Botulism presents a distinct clinical picture characterized by cranial nerve dysfunction, potentially progressing to bilateral, symmetrical, descending flaccid paralysis. This paralysis typically affects proximal muscles before distal ones and can escalate to respiratory failure and death. The severity of paralysis is directly related to the toxin dose. Patients are usually alert and oriented, although symptoms such as ptosis, ocular muscle paralysis, voice changes due to vocal cord paralysis, and gait disturbances from muscle paralysis can be mistakenly attributed to intoxication or altered mental states. Sensory deficits and pain are rare in botulism (3,42,43). Despite these recognizable features, botulism diagnosis is frequently delayed or overlooked.
Diagnostic Challenges in Botulism
While the progression of paralysis in botulism is considered unique, initial presentations can be misdiagnosed (3,14). Investigations into outbreaks have revealed cases initially misdiagnosed and only identified later by outbreak investigators. Instances where botulism cases were recognized post-discharge with alternative diagnoses highlight the potential for delayed or missed diagnoses (35,38) (CDC, unpublished data, 2016). Critical early treatment decisions for suspected botulism rely on clinical findings. Botulinum antitoxin, the specific treatment, should be administered promptly. Laboratory confirmation can take days, and delaying antitoxin for lab results in likely botulism cases can worsen outcomes (3,35,44,45). Diagnostic challenges are amplified by the variable spectrum of botulism signs and symptoms. A large foodborne outbreak saw delayed recognition, with initial misdiagnoses including myasthenia gravis, stroke, or psychiatric disorders (46), even though most patients exhibited classic botulism symptoms (46). Reviews and case series indicate botulism is often misdiagnosed as myasthenia gravis and Guillain-Barré syndrome (13,14,16,30,31). Differential diagnoses have included cerebrovascular accident, Lambert-Eaton syndrome, meningitis, encephalitis, and tick paralysis (13). A CDC review of 332 possible botulism cases from 1980–2016 showed treating physicians considered alternate diagnoses in 83% of cases, listing up to six other illnesses. Common differential diagnoses were Guillain-Barré syndrome (99 cases) and myasthenia gravis (76 cases). In 160 botulism cases (2009–2015), consulting physicians listed botulism first in 90% of cases, suggesting improved awareness but still highlighting diagnostic uncertainty in some instances.
In children and adolescents, differential diagnoses were noted in 22% of cases, with myasthenia gravis (28%), poisonings/intoxications (25%), Guillain-Barré syndrome (14%), and poliomyelitis (11%) being the most frequent (31). Misdiagnosis in botulism, even in outbreaks, occurs partly because it’s less common than conditions with similar symptoms, like myasthenia gravis and Guillain-Barré syndrome. Inadequate neurologic exams and failure to identify typical neurologic findings also contribute to missed diagnoses (26). Atypical presentations, such as asymmetric deficits, though rare, can further complicate diagnosis (33,34,38,47).
Botulism Signs and Symptoms: Key Clinical Indicators
Reviews and analyses supporting these guidelines (13,14,16,30,31,36) identified common botulism symptoms: dysphagia, blurred vision, slurred speech, difficulty speaking, hoarse voice, gastrointestinal issues, dry mouth, shortness of breath, and diplopia. Common signs included descending paralysis, ptosis, and ophthalmoplegia.
Botulism symptoms evolve over hours to days. Initial minor visual changes or abdominal discomfort (in foodborne cases) may precede progressive cranial palsies, followed by descending flaccid bilateral paralysis. Neurologic signs can range from mild cranial nerve findings like ptosis to extensive paralysis affecting cranial nerve-innervated, respiratory, extremity, and axial muscles. Early gastrointestinal symptoms (nausea, vomiting) are more frequent in foodborne botulism than other types (13,14,16). Vomiting was reported in 50% of foodborne botulism patients versus 5% in wound botulism (14). The cause of gastrointestinal symptoms—botulinum neurotoxin, other clostridial products, or food spoilage substances—is unclear. It’s also unknown if intentional food contamination with purified botulinum toxin would cause gastrointestinal symptoms (14). Constipation is a common early symptom in children (31). Infants and young children may not describe double vision; signs are more frequently reported than symptoms in this age group (31). Terminology for infant botulism neurologic manifestations differs; hypotonia, weak cry, and poor feeding were reported in infants with foodborne botulism but not older children (36).
Botulism is typically described as causing symmetric neurologic deficits, consistent with the toxin’s circulatory distribution to neuromuscular junctions (12). However, detailed case studies describe asymmetric neurologic deficits (47), and larger series report asymmetry or unilateral deficits in 6%–15% of patients (13,16). These data may be limited by chart abstractions; data may be incomplete, and reporting varies across providers. Unreactive pupils, expected in botulism, were reported in only 25% of confirmed cases (13). Rare symptoms include fever, nondescending paralysis, and altered mental status (13,31). Proximal muscles are typically affected before distal muscles, but equal or weaker distal muscles have been reported (13). Reasons for these rare findings may include inadequate neurologic exams, pre-existing focal deficits, concurrent infections, or rare variations of the classic syndrome.
Respiratory failure without preceding neurologic deficits is rarely the presenting symptom. Such presentation is improbable, likely indicating a missed or incomplete neurologic exam that would have revealed cranial nerve palsies preceding pharyngeal compromise and respiratory muscle paralysis.
In a series of 72 sporadic botulism cases, most patients presented with symptoms reflecting classic neurologic deficits (slurred speech, weakness, swallowing difficulty). However, some initial signs and symptoms were less indicative of botulism (gastrointestinal symptoms only, back pain with walker difficulty, altered consciousness, lip and tongue numbness) (CDC, unpublished data, 2016). Patients with less typical initial symptoms were more likely to have delayed botulism diagnosis (CDC, unpublished data, 2016).
Key Clinical Considerations for Botulism Diagnosis
- Recognize the broad spectrum of botulism signs and symptoms, ranging from limited cranial nerve palsies (e.g., ptosis) to respiratory failure and complete extremity paralysis.
- Be aware that respiratory compromise can occur early, not just from respiratory muscle weakness, but also from upper airway compromise due to cranial nerve muscle paresis, leading to pharyngeal collapse or secretion pooling.
Diagnostic and Management Recommendations for Botulism
- Consider botulism in patients suspected of myasthenia gravis or Guillain-Barré syndrome, and in those with unexplained symmetric cranial nerve palsies, with or without other muscle paresis.
- Perform thorough, serial neurologic examinations to detect botulism neurologic deficits and their progression.
- If botulism is suspected, immediately contact local or state health departments for emergency expert clinical consultation and, if indicated, request botulinum antitoxin from the CDC.
Ancillary Diagnostic Testing in Botulism
Background on Ancillary Tests
Routine lab tests, including complete blood counts, CSF examination, and radiology, are typically normal in botulism. Guillain-Barré syndrome often shows elevated CSF protein, especially after the first week (48). Mild CSF protein increases are infrequent in botulism (13). Brain imaging can rule out brainstem strokes causing nonlateralizing symptoms. The Tensilon (edrophonium) test, for myasthenia gravis diagnosis, is usually negative in botulism, though minimal responses have been reported (36).
Electrodiagnostic studies (repetitive nerve stimulation [RNS], electromyography [EMG], nerve conduction studies [NCSs]) aid in determining muscle weakness etiology. RNS involves electrically stimulating a motor nerve at low (2–5 Hz) or high frequency (30–50 Hz) and recording distal muscle response. EMG involves needle electrode insertion into muscle to record electrical activity at rest and during effort, showing motor unit potentials or action potentials. NCS involves electrical nerve stimulation and recording responses from sensory nerves (sensory NCS) or muscles (motor NCS) (49). Classical botulism findings include an increment in compound motor nerve action potential amplitude with 30–50 Hz RNS (50), fibrillation, reduced muscle unit recruitment, decreased muscle unit potential duration on EMG, and decreased motor-evoked amplitude on NCS with otherwise normal findings (49). However, early in the disease, electrodiagnostic studies may be normal or near-normal and unhelpful.
EMG, RNS, and NCSs have limitations: operator-dependent, technically challenging, require specialized training and equipment, not universally available, time-consuming (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 30–50 Hz (49). Clinicians must remember paralyzed, intubated botulism patients are conscious unless sedated; explain testing procedures. Sensitivity and specificity of EMG, RNS, and NCSs for botulism diagnosis are unknown. Electrodiagnostic findings in other neuromuscular diseases (e.g., Miller Fisher Guillain-Barré variant) can mimic botulism (50,51). Single-fiber EMG with jitter measurement may be more sensitive (but less specific) than general EMG, requiring more expertise, equipment, and patient cooperation (52). Electrodiagnostic findings should always be interpreted with clinical, epidemiologic, and laboratory data.
Electrodiagnostic studies can assist botulism diagnosis in conventional, contingency, and crisis care settings. During outbreaks, they are less needed for typical cases. However, for unclear diagnoses, they can differentiate botulism from neuromuscular diseases like myasthenia gravis or Guillain-Barré syndrome, especially in sporadic cases. Early diagnostic certainty guides clinicians to use antitoxin for botulism versus plasmapheresis or immunoglobulin for Guillain-Barré syndrome. Electrodiagnostic findings may remain abnormal for weeks post-illness, useful in later stages when toxin is undetectable in serum. In outbreaks, electrodiagnostic evidence supports clinical and public health decisions. They were helpful in diagnosing botulism in an outbreak with atypical features (CDC, unpublished data, 2015). In contingency or crisis public health events, electrodiagnostic study feasibility decreases.
Recommendation for Ancillary Testing
- When possible, consider electrodiagnostic testing to aid suspected botulism diagnosis. Expert EMG, RNS, and NCSs can provide valuable diagnostic information.
Exposure Risk Factors and Botulism Diagnosis
Background on Risk Factors
Known botulism risk factors in patient history aid diagnosis. Wound botulism risks include injection drug use (especially black tar heroin). Foodborne botulism risks include home-canned food consumption (3). However, atypical exposures occur, so absence of typical risk factors does not exclude botulism. Multiple suspected cases, especially among related individuals, suggest a common-source outbreak and increase diagnosis 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 botulism cases and inform clinicians of suspected exposures for interviewing and linking other potential cases.
Recommendation Regarding Exposure Risk Factors
- Clinicians should inquire about exposure to known botulinum toxin sources, but remember that absence of such exposures does not rule out botulism.
Clinical Criteria Tool for Early Botulism Diagnosis in Critical Settings
Diagnosing botulism can be challenging. An evidence-based clinical criteria tool aids early identification in crisis or contingency care settings, where botulism probability is higher, and can also be used in conventional settings (Box 1) (36). Botulism cases from various sources were used to identify acute onset signs and symptoms, ranked by frequency to determine optimally sensitive criteria for botulism (Tables 3 and 4). The tool was refined to address missed cases, incorporating expert input from clinicians and other specialists. Ancillary tests like electrodiagnostics, neuroimaging, Tensilon tests, and lumbar puncture were excluded. The tool prioritizes objectivity and reproducibility for healthcare workers. Difficult-to-quantify signs (e.g., sluggish pupils) and early-unconfirmed epidemiologic risk factors were omitted. The tool is for children and adults, including pregnant women, and can be used by various healthcare workers after brief training during crises like large outbreaks. It is not a botulism diagnostic replacement for thorough exams and ancillary testing, but helps clinicians consider botulism, minimizing distractions from atypical findings (36). In conventional care, it can prompt botulism consideration for detailed evaluation. In crisis care, meeting criteria may warrant presumptive botulism treatment. Partially meeting criteria may categorize patients as medium likelihood for monitoring (Figures 1 and 2). Criteria fulfillment is not botulism diagnosis; conditions mimicking botulism, like myasthenia gravis and Guillain-Barré syndrome, may meet criteria. During outbreaks, “worried well” individuals without objective symptoms often seek care for subjective symptoms (53). Triage of these individuals can delay care for others. Large botulism outbreak response requires managing numerous persons seeking care unnecessarily and public education on symptoms requiring hospitalization.
Laboratory Confirmation of Botulism: Essential for Public Health
Critical initial treatment decisions for suspected botulism are based on clinical findings. Botulinum antitoxin, the only specific therapy, should be given as quickly as possible. Lab confirmation can take days, and delaying antitoxin for lab results in likely botulism cases can worsen outcomes (3,35,44,45).
Laboratory testing confirms clinically suspected cases, verifies antitoxin effectiveness against the specific botulinum neurotoxin serotype, and identifies neurotoxin in suspected food for safe removal and preventing further cases. Botulism confirmation in symptomatic individuals involves detecting: 1) botulinum neurotoxin in serum, stool, or gastric fluid; 2) botulinum neurotoxin-producing Clostridium species (C. botulinum, C. baratii, or C. butyricum) in stool or wound culture; or 3) botulinum neurotoxin in consumed food (3). Environmental testing is not used in foodborne botulism investigations. Only specific municipal and state public health labs and the CDC National Botulism Laboratory can perform lab confirmation. Public health labs offer free emergency specimen testing for possible botulism and provide specimen collection and shipment instructions.
Types of Botulism Laboratory Tests
The gold standard method for botulinum neurotoxin identification in specialized public health labs is the mouse bioassay (54). This requires mouse colonies and expertise in recognizing botulism signs in mice. Specimens are injected into mice with and without antitoxin, observed for up to 96 hours by experts for botulism signs. Results may be available within 24 hours if toxin levels are high; however, low levels causing human illness might not cause signs in mice. The mouse bioassay is the only FDA-approved method for lab confirmation of botulism. Other methods for detecting botulinum neurotoxin and toxin-producing Clostridium species can support clinical diagnosis.
Real-time polymerase chain reaction (PCR) tests, available in reference labs, detect bont genes A–G and identify botulinum neurotoxin-producing Clostridium in cultures. PCR detects DNA, not toxin protein, so toxin production confirmation requires another method like mouse bioassay. Mass spectrometry for botulinum neurotoxin (Endopep-MS) is highly sensitive and specific, differentiating serotypes A, B, E, and F within hours (55). This method is available at CDC and select public health labs.
Nonreference labs (e.g., hospital and clinical labs) usually cannot perform botulism lab confirmation because biochemical tests and mass spectrometry in these labs cannot detect botulinum neurotoxin or distinguish between toxin-producing Clostridia and nontoxigenic organisms. Occasionally, nonreference labs report C. sporogenes or C. botulinum identification in clinical specimens; reference lab testing often identifies these as C. sporogenes, which does not produce botulinum neurotoxin (CDC, unpublished data, 2018).
Specimen Collection and Transportation Guidelines
Serum specimens must be collected before botulinum antitoxin (BAT) treatment, as it neutralizes toxin, potentially leading to false negative results. Laboratory confirmation depends on clinicians recognizing botulism signs, contacting health departments for expert consultation (including lab testing discussion), and ordering prompt collection and transport of appropriate specimens (Table 5; Box 2) (2,3,28). For lab confirmation, collect clinical specimens as soon as botulism is suspected to detect toxin before irreversible neuronal binding and serum levels drop below assay detection limits. For adults, collect enough whole blood without anticoagulant for 10–15 mL serum (20–30 mL whole blood); smaller volumes are acceptable for children, with 4 mL serum minimum for mouse bioassay.
Collect 10–20 g stool, though smaller amounts may suffice; rectal swabs are acceptable for infants/young children. For constipated patients, use enemas with sterile nonbacteriostatic water and non–glycerin-containing suppositories; tap water can interfere with testing. Stool can be collected post-BAT treatment as Clostridium may persist even if serum toxin is neutralized (17); do not delay BAT for stool collection. Send suspect foods in original containers for expert lab analysis of appropriate specimen parts. Even containers with dried or sparse food have yielded positive results (CDC, unpublished data, 2016). If needed, send food in sterile, unbreakable containers. Refrigerate all clinical and food specimens immediately (36°F–46°F [2°C–8°C]) and maintain this temperature during transport; do not freeze. Specimens from exposed but asymptomatic persons are not routinely tested as toxin levels are likely below mouse bioassay detection limits. Rare exceptions include known high toxin exposures in research settings, where specimens and BAT can be given before illness onset.
Botulism confirmation in sporadic cases is valuable, ruling out alternative diagnoses and informing prognosis. In many cases, test results are negative despite clinical certainty, often due to delayed recognition and specimen collection, when serum toxin levels are below detection. In wound botulism, toxin-producing Clostridium may not always be detected in wound specimens, especially post-antibiotics.
Recommendations for Laboratory Testing
- Treat patients with suspected, symptomatic botulism with botulinum antitoxin based on clinical findings; do not await lab confirmation as results can take days and may be negative in botulism cases. (See Allergic Reactions and Other Side Effects of Botulinum Antitoxin for BAT risks and benefits.)
- Discuss specimen collection with expert consultants from CDC or local/state health departments.
- Collect specimens for botulism clinical diagnosis lab confirmation as soon as possible as toxin levels decrease over time (Table 5; Box 2). Obtain serum before BAT administration.
- Store and transport botulism testing specimens at refrigeration temperatures (36°F–46°F [2°C–8°C]); do not freeze.
