Eric Segal, MD

was one of the few bright spots of 2020, with many pharmacologic options emerging for patients. Over the past 10 years, some therapies offered marginal improvements in efficacy and adverse effect profile compared with earlier generations of antiseizure medications (ASMs). The mold was broken in 2020 with a paradigm shift in what clinicians consider effective therapies, and agents that offer a significant improvement in quality of life.

In 2020, ASMs to treat focal seizure in adults, as well as seizures in Dravet syndrome, received FDA approval. Cenobamate (Xcopri) is a novel tetrazole alkyl carbamate derivative thought to work on both sodium and gamma-aminobutyric acid channels. In phase 2 study results, adults with focal epilepsy had median seizure reductions of 55.6%, 38.7% had a 75% or greater seizure reduction, and 28.3% were seizure-free in a post hoc analysis of the maintenance phase.

 In a dose-comparison study of cenobamate by Krauss and colleagues, median seizure reduction of 400 mg/D was 55%, and in the maintenance phase of the modified intent-to-treat cohort, the same dosing resulted in 65% seizure reduction.

 Although it is not possible to directly compare these rates of seizure freedom and reduction with pivotal trials of other ASMs, these rates are higher than those shown in the meta-analysis and pooled analysis of lamotrigine, gabapentin, topiramate, tiagabine, levetiracetam, zonisamide, pregabalin, lacosamide, eslicarbazepine, perampanel, and brivaracetam.

 If real-world experience is similar to the results of these pivotal trials, cenobamate may represent a new threshold for ASM efficacy in the treatment of focal epilepsy.

Similar paradigm changes may be afoot in the treatment of Dravet syndrome. In 2017, a North American consensus panel recommended valproic acid or clobazam as first-line therapies, with stiripentol, topiramate, or ketogenic diet as second-line treatments.

 Also in 2017, cannabidiol (Epidiolex) was FDA approved after demonstrating a median seizure frequency reduction of 43%.

 Fenfluramine (Fintepla), FDA approved in 2020 as well, demonstrated median seizure frequency reduction of 75% in its pivotal trial.

 As in the case of cenobamate, head-to-head comparisons of Dravet-specific therapies such as stiripentol, fenfluramine, and cannabidiol cannot be made. However, such impressive seizure reductions seen with both cenobamate and fenfluramine beg the question: Should we consider redefining what is considered a “significant” seizure reduction?

The abortive therapy space in epilepsy had languished with a paucity of therapies until 2019. The most recent FDA approval prior to then occurred in 1997 with rectal diazepam (Diastat), designed to allow caregivers to give an emergency-use medication to abort acute repetitive seizures. At the end of 2019, clinicians were given permission to prescribe FDA-approved nasal midazolam (Nayzilam) for patients 12 years and older. Its ease of use and clear dosing guidelines make it a valuable option for teenagers and adults. In 2020, nasal diazepam (Valtoco) also became available to US prescribers for patients 6 years and older; its advantages include dosing flexibility and long shelf life. Both of these nasal therapies met a previously unmet need for children and adults with epilepsy: an agent that can be quickly administered with greater social acceptability.

The focuses of epilepsy studies currently underway range from tantalizing first-in-class medications, new uses of older therapies, and even gene therapy, giving hope for more exciting developments in the coming year, even as we can reflect on the advances that emerged in 2020 in both prophylactic and abortive treatments for epilepsy.

REFERENCES
1. Chung SS, French JA, Kowalski J, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. 

. 2020;94(22):e2311-e2322. doi:10.1212/ WNL.0000000000009530
2. Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. 

. 2020;19(1):38-48. doi: 10.1016/S1474-4422(19)30399-0
3. Vossler DG. Remarkably high efficacy of cenobamate in adults with focal-onset seizures: a double-blind, randomized, placebo-controlled trial. 

, 2020;20(2):85-87. doi:10. 1177/1535759720903032
4. Wirrell EC, Laux L, Donner E, et al. Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American consensus panel. 

, 2017;68:18-34. doi:10. 1016/j.pediatrneurol.2017.01.025
5. Devinsky O, Cross JH, Laux L, et al; Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. 

. 2017;376(21):2011-2020. doi:10.1056/NEJMoa1611618
6. Lagae L, Sullivan J, Knupp K, et al; FAiRE DS Study Group. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. 

. 2019;394(10216):2243-2254. doi:10. 1016/S0140-6736(19)32500-0

Articles

Despite 2020 being a challenging year for those in medicine, the epilepsy therapeutic space featured a number of key steps forward.

2020 Epilepsy Review: Much to Be Excited About

"The lack of significant changes in side effects in these 2 populations gives further reassurance that this is a safe treatment to give. This is really a game changer for our independent patients.”

 showed that diazepam nasal spray has similar effects in reducing the percentage of seizures regardless of concomitant use of other benzodiazepines as part of their antiseizure drug (ASD) regimen. The study, led by Eric Segal, MD, showed a similar number of seizure episodes for those using diazepam both with (90.4%) and without benzodiazepines (92.4%).

Although, among the notable findings, there was a higher proportion of patients who experienced treatment-emergent adverse events (TEAEs) when taking concomitant benzodiazepines (79.8%) than those without (61.5%). The real-world results add more clarity to diazepam’s clinical utility after it was 

 for the treatment of seizure clusters in January 2020.

Segal, director of pediatric epilepsy at HMN Hackensack University Medical Center, feels as though his study serves as an opportunity to change and improve patient practice. In an interview with 

, he outlined why the results may change the clinician perspective on prescribing it to their patients, and whether it could potentially lead to more singular prescriptions of diazepam nasal spray by itself.

Segal E, Tarquinio D, Miller I, et al. Evaluation of diazepam nasal spray in patients with epilepsy concomitantly using maintenance benzodiazepines: interim analysis from a phase 3, long-term, open-label safety study. Presented at AES 2020 Annual Meeting; December 4–8, 2020. Abstract 337.

Videos

The director of pediatric epilepsy at HMN Hackensack University Medical Center provided background on how his data may change how clinicians use diazepam nasal spray.

Eric Segal, MD: Diazepam Clinical Utility Regardless of Concomitant Benzodiazepines

"The take home message is that there doesn’t appear to be a significant tolerance to benzodiazepines at the prescribed doses emergently. And second, we don’t see any increased side effects in that population.”

Recently presented data virtually at the 2020 

American Epilepsy Society (AES) Annual Meeting

, December 4–8, 2020, suggest that diazepam nasal spray remains effective in reducing the percentage of seizures regardless of whether patients concomitantly use other benzodiazepines as part of their daily antiseizure drug (ASD) regimen. The study, led by Eric Segal, MD, found that the percentage of seizure episodes using a single dose of the nasal spray was similar for those with concomitant benzodiazepines (90.5%) compared to those without (92.4%).

Segal, director, pediatric epilepsy, Northeast Regional Epilepsy Group, co-director, epileptology, Hackensack Meridian Health, and assistant professor of pediatrics and neurology, Hackensack Meridian School of Medicine, posed 2 questions in relation to his study. The first: do the patients who take benzodiazepines have a tolerance? And the second: would there be issues with giving more benzodiazepines on top of their daily ASD regimen?

, Segal detailed some of the findings and the answers to those questions, while also providing background on the history of diazepam nasal spray and why these results have such significance.

The director of pediatric epilepsy at the Northeast Regional Epilepsy Group discussed his study presented at AES 2020 which involved the effectiveness of diazepam nasal spray regardless of treatment regimen.

Eric Segal, MD: Effects of Diazepam Amid Concomitant Benzodiazepine Use

I first learned about the therapeutic benefits of cannabis for epilepsy during a Dravet syndrome conference in 2012. There, multiple families from the few states that offered medical marijuana for children extolled its virtues even though their own providers could not guide them through the dosing and adverse effects (AEs) of this therapeutic class.

Now, 7 years later, parents of children with newly diagnosed epilepsy frequently request a cannabis-derived option before conventional antiepileptic drugs. Shortly after the 2013 release of Sanjay Gupta’s CNN special Weed,

 the great impact of cannabis-derived products such as cannabidiol (CBD) was felt strongly within the neurology community. Because of conflicting state and federal regulations, as well as technical challenges in studying plant-based medicines, no large-scale studies using CBD in patients with epilepsy had been conducted until an open-label trial using CBD was published less than 4 years ago.

As most US-based clinicians have not received training in the therapeutic uses of cannabinoids, practitioners have had to overcome a significant knowledge deficit in a short period of time.

 Since 2014, multiple positive, open-label and randomized, placebo-controlled trials have been conducted, helping to create a new class of antiepileptic therapies for patients. However, given the regulatory and complex chemical nature of cannabis-derived therapies, there remains a significant amount of misinformation regarding available varieties, safety, and efficacy of this therapy.

The term cannabinoid can encompass phytocannabinoids, which are derived from the cannabis plant, synthetic cannabinoids produced in a lab, and endocannabinoids, which are endogenous neurotransmitters that bind to cannabinoid receptors throughout the body. Epidiolex (cannabidiol; Greenwich Biosciences) is the only pharmaceutical-grade CBD approved for the treatment of seizures. Given the robust effect this compound has on difficult-to-control epilepsy syndromes such as Dravet and Lennox-Gastaut, its promise of consistent concentration of active compound and of a good tolerability profile has created high interest throughout the epilepsy community. However, this excitement must be tempered by reasonable expectations. Although this therapy can be effective, it is not a cure for epilepsy and does have AEs; after all, being derived from a plant does not preclude it from having end-organ effects.

Patients and practitioners alike need to be aware of both the benefits and limitations of this particular therapy.

Other plant-based CBD therapies, such as hemp products, may have similar efficacy and AE profiles as those of pharmaceutical-grade CBD. These options are attractive, as they are readily available for purchase online without the need for insurance approval or even a clinic visit. However, these types of cannabis-derived products have not undergone the same rigorous study needed to provide strong recommendations. Furthermore, patients may find administering hemp a challenge, as batch-to-batch consistency cannot be guaranteed in the same manner as that of an FDA-approved compound.

Medical marijuana is an additional option for residents of certain states. Each state has its own regulations and variety of strains of marijuana for purchase, which allows patients to access therapies that have significant levels of other cannabinoids besides CBD, such as tetrahydrocannabinol (THC). Unfortunately, animal models using THC have been found at times to produce proconvulsant effects.

Treat and colleagues have provided a helpful depiction of real-world experience using medical marijuana in pediatric patients in Colorado.

 They found that the average length of use of medical marijuana was 11.7 months, and relocation to Colorado was the only factor associated with perceived seizure benefit, as 65% of families had recently moved to Colorado versus 38% who were longtime residents.

Providers, patients, and their families have all struggled to educate themselves on the benefits and limitations of CBD and other cannabis-derived therapies. Although many families were skeptical of using marijuana-based therapies for epilepsy 5 years ago, more recently, families have been very eager to administer CBD without having full knowledge of the specific formulation they are asking for.

When this topic arises in an office visit, I will frequently dedicate the entire time to discussing the differences among pharmaceutical-grade CBD, hemp products, and medical marijuana. For additional information, I often direct families to the Epilepsy Foundation’s online resource on medical marijuana and epilepsy.

 Although most people’s expectations are tempered by the end of the visit, my goal is only to inform—never deflate&mdash;a person’s hope for this or any other reasonable therapy.

Despite the challenges and limitations of cannabis-derived products, clinicians and patients should understand that this class of therapy is a legitimate treatment option for patients with epilepsy.

All told, I am personally open to using CBD-based therapies in addition to conventional antiepileptic therapies for patients with difficult-to-treat epilepsy. Given the possibility of lack of consistency of active ingredients and the lack of rigorous investigation, I caution patients and caregivers who are interested in or currently using hemp oils or medical marijuana. However, I have hope that increased access to these therapies, as well as ongoing studies, will help increase prescribers’ understanding of and comfort with this class.

Disclosure: Dr Segal reports relationships with Greenwich Biosciences, Zogenix, Nutricia, Lineagen, Novartis, Lundbeck, Celgene, Encoded Therapeutics, and Eisai. 

1. Weed - Sanjay Gupta [transcript]. CNN. Turner Broadcasting. August 2013.

2. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. 

 2016;15(3):270-278. doi: 10.1016/ S1474-4422(15)00379-8.

3. Szaflarski M, McGoldrick P, Currens L, et al. Cannabinoid knowledge and attitudes among US healthcare providers. Presented at: 2019 American Epilepsy Society Annual Meeting; November 30-December 4, 2016; New Orleans, LA. Abstract 3.469. aesnet.org/meetings_events/ annual_meeting_abstracts/view/555794.

4. Highlights of prescribing information: Epidiolex. FDA website. www.accessdata.fda.gov/drug- satfda_docs/label/2018/210365lbl.pdf. Accessed May 12, 2019.

5. Szaflarski JP, Bebin EM. Cannabis, cannabidiol, and epilepsy—from receptors to clinical response.

2014;41:277-282. doi: 10.1016/j.yebeh.2014.08.135.

6. Treat L, Chapman KE, Colborn KL, Knupp KG. Duration of use of oral cannabis extract in a cohort of pediatric epilepsy patients. 

 2017;58(1):123-127. doi: 10.1111/epi.13617.

7. Patel D and Kiriakopoulos E. Medical marijuana and epilepsy. Epilepsy Foundation . epilepsy.com/learn/treating-seizures-and-epilepsy/other-treatment-approaches/medical-mari- juana-and-epilepsy. Updated July 2018. Accessed May 12, 2019. 

A lot of hype and hope surround this treatment class, making reasonable expectations difficult to form for practitioners and patients alike.

Eric Segal, MD

Articles

2020 Epilepsy Review: Much to Be Excited About

Eric Segal, MD: Diazepam Clinical Utility Regardless of Concomitant Benzodiazepines

Eric Segal, MD: Effects of Diazepam Amid Concomitant Benzodiazepine Use

State of CBD: Thoughts From a Prescriber

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