Non-Convulsive Status Epilepticus (NCSE):Our Experience at a Tertiary Care Center

Brennen Bittel, DOClinical Neurophysiology Fellow

Overview Background

information: Epidemiology Clinical features Electrographic definition

EDX pitfalls Treatment Pathology Outcomes

KU Data 2009-2013

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 comaCelesia 1976, Tomson 1992, Drislane 2000, Towne 2000

Definition1. Diminished level of consciousness,

confusion

2. Epileptiform EEG (continuous or discrete)

3. Response to treatment??

1. Change in mental status- Semiology Ambulatory confused patients, mildly

confused hospitalized patients

Lethargic and comatose patients in intensive care units

Diminished Level of Consciousness, Confusion

Clinical presentations

NCSE

CPSE(complex partial SE)

ESE(electrographic SE)

SPSE(Simple partial SE)

ASE(absence SE)

Intermittent Continuous

20-40%

35-40%

Krumholz 1999, Meierkord 2007

NCSE

ASE(absence SE)

CPSE(complex partial SE)

ESE(electrographic SE) SPSE

(Simple partial SE)

Continuous Intermittent

• Confused• Bizarre behavior• Fluctuations• +/- automatisms• Aphasia

Stuporous Comatose GTC at onset Medical illness

Other sxs/signs Agitation Lethargy Mutism Disruptive behavior Staring Laughter Crying Rigidity Perseveration

Subtle motor movements

Hallucinations

DDx Metabolic/toxic encephalopathy Complicated migraine/aura Prolonged post-ictal state Psychiatric disorders Substance abuse/withdrawal/intoxication

DTs TIA Transient global amnesia

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

Epileptiform EEG

2. Epileptiform EEG Frequency Morphology Evolution Rhythmicity

Treiman criteria- GCSE

Five characteristic stages:1. Discrete seizures2. Merging seizures3. Continuous seizures4. Continuous seizures with brief "flat" periods on the

EEG -- (usually no convulsions)

5. Prolonged flat periods with periodic discharges -- (usually no convulsions)

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 Criteria1. Incrementing onset: voltage

or slowing2. Decrementing offset:

voltage or frequency3. Post-discharge slowing or

voltage attenuation4. Significant improvement in

clinical state or baseline EEG after AED***

Walker 20051. 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.

EEG Diagnosis

Inevitably subjective

Which tracing shows NCSE?

PLEDS

Triphasic waves

GPEDS

L Temp/parietal CPSE

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

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

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

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

PLEDs

PLEDs regression- 1 week later

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

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

CJD – EEG progression

Patients at risk1. Following seizures or GCSE

-- Up to 50% in NCSE after convulsions cease

2. AMS with subtle motor signs3. AMS in epileptic w/ acute medical illness4. Post-stroke pt faring worse or recovery

halted5. Elderly pt with AMS (post BZD withdrawal)DeLorenzo 1998, Drislane 2000

Risk factors Mental status changes

ICH SAH Large vessel CVA Meningoencephalitis CHI/TBI Tumor Post-surgical

Drislane 2000

3. Treatment Response Treatment response less often considered

diagnostic Clinical response may be delayed hours to days

Shneker 2003

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

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

Anesthesia No consensus on NCSE

More harm than good? Hypotension Sepsis/line infection DVT

Ultimate effect on brain? Outcomes…

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

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

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

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

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

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?

KU Data

KU Cohort Objective:

Review and describe non-convulsive status epilepticus (NCSE) cases Etiology Co-morbidities Medical treatment Clinical outcomes

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

DataDemographics 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

Data 35% (8): Automatism, subtle motor mvts

Head turning Subtle limb, facial, tongue movements Eyelid flutter

22% (5): eye deviation

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

Data- CPSE (17)

Data- ESE (3)

Etiology Severe sepsis

OLT, ESRD on HD (2) CJD

+14-3-3 Characteristic MRI (2)

DataCPSE

AEDs: 1st: 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:

1st: PHT (3) 2nd: Keppra (3) Vimpat, PHB, topiramate (1)

Anesthesia: 1st: Propofol (2)

Transition to Pentobarb = Versed

1pt: no tx

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

Age 56

LOS 23.7 d

ICU 10 d

VEEG 6.5 d

AEDs 2

Sedation 4.5 d

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

Data CPSE ESE

Time to resolution: Refractory (2) Transition to PLEDs (1)*

Data CPSE

Outcome: Death - 41% LTACH/SNF - 18% Home – 29% Rehab – 12%

One death within 30d

ESE Outcome:

Death or hospice – 100%

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)*

CPSE

5/17 (29%): Sepsis Death or hospice- 4pts

CJD MS Peritumoral stroke Inflammatory WM lesions

LTACH- 1pt Hx of epilepsy

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)

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

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

Thanks

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

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.

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.

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.

Thank you

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