By: Jason Ifeanyi, PharmD Candidate c/o 2022

              Epilepsy is a highly prevalent neurological disorder caused by unusual nerve cell activity, and is among one of the most common disease states encountered today in clinical practice. Each year around 150,000 Americans are diagnosed with epilepsy.¹ Epilepsy is defined by the World Health Organization (WHO) as a “chronic noncommunicable disease…characterized by recurrent seizures, which are brief episodes of involuntary movement that may involve a part of the body (partial) or the entire part of the body (generalized) and are sometimes accompanied by loss of consciousness and control of bowel or bladder function.”² When thinking of antiepileptic drugs (AEDs), we oftentimes think of valproic acid (Depakote®), phenytoin (Dilantin®), carbamazepine (Tegretol ®), topiramate (Topamax ®), and levetiracetam (Keppra®), to name a few. This is for good reason, as these are AEDs that have been around for many years and have shown efficacy in numerous seizure types. One AED that may not be as commonly known is cannabidiol (Epidiolex ®). Cannabidiol is a novel AED used in the treatment of multiple seizure types, one of which is Dravet’s syndrome, a rare form of drug-resistant epilepsy that affects a significant percentage of the United States (US) population. Currently, three medications have an Food and Drug Administration (FDA)-approved indication for DS, one of which is cannabidiol. As aspiring healthcare clinicians, it is our duty to optimize patient health-related outcomes. In order to achieve this goal in patients struggling with Dravet’s syndrome, we must have a sound understanding of the disease state along with the medications used in their treatment.

Dravets syndrome (DS), also known as polymorphic epilepsy in infancy (PMEI) or severe myoclonic epilepsy in infancy (SMEI), is a rare form of drug-resistant epilepsy that affects an estimated 1 in 15,700 individuals in the US. DS oftentimes begins in the first year of life in an otherwise healthy infant.³ The first seizure experienced by patients with this syndrome will oftentimes be febrile and may be a tonic-clonic seizure or a seizure involving clonic movements on one side of the body.³ For reference, a tonic-clonic seizure is a type of seizure also known as a convulsion, that involves both stiffening  (tonic) and rhythmical jerking (clonic) of the muscles.⁴ There are other seizure types that may be seen in DS as well, such as myoclonic, atypical absence, tonic, focal aware or impaired awareness seizures (partial). Regardless of the type, seizures seen in DS are often long (more than 5 minutes) and can  result in a life-threatening emergency seizure known as status epilepticus.³ Status epilepticus is defined as having a seizure that lasts longer than 5 minutes, or having more than 1 seizure within a 5 minute period, without returning to a normal level of consciousness between episodes.⁵ After the first febrile seizure, seizures can happen without a fever, but patients may be more sensitive to infections and frequently have seizures when they are sick or have a fever. ^3,6,7

Most cases of DS are due to severe mutations in the gene coding for the sodium voltage-gated channel alpha 1 subunit (SCN1A). In fact, 80% of patients with DS have an SCN1A mutation. This mutation causes problems with the way sodium ion channels in the brain work, which can affect the electrical activity in the brain and can ultimately lead to a seizure.⁸ Genetic testing is recommended for patients who display any of the following: two or more prolonged (more than 10 minutes) seizures by age 1, one prolonged seizure and a hemi-clonic seizure (seizure causing rhythmic jerking in one side of the body) by age 1, two seizures that affect alternating sides of the body, or a seizure onset before 18 months of age, followed by myoclonic seizures, absence seizures, or both type of seizures (myoclonic and absence). With that being said, not all SCN1A mutations are associated with DS, and some mutations are associated with other forms of epilepsy that are not as severe as DS.⁷ This means that genetic blood tests are not 100% conclusive, since they do not screen for all mutations that cause DS. Complicating matters even further, diagnosis depends on the child’s history of seizures and other symptoms that emerge as seizures progress. The usual tests used to evaluate epilepsy such as magnetic resonance imaging (MRI) and electroencephalogram (EEG) can sometimes appear normal at first in babies with DS, which has many experts believing that some children are never correctly diagnosed.⁷ 

Between the ages of 1-5 years old, many children begin to show signs of developmental delay as well as other health issues including poor coordination, ataxic (unsteady) gait, impaired speech development, frequent infections, slowed growth and poor weight gain, and behavioral issues like hyperactivity and irritability.⁷ While medications certainly play a role in the management of DS, as aspiring healthcare clinicians one should always be looking for nonpharmacologic approaches to optimize patient outcomes.  One such approach involves counseling patients to avoid common seizure triggers including overheating (e.g., hot baths, strenuous exercise), sudden temperature changes in the environment whether hot or cold, fevers (can be treated with antipyretics), flashing lights and stress, to name a few.^3,7

A popular form of nonpharmacologic treatment in patients who are not obtaining adequate control of seizures despite the appropriate use of AED’s is a ketogenic diet, which is high in fat and low in carbohydrates.^9,10 Although the exact mechanism is poorly understood, clinical experience with the ketogenic diet has shown that both the low sugar and high fat component uniquely alters the excitability of the brain, which reduces the tendency to generate seizures.⁹ Another nonpharmacologic treatment approach that may be employed is the use of vagal nerve stimulation (VNS). This form of treatment is usually considered when medications are not working. VNS involves implanting a small device in the patients neck, around the vagus nerve. The device sends regular electric signals from the vagus nerve to the brain, which may interrupt a seizure or prevent a seizure from happening to begin with.⁷ Despite the clear utility of nonpharmacologic approaches, many patients will ultimately need to use AEDs to obtain maximum seizure control and live a healthier quality of life.

Cannabidiol (Epidiolex®) is currently one of three novel AED’s with an FDA indication for treatment in DS, with the other two being fenfluramine (Fintepla®) and stiripentol (Diacomit®). Cannabidiol, the active ingredient in Epidiolex, is a cannabinoid that naturally occurs in the Cannabis sativa L. plant. Receiving FDA approval on June 25th of 2018,  FDA on-label indications include the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), tuberous sclerosis complex (TCS), and Dravets syndrome (DS) in patients at least 1 year of age, with the latter being the major focus of this discussion. At present, not much is known about the precise mechanism by which cannabidiol exerts its anticonvulsant effects in humans. Cannabidiol does not appear to exert its anticonvulsant effects through interaction with cannabinoid receptors.¹¹

Efficacy of cannabidiol in the treatment of DS was established with one randomized, double-blind, placebo-controlled trial which studied 120 patients 2-18 years of age. The intervention (cohort of 61 patients) was cannabidiol at a dose of 20 mg/kg/day, and the comparator (cohort of 59 patients) was a placebo. Participation in the study included patients with a documented history of diagnosed DS that was not completely controlled by current AEDs, with or without VNS or a ketogenic diet. Participants took one or more AEDs at a dose that had been stable for at least 4 weeks. During a 4-week baseline period, patients were required to have at least 4 convulsive seizures while on stable AED therapy. The baseline period was followed by a 2-week titration and a 12-week maintenance period. The primary outcome measured was the percentage change from baseline in the frequency (per 28 days) of convulsive seizures (including atonic, tonic, clonic and tonic-clonic seizures). Baseline period median seizure frequency was 15 in the placebo group and 12 in the cannabidiol group. Results from this study showed that the median percent reduction from baseline in the frequency of convulsive seizures was significantly greater (p < 0.01) for cannabidiol 20 mg/kg/day (39%) compared to placebo (13%). Furthermore, 4 of the 60 patients treated with cannabidiol reported no convulsive seizures during the maintenance period, compared to 0 patients in the placebo group.^11,12

Cannabidiol is currently available as a 100mg/ml oral solution. Patients and caregivers will need to utilize either a calibrated 1ml or 5ml oral syringe provided by the manufacturer to withdraw and administer the correct dose from the bottle. The recommended starting dose in patients with DS is 2.5 mg/kg/day by mouth twice daily which yields a total daily dose of 5 mg/kg/day. After 1 week, the dose can be further increased to a maintenance dose of 5 mg/kg by mouth twice daily (10 mg/kg/day). Based on individual clinical response and tolerability, cannabidiol can be increased to a maximum recommended maintenance dose of 10mg/kg by mouth twice daily (total daily dose 20 mg/kg/day). Patients with hepatic impairment should have their dosage adjusted accordingly based on recommendations which can be found in the Epidiolex product information.¹¹ The most common adverse effects are those that occurred in greater than 10% of patients on cannabidiol during trials and had higher occurrence rates than in placebo. These include somnolence (feeling sleepy or drowsy)¹³, decreased appetite, diarrhea, transaminase elevations, rash, fatigue, malaise, asthenia (abnormal physical weakness or lack of energy)¹⁴, insomnia and infections.¹¹ Although cannabidiol poses significant health benefits for patients struggling with DS, there are precautions that need to be taken into consideration, one of which is hepatotoxicity. Dose-related elevations of liver transaminases have been reported, some resulting in hospitalization.¹¹ Transaminases include alanine transaminase (ALT) and aspartate aminotransferase (AST). These are both enzymes produced by the liver. Elevation in any of these enzymes could be a marker for potentially serious liver damage.¹⁵

Prior to initiating treatment with cannabidiol, clinicians should obtain serum AST, ALT, and total bilirubin levels. These labs should also be obtained at 1 month, 3 months and 6 months when initiating treatment, and periodically thereafter as clinically indicated. Clinicians should obtain these labs within 1 month of changing the dose, or if there is an addition or change in medications that are also known to affect the liver, such as valproic acid.¹¹ Besides obtaining labs, clinicians should also counsel patients on the clinical signs of liver toxicity that should prompt medical referral. These clinical signs include unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, jaundice and/or dark urine. Other warnings for cannabidiol include the risk of somnolence and sedation, suicidal behavior and ideation, hypersensitivity reactions, and withdrawal of AEDs.¹¹ Patients should be advised to avoid driving or operating heavy machinery until they have gained sufficient experience with cannabidiol and can gauge whether their ability to safely drive or operate machinery will be adversely impaired or not. Patients initiated on cannabidiol should be monitored for the emergence of or worsening of depression, suicidal thoughts or behavior, or any other changes in mood or behavior that may be unusual. There have been reports of hypersensitivity reactions with cannabidiol including itching, redness and angioedema that required treatment with corticosteroids and antihistamines. Patients should be counseled on signs and symptoms of hypersensitivity reactions, and advised to seek medical attention immediately should such a reaction occur. Use of cannabidiol is contraindicated in patients with a prior hypersensitivity reaction to cannabidiol or any of the ingredients in the product formulation, one of which includes sesame seed oil. As with most AEDs, patients and clinicians alike should avoid abrupt discontinuation of cannabidiol, as this may result in an increased seizure frequency and risk for status epilepticus. ¹¹

In conclusion, Dravets syndrome is a rare form of drug-resistant epilepsy affecting a significant percentage of the US population. Patients with this syndrome will oftentimes need to be on multiple AEDs to control their seizures and obtain a better quality of life. Every attempt should be made to employ nonpharmacological approaches, such as avoiding common triggers for seizures, as well as the use of VNS and/or a ketogenic diet in patients who are not deriving adequate control from their current seizure medications. Currently 3 medications are FDA-approved for the treatment of patients struggling with DS, with cannabidiol being FDA-approved for treatment in patients 1 year of age and older. Caution must be exercised in patients with hepatic impairment, and strict monitoring of liver function tests must be employed to prevent hepatotoxicity. As aspiring healthcare clinicians, it is imperative that we stay well-informed on rarer disease states such as DS, as well as medications used in their management so we can better optimize patient health-related outcomes.

References

1. Epilepsy: Facts, Statistics, and You. Healthline. https://www.healthline.com/health/epilepsy/facts-statistics-infographic. Published 2021. Accessed August 5, 2021
2. Epilepsy. Who.int. https://www.who.int/news-room/fact-sheets/detail/epilepsy. Published June 20, 2019. Accessed August 5, 2021
3. Types of Epilepsy Syndromes. Epilepsy Foundation. https://www.epilepsy.com/learn/types-epilepsy-syndromes/dravet-syndrome. Accessed August 6, 2021.
4. Types of Seizures. Epilepsy Foundation. https://www.epilepsy.com/learn/types-seizures/tonic-clonic-seizures. Accessed August 1, 2021.
5. Status Epilepticus. Hopkinsmedicine.org. https://www.hopkinsmedicine.org/health/conditions-and-diseases/status-epilepticus. Accessed August 2, 2021.
6. What is Dravet Syndrome?. Dravet Syndrome Foundation. https://www.dravetfoundation.org/what-is-dravet-syndrome/. Accessed August 1, 2021.
7. Dravet Syndrome. ucsfbenioffchildrens.org. https://www.ucsfbenioffchildrens.org/conditions/dravet-syndrome. Accessed August 1, 2021.
8. SCN1A gene: MedlinePlus Genetics. Medlineplus.gov. https://medlineplus.gov/genetics/gene/scn1a/#conditions. Accessed August 1, 2021.
9. Ketogenic Diet For Epilepsy / Seizures. Cleveland Clinic. https://my.clevelandclinic.org/health/treatments/7156-ketogenic-diet-keto-diet-for-epilepsy. Accessed August 1, 2021.
10. Epilepsy Society. https://epilepsysociety.org.uk/about-epilepsy/treatment/ketogenic-diet. Accessed August 2, 2021.
11. EPIDIOLEX® (cannabidiol). EPIDIOLEX.com. https://www.epidiolex.com/. Accessed August 9, 2021.
12. Antiepileptic Efficacy Study of GWP42003-P in Children and Young Adults With Dravet Syndrome (GWPCARE1) – Full Text View – ClinicalTrials.gov. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02091375. Accessed August 1, 2021.
13. Medical Definition of Somnolence. Rxlist.com. https://www.rxlist.com/somnolence/definition.htm. Accessed August 1, 2021.
14. Medical Definition of Asthenia. Rxlist.com. https://www.rxlist.com/asthenia/definition.htm. Accessed August 1, 2021.
15. Overview of ALT and AST Liver Enzymes. Verywell Health. https://www.verywellhealth.com/liver-enzymes-1759916. Accessed August 1, 2021.

Published by Rho Chi Post