status epilepticus...

status epilepticus...

1. MANAGEMENT OF STATUS EPILEPTICUS WITH RECENT GUIDELINES Dr. RAHI KIRAN SR I NEUROLOGY GOVT MEDICAL COLLEGE, KOTA

2. Incidence Worldwide incidence of Convulsive Status Epilepticus - 3.8 to 38 per lakh per year in children. - 6 to 27 per lakh per year in adults. Bimodal peak distribution, with peaks in children and elderly. No community based incidence studies in India but is expected to be high because of high prevalence of epilepsy, CNS infections and treatment gap. J K Murthy Convulsive status epilepticus API India 2013

3. Incidence In approximately 50% cases, there is no prior history of epilepsy. Males are affected more compared to females partly attributed to lower seizure threshold in males. Mortality rates range between 10.5-28%. Neurological or cognitive sequelae in convulsive SE occur in 11- 16 % patients. J K Murthy Convulsive status epilepticus API India 2013

4. Factors associated with poor outcome after generalised SE : Underlying etiology De novo development in hospitalised patients Older age Associated medical complication Duration of seizures Focal neurological signs at onset

5. Status epilepticus –common etiology 1. Low AED levels - 35% 2. Stroke - 20% 3. Alcohol withdrawal - 15% 4. Anoxic brain injury - 15% 5. Metabolic disturbances - 15% 6. Remote brain injury/ cong. malformations - 20% 7. Infections - 5% 8. Brain neoplasms - 5% 9. Idiopathic - 5%

6. Status epilepticus –common etiology - INDIA According to an Indian study, the etiology of SE was 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) 257:224-229)

7. Definition The first definition of Status Epilepticus came from Clark and Prout as “ maximal development of epilepsy in which seizures are so frequent that coma and exhaustion are continuous between seizures.” The first official definition of SE which was accepted by International League Against Epilepsy (ILAE) in 1964 and modified in 1971 as “a seizure that persists for sufficient length of time or repeated frequently enough that recovery between attacks does not occur.”

8. Operational Definition Status Epilepticus is defined as 5 minutes or more of : 1.continuous clinical and/or electrographic seizure activity or 2. recurrent seizure activity without recovery (returning to baseline) between seizures complex partial status epilepticus - 10 minutes

9. Clinical features Genaralized convulsive status epileptics- Self-perpetuating generalized tonic- clonic seizure or of a series of generalized tonic- clonic seizures without return to consciousness in between seizures. Initial compensatory phase -sympathetic overdrive increased C.O. increased BP increased blood lactate levels

10. Clinical features Decompensation –homeostatic faliure Cardiorespiratory collapse Electrolyte imbalance Rhabdomyolysis & delayed tubular necrosis Hyperthermia Multi organ Failure Raised ICP & cerebral oedema

11. Clinical features Nonconvulsive status epilepticus Diverse - severe impairment of consciousness to subtle phenomena. Motor manifestations if any –needs careful CNS exam. Often mistaken for psychiatric disorders.

12. Refractory status epilepticus (RSE) defined as SE persisting despite sufficient dose of benzodiazepines and at least one antiepileptic drug (AED), irrespective of time.  Nearly 23 to 48% of status epilepticus are refractory. Clinical features

13. Malignant / Super- refractory status epilepticus (SRSE) defined as SE that continues for 24 hours or more after the use of anesthetic therapy, including cases that recur on weaning of the anesthestic agent. 22% of the patients with SE. Needs combination therapy (AED & Anesthetic drugs) . Clinical features

14. MANAGEMENT OF STATUS EPILEPTICUS

15. Termination of Status Epilepticus Prevention of Seizure Recurrence Management of Precipitating cause Management of complications AIMS

16. All patients Obtain IV access Monitor vital signs (ABC). 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 Approach: Diagnostic workup

17. Continuous EEG Monitoring The use of cEEG is usually required for the treatment of SE. Continuous EEG monitoring should be initiated within 1 h of SE onset if ongoing seizures are suspected. The duration of cEEG monitoring should be at least 48 h in comatose patients to evaluate for non-convulsive seizures.

18. Brophy, et al NCC 2012 Recent clinical seizure or SE without return to baseline >10 min Coma, including post-cardiac arrest Epileptiform activity or periodic discharges on initial 30 min EEG Suspected non-convulsive seizures in patients with altered mental status Indications for cEEG in SE

19. INDIVIDUAL DRUGS

20. Benzodiazepines Drug of choice for out of hospital as well as in-hospital treatment. Effective in terminating seizures in 59-78 % cases. Lorazepam is the DOC for IV administration. Midazolam is the DOC for IM administration. Rectal Diazepam is effective in children. Other routes are buccal Midazolam and intranasal Midazolam (not commonly used)

21. Benzodiazepines Diazepam - 10mg IV push over 30-60 seconds - repeat after 10-15mins, upto 40mg (5mg/min) -Repeat after 2-4hrs. (max 100mg/day) - bolus dose should be given in undiluted form at rate not exceeding 2-5 mg/min. Lorazepam 0.1- 0.15 mg/kg i.v , upto 4-6 mg over 1-2 minutes If SE persists, repeat every 5-10 minutes

22. Benzodiazepines Diazepam More lipid soluble, hence short distribution half-life. Anti-seizure effect 15-30min. Sufficient cerebral levels are achieved within 1 min of IV administration and about 20 mins after rectal administration. Elimination half life abt 24 hrs (may accumulate)

23. Lorazepam Has emerged as preferred BZD for treatment of SE Less lipid distribution with distribution half life of 2-3 hours So Fast acting, longer lasting compared to Diazepam Longer therapeutic half-life. Anti-seizure effect for 6-12hrs. 2mg dose, upto a max dose of 8mg in total Main disadvantage is rapid devlopment of tolerance, hence repeated doses are less effective and has no role in long term therapy. Benzodiazepines

24. If Benzodiazepines are successful in stopping GCSE, the decision to add another agent depends on the underlying etiology . If the etiology is reversible (e.g . metabolic or toxic factors), BZDs may be the only treatment . Another longer-acting AED is needed if the underlying etiology is not rapidly reversible. Benzodiazepines

25. Seizures continuing / Stage of Established Seizure In patients taking Sodium Valproate -25mg/kg iv sodium valproate can be tried who may be sub therapeutic. Phenytoin :- 20mg/kg Bolus dose IV at the rate of 50mg/min . Fosphenytoin :- 20mg PE/kg Bolus dose IV at the rate of 150mg/min Above drugs have advantage that they lack sedative effects.

26. Phenytoin Fosphenytoin 15-20 mg/kg i.v . @50mg/min 100 mg phenytoin = 20 mg PE/kg i.v @ 150mg/min Fosphenytoin 150 mg Extravasation causes severe tissue injury Extravasation well tolerated Onset 5-10 min Onset 10-30 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

27. Fosphenytoin Vs. Phenytoin Fosphenytoin injection has the following advantages over phenytoin 100% bioavailability better tolerated at site of injection . can be given IV more rapidly . can be given IM when cardiac monitoring is not necessary But has the following disadvantages conversion of fosphenytoin to phenytoin takes about 15 minutes . Hence inappropriate for the initial treatment of status epilepticus (SE). transient paraesthesia and pruritus occur more frequently than with phenytoin. the use of phenytoin equivalents may be confusing.

28. Used in SE when BZD and Phenytoin have failed. Loading dose – 15-20 mg/kg, 20 mg/kg, at a rate of less than 100 mg/min. If the EEG continues to show ictal activity, anesthesia has to be deepened to a burst-suppression pattern and even to complete suppression in some cases Causes sedation and hypotension, so airway protection should be done. Diluted in Polyethylene Glycol which results in complications like renal failure, myocardial depresion and seizures. Thiopentone

29. Thiopentone Most troublesome S/E- hypotension (may require pressor therapy) Tendency to accumulate Caution advised in elderly or in cardiac, hepatic or renal diseases. Aqueous solution is unstable if exposed to air.

30. Sodium valproate FDA approved use in SE in 1997 Parenteral loading is done when oral therapy is not possible. Broadspectrum action and is also useful in absence and myoclonic SE. Patients not responding to 2 first line AEDs may be given parenteral sodium valproate , especially in setting where intubation and artificial ventilation are not feasible.

31. Paraldehyde Is used as an alternative to Diazepam in early SE where IV administration is difficult or conventional AED are contraindicated or proved ineffective. Given rectally or I/M with fast and complete absorption with rapid onset of action. Seizure tend to recur after initial control. Inappropriately diluted or decomposed drug is highly toxic. Given at a dose of 0.4 mg/kg PR, Diluted in NS or olive oil for rectal or I/M route.(10ml of 10% sol.) Epilepsy; draft full guideline, Appendix C: December 2003

32. Propofol Nonbarbiturate anesthetic Highly lipid soluble with high volume of distribution resulting in rapid and short lived action. Causes profound respiratory and cerebral depression requiring assisted ventilation. May cause involuntary movements which are not to be confused with seizures 2 mg/kg bolus dose followed by 5-10 mg/kg/hr infusion.

33. Levetiracetam S- enantiomer of Piracetam Was introduced for treatment of SE in 2006 Insufficient data exist in adults about the efficacy of levetiracetam as either initial or second therapy (level U). Several case reports its use in SE. European federation of neurological societies proposes its usefulness in refractory complex partial SE. ( Meiekord H et al, EFNS guideline on the management of status epilepticus in adults, Eur Journal 2010)

34. Levetiracetam has been used to control SE, typically as second line drug. Levels peak within 2 hrs. Steady state in 2 days. No significant interactions. Mishra et al (2012) used LEV 20 mg./kg over 15 min. and compared with Lorezepam 0.1 mg./kg over 2 to 4 min. in 79 patients. Control was comparable (76.3% and 75.6%). 24 Hour seizure control was also similar. But hypotension and requirement of mechanical ventilation was significantly higher in Lorazepam group. Levetiracetam

35. Lacosamide In addition to anticonvulsant property, it has shown potential to retard kindling induced epileptogensis . There have been several small studies which have shown the efficacy of intravenous lacosamide in SE. A randomized controlled trial has shown a comparable efficacy and side effect profile in controlling lorazepam resistant SE ( Misra   et al . 2017 – LCM vs VPA comparable in LOR resistant SE).

36. Refractory Status Epilepticus Dubey D, Kalita J, Misra UK. Status epilepticus : Refractory and super-refractory. Neurol India 2017;65, Suppl S1:12-7 The treatment of RSE and SRSE is not evidence based. Refractory SE therapy recommendations should consist of continuous infusion AEDs, but vary by the patient ’ s underlying condition During the transition from continuous infusion AEDs in RSE, it is suggested to use maintenance AEDs and monitor for recurrent seizures by cEEG during the titration period. A period of 24–48 h of electrographic control is recommended prior to slow withdrawal of continuous infusion AEDs for RSE

37. Refractory Status Epilepticus Propofol , midazolam , and thiopental are commonly used first-line anesthetics for RSE thiopental often being reserved for use as a second-line anesthetic for those patients still refractory after these initial medications. A systematic review comparing pentobarbital, midazolam , and propofol found no significant difference in overall mortality In the absence of randomized data to guide management decisions, selection of an anesthetic should be individualized 

38. Propofol :- 2mg/kg IV bolus,Repeat if necessary, followed by infusion (2 – 10 mg/kg/hr) Thiopental :- 3-5 mg/kg IV bolus over 20 sec. followed by IV infusion(3-5mg/kg/hr) Midazolam :-(0.1-0.2mg/kg bolus, then 0.05-0.5mg/kg/hour) titrated to effect. Neuromuscular Blocking Agents : If seizures have been controlled for 12hrs., reduce the dose over further 12hrs. If seizure recurs again GA agent should be given Refractory Status Epilepticus

39. Lowenstein DH, Status Epilepticus , NEJM (1998) No difference has been found in mortality in groups treated with either of these agents. Pentobarbital was associated with lower frequency of acute treatment failures and breakthrough seizures. Superior pharmacokinetics and adverse effects profile makes Propofol preferred drug in Refractory status epilepticus in children as well as adults Refractory Status Epilepticus

40. Refractory Status Epilepticus No definitive data exist to determine what adequate burst-suppression entails and how long it should be maintained. Convention is to aim for 1 to 2 seconds of cerebral activity with 10-second interburst intervals of background suppression for a total of 24 to 48 hours before attempting to lighten sedation.  Dosing of continuous infusion AEDs for RSE should be titrated to cessation of electrographic seizures or burst suppression

41. Super Refractory Status Epilepticus IV ketamine infusion inhaled anesthetics isoflurane and desflurane   Magnesium - no significant toxicity ,drawbacks, evidence of experimental benefit, Recommended use in all cases of super-refractory status epilepticus , (initial intravenous bolus and then infusion at a dose that increases the serum level to ~3.5 mmol /l.)

42. IMPORTANT POINT Along with emergency control of SE, maintenance therapy should be started to prevent recurrence of seizures. In patients known to have epilepsy, their usual AED can be continued depending on serum AED levels. In patients presenting for the first time as SE, drugs like Phenytoin or Sodium Vaproate used to control the status can be continued as maintenance therapy.

43. American Epilepsy Society Guideline (February 2016) In adults with convulsive status epilepticus , im midazolam , iv lorazepam , iv diazepam and iv phenobarbital are established as efficacious as initial therapy (Level A). Im midazolam has superior effectiveness compared to iv lorazepam in adults with convulsive status epilepticus without iv access (Level A).

44. In children, iv lorazepam and iv diazepam are established as efficacious at stopping seizures lasting at least 5 minutes (Level A) rectal diazepam, im midazolam , intranasal midazolam and buccal midazolam are probably effective (Level B). No significant difference in effectiveness between iv lorazepam and iv diazepam in adults or children with convulsive status epilepticus (Level A). American Epilepsy Society Guideline (February 2016)

45. Respiratory and cardiac symptoms are the most common treatment-emergent adverse events asso . with iv anticonvulsant drug administration in adults with convulsive status epilepticus (Level A). The rate of respiratory depression in patients with convulsive status epilepticus treated with benzodiazepines is lower than in patients with convulsive status epilepticus treated with placebo indicating that respiratory problems are an important consequence of untreated convulsive status epilepticus (Level A). American Epilepsy Society Guideline (February 2016)

46. When both are available, fosphenytoin is preferred over phenytoin based on tolerability but phenytoin is an acceptable alternative (Level A). In adults, compared to the first line therapy, the second therapy is less effective while the third therapy is substantially less effective (Level A). In children, the second therapy appears less effective and there are no data about third therapy efficacy (Level C). American Epilepsy Society Guideline (February 2016)

47. Insufficient data exist in adults about the efficacy o levetiracetam as either initial therapy (level U). The guideline’s treatment algorithm is not age specific as the pathophysiology of status epilepticus and anticonvulsant drug effects on neuronal receptors are the same from infants through adults, permitting a unified approach for all patients older than neonates. American Epilepsy Society Guideline (February 2016)

48. Emerging therapies Inhalational Anaesthetic agents ( isoflurane and desflurane ) Attractive features include efficacy, rapid onset of action, ability to titrate according to EEG. Both drugs in endtidal concentrations of 1.2-5% achieved an EEG burst suppression and termination of seizure activity within minutes. However further studies are needed in this field. Mirasattari et al, treatment of refractory status epilepticus with inhalational anaesthetic agents : Isoflurane & Desflurane , Arch Neurology 2004

49. Ketamine an NMDA receptor antagonist Experimental studies have demonstrated synergistic action of diazepam and ketamine in termination SE. No RCT till now. Efficacy in extremely refractory SE has been documented in both children and adults. No cardiac depressant properties, hence doesnot cause hypotension. Dose – 50 mg bolus f/b 100 mg/hr Shorovan M et al,The treatment of refractory status epilepticus Brain 2011

50. Ketogenic diet Diet high in fat and low in carbohydrates Induces ketosis in body and thought to suppress seizures by release of Leptin . Exact mechanism remains unknown. Conclusive experimental evidence of any such action is lacking.

51. Shorovan M et al,The treatment of refractory status epilepticus Brain 2011 Rationale that refractory SE may be due to antibodies directed against neural elements. Increasing recognition the role of inflammation in epileptogenesis . SE may be the initial presenting feature of some immune mediated encephalopathies . Steroids and Immunotherapy

52. Nonpharmacological treatments Resective surgery Vagal nerve stimulation Hypothermia- decrease brain metabolism which is neuroprotective . Electroconvulsive therapy – only reports available.

53. Recurrent transcranial magnetic stimulation ( rTMS )  a continuous train of low frequency (≤1 Hz) pulses results in cortical suppression Several case reports available, no large studies Nonpharmacological treatments

54. Future studies The current National Institute of Neurological Disorders and Stroke funded ESETT trial compares IV fosphenytoin , levetiracetam and valproate in children and adults with status epilepticus who did not respond to initial benzodiazepine therapy. ESETT is designed to be a class I RCT that will identify the optimal second therapy for benzodiazepine-resistant status epilepticus - results awaited

55. THANK YOU

56. References Glauser , Tracy & Shinnar , Shlomoet al. Evidence-Based Guidline : Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Currents.2016 .16. 48-61. 10.5698/1535-7597-16.1.48. Review article-Status Epilepticus -Lawrence J . Hirsch,MD,FAAN : Nicolas Gaspard,MD,Phd-2013 Guidelines for evaluation and management of status epilepticus Neurocritical Care Society 2012 article-Status Epilepticus -Lawrence J . Hirsch,MD,FAAN : Nicolas Gaspard,MD,Phd-2013 J K Murthy Convulsive status epilepticus API India 2013 Dubey D, Kalita J, Misra UK. Status epilepticus : Refractory and super-refractory. Neurol India 2017;65, Suppl S1:12-7

57. Levetiracetam IV- Efficacy and Safety Thongplew and collegues reviewed the clinical use, efficacy, and outcomes of intravenous levetiracetam in adults with status epilepticus. Results: 34 prescriptions for intravenous levetiracetam in patients with status epilepticus were noted. All patients had at least one co-morbidity condition The seizure control rate was 61.8% 41.2% survived and had an improved status at discharge. Neurology Asia 2013; 18(2) : 167 – 175 Intravenous levetiracetam has good efficacy and may be a good option for status epilepticus.

58. Levetiracetam IV- Alternative to Lorazepam Randomized, open labeled pilot study compared the efficacy and safety of levetiracetam and lorazepam in status epilepticus . Patients with convulsive or subtle convulsive SE were randomized to Levitiracetam 20 mg/kg IV over 15 min or Lorazepam 0.1 mg/kg over 2-4 min. J Neurol. 2012 Apr;259(4):645-8 Levetiracetam Lorazepam In first instant, SE controlled 76.3 75.6 In those resistant, SE controlled 70.0 88.9 24-h freedom from seizure 79.3 67.7 Lorazepam Significantly higher need of artificial ventilation Insignificantly higher frequency of hypotension For the treatment of SE, levetiracetam is an alternative to lorazepam and may be preferred in patients with respiratory compromise and hypotension.