STATUS STATUS EPILEPTICUSEPILEPTICUS

Richard L. Friederich, MD Richard L. Friederich, MD Pediatric NeurologyPediatric NeurologyRoseville Kaiser PermanenteRoseville Kaiser Permanente

DisclosureDisclosure

Under the IMQ/CMA Standards for Commercial Support, Under the IMQ/CMA Standards for Commercial Support, everyone who is in a position to control the content of an everyone who is in a position to control the content of an education activity must disclose all relevant financial education activity must disclose all relevant financial relationships with any commercial interest. A relationships with any commercial interest. A “commercial interest” includes any proprietary entity “commercial interest” includes any proprietary entity producing health care goods or services, with the producing health care goods or services, with the exemption of non-profit or government organizations and exemption of non-profit or government organizations and non-health care related companies. A financial non-health care related companies. A financial relationship is relevant if it pertains to the activity’s relationship is relevant if it pertains to the activity’s content matter including any related health care products content matter including any related health care products or services to be discussed or presented.or services to be discussed or presented.

Dr Rich Friederich, has disclosed that he has no relevant Dr Rich Friederich, has disclosed that he has no relevant relationships with commercial or industry organizations. relationships with commercial or industry organizations. The CME Department has reviewed the disclosure The CME Department has reviewed the disclosure information for the planners for this program and they do information for the planners for this program and they do not have relationships that present a relevant conflict of not have relationships that present a relevant conflict of interest.interest.

To better understand what status To better understand what status epilepticus isepilepticus is

To better appreciate importance of To better appreciate importance of early intervention in SEearly intervention in SE

To better appreciate importance of To better appreciate importance of a protocol for treating SEa protocol for treating SE

GoalsGoals

ED call:ED call: 4 y/o4 y/o

brought in after a 4 minute GTC sz at homebrought in after a 4 minute GTC sz at home

1st seizure ever1st seizure ever

still post-ictalstill post-ictal

ED doc asks for the loading dose of ED doc asks for the loading dose of DilantinDilantin

What do you tell them?What do you tell them?

STATUS EPILEPTICUS -- DEFINITIONSTATUS EPILEPTICUS -- DEFINITION

Formal: seizure or series of seizures producing a Formal: seizure or series of seizures producing a lasting epileptic conditionlasting epileptic condition

Informal: seizure activity lasting 30 minutesInformal: seizure activity lasting 30 minutes

nearly all self-limiting seizures cease w/in 5 nearly all self-limiting seizures cease w/in 5 minutesminutes

Impending status epilepticus: sz > 5 minutesImpending status epilepticus: sz > 5 minutes

application: any ongoing seizure activity >5 application: any ongoing seizure activity >5 minutesminutes

STATUS EPILEPTICUS -- STATUS EPILEPTICUS -- EPIDEMIOLOGYEPIDEMIOLOGY

~100,000 per year in ~100,000 per year in USAUSA

16% of patients with 16% of patients with epilepsyepilepsy

1/4 occur in pts < 1 1/4 occur in pts < 1 y/oy/oif sz onset <1 y/o, if sz onset <1 y/o,

70% will have SE 70% will have SE 135-156 per 100,000 135-156 per 100,000

per year in <1 y/oper year in <1 y/o

ApplicationsApplications

No absolute need to bolus a seizure No absolute need to bolus a seizure which has already ceasedwhich has already ceased

No long term prophylaxis for most 1No long term prophylaxis for most 1stst time seizurestime seizuresExceptions: Initial presentation status Exceptions: Initial presentation status

epilepticusepilepticus

focal seizurefocal seizure

strong (+) FHxstrong (+) FHx

ED callED call

21 month old 21 month old

presents with a temperature of 104presents with a temperature of 104

seizure which lasts 40 minutesseizure which lasts 40 minutes

stops with a single dose of Ativanstops with a single dose of Ativan

because the seizure is prolonged, the ED because the seizure is prolonged, the ED physician wants to do a CT. “After all, status physician wants to do a CT. “After all, status is unusual with febrile seizures” (?)is unusual with febrile seizures” (?)

What are the most common causes of S.E. in What are the most common causes of S.E. in children?children?

STATUS EPILEPTICUS – STATUS EPILEPTICUS – MOST COMMON CAUSESMOST COMMON CAUSES

ChildrenChildrenfever fever 36%36%

med change 20%idiopathicidiopathic 9%9%

metabolicmetabolic 8%8%

CNS infectionCNS infection 5%5%

HIEHIE 5%5%

traumatrauma 3%3%

CVACVA 3%3%

EtOH/drugEtOH/drug 2%2%

tumortumor 1%1%

AdultsAdultsCVACVA 25%25%med change 19%EtOH/drugEtOH/drug 12%12%AnoxiaAnoxia 11%11%MetabolicMetabolic 9%9%IdiopathicIdiopathic 8%8%FeverFever 5%5%TraumaTrauma 5%5%TumorTumor 4%4%CNS infectionCNS infection 2%2%

DeLorenzoDeLorenzo 19921992

11stst sz - neuroimaging sz - neuroimaging

Neuroimaging suggested for first time Neuroimaging suggested for first time seizureseizureRecommended if SE, focal, or abnl Recommended if SE, focal, or abnl

neuro examneuro examMRI better than CTMRI better than CT

You are called to the ED, to await an You are called to the ED, to await an ambulance responding to a call with a 6 ambulance responding to a call with a 6 y/o boy with spastic quad CP and his y/o boy with spastic quad CP and his first-ever seizure, which started 25 first-ever seizure, which started 25 minutes ago. minutes ago.

What is the best treatment to stop the What is the best treatment to stop the seizures?seizures?

In-home treatmentIn-home treatment

Diazepam given in the Diazepam given in the homehome PR gel form (Diastat)PR gel form (Diastat) IV valium given PR or IV valium given PR or

IV IV no difference between no difference between

PR or IV valiumPR or IV valium

Fosphenytoin given in Fosphenytoin given in the homethe home

By extrapolation, other By extrapolation, other PR meds may be as wellPR meds may be as well

duration SE, duration SE, duration duration hosp, hosp, incidence of incidence of intubation, intubation, incidence of incidence of sz recurrence in ED sz recurrence in ED

Alldredge, Ped Neuro ‘95Alldredge, Ped Neuro ‘95

0

10

20

30

40

50

60

70

80

<30 <60 <90 <120 >120

Seizure Duration (min)

Lowenstein,Lowenstein, 19931993

Responsiveness to AEDResponsiveness to AED

6 y/o boy with spastic quad CP and his 6 y/o boy with spastic quad CP and his first-ever seizurefirst-ever seizure

started 25 minutes agostarted 25 minutes ago

No meds are given at homeNo meds are given at home

You run over your mental check list of You run over your mental check list of the order in which you will approach the order in which you will approach

things. What are the first three things?things. What are the first three things?

A = AirwayA = Airway

B = BreathingB = Breathing

C = CirculationC = Circulation

The patient arrives, still seizingThe patient arrives, still seizing

ABC’s are OKABC’s are OK

Realizing that in a real scenario you will Realizing that in a real scenario you will simultaneously approach both the simultaneously approach both the diagnostic and therapeutic aspects: diagnostic and therapeutic aspects:

What are the drugs you will try?What are the drugs you will try?What are their doses?What are their doses?What is the sequence?What is the sequence?

STATUS EPILEPTICUS -- TREATMENTSTATUS EPILEPTICUS -- TREATMENT

• ABC’sABC’s

• Quick evaluationQuick evaluation

• Confirm diagnosisConfirm diagnosis

• OO22, glucose (+/- , glucose (+/- 100mg thiamine), 100mg thiamine), [vitamin B6][vitamin B6]

• treat underlying treat underlying etiologyetiology• Labs: levels, Na, Labs: levels, Na,

glucose, Caglucose, Ca

• AnticonvulsantsAnticonvulsants• BenzodiazepinesBenzodiazepines• Diazepam 0.3 Diazepam 0.3

mg/kg (max mg/kg (max 10mg)10mg)

• Lorazepam 0.1 Lorazepam 0.1 mg/kg (max 4mg)mg/kg (max 4mg)

• 20 mg/kg rule 20 mg/kg rule • phenobarbphenobarb• fosphenytoinfosphenytoin• valproatevalproate• levetiracetamlevetiracetam

STATUS EPILEPTICUS -- STATUS EPILEPTICUS -- ANTICONVULSANTSANTICONVULSANTS

Administer Administer over over

PeakPeak Half-lifeHalf-life

LorazepamLorazepam 1-2 min1-2 min 2-5 min2-5 min 6-16h 6-16h

DiazepamDiazepam 1-2 min 1-2 min 2-5 min 2-5 min 30 min30 min

PhenobarbPhenobarb 5-10 min5-10 min 5-30 min5-30 min 72 hour72 hour

FosphenytoinFosphenytoin 10 min10 min 5-30 min5-30 min 20 hour20 hour

LevetiracetamLevetiracetam 15-30 min15-30 min 30-60 min30-60 min 20 hour20 hour

ValproateValproate 5-10 min5-10 min 20 min20 min 8 hour8 hour

STATUS EPILEPTICUS – STATUS EPILEPTICUS – ANTICONVULSANT PROS/CONSANTICONVULSANT PROS/CONS

•DiazepamDiazepam•Rapid efficacyRapid efficacy•Short effective half Short effective half life (high fat life (high fat solubility)solubility)•Always requires 2Always requires 2ndnd drugdrug

•LorazepamLorazepam•Rapid efficacyRapid efficacy•Longer half life Longer half life efficacyefficacy

•Benzodiazepines lose Benzodiazepines lose efficacy as SE efficacy as SE progressesprogresses

• Phenytoin adverse effectsPhenytoin adverse effects• Arrhythmias, Arrhythmias,

hypotensionhypotension• Ppt out in glucose sol’nPpt out in glucose sol’n• Local phlebitisLocal phlebitis• Cannot give IMCannot give IM

• phenytoin may worsen phenytoin may worsen myoclonic szsmyoclonic szs

• Fosphenytoin very Fosphenytoin very expensiveexpensive

• levetiracetam may have levetiracetam may have neuroprotective effectneuroprotective effect

STATUS EPILEPTICUS STATUS EPILEPTICUS NEUROPHYSIOLOGYNEUROPHYSIOLOGY

failure of cellular mechanisms to prevent sustained failure of cellular mechanisms to prevent sustained seizure activityseizure activitypersistent excitation of NMDA receptorspersistent excitation of NMDA receptorsineffective inhibition at GABA receptorsineffective inhibition at GABA receptors

2 phases2 phasesActivationActivationMaintenanceMaintenance

Becomes self-sustaining after 15-30 minutesBecomes self-sustaining after 15-30 minutesGABA receptor isoforms change and become GABA receptor isoforms change and become

ineffectiveineffectivePhenobarb, benzodiazepines work on GABAPhenobarb, benzodiazepines work on GABA

STATUS EPILEPTICUS – STATUS EPILEPTICUS – ANTICONVULSANT SEQUENCE ANTICONVULSANT SEQUENCE

RATIONALERATIONALE

VA SE Cooperative VA SE Cooperative Study GroupStudy Group

NEJM NEJM 17Sep98;339(12):792-817Sep98;339(12):792-8Efficacy GTC SE 384 ptsEfficacy GTC SE 384 pts

lorazepam 64.9 %lorazepam 64.9 %phenobarbital 58.2 %phenobarbital 58.2 %diazepam then diazepam then phenytoin 55.8 %phenytoin 55.8 %phenytoin 43.6%phenytoin 43.6%

Key pointsKey points Administer meds early Administer meds early

and quicklyand quickly Protocol more effective, Protocol more effective,

regardless of sequence regardless of sequence (meds given quicker)(meds given quicker)

Benzos and phenobarb Benzos and phenobarb effective earlyeffective early

PHT, VPA, LVT effective PHT, VPA, LVT effective laterlater

Midazolam for failureMidazolam for failure

Suggested protocolSuggested protocol

Lorazepam 0.1 mg/kg IV or PRLorazepam 0.1 mg/kg IV or PR

Repeat lorazepam 0.1 mg/kg in 5 minutes Repeat lorazepam 0.1 mg/kg in 5 minutes (draw up after 3 minutes)(draw up after 3 minutes)

Phenytoin/fosphenytoin 20 mg/kg in 5 Phenytoin/fosphenytoin 20 mg/kg in 5 minutesminutes

Phenobarb 20 mg/kg in 5 minutesPhenobarb 20 mg/kg in 5 minutes

Phenytoin/fosphenytoin 10mg/kg in 5 minutesPhenytoin/fosphenytoin 10mg/kg in 5 minutes

While you are working through your While you are working through your anticonvulsant treatment, what anticonvulsant treatment, what diagnostic work-up are you diagnostic work-up are you considering?considering?

STATUS EPILEPTICUS -- STATUS EPILEPTICUS -- EVALUATIONEVALUATION

H&PH&P

Blood: ‘lytes, glucose, Ca, BUN, CBC, Blood: ‘lytes, glucose, Ca, BUN, CBC, ABG, LFT, AED level, tox chromatographyABG, LFT, AED level, tox chromatography

Urine: toxicology screenUrine: toxicology screen

Febrile: culture blood, urine, CSF; plus Febrile: culture blood, urine, CSF; plus CXRCXR

CT or MRI if no etiology or have suspicionCT or MRI if no etiology or have suspicion

If he fails to respond to initial meds, If he fails to respond to initial meds, what else should you think about?what else should you think about?

Considerations for SE AED Considerations for SE AED failurefailure

Phenytoin level >35Phenytoin level >35

CBZ or PHT for primary generalized szCBZ or PHT for primary generalized sz

Symptomatic (glu or Na abnl, drug or Symptomatic (glu or Na abnl, drug or med, etc)med, etc)

<18 m/o: B6 dependency<18 m/o: B6 dependency

<6 m/o: Folinic acid responsive <6 m/o: Folinic acid responsive epilepsyepilepsy

Refractory STATUS Refractory STATUS EPILEPTICUSEPILEPTICUS

• Definition: Definition: • > 60 minutes, or > 60 minutes, or

failed failed ≥2 ≥2 anticonvulsantsanticonvulsants

• Rx options: to produce Rx options: to produce burst suppression EEGburst suppression EEG• MidazolamMidazolam• 0.2 mg/kg bolus0.2 mg/kg bolus• then 1-10 then 1-10

g/kg/ming/kg/min• PentobarbPentobarb• 15 mg/kg bolus15 mg/kg bolus• then 1-5 mg/kg/hrthen 1-5 mg/kg/hr

• propofol propofol contraindicated in contraindicated in childrenchildren

• can cause fatal can cause fatal myocardial failure, myocardial failure, metabolic acidosis, metabolic acidosis, hypoxia, rhabdohypoxia, rhabdo

His seizure resolves after His seizure resolves after 33 doses of doses of Ativan, and Ativan, and 2 2 doses of Fosphenytoin. doses of Fosphenytoin. After two hours he is still “post-ictal”. After two hours he is still “post-ictal”. What should you think about?What should you think about?

STATUS EPILEPTICUS -- TYPESSTATUS EPILEPTICUS -- TYPES

GeneralizedGeneralizednon-convulsivenon-convulsiveconvulsiveconvulsive

PartialPartial

PsychogenicPsychogenic

NON-CONVULSIVE GENERALIZED NON-CONVULSIVE GENERALIZED STATUSSTATUS

““Spike-wave stupor”Spike-wave stupor”

mental dullness, confusion, clumsinessmental dullness, confusion, clumsiness

slow or monosyllabic speechslow or monosyllabic speech

EEG diagnosisEEG diagnosis

diazepam universally effectivediazepam universally effective

PSYCHOGENIC STATUSPSYCHOGENIC STATUS

25-50% also have epileptic seizures25-50% also have epileptic seizures

differentiating from statusdifferentiating from statusnon-noxious stimulinon-noxious stimulinoxious stimulinoxious stimulipresentationpresentationEEGEEG

Why is there a sense of urgency Why is there a sense of urgency when treating status epilepticus?when treating status epilepticus?

STATUS EPILEPTICUS -- SEQUELAESTATUS EPILEPTICUS -- SEQUELAE

3 factors3 factors1) damage by acute insult1) damage by acute insult2) systemic stress from motor 2) systemic stress from motor

convulsionsconvulsions- exhaustion of metabolic supply- exhaustion of metabolic supply

3) injury from repetitive electrical 3) injury from repetitive electrical discharges in CNS and glutamate discharges in CNS and glutamate releaserelease

STATUS EPILEPTICUS -- SYSTEMIC STATUS EPILEPTICUS -- SYSTEMIC STRESSSTRESS

• Cardiovascular--rate, Cardiovascular--rate, rhythm, BPrhythm, BP

• Respiratory--Respiratory--insufficiency, pulmonary insufficiency, pulmonary edemaedema

• BiochemicalBiochemical• acidosis, BUN, acidosis, BUN,

potassiumpotassium• glucose, sodium, glucose, sodium,

hypoxemiahypoxemia

• Autonomic -- fever, Autonomic -- fever, secretionssecretions

• Renal -- Renal -- rhabdomyolosis, ARFrhabdomyolosis, ARF

ShorvonShorvon 20012001

STATUS EPILEPTICUS -- MORBIDITY STATUS EPILEPTICUS -- MORBIDITY & & MORTALITYMORTALITY

3-15% mortality3-15% mortality

5-40% residual neurologic deficit5-40% residual neurologic deficit

most closely related to etiology of most closely related to etiology of statusstatus

Maytal study (children):Maytal study (children):Idiopathic, noncompliance, & Idiopathic, noncompliance, &

febrile status had NO M&Mfebrile status had NO M&M