Transcript Pterins and monoamine metabolites in rabies

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
7 attempts at treating rabies with
Milwaukee protocol
(excluding index survivor)
• Concrete
mechanisms and
physiology
identified
0.75
1.00
Kaplan-Meier survival estimates, by Milw
0.25
0.50
p= .0037
0.00
• 2 “good attempts”
that fulfill
assumptions and
use ketamine, a
benzodiazepine,
amantadine and
ribavirin
0
20
40
analysis time
Milw = 0
60
Milw = 1
80
Marburg, Germany
Transplant (+ rabies) recipient
Marburg z-score by age
60
hospitalized
z-score
BH4, HVA, 5-HIAA
15
EEG flat
MRA low flow
brain liquefaction
10
40
5
NOx
0
-5
5-HIAA
HVA
BH4
-10
Fe
b
20
0
r
Ma
Ap
r
y
Ma
Ju
n
NO2+NO3 (uM)
20
BH4 as Achilles’ heel for CNS
mM
mM
nM
Nitric oxide synthases
O2●-
ONOO-
ARG
BH4
NO
+ citrulline
qBH2
Kone BC (2003) Am J Physiol Renal Physiol 285: F178
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
Transcranial doppler ultrasound
V
Flow = VA = kDPr4
A
RI = (Vmax-Vmin) = 1.0
Vmax
Bad
Vmax
Vmin
Vmean
TAMMv
Good
Indianapolis
ta
liz
sf atio
er
n
400
• HD 10:
Seizure by EEG
Flat EEG
• HD 12 TCD: vasospasm
1.4
• HD 20: increased edema
– Venous sinus thrombosis
Li
m
it
ca
r
e
EV
D
S
F l ei z
at ur
EE e
G
7
14
21
28
180
160
140
1.0
120
PI MCA
0.8
100
0.6
80
60
0.4
40
Nitroprusside
0.2
0
7
20
ICP
Vasopressor
0.0
MMWR (2007) 56: 361
an
200
0
1.2
Pulsatility Index
– EEG responds
– MCA velocities remain high
Tr
0
• HD 13: cerebral edema
• HD 14:
TAMv
MCA
100
– Nitroprusside 0.2ug/kg/min
– External ventricular drain
– BH4 at CNS doses
200
0
14
Hospital Day
21
28
Intracranial Pressure
– HD 6 normal
– Vasopressors begun
TAMv
• Recommended daily TCD
Velocity (cm/s)
300
H
os
pi
(bat strain)
Vmax MCA
H
is ear
op t
ro blo
te c
Se ren k
Fl iz ol
at ur
EE e
G
C
er
eb
ra
le
de
m
a
2
ty
pe
1.5
1.0
0.5
0.0
1.0
0
7
14
21
28
Resistive Index
0.8
20
0.6
15
0.4
10
0.2
5
0.0
0
0
MMWR (2007) 56: 361
25
X Data
• HD 6: Vasospasm
– Reversed by BH4
2mg/kg/8h
2.0
7
14
Hospital Day
21
28
BH4 mg/kg/24h
Arg g/kg/dose
– On vasopressors
– BH4 2 mg/kg/24h
– Daily TCD
Blood velocity (m/s)
• HD 1: 2 arrests
2.5
1
(dog strain)
ty
pe
3.0
H
Ar osp
re i t
st ali
x ze
2 d
Oakland
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
– Increase in CSF protein
H
is ear
op t
ro blo
te c
Se ren k
Fl iz ol
at ur
EE e
G
C
er
eb
ra
le
de
m
a
2
ty
pe
1
2.0
1.5
1.0
0.5
0.0
1.0
0
7
14
21
28
25
0.8
20
0.6
15
0.4
10
0.2
5
0.0
0
0
7
14
Hospital Day
21
28
BH4 mg/kg/24h
Arg g/kg/dose
X Data
Resistive Index
• 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
Blood velocity (m/s)
2.5
ty
pe
3.0
H
Ar osp
re i t
st ali
x ze
2 d
Oakland
– Sudden drop in MCA
velocity
– No comparables for PI
– Sudden drop in ICP
Li
m
it
ca
r
e
EV
D
S
Fl eiz
at ur
EE e
G
200
TAMv
MCA
100
0
1.4
200
0
7
14
21
28
180
1.2
160
140
1.0
120
PI MCA
0.8
100
0.6
80
60
0.4
40
Nitroprusside
0.2
Vasopressor
0.0
0
7
20
ICP
0
14
Hospital Day
21
28
Intracranial Pressure
Pulsatility Index
– Increase in CSF protein
Vmax ICA
Vmax
• HD 17 TCD:
Velocity (cm/s)
300
Vmax MCA
H
Indianapolis
os
p
Tr itali
z
an
sf atio
er
n
400
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
Why does rabies virus kill?
• Cranial artery spasm
–
–
–
–
BH4 + L-arginine
Ca++ channel blockers
“Triple H” therapy
Hypercarbia
1.00
0.75
0.50
0.25
– Subset of symptoms
– Wasting
Kaplan-Meier survival estimates, by Milw
0.00
• BH4 and
neurotransmitter
deficiency
0
20
40
analysis time
Milw = 0
60
Milw = 1
[email protected]
www.mcw.edu/rabies
80