Knowledge on rare diseases and orphan drugs

Epidemiology depends on the control level of the pathogen and its animal vectors, so the rabies is much more prevalent in the developing world than in developed countries. The WHO estimates that around 50,000 persons die each year from rabies.

Rabies evolution follows a three steps path. After a contact (bite) with an infected animal, incubation lasts 20 to 90 days while patients remain asymptomatic. This duration varies with the quantity and the location of the inoculum. It can extend to several years in rare cases. The second phase, the prodromal period, lasts 2 to 10 days and is characterized by paresthesia or pain at the inoculation site. Other nonspecific symptoms may occur, including malaise, anorexia, headaches, fever, chills, pharyngitis, nausea, emesis, diarrhea, anxiety, agitation, insomnia and depression. The third phase is the most distinctive one, named the acute neurologic period. It is associated to clear central nervous system (CNS) involvement, its duration is 2 to 7 days and it can be of two kinds: the furious rabies or the paralytic rabies. In the first case, patients show agitation, hyperactivity, restlessness, trashing, biting, confusion or hallucinations. Hydrophobia and aerophobia are pathognomonic for rabies and occur in 50% of patients. After hours or days these signs appear by bouts - during less than 5 minutes - alternating with calm phases of lucidity. Seizures may occur. The terminal evolution of this phase is cardiorespiratory arrest or paralysis. In the second case, also named apathetic rabies, paralysis develops from the outset with fever, headache and nuchal rigidity. In both cases, the terminal evolution, if untreated, is coma and death.

Rabies is caused by infection of a virus of the Lyssavirus genus. Infection occurs in a large majority through the bite of a rabid dog and more generally through contact of broken skin or mucous membrane with infected saliva, CNS tissue or aerosolized secretions from infected animals. Lyssavirus are neurotropic viruses that escape immune system invading peripheral nerve ending. Incubation duration depends on the time needed to invade the CNS.

Diagnosis is based on clinical examination, early signs being paresthesia or pain at the inoculum site, and firmly relies on PCR detection of viral RNA in the saliva, the cerebrospinal fluid (CSF) or in a nuchal skin biopsy, on blood or CSF serological findings.

Tetanus is the main differential diagnosis which also includes other types of encephalomyelitis and neuropaludism.

Standardized vaccination procedures are established for pre- or post-exposure situations. In case of exposition, rapid washing, antisepsis and vaccine administration could be associated to a serotherapy protocol consisting of immunoglobulins injection at the inoculum site. Each infection has to be declared.

If not treated, rabies is always fatal. Treatment has to be administrated during the incubation period to be efficient.

Last update: October 2011 - Expert reviewer(s): Dr Hervé BOURHY