Discussion
headache, attack-frequency, fracture, dislocation
ADVERSE EVENTS, THIGH DISEASE, CLUSTER HEADACHE, STAGGERED, EVENTS
In this study, we prospectively and structurally assessed the long-term effectiveness, safety and tolerability of ONS in 88 patients with MICCH who had initially completed the 48-week randomised, double-blind, electrically dose-controlled ICON trial. Both ICON responders and non-responders were followed for at least two years with a mean of four years and a total of 370 person-years which is 84% of a potential maximum total duration of 442 person years. After 3 years of follow-up, 60/88 (68%) participants were still active, and after five years, 32/88 (36%); three participants could be followed for 8.5 years. The majority of participants who were ≥50% responders at the end of the ICON study remained responder for most of the follow-up period, and more than one third of initial non-responders became ≥50% responders. Mean group attack-frequency and the SF-36 general health scores also remained improved for at least 5 years. Remarkably, most participants, even those in whom attack frequency did not significantly decrease, reported subjective improvement and would recommend ONS to other patients with MICCH. ONS was generally well-tolerated. Most SAEs were due to a short hospital stay for hardware replacement. The overall incidence per person-year for SAEs was 0.62, for hardware-related SAEs 0.37, for non-hardware-related SAEs 0.24, for additional hardware-related surgery 0.35 and for all non-serious AEs 1.83.ONS is a relatively new, minimally invasive and reversible prophylactic treatment for MICCH. Small open-label case seriesThe results are in good agreement with those of other retrospectiveIt was notable that even participants without an objective reduction in attack frequency reported subjective improvement and satisfaction, and continued ONS therapy. This was probably due to a reduction in attack severity and an improved response to acute and prophylactic medical treatment, as in the ICON study and other trials.As in other studies,In the ICON study, we used non-rechargeable implantable pulse generators (IPGs) and hardware originally developed for epidural spinal cord stimulation, which increased the risk of fracture or dislocation of the leads when used for ONS. However, for necessary replacements during follow-up, we were able to use (i) rechargeable IPGs, reducing the need for surgical battery replacement; (ii) new, more flexible electrodes that adapt better to the shape of the skull, reducing the risk of fracture; and (iii) tined leads, reducing the risk of dislocation. The number of hardware-related additional surgeries was 0.35 per person-year, which is similar to other ONS studies.We found no significant predictors of long-term response, consistent with previous studies.Important strengths of this follow up study include (i) the large sample size, with both responders and non-responders to 48 weeks ONS at the start of the follow up, minimising the risk of a large selection bias; and (ii) the long and structured prospective follow-up period with a high retention rate of 73/88 (83%) active participants at the end of the predetermined minimum follow-up of two years, i.e. three years after ONS implantation. In fact, the majority of participants in the L-ICON follow-up study were followed even longer than two years because they were included only after they had each completed the 48-week ICON study, the inclusion for the ICON study was spread over many years, and because the L-ICON follow-up took place in parallel with the ICON study. Of the 88 participants who started follow-up, 61 (69%) could be followed ≥3 years, 33 (38%) ≥5 years and 3 (3%) for as long as ≥8.5 years. Based on the actual, compared to the potential maximum duration of follow up–because not all participants started at the same time -, drop out accounted for only 16% of the total person years.Apart from drop-out and loss-to-follow-up, events that reflect everyday practice and are unavoidable in this type of study, other limitations should be considered. Not all participants in the ICON study took part in the L-ICON follow up. A total of 19 participants from the ICON trial who did not participate in the L-ICON were missing completely at random (i) N = 11 did not live in the Netherlands and thus were not approached to participate in L-ICON for logistical reasons; and (ii) N = 8 were not approached because these patients had started the ICON study very late and therefore would have ended the ICON study very late; inclusion of these 8 patients would have delayed the end of the L-ICON study by at least two years. Therefore, their missingness should not have biased the results. Furthermore, no differences were observed between participants and non-participants in key demographic and clinical characteristics at baseline. Moreover, response rates during the ICON study did not differ between L-ICON participants and non-participants. Finally, response rates in the ICON study did not correlate with the likelihood of participating in the L-ICON study.The main statistical analysis was performed for a follow-up of 5 years after completion of the ICON trial. Because of the research design (staggered inclusion), not everybody had an equally long follow-up, therefore missing data are unavoidable. The reasons for missingness should be considered very carefully as non-random missingness could bias the results. Most of the missing data after 5 years of follow-up is due to the fact that, because of the staggered inclusion, these participants had not yet reached 5 years of follow-up after completion of the ICON trial when the study ended (n = 24 cases, Moreover, in an effort to address these missing data and minimise selection bias and biased data loss, we used the full observations as a template for the incomplete observations by using multiple imputations that allowed us to use the data from all ICON trial participants, including those who showed no effect in or completed the ICON trial. By assuming that the missingness of the data is (completely at) random, it is reasonable to extrapolate the measurements. The assumption is that if measurements are stopped in a participant, the future data will behave similarly to the data of similar participants who did remain in the study. To illustrate the robustness of our data, we also performed an analysis without imputed data which showed similar data to those with imputations (As with all headache studies, we had to rely on self-reported data on attack frequency and adverse events. However, we believe the data are accurate and complete. Although prospective recording of attacks immediately after each attack using an electronic diary is considered the most optimal and reliable way to measure attack frequency, it is also the most burdensome for patients.Finally, all participants previously did not respond (sufficiently) to an optimal dose of, or were intolerant of and/or had a contraindication to verapamil and lithium, as well as at least one of the other recommended treatments for cluster headache: methysergide, topiramate or gabapentin. During the L-ICON follow-up study, all participants received individually optimised treatments and were allowed to use any prophylactic drug in addition to ONS. However, these drugs had previously proven ineffective for these patients and no new drugs had become available during the ICON and L-ICON studies. We therefore conclude that the observed effects were due to ONS and not to other concurrent prophylactic medications. Because of the extremely high disease burden, several neuromodulatory options with a wide range of targets such as sphenopalatine ganglion block and stimulation, vagal nerve stimulation, greater occipital nerve blocks and stimulation, and even deep brain stimulation (DBS) have been explored with mixed results.