Are We Getting Closer to the Treatment of Rabies?

Rodney E Willoughby Jr

Disclosures

Future Virology. 2009;4(6):563-570. 

In This Article

Unique Pathophysiology

Adding to the burden of rabies is the 100% fatality rate and sheer horror of the disease. Rabies is characterized by anxiety, sleeplessness, hallucinations, panic and aggression. Cognitive function is preserved until very late in the course, when coma supervenes. In between attacks of hydrophobic and aerophobic spasms, the patient can cogently communicate their suffering to relatives and medical staff.

It is unclear how rabies becomes fatal. While the death is medically violent – with respiratory spasms and profound swings in temperature, blood pressure and heart rate – there is very little anatomically wrong with the brain at autopsy. Wild-type rabies virus infection is noncytopathic and poorly apoptotic.[4] Histological inflammation is minimal and generally limited to perivenular lymphocytes. Highly passaged (fixed) rabies viruses produce ultrastructural changes evident by electron microscopy in mice moribund with rabies. Findings are inconsistent between models using alternate clones of the mouse-adapted challenge virus standard strain[5,6] and disagree with ultrastructural studies carried out in wild-type skunk rabies.[7] There have been three rabies survivors with excellent recoveries, suggesting that such ultrastructural changes are artifactual, imperfectly penetrant or reversible.[8–10]

For over 40 years, because of the marked disparity in clinical signs, outcome and the histological findings, experts have postulated that rabies must be caused by a disorder of neurotransmission. This is plausible because the best-characterized rabies virus receptor is the nicotinic acetylcholine receptor.[11] This hypothesis has been variously explored over the years, but without a dominant thread. With one exception, studies on neurotransmitter dysfunction in rabies used fixed rabies viruses that differ from wild-type rabies viruses in pathogenesis.[12] We recently reported a regular association of tetrahydrobiopterin (BH4) deficiency with human rabies. BH4 is an essential cofactor for the synthesis of catecholamine (dopamine and norepinephrine) and indoleamine (serotonin and melatonin) neurotransmitters. Severe deficiencies of dopamine and serotonin metabolism in association with BH4 deficiency are documented in all of the five patients with rabies studied to date.[13,14]

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