Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex

Hess EJ, Moody KA, Geffrey AL, Pollack SF, Skirvin LA, Bruno PL, Paolini JL, Thiele EA. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016 Oct;57(10):1617-1624.

Abstract

OBJECTIVE:

Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder with highly variable expression. The most common neurologic manifestation of TSC is epilepsy, which affects approximately 85% of patients, 63% of whom develop treatment-resistant epilepsy. Herein, we evaluate the efficacy, safety, and tolerability of cannabidiol (CBD), a nonpsychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seizures in the setting of TSC.

METHODS:

Eighteen of the 56 patients who have enrolled in our current expanded-access study of cannabidiol for patients with treatment-resistant epilepsy carry a diagnosis of TSC. After an initial baseline period of 1 month, patients began treatment with CBD. The initial dose of 5 mg/kg/day was increased by 5 mg/kg/day every week up to a maximum dose of 50 mg/kg/day, if tolerated. Weekly seizure frequencies, percent change in seizure frequencies, and responder rates were calculated during the 2nd, 3rd, 6th, 9th, and 12th month of treatment with CBD.

RESULTS:

The median weekly seizure frequency during the baseline period was 22.0 (interquartile range [IQR] 14.8-57.4), which decreased to 13.3 (IQR 5.1-22.1) after 3 months of treatment with cannabidiol. The median percent change in total weekly seizure frequency was -48.8% (IQR -69.1% to -11.1%) after 3 months of treatment. The 50% responder rates over the course of the study were 50%, 50%, 38.9%, 50%, and 50% after 2, 3, 6, 9, and 12 months of treatment with CBD, respectively. In patients taking clobazam concurrently with CBD (n = 12), the responder rate after 3 months of treatment was 58.3%, compared to 33.3% in patients not taking clobazam (n = 6). Twelve (66.7%) of 18 patients in this study experienced at least one adverse event thought possibly related to CBD; the most common adverse events were drowsiness (n = 8, 44.4%), ataxia (n = 5, 27.8%), and diarrhea (n = 4, 22.2%).

SIGNIFICANCE:

Although double-blind, placebo-controlled trials are still necessary, these findings suggest that cannabidiol may be an effective and well-tolerated treatment option for patients with refractory seizures in TSC.

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Katherine Nickels (2017) Cannabidiol in Patients With Intractable Epilepsy Due to TSC: A Possible Medication But Not a Miracle. Epilepsy Currents: March/April, Vol. 17, No. 2, pp. 91-92.

Given the high likelihood of intractability of epilepsy due to TSC, multiple treatments for treatment-resistant epilepsy in patients with TSC have been studied, including vigabatrin, everolimus, clobazam, and a ketogenic diet. Vigabatrin has demonstrated efficacy in infantile spasms and as adjuvant therapy for intractable focal epilepsy due to TSC. When vigabatrin was used in 49 patients with focal epilepsy receiving two or more AEDs, >50% seizure reduction was seen in 30%; and 24.5% were seizure free or had >90% reduction in seizures. Similarly, 60% (12/20) of patients treated with everolimus showed >50% reduction in their refractory seizures (overall seizure reduction 69%) at 12 weeks, and efficacy was maintained in 83% (15/18) who continued the 4-year extension phase (6). In a retrospective study of clobazam in patients with TSC and treatment-resistant epilepsy, 69% had >50% reduction in seizures, although this was maintained in only six (19%) at 12 months. When 12 children with TSC and treatment-resistant epilepsy were treated with a ketogenic diet, 92% had >50% reduction of seizures at 6 months . Therefore, multiple potentially effective treatments exist for patients with intractable epilepsy due to TSC, although some patients continue to have poorly controlled seizures.

In the study of CBD in patients with intractable epilepsy and TSC by Hess et al., the median reduction in seizure frequency was 48.8%, and approximately 50% of patients demonstrated a >50% reduction in seizures. This response was maintained during the 12-month follow-up. Those also taking clobazam had a responder rate of 58.3% versus 33.3% for those not taking clobazam. These findings suggest that CBD is a potential antiseizure medication for intractable epilepsy due to TSC. However, we must be cautious when comparing these results to the expectations of patients and their families. While patients may view CBD as a promising therapy that helps when other AEDs fail, the efficacy of CBD for intractable epilepsy is comparable to the efficacy of vigabatrin, everolimus, and a ketogenic diet (50% of patients with >50% seizure reduction vs 30%, 60%, and 92%, respectively). Clobazam also led to improvement in seizures, although this response was only present in a minority of patients (19% with >50% reduction) at 12 months.

Those taking clobazam and CBD had a higher responder rate. Perhaps this is due to the previously documented interaction between CBD and clobazam that leads to significantly elevated clobazam and norclobazam levels. Furthermore, CBD is not without side effects. Side effects commonly seen with other AEDS, including drowsiness, ataxia, diarrhea, and agitation, were reported in 66.7% of patients, although none were considered to be serious CBD-related adverse events.

Overall, the prospect of another potentially effective and well-tolerated AED for intractable epilepsy should always be viewed positively. However, we must have reasonable expectations for CBD. Through multiple studies it is demonstrating itself to be a potentially effective, well-tolerated AED, but it is far from a miracle cure.