Convulsive Status epilepticus Dr. Jithangi Wanigasinghe Senior Lecturer Consultant Paediatric Neurologist MPhil, MD, DCH

Scope What is CSE in the ED? What are we dealing with? What do we do? Operational definition and new definition What are we dealing with? Underlying aetiology What do we do? Optimal management

Definition Single seizure lasting more than 30-min duration or a series of epileptic seizures during which function is not regained between ictal events in a 30-min period Commission of Epidemiology and prognosis ILAE 1993

Operational definition for management of SE Generalized, convulsive status epilepticus in adults and older children refers to a 5 min of (a) continuous seizures or (b) two or more discrete seizures between which there is incomplete recovery of consciousness Lowenstein D H 1999

New definition of CSE Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. Trinka E. 2015

Conceptual definition with two operational time points Onset t1 t2 Length of the seizure and the time point (t1) beyond which the seizure should be regarded as “continuous seizure activity.” The time of ongoing seizure activity after which there is a risk of long-term consequences

Epidemiology 50 per 100,000 population Highest in children Bimodal increase in incidence Significant mortality 22%-23% for children 26% for adults Neurological morbidity in 11-16% Refractory SE (RSE) is common (31-44%)

Stages of SE Early phase Stage 1 Premonitory SE, Impending SE 5-10 min Established SE 10-30 min Stage 2 Refractory SE Subtle SE, stuporous SE Stage 3 30-120 min Super-refractory SE : SE that continuous in spite of treatment with anaesthetics for > 24 hrs >24 h Stage 4

Scope What is CSE in the ED? What are we dealing with? What do we do? Operational definition and new definition What are we dealing with? Underlying aetiology What do we do? Optimal management

Underlying aetiology Commonest single group of causes is acute symptomatic aetiology Same for adults and children In adults CVA commonest in developed countries and elderly CNS infections commonest in developing countries Murthy J M K

Epilepsy and Behavior 2015

Causes of CSE in children Hypoxic brain injury CNS Infections Traumatic brain injury Metabolic derangements CNS demyelinataion Vascultis, Autoimmune encephalitis Shorvon S 2006

Acute symptomatic 9 (31%) Febrile status 4 (13%) Remote symptomatic 4 (13%) Epilepsy 7 (24%) Unclassified 2 (06%) n=29

Scope What is CSE in the ED? What are we dealing with? What do we do? Operational definition What are we dealing with? Underlying aetiology What do we do? Optimal management

Therapeutic principles Address pathophysiology GABAA Agonists NMDA antagonists multiple receptors or ion channels Rx plan according to stages Considerations ease of administration onset of action (rapid) duration of action (intermediate to long) spectrum of activity (broad) minimal morbidity

Therapeutic principles Commence rapidly and continue sequentially Use therapeutic doses ALWAYS Critical care treatment and monitoring Treatment of underlying cause Commencement of neuro-protective mechanisms Constant management of complications

Stages of SE Early phase Stage 1 Premonitory SE, Impending SE 5-10 min Established SE 10-30 min Stage 2 Refractory SE Subtle SE, stuporous SE Stage 3 30-120 min Super-refractory SE : SE that continuous in spite of treatment with anaesthetics for > 24 hrs >24 h Stage 4

Stages of SE BDZ first choice for out-of- hospital Mx Early phase (MAY BE PRE or IN HOSPITAL) Premonitory SE, Impending SE 5-10 min BDZ first choice for out-of- hospital Mx IV – Lorazipam (Alldredge BK 2001) IM – Midazolam Rectal Diazepam in children (Dreifuss FE 1998) IV Diazepam Nasal or buccal – MDZ (Scott RC 1999, McIntyre J 2005) Clear benefit of prehospital Rx with LRZ or DZP

Early phase SE Trinka E 2015

Key highlights Out of hospital administration Clear benefit shown due to early SE abolition Buccal MDM favoured over DZP In hospital when resuscitation facilities available Use the IV preparations recommended Lorazepam favoured

Stages of SE Second-line drugs when BDZ fail to terminate 5-10 min Established SE 10-30 min Stage 2 water solubility and neutral pH more rapid administration with less adverse effects compatibility with all IV fluids Second-line drugs when BDZ fail to terminate IV phenytoin/fosphenytoin IV phenobarbate IV sodium valproate IV leveteracetam No clear evidence to support one over the other for CSE termination

Established status Trinka E 2015

Stages of SE NO RCTs Continuous infusion (cIV) of anesthetic agents: 5-10 min 10-30 min Stage 3 Refractory SE Subtle SE, stuporous SE 30-120 min NO RCTs Continuous infusion (cIV) of anesthetic agents: Thiopental/ pentabarbital, midazolam and propofol (Shorvon S 2012) Successful Rx with propofol in 2/3 of RSE For 24–48 hours of electrographic control by cEEG monitoring Dosing titrated to cessation of electrographic seizures or burst suppression

Propofol: IV bolus 2 mg/kg, repeated if necessary, followed by a continuous infusion of 5–10 mg/kg/hour initially, reducing to maintain a burst suppression (usually 1–3 mg/kg/hour) Thiopental: IV bolus 100–250 mg given over 20 s with further 50 mg boluses every 2–3 min until seizures are controlled, followed by a continuous IV infusion to maintain a burst suppression (usually 3–5 mg/kg/hour) Midazolam: IV bolus 0.1–0.3 mg/kg at a rate not exceeding 4 mg/min initially, followed by a continuous IV infusion to maintain a burst suppression pattern (0.05–0.4 mg/kg/hour).

Stages of SE No RCTS Use different conventional AEDs – TPM (via NG), Lacosamide, LEV Inhalational agents - isoflurane and desflurane IVIG, High dose steroids Ketamine (NMDA receptor Antagonist) Budesonide Ketogenic diet Magnesium Sulphate, pyridoxine Epilepsy surgery, Vagal nerve stimulation, DBS 5-10 min 10-30 min 30-120 min Super-refractory SE : SE that continuous in spite of treatment with anaesthetics for > 24 hrs >24 h Stage 4 10-15% of all CSE Outcome – 35% mortality, 35% recovery to baseline (Shorvon S 2012)

Anaesthetics in SRE How long to use? Complications of anaesthesia Exotoxic damage already occurred ?Risk of anaesthesia exceed risk of SE? Complications of anaesthesia How to cycle? Initially 24-48 hour cycles and then longer Should one switch anaesthetics? Prolonged propofol carries specific risk What stage to switch ?? NO DATA ON THESE POINTS

Anti Epileptic drug therapy Approach to use AEDs in SRE (via NG / PEG) Purpose – coverage when anaesthetic effects are withdrawn Principles Polytherapy with two High dose Avoid frequent switching Favour those with lower interaction potential, predictable kinetics and without renal or hepatic toxicity Avoid GABAergic AEDs

Concommittent multimodal approach

Common reasons for treatment failure Under-dosing at the stage of established SE Neglecting maintenance therapy Misdiagnosis- i.e. psychogenic nonepileptic status, drug-induced or metabolic encephalopathy Failure to identify and treat the underlying etiology Failure to address Iry complications

Continuous EEG (cEEG) monitoring Initiated for RSE (after one hour) Useful for titration of other maintenance AEDs Duration – at least 48 hours if NCSE treatment endpoints for cEEG monitoring cessation of nonconvulsive seizures diffuse beta activity burst suppression 8–20 seconds’ intervals complete suppression of EEG

Supportive management Assisted ventilation and cardiovascular monitoring Vasopressor agents Cerebral oedema lowering agents Continuation of maintenance AEDs Brain cooling

Systemic complications of SRE Complications due to therapy with inhalational Anaesthetics Hypothermia, infection, death Complications due to prolonged ICU stay and immobility PE, DVT Pulmonary complications Sepsis,colitis Skin complications, fungal infections Critical illness nopathy/ neuropathy

Systemic complications of SRE Complications due to status and treatment Complications due to treatment

Prognostic factors Poor outcome related to underlying etiology de novo development of SE in hospitalized patients older age impairment of consciousness duration of seizures focal neurological signs at onset presence of medical complications

Summary What is CSE in the ED? What are we dealing with? Operational definition What are we dealing with? Underlying aetiology What do we do? Optimal management