Abstract text (incl. figure legends and references)
QUESTION- Which is the best preventive treatment strategy for Refractory Chronic Cluster Headache (rCCH) based on current scientific evidence? METHODS- The review and meta-analysis were performed following PRISMA guidelines. The protocol was registered in PROSPERO (ID CRD42021290983). The search was performed on September 2021 on databases Pubmed, Embase and Cochrane. Studies of preventive strategies for rCCH defined by the European Headache Federation criteria were selected. For risk of bias assessment, the Cochrane Handbook Risk Of Bias tool was used for randomized clinical trials (RCT) and ROBINS-E was used for observational studies (OS). RESULTS- 43 articles met the inclusion criteria. The largest number of articles studied occipital nerve stimulation (ONS) accounting for 1 ECA and 11 OS for a total of 436 patients, followed by deep brain stimulation (DBS): 1 RCT and 8 OS; 118 patients. All ONS studies reported a significant reduction in attack frequency and the 50% responder rate ranged from 29.4% to 80.0%. Meta-analysis of ONS studies revealed a pooled 50% responder rate of 57.3% (95%CI 0.48-0.67, p<0.001). DBS studies reported a 50% responder rate of 50-100%, with a pooled result of 71.6% (95%CI 0.45-0.978, p<0.001). Reported adverse events (AE) were more serious in DBS studies. The remaining 24 articles (anti-CGRP pathway drugs, ketamine-magnesium infusions, serial occipital nerve blocks, clomiphene, onabotulinum toxin A, ketogenic diet, sphenopalatine ganglion radiofrequency or stimulation, vagus nerve stimulation, percutaneous bioelectric current stimulation, upper cervical cord stimulation and vidian neurectomy) present weaker results or have poorer quality of evidence. CONCLUSIONS- Considering the quality of the published studies, their results and the profile of AE, ONS could be the first therapeutic strategy for patients with rCCH based on the current evidence.