1. Non-Convulsive Status Epilepticus (NCSE): Our Experience at a Tertiary Care Center Brennen Bittel, DO Clinical Neurophysiology Fellow

2. Overview Background information:  Epidemiology  Clinical features  Electrographic definition EDX pitfalls  Treatment  Pathology  Outcomes KU Data  2009-2013

3. Incidence/prevalence SE* in emergency room or intensive care units ~ 150,000/yr NCSE:  25 % of all SE  1.5 – 60/100,000/yr 34% of all SE in a tertiary care center 27% of ICU pts w/ altered mental status 8% of pts in coma Celesia 1976, Tomson 1992, Drislane 2000, Towne 2000

4. Definition 1. Diminished level of consciousness, confusion 2. Epileptiform EEG (continuous or discrete) 3. Response to treatment??

5. 1. Change in mental status- Semiology Ambulatory confused patients, mildly confused hospitalized patients Lethargic and comatose patients in intensive care units

6. Diminished Level of Consciousness, Confusion

8. Clinical presentations

10. NCSE CPSE (complex partial SE) ESE (electrographic SE) SPSE (Simple partial SE) ASE (absence SE) IntermittentContinuous 20-40% 35-40% Krumholz 1999, Meierkord 2007

11. Confused Bizarre behavior Fluctuations +/- automatisms Aphasia Stuporous Comatose GTC at onset Medical illness

12. Other sxs/signs Agitation Lethargy Mutism Disruptive behavior Staring Laughter Crying Rigidity Perseveration Subtle motor movements Hallucinations

13. DDx Metabolic/toxic encephalopathy Complicated migraine/aura Prolonged post-ictal state Psychiatric disorders Substance abuse/withdrawal/intoxication  DTs TIA Transient global amnesia

14. Husain 2003 12 in the NCSE group and 36 in the non- NCSE group  100% sensitivity  Ocular movements Rhythmic blinking, deviation, nystagmus, rhythmic hippus  Recent or remote risk factor for seizure Previous stroke, tumor, previous neurosurgery, dementia, epilepsy, and meningitis

15. Epileptiform EEG

16. 2. Epileptiform EEG Frequency Morphology Evolution Rhythmicity

17. Frequency

18. Treiman criteria- GCSE Five characteristic stages: 1. Discrete seizures 2. Merging seizures 3. Continuous seizures 4. Continuous seizures with brief "flat" periods on the EEG -- (usually no convulsions) 5. Prolonged flat periods with periodic discharges -- (usually no convulsions)

19. Young 1996- NCSE Primary Criteria 1. Repetitive generalized or focal spikes, sharp waves, spike-wave or sharp-slow wave complexes at >3/sec 2. Repetitive generalized or focal spikes, sharp waves, spike-wave or sharp-slow wave complexes at >3/sec AND #4 3. Sequential rhythmic waves and 1-3, +/- 4 Secondary Criteria 1. Incrementing onset: voltage or slowing 2. Decrementing offset: voltage or frequency 3. Post-discharge slowing or voltage attenuation 4. Significant improvement in clinical state or baseline EEG after AED***

20. Walker 2005 1. Frequent/continuous focal electrographic szs, with ictal patterns that wax and wane with change in amplitude, frequency, and/or spatial distribution. 2. Frequent/continuous generalized spike-wave discharges in pts without a previous history of epileptic encephalopathy or epilepsy syndrome. 3. Frequent/continuous generalized spike-wave discharges, which showed significant changes in intensity or frequency (usually a faster frequency) when compared to baseline EEG, in patients with an epileptic encephalopathy or epilepsy syndrome 4. PLEDs/ BIPEDs in patients in coma in the aftermath of a generalized tonic– clonic status epilepticus (subtle status epilepticus). 5. EEG patterns that were less easy to interpret included: Frequent/continuous EEG abnormalities (spikes, sharp-waves, rhythmic slow activity, PLEDs, BIPEDs, GPEDs, triphasic waves) in patients whose EEGs showed no previous similar abnormalities, in the context of acute cerebral damage (e.g., anoxic brain damage, infection, trauma). 6. Frequent/continuous generalized EEG abnormalities in pts w/ epileptic encephalopathies in whom similar interictal EEG patterns were seen, but in whom clinical symptoms were suggestive of NCSE.

21. EEG Diagnosis Inevitably subjective

22. Which tracing shows NCSE?

23. PLEDS

24. Triphasic waves

25. GPEDS

26. L Temp/parietal CPSE

27. Diagnostic pitfalls PLEDs, BiPLEDs, GPEDs, SIRPIDs Encephalopathy Status myoclonus CJD

28. PLEDs No absolute frequency criterion can be used to distinguish PLEDs from seizures Frequency  1 - 4 seconds (short periodicity)  >4 seconds (long periodicity) Acute, serious neurologic illness  Mortality is high—up to 50% within 2 months Walsh 1987

29. PLEDs Associated with: Stroke (the most common cause in many reports) Tumors Infections- Viral (acute and chronic) Metabolic disturbances Head injury SDH Anoxia Brain abscess Congenital lesions Tuberous sclerosis Multiple sclerosis Creutzfeld–Jakob disease

30. PLEDs 80-90% of pts had recent clinical seizures  66% had some form of SE Risk for more seizures  Half patients without prior epilepsy developed subsequent epilepsy Most PLEDs will resolve after days to weeks Part of an ictal-interictal spectrum Snodgrass 1989, Kaplan 2007, Chong 2005, Walsh 1987

31. PLEDs

32. PLEDs regression- 1 week later

33. Triphasic waves Seen commonly in metabolic encephalopathies  Classically in renal or hepatic failure Bursts 1-2Hz  Blunted, low-moderate amplitude  Dominant positive second phase, slow rise Phase lag  not seen in NCSE Increased with stimulation  not seen in NCSE Sometimes suppressed with BZDs (40-60%)  Kaplan 2006

35. Encephalopathies w/Epileptic Features Reversible  Usually no hx of epilepsy  Medication related BZD withdrawal Cephalosporin Abx Ifosfamide Baclofen Psychotropics Rhythmic, semirhythmic delta Drislane 2000 Irreversible  Post-anoxic  Creutzfeld-Jacob Importance of c-VEEG  Look for subtle clinical changes a/w rhythmicity

37. CJD – EEG progression

38. Patients at risk 1. Following seizures or GCSE -- Up to 50% in NCSE after convulsions cease 2. AMS with subtle motor signs 3. AMS in epileptic w/ acute medical illness 4. Post-stroke pt faring worse or recovery halted 5. Elderly pt with AMS (post BZD withdrawal) DeLorenzo 1998, Drislane 2000

39. Risk factors Mental status changes  ICH  SAH  Large vessel CVA  Meningoencephalitis  CHI/TBI  Tumor  Post-surgical Drislane 2000

40. 3. Treatment Response Treatment response less often considered diagnostic  Clinical response may be delayed hours to days  Shneker 2003

41. Treatment CPSE  BZDs  IV AEDs  Usually recurs ESE  60% respond to initial BZD (clinical delay)  15% resistant to BZD  Require IV AEDs +/- Anesthesia Granner 1994, Shneker 2003

42. Anesthesia- Claassen 2002 193 pts w/ refractory SE  Tx with midazolam vs propofol vs pentobarbitol Midazolam  Increased breakthrough seizures  Less hypotension Pentobarbitol  Lowest treatment failure/recurrence  More hypotension Refractory NCSE- more common with propofol and midazolam No standardized treatment regimen for use of anesthesia in SE

43. Anesthesia No consensus on NCSE  More harm than good? Hypotension Sepsis/line infection DVT  Ultimate effect on brain? Outcomes…

44. Pathologic changes Animal models  Induced GCSE, up to 5 hours, in baboons  Hippocampal volume loss ↑ with frequent, prolonged seizures ↓ if paralytic used to abolish convulsions  Hyperpyrexia, hypotension, hypoxia, acidosis, and hypoglycemia  Changes in high-frequency (10Hz) vs low frequency (1Hz) discharges Bertram 1990

45. Pathologic changes Human autopsy studies  GCSE > epilepsy w/o SE > normal  Synergistic damage Increase in excitatory neurotransmitters Metabolic changes (lactate, pyruvate) Earnest 1992, Kruhmholz 1995

46. Outcomes: Mortality Vary highly based on the underlying etiology of the condition  Brain tumors (30-40%)  Acute stroke (35%)  Epilepsy (3%) Duration of seizures  43 ICU pts in NCSE on VEEG <10h = death in 10% >20h = death in 85% Age > 60y Rarely fatal in isolation  Young 1996, Meierkord 2007, Towne 1994

47. Outcomes: Morbidity CPSE  No difference between continuous and intermittent electrographic sz activity Return to baseline cognitive status (n=20) Cognitive decline, memory issues (n=10) ESE  Determined by primary etiology  Tend to have poorer prognosis Drislane 1999, Cockerell 1994, Krumholz 1995

48. Outcomes: MICU vs NICU 168 visits over 3 yrs  27% NICU More pts w/ stroke More CPSE Avg age: 59 Alert/somnolent pts Fewer pts intubated, more tracheostomized Varelas 2013  73% MICU More toxic/metabolic enceph More GCSE Avg age: 51 Obtunded/comatose pts Higher APACHE 2 scores

49. APACHE II Acute Physiology and Chronic Health Evaluation II

50. MICU vs NICU No difference in outcomes  Length of ICU/hospital stay  Functional status at discharge (mRS) Limitations:  Smaller NICU population  Neuro illness with longer recovery period?

51. KU Data

52. KU Cohort Objective:  Review and describe non-convulsive status epilepticus (NCSE) cases Etiology Co-morbidities Medical treatment Clinical outcomes

53. KU Cohort Methods:  Medical records reviewed from Jan 2009-2013 ICD9 for status epilepticus, at discharge CPT code for video-EEG monitoring ICU room charge during hospital stay  Patients selected based on the following inclusion criteria: Age: 10- 110 years of age Diagnosis made utilizing routine or continuous video electroencephalogram Patients with hypoxic-ischemic brain injury were excluded

54. Data Demographics 56 charts reviewed 23 cases identified  M: 9  F: 14 Average age: 54 Presentation 30% (7):  GTC, tonic seizure(s) 48% (11):  confusion, lethargy, somnolent 22% (5):  obtunded, stuporus, comatose

55. Data 35% (8): Automatism, subtle motor mvts  Head turning  Subtle limb, facial, tongue movements  Eyelid flutter 22% (5): eye deviation

56. Data CPSE (74%)  LOS: 19.2 d  ICU: 11.1 d  VEEG: 6.1 d  # AEDs: 2.6  Anesthesia: 4.6 d ESE (13%)  LOS: 45.7 d  ICU: 20.7 d  VEEG: 8 d  # AEDs: 3  Anesthesia: 7.5 d

57. Data- CPSE (17)

58. Data- ESE (3) Etiology  Severe sepsis OLT, ESRD on HD  (2) CJD +14-3-3 Characteristic MRI (2)

59. Data CPSE  AEDs: 1 st : PHT (73%) Increase dose of AED Sedation VPA or Vimpat Anesthesia:  Propofol (9/13) 2pt + Versed  Ketamine, pentobarb  Versed (3/13)*  Pentobarb (1/13)* ESE  AEDs: 1 st : PHT (3) 2 nd : Keppra (3) Vimpat, PHB, topiramate (1) Anesthesia:  1 st : Propofol (2) Transition to  Pentobarb = Versed  1pt: no tx

60. EEG diagnosis not reported/unclear (3)  Pt#1: OLT on prograf L facial movements  Pt#2: Brain tumor 3 GTC szs prolonged postictal  Pt#3: Hx of epilepsy, liver failure Poor responsiveness, eye flutter Age56 LOS23.7 d ICU10 d VEEG6.5 d AEDs2 Sedation4.5 d

61. Data CSF:  46% abnormal (6/13) 5/13: ≤ 15 WBCs (lymph)  Meningoencephalitis (3)  Inflamm WMD  CJD +14-3-3 (1) Imaging  22/23* 5 CT 17 MRI

62. Data CPSE ESE Time to resolution:  Refractory (2)  Transition to PLEDs (1)*

63. Data CPSE  Outcome: Death - 41% LTACH/SNF - 18% Home – 29% Rehab – 12%  One death within 30d ESE  Outcome: Death or hospice – 100%

64. CPSE Outcomes Home (29%) : 51.2 y  Epilepsy (2)  Remote stroke (1)  Autoimmune enceph/SDH (1)  Tumor (1) Rehab (12%): 57.5 y  Post-stroke epilepsy  Autoimmune enceph LTACH/SNF (18%): 44 y  Epilepsy + illness or NC (3) Death (41%): 55.6 y  Peritumoral stroke  Remote stroke + sepsis  Inflam WM lesions*  CJD*  MS + sepsis  Meningoencephalitis (2)*

65. CPSE 5/17 (29%): Sepsis  Death or hospice- 4pts CJD MS Peritumoral stroke Inflammatory WM lesions  LTACH- 1pt Hx of epilepsy

66. Clinical outcome- CPSE Follow-up in 5/10  2 pt: no new cognitive deficits Epilepsy + NC <8 hr, <24h  3 pt: memory impairment, assistance w/ ADLs, cognitive decline Tumor, AIE, menignoencephalitis <96h, unknown (2)

67. Limitations Limited number of patients  Majority from 2012, only 3 from 2009, 1 from 2010 Inclusion of patients with CJD  100% mortality  Encephalopathy with epileptic features Documentation, access to archived studies Lack of clinical follow-up information No cases of NCSE in acute stroke

68. Conclusions Outcomes worse is ESE Worse if underlying dx is CJD Underlying epilepsy portends better outcome Longer duration of uncontrolled NCSE  adverse cognitive impact Pt’s treated with Versed as initial agent, worse outcomes (2/3) death Outcomes worse when pt diagnosed with sepsis

69. Thanks Nancy Hammond, MD Utku Uysal, MD Ivan Osorio, MD William Nowack, MD Rhonda Reliford

70. References Celesia CG. Modern concepts of status epilepticus. JAMA 1976: 235:1771-4. Tomson T, Svanbog, E, Wedlund J.E. Nonconvulsive status epilepticus: high incidence of complex partial status. Epilepsia. 1986;27:276-85. Drislane F. Presentation, Evaluation, and Treatment of Nonconvulsive Status Epilepticus. Epilepsy and Behavior. 2000;1:301-314. Towne AR. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology. 2000;54(2):340-4. Krumholz A. Epidemiology and evidence for morbidity of nonconvulsive status epilepticus. J Clin Neurophysiology. 1999;16(4):314-22. Meierkord H. The risk of epilepsy after status epilepticus in children and adults. Epilepsia. 2007; 48 suppl 8:94-5. Husain AM, Horn GJ, Jacobson MP. Non-convulsive status epilepticus: Usefulness of clinical features in selecting patients for urgent EEG. J. Neurol Neurosurg Psychiatry. 2003 Feb;74(2):189-91. Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: An investigation of variables associated with mortality. Neurology. 1996 Jul;47(1):83-9. Treiman DM, Walton NY, Kendrick C. A progressive sequence of electrographic changes during generalized convulsive status epilepticus. Epilepsy Res. 1990;5:49-60. Walker M. Nonconvulsive status epilepticus: Epilepsy research foundation workshop reports. Epileptic Disord. 2005 Sep;7(3):253-96. Walsh JM, Brenner RP. Periodic lateralized epileptiform discharges: long-term outcome in adults. Epilepsia 1987;28:533– 6.

71. References Snodgrass SM, Tsuburaya K, Ajmone-Marsan C. Clinical significance of periodic lateralized epileptiform discharges: Relationship with status epilepticus. J Clin Neurophysiol. 1989 Apr;6(2):159-72. Kaplan PW. EEG criteria for nonconvulsive status epilepticus. Epilepsia. 2007;48 Suppl 8:39-41. Chong DJ, Hirsch LJ. Which EEG patterns warrant treatment in the critically ill? Reviewing the evidence for treatment of periodic epileptiform discharges and related patterns. J Clin Neurophysiol. 2005 Apr;22(2):79-91. Kaplan PW. EEG monitoring in the intensive care unit. Am J Electroneurodiagnostic Technol. 2006 Jun;46(2):81-97. DeLorenzo RJ, et al. Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia. 1998 Aug;39(8):833-40. Shneker BF, Fountain NB. Assessment of acute morbidity and mortality in nonconvulsive status epilepticus. Neurology. 2003 Oct 28;61(8):1066-73. Granner MA, Lee SI. Nonconvulsive status epilepticus: EEG analysis in a large series. Epilepsia.1994 Jan-Feb;35(1):42-7. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia. 2002 Feb;43(2):146-53. Lothman EW, et al. Recurrent spontaneous hippocampal seizures in the rat as a chronic sequela to limbic status epilepticus. Epilepsy Res. 1990 Jul;6(2):110-8.

72. References Earnest MP, Thomas GE, Eden RA, Hossack KF. The sudden unexplained death syndrome in epilepsy: demographic, clinical, and postmortem features. Epilepsia. 1992 Mar-Apr;33(2):310-6. Krumholz A. Complex partial status epilepticus accompanied by serious morbidity and mortality. Neurology. 1995 Aug;45(8):1499-504. Drislane FW. Evidence against permanent neurologic damage from nonconvulsive status epilepticus. J Clin Neurophysiol. 1999 Jul;16(4):323-31 Cockerell OC, Walker MC, Sander JW, Shorvon SD. Complex partial status epilepticus: a recurrent problem. J Neurol Neurosurg Psychiatry.1994 Jul;57(7):835-7. Varelas PN, et al. Emergent EEG: indications and diagnostic yield. Neurology. 2003 Sep 9;61(5):702-4.

73. Thank you Questions? Comments?