The Metabolic Face of Migraine. Abnormalities in Energy Metabolism, Mitochondrial Functioning, Oxidative Stress and the Therapeutic Potential of Ketone Bodies in Migraine

Migraine – a common, complex, and debilitating headache disorder - can be regarded as a conserved (mal)adaptive response pattern that occurs in genetically predisposed individuals with a mismatch between the brain’s energy reserve and workload. Given the high prevalence of migraine it seems unlikely that migraine genotypes have not conferred some evolutionary advantage. Technological advances, such as those in neuroimaging and genetics, have enabled the examination of different aspects of (cerebral-) metabolism in migraine patients, while recent complementary animal research has highlighted possible mechanisms in migraine pathophysiology. An increasing amount of evidence – much of it clinical - points towards migraine being a response to cerebral energy deficiency, or oxidative stress levels that exceeding antioxidant capacity. The attack itself might then help to restore brain energy homeostasis and reduce potentially harmful oxidative stress levels.
The current PhD thesis is divided into two major topics: 1.) Metabolic abnormalities in migraine 2.) The potential migraine-protective mechanisms and the efficacy and safety of a potentially novel migraine prophylaxis: ketone bodies (KBs). These two topics are divided into 5 major sections, as presented in chapters 2 and 4.
In the first major section of the thesis, the Nature Neurology review discusses the evidence for abnormalities in energy metabolism and mitochondrial functioning in migraine with a particular focus on clinical data, including neuroimaging, biochemical, genetic, and therapeutic studies, and their relation with the abnormal sensory processing and cerebral hyperresponsivity found in migraine patients between attacks. Experimental data is examined to elaborate on potential mechanisms of such metabolic abnormalities with regards to migraine attack generation. Finally, potential treatments targeting cerebral metabolism, such as nutraceuticals, ketone bodies, and dietary interventions are highlighted.
Despite increasing evidence pointing towards the role of mitochondrial functioning, energy metabolism and oxidative stress in migraine pathophysiology, not all previous research has been conclusive and some mitochondrial function / oxidative stress markers have not yet been examined in migraine. To address this insufficiency, 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), as described in the second major section of the thesis. It was determined that the majority of patients had abnormally low ALA and lactate levels (87.5% and 72%, respectively). About half (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 no one’s HbA1c was above 5.6%. The oxLDL levels were normal in all but one patient. This original research study provides further evidence for the 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 required to replicate these results, in particular a comparison with a control group.
The increased understanding of migraine metabolism offers exciting novel and likely well-tolerated therapeutic opportunities. The ketogenic diet (KD), a diet that mimics fasting and leads to the elevation of KBs, is a therapeutic intervention targeting cerebral metabolism that has recently shown great promise in the prevention of migraine. KBs are an alternative fuel source for the brain and are hence likely able to circumvent some of the abnormalities in glucose metabolism and transport found in migraine. In addition, recent research has shown that KBs – D-β-hydroxybutyrate (D-BHB) in particular – are more than metabolites: As signalling molecules, they have the potential to positively influence other pathways commonly believed to be part of migraine pathophysiology, including mitochondrial functioning, oxidative stress, cerebral excitability, inflammation, and the gut microbiome. In the third major section of the thesis, the Nutrients review describes the mechanisms by which the presence of KBs, D-BHB in particular, could influence such migraine pathophysiological mechanisms. Common abnormalities in migraine are summarised with a particular focus on clinical data, including phenotypic, biochemical, genetic, and therapeutic studies. Experimental animal studies will be discussed to elaborate on the potential therapeutic mechanisms of elevated KBs in migraine pathophysiology with a particular focus on the actions of D-BHB. In complex diseases such as migraine a therapy that can target multiple possible pathogenic pathways seems advantageous. Further research is needed to determine whether the absence / restriction of dietary carbohydrates, the presence of KBs or both are of primary importance for the migraine protective effects of the KD.
A proof-of-concept-open-label pilot study on ten treatment refractory patients (age range: 25-61 years, 1 male, attack frequency range: 6-24 migraine days/months) was conducted to 1) assess the pharmacokinetics of a one-time dose of various ketogenic substances (L-Lysine, L-Leucine, racemic and D- beta-hydroxybutyrate (βHB) mineral salts) and 2) examine the effect of a one month supplementation with daily 20g racemic βHB, 40g racemic βHB, 10g racemic or 10g D- βHB on migraine days compared to a one month baseline period. As described in the fourth major section of the thesis, it was observed that 10g racemic βHB (n=5) lead to a quick elevation in blood βHB levels (peak 0.62mmol/l after 1 hour, SEM=0.08). The one month of intervention with 20g of racemic βHB per day led to an average reduction of 51% in migraine days compared to baseline could be observed (mean baseline = 16.25 days, SEM= 3.71; mean after βHB= 8 days, SEM= 2.92). This perceived benefit from βHB seemed to coincide with a drop in average peak βHB blood levels from 0.62 mmol/l to 0.3 mmol/l after 1-2 weeks of ingestion. While this heterogeneous patient data from a small sample may not lead to conclusive deductions, they warrant the conduction of a controlled clinical trial to assess the potential efficacy and safety of exogenous ketogenic substances in migraine prevention.
To address the above shortcoming, a randomised, placebo-controlled, double-blind, crossover, single-centre trial was planned and undertaken at the University Hospital of Basel, Switzerland. As discussed in the fifth major section of the thesis, 45 episodic migraineurs (5-14 migraine days/months), with or without aura, aged between 18 and 65 years, were recruited at various headache clinics in Switzerland, Germany, and Austria and via internet announces. After a 4-week baseline period, patients were randomly allocated to one of the two trial arms and received either the βHB mineral salt or placebo for 12 weeks. This was followed by a 4-week washout period, a subsequent second baseline period and finally another 12-week intervention with the alternative treatment. Co-medication with triptans (10 days per months) or analgesics (14 days per months) was permitted. The primary outcome was the mean change from baseline in number of migraine days (meeting ICHD-3 criteria) during the last 4 weeks of intervention compared to placebo. Secondary endpoints included mean changes in headache days of any severity, acute migraine medication use, migraine intensity as well as migraine and headache related disability. In addition to routine laboratory analysis, exploratory outcomes were: genetic profiling and expression analysis, oxidative and nitrosative stress, serum cytokine analysis, as well as blood βHB and glucose analysis (pharmacokinetics). A crossover design was chosen, as it greatly improves statistical power and participation rates, without increasing costs. To our knowledge this is the first controlled trial using βHB salts world-wide. If proven effective and safe, βHB might not only offer a new prophylactic treatment option for migraine patients, but might additionally pave the way for clinical trials assessing its use in other neurological diseases with a metabolic component, such as Alzheimer’s Disease.