Ophthalmologic Manifestations of Botulism 

Updated: May 19, 2016
Author: Bhupendra C K Patel, MD, FRCS; Chief Editor: Hampton Roy, Sr, MD 

Overview

Practice Essentials

Botulism, although rare, is a potentially lethal illness caused by the botulinum toxin produced by Clostridium botulinum and other clostridial species.

Botulism causes cranial nerve palsies and flaccid paralysis of involuntary muscles and may result in respiratory compromise.

Early diagnosis is essential. Intensive supportive care and administration of botulinum antitoxin are vital.

Administration of human-derived botulinum antitoxin in suspected infant botulism cases decreases the length of hospitalization, intensive care unit admission, and mechanical ventilation.

Botulism must be reported to state public health departments and the Centers for Disease Control and Prevention at 770-488-7100.

Prevention involves keeping wounds clean and safe food preparation and food-canning techniques.

Honey should not be fed to children younger than 12 months based on multiple studies that have identified the association of honey consumption with infant botulism cases. This is supported by all major pediatric organizations.

Background

Botulism is a disease caused by the neurotoxins of Clostridium botulinum. This microorganism is a spore-forming, gram-positive, anaerobic bacillus, which may exist in soil or marine sediments throughout the world. The neurotoxin causes a paralytic disease with blockade of neuromuscular conduction. Botulism is characterized by symmetric cranial nerve palsy, often followed by flaccid paralysis of involuntary muscles, which can result in respiratory compromise and death.

Botulism generally is seen in 4 clinical scenarios, as follows: (1) the ingestion of preformed toxins in food contaminated with C botulinum, (2) contamination of wounds by C botulinum, (3) colonization of the intestine by C botulinum in infants younger than 1 year, and (4) iatrogenic botulism due to injection of botulinum toxin.

Despite the uncommon nature of the disease, patients with botulism may present to an ophthalmologist with visual symptoms.

Purified botulinum toxin type A, in the form of BOTOX® purified neurotoxin complex, has been used therapeutically in the treatment of certain forms of strabismus and in blepharospasm associated with facial dystonia, including benign essential blepharospasm.[1]

Pathophysiology

C botulinum is a heterogeneous group of spore-forming, anaerobic, gram-positive microorganisms. Organisms of types A to G are distinguished by the antigenic specificities of their toxins. Eight distinct toxins have been described (ie, A, B, C1, C2, D, E, F, G).[2] In rare instances, a single strain of organism may produce more than one toxin. All toxins except C2 are neurotoxins; C2 is a cytotoxin of uncertain clinical significance. Toxin types A, B, E, and, in rare cases, F cause human disease; types C and D cause avian and nonhuman mammalian disease.[3]

Rarely, clostridial species other than C botulinum have been reported to cause disease, including rare toxin-forming strains of Clostridium butyricum and Clostridium baratii.

Clostridial spores are highly heat resistant, with inactivation requiring exposure to a temperature of 120°C. However, the toxin may be inactivated by exposure to a temperature of 100°C for 10 minutes.

Botulinum neurotoxins, whether directly ingested, produced in a C botulinum contaminated wound, or produced by C botulinum colonization within the intestines, enter the vascular system and are transported to peripheral cholinergic nerve terminals. The peripheral cholinergic nerve terminals involved include neuromuscular junctions, cholinergic parasympathetic nerve endings, and some peripheral ganglia. The toxin causes blockade of neuromuscular conduction by binding to receptor sites on presynaptic motor nerve terminals, entering the nerve terminal, and inhibiting the release of acetylcholine by proteolysis of components of the neurotransmitter exocytosis apparatus.

Blockade of neurotransmitter release at the nerve terminal is considered permanent. Evidence exists that the axon may sprout new terminals and allow recovery of neurotransmission.

Botulism is generally seen in 3 clinical scenarios, based on the mode of acquisition, as follows:

  • Food poisoning: This follows the ingestion of preformed toxins in food contaminated with C botulinum.

  • Wound infection: Infection of wounds by C botulinum most commonly occurs where wounds are contaminated heavily with soil or water. Spores may germinate into toxin-producing vegetative microorganisms.

  • Infant botulism: This results from intestinal colonization of organisms in infants younger than 1 year.[4, 5] The immature intestine system allows abnormal colonization. Toxin is produced in and absorbed from the gut, following ingestion of ingested spores. More recently, adult intestinal colonization botulism has been described in association with intestinal disease causing disturbance in normal intestinal flora.

Epidemiology

Frequency

United States

Overall, approximately 110 cases of botulism are reported annually in the United States.

Food-borne botulism is responsible for an average of 30 reported cases per year in the United States.[6] Since 1950, the average number of outbreaks per year is 9.4. In the United States, the geographic distribution of cases by toxin type generally coincides with the organism type found in the local environment. Toxin type A is the most predominant type west of the Rocky Mountains; type B generally is distributed but is more common in the eastern United States; while type E is found in the Great Lakes region and Alaska. In the United States, type A accounts for 60% of cases, type B 18%, and type E 22%. Home-processed foods are responsible for most outbreaks. Type E outbreaks are associated with fish products.

Infant botulism was first recognized as a disease in 1976. Infant botulism is responsible for about 60 cases each year; hence, it is now the most frequent form of the disease in the United States in recent years. Average annual incidence is approximately 1.9 per 100,000 live births. Mean age at onset is about 13 weeks but ranges from 1-63 weeks. Infant botulism is underrecognized and underreported.

Wound botulism is rare, with only several reports annually in the United States.

International

Human botulism occurs worldwide.

Food-borne botulism is responsible for almost 1000 cases worldwide each year.

Mortality/Morbidity

Mortality and morbidity from botulism vary according to the mode of acquisition.

For food-borne disease with current medical supportive care, the US case-fatality rate for the period 1976-1984 was about 7.5%.[6] Type A disease is generally more severe than type B, with greater need for ventilatory support and longer disease course. The case-fatality rate for type A is about 10% and for type B is about 5%. Mortality from botulism is higher amongst patients older than 60 years compared to younger patients. The case-fatality rate for those older than 60 years was 30%. The average duration of pulmonary support for those requiring mechanical ventilation is 6-8 weeks. Some patients experience residual weakness and autonomic dysfunction for as long as 1 year.

The case-fatality rate for wound botulism is 10%. Survivors experience significant long-term morbidity.

Infant botulism has a case-fatality rate of 1.3%. Generally, symptoms progress for 2 weeks and then stabilize for 3 weeks, before recovery begins. The average length of infant inpatient hospital is about 4 weeks, although excretion of organisms may continue for several months after discharge, and a 5% relapse rate exists.

Race

While no racial predilection exists, geographic distribution toxin type coincides with the organism type found in the local environment.

Sex

No sexual predilection exists.

Prognosis

Botulinum toxin binds irreversibly to the neuromuscular junction synapses. Neurologic recovery occurs when new motor endplates are regenerated, which may take weeks to months. Some symptoms of botulism may persist for as long as a year.

Intensive supportive care in the United States has improved the prognosis of botulism. Mortality has decreased from 60% in the 1950s to 5% overall today and less than 1% among those who are hospitalized. The fatality rate remains high in other parts of the world where supportive care is not available. Larger doses of ingested toxin results in higher morbidity and mortality rates. Mortality rates are also higher in type A than type B or C toxin disease.

Infants with botulism generally recover after 2-3 weeks, with most making gradual improvement over a period of 2 months.

Common complications include respiratory failure, which may require mechanical ventilation, and secondary infections such as pneumonia, urinary tract infection, and C difficile-associated colitis.

Patient Education

Transmission of toxin does not occur person-to-person, but meticulous handwashing is essential.

Soiled diapers of infants with botulism should be autoclaved because they can contain botulinum neurotoxin and spores. Spores can contaminate open skin lesions of caretakers, resulting in wound botulism. Caretakers with hand wounds should avoid handling soiled diapers.

Botulism must be reported immediately to the local state health department. This is important to obtain diagnostic aid, to determine appropriate collection and handling of specimens, and to obtain prompt antitoxin delivery.

Owing to the association of honey consumption with infant botulism, it has been suggested that honey should not be given to babies younger than 12 months.

Education about safe practices in food preparation and home-canning methods should be promoted. To kill C botulinum spores, a pressure cooker must be set to 116°C. Toxin destruction requires cooking of foods until their internal temperature is 85°C for 10 minutes. Bulging food containers should be discarded, as they may contain gas produced by C botulinum. Food that appears spoiled should be discarded.

 

Presentation

History

The diagnosis of botulism requires a high degree of clinical suspicion. Although laboratory confirmation is required, the diagnosis should be suspected on clinical findings, in those patients with an appropriate history and physical (particularly neurologic) examination.

Food poisoning

The severity of illness varies from a mild condition to a very serious disease with death within 24 hours. The incubation period is generally 18-36 hours; however, it may vary from several hours to several days.

The initial symptoms are usually those of motor cranial nerve involvement with onset of diplopia, dysphonia, and dysphagia. A generally symmetric descending paralysis follows. Abdominal pain, with nausea and vomiting may precede or follow paralysis. A dry mouth and throat reflect cholinergic parasympathetic disturbance. Patients generally remain alert and responsive. Sensory deficits, besides blurred vision, have been reported only in rare cases.

Wound infection[7]

The incubation period averages about 7 days. Wound botulism may occur in any wound contaminated by soil or water.

Symptoms are generally the same as those seen in food-borne botulism, except gastrointestinal symptoms are absent. The source wound may appear relatively benign. Wound infections associated with intravenous drug needle puncture sites are becoming an important cause.

Infant botulism[8]

The incubation period varies from 3-30 days. In this form of botulism, the severity ranges from mild illness with failure to thrive to severe paralysis with respiratory failure.

Infant botulism causes acute bulbar dysfunction. The first sign of the disease may be constipation. Other features include lethargy, hypotonia with poor head control, poor feeding, with difficulty in sucking and swallowing, and pooled oral secretions. Respiratory failure occurs in up to one half of diagnosed infants.

The identification of contaminated honey as a source of spores has lead to the recommendation that honey should not be given to infants younger than 1 year. Susceptibility decreases with age as the normal intestinal flora develops.

Physical

The major systemic features of botulism involve motor weakness or paralysis. Paralysis begins with cranial nerve involvement and progresses caudally to involve extremities.

Clinical physical findings involve the following:

  • Symptoms of motor cranial nerve involvement with onset of dysarthria, dysphonia, and dysphagia may be present.

  • A generally symmetric descending paralysis occurs, with involvement of neck, arms, thorax, and legs.

  • Respiratory difficulties occur with intercostal and diaphragmatic weakness.

  • Autonomic features are to be expected, reflecting cholinergic neurotransmission disruption, with impairment of salivary secretion, paralytic ileus, constipation, and urinary retention.

  • Postural hypotension may be present.

  • The gag reflex may be suppressed.

  • Typically, patients are afebrile.

Ophthalmic manifestations may reflect the anticholinergic effects of the neurotoxins.[9, 10]

  • Accommodation paresis, with blurred vision

  • Pupil dysfunction with mydriasis and poorly reactive pupils

  • Dry eye symptoms with impairment of lacrimation

Ophthalmic manifestations may reflect a deficit at the neuromuscular junction.[11, 12, 9, 10]

  • Oculoparesis or ophthalmoplegia manifests as diplopia.

  • Blepharoptosis is common.

  • Nystagmus may be noted.

Ocular manifestations may be the manifesting features of botulism. However, their absence does not exclude this disease, since the various toxins appear to involve the ocular system to various degrees. Neurotoxin A may have no specific ophthalmic manifestations.

In wound botulism, the symptoms are generally the same as those seen in food-borne botulism, except gastrointestinal symptoms are lacking.

In the infant, the clinical examination may note neurologic features of ptosis, ophthalmoplegia, weak gag reflex, and poorly reactive pupils, in addition to systemic features of generalized muscle weakness with hypotonia and a weak cry.

Causes

Botulism is a disease caused by the neurotoxins of C botulinum.

 

DDx

Diagnostic Considerations

An absence of bulbar paralysis excludes the diagnosis of botulism.

A botulism outbreak should be suspected when there is clustering of cases of the neurologic syndrome. The differential diagnoses of foodborne botulism includes myasthenia graves, Guillain-Barre syndrome, cerebrovascular accident, Eaton-Lambert syndrome, paralytic shellfish poisoning, chemical intoxication, tick paralysis, and psychiatric disease.

An edrophonium test is performed to exclude myasthenia gravis. In myasthenia gravis, there is sparing of pupillary and oculomotor function. In Guillain-Barre syndrome, protein content in cerebrospinal fluid is elevated in the absence of cells. Guillain-Barre syndrome also shows more typical electromyography findings that distinguish it from botulism.

Infants with botulism are frequently admitted with a diagnosis of sepsis. When hypotonia progresses, other conditions considered include hypothyroidism, inborn errors of metabolism, poliomyelitis, encephalitis, and poisoning. 

Differential Diagnoses

 

Workup

Approach Considerations

Diagnosis of botulism requires a thorough clinical history, assessment of the timing and progression of neurologic symptoms, assessment of recent diet, assessment of bowel habits, and a high index of suspicion.[13]

Most initial laboratory findings are normal, except for mild dehydration, especially in infants.

A diagnosis of botulism is confirmed via detection of the organism or botulinum toxin in stool, serum, would exudates, tissue specimens, or the implicated food source. As C botulinum is not part of normal flora in infants or adults, culture that is positive for C botulinum in a symptomatic patient should be considered diagnostic of botulism. Botulinum toxin is detected in serum or stool specimens in approximately 46% of clinically diagnosed cases. In foodborne cases, serum toxin assay results may remain positive for up to 16 days after admission, and stool cultures grow C botulinum in approximately 70% of cases.

In infant botulism, toxin is detected in a serum specimen only early in the course of the illness and before antitoxin administration. Serum toxin assay results are positive in only 1% of reported cases of infant botulism in the United States.

Stool, enema, and gastric aspirates are cultured and examined for toxin assay. Suspect foods should be collected.

A mouse neutralization assay is used to detect toxin from specimens; this is the most sensitive and specific method of assay available.

Enriched media are needed to culture and isolate C botulinum.

Severity and duration of the illness have been reported to be worse in cases due to type A than type B toxin.

Laboratory Studies

The diagnosis of botulism requires a high degree of clinical suspicion. The diagnosis must be considered in an afebrile patient with progressive descending paralysis, especially in the presence of gastrointestinal symptoms.

Serum toxin bioassay: The demonstration of toxin in serum involves a bioassay in mice. The identification of the toxin type is performed by a mouse toxin neutralization test.

Isolation of organism by culture

Food-borne: The demonstration of organism (or its toxin) in vomitus, gastric aspirate, or feces is highly suggestive of the diagnosis of botulism, because intestinal carriage is rare. Anaerobic cultures are required. Early cases of botulism are more likely to involve diagnosis by toxin assay, whereas later cases are more likely to yield a positive specimen culture.

Wound culture: In wound botulism, wound cultures yielding the organism are highly suggestive of botulism.

Source culture: Isolation of the organism from food without toxin is not sufficient for a diagnosis.

Other Tests

Electrophysiology: Nerve conduction velocity is normal.

Electromyography shows a distinctive pattern of brief, small-amplitude, overly abundant motor unit potentials.

 

Treatment

Approach Considerations

As botulism neurotoxin binds irreversibly, administration of antitoxin does not reverse paralysis. Neurologic recovery occurs only when motor neurons regenerate, which may take weeks to months. Therefore, intensive respiratory and nutritional support is vital.

Medical Care

Supportive care for the duration of the paralytic illness, with extensive nursing support, is the mainstay of treatment.

Ventilatory support: In adults, ventilatory support will be needed in as many as one third of cases. Pulse oximetry, arterial blood gas analysis, and spirometry should be monitored. Mechanical ventilation is considered when vital capacity is less than 30% of predicted.

Parenteral nutrition may be required in view of gastrointestinal disturbance.

Urinary catheterization may be required for urinary retention.

Antitoxin

In food-borne illness, trivalent (types A, B, and E) equine antitoxin should be administered, with antitoxin neutralizing botulinum toxin not yet bound to nerve terminals. Therefore, the antitoxin should be given as soon as possible, prior to receiving laboratory confirmation of diagnosis. Antitoxin neutralizes circulating neurotoxin molecules that have not yet bound to nerve endings. The recommended dose of botulism antitoxin in adults is one vial per patient as a single dose. Hypersensitivity reaction to the antitoxin occur in about 9% of patients treated with equine sera, so skin testing should be performed before administration.

Botulism immune globulin intravenous

Botulism immune globulin intravenous (human) (BIG-IV; also called BabyBig) is FDA-approved for the treatment of infant botulism caused by C botulinum type A or type B. It should be administered urgently and has been shown to be safe and effective. It reduces mean hospital stay per case from 5.5 weeks to 2.5 weeks. Administration of BIG-IV has also been shown to decrease days of mechanical ventilation, days of intensive care unit stay, and overall hospital stays.

Antibiotic therapy

Antibiotics may be helpful in the eradication of C botulinum in wound botulism, but they appear to have no role in infant botulism or in botulism of food poisoning. Remember that aminoglycoside antibiotics and tetracyclines may increase neuromuscular blockade by impairment of neuronal calcium entry and may potentiate the toxin paralytic effects, precipitating acute respiratory arrest in infants with unsuspected botulism patients.

Antibiotics are otherwise reserved for treatment of secondary bacterial infections (eg, pneumonia, urinary tract infections).

Surgical Care

Wound botulism requires exploration and wound debridement immediately after antitoxin administration. Anaerobic cultures should be obtained and penicillin at 250,000-400,000 U/kg/day for 10-14 days is administered.

 

Medication

Medication Summary

Antitoxin appears to be the only effective medication. Guanethidine has been used and shown to be not effective, despite reports of improvement in accommodative paresis.

In infant botulism, intravenous therapy with botulism immune globulin (BIG), which was approved by the US Food and Drug Administration (FDA) in 2003, is recommended to shorten the duration and to diminish the potential complications.

Antitoxins

Class Summary

Trivalent (types A, B, and E) equine botulism antitoxin should be used in the presence of food-borne botulism.

Botulinum antitoxin

Intravenous administration of one vial of botulism antitoxin results in serum levels of type A, B, and E antibodies capable of neutralizing serum toxin concentrations in excess of those reported for botulism patients. Circulating antitoxins have a half-life of 5-8 days.

 

Follow-up

Further Inpatient Care

Prolonged support, particularly respiratory support, may be required.

Deterrence/Prevention

Botulism is a public health emergency.

Rapid epidemiologic investigation is critical to prevent further cases if hazardous foodstuffs are still available for consumption.

State health departments should be contacted.

Prognosis

With early detection and appropriate support, long-term outlook is good. See Mortality/Morbidity for mortality figures.

Patient Education

As many US outbreaks of food-borne botulism are due to improperly preserved home-canned foods, provide education about the appropriate cooking time, pressure, and temperature required to destroy spores. Refrigeration of incompletely processed foods is required. Emphasize education about the effectiveness of boiling home-canned vegetables to destroy toxins.

For excellent patient education resources, see eMedicineHealth's patient education article BOTOX® Injections.