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Use of cannabidiol in the treatment of epilepsy: Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex

SUMMARY OBJECTIVE: The objective of this systematic review with meta-analysis was to evaluate the efficacy, safety, and short- and long-term tolerability of cannabidiol (CBD), as an adjunct treatment, in children and adults with Dravet syndrome (SD), Lennox-Gataut syndrome (LGS), or tuberous sclerosis complex (TSC), with inadequate control of seizures. METHODS: This systematic review was conducted through a search for scientific evidence in the Mediline/PubMed, Central Cochrane, and ClinicalTrials.gov databases until April 2022. Selected randomized clinical trials (RCTs) that presented the outcomes: reduction in the frequency of seizures and total seizures (all types), number of patients with a response greater than or equal to 50%, change in caregiver global impression of change (CGIC) (improvement ≥1 category on the initial scale), adverse events (AEs), and tolerability to treatment. This review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses. RESULTS: Notably, six RCTs were included, with a total of 1,034 patients with SD, LGS, and TSC, of which 3 were open-label extension RCTs. The meta-analysis of the studies showed that the use of CBD as compared with placebo, in patients with convulsive seizures refractory to the use of medications, reduces the frequency of seizures by 33%; increases the number of patients with a reduction ≥50% in the frequency of seizures by 20%; increases the number of patients with absence of seizures by 3%; improves the clinical impression evaluated by the caregiver or patient (S/CGIC) in 21%; increases total AEs by 12%; increases serious AE by 16%; increases the risk of treatment abandonment by 12%; and increases the number of patients with transaminase elevation (≥3 times the referral) by 15%. CONCLUSIONS: This systematic review, with meta-analysis, supports the use of CBD in the treatment of patients with seizures, originated in DS, LGS, and TSC, who are resistant to the common medications, presenting satisfactory benefits in reducing seizures and tolerable toxicity.


INTRODUCTION
Epilepsy is one of the most common neurological disorders 1 . About one-third of all patients with epilepsy have drug-resistant seizures. The International League Against Epilepsy defines drug-resistant epilepsy as the "failure of ≥2 appropriate and tolerated antiepileptic drugs (either as monotherapy or in combination) to achieve the sustained freedom of seizures" 2 . Inadequate seizure control significantly affects the quality of life and cognitive function of these patients. Drug-resistant epileptic syndromes are associated with significant comorbidity and high rates of cognitive impairment, as well as psychiatric and physical disability. Currently, cannabidiol (CBD) is being used for three epileptic syndromes: Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (CST). Both LGS and DS are early-onset encephalopathic epileptics with poor prognosis and associated with comorbidities.
LGS is a severe epileptic encephalopathy of varying presentation and is associated with high rates of seizure-related injury and cognitive impairment 3-5 . LGS has an incidence of approximately 1:4,000 births; estimates of uncertain prevalence, possibly around 15/100,000.
DS is rare, intractable, occurs in early childhood and is characterized by prolonged and recurrent partial crises at onset, with progression to generalized polymorphic seizures resulting in developmental delay, cognitive impairment, and increased mortality. SD has an incidence of approximately 1:20,000 births; estimates of uncertain prevalence, possibly around 3/100,000. SD is believed to account for approximately 7% of all severe epileptics initiated before 3 years of age [6][7][8] .
CBD was also evaluated under conditions with mainly focal seizures, such as TSC. TSC is a genetic disease that can Rev Assoc Med Bras 2022;68(10):1345-1357 present in any part of the body. The most common manifestations include benign tumors in the skin, brain, kidneys, lung, and heart that cause organic dysfunction 9 . The reported incidence ranges from 1 per 5,800 to 10,000 live births 9 and the prevalence of 1/20,000 people in the UK 9 . Cannabis has been used to treat epilepsy since antiquity, and interest in cannabis-based therapies has increased in the past decade. CBD, which is one of the main constituents of the Cannabis sativa plant, has anticonvulsant properties and does not produce euphoric or intrusive side effects 10 . The lack of regulation and standardization in the medicinal cannabis industry, however, raises concerns about the composition and consistency of the products that are dispensed 11 . Pharmaceutical grade oral CBD solution is the first product made directly from the cannabis plant, rather than created synthetically, to be authorized by regulatory agencies and the first of a new class of anticonvulsant drugs.

OBJECTIVE
The aim of this study was to assess the efficacy, safety, and short-and long-term tolerability of CBD, as an adjuvant treatment in children and adults with inadequately controlled DS, LGS, or TSC.

METHODS
This systematic review will be carried out in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 12 .
A clinical doubt arises: what is the impact of CBD use on outcomes reducing the frequency of seizures and total seizures (all types), number of patients with a response equal to or greater than 50%, impression of clinical improvement by the patient or caregiver, adverse events (AEs), and tolerability to treatment?
The eligibility criteria of the studies are as follows: The following data were extracted from the studies: author name and year of publication, population studied, methods of intervention and comparison, absolute number of events reductions in the frequency of seizures and total seizures (all types), number of patients with response equal to or greater than 50%, impression of clinical improvement by the patient or caregiver (CGIC), AEs, in addition to follow-up time. The results of the median percentage change (minimum -maximum) in relation to baseline in the monthly frequency of seizures were also extracted.
The risk of bias scans for RCTs will be assessed using the rob 2 tool items 13 , plus other key elements, and expressed as low, moderate, serious or critical risk of bias, and no information. For cohort studies, the tool currently recommended by the Cochrane Collaboration will be used to assess the risk of bias in estimates of effectiveness and safety in nonrandomized Risk of Bias In Non-Randomized Studies -of Interventions (ROBINS-I) intervention studies 13 . ROBINS-I evaluates seven domains of bias, classified by moment of occurrence. The bias risk assessment will be conducted by two independent reviewers (AS and IF), and in case of disagreements, a third reviewer (WB) can deliberate on the evaluation. The quality of evidence will be extrapolated from the risk of bias obtained from the study(s) (if there is no meta-analysis) using the TERMINOLOGY GRADE 14 in very low, low, and high, and through the software GRADE pro 15 (if there is meta-analysis) in very low, low, moderate, and high.
The results for categorical outcomes will be expressed by the difference in risk (DR) between CBD therapy and placebo treatment. If the DR between groups is significant (95% confidence), this will be expressed with the 95% confidence interval (95%CI) and a number needed to treat (NNT) or to produce a Harm (NNH). In continuous measures, the results are expressed as mean difference or median difference with 95%CIs. Data from observational studies are reported as the percentage of participants who experienced a result.
If there is more than one study included with common outcomes, this will be aggregated through meta-analysis, using the RevMan 5.4 software 16 , with the overall risk difference with 95%CIs being the final measure used to support the synthesis of evidence, which will answer the clinical doubt of this assessment. The estimated size of the combined effects was performed by a fixed or random effect model after the evaluation of heterogeneity results. Heterogeneity was also calculated using the value I 2 . The results will be evaluated by study design (RCTs and observational cohorts) and presented individually.

Included studies
In the search for evidence, 145 articles were retrieved, and 15 studies evaluated the use of CBD plus usual therapy as compared with placebo in the treatment of patients with DS, LGS, and TCS or were observational cohort studies "open-label extension" (OLE). The 15 studies were assessed because they met the eligibility criteria for analysis of the full text. Of these 15 studies, 6 [17][18][19][20][21][22] ECRs and 3 [23][24][25] OLE studies were included to support this evaluation, whose characteristics are described in Tables 1 and 2, respectively. The excluded list and the reasons are available in the references and are shown in Figure 1 26 .
The six RCTs enrolled 1,034 patients with DS, LGS, and TSC, with 485 patients undergoing treatment with CBD (all dosages) compared to 325 placebo patients. This population was followed to measure the outcomes of reduction in the frequency of seizures and total seizures (all types), number of patients with response greater than or equal to 50%, change in CGIC, AEs, and tolerability to treatment. The follow-up was 14-16 weeks after the start of treatment (Table 3).
These patients who had previously participated in the RCTs were allowed to continue in an OLE study for each pivotal study (Table 1), evaluating the efficacy, safety, and tolerability of CBD in the long term (median on days ranging from 267 to 1,090; n=880).

Risk of bias in included studies
For this update of the review, a combination of two out of three review authors (from AS, IF, and WB) independently re-assessed the risk of bias in each included trial according to predefined criteria stated in the Methods section (Table 3 and Figure 2) 27 .
Regarding the risk of bias of the six RCTs included [13][14][15][16][17]27 , none of them were blinded by the evaluator and one did not perform a sample calculation, and the overall risk of the studies may be considered nonsevere ( Table 3).
The assessment of the risk of bias in the observational cohort OLE studies was made with the use of the ROBINS-I tool.
The three studies included [23][24][25] presented a risk of critical bias to the loss domain (bias due to missing data), while all other domains presented a low risk of bias. Therefore, the overall risk of bias can be considered moderate ( Figure 2).

Results of randomized clinical trials
Five studies18-22, assessing 726 participants, allowed the evaluation of the outcome "absolute reduction in seizures" treated with CBD as compared to placebo, with a follow-up time of 12-16 weeks. This analysis demonstrated increase in the number of patients who obtained absolute reduction in the frequency of seizures [risk difference (RD)=0.31 (95%CI 0.18-0.44; I2=77%)], NNT=3. Moderate evidence quality (Analysis 1.1; Figure 3 and Table 2).
Five studies18-22, assessing 726 participants, have been submitted for a meta-analysis and demonstrated a less difference in the outcome "number of patients with absence of seizures" comparing treatment CBD as to placebo, with a follow-up time of 12-16 weeks [RD=0.03 (95%CI 0.01-0.03; I2=44%)]. Moderate evidence quality (Analysis 1.3; Figure 5 and Table 2).
AEs, six studies17-22, assessing 733 participants, evaluated the "frequency of total adverse events" (any), with a follow-up time of 4-16 weeks, comparing the use of CBD to placebo. This  The risk in the intervention group (and its 95%CI) is based on the risk assumed from the comparator group and the relative effect of the intervention (and its 95%CI). RR: risk ratio.
GRADE Working Group grades of evidence high certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very less confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
The "risk of treatment abandonment" was evaluated in six studies17-22, assessing 741 participants, and the follow-up time was 4-16 weeks. CBD increased the risk of treatment abandonment in the patients who received CBD as compared to placebo [RD=0.12 (95%CI 0.06-0.17; I2=50%)], NNH=8. High evidence quality (Analysis 1.7; Figure 9 and Table 2).    Meta-analysis of studies17-22, assessing 721 participants, with a follow-up time of 4-16 weeks, evaluated the number of patients with "transaminase elevation (≥3 times the reference)" comparing the use of CBD to placebo. This analysis demonstrated an increased risk of transaminase elevation ≥3 times the reference value in patients who received CBD, as compared to placebo [RD=0.15 (95%CI 0.05-0.24; I2=85%)], NNH=6. Low evidence quality (Analysis 1.8; Figure 10 and Table 2).

RESULTS OF THE "OPEN-LABEL EXTENSION" Safety and tolerability
Three OLE studies [23][24][25] allow the evaluation of treatment-emergent adverse events (TEAEs) in the use of CBD, in different types of primary seizures, and in the long term (median treatment time between 267 and 1,090 days). AEs for LGS, DS, and CTS groups are summarized by pathology in Table 4 The most commonly reported TEAEs were pyrexia and others related to the gastrointestinal tract, including diarrhea, vomiting, and reduced appetite, but also neurological issues including drowsiness.
Overall, the reported TEAEs, including the observed frequencies and severity, are comparable with previous observations of pivotal assays.
The percentage of patients who permanently discontinued treatment with CBD was 9.4% (n=83). The most common reasons were seizures and increased liver enzymes. Both are events known to cause the discontinuation of CBD treatment.

Randomized clinical trials
The use of CBD in patients with DS, LGS, and TSC as compared to placebo, follow-up time of 12-16 weeks: • Shows an absolute reduction in the frequency of seizures of 33%; three patients for one benefit (NNT=3) are needed. Moderate evidence quality. • Increases the number of patients with a 50% reduction in the frequency of seizures by 20%; NNT=5. High evidence quality. • Increases the number of patients with absence of seizures by 3%; NNT=33. Moderate evidence quality. • Improves the change in S/CGIC by 21%; NNT=5.
High evidence quality. • Increases all AEs by 12%, and it is necessary to treat eight patients to obtain damage (NNH=8). Very low evidence quality. • Increases serious AEs by 16%; NNH=6. Quality of evidence was moderate. • Increases the risk of treatment abandonment by 12%; NNH=8. High evidence quality. • Increases the number of patients with transaminase elevation (≥3 times the reference) by 15%; NNH=6. Low evidence quality.

Observational studies' cohort "open-label extension"
In treatment with CBD of different types of primary seizure, in the long term (follow-up median 1-3 years): • 95.8% of all patients have at least one TEAE with CBD; • The rate of severe TEAEs can be up to 36%;