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Status Epilepticus

- Non-IV alternatives - Midazolam (Versed): 10 mg IM, buccal, or intranasal (onset 5 to 10 minutes) (2,3,6)[A]. Use concentrated IV solution. - Lorazepam (SL or intranasal) (1)[A] - Rectal diazepam (Valium) (1,4)[A] - Pediatric 2 to 5 years: 0.5 mg/kg; 6 to 11 years, 0.3 mg/kg; >12 years, refer to adult dosing - Adult: 10 mg once; may repeat once if necessary - Use gel (Diastat) or IV solution.

- FOR REFRACTORY STATUS EPILEPTICUS - Admit to ICU and induce anesthesia/drug coma and follow continuous EEG; adjust to keep EEG at burst suppression (1)[B]. - Consider transfer to a high-volume center (1)[C]. - Intubate and ventilate - Use short-acting rocuronium 0.6 to 1 mg/kg (to avoid hyperkalemia) as paralytic agent. - Maintain anesthetic for 24 hours; then taper gradually over 12 to 24 hours while adjusting maintenance anticonvulsant therapy. - Consider ICP monitoring and induced hypothermia. - If febrile, treat and cool. - Drug choices (use ONE) - Propofol (Diprivan) (1,2)[B] - 1 to 2 mg/kg IV bolus at rate of 2 mg/min (in elderly, halve initial dose) - Follow with 33 to 167 Ä ╝g/kg/min IV; titrated to EEG - Less tissue accumulation

- Additional considerations if seizures persist - Topiramate (1,2)[C] - Ketamine (2)[C]

- Contraindications - Propofol in allergy to soybean oil, egg, lecithin, or glycerol - Barbiturates in acute intermittent porphyria - Valproate in hepatic disease, coagulopathy, and pregnancy (risk of neural tube defects)

- Precautions - Propofol: Prolonged use may cause propofol infusion syndrome (lactic acidosis, lipemia, cardiac and renal failure, systemic collapse, and death). Not approved in the United States for children <3 years. Strict aseptic technique is required. - Porphyria may be exacerbated by most drugs listed; exceptions are lorazepam, midazolam, propofol. - Diazepam IV: may cause thrombosis/phlebitis - Fosphenytoin (Cerebyx) and phenytoin - Abrupt withdrawal may precipitate status. Overdose may cause paradoxical inefficacy. - Monitor for arrhythmias, prolonged QT interval, and hypotension. Use caution in liver disease, hyperglycemia, the elderly, and pregnancy (increased risk of malformations and may lead to vitamin K deficiency " öbleeding problems in both mother and newborn).

para>Status epilepticus is a life-threatening emergency; rapid seizure control is critical, even before a definitive diagnosis is reached.

Increased seizure duration is correlated with poorer prognosis.

Status epilepticus is more likely to become refractory with delay of treatment.

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DESCRIPTION

  • Established status epilepticus: seizure lasting >5 minutes or >2 minutes with absence of recovery of consciousness between seizures
  • Tonic " ôclonic (grand mal or generalized convulsive) status is the most common and most serious form.
  • Refractory status epilepticus: Seizure that persists after treatment with adequate doses of initial benzodiazepine and second acceptable drug
  • System(s) affected: nervous
  • Synonym(s): status convulsivus

EPIDEMIOLOGY

Incidence

  • 41 to 61 cases per 100,000 per year<1/2 as unprovoked first seizure1/6 in patients with known epilepsy1/5 secondary to acute CVA1/10 in comatose ICU patients
  • Predominant sex: male > female
  • Bimodal age distribution: greatest number in those <1 year old or >60 years of age

Prevalence

In the United States, 125,000 to 195,000 patients per year present in generalized tonic " ôclonic status epilepticus, with 55,000 associated deaths and $4 billion in health care costs. é á

ETIOLOGY AND PATHOPHYSIOLOGY

  • Medical noncompliance (34%), history of remote CVA (24%), and acute CVA (22%) are the most common causes in adults.
  • In children, febrile status epilepticus is the most common etiology, accounting for 1/3 of cases.
  • Cerebrovascular: loss of autoregulation, focal ischemia, cerebral edema, cerebral sinus thrombosis, hemorrhage, mass, stroke
  • Intoxications: Agents include cocaine, tricyclic antidepressants, local anesthetics, lead, isoniazid, chloroquine, cephalosporins, penicillins, phenytoin, bupropion, ciprofloxacin, cyclosporine, theophylline, tacrolimus, tiagabine, organophosphates, or nerve-agent poisoning, synthetic cannabinoids.
  • Neuronal: stress injury, autonomic activation
  • Metabolic: lactic acidosis, CO2 narcosis, hyperkalemia, hypoglycemia, hyperglycemia, hyponatremia, hypophosphatemia, uremia
  • Cardiac: hypertension (followed by hypotension), ischemia, arrhythmias, high-output failure
  • Respiratory: increased secretions, lax tongue and possible airway obstruction, pneumothorax, neurogenic pulmonary edema, or aspiration
  • Renal: ATN from myoglobinuria after rhabdomyolysis
  • Infectious disease: meningitis, febrile seizure
  • Inflammatory: vasculitis, acute disseminated encephalomyelitis
  • Idiopathic, cryptogenic

Genetics

Familial links are suspected but not defined. Numerous genetic syndromes increase risk. é á

RISK FACTORS

  • Seizure disorder plus any precipitating insult
  • Prior history of status epilepticus (recurrence rate in children, 17%; in those with neurologic abnormality, 50%)

GENERAL PREVENTION

Established maintenance therapy with anticonvulsant medication é á

COMMONLY ASSOCIATED CONDITIONS

Premonitory status epilepticus (an increasing frequency of seizures) may precede convulsive status epilepticus. Treat early to prevent full status. é á

DIAGNOSIS

HISTORY

  • Previous seizures, drug history, toxic exposure, prior CVA
  • Elicit type of seizure
  • Generalized (tonic " ôclonic) convulsion is the most common form.

PHYSICAL EXAM

  • Neurologic exam: Look for localizing signs of CNS lesion; rule out nonepileptic status.
  • Postictal findings: fever, tachycardia, mydriasis, conjugate deviation of eyes, decreased corneal reflex, positive Babinski sign, Todd paralysis, fecal/urinary incontinence, injury (tongue, cheek, lips)

DIFFERENTIAL DIAGNOSIS

  • Psychogenic nonepileptic status; check EEG.
  • Special consideration: If patient is not awake 30 minutes after a seizure, check the EEG for nonconvulsive status.

DIAGNOSTIC TESTS & INTERPRETATION

  • Glucose (rapid determination); electrolytes, CBC, osmolarity, liver/renal function, serial troponins, CPK, calcium, magnesium, phosphate, coagulation profile
  • Arterial blood gases, carboxyhemoglobin
  • Anticonvulsant drug levels
  • Toxicology screens (urine and blood)
  • Noncontrast CT scan of brain in new-onset seizure
  • MRI or PET for more anatomic detail
  • CXR for ET tube position and to check for aspiration

Diagnostic Procedures/Other

  • Lumbar puncture: if meningitis is suspected
  • EEG: to differentiate nonepileptic seizures; to reveal nonconvulsive status epilepticus in comatose or paralyzed patient; to confirm successful treatment
  • Continuous EEG: to follow/manage therapy

TREATMENT

Simultaneous goals are to stop the seizure, find the cause, and prevent complications (1,2)[B]. é á

  • Support ABCs and monitor pulse oximetry, end-tidal CO2, BP, ECG, continuous EEG, and temperature.
  • Treat glucose if <60 mg/100 dL (thiamine, 100 mg IV/IM (promptly if deficiency suspected).50% dextrose, 50 mL IV (Pediatric: Use D25W; give 2 mL/kg slowly)
  • Establish two IV lines or an intraosseous (IO) line and obtain labs.
  • IV, IO, or IM lorazepam is preferred; although in the prehospital setting, IM midazolam can also be a first-line therapy (3)[A].
  • If seizure lasts >5 minutes, begin therapy with two drugs.

ALERT

If seizure persists after initial therapy with 2 drugs, do not delay; move on to second-line (refractory) treatment with anesthesia/drug coma.

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  • Hemodynamic instability may require fluid resuscitation or pressors.
  • Continue to pursue the underlying cause.
  • Refractory status epilepticus will often require endotracheal intubation. RSE occurs in approximately 1/3 of cases even with adequate initial therapy.

GENERAL MEASURES

  • Protect from injury, clear/suction airway, prevent tongue laceration.
  • If comatose, intubate, place NG tube, urinary catheter.

MEDICATION

ALERT

Begin therapy with two drugs: (i) a benzodiazepine to stop seizure and (ii) an antiepileptic drug to prevent recurrence or stop continuing seizure.

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First Line

  • EMERGENT INITIAL THERAPY to stop seizureLorazepam (Ativan) IV: preferred benzodiazepine (1,2,4,5)[A]4 mg IV, IM, or IO at 2 mg/min maxMay repeat q5 " ô10min â Ś 2Pediatric: 0.1 mg/kg IV at <2 mg/min to a maximum of 4 mgDiazepam (Valium) (1,2,4)[A]: 5 to 10 mg IV or IO at 5 mg/minPediatric: 0.3 mg/kg at <2 mg/min IV up to 10 mg totalMay repeat q5min â Ś 3Non-IV alternativesMidazolam (Versed): 10 mg IM, buccal, or intranasal (onset 5 to 10 minutes) (2,3,6)[A]. Use concentrated IV solution.Lorazepam (SL or intranasal) (1)[A]Rectal diazepam (Valium) (1,4)[A]Pediatric 2 to 5 years: 0.5 mg/kg; 6 to 11 years, 0.3 mg/kg; >12 years, refer to adult dosingAdult: 10 mg once; may repeat once if necessaryUse gel (Diastat) or IV solution.
  • URGENT CONTROL THERAPY to prevent recurrence or to stop continuing seizureFosphenytoin (Cerebyx; prodrug of phenytoin) (1,2)[B]20 mg phenytoin equivalents (PE) per kg IV, IM, or IO at 150 mg PE/min (follow BP, ECG)May add 5 to 10 mg PE/kg IV/IM if seizures persistMaintenance: 4 to 6 mg PE/kg/day in divided doses IV/IMPediatric: same doses as for an adult at <3 mg PE/kg/minGoal serum level (measured as phenytoin) of 10 to 20 mg/dLValproate (may be preferred over phenytoin and levetiracetam) (1)[A]20 to 40 mg/kg administered at 20 mg/minMaintenance: 3 to 6 mg/kg/minPediatric: 1.5 to 3 mg/kg/minAlternatives for fosphenytoinPhenytoin IV (1,2)[B]: 15 to 20 mg/kg IV at 50 mg/min; cardiac monitoring during initial infusion; risk for hypotension, bradycardia, arrhythmias increase with more rapid infusion rates.Goal serum level of 15 to 20 mg/dLMay have more cardiovascular side effects than fosphenytoinOther drug alternatives to consider if contraindication to phenytoin or valproate (1,2)[A]Levetiracetam: 1,000 to 3,000 mg IV at 500 mg/minPhenobarbital: 20 mg/kg IV at 50 mg/minMidazolam infusion: second-line
  • FOR REFRACTORY STATUS EPILEPTICUSAdmit to ICU and induce anesthesia/drug coma and follow continuous EEG; adjust to keep EEG at burst suppression (1)[B].Consider transfer to a high-volume center (1)[C].Intubate and ventilateUse short-acting rocuronium 0.6 to 1 mg/kg (to avoid hyperkalemia) as paralytic agent.Maintain anesthetic for 24 hours; then taper gradually over 12 to 24 hours while adjusting maintenance anticonvulsant therapy.Consider ICP monitoring and induced hypothermia.If febrile, treat and cool.Drug choices (use ONE)Propofol (Diprivan) (1,2)[B]1 to 2 mg/kg IV bolus at rate of 2 mg/min (in elderly, halve initial dose)Follow with 33 to 167 Ä ╝g/kg/min IV; titrated to EEGLess tissue accumulationMidazolam (Versed) (1,2,5)[B]0.2 mg/kg slow IV bolus injection, can repeat q5min up to 2 mg/kg total doseFollow with 0.1 to 0.2 mg/kg/hr IV.May go as high as 0.4 mg/kg/hr IVRecommended drug in hemodynamically unstable patientPentobarbital (1,2,5)[B]10 mg/kg IV loading dose at 50 mg/minFollow by continuous infusion of 1 to 4 mg/kg/hr; adjust based on EEG.Additional considerations if seizures persistTopiramate (1,2)[C]Ketamine (2)[C]
  • Investigational or anecdotal drugsIsoflurane (by inhalation), desflurane (by inhalation), thiopental, lidocaine, lacosamide, nimodipine, chlormethiazole, lamotrigine, propofol (by inhalation), dantrolene, immunologic therapy, ECT, transcranial magnetic stimulation
  • ContraindicationsPropofol in allergy to soybean oil, egg, lecithin, or glycerolBarbiturates in acute intermittent porphyriaValproate in hepatic disease, coagulopathy, and pregnancy (risk of neural tube defects)
  • PrecautionsPropofol: Prolonged use may cause propofol infusion syndrome (lactic acidosis, lipemia, cardiac and renal failure, systemic collapse, and death). Not approved in the United States for children <3 years. Strict aseptic technique is required.Porphyria may be exacerbated by most drugs listed; exceptions are lorazepam, midazolam, propofol.Diazepam IV: may cause thrombosis/phlebitisFosphenytoin (Cerebyx) and phenytoinAbrupt withdrawal may precipitate status. Overdose may cause paradoxical inefficacy.Monitor for arrhythmias, prolonged QT interval, and hypotension. Use caution in liver disease, hyperglycemia, the elderly, and pregnancy (increased risk of malformations and may lead to vitamin K deficiency " öbleeding problems in both mother and newborn).Phenytoin: Infiltration may cause local ischemia (purple glove syndrome).Valproate: may decrease platelet function and cause hyperammonemic encephalopathy, pancreatitis, or hepatotoxicity
  • Significant possible interactionsFosphenytoin/phenytoin: May increase serum levels and toxicity of warfarin, disulfiram, phenylbutazone, and isoniazid; decrease dose with renal insufficiency.Valproate: may increase toxicity of phenytoin/fosphenytoin

ADDITIONAL THERAPIES

  • In suspected alcoholism: thiamine, 100 mg IV/IM (before or promptly after dextrose)
  • If blood sugar is low or cannot be measured: 50% dextrose, 50 mL IVPediatric: Use D25W; give 2 mL/kg slowly.
  • If pupils are miotic or opioid overdose is suspected: naloxone (Narcan): 2 mg IV (in divided doses); may require continuous infusionPediatric: 0.1 mg/kg IV, up to 2 mg slowly
  • If isoniazid poisoning is suspected: pyridoxine
  • If meningitis is strongly suspected, consider empiric antibiotic treatment.
  • For nerve agents and organophosphates: Give atropine, benzodiazepine, and pralidoxime (2-PAM).
  • If suspected eclampsia of pregnancy: magnesium, 2 to 6 g IV followed by 2 mg/hr infusion (see section on "Preeclampsia and Eclampsia (Toxemia of Pregnancy) " Ł
  • If hyponatremia, 100 mL 3% NaCl (see section on "Hyponatremia " Ł)

SURGERY/OTHER PROCEDURES

Experimental: surgical excision of epileptic focus or propagation pathways; vagal nerve stimulator; hypothermia, electroconvulsive therapy é á

INPATIENT CONSIDERATIONS

Discharge Criteria

Seizures controlled; therapeutic anticonvulsant levels é á

ONGOING CARE

PATIENT EDUCATION

Reinforce importance of continuing anticonvulsant medications, avoiding alcohol, and seeking help if seizure frequency increases. é á

  • Epilepsy Foundation: 1-800-332-1000, http://www.epilepsy.com
  • Epilepsy U.S. National Library of Medicine: http://www.nlm.nih.gov/medlineplus/epilepsy.html

PROGNOSIS

  • Prolonged seizures (>5 min) may cause neurologic injury or death.
  • Worse prognosis if structural brain lesion, vascular lesion, or brain tumor is source
  • Reported mortality is 19 " ô27% in adults, 3 " ô19% in children, extremely high in neonates, and up to 76% in the elderly.
  • With seizure duration >1 hour, mortality is 37%; for >4 hours, mortality is 50%; >12 hours, mortality is 80%.

COMPLICATIONS

Morbidity/mortality is usually related to underlying CNS pathology; stress from repeated seizures (e.g., hyperthermia, acidosis, hypotension, cardiac arrest, rhabdomyolysis, renal failure, or aspiration pneumonia), or complications of treatment instituted. é á

REFERENCES

11 Brophy é áGM, Bell é áR, Claassen é áJ, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3 " ô23.22 Varelas é áPN, Spanaki é áMV, Mirski é áMA. Status epilepticus: an update. Curr Neurol Neurosci Rep. 2013;13(7):357.33 Silbergleit é áR, Durkalski é áV, Lowenstein é áD, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366(7):591 " ô600.44 Prasad é áK, Al-Roomi é áK, Krishnan é áPR, et al. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev. 2009;(4):CD003723.55 Foreman é áB, Hirsch é áLJ. Epilepsy emergencies: diagnosis and management. Neurol Clin. 2012;30(1):11 " ô41.66 Sofou é áK, Kristj â ínsd â │ttir é áR, Papachatzakis é áNE, et al. Management of prolonged seizures and status epilepticus in childhood: a systematic review. J Child Neurol. 2009;24(8):918 " ô926.

SEE ALSO

Seizure Disorders; Seizures, Febrile é á

CODES

ICD10

  • G40.901 Epilepsy, unsp, not intractable, with status epilepticus
  • G40.401 Oth generalized epilepsy, not intractable, w stat epi
  • G40.411 Oth generalized epilepsy, intractable, w status epilepticus
  • G40.801 Other epilepsy, not intractable, with status epilepticus
  • G40.911 Epilepsy, unspecified, intractable, with status epilepticus
  • G40.301 Generalized idiopathic epilepsy and epileptic syndromes, not intractable, with status epilepticus
  • G40.311 Generalized idiopathic epilepsy and epileptic syndromes, intractable, with status epilepticus
  • G40.201 Local-rel symptc epi w cmplx prt seiz, not ntrct, w stat epi
  • G40.111 Local-rel symptc epi w simple part seiz, ntrct, w stat epi
  • G40.501 Epileptic seiz rel to extrn causes, not ntrct, w stat epi
  • G40.101 Local-rel symptc epi w simp part seiz, not ntrct, w stat epi
  • G40.011 Local-rel idio epi w seiz of loc onset, ntrct, w stat epi
  • G40.811 Lennox-Gastaut syndrome, not intractable, w stat epi
  • G40.211 Local-rel symptc epi w cmplx partial seiz, ntrct, w stat epi

ICD9

  • 345.3 Grand mal status
  • 345.10 Generalized convulsive epilepsy, without mention of intractable epilepsy
  • 345.00 Generalized nonconvulsive epilepsy, without mention of intractable epilepsy
  • 345.80 Other forms of epilepsy and recurrent seizures, without mention of intractable epilepsy

SNOMED

  • Status epilepticus (disorder)
  • grand mal status (disorder)
  • Nonconvulsive status epilepticus (disorder)
  • Non-convulsive simple partial status epilepticus (disorder)
  • Grand mal status epilepticus, non-refractory (disorder)
  • Grand mal status epilepticus, refractory (disorder)
  • Complex partial status epilepticus, non-refractory (disorder)
  • Complex partial status epilepticus, refractory (disorder)

CLINICAL PEARLS

  • Status epilepticus is life-threatening; begin treatment immediately even before etiology is known.
  • Start with IV lorazepam or IM midazolam and add antiepileptic urgently.
  • If not controlled with first-line drugs, admit to ICU and induce general anesthesia/drug coma.
  • Morbidity/mortality increases with seizure duration.