Status Epilepticus (SE): Diagnosis and Management Edward Sloan, MD, MPH Associate Professor Department of Emergency Medicine University of Illinois College of Medicine-Chicago Chicago, IL

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Status Epilepticus (SE)Diagnosis and
ManagementEdward Sloan, MD, MPHAssociate
ProfessorDepartment of Emergency
MedicineUniversity of Illinois College of
Medicine-ChicagoChicago, IL
FERNE Edward P. Sloan, MD, FACEP
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Objectives

• Definitions
• SE
• Subtle SE
• Refractory SE
• Diagnosis
• Clinical exam
• Diagnostic testing
• EEG
• Management

FERNE Edward P. Sloan, MD, FACEP
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SE Questions

• How is SE Defined?
• What is Subtle SE?
• How is Subtle SE Diagnosed?
• How is SE Acutely Managed?
• What is Refractory SE?
• How is Refractory SE Managed?

FERNE Edward P. Sloan, MD, FACEP
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SE Epidemiology

• 50,000-150,000 Cases annually
• 50 Cases per 100,000 population
• Infants and elderly greatest risk
• Etiology acute insult, chronic epilepsy, new
  onset
• DeLorenzo et al. Neurology 1996461029.
• DeLorenzo et al. J Clin Neurophysiol 199512316.
• DeLorenzo et al. Epilepsia 199233(Suppl 4)S15.
• Hauser. Neurology 199040(Suppl 2)9.

FERNE Edward P. Sloan, MD, FACEP
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SE Etiology
Drug Toxicity
Etiologies of SE in 154 patients
FERNE Edward P. Sloan, MD, FACEP
Lowenstein and Alldredge. Neurology. 199343483.
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SE Definition

• Needed for epidemiologic and clinical trials
• Historical definitions
• Two seizures within 30 min, no a lucid interval
• One seizure gt30 min duration
• More recent definitions more aggressive
• Two seizures over any interval, no a lucid
  interval
• One seizure of gt10 min duration
• Gastault. Adv Neurol 19833415.
• Lowenstein. N Eng J Med 1998338970-976
• Treiman. Epilepsia 199334(Suppl 1)S2.

FERNE Edward P. Sloan, MD, FACEP
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SE Classification

• Generalized convulsive SE
• Primarily and secondarily generalized
• Overt Generalized or major motor SE
• Subtle Myoclonic SE, electical SE
• Nonconvulsive SE Epileptic twilight state
• Complex partial SE
• Absence SE Spike-wave stupor
• Simple partial SE
• No impairment of consciousness

Treiman. Epilepsia 199334(Suppl 1)S2. Treiman,
J Clin Neurophys 199512(4)343-362.
FERNE Edward P. Sloan, MD, FACEP
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SE Mechanism

• Abnormal discharge by a few unstable neurons
• Propagation by recruitment of normal neurons
• Failure of normal inhibitory neurotransmitters
  (GABA)
• Enhancement of excitatory neurotransmitters
• (glutamate, aspartate, acetylcholine)
• Interference with normal metabolic processes
• glucose, 02 metabolism
• Na, Ca, K, Cl- ion shifts
• Fountain et al. J Clin Neurophysiology
  199512326.

FERNE Edward P. Sloan, MD, FACEP
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SE Duration and Mortality

• SE gt60 min 10-fold greater 30-day mortality
  (32 vs 2.7)
• Worse outcome associated with
• Longer duration SE
• SE refractory to first-line therapy

DeLorenzo et al. Epilepsia 199233(Suppl
4)S15. Lowenstein, and Alldredge. Neurology
199343483.
FERNE Edward P. Sloan, MD, FACEP
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Subtle Status Epilepticus

• Non-convulsive
• Persistent ictal discharges
• Electrical-mechanical dissociation (EMD)
• Late finding after GCSE
• Significant M M
• Treiman, J Clin Neurophys. 199512(4)343-362.

FERNE Edward P. Sloan, MD, FACEP
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Subtle SE Incidence Post-GCSE Frequency

• Requires immediate EEG monitoring
• VA SE study 20
• Post - GCSE study 14
• DeLorenzo et al. Epilepsia 199839(8)833-840.
• Treiman et al. N Eng. J Med 1998339792-798.

FERNE Edward P. Sloan, MD, FACEP
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Subtle SE Outcome

• Related to serious underlying pathology
• Post-arrest hypoxic encephalopathy
• Much higher mortality
• VA SE study 65 (vs 27)
• Post - CGSE study 50 (vs 15)
• DeLorenzo et al. Epilepsia 199839(8)833-840.
• Treiman et al. N Eng. J Med 1998339792-798.

FERNE Edward P. Sloan, MD, FACEP
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Subtle SE Diagnosis

• AMS unresponsiveness gt20-30 minutes
• Prolonged post-ictal state
• Idiosyncratic behaviors
• Agitation, speech arrest, confusion

FERNE Edward P. Sloan, MD, FACEP
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SE ManagementGeneral Principles

• ABCs
• Glucose determination
• Thiamine / narcan
• Antiepileptic drug (AED) therapy
• Lowenstein and Alldredge N Eng. J Med
  1998338970-976.

FERNE Edward P. Sloan, MD, FACEP
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SE ManagementClinical Diagnosis

• AMS
• Todds paralysis
• Hypertension early BP rise, then hypotension
• Fever 49 have temperature gt100.5 Fo
• Wijkicks and Hubmayr. Mayo Clin Proc
  1994691044.
• Aminoff and Simon. Am J Med 198069657.

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SE Clinical EvaluationLaboratory Testing

• Lactic acidosis 30 will reach blood pH lt7.00
• Hypercarbia 84 will have increased pCO2
• Leukocytosis without bands
• Neuron-specific enolase highest in NCSE
• Aminoff and Simon. Am J Med 198069657.
• DeGiorgio et al. Neurology 199952746-749
• Orringer et al. N Engl J Med 1977297796.
• Wijkicks and Hubmayr. Mayo Clin Proc
  1994691044.

FERNE Edward P. Sloan, MD, FACEP
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SE Clinical EvaluationLumbar Puncture

• Three indications
• Immunocompromise
• Meningeal signs
• Persistent AMS
• Not mandated for fever alone
• CSF pleocytosis 2-18 have gt5 PMNs

ACEP. Ann Emerg Med 199322987. Aminoff and
Simon. Am J Med 198069657.
FERNE Edward P. Sloan, MD, FACEP
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ACEP/AAN/AANS/ASN Neuroimaging Guidelines
Emergent neuroimaging recommended for

• New focal deficit
• Persistent AMS
• Fever
• Persistent headache history

• Recent trauma
• Cancer
• Anticoagulation
• AIDS

AAN American Academy of Neurology AANA
American Association of Neurological Surgeons
ACEP American College of Emergency
Physicians ASN American Society of
Neuroradiology. ACEP, AAN, AANS, ASN. Ann Emerg
Med 199627114.
FERNE Edward P. Sloan, MD, FACEP
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SE Clinical EvaluationEncephalography

• Three emergent EEG indications
• Prolonged (gt30 min) AMS
• SE requiring neuromuscular paralysis
• SE requiring pentobarbital coma or general
  anesthesia
• Needs to be arranged emergently

Kaplan. Epilepsia 199637643. Privitera and
Strawsburg. Emerg Med Clin N Am 1994121089.
FERNE Edward P. Sloan, MD, FACEP
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SE Treatment ProtocolsEpilepsy Foundation of
America

• Consensus expert opinion
• Make the first drug work
• Dose adequately
• Benzodiazepines, phenytoins, barbituates
• High dose phenytoin (30 mg / kg)
• Working Group on Status Epilepticus. JAMA
  1993270854.

FERNE Edward P. Sloan, MD, FACEP
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SE Treatment ProtocolsVA Cooperative Study

• Four therapies, effectiveness at 20 min
• EEG confirmation
• Lorazepam, phenobarbital, diazepam phenytoin,
  and phenytoin
• Lorazepam best (65) vs. phenytoin
• Phenytoin alone sub-optimal (42)
• No difference with fosphenytoin?
• Treiman. N Eng J Med 1998339792-798

FERNE Edward P. Sloan, MD, FACEP
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Refractory SEIncidence and Outcomes

• SE not responsive to benzodiazepines and
  phenytoins.
• Up to 6000 cases of refractory SE annually
• Often indicative of progressive CNS disorder
• Refractory SE relatively rare in ED
• Overall mortality 20 - 30
• Bleck. Neurology Chron 199221.
• Kumar et al. Crit Care Med 199220483.
• Jagoda et al. Ann Emerg Med 1993221337.
• Labar et al. Neurology 1994441400.

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Refractory SE Management

• Outcome likely related to cause of SE
• Many anecdotal reports no controlled trials
• Inhalation anesthetics less useful
• Neuromuscular blockade not an anticonvulsant
• Bleck. Neurology Chron 199221.
• Kumar et al. Crit Care Med 199220483.
• Jagoda et al. Ann Emerg Med 1993221337.
• Labar et al. Neurology 1994441400.

FERNE Edward P. Sloan, MD, FACEP
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Refractory SE Management

• Pentobarbital
• 5 mg/kg
• load at 25 mg/min 2.5 mg/kg/h maintenance dose
• Propofol
• 2 mg/kg load 7 to 10 mg/kg/h maintenance
• Midazolam
• Bolus intravenous 200 microgram/kg
• Infusion 0.75-11 microgram/kg/min

Labar et al. Neurology 1994441400. Parent JM,
Lowenstein DH. Neurology 1994441837 Shorvon. J
Neurol Neurosurg Psychiatry 199356125. Towne
J Emerg Med 199917323 Van Ness. Epilepsia
19903161.
Bleck. Neurology Chron 199221. Jagoda et al.
Ann Emerg Med 1993221337. Jagoda and Riggio.
Ann Emerg Med 1993221337. Kuisma and Roine.
Epilepsia 1995361241. Kumar et al. Crit Care
Med 199220483.
FERNE Edward P. Sloan, MD, FACEP
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SE Management OptionsDrug Therapies

• IV Phenytoin High dose (30 mg/kg)
• IV Fosphenytoin Rapid infusion in GCSE
• IV Valproate Absence complex partial SE
• IV Lidocane Anecdotal efficacy reports

Allen et al. Epilepsia 199536(Suppl 4)90.
Alehan et al. Neurology 199952889-890. Browne
et al. Neurology 199646(Suppl 1)S3. Eldon et
al. Clin Pharmacol Ther 199353212. Giroud et
al. Drug Invest 19935154.
Kugler et al. Neurology 199646(Suppl)A176. Ramsey
and DeToledo. Neurology 199646(Suppl
1)S17. Walker and Slovis. Acad Emerg Med
19974918. Willert et al. Neurology
199952889-890 Working Group on Status
Epilepticus. JAMA 1993270854
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SE Management OptionsAlternative Parenteral
Routes

• Midazolam IM Best IM benzodiazepine
• Fosphenytoin IM Therapeutic by 30 minutes
• Diastat PR Rapid rectal absorption
• Phenobarbital IM Not recommended
• Dean et al. Epilepsia 199334(Suppl 6)111.
• Garnett et al. Neurology 199545(Suppl 4)A248.
• Parent JM, Lowenstein DH. Neurology 1994441837
• Ramsey and DeToledo. Neurology 199646(Suppl
  1)S17.
• Towne J Emerg Med 199917323-328
• Wilder et al. Arch Neurol 199653764.

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SE Unique PopulationsToxic Ingestions

• INH overdose Pyridoxine (B6) 5g IVP x 6
• EtOH Lorazepam (prevention also)
• Phenytoins likely not effective in
• Cocaine
• Cyclic antidepressants
• Theophylline

Koppel et al. Epilepsia 199637875. Lin et al.
Ann Emerg Med 19952575. Orlowski et al. Ann
Emerg Med 19881773. Pauloucet et al. Ann
Emerg Med 198817135. Shannon. Ann Intern Med
19931191161. Wason et al. JAMA 19812461102.
Brent et al. Arch Intern Med 19901501751.
Callaham and Kassel. Ann Emerg Med
1985141. DOnofrio et al. N Engl J Med
1999340915-919. Haverkos et al. Ann
Pharmacother 1994281347. Henderson et al.
Anaesth Intensive Care 19922056. Holland et al.
Ann Emerg Med 199221772.
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SE Unique PopulationsOther Subgroups

• TBI Sz prophylaxis acutely
• Stroke Prophylaxis in high risk patients
• Pregnancy Mg prevents and treats
• Psychogenic Functional disorder, Rx
• Arboix et al. Neurology 1996471429.
• Jagoda et al. Am J Emerg Med 199311626.
• Jagoda et al. Am J Emerg Med 19951331.
• Lewis, et al. Ann Emerg Med 1993221114.
• Temkin et al. N Engl J Med 1990323497.

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Research HorizonsPHTSE Trial

• Blinded, placebo-controlled, comparative trial
• diazepam vs lorazepam vs placebo
• 2 injections, then standard care
• 65 seizing at time of ED arrival
• 55 ICU admission rate
• 20 HIV infection rate
• Study not yet completed awaiting final results
• Alldrede et al. Epilepsia 199536(Suppl 4)44.

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Research HorizonsER Seizure Study Group

• EMS Seizing rate lt5
• ER Seizing rate lt5
• Status epilepticus lt5
• Admission rate 26

Gibbs et al. Ann Emerg Med 199832S19-S20.
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SE Conclusions

• SE is a common problem
• SE causes significant M M
• Therapy can be optimized
• Outcome can be enhanced
• ED management critical

FERNE Edward P. Sloan, MD, FACEP
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SE Recommendations

• Aggressively treat seizures
• Dose adequately
• Be aware of options
• Suspect NCSE
• Use EEG liberally

FERNE Edward P. Sloan, MD, FACEP
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SE Recommendations

• Develop a SE protocol
• Make all therapies available
• Make EEG a stat test
• Work with neurologists, NS
• Optimize patient outcome

FERNE Edward P. Sloan, MD, FACEP
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All are true statements about Status epilepticus
(SE) except

• a. It is defined by two seizures that occur
  without a lucid interval.
• b. By definition, all SE is associated with SE
  definitions include any seizure of duration gt
  10 minutes.
• d. The most common etiologies for SE include
  antiepileptic drug (AED) withdrawal and alcohol
  withdrawal.
• e. SE of longer duration is associated with a
  higher mortality.

FERNE Edward P. Sloan, MD, FACEP
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All are true statements about Stutus Epilepticus
(SE) except

• Answer b.
• Although generalized convulsive SE(GCSE) is
  associated with tonic-clonic motor activity,
  other forms such as complex partial or absence SE
  can exist with this motor activity.

FERNE Edward P. Sloan, MD, FACEP
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All are true statements about subtle SE except

• a. By definition, subtle SE is not associated
  with generalized tonic-clonic motor activity.
• b. Subtle SE requires EEG monitoring in order to
  be diagnosed clinically.
• c. In subtle SE, the EEG shows persistent ictal
  discharges.
• d. Because there is not generalized tonic-clonic
  motor activity, subtle SE has a lower mortality
  rate than does GCSE.
• e. Subtle SE occurs as a late finding of
  prolonged GCSE.

FERNE Edward P. Sloan, MD, FACEP
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All are true statements about subtle SE except

• Answer d.
• Because subtle SE is a late finding of prolonged
  GCSE, it carries a much higher mortality than
  GCSE, up to 50-65 in some studies.

FERNE Edward P. Sloan, MD, FACEP
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All are true statements regarding adult SE except

• a. Fever can occur as a result of GCSE without
  the presence of a CNS infection as the fever
  source
• b. Lumbar puncture is required for all SE
  patients who have a fever.
• c. Lactic acidosis, leukocytosis, and
  hypercarbia can be in SE.
• d. Guidelines exist that describe the role of
  neuroimaging in seizures and SE
• e. The diagnosis of refractory SE is made when
  initial therapies fail.

FERNE Edward P. Sloan, MD, FACEP
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All are true statements regarding adult SE except

• Answer b.
• Although a lumbar puncture should be considered
  in all patients with SE and fever, in the awake
  patient without meaningful signs and a fever
  source, an LP may not be necessary.

FERNE Edward P. Sloan, MD, FACEP
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All are true statements regarding the use of EEG
in SE except

• a. Patients who remain comatose for gt 30
  minutes may be in subtle SE, requiring EEG
  monitoring.
• b. All patients requiring neuromuscular
  blockage require EEG monitoring.
• c. All patients requiring pentobarbital coma
  require EEG monitoring.
• d. EEG monitoring can only be done with a
  multiple lead EEG machine.
• e. When considering subtle SE, EEG monitoring
  should be performed emergently in the ED or ICU.

FERNE Edward P. Sloan, MD, FACEP
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All are true statements regarding the use of EEG
in SE except

• Answer d.
• Two channel EEG monitoring can be performed
  using the modular monitoring systems present in
  most EDs.

FERNE Edward P. Sloan, MD, FACEP
42
All are true statements regarding the initial
management of SE except

• a. Lorazepam has been shown to be superior to
  other benzodiazepines in SE management.
• b. Glucose determination, thiamine, and narcan
  are important initial therapies.
• c. Most treatment failures relate to inadequate
  dosing, not drug therapy choice.
• d. Phenytoins can be given in high doses (up to
  30 mg/kg) in SE.
• e. Propofol or phenobarbital can be used to
  treat SE if benzodiazepines and phenytoins are
  not effective.

FERNE Edward P. Sloan, MD, FACEP
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All are true statements regarding the initial
management of SE except

• Answer a.
• No simple benzodiazepine has been shown to be
  superior to another for the treatment of SE.

FERNE Edward P. Sloan, MD, FACEP
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If IV access is not available, the following are
possible drugs and routes except?

• a. IM midazolam
• b. IM fosphenytoin
• c. IM phenobarbital
• d. PR diazepam
• e. PR diazepam gel

FERNE Edward P. Sloan, MD, FACEP
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All are true statements regarding the use of EEG
in SE except

• Answer c.
• IM phenobarbital is not recommended because of
  soft tissue toxicity.

FERNE Edward P. Sloan, MD, FACEP