Clinical Decisions in Seizure Management Clinical Decisions in Seizure Management

Andy Jagoda, MD, FACEPAndy Jagoda, MD, FACEPProfessor of Emergency MedicineProfessor of Emergency MedicineMount Sinai School of MedicineMount Sinai School of Medicine

New York, New YorkNew York, New York

ObjectivesObjectives

• Introduce the process of how clinical policies / practice Introduce the process of how clinical policies / practice guidelines are developedguidelines are developed

• Provide an overview of seizures from the prospective of Provide an overview of seizures from the prospective of emergency medicine practiceemergency medicine practice

• Present the recommendations from the upcoming ACEP Present the recommendations from the upcoming ACEP clinical policy on seizure managementclinical policy on seizure management

Seizure Clinical PolicySeizure Clinical Policy

• Frequently seen in the EDFrequently seen in the ED

• Symptom of potentially life threatening diseaseSymptom of potentially life threatening disease

• Associated with potential morbidity and mortalityAssociated with potential morbidity and mortality

• ACEP Seizure Clinical PolicyACEP Seizure Clinical Policy

• 1993 - Approach based1993 - Approach based

• 1997 - Revision1997 - Revision

• 2003 – Critical questions; evidence based2003 – Critical questions; evidence based

Seizure Epidemiology in Emergency MedicineSeizure Epidemiology in Emergency Medicine

• 1% of adult ED visits1% of adult ED visits• 2% of pediatric ED visits2% of pediatric ED visits• Most common ED etiologies are not epilepsy related:Most common ED etiologies are not epilepsy related:

• AlcoholismAlcoholism• StrokeStroke• TraumaTrauma• CNS infectionCNS infection• Metabolic / ToxinMetabolic / Toxin• TumorTumor• Fever in childrenFever in children

• 50,000 – 100,000 ED cases of status epilepticus annually50,000 – 100,000 ED cases of status epilepticus annually• 20% mortality20% mortality

Population based study of the epidemiology of status Population based study of the epidemiology of status epilepticusepilepticus

• Most epidemiology studies focus on patients Most epidemiology studies focus on patients with epilepsy and not on the epidemiology of with epilepsy and not on the epidemiology of seizures seizures per seper se

• Fewer than half the cases of status identified Fewer than half the cases of status identified were managed by a neurologistwere managed by a neurologist

• Over 50% of status cases occurred in patients Over 50% of status cases occurred in patients with no prior history of epilepsywith no prior history of epilepsy

Delorenzo et al. Neurology 1996; 46:1029-1035

Seizure Practice GuidelinesSeizure Practice Guidelines

• Treatment of convulsive status epilepticus. Epilepsy Foundation of Treatment of convulsive status epilepticus. Epilepsy Foundation of America. JAMA 1993; 270:854-859.America. JAMA 1993; 270:854-859.

• The neurodiagnostic evaluation of the child with first simple febrile The neurodiagnostic evaluation of the child with first simple febrile seizure. AAP. Pediatrics 1996; 97:769-775.seizure. AAP. Pediatrics 1996; 97:769-775.

• The role of phenytoin in the management of alcohol withdrawal The role of phenytoin in the management of alcohol withdrawal syndrome. Am Soc Addiction Med 1994 / 1998syndrome. Am Soc Addiction Med 1994 / 1998

• Evaluating the first nonfebrile seizure in chilren. AAN. Neurology Evaluating the first nonfebrile seizure in chilren. AAN. Neurology 2000; 55:616-623.2000; 55:616-623.

• Role of antiseizure prophylaxis following head injury. BTF / AANS. J Role of antiseizure prophylaxis following head injury. BTF / AANS. J Neurotrauma 2000; 17:549-553.Neurotrauma 2000; 17:549-553.

• Treatment of the child with a first unprovoked seizure. AAN. Treatment of the child with a first unprovoked seizure. AAN. Neurology 2003; 60:166-175Neurology 2003; 60:166-175

• Antiepileptic drug prophylaxis in severe traumatic brain injury. Antiepileptic drug prophylaxis in severe traumatic brain injury. Neurology 2003; 60:10-16Neurology 2003; 60:10-16

ACEP Clinical PolicyACEP Clinical Policy

• Identify questions of clinical importance to Identify questions of clinical importance to emergency department management of patients emergency department management of patients with seizureswith seizures

• Analyze the quality of data available related to Analyze the quality of data available related to acute management of patients with seizuresacute management of patients with seizures

• Differentiate anectodal experience from practice Differentiate anectodal experience from practice supported by evidence supported by evidence

ACEP Clinical PolicyACEP Clinical Policy

1.1. What lab tests are indicated in the otherwise healthy adult patient with a What lab tests are indicated in the otherwise healthy adult patient with a new onset seizure who has returned to a baseline normal neuro status? new onset seizure who has returned to a baseline normal neuro status?

2.2. Which new onset seizure patients who have returned to a normal Which new onset seizure patients who have returned to a normal baseline require neuroimaging in the ED? baseline require neuroimaging in the ED?

3.3. Which new onset seizure patients who have returned to normal baseline Which new onset seizure patients who have returned to normal baseline need to be admitted to the hospital and / or started on an AED? need to be admitted to the hospital and / or started on an AED?

4.4. What are effective phenytoin dosing strategies for preventing sz What are effective phenytoin dosing strategies for preventing sz recurrence in patients who present to the ED with a subtherapeutic recurrence in patients who present to the ED with a subtherapeutic serum phenytoin level? serum phenytoin level?

5.5. What agent(s) should be administered to a patient in status who What agent(s) should be administered to a patient in status who continues to seize despite a loading dose of a benzodiazepine and a continues to seize despite a loading dose of a benzodiazepine and a phenytoin? phenytoin?

6.6. When should an EEG be performed in the ED?When should an EEG be performed in the ED?

A 20 year old female with no known medical problems A 20 year old female with no known medical problems has a generalized tonic clonic seizure that lasts 2 minutes. has a generalized tonic clonic seizure that lasts 2 minutes. After a short postictal period, she returns to her baseline, After a short postictal period, she returns to her baseline, feels well, has a normal physical and neurologic exam. feels well, has a normal physical and neurologic exam. Which of the following laboratory tests is not indicated in Which of the following laboratory tests is not indicated in the ED?the ED?

• Pregnancy testPregnancy test• ElectrolytesElectrolytes• GlucoseGlucose• CSF analysisCSF analysis• CT CT

The patient is worked-up as an outpatient and diagnosed The patient is worked-up as an outpatient and diagnosed with a seizure disorder. She is treated with phenytoin, with a seizure disorder. She is treated with phenytoin, 300 mg qhs. She is brought to the ED by EMS status post 300 mg qhs. She is brought to the ED by EMS status post a “typical” event but back to baseline. Her serum a “typical” event but back to baseline. Her serum phenytoin level is <1 ug/ml. Which of the following is phenytoin level is <1 ug/ml. Which of the following is the best management plan? the best management plan?

• Fosphenytoin, 20 PE/kg, IM in the deltoidFosphenytoin, 20 PE/kg, IM in the deltoid• Fosphenytoin, 20 PE/kg, IV at 300 mg/minFosphenytoin, 20 PE/kg, IV at 300 mg/min• Phenytoin, 20 mg/kg IV at 150 mg/minPhenytoin, 20 mg/kg IV at 150 mg/min• Phenytoin, 20 mg/kg po and discharge after 4 hrsPhenytoin, 20 mg/kg po and discharge after 4 hrs• Lorazepam, 2 mg, IV and discharge after one hourLorazepam, 2 mg, IV and discharge after one hour

While in the ED, she goes into status epilepticus. While in the ED, she goes into status epilepticus. The seizures do not stop despite lorazepam, 10 The seizures do not stop despite lorazepam, 10 mg, and phenytoin 20 mg/kg. Which of the mg, and phenytoin 20 mg/kg. Which of the following is following is notnot a reasonable third line therapy? a reasonable third line therapy?

• A second half load of phenytoin (10 mg /kg)A second half load of phenytoin (10 mg /kg)

• Phenobarbital, 20 mg / kgPhenobarbital, 20 mg / kg

• Pentobarbital, 3 mg / kgPentobarbital, 3 mg / kg

• Propofol, 1 mg / kgPropofol, 1 mg / kg

• Vecuronium, .1 mg /kgVecuronium, .1 mg /kg

What laboratory tests are indicated in the ED What laboratory tests are indicated in the ED evaluation of a patient with a new onset sz?evaluation of a patient with a new onset sz?

• Studies limited by heterogenous populations• No Class I studies

• Prospective studies limited by design flaws• CPK and prolactin levels are of limited value in

the ED

Turnbull. Utility of laboratory studies in the ED in patients with a new onset sz. Turnbull. Utility of laboratory studies in the ED in patients with a new onset sz. Ann Emerg Med 1990; 19:373-377. Prospective. 136 patients)Ann Emerg Med 1990; 19:373-377. Prospective. 136 patients)

Nypaver. ED laboratory evaluation of hcildren with seizures: Dogma or Nypaver. ED laboratory evaluation of hcildren with seizures: Dogma or dilemma? Ped Emerg Care 1992; 8:13-21. Retrospective 308 patients) dilemma? Ped Emerg Care 1992; 8:13-21. Retrospective 308 patients)

Lumbar PunctureLumbar Puncture

• A LP in the ED is not indicated if the patient:A LP in the ED is not indicated if the patient:• Is not immunocompromisedIs not immunocompromised• Has returned to baseline Has returned to baseline • Has no fever or meningeal signsHas no fever or meningeal signs

• There are no cases reported of meningitis presenting as There are no cases reported of meningitis presenting as a simple tonic clonic seizurea simple tonic clonic seizure

• Postictal pleocytosis (>5 polys in the CSF) has been Postictal pleocytosis (>5 polys in the CSF) has been reported in 2 - 18% of patients who have had a GTCS reported in 2 - 18% of patients who have had a GTCS

Pesola G,. New onset generalized seizures in patients with AIDS.Pesola G,. New onset generalized seizures in patients with AIDS.Acad Emerg Med. 1998; 5:905-911. Retrospective review, 26 patientsAcad Emerg Med. 1998; 5:905-911. Retrospective review, 26 patients

Green S,. Can seizures be the sole manifestation of meningitis in febrile children? Green S,. Can seizures be the sole manifestation of meningitis in febrile children? Pediatrics 1993; 92:527-534. Retrospective. 503 casesPediatrics 1993; 92:527-534. Retrospective. 503 cases

What lab tests are indicated in the otherwise healthy adult What lab tests are indicated in the otherwise healthy adult patient with a new onset seizure who has returned to a patient with a new onset seizure who has returned to a

baseline normal neuro status?baseline normal neuro status?(outcome measure is abnormal test that changes (outcome measure is abnormal test that changes

management)management)

• Level A recommendations: NoneLevel A recommendations: None

• Level B recommendations:Level B recommendations:

• Determine a serum glucose and sodium on patients Determine a serum glucose and sodium on patients with a first time seizure with no co-morbidities who with a first time seizure with no co-morbidities who have returned to their baselinehave returned to their baseline

• Obtain a pregnancy test in women of child bearing ageObtain a pregnancy test in women of child bearing age

• Perform a LP after a head CT either in the ED or after Perform a LP after a head CT either in the ED or after admission on patients who are immunocompromisedadmission on patients who are immunocompromised

Neuroimaging: Head CT and MRNeuroimaging: Head CT and MR

• Three per cent to 41% of patients with a first Three per cent to 41% of patients with a first time seizure have an abnormal head CTtime seizure have an abnormal head CT

• Imaging is dependent on the urgency of the Imaging is dependent on the urgency of the evaluation and patient stabilityevaluation and patient stability

• Literature interpretation depends on outcome Literature interpretation depends on outcome measure usedmeasure used

Tardy. AJEM. 1995; 13:1-5. Retrospective review. 247 patients. Tardy. AJEM. 1995; 13:1-5. Retrospective review. 247 patients.

Henneman AEM 1994; 24:1108-1114. Retrospective. 294 patients). Henneman AEM 1994; 24:1108-1114. Retrospective. 294 patients).

Neuroimaging in New Onset SeizuresNeuroimaging in New Onset Seizures

• ACEP, AAN, AANS, ASNR. Practice Parameter: ED ACEP, AAN, AANS, ASNR. Practice Parameter: ED neuroimaging in the seizure pt. Ann Emerg Med 1996; neuroimaging in the seizure pt. Ann Emerg Med 1996; 27:114-118. Evidence based practice guideline27:114-118. Evidence based practice guideline• Emergent CT for patients with altered mental status, Emergent CT for patients with altered mental status,

trauma, focal exam, immunocompromise, fever, co-trauma, focal exam, immunocompromise, fever, co-morbitiditymorbitidity

• Patients who are alert with a nonfocal exam can have Patients who are alert with a nonfocal exam can have an outpatient studyan outpatient study

• Focal abnormalities on CT are reported in up to 40% of Focal abnormalities on CT are reported in up to 40% of patients with new onset seizures; up to 20% have non-patients with new onset seizures; up to 20% have non-focal examsfocal exams

• MRI is better than CT in detecting subtle lesions (e.g., MRI is better than CT in detecting subtle lesions (e.g., hippocampal sclerosis) but impact on care is controversialhippocampal sclerosis) but impact on care is controversial

Which new onset seizure patients who have returned to a Which new onset seizure patients who have returned to a normal baselinenormal baseline require neuroimaging in the ED? require neuroimaging in the ED?

(outcome measure: abnormal CT)(outcome measure: abnormal CT)

• Level A recommendations: NoneLevel A recommendations: None

• Level B recommendations:Level B recommendations:

• When feasible, perform a head CT of the brain in the When feasible, perform a head CT of the brain in the ED on patients with a first time seizureED on patients with a first time seizure

• Deferred outpatient neuroimaging may be utilized Deferred outpatient neuroimaging may be utilized when reliable follow-up is availablewhen reliable follow-up is available

Treatment of First Time Seizures Treatment of First Time Seizures

• Coordinated care with neurologist / primary care providerCoordinated care with neurologist / primary care provider• Decision to initiate AED treatment depends on the risk of Decision to initiate AED treatment depends on the risk of

recurrence, ie, etiologyrecurrence, ie, etiology• Etiology, CT and EEG findings are the strongest predictorsEtiology, CT and EEG findings are the strongest predictors• Recurrence risk is up to 20% within the first 24 hoursRecurrence risk is up to 20% within the first 24 hours

• 23% to 71% within 2 years23% to 71% within 2 years• Patients needing immediate AED treatment can be loaded with Patients needing immediate AED treatment can be loaded with

oral or IV phenytoin; IM forphenytoin; IV valproic acid oral or IV phenytoin; IM forphenytoin; IV valproic acid • Decision to admit depends on assessed risk of recurrence, Decision to admit depends on assessed risk of recurrence,

patient compliance, and patients social circumstancespatient compliance, and patients social circumstances

Which new onset seizure patients who have returned to Which new onset seizure patients who have returned to normal baseline need to be admitted to the hospital and / normal baseline need to be admitted to the hospital and /

or started on an AED? or started on an AED? (outcome measure: short term morbidity or mortality)(outcome measure: short term morbidity or mortality)

• Level A recommendations: NoneLevel A recommendations: None

• Level B recommendations: NoneLevel B recommendations: None

• Level C recommenations:Level C recommenations:

• Patients with a normal neurologic examination can be Patients with a normal neurologic examination can be discharged from the ED with outpatient follow-updischarged from the ED with outpatient follow-up

• Patients with a normal neurologic examination and no Patients with a normal neurologic examination and no co-morbidities and no know structural brain disease do co-morbidities and no know structural brain disease do not need to be started on an anti-epileptic drug in the not need to be started on an anti-epileptic drug in the EDED

AED LoadingAED Loading

• In patients who have seized and returned to baseline, no In patients who have seized and returned to baseline, no AED loading strategy has been shown to be superior in AED loading strategy has been shown to be superior in preventing seizure recurrencepreventing seizure recurrence

• No outcome studies exist comparing loading strategiesNo outcome studies exist comparing loading strategies

• IV phenytoin achieves therapeutic serum levels by the end IV phenytoin achieves therapeutic serum levels by the end of the infusionof the infusion

• IM fosphenytoin achieves therapeutic serum levels within IM fosphenytoin achieves therapeutic serum levels within one hour post injection one hour post injection

• PO phenytoin, 19 mg/kg in males and 25 mg/kg in females PO phenytoin, 19 mg/kg in males and 25 mg/kg in females single dose achieves therapeutic serum levels in 4 hourssingle dose achieves therapeutic serum levels in 4 hours

Ratanakorn. J Neuro Sci 1997; 147:89-92Van der Meyden. Epilepsia 1994; 35:189-194

What are effective phenytoin dosing strategies for preventing What are effective phenytoin dosing strategies for preventing sz recurrence in patients who present to the ED with a sz recurrence in patients who present to the ED with a

subtherapeutic serum phenytoin level? subtherapeutic serum phenytoin level? (outcome measure: short term seizure recurrence)(outcome measure: short term seizure recurrence)

• Level A recommendations. None specified.Level A recommendations. None specified.• Level B recommendations. None specified.Level B recommendations. None specified.• Level C recommendations:Level C recommendations:

• Administer an intravenous or oral loading Administer an intravenous or oral loading dose of phenytoin or intravenous or dose of phenytoin or intravenous or intramuscular fosphenytoin, and restart daily intramuscular fosphenytoin, and restart daily oral maintenance dosing. oral maintenance dosing.

While in the ED, she goes into status epilepticus. While in the ED, she goes into status epilepticus. The seizures do not stop despite lorazepam, 10 The seizures do not stop despite lorazepam, 10 mg, and phenytoin 20 mg/kg. Which of the mg, and phenytoin 20 mg/kg. Which of the following is following is notnot a reasonable third line therapy? a reasonable third line therapy?

• Midazolam, .2 mg/kg; .1 mg/kg/hrMidazolam, .2 mg/kg; .1 mg/kg/hr

• Phenobarbital, 20 mg / kgPhenobarbital, 20 mg / kg

• Pentobarbital, 5-15 mg / kg; 2 mg/kg/hr Pentobarbital, 5-15 mg / kg; 2 mg/kg/hr

• Propofol, 1 mg / kg; 4 mg/kg/hrPropofol, 1 mg / kg; 4 mg/kg/hr

• Vecuronium, .1 mg /kgVecuronium, .1 mg /kg

STATUS EPILEPTICUSSTATUS EPILEPTICUS

• 126,000 - 195,000 cases in the US / year126,000 - 195,000 cases in the US / year

• 25% of cases are NCSE or SGCSE25% of cases are NCSE or SGCSE

• 22% mortality in convulsive status 22% mortality in convulsive status

• 26% in adults, 3% in children26% in adults, 3% in children

• Undetermined in NCSE or SGCSEUndetermined in NCSE or SGCSE

• M & M associated with:M & M associated with:

• Underlying etiologyUnderlying etiology

• Co-morbidityCo-morbidity

• Duration of eventDuration of event

NONCONVULSIVE STATUS EPILEPTICUSNONCONVULSIVE STATUS EPILEPTICUS

• NCSE vs SCSENCSE vs SCSE• Prognosis worse with SCSEPrognosis worse with SCSE

• Clinical characteristicsClinical characteristics• mild cognitive deficits to comamild cognitive deficits to coma**

• Incidence: 14% after CSEIncidence: 14% after CSE****• Diagnosis: Clinical and EEGDiagnosis: Clinical and EEG• TreatmentTreatment

* * Tomson. Epilepsia 1992;33:829-835Tomson. Epilepsia 1992;33:829-835** DeLorenzo. Epilepsia 1998; 39:833-840** DeLorenzo. Epilepsia 1998; 39:833-840

STATUS EPILEPTICUS: SE Working GroupSTATUS EPILEPTICUS: SE Working Group(Consensus Document)(Consensus Document)

• Management must simultaneously address:Management must simultaneously address:• Stabilization: ABCsStabilization: ABCs• Diagnostic testing including (including rapid glucose)Diagnostic testing including (including rapid glucose)• Pharmacologic interventionsPharmacologic interventions

• Drug therapyDrug therapy• Lorazepam .1 mg/kg at 2 mg/min Lorazepam .1 mg/kg at 2 mg/min

• If diazepam is used, phenytoin must be started If diazepam is used, phenytoin must be started simulatneouslysimulatneously

• Phenytoin 20 mg/kg at 25-50 mg/min (fosphenytoin 20 mg/kg Phenytoin 20 mg/kg at 25-50 mg/min (fosphenytoin 20 mg/kg at 150 mg/min)at 150 mg/min)

• Repeat phenytoin 5 mg/kg Repeat phenytoin 5 mg/kg • Phenobarbital 20 mg/kg at 100 mg/min Phenobarbital 20 mg/kg at 100 mg/min • Valproic acid 20 mg/kg Valproic acid 20 mg/kg

Epilepsy Foundation of America. JAMA 1993;270:854-859

VA COOPERATIVE STUDYVA COOPERATIVE STUDY

• Prospective study: 384 patients in CSEProspective study: 384 patients in CSE

• Four treatment regimensFour treatment regimens

• Phenytoin 18 mg/kgPhenytoin 18 mg/kg

• Diazepam plus phenytoinDiazepam plus phenytoin

• Phenobarbital 15 mg/kgPhenobarbital 15 mg/kg

• Lorazepam .1 mg/kgLorazepam .1 mg/kg

• No difference among the four groups in recurrance of No difference among the four groups in recurrance of seizures or mortality at 12 hours or 30 daysseizures or mortality at 12 hours or 30 days

• Trend in favor of lorazepam; easiest to useTrend in favor of lorazepam; easiest to use

NEJM 1998;339:792-798NEJM 1998;339:792-798

Refractory Status EpilepticusRefractory Status Epilepticus

• Systematic review of the literatureSystematic review of the literature• 28 studies; 193 patients28 studies; 193 patients• 48% mortality48% mortality

• Compared propofol, midazolam, and pentobarbitalCompared propofol, midazolam, and pentobarbital• Outcome: EEG burst suppressionOutcome: EEG burst suppression

• Pentobarbital (13mg/kg load followed by 2 Pentobarbital (13mg/kg load followed by 2 mg/kg/hr infusion) found to be more effective but mg/kg/hr infusion) found to be more effective but associated with higher incidence of hypotensionassociated with higher incidence of hypotension

Claassen. Epilepsia 2002; 43:146-153.

What agent(s) should be administered to a patient in status What agent(s) should be administered to a patient in status who continues to seize despite a loading dose of a who continues to seize despite a loading dose of a

benzodiazepine and a phenytoin? benzodiazepine and a phenytoin? (outcome measure: cessation of motor activity)(outcome measure: cessation of motor activity)

• Level A recommendations. None specified.Level A recommendations. None specified.• Level B recommendations. None specified.Level B recommendations. None specified.• Level C recommendations:Level C recommendations:

• Administer 1 of the following agents Administer 1 of the following agents intravenously: “high-dose phenytoin,” intravenously: “high-dose phenytoin,” phenobarbital, valproic acid, midazolam phenobarbital, valproic acid, midazolam infusion, pentobarbital infusion, or propofol infusion, pentobarbital infusion, or propofol infusion.infusion.

DIFFERENTIAL DIAGNOSIS OF PROLONGED DIFFERENTIAL DIAGNOSIS OF PROLONGED POSTICTAL STATEPOSTICTAL STATE

• Intracranial catastropheIntracranial catastrophe

• HypoglycemiaHypoglycemia

• Drug effectDrug effect

• SCSESCSE

• NCSENCSE

When should an EEG be performed in the ED?When should an EEG be performed in the ED?

• Level A recommendations. None specified.Level A recommendations. None specified.

• Level B recommendations. None specified.Level B recommendations. None specified.

• Level C recommendations:Level C recommendations:

• Consider an emergent EEG in patients suspected of Consider an emergent EEG in patients suspected of being in nonconvulsive status epilepticus or in subtle being in nonconvulsive status epilepticus or in subtle convulsive status epilepticus, patients who have convulsive status epilepticus, patients who have received a long-acting paralytic, or patients who are in received a long-acting paralytic, or patients who are in a drug-induced coma.a drug-induced coma.

SummarySummary

• Evidence based clinical policies are useful tools in Evidence based clinical policies are useful tools in clinical decision makingclinical decision making

• Clinical policies do not create a “standard of care” Clinical policies do not create a “standard of care” but do provide a foundation for clinical practice at but do provide a foundation for clinical practice at a national levela national level

• The current literature on acute seizure The current literature on acute seizure management does not support the creation of any management does not support the creation of any “level A” recommendations“level A” recommendations• Only 2 of the 6 clinical questions have Only 2 of the 6 clinical questions have

sufficient evidence to support “level B” sufficient evidence to support “level B” recommendationsrecommendations

• 4 of the 6 recommendations are “level C”4 of the 6 recommendations are “level C”