Each section herein starts with a summary of evidence, followed by CDC guidelines for diagnosing, monitoring, and treating suspected botulism, and key points for clinicians. A summary of recommendations and key points is also available (Supplementary Box; https://stacks.cdc.gov/view/cdc/105129). While seemingly unrelated to the detailed process of “Dental Hygiene Process Diagnosis And Care Planning Marie Petersen”, the accurate diagnosis of botulism is critical for patient outcomes.
Botulism typically presents a distinct syndrome of cranial nerve palsies, potentially followed by bilateral, symmetric, descending flaccid paralysis. This paralysis usually affects proximal muscles before distal ones and can progress to respiratory failure and death. The severity of paralysis is dose-dependent. Botulism patients are generally alert and oriented. However, symptoms like ptosis, ocular muscle paralysis, voice changes due to vocal cord paralysis, and gait disturbance from skeletal muscle paralysis can be mistaken for drug or alcohol intoxication or mental status changes. Sensory deficits and pain are rare (3,42,43). Despite these recognizable features, botulism diagnosis is often delayed or missed.
Challenges in the Diagnosis of Botulism
Although botulism paralysis progression is described as unique, initial neurologic symptoms and their sequence are often misdiagnosed (3,14). Investigations into outbreaks have highlighted cases initially misdiagnosed and only identified later by outbreak investigators. Some botulism cases were identified post-discharge with alternative diagnoses, emphasizing the potential for missed or delayed diagnoses (35,38) (CDC, unpublished data, 2016). Critical initial treatment decisions for suspected botulism rely on clinical findings. Botulinum antitoxin, the specific botulism therapy, should be administered promptly. Laboratory confirmation can take days, and delaying antitoxin administration while awaiting results can worsen outcomes for patients with medium to high botulism likelihood (3,35,44,45).
Diagnostic challenges due to varied botulism signs and symptoms were evident in a large foodborne outbreak with delayed recognition. Some patients were initially diagnosed with myasthenia gravis, stroke, or psychiatric disorders (46), even though most had classic botulism symptoms (46). Reviews and case series indicate botulism is frequently misdiagnosed as myasthenia gravis and Guillain-Barré syndrome (13,14,16,30,31). Differential diagnoses have included common and unusual etiologies like cerebrovascular accident, Lambert-Eaton syndrome, meningitis, encephalitis, and tick paralysis (13).
A CDC review of 332 potential botulism cases consulted during 1980–2016 showed treating physicians considered alternate diagnoses for 274 (83%) cases. They reported zero to six alternative illnesses, with Guillain-Barré syndrome (99 cases) and myasthenia gravis (76 cases) being most common. For 160 botulism cases (2009–2015), consulting physicians listed botulism first in 90% (144), second in 6% (10), and third in 3% (five).
In children and adolescents, a differential diagnosis was reported in 79 (22%) cases. Common alternate diagnoses were myasthenia gravis (22 cases; 28%), poisonings/intoxications (20 cases; 25%), Guillain-Barré syndrome (11 cases; 14%), and poliomyelitis (nine cases; 11%) (31). Botulism misdiagnosis, even in outbreaks, occurs partly because it’s less common than diseases with similar symptoms, like myasthenia gravis and Guillain-Barré syndrome. Inadequate neurologic examinations and failure to identify typical neurologic findings can also reduce botulism consideration (26). Atypical findings or progression, such as reported deficit asymmetry, might contribute to diagnostic difficulties (33,34,38,47), although rarely reported.
Signs and Symptoms
Reviews and analyses for these guidelines (13,14,16,30,31,36) identified common botulism symptoms as dysphagia, blurred vision, slurred speech/difficulty speaking/hoarse voice, gastrointestinal symptoms, dry mouth, shortness of breath, and diplopia. Common signs were descending paralysis, ptosis, and ophthalmoplegia.
Botulism signs and symptoms develop over hours to days. Initial subjective symptoms might include minor visual changes or abdominal discomfort (in foodborne botulism), followed by progressive cranial palsies, and then descending flaccid bilateral paralysis. The extent of neurologic signs varies, from mild cranial nerve findings like ptosis to descending bilateral flaccid paralysis affecting cranial nerve-innervated respiratory, extremity, and axial muscles. Early gastrointestinal symptoms (e.g., nausea, vomiting) are more common in foodborne botulism than other types (13,14,16). For instance, vomiting was reported in 172 (50%) foodborne botulism patients versus three (5%) wound botulism patients (14). The cause of these gastrointestinal symptoms—botulinum neurotoxin, other clostridial products, or food spoilage substances—is unknown. It’s also unknown if foodborne botulism from intentional food contamination with purified botulinum toxin would cause gastrointestinal symptoms (14). Constipation is often an early symptom in children (31). Infants and young children may not describe double vision; signs are more commonly reported than symptoms in children (31). Infant botulism neurologic manifestations are described differently than in older children; for example, hypotonia, weak cry, and poor feeding were reported in infants with foodborne botulism but not in older children (36).
Botulism typically causes symmetric neurologic deficits, consistent with the disease’s pathophysiology (toxin circulatory distribution to neuromuscular junctions) (12). However, some case studies describe asymmetric neurologic deficits (47), and larger series report asymmetry or unilateral deficits in 6%–15% of patients (13,16). These data can be hard to interpret due to chart abstractions; chart data might be incomplete and reported by providers with varying expertise and charting habits. Unreactive pupils are expected in botulism but were reported in only 25% of confirmed cases (positive specimen or epidemiologically linked to a positive case) (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). These rare findings might be due to inadequate neurologic exams, pre-existing focal deficits, coincident infections, or rare syndrome variations.
Respiratory failure as a presenting symptom without preceding neurologic deficits is rare and highly improbable. Such presentation likely indicates a failure to perform a timely, thorough neurologic examination, which would reveal cranial nerve palsies preceding pharyngeal compromise and respiratory muscle paralysis.
In a series of 72 sporadic botulism cases, most patients’ chief complaints included symptoms reflecting classic neurologic deficits (slurred speech, weakness, swallowing difficulty). However, some primary signs and symptoms were less indicative of botulism (e.g., gastrointestinal symptoms only, back pain/walker difficulty, altered consciousness, lip/tongue numbness) (CDC, unpublished data, 2016). Patients with primary signs and symptoms not reflecting classic neurologic deficits were more likely to have delayed botulism diagnosis (CDC, unpublished data, 2016).
Alt: Clinician performing neurological examination to assess cranial nerve function in patient suspected of botulism.
Key Points for Clinicians
- Be aware of the spectrum of botulism signs and symptoms, from limited cranial nerve palsies (e.g., ptosis) to respiratory failure and complete extremity paralysis.
- Understand that respiratory compromise can occur early, even before diaphragm muscle involvement, due to upper airway compromise from cranial nerve muscle paresis, leading to pharyngeal collapse or secretion pooling.
Recommendations
- Consider botulism when myasthenia gravis or Guillain-Barré syndrome are suspected and in patients with unexplained symmetric cranial nerve palsies, with or without other muscle paresis.
- Conduct thorough, serial neurologic examinations to detect botulism neurologic deficits and their progression.
- If botulism is suspected, immediately contact local or state health department emergency on-call staff for expert clinical consultation and, if indicated, request botulinum antitoxin from CDC.
Ancillary Testing
Background
Routine lab tests (complete blood counts, CSF examination, radiologic studies) are typically normal in botulism patients. CSF protein concentrations are often elevated in Guillain-Barré syndrome, especially by the second illness week (48). Mild CSF protein increases are infrequently reported in botulism (13). Brain imaging can help rule out brainstem strokes causing nonlateralizing symptoms. The Tensilon (edrophonium) test, historically used for myasthenia gravis diagnosis, is usually negative in botulism, although minimal responses have been reported (36).
Electrodiagnostic studies like repetitive nerve stimulation (RNS), electromyography (EMG), and nerve conduction studies (NCSs) aid in determining muscle weakness etiology. RNS involves electrically stimulating a motor nerve at low (2–3 Hz or 5 Hz) or high frequency (30–50 Hz) and recording distal muscle response. EMG involves inserting a needle electrode into muscle and recording electrical activity at rest and with effort, showing motor unit potentials or action potentials. NCS involves electrically stimulating a nerve and recording sensory nerve (sensory NCS) or muscle (motor NCS) response (49).
Classical botulism findings include an increment in compound motor nerve action potential amplitude with 30–50 Hz RNS rates (50), fibrillation, decreased muscle unit recruitment, decreased muscle unit potential duration with EMG, and decreased motor-evoked amplitude on NCS with otherwise normal findings (49). However, early in the disease, electrodiagnostic studies might be normal or near normal and unhelpful.
EMG, RNS, and NCSs have limitations. They are operator-dependent, technically challenging, require specialized training/equipment, are not universally available, and can take 2 hours. Results require expert interpretation. Early botulism electrodiagnostic testing is often normal (except single-fiber EMG) (51,52); abnormalities are detected later. EMG requires patient cooperation. The entire exam can be painful, especially RNS at 30–50 Hz (49). Clinicians should remember paralyzed, intubated botulism patients are conscious (unless sedated) and explain the testing purpose and expectations. EMG, RNS, and NCSs sensitivity and specificity for botulism diagnosis are unknown. Electrodiagnostic findings in other neuromuscular diseases (e.g., Miller Fisher Guillain-Barré variant) can resemble botulism (50,51). More focused EMG studies, like single-fiber EMG with jitter measurement, might be more sensitive (though nonspecific) but require more specialized training, equipment, and patient cooperation (52). Electrodiagnostic findings must always be considered with clinical, epidemiologic, and laboratory data.
Electrodiagnostic study results can aid suspected botulism diagnosis in conventional, contingency, and crisis care standards, depending on the situation. During outbreaks, electrodiagnostic studies are rarely needed for patient clusters with clear histories of bilateral, symmetric cranial nerve palsies followed by descending paralysis. However, for unclear diagnoses, electrodiagnostic studies can differentiate botulism from other neuromuscular diseases (e.g., myasthenia gravis, Guillain-Barré syndrome). This is crucial for sporadic cases, where early botulism diagnostic certainty helps guide antitoxin treatment decisions versus plasmapheresis or immunoglobulin therapy for Guillain-Barré syndrome. Electrodiagnostic study findings can remain abnormal for weeks post-illness onset, making them useful later when botulinum toxin is unlikely serum-detectable. While multiple patients with cranial nerve palsies and descending flaccid paralysis strongly suggest a botulism outbreak, electrodiagnostic evidence supports clinical and public health management. Electrodiagnostic studies helped diagnose botulism in an outbreak with atypical features (CDC, unpublished data, 2015). In public health events requiring contingency or crisis care standards, electrodiagnostic study feasibility decreases.
Recommendation
- When feasible, consider electrodiagnostic testing to assist in suspected botulism case diagnosis. EMG, RNS, and NCSs, when expertly conducted and interpreted, can provide useful diagnostic data.
Exposure Risk Factors and Botulism Diagnosis
Background
Known botulism risk factors in a patient’s history can focus clinical attention on the diagnosis. Wound botulism risk factors include injection drug use (especially black tar heroin), and foodborne botulism risk factors include home-canned food consumption (3). However, atypical and novel exposures also cause botulism, so absence of typical risk factors doesn’t rule out the disease. Multiple suspected botulism cases, especially among related individuals, suggest a common-source outbreak, increasing diagnosis likelihood (3). However, geographically dispersed, unconnected cases don’t exclude a botulism outbreak from a widely distributed, seemingly innocuous product. Public health authorities should immediately investigate all suspected botulism cases and promptly inform clinicians about suspected exposures, enabling them to interview other patients with compatible signs and symptoms and potentially link them to the outbreak.
Recommendation
- Clinicians should ask patients about potential exposures to well-described botulinum toxin sources, remembering that absence of such exposures doesn’t exclude botulism.
Alt: Various jars of improperly home-canned goods, representing a high-risk food source for foodborne botulism.
Clinical Criteria Tool for Early Diagnosis of Botulism in Crisis and Contingency Settings
Diagnosing botulism can be challenging. An evidence-based clinical criteria tool was developed to aid early botulism identification in crisis or contingency care settings, where botulism probability increases above extremely rare levels. This tool can also be used in conventional settings (Box 1) (36). Botulism cases from various sources were used to identify acute botulism onset signs and symptoms, compared and ranked by frequency to identify optimally sensitive criteria (Tables 3 and 4). The tool was modified to account for reasons illnesses were missed, and expert clinician input was applied to the criteria. Ancillary results (electrodiagnostic, neuroimaging, Tensilon tests, lumbar puncture) were not included. The tool was designed for maximum objectivity and reproducibility among healthcare workers. Therefore, frequently occurring but hard-to-quantify signs (e.g., sluggishly reactive pupils) were excluded. Epidemiologic risk factors, often unconfirmed early in investigations when severely ill patients seek care, were also omitted. The tool is for children and adults, including pregnant women, and can be used by various healthcare workers without supervision after brief training during contingency and crisis situations like large outbreaks. It’s not meant to replace thorough physical exams and ancillary testing or to diagnose botulism. Instead, it helps clinicians consider botulism diagnosis, avoiding distractions from atypical or incidental findings (36). In conventional care, the tool can prompt botulism consideration, followed by detailed evaluation. In crisis care, meeting these criteria alone might be enough to treat for presumed botulism. Meeting some criteria might categorize patients as medium botulism likelihood, requiring monitoring (Figures 1 and 2). Criteria fulfillment isn’t diagnostic; patients with illnesses commonly confused with botulism, like myasthenia gravis and Guillain-Barré syndrome, might meet them. During outbreaks, “worried well” persons (anxious about illness during outbreaks) without objective botulism signs/symptoms often seek hospital care for subjective symptoms (53). Triaging these patients can be time-consuming and delay treatment for others. Large botulism outbreak response requires managing numerous patients seeking care unnecessarily and educating the public about signs/symptoms not requiring hospital visits.
Laboratory Testing
Critical initial botulism treatment decisions are based on clinical findings. Botulinum antitoxin should be administered as quickly as possible. Laboratory confirmation can take days, and delaying antitoxin for laboratory results can worsen outcomes (3,35,44,45).
Laboratory testing confirms clinically suspected cases, verifies antitoxin effectiveness against the causing serotype, and demonstrates (or confirms epidemiologically) botulinum neurotoxin in suspected food to remove the source and prevent further illnesses. Botulism confirmation in symptomatic persons 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 isn’t done in foodborne botulism investigations. Laboratory confirmation is performed by specific municipal and state public health laboratories and CDC’s National Botulism Laboratory. Public health labs offer free emergency specimen testing and provide detailed collection/shipment instructions.
Types of Botulism Tests
The gold standard 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 intraperitoneally into mice with and without antitoxin, observed up to 96 hours for botulism signs by expert technicians. Results might be available within 24 hours if specimen toxin levels are high; however, low toxin levels causing human illness might not cause mouse signs. The mouse bioassay is the only FDA-approved method for laboratory botulism confirmation. However, other methods detecting/identifying botulinum neurotoxin and botulinum neurotoxin–producing Clostridium can support clinical botulism 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 methods like mouse bioassay. Mass spectrometry (Endopep-MS) for botulinum neurotoxin detection is highly sensitive and specific, differentiating serotypes A, B, E, and F within hours (55). It’s available at CDC and limited public health labs.
Laboratory botulism confirmation is usually impossible in nonreference labs (e.g., hospital/clinical labs) because their biochemical tests and mass spectrometry cannot detect botulinum neurotoxin or differentiate toxin-producing Clostridia from nontoxigenic organisms. Occasionally, CDC is notified of nonreference labs identifying C. sporogenes or C. botulinum in clinical specimens; reference lab testing usually identifies C. sporogenes, which doesn’t produce botulinum neurotoxin (CDC, unpublished data, 2018).
Collection and Transportation of Specimens
Serum specimens must be collected before BAT treatment because it neutralizes botulinum toxin, potentially misleadingly indicating toxin absence. Laboratory botulism confirmation depends on clinicians recognizing botulism signs/symptoms, contacting state/local health departments for expert clinical consultation (including lab testing discussion), and ordering appropriate specimen collection and rapid transport (Table 5; Box 2) (2,3,28). For lab confirmation, early clinical specimen collection is essential to detect botulinum toxin, if present, before it irreversibly binds within neurons and falls below assay detection levels in serum, stool, or gastric fluid. For adults, collect enough whole blood without anticoagulant to yield 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 are sometimes sufficient; rectal swabs from infants/young children are acceptable. For constipated patients, collect stool via enema with (preferably) sterile nonbacteriostatic water and non–glycerin-containing suppositories; tap water can interfere with testing and is not recommended. Stool may be collected post-BAT treatment because Clostridium organisms might persist in stool even if serum toxin is neutralized (17); BAT treatment should not be delayed for stool collection. Suspect foods should be sent in original containers for expert lab determination of testable food parts. Even containers with dried/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. Specimens from exposed but asymptomatic persons are not routinely tested because their toxin levels are likely below mouse bioassay detection limits. Rare exceptions include known high toxin level exposures in research labs, where clinical specimens can be obtained and BAT administered before illness onset.
Sporadic case botulism confirmation is valuable, eliminating alternative diagnoses/treatments and providing prognosis. Test results are negative in a significant proportion of cases despite near-certain clinical diagnosis, typically due to delayed botulism recognition leading to late specimen collection, when serum toxin levels have fallen below laboratory test detection limits. In wound botulism, botulinum neurotoxin–producing Clostridium species are not always detected in wound specimens, especially post-antibiotics.
Recommendations
- Treat patients with suspected, symptomatic botulism with botulinum antitoxin based on clinical findings; do not await laboratory confirmation, as results may take days and can be negative in botulism patients. (For BAT risks/benefits, see Allergic Reactions and Other Side Effects of Botulinum Antitoxin.)
- Discuss specimen collection with expert consultants from CDC or local/state health departments.
- Collect specimens for laboratory confirmation of clinical botulism diagnosis as soon as possible because 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.
