Postdromal symptoms in migraine: a REFORM study

The present investigation is part of the larger parental Registry for Migraine (REFORM) study and was carried out at a single tertiary care unit [11]. The study protocol received approval from the relevant ethics committee and data protection agency. Furthermore, the study was conducted in adherence with the principles outlined in Helsinki Declaration, 7th revision [25]. All participants provided written informed consent before any study-related tasks or procedures were performed. A detailed description of the methods used in the parental study can be found elsewhere [11].

Design

The results presented herein are based on cross-sectional, retrospective observational data. The primary recruitment source was adult individuals diagnosed with migraine from the outpatient clinic of a single tertiary care unit. The enrolment period spanned from September 2020 to June 2022. Potential participants underwent an initial screening via phone. Following this, eligible participants were invited for an on-site visit. Each participant underwent a neurologic examination and a semi-structured interview. Furthermore, they were asked to complete various electronic patient-reported outcome measures (PROMs).

Participants

Eligible participants were individuals aged 18 years and above, diagnosed with either migraine with or without aura in accordance with the ICHD-3 criteria [24]. Furthermore, participants were required to have experienced, on average, a minimum of 4 monthly migraine days in the three months before enrolment. The key exclusion criteria were onset of migraine after 50 years of age, history of cluster headache or hemiplegic migraine, inability to distinguish migraine from other types of headaches, and being pregnant or breastfeeding. For the present investigation, we also excluded individuals who experienced continuous and unremitting daily headache. For a complete list of inclusion and exclusion criteria, please refer to Supplemental Table 1.

Table 1 Demographics and baseline characteristics of the study populationProcedures

The semi-structured interview was conducted to obtain demographics, headache characteristics, and full medical history. Within the course of the interview, participants were educated on the distinct phases of a migraine attack. This was followed by a series of questions about both premonitory and postdromal symptoms. To ascertain the latter, participants were asked to list all symptoms manifesting within 48 h after the resolution of pain in a migraine attack (i.e., unprompted reporting). If clarity was required, the question was rephrased or explained using a drawing of the migraine phases, omitting mention of specific symptoms. Following this, participants were enquired regarding the occurrence of 16 pre-defined symptoms using close-ended questions (prompted reporting). Participants were also offered the option to introduce additional symptoms. Data regarding premonitory symptoms and triggers factors were also obtained in a similar manner. In addition, participants were asked about comorbid conditions – these were verified using electronic medical records when available.

PROMs were administered and stored using the Research Electronic Data Capture (REDCap) software. The administered questionnaires comprised the Migraine Disability Assessment (MIDAS), Six-Item Headache Impact Test (HIT-6), World Health Organization Disability Assessment 2.0 (WHODAS 2.0), alongside other PROMs reported elsewhere [11].

Definitions

Postdromal symptoms were defined in accordance with the ICHD-3 definition [24]. The latter characterizes postdromal symptoms, lasting up to 48-h, and follows the resolution of pain in a migraine attack with or without aura. Moreover, premonitory symptoms were defined as symptoms occurring 2 to 48 h prior to the onset of pain in a migraine attack. This definition aligns with the description in both ICHD-2 and ICHD-3β [26, 27].

Migraine disability assessment

The MIDAS questionnaire is a self-report instrument, evaluating headache-related disability in individuals with migraine [20]. MIDAS accounts for the number of days on which work/school, household chores, or non-work activities were prevented or impaired due to headache. The appraisal period is the past 90 days. The calculated score can be stratified into little or no disability (0–5), mild disability (6–10), moderate disability (11–20) and severe disability (≥ 21). MIDAS’ upper limit is a score of 450.

Headache impact test

HIT-6 is a self-report instrument with six items, assessing headache-related burden [23]. The appraisal period is the past four weeks for the final three questions, while there is no explicit appraisal period for the remaining questions. Each item is scored from 6 to 13, with a total score ranging from 36 to 78 points. The total score can then be categorized into little or no impact (≤ 49), some impact (50–59), substantial impact (56–59) and severe impact (60–78).

World Health Organization disability assessment schedule 2.0

The WHODAS 2.0 questionnaire is a 12-item instrument to assess disability due to health conditions [5]. The appraisal period is the past 30 days, and each question is rated on a 5-point scale, ranging from “not at all” to “extremely difficult”. The total score ranges from 12 to 60 points.

Outcomes

The primary objective was to estimate the proportion of participants listing postdromal symptoms (i.e., ≥ 1 symptom) using prompted reporting and in adherence with the ICHD-3 definition [24]. The secondary objectives were exploring differences between prompted and unprompted reporting in terms of the proportion of participants with ≥ 1 postdromal symptom. A similar comparison was made for the total number of postdromal symptoms per participant using the two means of enquiry. Another objective was to examine whether the likelihood of reporting postdromal symptoms was affected by certain clinical factors. This included age, gender, migraine with aura, chronic migraine, medication-overuse headache (MOH), monthly migraine days, migraine duration, migraine severity, current use of triptans, current use of preventive migraine medication, premonitory symptoms, and trigger factors. Moreover, we explored whether MIDAS, HIT-6 and WHODAS 2.0 scores/grades differed between participants with and without postdromal symptoms. Finally, we assessed if correlations existed between the number of postdromal symptoms with the total score of MIDAS, HIT-6, and WHODAS 2.0 individually.

Statistical analysis

Participant demographics and clinical characteristics were summarized using descriptive statistics. Categorical data are presented as frequency counts (n) and percentages (%). The distribution of continuous data was assessed for normality using the Kolmogorov–Smirnov test. Means and standard deviations (SD) were then used for data following a normal distribution, while medians and interquartile ranges (IQR) were used for skewed data.

McNemar’s test was used for analyses of paired nominal data, while the Mann–Whitney U test was performed non-parametric continuous data. For categorical data involving three or more groups, Fisher’s exact test was used. Correlation analyses were performed using Spearman’s rank correlation and presented with the correlation coefficient, ρ, and P values. To assess factors that influence the likelihood of reporting postdromal symptoms, we applied a 2-step approach. First, each pre-defined factor was assessed using logistic regression. Those that were significant, exhibiting P values ≤ 0.05, were then tested using binominal logistic regression and reported as odds ratios (ORs) with 95% confidence intervals (95% CI) and corresponding P values. The Bonferroni correction was applied to the binominal logistic regression. The threshold for statistical significance was set at P-values ≤ 0.05. All analyses were performed in R (version 4.2.0).

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