Status epilepticus and refractory status epilepticus

Status epilepticus and refractory status epilepticus

1. Status Epilepticus Dr Sooraj Patil Moderator- Dr Abhishek Pathak

2. Introduction Status epilepticus (SE) is a series of uninterrupted seizures which result in an impairment of normal brain function, which if not treated as a medical emergency results in high morbidity and mortality Overall annual incidence of 10-41 per 100,000 people Bimodal peak distribution, with peaks in children and elderly J K Murthy Convulsive status epilepticus API India 2013 2013 Frequency of refractory status epilepticus in status epilepticus patients = 31-44% & 20% RSE will bcm SRSE Approximately 50% cases, there is no prior history of epilepsy(NORSE) Mortality rates range between 10.5-28% for SE Neurological or cognitive sequelae in convulsive SE occur in 11- 16 % patients

3. Definition SE was defined as more than 30 min of either (1) continuous seizure activity or (2) two or more sequential seizures without full recovery of consciousness between them The International League Against Epilepsy (ILAE) Operational definition of SE , which suggests starting treatment if seizures do not spontaneously stop within 5 min

4. The new definition of SE SE is a condition resulting either from the failure of the mechanisms responsible for seizure termination or From the initiation of mechanisms that lead to abnormally prolonged seizures (after time point t1). It is a condition that 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

5. Classification of SE With prominent motor symptoms Convulsive SE (CSE, synonym: tonic– clonic SE) Generalized convulsive Focal onset evolving into bilateral convulsive SE Unknown whether focal or generalized Myoclonic SE (prominent epileptic myoclonic jerks) With coma & Without coma Focal motor Repeated focal motor seizures (Jacksonian) Epilepsia partialis continua (EPC) Adversive status Oculoclonic status Ictal paresis (i.e., focal inhibitory SE) Tonic status Hyperkinetic SE Without prominent motor symptoms NCSE with coma NCSE without coma Typical absence status Atypical absence status Myoclonic absence status Focal a Without impairment of consciousness (aura continua, with autonomic, sensory, visual, olfactory, gustatory, emotional/psychic/experiential, or auditory symptoms) Aphasic status With impaired consciousness Unknown whether focal or generalized Autonomic SE

6. Etiology of SE Known (i.e., symptomatic) Acute (e.g., stroke, intoxication, malaria, encephalitis, etc.) Remote (e.g., posttraumatic, postencephalitic, poststroke, etc.) Progressive (e.g., brain tumor , Lafora’s disease and other PMEs,dementias ) SE in defined electroclinical syndromes Unknown (i.e., cryptogenic)

7. Epidemiology of status epilepticus in adults: A population‐based study on incidence, causes, and outcomes ( 26 November 2018 )

8. Etiology in SE According to an Indian study, the etiology of SE Infection in 53.8%, drug default in 7.9%, metabolic in 14.5%, Stroke in 12.8% and miscellaneous in 11% of patients Infection as an etiology was more common in children, drug default and metabolic causes in adult and stroke in elderly Mortality = 29% (elderly >> children) A clinical, radiological and outcome study of status epilepticus, India J Neurology (2010) 257:224-2292013

9. Systemic and cerebral pathophysiological changes associated with seizures and convulsive status epilepticus Compensation (< 30 minutes) Increased cerebral blood flow Cerebral energy requirements matched by supply of oxygen and glucose Increased glucose concentration in the brain Increased catecholamine release Increased cardiac output Decompensation (> 30 minutes) Failure of cerebral autoregulation Hypoglycaemia Hypoxia Acidosis Hyponatraemia Hypo/hyperkalaemia Disseminated intravascular coagulation Leucocytosis Falling blood pressure Falling cardiac output Rhabdomyolysis

10. Pathophysiology of SE

11. Time to Treatment in SE The sooner treatment is initiated, the better the chances of success, and the lower the risk for adverse consequences

12. Factors associated with poor outcome in SE Duration of seizures (most important) Sensorium at presentation Underlying aetiology (Stroke, Anoxic & infection) De novo development in hospitalised patients Older age Associated medical complication Focal neurological signs at onset Symptomatic SE, young patient, low AED levels better prognosis

13. Predictor scoring in SE- STESS Status Epilepticus Severity Score (STESS) A tool to orient early treatment strategy J Neurol (2008) 255:1561–1566

14. Predictor scoring in EMSE- EACE Epidemiology-Based Mortality Score in Status Epilepticus (EMSE) Neurocritical Care 22(2) · November 2014

15. Major drugs in SE Drug Latency in min Duration in hours Lorazepam IV 3-10 12-24 Diazepam rectal 5-15 <1 Diazepam IV 1-5 <1 Midazolam IV 10-30 <1 Midazolam IM/buccal 5-10 <1 Phenytoin 10-30 12-24 Fosphenytoin 10-30 12-24 Phenobarbitone 5-30 48-72 Valproate <20 8-24

16. Goals of treatment in SE Termination of Status Epilepticus Prevention of Seizure Recurrence Management of Precipitating cause Management of complications

17. Appro a c h : Dia g no s tic work u p All patients Monitor vital signs (ABC). Obtain IV access Head CT (appropriate for most cases) Labs: blood glucose, CBC, renal function tests, Calcium, Magnesium, electrolytes, AED levels. cEEG monitoring (preferably) Consider based on clinical presentation Brain MRI Lumbar puncture Toxicology panel (i.e. isoniazid, TCAs, theophylline, cocaine, sympathomimetics, organophosphates, cyclosporine) Other relevant investigations as per the need

18. S T A T U S E P ILE P TICU S Rap i d IV ac c e s s a v ai l abl e NO IM Midazolam 0.2mg/kg (max 10mg) OR Buccal or Intranasal Midazolam 0.5mg/kg (max10mg) Y E S IV L O R AZ E P AM 0.1m g /k g s l o w pu s h (m a x 4mg) Rate- maximum rate of 2 mg/minute R epe a t IV L O R AZ E P AM 0.1m g /kg s l ow p u sh If Seizure donot stop in 5 minutes If Seizure do not stop in 5 minutes, Achieve IV access S h if t t o 2 n d li n e dru g s If Seizure donot stop in 5 minutes IV Phenytoin 20mg/kg @ 50mg/min OR IV Fosphenytoin 3 0 mg/kg @ 150 mg/min If Se i z u r e do no t s t o p in 20 mi nu t es If possibility of subttherapeutic levels, Valproate 20-40 mg/kg @ 5-10 mg/kg/min max 3 gm If Seizure donot stop in 10 mi nu t es Airway- Breathing- Circulation OXYGEN + POSITIONING History- AED , DRUGS, TRAUMA RBS & Blood tests, another IV cannula

19. PHT @ 5mg/kg or fPHT @ 7.5 mg/kg IV Phenobarbitone 20mg/kg @ 100mg/min f/by 3-5 mg/kg.hr cont infusion OR IV Midazolam 0.2 mg/kg loading dose f/by 0.1-0.4 mg/kg/ hr cont infusion OR IV Propofol 2mg/kg bolus f/by 2-10 mg/kg/ hr cont infusion OR IV Pentobarbital 5 mg/kg loading dose f/by 1-3 mg/kg/ hr cont infusion If seizure persists after 24 hrs Super refractory status epilepticus Alternative drug Valproate 40- 60 mg/kg @ 5-10 mg/kg/min Al t e r n a ti v e Drug Levitiracetam 20-30mg/kg @ 5 mg/kg/min S e i z u r e n ot c o n t r ol l ed Se i z u r e not c o n t r o ll ed Refractory Status Epilepticus

20. 1998 Veteran’s Affairs SE study Lorazepam vs Phenytoin Lorazepam (0.1 mg/kg), diazepam (0.15 mg/kg) followed by phenytoin (18 mg/kg), phenobarbital (18 mg/kg), and phenytoin alone (18 mg/kg) in adults  Differential anticonvulsant efficacy was found in overt status epilepticus where the four treatment arms had an overall difference ( p = 0.02) for the primary outcome variable. Only one head-to head comparison met the pre-specified statistical significance difference: lorazepam was superior to phenytoin ( p = 0.002) Evidence-Based Guideline Epilepsy Curr . 2016 Jan-Feb; 16(1): 48–61.

21. 2001 Alldredge trial IV Lorazepam vs Diazepam 205 adult patients with status epilepticus randomized to one of 3 different treatments initiated outside the hospital by paramedics: IV lorazepam (2 mg, n=66) IV diazepam (5 mg, n=68) IV placebo (n=71) A repeat dose of study drug could be done if the seizure continued after 4 minutes (for a maximum lorazepam dose of 4 mg and diazepam dose of 10 mg) Both lorazepam and diazepam were superior to placebo: lorazepam (59.1%) > placebo (21.1%) (OR, 4.8; 95% CI: 1.9–13.0) diazepam (42.6%) > placebo (21.1%) (OR, 2.3; 95% CI: 1.0–5.9) Evidence-Based Guideline Epilepsy Curr . 2016 Jan-Feb; 16(1): 48–61.

22. 2012 RAMPART study IM Midazolam (prehospital) vs IV Lorazepam 893 participants with SE (748 adults and 145 children) were randomized to one of two treatments in a non-inferiority comparison (pre-specified non-inferiority margin of 10%): Intramuscular midazolam (10 mg or 5 mg in children weighing 13–40 kg, n=448) IV lorazepam (4 mg or 2 mg in children weighing 13–40 kg, n=445) Primary efficacy endpoint was achieved in 73% of subjects in the IM midazolam group compared with 63% in the IV lorazepam group giving an absolute difference between groups of 10% (95% CI: 4.0–16.1) Evidence-Based Guideline Epilepsy Curr . 2016 Jan-Feb; 16(1): 48–61.

23. VA vs other AEDs RCTs Five open-label class III initial therapy RCTs examined the efficacy of IV valproic acid ( n =  2) , IV phenytoin ( n =  2) , IV phenobarbital ( n =  1), IV diazepam plus phenytoin ( n =  1) , IV levetiracetam ( n =  1) , rectal diazepam ( n =  1) , and IV lorazepam ( n =  1)  Valproic acid had higher efficacy than phenytoin in one study (valproic acid, 66%, vs phenytoin, 42%;  p  = 0.046)  Sodium valproate vs phenytoin in status epilepticus: a pilot study. Misra UK, Kalita J, Patel R Neurology. 2006 Jul 25; 67(2):340-2 VA similar to phenytoin in the other (valproic acid, 87.8%, vs phenytoin, 88%) Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin Acta Neurol Scand. 2008

24. IM midazolam, IV lorazepam, IV diazepam (with or without phenytoin) are established as efficacious at stopping seizures lasting at least 5 minutes (level A). IM midazolam has superior effectiveness compared with IV lorazepam in adults with convulsive status epilepticus without established IV access (level A). IV lorazepam is more effective than IV phenytoin in stopping seizures lasting at least 10 minutes (level A). Conclusion of studies Evidence-Based Guideline Epilepsy Curr . 2016 Jan-Feb; 16(1): 48–61.

25. Conclusion of studies IV valproic acid has similar efficacy to IV phenytoin or continuous IV diazepam as second therapy after failure of a benzodiazepine (level C). Insufficient data exist in adults about the efficacy of levetiracetam as either initial or second therapy (level U). Evidence-Based Guideline Epilepsy Curr . 2016 Jan-Feb; 16(1): 48–61.

26. Is IV Fosphenytoin More Effective Than IV Phenytoin? A Class III single-dose, randomized, double-blind, class III tolerability study in patients needing infusion of phenytoin compared Insufficient data exist about the comparative efficacy of phenytoin and fosphenytoin (level U). Fosphenytoin is better tolerated compared with phenytoin (level B). When both are available, fosphenytoin is preferred based on tolerability, but phenytoin is an acceptable alternative (level B) Evidence-Based Guideline Epilepsy Curr . 2016 Jan-Feb; 16(1): 48–61.

27. Phenytoin Fosphenytoin •15-20 mg/kg i.v. @50mg/min 100 mg phenytoin 20 mg PE/kg i.v @ 150mg/min Fosphenytoin 150 mg pH 12 Extravasation causes severe tissue injury pH 8.6 Extravasation well tolerated Onset 10-30 min Onset 5-10 min •May cause hypotension, dysrhythmia (may be because of rapid administration and propylene glycol which is used as diluent) less cardiac complications as it is water soluble and propylene glycol is not used as diluent. Cheap Expensive

28. When Does Anticonvulsant Efficacy Drop Significantly The efficacy of each successive blinded treatment was: First AED 55.5% Second AED 7.0% Third AED 2.3% Four or more AEDs 23.2% No AED was successful 11.7% If the patient did not respond to lorazepam or phenytoin, the response rate to 3 rd AED was 2.3% the second anticonvulsant administered is less effective than the first “standard” anticonvulsant, while the third anticonvulsant administered is substantially less effective than the first “standard” anticonvulsant (level A). After How Many Different Anticonvulsants Does Status Epilepticus Become Refractory? 1998 class I Veterans Affairs SE study

29. Refractory & Super-refractory SE Refractory status epilepticus -either clinical or electrographic seizures that persist after adequate doses of an initial benzodiazepine and an acceptable second-line antiseizure drug Super-refractory status epilepticus - seizures continue to recur 24hours or more after the onset of anasthetic therapy Acute repetitive seizures- 3 or more seizures within 24 hours for patients whose habitual seizure frequency is fewer than 3 seizures/day with relatively preserved sensorium in between

30. Refractory status epilepticus Up to 23 - 30 % status epilepticus will turn out refractory, standard definition 30-60 min will prolong neuronal injury Failure to respond to second AED (proper dose) should be treated as RSE

31. Refractory status epilepticus IV Phenobarbitone 20mg/kg @ 100mg/min f/by 3-5 mg/kg.hr cont infusion OR IV Midazolam 0.2 mg/kg loading dose f/by 0.1-0.4 mg/kg/hr cont infusion OR IV Propofol 2mg/kg bolus f/by 2-10 mg/kg/hr cont infusion OR IV Pentobarbital 5 mg/kg loading dose f/by 1-3 mg/kg/hr cont infusion If seizure persists after 24 hrs, try emerging novel therapies : Ketamine bolus 0.5-4.5 mg/kg infusion (upto 5 mg/kg/hr ) ; Immunomodulation IV Methylprednisolone or IVIg; Resective surgery ; Ketogenic diet ; hypothermia Review history Examine for any focality Check records Check dose and Drug Counsel family ICU call and shift

32. C-EEG in RSE Need for Continuous EEG 15- 20 % will bcm NCSE Difficult to differentiate post ictal vs NCSE Electromechanical dissociation in subtle GCS To titrate dose of IV anaesthetics Decide when to taper AEDs C-EEG should be started within 1 hours with frequent review EEG bursts are associated with phasic synaptic depolarizing cellular potentials (Action potential) Target of EEG is to achieve burst suppression pattern

33. Burst suppression EEG EEG - brief bursts of spikes, sharp waves, or slow waves of relatively high amplitude alternating with periods of relatively flat EEG or isoelectric period (usually >10 s IBI, < 10mvolt) No association between a specific interburst interval and outcome has been identified Targeting clinical seizures is most important EEG characteristics of the bursts rather than IBI on C-EEG Percent of bursts with epileptiform features Maximum amplitude of bursts and monomorphic bursts Burst suppression ratio or IBI doesn’t effect outcome EEG Characteristics of Successful Burst Suppression for Refractory Status Epilepticus Neuro crit 2016 Does burst-suppression achieve seizure control in refractory status epilepticus? BMC Neurology 2017 Burst suppression doesn’t correlate with outcome or recurrence in RSE

34. Treatment of resistant SE Drug Loading dose Maintenance dose Side effects Midazolam 0.2–0.4 mg/kg IV every 5 min until Seizures controlled. Maximum dose: 2 mg/kg 0.1–2.0 mg/kg/h Respiratory depression, hypotension Propofol 2 mg/kg IV every 5 min until seizures controlled. Maximum dose: 10 mg/kg 30–200 mcg/kg/min Avoid ≥ 80 mcg/kg/min for ≥ 48 h Hypotension, propofol infusion Syndrome (PRIS) Movement ds Pentobarbitol 5 mg/kg IV up to 50 mg/min every 5 min until seizures are controlled or a Maximum loading dose of 15 mg/kg 0.5–5 mg/kg/h Hypotension, adynamic ileus, respiratory depression, hepatotoxicity, Prolonged sedation Ketamine 1 mg/kg loading Maximum 5mg/kg 0.5 to 10 mg/kg/hour Hypertension, hallucination, arrhythmia, increased ICP

35. Midazolam Rapidly acting, short duration 0.8 to 2.8 hours Most commonly used 3 rd line agent, commonly available Associated with tachyphylaxis, necessitating gradually higher doses. Hypotension in 40-50 % and respiratory depression needs support 51% of patients had breakthrough seizures within the first 6 h of MDZ treatment (vs 15% on propofol and 12% on pentobarbital) 63% of patients had withdrawal seizures when tapering MDZ (compared to 46% on propofol and 43% on pentobarbital) High-dose midazolam infusion for refractory status epilepticus. Neurology 2014

36. Propofol Propofol IV anesthetic acts by direct activation of GABA-A receptors , inhibition of NMDA receptors. Rapid onset of action - decreases cerebral oxygen utilization - reduces ICP Hypotension required pressors in 22– 55% of patients. Propofol infusion syndrome (PRIS) - metabolic acidosis, rhabdomyolysis, renal failure, hypertriglyceridemia, refractory bradycardia, and cardiac failure

37. Barbiturates Thiopental & Pentobarbitone (active metabolite of thiopental) Augmenting transmission at the GABA receptor Lower body temperature - may have neuroprotective effects High doses - loss of brainstem reflexes and an isoelectric pattern on EEG & long duration of effect Strong anaesthetic agent, almost always controls seizures up to 90 % pentobarbital safe and efficacious in the treatment of super-refractory status epilepticus: a cohort study. Crit Car 2014

38. Role of Ketogenic diet The Feasibility, Safety and  Efectiveness of a Ketogenic Diet for Refractory Status Epilepticus in Adults in the Intensive Care Unit Neurocrit Care 2018

39. Role of Ketogenic diet KD initiation and implementation is not always practical Randomized placebo controlled studies are needed to fully determine if KD is safe and effective among patients with SRSE KD can be considered in pediatric patients in limited options but need further well powered studies

40. Autoimmunity in SE

41. Autoimmunity in SE APE score of 4 or greater had a sensitivity of 82.6% and a specificity of 82.0% for detecting a positive antibody RITE score of 7 or greater predicted a favorable seizure outcome and had a sensitivity of 87.5% and specificity of 83.8%

42. Therapies in SRSE

43. Management of NCSE

44. EEG criteria for NCSE Salzburg

45. Management of NCSE

46. Thank you 2013 to 2019 OCTOBER