Methods
This was a prospective real-world evidence study of 60 patients with chronic migraine who attended a General Neurology Clinic in Perth, Western Australia between July 2017 and February 2019 who were eligible for Pharmaceutical Benefits Scheme (PBS)-subsidised onabotulinumtoxinA treatment. We investigated comorbidities of cognitive and mood changes at baseline and at 6 weeks and 12 weeks following treatment. Patients gave informed consent.
In Australia, to be eligible for PBS-subsidised onabotulinumtoxinA treatment for the prophylaxis of chronic migraine, patients need to be aged 18 years or older, under the care of a neurologist and had experienced an average of 15 or more headache days per month, with at least eight migraine days per month over a period of 6 months or longer. PBS eligibility also required poor efficacy and/or intolerability of at least three preventive migraine medications. We excluded patients with medication overuse headaches (MOH) from the study. To control for medication effect during intra-subject testing, patients continued all their existing regular medications including other concurrent oral migraine preventive medications and antidepressants, with doses of these medications remaining stable during the entire 12 weeks of the study. Using a headache diary, patients recorded headache days (defined as a 24-hours period in which a headache of mild to moderate intensity lasted at least 1 hour) and migraine days (defined as high intensity, lateralised pain with a significant impairment on daily activities) and the number of days on which they used symptomatic medication, particularly triptans. A computerised cognitive test was performed at baseline (prior to onabotulinumtoxinA treatment) and at 6 weeks and 12 weeks post-treatment. Patients were asked to perform all cognitive tests during the inter-ictal state with no headache symptoms for at least 24 hours before testing. Patients were instructed to refrain from alcoholic beverages or over-the-counter medications for at least 48 hours before cognitive testing and not to consume caffeinated beverages at least 24 hours before testing.
The computerised cognitive test used a purpose-specific website made available by UBrain (www.ubrain.com.br). The validation of this methodology has been previously published in the context of cognitive screening in multiple sclerosis.25 Our study platform tested patients’ information processing speed, attention, working memory (WM) and episodic memory using a self-paced computerised system. The test consisted of three different tasks, using a set of universal, very simple stimuli presented in a visual game-like interface. Participants were asked to perform at least one practice test prior to each clinic-based test. This allowed for familiarisation of the system while limiting practice effects. The cognitive testing included the following: the first task, testing psychomotor (processing) speed (Simple Reaction Test (SRT)), required participants to press the ‘YES’ button as soon as a soccer ball appeared on the screen. The second task, testing visual attention (Choice Reaction Test (CRT)), required participants to press the ‘YES’ button if the soccer ball appearing was red, otherwise to press the ‘NO’ button. The third task (Learning Test) required participants to press ‘YES’ or ‘NO’ button if the card displayed had been seen before in the testing session. The final task, testing WM (One Back Test), required participants to press the ‘YES’ or ‘NO’ button if the card displayed was the same as the immediately previous card. The cards presented consisted of a combination of four colours, four shapes and eight numbers, allowing for 128 unique possibilities in stimuli. All tasks had a prestimulus interval of 1000 ms and a 100–5000 stimulus interval between 0–1000 ms. The cards were presented using random order, timing and correct response, allowing a very large number of equivalent alternate forms of the tasks to be generated. The speed tests were measured in milliseconds and the accuracy tests were expressed as percentage of correct responses. The total cognitive test battery duration was 10–15 min. Patients were asked to rate their cognitive performance using a subjective scale at baseline and at 6 weeks post-onabotulinumtoxinA treatment, where 1=much worse than normal, 2=worse than normal, 3=normal, 4=better than normal and 5=much better than normal.
Prior to the onabotulinumtoxinA treatment (baseline) and at 6-weeks follow-up, questionnaires assessing anxiety and depression status were also administered. Participants rated their level of anxiety (using a simple 10 points Likert-type scale from ‘None’ to ‘Very anxious’). PSWQ-PW26 assessed anxiety during the past week using subjective ratings for 15 simple statements (maximum score 90). PHQ-927 assessed mood using a subjective rating of nine short statements covering mood and somatic symptoms of depression over the past 2 weeks (maximum score 27, mild depression ≥5).
All patients received onabotulinumtoxinA injections at baseline in accordance with the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) 2 protocol.28 29 Study injections were administered by the principal investigator (SH) using a 31 fixed-site, fixed dose, intramuscular injection protocol (minimum total dose of 155U) across seven specific head/neck muscle areas and ‘follow the pain’ strategy with additional dosing at the investigator’s discretion (maximum dose 195U).
Outcome measures
The primary efficacy measure in this study was change from baseline in total headache days per month at 6 weeks and 12 weeks as assessed by patients’ daily diaries. Change from baseline in migraine days per month at 6 weeks and 12 weeks was also assessed. A subgroup analysis was performed in patients who experienced ≥75%, ≥50%, or ≤25% reductions in headache and/or migraine days. Clinical response was classified as excellent (≥75% reduction in headache and/or migraine days), good (≥50% reduction in headache and/or migraine days) or poor (≤25% reduction in headache and/or migraine days). Exploratory outcome measures included change from baseline in cognitive parameters including SRT, CRT and WM speed and SRT, CRT, WM accuracy at 6 weeks and 12 weeks as well as change from baseline in PHQ-9 and PSWQ-PW (depression and anxiety) scores at 6 weeks.
Statistical analysis
Changes from baseline in frequencies of total headache days and migraine days were analysed as mean changes from baseline using 1-tailed paired t-test. Data was presented as means and SD for continuous data or medians and IQRs when data was skewed. To account for missing data, we used linear mixed models for repeated measures to compare within group differences for the PHQ9, PSWQ-PW and speed variables, with mean differences and their 95% CIs produced. Unlike other statistical methods, linear mixed models have the ability to give unbiased results in the presence of missing data, without the need for listwise deletion and therefore not compromising both power and bias of the study. For accuracy variables, changes in scores between each time point were calculated with median difference and their corresponding 95% CIs produced with statistical significance determined using the non-parametric Wilcoxon signed rank test. For mean or median difference, a negative value would indicate a reduced score from the first to second time point. For speed variables, a reduced score would indicate improvement, whereas for accuracy scores, an increase would indicate an improvement. The association between clinical response scores and baseline accuracy, speed, PHQ-9 and PSWQ-PW was investigated using Analysis of Variance (ANOVA) and box plots. The association between questionnaires (PHQ-9 and PSWQ-PW) was tested using Pearson’s correlation coefficients and scatter plots. Paired t-tests were analysed using Excel and all other data analysed using Strata V.14.1. Statistical significance was considered p<0.05.
