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