1. Status Epilepticus (SE): Diagnosis and Management Edward Sloan, MD, MPH Associate Professor Department of Emergency Medicine University of Illinois College of Medicine-Chicago Chicago, IL

2. Edward Sloan, MD, MPH Objectives Definitions – SE – Subtle SE – Refractory SE Diagnosis – Clinical exam – Diagnostic testing – EEG Management

3. Edward Sloan, MD, MPH Case A 37 year old male is brought to the emergency department by EMS because of a seizure at home. The patient had a generalized tonic-clonic seizure prior to going to bed. The seizure lasted for approximately ten minutes, followed by a period of unresponsiveness during EMS transport. The patient has a long history of post-traumatic seizures that are managed with phenytoin and phenobarbital. There has been neither recent illness nor recent head trauma. In the emergency department, the patient is still unresponsive.

4. Edward Sloan, MD, MPH SE Questions How is SE Defined? What is Subtle SE? How is Subtle SE Diagnosed? How is SE Acutely Managed? What is Refractory SE? How is Refractory SE Managed?

5. Edward Sloan, MD, MPH All are true statements about Status epilepticus (SE) except: a. It is defined by two seizures that occur without a lucid interval. b. By definition, all SE is associated with SE definitions include any seizure of duration > 10 minutes. d. The most common etiologies for SE include antiepileptic drug (AED) withdrawal and alcohol withdrawal. e. SE of longer duration is associated with a higher mortality.

6. Edward Sloan, MD, MPH All are true statements about Stutus Epilepticus (SE) except: Answer: b. Although generalized convulsive SE(GCSE) is associated with tonic-clonic motor activity, other forms such as complex partial or absence SE can exist with this motor activity.

7. Edward Sloan, MD, MPH All are true statements about subtle SE except: a. By definition, subtle SE is not associated with generalized tonic-clonic motor activity. b. Subtle SE requires EEG monitoring in order to be diagnosed clinically. c. In subtle SE, the EEG shows persistent ictal discharges. d. Because there is not generalized tonic-clonic motor activity, subtle SE has a lower mortality rate than does GCSE. e. Subtle SE occurs as a late finding of prolonged GCSE.

8. Edward Sloan, MD, MPH All are true statements about subtle SE except: Answer: d. Because subtle SE is a late finding of prolonged GCSE, it carries a much higher mortality than GCSE, up to 50-65% in some studies.

9. Edward Sloan, MD, MPH All are true statements regarding adult SE except: a. Fever can occur as a result of GCSE without the presence of a CNS infection as the fever source b. Lumbar puncture is required for all SE patients who have a fever. c. Lactic acidosis, leukocytosis, and hypercarbia can be in SE. d. Guidelines exist that describe the role of neuroimaging in seizures and SE e. The diagnosis of refractory SE is made when initial therapies fail.

10. Edward Sloan, MD, MPH All are true statements regarding adult SE except: Answer: b. Although a lumbar puncture should be considered in all patients with SE and fever, in the awake patient without meaningful signs and a fever source, an LP may not be necessary.

11. Edward Sloan, MD, MPH All are true statements regarding the use of EEG in SE except: a. Patients who remain comatose for > 30 minutes may be in subtle SE, requiring EEG monitoring. b. All patients requiring neuromuscular blockage require EEG monitoring. c. All patients requiring pentobarbital coma require EEG monitoring. d. EEG monitoring can only be done with a multiple lead EEG machine. e. When considering subtle SE, EEG monitoring should be performed emergently in the ED or ICU.

12. Edward Sloan, MD, MPH All are true statements regarding the use of EEG in SE except: Answer: d. Two channel EEG monitoring can be performed using the modular monitoring systems present in most EDs.

13. Edward Sloan, MD, MPH All are true statements regarding the initial management of SE except: a. Lorazepam has been shown to be superior to other benzodiazepines in SE management. b. Glucose determination, thiamine, and narcan are important initial therapies. c. Most treatment failures relate to inadequate dosing, not drug therapy choice. d. Phenytoins can be given in high doses (up to 30 mg/kg) in SE. e. Propofol or phenobarbital can be used to treat SE if benzodiazepines and phenytoins are not effective.

14. Edward Sloan, MD, MPH All are true statements regarding the initial management of SE except: Answer: a. No simple benzodiazepine has been shown to be superior to another for the treatment of SE.

15. Edward Sloan, MD, MPH If IV access is not available, the following are possible drugs and routes except? a. IM midazolam b. IM fosphenytoin c. IM phenobarbital d. PR diazepam e. PR diazepam gel

16. Edward Sloan, MD, MPH All are true statements regarding the use of EEG in SE except: Answer: c. IM phenobarbital is not recommended because of soft tissue toxicity.

17. Edward Sloan, MD, MPH SE Epidemiology 50,000-150,000 Cases annually 50 Cases per 100,000 population Infants and elderly: greatest risk Etiology: acute insult, chronic epilepsy, new onset DeLorenzo et al. Neurology 1996;46:1029. DeLorenzo et al. J Clin Neurophysiol 1995;12:316. DeLorenzo et al. Epilepsia 1992;33(Suppl 4):S15. Hauser. Neurology 1990;40(Suppl 2):9.

18. Edward Sloan, MD, MPH SE Etiology Etiologies of SE in 154 patients Lowenstein and Alldredge. Neurology. 1993;43:483. Drug Toxicity

19. Edward Sloan, MD, MPH SE Definition Needed for epidemiologic and clinical trials Historical definitions –Two seizures within 30 min, no a lucid interval –One seizure >30 min duration More recent definitions more aggressive –Two seizures over any interval, no a lucid interval –One seizure of >10 min duration Gastault. Adv Neurol 1983;34:15. Lowenstein. N Eng J Med 1998;338:970-976 Treiman. Epilepsia 1993;34(Suppl 1):S2.

20. Edward Sloan, MD, MPH SE Classification Generalized convulsive SE: –Primarily and secondarily generalized –Overt: Generalized or major motor SE –Subtle: Myoclonic SE, “electical” SE Nonconvulsive SE : Epileptic twilight state –Complex partial SE –Absence SE: Spike-wave stupor Simple partial SE –No impairment of consciousness Treiman. Epilepsia 1993;34(Suppl 1):S2. Treiman, J Clin Neurophys 1995;12(4):343-362.

21. Edward Sloan, MD, MPH SE Mechanism Abnormal discharge by a few unstable neurons Propagation by recruitment of normal neurons Failure of normal inhibitory neurotransmitters (GABA) Enhancement of excitatory neurotransmitters –(glutamate, aspartate, acetylcholine) Interference with normal metabolic processes –glucose, 02 metabolism –Na+, Ca++, K+, Cl- ion shifts Fountain et al. J Clin Neurophysiology 1995;12:326.

22. Edward Sloan, MD, MPH SE Duration and Mortality SE >60 min: 10-fold greater 30-day mortality (32% vs 2.7%) Worse outcome associated with –Longer duration SE –SE refractory to first-line therapy DeLorenzo et al. Epilepsia 1992;33(Suppl 4):S15. Lowenstein, and Alldredge. Neurology 1993;43:483.

23. Edward Sloan, MD, MPH Subtle Status Epilepticus Non-convulsive Persistent ictal discharges Electrical-mechanical dissociation (EMD) Late finding after GCSE Significant M & M Treiman, J Clin Neurophys. 1995;12(4):343-362.

24. Edward Sloan, MD, MPH Subtle SE Incidence: Post-GCSE Frequency Requires immediate EEG monitoring VA SE study: 20% Post - GCSE study:14% DeLorenzo et al. Epilepsia 1998;39(8):833-840. Treiman et al. N Eng. J Med 1998;339:792-798.

25. Edward Sloan, MD, MPH Subtle SE Outcome Related to serious underlying pathology Post-arrest hypoxic encephalopathy Much higher mortality –VA SE study: 65% (vs 27%) –Post - CGSE study:50% (vs 15%) DeLorenzo et al. Epilepsia 1998;39(8):833-840. Treiman et al. N Eng. J Med 1998;339:792-798.

26. Edward Sloan, MD, MPH Subtle SE Diagnosis AMS: unresponsiveness >20-30 minutes Prolonged post-ictal state Idiosyncratic behaviors Agitation, speech arrest, confusion

27. Edward Sloan, MD, MPH SE Management: General Principles ABCs Glucose determination Thiamine / narcan Antiepileptic drug (AED) therapy Lowenstein and Alldredge N Eng. J Med 1998;338:970-976.

28. Edward Sloan, MD, MPH SE Management: Clinical Diagnosis AMS Todd’s paralysis Hypertension: early BP rise, then hypotension Fever: 49% have temperature >100.5 Fo Wijkicks and Hubmayr. Mayo Clin Proc 1994;69:1044. Aminoff and Simon. Am J Med 1980;69:657.

29. Edward Sloan, MD, MPH SE Clinical Evaluation: Laboratory Testing Lactic acidosis: 30% will reach blood pH <7.00 Hypercarbia: 84% will have increased pCO2 Leukocytosis without bands Neuron-specific enolase: highest in NCSE Aminoff and Simon. Am J Med 1980;69:657. DeGiorgio et al. Neurology 1999;52:746-749 Orringer et al. N Engl J Med 1977;297:796. Wijkicks and Hubmayr. Mayo Clin Proc 1994;69:1044.

30. Edward Sloan, MD, MPH SE Clinical Evaluation: Lumbar Puncture Three indications: – Immunocompromise – Meningeal signs – Persistent AMS Not mandated for fever alone CSF pleocytosis: 2%-18% have >5 PMNs ACEP. Ann Emerg Med 1993;22:987. Aminoff and Simon. Am J Med 1980;69:657.

31. Edward Sloan, MD, MPH ACEP/AAN/AANS/ASN Neuroimaging Guidelines –Recent trauma –Cancer –Anticoagulation –AIDS –New focal deficit –Persistent AMS –Fever –Persistent headache history AAN = American Academy of Neurology; AANA= American Association of Neurological Surgeons; ACEP = American College of Emergency Physicians; ASN = American Society of Neuroradiology. ACEP, AAN, AANS, ASN. Ann Emerg Med 1996;27:114. Emergent neuroimaging recommended for:

32. Edward Sloan, MD, MPH SE Clinical Evaluation: Encephalography Three emergent EEG indications: – Prolonged (>30 min) AMS – SE requiring neuromuscular paralysis – SE requiring pentobarbital coma or general anesthesia Needs to be arranged emergently Kaplan. Epilepsia 1996;37:643. Privitera and Strawsburg. Emerg Med Clin N Am 1994;12:1089.

33. Edward Sloan, MD, MPH SE Treatment Protocols: Epilepsy Foundation of America Consensus expert opinion Make the first drug work Dose adequately Benzodiazepines, phenytoins, barbituates High dose phenytoin (30 mg / kg) Working Group on Status Epilepticus. JAMA 1993;270:854.

34. Edward Sloan, MD, MPH SE Treatment Protocols: VA Cooperative Study Four therapies, effectiveness at 20 min EEG confirmation Lorazepam, phenobarbital, diazepam & phenytoin, and phenytoin Lorazepam best (65%) vs. phenytoin Phenytoin alone sub-optimal (42%) No difference with fosphenytoin? Treiman. N Eng J Med 1998;339:792-798

35. Edward Sloan, MD, MPH Refractory SE: Incidence and Outcomes SE not responsive to benzodiazepines and phenytoins. –Up to 6000 cases of refractory SE annually Often indicative of progressive CNS disorder Refractory SE relatively rare in ED Overall mortality: 20% - 30% Bleck. Neurology Chron 1992;2:1. Kumar et al. Crit Care Med 1992;20:483. Jagoda et al. Ann Emerg Med 1993;22:1337. Labar et al. Neurology 1994;44:1400.

36. Edward Sloan, MD, MPH Refractory SE Management Outcome likely related to cause of SE Many anecdotal reports; no controlled trials Inhalation anesthetics less useful Neuromuscular blockade not an anticonvulsant Bleck. Neurology Chron 1992;2:1. Kumar et al. Crit Care Med 1992;20:483. Jagoda et al. Ann Emerg Med 1993;22:1337. Labar et al. Neurology 1994;44:1400.

37. Edward Sloan, MD, MPH Refractory SE Management Pentobarbital –5 mg/kg –load at 25 mg/min; 2.5 mg/kg/h maintenance dose Propofol –2 mg/kg load; 7 to 10 mg/kg/h maintenance Midazolam –Bolus intravenous 200 microgram/kg –Infusion 0.75-11 microgram/kg/min Shorvon. J Neurol Neurosurg Psychiatry 1993;56:125. Towne: J Emerg Med 1999;17:323 Van Ness. Epilepsia 1990;31:61. Bleck. Neurology Chron 1992;2:1. Jagoda et al. Ann Emerg Med 1993;22:1337. Jagoda and Riggio. Ann Emerg Med 1993;22:1337. Kuisma and Roine. Epilepsia 1995;36:1241. Kumar et al. Crit Care Med 1992;20:483. Labar et al. Neurology 1994;44:1400. Parent JM, Lowenstein DH. Neurology 1994;44:1837

38. Edward Sloan, MD, MPH SE Management Options: Drug Therapies IV Phenytoin: High dose (30 mg/kg) IV Fosphenytoin: Rapid infusion in GCSE IV Valproate: Absence complex partial SE IV Lidocane: Anecdotal efficacy reports Allen et al. Epilepsia 1995;36(Suppl 4):90. Alehan et al. Neurology 1999;52:889-890. Browne et al. Neurology 1996;46(Suppl 1):S3. Eldon et al. Clin Pharmacol Ther 1993;53:212. Giroud et al. Drug Invest 1993;5:154. Kugler et al. Neurology 1996;46(Suppl)A176. Ramsey and DeToledo. Neurology 1996;46(Suppl 1):S17. Walker and Slovis. Acad Emerg Med 1997;4:918. Willert et al. Neurology 1999;52:889-890 Working Group on Status Epilepticus. JAMA 1993;270:854

39. Edward Sloan, MD, MPH SE Management Options: Alternative Parenteral Routes Midazolam IM: Best IM benzodiazepine Fosphenytoin IM: Therapeutic by 30 minutes Diastat PR: Rapid rectal absorption Phenobarbital IM: Not recommended Dean et al. Epilepsia 1993;34(Suppl 6):111. Garnett et al. Neurology 1995;45(Suppl 4):A248. Parent JM, Lowenstein DH. Neurology 1994;44:1837 Ramsey and DeToledo. Neurology 1996;46(Suppl 1):S17. Towne: J Emerg Med 1999;17:323-328 Wilder et al. Arch Neurol 1996;53:764.

40. Edward Sloan, MD, MPH SE Unique Populations: Toxic Ingestions INH overdose: Pyridoxine (B6) 5g IVP x 6 EtOH: Lorazepam (prevention also) Phenytoins likely not effective in: – Cocaine – Cyclic antidepressants – Theophylline Orlowski et al. Ann Emerg Med 1988;17:73. Pauloucet et al. Ann Emerg Med 1988;17:135. Shannon. Ann Intern Med 1993;119:1161. Wason et al. JAMA 1981;246:1102. Brent et al. Arch Intern Med 1990;150:1751. Callaham and Kassel. Ann Emerg Med 1985;14:1. D’Onofrio et al. N Engl J Med 1999;340:915-919. Haverkos et al. Ann Pharmacother 1994;28:1347. Henderson et al. Anaesth Intensive Care 1992;20:56. Holland et al. Ann Emerg Med 1992;21:772. Koppel et al. Epilepsia 1996;37:875. Lin et al. Ann Emerg Med 1995;25:75.

41. Edward Sloan, MD, MPH SE Unique Populations: Other Subgroups TBI: Sz prophylaxis acutely Stroke: Prophylaxis in high risk patients Pregnancy: Mg++ prevents and treats Psychogenic: Functional disorder, Rx Arboix et al. Neurology 1996;47:1429. Jagoda et al. Am J Emerg Med 1993;11:626. Jagoda et al. Am J Emerg Med 1995;13:31. Lewis, et al. Ann Emerg Med 1993;22:1114. Temkin et al. N Engl J Med 1990;323:497.

42. Edward Sloan, MD, MPH Research Horizons: PHTSE Trial Blinded, placebo-controlled, comparative trial –diazepam vs lorazepam vs placebo –2 injections, then standard care 65% seizing at time of ED arrival 55% ICU admission rate 20% HIV infection rate Study not yet completed; awaiting final results Alldrede et al. Epilepsia 1995;36:(Suppl 4):44.

43. Edward Sloan, MD, MPH Research Horizons ER Seizure Study Group EMS Seizing rate:<5% ER Seizing rate:<5% Status epilepticus:<5% Admission rate:26% Gibbs et al. Ann Emerg Med 1998;32:S19-S20.

44. Edward Sloan, MD, MPH SE Management: Case Management Prolonged seizure (20 min) in ED High dose benzodiazepines Rapid infusion fosphenytoin Prolonged AMS –Neuro consult –Stat CT in ED –EEG on arrival to ICU (< 90 minutes) –Work-up neg, awake within 12 hours

45. Edward Sloan, MD, MPH SE Conclusions SE is a common problem SE causes significant M & M Therapy can be optimized Outcome can be enhanced ED management critical

46. Edward Sloan, MD, MPH SE Recommendations Aggressively treat seizures Dose adequately Be aware of options Suspect NCSE Use EEG liberally

47. Edward Sloan, MD, MPH SE Recommendations Develop a SE protocol Make all therapies available Make EEG a “stat” test Work with neurologists, NS Optimize patient outcome