Subtype shift, relapse rate and risk factors of frequent relapse in cluster headache: A multicenter, prospective, longitudinal observation

Aim: To prospectively determine subtype shift, relapse rate and risk factors of frequent relapse in cluster headache (CH). Methods: This multicenter cohort study recruited patients with CH at baseline visits between September 2016 and January 2019 and planned to prospectively follow them up for up to five years. The subtype (episodic vs. chronic) was reassessed at baseline visit 2 (2–4 weeks) and serial follow-up visits if unremitted. We assessed the subtype shift of the index bout (i.e. the bout at the baseline visit) in all patients and relapse rates in those with episodic CH who were in an active bout at the time of recruitment. Relapse (i.e. bout recurrence) was prospectively collected via clinic visit or telephone interview at 3 ± 1 months, 1, 2, 3, 4 and 5 years (each ±6 months) after the baseline visit. Risk factors of frequent relapse were analyzed by comparing the incidence rate ratio (IRR) of relapse using Poisson regression analysis (model 1, static variables in all patients; model 2, time-related variables in patients with two or more lifetime bouts) accounted for different follow-up periods using an offset term. Results: In 295 patients (58 with first-ever bouts) enrolled, CH subtypes were episodic, chronic and unclassified in 252, 11 and 32 at baseline. At baseline V2, CH subtype was re-determined to be chronic in seven (12.1%) of 58 patients with first-onset CH (“primary chronic CH”) and nine (3.8%) of 237 with a history of episodic CH (“secondary chronic CH”). When excluding known chronic CHs at baseline, the incidence of chronic CH newly found during a prospective observation was 3.8% in patients with first-onset CH and 1.4% in those with a history of episodic CH. In 244 patients with episodic CH in an active bout at the time of recruitment, the relapse rate was 0.29 (95% confidence interval (CI) = 0.27–0.32; p < 0.001) per person-year after 5.9 ± 1.37 follow-up visits over a mean duration of 4.2 ± 1.32 years. Models 1 and 2 indicated that age (adjusted IRR = 0.97; 95% CI = 0.95–0.98), longer disease duration (adjusted IRR = 0.97; 95% CI = 0.95–1.00), first-ever bout (adjusted IRR = 0.35; 95% CI = 0.20–0.57), regular (one or more per week) alcohol consumption (adjusted IRR = 0.60; 95% CI = 0.45–0.81), and longer between-bout interval of previous bouts (adjusted IRR = 0.72; 95% CI = 0.60–0.87) were associated with less relapse. Seasonal rhythmicity (adjusted IRR = 1.66; 95% CI = 1.20–2.33) and increasing attack intensity across bouts (adjusted IRR = 1.66; 95% CI = 1.06–2.59) were associated with frequent relapse. Conclusions: The present study provides data on the subtype shift and relapse rate of CH based on the prospective observation. Although our observation is only limited to a five-year time frame, our findings may suggest that disease activity increases after onset and then regress with age and time, and that seasonal rhythmicity and increasing attack intensity across bouts indicate higher propensity to relapse.