History of Suspected Association

Diphtheria toxin causes a toxic peripheral neuropathy in about 20 percent of cases (Mortimer, 1988), but diphtheria toxin has not been found to be associated with central nervous system (CNS) disease such as encephalopathy. Tetanus is a neurologic disease characterized by severe lower motor neuron hyperexcitability with consequent muscle spasms produced by the potent neurotoxin tetanospasmin (Wassilak and Orenstein, 1988).

Diphtheria and tetanus toxoids are generally given together as Td in adults and as DT or DPT (a combination that includes vaccine directed against pertussis) in children. DT and Td differ because of the lower concentration of diphtheria toxoid in the preparation for adults. Monovalent diphtheria and monovalent tetanus toxoids are also available. Pertussis as a clinical disease has long been known to cause encephalopathy, as discussed in detail by the Institute of Medicine (1991). The possibility that immunization against pertussis was responsible for serious adverse neurologic events leading to encephalopathy was raised as early as 1933, with concerns continuing to be reported through the present. Several large epidemiologic studies were designed to study the association between DPT and acute neurologic events in children. From those studies, information regarding DT was also obtained because of the lack of universal acceptance of DPT. The National Childhood Encephalopathy Study (Alderslade et al., 1981) and the North West Thames study (Pollock and Morris, 1983) provide some information on encephalopathy and DT. Additionally, two case-control studies in Italy (Crovari et al., 1984; Greco, 1985) were carried out to investigate a clinical observation that encephalopathy in several children was temporally related to DT immunization.

Evidence for Association

Biologic Plausibility

Although tetanus toxin can reach the CNS, it is not clearly associated with encephalopathy. The neurologic sequelae of tetanus have been described. Symptoms experienced by patients after recovery from tetanus include irritability, sleep disturbances, myoclonus, decreased libido, postural hypotension, and abnormalities on electroencephalograms (Illis and Taylor, 1971). The symptoms disappeared within 2 years of recovery from tetanus. These were attributed by the author as secondary to the action of tetanus toxin on inhibitory synapses in the CNS. The neurologic consequences of diphtheria are primarily peripheral neuropathy.

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