Survival after Treatment of Rabies with Induction of Coma

Department of Pediatric Infectious Diseases, Medical College of Wisconsin, Milwaukee, USA.
New England Journal of Medicine (Impact Factor: 55.87). 07/2005; 352(24):2508-14. DOI: 10.1056/NEJMoa050382
Source: PubMed


We report the survival of a 15-year-old girl in whom clinical rabies developed one month after she was bitten by a bat. Treatment included induction of coma while a native immune response matured; rabies vaccine was not administered. The patient was treated with ketamine, midazolam, ribavirin, and amantadine. Probable drug-related toxic effects included hemolysis, pancreatitis, acidosis, and hepatotoxicity. Lumbar puncture after eight days showed an increased level of rabies antibody, and sedation was tapered. Paresis and sensory denervation then resolved. The patient was removed from isolation after 31 days and discharged to her home after 76 days. At nearly five months after her initial hospitalization, she was alert and communicative, but with choreoathetosis, dysarthria, and an unsteady gait.

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    • "Once clinical disease develops, rabies is invariably fatal. The Milwaukee Protocol combination of therapies was proposed to aid survival with the exemplar being an unimmunised 15-year old girl with bat rabies in 2004 [8]. The supportive coma-induction, anti-excitatory and antiviral therapies aim to minimise neurological disturbance whilst the immune response confers sterilizing immunity and virus is eliminated. "
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    ABSTRACT: Human rabies infection continues to be a significant public health burden globally, and is occasionally imported to high income settings where the Milwaukee Protocol for intensive care management has recently been employed, with limited success in improving survival. Access to molecular diagnostics, pre- and post-mortem, and documentation of pathophysiological responses while using the Milwaukee protocol, can add useful insights for the future of rabies management. A 58-year-old British Asian woman was referred to a regional general hospital in the UK with hydrophobia, anxiety and confusion nine weeks after receiving a dog bite in North West India. Nuchal skin biopsy, saliva, and a skin biopsy from the site of the dog bite wound, taken on the day of admission, all demonstrated the presence of rabies virus RNA. Within 48 hours sequence analysis of viral RNA confirmed the diagnosis and demonstrated that the virus was a strain closely related to canine rabies viruses circulating in South Asia. Her condition deteriorated rapidly with increased agitation and autonomic dysfunction. She was heavily sedated and intubated on the day after admission, treated according to a modified Milwaukee protocol, and remained stable until she developed heart block and profound acidosis and died on the eighth day. Analysis of autopsy samples showed a complete absence of rabies neutralizing antibody in cerebrospinal fluid and serum, and corresponding high levels of virus antigen and nucleic acid in brain and cerebrospinal fluid. Quantitative PCR showed virus was also distributed widely in peripheral tissues despite mild or undetectable histopathological changes. Vagus nerve branches in the heart showed neuritis, a probable Negri body but no demonstrable rabies antigen. Rapid molecular diagnosis and strain typing is helpful in the management of human rabies infection. Post-mortem findings such as vagal neuritis highlight clinically important effects on the cardiovascular system which are typical for the clinical course of rabies in humans. Management guided by the Milwaukee protocol is feasible within well-resourced intensive care units, but its role in improving outcome for canine-derived rabies remains theoretical.
    Full-text · Article · Apr 2014 · Virology Journal
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    • "RABV has 75 nm in diameter and 150–300 nm in length, with a spiked envelope formed by the G glycoprotein and M matrix protein, with a ribonucleocapsid formed by the L RNA-dependent RNA-polymerase, P phosphoprotein and N nuceloprotein containing the 12 kb negative-sense single-stranded non-segmented RNA (Kaplan 1996; Tordo and Poch, 1998; Wunner 1991). The search for antivirals against rabies is one of the frontiers in the field but, despite a protocol (the Milwaukee Protocol) based on ketamin, ribavirin, midazolam and amantadin was successful after the treatment of a human patient (Willoughby et al., 2005), it was shown as not reproducible. RNA interference is an alternative as antiviral technology against RABV already shown as effective in vitro in cell cultures (Brandão et al., 2007; Israsena et al., 2009), but no reports on its in vivo use exist hitherto. "
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    ABSTRACT: Rabies is a zoonotic disease that affects all mammals and leads to more than 55,000 human deaths every year, caused by rabies virus (RABV) (Mononegavirales: Rhabdoviridae: Lyssavirus). Currently, human rabies treatment is based on the Milwaukee Protocol which consists on the induction of coma and massive antiviral therapy. The aim of this study was to assess the decrease in the titer of rabies virus both in vitro and in vivo using short-interfering RNAs. To this end, three siRNAs were used with antisense strands complementary to rabies virus nucleoprotein (N) mRNA. BHK-21 cells monolayers were infected with 1000 to 0.1 TCID50 of PV and after 2 hours the cells were transfected with each of tree RNAs in separate using Lipofectamine-2000. All three siRNAs reduced the titer of PV strain in a least 0.72 logTCID50/mL and no cytotoxic effect was observed in the monolayers treated with Lipofectamine-2000. Swiss albino mice infected with 10.000 to 1 LD of PV strain by the intracerebral route were also transfected after two hours of infection with a pool 3 siRNAs with Lipofectamine-2000 by the intracerebral route, resulting in a survival rate of 30% in mice inoculated with 100 LD50, while the same dose led to 100% mortality in untreated animals. Lipofectamine-2000 showed no toxic effect in control mice. These results suggest that intracerebral administration of siRNAs might be an effective antiviral strategy for rabies.
    Full-text · Article · Nov 2013
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    • "Although human rabies is known to be almost 100% fatal, the reported survival of a teenager who developed rabies following a bat bite in USA using the “Milwaukee Protocol” in 2005 [16] has revived interest in the medical community to attempt experimental therapeutic approaches. The potential for treatment provides an additional impetus to try to make the diagnosis as soon as possible [17] and hence antemortem laboratory diagnosis has assumed greater significance in recent years. "
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    ABSTRACT: Rabies, an acute progressive, fatal encephalomyelitis, transmitted most commonly through the bite of a rabid animal, is responsible for an estimated 61,000 human deaths worldwide. The true disease burden and public health impact due to rabies remain underestimated due to lack of sensitive laboratory diagnostic methods. Rapid diagnosis of rabies can help initiate prompt infection control and public health measures, obviate the need for unnecessary treatment/medical tests, and assist in timely administration of pre- or postexposure prophylactic vaccination to family members and medical staff. Antemortem diagnosis of human rabies provides an impetus for clinicians to attempt experimental therapeutic approaches in some patients, especially after the reported survival of a few cases of human rabies. Traditional methods for antemortem and postmortem rabies diagnosis have several limitations. Recent advances in technology have led to the improvement or development of several diagnostic assays which include methods for rabies viral antigen and antibody detection and assays for viral nucleic acid detection and identification of specific biomarkers. These assays which complement traditional methods have the potential to revolutionize rabies diagnosis in future.
    Full-text · Article · Nov 2013 · The Scientific World Journal
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