Study design
We designed an unblinded longitudinal interventional study to evaluate the effect of HEP education in people with migraine.
Participant selection
Consecutive people with migraine treated at our Headache Centre were screened for enrolment from March 2018 to September 2019. Migraine was diagnosed according to the International Classification of Headache Disorders.[8] Screening visit included an accurate medical history interview, clinical examination and anthropometric assessment (height, weight, body mass index-BMI).
Among the 240 screened people affected by migraine, people were enrolled if the following inclusion and exclusion criteria were fulfilled:
- inclusion criteria: diagnosis of Migraine with Aura or Migraine without Aura, age> 18-year-old.
- exclusion criteria: BMI > 30, cancer, inflammatory bowel disease, celiac disease, type 1 diabetes, chronic renal insufficiency, and other neurological disorders.
We excluded 36 people with migraine for BMI>30 that were referred to nutritional counseling.
For those people respecting screening criteria, additional criteria for exclusion were: failure to show at control visits and change in prophylactic therapy at baseline (dropouts).
Figure 1 summarizes the study design: a longitudinal study consisting of three visits: a screening visit (T-12), a baseline visit after 12 weeks (T0) and a follow-up visit (T12).
At T-12, the 204 eligible people signed the informed consent and filled a Frequency Food Questionnaire (FFQ) to assess their dietary habits and migraine disability clinical scales concerning the previous three months. All people received prophylactic treatment indications as appropriate.[9] At T0, 34 people failed to attend the control visit, the remaining eligible people underwent the assessments again (FFQ, migraine disability scales, BMI). They were all educated about the indications of the HEP by a nutritional biologist. Of these, 51 people requiring a change in preventive therapy were considered dropouts. At T12, 22 people did not show up. Finally, 97 people underwent all the evaluations and were included in the study. The study was approved by our Local Ethical committee (prot 6.18TS ComET CBM).
Anthropometric measurements
People’ weight and height were measured at T-12, T0 and T12. People were weighed while wearing light clothes (i.e. no sweaters, jackets, or belts) and without shoes to avoid possible confounders for repeated measurement (including seasonal differences). Weight was measured to the nearest 0.1 kg. Height was measured to the nearest 0.1 cm using a stadiometer, while the person was in a standing position with shoes removed, the shoulders were relaxed while looking straight ahead with the Frankfurt plane horizontal (scale and stadiometer, Fazzini, Milan, Italy).[10] BMI was calculated from the height and weight data, using the “weight (kg)/height2 (m)” equation.
Migraine attack frequency and disability assessment
Monthly migraine days and disability were assessed in all people at T-12, T0 and T12. Headache diaries were obtained from people recording the number of migraine days and of acute treatment drug consumption over the last month. All people were treated at our Headache center and already educated about corrected diary compilation. Migraine disability was assessed by a validated Italian version of the Migraine disability assessment score (MIDAS) questionnaire[11]. MIDAS is a semi-quantitative score measuring migraine days (MIDAS A), pain intensity (MIDAS B) and days of absence or reduced activity at work or on household due to headaches (MIDAS score) in the previous three months.
Dietary Assessment and Education
Food intake was assessed in all people at T-12, T0 and T12. Dietary intake over the previous 12 weeks was evaluated using a modified version of a semi-quantitative food frequency questionnaire (FFQ) validated in the Italian population. [12] This questionnaire includes a list of 110 food items. For the aim of the current study, i.e. adherence to the healthy plate advice, we added in the “cereals and bread” section further items: spelt, barley and whole-wheat breakfast cereals with a total count of 113 food items. Before completing the FFQs, people were instructed on “serving size” amounts according to the Italian Society of Human Nutrition.[13] The FFQs were self-administered; however, a nutritionist was available in case participants felt insecure about compilation.
While filling the questionnaire people were asked to reply to some additional questions:
At T-12, T0, and T12:
- Q1: “how many liters of water do you drink a day?”
At T0
- Q2: “In your experience, do you think that a healthy diet can help improving headaches?
At T12
- Q3: “were you able to follow the healthy eating plate advice?”
- Q4: “were you able to reduce sugar daily consumption?’”
- Q5: “were you able to reduce salt use as flavor enhancer?’”
- Q6: “were you able to exercise at least 30 minutes a day’”
- Q7: “In your experience, do you think that the healthy eating plate advice helped you in improving headaches?”
People with migraine were required to answer “yes” or “no” to questions Q2-Q7.
At T0, after filling the questionnaires, all subjects were instructed by nutritional biologists about HEP and received a colored printed image of the HEP as well as the Italian written indications.[7]
To assess adherence to the HEP diet, we created a score (HEP score) ranging from 0 to 10 where one point was scored if each HEP indication was followed according to the results of the FFQ (Table 1).
Food intake frequency was calculated as weekly consumption, while water drinking on a daily basis. We calculated changes as differences in BMI, food intake frequency, HEP scores and disability measures (MIDAS score, MIDAS A and MIDAS B) from T0 to T12. Variation in the last month migraine days and drug intake frequencies was calculated as rates ((T12-T0)/T0). Since most people were already on pharmacological prophylactic treatment, we considered RESPONDERS people that achieved at least a 30% reduction in monthly migraine days from T0 to T12. The reduction in headache frequency is to be intended as a further reduction after the effect of the ongoing prophylactic treatment, unchanged throughout the study. This is in line with other migraine clinical settings where the expected benefit is mild.[14] Table 2 summarizes food groups. For the statistical analysis, we grouped as TOTAL CARBs the sum of refined cereals-potatoes and high carb breakfast – snacks intake frequencies, as TOTAL WHOLE-GRAINs the sum of whole-grain breakfast and cereals intake frequencies, as HEALTHY PROTEINs the sum of fish and legumes intake frequencies, as OTHER PROTEIN the sum of white meat, egg, and cheese intake frequencies.
Statistical Analysis
Statistical analyses were performed using SPSS 25.0; SPSS Inc., Chicago, IL, USA. Differences were considered significant at the p < .050 level. The sample size was based on our previous experience with this design and further amplified.[15] Data distribution was assessed by the Kolmogorov-Smirnov test. Data of continuous variables are presented as mean values ± standard deviation (SD). Median values with inter-quartile ranges (IQr) were provided for non-normally distributed variables. Analysis of variance (ANOVA) for normally distributed variables was performed according to RESPONDER status; otherwise, the nonparametric Mann-Whitney U test was adopted. The two-tailed Fisher exact test was used for dichotomous variables. To assess changes over time in food intake, paired t-test or Friedman analysis of rank were adopted.
Multivariable logistic regression analysis was used to assess the association of RESPONDER status with age, sex, and all those variables which differed significantly (P<.050) in comparison with NON-RESPONDER.