Topic Editor: Grant E. Fraser, M.D., FRACGP, FACRRM, ASTEM
Review Date: 12/10/2012
Definition
Status epilepticus (SE) is a serious neurologic disorder characterized by a prolonged, continuous seizure of >30 minutes, or "two or more sequential seizures without full recovery of consciousness between seizures."
Description
- Status epilepticus (SE) is a neurological emergency with high mortality and morbidity
- The indigenous inhibitory mechanisms in the brain that terminate a seizure are not effective in SE
- Continuous or repetitive seizures lasting for >60 min despite treatment with a benzodiazepine and another standard anticonvulsant is defined as refractory status epilepticus (RSE)
- SE should be diagnosed and treated as early as possible to avoid the refractory state and to ensure that the best patient outcome
- Classification: There is no consensus on a classification system for SE, although SE may be considered convulsive or nonconvulsive based on clinical observation of overt convulsions. Some clinicians classify SE according to whether the seizures arise from a localized region of the cortex (partial) or from both hemispheres of the brain (generalized)
- Convulsive SE:
- On the basis of seizure type, SE is further classified as tonic-clonic SE, tonic SE, clonic SE, or myoclonic SE
- Generalized convulsive SE (GCSE) is the most common form observed in clinical practice. It is manifested as prolonged convulsions with impaired consciousness
- Nonconvulsive status epilepticus (NCSE):
- Continuous generalized electrical seizure for at least 30 min with no physical convulsion is referred to as NCSE
- NCSE is characterized by abnormal mental status, unresponsiveness, ocular motor abnormalities, coma, persistent electrographic seizures, with potential response to anticonvulsants
- NCSE is further classified as either generalized (absence) or focal (complex partial) SE
- Simple partial SE is defined by prolonged focal seizures, such as isolated hand jerking, with intact consciousness
Epidemiology
Incidence/Prevalence
- In Europe and the U.S., the incidence is ~20/100,000 patients
- Incidence in developing nations is thought to be higher, although accurate data on SE is not available
- Approximately 55,000 SE related deaths occur annually in the U.S.
- Short and long term mortality rates depend on numerous factors including etiology and age; 30-day mortality ranges from 8% to 22%, with 10-year mortality of 43%
- NCSE comprises 25% to 50% of SE cases
Age- There is a bimodal distribution with peaks in children aged <2 years (mean age 4.4 years in pediatrics) and in the adults>60 years
- Incidence of SE among the elderly is higher than in the general population
Gender- Men are more frequently affected than women
Race- Blacks have a higher incidence of SE than other races
Risk Factors - Age extremes (young or elderly)
- Alcohol withdrawal
- Alzheimer's Dementia
- Anoxia
- Antiepileptic drug withdrawal or non-compliance with antiepileptic therapy
- Autism
- Autoimmune diseases
- Benzodiazepine or barbiturate withdrawal
- Brain tumor or other central nervous system lesion
- Cerebral palsy
- Eclampsia
- Encephalitis
- Epilepsy or prior SE
- Febrile illness (in children
6 years of age) - Genetic predisposition
- Head trauma (acute or in past)
- Hypoglycemia
- Intracranial hemorrhage
- Isoniazid (INH) overdose
- Meningitis
- Metabolic disorders
- Neurodegenerative disorders
- Porphyria (often refractory SE)
- Serotonergic drug use (serotonin syndrome)
- Stimulant abuse (amphetamines, MDMA, cocaine)
- Stroke
- Tricyclic antidepressant overdose
Etiology
- Alcohol withdrawal or intoxication
- Anoxia or hypoxia
- Cardiac arrest
- Cerebral tumors or trauma (especially involving the frontal lobe)
- Cerebrovascular disease
- Congenital or perinatal causes (e.g. cerebral palsy)
- Drug overdose (TCA's, INH, stimulants such as amphetamines, MDMA, cocaine)
- Eclampsia
- Febrile seizures in children
- Genetic disorderd
- Idiopathic
- Intracranial infection (meningitis/encephalitis)
- Immunological disorders
- Metabolic disorders: hyponatremia, hypoglycemia, uremia
- Mitochondrial disorders
- Noncompliance with anticonvulsant drug regimens
- Preexisting seizure disorder
- Pregnancy-related eclampsia
- Serotonin syndrome
- Stroke
- Toxin-induced SE
- Withdrawal from antiepileptics, benzodiazepines or barbiturates
History
Patients may present with a history of:
- Behavioral changes, withdrawal, or irritability
- Change in or withdrawal of antiepileptic medications
- Drug/alcohol use or withdrawal
- Family history of seizures
- Fever
- Head trauma
- Neurological or congenital abnormalities
- Prior seizures
- Stimulant or serotonergic drug use
Physical findings on examination
- In generalized convulsive SE (GCSE), patients may present with tonic and/or clonic activity, cyanosis, frothing, respiratory depression, unconsciousness, incontinence, and tongue biting
- Other neurological findings in GCSE include ocular deviation, fine nystagmus, or subtle jaw, lip, finger, or eyelid twitch progressing to electrical activity without physical correlation
- In non-convulseive SE (NCSE), there is continuous generalized electrical seizure activity for at least 30 minutes without physical convulsions
- NCSE clinical manifestations include coma, somnolence, altered affect, fugue states, aphasia, abnormal autonomic/vegetative symptoms, delusions, agitation, confusion, hallucinations, nystagmus, unusual behaviors, and paranoia
- Postictal findings include autonomic disturbances, such as tachycardia, cardiac arrhythmia, hyperventilation (to compensate and recover from metabolic acidosis), hypertension, fever, hypersalivation, mydriasis, positive Babinski sign, decreased corneal reflex, and vomiting
Blood test findings
Blood tests are typically required emergently
- Blood glucose: Hypoglycemia may precipitate SE and is a critical test to obtain on presentation
- Complete Blood Count: Elevated white blood cell counts generally are of no value as they simply represent a stress reaction to the seizure. It is not uncommon to have WBC's >20,000/hpf, with a left shift, with SE. It is unclear how to interpret this in relation to whether an infective cause might be present. A low platelet count may increase concern regarding an infective cause
- Serum electrolytes: Electrolyte level abnormalities, hypernatremia, hyponatremia (e.g. water intoxication with MDMA), hypoglycemia, hyperkalemia may be present
- Renal function test: Elevated serum creatinine level may be present
- Toxicological screening: May be useful; however, ECG findings, history, and physical examination findings are generally sufficient to rule out or include drug abuse or overdose
- Antiepileptic drug levels in patients taking such medications
- Metabolic and genetic testing: For consideration in children to evaluate for inborn errors of metabolism
- Arterial blood gases
- To assist in the determination on whether intubation and ventilatory support are needed. Respiratory or metabolic acidosis are often present in SE
- Prolonged decreased alertness and ongoing seizure activity despite medications typically indicates need for intubation and ventilatory support (regardless of ABG findings)
Other diagnostic tests
Lumbar puncture
- This test is indicated when a patient with SE requires evaluation for either infection or hemorrhage
Radiographic findings
- Electroencephalography
- EEG is the standard test for diagnosis and management of SE and helps classify the epilepsy as focal or generalized. 24-hr EEG may be necessary to establish diagnosis and to ensure recurrent seizures are not missed. Generalized, diffuse, or focal ictal discharge are observed.
- Unfortunately, EEG is rarely available acutely in the emergency department.
- CT scan
- CT scan of brain is reasonable to exclude hemorrhage or mass lesion in cases of SE, focal seizure, neurologic deficit, or trauma
- Head MRI
- MRI is more sensitive than CT scan; it will show an abnormality in 10% to 20% of patients with a generalized tonic-clonic seizure and a normal CT scan. Cytotoxic and vasogenic edema, hyperperfusion of the epileptic region, and alteration of the leptomeningeal blood-brain barrier may be observed. Patient's with SE undergoing MRI typically will be intubated and receiving ventilatory support and sedation.
Generalized convulsive SE
- Acute ballismus or chorea
- Clonus
- Decerebrate spasms
- Malignant hyperthermia
- Myoclonus
- Neuroleptic malignant syndrome
- Paroxysmal dyskinesia
- Periodic limb movement disorder
- Psychogenic seizures
- Shivering
- Status dystonicus
- Tetanus
- Tremor
Partial SE
- Asymmetric tremor
- Blepharospasm
- Focal dystonia
- Hemifacial spasm
- Myoclonic jerks
- Palatal myoclonus
- Paroxysmal nocturnal dyskinesia
- Tic disorder
Nonconvulsive SE
- Akinetic mutism
- Akinetic rigidity
- Amnesia, Total Global Amnesia (TGA)
- Atonic disorders
- Cataplexy
- Catatonia
- Cognitive disorders
- Encephalitis
- Encephalopathy
- Locked-in syndrome
- Periodic paralysis
- Psychiatric disorders
- Psychogenic seizures
- Sleep disorders
Treatment
- The focus is maintenance of ABCs (Airway/Breathing/Circulation), along with treatment is terminate the convulsions with appropriate pharmacotherapy
- The first step in the management of a patient with SE is to ensure adequate airway, breathing, and circulation. If the airway is clear and intubation is not immediately required, blood pressure, heart rate and cardiac rhythm should be assessed and high flow oxygen applied
- If appropriate pharmacotherapy results in the seizure being brought under control, the cause of SE should be evaluated, and precautions taken to prevent complications and seizure recurrence
- In the event initial pharmacotherapy with benzodiazepines plus at least one typical anticonvulsant is unsuccessful in terminating the seizure; the patient has refractory SE and usually requires airway support (intubation) and additional pharmacological therapy
- Once the seizure has terminated, the next steps include assessment of the etiology, appropriate laboratory testing, and ongoing needs for anticonvulsants
- In the pre-hospital setting, appropriate supportive care includes maintenance of a patent airway, application of high flow oxygen, assessment of blood glucose, and administration of benzodiazepines when seizure continues beyond 5 mintues
- Hypoglycemia may precipitate SE. If hypoglycemia is suspected, 50 mL of 50% glucose should be administered immediately by IV bolus
- Thiamine should be given after glucose infusion in chronic alcoholics, as some literature supports an increased risk of Wernicke's encephalopathy in such patients
- Monitor oximetry to ensure adequate oxygenation. Venous blood gas can be used to examine degree of acidosis and any CO2 retention. If oximetry is not adequately correlating or if the patient is intubated (or intubation being considered) arterial blood gas is indicated, along with consideration of placing an arterial line
- Patients should be monitored for recurrent seizures with EEG for at least 24 hours after an episode
- Hyperthermia should be treated with passive cooling and adequate hydration maintained to prevent myoglobin-induced renal failure (rhabdomyolysis)
- As most simple seizures last for 5 minutes, those which do not spontaneously resolve within 5 minutes (and are not due to hypoglycemia) should have prompt benzodiazepines and thereafter should be considered for loading with standard anticonvulsant drugs (e.g. phenytoin, valproate, phenobarbital, levetiracetam)
- Patients who do not respond to first-line therapy (e.g. benzodiazepines) are considered to have RSE, and are at higher risk of complications, extended hospital stay, and mortality
- RSE patients should generally be intubated and ventilated, administered more aggressive pharmacotherapy, and be admitted to ICU
Pharmacological management
- Pharmacologic therapy aims for rapid seizure termination and prevention of recurrence. Ideally, such therapies would not further worsen consciousness level or create additional adverse effects on the cardiovascular and/or respiratory systems of the seizure and to prevent its recurrence, without affecting consciousness level, and avoiding adverse effects on cardiovascular and respiratory systems
- Both clinical and EEG termination of seizures within 20 minutes, with no recurrence within 60 minutes from the start of therapy is considered successful treatment
Benzodiazepines
- Benzodiazepines (diazepam, lorazepam, midazolam) are the first-line drugs for termination of SE. Benzodiazepines are associated with the risk of excessive sedation, respiratory depression, and hypotension
- Midazolam is commonly utilized as it can be administered buccal, intranasal, IM or IV. Other options include IV/IM lorazepam or diazepam, or diazepam PR. Lorazepam is preferred over diazepam due to its longer anticonvulsant effect (>6 hrs) and less risk of respiratory depression
- In prehospital management, administer lorazepam or midazolam if venous access is available. Consider buccal, nasal, or intramuscular midazolam, or rectal diazepam in the absence of venous access
Hydantoin
- Hydantoins, either fosphenytoin or phenytoin are typical second-line therapy in SE. Fosphenytoin has advantages over phenytoin as phenytoin carries some risk of cardiac arrhythmia and hypotension. Fosphenytoin (max 150 mg/min) also has the advantage of a more rapid infusion time than phenytoin (max 50 mg/min)
Valproate IV route
- May be a therapeutic option for patients with cardiorespiratory impairment or used as a second or third line therapy
- Valproate is nonsedating, able to be rapidly infused, and is both well tolerated and effective in patients with SE
Levetiracetam IV route
- May be a therapeutic option for patients with cardiorespiratory impairment or used as a second or third line therapy
- Levetiracetam is nonsedating, able to be rapidly infused, and is both well tolerated and effective in patients with SE
Phenobarbital IV route
- A long-acting barbiturate, phenobarbital is typically used in patients who have failed to respond to first and second line therapies
- This agent is effective in termination of SE, but often results in significant airway compromise. As patients who have failed other therapies should generally already be intubated and have a protected airway, administration is generally safe in that setting
Propofol
- Propofol is CNS depressant, commonly used for the induction and maintenance of anesthesia, and for sedation in the ICU
- Propofol is a reasonable therapy for refractory SE
Thiopental
- Barbiturate – anesthetic agent used to treat refractory SE
- No clear evidence of superiority to Propofol (or vice-versa)
Topiramate
- In a small study, nasogastric topiramate along with conventional anticonvulsants was found to be effective in treating RSE
Medications indicated with specific doses
Benzodiazepines
- Diazepam [IM/IV]
- Lorazepam [IM/IV]
- Midazolam [IM/IV]
Hydantoins- Phenytoin [IM/IV]
- Fosphenytoin [IM/IV]
Other Agents- Phenobarbital [IM/IV]
- Propofol [IV]
- Valproate [IV]
- Levetiracetam [IV]
Dietary or Activity restrictions
- Patients should be advised to follow a ketogenic diet (high fat, adequate protein, low carbohydrate), a diet enriched in polyunsaturated fatty acids or generally restrict calorie intake
- Excess intake of glutamate and caffeine should be restricted as they may worsen seizures
- Sleep deprivation and other provoking factors (flashing lights, video games) should be avoided
- Patients should be restricted from driving, operating machinery or participating in activities which could harm themselves (swimming alone, climbing up a ladder, working on roof, etc.) or others in the event of repeat seizure, consistent with local laws
Disposition
Admission criteria
- SE is a medical emergency which needs aggressive therapy and ICU admission
Discharge Criteria- Clinically stable patients with seizure resolution and 24 hours of observation can be discharged, with appropriate outpatient followup and activity restrictions
- Patients should generally be discharged on a regular oral anticonvulsant medication
Prevention
- In patients with previous history of SE, adequate maintenance therapy should be instituted to prevent relapse
- If a seizure lasts >5 minutes, treatment with midazolam (buccal, IN) or rectal diazepam by trained caregiver may prevent the evolution of seizures to SE
- Educate family and caregivers regarding first aid for seizures
Prognosis
- In large hospital-based studies mortality due to SE varies from 3% to 50%
- High mortality from SE is associated with longer duration of seizures, older age of onset (>70 yrs), and underlying etiology (CNS infection, anoxia, stroke)
- Cardiovascular changes during status epilepticus, medical complications and overtreatment may also affect overall mortality
- Morbidity associated with SE includes epilepsy, cognitive impairment, incoordination, motor weakness, dysphasia, dysarthria and visual field defects
- Refractory SE has a worse prognosis with almost 50% mortality
- A 2012 study that excluded anoxic RSE patients demonstrated that 3/4ths had a poor outcome, with mortality of 32%. The conclusion was that "achieving control of the SE without requiring prolonged drug-induced coma or severe electroencephalographic suppression portends better prognosis."
Pregnancy/Pediatric effects on condition
- Prenatal exposure to antiepileptic drug use is associated with a significantly increased risks of fetal abnormalities and fetal death
- When treating pregnant women who have epilepsy, the risks of increased seizures versus the risks of antiepileptic drug use must be weighed carefully
- SE is more common in children aged >2 years (mean age 4.4 years)
- The most common causes of SE in children >1 year are prolonged febrile seizures and acute symptomatic seizures
- In older children, SE occurs mostly in those with a history of epilepsy who also have neurological abnormalities
ICD9-CM
- 345.3 Grand mal status, epileptic
ICD-10-CM
- G41 Status epilepticus
- G41.0 Grand mal status epilepticus
- G41.1 Petit mal status epilepticus, Epileptic absence status
- G41.2 Complex partial status epilepticus
- G41.8 Other status epilepticus
- G41.9 Status epilepticus, unspecified
