Rabies: ancient yet contemporary cause of encephalitis
Authors: François Sellal, Françoise Stoll-Keller
Journal: The Lancet (2005)

Christoph Schankin et al1Schankin CJ Birnbaum T Linn J et al.A fatal encephalitis.Lancet. 2005; 365: 358Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar 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.2Colemann PG Févre EM Cleaveland S Estimating the public health impact of rabies.Emerg Infect Dis. 2004; 10: 140-142Crossref PubMed Scopus (117) Google Scholar 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,3Galperine T Neau D Moiton MP Rotivel Y Ragnaud JM The risk of rabies in France and the illegal importation of animals from rabid endemic countries.Presse Med. 2004; 33: 791-792Crossref PubMed Google Scholar and new reservoirs in Scotland in indigenous insectivorous bats.4Nathwani D McIntyre PG White K et al.Fatal human rabies caused by European bat lyssavirus type 2a infection in Scotland.Clin Infect Dis. 2003; 37: 598-601Crossref PubMed Scopus (85) Google Scholar 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.5Warrell MJ Warrell DA Rabies and other lyssavirus diseases.Lancet. 2004; 363: 959-969Summary Full Text Full Text PDF PubMed Scopus (241) Google Scholar 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.6Badrane H Tordo N Host switching in Lyssavirus history from the Chiropterato the Carnivora orders.J Virol. 2001; 75: 8096-9004Crossref PubMed Scopus (310) Google Scholar 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.5Warrell MJ Warrell DA Rabies and other lyssavirus diseases.Lancet. 2004; 363: 959-969Summary Full Text Full Text PDF PubMed Scopus (241) Google Scholar 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.7Morimoto K Patel M Corisdeo S et al.Characterization of a unique variant of bat rabies virus responsible for newly emerging human rabies cases in North America.Proc Natl Acad Sci USA. 1996; 93: 5653-5658Crossref PubMed Scopus (197) Google Scholar More puzzling are the recent rabies cases in four transplant patients.8Dietzschold B Koprowski H Rabies transmission from organ transplants in the USA.Lancet. 2004; 364: 648-649Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar 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.9Ray NB Ewalt LC Lodmell DL Rabies virus replication in primary murine bone marrow macrophages and in human and murine macrophage-like cell lines: implication for viral persistence.J Virol. 1995; 69: 764-772PubMed Google Scholar 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.8Dietzschold B Koprowski H Rabies transmission from organ transplants in the USA.Lancet. 2004; 364: 648-649Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar 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.10Laothamas J Hemachuda T Mitrabhakdi E Wannakrairot P Tulayadaechanont S MR imaging in human rabies.Am J Neuroradiol. 2003; 24: 1102-1109PubMed Google Scholar 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.11Hemachudha T Laothamatas J Rupprecht CE Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges.Lancet Neurol. 2002; 1: 101-109Summary Full Text Full Text PDF PubMed Scopus (308) Google Scholar, 12Hemachudha T Wacharapluesadee S Antemortem diagnosis of human rabies.Clin Infect Dis. 2004; 39: 1085-1086Crossref PubMed Scopus (38) Google Scholar Since 1970, there have been medical reports of five patients who survived rabies encephalitis.5Warrell MJ Warrell DA Rabies and other lyssavirus diseases.Lancet. 2004; 363: 959-969Summary Full Text Full Text PDF PubMed Scopus (241) Google Scholar 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. We declare that we have no conflict of interest.