Nocturnal Plasma Melatonin Levels in Migraine: A Preliminary Report

We determined by radioimmunoassay plasma melatonin levels on blood samples drawn at 11 p.m. in migraine patients and control subjects. Ninety-three cephalalgic outpatients (75 females, 18 males) were compared to a control group (24 females, 22 males) matched according to age. Patients were divided into subgroups presenting common migraine (n = 38); ophthalmic migraine (n = 12); and tension headache associated with ophthalmic or common migraine (n = 24), and associated depressive status (n = 19). Statistical analysis revealed a decrease in plasma melatonin levels for the entire migraine population, compared to the control one, and a heterogeneity in both controls and patients; this heterogeneity was found mainly in the depressive and tension headache subgroups. When the migraine population--from which the depressive patients were excluded--was divided into male and female subgroups, a decrease in plasma melatonin levels was observed only for the female subgroups. Results are discussed with reference to the role of the pineal gland in the synchronization of the organism with the environmental conditions.     

GENETICS

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to accumulating neurologic deficits and dementia. CADASIL has been linked to nucleotide substitutions and deletions in the Notch3 gene. All the mutations described until now lead to unpaired cysteine residue in the epidermal growth factor-like repeats. The authors report a family with CADASIL carrying a deletion in the Notch3 gene that did not involve a cysteine residue.
Comment: At least 400 families from countries around the world have been described with CADASIL. The four classic features are migraine with aura, stroke, dementia, and psychiatric disturbances. Migraine with aura, especially familial hemiplegic migraine and migraine with prolonged aura, is linked genetically to CADASIL on chromosome 19, occurs in up to 30% of patients, and when present is usually the earliest symptom. Definitive diagnosis is by skin biopsy, with characteristic depositions surrounding degenerating smooth muscle cells in the media. —Stewart J. Tepper, MD     

Low income and education levels may cause medication overuse and chronicity in migraine patients

BACKGROUND: Frequent analgesic drug intake, especially in migraine patients, may induce the risk of medication overuse headache (MOH). The various conditions that may affect the development and the features of MOH have not been determined yet. AIM: To compare MOH patients with migraine as pre-existing headache and episodic migraine patients according to socioeconomic and educational variables. METHODS: Forty-six MOH patients with migraine as pre-existing headache and 61 migraine patients were included into study. The headache characteristics, socioeconomic and educational variables of MOH and migraine groups and subgroups divided according to the education (low/high education subgroups), and income (low/high income subgroups) levels were evaluated. RESULTS: We found that mean duration of education was shorter in MOH patients than migraine patients. There was a negative correlation between duration of education and duration of MOH. The mean duration of MOH was longer and rate of low-income level was higher in patients with low-education level. The duration of education was lower in MOH patients with low income. The frequency of migraine attacks and low-income rate was also higher in low-educated migraine patients. The duration of education was shorter in migraine patients with low income. CONCLUSION: We report that migraineurs with low socioeconomic status may have risk of developing MOH. A better identification of patients at risk of drug-associated headache may contribute to improved health in a group of patients with MOH.     

Acetazolamide acts on neuromuscular transmission abnormalities found in some migraineurs

Mild subclinical impairment of neuromuscular transmission can be detected with single-fibre electromyography (SFEMG) in subgroups of patients suffering from migraine and could be due to dysfunctioning Ca2+-channels on motor axons controlling stimulation-induced acetylcholine release. Acetazolamide, which is thought to ameliorate ion channel function, was shown effective in familial hemiplegic migraine and episodic ataxia type 2, both of which are associated with mutations of the neuronal Ca2+-channel gene CACNA1A, as well as in aura status. We treated therefore in an open pilot study five non-hemiplegic migraineurs showing mild SFEMG abnormalities with acetazolamide for several weeks. This was followed by a normalization of SFEMG recordings in all patients and by clinical improvement in four. These results support the assumption that the subclinical impairment of neuromuscular transmission found in certain migraineurs might be due to dysfunctioning Ca2+-channels.     

Calcitonin gene-related peptide does not cause migraine attacks in patients with familial hemiplegic migraine

(Headache 2011;51:544‐553) Background.— Calcitonin gene‐related peptide (CGRP) is a key molecule in migraine pathogenesis. Intravenous CGRP triggers migraine‐like attacks in patients with migraine with aura and without aura. In contrast, patients with familial hemiplegic migraine (FHM) with known mutations did not report more migraine‐like attacks compared to controls. Whether CGRP triggers migraine‐like attacks in FHM patients without known mutations is unknown. Objective.— In the present study we therefore examined the migraine‐inducing effect of CGRP in FHM patients without known mutations and healthy controls. Methods and design.— Eleven patients suffering from FHM without known mutations and 11 controls received an intravenous infusion of 1.5 µg/minute CGRP over 20 minutes. The study design was a balanced and controlled provocation study. Headache and other migraine symptoms were scored for 1 hour and self‐recorded hourly thereafter until 13‐hour postinfusion. Results.— We found no difference in the incidence of migraine‐like attacks between the 2 groups, with 9% (1 of 11) of patients and 0% (0 of 10) of controls reporting migraine‐like headache (P = 1.00). CGRP infusion did not induce aura symptoms in any of the participants. There was no difference in the incidence of CGRP‐induced delayed headaches between the groups (P = .18). Conclusion.— In contrast to patients suffering from migraine with aura and without aura, CGRP infusion did not induce more migraine‐like attacks in FHM patients without known mutations compared to controls. It seems that the majority of FHM patients with and without known mutation display no sensitivity to CGRP signaling compared to common types of migraine.     

Impact of Baseline Characteristics on the Efficacy and Safety of Eptinezumab in Patients With Migraine: Subgroup Analyses of PROMISE-1 and PROMISE-2

PurposeIn the PROMISE-1 (Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-1) and PROMISE-2 (Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-2) clinical trials, eptinezumab 100 mg and 300 mg met the primary efficacy end point, significantly reducing mean monthly migraine days across weeks 1 to 12. Clinical efficacy was also shown across key secondary end points. However, to determine if clinical efficacy varies across subgroups, it is necessary to determine efficacy in patients with different sociodemographic features and headache characteristics. These post hoc analyses of patients in PROMISE-1 and PROMISE-2 evaluated the impact of intrinsic factors on the efficacy and safety of eptinezumab in subgroups defined according to baseline demographic and migraine disease characteristics.MethodsPROMISE-1 and PROMISE-2 were Phase III, parallel-group, double-blind, randomized, placebo-controlled trials of repeat quarterly intravenous infusions of eptinezumab or placebo in adults with episodic (PROMISE-1) or chronic (PROMISE-2) migraine.FindingsDemographic and baseline characteristics were similar across treatment groups in both the PROMISE-1 and the PROMISE-2 studies. Analyses did not show a clear pattern of baseline demographic characteristics driving treatment effects except for the obesity subgroups. For the ≥50% migraine responder rate in the obese class I (body mass index 30.0–35.0 kg/m²) subgroup, although separation from placebo was not as large (<10% separation compared with ≥10% separation across most baseline demographic factors), both doses showed improved ≥50% migraine responder rate compared with placebo, with slightly better results in patients receiving eptinezumab 300 mg.ImplicationsEptinezumab treatment showed consistent clinically relevant reductions from baseline in mean monthly migraine days compared with placebo based on ≥50% migraine responder rate across clinically important intrinsic subgroups of adults with episodic or chronic migraine. ClinicalTrials.gov identifiers: NCT02559895 (PROMISE-1) and NCT02974153 (PROMISE-2).     

Mitochondrial dysfunction and migraine: evidence and hypotheses

The molecular basis of migraine is still not completely understood. An impairment of mitochondrial oxidative metabolism might play a role in the pathophysiology of this disease, by influencing neuronal information processing. Biochemical assays of platelets and muscle biopsies performed in migraine sufferers have shown a decreased activity of the respiratory chain enzymes. Studies with phosphorus magnetic resonance spectroscopy ((31)P-MRS) have demonstrated an impairment of the brain oxidative energy metabolism both during and between migraine attacks. However, molecular genetic studies have not detected specific mitochondrial DNA (mtDNA) mutations in patients with migraine, although other studies suggest that particular genetic markers (i.e. neutral polymorphisms or secondary mtDNA mutations) might be present in some migraine sufferers. Further studies are still needed to clarify if migraine is associated with unidentified mutations on the mtDNA or on nuclear genes that code mitochondrial proteins. In this paper, we review morphological, biochemical, imaging and genetic studies which bear on the hypothesis that migraine may be related to mitochondrial dysfunction at least in some individuals.     

Cerebrospinal fluid analyses in migraine patients and controls

To investigate the role of central neurotransmitters in the pathogenesis of migraine, we measured cerebrospinal fluid (CSF) levels of certain amino acids (glycine, taurine, glutamine) and metabolites of biogenic amines (5-hydroxyindoleacetic acid and homovanillic acid) in 38 migraine patients and compared them with the levels from 10 headache-free controls. The levels of taurine, glycine and glutamine were significantly higher in the migraine patients (p < 0.0001 for taurine and glycine; p < 0.0009 for glutamine); there were no significant differences among the three migraine subgroups (infrequent migraine, frequent migraine and transformed migraine). In seven patients subsequently treated with divalproex sodium, CSF taurine levels decreased significantly from pretreatment baseline values. These data support the concept that migraine is at least in part a disorder of central neurotransmission.     

R583Q CACNA1A variant in SHM1 and ataxia: case report and literature update

Familial hemiplegic migraine (FHM) type 1 is a rare monogenic dominant autosomal disease due to CACNA1A gene mutations. Besides the classical phenotype, mutations on CACNA1A gene are associated with a broader spectrum of clinical features including cerebellar ataxia, making FHM1 a complex channelopathy. We report the case of a patient carrying the p.Arg583Gln mutation affected by hemiplegic migraine and late onset ataxia and we performed a literature review about the clinical features of p.Arg583Gln. Although p.Arg583Gln mutations are associated with a heterogeneous phenotype, carriers present cerebellar signs which consisted generally in ataxia and dysmetria, with intention tremor appearing mostly in advanced age, often progressive and permanent. The heterogeneous spectrum of CACNA1A gene mutations probably causes sporadic hemiplegic migraine (SHM) to be misdiagnosed. Given the therapeutic opportunities, SHM/FHM1 should be considered in differential diagnosis of patients with cerebellar ataxia and migraine with aura.     

The prevalence of migraine in patients with bipolar and unipolar affective disorders

There is a well-known association between migraine and affective disorders, but the information is sparse concerning the prevalence of migraine in subgroups of the affective disorders. The present study was undertaken to investigate the prevalence of migraine in unipolar depressive, bipolar I and bipolar II disorders. Patients with major affective disorders (n = 62), consecutively admitted to an open psychiatric ward, were examined with a semi-structured interview based on DSM-IV diagnostic criteria, combined with separate criteria for affective temperaments. Diagnosis of unipolar and bipolar I disorders followed the DSM-IV criteria, while bipolar II disorder encompassed patients with either discrete hypomanic episodes or a cyclothymic temperament. Migraine was diagnosed according to IHS-criteria. Symptoms of migraine were found to be common in these patients, both in those with unipolar depression (46% prevalence of migraine) and in those with bipolar disorders (44% prevalence). Among the bipolar patients there was, however, a striking difference between the two diagnostic subgroups, with a prevalence of 77% in the bipolar II group compared with 14% in the bipolar I group (P = 0.001). These results support the contention that bipolar I and II are biologically separate disorders and point to the possibility of using the association of bipolar II disorder with migraine to study both the pathophysiology and the genetics of this affective disorder.     

The molecular genetics of migraine

Within the past decade it has been possible to identify susceptibility gene loci that predispose to migraine using genetic markers distributed across the human genome. Five new loci with significant linkage to common types of migraine--migraine with or without aura--have been identified on four different chromosomes using a genome-wide screen approach. So far, only the locus on 4q has been replicated but no specific, disease-causing mutations have been described in these common forms of migraine. The best genetic evidence providing molecular insight into migraine still comes from the mutations detected in a rare Mendelian form of migraine with aura--familial hemiplegic migraine (FHM). In 50%-70% of FHM families, mutations in the calcium channel gene CACNA1A in chromosome 19p13 have been identified. In some families, mutations in the ATP1A2 gene encoding the alpha2 subunit of the Na+, K+-ATPase are associated with FHM, linked to 1q23. Here we discuss the current knowledge of the heritability of migraine and rare migraine variants as models for understanding the pathophysiology of common migraine and animal models that might contribute to understanding common forms of migraine.     

The 1246G-->A polymorphism of the HCRTR2 gene is not associated with migraine

Studies in experimental animals have suggested that the hypocretin/orexin system may be involved in migraine pathophysiology. Using a case-control design study, we genotyped 246 migraine patients and 239 healthy controls for the 1246G-->A polymorphism of the hypocretin receptor 2 (HCRTR2) gene. Genotypic and allelic frequencies of the examined polymorphism were similarly distributed between cases and controls (chi2 = 2.22, P = 0.14 and chi2 = 2.45, P = 0.29, respectively). When different migraine subgroups were compared (migraine with aura vs. migraine without aura and episodic vs. chronic migraine) no significant difference was found. Comparison of the clinical features of the disease with the 1246G-->A genotypes showed no significant difference. Our data suggest that the HCRTR2 gene is not a genetic risk factor in migraine.     

Familial hemiplegic migraine type 1 shows no hypersensitivity to nitric oxide

Familial hemiplegic migraine type 1 (FHM-1) is a dominantly inherited subtype of migraine with aura and transient hemiplegia associated with mutations in the CACNA1A gene. FHM-1 shares many phenotypical similarities with common types of migraine, indicating common neurobiological pathways. Experimental studies have established that activation of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a crucial role in migraine pathophysiology. Therefore, we tested the hypothesis that CACNA1A mutations in patients with FHM-1 are associated with hypersensitivity to NO-cGMP pathway. We included eight FHM-1 patients with R583Q and C1369Y mutations and nine healthy controls, who received intravenous infusions of 0.5 microg kg(-1) min(-1) glyceryl trinitrate (GTN) over 20 min. We recorded: headache intensity on a verbal rating scale; mean flow velocity in the middle cerebral artery (V(meanMCA)) by transcranial Doppler; diameter of the superficial temporal artery (STA) by Dermascan. One patient reported migraine without aura 5 h after start of the GTN infusion. No aura was reported. The AUC(headache) in the immediate phase was more pronounced in patients than in controls (P = 0.01). In the 14 h following GTN infusion, there was no difference in the AUC(headache) between patients and controls (P = 0.17). We found no difference in the AUC(VmeanMCA) (P = 0.12) or AUC(STA) (P = 0.71) between FHM-1 patients and controls. None of the control persons reported migraine-like headache. FHM-1 patients do not show hypersensitivity of the NO-cGMP pathway, as characteristically seen in migraine patients with and without aura. This indicates that the pathophysiological pathways underlying migraine headache in FHM-1 may be different from the common types of migraine.     

Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma

To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell-like (ABC), germinal center B cell-like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch mu (Smu) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within Sgamma and other illegitimate switch recombinations. Sequence analysis revealed ongoing Smu deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase-dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within Smu in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB.     

Involvement of a Ca 2+ Channel Gene in Familial Hemiplegic Migraine and Migraine With and Without Aura

A gene for familial hemiplegic migraine, a subtype of migraine with aura, was assigned to chromosome 19p13. In this region, we identified a brain-specific P/Q-type calcium channel α1a-subunit gene, CACNA1A, with 47 exons covering 300 kb. Sequencing of all exons and their flanking surroundings revealed polymorphic variations, including a (CA)0-repeat anti a (CAG)n-repeat in the 34 untranslated region. In patients with familial hemiplegic migraine, we found four different missense mutations in conserved functional domains. One of the mutations has occurred on two different haplotypes in unrelated familial hemiplegic migraine families. Moreover, in episodic ataxia type 2, we found two mutations disrupting the reading frame. Thus, familial hemiplegic migraine and episodic ataxia type 2 can be considered as allelic channelopathies. Involvement of this familial hemiplegic migraine locus in migraine with and without aura was demonstrated by sib-pair analysis. We showed an increase of shared marker alleles of locus D19S394 , which is tightly linked to the gene. The association between the α1A calcium channel and familial hemiplegic migraine, and the increase of shared alleles in migraine-affected sib-pairs, have uncovered a new pathway for the pathophysiology of migraine. This finding may provide a rationale for the development of specific prophylactic therapy for migraine and other (paroxysmal) cerebral disorders.     

How Well Does the ICHD 3 (Beta) Help in Real-Life Migraine Diagnosis and Management?

Classification has played a major role in the diagnosis of primary headache conditions including migraine with and without aura. With many updates and changes, the International Classification of Headache Disorders (ICHD)-3 beta is currently considered as the gold standard for classification of migraine and other headaches. Correct diagnosis of migraine and its subtypes is a first step toward appropriate treatment and crucial to minimizing disability and optimizing health-related quality of life. The ICHD-3 beta version represents the state of the art in migraine diagnosis but is expected to evolve as biological knowledge advances. Future research should focus on identification of biologically homogeneous subgroups of migraine based on genes and biomarkers.     

The molecular genetics of migraine

Within the past decade it has been possible to identify susceptibility gene loci that predispose to migraine using genetic markers distributed across the human genome. Five new loci with significant linkage to common types of migraine – migraine with or without aura – have been identified on four different chromosomes using a genome‐wide screen approach. So far, only the locus on 4q has been replicated but no specific, disease‐causing mutations have been described in these common forms of migraine. The best genetic evidence providing molecular insight into migraine still comes from the mutations detected in a rare Mendelian form of migraine with aura – familial hemiplegic migraine (FHM). In 50%–70% of FHM families, mutations in the calcium channel gene CACNA1A in chromosome 19p13 have been identified. In some families, mutations in the ATP1A2 gene encoding the α2 subunit of the Na ⁺ , K ⁺ ‐ATPase are associated with FHM, linked to 1q23. Here we discuss the current knowledge of the heritability of migraine and rare migraine variants as models for understanding the pathophysiology of common migraine and animal models that might contribute to understanding common forms of migraine.     

Migraine genetics: An update

A growing interest in genetic research in migraine has resulted in the identification of several chromosomal regions that are involved in migraine. However, the identification of mutations in the genes for familial hemiplegic migraine (FHM) forms the only true molecular genetic knowledge of migraine thus far. The increased number of mutations in the FHM1 (CACNA1A) and the FHM2 (ATP1A2) genes allow studying the relationship between genetic findings in both genes and the clinical features in patients. A wide spectrum of symptoms is seen in patients. Additional cerebellar ataxia and (childhood) epilepsy can occur in FHM1 and FHM2. Functional studies show a dysfunction in ion transport as the key factor in the pathophysiology of (familial hemiplegic) migraine that predict an increased susceptibility to cortical spreading depression—the underlying mechanism of migraine aura.     

Migraine genetics

The genetics of migraine is a fascinating and moving research area. Familial hemiplegic migraine, a rare subtype of migraine with a Mendelian pattern of inheritance, is caused by mutations in the chromosome 19 CACNA1A gene in approximately 75% of the families. The finding of mutations in an ionchannel subunit defines migraine as a channelopathy (eg, epilepsy). The genetics of the more frequent variants, migraine with and without aura, is more complex. Several loci have been studied in families and case-control studies, but need to be confirmed.     

Multiplex ligation-dependent probe amplification identification of whole exon and single nucleotide deletions in the CFTR gene of Hispanic individuals with cystic fibrosis

A disparity between Caucasian and Hispanic mutation detection for cystic fibrosis continues to exist, although the carrier frequency is only moderately lower in Hispanics. We aimed to identify exonic rearrangements that remained undetected by conventional methods. In seven of 32 cystic fibrosis-affected self-identified Hispanics for whom only one or no mutations were identified by extensive molecular testing, exon deletions appeared to be present with a multiplex ligation-dependent probe amplification (MLPA) assay. Two recurrent deletions (of exons 2-3 and exons 22-23) were identified in one and three patients, respectively (12.5%, 11.1% of unidentified alleles). Two apparently novel deletions (exons 6b and 20) were identified in three additional patients. Subsequent sequencing to characterize deletion breakpoints, however, identified single nucleotide deletions at the probe binding sites close to the ligation point. All resulted in false positive MLPA deletion signals. Interestingly, these mutations were not common in Caucasians, and one (935delA) was common in U.S. Hispanics. On examination of all probe binding sites, we identified a total of 76 reported mutations and five silent variants that immediately surrounded the MLPA ligation sites, with 22 occurring in non-Caucasians. These mutations are not all rare. Thus, apparent exon deletions by MLPA may indicate the presence of both large deletions and point mutations, with important implications for pan-ethnic MLPA testing in cystic fibrosis and other genetic conditions.