Article

Migraine improvement during short lasting ketogenesis: A proof-of-concept study

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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.

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... 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]. ...
Article
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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. ...
Article
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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. ...
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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. ...
Article
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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.
... The study demonstrated a significant improvement in headache related features including the number and frequency of headache episodes, and lower doses of specific medication. A continuous improvement for two months after stopping the diet was observed [43]. Messier et al., in a study conducted on 399 adults with knee ostheoathritis observed that after 18 months of diet and exercise, only diet groups had greater improvement in pain. ...
... Of all pain categories defined most recently by the European Pain Federation [1], most trials referred to chronic musculoskeletal pain, i.e., low back pain (4 trials) [52,55,64,68], knee osteoarthritis in obese patients (3 trials) [44,46,74], fibromyalgia (7 trials) [45,47,56,59,61,62,78], neck pain and stiffness (1 trial) [79], musculoskeletal pain or peripheral neuropathy due to cancer treatment (3 trials) [64,69,70], chronic headache or migraine (6 trials) [43,48,49,51,66,67], generalized chronic musculoskeletal pain (2 trials) [54,72], diabetic neuropathy [50,71], taxol-induced neuropathic pain [63], or abdominal pain (10 trials) [53,57,58,60,65,71,73,[75][76][77]80]. A synthesis is provided in Table 2 (Table 2). ...
... Short-lasting ketogenesis considerably improved the quality of headache and the number of migraine attacks in a model of one-month very-low-calorie ketogenic diet followed by a five-month standard low-calorie diet. The improvement persisted even after six-months follow-up [43]. Ketogenic diet is thought to restore brain excitability and to counteract neuroinflammation in migraine, being used with comparable efficient results in refractory pediatric epilepsy [122]. ...
Article
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Pain is one of the main problems for modern society and medicine, being the most common symptom described by almost all patients. When pain becomes chronic, the life of the patients is dramatically affected, being associated with significant emotional distress and/or functional disability. A complex biopsychosocial evaluation is necessary to better understand chronic pain, where good results can be obtained through interconnected biological, psychological, and social factors. The aim of this study was to find the most relevant articles existent in the PubMed database, one of the most comprehensive databases for medical literature, comprising dietary patterns to alleviate chronic pain. Through a combined search using the keywords “chronic pain” and “diet” limited to the last 10 years we obtained 272 results containing the types of diets used for chronic pain published in the PubMed database. Besides classical and alternative methods of treatment described in literature, it was observed that different diets are also a valid solution, due to many components with antioxidant and anti-inflammatory qualities capable to influence chronic pain and to improve the quality of life. Thirty-eight clinical studies and randomized controlled trials are analyzed, in an attempt to characterize present-day dietary patterns and interventions to alleviate chronic pain.
... 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. ...
Article
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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. ...
Article
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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.
... Small (1-2 patients) case reports have noted migraine improvement in those on a ketogenic diet [74,75] and a proof-of-concept study demonstrated a significant reduction in attack frequency and number of days with headaches during the first month of ketogenesis [76]. A recent study observed alterations in cortical excitability as measured by visual and somatosensory-evoked potentials, in addition to reduced attack frequency and duration following one month of dieting [77]. ...
... However, the efficacy of this diet remains under scrutiny [78], and a pilot study of the modified Atkins diet (high-fat low-carbohydrates) for chronic daily headache in adolescents demonstrated no protective effect [79]. Moreover, although studies have demonstrated initial positive effects, clinical variables appear to worsen following the initial month of dieting, after which patients are out of the ketogenic phase [76]. There has been no strong evidence to outline the most conclusive diet for migraine prophylaxis and it is yet to be determined if it is the weight loss which is effective rather than the components of the diet. ...
Article
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Migraine is a highly prevalent and disabling primary headache disorder, however its pathophysiology remains unclear, hindering successful treatment. A number of key secondary headache disorders have headaches that mimic migraine. Evidence has suggested a role of mitochondrial dysfunction and an imbalance between energetic supply and demand that may contribute towards migraine susceptibility. Targeting these deficits with nutraceutical supplementation may provide an additional adjunctive therapy. Neuroimaging techniques have demonstrated a metabolic phenotype in migraine similar to mitochondrial cytopathies, featuring reduced free energy availability and increased metabolic rate. This is reciprocated in vivo when modelling a fundamental mechanism of migraine aura, cortical spreading depression. Trials assessing nutraceuticals successful in the treatment of mitochondrial cytopathies including magnesium, coenzyme q10 and riboflavin have also been conducted in migraine. Although promising results have emerged from nutraceutical trials in patients with levels of minerals or vitamins below a critical threshold, they are confounded by lacking control groups or cohorts that are not large enough to be representative. Energetic imbalance in migraine may be relevant in driving the tissue towards maximum metabolic capacity, leaving the brain lacking in free energy. Personalised medicine considering an individual's deficiencies may provide an approach to ameliorate migraine.
... A ketogenic diet is more beneficial to patients with migraine compared with a low-calorie diet. A low-calorie diet is not beneficial for migraineurs (n = 108) [173]. In another study, a ketogenic diet significantly improved headache features and decreased the frequency of attacks and the use of medications in these patients. ...
... Although the frequency of headache was reduced in patients who consumed a ketogenic diet, the frequency of headache during the transition period was worse. However, the frequency of headache improved significantly in the low-calorie diet group after the 3-and 6-month follow-up visits [173]. ...
Article
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Migraine is a neurological ailment that is characterized by severe throbbing unilateral headache and associated with nausea, photophobia, phonophobia and vomiting. A full and clear mechanism of the pathogenesis of migraine, though studied extensively, has not been established yet. The current available information indicates an intracranial network activation that culminates in the sensitization of the trigemino-vascular system, release of inflammatory markers, and initiation of meningeal-like inflammatory reaction that is sensed as headache. Genetic factors might play a significant role in deciding an individual's susceptibility to migraine. Twin studies have revealed that a single gene polymorphism can lead to migraine in individuals with a monogenic migraine disorder. In this review, we describe recent advancements in the genetics, pathophysiology, diagnosis, treatment, management, and prevention of migraine. We also discuss the potential roles of genetic and abnormal factors, including some of the metabolic triggering factors that result in migraine attacks. This review will help to accumulate current knowledge about migraine and understanding of its pathophysiology, and provides up-to-date prevention strategies.
... 79 To prevent or protect against migraines, elevated ketone bodies may reduce neuroinflammation, inhibit oxidative stress, and modulate mitochondrial function. 80 Ketotherapeutic benefits for migraines have been known for almost 100 years. 81 In recent studies, consumption of a very low carbohydrate (<30 g/day) and low-calorie KD was associated with significant reductions in the number of migraine attacks per month (76% drop) and the number of days with headaches (82% drop). ...
... 81 In recent studies, consumption of a very low carbohydrate (<30 g/day) and low-calorie KD was associated with significant reductions in the number of migraine attacks per month (76% drop) and the number of days with headaches (82% drop). 80,82 One subject had complete remission of migraine headaches. 83 Relief was observed within a few days of diet initiation. ...
Article
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Background The ketone bodies β‐hydroxybutyrate and acetone are generated as a by‐product of the fat metabolism process. In healthy individuals, ketone body levels are ∼0.1 mM for blood β‐hydroxybutyrate (BOHB) and ∼1 ppm for breath acetone (BrAce). These levels can increase dramatically as a consequence of a disease process or when used therapeutically for disease treatment. For example, increased ketone body concentration during weight loss is an indication of elevated fat metabolism. Ketone body measurement is relatively inexpensive and can provide metabolic insights to help guide disease management and optimize weight loss. Methods This review of the literature provides metabolic mechanisms and typical concentration ranges of ketone bodies, which can give new insights for these conditions and rationale for measuring ketone bodies. Results Diseases such as heart failure and ketoacidosis can affect caloric intake and macronutrient management which can elevate BOHB 30‐fold and BrAce 1,000‐fold. Other diseases associated with obesity such as brain dysfunction, cancer, and diabetes may cause dysfunction because of an inability to use glucose, an excessive reliance on glucose, or poor insulin signaling. Elevating ketone body concentrations (e.g., nutritional ketosis) may improve these conditions by forcing utilization of ketone bodies, in place of glucose, for fuel. During weight loss, monitoring ketone body concentration can demonstrate program compliance and can be used to optimize the weight loss plan. Conclusions The role of ketone bodies in states of pathologic and therapeutic ketosis indicates that accurate measurement and monitoring of BOHB or BrAce will likely improve disease management. Bariatric surgery is examined as a case study for monitoring both types of ketosis. This article is protected by copyright. All rights reserved.
... A proof of concept study in 2015 presented that weight loss could result in symptom improvement. 73 Based on a pilot study published in 2019, 11 enhancing the quality of diet and maintaining a healthy weight, could improve some clinical features of migraine. In this open, and nonrandomized study, women with migraine received an individualized diet plan, which was based on a professional nutritional diagnosis. ...
... 90 This diet acts in a similar way to fasting, where ketone bodies are elevated and can be used as an alternative source of energy to correct abnormalities in glucose metabolism reported in migraine. Some reports, including a proof of concept study, 73 have demonstrated beneficial effects of a ketogenic diet to reduce migraine frequency. Recently, an alternative method has been considered to apply exogenous ketogenic substances. ...
Article
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Parisa Gazerani1,2 1Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark; 2Pharmacy, Department of Life Sciences and Health, Faculty of Health Sciences, OsloMet, Oslo, NorwayCorrespondence: Parisa GazeraniDepartment of Health Science and Technology, Faculty of Medicine, Aalborg University, Fredrik Bajers Vej 5B, Aalborg East, 9220, DenmarkEmail gazerani@hst.aau.dkAbstract: Migraine is a common headache with a large negative impact on health. Several endogenous and exogenous factors can influence the severity and frequency of migraine, for example, lifestyle factors including dietary factors. Consequently, lifestyle modifications and dietary considerations have been reported beneficial to moderate clinical features of migraine. Much effort has been invested in determining the lifestyle factors (eg, stress, exercise, sleep, and diet) that trigger migraine to develop recommendations and guidelines for prevention. Diet has also been investigated with a major focus on the content of the diet and to a lesser extent on the amount, pattern, and quality of diet. Identification of dietary factors in migraine has led to nutritional interventions with a major focus on elimination of triggers, and weight control strategies. Several so-called migraine diets have consequently been proposed, for example, the ketogenic diet. Some theories have considered epigenetic diets or functional food to help in altering components of migraine pathogenesis; however, these theories are less investigated. In contrast, evidence is being accumulated to support that some mechanisms underlying migraine may alter dietary choices, for example type, amount, or patterns. Since a causative relationship is not yet established in migraine-diet relationship as to which comes first, this concept is equally valuable and interesting to investigate. Only limited epidemiological data are available to demonstrate that dietary choices are different among patients with migraine compared with individuals without migraine. Differences are reflected on quality, composition, pattern, and the amount of consumption of dietary components. This view emphasizes a potential bidirectional relationship between migraine and diet rather than a one-way influence of one on the other. This targeted review presents examples from current literature on the effects of diet on migraine features and effects of migraine on dietary choices to draw a perspective for future studies.Keywords: migraine, headache, diet, food, dietary pattern, lifestyle
... The diet period was associated with greater reductions in weight and migraine pain, as well as total cholesterol [29]. In another recent proof-ofconcept study, Di Lorenzo et al. [30] assessed migraine improvement during short-term ketogenesis. Two parallel groups of migraineurs were blinded to weight-loss intervention: one group was placed on a 1-month very-low-calorie ketogenic diet (KD) followed by a 5-month standard lowcalorie diet (SD), and the other group was placed on a 6month SD. ...
... No significant difference in BMI reduction was noted between diet groups. Rather than weight loss per se, the authors speculated that the underlying mechanisms resulting in enhanced KD effectiveness might be related to more efficient mitochondrial energy metabolism and a concomitant reduction in neuroinflammation [30]. These two factors have also been identified, in part, as weight-independent benefits of metabolic surgery [31,32]. ...
Article
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Obesity is a common outcome of traumatic brain injury (TBI) that exacerbates principal TBI symptom domains identified as common areas of post-TBI long-term dysfunction. Obesity is also associated with increased risk of later-life dementia and Alzheimer’s disease. Patients with obesity and chronic TBI may be more vulnerable to long-term mental abnormalities. This review explores the question of whether weight loss induced by bariatric surgery could delay or perhaps even reverse the progression of mental deterioration. Bariatric surgery, with its induction of weight loss, remission of type 2 diabetes, and other expressions of the metabolic syndrome, improves metabolic efficiency, leads to reversal of brain lesions seen on imaging studies, and improves function. These observations suggest that metabolic/bariatric surgery may be the most effective therapy for TBI.
... Although already described in a case study as early as 1928 [59], the possible beneficial effects of ketosis in migraine prevention remained unexplored until recent preliminary reports on 3 patients [60,61]. A few years later, Di Lorenzo et al. conducted the first trial evaluating ketogenic diet for attack prevention in overweight female migraineurs [62]. Attack frequency, days with headache, and analgesic consumption all significantly decreased while patients were on the ketogenic diet compared to a standard low-calorie diet [62]. ...
... A few years later, Di Lorenzo et al. conducted the first trial evaluating ketogenic diet for attack prevention in overweight female migraineurs [62]. Attack frequency, days with headache, and analgesic consumption all significantly decreased while patients were on the ketogenic diet compared to a standard low-calorie diet [62]. The same group analyzed cortical responsiveness using visual and somatosensory evoked potentials in patients during a ketogenic regime, and observed a normalization of the previously abnormal electrophysiological profile [63]. ...
Article
Introduction: Most preventive migraine treatments modify the brain’s excitation/inhibition balance and/or serotonin metabolism, which likely accounts for their unfavourable adverse effect profile. Novel biological therapies blocking CGRP transmission are effective and much better tolerated, but they are expensive and may not influence brain dysfunctions upstream in the pathophysiological cascade of migraine, including premonitory and aura symptoms. Biochemical and clinical studies suggest that there may be another complimentary treatment strategy, the one that targets the underestimated metabolic facet of migraine pathophysiology. Areas covered: After a brief description of the metabolic abnormalities found in migraine patients, we will review and discuss published data on metabolic treatments of migraine. There is evidence that high dose riboflavin and co-enzyme Q10 are effective for the prevention of migraine and quasi devoid of adverse effects. Response rates are close to those of topiramate, propranolol, and CGRP/CGRPrec mAbs. The evidence is weaker for thioctic acid. Dietary and pharmacological strategies inducing ketosis are novel promising approaches for which preliminary trials with favourable outcomes have been published. Expert opinion: Metabolic treatments of migraine constitute an effective, well-tolerated, inexpensive, and evidence-supported therapeutic option for migraine prophylaxis, and may be considered as first treatment line in many patients, including in children and adolescents.
... 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. ...
Article
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]. ...
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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]. ...
Article
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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). ...
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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]. ...
Article
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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). ...
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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.
... Importantly, 'physiological' levels of BHB (regulated ≤7 mM), the major circulating ketone, are safe and likely played a role in the survival of early man [7]; humans can produce~150 g of ketone bodies each day during a prolonged fast [8]. Endogenous ketosis has historically been used to treat intractable seizures [3], and is under investigation for use in other clinical conditions such as type 2 diabetes [9,10], migraine [11][12][13], and glioblastoma [14,15]. Evidence suggests ketone bodies could be directly responsible for some of the beneficial molecular changes associated with dietary modifications (i.e., caloric restriction and time-restricted feeding) that can increase health span and lifespan across a variety of species [16]. ...
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Nutritional ketosis is a state of mildly elevated blood ketone concentrations resulting from dietary changes (e.g., fasting or reduced carbohydrate intake) or exogenous ketone consumption. In this study, we determined the tolerability and safety of a novel exogenous ketone diester, bis-hexanoyl-(R)-1,3-butanediol (BH-BD), in a 28-day, randomized, double-blind, placebo-controlled, parallel trial (NCT04707989). Healthy adults (n = 59, mean (SD), age: 42.8 (13.4) y, body mass index: 27.8 (3.9) kg/m2) were randomized to consume a beverage containing 12.5 g (Days 0–7) and 25 g (Days 7–28) of BH-BD or a taste-matched placebo daily with breakfast. Tolerability, stimulation, and sedation were assessed daily by standardized questionnaires, and blood and urine samples were collected at Days 0, 7, 14, and 28 for safety assessment. There were no differences in at-home composite systemic and gastrointestinal tolerability scores between BH-BD and placebo at any time in the study, or in acute tolerability measured 1-h post-consumption in-clinic. Weekly at-home composite tolerability scores did not change when BH-BD servings were doubled. At-home scores for stimulation and sedation did not differ between groups. BH-BD significantly increased blood ketone concentrations 1-h post-consumption. No clinically meaningful changes in safety measures including vital signs and clinical laboratory measurements were detected within or between groups. These results support the overall tolerability and safety of consumption of up to 25 g/day BH-BD.
... Comorbidity between migraine and obesity as well as the role of several dietary factors in headache attacks prompted the investigations of different dietary regimens for migraine prevention (Gazerani, 2020;Hindiyeh et al., 2020). Finally, the ketogenic diet, a diet that leads to the elevation of ketone bodies, has shown great promise in the prevention of migraines (Di Lorenzo et al., 2015. ...
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Despite that it is commonly accepted that migraine is a disorder of the nervous system with a prominent genetic basis, it is comorbid with a plethora of medical conditions. Several studies have found bidirectional comorbidity between migraine and different disorders including neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metaboloendocrine, and immunological conditions. Each of these has its own genetic load and shares some common characteristics with migraine. The bidirectional mechanisms that are likely to underlie this extensive comorbidity between migraine and other diseases are manifold. Comorbid pathologies can induce and promote thalamocortical network dysexcitability, multi-organ transient or persistent pro-inflammatory state, and disproportionate energetic needs in a variable combination, which in turn may be causative mechanisms of the activation of an ample defensive system with includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This strategy is designed to maintain brain homeostasis by regulating homeostatic needs, such as normal subcortico-cortical excitability, energy balance, osmoregulation, and emotional response. In this light, the treatment of migraine should always involves a multidisciplinary approach, aimed at identifying and, if necessary, eliminating possible risk and comorbidity factors.
... 28,90 Similarly, it is premature to ascribe food diets with beneficial effects on migraine because studies have found that patients benefited from both the intervention diet and control diets. 91,92 Additionally, some evidence suggests that weight loss might reduce the frequency of headache days in individuals with migraine. 93,94 Thus, highquality research is needed to confirm the effect of dietary approaches in the clinical management of migraine. ...
Article
Migraine is a highly disabling neurological disorder that directly affects more than 1 billion individuals worldwide. Available treatment options differ between countries and include acute, preventive, and non-pharmacological therapies. Because of major progress in the understanding of migraine pathogenesis, novel mechanism-based medications have emerged and expanded the armamentarium of treatments. We provide a comprehensive overview of the current standard of care that will enable informed clinical management. First, we discuss the efficacy, tolerability, and safety profile of various pharmacological therapies for acute and preventive treatment of migraine. Second, we review the current knowledge on non-pharmacological therapies, such as neuromodulation and biobehavioural approaches, which can be used for a multidisciplinary approach to clinical management. Third, we emphasise that any effective treatment strategy starts with building a therapeutic plan tailored to individual clinical characteristics, preferences, and needs. Finally, we explore the outlook of emerging mechanism-based treatments that could address unmet challenges in clinical management of migraine.
... Finally, other dietary regimens aim at reducing the intake of nutritional compounds (lipids, carbs, and sodium) with hypothetical multiple effects on metabolism. Among these, the ketogenic diet, based on strict carb restriction, has shown promising results in migraine prevention [6], attracting great interest among migraineurs [7]. At the same time, non-scientifically tested diets are diffusely proposed on the web. ...
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We aimed at evaluating the effect of the Healthy Eating Plate (HEP) education on migraine frequency and disability. At three evaluation times (T-12 = screening, 12 weeks before the intervention; T0 = time of the educational HEP intervention; and T12 = 12-week follow-up), the enrolled subjects underwent assessment of anthropometric and dietary patterns, monthly migraine days (MMDs), and disability scales (Migraine Disability Assessment score (MIDAS), MIDAS A, MIDAS B). The HEP score estimated adherence to dietary advice. We enrolled 204 out of 240 screened migraineurs, of these, 97 patients completed the follow-up. We defined ADHERENTS as patients presenting an increase in HEP scores from T0 to T12 and RESPONDERS as those with a reduction of at least 30% in MMDs. ADHERENTS presented a significant decrease in MMDs from T0 to T12. In particular, RESPONDERS reduced red, processed meat and carb intake compared to NON-RESPONDERS. Reduction in carb consumption also related to a decrease in perceived disability (MIDAS) and headache pain intensity (MIDAS B). Logistic regression confirmed that the HEP score increase and total carb decrease were related to a reduction in MMDs. This study showed that adherence to the HEP advice, particularly the reduction in carb, red and processed meat consumption, is useful in migraine management, reducing migraine frequency and disability. Trial registration: ISRCTN14092914.
... Among 98 articles screened after exclusion of duplicates and irrelevant titles (articles unfit with the outcomes of the metaanalysis, reviews, qualitative studies or studies that did not report the appropriate outcomes), 8 articles remained eligible for inclusion in the meta-analysis (Fig. 1). Two articles [10,11] reported studies on different populations that were treated separately and then a total of 10 primary studies were extracted and finally included in the meta-analysis. The agreement between the reviewers was 98% for the first screen and 97% for the full-text search. ...
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Background The aim of this study was to perform a meta-analysis on the effect of weight loss obtained by bariatric surgery or behavioral intervention on migraine frequency and indices of severity.Materials and MethodsA search through Pubmed/Medline, ISI-web of knowledge, and Google Scholar retrieved 10 studies (n = 473). Selected outcomes were Headache Frequency, Pain Severity, Disability, and Attack Duration while BMI, BMI change, type of intervention (bariatric vs. behavioral), and type of population (adult vs. pediatric) were used for moderators and meta-regression analysis.ResultsRandom effect meta-analysis shows that weight loss yields significant reductions in Headache Frequency (ES − 0.78, p < 0.0001), Pain Severity (ES − 1.04, p < 0.0001), Disability (ES −0.68, p < 0.0001), and Attack Duration (ES − 0.25, p = 0.017). Improvement in migraine was not correlated either to the degree of obesity at baseline or the degree of weight reduction. The effect on migraine was similar when weight reduction was obtained with bariatric surgery or behavioral intervention and was comparable in adult and pediatric populations.Conclusions Weight loss improves characteristics of migraine headache in patients who have obesity independently of the type of intervention and the amount of weight loss. The mechanisms underlying the link between obesity, weight loss, and migraine headache may include chronic inflammation, obesity comorbidities, and overlapping behavioral and psychological risk factors.
Chapter
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.
Chapter
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.
Article
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.
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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.
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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.
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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
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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].
Chapter
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.
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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.
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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.
Article
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
Chapter
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.
Chapter
Obesity, weight management, and nutrition are more often discussed in the setting of cardiovascular health; however, their relevance extends into various other bodily systems, including the nervous system. Primary headache disorders are inherent brain conditions not attributable to other bodily causes. The pathophysiology behind head pain is quite complex due to the underlying multifactorial mechanisms. However, there are factors, both intrinsic and extrinsic, which can contribute to the worsening of an already predisposed brain to further headache attacks. Controlling these factors can lead to better headache management and improved quality of life. This chapter will begin with an overview of obesity and the evidence supporting its connection to chronic daily headache (CDH). The impact of weight loss on headache will be reviewed through its association with body mass index. Next, a generalized overview of nutrition as a trigger to certain headache disorders will be discussed. Attention will be directed toward particular ingredients and diets speculated to play a part in headache control. Lastly, a review of the principal components of a diary and suggestions on how to perform an elimination diet for proper nutritional trigger identification will be presented.
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Ketogenic dietary therapies (KDTs) have been in use for refractory paediatric epilepsy for a century now. Over time, KDTs themselves have undergone various modifications to improve tolerability and clinical feasibility, including the Modified Atkins diet (MAD), medium chain triglyceride (MCT) diet and the low glycaemic index treatment (LGIT). Animal and observational studies indicate numerous benefits of KDTs in paediatric neurological conditions apart from their evident benefits in childhood intractable epilepsy, including neurodevelopmental disorders such as autism spectrum disorder, rarer neurogenetic conditions such as Rett syndrome, Fragile X syndrome and Kabuki syndrome, neurodegenerative conditions such as Pelizaeus-Merzbacher disease, and other conditions such as stroke and migraine. A large proportion of the evidence is derived from individual case reports, case series and some small clinical trials, emphasising the vast scope for research in this avenue. The term 'neuroketotherapeutics' has been coined recently to encompass the rapid strides in this field. In the 100th year of its use for paediatric epilepsy, this review covers the role of the KDTs in non-epilepsy neurological conditions among children.
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Background: Migraine is a chronic medical problem and sometimes progressive disorder characterized by recurrent episodes of headache. Nutritional factors can reduce and prevent the severity and frequency of migraine. Objectives: This study aimed to assess the relationship between major dietary patterns and disease severity among migraine patients. Methods: This cross-sectional study included 266 females (18 - 50 years old) who attend neurology clinics of Sina and Khatam Alanbia hospitals, and a professional headache clinic, both in Tehran, Iran, for episodic migraine diagnosis in 2016. The participants’ data was gathered using a general questionnaire and medical history. Dietary intake was assessed using a 147-item semi-quantitative food frequency questionnaire (FFQ). Anthropometric measurements were taken for all cases. visual analog scale (VAS) and migraine disability assessment (MIDAS) questionnaires were used by a neurologist for assessing migraine disability and pain severity, respectively. Also, principal component analysis (PCA) was used to identify major dietary patterns. The association between dietary patterns and disease severity was evaluated using multinomial logistic regression. Results: Using the PCA, two major dietary patterns, including the healthy and unhealthy diet, were identified. More adherence to the healthy dietary pattern (high in fruits, fruit juices, and dried fruits, vegetables, whole grains, liquid oil, brains, beans, low-fat dairy, and white meat) was associated with a lower VAS score after adjusting for energy intake, BMI, water intake, and increased salt intake (OR = 1.82, 95% CI = 0.96 - 3.44, P-trend < 0.005). The intensity of migraine headache increased by 82% in the lowest adherence to this pattern compared to the most adherence. There was no significant association between healthy and unhealthy dietary patterns with MIDAS before and after controlling for confounding variables. Conclusions: This study showed that adherence to a healthy dietary pattern reduces the severity of pain in migraine patients. However, further studies are needed to evaluate the relationship between the unhealthy dietary pattern and the severity of migraine symptoms.
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Increasing evidence points towards the role of mitochondrial functioning, energy metabolism, and oxidative stress in migraine. However not all previous research has been conclusive and some mitochondrial function/oxidative stress markers have not yet been examined. To this end, alpha-lipoic acid (ALA), total thiols, total plasma antioxidant capacity (TAC), lipid peroxide (PerOx), oxidised LDL (oxLDL), HbA1c and lactate were determined in the serum of 32 higher frequency episodic migraineurs (5–14 migraine days/ months, 19 with aura, 28 females) in this cross-sectional study. The majority of patients had abnormally low ALA and lactate levels (87.5% and 78.1%, respectively). 46.9% of the patients had abnormally high PerOx values, while for thiols and TAC over one third of patients had abnormally low values (31.2% and 37.5%, respectively). 21.9% of patients had abnormally low HbA1c and none had an HbA1c level above 5.6%. oxLDL was normal in all but one patient. This study provides further evidence for a role of oxidative stress and altered metabolism in migraine pathophysiology, which might represent a suitable therapeutic target. ALA, being too low in almost 90% of patients, might represent a potential biomarker for migraine. Further research is needed to replicate these results, in particular a comparison with a control group. This study is part of the trial registration: ClinicalTrials.gov: NCT03132233, registered on 27.04.2017, https://clinicaltrials.gov/ct2/show/NCT03132233 .
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Headache is the world's seventh most significant cause of disability-adjusted-life in people aged between 10 and 14 years. Therapeutic management is based on pharmacological approaches and lifestyle recommendations. Many studies show associations between each migraine-promoting lifestyle, behavioral triggers, frequency, and intensity of headaches. Nevertheless, the overall aspects of this topic lack any definitive evidence. Educational programs advise that pediatric patients who suffer from migraines follow a correct lifestyle and that this is of the utmost importance in childhood, as it will improve quality of life and assist adult patients in avoiding headache chronicity, increasing general well-being. These data are important due to the scarcity of scientific evidence on drug therapy for prophylaxis during the developmental age. The “lifestyle recommendations” described in the literature include a perfect balance between regular sleep and meal, adequate hydration, limited consumption of caffeine, tobacco, and alcohol, regular physical activity to avoid being overweight as well as any other elements causing stress. The ketogenic diet is a possible new therapeutic strategy for the control of headache in adults, however, the possible role of dietary factors requires more specific studies among children and adolescents. Educational programs advise that the improvement of lifestyle as a central element in the management of pediatric headache will be of particular importance in the future to improve the quality of life of these patients and reduce the severity of cephalalgic episodes and increase their well-being in adulthood. The present review highlights how changes in different aspects of daily life may determine significant improvements in the management of headaches in people of developmental age.
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Background and purposeKetogenic diet (KD) is based on restriction of carbohydrate intake. Metabolism is forced to obtain energy starting from β-oxidation of fatty acids which, turned into ketone bodies, can also be used by central nervous system (CNS). KD use in treatment of chronic migraine has recently been considered. We set out to verify modification of symptoms in patients with refractory chronic migraine in response to KD.Methods Fifty patients were enrolled of which 38 completed the procedures the study and 23 were considered in the statistics. All of the patients considered in our study were affected by medication overuse headache (MOH). They were on a KD for 3 months. The following parameters have been checked at t = 0 and every 30 days for 6 months: migraine episode length (n. hours/day), frequency (n. days/month), level of pain of every episode measured on a scale from 1 to 3 (1 = mild; 2 = moderate; 3 = severe), and n. analgesic drugs taken/month.ResultsDays with symptoms decreased from 30 (median value) to 7.5 with p < 0.0001. The duration of the migraine episodes decreased from 24 h (median value) to 5.5 h with p < 0.0016. The patients’ pain level, initially at maximum value for 83% of the participants, improved for 55% of them (p < 0.0024). The number of drugs taken in a month decreased from 30 doses (median value) to 6 doses.Conclusions It can be stated that a 3-month KD resulted in a reduction of painful symptoms of drug refractory chronic migraine. This result may suggest an improvement in quality of life of the patients, even without a tabulated data collection.
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Chronic painful conditions are associated with neuronal inflammation. Metabolic therapy with a ketogenic/low-carbohydrate (sugar) diet can reduce seizure activity and systemic inflammation representing a useful adjunct approach to improve the outcome of peripheral nerve surgery. Motivated patients may achieve benefits by lowering carbohydrate intake and focusing on low glycemic index and anti-inflammatory food. This is a healthy lifestyle choice particularly beneficial during the few weeks before and after surgery.
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Background This pilot trial aimed to investigate whether modified short-term fasting (mSTF) reduces the incidence of chemotherapy-induced toxicities and whether an initial ketogenic diet (KD) as fasting supportive diet reduces fasting-related discomfort and improves the compliance. Methods In this controlled cross-over trial, gynaecologic cancer patients undergoing chemotherapy with a minimum of 4 cycles fasted for 96 h during half of their chemotherapy cycles and consumed a normocaloric diet during the other chemotherapy cycles. The caloric intake during mSTF was restricted to 25% of each patient’s daily requirement. In addition, half of the patients should eat a 6-day normocaloric KD prior to each mSTF period to investigate a KD’s hunger-suppression effect. Chemotherapy-induced toxicities, fasting-related discomfort, body composition, quality of life, laboratory values, and compliance were assessed at each chemotherapy. Results Thirty patients aged 30–74 years (median 54 years) completed the study. During mSTF the frequency and severity score of stomatitis [− 0.16 ± 0.06; 95% CI -0.28 - (− 0.03); P = 0.013], headaches [− 1.80 ± 0.55; 95% CI -2.89 – (− 0.71); P = 0.002], weakness [− 1.99 ± 0.87; 95% CI -3.72 – (− 0.26); P = 0.024] and the total toxicities’ score were significantly reduced [− 10.36 ± 4.44; 95% CI -19.22 - (− 1.50); P = 0.023]. We also observed significantly fewer chemotherapy postponements post-mSTF, reflecting improved tolerance of chemotherapy [− 0.80 ± 0.37; 95% CI -1.53 – (− 0.06); P = 0.034]. A significant reduction in mean body weight by − 0.79 ± 1.47 kg during mSTF was not compensated and remained until study’s conclusion (P < 0.005). On average, Insulin [− 169.4 ± 44.1; 95% CI -257.1 – (− 81.8); P < 0.001] and Insulin-like growth factor 1 levels [− 33.3 ± 5.4; 95% CI -44.1 – (− 22.5); P < 0.001] dropped significantly during fasting. The KD as a fasting supportive diet neither reduced fasting-related discomfort nor improved compliance of our fasting regimen. Conclusion MSTF is safe and feasible in gynaecologic cancer patients. Our results indicate that mSTF during chemotherapy can reduce chemotherapy-induced toxicities and enhance the tolerance of chemotherapy. Larger clinical trials are required to recommend mSTF for cancer patients. Trial registration germanctr.de: DRKS00011610, registered 30 January, 2017.
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Medical nutrition therapy is a therapeutic approach to treat medical conditions and their associated symptoms via using a specifically tailored diet devised under the supervision of a doctor and a registered dietitian or nutrition professional. Ketogenic diet primarily consists of the high amount of fats, a moderate amount of proteins, and very low carbohydrates. It is known to stimulate the metabolic effects of starvation by forcing the body to use primarily fat as a fuel source. Ketogenic diet was developed in the 1920s. Nowadays, it is gaining considerable attention as a potential weight-loss strategy because of the low-carb diet. However, it is being considered for use in several diseases/disorders also because of the beneficial effects on the metabolic health and nervous system. This review revisits the therapeutic potential of ketogenic diets in many pathological conditions and its role as a medical nutrition therapy. It also talks about the ill effects that the keto diet can have in case of self-usage and monitoring.
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Background: In recent years, the role of neuroinflammation and oxidative stress in migraine pathogenesis has achieved considerable interest; however, to date findings are equivocal. Thus, the objective of this study was to investigate biomarkers of oxidative stress in episodic and chronic migraineurs (EM and CM patients) and controls. Methods: Forty-four patients with EM, 27 individuals with CM and 19 age-sex-matched controls were enrolled. After collecting data on demographic and headache characteristics, blood samples were collected and analyzed to detect serum levels of oxidative stress biomarkers (malondialdehyde (MDA) and nitric oxide (NO)); total antioxidant capacity using Trolox equivalent antioxidant capacity (TEAC) assay; and antioxidant enzymes (catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase-1 (GPx-1)). Results: Serum levels of CAT and SOD were significantly lower in the CM group than the EM group and controls. However, serum GPx-1 levels of the CM patients were slightly higher than the EM patients and controls (P-value≤0.001). CM patients had lower mean TEAC values than EM patients and controls. In addition, serum levels of NO and MDA were significantly elevated among subjects with CM compared to EM and control individuals (P-value≤0.001). Pearson correlation analysis revealed negative correlations between the number of days of having headaches per month and serum concentrations of the two antioxidant enzymes CAT (r = - 0.60, P-value< 0.001) and SOD (r = - 0.50, P-value< 0.001) as well as TEAC values (r = - 0.61, P-value< 0.001); however, there were positive correlations between headache days and serum GPx-1 levels (r = 0.46, P-value< 0.001), NO (r = 0.62, P-value< 0.001), and MDA (r = 0.64, P-value< 0.001). Conclusion: Present findings highlighted that chronic migraineurs had lower total non-enzymatic antioxidant capacity and higher oxidative stress than episodic migraineurs and control individuals. Although more studies are needed to confirm these data, applying novel prophylactic medications or dietary supplements with antioxidant properties could be promising in migraine therapy.
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The global prevalence of migraine as a primary headache has been estimated as 14.4% in both sexes. Migraine headache has been ranked as the highest contributor to disability in under 50 years old population in the world. Extensive research has been conducted in order to clarify the pathological mechanisms of migraine. Although uncertainties remains, it has been indicated that vascular dysfunction, cortical spreading depression (CSD), activation of the trigeminovascular pathway, pro-inflammatory and oxidative state may play a putative role in migraine pain generation. Knowledge about pathophysiological mechanisms of migraine should be integrated into a multimodal treatment approach to increase quality of life in patients. With respect to this, within the integrative health studies growing interest pertains to dietary interventions. Although the number of studies concerning effects of diet on headache/migraine is not yet very large, the current article will review the available evidence in this area. All publications on headache/migraine and dietary interventions up to May 2019 were included in the present review through a PubMed/MEDLINE and ScienceDirect database search. According to the current findings, Ketogenic diet and modified Atkins diet are thought to play a role in neuroprotection, improving mitochondrial function and energy metabolism, compensating serotoninergic dysfunction, decreasing calcitonin gene-related peptide (CGRP) level and suppressing neuro-inflammation. It can also be speculated that prescription of low glycemic diet may be promising in headache/migraine control through attenuating the inflammatory state. Moreover, obesity and headaches including migraine could be attributed to each other through mechanisms like inflammation, and irregular hypothalamic function. Thereby, applying dietary strategies for weight loss may also ameliorate headache/migraine. Another important dietary intervention that might be effective in headache/migraine improvement is related to balance between the intake of essential fatty acids, omega-6 and omega-3 which also affect inflammatory responses, platelet function and regulation of vascular tone. Regarding elimination diets, it appears that targeted these diets in migraine patients with food sensitivities could be effective in headache/migraine prevention. Taken together, dietary approaches that could be considered as effective strategies in headache/migraine prophylaxis include weight loss diets in obese headache patients, ketogenic and low-calorie diets, reducing omega-6 and increasing omega-3 fatty acid intakes.
Article
Background and purpose: Ketogenic diets are being explored as a possible treatment for several neurological diseases, but the physiologic impact on the brain is unknown. The objective of this study was to evaluate the feasibility of 3T MR spectroscopy to monitor brain ketone levels in patients with high-grade gliomas who were on a ketogenic diet (a modified Atkins diet) for 8 weeks. Materials and methods: Paired pre- and post-ketogenic diet MR spectroscopy data from both the lesion and contralateral hemisphere were analyzed using LCModel software in 10 patients. Results: At baseline, the ketone bodies acetone and β-hydroxybutyrate were nearly undetectable, but by week 8, they increased in the lesion for both acetone (0.06 ± 0.03 ≥ 0.27 ± 0.06 IU, P = .005) and β-hydroxybutyrate (0.07 ± 0.07 ≥ 0.79 ± 0.32 IU, P = .046). In the contralateral brain, acetone was also significantly increased (0.041 ± 0.01 ≥ 0.16 ± 0.04 IU, P = .004), but not β-hydroxybutyrate. Acetone was detected in 9/10 patients at week 8, and β-hydroxybutyrate, in 5/10. Acetone concentrations in the contralateral brain correlated strongly with higher urine ketones (r = 0.87, P = .001) and lower fasting glucose (r = -0.67, P = .03). Acetoacetate was largely undetectable. Small-but-statistically significant decreases in NAA were also observed in the contralateral hemisphere at 8 weeks. Conclusions: This study suggests that 3T MR spectroscopy is feasible for detecting small cerebral metabolic changes associated with a ketogenic diet, provided that appropriate methodology is used.
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Background: The gastrointestinal symptoms of migraine attacks have invited numerous dietary hypotheses for migraine etiology through the centuries. Substantial efforts have been dedicated to identifying dietary interventions for migraine attack prevention, with limited success. Meanwhile, mounting evidence suggests that the reverse relationship may also exist - that the biological mechanisms of migraine may influence dietary intake. More likely, the truth involves some combination of both, where the disease influences food intake, and the foods eaten impact the manifestations of the disease. In addition, the gut's microbiota is increasingly suspected to influence the migraine brain via the gut-brain axis, though these hypotheses remain largely unsubstantiated. Objective: This paper presents an overview of the strength of existing evidence for food-based dietary interventions for migraine, noting that there is frequently evidence to suggest that a dietary risk factor for migraine exists but no evidence for how to best intervene; in fact, our intuitive assumptions on interventions are being challenged with new evidence. We then look to the future for promising avenues of research, notably the gut microbiome. Conclusion: The evidence supports a call to action for high-quality dietary and microbiome research in migraine, both to substantiate hypothesized relationships and build the evidence base regarding nutrition's potential impact on migraine attack prevention and treatment.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.