Clinical Decisions in Seizure Management Andy Jagoda, MD, FACEP Professor of Emergency Medicine Mount Sinai School of Medicine New York, New York

Objectives Introduce the process of how clinical policies / practice guidelines are developedIntroduce the process of how clinical policies / practice guidelines are developed Provide an overview of seizures from the prospective of emergency medicine practiceProvide an overview of seizures from the prospective of emergency medicine practice Present the recommendations from the upcoming ACEP clinical policy on seizure managementPresent the recommendations from the upcoming ACEP clinical policy on seizure management

Seizure 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 Approach based Approach based Revision Revision 2003 – Critical questions; evidence based2003 – Critical questions; evidence based

Seizure 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 epilepticus Most epidemiology studies focus on patients with epilepsy and not on the epidemiology of seizures per seMost epidemiology studies focus on patients with epilepsy and not on the epidemiology of seizures per se Fewer than half the cases of status identified were managed by a neurologistFewer than half the cases of status identified were managed by a neurologist Over 50% of status cases occurred in patients with no prior history of epilepsyOver 50% of status cases occurred in patients with no prior history of epilepsy Delorenzo et al. Neurology 1996; 46:

Seizure Practice Guidelines Treatment of convulsive status epilepticus. Epilepsy Foundation of America. JAMA 1993; 270: Treatment of convulsive status epilepticus. Epilepsy Foundation of America. JAMA 1993; 270: The neurodiagnostic evaluation of the child with first simple febrile seizure. AAP. Pediatrics 1996; 97: The neurodiagnostic evaluation of the child with first simple febrile seizure. AAP. Pediatrics 1996; 97: The role of phenytoin in the management of alcohol withdrawal syndrome. Am Soc Addiction Med 1994 / 1998The role of phenytoin in the management of alcohol withdrawal syndrome. Am Soc Addiction Med 1994 / 1998 Evaluating the first nonfebrile seizure in chilren. AAN. Neurology 2000; 55: Evaluating the first nonfebrile seizure in chilren. AAN. Neurology 2000; 55: Role of antiseizure prophylaxis following head injury. BTF / AANS. J Neurotrauma 2000; 17: Role of antiseizure prophylaxis following head injury. BTF / AANS. J Neurotrauma 2000; 17: Treatment of the child with a first unprovoked seizure. AAN. Neurology 2003; 60: Treatment of the child with a first unprovoked seizure. AAN. Neurology 2003; 60: Antiepileptic drug prophylaxis in severe traumatic brain injury. Neurology 2003; 60:10-16Antiepileptic drug prophylaxis in severe traumatic brain injury. Neurology 2003; 60:10-16

ACEP Clinical Policy Identify questions of clinical importance to emergency department management of patients with seizuresIdentify questions of clinical importance to emergency department management of patients with seizures Analyze the quality of data available related to acute management of patients with seizuresAnalyze the quality of data available related to acute management of patients with seizures Differentiate anectodal experience from practice supported by evidenceDifferentiate anectodal experience from practice supported by evidence

ACEP Clinical Policy 1.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? 2.Which new onset seizure patients who have returned to a normal baseline require neuroimaging in the ED? 3.Which new onset seizure patients who have returned to normal baseline need to be admitted to the hospital and / or started on an AED? 4.What are effective phenytoin dosing strategies for preventing sz recurrence in patients who present to the ED with a subtherapeutic serum phenytoin level? 5.What agent(s) should be administered to a patient in status who continues to seize despite a loading dose of a benzodiazepine and a phenytoin? 6.When should an EEG be performed in the ED?

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

The patient is worked-up as an outpatient and diagnosed with a seizure disorder. She is treated with phenytoin, 300 mg qhs. She is brought to the ED by EMS status post a “typical” event but back to baseline. Her serum phenytoin level is <1 ug/ml. Which of the following is the best management plan? Fosphenytoin, 20 PE/kg, IM in the deltoid Fosphenytoin, 20 PE/kg, IM in the deltoid Fosphenytoin, 20 PE/kg, IV at 300 mg/min Fosphenytoin, 20 PE/kg, IV at 300 mg/min Phenytoin, 20 mg/kg IV at 150 mg/min Phenytoin, 20 mg/kg IV at 150 mg/min Phenytoin, 20 mg/kg po and discharge after 4 hrs Phenytoin, 20 mg/kg po and discharge after 4 hrs Lorazepam, 2 mg, IV and discharge after one hour Lorazepam, 2 mg, IV and discharge after one hour

While in the ED, she goes into status epilepticus. The seizures do not stop despite lorazepam, 10 mg, and phenytoin 20 mg/kg. Which of the following is not 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 / kg Phenobarbital, 20 mg / kg Pentobarbital, 3 mg / kg Pentobarbital, 3 mg / kg Propofol, 1 mg / kg Propofol, 1 mg / kg Vecuronium,.1 mg /kg Vecuronium,.1 mg /kg

What laboratory tests are indicated in the ED 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. Ann Emerg Med 1990; 19: Prospective. 136 patients) Nypaver. ED laboratory evaluation of hcildren with seizures: Dogma or dilemma? Ped Emerg Care 1992; 8: Retrospective 308 patients)

Lumbar 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 baselineHas returned to baseline Has no fever or meningeal signsHas no fever or meningeal signs There are no cases reported of meningitis presenting as a simple tonic clonic seizureThere are no cases reported of meningitis presenting as a simple tonic clonic seizure Postictal pleocytosis (>5 polys in the CSF) has been reported in % of patients who have had a GTCSPostictal pleocytosis (>5 polys in the CSF) has been reported in % of patients who have had a GTCS Pesola G,. New onset generalized seizures in patients with AIDS. Acad Emerg Med. 1998; 5: Retrospective review, 26 patients Green S,. Can seizures be the sole manifestation of meningitis in febrile children? Pediatrics 1993; 92: Retrospective. 503 cases

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? (outcome measure is abnormal test that changes management) Level A recommendations: NoneLevel A recommendations: None Level B recommendations:Level B recommendations: Determine a serum glucose and sodium on patients with a first time seizure with no co-morbidities who have returned to their baselineDetermine a serum glucose and sodium on patients with a first time seizure with no co-morbidities who have 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 admission on patients who are immunocompromisedPerform a LP after a head CT either in the ED or after admission on patients who are immunocompromised

Neuroimaging: Head CT and MR Three per cent to 41% of patients with a first time seizure have an abnormal head CTThree per cent to 41% of patients with a first time seizure have an abnormal head CT Imaging is dependent on the urgency of the evaluation and patient stabilityImaging is dependent on the urgency of the evaluation and patient stability Literature interpretation depends on outcome measure usedLiterature interpretation depends on outcome measure used Tardy. AJEM. 1995; 13:1-5. Retrospective review. 247 patients. Henneman AEM 1994; 24: Retrospective. 294 patients).

Neuroimaging in New Onset Seizures ACEP, AAN, AANS, ASNR. Practice Parameter: ED neuroimaging in the seizure pt. Ann Emerg Med 1996; 27: Evidence based practice guidelineACEP, AAN, AANS, ASNR. Practice Parameter: ED neuroimaging in the seizure pt. Ann Emerg Med 1996; 27: Evidence based practice guideline Emergent CT for patients with altered mental status, trauma, focal exam, immunocompromise, fever, co- morbitidityEmergent CT for patients with altered mental status, trauma, focal exam, immunocompromise, fever, co- morbitidity Patients who are alert with a nonfocal exam can have an outpatient studyPatients who are alert with a nonfocal exam can have an outpatient study Focal abnormalities on CT are reported in up to 40% of patients with new onset seizures; up to 20% have non- focal examsFocal abnormalities on CT are reported in up to 40% of patients with new onset seizures; up to 20% have non- focal exams MRI is better than CT in detecting subtle lesions (e.g., hippocampal sclerosis) but impact on care is controversialMRI is better than CT in detecting subtle lesions (e.g., hippocampal sclerosis) but impact on care is controversial

Which new onset seizure patients who have returned to a normal baseline require neuroimaging in the ED? (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 ED on patients with a first time seizureWhen feasible, perform a head CT of the brain in the ED on patients with a first time seizure Deferred outpatient neuroimaging may be utilized when reliable follow-up is availableDeferred outpatient neuroimaging may be utilized when reliable follow-up is available

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 recurrence, ie, etiologyDecision to initiate AED treatment depends on the risk of recurrence, 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 oral or IV phenytoin; IM forphenytoin; IV valproic acidPatients needing immediate AED treatment can be loaded with oral or IV phenytoin; IM forphenytoin; IV valproic acid Decision to admit depends on assessed risk of recurrence, patient compliance, and patients social circumstancesDecision to admit depends on assessed risk of recurrence, patient compliance, and patients social circumstances

Which new onset seizure patients who have returned to normal baseline need to be admitted to the hospital and / or started on an AED? (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 discharged from the ED with outpatient follow-upPatients with a normal neurologic examination can be discharged from the ED with outpatient follow-up Patients with a normal neurologic examination and no co-morbidities and no know structural brain disease do not need to be started on an anti-epileptic drug in the EDPatients with a normal neurologic examination and no co-morbidities and no know structural brain disease do not need to be started on an anti-epileptic drug in the ED

AED Loading In patients who have seized and returned to baseline, no AED loading strategy has been shown to be superior in preventing seizure recurrenceIn patients who have seized and returned to baseline, no AED loading strategy has been shown to be superior in preventing seizure recurrence No outcome studies exist comparing loading strategiesNo outcome studies exist comparing loading strategies IV phenytoin achieves therapeutic serum levels by the end of the infusionIV phenytoin achieves therapeutic serum levels by the end of the infusion IM fosphenytoin achieves therapeutic serum levels within one hour post injectionIM fosphenytoin achieves therapeutic serum levels within one hour post injection PO phenytoin, 19 mg/kg in males and 25 mg/kg in females single dose achieves therapeutic serum levels in 4 hoursPO phenytoin, 19 mg/kg in males and 25 mg/kg in females single dose achieves therapeutic serum levels in 4 hours Ratanakorn. J Neuro Sci 1997; 147:89-92 Van der Meyden. Epilepsia 1994; 35:

What are effective phenytoin dosing strategies for preventing sz recurrence in patients who present to the ED with a subtherapeutic serum phenytoin level? (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 dose of phenytoin or intravenous or intramuscular fosphenytoin, and restart daily oral maintenance dosing.Administer an intravenous or oral loading dose of phenytoin or intravenous or intramuscular fosphenytoin, and restart daily oral maintenance dosing.

While in the ED, she goes into status epilepticus. The seizures do not stop despite lorazepam, 10 mg, and phenytoin 20 mg/kg. Which of the following is not 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/hrPentobarbital, 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 EPILEPTICUS 126, ,000 cases in the US / year126, ,000 cases in the US / year 25% of cases are NCSE or SGCSE25% of cases are NCSE or SGCSE 22% mortality in convulsive status22% 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 EPILEPTICUS NCSE vs SCSENCSE vs SCSE Prognosis worse with SCSEPrognosis worse with SCSE Clinical characteristicsClinical characteristics mild cognitive deficits to coma*mild cognitive deficits to coma* Incidence: 14% after CSE**Incidence: 14% after CSE** Diagnosis: Clinical and EEGDiagnosis: Clinical and EEG TreatmentTreatment * Tomson. Epilepsia 1992;33: ** DeLorenzo. Epilepsia 1998; 39:

STATUS EPILEPTICUS: SE Working Group (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/minLorazepam.1 mg/kg at 2 mg/min If diazepam is used, phenytoin must be started simulatneouslyIf diazepam is used, phenytoin must be started simulatneously Phenytoin 20 mg/kg at mg/min (fosphenytoin 20 mg/kg at 150 mg/min)Phenytoin 20 mg/kg at mg/min (fosphenytoin 20 mg/kg at 150 mg/min) Repeat phenytoin 5 mg/kgRepeat phenytoin 5 mg/kg Phenobarbital 20 mg/kg at 100 mg/minPhenobarbital 20 mg/kg at 100 mg/min Valproic acid 20 mg/kgValproic acid 20 mg/kg Epilepsy Foundation of America. JAMA 1993;270:

VA 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 seizures or mortality at 12 hours or 30 daysNo difference among the four groups in recurrance of seizures 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:

Refractory 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 mg/kg/hr infusion) found to be more effective but associated with higher incidence of hypotensionPentobarbital (13mg/kg load followed by 2 mg/kg/hr infusion) found to be more effective but associated with higher incidence of hypotension Claassen. Epilepsia 2002; 43:

What agent(s) should be administered to a patient in status who continues to seize despite a loading dose of a benzodiazepine and a phenytoin? (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 intravenously: “high-dose phenytoin,” phenobarbital, valproic acid, midazolam infusion, pentobarbital infusion, or propofol infusion.Administer 1 of the following agents intravenously: “high-dose phenytoin,” phenobarbital, valproic acid, midazolam infusion, pentobarbital infusion, or propofol infusion.

DIFFERENTIAL DIAGNOSIS OF PROLONGED POSTICTAL STATE Intracranial catastropheIntracranial catastrophe HypoglycemiaHypoglycemia Drug effectDrug effect SCSESCSE NCSENCSE

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

Summary Evidence based clinical policies are useful tools in clinical decision makingEvidence based clinical policies are useful tools in clinical decision making Clinical policies do not create a “standard of care” but do provide a foundation for clinical practice at a national levelClinical policies do not create a “standard of care” but do provide a foundation for clinical practice at a national level The current literature on acute seizure management does not support the creation of any “level A” recommendationsThe current literature on acute seizure management does not support the creation of any “level A” recommendations Only 2 of the 6 clinical questions have sufficient evidence to support “level B” recommendationsOnly 2 of the 6 clinical questions have sufficient evidence to support “level B” recommendations 4 of the 6 recommendations are “level C”4 of the 6 recommendations are “level C”