Ophthalmologic Manifestations of Botulism

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 bacillus was first called "botulinus," causing the "botulinus syndrome" when it was discovered by van Ermengem in 1895. ^[1]  He showed the occurence of ptosis, mydriasis, paralysis of accommodation, diplopia, and limitation of ocular movements in his initial presentation. Other early studies by Roemer and Stein in 1904 in which they experimented on monkeys showed the occurence of ptosis, mydriasis, paralysis of accommodation, and third nerve palsy. ^[2]

The neurotoxin causes a paralytic disease with blockade of neuromuscular conduction. Botulism is characterized by symmetric cranial nerve palsy, and often is followed by flaccid paralysis of involuntary muscles, which can result in respiratory compromise and death.

Botulism generally is seen in four 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. ^[3]

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, for cosmetic reasons (to reduce glabellar lines and smile lines), and in blepharospasm associated with facial dystonia, including benign essential blepharospasm. ^[4]

IC 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). ^[5] 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. ^[6]

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 may be seen in different 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. ^{[7, 8]} 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 a disturbance in normal intestinal flora.

• Inhalational botulism where there is exposure to aerosolized botulinum neurotoxin.

• Iatrogenic botulism occurs after injection of botulinum toxin for cosmetic or therapeutic purposes which was approved by the Food and Drug Administration (FDA) of the USA in 2002. ^[9]

Frequency

United States

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

Foodborne botulism is responsible for an average of 30 reported cases per year in the United States. ^[10] 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; whereas 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.

Inhalational botulism occurs when purified botulinum toxin is produced and weaponized for biological warfare. ^[11]

Botulism needing inpatient therapy was reported after use of botulinum toxin for cosmetic and therapeutic purposes in 86 patients in 2018. ^[12]

International

Human botulism occurs worldwide.

Foodborne 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 foodborne disease with current medical supportive care, the US case-fatality rate for the period 1976-1984 was about 7.5%. ^[10] 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 among patients older than 60 years compared with 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 to 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.

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 result in higher morbidity and mortality rates. Mortality rates also are 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.

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.