Res- piratory compromise may occur due to upper airway obstruction and/or to diaphragmatic weakness. There are typically no sensory symptoms.
characteristically begins with lethargy and poor feeding, usually accompanied by constipation.
This is typically followed by weakness of bulbar and limb muscles, hypotonia, loss of head control, poor sucking ability, and decreased movements. Autonomic involvement is common with constipation, tachycardia, hypotension, neurogenic bladder, and dry mouth.
Adult i ntestinal b otulism
The pathogenesis of adult intestinal botulism is similar to that of infant botulism. Only a few cases have been recognized, and most have occurred postoperatively, or in adults with under- lying pathology of the gastrointestinal tract causing an alteration of the normal gut fl ora, including prior antimicrobial therapy, achlorhy- dria, Crohn ’ s disease, or surgery. Diagnosis is established by isolation of the organism or toxin from fecal samples.
Inhalational b otulism
This form of botulism is caused by inhalation of aerosolized, pre - formed toxin which is absorbed into the circulation through the lungs. The use of aerosolized toxin as an agent of bioterrorism has the potential to lead to high numbers of casualties.
Iatrogenic b otulism
This refers to generalized weakness or autonomic dysfunction related to the use of botulinum toxin as a therapeutic agent.
Differential d iagnosis
The diagnosis should be suspected in an alert patient presenting with an acute onset of des- cending, painless paralysis without sensory involvement. Clinical suspicion may be increased in the case of an outbreak where there is a history of a common source of food exposure. The dif- ferential diagnosis for botulism may be system- atically broken down into central, peripheral nerve, neuromuscular junction, and muscular causes as shown in Table 17.1 .
Given the widespread pure motor dysfunction, three broad categories of disorders should be considered: myopathy, motor neuropathy/
neuronopathy, and neuromuscular junction disease. Few myopathies produce rapidly pro- Wound b otulism
Wound botulism is caused by infection of a con- taminated wound with C. botulinum (a natural contaminant of soil throughout the USA), with subsequent absorption of locally produced toxin into the circulation. First reported almost exclu- sively in patients with traumatic and surgical wounds, it is more recently associated with injec- tion drug users, and in particular with subcuta- neous injection of heroin in a method called “ skin popping, ” designed to slowly release the drug. Infection is believed to result from C. botu- linum spores contaminating the heroin. After injection, the spores germinate in an anaerobic tissue environment and release toxin. The pres- ence of skin abscesses may suggest the diagnosis, but the clinical diagnosis is often challenging.
Maxillary sinusitis associated with intranasal cocaine use has rarely been the source of wound botulism. The clinical syndrome of wound botulism closely resembles classic botulism, save for the absence of gastrointestinal symptoms.
The diagnosis is established by detection of the organism in the wound or toxin from the circulation.
Infant b otulism
Infant botulism is caused by ingestion of C. botu- linum spores, which colonize the gastrointestinal tract and produce toxin that is absorbed into the circulation. The source of spores in most cases is unknown, although the more common sources of infection for infants appear to be honey and environmental exposure. The age of onset is between 3 weeks and 8 months, with most cases occurring before the age of 6 years. The disease
and there is an absence of sensory symptoms or signs.
• Prominent oculobulbar and facial weakness are early manifestations with pupillary abnormalities in 50%.
• Patients are afebrile unless a concurrent infection is present.
• Nausea, vomiting, and diarrhea often precede or accompany neurological manifestations in food - borne botulism.
Table 17.1. Diagnostic considerations in a patient presenting with acute weakness with prominent ocular/bulbar involvement
Etiology Distinguishing features/Ancillary tests
Central nervous system Brain - stem strokes Demyelination
Rhombencephalitis/Infections Thiamin defi ciency
Altered sensorium, long tract signs, upgoing toes,
abnormalities of hearing, facial sensory loss; nystagmus and ataxia if present would be incompatible with botulism and suggest CNS/alternate etiology. Test: MRI of the brain, lumbar puncture
Anterior horn hell Poliomyelitis West Nile virus
Fever, meningeal signs. Classically asymmetric fl accid paralysis. CSF pleocytosis. West Nile serology
Peripheral nerve
a. Guillian – Barr é syndrome (GBS) a
b. Miller - Fisher syndrome a c. Heavy metal poisoning a d. Lyme disease
e. Tick paralysis f. Diphtheria g. Porphyria
h. Critical illness neuropathy/
myopathy i. Sarcoidosis j. Marine poisoning:
saxitoxin tetrodotoxin ciguatera toxin
a. GBS is usually associated with sensory symptoms at onset.
NCS/EMG shows demyelination. LP: albuminocytological dissociation
b. Ataxia, anti - GQ1b antibodies in Miller - Fisher syndrome c. Urine, blood heavy metal screen
d. Lyme serology, CSF Lyme PCR, CSF studies e. Usually children. Search skin for tick exposure f. Check for tonsillar exudates, culture
g. Porphyria screen
h. Neuropathic/myopathic fi ndings in light of severe systemic illness, steroid use
i. Radicular pattern, sensory involvement. Chest radiograph/
imaging, serum ACE levels, MRI of the brain and spine as indicated. CSF studies
j. Prominent sensory symptoms, pure motor presentation is very unusual
Neuromuscular junction a. Myasthenia gravis a b. Lambert – Eaton syndrome a c. Aminoglycosides,
neuromuscular blocking agents (drugs, venoms, Mg 2 + )
d. Organophosphate poisoning
a, b. Subacute/chronic onset. Arefl exia may be seen in LES but not in MG. NCS/EMG may show a decrement with repetitive nerve stimulation in MG and LEMS. Low baseline CMAPs with prominent facilitation seen with the latter. Serological studies:
anti - AChR, anti - MuSK, anti - voltage - gated calcium channel antibodies maybe helpful. Organophosphate poisoning shows prominent oral/respiratory secretions, pinpoint pupils
Muscle disease a. Polymyositis a b. Dermatomyositis a c. Periodic paralysis d. Muscular dystrophy (oculopharyngeal muscular dystrophy, mitochondrial disorders)
Elevated serum creatine kinase in (a, b). NCS/EMG shows prominent spontaneous activity and myopathic features on EMG
(c) Serum hypokalemia/hyperkalemia. History of repeated episodes with recovery in between. Respiratory, autonomic, extraocular involvement extremely rare
Muscular dystrophies have normal pupillary refl exes, diplopia is rare
a More common etiologies.
ACE, angiotensin - converting enzyme; AChR, acetylcholine receptor; CMAP, compound muscle action potential; CNS, central nervous system; CSF, cerebrospinal fl uid; EMG, electromyography;
LEMS, Lambert – Eaton myasthenic syndrome; LES, Lambert – Eaton syndrome; LP, lumbar puncture;
MG, myasthenia gravis; MRI, magnetic resonance imaging; NCS, nerve conduction studies; PCR, polymerase chain reaction.
cord, and cerebrospinal fl uid (CSF) glucose, protein, and cell count.
Electrophysiological fi ndings in b otulism A low - amplitude compound muscle action potential (CMAP) in a clinically weak muscle is seen in up to 85% of botulism cases. However, the sensitivity of this fi nding may be as low as 50%
when testing is limited to distal muscles rou- tinely performed in the electromyography (EMG) laboratory. A decremental response ( > 10% reduc- tion in amplitude or area) on slow repetitive nerve stimulation (2 – 5 Hz) is seen in both presy- naptic and postsynaptic disorders of the neu- romuscular junction, including botulism (Figure 17.2 ). Post - tetanic facilitation, after 10 s of max- imal isometric exercise or with high - frequency repetitive stimulation at 30 – 50 Hz is seen in up to 62% of botulism cases. The degree of facilitation is modest, typically ranging from 20% to 60%, whereas facilitation in LES is typically 100 – 300%.
Needle EMG shows motor units with myo- pathic features or mixed myopathic – neuropathic features in more severe cases. Single - fi ber EMG shows evidence of increased jitter and blocking in virtually all cases of botulism, but increased jitter is not specifi c for botulism. The fi nding of normal jitter in a clinically weak muscle effectively excludes a disorder of neuromuscular transmission.
Microbiological d iagnosis of b otulism
Establishing a microbiological diagnosis involves detection of the toxin in samples from serum, stool, gastric aspirate, and wound aspirate. The gold standard for laboratory diagnosis remains the mouse lethality assay. The test is expensive, restricted to a few specialized centers, and results are delayed. False - positive and false - negative results are reported and a negative test does not exclude the diagnosis. Alternate immunological methods remain investigational. Polymerase chain reaction (PCR) assays are used for the detection of C. botulinum toxin genes in food and fecal samples.
Detection of toxin in the stool, serum, or wound, and isolation of C. botulinum using anaerobic culture methods from relevant samples, are methods for making the diagnosis of infant, wound, and adult intestinal botulism.
gressive weakness and early bulbar/respiratory signs. Although the periodic paralyses may cause acute paralysis, involvement of ocular and facial muscles is rare.
The presence of sensory symptoms, prodromal viral or diarrheal illness, and an ascending pattern of weakness suggests Guillain – Barr é syn- drome (GBS). However, early in the course, it may be diffi cult to differentiate some GBS variants, such as the Miller - Fisher syndrome (MFS) or the cervical – pharyngeal – brachial variant, from bot- ulism. Anti - GQ1b antibodies may be helpful in this clinical scenario, but results of testing may be delayed. Electrophysiological testing (showing the typical fi ndings of demyelination) is required to rule out GBS or MFS. Tick paralysis classically has an ascending pattern resembling GBS and a careful search of the skin, especially the scalp, for tick exposure helps make the diagnosis. Polio- myelitis and West Nile infections usually cause asymmetric weakness, in association with a febrile onset and signs of meningeal irritation.
The neuromuscular junction transmission dis- orders – myasthenia gravis (MG) and Lambert – Eaton syndrome (LES) – resemble botulism in that they result in weakness caused by abnormal neuromuscular transmission. In addition to weakness, arefl exia and autonomic involvement are common to both LES and botulism, but, in LES, cranial nerve involvement is typically not conspicuous and respiratory failure is rare.
The facilitation/potentiation of muscle stretch refl exes, reported in LES, has not been observed in botulism. In MG, refl exes are typically pre- served unless there is severe limb weakness.
Serological studies for MG, and for LES, if posi- tive, help make the distinction. The major distin- guishing feature is that MG and LES present in a subacute to chronic manner while botulism is acute and progresses precipitously. Hyper- magnesemia or the administration of other drugs adversely affecting neuromuscular transmission may cause rapid neuromuscular blockade, but is ruled out by the history.
Diagnosis of b otulism
The clinical diagnosis of botulism is supported by electrophysiological and microbiological studies. Important investigations that should be normal in botulism include: complete blood count (CBC), imaging of the brain and spinal
should be made on an individual basis by moni- toring of upper airway patency and deterioration of respiratory fl ow volumes and pressures.
Arterial hypoxemia and hypercapnia occur late in impending respiratory failure and are insensi- tive for guiding decisions about intubation.
Supportive management of blood pressure, urinary retention, and constipation is needed with autonomic failure. In food - borne cases, pur- gatives and activated charcoal may be adminis- tered if there is concern for residual unabsorbed toxin in the gastrointestinal tract.
Administration of a ntitoxin
The decision to administer antitoxin should be made early (within fi rst 24 h) in suspected cases without waiting for laboratory confi rmation, because the antitoxin neutralizes circulating toxin but has no effect on internalized and bound toxin. Antitoxin use does not ameliorate estab- lished weakness, but may help prevent progres- sion. In the USA, antitoxin is made available by the Centers for Disease Control (CDC) through the state and local public health departments.
In the USA, licensed bivalent equine antiserum In suspected inhalational cases the toxin is
believed to be present for up to 24 hours in upper airway secretions; however, the utility of nasopha- ryngeal secretions in establishing the diagnosis is unknown.
Treatment of b otulism
Botulism is a reportable disease. Clinicians should be familiar with state, provincial, or country reporting requirements, emergency contact numbers, and, if indicated, the process for release of antitoxin.
The cornerstones of treatment remain sup- portive care and early administration of antitoxin.
The case fatality rate is approximately 15% for wound botulism, approaches 5% for food - borne cases, and is less than 5% for infant botulism.
Death usually occurs from respiratory failure or from complications such as pneumonia.
Supportive c are
All patients should be admitted to the intensive care unit (ICU) for monitoring of upper airway patency and respiratory function. The decision to intubate and institute mechanical ventilation
Figure 17.2. Top: repetitive nerve stimulation at 3 Hz of the left abductor digiti minimi (Abd Dig Min) and left abductor pollicis brevis (Abd Poll Brevis) muscles. Bottom: high - frequency repetitive nerve stimulation showing modest pseudofacilitation in the abductor pollicis brevis muscle.
LAbd dig min C8, T1
a. Decrement—21% b. Decrement—9.5%
LAbd poll brevis C8, T1
LAbd poll brevis C8, T1
c. 30 Hz Stimulation, baseline CMAP amplitude—9.4 mV; Facilitation (19—1); 29.2%
strated reduced duration of hospital stay, ICU stay, duration of mechanical ventilation, and duration of tube/intravenous feeding.
Additional a spects of t reatment
Antibiotics are not indicated in classic and infant botulism, and may worsen illness in infants not treated with BIG - IV due to systemic absorption of toxins released into the gut from bacterial lysis.
In all cases, aminoglycosides and macrolides should be avoided in treatment of secondary infections to prevent further deleterious effects on neuromuscular transmission. Wound debri- dement should be performed in all cases of wound botulism and antibiotics should be given after administration of antitoxin to prevent wors- ening of symptoms from toxins released from antibiotic - induced bacterial lysis. Acetylcholine- sterase inhibitors are not usually benefi cial although 3,4 - diaminopyridine may improve strength but not respiratory function.
Conclusion
Botulism is a life - threatening infection caused by neurotoxins secreted by Clostridium botulinum . Diagnosis is based on the clinical history and physical examination, with supporting evidence from electrophysiological and laboratory studies.
Close coordination with regulatory health authorities is necessary to establish the diagnosis and to initiate prompt administration of anti- toxin. Effective treatment involves not only early administration of antitoxin, but high - quality supportive treatment in an intensive care setting.
Depending on the initial severity of illness, recov- ery may be quite prolonged, with many patients continuing to have symptoms a year or longer after the onset of illness.
Bibliography
Arnon SS , Schechter R , Maslanka SE , Jewell NP , Hatheway CL . Human botulism immune glob- ulin for the treatment of infant botulism . N Engl J Med 2006 ; 354 : 445 – 7 .
Bleck TP . Clostridium botulinum (botulism) . In:
Mandell GL , Bennett JE , Dolin R (eds), Principles and Practice of Infectious Diseases , 5th edn. Philadelphia, PA : Churchill Livingstone , 2000 : 2443 – 548 .
against types A, B, and an investigational mono- valent type E antiserum are available through the CDC. In cases where the type of toxin is unknown, it is recommended that all three types be admin- istered. The bivalent A and B antitoxin or mono- valent E antitoxin can be administered in cases where the type has been identifi ed.
caution!
During administration of antitoxin, the following reactions may occur:
• Anaphylaxis
• Thermal reactions (usually occurring 20 min to 1 h after administration and characterized by chills, dyspnea, and a rapid rise in temperature)
• Serum sickness (occurring within 14 days after administration and characterized by fever, urticaria or a maculopapular rash, arthritis, or arthralgias, and
lymphadenopathy).
Skin testing for hypersensitivity should be performed on all patients before they receive antitoxin. If skin testing is positive, the patient can be desensitized over several hours before the full dose of antitoxin is
administered.
Diphenhydramine and epinephrine should be available during administration of antitoxin, and the patient should be kept under careful observation for 1 – 2 h after administration (then under close surveillance for a full 24 h).
Hypersensitivity reactions including urticaria, serum sickness, febrile reactions, and anaphy- laxis are reported in 9% of cases. Diphenhydramine and epinephrine should be available during administration. Botulism immune globulin (BIG - IV) is a bivalent human antiserum approved by the Food and Drug Administration (FDA) in 2003 for the treatment of infant botulism. BIG - IV is available through the California Department of Health Services. A 5 - year, randomized, double - blind, placebo - controlled trial of BIG - IV demon-
Kongsaengdao S , Samintarapanya K , Rusmeechan S , et al. Electrophysiological diagnosis and pat- terns of response to treatment of botulism with neuromuscular respiratory failure . Muscle Nerve 2009 ; 40 : 271 – 8 .
Lindstrom M , Korkeala H . Laboratory diagnosis of botulism . Clin Microbiol Rev 2006 ; 19 : 298 – 314 .
Maselli RA . Pathogenesis of human botulism . Ann N Y Acad Sci 1998 ; 841 : 122 – 39 .
Maselli RA , Bakshi N . Botulism . Muscle Nerve 2000 ; 23 : 1137 – 44 .
Padua L , Aprile I , Monaco ML , et al. Neur- ophysiological assessment in the diagnosis of botulism: usefulness of single fi ber EMG . Muscle Nerve 1999 ; 22 : 1388 – 92 .
Souyah N , Karim H , Kamin SS et al. ( 2006 ) Severe botulism after focal injection of botulinum toxin . Neurology. 67 ( 10 ) , 1855 – 1856 .
Department of Public Health, California.
Botulism , 2005 . Online. Available at: www.
sfcdcp.org/botulism.html#providers (accessed July 26, 2010).
Cherrington M . Clinical spectrum of botulism . Muscle Nerve 1998 ; 21 : 701 – 10 .
Centers for Disease Control and Prevention . Botulism: Treatment overview for clinicians . Online. Available at: www.bt.cdc.gov/agent/
Botulism/clinicians/treatment.asp (accessed July 26, 2010 ).
Center for Infectious Disease Research and Policy (CIDRAP) . Botulism: Current, comprehensive information on pathogenesis, microbiology, epidemiology, diagnosis, and treatment , 2009 . Online. Available at: www.cidrap.umn.edu/
cidrap/content/bt/botulism/index.html (acc- essed July 31, 2010).
Davis LE , King MK . Wound botulism from heroin skin popping . Curr Neurol Neurosci Rep 2008 ; 8 : 462 – 8 .
Gupta A , Sumner CJ , Castor M , et al. Adult botu- lism type F in the United States, 1981 – 2002 . Neurology 2005 ; 65 : 1694 – 700 .
Juel VC , Bleck TP . Botulism . In: Fink MP , Abraham E , Vincent J - L , Kochanek PM (eds), Textbook of Critical Care , 5th edn. Philadelphia, PA : Elsevier Saunders , 2005 : 1405 – 10 .
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18
Lambert – Eaton Myasthenic Syndrome
Michael W. Nicolle
Department of Clinical Neurological Sciences, University of Western Ontario, and Myasthenia Gravis Clinic, University Hospital, London, ON, Canada
Pathophysiology
To understand the diagnosis and treatment of Lambert – Eaton myasthenic syndrome (LEMS), it is helpful to understand neuromuscular trans- mission (NMT). Voltage - gated calcium channel (VGCC) antibodies reduce Ca 2 + infl ux into the presynaptic nerve terminal, resulting in NMT failure at muscle fi bers and cholinergic transmis- sion failure at autonomic synapses. The effects of VGCC antibodies are transiently overcome by increasing presynaptic nerve terminal Ca 2 + content after high - frequency nerve depolariza- tion, which increases acetylcholine (ACh) release.
Thus, a maximal voluntary contraction (MVC) of muscle or high - frequency stimulation (HFS) of nerves in the electromyography (EMG) lab explains the clinical phenomenon of a transient increase in deep tendon refl exes and perhaps strength after an MVC, and the characteristic electrophysiological fi ndings in LEMS (see below). In approximately half of LEMS cases, an underlying malignancy is found, with a small cell lung cancer (SCLC) in most paraneoplastic LEMS (P - LEMS). Non - paraneoplastic LEMS (NP - LEMS) is a primary autoimmune disease.
science revisited
neuromuscular transmission The steps involved in neuromuscular transmission are:
• Motor nerve depolarization produces action potentials
• Sodium enters the nerve through voltage - gated sodium channels
• Repolarization of motor nerves, stopping action potential propagation
• Potassium leaves the nerve through voltage - gated potassium channels • Opening of presynaptic nerve terminal
VGCCs in response to nerve terminal depolarization, allowing calcium to enter the nerve terminal
• Migration and exocytosis of ACh - containing vesicles
• Binding of released ACh to ACh receptors (AChR) on the muscle surface
• ACh binds transiently to the AChR before being released and metabolized by
acetylcholinesterase (AChE), or diffusing away
Neuromuscular Disorders, First Edition. Edited by Rabi N. Tawil, Shannon Venance.
© 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.