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Migraine improvement during short lasting ketogenesis: A proof-of-concept study
European Journal of Neurology
Abstract
Background and purposeKetogenesis is a physiological phenomenon due to starvation or a ketogenic diet (KD), a drastic restricted carbohydrate dietary regimen that induces lipid metabolism and ketone body synthesis. Two patients whose migraines disappeared only during, and not outside, cycles of very-low-calorie KD performed to reduce their weight were recently observed. To confirm our observation, in a dietitian clinical setting two parallel groups of migraineurs, one receiving a 1-month very-low-calorie KD prescription followed by a 5-month standard low-calorie diet (SD) and the other a 6-month SD, were followed.Methods
Ninety-six overweight female migraineurs were enrolled in a diet clinic and blindly received a KD (n = 45) or an SD (n = 51) prescription. Mean monthly attack frequency, number of days with headaches and tablet intake were assessed before and 1, 2, 3 and 6 months after diet initiation.ResultsIn the KD group, the baseline attack frequency (2.9 attacks per month), number of days with headaches (5.11 days per month) and tablet intake (4.91 doses per month) were significantly reduced after the first month of diet (respectively 0.71, 0.91, 0.51; overall, KD versus baseline, P < 0.0001). During the transition period (first versus second month), the KD group showed a transient worsening of each clinical headache variable (respectively 2.60, 3.60, 3.07), despite being improved compared with baseline, with continuous improvement up to month 6 (respectively 2.16, 2.78, 3.71). In the SD group, significant decreases in the number of days with headaches and tablet intake were observed only from month 3 (P < 0.0001), and in attack frequency at month 6 (P < 0.0001).Conclusions
The underlying mechanisms of KD efficacy could be related to its ability to enhance mitochondrial energy metabolism and counteract neural inflammation.
... 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][12][13][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. ...
... 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-calorieketogenic-diet (VLCKD) [11,12,17,18], the Modified Atkins Diet (MAD) [18][19][20][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. ...
... 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]. ...
Aims
The evidence supporting the efficacy of dietary preventive therapy in migraine is rising, particularly regarding the ketogenic diet. However, less evidence exists for the Low-Glycemic Index Diet and the 2:1 KD. This retrospective single-center real-life study aims to evaluate the efficacy of a 2:1 ketogenic diet and a Low-Glycemic-index Diet in chronic and high-frequency episodic migraine.
Methods
Sixty patients with high-frequency episodic and chronic migraine were treated with either a Low-Glycemic-index diet (39 patients) or a 2:1 (21 patients) ketogenic diet for three months. We collected data on the migraine frequency and intensity and the MIDAS and HIT-6 scores through the headache diary. Anthropometric measurements (BMI, fat mass, free fat mass, and weight) were also collected and analyzed similarly. Data obtained at the baseline and after three months of each diet were compared.
Results
Migraine intensity, frequency, MIDAS and HIT-6 scores, fat mass, weight, and BMI improved in both diet groups.
Conclusions
Both diets are effective in reducing migraine symptoms and migraine-related disability.
... It has recently gained attention in the field of headache after the description of some cases of migraine improvement with such a dietetic regimen [13,14]. After these initials observations, evidence supporting an efficacy of KD in migraine treatment rapidly grew [15][16][17], and clinical recommendations on optimal practice to treat patients with headaches using KD have recently been published [10]. ...
... Considering this effects of KD and following the report of some cases of migraine improvement in patients following this kind of diet [13,14], the possibility of using KD in migraine was firstly corroborated by a proof-of-concept study in overweight migraine patients in which one group received a very low-calorie KD for 1 month followed by 5 months of low-calorie diet with progressive carbohydrate reintroduction, while the other received a standard low-calorie diet for 6 months [12]. In this study, headache days reduction was observed in both groups, but it was markedly greater in the KD group after 1 month, and it was followed by a worsening during the period of transition to a standard low-calorie diet, thus suggesting an efficacy of ketosis on migraine [15]. A subsequent double-blind crossover trial compared a VLCKD and a very low-calorie non-ketogenic diet (VLCnKD). ...
... Data on this specific aspect in the literature are scarce and have not been previously supported by bioimpedance analysis. In the aforementioned proof-of-concept study by Di Lorenzo et al., KD patients showed a greater reduction in BMI, but when carbohydrates were reintroduced, a rebound of the headache was observed despite the benefit on weight loss [15]. In another study of the same group, VLCKD was significantly more effective than VLCnKD despite inducing similar weight loss [16]. ...
The ketogenic diet (KD) is gaining attention as a preventive treatment for migraine, which is sustained by many pre-clinical and clinical data. KD is also used for weight loss, and there is a relation between migraine and weight excess, but it is speculated that KD efficacy on migraine may go beyond this effect. We conducted a retrospective observational study on 23 migraine patients who received a KD and were evaluated at the baseline and then after 3 months both from a neurological and a nutritional point of view, including body mass composition analysis. We observed a reduction in monthly headache days (12.5 ± 9.5 vs. 6.7 ± 8.6; p < 0.001) and in days of acute medication intake (11.06 ± 9.37 vs. 4.93 ± 7.99; p = 0.008). We also observed a reduction in patients’ weight (73.8 ± 15.2 vs. 68.4 ± 14.6; p < 0.001) and BMI (26.9 ± 6.2 vs. 23.7 ± 8.1; p < 0.001) with a decrement of the fat mass (28.6 ± 12.5 vs. 20.6 ± 9.8; p < 0.001). Patients who responded to KD and those who did not had no differences with respect to weight or fat mass loss. These data corroborate the utilization of KD as a preventive treatment for migraine and suggest that the efficacy of such an intervention is not only due to weight or fat mass loss but probably relies on other mechanisms specific to KD.
... Regarding the general characteristics of the articles selected for review ( Table 2) [44][45][46][47][48][49][50][51][52][53] , the oldest publication dates from 1928 44 , and the most recent was published in 2019. [45][46][47] Most studies were conducted in Italy (n ¼ 5 articles; 50%), [46][47][48][49][50] followed by studies conducted in the United States (n ¼ 3 articles; 30%), 44,50,52 1 report from Turkey (10%), 53 and 1 Austrian study (10%). ...
... Regarding the general characteristics of the articles selected for review ( Table 2) [44][45][46][47][48][49][50][51][52][53] , the oldest publication dates from 1928 44 , and the most recent was published in 2019. [45][46][47] Most studies were conducted in Italy (n ¼ 5 articles; 50%), [46][47][48][49][50] followed by studies conducted in the United States (n ¼ 3 articles; 30%), 44,50,52 1 report from Turkey (10%), 53 and 1 Austrian study (10%). 45 By type of study design, the articles included in this review were case reports (n ¼ 2), 45,48 case series (n ¼ 3), 44,51,52 a cohort study (n ¼ 1), 49 a case-control study (n ¼ 1), 50 a nonrandomized controlled trial (n ¼ 1) 47 , and randomized controlled trials (n ¼ 2). ...
... 44 Three studies reported author-related conflicts of interest. 46,49,52 Two studies were randomized, 46,53 2 studies were nonrandomized, 47,50 and randomization did not apply to 6 studies. 44,45,48,49,51,52 Three studies were single or double blinded 46,47,49 ; in 3 studies, blinding was not performed 48,50,52 ; in 2 studies, blinding information was not provided 44,51 ; and in 2 studies, blinding was not applicable. ...
Context
Migraine is a headache of variable intensity that is associated with focal and systemic symptoms. A ketogenic diet (KD), a very-low-carbohydrate diet with a proportional increase in fat, causes brain metabolic alterations, which could be beneficial for some neurologic conditions.
Objective
A systematic review was conducted to assess the efficacy and tolerability of KD in preventing migraine in adolescents and adults.
Data sources
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standard was used to review articles found in the PubMed, EMBASE, Scopus, Web of Science, LILACS, LIVIVO, Science Direct, and Cochrane Central Register of Controlled Trials databases. The Google Scholar, DOAJ, ProQuest, and OpenGrey databases were included.
Data Extraction
The population, intervention, comparison, outcome, and study design strategy included assessing the quality of the evidence using Grading of Recommendations Assessment Development and Evaluation and the risk of bias after applying the JBI critical appraisal tools.
Data Analysis
Most of the 10 selected studies reported that KD reduced the number and severity of migraine attacks in patients, with few reported adverse effects. The evidence on the effectiveness of the KD is low, so whether the final effect is due to the treatment remains inconclusive.
Conclusions
This study represents an initial effort to systematize information on the efficacy and tolerability of KD and its variations in the prevention of migraine.
Systematic Review Registration
PROSPERO registration no. CRD42020186253
... Furthermore, two additional cases have been reported [40] of obese patients with episodic migraine (<15 days/month) who improved with a VLCKD. To confirm this observation, the same authors performed a proof-of-concept study [41] comparing two weight-loss diet regimens in 95 patients with episodic migraine: one VLCKD, the other hypocaloric non-ketogenic. The study design followed the group of patients while on KD for a single month, followed by another 5 months of a progressive re-introduction of a nonketogenic diet: one month of progressive reintroduction of carbohydrates in which patients continued to take nutraceutical supplements (vitamins and minerals) used also during the diet; one month of reintroduction of carbohydrates in the absence of these supplements; 3 months of "standard" weight-loss diet, similar to the one followed by the other group that had not undergone KD. ...
... In contrast, in obese subjects a high total fat free mass (lean mass) would seem to be a protective factor against the development of migraine [140]. In addition, it has been reported that weight loss may lead to an improvement in the frequency of migraine attacks [41,141,142]. Therefore, it is conceivable that reducing fat mass and preserving/increasing lean mass may be protective against migraine. ...
... In Italy, the VLCKD protocols are widely used for weight loss, generally not used in the neurological field as ketogenic therapies. However, these protocols have been used on numerous obese patients by all centers in our working group and their efficacy on migraine has been repeatedly reported in the literature [39][40][41][42]. The use of these diets should be limited to no more than 12 consecutive weeks [34], at the end of which the patient either exits the state of ketosis (even receiving the indication to follow a maintenance diet of LGIT or Mediterranean type without added sugars), or transit to a normo-caloric KD of longer duration. ...
Headaches are among the most prevalent and disabling disorders and there are several patients’ unmet needs in current pharmacological options, while a growing interest is focusing on nutritional approaches as non-pharmacological treatments. Among these, the most promising seems to be the ketogenic diet (KD). Exactly 100 years ago, KD was used to treat pediatric forms of drug-resistant epilepsy, but progressively applications of this diet also involved adults and other neurological disorders. Evidence of KD effectiveness in migraine comes from 1928, but in the last years different groups of research and clinicians paid attention to this therapeutic option to treat patients with drug resistant migraine and cluster headache, and/or comorbid with metabolic syndrome. Here we describe all the existing evidence on the potential benefits of KDs in headaches, explore in deep all the potential mechanisms of action involved in the efficacy, and synthesize results of working meetings of an Italian panel of experts on this topic. Aim of the working group is the creation of a consensus on indications and clinical practice to treat with KDs patients with headache. The results here we present are the base for further improvement in the knowledge and application of KDs in the treatment of headaches.
... Furthermore, two additional cases have been reported [40] of obese patients with episodic migraine (<15 days/month) who improved with a VLCKD. To confirm this observation, the same authors performed a proof-of-concept study [41] comparing two weight-loss diet regimens in 95 patients with episodic migraine: one VLCKD, the other hypocaloric non-ketogenic. The study design followed the group of patients while on KD for a single month, followed by another 5 months of a progressive re-introduction of a nonketogenic diet: one month of progressive reintroduction of carbohydrates in which patients continued to take nutraceutical supplements (vitamins and minerals) used also during the diet; one month of reintroduction of carbohydrates in the absence of these supplements; 3 months of "standard" weight-loss diet, similar to the one followed by the other group that had not undergone KD. ...
... In contrast, in obese subjects a high total fat free mass (lean mass) would seem to be a protective factor against the development of migraine [140]. In addition, it has been reported that weight loss may lead to an improvement in the frequency of migraine attacks [41,141,142]. Therefore, it is conceivable that reducing fat mass and preserving/increasing lean mass may be protective against migraine. ...
... In Italy, the VLCKD protocols are widely used for weight loss, generally not used in the neurological field as ketogenic therapies. However, these protocols have been used on numerous obese patients by all centers in our working group and their efficacy on migraine has been repeatedly reported in the literature [39][40][41][42]. The use of these diets should be limited to no more than 12 consecutive weeks [34], at the end of which the patient either exits the state of ketosis (even receiving the indication to follow a maintenance diet of LGIT or Mediterranean type without added sugars), or transit to a normo-caloric KD of longer duration. ...
Headaches are among the most prevalent and disabling neurologic disorders and there are several unmet needs as current pharmacological options are inadequate in treating patients with chronic headache, and a growing interest focuses on nutritional approaches as non-pharmacological treatments. Among these, the largest body of evidence supports the use of the ketogenic diet (KD). Exactly 100 years ago, KD was first used to treat drug-resistant epilepsy, but subsequent applications of this diet also involved other neurological disorders. Evidence of KD effectiveness in migraine emerged in 1928, but in the last several year’s different groups of researchers and clinicians began utilizing this therapeutic option to treat patients with drug-resistant migraine, cluster headache, and/or headache comorbid with metabolic syndrome. Here we describe the existing evidence supporting the potential benefits of KDs in the management of headaches, explore the potential mechanisms of action involved in the efficacy in-depth, and synthesize results of working meetings of an Italian panel of experts on this topic. The aim of the working group was to create a clinical recommendation on indications and optimal clinical practice to treat patients with headaches using KDs. The results we present here are designed to advance the knowledge and application of KDs in the treatment of headaches.
... Of the five trials for caloric restriction and/or fasting, all showed an improvement on pain symptoms [75][76][77][78][79]. It should be noted that for two of these trials, the impact on pain may have been mediated by weight loss causing less stress on the knee joints [76,78], and one trial was using specialized, low in fermentable oligo-, di-or mono-saccharides and polyols (low FODMAP) diet, albeit calorie consumption was reduced in the treatment group [79]. ...
... It should be noted that for two of these trials, the impact on pain may have been mediated by weight loss causing less stress on the knee joints [76,78], and one trial was using specialized, low in fermentable oligo-, di-or mono-saccharides and polyols (low FODMAP) diet, albeit calorie consumption was reduced in the treatment group [79]. Sources of pain in these trials varied, from migraine [75], knee joint pain [76,78], fibromyalgia [77] and gastro-intestinal [79], so fasting and caloric restriction for pain treatment may be less useful for generalized pain treatment. ...
Many people in the USA have lost their lives or become addicted to opioids via prescription opioids given for chronic pain. The chronic pain epidemic has emerged due to a convergence of factors, including the medicalization of pain as well as injuries happening in the workplace, in the home, or during recreation. Opioid prescriptions rose precipitously from the late 1990’s through to approximately 2020, and despite public awareness, still are increasing. This review examines literature on integrative approaches to chronic pain as delineated by pain type. The review is organized by the most common causes of chronic pain, and randomized controlled trials, meta-analyses and systematic reviews are extracted for each cause of chronic pain. Several promising interventions may alleviate chronic pain of some causes, and some interventions may work across pain causes. Lowering inflammation through dietary or lifestyle regimens may be a general way of reducing pain. Pain can be alleviated through several adjunctive and integrative treatment approaches, which may serve to lower the need for opioid medication.
... This is consistent with the diet recommendations provided to patients with VM, which includes avoiding dietary triggers such as processed meats, alcohol, and aged cheeses [41,46]. There are also a number of clinical trials observing the benefits of a ketogenic diet (KD) in migraine prophylaxis, reducing attack frequency and intensity [49][50][51][52]. The mechanism of the ketogenic diet is thought to be related to the enhancement of mitochondrial metabolism and reduction in neural inflammation [50]. ...
... There are also a number of clinical trials observing the benefits of a ketogenic diet (KD) in migraine prophylaxis, reducing attack frequency and intensity [49][50][51][52]. The mechanism of the ketogenic diet is thought to be related to the enhancement of mitochondrial metabolism and reduction in neural inflammation [50]. Therefore, a ketogenic diet could also be considered for VM prophylaxis for patients with the premutation. ...
Background: Vestibular migraine (VM) is one of the most common causes of recurrent vertigo and presents with a history of spontaneous or positional vertigo with a history of migraine headaches. While research has identified a high prevalence of migraine headaches and vestibular deficits among fragile X premutation carriers, there has been no discussion about VM within this population. Objective: This case series and review seeks to describe the clinical characteristics and pathophysiology of VM among individuals with the fragile X premutation. We also seek to discuss treatment and future steps in addressing VM in this population. Methods: A review of the literature regarding vestibular migraine and presentation of migraine headaches and vestibular deficits among premutation carriers was performed. A detailed clinical history of migraine headaches and vertigo was obtained from three patients with the fragile X premutation seen by the senior author (RJH). Results: All three cases first developed symptoms of migraine headaches earlier in life, with the development of VM near menopause. Two of the three cases developed progressive balance issues following the development of VM. All three cases found that their VM episodes were improved or resolved with pharmacological and/or lifestyle interventions. Conclusions: It is important to recognize VM among premutation carriers because beneficial treatments are available. Future studies are needed regarding the prevalence of VM and the relationship to subsequent FXTAS. The pathophysiology of VM remains uncertain but possibilities include mitochondrial abnormalities, cranial nerve VIII toxicity secondary to neurotoxic protein accumulation, and calcitonin gene-related peptide (CGRP) signaling dysfunction due to altered levels of fragile X messenger ribonucleoprotein (FMRP).
... Of the sixty-four publications reporting neurological outcomes (Table 2), twenty-two provided measures on cortical excitability (nineteen epilepsy studies (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) , one narcolepsy (40) , one glucose transporter-1 deficiency syndrome (41) and one general physiology (42) ). Additional categories included fifteen psychological publications (eleven mood and/or cognition (43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55) , one schizophrenia (56) and one orexinergic system (57) ), twelve neurodegenerative disease publications (three Alzheimer's disease (58)(59)(60) , three multiple sclerosis (61)(62)(63) , three cognitive impairment (64)(65)(66) and three Parkinson's disease (67)(68)(69) ), seven migraine publications (70)(71)(72)(73)(74)(75)(76) , two musculoskeletal studies (one hip osteoarthritis/pain (77) and one knee osteoarthritis/pain (78) ), two autonomic nervous system studies (one sympathetic activation (79) and one heart rate variability (80) ), two nervous system bioenergetics papers (one cerebral glucose uptake (81) and one cerebral blood flow (82) ), one spinal cord injury paper (83) and one traumatic brain injury paper (84) . Half of the included studies were randomised controlled trials (RCT) (n = 32), thirty were prospective single or two-arm studies, and two were case series (41,70) . ...
... Energy intake varied between studies; most reported ad libitum food intake or intake formulated for weight maintenance (n = 43), eight had mild-to-moderate calorie restriction (27,37,43,44,47,68,79,81) , six were very low-calorie (<800 kcal per day) (52,53,57,72,76,77) , three had combined protocols (51,71,73) and did not specify energy intake (56,67,70) . Weight loss prepost intervention was common (n = 45), but not always significant. ...
Dietary restriction of carbohydrate has been demonstrated to be beneficial for nervous system dysfunction in animal models and may be beneficial for human chronic pain. The purpose of this review is to assess the impact of a low-carbohydrate/ketogenic diet on the adult nervous system function and inflammatory biomarkers to inform nutritional research for chronic pain. An electronic data base search was carried out in May 2021. Publications were screened for prospective research with dietary carbohydrate intake <130g/day and duration of ≥2 weeks. Studies were categorised into those reporting adult neurological outcomes to be extracted for analysis and those reporting other adult research outcomes Both groups were screened again for reported inflammatory biomarkers. From 1548 studies there were 847 studies included. Sixty-four reported neurological outcomes with 83% showing improvement. Five hundred and twenty-three studies had a different research focus (metabolic n=394, sport/performance n=51, cancer n=33, general n=30, neurological with non-neuro outcomes n=12, or gastrointestinal n=4). The second screen identified 63 studies reporting on inflammatory biomarkers with 71% reporting a reduction in inflammation. The overall results suggest a favourable outcome on the nervous system and inflammatory biomarkers from a reduction in dietary carbohydrates. Both nervous system sensitisation and inflammation occur in chronic pain and the results from this review indicate it may be improved by low-carbohydrate nutritional therapy. More clinical trials within this population are required to build on the few human trials that have been done.
... The review identified that six of the seven included studies reported indicators of KDT efficacy in headache prophylaxis. Effects varied from reduced migraine frequency and intensity to migraine resolution [2,[16][17][18][19][20][21]. However, the review highlighted limitations due to poor methodologies and weak study designs, including lack of control groups and small sample sizes. ...
... This suggests that, while side effects do occur during KDT, other improvements to migraine frequency, severity and duration, which were not able to be detected in this study, may occur that outweigh the reported side effects, improving overall quality of life. Additionally, the consistency of testing and reporting urinary ketones was poor within this study, which has important implications, as ketosis needs to be maintained in order to allow for the evaluation of whether there is an improvement in migraine outcomes directly related to KDT [17]. Future research should consider automated reminders, such a text-messages or emails, to measure and record ketone levels. ...
Migraine is the third most common condition worldwide and is responsible for a major clinical and economic burden. The current pilot trial investigated whether ketogenic diet therapy (KDT) is superior to an evidence-informed healthy “anti-headache” dietary pattern (AHD) in improving migraine frequency, severity and duration. A 12-week randomised controlled crossover trial consisting of the two dietary intervention periods was undertaken. Eligible participants were those with a history of migraines and who had regularly experienced episodes of moderate or mildly intense headache in the previous 4 weeks. Migraine frequency, duration and severity were assessed via self-report in the Migraine Buddy© app. Participants were asked to measure urinary ketones and side effects throughout the KDT. Twenty-six participants were enrolled, and 16 participants completed all sessions. Eleven participants completed a symptom checklist; all reported side-effects during KDT, with the most frequently reported side effect being fatigue (n = 11). All completers experienced migraine during AHD, with 14/16 experiencing migraine during KDT. Differences in migraine frequency, severity or duration between dietary intervention groups were not statistically significant. However, a clinically important trend toward lower migraine duration on KDT was noted. Further research in this area is warranted, with strategies to lower participant burden and promote adherence and retention.
... Previous studies have reported the effectiveness of KDs in the treatment of migraine, but their observation period was limited to a few weeks or months. Most of these studies used the very low-calorie ketogenic diet (VLCKD) and MAD [17][18][19][20][21][22][23]. When KD was compared with non-ketogenic diets, the former proved to be more effective in reducing attack frequency and tablet use [22]. ...
Despite advances in pharmacological therapies, migraine patients are often drug resistant. Further therapeutic options in this field are, therefore, desirable. Recent studies have highlighted the efficacy of ketogenic diet (KD) on improving migraine, but data on their long-term efficacy and safety are lacking. In this study, we retrospectively evaluated the long-term effectiveness of the modified Atkins ketogenic diet (MAD) in episodic or chronic drug-resistant migraine patients. 52 patients diagnosed with episodic or chronic drug-resistant migraine under modified Atkins ketogenic diet (MAD) were evaluated. In total, 41 patients followed the diet for 6 months and 33 for 12 months. After both 6 and 12 months, frequency, length, and intensity of migraine episodes, as well as the number of medications significantly decreased with respect to the start of the diet. Body mass index, high sensitivity PCR, diastolic blood pressure, fasting plasma insulin and HOMA index were also significantly reduced both after 6 and 12 months. No major metabolic changes were observed during MAD treatment. In conclusion, KD has been shown to be effective and safe in the long-term treatment of drug-resistant migraine. A high dropout rate still remains an important factor, which often limits its use.
... [7] Recent studies suggest that maintaining a state of ketosis may be associated with a reduction in migraine frequency, decreased severity of attacks, and a reduced need for strong analgesics. [8][9][10] ...
Introduction Migraine, a common neurological disorder, significantly reduces quality of life, particularly among women. Despite advancements in treatment, therapeutic options remain limited, and side effects are common. The ketogenic diet (KD), characterized by low carbohydrate and high fat intake, has shown promise in reducing migraine frequency and severity. Aim of the study The aim of this study is to review the literature on the effectiveness of of the ketogenic diet on the frequency of migraine attacks and their severity. Materials This review analyzed two studies by Di Lorenzo et al. (2018) and Caprio et al. (2023), both demonstrating that KD significantly reduced migraine days compared to non-ketogenic diets. Additional benefits included reduced inflammatory markers and improved body weight. Results While findings are promising, limitations such as small sample sizes, focus on overweight individuals, and lack of long-term safety data highlight the need for larger studies. Conclusions KD offers potential as an effective alternative for managing migraines, but further research is required to confirm its benefits and safety.
... To amend the impaired metabolic state of the brain, the elevation of ketone bodies (KB) through a ketogenic diet (KD) or ketosis has been proposed and implemented, allowing the energydeficient brain to utilize KB as an alternative energy substrate in the metabolic pathways (Maggioni et al., 2011;Di Lorenzo et al., 2015), thereby increasing glucose transport and cerebral metabolism, decreasing cerebral excitability and alleviating oxidative stress (Hartman et al., 2007;Ma et al., 2007;Stafstrom and Rho, 2012). Exogenous KB supplementation has been proposed in migraineurs to circumvent prolonged periods of fasting or stringent KD (Gross E. C. et al., 2019). ...
Background: Emerging findings propose that the pathophysiology of migraine may be associated with dysfunctional metabolic mechanisms. Recent findings suggest that migraine attacks are a response to the cerebral energy deficit, and ingestion of ketone bodies stabilizes the generation of a migraine attack. Based on these findings, ketone body supplementation is postulated as a prophylactic treatment approach to restore cerebral metabolism deficiency. Metabolic markers are unexplored after exogenous ketone body supplementation in episodic migraineurs. Therefore, the present single-arm uncontrolled explorative analysis evaluated blood ketone body and glucose concentration after short and long-term 6 g exogenous DL-Mg-Ca-beta-hydroxybutyrate (DL-βHB) supplementation.
Methods: The presented data are part of the MigraKet randomized-control cross-over clinical trial of 41 episodic migraineurs (Number NCT03132233). Patients were given a single dose of 6 g DL-βHB. Ketone body and glucose blood concentration were assessed before intake, 20, and 40 min after DL-βHB intake. Ketone body, glucose concentration and glycated hemoglobin values were evaluated after 12 weeks of 18 g DL-βHB ingestion (total dose), taken three times daily (6g/dose; 3x/day). Linear models explored the association between the ketone body and glucose levels.
Results: Ketone body concentration increased within-group to a mean of 0.46 (0.30) mmol/L after 40 min post- DL-βHB supplementation [estimate = 0.24 mmol/L, CI = (0.20.0.27), p < 0.01]. This within-group increase of ketone body concentration did not change after repeated daily intake of DL-βHB supplementation over 12 weeks [estimate = 0.00 mmol/L, CI = (−0.03.0.04), p = 0.794]. DL-βHB intake significantly reduced blood glucose concentration within-group from a mean baseline of 4.91 (0.42) mmol/L to 4.75 (0.47) mmol/L 40 min post-DL-βHB supplementation [estimate = −0.16 mmol/L, CI = (−0.15, 0.03), p < 0.01]. Repeated DL-βHB supplementation for 12 weeks showed no change within-group in acute ketone bodies concentration [estimate = 0.00 mmol/L, CI = (−0.03.0.04), p = 0.794] and in the HbA1c value [estimate = 0.02, CI = (−0.07.0.11), p = 0.69].
Conclusion: A single dose of 6 g DL-βHB significantly elevated blood ketone bodies and decreased blood glucose concentration within-group in episodic migraineurs. Long-term DL-βHB supplementation for 12 weeks showed no effect within-group on acute ketone body concentration and had not impact on HbA1c. The elevation of the ketone body concentration was moderate, indicating that nutritional ketosis was not reached. Therefore, a dose higher than 6 g of DL-βHB is required to reach the nutritional level of ketosis. ClinicalTrials.gov Identifier: NCT03132233.
... Some research indicates that ketogenic diets may be beneficial in preventing migraines. [54][55][56][57][58][59] The potential mechanisms of how ketosis may impact migraine have been identified. 23 Ketosis may reduce inflammation, oxidative stress, cerebral excitability, and cortical spreading depression, while increasing mitochondrial function, glucose transport, digestive health, and improving the microbiome. ...
Migraine is considered a common primary headache disorder with unclear etiology. Established medications that are considered effective for migraine prophylaxis include pro-pranolol, metoprolol, topiramate, and amitriptyline. Lifestyle management including diet, exercise, sleep, stress reduction, and counseling are encouraged. The importance of dietary factors as triggers for migraines is uncertain. This case report describes the management and symptomatic improvement of migraines with a ketogenic diet in a 20-year-old obese woman. INTERVENTION AND OUTCOME After adhering to a ketogenic diet and lifestyle modifications for 3 months, an obese patient experienced a dramatic reduction in the frequency, intensity, and duration of migraines, lost 25 pounds, and regained a normal active lifestyle. Migraines decreased from one per day to one per week after 2 weeks, and no migraines were reported after 3 months of dietary modification with a ketogenic diet. CONCLUSION A ketogenic diet may be an effective tool to improve the management of migraines.
... Metabolic approaches to migraine prevention, such as a ketogenic diet (KD), which to some extent mimics the state of fasting, have been shown to be migraine protective [44][45][46][47][48][49] . The KD was developed over 100 years ago, after the observation that prolonged fasting has antiepileptic properties 50 . ...
Emerging evidence suggest migraine is a response to cerebral energy deficiency or oxidative stress in the brain. Beta-hydroxybutyrate (BHB) is likely able to circumvent some of the meta-bolic abnormalities reported in migraine. Exogenous BHB was given to test this assumption and, in this post-hoc analysis, multiple metabolic biomarkers were identified to predict clinical improvements. A randomized clinical trial, involving 41 patients with episodic migraine. Each treatment period was 12 weeks long, followed by eight weeks of washout phase / second run-in phase before entering the corresponding second treatment period. The primary endpoint was the number of migraine days in the last 4 weeks of treatment adjusted for baseline. BHB re-sponders were identified (those with at least a 3-day reduction in migraine days over placebo) and its predictors were evaluated using Akaike’s Information Criterion (AIC) stepwise boot-strapped analysis and logistic regression. Responder analysis showed that metabolic markers could identify a “metabolic migraine” subgroup, which responded to BHB with a 5.7 migraine days reduction compared to the placebo. This analysis provides further support for a “metabolic migraine” subtype. Additionally, these analyses identified low-cost and easily accessible biomarkers that could guide recruitment in future research on this subgroup of patients.
This study is part of the trial registration: ClinicalTrials.gov: NCT03132233, registered on 27.04.2017, https://clinicaltrials.gov/ct2/show/NCT03132233
... 59 Three small studies suggest the ketogenic diet could have benefit for people with migraine, although the effect does not extend past transition away from the diet, adherence is challenging, and the effect might not be larger than that attained through other diets (table 2). 46,47,50,60 Further research is needed to record the safety, appropriateness, and feasibility of sustaining a ketogenic diet to reduce migraine days. ...
Migraine, a common and disabling neurological disorder, is among the top reasons for outpatient visits to general neurologists. In addition to pharmacotherapy, lifestyle interventions are a mainstay of treatment. High-quality daily diary studies and intervention studies indicate intraindividual variations in the associations between lifestyle factors (such as stress, sleep, diet, and physical activity) and migraine attack occurrence. Behaviour change interventions can directly address overlapping lifestyle factors; combination approaches could capitalise on multiple mechanisms. These findings provide useful directions for integration of lifestyle management into routine clinical care and for future research.
... Regarding the changes in weight loss and migraine characteristics, all studies encompass similar results [6,11,[16][17][18][19][20][21]. Novack et al. indicated the frequency of attacks in a month, duration of headaches without treatment, headache diagnostic characteristics (e.g., aura before the attack, nausea, photophobia, and phonophobia), interruption of daily activities, and MIDAS improvement within 6 months after surgery [11]. ...
Background
Obesity makes migraine more prevalent and severe. Serum level of calcitonin gene-related peptide (CGRP) is associated with the severity of migraine attacks. Although the effect of weight and bariatric surgery has been studied on migraine, the role of CGRP in migraine remission after weight loss surgery needs more investigation.
Methods
Patients with severe obesity who were bariatric surgery candidates and had been diagnosed with chronic migraine were included in this study. Weight, BMI, number of days with headache in the past 3 months, and severity of headaches in 10-point Likert VAS, Migraine Disability Assessment Scale (MIDAS) and Migraine Specific Quality of life (MSQ) questionnaire scores, and serum CGRP levels were evaluated before and within 6–10 months after surgery.
Result
Sixty patients with chronic migraine with severe obesity were included. Ninety-five percent of patients reported a significantly lower number of attacks (21 to 8, p < 0.001) and severity of headaches within 90-day (7.7 to 4.8, p < 0.001); MIDAS (64.4 to 25.5, p < 0.001) and MSQ scores (44.6 to 26.8, p < 0.001) and CGRP level (252.7 to 130.1, p < 0.001) were significantly reduced after surgery with a mean follow-up of 7.5 months. Changes in MIDAS, MSQ, and CGRP were significantly associated with weight-related variables.
Conclusion
Bariatric surgery decreases the frequency of migraine attacks, lessens the severity of headaches, and improves the quality of life and disability as well as CGRP plasma levels, suggesting CGRP as a possible etiology in the migraine-obesity link.
Graphical abstract
... For example, the National Headache Foundation [54], the American Migraine Foundation [55,56] and the German Migraine and Headache Society [57] published dietary recommendations for migraine patients. The importance of nutritional adjustments is the subject of various clinical studies and review papers on which these recommendations are based [25][26][27]35,[58][59][60][61][62][63][64][65]. ...
Migraine is a headache disorder associated with a high socioeconomic burden. The digital therapeutic sinCephalea provides an individualized low-glycemic diet based on continuous glucose measurement and is intended to provide a non-pharmacological migraine prophylaxis. We performed two prospective studies with migraine patients who used sinCephalea over a period of 16 weeks. The patients used a headache diary and recorded their migraine-related daily life impairments using the assessment tools HIT-6 and MIDAS for a pre versus post comparison. In addition, continuous glucose data of patients were compared to healthy controls. In both studies, patients reported a reduction of headache and migraine days as well as reductions in HIT-6 and MIDAS scores. More specifically, migraine days decreased by 2.40 days (95% CI [−3.37; −1.42]), HIT-6 improved by 3.17 points (95% CI [−4.63; −1.70]) and MIDAS by 13.45 points (95% CI [−22.01; −4.89]). Glucose data suggest that migraine patients have slightly increased mean glucose values compared to healthy controls, but drop into a glucose range that is below one’s individual standard range before a migraine attack. In conclusion, sinCephalea is a non-pharmacological, digital migraine prophylaxis that induces a therapeutic effect within the range of pharmacological interventions.
... The ketogenic diet is also known to alter gut microbiota (Newell et al. 2016). A study of 96 females with migraine on a ketogenic diet showed a decrease in attack frequency, number of days with headache, and medication intake starting at 1 month after switching to the ketogenic diet that continued the improvement throughout the 6 month study (Di Lorenzo et al. 2015). A case report also showed a decrease in migraine frequency following a ketogenic diet and noted that the therapeutic effect of the ketogenic diet on migraine continued after cessation of the diet (Strahlman 2006). ...
Migraine is a leading cause of disability among the adult population and is a significant burden on the economies of the world. Studies into the underlying causes of migraine have spanned centuries but its underlying mechanisms are still not fully understood. In recent years, accumulating evidence implicates that microbiota-mediated gut-brain crosstalk may contribute to the pathogenesis of migraine. This review provides a brief account of the history of migraine theories and summarizes the recent studies showing how gut microbiota is involved in the pathophysiology of migraine. Future research perspectives for better understanding the role of the gut microbiota in migraine are also discussed.
... The benefits of a standard ketogenic diet appear to extend to patients with chronic refractory migraine and include reduction in use of acute medication, reduction in hours per day with migraine symptoms, and reduction in monthly days with migraine [14]. It appears that actively and successfully following a ketogenic diet may help reduce migraine days, but that this benefit does not last when the diet is terminated [15]. ...
Purpose of Review
To describe the most recent findings related to lifestyle behaviors and migraine.
Recent Findings
An individualized conceptualization of how lifestyle factors impact migraine activity has increased our understanding of the role of behavioral interventions for episodic migraine. Healthy diets of several types have been associated with migraine attack reduction, whereas disruptions in diet like skipping meals are associated with migraine attack onset. Both aerobic activity and lower intensity yoga interventions show promise for migraine prevention. Sleep disruption has been associated with migraine day and may have a bi-directional relationship. Both increases and decreases in stress have been associated with migraine activity.
Summary
Evidence is converging around the principle that highly unusual disruptions in daily routine are particularly associated with migraine attack onset and that a consistent healthy lifestyle is a key feature of effective behavioral migraine prevention strategies.
... In Parkinson's disease, where cells experience abnormal energy metabolism, oxidative stress, inflammation, and increased apoptosis, the ketogenic diet improves both motor and non-motor symptoms (99,100). In migraines, where migraines are thought to be triggered by cerebral energy deficiencies or oxidative stress, the ketogenic diet reduces migraine frequency, severity, and medication use (101,102). In epilepsy, where mitochondrial bioenergetics are impaired, the ketogenic diet has been used since the 1920s in children to reduce seizures and has been increasingly used in adults with drug resistant epilepsy (103,104). ...
Traumatic brain injury (TBI) represents a significant health crisis. To date, no FDA approved pharmacotherapies are available to prevent the neurological deficits caused by TBI. As an alternative to pharmacotherapy treatment of TBI, ketones could be used as a metabolically based therapeutic strategy. Ketones can help combat post-traumatic cerebral energy deficits while also reducing inflammation, oxidative stress, and neurodegeneration. Experimental models of TBI suggest that administering ketones to TBI patients may provide significant benefits to improve recovery. However, studies evaluating the effectiveness of ketones in human TBI are limited. Unanswered questions remain about age- and sex-dependent factors, the optimal timing and duration of ketone supplementation, and the optimal levels of circulating and cerebral ketones. Further research and improvements in metabolic monitoring technology are also needed to determine if ketone supplementation can improve TBI recovery outcomes in humans.
There is no consensus yet on the dietary treatment of migraine, which causes headaches and recurrent attacks and is caused by vascular, biochemical, neurogenic or platelet-based causes. However, various dietary patterns, such as the Mediterranean diet and DASH, have come to the fore. Dietary components may affect migraine clinical outcomes by improving vasodilation, systemic inflammation, and cerebral glucose metabolism pathways. The Mediterranean diet has a neuroprotective role by preventing excessive release of inflammatory mediators and reducing neuroinflammation, pain stimulation, oxidative stress, and lipid peroxidation. The Mediterranean diet is associated with a lower risk of severe headache or migraine and may be a strategy for reducing migraine duration, frequency, and severity. The DASH diet model, which includes plant-based foods with low sodium content, has gained popularity because of its therapeutic effect on systemic inflammatory processes and its antimigraine properties. DASH may help alleviate migraine symptoms by preventing oxidative stress, endothelial dysfunction, and neuroinflammation. In addition, DASH has been associated with reducing the severity and frequency of migraine attacks because of its low sodium-induced antivasodilator effect.
Introduction: Migraine is a prevalent neurological disorder characterized by recurrent headaches with autonomic and neurological symptoms, significantly impacting quality of life globally. Its pathogenesis involves genetic, neurological, inflammatory, and metabolic factors, with insulin resistance and metabolic dysfunction increasingly recognized as important contributors. Historically, it has been known that certain foods can trigger migraine attacks, which led for many years to the recommendation of elimination diets—now understood to primarily target histamine-rich foods. Over the past two decades, attention has shifted toward underlying metabolic disturbances, leading to the development of dietary approaches specifically aimed at addressing these dysfunctions. Methods: A scoping literature review was conducted using PubMed and Embase to evaluate the relationships among migraine, insulin-related mechanisms, neurogenic inflammation, and dietary interventions. Initial searches focused on “MIGRAINE AND (neurogenic inflammation)” (2019–15 April 2025), followed by expanded searches from 1950 onward using terms such as “MIGRAINE AND (insulin, insulin resistance, hyperinsulinism)”, and “MIGRAINE AND (diet, dietary, nutrition, nutritional)”. A specific search also targeted “(INSULIN OR insulin resistance OR hyperinsulinism) AND (neurogenic inflammation)”. Abstracts were screened, full texts were retrieved, and duplicates or irrelevant publications were excluded. No filters were applied by article type or language. Systematic reviews and meta-analyses were prioritized when available. Results: Migraine pathogenesis involves trigeminovascular system activation, neurogenic inflammation mediated by CGRP and PACAP, immune dysregulation, mast cell activation, and cortical spreading depression (CSD). Emerging evidence highlights significant associations between migraine, insulin resistance, and hyperinsulinism. Hyperinsulinism contributes to migraine through TRPV1 sensitization, increased CGRP release, oxidative stress, mitochondrial dysfunction, and systemic inflammation. Metabolic dysfunction, including obesity and insulin resistance, exacerbates migraine severity and frequency. Dietary interventions, particularly anti-inflammatory, Mediterranean, and ketogenic diets, show promise in reducing migraine frequency and severity through mechanisms involving reduced inflammation, oxidative stress, improved mitochondrial function, and glucose metabolism stabilization. Conclusions: The interplay between insulin resistance, metabolic dysfunction, and neuroinflammation is crucial in migraine pathophysiology. Targeted dietary interventions, including ketogenic and Mediterranean diets, demonstrate significant potential in managing migraines, emphasizing the need for personalized nutritional strategies to optimize therapeutic outcomes.
Many migraine triggers, such as stress, sleep deprivation, fatigue, strenuous exercise, and fasting, are potentially linked to disturbances in brain energy metabolism, mitochondrial function, and oxidative stress. Alongside efforts to avoid modifiable factors, prophylactic migraine treatments that target brain energy metabolism have garnered increasing attention. However, the current evidence supporting the use of energy-modulating drugs in migraine treatment guidelines remains weak. This narrative review explores the relationship between energy metabolism and cortical spreading depression susceptibility, metabolic alterations in migraine (including glucose and insulin metabolism, insulin resistance, lipid metabolism, and energy metabolism imaging markers), oxidative stress and antioxidant defenses, mitochondrial dysfunction, and the role of energy metabolism-targeted medications in migraine management. Nutrients may help improve mitochondrial function, thereby alleviating brain energy metabolism deficits and oxidative stress in migraine.
Purpose of Review
This review synthesizes the latest updates in the literature on the connection between fasting and migraine, examining both clinical outcomes and underlying pathophysiological mechanisms.
Recent Findings
Although no studies have specifically explored fasting as a therapeutic intervention for migraine, various retrospective analyses suggest that fasting might worsen migraine symptoms in the short term. On the other hand, recent investigations, including several randomized controlled trials, have shown that ketogenic diets significantly reduce the number of migraine days and decrease inflammation markers. Additional research has shown improvements in disability assessments, as indicated by VAS, MIDAS, and HIT-6 scores. These benefits are not replicated by merely administering ketone bodies. Furthermore, genetic studies have found a link between glycemic processing and the occurrence of migraine.
Summary
There is accumulating evidence that ketogenesis can reduce both the frequency and disability associated with migraine, likely through the reduction of systemic inflammatory markers and diminished cortical excitability. However, the potential benefits of intermittent fasting on migraine prevention remain underexplored and warrant further investigation.
Objective
Since the habituation deficit of evoked potentials could be related to abnormal thalamocortical drive, we searched for a modulatory effect of ketogenic diet (KD) on somatosensory-evoked thalamo-cortical activity. KD is effective in preventing migraine. Previous studies showed that KD normalises habituation of somatosensory and visual cortical evoked responses in parallel with a decrease in of migraine attack frequency.
Methods
We electrically stimulated the median nerve at the wrist to record somatosensory high-frequency oscillations (HFOs) in twenty patients with episodic migraine with and without aura before and after one month of normo- (n = 9) or hypocaloric KD (n = 11). For pre-synaptic thalamocortical and post-synaptic cortical HFOs, we measured the latency of the negative oscillatory maximum, the intra-burst frequency, the number of negative peaks, and the maximum peak-to-peak amplitude.
Results
In the total group of patients, the one-month KD significantly increased the latency of the negative oscillatory maximum in pre-synaptic, i.e. thalamocortical activity (t = 2.70, p = 0.015) and in post-synaptic HFOs, i.e. cortical activity (t = 3.08, p = 0.006). This effect could be attributed to hypo-caloric KD, as it was not found after normo-caloric KD. Other HFO parameters, such as amplitude, duration, or number of oscillations, were not affected.
Conclusions
A 1-month hypo-caloric KD is able to delay the propagation of neuronal activity through the thalamo-cortical network. This effect does not seem to be correlated with the therapeutic efficacy of KD, but rather to low-calorie intake.
Significance
Our results imply that consuming a restricted amount of calories could alter the balance between central excitation and inhibition in migraine.
Purpose:
To our knowledge, no studies have evaluated the association between dietary glycemic index (GI) and glycemic load (GL) with migraine-related clinical symptoms.
Methods:
This cross-sectional study was conducted among 266 women with episodic migraine. The migraine disability assessment (MIDAS) was used to evaluate migraine-related disability in the recent three months. Visual analogue scales (VAS) were also employed to examine migraine-related pains. Glycemic index and glycemic load indices were calculated using the nutritional information obtained from the food frequency questionnaire.
Results:
The study participants had a mean age of 34.32 ± 7.86 years. It was observed that individuals in the quartile 4 of GI and GL reported significantly higher consumption of calories, carbohydrates, proteins, and fats (P < 0.05). In the unadjusted models, those in the quartile 4 of GI and GL had significantly increased odds of experiencing severe pain (based on VAS score) (OR = 2.09, 95% CI = 1.37-2.70, P < 0.001 for dietary GI, and OR = 1.75, 95% CI = 1.16-2.79, P = 0.005 for dietary GL). Additionally, compared to participants in the quartile 1 of GI and GL, those in the quartile 4 of GI and GL were more likely to suffer from severe disability (P < 0.05).
Conclusion:
We found a significant positive correlation between the consumption of foods with higher GI and GL and the clinical conditions related to migraine disease. However, due to the cross-sectional nature of the study, it is not possible to establish a cause-and-effect relationship for the observed results.
Context:
Intermittent fasting, a new-age dietary concept derived from an age-old tradition, involves repetitive cycles of fasting/calorie restriction and eating.
Objective:
We aim to take a deep dive into the biological responses to intermittent fasting, delineate the disease-modifying and cognitive effects of intermittent fasting, and also shed light on the possible side effects.
Methods:
Numerous in vitro and in vivo studies were reviewed, followed by an in-depth analysis, and compilation of their implications in health and disease.
Results:
Intermittent fasting improves the body's stress tolerance, which is further amplified with exercise. It impacts various pathological conditions like cancer, obesity, diabetes, cardiovascular disease, and neurodegenerative diseases.
Conclusion:
During dietary restriction, the human body experiences a metabolic switch due to the depletion of liver glycogen, which promotes a shift towards utilising fatty acids and ketones in the system, thereby significantly impacting adiposity, ageing and the immune response to various diseases.
Aims
There is limited evidence on the link between diet quality and migraine headaches. The present study aimed to evaluate the association between dietary diversity score (DDS), as a good representative of overall diet quality, and clinical features of migraine headaches.
Methods
In total, 262 subjects (224 females and 34 males), aged 20 to 50 years old were included in the present cross-sectional study. The migraine headache was diagnosed according to the third edition of the International Classification of Headache Disorders (ICHD-3). Clinical features of migraine headaches including frequency, severity, and duration of migraine headaches, headache impact test-6 (HIT-6), and serum levels of nitric oxide (NO) were assessed by standard procedures. The dietary intake of participants has been assessed by a validated 168-item food frequency questionnaire (FFQ) and used to calculate DDS. The association between DDS and clinical variables of migraine headaches was investigated using multiple linear regression analysis, and the beta (β) estimates with 95% confidence intervals (CIs) were reported.
Results
A significant inverse association was found between DDS and headache frequency (β = −2.19, 95% CI: −4.25, −0.14) and serum levels of NO (β = −6.60, 95% CI: −12.58, −0.34), when comparing patients in the third tertile of DDS to those in the first tertile. The association remained significant and became stronger after adjustment for confounders for both outcomes of headache frequency (β = −3.36, 95% CI: −5.88, −0.84) and serum levels of NO (β = −9.86, 95% CI: −18.17, −1.55). However, no significant association was found between DDS with HIT-6 score, migraine headache duration, and severity.
Conclusion
The present study demonstrates that higher dietary diversity is correlated with lower migraine frequency and serum levels of NO.
Substance use disorders (SUD) can lead to serious health problems, and there is a great interest in developing new treatment methods to alleviate the impact of substance abuse. In recent years, the ketogenic diet (KD) has shown therapeutic benefits as a dietary therapy in a variety of neurological disorders. Recent studies suggest that KD can compensate for the glucose metabolism disorders caused by alcohol use disorder by increasing ketone metabolism, thereby reducing withdrawal symptoms and indicating the therapeutic potential of KD in SUD. Additionally, SUD often accompanies increased sugar intake, involving neural circuits and altered neuroplasticity similar to substance addiction, which may induce cross-sensitization and increased use of other abused substances. Reducing carbohydrate intake through KD may have a positive effect on this. Finally, SUD is often associated with mitochondrial damage, oxidative stress, inflammation, glia dysfunction, and gut microbial disorders, while KD may potentially reverse these abnormalities and serve a therapeutic role. Although there is much indirect evidence that KD has a positive effect on SUD, the small number of relevant studies and the fact that KD leads to side effects such as metabolic abnormalities, increased risk of malnutrition and gastrointestinal symptoms have led to the limitation of KD in the treatment of SUD. Here, we described the organismal disorders caused by SUD and the possible positive effects of KD, aiming to provide potential therapeutic directions for SUD.
Introduction
Headaches are a prevalent disorder worldwide, and there is compelling evidence that certain dietary interventions could provide relief from attacks. One promising approach is ketogenic therapy, which replaces the brain's glucose fuel source with ketone bodies, potentially reducing the frequency or severity of headaches.
Aim
This study aims to conduct a systematic review of the scientific literature on the impact of ketosis on migraine, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method.
Results
After a careful selection process and bias evaluation, 10 articles were included in the review, primarily from Italy. The bias assessment indicated that 50% of the selected articles had a low risk of bias in all domains, with the randomization process being the most problematic domain. Unfortunately, the evaluation of ketosis was inconsistent between articles, with some assessing ketonuria, some assessing ketonemia, and some not assessing ketosis levels at all. Therefore, no association could be made between the level of ketosis and the prevention or reduction of migraine attacks. The ketogenic therapies tested in migraine treatments included the very low-calorie ketogenic diet (VLCKD, n = 4), modified Atkins diet (MAD, n = 3), classic ketogenic diet (cKDT, n = 2), and the administration of an exogenous source of beta-hydroxybutyrate (BHB). The meta-analysis, despite reporting high heterogeneity, found that all interventions had an overall significant effect (Z = 9.07, p < 0.00001; subgroup differences, Chi2 = 9.19, dif = 3, p = 0.03; I², 67.4%), regardless of the type of endogenous or exogenous induction of ketosis.
Conclusion
The initial findings of this study suggest that metabolic ketogenic therapy may provide some benefit in treating migraines and encourage further studies, especially randomized clinical trials with appropriate and standardized methodologies. The review strongly recommends the use of the adequate measurement of ketone levels during ketogenic therapy to monitor adherence to the treatment and improve knowledge of the relationship between ketone bodies and efficacy.
Systematic review registration
https://www.crd.york.ac.uk/prospero/, identifier: CRD42022330626.
Objective/background:
Migraine patients are frequently affected by sleep complaints. The ketogenic diet (KD) is an option for the treatment of migraine. Our aim was: 1) to assess the effects of KD on sleep complaints in patients affected by migraine and 2) to verify if sleep changes were related to the effects of the diet on headache symptoms.
Patients/methods:
From January 2020 to July 2022 we consecutively enrolled 70 migraine patients who were treated with KD as a preventive therapy. We collected information regarding: 1) anthropometric measures; 2) migraine intensity, frequency and disability; 3) subjective sleep complaints, i.e. insomnia, sleep quality, by the Pittsburgh Sleep Quality Index (PSQI), and excessive Daytime Sleepiness (EDS), by the Epworth Sleepiness Scale (ESS).
Results:
After 3 months of KD therapy, anthropometric measures considerably changed, i.e. body mass index and free fat mass, and migraine significantly improved, i.e. lower intensity, frequency and disability. Regarding sleep, we observed that insomnia affected a decreased rate of patients (T0: 60% versus T1: 40%, p < 0.001). Similarly, patients with poor sleep were significantly less after KD therapy (T0: 74.3% versus T1: 34.3%, p < 0.001). Finally, EDS prevalence declined at the follow-up (T0: 40% versus T1: 12.9%, p < 0.001). Sleep features modifications were not correlated with migraine improvements and with anthropometric changes.
Conclusions:
For the first time we demonstrated that KD may improve sleep complaints in migraine patients. Interestingly, the positive effect of KD on sleep is independent of migraine improvements and anthropometric modifications.
Tension-type headache is the second most common cause of chronic pain in the Global Burden of Disease, affecting an estimated population of nearly 900 million new cases per year. The estimated prevalence of tension-type headache is enormous, with a very high variability from 10% up to 86% in young subjects. The global prevalence of the chronic form is equally important because it covers about two 3% of the global population. Despite such an important epidemiological economic impact, tension-type headache causes less disability than migraine. In terms of years of life lived with disabilities the comorbidities of tension-type headache are often similar to those of migraine such as anxiety, depression, sleep disturbances and other pain disorders including migraine itself. The physiopathology of the tension-type headache is mainly based on genetic factors, myofascial mechanisms and chronicization mechanisms such as sensitization, therefore peripheral mechanisms and vascular factors are mostly unimportant. The central factors are important in the transformation from the episodic form to the chronic one. Unfortunately, the non-exact definition of the pathophysiology and the moderate burden impact and even a modest economic impact has left the tension-type headache, from a therapeutic point of view, still with old generation drugs, with no new compounds dedicated to this pathology for many decades. However, being a pathology with a great impact in the general population, it is useful to know the most important lines of research and any updates also in the field of complementary medicine that can guide the clinician in his/her daily practice.
Ketogenic diets have been used to treat epilepsy for nearly a century. Alongside enduring clinical success with a ketogenic diet, metabolism’s critical role in health and in diseases in the central nervous system and throughout the body is increasingly appreciated. Furthermore, metabolism-based strategies have been proven equal or even superior to pharmacological treatments in specific cases and for specific diseases. Rather than causing unwanted off-target pharmacological side effects, addressing metabolic dysfunction can improve overall health simultaneously. Enduring interest in the ketogenic diet’s proven efficacy in stopping seizures and emerging efficacy in other disorders has fueled renewed efforts to determine key mechanisms and diverse applications of metabolic therapies. In parallel, multiple strategies are being developed to mobilize similar metabolic benefits without reliance on such a strict diet. Research interest in metabolic therapies has spread into laboratories and clinics of every discipline, and could yield entirely new classes of drugs and treatment regimens. This work is the first comprehensive scientific resource on the ketogenic diet, covering the latest research into the mechanisms, established and emerging applications, metabolic alternatives, and implications for health and disease. Experts in clinical and basic research share their research into mechanisms spanning from ion channels to epigenetics, their insights based on decades of experience with the ketogenic diet in epilepsy, and their evidence for emerging applications ranging from autism to Alzheimer’s disease to brain cancer.
Ketogenic diets have been used to treat epilepsy for nearly a century. Alongside enduring clinical success with a ketogenic diet, metabolism’s critical role in health and in diseases in the central nervous system and throughout the body is increasingly appreciated. Furthermore, metabolism-based strategies have been proven equal or even superior to pharmacological treatments in specific cases and for specific diseases. Rather than causing unwanted off-target pharmacological side effects, addressing metabolic dysfunction can improve overall health simultaneously. Enduring interest in the ketogenic diet’s proven efficacy in stopping seizures and emerging efficacy in other disorders has fueled renewed efforts to determine key mechanisms and diverse applications of metabolic therapies. In parallel, multiple strategies are being developed to mobilize similar metabolic benefits without reliance on such a strict diet. Research interest in metabolic therapies has spread into laboratories and clinics of every discipline, and could yield entirely new classes of drugs and treatment regimens. This work is the first comprehensive scientific resource on the ketogenic diet, covering the latest research into the mechanisms, established and emerging applications, metabolic alternatives, and implications for health and disease. Experts in clinical and basic research share their research into mechanisms spanning from ion channels to epigenetics, their insights based on decades of experience with the ketogenic diet in epilepsy, and their evidence for emerging applications ranging from autism to Alzheimer’s disease to brain cancer.
Migraine is a prevalent heterogeneous neurological disorder, enumerated as the eighth most disabling neurological disorder by the World Health Organization. The growing advancement in technology and investigation of various facets of cerebral metabolism in migraine has shed light to metabolic mechanisms in migraine pathophysiology. A growing number of clinical research postulates migraine as a reaction to oxidative stress levels that go beyond antioxidant capacity or cerebral energy deficiency. This has become an extremely attractive subject area and over the past years there has also been a sustained research activity in using ketone bodies (KB) as a novel potential migraine prophylaxis. Not much epidemiological research has been conducted to exhibit the efficacy of ketone bodies in abnormal metabolism in migraine pathophysiology. Therefore, a better understanding of ketone bodies in metabolic migraine may provide novel therapeutic opportunities. The goal of this review is to assess present understanding on potential migraine triggers, as well as how ketogenic interventions support metabolic disability in migraines and address the therapeutic importance of ketones in migraine treatment, accenting clinical studies (including neuroimaging and therapeutic studies). This review is intended to demonstrate existing literature on the effects of ketone bodies on metabolic migraine traits to guide the readership through current concepts and foster a perspective for future research.
Fasting has been widely studied in both prevention and treatment of many neurologic disorders. Some conditions may be prevented with any type of fasting, while some may require a stricter regimen. Fasting reduces weight, fasting blood glucose, and insulin resistance, and favorably alters the gut biome and the immune system. This article discusses various versions of fasting that have been studied as well as the known and theoretical mechanisms of how fasting effects the body and the brain. This article will then review evidence supporting the potential preventive and treatment effects of fasting in specific neurologic disorders including ameliorating the symptoms of Parkinson's disease, improving cognition in Alzheimer's disease, reducing migraine frequency and intensity, and reducing seizure frequency in epilepsy.
Purpose of Review
Discuss the state of the literature for the treatment of comorbid epilepsy and cognitive dysfunction, specifically focusing on the older adult.
Recent Findings
Epilepsy and cognitive dysfunction are neuronal network disorders with converging molecular underpinnings. Anti-seizure medication is not obligatory after the first instance of a seizure in the setting of cognitive dysfunction. In the absence of randomized controlled trials, current practice is largely based on individual clinical presentation and estimated risk of recurrence. Screening for epilepsy in the context of cognitive dysfunction and cognitive dysfunction in the context of epilepsy should occur early and often throughout treatment.
Summary
Decreasing central nervous system polypharmacy is highly recommended in elderly patients, and early cognitive/epilepsy screening may improve both treatment and clinical outcomes. Neuromodulatory techniques and diet modifications are promising treatments that would benefit from additional research. Overall, elucidating the pathological mechanisms that connect epilepsy and cognitive impairment in this population could help direct future treatments.
Despite well-documented evidence on dietary migraine triggers, the role of nutrition in its treatment remains a contentious topic. The objective was to investigate the effect of major dietary interventions on migraine adult patients. A structured literature search was undertaken using PubMed, Web of Science, and Scopus from the database’s establishment until February 16, 2022. Data on migraine frequency, duration, and intensity, as well as adverse events, were gathered from randomized control trials (RCTs) that investigated the effects of major dietary patterns in migraine patients ≥ 18 years. The Cochrane Collaborations risk-of-bias tool was used to assess the quality of included studies. Five RCTs with a total of 645 individuals were included, with two major dietary patterns, Dietary Approaches to Stop Hypertension (DASH) diet (three studies) and ketogenic diet (KD) (two studies), averaging 12 weeks in duration. Overall, the evidence was of average quality. Most of the trials showed a reduction in migraine attack frequency, duration, or severity. Patients with KD reported the number of side effects. According to the current data, both the DASH diet and the KD may have some benefits for migraine sufferers. Given the small number of trials included and the equivocal outcomes, the conclusions of this study should be regarded with caution. More high-quality, long-term research is needed.
Obesity and headache disorders are two very common conditions in the general population that have been increasing in incidence over the last decades. Recent studies have shown a significant relationship between obesity and headaches, particularly migraine, with an important role in whether the disease is chronic. On the other hand, no such association was found with tension-type headaches. Studies showing an overlapping of hunger-control pathways and those involved in the pathophysiology of migraine may justify the close association between obesity and migraine. Moreover, a secondary headache for which obesity is a strong risk factor is idiopathic Intracranial Hypertension (pseudotumor cerebri), with several studies showing the impact of weight reduction/bariatric surgery in the treatment of the disease. In conclusion, since obesity is a modifiable risk factor, it is important for physicians treating patients with headaches, and particularly migraine, to be aware of the association between these two disorders.
Keywords:
Body Mass Index; Obesity; Headaches; Migraine without Aura; Pseudotumor Cerebri
Objectives
Chronic pain (CP) is an unpleasant emotional and sensory experience that can be accompanied by tissue damage that persists for more than 3 months. Recent studies show that certain nutritional strategies can help to improve pain, so this study is aimed to systematically review scientific evidence to understand and map the effect of the use of nutritional strategies on the presence or intensity of chronic non-cancer pain (CNCP) and the association of these nutritional aspects with the presence or intensity of CNCP.
Study design
A systematic review.
Methods
Two independent researchers searched for randomized clinical trials (RCTs) and observational studies that explored the relationship between nutrition and CNCP in adults from 2010 to 2020 in PubMed, Web of Science, Scopus, and Cochrane Library databases. A total of 24 studies were included, of which 20 were RCTs and 4 were observational studies. They are classified into the administration of nutritional supplements, dietary modification, and incorporation of food.
Results
Of these studies, those that have a significant effect on pain are dietary modification and the use of nutritional supplements. On the other hand, the main results from the few observational studies included in this review point to the existence of an association relationship between less pain and a ketogenic or hypocaloric diet or adherence to the Mediterranean diet.
Conclusion
Dietary modification seems to be one plausible therapeutic option to improve and relieve CNCP. However, more research is needed in this regard to obtain better conclusions.
Systematic Review Registration
[www.crd.york.ac.uk/prospero], identifier [CRD42021226431].
A disease intrinsically jeopardized as migraine needs multiple management approaches in the treatment process. Thinking that the drug alone, albeit innovative, efficient, safe, can play the role of gold player can sometimes lead to error. The pharmacological management should include integration and compliance in special situations such as emergency, pregnancy, age. Therefore, it is necessary to have a holistic vision of the treatment where psychobehavioral support, and in particular cases neuromodulatory and complementary alternative medicine, can be not a substitute but an integrative part of it.
Działania niepożądane, interakcje lekowe, a także farmakooporność mogą w znacznym stopniu utrudniać farmakologiczne leczenie migreny. W związku z tym coraz częściej stosuje się niekonwencjonalne i niefarmakologiczne metody leczenia. W szczególności nieinwazyjna neuromodulacja, blokady nerwów obwodowych, nutraceutyki i metody behawioralne są dobrze tolerowane i wskazane dla określonych grup pacjentów, takich jak młodzież, kobiety w ciąży i pacjenci, którzy z różnych powodów muszą lub chcą ograniczyć farmakoterapię. Metody te są coraz częściej postrzegane jako ważna opcja terapeutyczna w leczeniu migreny, konieczne są jednak dalsze badania nad ich skutecznością, także w odniesieniu do efektów długoter minowych, zwłaszcza że skuteczności części metod niekonwencjona lnych (np. kannabinoidów) dotychczas nie zweryfikowano w dobrej jakości badaniach naukowych.
Celem pracy jest przedstawienie i omówienie głównych metod wspomagających leczenie farmakologiczne migreny na podstawie aktualnego piśmiennictwa.
Background
Obesity confers adverse effects to every system in the body including the central nervous system. Obesity is associated with both migraine and idiopathic intracranial hypertension (IIH). The mechanisms underlying the association between obesity and these headache diseases remain unclear.
Methods
We conducted a narrative review of the evidence in both humans and rodents, for the putative mechanisms underlying the link between obesity, migraine and IIH.
Results
Truncal adiposity, a key feature of obesity, is associated with increased migraine morbidity and disability through increased headache severity, frequency and more severe cutaneous allodynia. Obesity may also increase intracranial pressure and could contribute to headache morbidity in migraine and be causative in IIH headache. Weight loss can improve both migraine and IIH headache. Preclinical research highlights that obesity increases the sensitivity of the trigeminovascular system to noxious stimuli including inflammatory stimuli, but the underlying molecular mechanisms remain unelucidated.
Conclusions
This review highlights that at the epidemiological and clinical level, obesity increases morbidity in migraine and IIH headache, where weight loss can improve headache morbidity. However, further research is required to understand the molecular underpinnings of obesity related headache in order to generate novel treatments.
Background
Several studies propose that brain energy deficit might be partially involved in the pathophysiology of migraine. Previously, studies demonstrated that ketogenic diet causes a substantial reduction in migraine frequency. Since the ketogenic diet is restricting and its adherence is difficult, we proposed to supplement ketone bodies exogenously to provide a prophylactic effect in migraineurs.
Aim
To evaluate the prophylactic effect of exogenous DL-beta-hydroxybutyrate supplementation in episodic migraineurs.
Methods
A double-blind, placebo-controlled, randomised crossover trial was conducted, involving 41 patients with episodic migraine. Patients were randomised 1:1 into placebo or beta-hydroxybutyrate group before entering the first treatment period. Each treatment period was 12 weeks long, followed by four weeks of washout phase and four weeks of run-in phase before entering into the corresponding second treatment period. The primary endpoint was the number of migraine days in the last four weeks of treatment, adjusted for baseline.
Results
We observed no clinically significant amelioration of migraine frequency or intensity under DL-beta-hydroxybutyrate treatment as compared to placebo regarding number of migraine days (mean difference [95% CI]: −1.1[−5.07, 2.85]), migraine intensity (0–10 VAS: 1.5[−0.8, 3.7]).
Conclusion
The selected dose of supplemented exogenous DL-beta-hydroxybutyrate did not demonstrate efficacy in episodic migraineurs. ClinicalTrials.gov Identifier: NCT03132233
Although many medications are currently available in the prevention and treatment of migraines, lifestyle modifications are still recommended to modify symptoms. The role of dietary and nutritional factors in causing as well as treating headache disorders has been widely studied. In this chapter, we review research related to common food triggers and IgG food sensitivity testing to prescribe an elimination diet. Prospective studies on various types of comprehensive diets such as the ketogenic diet, the modified Atkins diet, low glycemic index diet, and low-fat diet will also be summarized. Comprehensive diets do not require the exclusion of food triggers but the quantitative adjustment of micronutrients, protein, carbohydrates, and fats. Comorbid conditions such as obesity, irritable bowel syndrome, and celiac disease will be also examined in the context of migraines and studies on condition-specific dietary modifications evaluated. Finally, brain energy metabolism in migraineurs and its relationship to nutrient deficiencies will also be discussed in conjunction with the use of nutraceuticals and phytomedicine to improve migraine symptoms.
The ketogenic diet is a high-fat, low-carbohydrate diet long used to treat refractory epilepsy; ketogenesis (ketone body formation) is a physiological phenomenon also observed in patients following lowcarbohydrate, low-calorie diets prescribed for rapid weight loss. We report the case of a pair of twin sisters, whose high-frequency migraine improved during a ketogenic diet they followed in order to lose weight. The observed time-lock between ketogenesis and migraine improvement provides some insight into how ketones act to improve migraine.
The phenomena of habituation and sensitization are considered most useful for studying the neuronal substrates of information processing in the CNS. Both were studied in primary headaches, that are functional disorders of the brain characterized by an abnormal responsivity to any kind of incoming innocuous or painful stimuli and it's cycling pattern over time (interictal, pre-ictal, ictal). The present review summarizes available data on stimulus responsivity in primary headaches obtained with clinical neurophysiology. In migraine, the majority of electrophysiological studies between attacks have shown that, for a number of different sensory modalities, the brain is characterised by a lack of habituation of evoked responses to repeated stimuli. This abnormal processing of the incoming information reaches its maximum a few days before the beginning of an attack, and normalizes during the attack, at a time when sensitization may also manifest itself. An abnormal rhythmic activity between thalamus and cortex, namely thalamocortical dysrhythmia, may be the pathophysiological mechanism subtending abnormal information processing in migraine. In tension-type headache (TTH), only few signs of deficient habituation were observed only in subgroups of patients. By contrast, using grand-average responses indirect evidence for sensitization has been found in chronic TTH with increased nociceptive specific reflexes and evoked potentials. Generalized increased sensitivity to pain (lower thresholds and increased pain rating) and a dysfunction in supraspinal descending pain control systems may contribute to the development and/or maintenance of central sensitization in chronic TTH. Cluster headache patients are chrarcterized during the bout and on the headache side by a pronounced lack of habituation of the brainstem blink reflex and a general sensitization of pain processing. A better insight into the nature of these ictal/interictal electrophysiological dysfunctions in primary headaches paves the way for novel therapeutic targets and may allow a better understanding of the mode of action of available therapies.
Research increasingly suggests that obesity is an exacerbating factor for migraine. However, it is less clear whether weight loss may help to alleviate migraine in obese individuals. We examined whether weight loss after bariatric surgery is associated with improvements in migraine headaches.
In this prospective observational study, 24 patients who had migraine according to the ID-Migraine screener were assessed before and 6 months after bariatric surgery. At both time points, patients had their weight measured and reported on frequency of headache days, average headache pain severity, and headache-related disability over the past 90 days via the Migraine Disability Assessment questionnaire. Changes in headache measures and the relation of weight loss to these changes were assessed using paired-sample t tests and logistic regression, respectively.
Patients were mostly female (88%), middle-aged (mean age 39.3), and severely obese (mean body mass index 46.6) at baseline. Mean (±SD) number of headache days was reduced from 11.1 ± 10.3 preoperatively to 6.7 ± 8.2 postoperatively (p < 0.05), after a mean percent excess weight loss (%EWL) of 49.4%. The odds of experiencing a ≥50% reduction in headache days was related to greater %EWL, independent of surgery type (p < 0.05). Reductions in severity were also observed (p < 0.05) and the number of patients reporting moderate to severe disability decreased from 12 (50.0%) before surgery to 3 (12.5%) after surgery (p < 0.01).
Severely obese migraineurs experience marked alleviation of headaches after significant weight reduction via bariatric surgery. Future studies are needed to determine whether more modest, behaviorally produced weight losses can effect similar migraine improvements.
Medication-overuse headache (MOH) is a frequent, disabling disorder. Despite a controversial pathophysiology convincing evidence attributes a pivotal role to central sensitization. Most patients with MOH initially have episodic migraine without aura (MOA) characterized interictally by an absent amplitude decrease in cortical evoked potentials to repetitive stimuli (habituation deficit), despite a normal initial amplitude (lack of sensitization). Whether central sensitization alters this electrophysiological profile is unknown. We therefore sought differences in somatosensory evoked potential (SEP) sensitization and habituation in patients with MOH and episodic MOA.
We recorded median-nerve SEPs (3 blocks of 100 sweeps) in 29 patients with MOH, 64 with MOA and 42 controls. Episodic migraineurs were studied during and between attacks. We measured N20-P25 amplitudes from 3 blocks of 100 sweeps, and assessed sensitization from block 1 amplitude, and habituation from amplitude changes between the 3 sequential blocks.
In episodic migraineurs, interictal SEP amplitudes were normal in block 1, but thereafter failed to habituate. Ictal SEP amplitudes increased in block 1, then habituated normally. Patients with MOH had larger-amplitude block 1 SEPs than controls, and also lacked SEP habituation. SEP amplitudes were smaller in triptan overusers than in patients overusing nonsteroidal anti-inflammatory drugs (NSAIDs) or both medications combined, lowest in patients with the longest migraine history, and highest in those with the longest-lasting headache chronification.
In patients with MOH, especially those overusing NSAIDs, the somatosensory cortex becomes increasingly sensitized. Sensory sensitization might add to the behavioral sensitization that favors compulsive drug intake, and may reflect drug-induced changes in central serotoninergic transmission.
In migraine, an interictal reduction of mitochondrial energy metabolism and a preventive effect of high-dose riboflavin were reported. To explore the relation between the two, we tested if the therapeutic response to riboflavin is associated with specific mitochondrial DNA (mtDNA) haplogroups. We focused our attention on haplogroup H, which is known to differ from others in terms of energy metabolism.
Sixty-four migraineurs completed a 4-month open trial with riboflavin (400 mg QD) and were genotyped blindly for mtDNA haplogroups.
Forty patients responded to riboflavin treatment and 24 were nonresponders. The mtDNA haplogroup H was found in 29 subjects (20 migraine without aura, 9 migraine with aura). Riboflavin responders were more numerous in the non-H group (67.5%). Conversely, nonresponders were mostly H (66.7%). The difference between the two groups was significant (chi(2) = 7.07; p = 0.01). The presence of aura had no influence on riboflavin's effectiveness (chi(2) = 0.113; p = 0.74) and was not associated with a particular haplogroup (chi(2) = 0.55; p = 0.46).
In this pharmacogenetic study, riboflavin appears to be more effective in patients with migraine with non-H mitochondrial DNA haplotypes. The underlying mechanisms are unknown, but could be related to the association of haplogroup H with increased activity in complex I, which is a major target for riboflavin. Our results may have ethnic implications, since haplogroup H is chiefly found in the European population.
A deficit of mitochondrial energy metabolism may play a role in migraine pathogenesis. We found in a previous open study that high-dose riboflavin was effective in migraine prophylaxis. We now compared riboflavin (400 mg) and placebo in 55 patients with migraine in a randomized trial of 3 months duration. Using an intention-to-treat analysis, riboflavin was superior to placebo in reducing attack frequency (p = 0.005) and headache days (p = 0.012). Regarding the latter, the proportion of patients who improved by at least 50%, i.e. "responders," was 15% for placebo and 59% for riboflavin (p = 0.002) and the number-needed-to-treat for effectiveness was 2.3. Three minor adverse events occurred, two in the riboflavin group (diarrhea and polyuria) and one in the placebo group (abdominal cramps). None was serious. Because of its high efficacy, excellent tolerability, and low cost, riboflavin is an interesting option for migraine prophylaxis and a candidate for a comparative trial with an established prophylactic drug.
Riboflavin, which improves energy metabolism similarly to coenzyme Q10 (CoQ10), is effective in migraine prophylaxis. We compared CoQ10 (3 x 100 mg/day) and placebo in 42 migraine patients in a double-blind, randomized, placebo-controlled trial. CoQ10 was superior to placebo for attack-frequency, headache-days and days-with-nausea in the third treatment month and well tolerated; 50%-responder-rate for attack frequency was 14.4% for placebo and 47.6% for CoQ10 (number-needed-to-treat: 3). CoQ10 is efficacious and well tolerated.
The full anticonvulsant effect of the ketogenic diet (KD) can require weeks to develop in rats, suggesting that altered gene expression is involved. The KD typically is used in pediatric epilepsies, but is effective also in adolescents and adults. Our goal was to use microarray and complementary technologies in adolescent rats to understand its anticonvulsant effect.
Microarrays were used to define patterns of gene expression in the hippocampus of rats fed a KD or control diet for 3 weeks. Hippocampi from control- and KD-fed rats were also compared for the number of mitochondrial profiles in electron micrographs, the levels of selected energy metabolites and enzyme activities, and the effect of low glucose on synaptic transmission.
Most striking was a coordinated upregulation of all (n = 34) differentially regulated transcripts encoding energy metabolism enzymes and 39 of 42 transcripts encoding mitochondrial proteins, which was accompanied by an increased number of mitochondrial profiles, a higher phosphocreatine/creatine ratio, elevated glutamate levels, and decreased glycogen levels. Consistent with increased energy reserves, synaptic transmission in hippocampal slices from KD-fed animals was resistant to low glucose.
These data show that a calorie-restricted KD enhances brain metabolism. We propose an anticonvulsant mechanism of the KD involving mitochondrial biogenesis leading to enhanced alternative energy stores.
Background:
Chronic cluster headache (CCH) is characterized by recurrent bouts of facial pain lasting up to 180 minutes in the absence of a long remission period.
Case:
We report the case of a 43-year-old male patient with treatment-resistant CCH, who improved with administration of transdermal rotigotine. We also evaluated the nociceptive blink reflex habituation that was reduced before the treatment (as is usual in CH patients) and normalized by transdermal rotigotine.
Conclusions:
We suggest that rotigotine could represent a further therapeutic option in the treatment of drug-resistant CCH.
We investigated whether chronic headache related to medication overuse (MOH) is associated with changes in brain mechanisms regulating inhibitory cortical responses compared with healthy volunteers and episodic migraineurs recorded between attacks, and whether these changes differ according to the drug overused.
We studied 40 MOH patients whose symptoms were related to triptans alone, non-steroidal anti-inflammatory drugs (NSAIDs) or both medications combined, 12 migraineurs and 13 healthy volunteers. We used high-intensity transcranial magnetic stimulation over the primary motor cortex to assess the silent period from contracted perioral muscles.
In MOH patients the cortical silent period differed according to the type of headache medication overused: in patients overusing triptans alone it was shorter than in healthy volunteers (44.7 ± 14.2 vs. 108.1 ± 30.1 ms), but similar to that reported in migraineurs (59.9 ± 30.4 ms), whereas in patients overusing NSAIDs alone or triptans and NSAIDs combined duration of silent period was within normal limits (80.6 ± 46.4 and 103.8 ± 47.2 ms).
Compared with episodic migraineurs, MOH patients overusing triptans have no significant change in cortical inhibition, whereas those overusing NSAIDs have an increase in cortical inhibitory mechanisms. We attribute these changes to medication-induced neural adaptation promoted by changes in central serotonin neurotransmission.
The efficacy of the ketogenic diet (KD) develops gradually over a period of 1-3 weeks, suggesting that adaptive changes in gene expression are involved in its anticonvulsant effects. Previously, microarrays were employed to define patterns of gene expression in the hippocampus of rats maintained on either a KD or a control diet for 3 weeks. The density of mitochondria in hippocampal tissue was assessed by electron microscopy. Levels of selected energy metabolites, enzyme activities, and the effect of low glucose on synaptic transmission were also investigated in hippocampal tissue taken from either KD- or control-fed animals. We found a coordinated up-regulation of transcripts encoding energy metabolism enzymes and a dramatic 46% increase in the density of mitochondria observed in neuronal processes. These changes were accompanied by an increased phosphocreatine (PCr):creatine (Cr) energy-store ratio. Consistent with heightened energy reserves, hippocampal synaptic transmission in KD-fed animals was maintained approximately 50% longer compared to controls after exposure to a mild metabolic stressor. Taken together, several lines of evidence indicate that the KD enhances energy production in the brain. As a consequence, brain tissue appears to become more resistant to metabolic stress. It is proposed...that the observed KD-induced enhancements in energy metabolism help to compensate for the metabolic deficits exhibited (interictally) within epileptic foci and transient failures of gamma-aminobutyric acid (GABA) ergic inhibition, which would otherwise favor the initiation and propagation of seizure activity.
We hypothesize that one mechanism of the anti-epileptic effect of the ketogenic diet is to alter brain handling of glutamate. According to this formulation, in ketotic brain astrocyte metabolism is more active, resulting in enhanced conversion of glutamate to glutamine. This allows for: (a) more efficient removal of glutamate, the most important excitatory neurotransmitter; and (b) more efficient conversion of glutamine to GABA, the major inhibitory neurotransmitter.
Fasting and other dietary regimens have been used to treat epilepsy since at least 500 BC. To mimic the metabolism of fasting, the ketogenic diet (KD) was introduced by modern physicians as a treatment for epilepsy in the 1920s. For two decades this therapy was widely used, but with the modern era of antiepileptic drug treatment its use declined dramatically. By the end of the twentieth century this therapy was available in only a small number of children's hospitals. Over the past 15 years, there has been an explosion in the use, and scientific interest in the KD. This review traces the history of one of the most effective treatments for childhood epilepsy.
To evaluate the rates, pattern, satisfaction with, and presence of predictors of complementary and alternative medicine (CAM) use in a clinical population of patients with cluster headache (CH).
One hundred CH patients attending one of three headache clinics were asked to undergo a physician-administered structured interview designed to gather information on CAM use.
Past use of CAM therapies was reported by 29% of the patients surveyed, with 10% having used CAM in the previous year. Only 8% of the therapies used were perceived as effective, while a partial effectiveness was reported in 28% of CAM treatments. The most common source of recommendation of CAM was a friend or relative (54%). Approximately 62% of CAM users had not informed their medical doctors of their CAM use. The most common reason for deciding to try a CAM therapy was that it offered a "potential improvement of headache" (44.8%). Univariate analysis showed that CAM users had a higher income, had a higher lifetime number of conventional medical doctor visits, had consulted more headache specialists, had a higher number of CH attacks per year, and had a significantly higher proportion of chronic CH versus episodic CH. A binary logistic regression analysis was performed and two variables remained as significant predictors of CAM use: income level (OR=5.7, CI=1.6-9.1, p=0.01), and number of attacks per year (OR=3.08, CI=1.64-6.7, p<0.0001).
Our findings suggest that CH patients, in their need of and quest for care, seek and explore both conventional and CAM approaches, even though only a very small minority finds them very satisfactory.
Ketone bodies (KB) have been shown to prevent neurodegeneration in models of Parkinson's and Alzheimer's diseases, but the mechanisms underlying these effects remain unclear. One possibility is that KB may exert antioxidant activity. In the current study, we explored the effects of KB on rat neocortical neurons exposed to hydrogen peroxide (H(2)O(2)) or diamide - a thiol oxidant and activator of mitochondrial permeability transition (mPT). We found that: (i) KB completely blocked large inward currents induced by either H(2)O(2) or diamide; (ii) KB significantly decreased the number of propidium iodide-labeled cells in neocortical slices after exposure to H(2)O(2) or diamide; (iii) KB significantly decreased reactive oxygen species (ROS) levels in dissociated neurons and in isolated neocortical mitochondria; (iv) the electrophysiological effects of KB in neurons exposed to H(2)O(2) or diamide were mimicked by bongkrekic acid and cyclosporin A, known inhibitors of mPT, as well as by catalase and DL - dithiothreitol, known antioxidants; (v) diamide alone did not significantly alter basal ROS levels in neurons, supporting previous studies indicating that diamide-induced neuronal injury may be mediated by mPT opening; and (vi) KB significantly increased the threshold for calcium-induced mPT in isolated mitochondria. Taken together, our data suggest that KB may prevent mPT and oxidative injury in neocortical neurons, most likely by decreasing mitochondrial ROS production.
This article is the first of a three-part series intended to enhance clinical pharmacists' understanding of methods frequently used in epidemiologic research and their applications. The basic tenets of epidemiology and uses for data derived from epidemiologic studies are given, along with a high-level overview of the differences between experimental and observational study designs. The defining characteristics of each of the observational study designs (case report or case series, ecologic, cross-sectional, cohort, case-control, nested case-control, and case-cohort) and the resultant strengths and limitations of the study designs are presented. Applications for observational studies in pharmacoepidemiology (including the case-crossover and case-time-control study designs) are discussed. Finally, points to consider when evaluating data from observational studies are addressed.
To examine the relationship between recurrent headache disorders (i.e., migraine and tension-type headache) and lifestyle factors (overweight, low physical activity, and smoking) in an unselected population study among adolescents.
In this cross-sectional study from Norway, a total of 5,847 students were interviewed about headache complaints and completed a comprehensive questionnaire including items concerning physical activity and smoking. In addition, they underwent a clinical examination with height and weight measurements. Adolescents with high physical activity who were not current smokers and not overweight were classified as having a good lifestyle status. These students were compared to those with 1 or more of the negative lifestyle factors present in regard to headache diagnosis and headache frequency.
In adjusted multivariate analyses, recurrent headache was associated with overweight (odds ratio [OR] = 1.4, 95% confidence interval [CI] 1.2-1.6, p < 0.0001), low physical activity (OR = 1.2, 95% CI 1.1-1.4, p = 0.002), and smoking (OR = 1.5, 95% CI 1.3-1.7, p < 0.0001). The prevalence of OR increased with more than 1 negative lifestyle factor present, evident for headache diagnoses and frequency.
The results from the present study show that overweight, smoking, or low physical activity are independently and in combination associated with recurrent headache among adolescents. The associations observed and the additive effect of these negative lifestyle factors on the prevalence of recurrent headache indicates possible targets for preventive measures.
We report two monochorionic twins that progressively developed, between ages 5 and 10, a combination of episodic neurological disorders including paroxysmal exercise-induced dyskinesia, migraine without or with aura, absence seizures and writer's cramp. CSF/serum glucose ratio was moderately decreased in both patients. Mutational analysis of SLC2A1 gene identified a de novo heterozygous missense mutation in exon 4. This novel mutation has been previously showed to disrupt glucose transport in vitro. Both patients showed immediate and near-complete response to ketogenic diet. This clinical observation suggests that a high index of suspicion for GLUT1 deficiency syndrome is warranted in evaluating patients with multiple neurological paroxysmal events.
The ketogenic diet has long been recognized as an effective treatment for medically refractory epilepsy. Despite nearly a century of use, the mechanisms underlying its clinical efficacy remain unknown. One of the proposed hypotheses for its anti-epileptic actions involves increased GABA concentration in the brain due to ketone bodies that become elevated with a ketogenic diet. In recent years, the notion that astrocytes could play a role in the evolution of abnormal cortical excitability in chronic neurological disorders, such as epilepsy, has received renewed attention. The present study examined the effects of beta-hydroxybutyrate, a ketone body, on GABA metabolism in rat primary cultured astrocytes. When beta-hydroxybutyrate was added to culture medium, GABA-transaminase (GABA-T) mRNA expression was significantly suppressed in time- and dose-dependent manners. GABA-T enzymatic activity in beta-hydroxybutyrate-treated astrocytes was also suppressed, in accordance with its gene expression. These effects were evident after 3 days of culture, which might coincide with depleted intracellular glycogen. GABA transporter, GAT-1, gene expression was strongly suppressed in cultured astrocytes after 5 days of culture with beta-hydroxybutyrate, although other type of GABA transporters did not display significant changes. These results suggest that beta-hydroxybutyrate induced by ketogenic diet may increase GABA concentration in the epileptic brain by suppressing astrocytic GABA degradation, leading to antiepileptic effects.
The effects of chronic ketosis on cerebral metabolism were determined in adult rats maintained on a high-fat diet for approximately three weeks and compared to a control group of animals. The fat-fed rats had statistically significantly lower blood glucose concentrations and higher blood beta-hydroxybutyrate and acetoacetate concentrations; higher brain concentrations of bound glucose, glucose 6-phosphate, pyruvate, lactate, beta-hydroxybutyrate, citrate, alpha-ketoglutarate, alanine, and adenosine triphosphate (ATP); lower brain concentrations of fructose 1,6-diphosphate, aspartate, adenosine diphosphate (ADP), creatine, cyclic nucleotides, succinyl coenzyme A (CoA), acid-insoluble CoA, and total CoA; and similar brain concentrations of glucose, malate, calculated oxaloacetate, glutamate, glutamine, adenosine monophosphate, phosphocreatine, reduced CoA, acetyl CoA, sodium, potassium, chloride, and water content. The metabolite data in the chronically ketotic rats demonstrate an increase in the cerebral energy reserve and energy charge. These data also suggest negative modification of the enzymes phosphofructokinase, pyruvic dehydrogenase, and alpha-ketoglutaric dehydrogenase; positive modification of glycogen synthase; and possible augmentation of the hexose transport system. There was no demonstrable difference in brain pH, water content, or electrolytes in the two groups of animals. We speculate that the increased brain ATP/ADP ratio is central to most, if not all, the observed metabolic perturbations and may account for the increased neuronal stability that accompanies chronic ketosis.
The ketogenic diet is a clinically and experimentally effective anti-epileptic treatment whose molecular mechanism(s) of action remain to be elucidated. As a first step in defining its effects on regulation of fatty acid oxidation and ketogenesis at the genetic level, we have administered to rats: (1) a calorie-restricted ketogenic diet (KCR); (2) a calorie-restricted normal diet (NCR); or (3) a normal diet ad libitum (NAL). We have used RNase protection to co-assay diet-induced changes in abundance of the mRNA encoding the critical enzyme of ketogenesis from acetyl-CoA namely mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) in liver and brain, together with mRNAs encoding three other key enzymes of fatty acid oxidation. We demonstrate that NCR-fed rats exhibit a significant 2-fold increase in liver mHS mRNA compared to NAL-fed rats, and that KCR-fed rats exhibit a significant 2-fold increase in both liver and brain mHS mRNA compared to NAL-fed rats. Our results demonstrate, for the first time, the effect of a ketogenic diet on gene expression in brain, and suggest possible anti-epileptic mechanisms for future investigation.
Migraine is a highly prevalent and disabling illness that remains substantially undiagnosed in primary care. Because of the potential value of a screening tool, the current study was designed to establish the validity and reliability of a brief, self-administered migraine screener in patients with headache complaints in the primary care setting.
A total of 563 patients presenting for routine primary care appointments and reporting headaches in the past 3 months completed a self-administered migraine screener. All patients were then referred for an independent diagnostic evaluation by a headache expert, of whom 451 (80%) completed a full evaluation. Migraine diagnosis was assigned based on International Headache Society criteria after completing a semi-structured diagnostic interview.
Of nine diagnostic screening questions, a three-item subset of disability, nausea, and sensitivity to light provided optimum performance, with a sensitivity of 0.81 (95% CI, 0.77 to 0.85), a specificity of 0.75 (95% CI, 0.64 to 0.84), and positive predictive value of 0.93 (95% CI, 89.9 to 95.8). Test-retest reliability was good, with a kappa of 0.68 (95% CI, 0.54 to 0.82). The sensitivity and specificity of the three-item migraine screener was similar regardless of sex, age, presence of other comorbid headaches, or previous diagnostic status.
The three-item ID Migraine migraine screener was found to be a valid and reliable screening instrument for migraine headaches. Its ease of use and operating characteristics suggest that it could significantly improve migraine recognition in primary care.
This review outlines the molecular sensors that reprogram cellular metabolism in response to the ketogenic diet (KD). Special emphasis is placed on the fasting-, fatty acid- and drug-activated transcription factor, peroxisome proliferator-activated receptor alpha (PPARalpha). The KD causes a switch to ketogenesis that is coordinated with an array of changes in cellular lipid, amino acid, carbohydrate and inflammatory pathways. The role of both liver and brain PPARalpha in mediating such changes will be examined, with special reference to the anti-epileptic effects not only of the KD but a range of synthetic anti-epileptic drugs such as valproate. Finally, the implications of the KD and activated brain PPARalpha will be discussed in the context of their potential involvement in a range of disorders of neuro-degeneration and neuro-inflammation.
The use of complementary and alternative medicine (CAM) in migraine is a growing phenomenon about which little is known. This study was undertaken to evaluate the rates, pattern and presence of predictors of CAM use in a clinical population of patients with different migraine subtypes. Four hundred and eighty-one migraineurs attending a headache clinic were asked to undergo a physician-administered structured interview designed to gather information on CAM use. Past use of CAM therapies was reported by 31.4% of the patients surveyed, with 17.1% having used CAM in the previous year. CAM therapies were perceived as beneficial by 39.5% of the patients who had used them. A significantly higher proportion of transformed migraine patients reported CAM treatments as ineffective compared with patients suffering from episodic migraine (73.1% vs. 50.7%, P < 0.001). The most common source of a recommendation of CAM was a friend or relative (52.7%). In most cases, migraineurs' recourse to CAM treatments was specifically for their headache (89.3%). Approximately 61% of CAM users had not informed their medical doctors of their CAM use. The most common reason for deciding to try a CAM therapy was that it offered a 'potential improvement of headache' (47.7%). The greatest users of CAM treatments were: patients with a diagnosis of transformed migraine; those who had consulted a high number of specialists and reported a higher lifetime number of conventional medical visits; those with a comorbid psychiatric disorder; those with a high income; and those whose headache had been either misdiagnosed or not diagnosed at all. Our findings suggest that headache clinic migraine patients, in their need of and quest for care, seek and explore both conventional and CAM approaches. Physicians should be made aware of this patient-driven change in the medical climate in order to prevent misuse of healthcare resources and to be better equipped to meet patients' needs.
To assess the influence of the body mass index (BMI) on the prevalence and severity of chronic daily headache (CDH) and its most frequent subtypes, transformed migraine (TM) and chronic tension-type headache (CTTH).
The authors gathered information on headache, medical features, height, and weight using a computer-assisted telephone interview. Participants were divided into five categories, based on BMI: underweight (<18.5), normal weight (18.5 to 24.9), overweight (25 to 29.9), obese (30 to 34.9), and morbidly obese (>35). The prevalence and severity of CDH, TM, and CTTH were assessed. Multivariate analyses modeling these diagnoses as a function of BMI were conducted.
Among 30,215 participants, the prevalence of CDH was 4.1%; 1.3% had TM and 2.8% CTTH. In contrast with the normal weight group (3.9%), the prevalence of CDH was higher in obese (5.0% [odds ratio (OR) = 1.3, 95% CI = 1.1-1.6]) and morbidly obese (6.8% [OR = 1.8, 95% CI = 1.4 to 2.2]). BMI had a strong influence on the prevalence of TM, which ranged from 0.9% of the normal weighted to 1.2% of the overweight (OR = 1.4 [1.1 to 1.8]), 1.6% of the obese (OR = 1.7 [1.2 to 2.43]), and 2.5% of the morbidly obese (OR = 2.2 [1.5 to 3.2]). The effects of the BMI on the prevalence of CTTH were just significant in the morbidly obese group. Adjusted analyses showed that obesity was associated with CDH and TM but not CTTH.
Chronic daily headache and obesity are associated. Obesity is a stronger risk factor for transformed migraine than for chronic tension-type headache.
Dietary protocols that increase serum levels of ketones, such as calorie restriction and the ketogenic diet, offer robust protection against a multitude of acute and chronic neurological diseases. The underlying mechanisms, however, remain unclear. Previous studies have suggested that the ketogenic diet may reduce free radical levels in the brain. Thus, one possibility is that ketones may mediate neuroprotection through antioxidant activity. In the present study, we examined the effects of the ketones beta-hydroxybutyrate and acetoacetate on acutely dissociated rat neocortical neurons subjected to glutamate excitotoxicity using cellular electrophysiological and single-cell fluorescence imaging techniques. Further, we explored the effects of ketones on acutely isolated mitochondria exposed to high levels of calcium. A combination of beta-hydroxybutyrate and acetoacetate (1 mM each) decreased neuronal death and prevented changes in neuronal membrane properties induced by 10 microM glutamate. Ketones also significantly decreased mitochondrial production of reactive oxygen species and the associated excitotoxic changes by increasing NADH oxidation in the mitochondrial respiratory chain, but did not affect levels of the endogenous antioxidant glutathione. In conclusion, we demonstrate that ketones reduce glutamate-induced free radical formation by increasing the NAD+/NADH ratio and enhancing mitochondrial respiration in neocortical neurons. This mechanism may, in part, contribute to the neuroprotective activity of ketones by restoring normal bioenergetic function in the face of oxidative stress.
The ketogenic diet is a valuable therapeutic approach for epilepsy, one in which most clinical experience has been with children. Although the mechanism by which the diet protects against seizures is unknown, there is evidence that it causes effects on intermediary metabolism that influence the dynamics of the major inhibitory and excitatory neurotransmitter systems in brain. The pattern of protection of the ketogenic diet in animal models of seizures is distinct from that of other anticonvulsants, suggesting that it has a unique mechanism of action. During consumption of the ketogenic diet, marked alterations in brain energy metabolism occur, with ketone bodies partly replacing glucose as fuel. Whether these metabolic changes contribute to acute seizure protection is unclear; however, the ketone body acetone has anticonvulsant activity and could play a role in the seizure protection afforded by the diet. In addition to acute seizure protection, the ketogenic diet provides protection against the development of spontaneous recurrent seizures in models of chronic epilepsy, and it has neuroprotective properties in diverse models of neurodegenerative disease.
Migraine and obesity are associated in several ways. First, both are prevalent and disabling disorders influenced by genetic and environmental risk factors. Second, migraine with aura, as obesity, seems to be a risk factor for cardiovascular events. Finally, large population-based studies suggest that obesity is a risk factor for chronic migraine after adjusting for comorbidities. In this article, we discuss plausible mechanisms that may account for this association. Several of the inflammatory mediators that are increased in obese individuals are important in migraine pathophysiology, including interleukins and calcitonin gene-related peptide (CGRP). These mediators may increase the frequency, severity, and duration of migraine attacks per se, which in turn would cause central sensitization. Repeated central sensitization may be associated with permanent neuronal damage close to the periaqueductal gray area, with poor modulation to pain. Obesity is also a state of sympathetic activation, which may contribute to increase in headache frequency. Furthermore, the levels of adiponectin are decreased in obesity. At low but not normal levels, adiponectin is nociceptive. Shared biologic predisposition may also play a major role. Orexins modulate both pain and metabolism. Dysfunction in the orexins pathways seems to be a risk factor for both conditions. Finally, conditions that are comorbid to both states (e.g., depression, sleep apnea) may also make the relationship between both diseases more complex.
The ketogenic diet (KD) is a high fat and low carbohydrate and protein diet. It is used in the clinical treatment of epilepsy, in order to decrease cerebral excitability. KD is usually composed by long-chain triglycerides (LCT) while medium-chain triglycerides (MCT) diet is beginning to be used in some clinical treatment of disorders of pyruvate carboxylase enzyme and long-chain fatty acid oxidation. Our study aimed to analyze the effects of medium- and long-chain KD on cerebral electrical activity, analyzing the propagation of the phenomenon of cortical spreading depression (CSD). Three groups of weaned rats (21 days old) received, for 7 weeks, either a control (AIN-93G diet), or a MCT-KD (rich in triheptanoin oil), or a LCT-KD (rich in soybean oil). They were compared to another three groups (21 days old) receiving the same diets for just 10 days. CSD propagation was evaluated just after ending the dietary treatments. Results showed that short-term KD treatment resulted in a significant reduction of the CSD velocity of propagation (control group: 4.02+/-1.04mm/min; MCT-KD: 0.81+/-1.46mm/min and LCT-KD: 2.26+/-0.41mm/min) compared to the control group. However, long-term treatment with both KDs had no effect on the CSD velocity (control group: 3.10+/-0.41mm/min, MCT-KD: 2.91+/-1.62mm/min, LCT-KD: 3.02+/-2.26mm/min) suggesting that both short-term KDs have a positive effect in decreasing brain cerebral excitability in young animals. These data show for the first time that triheptanoin has an effect on central nervous system.