Cannabidiol for Status Epilepticus: A Case of Unrealistic Expectations

CASE REPORT

An 18-year-old man, who lives in New Zealand, presents with new-onset generalized convulsive status epilepticus after a short, non-specific illness characterized by fever and myalgia.¹ The initial MRI scan of the brain is normal, and a lumbar puncture reveals normal cerebrospinal fluid (CSF) protein levels, no glucose, and no blood cells. An autoimmune etiology is considered, and daily methylprednisolone is started. The patient is also given appropriate antiepileptic drugs (AEDs).

Three days after presentation, he is transferred to a regional hospital, where he receives care in the intensive care unit (ICU) and is anesthetized, intubated, and ventilated.

Laboratory and imaging results

Serum biochemistry results are normal. A full neurologic antibody screen of both CSF and serum is negative. Blood and CSF cultures show no growth.

Results of repeated brain MRI scans and lumbar puncture are normal. CT scans of the chest, abdomen, and pelvis are normal, as is a testicular ultrasound scan.

Diagnosis

The patient receives a presumptive diagnosis of cryptogenic new-onset refractory status epilepticus (NORSE), with a suspected autoimmune etiology.

Treatment course

High-dose methylprednisolone is started, followed by intravenous (IV) immunoglobulin and five cycles of plasma exchange. Because of lack of response to these treatments, the patient also receives trials of prednisolone, cyclophosphamide, and rituximab-all to no effect.

To protect the brain, he is maintained on burst suppression, which is confirmed by continuous electroencephalographic monitoring. Repeated attempts to wake the patient confirm multifocal, bilateral sustained electrographic seizures. He undergoes several failed trials of AEDs, including pyridoxine, phenobarbitone, phenytoin, sodium valproate, lacosamide, and levetiracetam. A ketogenic diet is also attempted, with no reduction in seizures.

For sedation, he receives midazolam throughout his ICU course. He also undergoes failed trials of concomitant propofol, diazepam, thiopentone, and ketamine.

After the patient spends 2 months in the ICU, his family requests a trial of cannabidiol (CBD) oil, which is not available in New Zealand. A literature review reveals no support for the treatment, and the hospital ethics committee is consulted. Given the patient’s poor prognosis, the inability to attain seizure freedom, and the family’s strong desire to try CBD, the ethics board agrees to a trial of the agent.

Elixinol (18% CBD) is obtained from the United States with permission from the New Zealand government. It is administered at 2.5 mg/kg via nasogastric tube, along with concomitant IV levetiracetam, lacosamide, and phenobarbitone. Dosages of the latter two drugs are decreased because of the risk of toxicity. Four days after CBD oil is started, the phenobarbitone level is within normal range. Checking lacosamide levels is not possible.

Over 2 weeks, the dose of Elixinol is increased to a maximum of 24 mg/kg. At that time, attempts are made to lighten the patient’s sedation, but the underlying electroencephalogram remains unchanged.

In consultation with the clinical team, the family agrees that further treatment is unlikely to succeed and opts for palliative care. CBD is continued at the family’s request. The patient dies after withdrawal of treatment, 88 days after presentation.

Next: the case discussion

Discussion

This is the first report of the use of CBD to treat status epilepticus.¹

The use of CBD to treat epilepsy has garnered much attention, especially in the outpatient setting. For some, CBD may represent a “natural product,” with fewer adverse effects than AEDs. Patients may think they have little to lose by trying it.

However, this may not be the case. A 2014 systematic review by the American Academy of Neurology concluded that not enough evidence exists to support or deny the efficacy of cannabinoids in the treatment of epilepsy. Yet, these agents have been linked to increased seizures, increased levels of AEDs, and cognitive impairment, as well as rare cases of suicide and death.²

In 2018, the American Epilepsy Society stated that research has progressed on the use of CBD for refractory epilepsy. The results of several double-blind randomized controlled trials suggested that the agent may be moderately more effective than placebo for treating seizures in Lennox-Gastaut syndrome and Dravet syndrome. However, the studies also found that CBD has more adverse effects and drug-drug interactions than placebo. The statement concluded:

“The results of these scientifically rigorous randomized clinical trials provide hope for the eventual development of a pharmaceutical formulation of purified CBD to treat epilepsy, but such a product is not currently available in the U.S. or FDA approved for patient use.”³

In this tragic case of a teenager with NORSE, CBD-while ultimately ineffective-may have addressed a need by the family to try everything, which in turn may have facilitated transition to palliative care.

The cause of NORSE remains unknown. Affected individuals are often young, with no history of epilepsy, and have a febrile prodrome. They may have initial CSF pleocytosis suggestive of an infective or autoimmune etiology. The outcome is often fatal, or results in severe neurological sequelae.⁴

Research offers little guidance on the treatment of refractory status epilepticus. Guidelines issued by the Neurocritical Care Society in 2012 recommend continuous infusion of AEDs after failure of bolus intermittent therapy.⁵ AEDs commonly recommended for continuous infusion include midazolam, propofol, and pentobarbital. Evidence is insufficient to recommend a preferred agent.

At the time of the guidelines, no data existed to guide intensity and duration of treatment. Also, the number of trials of electrographic seizure control before deeming therapy to be futile had not been defined. Reports exist of functional recovery after weeks to months of treatment for refractory status epilepticus.⁴

Take-home points

• The case concerns a teenager with presumed new-onset refractory status epilepticus (NORSE) of unknown origin, which did not respond to multiple trials of antiepileptic drugs, immunotherapy, and cannabidiol

• Evidence suggests that cannabidiol may be moderately effective for treating refractory seizures in some genetic disorders, but it has more adverse effects than placebo

• NORSE is often fatal

References:

1. Rosemergy I, Adler J, Psirides A. Cannabidiol oil in the treatment of super refractory status epilepticus. A case report. Seizure. 2016;35:56-58.

2. Koppel BS, Brust JC, Fife T, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82:1556-1563.

3. American Epilepsy Society. AES position on cannabis as a possible treatment for epileptic seizures. March 20, 2018. Accessed September 16, 2018.

4. Gall CR, Jumma O, Mohanraj R. Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early immunotherapy. Seizure. 2013;22:217-220.

5. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17:3-23.