Approach Considerations
Etiology plays an important role in management and prognosis of status epilepticus (SE) as mortality and morbidity is increased in acute symptomatic seizures from neurological or systematic insults. [5, 6, 7, 8] Etiology varies significantly throughout the lifespan with cerebrovascular pathology being the most frequent cause of SE in adults and fever/infection being the most common cause in pediatric patients.
Treatment of the underlying etiology can be crucial in gaining seizure control and, as such, diagnostic testing should be performed expeditiously. However, not every patient requires the same investigations and the work-up should be guided by history and physical. [9] As per the sample management algorithm above, diagnostic work-up (laboratory testing, EEG, imaging) should be performed concurrently with anti-seizure treatments following stabilization of the patient.
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CBC with differential for signs of infections while being aware of the transient leukocytosis that can occur in prolonged seizures
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Electrolytes, extended electrolytes (magnesium, phosphorus and calcium) - abnormalities can provide clues to a diagnosis or be the SE trigger directly
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Full septic work-up, especially in febrile patients, infants, immunocompromised patients, and prolonged SE of unknown etiology
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If no signs of raised intracranial pressure, lumbar puncture with opening pressure measurement should be performed, especially in febrile patients, infants, immunocompromised patients, and prolonged SE of unknown etiology
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Drug levels in those taking anti-seizure medications
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Urine and blood toxicology screens
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Obtain imaging studies based on likely etiologies; stabilize all children before performing CT or MRI studies. Be aware that prolonged seizures can result in MRI changes that can mimic ischemia and inflammation
Refractory and prolonged SE needs further workup if routine blood work, brain MRI, and microbiological studies in serum and CSF do not provide clues to the etiology of the seizures. The following investigations are considered:
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Screens for inborn errors of metabolism in patients with history suggestive of a metabolic disorder: unexplained neonatal encephalopathy and developmental delay, neurologic deterioration during an acute illness; unusual odors to the urine; unexplained acidosis or coma. Urine organic acids, serum amino acids, porphyrins (porphyria), sulfites (sulfite oxidase deficiency and molybdenum co-factor deficiency), ammonia, lactate, carnitine profile
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Rapid genetic testing (whole exome or epilepsy panel) for prolonged/refractory SE
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Serum T4, T3, thyrotropin, and antiperoxidase antibody (autoimmune epilepsy)
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Autoimmune encephalitis panel - CSF and serum (eg. serum and CSF NMDA-R antibody)
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Other paraneoplastic antibodies (anti Hu, Yo, Ri)
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Ultrasound/CT/MRI of testes and abdomen to look for solid tumors
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Serological markers for collagen-vascular disorders
Every patient who presents with SE requires an EEG and thus making immediate arrangements for an EEG is advisable; however, treatment should not be delayed to wait for EEG results.
EEG is crucial in differentiating between the various classifications of SE: generalized or focal convulsive SE, nonconvulsive SE (NCSE), and absence SE. While convulsive SE occurs with clear clinical signs (tonic, tonic-clonic, clonic motor movements), nonconvulsive and absence status epilepticus (NCSE) is associated with altered awareness without overt clinical signs, or altered awareness with subtle motor signs, such as minimal eyelid blinking. Ongoing ictal activity in NCSE can be missed without EEG monitoring and since the risk of brain injury increases with the length of SE, timely recognition of ongoing seizures is vital.
Furthermore, an EEG done at the time of SE can determine if the electrographic discharges are focal or generalized (making early imaging more important with focal discharges and helping to decide on optimal therapy) as well as distinguish an epileptic event from a nonepileptic event (pseudoseizures or paroxysmal non-epileptic seizures), changing the management needed.
Lab Studies
The choice of laboratory studies is based on age and likely etiologies. They may include the following:
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Blood glucose level
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Complete blood count (CBC)
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Electrolyte levels
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Calcium and magnesium levels, particularly in neonates
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Arterial blood gases
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Toxicology screen
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Anticonvulsant levels (if indicated by history of ingestion or known therapy) [43]
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Full septic work-up including lumbar puncture
Stabilization phase studies
While attending to the patient’s airway, breathing, and circulation (ABCs) and inserting an intravenous (IV) line, obtain a CBC and tests for levels of anticonvulsant medication, electrolytes, blood urea nitrogen (BUN) and creatinine, calcium, and magnesium.
Serum glucose measurement is particularly important if the child or another household member uses insulin or other hypoglycemic agents; hypoglycemia may be a contributing factor or cause of seizures. Rapid bedside glucose measurement is essential.
The CBC may show elevation of the white blood cell (WBC) count in patients with infection. However, an elevated WBC count may be due to demargination, returning to reference ranges over 12-24 hours.
Calcium and magnesium measurement may be important, especially for infants fed with cows' milk. It is also valuable in older patients with disorders that may produce imbalances in these elements (eg, renal failure, hypoparathyroidism).
Other necessary tests may include urine/serum toxicology, especially in teenagers with unexplained seizures. If school-aged children who have cats (particularly kittens) at home present with unexplained mental status changes and prolonged seizures, evaluate for catscratch fever by measuring indirect fluorescent antibody titers to Bartonella henselae. A lumbar puncture is commonly indicated in children with GTCSE, especially those with unexplained fever or mental status changes preceding or following the seizure episode.
Continued evaluation
Continue evaluation after seizures are controlled. Basic tests recommended by the Epilepsy Foundation Working Group on Status Epilepticus include liver function tests (LFTs), toxicology screen, and brain imaging. [44]
After an SE episode, perform a lumbar puncture for individuals with fever or other evidence of CNS infection. Remember that febrile convulsive status may be associated with CNS infection without typical meningeal signs. Brain imaging should be part of the workup for status epilepticus prior to lumbar puncture for patients with acute neurologic changes suggesting increased intracranial pressure.
Imaging Studies
Imaging studies are indicated in patients with convulsive status epilepticus (CSE) after stabilization. A head CT scan is the preferred initial study due to its rapid accessibility and ability to identify life-threatening conditions such as intracranial hemorrhage, cerebral edema, midline shift, fracture, hydrocephalus, or mass lesion.
If increased intracranial pressure is suspected, CT imaging should be obtained prior to lumbar puncture.
Once stabilized, a brain MRI (with and without gadolinium contrast) can be performed. MRI evaluation is of particular importance in patients with histories of neurologic (including mental status) changes or who have deficits on the neurologic examination that persist after cessation of seizures. All children with focal seizures preceding or leading to the episode of CSE should undergo brain MRI.
Brain imaging may be unnecessary for patients who have already had MRI performed as part of a work-up for epilepsy or when the cause or precipitant for their episode of SE is obvious (eg, low anticonvulsant levels, acute infection).
On follow-up, many patients with documented a priori normal MRI findings may develop an increased T2, diffusion, and fluid attenuated inverted recovery (FLAIR) signal. This is especially true in cases of prolonged partial seizures leading to secondary GTCSE. Most of these changes are due to transient vasogenic or cytotoxic edema.
Electroencephalography
While acute stabilization and initial seizure management should not be delayed while awaiting EEG electrode placement, a patient should have EEG monitoringin place as soon as possible, as it plays a crucial role in management of SE.
During a prolonged convulsive seizure, EEG manifestations often follow a sequence of repetitive focal seizures progressing into discrete diffuse tonic-clonic seizures that eventually become fused (ie, continuous EEG seizure). Eventually, in prolonged SE, the EEG can progress through a variety of rhythmic, repetitive, and periodic patterns. A patient who arrives at the ED may be at any of these EEG stages; historical information concerning seizure progression usually correlates with stage.
Patients who require continuous infusion with a barbiturate or benzodiazepine should undergo continuous EEG monitoring.
As SE progresses and is complicated by increasing doses and numbers of sedating medications, the EEG can become more difficult to interpret, with various degrees of suppression, slowing, rhythmicity, and periodicity that are not always clearly ictal. Knowing when not to escalate treatment further is an important part of SE management, and the EEG is crucial in deciding when someone's seizure has stopped.
Several possibilities exist to explain persistent decreased consciousness following the end of a clinical seizure: nonconvulsive status epilepticus (NCSE), postictal state–related depression and unresponsiveness from metabolic (renal and hepatic) or anoxic encephalopathies. Without EEG monitoring, it can be impossible to differentiate these etiologies.
In 2021, the American Clinical Neurophysiology Society published an updated guideline on Standardized Critical Care EEG Terminology [45] to help standardize critical care EEG reporting. While a detailed discussion of that topic is beyond the scope of this article, clinical examination (state changes, autonomic changes) combined with careful interpretation by a trained electroencephalographer is required to help guide ICU management.
Finally, EEG recording of the ictal events helps in differentiating convulsive status epilepticus (SE) from non-epileptic seizures (paroxysmal non-epileptic seizures - PNES) and pseudoseizures.
Workup for Prolonged Refractory Status Epilepticus
Seizures not responding to the first- and second-lines drugs (initial doses of benzodiazepines, IV phenytoin/fosphenytoin, Keppra, valproic acid, phenobarbital) should be considered refractory status epilepticus (RSE). Prolonged refractory status epilepticus (seizures persisting beyond 24 h) needs further work-up if routine blood work, MRI of the brain, and microbiological studies in serum and cerebrospinal fluid (CSF) do not provide clues to the etiology of the seizures.
Ongoing work-up for refractory SE may include:
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Screens for inborn errors of metabolism in patients with history suggestive of a metabolic disorder: unexplained neonatal encephalopathy and developmental delay, neurologic deterioration during an acute illness; unusual odors to the urine; unexplained acidosis or coma. Urine organic acids, serum amino acids, porphyrins (porphyria), sulfites (sulfite oxidase deficiency and molybdenum co-factor deficiency), ammonia, lactate, carnitine profile
-
Genetic testing (whole exome or epilepsy panel) for prolonged/refractory SE
-
Serum T4, T3, thyrotropin, and antiperoxidase antibody (autoimmune epilepsy)
-
Autoimmune encephalitis panel - CSF and serum (eg, serum and CSF NMDA-R antibody)
-
Other paraneoplastic antibodies (anti Hu, Yo, Ri)
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Ultrasound/CT/MRI of testes and abdomen to look for solid tumors - associated with paraneoplastic antibodies and autoimmune encephalitis
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Serological markers for collagen-vascular disorders
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Repeat MRI brain with gadolinium
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Cerebral angiography (CT angiography or conventional 4-vessel angiography) to look for evidence of vasculitis if an autoimmune disorder is suspected
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CSF neurotransmitters
If these investigations do not identify the etiology of seizures within a week, a brain biopsy should be considered.
Investigators have developed an automated identification quality measurement for pediatric convulsive SE and refractory convulsive SE (RCSE) that has the potential to allow automated time-to-treatment calculation and assess RCSE quality. [46]
A multidisciplinary team should be convened in the setting of refractory SE to include specialists from Pediatric Neurology, Critical Care, Rheumatology, Genetics, and Infectious Disease.
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Pediatric Status Epilepticus. Treatment algorithms for convulsive status epilepticus.
Tables
Step |
Medication |
Dose |
Alternatives |
Step 2 (5-10 min) |
Diazepam (Valium) |
5-20 mg IV slowly; not to exceed infusion rate of 2 mg/min; pediatric dose is 0.3 mg/kg |
If IV line is unavailable, use rectally administered (PR) diazepam at 0.5 mg/kg (not to exceed 10 mg) or midazolam (Versed) at 0.2 mg/kg IM*, IV, or intranasal* |
Lorazepam* (Ativan) |
2-4 mg IV slowly*; not to exceed infusion rate of 2 mg/min or 0.05 mg/kg over 2-5 min; pediatric dose is 0.05-0.1 mg/kg |
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Step 3 (10-30 min) |
Phenytoin (Dilantin) or fosphenytoin (Cerebyx)† |
Phenytoin:20 mg/kg IV over 20 min; not to exceed infusion rate of 1 mg/kg/min; do not dilute in 5% dextrose in water (D5W) Fosphenytoin: 15-20 mg/kg IV; not to exceed infusion rate of 2 mg/kg/min or 150 mg/min whichever is slower; dilute in D5W or NS |
Sodium valproate 40 mg/kg IV, max 3000 mg or levetiracetam 60 mg/kg IV, max dose 4500 show equal efficacy to fosphenytoin. If unsuccessful, administer phenobarbital 10-20 mg/kg IV (not to exceed 700 mg IV); phenobarbital may be used in infants before phenytoin; be prepared to intubate patient; closely monitor hemodynamics and support blood pressure as indicated. |
Step 4 (30+ min)‡ |
Pentobarbital anesthesia (patient already intubated) |
Loading dose: 5-7 mg/kg IV; may repeat 1-mg/kg to 5-mg/kg boluses until EEG exhibits burst suppression; closely monitor hemodynamics and support blood pressure as indicated Maintenance dose: 0.5-3 mg/kg/h IV; monitor EEG to keep burst suppression pattern at 2-8 bursts/min |
Midazolam* infusion loading dose: 100-300 mcg/kg IV followed by IV infusion of 1-2 mcg/kg/min; increase by 1-2 mcg/kg/min every 15 min if seizures persist (effective range 1-24 mcg/kg/min); closely monitor hemodynamics and support blood pressure as indicated; when seizures stop, continue same dose for 48 h then wean by decrements of 1-2 mcg/kg/min every 15 min Propofol* initial bolus: 2 mg/kg IV; repeat if seizures continue and follow by IV infusion of 5-10 mg/kg/h, if necessary, guided by EEG monitoring; taper dose 12 h after seizure activity stops; closely monitor hemodynamics and support blood pressure as indicated With phenobarbital-induced anesthesia, repeated boluses of 10 mg/kg are administered until cessation of ictal activity or appearance of hypotension; closely monitor hemodynamics and support blood pressure as indicated |
*Not approved by the FDA for the indicated use. †Doses for fosphenytoin administered in phenytoin equivalents (PE). ‡An alternative third step preferred by some authors is midazolam administered by continuous IV infusion with a loading dose 0.1-0.3 mg/kg followed by infusion at a rate of 0.1-0.3 mg/kg/h. |
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