Discussion
idiopathic adult-onset BPS, epilepsy, spasm, spasms, epileptic
EPILEPSY, ADVERSE EVENTS, DISEASE, FLUTTERING, EPILEPTIC
Despite recreational legalization in several states, and growing attention over the last several decades, cannabinoids have been poorly studied in the medical literature. This lack of research can be attributed to the fact that usage of marijuana-derived products still constitutes a federal offense, and because there has been little distinction made between different cannabinoids.Additionally, BPS itself is a challenging disease to accurately quantify. The difficulties of clinical assessment have led to numerous clinical rating scales, many of which have reasonable levels of internal consistency, but poor inter-rater agreement.Daily 200 mg of sublingual CBD was found to be well-tolerated, without adverse events, and provided statistically significant improvements in several BPS parameters – namely median maximum eyelid closure velocity and median duration of eyelid closures. There was either no significant differences or the only difference was between baseline and placebo in number of eyelid closures and median eyelid closure amplitude, suggesting that Botox worked as we would have expected. It is not yet clear if there is a linear relationship between the change in magnitude of these parameters and a clinically significant improvement in patients with BPS. Our clinical rating scale, JRS, hinted at a modest change, but was not statistically significant. This was not unexpected given the underpowered nature of the study to assess treatment effect. The JRS has been argued by some to have a poor definition of spasm, with a lack of attention to specific clinical features, and poor sensitivity to smaller changes in severity and frequency. It was used in this study, as historically, it has been the most widely used severity scale. A more modern scaleAlthough our digital video strategy has the potential to measure a significantly higher number of variables present during the motion of the eyeblink, our small team and scope were limited in this initial study. Nevertheless, our dataset included 1.6 million video frames from 12 patients, and running quantitative analyses is time-intensive. With scant support from the literature regarding kinematic analysis, we constructed a short list of applicable variables and analyzed the four reported. We suspect this type of analysis will grow more popular, and a recent article has used similar variables.Whereas the increased eyelid closure velocity and decreased duration are more easily interpreted in the context of BPS, the change in amplitude of the closure is more challenging. One might assume that spasms tend to decrease the amplitude, but we noted consistent high amplitude closures in some patients, and preceding spasms in others. Some data has suggested that hyper-excitability of brainstem neurons in BPS can lead to an increase in the amplitude of the closure reflex and a prolongation of the duration of the eyelid closure.Additionally, we included conversation states and lighting conditions as covariates in our analysis to account for their potential influence on the outcomes of interest. Upon examining the coefficients and The dosage in this study was limited by safety considerations, as this was an initial feasibility study. The authors recommend a future study of up to five times the current study's dosing (which more closely approximates the dosing used in clinical practice for epilepsy)Of note, blink time courses in patients with BPS can be highly idiosyncratic, with extended durations from partially closed lids, and multiple lid fluttering behavior that does not conform to the concept of discrete closures. Under these circumstances, no definition of a discrete “eyelid closure” can be expected to be fully satisfactory under all circumstances. The 50% amplitude criterion used and discussed in Methods was found to perform well for all participants. The example in Regarding the 30 Hz sampling rate of the analysis, although not ideal for specifying fine details of regular eyelid closures time courses lasting 100 to 200 milliseconds, the rate is sufficient to ensure that all closures were captured, and to specify the durations of eye closures longer than typical to a sampling resolution of 33 ms. Given this, we found that the high-resolution video recording analysis was able to track and measure kinematic responses in BPS, and may serve as an effective method for objective measurement of the response to treatment in future studies.There are many alternatives for the time frames and testing periods of our study. Notably, in the clinical trials of Epidiolex for epilepsy, the maintenance period was 12 weeks and changes in epileptic activity were noted to occur within 4 weeks.Epidiolex CBD dosing was selected based on internal data from our original, retrospective reviewThe small sample size itself was deemed appropriate for a feasibility study. It was practical for an early-stage investigation within a single clinical location, whereas providing the critical preliminary information for planning subsequent larger studies.Finally, although the authors understand that clinical relevance is of particular importance, we believe that BPS is a complex condition in which the traditional “gold standard” of clinical assessment is inadequate. Most clinical assessment scales are subjective and have difficulty interpreting the wide and varied movements that we see in BPS. We believe our objective kinematic analysis is a more sensitive and precise method of quantification, and with further time and study may provide the basis for a more accurate assessment.In summary, despite the study limitations, this pilot feasibility study demonstrated via a unique kinematic objective analysis that low dose CBD may be a useful adjunct to traditional BTX injections for the treatment and symptom abatement of idiopathic adult-onset BPS. Further study with higher dosing is warranted.