Deficient energy metabolism is associated with low free magnesium in the brains of patients with migraine and cluster headache

We used phosphorus magnetic resonance spectroscopy to assess in vivo the brain cytosolic free magnesium concentration and the free energy released by the reaction of adenosine triphosphate (ATP) hydrolysis (DeltaG(ATPhyd)), the latter being an index of the cell's bioenergetics condition. We studied 78 patients with migraine in attack-free periods (7 with migraine stroke, 13 with migraine with prolonged aura, 37 with migraine with typical aura or basilar migraine, and 21 with migraine without aura), and 13 patients with cluster headache. In the occipital lobes of all subgroups of migraine and in cluster headache patients cytosolic free [Mg(2+)] as well as the free energy released by the reaction of ATP hydrolysis were significantly reduced. Among migraine patients, the level of free energy released by the reaction of ATP hydrolysis and the cytosolic free [Mg(2+)] showed a trend in keeping with the severity of clinical phenotype, both showing the lowest values in patients with migraine stroke and the highest in patients with migraine without aura. These results support our current hypothesis that the reduction in free [Mg(2+)] in tissues with mitochondrial dysfunction is secondary to the bioenergetics deficit, and are against a primary role of low brain cytosolic free [Mg(2+)] in causing the bioenergetics deficit in headache.     

Progress in clinical neurosciences: Migraine-stroke: a causal relationship, but which direction?

A significant association between migraine and ischemic stroke has been demonstrated in population and case-control studies. The risk of ischemic stroke appears to be higher in migraine with aura (MWA) than migraine without aura (MwoA). Migraine-stroke comprises a number of distinct entities, including migrainous infarction, in which ischemic stroke occurs during an attack of MWA and migraine-related stroke, in which the causal link is less clear. Migrainous infarction accounts for only one-third of migraine-stroke, strokes may occur during attacks of MwoA, and a number of cerebrovascular disorders may present as MWA or MwoA. Migraine may occur as a consequence of conditions that are known to cause stroke; therefore it remains to be determined whether migraine predisposes to stroke in the absence of any known disease associations, if it is an epiphenomenon of an underlying stroke diathesis, or if it requires the presence of another stroke risk factor to produce cerebral ischemia. Furthermore, it is unclear if ischemia results in migraine more often than migraine results in ischemia. Careful clinical studies that evaluate this bidirectional relationship are needed to determine why migraine patients are subject to a higher risk of ischemic stroke.     

Familial migraine with and without aura: clinical characteristics and co-occurrence

Migraine with aura (MwA) and migraine without aura (MwoA) are the two common forms of migraine. Many migraine patients suffer from both kinds of attacks. In a questionnaire-based study using the current International Headache Society (IHS) criteria we determined the clinical characteristics and occurrence of MwA + MwoA in 1000 migraine patients belonging to 210 Finnish migraine families. Nine hundred and six patients were able to indicate whether they suffered from MwA (but not MwoA), migraine aura without headache (migraine equivalent) (but not MwA) or MwA and MwoA. Of these patients, 3.2% had experienced MwoA, 11.1% MwA, 40.6% MwA + MwoA, 23.5% MwoA and 20.3% MwA-like symptoms not meeting the IHS criteria. The high prevalence of MwA attacks in the families studied supports the belief that aura has a strong hereditary component. The MwA + MwoA patients had significantly more severe attacks, more typical headache and more prodromal symptoms than the MwA and MwoA subjects. Therefore, it is possible that there is a continuum with pure MwA at the neural and pure MwoA at the headache end of the spectrum, and MwA + MwoA lying in between the two. The MwA + MwoA patients would thus be liable to both types of migraine, making their attacks more characteristic and more severe. This would also explain why the co-occurrence of MwA and MwoA is more common in the clinic compared with population based epidemiological studies. These findings have consequences for future research on liability genes for migraine.     

无先兆偏头痛发作间期的静息态功能磁共振研究

目的本研究采用静息态功能磁共振(rf MRI)方法通过对比无先兆偏头痛(Mwo A)患者与健康对照的大脑自发脑活动的局部一致性(Re Ho)差异,为偏头痛的发病机制提供新的见解。方法对23例发作间期的Mwo A患者和25例性别、年龄、受教育程度相匹配的健康被试者进行临床资料的采集及rf MRI检查。应用Re Ho方法分析每个被试者大脑的相邻体素的血氧水平依赖(BOLD)信号在同一时间序列中波动的一致性,并对两组被试者的Re Ho值的脑图行统计学分析。结果与对照组Re Ho脑图相比,偏头痛组右侧丘脑、右侧壳核、右侧前额叶皮质及右侧海马的Re Ho值显著高于对照组(P0.05)。结论 Mwo A患者发作间期疼痛处理及调节与应激反应相关的脑区存在功能异常。     

Structural brain abnormalities in patients with vestibular migraine

New advances in understanding the pathophysiology of vestibular migraine (VM) have suggested a large overlap between migraine and vestibular pathways. We explored the regional distribution of gray (GM) and white matter (WM) abnormalities in VM patients in comparison to migraine patients with (MWA) and without aura (MWoA) and their correlations with patients’ clinical manifestations. Using a 3.0 Tesla scanner, brain T2-weighted and 3D T1-weighted MRI scans were acquired from 19 VM, 19 MWA, 19 MWoA and 20 age-matched controls. GM and WM volumetric abnormalities were estimated using voxel-based morphometry (SPM12). Compared to controls, migraine patients had decreased GM volume of the left cerebellum and an increased GM volume of the left temporal lobe. VM patients had a selective GM volume increase of frontal and occipital regions compared to controls and the other two groups of migraineurs and no regions with decreased GM volume. Compared to MWoA and MWA, VM had increased GM volume of the left thalamus. Regional GM abnormalities did not correlate with disease duration and attack frequency. No WM volumetric differences were detected between migraine patients and controls. These results show that GM volume abnormalities of nociceptive and multisensory vestibular brain areas occur in VM patients. Overall, our findings suggest that an abnormal brain sensitization might lead to a dismodulation of multimodal sensory integration and processing cortical areas in VM patients.     

Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine

Migraine aura is probably caused by cortical-spreading depression. No treatment for acute and severe migraine aura has been described previously. The effect of ketamine (25 mg intranasally) was studied in 11 patients with severe, disabling auras resulting from familial hemiplegic migraine. In five patients ketamine reproducibly reduced the severity and duration of the neurologic deficits, whereas in the remaining six patients no beneficial effect was seen. Ketamine offers, for the first time, a possible treatment option for severe and prolonged aura.     

The concept of migraine as a state of central neuronal hyperexcitability

This article explores the hypothesis that migraine with aura is associated with a state of central neuronal hyperexcitability. The authors propose that this central neuronal hyperexcitability involves overactivity of the excitatory amino acids, glutamate, and possibly aspartate. Stimuli that activate the migraine attack evoke neuronal depolarization, slow depolarization shifts, and spreading suppression of spontaneous neuronal activity possible by glutamate and K+ dependent mechanisms. A low brain Mg2+ and consequent reduced gating of glutamatergic receptors may provide the link between the physiologic threshold for a migraine attack and the mechanisms of the attack itself by promoting glutamate hyperactivity, neuronal hyperexcitability, and susceptibility to glutamate-dependent spreading depression.     

Low brain intracellular free magnesium in mitochondrial cytopathies.

The authors studied, by in vivo phosphorus magnetic resonance spectroscopy (31P-MRS), the occipital lobes of 19 patients with mitochondrial cytopathies to clarify the functional relation between energy metabolism and concentration of cytosolic free magnesium. All patients displayed defective mitochondrial respiration with low phosphocreatine concentration [PCr] and high inorganic phosphate concentration [Pi] and [ADP]. Cytosolic free [Mg2+] and the readily available free energy (defined as the actual free energy released by the exoergonic reaction of ATP hydrolysis, i.e., deltaG(ATPhyd)) were abnormally low in all patients. Nine patients were treated with coenzyme Q10 (CoQ), which improved the efficiency of the respiratory chain, as shown by an increased [PCr], decreased [Pi] and [ADP], and increased availability of free energy (more negative value of deltaG(ATPhyd)). Treatment with CoQ also increased cytosolic free [Mg2+] in all treated patients. The authors findings demonstrate low brain free [Mg2+] in our patients and indicate that it resulted from failure of the respiratory chain. Free Mg2+ contributes to the absolute value of deltaG(ATPhyd). The results also are consistent with the view that cytosolic [Mg2+] is regulated in the intact brain cell to equilibrate, at least in part, any changes in rapidly available free energy.     

Cortical hyperexcitability in migraine patients before and after sodium valproate treatment.

DC-magnetoencephalography (DC-MEG)waveforms arising during migraine aura were used to determine the effectiveness of prophylactic medication therapy on neuronal hyperexcitability. Nine patients were prescribed valproate (Depakote) for migraine prophylaxis. MEG scans were recorded during visual stimulation before commencing medication and again after 30 days of daily use of valproate. Cortical brain activity was recorded during stimulation with a black-and-white circular checkerboard pattern alternating at 8 Hz and were analyzed with MR-FOCUSS. Large-amplitude DC-MEG signals, imaged to extended areas of occipital cortex, were seen before therapy. After 30 days of prophylactic treatment, reduced DC-MEG shifts in the occipital cortex and reduced incidence of migraine attacks were observed. Using visual stimulation, the authors demonstrated the hyperexcitability of widespread regions throughout occipital cortex in migraine patients, explaining the susceptibility for triggering spreading cortical depression and migraine aura. This study confirms that MEG can noninvasively determine the status of neuronal excitability before and after therapy. This finding may be helpful in determining which prophylactic medications will be most effective in reducing hyperexcitability in particular patients.     

Cerebrovascular reactivity to l-arginine in the anterior and posterior cerebral circulation in migraine patients

Perko D, Pretnar‐Oblak J, Šabovič M, Žvan B, Zaletel M. Cerebrovascular reactivity to l‐arginine in the anterior and posterior cerebral circulation in migraine patients.
Acta Neurol Scand: 2011: 124: 269–274.
© 2011 John Wiley & Sons A/S. Objective – Cerebral infarction preferentially affects the posterior cerebral artery distribution in migraine patients. The results obtained from the few known studies that have compared the anterior and posterior cerebral endothelial function are contradictory. To the best of our knowledge, cerebrovascular reactivity to L‐arginine (CVR), measured by transcranial Doppler sonography (TCD), has not been previously used to determine the posterior cerebral endothelial function in migraine patients with (MwA) and without aura (MwoA). Materials and methods – Forty migraine patients without comorbidities (20 MwA, 20 MwoA) and 20 healthy subjects were included. By employing strict inclusion criteria, we avoided the possible vascular risk factors. Mean arterial velocity in the middle cerebral artery (MCA) and the posterior cerebral artery (PCA) was measured by TCD before and after infusion of L‐arginine, and CVR to L‐arginine was then calculated. Results – All migraine patients had lower CVR to L‐arginine in PCA (P = 0.002) and similar in MCA (P = 0.29) compared to healthy subjects. This difference was also present in MwA and MwoA compared to healthy subjects (P = 0.003). Conclusions – Lower CVR to L‐arginine in PCA in migraine patients could associate migraine and cerebral infarcts that are more common in the posterior cerebral artery distribution.     

Visual evoked potential latency, amplitude and habituation in migraine: a longitudinal study.

OBJECTIVE: It has not been previously studied with a paired longitudinal design if visual excitability changes occur in the preattack period across the migraine cycle, or how excitability and habituation relate to migraine-attack severity, clinical photophobia and serotonin metabolism. METHODS: Monocular 62' check reversals were applied in 33 adult migraine patients without aura (MwoA), 8 with aura (MA) and 31 controls. VEP was recorded in four blocks of 50 stimuli. P1 (P100) and N2 (N145) latency and N1P1 and P1N2 amplitude were measured. Serotonin was measured in plasma and platelets sampled before each session. Sessions were classified as preattack, attack, postattack or interictal. RESULTS: Migraine patients had significantly higher P1N2 amplitude before the attack compared to a paired interictal recording (n=13, p=0.03), but habituation difference was not found. MA patients had significantly higher P1N2 and N1P1 amplitude than controls and MwoA. P1 latency correlated positively with headache history duration. During attack, a positive correlation between P1N2 amplitude habituation and serotonin emerged in MA patients. CONCLUSIONS: Increased VEP P1N2 amplitude was observed within a few days before the attack. Visual cortex excitability seems to be generally increased in MA as compared to MwoA patients and controls. SIGNIFICANCE: Increased excitability of the visual cortex seems to be detectable in the preattack state, supporting the concept of a cyclic CNS dysfunction in migraine.     

Evaluation of placebo use in migraine without aura, migraine with aura and episodic tension-type headache acute attacks

This study presents an evaluation of placebo response in the acute treatment of migraine with or without aura and episodic tension type headache. We studied patients admitted between March 1st,1997 and November 31st,1999 in two Emergency Room Units. Three groups had been defined, each one with 30 participants: migraine without aura (MWOA), migraine with aura (MWA) and episodic tension-type headache (ETTH). Patients were participating of a randomized study to evaluate efficacy of 4 different drugs; those randomized to receive placebo were included. We evaluated pain and associated symptoms. After one hour of placebo administration, 50% of MWOA patients, 23.3% of MWA and 26.7% of ETTH had presented pain relief. The mean of this relief, evaluated by the numerical pain scale, was 41.6%, 23.1% and 36%, respectively. Use of placebo is essential in evaluating the therapeutic role of drugs used in the treatment of acute headache.     

Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management

Hemiplegic migraine is a rare form of migraine with aura that involves motor aura (weakness). This type of migraine can occur as a sporadic or a familial disorder. Familial forms of hemiplegic migraine are dominantly inherited. Data from genetic studies have implicated mutations in genes that encode proteins involved in ion transportation. However, at least a quarter of the large families affected and most sporadic cases do not have a mutation in the three genes known to be implicated in this disorder, suggesting that other genes are still to be identified. Results from functional studies indicate that neuronal hyperexcitability has a pivotal role in the pathogenesis of hemiplegic migraine. The clinical manifestations of hemiplegic migraine range from attacks with short-duration hemiparesis to severe forms with recurrent coma and prolonged hemiparesis, permanent cerebellar ataxia, epilepsy, transient blindness, or mental retardation. Diagnosis relies on a careful patient history and exclusion of potential causes of symptomatic attacks. The principles of management are similar to those for common varieties of migraine, except that vasoconstrictors, including triptans, are historically contraindicated but are often used off-label to stop the headache, and prophylactic treatment can include lamotrigine and acetazolamide.     

Familial hemiplegic migraine with cerebellar ataxia and paroxysmal psychosis

Familial hemiplegic migraine is a rare autosomal dominant disorder associated with stereotypic neurologic aura phenomena including hemiparesis. So far two chromosomal loci have been identified. Families linked to the chromosome 19 locus display missense mutations within the CACNL1A4 gene. Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with migraine attacks. Based on the clinical and haplotype evidence indicating linkage to chromosome 19 in this family, we hypothesize that a dysfunction of the mutated calcium channel may be involved not only in the development of hemiplegic migraine but also in the acute psychotic episodes observed in these patients.     

Serotonin 2C receptor gene Cys23Ser polymorphism: a candidate genetic risk factor of migraine with aura in Japanese population

OBJECTIVES: The goal of this study is to clarify the association between migraine and Serotonin 2C receptor Cys23Ser polymorphism in Japanese population. MATERIALS AND METHOD: This study included 37 individuals with migraine with aura (MWA), 80 with migraine without aura, 43 with tension type headache (TH) and 360 with controls. The genotypes of Cys23Ser polymorphism were confirmed by polymerase chain reaction-restriction fragment length polymorphism techniques. RESULTS: The Ser allele frequency in control subjects is much less than that in Caucasian population. The Ser allele frequency in patients with MWA was higher than that in control subjects. CONCLUSION: The present study provides that 5HTR2c Cys23Ser polymorphism may be associated with MWA in Japanese population.     

Structural abnormalities in the thalamus of migraineurs with aura: A multiparametric study at 3 T

Background and objectives: The thalamus exerts a pivotal role in pain processing and cortical excitability control, and migraine is characterized by repeated pain attacks and abnormal cortical habituation to excitatory stimuli. This work aimed at studying the microstructure of the thalamus in migraine patients using an innovative multiparametric approach at high‐field magnetic resonance imaging (MRI). Design: We examined 37 migraineurs (22 without aura, MWoA, and 15 with aura, MWA) as well as 20 healthy controls (HC) in a 3‐T MRI equipped with a 32‐channel coil. We acquired whole‐brain T1 relaxation maps and computed magnetization transfer ratio (MTR), generalized fractional anisotropy, and T2* maps to probe microstructural and connectivity integrity and to assess iron deposition. We also correlated the obtained parametric values with the average monthly frequency of migraine attacks and disease duration. Results: T1 relaxation time was significantly shorter in the thalamus of MWA patients compared with MWoA (P < 0.001) and HC (P ≤ 0.01); in addition, MTR was higher and T2* relaxation time was shorter in MWA than in MWoA patients (P < 0.05, respectively). These data reveal broad microstructural alterations in the thalamus of MWA patients compared with MWoA and HC, suggesting increased iron deposition and myelin content/cellularity. However, MWA and MWoA patients did not show any differences in the thalamic nucleus involved in pain processing in migraine. Conclusions: There are broad microstructural alterations in the thalamus of MWA patients that may underlie abnormal cortical excitability control leading to cortical spreading depression and visual aura. Hum Brain Mapp 35:1461–1468, 2014. © 2013 Wiley Periodicals, Inc.     

Hemiplegic migraine induced by exertion

BACKGROUND: It is known that exertion can aggravate migraine headache. However, the relationship between exertion and migraine aura is unknown. OBJECTIVE: To study the relationship between exertion and migraine aura. DESIGN: Case report. SETTING: Tertiary care hospital. PATIENT: A 67-year-old man presented with recurrent attacks of exertion-induced hemiplegic migraine. Since the hemiparetic attacks were exertion induced, they were initially ascribed to recurrent transient ischemic attacks. However, the clinical picture, normal findings on cerebral angiography and neuroimaging (during the period of hemiparesis), lack of response to treatment with antiplatelets and anticoagulants, and successful treatment with verapamil suggested that the hemiparesis was not due to ischemia, but was indeed a migraine aura. We suggest that exertion induced the aura of hemiparesis by lowering the threshold for the development of cortical spreading depression. Even though our patient had no family history of hemiplegic migraine, a mutation in an ion channel gene (eg, the CACNA1A gene on chromosome 19) might account for his episodic attacks. CONCLUSION: Migraine aura should be included in the differential diagnosis of exertion-induced focal neurologic deficit.     

Migraine without aura: comparison with cervicogenic headache. Vågå study of headache epidemiology

Objectives –  To study migraine without aura (MwoA) prevalence in the commune of Vågå, Norway; 1838 (18- to 65-year-old) individuals were included. A special search was made for cervicogenic characteristics in MwoA, as it has been claimed that such characteristics may frequently be present. A comparison with cervicogenic headache (CEH) was made.
Methods –  The MwoA and tension-type headache (T-TH) diagnosis was based on IHS criteria. CEH diagnosis was based on the principles of The Cervicogenic Headache International Study Group.
Results –  There were 562 cases of MwoA; prevalence: 31%. There were 425 cases of 'pure' MwoA, i.e. without coexisting T-TH. These 'pure' cases were used for extracting MwoA symptoms. The female/male ratio was 1.69, the corresponding ratio in CEH being 0.71. Typical MwoA symptoms such as nausea/photophobia were most frequently found in migraine. This difference amounted to a factor of ≥2.6. On the other hand, typical CEH traits, like mechanical pain provocation and 'posterior' onset of exacerbations, occurred more frequently in CEH than in MwoA. The difference amounted to a factor of two or more.
Conclusions –  MwoA and CEH have clearly different characteristics. The differences between MwoA and CEH are staggering. It is unlikely that migraine and CEH are linked in a nosological sense.     

Metabolic kinetics in the brains in infants with IUGR, respiratory distress syndrome, seizures and asphyxia]

31-P magnetic resonance spectroscopy (MRS) allows noninvasive measurements of cerebral phosphorus compounds: ATP, phosphocreatine (PCr), inorganic phosphate (Pi), phosphomonoesters (PME) and phosphodiesters (PDE). In this paper we reported our MRS data from the brains of infants with intrauterine growth retardation, respiratory distress syndrome, neonatal seizures or neonatal asphyxia, and discussed the possibilities to prevent brain damage due to these perinatal troubles.     

Preliminary observations on brain energy metabolism in migraine studied by in vivo phosphorus 31 NMR spectroscopy

We measured brain energy phosphate metabolism and intracellular pH (pHi) in a cross-sectional study of migraine patients by in vivo phosphorus 31 NMR spectroscopy. During a migraine attack the ratio ATP/total phosphate signal (mole % ATP) was preserved, but there was a decrease in mole % phosphocreatine (PCr) and an increase in mole % inorganic phosphate (Pi) resulting in a decrease of the PCr/Pi ratio, an index of brain phosphorylation potential. This was found in classic but not common migraine. Mole % Pi was also increased in combined brain regions between attacks. There was no alteration in brain pHi during or between attacks. Energy phosphate metabolism but not pHi appears disordered during a migraine attack.