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Human rabies includes generalized cranial artery spasm that responds to tetrahydrobiopterin, L-arginine or nitroprusside R.E. Willoughby, A. Roy-Burman,

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Presentation on theme: "Human rabies includes generalized cranial artery spasm that responds to tetrahydrobiopterin, L-arginine or nitroprusside R.E. Willoughby, A. Roy-Burman,"— Presentation transcript:

1 Human rabies includes generalized cranial artery spasm that responds to tetrahydrobiopterin, L-arginine or nitroprusside R.E. Willoughby, A. Roy-Burman, K.W. Martin, J.C. Christensen, D.F. Westenkirschner, J.D. Fleck, C. Glaser, C.E. Rupprecht and K. Hyland

2 7 attempts at treating rabies with Milwaukee protocol (excluding index survivor) 2 good attempts that fulfill assumptions and use ketamine, a benzodiazepine, amantadine and ribavirin Concrete mechanisms and physiology identified p=.0037

3 Marburg, Germany Transplant (+ rabies) recipient

4 BH4 as Achilles heel for CNS M M nM

5 Nitric oxide synthases Kone BC (2003) Am J Physiol Renal Physiol 285: F178 ARG BH4 O 2 - NO + citrulline qBH2 ONOO -

6 Nitric Oxide Synthase (eNOS, nNOS) in cranial arteries NO is smooth muscle relaxant Not well known: neuronal NOS in vessel adventitia –accounts for 10% of systemic vasodilator tone –accounts for 50% of cranial vasodilator tone Rabies is neurotropic –nNOS >> eNOS Toda N (2000) Neuroscience 96: 393 Pluta RM (2005) Pharmacol Ther 105: 23

7 Transcranial doppler ultrasound V A Flow = VA = k Pr 4 BadGood Vmax Vmin Vmax RI = (Vmax-Vmin) = 1.0 Vmean TAMMv

8 Indianapolis (bat strain) Recommended daily TCD –HD 6 normal –Vasopressors begun HD 10: Seizure by EEG Flat EEG HD 12 TCD: vasospasm –Nitroprusside 0.2ug/kg/min HD 13: cerebral edema –External ventricular drain –BH4 at CNS doses HD 14: –EEG responds –MCA velocities remain high HD 20: increased edema –Venous sinus thrombosis MMWR (2007) 56: 361

9 Oakland (dog strain) HD 1: 2 arrests –On vasopressors –BH4 2 mg/kg/24h –Daily TCD HD 6: Vasospasm –Reversed by BH4 2mg/kg/8h MMWR (2007) 56: 361

10 Cranial artery spasm in rabies Seen early, hospital day 6-10 (mean HD8) Global, including internal carotid + MCA Transcranial doppler: high velocity, normal resistance Responsive to 6 mg/kg/24h BH4 - OR - low dose 0.1-0.2 ug/kg/min nitroprusside

11 Oakland HD 11 TCD: –Decreased velocity –Increased RI No cerebral edema Low opening pressure –Reversed by CNS dosing of BH4 20mg/kg/24h + L-arginine IV 0.5g/kg/12h –Increase in CSF protein

12 Indianapolis HD 17 TCD: –Sudden drop in MCA velocity –No comparables for PI –Sudden drop in ICP –Increase in CSF protein

13 Cranial artery spasm in rabies Small numbers, n=3/3 when looked for Sporadic correlations with MRA, brain scan Associated with declines in EEG Type 1 (high velocity, normal RI) day 6-10 –Responsive to BH4 6 mg/kg/day Type 2 (low velocity, high RI) day 13-17 –7 days after type 1 –Responsive (in part) to BH4 20 mg/kg/day + L-arginine 1.0 mg/kg/day given slowly –Associated with increased CSF protein

14 Why does rabies virus kill? BH4 and neurotransmitter deficiency –Subset of symptoms –Wasting Cranial artery spasm –BH4 + L-arginine –Ca ++ channel blockers –Triple H therapy –Hypercarbia rewillou@mcw.edu www.mcw.edu/rabies


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