2:1 ketogenic diet and low-glycemic-index diet for the treatment of chronic and episodic migraine: a single-center real-life retrospective study

Migraine is one of the most frequent neurological diseases. It mainly affects patients in their most productive years. It can cause very high disability and poor quality of life, up to being classified as the second leading cause of disability worldwide [1]. There is a strong need in clinical practice to use practical approaches in the preventive treatment of migraine to reduce the burden of this disease. Although new preventive therapies for migraine, the Calcitonin Gene-Related Peptide monoclonal antibodies (CGRP mAbs), have proven to be very effective, some patients did not respond optimally; this is the case of overweight patients with migraine [2].

For this reason, non-pharmacological preventive therapies are rising these years, offering a promising approach even in combination with conventional pharmacotherapies [3, 4]. Among the non-pharmacological preventive treatments for migraine, nutritional interventions have been studied to offer innovative therapeutic strategies for primary headaches to avoid adverse events and drug interactions [5‐7]. Moreover, there is strong evidence that the Ketogenic Diet (KD) has important therapeutic implications in several neurological diseases, influencing neuronal plasticity and exerting neuroprotective effects [8]. KD has been tested with significant efficacy in treating migraine [9]. Although its mechanism of action is not yet fully elucidated, it improves brain metabolism and excitability, mitigating neuro-inflammation through the production of ketone bodies [10]. To date, KD therapy has been successfully applied in drug-resistant migraine and cluster headache [11‐14]; these studies have prompted the experts in nutrition and headache to publish the clinical recommendation for the application of KD in patients with headache [15]. Several ketogenic diets are proposed for the treatment of migraine, and they have in common the restriction of carbohydrates and an adequate protein intake, differentiating according to the variation of the lipid-to-carbohydrate and protein ratio. These include the low-glycemic-index diet (LGID) [16], the low-calorie-ketogenic-diet (LCKD) [17], the very-low-calorie-ketogenic-diet (VLCKD) [11, 12, 17, 18], the Modified Atkins Diet (MAD) [18‐21], and the Classic KD [17, 19]. Classic KD is a low carbohydrate diet based on a drastic reduction in carbohydrate intake, associated with a relative increase in the proportion of fats and regular intake of proteins. During KD, without exogenous glucose as an energy source, fatty acids are mobilized from fat deposits and transported to the liver for conversion into ketone bodies (acetoacetate, β-hydroxybutyric acid, and acetone). The ketone bodies are then distributed to metabolically active tissues, namely skeletal muscle, brain, and heart, representing an essential energy source as they are converted into acetyl coenzyme A (acetyl-CoA), the substrate of the Krebs cycle. Experts suggest a 3:1 or 4:1 KD ratio in treating migraine as a preventive therapy, while the 2:1 KD ratio is less studied in this setting [15].

The LGID is characterized by a high daily intake of fats (60%), a low intake of carbohydrates (40-60 g) with a glycemic index < 50 (low tendency to increase to elevate blood glucose), and an intake of proteins of about 30%; the LGID has proven to be effective in epileptic patients that are unable to undergo KD due to scarce tolerability or palatability. LGID exerts its actions through the induction of the production of ketone bodies, although less pronounced than classic KD, and the prevention of dramatic fluctuations in blood glucose. There is limited data regarding the use of LGID in the migraine setting in the literature [16, 22]. Still, its application is encouraged in migraineurs that present scarce tolerability to classical KD [15]. The present study aims to retrospectively investigate the efficacy and impact on the quality of life of two different diet protocols (LGID and 2:1 KD) in patients with high-frequency episodic and chronic migraine, assessed with validated migraine-specific questionnaires such as Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6); moreover. Moreover, we evaluated the adverse events and the effect on anthropometric features of the two diets.

Thirty-nine patients (31 females and eight males) were treated with a Low-Glycemic-index diet, while twenty-one (17 females and four males) were treated with a 2:1 ketogenic diet. Most of our population was composed of female patients (80%), in agreement with the migraine prevalence data in the literature [25]. Twenty-three patients in the LGID group presented chronic migraine, while 16 had high-frequency episodic migraine; in the 2:1 KD group, ten patients out of 21 had chronic migraine, and the remaining had high-frequency episodic migraine.

Detailed characteristics of the two groups are described in Table 1.

Both groups presented a statistically significant reduction in migraine days/month and intensity; MIDAS and HIT-6 scales also improved significantly. Both chronic and high-frequency episodic migraineurs in each group had significant improvement in these variables. The detailed statistics are presented in Table 2.

After three months of therapy, the LGID and 2:1 ketogenic diet group had significantly reduced BMI, weight, and Fat Mass. The Fat-Free Mass was preserved regardless of the ketogenic ratio (see Table 3). Both chronic and high-frequency episodic migraineurs in each group presented the same results. The 2:1 KD group showed a significant increase in the phase angle; this significance was lost when the group was divided into chronic and high-frequency episodic migraine.

The LGID group reported constipation (12.82%), diarrhea (2.56%), abdominal pain (23.08%), and nausea (2.56%) as adverse events of the diet, while the 2:1 KD group reported constipation (23.81%) and abdominal pain (23.81%); there were no significant differences between the two groups (see Table 4). The symptoms were mild and occurred during the first month of the diet.

Considering responders (≥ 50% reduction of migraine days) and not responders (< 50% reduction of migraine days) in both groups, the response rate was identical: 26/39 (66.67%) and 14/21 (66.67%) responders in the LGID group 2:1 KD group respectively.

In our study, LGID and 2:1 KD improved migraine intensity and frequency in high-frequency episodic and chronic migraineurs; both MIDAS and HIT-6 scales significantly improved. Efficacy data for KD and LGID are comparable with the literature [11, 14, 16, 17, 19], although the previous studies did not evaluate the HIT-6 and MIDAS scales. The efficacy of these diet regimes on migraine probably derives from a combination of factors: neurophysiological modulation with a secondary effect on cortical spreading depression, improvement of cerebral energy metabolism by acting on the mitochondrion, reduction of oxidative stress, anti-inflammatory effect, epigenetic modulation, improvement of the glutamate/GABA balance, modulation of ion channels, improvement of intracerebral glucose metabolism, correction of the metabolic syndrome, prevention of pronounced fluctuations in blood glucose, although the precise underlying mechanisms remain to be clarified [15]. Both dietary treatments reduced BMI, weight, and FM, as previously described for KD; this was true in chronic and high-frequency episodic migraine [11, 14]. ICW, ECW, and FFM did not modify significantly, according to the literature [14]. Overall, it is well known that improving migraine frequency and intensity is also linked to weight, FM, and BMI reduction, regardless of the type of diet used [11].

Moreover, the phase angle, a marker of inflammatory status [26], improved significantly in the 2:1 KD group; this could relate to a higher degree of ketone bodies production leading to a more pronounced anti-inflammatory activity. However, the significance of this finding is lost when considering the groups with chronic headaches and those with episodic high-frequency headaches, probably due to the low sample size. In our study, although the dietary protocols have proven to be effective in improving migraine three months after their application, it is impossible to determine the onset of their action in mitigating migraine symptoms. Interestingly, conflicting results emerge about the efficacy of KD therapy at one month of treatment: some studies, indeed, do not achieve satisfactory results when compared with other prophylactic therapies [16], while in others, KD appears to be effective already in the first month [11, 12, 18, 21]. The migraineurs examined have a clinically relevant burden from migraine, considering the number of pharmacological prophylaxes previously used, the number of symptomatic medications taken monthly, and the medication overuse headache (MOH) rate. The efficacy data collected on this population further corroborate the effectiveness of such dietary regimens on migraine. However, dietary intervention should be considered differently than pharmacological intervention due to a different mechanism of action, especially considering the new therapies directed against CGRP. However, the evidence shows that the nutritional approach can be a valuable weapon against migraine as a single therapy or combined with currently available pharmacological prophylactic therapies.

KD 2:1 and LGID diets are safe with usually minor adverse effects. The side effects found in our patient cohort aligned with the literature data [15]. The number of diet dropouts in our study was 22% (17/77 patients), comparable to that found in the literature [14].

Both LGID and 2:1 Ketogenic Diet therapy effectively reduced migraine symptoms and migraine-related disability. Each diet reduced weight and BMI, primarily due to fat mass loss. Further studies with larger samples and prospective design are necessary to confirm our results.