title: Generalised cranial artery spasm in human rabies.
abstract: In 2004, a teenager survived bat-associated rabies through the Milwaukee protocol (MP). This survivor and another patient with dog-associated rabies were found to have developed deficiencies of tetrahydrobiopterin (BH4) and associated neurotransmitters. BH4 is also essential for neuronal nitric oxide synthase (nNOS), so rabies is predicted to cause constriction of cerebral arteries. We assume that rabies virus, which almost exclusively targets neurons, would disproportionately affect cerebral over systemic perfusion by disrupting nNOS and lead to generalised cerebral artery spasm. Cranial artery vasospasm, therefore, was actively sought in two rabies patients, with the intention to specifically treat with BH4 and L-arginine when necessary. Flow velocities and resistive (RI) or pulsatility indices (PI) of middle cerebral arteries (MCA) were obtained by transcranial doppler ultrasound (TCD). A survival analysis of 8 attempts at the MP is presented. Of these, two cases are reported here. The first case is one child with bat-associated rabies who developed severe bilateral MCAspasm on hospital day (HD)-10 that responded to very low dose (0.2 mcg/kg/min) nitroprusside. The second case, a child with dog-associated rabies, developed spasm of MCA on HD-6 that responded to 6 mg/kg/day BH4. A second spasm with high RI (without cerebral oedema or increased intracranial pressure) responded to 20 mg/kg/day BH4 and 0.5 g/kg/dose L-arginine. Review of the TCD of the first child showed a similar second spasm seven days after first episode. Cerebral artery vasospasm occurred in the two children with rabies, but was clinically silent by standard monitoring. Spasm responded to drugs directed at the NOS pathway. Animal models for treatment of rabies are sorely needed to evaluate therapy.
authors.affiliation: Medical College of Wisconsin, Milwaukee, Wisconsin 53201-1997, USA. rewillou@mcw.edu
authors.forename: R E
authors.initials: RE
authors.lastname: Willoughby
authors.forename: A
authors.initials: A
authors.lastname: Roy-Burman
authors.forename: K W
authors.initials: KW
authors.lastname: Martin
authors.forename: J C
authors.initials: JC
authors.lastname: Christensen
authors.forename: D F
authors.initials: DF
authors.lastname: Westenkirschner
authors.forename: J D
authors.initials: JD
authors.lastname: Fleck
authors.forename: C
authors.initials: C
authors.lastname: Glaser
authors.forename: K
authors.initials: K
authors.lastname: Hyland
authors.forename: C E
authors.initials: CE
authors.lastname: Rupprecht
mesh_terms: D000818:Animals; D001120:Arginine / Q000627:therapeutic use; D001708:Biopterins / Q000031:analogs & derivatives / Q000627:therapeutic use; D001783:Blood Flow Velocity; D002536:Cerebral Arteries / Q000187:drug effects / Q000473:pathology*; D002560:Cerebrovascular Circulation; D002648:Child; D002685:Chiroptera / Q000821:virology*; D004283:Dog Diseases / Q000635:transmission; D004285:Dogs; D006801:Humans; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D009599:Nitroprusside / Q000627:therapeutic use; D011818:Rabies / Q000188:drug therapy / Q000473:pathology* / Q000635:transmission / Q000662:veterinary; D016896:Treatment Outcome; D017585:Ultrasonography, Doppler, Transcranial / Q000379:methods; D020301:Vasospasm, Intracranial / Q000188:drug therapy / Q000473:pathology* / Q000821:virology; D015047:Zoonoses
chemical_list: D009599:Nitroprusside; D001708:Biopterins; D001120:Arginine; D019001:Nitric Oxide Synthase; C003402:sapropterin