EM Didactic: Status Epilepticus

Background

Status Epilepticus (SE) is the second-most frequent life-threatening neurological emergency after stroke that bears considerable risks of morbidity and mortality. SE requires emergent, targeted treatment to reduce patient morbidity and mortality but the treatment strategies vary substantially from one institution to another due to the lack of data to support one treatment over another. Rapid control of seizures is fundamental to the emergency treatment of SE. Adverse effects may include systemic problems arising from seizures (e.g., impaired ventilation, pulmonary aspiration, and metabolic aberrations) or due to direct neuronal cellular injury from excitotoxicity.

Definition and Classification

SE is defined as 5 min or more of continuous clinical and/or electrographic seizure activity or recurrent seizure activity without recovery between seizures
SE is further classified as either convulsive SE (convulsions that are associated with rhythmic jerking of the extremities) or non-convulsive SE (seizure activity seen on EEG without the clinical findings associated with convulsive SE)
Refractory SE (RSE) should be defined as SE that does not respond to the standard treatment regimens, such as an initial benzodiazepine followed by another AED. Although some experts consider failure of the first drug i.e. BZD to terminate seizure as RSE.

Rationale for changing the traditional 30 minutes definition to 5 minutes

Animal data suggests that permanent neuronal injury may occur before the traditional definition of 30 min of continuous seizure activity have passed. Evidence also demonstrates that seizures that do not cease in 5-10 minutes are less likely to terminate without intervention (Pharmacoresistance).

Pathophysiology

In short - excess excitation and reduced inhibition. However, the failure of inhibitory processes is increasingly thought to be the major mechanism leading to SE.

Excitatory neurotransmitters: Glutamate, NMDA

Inhibitory neurotransmitters: GABA

Most seizures terminate spontaneously within several minutes but with continuing seizures, inhibitory GABA receptors are internalized in clathrin coated vesicles and at the same time, excitatory N-methyl-d-aspartate (NMDA) receptors may be mobilized to the membrane. This receptor trafficking results in a decreased inhibitory control and increased excitation that may lead to continuing status epileptics. The internalization of GABA receptors may explain the clinical finding that benzodiazepines are less effective as seizure durations increase.

Possible Etilogy

AED Non-Compliance
Stroke
Hypoxic injury, Traumatic Brain Injury
Drugs and Toxins (eg, cocaine, theophylline, INH)
Withdrawal (Opioid, BZD, Barbiturates, Alcohol)
Electrolyte abnormalities
Renal Failure, Liver Failure
Neoplasms
CNS infections (eg, meningitis, brain abscess, encephalitis)
Autoimmune Encephalitis

Management

All patients need a

Fingerstick glucose

Vital signs monitoring

Head computed tomography (CT) scan is required for most

Order laboratory test: blood glucose, complete blood count, basic metabolic panel, calcium (total and ionized), magnesium, AED levels.

Continuous electroencephalograph (EEG) monitoring

Consider these based on clinical presentation

Brain magnetic resonance imaging (MRI)

Lumbar puncture (LP)

Comprehensive toxicology panel including toxins that frequently cause seizures (i.e. isoniazid, tricyclic antidepressants, theophylline, cocaine, sympathomimetics, alcohol, organophosphates, and cyclosporine)

Other laboratory tests: liver function tests, arterial blood gas, AED levels, toxicology screen (urine and blood), and inborn errors of metabolism.

The treatment of convulsive SE should occur rapidly and continue sequentially until clinical seizures are halted. The goal of treatment is to stop the seizures (both clinical and electrographic) as soon as possible. The initial treatment strategy includes simultaneous assessment and management of airway, breathing, and circulation (obtain IV access, administer O2, and securing the airway as needed), seizure abortive drug treatment, screening for the underlying cause of SE, and immediate treatment of life-threatening causes of SE (e.g., meningitis).

Benzodiazepines are the drugs of choice. Lorazepam is the drug of choice for IV administration and Midazolam is the drug of choice for IM administration. Early intubation is advisable if continuous intravenous AEDs are necessary.

Options for RSI meds include Propofol and Ketamine and this is a scenario where you might consider skipping the paralytics. If you are using them, beware of succinyl choline induced hyperkalemia in prolonged seizures or a chronic neurological illness. If you are using Rocuronium, get the continuous EEG to pick convulsions in a paralysed patient.

The diagnostic labs are selected depending on the patient’s history and physical examination. Not every diagnostic study is required in every patient. For instance, a lumbar puncture is needed if there is any suspicion of a central nervous system (CNS) infection, but may not be required if patients gives a history of AED non-compliance.

Dosing and Considerations when using second and third line agents

Dosing of continuous infusion AEDs for RSE should be titrated to cessation of electrographic seizures or burst suppression.

Propofol comes with issues like severe hypotension and propofol related infusion syndrome. Midazolam appears to be safer and less hypotensive. Be prepared to start a vasopressor drip to maintain blood pressure or switch to ketamine.

Alternative therapies: Reserve these therapies for patients in RSE

Ketamine (3 mg/kg IV followed by an infusion of at least 1 mg/kg/hr up to 10 mg/kg/hr.)
Hypothermia
Inhales Anesthetics (Isoflurane)
Ketogenic Diet
Steroids, ACTH
Immunomodulation (IVIG or Plasma Exchange)
Electroconvulsive therapy
Vagus Nerve Stimulation
Repetitive Transcranial Magnetic Stimulation
Surgical Management

Medications are more likely to terminate seizures when given closer to the seizure onset and they decrease in effectiveness as seizure duration increases, most likely related to changes in the neuronal gamma aminobutyric acid (GABA) receptor subunit composition as a function of time.

Rationale for using Ketamine

There is growing evidence that increasing refractoriness to treatment is partly the result of progressive impairment of GABA mediated inhibition as a result of internalization of GABA receptors under conditions of sustained excitability. Due to this internalisation , GABAergic drugs dare less likely to work for sustained SE. There is also evidence for increased numbers of N-methyl-D-aspartic acid (NMDA) receptors at the synaptic membrane that results in increased sensitivity to excitatory neurotransmitters. The rationale behind using Ketamine is an attempt to antagonise the excitatory NMDA system as GABAergic system is impaired.

Take Home

Seizure onset to drug delivery time is more important then debating which BZD works better. Be aggressive while treating SE because pharmacoresistance develops over minutes.

Never forget that NCSE can present as coma and maintain a low threshold for obtaining a bedside EEG.

Ketamine is definitely an option for refractory status epilepticus.

Further Reading:

Shinnar S, Berg AT, Moshe SL, Shinnar R. How long do new-onset seizures in children last? Ann Neurol 2001;49:659-64.
Gaspard N, Foreman B, Judd LM, et al. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multi-center study. Epilepsia. 2013;54(8):1498-1503. doi:10.1111/epi.12247.
Treatment of Refractory Status Epilepticus: Literature Review and a Proposed Protocol Nicholas S. Abend, MD and Dennis J. Dlugos
Glauser, Tracy, et al. "Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society." Epilepsy Currents 16.1 (2016): 48-61.
Rossetti, Andrea O., and Thomas P. Bleck. "What's new in status epilepticus?." Intensive care medicine 40.9 (2014): 1359.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731413/pdf/nihms481665.pdf
Emergency Medicine Practice - Evidence Based Medicine - Clinical Decision Making In Seizures And Status Epilepticus
Lowenstein, Daniel H., and Brian K. Alldredge. "Status epilepticus." New England Journal of Medicine 338.14 (1998): 970-976.
www.neurocriticalcare.org
Brophy, Gretchen M., et al. "Guidelines for the evaluation and management of status epilepticus." Neurocritical care 17.1 (2012): 3-23.