Very-low-calorie ketogenic diet vs hypocaloric balanced diet in the prevention of high-frequency episodic migraine: the EMIKETO randomized, controlled trial

Abstract

Background: Migraine is the second world's cause of disability. Among non-pharmacological treatments, nutritional intervention, particularly ketogenic diet, represents one of the most promising approaches.

Methods: This a prospective, single center, randomized, controlled study aimed at evaluating the efficacy of a very low-calorie ketogenic diet (VLCKD) compared to a hypocaloric balanced diet (HBD) in migraine prophylaxis in patients affected by high-frequency episodic migraine (HFEM) with a Body Mass Index (BMI) > 27 kg/m². Fifty-seven patients were randomly assigned to a VLCKD (group 1) or HBD (group 2). Group 1 patients followed a VLCKD for 8 weeks, followed by a low calorie diet (LCD, weeks 9-12), and a HBD (weeks 13-24), whereas group 2 patients followed a HBD from week 0 to 24. Anthropometric indexes, urine and blood chemistry were assessed at enrollment, baseline, weeks 4, 8, 12, and 24. Migraine characteristics were evaluated at baseline, weeks 8, 12 and 24. Change in monthly migraine days (MMDs) at weeks 5-8 compared to baseline was the primary endpoint. Secondary endpoints encompassed changes in visual analogue scale (VAS), Headache Impact Test-6 (HIT-6) and Short Form Health Survey-36 (SF-36) scores. We also studied effects on circulating lymphocytes and markers of inflammation, changes in plasma aldosterone and renin levels before and after VLCKD or HBD treatment.

Results: Reduction from baseline in MMDs was greater in VLCKD compared to HBD group at week 8 (p = 0.008), at week 12 (p = 0.007), when ketosis had been interrupted by carbohydrates reintroduction, and at week 24 (p = 0.042), when all patients were following the same dietary regimen. Quality of life scores (SF-36) were improved in VLCKD group at week 8 and 12, and were also improved in HBD group, but only at week 12. Weight-loss was significantly higher in VLCKD group at week 8 (p = 0.002) and week 12 (p = 0.020). At the end of the study weight loss was maintained in VLCKD group whereas a slight weight regain was observed in HBD group. Inflammatory indexes, namely C reactive protein (CRP), neutrophil to lymphocyte ratio (NLR) and total white blood cell count (WBC) were significantly reduced (p < 0.05) in VLCKD group at week 12. Aldosterone plasma level were significantly increased in both groups at week 8, particularly in VLCKD group. However, electrolytes and renin plasma levels were never altered throughout the study in both groups.

Conclusions: VLCKD is more effective than HBD in reducing MMD in patients with HFEM and represents an effective prophylaxis in patients with overweight/obesity. Trial registration ClinicalTrials.gov identifier: NCT04360148.

Keywords: Aldosterone; Diet; Inflammatory state; Ketone bodies; Migraine treatment; Pain; Prevention; Rehabilitation; VLCKD; Weight loss.

Fig. 1

Emiketo: visits’ timeline

Fig. 2

Variations in monthly migraine days (MMDs) in VLCKD and HBD groups at weeks 0, 8, 12 and 24 (V2, V5, V6 and V7)

Fig. 3

A Variations in mean weight loss in VLCKD and HBD groups at week 0, 8, 12 and 24. B Variations in waist circumference (cm) in VLCKD and HBD groups at week 0, 8, 12 and 24

Fig. 4

Adherence scores in VLCKD and HBD groups at weeks 4, 8 and 12

Fig. 5

Box blot of mean change in WBC (A), Neutrophils (B), CRP (C), NLR (D), at week 4, week 8 and week 12 in VLCKD group and HBD group

Fig. 6

Changes in Treg/Th17 ratio at week 4 and week 8 in VLCKD group and HBD group

Fig. 7

Box blot of mean change in serum aldosterone at baseline (week 0), week 8 and week 12 in VLCKD group (A) and HBD group (B). Box blot of mean change in serum renin at baseline (week 0), week 8 and week 12 in VLCKD group (C) and HBD group (D)