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]. This has primarily been confined to its use in the outpatient setting. We report the use of a cannabidiol whole plant extract (Elixinol™) in the treatment of a patient with super refractory status epilepticus (SRSE) in the setting of new-onset refractory status epilepticus (NORSE) syndrome.
2. Case report
An 18 year old male was transferred to Wellington Regional Hospital in New Zealand three days after presenting with new onset generalised convulsive status epilepticus. The patient had presented after a short, non-specific illness comprising fever and myalgia. Prior to arrival in the tertiary centre he had undergone an MRI scan of the brain (normal) and lumbar puncture (normal CSF protein and glucose, no white blood cells). He was transferred on appropriate antiepileptic drug (AED) treatment and having been anaesthetised, intubated, and ventilated. Prior to transfer, the possibility of an autoimmune aetiology had been considered and the patient was receiving daily methylprednisolone (Fig. 1).
Repeat MRI scan and lumbar puncture in the receiving hospital were normal. CT scans of his chest, abdomen and pelvis and testicular ultrasound were normal. Blood and CSF cultures showed no growth. Serum biochemistry was normal. A full neurological antibody screen was negative in CSF and serum. A presumptive diagnosis of NORSE syndrome with an autoimmune basis was made and treatment with high dose methylprednisolone was continued [
] followed by treatment with intravenous immunoglobulin and plasma exchange. Rituximab and cyclophosphamide were subsequently commenced. Throughout this period, the patient was maintained in burst suppression, confirmed by continuous EEG monitoring.
Repeated attempts at waking the patient confirmed multifocal, bilateral sustained electrographic seizures. Numerous AED trials were attempted as was a ketogenic diet, however no reduction in seizures was achieved.
After two months of intensive intervention, the patient's family requested that cannabidiol (CBD) oil be trialled. Although Sativex™ (delta-9-tetrahydrocannabinol (THC) and cannabidiol) is available in New Zealand (with permission from the Ministry of Health) for the treatment of spasticity and spasms, CBD oil is not.
A literature review confirmed a number of articles describing the use of CBD oil in the paediatric out-patient setting (see Supplementary material). However there was no information regarding its use in status epilepticus (SE); therefore its use in this setting raised significant ethical and clinical issues.
With no supporting evidence for the therapeutic benefit of CBD oil in SE, it was not possible to seek the approval of regulatory authorities arguing proven efficacy. It was also difficult to assess the risk of harm. The patient's family however expressed strong, unwavering beliefs that CBD oil treatment would be beneficial.
The hospital ethics committee was consulted about these competing uncertainties. They concluded that, given the probable poor prognosis of NORSE, the inability to attain seizure freedom with existing AEDs and immunotherapy, combined with the strong wishes of the family, it was on balance ethically reasonable to trial CBD oil.
Consequently, the hemp plant extract Elixinol™ (containing 18% CBD) was sourced from the United States of America following New Zealand government ministerial permission. The clinical team (neurologists, intensivists and a palliative care physician) were cognisant of potential problems related to toxicity. At the time of CBD product administration, the patient was also receiving intravenous levetiracetam, lacosamide and phenobarbitone. Doses of the latter two agents were decreased to reduce the risk of toxicity through inhibition of cytochrome P450 (CYP) enzymes, particularly CYP3A and CYP2C [
]. A phenobarbitone level was checked four days after commencing the CBD product and the level was within normal range (83 μmol/L, normal range 65–130 μmol/L). It was not possible to check a lacosamide level.
The recommended dose of Elixinol in the outpatient setting for the treatment of epilepsy is variable with reported ranges between 1 and 40 mg/kg. In this case we commenced treatment at 2.5 mg/kg/day, increasing over the course of two weeks to a maximum of 24 mg/kg/day. The product was administered by the intensive care nursing staff via a nasogastric tube.
After two weeks of treatment with the CBD product in conjunction with other agents, an attempt was made to lighten the patient's sedation. The underlying EEG confirmed unchanged, sustained, bilateral electrographic seizures (Fig. 2). Clinical focal and generalised seizures again occurred. After discussion with the family, it was agreed that further interventions were unlikely to be successful and the family's wish was to de-escalate treatment which was in agreement with the clinical recommendation.
Over the following days, antiepileptic drug doses were reduced along with sedating agents. The CBD product continued to be administered at the family's request. The patient subsequently died following withdrawal of treatment, 88 days after presenting to hospital.
While there is increasing evidence for the use of CBD products in the setting of epilepsy, there are no reports regarding its use in the setting of convulsive status epilepticus. There may also be a mismatch in the attribution of reported benefits of these products between medical staff and family members [
]. Furthermore there may be an assumption that ‘natural’ products carry a low risk and therefore there is little to lose by trying them. In this instance, the option of using CBD products was raised by the family, not the clinical team. The view of the ethics committee, that CBD whole plant extract could be considered ethically reasonable in a situation where all other treatments had failed, was helpful to both parties.
While NORSE has a poor prognosis, the use of CBD whole plant extract in this patient had no effect upon the underlying seizure illness. The nursing and medical staff never observed any improvement in the patient's level of awareness and there was never an improvement in the underlying EEG.
While the treatment was ultimately unsuccessful, we feel the use of CBD whole plant extract was justified as it addressed an immutable need for the family who were forced to deal with a very tragic scenario. Its use and subsequent failure in this setting helped facilitate the subsequent transition to a palliative approach.
Conflict of interest statement
The authors of this article have no conflicts of interest.