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Respiration, Seizures and SUDEP-
Possible Prevention Approaches June 23, 2012
Carl L. Faingold Ph.D., Distinguished Professor of
Pharmacology, and Neurology, Southern Illinois Univ.
School of Medicine, Springfield, IL
Colleagues: Marcus Randall, Sri Tupal,
Yashanad Mhaskar, Victor Uteshev
Partners Against Mortality in Epilepsy Conference – June 21-24, 2012
1
• To understand which brain neurochemicals may contribute to SUDEP and their mechanisms
• To consider possible drugs to prevent SUDEP based on these neurochemicals
• To consider possible drugs to avoid in patients who might be susceptible to SUDEP based on these neurochemicals
Disclosures: NONE
Learning Objectives
2
DBA Mouse Models of SUDEP (Death is due to Seizure-Induced Depressed Respiration )
1. DBA mice exhibit sound-induced audiogenic seizures that are fatal (SUDEP model) without resuscitation
2. Seizure-induced sudden death in DBAs results from respiratory arrest leading to cardiac arrest
3. Serotonin (5-Hydroxytryptamine, 5-HT) is a brain chemical that is excitatory to normal respiration & is released during seizures
4. Increasing 5-HT in brain prevents SUDEP in DBA mice 5. Adenosine is a brain chemical that inhibits normal
respiration & is released during seizures --------------------PRELIMINARY DATA----------------------- 6. Increasing adenosine increases sudden death in DBA
mice 7. Adenosine antagonist blocks sudden death in DBA
mice 3
DBA Mouse Video
Acoustic Stimulus 122 dB SPL Seizure behaviors 1. Wild Running 2. Generalized Tonic-Clonic convulsion 3. Tonic Extension
Resulting in Respiratory Arrest
Respirator
Sudden Death
4
Respiration, in a DBA/1 mouse quantified using the whole-body plethysmography
(EMKA Technologies, Paris, France), before (blue area left of the arrow), during, &
after (red area right of the arrow) an auditory stimulus (solid arrow) that induces
seizures, including respiratory depression and death (open arrow). The starting
point of the tonic seizure is indicated by a black dot. (Faingold et al., Prelim data)
Respiration Changes in a DBA/1 Mouse
Induced by Seizure Stimulus
Tonus
.
30 sec
5
DBA Mouse ECG- Induced by Seizure
A: typical ECG in DBA/1 mouse- non-seizure (anesthetized, ketamine/xylazine )
B-D: ECG changes associated with seizure-induced respiratory arrest (RA).
B: reduced ECG rate immediately after RA
C: ECG rate and pattern ~17 sec following RA onset (same mouse)
D: the ECG is nearly absent in the same mouse 295 sec post RA onset
The ECG was completely absent subsequent to this trace.).
(Trace length = 5 sec,
amplitude in A = 0.5 mv,
B-D = 0.4 mv,
Configuration: 2 forelimb
needle electrodes plus
ground
Normal- DBA DBA During Respiratory Arrest
5 sec
RA+5 sec 17 sec 295 sec Pre- Sz
(Faingold et al., Epilepsy & Behav.2010)
6
20 µV
1 min
EEG Changes in a DBA/1 Mouse
Induced by Seizure (Prelim. Data)
Pre-Seizure Seizure Post-Seizure
EEG “shut down”
7
Brainstem
Seizure
Network
Brainstem
Respiratory
Network RVLM
CSF +
blood
DEATH
Respiratory
Arrest
Cardiac
Arrest
+
-
Acoustic
Stimulus
Diagram of Audiogenic Seizure & Respiratory Network
Post-ictal
Depression
Neuroactive substances
RVLM= rostral ventral lateral medulla
physical
obstruction
serotonin
8
mg/kg, ip
N 10 8 9 5
% R
es
pir
ato
ry a
rre
st
SSRIs -Fluoxetine Blocks Respiratory Arrest
(doses that do not block seizures) in DBA/1 mice
* *
Faingold et al.,Epilepsy Behav. 22 (2):186-190, 2011. 9
5-HT antagonist (cyproheptadine) induces respiratory arrest following seizures
(Wilcoxon signed ranks test; ** P<0.01; # P<0.005)
#
% R
es
pir
ato
ry a
rre
st
(22 day old) (22 day old)
13 9 14 7 3 10
**
0
20
40
60
80
100
1 2
CO
NT
RO
L
CO
NT
RO
L
DR
UG
D
RU
G
DR
UG
D
RU
G
RE
CO
VE
RY
R
EC
OV
ER
Y
Post-
Dru
g
N
#
% R
es
pir
ato
ry a
rre
st
(22 day old) (22 day old)
13 9 14 7 3 10
**
0
20
40
60
80
100
Dose (mg/kg)
CO
NT
RO
L
CO
NT
RO
L
DR
UG
D
RU
G
DR
UG
D
RU
G
RE
CO
VE
RY
P
ost-
Dru
g
N
Tupal & Faingold: Epilepsia 47:21, 2006
In DBA/2 Mice that do NOT show RA (10%)
10
% R
esp
ira
tory
Arr
est
* S
ali
ne
Sali
ne
Sali
ne
Flu
oxet
ine
Flu
oxet
ine
Flu
oxet
ine
0
50
100
Pre-Drug
Fluoxetine 5 days at 20 mg/kg/day i.p.
Post –Drug (24-72 hr)
Sali
ne
Sali
ne
Sali
ne
Flu
oxet
ine
Flu
oxet
ine
Chronic (5-day) Fluoxetine (SSRI) Blocks
Respiratory Arrest in DBA/1 mice
5 days
Faingold et al.,Epilepsy Behav.
22 (2):186-190, 2011.
11
Fluoxetine (Fluox) Acts in the brain to block Respiratory
Arrest (RA) in DBA/1 mice (Preliminary Data)
Focal bilateral microinjection of
fluoxetine, [(3.5 nmol/side) in 0.1 μl
(over 30 sec)] (but not saline) into
respiratory center (rostral ventral
lateral medulla, RVLM) blocked
RA but did not block tonic
seizures. 0
10 20 30 40 50 60 70 80 90
100
Control Fluox Post-Drug
TE RA TE RA TE RA
% S
eiz
ure
Beh
avio
r
0 10 20 30 40 50 60 70 80 90
100
Control Fluox Post-Drug
% S
eiz
ure
Beh
avio
r
To
nic
Seiz
ure
Resp
irato
ry A
rrest
To
nic
Seiz
ure
To
nic
Seiz
ure
Resp
irato
ry A
rrest
Resp
irato
ry A
rrest
RVLM
1. Fluox injected directly in the brain blocks RA
2. Systemic injection of 5-HT7 agonist (AS-19), which acts on the spinal cord
does NOT block RA and is toxic (in high doses)
12
% C
on
tro
l (A
pn
ea/h
r)
SSRI (Paroxetine) Effects on Sleep Apnea- Humans
Co
ntr
ol
Co
ntr
ol
Paro
xe
tin
e
Paro
xe
tin
e
* *
* P = 0.01
*
** P = 0.003 (ANOVA)
During Total
Night Sleep
During NREM#
Sleep Only
# Apnea during
REM sleep was
NOT affected
(Kraiczi et al., Sleep 22 (1):
61-67, 1999.)
@ 20 mg/day- 6 weeks,
Randomized double-blind
placebo controlled 13
Adenosine in Respiration & Seizures
• Adenosine receptors are localized in brainstem respiratory centers
and regulate respiration (decrease)
• Adenosine is released during seizures and may contribute to post-ictal
depression (PID) of respiration
Adenosine agonists (A1) prolong PID in epilepsy models
• Abnormal levels of Adenosine A1 receptors occur in human epilepsy
• Adenosine extracellular levels rise in epileptic patients after seizures
• Adenosine antagonists shorten the duration of PID
• Adenosine A1 and A2 A agonists are effective anticonvulsants
• Adenosine receptor blockers may be effective in preventing respiratory a
arrest during seizures.
• Adenosine significantly enhances the incidence of respiratory arrest f
following seizures in DBA/2 mice not exhibiting this response
(preliminary studies)
• Adenosine antagonist reduces respiratory arrest following seizures in
DBA/2 mice (preliminary studies ) 14
Most Human SUDEP Occurs After Seizure
(Post-Ictal State) Post-Ictal State Aspects
• Depressed Consciousness
• Depressed Respiration
• Depressed Heart Rate/ Dysrrythmia
• Cerebral “Shutdown”
Neuroactive Substances Involved in the Post-Ictal State
• Serotonin (5-HT)- Respiration
• Adenosine
• Opioid peptides
• Nitric oxide
• Endocannabinoids Fisher and Schachter. (2000) Epilepsy
Behav. 1 (1):52-59, 2000.
Wallace, et al.,(2002). Eur.J.Pharmacol.,
452(3): 295-301.
Respiration
15
Shen, H. Y. ,T. Li, and D. Boison. Epilepsia 51 (3):465-468, 2010.
Adenosine Model of SUDEP Adenosine
breakdown Convulsant
Death
Adenosine
breakdown Convulsant
Caffeine
16
Adenosine increases respiratory arrest
following seizures [Non-RA DBA/2 Mice]
* P<0.05(Wilcoxon signed ranks test;)
*
0
20
40
60
DR
UG
D
RU
G
RE
CO
VE
RY
R
EC
OV
ER
Y
N = 14
*
% R
es
pir
ato
ry a
rre
st
0
20
40
60
CO
NT
RO
L
AD
EN
OS
INE
Po
st-
Dru
g
(2 mg/kg)
17
Adenosine Blood Levels DBA/1
Mice (prelim data)
Se
izu
re
No
Se
izu
re
nM
A
den
os
ine
18
Seizure
Network
Respiratory
Network RVLM
CSF +
blood 5-HT
DEATH
Respiratory
Arrest
Cardiac
Arrest
+
-
Acoustic
Stimulus
5-HT & Adenosine – Opposite Effects on SUDEP
Post-ictal
Depression
Neuroactive substances
RVLM= rostral ventral lateral medulla
5-HT fluoxetine
Adenosine
& others
physical
obstruction 19
SSRI Effect & Safety in
Epilepsy Patients •D. Kondziella and F. Asztely. Acta Neurol.Scand. 119 (2):75-80, 2009. Don't be afraid to treat depression in patients with epilepsy!
•Thomé-Souza MS, Kuczynski E, Valente KD. Epilepsy Behav. 2007 May;10(3):417-25. 2007. Sertraline and fluoxetine: safe treatments for children and adolescents with epilepsy and depression.
•Bateman, L.M., C. S. Li, T. C. Lin, and M. Seyal. Epilepsia 51 (10):2211-2214, 2010. Serotonin reuptake inhibitors are associated with reduced severity of ictal hypoxemia in medically refractory partial epilepsy. 20
1. Human SUDEP is often associated with seizure and respiratory depression.
2. Serotonin (5-HT) is released during seizures and normally enhances respiration especially when CO2 is elevated.
3. DBA mice are models of SUDEP that die from respiratory arrest, which can be prevented by prompt resuscitation.
4. SSRIs enhance 5-HT action and prevent seizure-induced death in DBA mice and a 5-HT antagonist increases sudden death.
5. Clinical evidence suggests that SSRIs will reduce seizure-induced respiratory depression in certain patients.
6. Adenosine is released during seizures and reduces respiration.
7. Adenosine increase sudden death in DBA mice, and an adenosine antagonist reduces it.
8. The balance between release of neurochemicals that excite respiration (e.g., 5-HT) and agents that inhibit respiration (e.g., adenosine) may determine the degree of respiratory depression occurring during a patient’s seizure and susceptibility to SUDEP.
Summary and Conclusions
21
Future Research
ANIMALS
• Further work on selective 5-HT drugs in DBA Mice
• Work on selective adenosine drugs in DBA Mice
• Evaluate other potential SUDEP affecting neurochemicals in DBA mice (e.g., endorphins)
PATIENTS
• Prospectively evaluate SSRIs effect in epilepsy patients
• Evaluate large public health data base on SSRIs and SUDEP (Sweden?)
• Evaluate seizure-induced release of neurochemicals in blood to personalize prevention treatments
22
Impact on Clinical Care and Practice
•Use of SSRIs should be considered in the patient
population most likely to be subject to SUDEP
(NOT FDA approved)
•Care should be exercised in giving serotonin
blocking drugs to epilepsy patients
•Patient blood levels of neurochemicals should be
drawn after each seizure in the EMU for
neurochemical analysis
23
(Don Quixote
by Picasso)
Thank You
Tilting at Windmills of the Mind (Arremetiendo Contra los Molinos de Mente
24
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