4 CHAPTER 4 78 Here, we compared CSF levels of eCBs in a large cohort of people with migraine with aura and without aura and healthy controls. We sought to detect differences in the endocannabinoid system and identify diagnostic biomarkers that distinguish these clinical entities taking comorbid depressive symptomatology into account. Methods Study design and participants The study population has been described in Onderwater et al.29 In brief, we enrolled n = 198 individuals with migraine (n = 100 migraine with aura and n = 98 migraine without aura) and n = 96 healthy controls and group-matched them for age (using 5-year strata) and sex. Migraine was diagnosed according to the International Classification of Headache Disorders (ICHD) by experienced physicians (supervised by G.M.T. and M.D.F.).1 All participants were between 18 and 65 years and had a body mass index (BMI) between 18 and 28. Individuals suffering from migraine did not use acute migraine drugs on more than 8 days per month. Healthy volunteers had no obvious signs or symptoms of a disease and had no history of headache (except for infrequent tension-type headaches) or other pain-related syndromes. They also did not have first-degree relatives with migraine or trigeminal autonomic cephalalgia. Other exclusion criteria were (1) severe psychiatric disorder, (2) history of oncological disease, or (3) contra-indication for lumbar puncture (LP) (signs and symptoms of increased intracranial pressure, local skin infection, or a coagulopathy including use of anti-coagulant drugs or platelet-inhibitors). Participants were asked to fill out a questionnaire on the day of the LP that included questions related to their migraine characteristics and possible history of depression. To compute lifetime depression, additional questionnaires were preferentially completed on the day of LP, but otherwise extracted from electronic medical records. The presence of lifetime depression was determined based on previously described criteria.30 In short, symptoms of depression were determined using validated cut-off scores for the Hospital Anxiety and Depression Scale (HADS) and the Center for Epidemiologic Studies Depression Scale (CES-D). The HADS questionnaire has been used in clinical studies as it intrinsically corrects for the overlap between symptoms of somatic diseases and depression (e.g., lack of sleep, changes in appetite). Lifetime depression was defined as HADS-D ≥ 8 or CES-D ≥ 16 or (past) depression diagnosed by a physician or (past) use of antidepressants for depression. The study was conducted according to the criteria of the Declaration of Helsinki and was approved by the Leiden University Medical Center institutional ethics committee. All participants provided written informed consent prior to participation in the study. Cerebrospinal fluid collection Sampling and handling of CSF samples was described in Onderwater et al.29 In brief, the time of the LP was between 8:30 a.m. and 1:00 p.m. and in random order to minimize diurnal and seasonal
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