Rabies: ancient yet contemporary cause of encephalitis.

Christoph Schankin et al recently reported a patient who developed rabies encephalitis on his return from India. This report provides an opportunity to recall that rabies is not only an old fatal disease, whose first description dates from the 23rd century BC, but also a re-emerging zoonosis. Although preventable by vaccination, rabies is still not effectively controlled and its true impact is largely underestimated.

Except in Australia, Japan, and Scandinavia, animal rabies occurs on all continents, with the dog as the principal vector and reservoir of Lyssavirus. In western Europe, control of stray dogs and campaigns of oral vaccination of dogs and wild animals, especially foxes, has led to a significant reduction in the number of rabies cases. Since 2001, France has been considered free of rabies, and the UK is said to never have had an indigenous case. These satisfactory results are questioned by recent data showing risks associated with illegally imported animals from infected countries, and new reservoirs in Scotland in indigenous insectivorous bats. In North America, bats are the main vector of rabies, because 32 of the 35 most recent cases of human rabies were caused by bat strains of the virus.

Lyssaviruses are single-stranded RNA viruses. Because their genome is replicated by a polymerase devoid of a proof-reading mechanism, they are fast-evolving organisms capable of adapting to new hosts, which makes them among the most dangerous pathogens, like HIV, the coronavirus that causes severe acute respiratory syndrome, and influenza virus. Molecular studies have estimated that Lyssaviruses have already switched from the Chiroptera to the Carnivora order, probably between 888 and 1459 years ago.

The usual mode of transmission is through the bite of an infected animal or, more rarely, scratching and licking, as in Schankin et al's case. The reality is less straightforward: in 32 US cases caused by bat strains of virus, only 12 had physical contact with a bat. The silver-haired bat variant, responsible for some of these newly emerging cases in North America, is not associated with any known history of conventional exposure. This variant has a unique cellular tropism and can replicate in epidermal cells and then penetrate a nerve. Hence, only a small superficially administered quantity of this virus is sufficient to cause infection and death.

More puzzling are the recent rabies cases in four transplant patients. They all received various organs (lung, liver, kidney) from the same donor, who was not diagnosed with rabies before death. These cases raise the question of the possible spread of virus variants into solid organs via blood vessels. This idea is supported by studies indicating that rabies virus can infect macrophages.

In human beings, one should consider rabies in the diagnosis of neuropsychiatric disorders in a patient who has been in contact with animals and has been in an infected country. The encephalitic presentation, as in Schankin et al's case, is unmistakable, but the paralytic presentation, present in about 20% of cases, might mimic other diseases, such as acute disseminated encephalopathy. The organ donor mentioned above had a clinical picture mimicking subarachnoid haemorrhage. Moreover, rabies virus variants might be responsible for cryptic forms of the disease.

Both clinical presentations detailed above of human rabies share similar imaging patterns—ie, mild hyperintensity changes in the brain stem, hippocampus, hypothalamus, deep subcortical white matter, and deep grey matter on T2-weighted MRI. Enhancement with gadolinium seems to show up on images only late, when the patient becomes comatose.

Rapid and accurate detection of rabies virus in specimens is required when rabies is suspected. RT-PCR can detect rabies virus RNA in central nervous system tissue, saliva, spinal fluid, tears, skin biopsy samples, and urine within 3 days after clinical onset, and should be developed for use even in the laboratory conditions prevailing in developing countries.11, 12

Since 1970, there have been medical reports of five patients who survived rabies encephalitis. However, they all had severe sequelae. Therefore, today, the recommendation remains treatment before any clinical sign. Wound soap-washing and postexposure vaccination are the only means of preventing human death, but the best prophylaxis would be the elimination of animal rabies.