Human rabies includes generalized cranial artery spasm that responds to tetrahydrobiopterin, Largini

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, GermanyTransplant ( rabies) recipient
4
BH4 as Achilles heel for CNS
mM
mM
nM
5
Nitric oxide synthases
O2?-
NO citrulline
ONOO-
ARG
BH4
qBH2
Kone BC (2003) Am J Physiol Renal Physiol 285
F178
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 gtgt eNOS

Toda N (2000) Neuroscience 96 393 Pluta RM
(2005) Pharmacol Ther 105 23
7
Transcranial doppler ultrasound
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, n3/3 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

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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_at_mcw.edu www.mcw.edu/rabies