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Cannabidiol in refractory status epilepticus

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A UK-based study found that 4% of admissions to a tertiary paediatric intensive care unit (PICU) over a 10-year period were due to refractory status epilepticus (RSE) – seizures which fail to terminate despite appropriate first and second-line treatments.

Of those patients admitted with RSE, a subset will go on to develop super-refractory status epilepticus (SRSE). SRSE can develop in patients with no prior history of a seizure disorder, such as in NORSE (New Onset Resistant Status Epilepticus) or FIRES (Febrile Infection-Related Epilepsy Syndrome) and those patients with pre-existent seizure disorders. Super-refractory status epilepticus is associated with high morbidity and mortality and poses significant management challenges.

A 4-year-old boy is admitted to your PICU.

He has a diagnosis of epilepsy and was on multiple anti-seizure medications as well as a ketogenic diet.

He had been on the ward for some time due to increased seizure frequency, with the neurology team making changes to his anti-seizure medication in order to try and improve seizure control.

Unfortunately, today, he had a prolonged generalised tonic-clonic seizure that failed to terminate despite first and second-line treatments. The decision was made to progress to RSI.

Once admitted to the PICU, he was started on a midazolam infusion that was rapidly titrated from 200 micrograms/kg/hour to 1600 micrograms/kg/hour. A thiopentone infusion was then added to the mix.

Despite this, the CFAM still showed ongoing electrical seizure activity. Several treatment approaches were trialled, with little change in the clinical situation.

After talking with the Neurology team, the decision is made to introduce cannabidiol.

The Evidence

Through a largely patient-driven movement, cannabidiol has emerged as a candidate drug for improving the management of treatment-resistant epilepsies over the last four years.

There have been multiple international high-level reviews of the use of cannabis products performed by the likes of the World Health Organisation, NHS England, in conjunction with the Chief Medical Officer, American National Academies of Sciences, Engineering and Medicine, and the Australian Government. The effectiveness of cannabidiol has been studied in three randomised, double-blind, placebo-controlled trials involving 516 patients with either Lennox-Gastaut syndrome or Dravet syndrome. When taken with other medications, it may reduce the frequency of seizures by up to 50% when compared with placebo. 

What are the indications for cannabidiol?

The British Paediatric Neurology Association, in conjunction with NHS England, published guidance on the use of cannabis‐based products for medicinal use for children and young people with epilepsy.

They recommend the use of non‐licensed cannabis‐based products for medicinal use as a treatment of last resort for children who:-

a) Have an epilepsy that has proven intractable to treatment with conventional anti‐epileptic drugs

b) Have not responded to a ketogenic diet

c) Are not candidates for epilepsy surgery.

The decision has to be made by a Paediatric Neurology Consultant. Liver function test monitoring is required and treatment should be discontinued after four months if not effective.

Meanwhile, there is also a growing body of evidence relating to the use of cannabidiol in the management of super-refractory status epilepticus. Case series show a significant reduction in seizures when used in children with FIRES. Case reports also detail the successful use of cannabidiol as an adjunctive therapy in SRSE not associated with FIRES.

Research remains limited, with small sample sizes, open-label protocols and variability in dosage and timing of introduction of cannabidiol therapy. Despite this, it suggests that cannabidiol offers a potential benefit in a condition associated with significant morbidity and mortality. 

Cannabidiol has multiple molecular targets, and the exact mechanism of action is unknown. It bears little structural resemblance to other anti-seizure medications, and thus, it has been hypothesised that cannabidiol impacts neuronal function via multiple novel mechanisms.

Cannabidiol has been shown to have a specific anti-inflammatory effect, which may, in part, explain its therapeutic value in FIRES.

What are the side effects of cannabidiol therapy?

The most common side effects include lethargy, elevated liver enzymes, decreased appetite, diarrhoea, rash, malaise, weakness, poor quality sleep and behavioural problems. These side effects are dose-dependent and resolve with treatment de-escalation.

Cannabidiol may interact with other agents, specifically clobazam and sodium valproate, but multiple studies have concluded that it is a relatively safe anti-seizure medication.

Cannabidiol was introduced on day 21 of admission, alongside multiple combinations of conventional anti-seizure medications.

Within 14 days, the seizure frequency dropped before it stopped completely.

Other anti-seizure medication infusions were then weaned and stopped (lacosamide and clobazam were continued generally).

An EEG confirmed no evidence of ongoing seizure activity.

The patient was discharged to the care of the neurology team and, following a period of neuro-rehabilitation, could be discharged home.

Take Homes:

Refractory status epilepticus may progress to super-refractory status epilepticus, a condition associated with significant morbidity and mortality. 

Cannabidiol is a treatment option for children with Lennox-Gastaut Syndrome and Dravet Syndrome and also has an emerging role in the management of super-refractory status epilepticus, especially in cases of FIRES.

Cannabinol is a relatively safe medication but does require liver function test monitoring. It may interact with other medications, including clobazam and sodium valproate.

References

British Paediatric Neurology Association. Guidance on the use of cannabis-based products for medicinal use in children and young people with epilepsy. BPNA, 2021 https://bpna.org.uk/_common/show_unpro_doc.php?doc=BPNACBPMsguidanceupdatedOct2021_8b7f3bbc1af32e3ef188b6274100591f.pdf

Devinsky O., et al. Cannabidiol in patients with treatment‐resistant epilepsy: an open‐label interventional trial. The Lancet Neurology. 2016;15(3):270‐8

Devinsky O. et al. Trial of Cannabidiol for Drug‐Resistant Seizures in the Dravet Syndrome. The New England Journal of Medicine. 2017;376(21):2011‐20

Duda, J and Reinert, JP. Cannabidiol in refractory status epilepticus: a review of clinical experiences. Seizure. 2022;103:115-119

Fetta, A. et al. Cannabidiol in the acute phase of febrile infection-related epilepsy syndrome. Epilepsia Open. 2023;8:685-691

Galan F. et al. Cannabinoids for the treatment of Epilepsy. Current Treatment Options in Neurology. 2020; 22(14):1-14

Gofshteyn, JS et al. Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases. Journal of Child Neurology. 2017;32:35-40

Lacroix J, Deal C, Gauthier M, Rousseau E, Farrell CA. Admissions to a paediatric intensive care unit for status epilepticus: a 10-year experience. Critical Care Medicine. 1994;22(5):827–833

Lagae L. Long-term effects of cannabinoids on development/behaviour. Epileptic Disorders. 2020;22:33-37

Rajaraman, RR., Sankar. R., and Hussain, SA. Successful use of pure cannabinol for the treatment of super-refractory status epilepticus. Epilepsy and Behaviour Case Reports. 2018;10:141-144

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

Thiele EA., et al. Cannabidiol in patients with seizures associated with Lennox‐Gastaut syndrome (GWPCARE4): a randomised, double‐blind, placebo-controlled phase 3 trial. The Lancet. 2018; 391(10125):1085‐96

Vasquez, A., Farias-Moeller, R., and Tatum, W. Pediatric refractory and super-refractory status epilepticus. Seizure. 2019;68:62-71

Authors

  • Faith is a paediatric registrar currently working as a Paediatric Intensive Care and Simulation Fellow at Bristol Royal Hospital for Children. Her interests include Healthcare Ethics and Law, Medical Education and planning holidays that mainly revolve around food and wine.

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  • Clare has just completed her Paediatric Intensive Care training in Bristol, UK. Clare is about to go to Melbourne to undertake a post-CCT fellowship. She is excited for the warmer (hopefully!) weather and the outdoor lifestyle with plenty of coffee! In her spare time, she enjoys hanging out with friends over food, or being outside enjoying the fresh air.

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