Long-Term Impact in the Quality of Life of Patients with Drug-Resistant Epilepsy That Use Cannabidiol

Introduction: Epilepsy is considered a chronic neurological condition that manifests itself with seizures, where 30% - 40% of patients do not achieve control of their seizures despite proper management. Seizures represent a significant limitation in the patient’s daily activities and are often accompa-nied by emotional and relational difficulties that have a great impact on the quality of life of the patient and their families. Cannabidiol (CBD) has been found to be effective in controlling seizures and may also improve cognitive and behavioral abilities. Material and Methods: The Quality of Life of the Patient with Epilepsy (CAVE) scale was applied to patients with refractory epilepsies who use Cannabidiol (CBD) added to their base therapy, before the use of CBD and after 12 months of follow-up. The presentation of collateral effects was also evaluated. Results: Out of 34 patients, 26 (76.5%) increased their CAVE value at the end of the study and only 1 (2.9%) decreased. 19 (55.9%) improved in learning and behavior, 55.8% in the frequency of seizures and 79.4% reported a decrease in the intensity of seizures. There were other positive side effects such as improvement in alertness, language, sleep and behavior. The main side effects were mild and transitory, including drowsiness, and constipation. There was a correlation between the global perception of improvement and seizure control. Conclusions: This study shows that in the long term CBD improves the quality of life of patients with refractory epilep sies, through the control of seizures and the improvement of cognitive and behavioral functions.


Introduction
The World Health Organization defines Quality of Life (QoL) as the perception that an individual has of his place in existence, in the context of the culture and of the value system in which he lives and in relation to his objectives, his expectations, his norms, his concerns. Epilepsy is a chronic disease that has a great impact on the QoL of patients and their families. According to some authors, up to 58.3% of patients with epilepsy have a poor QoL due to the unexpectedness of new seizures, the probable associated injuries, the use of anticonvulsant drugs and their adverse effects [1] [2]. In addition, psychosocial problems, especially the great social stigma that still prevails around this pathology, are usually the main problem that affects the patient and the family with epilepsy [3].
Patients with Drug-Resistant epilepsy face even more complex clinical conditions, aggravated by factors such as the early onset of epilepsy, frequent and severe attacks and the use of polytherapy, all of which may cause a worse quality of life [2]. Besides, other factors that negatively affect the individual's QoL cannot be undermined, such as excessive fatigue, social isolation, low self-esteem, anxiety, depression, various degrees of cognitive dysfunction (mainly memory and concentration), lack of independence and great emotional and behavioral instability [2] [4].
In clinical practice, improving the QoL of patients with epilepsy is a daily challenge. There are many drugs used that, despite their benefits in seizures control, add more adverse effects to the scenario. For this reason, recent studies showing the effectiveness of Cannabidiol (CBD) in the control of seizures, especially in Dravet and Lennox Gastaut Syndromes [5] [6], are interesting, since, besides the seizure control, other positive side effects have also been reported. The most relevant positive effects are improvement in the level of alertness, memory, language, motor skills, sleep, mood, behavior and socialization [4] [7].
In the following section, we will assess the changes in the QoL of patients with Drug-Resistant epilepsy who have used CBD concomitantly with their base treatment for at least 12 months.

Study Design
This retrospective observational descriptive study evaluates QoL of patients with Drug-Resistant epilepsy that have been treated with antiepileptic medication associated with CBD for at least 12 months, through the use of diverse questionnaires that focus on seizures control and adverse effects caused by the use of multiple drugs.

Population
The study includes all the patients treated with antiepileptic medication associated with CBD for at least 12 months at the National Center for Epilepsy (NEC) in Quito-Ecuador.

Data Sources
For this study, we used secondary data collected by the health professionals at the NCE throughout the years of follow-up of their patients. We used two anonymized sources of information for the study: hand-written medical records and quality of life surveys.

Medical Records
The medical records start with a baseline in-depth interview of the patient's caregivers, followed by all the relevant details related to use of medication and CBD, including adverse effects; information that was used for the present study.

Survey
The health professionals at the NCE applied the CAVE Questionnaire at baseline and several times during follow-up for each patient. This questionnaire measures the impact of epilepsy on quality of life. It was carried out on the patient's relatives or caregivers, considering as a caregiver to whoever was in charge of the patient in their daily care and who, in turn, regularly attended the controls prior to the start of CBD and at the end of 12 months of treatment. The CAVE questionnaire is characterized as being easy and fast to apply, likewise practical and simple to interpret (level of certainty IIb-III-IV, grade of recommendation B-C).
CAVE is a scale designed in Spain, with which the negative impact of epilepsy on various functional aspects of the individual can be identified. Behavior, school attendance, learning, personal autonomy, social relationship, frequency and intensity of seizures and parents' opinions are evaluated. There are eight parameters, the first five of which are semi-objective, two objective items: frequency and intensity of seizures and a subjective item: parental opinion. Each item has a score range of 1 -5 points ("very bad" to "very good") and the total score is grouped into intervals that are expressed as a qualitative measure of QoL.
The points are distributed in the following manner: 0 -15 defines a bad QoL, 16 -23 a moderate QoL, 24 -31 a good QoL and 32 -40 a very good QoL. The optimal QoL scores 40 and the worst scores 8.

Statistical Analysis
Descriptive statistical analysis was carried out in the present study. The statistical software STATA 14.2 was used for the analysis of the data.
For further analysis, Spearman's nonparametric test was used to assess possible correlations between quantitative variables. The value of p < 0.05 is calculated as a measure of significance.

Ethical Concerns
Following Ecuadorian regulations, observational studies based on secondary data do not need an approval by an IRB when information is properly anonymized, as is our case.

Results
The general parameters of the patients included in the study are presented in are male. Out of these, 25 were younger than 10 years old (73.53%) and 9 (26.4%) patients were 10 years old or above. 25 (73.53%) of the patients have an age of onset of epilepsy before 1 and 9 (26.4%) older than 1 year.
Most patients do not have a family history of epilepsy, but a high proportion of them have pathological data of acquired abnormalities, either prenatal (73.5%), perinatal (55.9%) and/or postnatal history (58.8%). Within the prenatal history, the most relevant difficulties were fetal distress, followed by threatened abortions. Prematurity was the most common perinatal complication, followed by asphyxia. In consequence, the most prevalent comorbidities to epilepsy were psychomotor impairment (70.5%), autism (23.5%), and cerebral palsy (17.6%).

CAVE Evaluation
The    There is an increase in the regular and good category from 5 (14.7%) to 14 (41.2%), and in good and very good from 0 (0%) to 10 (29.4%). Figure 2 gives information about the improvement in the CAVE score is notorious and has an impact on the patient's quality of life. 26 of the 34 patients (76.5%) increased their CAVE score at the end of the study and only 1 (2.9%) decreased their score.
In Table 2 we describe any improvement that was reported from each patient and resulted in a change in the description based on the scale from a lower category to a higher category. For example, the change from "very bad" to "bad" is

Positive Side Effects
Throughout the study, we were able to observe that besides the decrease in seizures frequency, CBD intake resulted in several positive side effects regarding neurocognitive parameters. Table 3 represents the improvement in each one of is seen in each of the parameters, with learning, language and motor skills improving the most (91.2%), followed by awareness and sleep (88.2%), conduct and affectivity (85.3%) and finally aggression with a 12 patient improvement (35.3%). It is relevant to clarify that aggression was only followed up on patients that presented that trait at baseline, considering that the rest of the caregivers of the participants never reported aggression.

Negative Side Effects
The total number of patients with negative adverse effects throughout the study is shown in Figure 3, observing a decrease in patients with adverse effects from 13 (38.2%) patients after one month of follow up to 4 (11.8%) patients after 12 months.
In the first month, it is seen that the most prevalent adverse effect is drowsiness (11.8%), followed by constipation (8.8%). At 12 months drowsiness remains the most present but has decreased to 2 patients (5.9%) that present it, followed by fatigue and constipation presented in 1 patient (2.9%) each is shown in Figure 4.

Discussion
The current use of CBD is an important therapeutic option, not only for seizures control, but also for achieving positive changes in the QoL of the patient with epilepsy. Among the participants in our study, we were able to verify the changes in the QoL during a year of treatment with CBD. Prior to starting CBD treatment, 99.5% of patients reported a very poor QoL and, at best, regular, where none of the caregivers classified it as good or very good. Our results are similar to those presented by other authors where the majority of parents of children with epilepsy classify their life and that of their child as bad or very bad [2].
After 12 months of CBD use, changes in the QoL of 76.5% of our participants were very relevant, demonstrating an increase of up to 10 points in the QoL. A similar improvement was previously reported by Rosenberg    However, achieving seizures control is usually not enough to achieve a better QoL, this has also been described in patients undergoing epilepsy surgery that, despite achieving seizures control in the long term, other comorbidities remain, such as symptoms of anxiety and depression, which affect the QoL of the patient and his family [3].
It was interesting to observe how behavior improved in 55.9%, as well as social skills in 50% of patients, both very significant since patients with epilepsy have a 4.7 times greater risk of developing behavioral, relational and emotional problems compared to the general population [10]. In this same way, learning when evaluated by the CAVE scale also improved in 50% of patients, understanding this parameter as the ability to acquire a skill or knowledge. Some participants were able to be schooled after a period of treatment, 55.9% was able to attend special therapeutic or educational activities.
The autonomy parameter improvement of up to 32.3% when evaluated by the   [16], seeing an improved ability to learn, communicate and acquire motor skills, followed by a better alertness and better quality of sleep, conduct and affectivity. Even a small group that reported aggressiveness at the beginning of treatment noted significant improvement.
Finally, 64.7% of the parents had a positive opinion regarding CBD treatment, most of the patients do not report negative adverse effects, and if they existed, they were minimal and mainly occurred at the beginning of treatment. Those negative adverse effects were mostly somnolence, constipation and decrease in appetite, being all of these well tolerated, supporting the statement that CBD is generally well tolerated, as is reported by Anciones and Gil-Nagel [17]. Further research would be needed to evaluate if constipation was due to the treatment or to conditions of the patient, considering that it is a rare find when using CBD.
The main limitations in our study are due to the subjectivity that arises from the surveys that are responded by the caregivers, considering answers are due to their perception in most cases. Another important limitation is the relatively reduced sample size, nevertheless, similar studies use even smaller sample sizes.

Conclusion
In conclusion, the improvement in QoL achieved with CBD may be independent of seizures control, since it includes changes in cognitive, social and behavioral aspects [4] [16]. These results demonstrate that the same emphasis must be applied not only to achieve adequate seizures control but also to control other aspects of daily life that have a colossal impact on the individual and his family.