Botulism presents as a distinct clinical syndrome characterized by cranial nerve palsies, which may advance to bilateral, symmetrical, descending flaccid paralysis. This paralysis typically affects proximal muscles before distal ones and can escalate to respiratory failure and potential fatality. The severity of paralysis is directly related to the toxin dose. Patients are typically alert and oriented; however, manifestations such as ptosis, ocular muscle paralysis, voice alterations due to vocal cord paralysis, and gait disturbances from skeletal muscle paralysis can be mistakenly attributed to intoxication or altered mental status. Sensory deficits and pain are rare in botulism cases (3,42,43). Despite these recognizable features, botulism diagnosis is frequently delayed or overlooked.
Diagnostic Challenges in Botulism Management
While the progression of paralysis in botulism is often described as unique, its initial presentation can be misdiagnosed (3,14). Investigations into outbreaks have been instrumental in identifying initially misdiagnosed cases, sometimes even after patient discharge with incorrect diagnoses (35,38) (CDC, unpublished data, 2016). Effective initial management of suspected botulism hinges on prompt clinical assessment. Botulinum antitoxin, the only specific treatment, must be administered without delay. Waiting for laboratory confirmation, which can take several days, can negatively impact patient outcomes, especially in cases with a high or medium likelihood of botulism (3,35,44,45).
The variability in botulism symptoms was underscored during a large foodborne outbreak where initial diagnoses included myasthenia gravis, stroke, and psychiatric disorders (46), despite many patients exhibiting classic botulism signs (46). Reviews of literature and classical case series indicate that myasthenia gravis and Guillain-Barré syndrome are the most common misdiagnoses for botulism (13,14,16,30,31). A broad spectrum of conditions, from cerebrovascular accidents to Lambert-Eaton syndrome, meningitis, encephalitis, and tick paralysis, have been considered in the differential diagnosis (13).
A CDC review of 332 possible botulism cases between 1980 and 2016 showed that treating physicians considered alternative diagnoses in 83% of cases (274). These included up to six other potential illnesses, with Guillain-Barré syndrome (99 cases) and myasthenia gravis (76 cases) being the most frequently considered. Among 160 botulism cases from 2009 to 2015, botulism was the primary diagnosis for 90% of cases at the time of CDC consultation, but ranked second, third, or fourth in the remainder.
In pediatric and adolescent cases, differential diagnoses were noted in 22% (79 cases), commonly including myasthenia gravis (28%), poisonings/intoxications (25%), Guillain-Barré syndrome (14%), and poliomyelitis (11%) (31). Misdiagnosis is often due to botulism’s rarity compared to conditions with similar symptoms like myasthenia gravis and Guillain-Barré syndrome. Incomplete neurological examinations that fail to identify typical botulism signs also contribute to diagnostic oversights (26). Atypical presentations, such as asymmetric deficits, can further complicate diagnosis (33,34,38,47).
Recognizing Signs and Symptoms of Botulism
Evidence from guidelines (13,14,16,30,31,36) indicates that common symptoms reported by botulism patients include dysphagia, blurred vision, slurred speech, hoarseness, gastrointestinal issues, dry mouth, shortness of breath, and diplopia. Key signs are descending paralysis, ptosis, and ophthalmoplegia.
Botulism symptoms develop over hours to days. Initial minor symptoms like visual changes or abdominal discomfort (in foodborne cases) may precede progressive cranial palsies, followed by descending flaccid paralysis. The extent of neurological impact can range from mild cranial nerve findings to extensive paralysis affecting respiratory, extremity, and axial muscles. Gastrointestinal symptoms, such as nausea and vomiting, are more prevalent in foodborne botulism compared to other forms (13,14,16), reported in 50% of foodborne cases versus 5% of wound botulism cases (14). The cause of these gastrointestinal symptoms—whether from botulinum neurotoxin, other clostridial products, or food spoilage substances—remains unclear. It is also unknown if purified botulinum toxin in food would cause such symptoms (14). Constipation is frequently an early symptom in children (31). Infants and young children may not articulate symptoms like double vision, making signs more critical for diagnosis (31). In infants, neurological manifestations are described differently, with hypotonia, weak cry, and poor feeding noted in infant foodborne botulism cases (36).
While botulism is described as causing symmetrical deficits due to toxin distribution to neuromuscular junctions (12), some case studies report asymmetric deficits (47), with larger series indicating asymmetry in 6%–15% of patients (13,16). Data interpretation is challenging due to reliance on clinical chart abstractions, which may be incomplete or inconsistently reported. Unreactive pupils, expected in botulism, were noted in only 25% of confirmed cases in a large series (13). Rarely reported symptoms include fever, non-descending paralysis, and altered mental status (13,31). Proximal muscles are typically affected before distal muscles, but exceptions with equal or weaker distal muscles have been reported (13). These atypical findings may arise from inadequate neurological exams, pre-existing conditions, co-infections, or rare variations of the syndrome.
Respiratory failure as an initial symptom without preceding neurological deficits is highly unlikely and probably indicates a missed or incomplete neurological examination that would have revealed earlier cranial nerve palsies.
In a study of 72 sporadic botulism cases, chief complaints often reflected classic neurological deficits like slurred speech, weakness, and dysphagia. However, some initial symptoms were less typical, such as gastrointestinal issues alone, back pain with mobility issues, altered consciousness, and lip/tongue numbness (CDC, unpublished data, 2016). Patients with non-classical initial symptoms were more likely to experience delayed diagnosis (CDC, unpublished data, 2016).
Key Clinical Considerations for Botulism
- Recognize the broad spectrum of botulism signs and symptoms, from limited cranial nerve palsies (like ptosis) to severe respiratory failure and extensive paralysis.
- Be aware that early respiratory compromise can occur due to upper airway issues from cranial nerve muscle paresis, such as pharyngeal collapse or secretion pooling, even before diaphragm weakness is evident.
Diagnostic Recommendations for Botulism
- Consider botulism in patients suspected of having myasthenia gravis or Guillain-Barré syndrome, especially if they present with unexplained symmetric cranial nerve palsies, with or without other muscle weakness.
- Perform thorough and repeated neurological examinations to identify botulism-related deficits and monitor their progression.
- If botulism is suspected, immediately contact local or state health departments for expert clinical consultation and to request botulinum antitoxin from the CDC, if indicated.
Ancillary Diagnostic Testing in Botulism
Background on Ancillary Tests
Routine lab tests, including complete blood counts, CSF analysis, and radiology, are usually normal in botulism. In Guillain-Barré syndrome, CSF protein levels are often elevated, particularly in the second week (48). Mild CSF protein increases are infrequently reported in botulism (13). Brain imaging can rule out brainstem strokes that may mimic botulism symptoms. The Tensilon (edrophonium) test, historically for myasthenia gravis, is typically negative in botulism, though minimal responses have been noted (36).
Electrodiagnostic studies—repetitive nerve stimulation (RNS), electromyography (EMG), and nerve conduction studies (NCSs)—are valuable for diagnosing muscle weakness. RNS involves nerve stimulation at low (2–5 Hz) or high (30–50 Hz) frequencies and muscle response recording. EMG uses needle electrodes to assess muscle electrical activity at rest and during effort. NCS measures electrical responses of sensory nerves or muscles to nerve stimulation (49). Classical botulism findings include increased compound motor nerve action potential amplitude at 30–50 Hz RNS (50), fibrillation, reduced muscle unit recruitment, decreased muscle unit potential duration on EMG, and reduced motor-evoked amplitude on NCS with otherwise normal results (49). However, early in botulism, these tests may be normal and unhelpful.
EMG, RNS, and NCSs are operator-dependent, technically complex, require specialized training and equipment, and are not universally available. They can take up to 2 hours and require expert interpretation. Early in botulism, results are often normal (except single-fiber EMG) (51,52); abnormalities appear later. EMG requires patient cooperation and can be painful, especially RNS at high frequencies (49). Clinicians should explain the procedure to conscious, paralyzed, and intubated patients. The sensitivity and specificity of these tests for botulism are not precisely known. Electrodiagnostic findings in other neuromuscular diseases, like Miller Fisher syndrome, can resemble botulism (50,51). Single-fiber EMG with jitter measurement is more sensitive but less specific and requires even more specialized expertise and patient cooperation (52). Electrodiagnostic findings should always be interpreted with clinical, epidemiological, and laboratory data.
Electrodiagnostic studies can be useful in various care settings, from conventional to crisis standards. During outbreaks, they may be less critical for patients with typical cranial nerve palsies and descending paralysis. However, for unclear cases, they can differentiate botulism from other neuromuscular conditions like myasthenia gravis or Guillain-Barré syndrome. This is particularly important in sporadic cases where early diagnostic certainty guides antitoxin treatment versus plasmapheresis or immunoglobulin for Guillain-Barré syndrome. Abnormal electrodiagnostic results can persist for weeks, making them useful even when toxin is undetectable in serum. In outbreaks with atypical presentations, electrodiagnostic studies have been helpful (CDC, unpublished data, 2015). In crisis situations, the feasibility of electrodiagnostic studies decreases.
Recommendation for Ancillary Testing
- Consider electrodiagnostic testing to aid botulism diagnosis when feasible. Expertly performed and interpreted EMG, RNS, and NCSs can provide valuable diagnostic information.
Role of Exposure Risk Factors in Botulism Diagnosis
Background on Risk Factors
Identifying botulism risk factors in a patient’s history aids diagnosis. Wound botulism risks include injection drug use (especially black tar heroin). Foodborne botulism is linked to home-canned foods (3). However, atypical exposures can cause botulism, so their absence doesn’t exclude the diagnosis. Multiple suspected cases, particularly among connected individuals, suggest a common-source outbreak and increase diagnostic likelihood (3). Geographically dispersed, unconnected cases do not rule out a widespread outbreak from a seemingly innocuous product. Public health authorities should promptly investigate suspected cases and inform clinicians about potential exposures to identify and manage other cases.
Recommendation Regarding Exposure Risk Factors
- Clinicians should inquire about typical botulinum toxin sources, but recognize that the absence of these exposures does not rule out botulism.
Clinical Criteria Tool for Early Botulism Diagnosis in Crisis Settings
A clinical criteria tool assists in early botulism identification, especially in crisis or contingency settings where botulism probability increases (Box 1) (36). This tool, also applicable in conventional settings, uses frequency-ranked signs and symptoms of acute botulism onset from various sources (Tables 3 and 4). It was refined with expert input and excludes ancillary test results and difficult-to-quantify signs. Epidemiological risk factors, often unconfirmed early on, are also excluded. The tool is designed for objectivity and reproducibility across healthcare workers and is usable for all ages, including pregnant women, after brief training. It is not a diagnostic replacement but helps clinicians consider botulism, minimizing distractions from atypical findings (36). In conventional care, it prompts botulism consideration for detailed evaluation. In crisis care, meeting these criteria may justify presumptive botulism treatment. Partial criteria fulfillment may indicate medium likelihood, warranting monitoring (Figures 1 and 2). It is not definitively diagnostic; conditions like myasthenia gravis and Guillain-Barré syndrome may also meet criteria. During outbreaks, “worried well” individuals may seek care for subjective symptoms (53). Managing these cases efficiently and educating the public about non-urgent symptoms is crucial in large outbreaks to avoid treatment delays for true cases.
Laboratory Confirmation of Botulism
Prompt treatment decisions in suspected botulism cases rely on clinical findings. Botulinum antitoxin should be given immediately. Laboratory confirmation, taking several days, should not delay antitoxin administration in likely cases (3,35,44,45).
Laboratory testing confirms clinical suspicions, verifies antitoxin effectiveness against the specific toxin serotype, and identifies toxin in suspected food sources for safe removal and prevention of further cases. Botulism confirmation involves detecting botulinum neurotoxin in serum, stool, or gastric fluid; identifying toxin-producing Clostridium species (C. botulinum, C. baratii, or C. butyricum) in stool or wound cultures; or finding botulinum neurotoxin in consumed food (3). Environmental testing is not routine in foodborne botulism investigations. Only specialized public health labs, including the CDC National Botulism Laboratory, conduct these confirmations. Public health labs offer free emergency testing and guidance on specimen collection and shipment.
Types of Botulism Laboratory Tests
The mouse bioassay is the gold standard for botulinum neurotoxin identification in specialized public health labs (54). It requires mouse colonies and expert technicians to observe mice for botulism signs after specimen injection with and without antitoxin, over up to 96 hours. Results may be available within 24 hours for high toxin levels, but low levels causing human illness may not be detected in mice. The mouse bioassay is FDA-approved for botulism confirmation, but other methods can support clinical diagnosis.
Real-time PCR tests, available in reference labs, detect bont genes A–G and identify toxin-producing Clostridium species. PCR detects DNA, not toxin, requiring methods like mouse bioassay to confirm toxin production. Mass spectrometry (Endopep-MS) is highly sensitive and specific for serotypes A, B, E, and F, providing results within hours (55). It is available at the CDC and select public health labs.
Non-reference labs typically cannot confirm botulism due to limitations in detecting botulinum neurotoxin or differentiating toxin-producing Clostridia. Misidentification of C. sporogenes as C. botulinum by non-reference labs has been reported, highlighting the need for reference lab confirmation (CDC, unpublished data, 2018).
Specimen Collection and Transportation for Botulism Testing
Serum specimens must be drawn before antitoxin (BAT) administration because BAT neutralizes the toxin, potentially leading to false negative results. Laboratory confirmation depends on clinician recognition of botulism, consultation with public health departments, and timely collection and transport of appropriate specimens (Table 5; Box 2) (2,3,28). Early specimen collection is crucial to detect toxin before it binds irreversibly and becomes undetectable in serum, stool, or gastric fluid. For adults, collect 20–30 mL whole blood to yield 10–15 mL serum; less for children, with 4 mL serum minimum for mouse bioassay.
Collect 10–20 g stool, though smaller amounts or rectal swabs (for infants/children) are acceptable. For constipated patients, use sterile non-bacteriostatic water enemas and non-glycerin suppositories for stool collection; tap water is not recommended. Stool can be collected post-BAT, as Clostridium may persist even with neutralized serum toxin (17); BAT treatment should not be delayed for stool collection. Send suspect foods in original containers for expert testing. Even dried food remnants have yielded positive results (CDC, unpublished data, 2016). If needed, use sterile, unbreakable containers for food samples. Refrigerate all specimens (36°F–46°F [2°C–8°C]) immediately and maintain this temperature during transport; do not freeze. Testing asymptomatic exposed individuals is generally not useful as toxin levels are typically below detection limits, except in rare high-exposure scenarios (e.g., lab accidents) where pre-symptom BAT and specimen collection may be warranted.
Confirmation in sporadic cases aids in ruling out other diagnoses, guiding prognosis, and treatment. Negative test results are common despite clinical certainty, often due to delayed specimen collection after toxin levels decrease. In wound botulism, toxin-producing Clostridium may not always be detected in wound specimens, especially post-antibiotics.
Recommendations for Laboratory Testing
- Treat symptomatic, suspected botulism patients with botulinum antitoxin based on clinical findings, without waiting for lab confirmation which may be delayed or negative. (Refer to Allergic Reactions and Other Side Effects of Botulinum Antitoxin for BAT risks and benefits.)
- Discuss specimen collection with experts at the CDC or local/state health departments.
- Collect specimens for lab confirmation as early as possible, as toxin levels decrease over time (Table 5; Box 2). Obtain serum before BAT administration.
- Store and transport specimens refrigerated (36°F–46°F [2°C–8°C]); do not freeze.
