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A healthy 39 year old man was bitten on the ankle by his own apparently normal dog. After the incident the dog disappeared into the forest and was not seen again. Three days later the patient was seen at a provincial hospital in Vietnam and started on an alternate day regimen of suckling mouse brain postrabies exposure vaccination (SMBV). After the second dose, he felt unusually lethargic although he was still able to work. After the third dose, he became unrousable, and was transferred to the Centre for Tropical Diseases, Ho Chi Minh City, the referral hospital for infectious diseases in southern Vietnam. On admission, he was afebrile, confused, had slurred speech, and his Glasgow coma score was 13. He had mild spastic weakness of his left face, left arm, and both legs. Full blood count and results from routine biochemistry and chest radiography were all normal. The CSF: blood glucose ratio was 0.47 (63/140 mg%), the protein content was raised (78 mg/dl), and there was one lymphocyte/ml in the CSF. Screens for malaria toxoplasmosis, cryptococcus, and neurocysticercosis were negative, as was a CSF gram stain. The CSF was sterile after 2 weeks of culture. Brain MRI (Access Toshiba LPT 6.01p, 0.064 Tesla) showed areas of high signal throughout the white matter, and cystic-like change in the basal ganglion and right cerebellar hemisphere (figure A). These variably sized lesions were bilateral, widely distributed, asymmetric, and showed no evidence of haemorrhage or mass effect.
As paralytic rabies could not be excluded he was managed conservatively and the SMBV course was continued. On the 4th day after admission he deteriorated with a Glasgow coma score of 10, and was incontinent of urine and faeces with generalised spastic paraparesis. Methylprednisolone (500 mg/ day) was given for 5 days followed by a reducing course of prednisone for a presumptive diagnosis of postvaccination encephalitis. The SMBV was stopped. Within 72 hours of starting steroids there was a dramatic improvement in his neurological state. An MRI examination performed 4 weeks later showed a marked decrease in both size and number of brain lesions and no new lesions (figure B). After 6 weeks he was discharged talking, eating, walking, and continent but with some persistent emotional liability and mild memory impairment. A follow up MRI examination 5 weeks after discharge showed further improvement, apart from minor abnormalities in the basal ganglion, and generalised increase in ventricular size, consistent with residual cerebral atrophy.
Rabies is caused by an RNA virus, a member of theRhabdoviridae family, it infects mammals and can be transmitted to humans by contact, generally from an animal excreting the virus in the saliva. Rabies manifests as an acute encephalomyelitis, the development of which is almost invariably fatal. The distinction between rabies and postvaccine encephalitis is difficult and may be helped by antigen detection via a skin biopsy; however, this technique is not available in Vietnam.1Paralytic rabies could not be excluded in this patient and hence steroids were not used initially. Steroids have been reported to increase mortality in experimental animals with rabies, and it has been suggested that they may abrogate the immune response to the postexposure vaccine, thus precipitating uncontrolled rabies.2
There are three types of postexposure vaccine in use world wide. The Semple type (STV) is obtained from inactivated virus prepared on adult animal nerve tissue; it is inexpensive and relatively easy to produce. In India 3 million people receive postexposure courses of STV (phenolised sheep brain) antirabies vaccine each year.1These produce neurological reactions, including postvaccination encephalomyelitis, in up to 1 in 220 courses, with a 3% mortality.3 Clinical forms include a reversible mononeuritis multiplex, and meningoencephalitic and encephalomyelitic reactions. Myelin basic protein and related neural proteins from the nervous tissue of the animal on which the virus was cultivated stimulate an autoimmune reaction in the human nervous system.
Tolerance has been improved by the development of the suckling mouse brain vaccine (SMBV). The attenuated virus is cultured on immature mouse brain tissue, which contains little myelin, thus reducing the risk of complications. SMBV is inexpensive (US$1.5 per treatment course) and easily manufactured locally; it is the most widely used postexposure vaccine in Vietnam. Rare neurological reactions do occur with SMBV, Complications of the CNS have been reported to occur after vaccination with an incidence of 1:27000 treated people, with a 22% mortality4 The mortality was particularly high (90%) if there was extensive CNS involvement. The third type of vaccine available is the human diploid cell tissue culture vaccine (HDCV), which is both safe and efficacious. However, the recommended regimen is not affordable in most developing countries.
When we approached the Rabies Laboratory, Ministry of Agriculture and Fisheries, United Kingdom for advice in this case their comment was “why do you use the SMBV, can’t you use another vaccine”. Worldwide about 10 million people each year receive rabies vaccine after exposure; at the Centre for Tropical Diseases we treat 3000 people with dog bites annually. The cost of an HDCV in Vietnam, administered in its present regimen (1ml given for 5 days on days 0, 3, 7, 14, and 28 with an optional booster on day 90) is US$ 125, making the use of this vaccine unaffordable.
This is the first report to show the demyelinating CNS lesions on MRI, and their resolution after steroid therapy. It is relatively rare for patients to survive if they develop severe CNS effects after postexposure rabies vaccination. Although the incidence of reactions to SMBV is very much lower than STV, this report confirms that it does still occur. Both SMBV and STV are widely used throughout the developing world, and would be the vaccine administered to travellers exposed to animal bites in such countries. This case stresses the need for high dose steroids in postexposure vaccine encepahlitis and the urgent need for the development and deployment of a safe, and critically, affordable postrabies exposure vaccine regimen. The economic low dose multisite intradermal regimen using the HDCV provides an example of how this goal may be achieved although it is not yet widely accepted. Such a vaccine regimen (0.1 ml HDCV given at multisite injections on days 0, 7, 28, and 90) could be made affordable, and offers excellent protection without the risks of postexposure immune mediated encephalitis.5
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