Status Epilepticus refractory seizures .pptx

status epilepticus

1. Status Epilepticus

2. Outline Status Epilepticus (SE) Introduction Definition Etiology Investigations Diagnosis Treatment Other types of SE

3. Introduction Status epilepticus (SE) is a common medical emergency associated with high morbidity, if not mortality. Mortality from SE varies from 3–50% in different studies. In elderly patients, refractory status epilepticus (RSE) may lead to death in over 76% cases. It may be classified based solely on the presence or absence of convulsions, into convulsive SE (CSE) nonconvulsive SE (NCSE) Ann Indian Acad Neurol. 2009 Jul-Sep; 12(3): 140–153.

4. Definitions Over 30 years ago the ILAE defined SE as a convulsive seizure lasting > 30 minutes or a failure to recover function following a series of convulsive seizures over 30 minutes. In 1999 an Operational Definition was introduced that defined SE as ≥5 min of continuous seizure or two or more discrete seizures between which there is incomplete recovery of consciousness.

5. A new conceptual definition of status epilepticus with two operational dimensions (t1 and t2) is proposed; Time point t1 indicates when treatment should be initiated, and Time point t2 indicates when long-term consequences may appear Epilepsia , 56(10):1515–1523, 2015

6. Conceptual definition “SE 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 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.” Epilepsia , 56(10):1515–1523, 2015

7. Epidemiology Epidemiological data on SE in India is limited to a few single-center studies. In an Indian pediatric intensive care unit (PICU) study over 7 years, 53% had SE as their first seizure and only 60% had received any treatment prior to coming to the PICU. A recent multi-centric study on SE in children across 9 centers in India also reported similar findings: 82% acute symptomatic, <3% pre-hospital treatment, <20% deficit-free survival, and no uniform management protocol Indian Pediatr . 2014 Dec;51(12):975-90.

8. Etiology 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) Epilepsia , 56(10):1515–1523, 2015

9. Who is at risk? Between 4-8 children per 1000 are expected to experience CSE before age 15 years. most common medical neurological emergency in children. In >50% of children presenting with SE, it will be their first seizure. A history of status epilepticus - the most common risk factor for recurrent status epilepticus . Other common risk factors for pediatric SE include a younger age (<2 years), a symptomatic etiology (structural/metabolic); a history of an epileptic encephalopathy or a specific epilepsy syndrome (e.g. Dravet Syndrome).

10. Who is at risk ? ( Cont.) A population-based study from Finland in which 150 children with new-onset epilepsy were followed for more than 30 years (febrile status was excluded), found that 27% of these patients suffered at least one SE. Of these children, 90% presented with a status within the first two years following diagnosis .

11. FEBSTAT Study FEBSTAT is a prospective multicenter study investigating the consequences of febrile SE in childhood. Early results showed the median age was 1.3 years, the mean peak temperature was 39.5o C, and seizures lasted a median of 68.0 minutes. Seizures were continuous in 52% and behaviorally intermittent (without recovery in between) in 48%; most were partial (67%) and almost all (99%) were convulsive. Epilepsia . 2014 March ; 55(3): 388–395.

12. FEBSTAT Study - Intervention Febrile status often requires more than one drug to terminate, although this may reflect delayed administration. The median time from seizure onset to the first drug by the emergency medical services or the emergency department was 30 minutes . The mean seizure duration was 81 minutes for patients given medication prior to the emergency department and 95 minutes for those who did not . Reducing the time from seizure onset to anti-epileptic drug initiation was significantly related to shorter seizure duration. Epilepsia . 2014 March ; 55(3): 388–395.

13. FEBSTAT study - Other findings 22/226 imaged with MRI post FSE had hippocampal T2 hyperintensity . Of these 14 had follow up MRIs, 10 showed Hippocampal sclerosis on expert review, 12 had reduced hippocampal volume on volumetric assessment. Hippocampal malrotation was found in 20/226 patients with FSE (predominantly found on the left only, and more commonly in boys). This is suggestive that malrotation is a cortical malformation rather than a normal variant. Epilepsia . 2014 March ; 55(3): 388–395.

14. Metabolic Conditions Associated with SE Indian Pediatr . 2014 Dec;51(12):975-90.

15. Status Epilepticus - Investigations Indian Pediatr . 2014 Dec;51(12):975-90.

16. Diagnosis The diagnosis of CSE (tonic- clonic movements) is usually straightforward however, failure to recover between seizure episodes can make assessment difficult. Close observation of the ‘post- ictal ’ patient is important specifically for intermittent jerking or tonic stiffening. Differential Diagnosis: non-epileptic events (which are most common in patients with epilepsy) acute dyskinesias in patients with known cerebral palsy. Unless the history of non epileptic events is known, it is generally preferable to treat.

17. Mechanisms Involved in Transition of Single Seizure to SE Lancet Neurol. 2015 Jun;14(6):615-24.

18. Treatment - Anticonvulsant Usage in SE Indian Pediatr . 2014 Dec;51(12):975-90.

19. Highlighting the different sites of action of various anticonvulsants ‘Rational polypharmacy ’ – using multiple agents with different mechanisms. J Pediatr Pharmacol Ther 2015 Vol. 20 No. 4 •

20. Pre-hospital management Benzodiazepines are recommended as the initial drug of choice for treating SE. Midazolam Buccal /Nasal (0.3mg/kg)/IMI/IV(0.15mg/kg). There has been ongoing argument about Lorazepam vs Midazolam vs Diazepam with various methods of administration Buccal /Nasal/IM/IV.

21. IM Midazolam compared favourably with IV Lorazepam for seizure termination, hospital and ICU admission, ET intubation and seizure recurrence. The speed and ease of administration supported its use by paramedics as a first line agent.

22. Prospective observational cohort study. 81 patients (44 male) with a median age of 3.6 years(47% with known epilepsy, and 17% with previous SE). The first, second, and third AED doses were administered at a median time of 28 minutes, 40 minutes, and 59 minutes after SE onset. The first and second doses of non-benzodiazepine AEDs were administered at 69 minutes and 120 minutes . In the 64 patients with out-of-hospital SE onset, 40 ( 62.5% ) patients did not receive any AED before hospital arrival . In the hospital setting, the first and second in-hospital AED doses were given at 8 (5–15) minutes and 16 (10–40) minutes after SE onset Neurology 84 June 9, 2015

23. 2 nd line/Urgent treatment Approximately one third of SE patients continue to have seizures despite administration of adequate doses of benzodiazepines. There are no Class 1 clinical trials comparing the efficacy of currently available medications for the treatment of ‘Established’ S.E. Phenytoin vs Phenobarbitone vs Levetiracetam vs Valproate .

24. 2nd line/Urgent treatment (Cont.) The majority of guidelines worldwide (NICE, Canadian Pediatric Society, NSW Health Department, Boston Children’s Hospital) Would recommend Phenytoin / Fosphenytoin as the 1st choice agent. These choices are essentially based on the fact that these drugs have been available for much longer than any new AED. They are time-tested and there is abundant literature on their efficacy. Levetiracetam has some attractive features in that it has few drug interactions, no extravasation risk, not metabolized and delivered relatively quickly does not cause hypotension or arrhythmia. Studies in children have involved small numbers and the safety profile appears good.

25. A retrospective study comparing phenytoin , valproate and levetiracetam in 167 adults and a systematic evaluation of published evidence (predominantly case series, and only one randomised double blinded trial) suggest that levetiracetam and valproate have similar efficacy to phenytoin / fosphenytoin and phenobarbital . Potentially best results were obtained for Valproate . 2nd line/Urgent treatment (Cont.)

26. Second-line AEDs for Treatment of SE These alternative /second-line drugs are employed as adjunct AEDs for SE refractory to lorazepam and phenytoin before proceeding to anaesthetics Lancet Neurol. 2015 Jun;14(6):615-24.

27. Management of Generalized Convulsive Status Epilepticus : Pediatric patients J Pediatr Pharmacol Ther 2015;20(4):260–89.

28. Management of Generalized Convulsive Status Epilepticus : Pediatric patients… J Pediatr Pharmacol Ther 2015;20(4):260–89.

29. Management of Generalized Convulsive Status Epilepticus : Pediatric patients… J Pediatr Pharmacol Ther 2015;20(4):260–89.

30. Updated treatment algorithm for generalised convulsive SE: adults… Lancet Neurol. 2015 Jun;14(6):615-24.

31. Drug Management of SE in a Health Facility Indian Pediatr . 2014 Dec;51(12):975-90.

32. Supplementary Management Options in SE Indications for Mechanical Ventilation Glasgow coma scale score <8 Respiratory depression (irregular jerky breathing or apnea) due to SE or anesthetic agents Fluid-refractory shock Raised intracranial pressure Difficult-to-maintain airway Indications for Continuous EEG Monitoring Prolonged altered sensorium following cessation of clinical seizures* Clinical suspicion of non-convulsive status epilepticus All children receiving IV anesthetic agents Indian Pediatr . 2014 Dec;51(12):975-90.

33. Ketogenic Diet Studies Examining the Ketogenic Diet for SE 78% patients became seizure-free Most of the patients responded within 7-10 days of the initiation of nasogastrically administered ketogenic formulas Encephalitis and febrile-illness related epilepsy syndrome causing SE highly refractory to AEDs may be particularly amenable to dietary treatment J Child Neurol. 2013 Aug;28(8):1049-51.

34. Treatment of Non-convulsive SE Less well defined owing to a paucity of data. Most forms of non-convulsive SE are not associated with life-threatening systemic dysfunction and are therefore perceived as less of a medical emergency. Initial treatment: non-convulsive SE, including focal SE with or without dyscognitive features, and absence SE Similar to generalised convulsive SE Begins with benzodiazepines If seizure activity persists, a repeat dose of benzodiazepines should be considered, followed by an AED AEDs are often preferred rather than early escalation to anaesthetics . Lancet Neurol. 2015 Jun;14(6):615-24.

35. Guidelines for Follow-up Management of Children with SE New-onset SE: Further treatment decisions should be similar to that for a First seizure. Acute symptomatic seizures : Further treatment depends on the control of the precipitating event. SE in known epilepsy : After control of SE for 24 hours, tapering of drugs should be started with ‘last in, first out’ as the guiding principle. All the AEDs should preferably be stopped during hospital stay and the child discharged on: Augmented dose of the previous AED/s (if levels were sub-therapeutic or prescribed dose was less than maximum dose); Introduction of another appropriate AED (either replacement or addition), if previously receiving maximum doses of AED/s.

36. Refractory Status The Neurocritical Care Society (US) guideline states that “patients who continue to experience either clinical or electrographic seizures after receiving adequate doses of an initial benzodiazepine followed by a second acceptable anticonvulsant will be considered refractory.” Many protocols suggest infusions at this point, however – alternative second line agents ( levetiracetam / valproate / phenobarbitone ) have a role here, and may help avoid the need for intubation which often follows with benzodiazepine infusions, and almost invariably with thiopentone infusions. Continuous EEG monitoring is recommended at this point.

37. The Role of EEG The Neurocritical Care Society has recommended Continuous EEG monitoring is usually required for the monitoring of SE. It should be initiated within one hour of SE onset, and should continue for 48 hours to evaluate for non-convulsive status.

38. Continuous EEG (CEEG)monitoring The goal of CEEG is to maximize the early detection and treatment of seizures and, ultimately, to minimize secondary neuronal and systemic injuries that can arise from ictal activity. Studies suggest that seizures—including Non-convulsive Seizures—in the acutely injured brain can cause a variety of adverse physiological effects. Additionally, nonconvulsive seizures, especially when prolonged, have been independently associated with poor outcomes, including functional ability and quality of life.

39. Systematic review of VNS for RSE 17 articles met the inclusion/exclusion criteria, with 28 patients were treated Generalized RSE patients displayed a 76.0% rate of termination of RSE Focal status patients displayed only a 25.0% response rate Oxford level 4, GRADE D evidence for the use VNS for generalized RSE Epilepsy Res. 2015 May;112:100-13.

40. Super Refractory Status Super-refractory status epilepticus is defined as status epilepticus that continues or recurs 24h or more after the onset of anaesthetic therapy, including those cases where status epilepticus recurs on the reduction or withdrawal of anaesthesia . Indian Pediatr . 2014 Dec;51(12):975-90.

41. Treatment

42. Outcome Morbidity and mortality are largely related to status epilepticus cause, but duration is also important and is the only modifiable variable. Children with febrile status epilepticus or epilepsy-related status epilepticus have a 0–2% mortality whereas children with acute symptomatic status epilepticus have a 12 – 16% mortality. Of children without prior epilepsy, 30% had subsequent seizures.

43. Status Epilepticus : Think Time Time to treatment needs to be shorter. Response to treatment is time dependent. Morbidity and mortality are related to etiology and duration ( time ) of status epilepticus . Subsequent epilepsy may depend on the duration ( length of time ) of the status epilepticus . Prolonged seizures predict future prolonged seizures.

44. Important points Benzodiazepines at 5 minutes. Active management plans for patients with previous status and those at risk of status. Not more than 2 doses of benzodiazepine. 2 nd line agents can almost invariably be started the moment a child arrives in ED with a cannula .

45. Research Needs for SE in Children Epidemiology of SE in India Role of hypocalcemia in SE, especially in infants. Role of phenobarbitone and phenytoin as the initial AED after benzodiazepine. Management of SE-associated with neuroinfections . Outcome of SE in Indian children

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