|Ahead of print
Cannabidiol (CBD) in children with drug-resistant epilepsy: An initial experience from a developing country
Prem Chand1, Ammaar Mohammad Ali Abbasi1, Asra Wahid1, Jai K Das2
1 Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan
2 Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan; Institute of Global Health And Development, Aga Khan University, Karachi, Pakistan
|Date of Submission||29-May-2021|
|Date of Decision||04-Apr-2022|
|Date of Acceptance||11-Apr-2022|
|Date of Web Publication||12-Jul-2022|
Department of Pediatrics and Child Health, Aga Khan University, Stadium Road, P.O. Box 3500, Karachi 74800
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Context: Cannabidiol (CBD), used in conjunction with other antiepileptics, is gaining interest in managing drug-resistant epilepsy (DRE), which accounts for 10-20% of all childhood epilepsies worldwide. Aims: We highlight a first experience of using CBD amongst children with refractory epilepsy in a tertiary care hospital in Pakistan and its possible effect on seizure frequency and associated adverse outcomes. Settings and Design: A retrospective review, conducted at a pediatric neurology outpatient clinic at the AKUH, a tertiary care hospital in Karachi, Pakistan. Materials and Methods: We assessed children with DRE who were prescribed escalating doses of CBD from June 2019 to October 2020 at Aga Khan University, Pakistan. A descriptive analysis was performed, and improvement in seizure frequency and adverse effects (as reported by caregivers) were measured. Statistical Analysis Used: Statistical analyses were performed using IBM Statistical Package for the Social Sciences 21.0. Results: CBD was prescribed to 17 patients with DRE with a mean age of 5.52 ± 0.96 years, and 15 of them were boys. The mean baseline seizure frequency was 27.65 ± 3.59 episodes per day. All patients were stabilized on antiepileptics before administration of CBD and were started at an initial dose of 10 mg/kg/day, which was subsequently escalated, where needed. Our results showed that 70.6% of children reported an improvement in seizure frequency. The mean percentage reduction in seizure frequency at 12 weeks was 68.33% ± 7.55 from baseline; seven patients reported more than 75% improvement, and two patients became completely seizure-free. Nine patients reported minimal side effects. Conclusion: In this initial experience, we saw an improvement in overall seizure frequency in DRE patients, with tolerable adverse outcomes. The paper highlights an initial potential of using CBD in children with DRE in an LMIC, without drawing any firm conclusions. It highlights the potential for making a bigger change for which adequately designed and powered studies would be needed in such contexts to ascertain the actual impact.
Keywords: Cannabidiol, drug-resistant, epilepsy, refractory, seizures
| Introduction|| |
Refractory epilepsy or drug-resistant epilepsy (DRE) is defined as the failure of two or more adequately chosen and appropriately titrated antiseizure medications in controlling seizures. The limited evidence available suggests that DRE accounts for 20-30% of all childhood epilepsies., DRE is associated with neurodevelopmental delays, leading to cognitive, behavioral, and sensorimotor impairments and high mortality risk. Epileptic encephalopathies are one of the most common causes of DRE, and despite extensive research and a wide array of pharmacologic therapies, the frequency of seizures in such patients has been difficult to control.,
The therapeutic usefulness of CBD in the reduction of frequency of seizure episodes has been reported and was approved by Food and Drug Administration (FDA) in 2018 for Lennox Gastaut Syndrome(LGS) and Dravet Syndrome(DS) in patients older than 2 years of age., Since then oral Solution of Cannabidiol (CBD) has been widely used to treat refractory epilepsy in pediatric and adult patients, with various trials being carried out worldwide.,,
Several mechanisms of action for CBD with anticonvulsant properties have been postulated with some uncertainties about its exact mechanism in humans. CBD has a low affinity for endocannabinoid receptors compared to THC. Independent of activation of the endocannabinoid system, CBD exhibits its antiepileptic properties by acting as a partial negative modulator of the CB1 receptor. CBD blocks T-type voltage-gated Ca2+ channels and acts as an agonist at human vanilloid-type transient receptor potential receptors modulating intracellular calcium mobilization. Other possible mechanisms that still need more data to understand the action of CBD and its anti-epileptic properties include inhibition of intrasynaptic reuptake of adenosine, antagonism at G-coupled receptor protein 55(GRP55), activation of neuronal serotonin and glycine receptors, and modulation of the voltage-dependent anion-selective channel protein 1(VDAC1) and TNF-alpha release.,,
Acquiring CBD has high costs due to a lack of local production and high import costs that are unmet in a low-resource country like Pakistan. Strongly reported evidence, which is being studied around the globe, may be the driving force in recommending CBD as the first-line agent in DRE. Owing to the lack of data on CBD from developing South Asian countries and inflating costs, CBD use for DRE remains a unique and not well sought-after line of therapy in Pakistan. We share our experience of using CBD amongst pediatric patients aged less than 18 years with DRE who visited the pediatric neurology outpatient clinic at a tertiary care hospital in Karachi, Pakistan, and report the percentage improvement in seizure frequency and overall improvement in irritability and sleep pattern, as reported by the caregiver.
| Materials and Methods|| |
The objective of this study is to assess the effect of CBD use, in patients with DRE, on seizure frequency (which is defined as a percentage reduction in the number of episodes of seizure per day as reported by the caregiver).
The secondary objective of this study is to assess any adverse outcomes associated with CBD use.
A retrospective review of patient records was carried out for all pediatric patients (<18 years of age) with DRE who were prescribed CBD by a single pediatric neurologist between June 2019 to October 2020 at the Aga Khan University Hospital (AKUH), Karachi, Pakistan.
The study was conducted at a pediatric neurology outpatient clinic at the AKUH, which is a large tertiary care hospital in Karachi, Pakistan.
All patients of age less than 18 years with DRE who were administered CBD during June 2019 – October 2020 were included. Patients were stabilized on three to four anti-epileptics for four weeks prior to administering CBD. Subsequently, they were administered CBD oral solution for a period of 14 weeks. CBD oil is a locally available product manufactured by The Medics. This product is third-party tested with an ISO-certified lab with no THC component and is sourced in the USA. The product has undergone all quality control requirements and its quality is certified by Folium Biosciences. All patients were started on an initial dose of 10 mg/kg/day administered in two divided doses. This dose was sequentially escalated where there was no improvement on serial regular follow-ups to 20 mg/kg/day administered in two divided doses, followed by 30 mg/kg/day administered in three divided doses and 40 mg/kg/day administered in three divided doses. The duration of each dose was maintained for a week and the patient was assessed for improvement before escalating to a higher dose. If significant improvement was noted on a lesser or a specific dose, that dose was maintained throughout the treatment course.
Data collection and variables
Patients visiting the pediatric neurology outpatient clinic with DRE were administered CBD. All such cases were identified, and patient records were studied retrospectively through chart reviews. Baseline EEG activity before CBD administration was recorded in all patients. The variables assessed included patient demographics, previous seizure history, previously and currently administered anti-epileptics, CBD dosage, improvement in seizure frequency, sleep pattern, irritability, and adverse effects. We reviewed patient charts for retrospective data collection where patient files had a record of seizure improvement recorded by the physician at every visit. The attending documented improvement in seizure episodes at every visit, which the parents had captured and mentioned in their personal diary. Our primary objective was to determine the impact of CBD use on the patient’s seizure frequency (which is defined as a percentage reduction in the number of episodes of seizure per day as reported by the caregiver) at 4- and 12-weeks post initiation of CBD. Seizure reduction was further categorized according to four levels (<25%, 25-50%, 50-75%, and >75%) as reported by caregivers. Caregivers counted all seizure types that were countable per day before and after starting CBD and gave their subjective perception of the percentage decrease in frequency. Commonly reported adverse outcomes were closely assessed by the physician during clinical follow-up visits of each patient. These were also reported by parents on subsequent follow-up visits during the therapy. These outcomes were recorded in patient charts by the treating physician and were accessed during chart review.
All statistical analyses were performed using IBM Statistical Package for the Social Sciences 21.0. We performed a descriptive analysis and continuous variables were presented as mean ± standard error or median with interquartile range (IQR) depending on the normality assumption. Categorical variables were expressed as percentages with a 95% confidence interval (CI) using the exact binomial method. An ethical exemption was obtained from the Ethical Review Committee of the Aga Khan University Hospital, as this was a retrospective review of patient charts, and we did not gather any patient identifiers.
| Results|| |
Seventeen patients with DRE were administered CBD and were retrospectively reviewed in our study, of which 15 (88.2%) were boys. As shown in [Table 1], the mean age was 5.52 ± 0.96 years with a range of 1.5 - 14 years. The etiology of epilepsies were identified retrospectively in all patients and are displayed in [Figure 1]. Patients were seen to majorly have dropped attacks alongside myoclonic jerks and generalized tonic-clonic seizures. Patients were followed up for at least three months.
All patients had liver function enzymes within the normal range before starting CBD. All antiepileptics used before CBD administration and as concomitant treatment are shown in [Figure 2]. The mean number of antiepileptics used before CBD administration and concomitant to CBD were 3.94 and 3.06 each, respectively. Stabilization was achieved by administering a maximum dose of each antiseizure medication for four weeks before starting CBD. All patients required an escalation to 20 mg/kg/day by the end of week one. Only one patient did not require an escalation in dosage as he showed significant improvement in seizure frequency at the dose of 10 mg/kg/day.
[Table 2] gives an overview of the maximum dose used in our patients at the end of 12 weeks, with 30 mg/kg/day being the most frequently administered maximum dose, given to 10 out 17 patients.
Improvement in seizure frequency was seen in 12/17 (70.6%) patients at the end of 12 weeks. The mean improvement in seizure frequency at 4 weeks was noted to be 53.33% ±12.31, while the mean improvement at 12 weeks was 68.33% ± 7.55 from baseline. We classified improvement of seizure frequency as less than 25%, 25-50%, 51-75%, and more than 75%. At 12 weeks, none of the patients who reported improvement in seizure frequency had an improvement of less than 25%. Four patients had a mean improvement in seizure frequency ranging between 25%-50%, whereas one patient showed improvement between 51-75%. Seven patients reported a mean improvement of more than 75%, with two patients becoming completely seizure-free. No patients reported any worsening of seizure frequency, while five patients (29.4%) reported no beneficial effect of medication – CBD was discontinued for these patients after 6 weeks. Out of these five non-responders, one patient reported worsening irritability and poor sleep, whereas one patient reported diarrhea and increased somnolence.
Baseline EEG activity before CBD administration was recorded in all patients. The EEG findings were suggestive of multifocal and generalized discharges.
Out of the 17 patients, nine patients experienced adverse outcomes. These include diarrhea, decreased appetite, fever, somnolence and lethargy. Three patients were such who did not show any improvement in seizure frequency as well. At a dose of 20 mg/kg/day, only one patient out of the three patients reported an adverse effect of fever. Whereas five patients out of the ten reported adverse effects at a dose of 30 mg/kg/day and a dose of 40 mg/kg/day, three out of the four patients experienced adverse effects of decreased appetite, somnolence, and lethargy. Out of these nine patients, only two patients had more than one adverse outcome. One patient on a dose of 30 mg/kg/day experienced somnolence and diarrhea, while the other patient on a dose of 40 mg/kg/day complained of lethargy and somnolence. No patients complained of vomiting or fatigue.
| Discussion|| |
Epilepsy accounts for 0.75% of the global burden of disease with 80% of the patients residing in low and middle-income countries(LMICs). Around 30 to 40% of people with epilepsy have seizures that are uncontrolled by medication termed as DRE. At present there are a few widely used options available to treat such patients. These include a ketogenic diet, epilepsy surgery, vagal nerve stimulation, and treatment with CBD. Prior animal-based studies and recent increased use of CBD in many studies make it a suitable option to treat patients with DRE.,
In 2018, the FDA approved the use of purified CBD oral Solution for the treatment of two epileptic encephalopathy conditions - Lennox-Gastaut-Syndrome and Dravet syndrome. Furthermore, few trials and studies have highlighted the beneficial effects of concurrent CBD use with antiepileptics on seizure frequency in other epileptic syndromes.,,,,,,, A systematic review of 17 observational studies showed that CBD use resulted in 48.5% of patients having a 50% reduction in seizure frequency.
Large trials of administering CBD have mostly been used in developed countries. Despite the huge burden of epilepsy in LMICS, its use has not been widely studied. In Pakistan, no local pharmaceutical companies manufacture the FDA-approved oral CBD solution. Thus, if needed, it must be imported, which approximately costs 250,000PKR per month, making it an unfeasible option for our patients. The drug used in our study still costs PKR 30,000- 40,000 per month. Since patients pay out of their pocket for healthcare facilities, such a high amount becomes a significant burden. As a result, only those patients who could afford the treatment were included in our study, leading to limited sample size. Increasing costs and difficulty acquisition is a pertinent problem that prevents broad use of CBD amongst patients with DRE in Pakistan and many LMICs. Based on promising clinical trials conducted and published worldwide on children, we introduced CBD use in DRE patients for the first time in Pakistan and South Asia. Coming from an LMIC with limited resources, our experience details on the initial experience with an aim to enhance the awareness around the use of CBD in our region. The results are also as promising as reported in previous literature., Our retrospective study included 17 patients with DRE who were administered CBD along with stabilized concomitant antiseizure medication. Recent evidence suggests high dose and high plasma CBD level is more effective in controlling dropped attacks. Our team administered an initial dose of 10 mg/kg/day in two divided doses of 5 mg/kg/dose. This was tolerated in our patient population with minimal to no side effects. However, we had to escalate dosage according to patient needs. Most patients required a maximum dose escalation to 30 mg/kg/day, with only three patients requiring a maximum dose of 20 mg/kg/day. Out of these three patients, two became seizure-free by 4 weeks, and thus their dose was not increased.70% of the patients showed improvement in seizure frequency, with two of them becoming completely seizure-free. Seven patients had an improvement in seizure frequency of greater than 75%. None of our patients reported worsening of seizures, and no patients stopped the medication due severity of adverse events.
Although CBD use is associated with an overall reduction in seizure frequency, improvements in EEG patterns have not been widely reported. A few studies have tried to form a correlation between CBD use, seizure improvement, and EEG changes., This remained a challenge for us, as patients did not repeat an EEG post-treatment. The main reasons being a loss to follow-up and unaffordability. In patients who did get a post-treatment EEG, there were no significant changes in EEG pattern even though these patients had improved seizure frequency. This is concurrent with the findings published by Press et al. 2015.
Some published studies have spoken about the adjuvant use of CBD with multiple antiepileptics. The most commonly used concomitant antiepileptic drugs are clobazam and valproic acid,, stiripentol, levetiracetam, and topiramate. In addition, a recent systematic review highlighted increased concentration of clobazam concentration in patients receiving different doses of clobazam and CBD due to inhibition of CYP2C19. In such patients, the co-administered antiepileptic can be tapered once seizure frequency has decreased. Similar to what most trials followed, 82.3% of the patients were given three antiepileptics in addition to CBD, with only two patients requiring a fourth antiepileptic. Clobazam and valproic acid were the most used adjuvant drugs in almost all patients.
Interestingly, many studies have reported multiple side effects with the use of CBD for DRE. However, most of these side effects were mild to moderate, and tolerability and safety of the drug remains high, with a rare need to withdraw from the study.,,,,, This was seen in our study as well, with diarrhea, somnolence, and loss of appetite being the most common adverse events.
Our study is not without limitations. A significant fraction of our population travels from rural areas to seek treatment at tertiary care facilities. Increased travel time due to poor infrastructure facilities prevents regular follow up of patients. It is extremely challenging to comment on the prognoses of such patients with limited follow-up, subsequently, this results in the exclusion of these patients and a small sample size available for our study. Thus, it was difficult to draw any conclusions on the overall improvement of CBD amongst DRE patients. Furthermore, most patients were unable to repeat EEGs due to a lack of advanced health care facilities in their areas. Secondly, since most of our healthcare is dependent on out-of-pocket payment, patients are unable to afford repeat EEG investigations multiple times. Patients who were able to finance the costs usually brought in EEG reports from other hospitals instead of actual EEG patterns, which made it difficult for us to talk about the EEG pattern in a lot more detail. Due to a retrospective study design and poor patient compliance, we were only able to report data assessed from patient files and were unable to design a method of outcome reporting due to our study design. While taking the subjectivity of outcome measures into account, we have not drawn any conclusions or associations from our experience. We have meagerly reported our experience due to an improvement noted with CBD amongst DRE patients in our setting, which is a first in Pakistan to enhance its awareness and to push for adequate future studies.
| Conclusion|| |
In our experience, we saw an improvement in overall seizure frequency, sleep pattern, and irritability in DRE patients with few tolerable side effects. Acquiring CBD for medicinal purposes due to its exorbitant cost is a problem in Pakistan. More focus is needed to ascertain the effect of CBD, its dosage, and adverse effects in DRE with further large studies with adequate design and outcome measurement in these contexts to increase awareness and ease its acquisition in Pakistan and its regional countries.
Financial support and sponsorship
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Engel J Jr. Approaches to refractory epilepsy. Ann Indian Acad Neurol 2014;17:S12-7.
] [Full text]
Gadgil P, Udani V. Pediatric epilepsy: the Indian experience. J Pediatr Neurosci 2011;6:S126-9. [Full text]
Xue-Ping W, Hai-Jiao W, Li-Na Z, Xu D, Ling L. Risk factors for drug-resistant epilepsy: a systematic review and meta-analysis. Medicine (Baltimore) 2019;98:e16402.
Devinsky O, Verducci C, Thiele EA, Laux LC, Patel AD, Filloux F, et al
. Open-label use of highly purified CBD (epidiolex®) in patients with CDKL5 deficiency disorder and aicardi, dup15q, and doose syndromes. Epilepsy Behav 2018;86:131-7.
Dulac O. Epileptic encephalopathy. Epilepsia 2001;42 Suppl 3:23-6.
Lazaridis D, Eraikhuemen N, Williams K, Lovince J. Treatment of seizures associated with lennox-gastaut and dravet syndromes: a focus on cannabidiol oral solution. P T 2019;44:255-66.
Devinsky O, Patel AD, Cross JH, et al
. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. New England Journal of Medicine 2018;378:1888-97.
Szaflarski JP, Hernando K, Bebin EM, Gaston TE, Grayson LE, Ampah SB, et al
. Higher cannabidiol plasma levels are associated with better seizure response following treatment with a pharmaceutical grade cannabidiol. Epilepsy Behav 2019;95:131-6.
Gaston TE, Friedman D. Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy Behav 2017;70:313-8.
Huntsman RJ, Tang-Wai R, Shackelford AE. Cannabis for pediatric epilepsy. J Clin Neurophysiol 2020;37:2-8.
Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and epilepsy. Neurotherapeutics 2015;12:747-68.
IBM C. IBM SPSS Statistics for Windows. Armonk, NY: IBM Corp; 2012.
Trinka E, Kwan P, Lee B, Dash A. Epilepsy in Asia: disease burden, management barriers, and challenges. Epilepsia 2019;60:7-21.
Neubauer D, Perković Benedik M, Osredkar D. Cannabidiol for treatment of refractory childhood epilepsies: experience from a single tertiary epilepsy center in Slovenia. Epilepsy Behav 2018;81:79-85.
Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, et al
. CBD-enriched medical cannabis for intractable pediatric epilepsy: the current Israeli experience. Seizure 2016;35:41-4.
Gaston TE, Szaflarski M, Hansen B, Bebin EM, Szaflarski JP; UAB CBD Program. Quality of life in adults enrolled in an open-label study of cannabidiol (CBD) for treatment-resistant epilepsy. Epilepsy Behav 2019;95:10-7.
Devinsky O, Marsh E, Friedman D, et al
. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol 2016;15:270-8. DOI: 10.1016/s1474-4422(15)00379-8.
Caraballo R, Demirdjian G, Reyes G, Huaman M, Gutierrez R. Corrigendum to “effectiveness of cannabidiol in a prospective cohort of children with drug resistant epileptic encephalopathy in argentina” [seizure 80 (2020) 75-80]. Seizure 2020;80:283.
Stockings E, Zagic D, Campbell G, Weier M, Hall WD, Nielsen S, et al
. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry 2018;89:741-53.
Silvestro S, Mammana S, Cavalli E, Bramanti P, Mazzon E. Use of cannabidiol in the treatment of epilepsy: efficacy and security in clinical trials. Molecules 2019;24:1459.
Press CA, Knupp KG, Chapman KE. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav 2015;45:49-52.
Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al
; Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the dravet syndrome. N Engl J Med 2017;376:2011-20.
Lopera V, Rodríguez A, Amariles P. Clinical relevance of drug interactions with cannabis: a systematic review. J Clin Med 2022;11:1154.
Lattanzi S, Brigo F, Trinka E, Zaccara G, Cagnetti C, Del Giovane C, et al
. Efficacy and safety of cannabidiol in epilepsy: a systematic review and meta-analysis. Drugs 2018;78:1791-804.
[Figure 1], [Figure 2]
[Table 1], [Table 2]