1. Seizures in the Emergency Department MOHAMD MIKATI MD Director, Adult and Pediatric Epilepsy Program, Professor and Chairman, Department of Pediatrics, American University of Beirut

2. OUTLINE REVIEW OF AVAILABLE PROTOCOLS FOR THERAPY REVIEW OF AVAILABLE PROTOCOLS FOR THERAPY REVIEW OF GUIDELINES FOR INVESTIGATIONS REVIEW OF GUIDELINES FOR INVESTIGATIONS REVIEW OF CLASS I AND II COMPARATIVE EFFICACY STUDIES REVIEW OF CLASS I AND II COMPARATIVE EFFICACY STUDIES CONTORVERSIES AND CONCLUSIONS CONTORVERSIES AND CONCLUSIONS

3. REVIEW OF AVAILABLE PROTOCOLS FOR THERAPY REVIEW OF AVAILABLE PROTOCOLS FOR THERAPY

4. Treatment of Paediatric Generalized Convulsive Status Epilepticus (Canadian Guidelines) Position, airway, suction available secretions, 100% oxygen Verify adequacy of breathing and circulation Commence intravenous access with normal saline. Rapid glucose determination Diazepam 0.3mg/kg or Lorazepam 0.1 mg/kg intravenously with an infusion rate of <2mg/min Repeat Diazepam 0.3 mg/kg or Lorazepam 0.1 mg/kg intravenously up to 3 times Phenytoin 20 mg/kg IV. Infusion rate of 1 mg/kg/min Phenobarbital 20 mg/kg IV. Infusion rate of 1 mg/kg/min The elapsed seizure time is now approximately 45 minutes. Depending on the resources available, further intervention will be needed in consultation with a pediatric intensivist, anaesthetist, neurologist. Administer 1g/kg of 25% dextrose if hypoglycemia (4ml/kg) Diazepam 0.5mg/kg or paraldehyde 0.3 ml/kg may be given rectally if no IV access Transfer to intensive care unit for further treatment Emergency Paediatrics Section, Canadian Paediatric Society. Paediatrics & Child Health 1996; 1(2): 151-155

5. Management of Convulsive Status Epilepticus in Children (Baystate) Child presents with seizure activity Protect Airway Ensure Respiration Monitor Vital Signs with Cardiac and O2 Saturation Monitors Administer O2 Start IV* ABCs Brief History from Family or Witnesses Neuro Exam Hx PE Lorazepam 0.05-0.15 mg/kg IV slow push (Max 4 mg,) (may repeal x 1 after 20 minutes) Point-of-Care: Glucose Consider sending blood for: Ca++, Glucose BUN, Cr CBC w/diff Tox. And AC levels Blood Culture Electrolytes Lab** Respiratory depression may occur- be prepared to manage airway and support respiration. Midazolam *** 0.2mg/kg Intranasally or IM *Administer D5%/NS IV at 2/3 maintenance rate. **Lumbar Puncture is indicated if meningitis is suspected. ***Intranasal or IM Midazolam, 0.2mg/kg, has been used successfully to terminate CSE. Consider as an option if unable to achieve IV access. Jackson et al., 2002. Baystate Health System

6. Phenytoin 18-20 mg/kg IV @ 1 mg/kg/min (Max 50mg/min) OR Phenobarbital **** 20mg/kg IV @ 25-50 mg/min. See Text re history of allergy to either agent. Load #1 Have seizures Terminated? EKG Monitoring (dysrhythmias or hypotension may occur have atropine available) Respiratory Depression may occur-be prepared to manage airway airway and support respiration. Phenytoin 5-10 mg/kg IV @ 1 mg/kg/min (Max 50mg/min) OR Phenobarbital **** 5-10 mg/kg IV @ 25-50 mg/min Have seizures Terminated? Check phenytoin level 30 min post loading dose Phenytoin 5-10 mg/kg/day IV or PO in divided doses. (Max 300-400 mg/day) Administer q8h age<6yrs, q12h age>=6yrs Maintenance Yes Load #2 Midazolam 0.2 mg/kg slow IV push, followed by 0.045-0.6 mg/kg/hr continuous infusion. Adjust based on clinical response. No Yes Have seizures Terminated? Yes No Refractory CSE Next slide ****Maximum dose of phenobarbital is 40 mg/kg or 1 gram, whichever is greater, within 24 hours. About fosphenytoin: Fosphenytoin is recommended in reference to phenytoin when venous access may be difficult to establish or precarious. Jackson et al., 2002. Baystate Health System About Time: Status Epilepticus is defined as prolonged seizures that last over 30 minutes, or recurrent epileptic seizures during which the patient does not regain consciousness within a 30-minute period. Since most seizures terminate spontaneously within a few minutes, seizures that persist for more than 5 to 7 minutes should probably be treated as CSE. Management of Convulsive Status Epilepticus in Children (Baystate)

7. To be managed by pediatric intensivist/pediatric anesthesiologist/pediatric neurologist team To be managed by pediatric intensivist/pediatric anesthesiologist/pediatric neurologist team Continuous EEG monitoring Continuous EEG monitoring Vital signs monitoring Vital signs monitoring O saturation monitoring O 2 saturation monitoring Intubate Intubate Paralyze patient Paralyze patient Hemodynamic monitoring if indicated Hemodynamic monitoring if indicated Consider further diagnostic studies if appropriate, e.g.,CT Consider further diagnostic studies if appropriate, e.g.,CT Management of Convulsive Status Epilepticus in Children (Baystate) Jackson et al., 2002. Baystate Health System

8. Options include: Continue Midazolam Infusion Continue Midazolam Infusion Propofol Propofol  1-2 mg/kg. May repeat in 5 minutes, followed by 1-15 mg/kg/hr  Adjust dose based upon EEG monitoring results  Check EEG hourly once patient has achieved a stable response  Primary end-point is suppression of EEG spikes, secondary end-point is burst suppression Pentobarbital Pentobarbital  3-15 mg/kg IV over 1 hr, followed by 0.5-5 mg/kg/hr to suppress all epileptiform activity as above. (Cardiovascular toxicity can be life-threatening, and weakness post infusion can delay weaning from ventilatory support). Depacon Depacon  15-20 mg/kg IV load followed by 15 mg/kg/day IV in 4 doses (q 6hr). Monitor CBC, platelets, liver function. Avoid in patients with suspected mitochondrial dysfunction or liver disease. Pyridoxine Pyridoxine  Trial in an infant or toddler may be warranted Management of Convulsive Status Epilepticus in Children (Baystate) Jackson et al., 2002. Baystate Health System

9. Continue maintenance doses of phenytoin, tracking serum levels to determine optimum doses Continue maintenance doses of phenytoin, tracking serum levels to determine optimum doses Use intravenous fluids and low-dose dopamine to treat hypotension Use intravenous fluids and low-dose dopamine to treat hypotension Decrease dosage of propofol if there are any signs of cardiovascular compromise. Rhabdomyolysis is a risk after 12-18 hours of propofol administration Decrease dosage of propofol if there are any signs of cardiovascular compromise. Rhabdomyolysis is a risk after 12-18 hours of propofol administration Taper infusion at 12 hours to observe for further seizure activity. If seizures recur, reinstate infusion in intervals of at least 12 hours. Taper infusion at 12 hours to observe for further seizure activity. If seizures recur, reinstate infusion in intervals of at least 12 hours. Management of Convulsive Status Epilepticus in Children (Baystate) Jackson et al., 2002. Baystate Health System

10. The NICE Consensus Protocol for Treating Status Epilepticus in Children Airway Breathing Circulation Give high flow oxygen Measure blood glucose Confirm epileptic seizure Immediate IV access No IV access Immediate IV access No IV access 1. Lorazepam 0.1 mg/kg IV 1. Diazepam 0.5 mg/kg PR (give over 30-60 seconds) (give over 30-60 seconds) Seizure continuing at 10 minutes IV ACCESS Seizure continuing at 10 minutes Seizure continuing at 10 minutes IV ACCESS Seizure continuing at 10 minutes 2. Lorazepam 0.1 mg/kg IV2. Paraldehyde 0.4 ml/kg PR (give over 30-60 seconds) (give with the same volume of olive oil) (give over 30-60 seconds) (give with the same volume of olive oil) Seizure continuing at 10 minutes Seizure continuing at 10 minutes Seizure continuing at 10 minutes Seizure continuing at 10 minutes Call for senior help Call for senior help3. Protocol for treating status epilepticus in adults and Children, NICE, December 2003

11. 3. Phenytoin 18 mg/kg IV over 20 minutes or IF ALREADY ON PHENYTOIN GIVE PHENOBARBITONE 20 mg/kg IV OVER 10 MINUTES (use intraosseous route if still no IV access) AND PARALDEHYDE 0.4 ml/kg PR + same volume of olive oil if not already given AND CALL ON-CALL ANAESTHETIST OR INTENSIVE CARE MEDIC Seizure continues 20 minutes after commencing step 3 4. RAPID SEQUENCE INDUCTION OF ANAESTHESIA USING THIOPENTONE 4 mg/kg IV Transfer to intensive care unit Protocol for treating status epilepticus in adults and Children, NICE, December 2003 The NICE Consensus Protocol for Treating Status Epilepticus in Children

12. REVIEW OF GUIDELINES FOR INVESTIGATIONS REVIEW OF GUIDELINES FOR INVESTIGATIONS

13. Laboratory studies In Class I and II studies, results of laboratory studies usually did not contribute to diagnosis or management. Occasional single patients had hyponatremia or hypocalcemic, and in one ClassII study one had a positive cocaine screen. An exception to the small number of abnormal laboratory findings in the absence of specific suggestive features is in the under 6 month age group. Hyponatremia (<125 mM/L) was found to be associated with seizures in 70% of 47 infants younger than 6 months in a Class II study. Hirtz et al., 2000. Neurology 55: 616-623 Practice Parameter: Evaluating a First Nonfebrile Seizure in Children

14. EEG 10 Class I studies demonstrated the utility of the EEG in prognostications, for example 54% of children with an abnormal EEG had a recurrence compared with 25% of 165 children with a normal EEG (p < 0.001). EEG was also useful for diagnosis of the event, and for identification of the epilepsy syndrome. A Class I study published in 1998 in children and adults concluded that an EEG obtained within 24 hours of a seizure was more likely to contain epileptiform abnormalities than one done later (51% versus 34%). Hirtz et al., 2000. Neurology 55: 616-623 Practice Parameter: Evaluating a First Nonfebrile Seizure in Children

15. CT CT In Class I and II studies, only a small percentage of children (0 to 7%) had lesions on CT that altered or influenced management. The yield of abnormality on CT when the neurologic examination and EEG were normal was 5 to 10%. MRI scanning was preferable to CT in children following nonfebrile seizures. Hirtz et al., 2000. Neurology 55: 616-623 Practice Parameter: Evaluating a First Nonfebrile Seizure in Children

16. MRI There was one Class I report regarding MRI in children presenting with a first seizure and another Class I report of newly diagnosed epilepsy in children. Four (2%) had lesions seen on MRI or CT (two brain tumors, two neurocysticercosis) that potentially altered management.. 19 (33%) MRI scans were abnormal, but none of the children required [immediate] intervention on the basis of the MRI findings. In another the Class I study, 86% had neuroimaging, and none had abnormalities influencing immediate treatment or management decisions. A third Class I study reported that 3/43 children had an abnormal MRI, one showing hippocampal sclerosis and two showing single gray matter heterotopic nodules Two Class II six Class III reports showed similar findings.. Hirtz et al., 2000. Neurology 55: 616-623 Practice Parameter: Evaluating a First Nonfebrile Seizure in Children

17. Laboratory tests should be ordered based on individual clinical circumstances (option) Laboratory tests should be ordered based on individual clinical circumstances (option) Toxicology screening should be considered across the entire pediatric age group (option) Lumbar puncture is of limited value an and should be primarily used if there is concern about meningitis or encephalitis (option) EEG is recommended as part of the evaluation (standard) Hirtz et al., 2000. Neurology 55: 616-623 Practice Parameter: Evaluating a First Nonfebrile Seizure in Children

18. If a neuroimaging study is obtained MRI is the preferred modality (guideline) If a neuroimaging study is obtained MRI is the preferred modality (guideline) Emergent neuroimaging should be performed in a child of any age with Todd’s paresis or post ictal depression not quickly resolving (option) Nonurgent imaging studies with MRI should be seriously considered in any child with neurologic abnormalities and with partial seizures (option) Hirtz et al., 2000. Neurology 55: 616-623 Practice Parameter: Evaluating a First Nonfebrile Seizure in Children

19. REVIEW OF CLASS I AND II COMPARATIVE EFFICACY STUDIES REVIEW OF CLASS I AND II COMPARATIVE EFFICACY STUDIES

20. Therapy of Status: Comparative Efficacy Efficacy (%) Reference: Leppik et al.1983, JAMA. 249: 1452-1454

21. Therapy of Status: Comparative Efficacy Proportion of Patients in Status Epilepticus 0.0 0.2 0.4 0.6 0.8 1.0 0 1020304050 60 Minutes Placebo Diazepam Lorazepam Alldredge et al., 2001. N Engl J Med, 345(9):631-637

22. Therapy of Status: Comparative Efficacy Time in minutes Reference: Shaner et al.1988, Neurology. 38: 202-207.

23. Treiman et al. 1998, NEJM; 339(12):792-798. Therapy of Status: Comparative Efficacy Successful Treatment (%) Rx more successful in convulsive SE Than in subtle SE

24. Therapy of Neonatal Status Epilepticus: Comparative Efficacy Reference: Painter et al.1999, N Engl J Med. 341: 485-489. Efficacy (%)

25. Stages of Status Epilepticus 1. Discrete seizures with interictal slowing 2. Waxing and waning of ictal discharges 3. Continuous ictal discharges 4. Continuous ictal discharges punctuated by flat periods 5. Periodic epileptiform discharges on a flat background These last two stages correspond to refractory status epileptics which may difficult to detect (subtle seizures) difficult to treat, and is associated with long term sequeli.

26. Stage V Status Epilepticus Mikati et al., 2003. Epilepsy research, 55:9-19

27. Apoptosis after Status Epilepticus (Kainic Acid Model)

28. Treatment Response and Outcome in Patients with Refractory Status Epilepticus * ** * * P<0.01, ** P<0.001 Classen et al. Epilepsia Vol 43, No. 2, 2002

29. Treatment Response in Refractory Status Epilepticus According to Goal of Seizure Control Vs. EEG Background Suppression ** ** P<0.01 Classen et al. Epilepsia Vol 43, No. 2, 2002

30. Conclusions and Remarks There are effective initial therapies for status epilepticus, but what are the most effective initial therapy medications (consider the benzodiazepines, the newer options, intravenous valproate, and possibly levetiracetam), what do we do in the absence of more controlled studies. There are effective initial therapies for status epilepticus, but what are the most effective initial therapy medications (consider the benzodiazepines, the newer options, intravenous valproate, and possibly levetiracetam), what do we do in the absence of more controlled studies. What is the optimal approach to stage IV and V refractory status, knowing that most medications are not very effective? What is the optimal approach to stage IV and V refractory status, knowing that most medications are not very effective?

31. Conclusions and Remarks Is there a role for neuroprotective agents and strategies in the treatment of status? Is there a role for neuroprotective agents and strategies in the treatment of status? What do we do about neonatal status, do we treat EEG seizures like we do clinical seizures? What do we do about neonatal status, do we treat EEG seizures like we do clinical seizures? At present the key in the management is recognition of status as a medical emergency, the application of a justifiable institutional protocol, and individualization of therapy. At present the key in the management is recognition of status as a medical emergency, the application of a justifiable institutional protocol, and individualization of therapy.