Histoplasmosis of the nervous system
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In this article, the author reviews the clinical manifestations, diagnostic tests, and management of patients who present with botulism: foodborne, wound, adult intestinal toxemia, iatrogenic (following medical or cosmetic administration), and inhalational botulism. Recent information on wound and foodborne botulism is presented, along with diagnostic evaluations and treatments. New antitoxin treatment recommendations are included.
• Botulinum toxin is one of the most potent neurotoxins in the world and is lethal in small doses.
• Botulinum toxin acts at the neuromuscular junction. It interferes with proteins involved in acetylcholine vesicle fusion at the presynaptic nerve terminal, thereby blocking release into cholinergic synapses of the peripheral nervous system.
• Most cases of foodborne botulism come from improperly home-canned foods whose preparation does not destroy C botulinum spores.
• Wound botulism occurs through skin infections, with an increased incidence in people who inject drugs.
• The definitive diagnosis of botulism is made by demonstrating the presence of botulinum toxin in serum, stool, or suspected food, or isolation of C botulinum from a wound, along with supportive clinical and electrodiagnostic features.
• Frequent monitoring of respiratory function is critical – either by forced vital capacity or negative inspiratory force; consider elective intubation for forced vital capacity less than 30% of predicted.
• Laboratory confirmation is done by demonstrating the presence of botulinum toxin in serum, stool, or food, or by culturing Clostridium species from stool or a wound.
•The Centers for Disease Control and Prevention (CDC) recommend administration of botulinum antitoxin as soon as the diagnosis is suspected.
Botulism as a clinical entity was reported in 1897, when van Ermengem described the clinical, toxicological, and bacteriological features of an outbreak of foodborne botulism. He demonstrated that botulism was not due to an infection, but to an intoxication produced by a gram-positive, rod-shaped bacterium he named Bacillus botulinus, later called Clostridium botulinum. In the 1970s, Midura and Arnon identified infants developing paralysis following C botulinum colonization of the gastrointestinal tract, with subsequent release of botulinum toxin into the gut (58). Wound botulism was historically described in connection to traumatic injury. Its association with drug injection use was first reported in 1982 in New York City.
Before 1950, mortality from botulism was approximately 60% (25).
Although termed “botulinum neurotoxin” (BoNT), the toxin comes from 6 groups of bacteria: Clostridium botulinum I-IV, Clostridium baratii, and Clostridium butyricum (62). Botulinum toxin is a family of serologically related neurotoxins: types A, B, C1, D, E, F, G, and a variably classified H (28; 34).
Botulism classically presents with prominent cranial nerve palsies, followed by symmetric, descending, “flaccid paralysis” in an afebrile patient with normal mentation. The prominent cranial nerve palsies are loss of visual accommodation with blurred vision, external ophthalmoparesis, dysarthria, dysphagia, and facial weakness (53; 64). Limbs become weak over 1 to 3 days, potentially leading to quadriplegia. Deep tendon reflexes are typically normal or decreased. Patients often develop a dry mouth and fixed pupils. Weakness of respiratory muscles may require intubation and mechanical ventilation in up to two-thirds of patients (68). At hospital admission, up to 40% of patients may have respiratory symptoms, and these patients show a shorter median incubation time (19). Using defined criteria, Rao and colleagues collected cases (2002-2015) from the CDC for which botulism antitoxin was provided (68). Chatham Stephens’s systematic review of the literature (1932-2015) included 402 cases, 46% of whom were intubated. The most common signs and symptoms were dysphagia (65% to 86%), weakness (50% to 85%), blurred (36% to 80%) or double (49% to 76%) vision, dysarthria (78%), and ptosis (37%) (19; 68).
Autonomic symptoms include blurred vision, dry mouth, and reduced sweating. Topakian and colleagues found 5 of 5 patients with abnormal autonomic testing in foodborne botulism (82).The autonomic symptoms have been attributed to the abnormal sudomotor function and heart rate variability to posture (12).
Aside from infant botulism (discussed elsewhere), foodborne and wound botulism are the most common forms. Other syndromes include adult intestinal toxemia botulism, iatrogenic botulism, and inhalation botulism.
Foodborne botulism. After ingestion of food containing botulinum toxin, the mean incubation period is 2 days, with a range from 0.5 to 6 days (53). Gastrointestinal symptoms develop within 12 to 72 hours of ingestion: abdominal pain, nausea, and vomiting. In general, the longer the incubation period, the milder the symptoms.
In a review of United States cases of botulism A and B, over 70% of patients complained of dysphagia, dry mouth, double vision, dysarthria, fatigue, and arm weakness, and, on examination, had arm weakness and ptosis and were alert (45).
In general, intoxication from type A is more severe than from types B, E, or F, although the frequency of clinical signs and symptoms varies somewhat from outbreak to outbreak (88; 32).
Most cases of foodborne botulism come from improperly home-canned vegetables and meats that fail to destroy C botulinum spores. Anaerobic conditions, low acidity (pH> 4.6), low salt and sugar concentrations, and temperatures higher than 39°F (4°C) promote germination of C botulinum spores and botulinum toxin production (15). Reports have identified numerous sources: potato salad (13); carrot juice containing botulinum toxin type A (15); roasted mushrooms, bamboo shoots, and fermented tofu (soybean curd); brewing of Pruno, made from fermenting potato (69); stink heads; seal oil; pasta with jarred pesto; canned tomato sauce; and red hot chili pepper (Centers for Disease Control and Prevention 2014).
Wound botulism. Patients with wound botulism develop neurologic signs and symptoms similar to those in foodborne botulism. Wound botulism is caused by type A toxin and rarely type B (57; 85). The incubation period ranges from 4 to 51 days (40). Most, but not all, wounds appear infected. Individuals with wound botulism usually lack the gastrointestinal prodrome seen in foodborne infections. A rise in wound botulism cases has been seen in people who inject drugs (60). Skin infections, caused by a practice known as “skin popping” whereby users inject contaminated heroin subcutaneously or into muscle, increase risk for botulism. Skin popping can create an anaerobic environment of necrotic tissue in which BoNT can be readily formed and released. From 2001 to 2016, 353 wound botulism cases in the United States were reported to the Centers for Disease Control and Prevention; 291 were from California (13). In the past 3 years, 15 cases of wound botulism in Texas and 9 cases in California were reported in persons who inject drugs. The majority were men (83%) and 83% had skin abscesses. The most common symptoms were dysphagia, generalized weakness, dysarthria and visual problems; 88% required mechanical ventilation (67; 61). Black tar heroin, which is a cheaper, acetylated morphine, has been associated with increased injection site vein loss and soft tissue infections, thereby increasing abscess formation and Clostridial spore proliferation/contamination (79).
Adult intestinal toxemia botulism or adult intestinal colonization botulism. This entity is rarely reported and, therefore, not easily classified. It can present with nausea, vomiting, abdominal pain, constipation, and abdominal distension, lasting for weeks to months. Blurred vision, double vision, ptosis, dysarthria, and dysphagia follow in a typically alert and afebrile individual. The disease may progress to a descending, fairly symmetric flaccid weakness and eventual respiratory failure. Patients with bowel surgery or anomalies, or recent use of antimicrobials, are at risk, although adult intestinal toxemia botulism has rarely been reported in healthy individuals (35). It has been proposed that those with an abnormal gastrointestinal tract have bacterial flora changes that enable Clostridia organisms (C botulinum, C butyricum, C baratii) to colonize the gut (23). The in vivo toxin produced is then absorbed through the gut to produce botulism that may have a more protracted onset and duration. Recovery typically occurs over months. Of the 25 cases Harris and colleagues collected from the literature, 8 ultimately died (35). Toxin types were recorded in the following frequency: A in 40%, B in 24%, F in 20%, and E in 8%. Relapse of symptoms after antitoxin treatment has been reported to the Centers for Disease Control and Prevention, presumably from continued gastrointestinal in vivo toxin production (77). Intestinal colonization botulism is confirmed by detection of botulinum toxinin serum and/or stool, or isolation of neurotoxigenic clostridia from the stool. Clostridial spores may be identified in the stool, but as they are generally not harmful to healthy adults, may not be adequate to confirm the diagnosis. Toxin or isolation of clostridia from gastric aspirate has also been reported in cases. Key observations from several cases can help confirm adult intestinal toxemia botulism. These include prolonged excretion (10 – 100+ days) of viable Clostridium spores or neurotoxin in the stool, a high level of botulinum neurotoxin in the feces compared to serum, and persistent recurrence of disease symptoms (35).
Iatrogenic botulism following medical or cosmetic administration. Both botulinum A and B toxins are widely used as therapeutic and cosmetic medicines. The 50% lethal dose for an adult is about 3000 U of botulinum toxin, and therapeutic botulinum doses rarely exceed 400 U (10). In 18 cases of iatrogenic botulism from botulinum neurotoxin type A (BoNT/A), with ages ranging from 16 to 74 years, all patients had been treated for underlying neurologic disorders (54). The most common symptoms were dysphagia (56%) and upper, greater than lower, limb weakness (39%). Each of the following symptoms—diplopia, speaking difficulty, and face, tongue, or neck weakness—was found in 28% of cases. In the 2 cases with known outcome, spontaneous remission occurred over months. Eighty-six botulism cases caused by cosmetic injection of BoNT were diagnosed (03), with symptoms of headache, dizziness, insomnia, fatigue, blurred vision, eye opening difficulty, slurred speech, and dysphagia occurring up to 36 days after BoNT injection, (mean 2nd to 6th day postinjection). Interestingly, the dose of BoNT was negatively related to latent period. All patients were treated with antitoxin and discharged within 1 and 20 days. Cases of severe botulism have been reported following cosmetic procedures with unlicensed, highly concentrated botulinum preparations (22).
Inhalational botulism. Botulism acquired on the battlefield or in a laboratory may occur via inhalation of BoNT. Rare cases of botulism have occurred in technicians performing postmortem exams on animals that were exposed to BoNT/A, or in persons with or without sinusitis following inhalation of cocaine (52; 72) and in farmers or construction workers through inhalation related to work exposure. The signs and symptoms of inhalational botulism are similar to botulism acquired from ingestion of the toxin, except for the absence of gastrointestinal symptoms, and include difficulty swallowing, extremity weakness, speech problems, abnormal extraocular movements, and moderately dilated pupils. The incubation period for inhalational botulism is similar to that from ingestion of BoNT, ranging from 24 to 36 hours to several days, rarely as early as 4 to 12 hours post-exposure (25). Unusual outbreaks, large numbers of affected victims in different locations, or lack of a common food source should lead the physician to consider bioterrorism or biological warfare and promptly notify local health authorities.
Recovery is dependent on dose and toxin type. Rapidly progressing cases are more likely to require intubation. BoNT types A and E typically lead to a faster onset than type B (43). Patients who died had a shorter reported median incubation period and a shorter reported median time from illness onset to hospital admission (19).
Therapy with equine antitoxins became available in the early 1970s. Antitoxin cannot neutralize toxin once it is bound to the nerve receptors, and, therefore, does not reverse weakness. Antitoxin prevents progression of the symptoms, but not until up to 12 hours after administration. With adequate ventilatory assistance, tracheostomy, and improved intensive care support, botulism fatality rates are generally less than 10% (25). Although antitoxin can reduce the length of hospital stay and mechanical ventilation by several weeks, recovery remains slow, over weeks to months. Recovery of strength results from development of new neuromuscular junctions, which takes time (31). Significantly fewer deaths from botulism have been reported from the 1970s continuing up to 2015 (19). In literature series from 1980-2015, the case fatality ratio was 9%, highest in individuals over 70. The Centers for Disease Control and Prevention reports that roughly 5% of patients die (13). The clinical evidence for botulinum antitoxin efficacy in humans is based on retrospective analyses of small numbers of patients and animal studies. Although the evidence is limited, it is believed that early treatment, especially within 24 hours, is most effective in preventing paralysis progression.
Data from the Centers for Disease Control and Prevention on confirmed cases from the 2017 National Botulism Surveillance Summary included no deaths among roughly 31 wound botulism cases, 3 deaths among 21 foodborne cases, and 1 death in suspected adult intestinal colonization. Death usually occurs from respiratory failure due to respiratory muscle weakness or from pneumonia. Complications of all forms of botulism are those of long-term weakness, including aspiration pneumonia and decubiti. Patients often complain of fatigue, exercise intolerance, general weakness, dry mouth, and shortness of breath that may persist for over 1 year (55). Objectively, however, they usually have normal muscle strength. Patients seldom return to full-time work for months.
Vignette 1 (85). A 35-year-old male presented with 2 days of blurred and double vision, ptosis, and difficulty swallowing. Initial testing including MRI brain was normal, and he was sent home. Over days, his symptoms worsened, and he re-presented with slurred speech and facial weakness. Skin examination revealed no abscesses or open wounds. He was admitted to the hospital for possible stroke and treated for laryngitis.
Past medical history included methamphetamine use over many years. He had recently injected methamphetamine, mixed with water from a glass (sitting for an unknown time), intravenously, 36 hours before his symptoms began. The recent intravenous drug use raised suspicion for botulism.
Heptavalent botulinum antitoxin was provided by the Centers for Disease Control and Prevention and administered to the patient within 24 hours of admission to the hospital. He did not require ventilatory support, and his symptoms of double vision, ptosis, difficulty swallowing, and facial weakness gradually improved until hospital discharge 5 days after antitoxin administration. Serum obtained before antitoxin administration tested positive for BoNT type B by the BoNTEndopep-MS assay.
Vignette 2. A 54-year-old woman with a history of Crohn disease on immunosuppressant medications presented to an outside hospital with sudden-onset right ptosis, dysarthria, and shortness of breath, followed over days by diplopia, soft voice, proximal arm weakness, and difficulty swallowing. Symptoms were preceded by abdominal pain and distension. She was intubated 8 days after symptom onset.
On examination, she communicated by writing. Facial muscles, tongue, and neck were moderately weak, with complete ptosis and no diplopia. She had severe proximal, greater than distal, weakness in the upper, more than lower, extremities. Reflexes were mildly reduced. Although antibodies for myasthenia gravis were negative, she was treated presumptively for myasthenia gravis with a 5-day course of intravenous immunoglobulin. Repeat nerve conduction study showed small-amplitude motor responses, and EMG showed small, short duration motor unit action potentials with early recruitment, consistent with a myopathic pattern. She was treated with antitoxin and penicillin G 2 weeks into her course. Botulinum neurotoxin type A, both in serum and stool, was detected by the bioassay method (intraperitoneal inoculation of mice). One month later, she was weaned from tracheostomy, and after 2 months she ambulated with a walker and her swallowing study normalized. Because she was treated late in the course, this may have limited her response to botulism treatment. She also had underlying medical conditions requiring ongoing treatment and has not returned to her baseline. She had a transient recurrence of symptoms, and concern was raised for another occurrence of botulism. She was not retreated and gradually stabilized. These scenarios can be difficult to manage over time.
Botulism is caused by the release of botulinum neurotoxins, which are polypeptides that are naturally produced by the spore-forming, strictly anaerobic, gram-positive bacillus, Clostridium botulinum, as well as certain strains of Clostridium baratii (toxin type F) and butyricum (toxin type E). C botulinum is found ubiquitously in soil and aquatic sediments (77; 51).
Botulinum toxin is a family of serologically closely related neurotoxins: A, B, C1, D, E, F, G, and a variably classified type H or FA (28; 34). On a milligram-per-kilogram basis, botulinum toxin is the most potent biological toxin known. It has been estimated that 6 picograms or 5,000,000 molecules of botulinum toxin are sufficient to kill a mouse (37). The estimated human dose (assuming 70 kg weight) of BoNT/A lethal to 50% of a population that is exposed (LD50) based on animal studies is approximately 0.09 to 0.15 μg by intravenous administration, 0.7 to 0.9 μg by inhalation, and 70 μg by oral administration (25). Other reports include BoNT LD50 lies between 0.1 and 500 ng/kg (81).
BoNT must travel from the gut via the circulation to reach its final target, the neuromuscular junction (76; 42). Botulinum neurotoxins are not rapidly inactivated by the acid and proteolytic activity of stomach fluids. Botulinum toxin is released from bacteria as part of a noncovalent multimeric complex containing auxiliary proteins. This complex is formed by BoNTs and nontoxic neurotoxin-associated proteins. The nontoxic non-haemagglutinin component (NTNHA) plays an important role in protecting BoNTs from the gastrointestinal tract, and other subunits enable binding to the surface of intestinal cells for subsequent transcytosis of the neurotoxic complex from the apical membrane to the basolateral membrane of intestinal epithelium (81; 56). Once released, the BoNT progenitor complex sequesters E-cadherin in its monomeric form, blocking E-cadherin dimer formation, which weakens the transepithelial barrier. This process leads to bulk entry of neurotoxin into the bloodstream (81). After release, the toxin then reaches the lymph and blood circulations. The toxin does not cross the blood-brain barrier (78), but does cross the blood-nerve barrier.
All BoNTs are protoxins that target and enter motor nerve terminals at neuromuscular junctions. Binding of the botulinum toxin to its receptor is of high affinity but is reversible until the toxin is internalized into the cell. Internalization of the toxin occurs through a receptor-mediated endocytosis approximately one-half hour after binding (76). BoNTs are synthesized as single-chain polypeptides with a molecular weight of approximately 150 kDa. Subsequent enzymatic cleavage produces about a 50 kDa light chain (LC) polypeptide and a roughly 100 kDa heavy chain (HC) polypeptide that are linked via a single disulfide bond. A short linker region between the LC and HC needs to be cleaved by either bacterial or host proteases to convert the protoxin into its active form. The LC functions as a zinc-dependent protease, and the HC contains 2 functional 50 kDa domains: a C-terminal domain, which delivers the LC into the cytosol, and an N-terminal domain that recognizes specific cell-surface receptors. Although all BoNT serotypes inhibit acetylcholine release, their mechanisms of action, specific toxicities, and durations of persistence within the nerve cell differ. Mechanism of action is via different intracellular protein targets (there are 7 different cleavage sites within the 3 protein targets). After BoNT binds to high-affinity presynaptic receptors, it is transported into the nerve cell through a receptor-mediated endocytosis process. Acidification of the endosome triggers conformational changes of the toxins that lead to the N-terminal HC domain enabling the catalytic domain (LC) to translocate across the endosomal membrane into the cytosol of the peripheral cholinergic nerve cell. Once inside the cytosol, the LC blocks neurotransmitter acetylcholine release by selectively targeting and cleaving a specific set of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, which mediate fusion of synaptic vesicle membranes to the presynaptic membrane in neurons. The SNARE proteins and their sensitivities to BoNT are synaptosomal-associated protein of 25 kDa (SNAP-25; cleaved by BoNT/A, BoNT/C, BoNT/E62); syntaxin 1 (cleaved by BoNT/C); and synaptobrevin (also known as vesicle-associated membrane protein [VAMP]) (cleaved by BoNT/B, BoNT/D, BoNT/F, BoNT/G) (25; 27).
In foodborne botulism, the individual eats the preformed toxin. In infant botulism and adult intestinal toxemia botulism, C botulinum spores germinate in and produce toxin directly in the gastrointestinal tract (86). In wound botulism, anaerobic wound infections that contain C botulinum produce the toxin that is then systemically absorbed.
Because the muscle responds to botulism as if the nerve had been transected, biochemical changes develop in the paralyzed muscle fiber, inducing sprouting of the nerve terminal and the formation of a new neuromuscular junction. Thus, recovery from botulism occurs both by the sprouting of new synapses and by the nerve cell body producing new soluble N-ethylmaleimide-sensitive fusion proteins and transporting them down to the synapse via axoplasmic flow.
BoNT toxin types A, B, E, and F are the main toxins that affect humans. C botulinum strains that produce toxins A, B, and F are usually found in soil of geographic areas having low rain fall and moderate temperatures. Type A toxin-producing bacteria are found primarily west of the Mississippi river, and type B toxin-producing bacteria are found east of the Mississippi River. Type E toxin-producing bacteria are found in marine life and sediment around fresh water, particularly in Alaska and the Great Lakes region (39).
Epidemiology varies by location, reporting method, and year. Using defined criteria for botulism, Rao and colleagues collected cases from the Centers for Disease Control and Prevention for which botulism antitoxin was provided between 2002 to 2015 (68). Of 323 cases greater than 12 months of age, 70% were male. Toxin type A caused botulism in 82% of cases, (half wound, half foodborne), type E in 7%, type B in 6%, and type F in 3%.
In a study, the largest represented age group in 402 cases was 18 to 29 years, and the smallest group was younger than 70 years (19). Eighty-six percent were foodborne, and 14% were wound botulism cases. Thirty-seven percent were type A, 17% type B, 20% type E, and 1% type F (with 25% unknown). Forty-six percent of patients were intubated, and 66% received antitoxin.
In the 2017 botulism surveillance survey, 182 laboratory-confirmed botulism cases were reported to the Centers for Disease Control and Prevention: 77% infant, 10% foodborne, 10% wound, and 1% each iatrogenic and suspected adult intestinal colonization (CDC.gov accessed 12.5.2020).
Foodborne botulism. A published systematic review noted 197outbreaks between 1920 and 2014 (median number of cases per outbreak was 3, range 2 to 97), and 55% were in the United States. Most of these outbreaks were fewer than 11 cases and due to a point source, whereas commercial food-related outbreaks were larger. Toxin types A, B, E, and F were identified as the causative agent in 34%, 16%, 17%, and 1% of outbreaks, respectively (30). In the United States in 2017, cases were toxin A in 15 and toxin E in 4, with a median age of 42 years (13).
Wound botulism. Areas where skin popping is practiced, such as the southwest United States, experienced higher numbers of botulism due to black tar heroin use (67).
In Europe, botulism cases are often sporadic, suggesting that C botulinum spores might be present in the drug supply and environment at varying levels of contamination (60).
In the United States in 2017, 19 wound botulism cases were reported, 17 of which were among persons who inject drugs (13). Most were toxin type A (95%) and had a median age of 48 years.
Other. Guru and colleagues identified 35 cases of intestinal toxemia botulism described in the literature (33). Three species of Clostridia (botulinum, butyricum, and baratii) were incriminated as the cause, in 51%, 9%, and 31%, respectively. Toxin types were reported as A, B, E, and F in 29%, 17%, 9%, and 46%, respectively. Of 2 iatrogenic cases reported by the Centers for Disease Control and Prevention in 2017, toxin A caused one, and toxin B the other (13). The one case of adult intestinal colonization was the only reported death.
Foodborne botulism occurs when C botulinum spores are placed in an anaerobic environment and allowed to germinate and produce the toxin. C botulinum spores are capable of surviving 100°C for at least 6 hours, but they are killed at temperatures of 120°C for 5 minutes (07). Home canning with a pressure cooker will kill C botulinum spores. Most cases of foodborne botulism come from improperly home-canned food boiled at 100°C or contaminated foods not heated above 85°C to denature the toxin. At present, no method is known to prevent colonization of the gastrointestinal tract in infants or those with underlying gastrointestinal abnormality. Appropriate early debridement and cleaning of the wounds and administration of antibiotics, such as penicillin to kill the C botulinum, can help prevent wound botulism. No vaccine has preventative value after toxin exposure.
Those who have a high risk of toxin exposure, such as botulism laboratory workers or certain military personnel, may require vaccination. A bivalent recombinant vaccine against neurotoxin A and B may be protective against the A and B subtypes (48).
Research for the development of vaccines against botulism utilizes 2 approaches: (1) using a native botulinum toxin to generate chemically inactivated toxoid or (2) using recombinant techniques to engineer the toxin derivatives. These vaccines include DNA-based (plasmid- or vector-based), viral vector-based, and recombinant protein-based vaccines (80).
Subsequent publications announced that the modified toxin (M-BoNT/A1) elicits a potent immune response and can be a vaccine strategy against botulism (66).
The differential diagnosis for botulism includes Guillain-Barré syndrome, its variants, and myasthenia gravis, predominantly. Lambert-Eaton syndrome, diphtheric polyneuropathy, tick paralysis, brainstem stroke, curare poisoning, poliomyelitis, organophosphate intoxication, and nerve agent poisoning are also possibilities. These diagnoses should be seriously considered if the weakness fluctuates during the day, if there is objective loss of sensation in the hands and feet or signs of CNS involvement, or if the cerebrospinal fluid shows pleocytosis or elevated total protein. Helpful distinguishing tests include the “Tensilon” (this brand name was withdrawn from the market in 2015) test with intravenous injection of edrophonium chloride, if available (for myasthenia gravis), CSF exam (for Guillain-Barré syndrome and poliomyelitis), and potentially measurement of cholinesterase blood levels (for organophosphate or nerve agent intoxication).
Repetitive nerve stimulation may not distinguish botulism from myasthenia gravis or Lambert-Eaton syndrome, as any of these neuromuscular junction disorders can show compound muscle action potential amplitude decrement at low rates (2-3 Hz). With high (30-50 Hz) repetitive nerve stimulation or exercise, botulism and Lambert-Eaton syndrome, both affecting the presynaptic neuromuscular junction, often show an increment in compound muscle action potential amplitude. However, high rates of stimulation are not always tolerated, and exercising a severely weakened muscle maybe difficult. Identification of slowed nerve conduction speed on nerve conduction study points to Guillain-Barré syndrome and its variants.
CSF evaluations are typically normal. Electrodiagnostic studies provide additional support for the diagnosis of botulism, before the serologic and stool sample results return. Nerve conduction studies show small-amplitude compound muscle action potentials (CMAPs) with normal distal latencies, conduction velocities, and sensory nerve action potentials. As a presynaptic neuromuscular junction disorder, botulism shares electrodiagnostic features with Lambert-Eaton syndrome. Repetitive nerve stimulation at low rates (2 to 3 Hz) may show decrement in CMAP amplitude (65; 74). Facilitation (or increment) of CMAP amplitude is often seen after exercise or high-frequency (30-50 Hz) repetitive nerve stimulation. High-rate repetitive nerve stimulation leads to significant increase in calcium influx into the presynaptic terminal contributing to an increase in acetylcholine release. Compared to Lambert-Eaton syndrome, only about 60% of adult patients with botulism exhibit significant post-exercise facilitation, and the amount of post-exercise facilitation is typically less (30% to 100% versus > 100%), but the duration of facilitation is longer, typically over 2 minutes (46). Nonspecific EMG changes include low-amplitude and short-duration motor unit action potentials (typically a myopathic pattern). One explanation of this apparently incongruent finding is that blocking of neuromuscular transmission causes a large percentage of muscle fibers of a motor unit to fail to generate action potentials. The resultant action potential generated by the motor unit is diminished in amplitude and duration. Later in the clinical course, the EMG often demonstrates fibrillation potentials, a sign of muscle membrane instability. Single fiber electromyography is a very specific study that demonstrates evidence of neuromuscular junction abnormality-increased jitter and blocking (65). Nerve conduction study/EMG usually distinguishes between other causes of weakness, such as Guillain-Barré syndrome (or the Miller Fisher variant), myasthenia gravis, poliomyelitis, and tick paralysis (74). Normal electrodiagnostic studies do not exclude the diagnosis of botulism, particularly early in the disease.
Witoonpanich advocates for a post-10-second exercise single supramaximal stimulation to demonstrate post-exercise facilitation (using CMAP increment of at least 25% as confirmative), as seen in 95% of the 63 patients studied during an outbreak of foodborne botulism (87).
The definitive diagnosis of botulism is made by demonstrating the presence of botulinum toxin in serum, stool, or food, or by culturing C botulinum, C butyricum, or C baratii from stool or a wound. The standard diagnostic test for the presence of botulinum toxin is the mouse bioassay. Although seldom performed at most hospitals, this test is usually available at state reference laboratories or the Centers for Disease Control and Prevention. Only a biologic assay such as the mouse bioassay, or an appropriate cell-based assay, can selectively detect biologically active BoNTs, as well as all subtypes and novel BoNTs (63). The mouse bioassay involves mouse intraperitoneal inoculation with the patient's serum, or stool or food extracts, to determine whether the mouse becomes weak and dies over 48 hours. The serotype of the toxin is determined through administration of serotype-specific antitoxins prior to injection with the sample (41). Final results can take up to 4 days. Isolation of Clostridial organisms from stool, food samples, or wound material also strongly argues for the diagnosis. Stool, wound, and food samples must be cultured in special anaerobic enrichment broth media for 4 or more days and then media are tested for the presence of botulinum toxin (36). If toxin is present, the bacteria can then be specifically isolated. Despite ethical concerns, the mouse bioassay remains essential in the characterization of the many BoNT types as well as novel BoNTs. It is the only assay that can examine the pharmacodynamic properties of BoNTs and the pathological or pharmaceutical effects after intoxication (63).
BoNT detection methods include in vivo simulation assays, such as the hemidiaphragm assay and local injection assays, and numerous in vitro assays using immunological detection methods, endopeptidase assays, or a combination of the two such as the endopeptidase-mass spectrometry assay and cell-based assays. The Centers for Disease Control and Prevention performs mouse bioassay, mass spectrometry, and polymerase chain reaction on samples.
Neuronal cell-based assays can reliably and quantitatively detect BoNTs with greater sensitivity and less variation than the mouse bioassay. They have the potential to replace the mouse bioassay for the purpose of potency determination of specific pharmaceutical BoNT formulations. Neuronal cell-based assays can be easily standardized and detect only biologically active BoNTs if used at physiologically relevant doses, which is a requirement for potency determination of pharmaceutical BoNTs (63).
Endopeptidase mass spectrometry (Endopep-MS) assays require the use of serotype-specific antibodies. The antibodies are conjugated to magnetic beads and then added to a sample. The beads are removed and washed. Then, a substrate that imitates the toxin’s natural target is added. The solution is incubated, and the resulting mixture is analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The mass spectrometry detects any whole substrate and any cleaved fragments that result from incubation with the active toxin (41), but may not detect all subtypes of a novel SNARE-substrate or cleavage site.
Immunopolymerase chain reaction (Immuno-PCR) is an ELISA-type immunological test that uses polymerase chain reaction to increase amplification of the ELISA signal. The detection methodology relies on forming complexes of antigen and antibody, which is then bound to known DNA molecules instead of the normally used enzyme format. Once the binding has occurred to form the complex, the amplification of the DNA fragments, which are bound to the BoNT unique antibody, is implemented using traditional or real-time quantitative polymerase chain reaction (qPCR). Immuno-PCR detects botulinum neurotoxin serotype A to sensitivity levels similar to those associated with the mouse bioassay and can determine active toxin levels (41).
Laboratory confirmation of botulism acquired by inhalation may be limited as individuals may not develop an antibody response due to the small quantity of toxin protein required to cause botulism symptoms. If only toxin is inhaled without spores, then bacterial cultures will be negative. Toxin may be detectable in the nares for up to 24 hours post-exposure. An enzyme-linked immunosorbent assay or polymerase chain reaction of a nasal mucosal swab may be considered a diagnostic tool for inhalational exposure to botulinum toxin (detects contaminating bacterial DNA), but these tests have not been validated (25).
Again, although these tests aid in the confirmatory diagnosis, strong clinical suspicion is key to executing prompt treatment.
Treatment comprises supportive care, botulinum antitoxin, and potentially antibiotics and should begin as soon as the diagnosis is suspected (24; 71; 21). Patients with all forms of botulism require medical attention in an intensive care unit. They should be monitored carefully, particularly in the early stages of the disease because weakness may progress rapidly. The patient should undergo frequent respiratory monitoring and neurologic examinations for adequacy of gag and cough reflexes, ability to swallow and handle oropharyngeal secretions, and limb strength.
Monitoring for impending neuromuscular respiratory failure includes serial measurements with handheld bedside spirometry for forced vital capacity or negative inspiratory force. A normal vital capacity is approximately 65 mL/kg. A poor cough occurs at around 30 mL/kg. Typically, a vital capacity of less than 20 mL/kg ideal body weight or a rapidly declining vital capacity on serial measures are indications for elective endotracheal intubation (Chang 2019). Oxygen desaturation or hypoxemia with absolute or relative hypercarbia on arterial blood gas measurements does not develop until just before frank respiratory failure.
In the United States, the Centers for Disease Control and Prevention recommends administration of heptavalent (types A-G) botulinum antitoxin (HBAT) as soon as possible. The equine polyclonal antibody fragments F(ab)2 act against BoNT A through G. In the circulation the polyclonal antibody fragments bind to free BoNT. This prevents the BoNT from interacting with anchorage sites and protein receptors on the cholinergic nerve endings. In turn, this prevents BoNT internalization into the target cells (U.S. Food & Drug Administration 2020). Heptavalent equine antitoxin is available through the Centers for Disease Control and Prevention, the Alaska Division of Public Health, and the California Department of Public Health; antitoxin for infants is available from the California Department of Public Health (16). Fagan and coworkers determined that toxin was detected in 1 case for 11 days after ingestion (29). This finding supports administration of an antitoxin for up to 12 days after toxin ingestion, yet does not report a time when toxin is not present.
Each vial contains varying units of antitoxin against each botulinum type and sufficiently neutralizes circulating toxin found in all forms of botulism. The half-life of the circulating antitoxin is 5 to 7 days. The Centers for Disease Control and Prevention recommendation is administration of 1 vial (01). The antitoxin vial should be diluted 1:10 in 0.9% saline solution and administered by slow intravenous infusion 0.5 mL/min and gradually increased to a maximum 2 mL/min in adults. Administration of equine antitoxin may produce allergic reactions, and the antitoxin should not be given to individuals with known allergies to equine products.
To obtain the antitoxin, one should contact local and state health departments. In the United States, if local health departments are unavailable, the Centers for Disease Control and Prevention can be telephoned at (404) 639-2206 or at the emergency (during or after hours) number: (770) 488-7100.
Patients with wound botulism should have the wound surgically debrided and appropriate anaerobic cultures obtained. Penicillin should be administered for 10 to 14 days, ideally after the botulinum antitoxin is administered, as lysing C botulinum with the antibiotic will release more toxin. Metronidazole has been suggested as an alternative. The effectiveness of these agents in all forms of botulism has not been established (11). C botulinum type A and B strains and neurotoxigenic C baratii strains from California were highly susceptible to penicillin, 4 cephalosporins, moxifloxacin, and trimethoprim-sulfamethoxazole (04).
Antibiotics have no role in foodborne, iatrogenic, or inhalational botulism except to treat secondary bacterial infections. However, individuals with botulism may worsen clinically if they receive aminoglycoside antibiotics due to their potential to increase presynaptic neuromuscular blockade (49).
Attempting to remove unabsorbed botulinum toxin from the gut is controversial. Most studies have shown botulinum toxin absorption occurs mainly in the upper intestine, and it is unclear how much toxin is absorbed in the colon. If the food suspected of containing botulinum toxin was recently consumed and the patient does not have an ileus, use of cathartics (not containing magnesium, as it might worsen the neuromuscular blockade) or enemas can be considered as a way of removing nonabsorbed toxin from the gut (75). Feeding should be done cautiously, usually through a nasogastric tube, when bowel sounds are present.
Research studies for identification and use of nonantitoxin treatment strategies have led to other proposed treatments (not approved by the FDA), including guanidine hydrochloride, 3,4-diaminopyridine, and plasma exchange, but further clinical trials are needed to investigate their usefulness (17). The catalytic properties of subtypes of light-chain botulinum toxin A (LC/A) may play a role in designing small molecule inhibitors for treatment (38). Single-chain antibodies have been shown to be efficacious but are limited by their shorter lives in circulation. Huang and colleagues engineered mouse red cells to express these single-domain antibodies (VHHs) and described the protective properties to lethal doses of the toxin (44). Voltage-gated calcium-channel agonists in combination with 3,4-DAP may have some therapeutic benefit as well (06). Some relatively newer agents may offer therapeutic relevance, such as quinolinol inhibitors, which inhibit SNAP-25 cleavage, and picolinic acids, which inhibit the beta-exocite (09; 08). The identification of acoric acid 1 as a potential scaffold against BoNT suggests that herbal treatment may play an adjunctive role (89). However, the relevance in a clinical setting remains to be seen. A systematic review and meta-analysis of case reports and treatments with antitoxins from 1923 to 2016 showed that therapeutic agents other than antitoxin offered no clear benefit (59).
There are no guidelines for postexposure prophylaxis. Kodihalli and colleagues described the therapeutic efficacy of equine antitoxin in Rhesus monkeys as a postexposure prophylaxis treatment (50). The antitoxin completely protected the monkeys, delayed the progression of signs (muscular weakness, respiratory distress, oral/nasal discharge), and reduced the severity of the disease and subsequent death.
The clinical evidence for botulinum antitoxin efficacy in humans is based on retrospective analyses of small numbers of patients and animal studies. Guinea pigs intoxicated with serotypes A, B, C, D, E, F, or G treated with BAT had enhanced survival compared to placebo (p< 0.0001) and arrested or mitigated progression of clinical signs of botulism (05). Similar efficacy has been shown in Rhesus macaques (50) and, for some serotypes, in a rabbit spirometry model (26). In treated patients, the antitoxin was safe and provided clinical benefit. Improvements in any botulism sign or symptom were detected a median of 2.4 days, and in muscle strength a median of 4.8 days, after treatment (90). Timely administration of antitoxin reduces mortality (59). In a systematic review of patients who received botulinum antitoxin, 86% (n = 229/267) survived, compared with 53% (n = 72/135) who did not receive antitoxin (P < .0001) (19).
The time to full recovery varies by the type of toxin and the intensity of the exposure. Botulinum type A is the most toxic, whereas type E is the least. Patients requiring ventilator assistance often report that they continue to have marked fatigue up to a year or more (55). In experimental animal studies and human volunteers who were given IM injections of the toxin to paralyze specific muscles, recovery of normal muscle function required 12 months (47). A major factor contributing to the persistence of intoxication is the long half-life of the catalytic light chain, which remains enzymatically active months after entry into cells. The light chain is metabolized by ubiquitination and evades breakdown by means of a deubiquitinating enzyme. The development of specific deubiquitinating inhibitors could be useful (20).
Experience with HBAT suggests the incidence of allergic reactions (eg, urticaria, serum sickness, or other reactions suggestive of hypersensitivity) is 1% to 2% (73). Diphenhydramine and epinephrine should be immediately available during the antitoxin administration for possible allergic reaction. A joint task force report by the major infectious disease public health departments concluded that skin testing prior to administration of HBAT in a mass botulinum toxin exposure is not indicated. As only 10% of treated botulism patients get tested, only 4 of 5 patients with anaphylaxis had skin testing, and the skin testing procedure is time consuming, there are inadequate data for skin testing recommendations for individual cases (73). The IgG-Fc (receptor-binding fragment) is mostly involved in the hypersensitivity reactions and is commonly removed from heterogenous preparations.
Treatments on the horizon. New-generation therapies are based on a combination of humanized monoclonal antibodies (MAbs), which exhibit improved safety and pharmacokinetics. In a mouse model, homologous Fc increased the potency of the antibotox MAbs by 1 magnitude and increased efficacy, arguing for development of human monoclonal antibodies as treatment (83). To develop recombinant antibodies that neutralize botulinum neurotoxins, heavy and light chains (HC and LC) of the BoNT serotypes A, B, and E were targeted to achieve a synergistic effect (oligoclonal antibodies). For antibody isolation, macaques were immunized, followed by the generation of immune phage-display libraries. Antibodies were selected from these libraries against the holotoxin and further analyzed in in vitro and ex vivo assays. For each library, the best ex vivo neutralizing antibody fragments were germline-humanized and expressed as immunoglobulin G (IgGs). The IgGs were tested in vivo, in a standardized model of protection, and challenged with toxins obtained from collections of Clostridium strains. Protective antibody combinations against BoNT/A and BoNT/B were evident, and for BoNT/E, the anti-LC antibody alone was found highly protective (70). This pentavalent oligoclonal antibody combination may be suitable for further development.
Limited animal studies suggest that botulinum toxin, type A or B, does not cross the placenta.
Treatment of pregnant females includes the same management protocol of using antitoxin with supportive management. A systematic review of botulism in pregnancy (with case reports of 16 patients) showed no neonatal losses or cases of congenital botulism, and there were no adverse maternal or neonatal effects with botulinum antitoxin therapy among 11 treated patients (02).
In general, anesthetics that may have prolonged neuromuscular blockade should be minimized. In patients with botulism, the half-life of iatrogenic neuromuscular blockade persists much longer than in healthy individuals.
B Jane Distad MD
Dr. Distad of University of Washington has no relevant financial relationships to disclose.See Profile
Christina M Marra MD
Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.See Profile
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