Presenter Disclosure

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1 Presenter Disclosure Presenter s name: Wanida Nuwisait, Department of Physiology, Faculty of Medicine, University of Toronto I do not have an affiliation (financial or otherwise) with a commercial organization

2 Brainstem seizures and associated cardiorespiratory depression following intrahippocampal 4-AP application in freely-moving rats Wanida Nuwisait Department of Physiology, Faculty of Medicine, University of Toronto

3 Cardiorespiratory effects of seizures and epilepsy Acute, severe cardiorespiratory dysfunction sudden death Repeated cardiorespiratory changes chronic hypoxic brain damage (Schridde et al., 28; Choy et al., 214). Brainstem seizure-induced cardiorespiratory changes observe 4-AP-induced brainstem discharges Cardiorespiratory activity correlation perturb mimic Brainstem discharge termination (Phenytoin) Brainstem activation (electrical stimulation) Block cardiorespiratory depression Cardiorespiratory depression necessity sufficiency

4 Methods: Local field potentials EKG and respiration GND Right hippocampus: (injection site) Left cortex Neck muscle Right brainstem Twisted Bipolar electrode Bipolar electrodecannula combo Piezoelectric pulse transducer

5 Rats were re-divided into 4 groups based on seizure type, behavioral seizure state, brain regions affected by seizures/se and mortality Group 4-AP concentration seizure stage seizure type Brain regions affected by seizures/se no. of rats no. of seizures/se bursts analyzed Mortality 1. Isolated seizure.25 mm stage 1-2 brief partial seizure + 2nd generalized seizure HC, CT 6 39 No 2. SE-BS 4 mm stage 3-4 type 2, partial SE HC, CT 6 12 No 3. SE+BS (survival) 4 mm(1 rats), 24 mm (3 rats) stage 5-7 type 3, convulsive SE HC, CT, BS 4 45 No 4. SE+BS (death) 24 mm stage 5-7 type 3, convulsive SE HC, CT, BS 5 8 Yes Clinically, status epilepticus (SE) was defined as a seizure activity lasting 5 min or longer or intermittent seizures without returning to baseline consciousness between them (Brophy et al., 212).

6 RR (% of baseline) HR (% of baseline) RR (% of baseline) HR (% of baseline) Respiration rate Effects of i.h. administration of 4-AP on cardiorespiratory function w/o BS SE+BS SE+BS (survival) (death) CSF isolated SZ SE-BS n=3 n=6 n=6 n=4 n=5 with BS isolated SZ SE-BS SE+BS (survival) SE+BS (death) CSF Heart rate CSF isolated SZ w/o BS SE-BS with BS SE+BS (survival) n=3 n=6 n=6 n=4 n=5 SE+BS (death) isolated SZ SE-BS SE+BS (survival) SE+BS (death) CSF min min

7 % of baseline % of baseline Different time course of respiratory and cardiac response to brainstem seizures BS death BS survival -1-2 HR HR RR RR min min RR was dropped in a greater degree than HR The trough of RR is earlier than the trough of HR.

8 Central mechanisms underlying brainstem seizure-related cardiorespiratory depression cardiorespiratory depression observed in our rats was initiated by brainstem seizures rather than by peripheral mechanisms ex. Neurogenic pulmonary edema Immediate onset continuous seizure in the hippocampus with intermittent spread to parietal cortex and brainstem at 1 min after i.h. administration of 24 mm 4-AP

9 Time-course of acute seizure-related death HC RR HR Cortical EEG Suppression 1-2 min Respiratory arrest 1-3 min Cardiac arrest HC RR HR HC RR HC,RR HR HC,RR HR Representative tracings from rat 2

10 Phenytoin (1 mg/kg, i.p.) terminated brainstem seizure induced cardiorespiratory depression 1 min 2 hr 24 hr 4-AP PHT Stop recording 1-min recording Respiration rate Heart rate

11 RR (% of baseline) HR (% of baseline Electrical stimulation significantly decreased heart rate and respiration rate Respiration rate Heart rate awake SWS awake SWS Hz 5Hz 8Hz 5Hz Hz 5Hz 8Hz 5Hz # # The threshold for RR changes are lower than the threshold for HR changes..5 ms biphasic square wave pulses, suprathreshold current intensity

12 8 Hz, awake,.55 ma Cortex.25 mv Brainstem EKG Respiration Cortex 5 Hz, awake,.15 ma 1 s.25 mv Brainstem EKG Respiration 1 s

13 Conclusions 1. Focal unilateral intrahippocampal 4-AP injection in young adult rats causes continuous hippocampal seizures and recurrent cortical seizures, and within 1 min these cerebral seizures are associated with brainstem seizures 2. Spread of seizure activity, triggered by a unilateral hippocampal focus, to the brainstem slows respiration and heart rate 3. Animal mortality is associated with initial cortical EEG flattening precedes or is concomitant with the end of the final brainstem seizure followed by respiratory arrest and 1-3 minutes later, cardiac arrest. 4. Phenytoin prevents mortality associated with decreased frequency of later brainstem seizures 5. Brainstem electrical stimulation also slows respiration and heart rate.

14 Acknowledgements Supervisor : Peter Carlen, MD FACES foundation, USA Collaborators : Martin del Campo, MD, Krembil Research Institute Orrin Devinsky, MD, NYU Medical Center