Emerging treatments for the primary headache disorders.

Migraine and cluster headache are common, episodic, often chronic and disabling disorders of the brain. Although there are many standard treatment techniques, none are ideal. This article reviews various novel pharmacologic and device-related treatments for migraine and cluster headache. Emphasis is given to recent advances in the development of monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) and its receptor, including promising results from phase 2 trials studying the safety and efficacy of LY2951742, ALD403 and TEV-48125, three anti-CGRP mAbs. Other new pharmacologic treatments discussed include the 5-HT1F receptor agonist lasmiditan and glial cell modulator ibudilast. Also reviewed is neuromodulation for migraine and cluster headache, including promising recent results of randomized controlled trials studying sphenopalatine ganglion stimulation, trigeminal nerve stimulation, transcutaneous vagus nerve stimulation, and transcranial magnetic stimulation. Finally, we discuss patch, inhaled, and intranasal methods of triptan and dihydroergotamine delivery.

[Genetics of primary headache syndromes]. / Genetik primärer Kopfschmerzen.

Migraine has an important genetic component. The prototypic monogenic form of migraine is hemiplegic migraine, a rare subtype of migraine with aura, for which three causative genes have been identified. Studies of transgenic animal models have substantially improved our understanding of the molecular pathophysiology of this monogenic model disease as well as of migraine in general. Beyond this, there are other (rarer) monogenic forms of migraine, e.g., in the context of hereditary mostly vascular syndromes such as CADASIL. By contrast, the common types of migraine with and without aura are genetically complex. With the identification of the first robust genetic risk variants in large genome-wide association studies, our knowledge in this still dynamically expanding field has substantially increased. This review summarizes the current status of migraine genetics, with a special focus on hemiplegic migraine as well as the most recent findings in complex migraine genetics. In addition, the first preliminary findings on the genetics of other types of primary headache disorders (cluster headache, tension-type headache) are briefly reviewed.

Baroreflex failure, sympathetic storm, and cerebral vasospasm in fibulin-4 cutis laxa.

Sudden, severe, and life-threatening, the crises associated with baroreflex failure are diagnostically challenging, particularly in children, a population in which it has rarely been described. The baroreflex failure syndrome results from impaired afferent baroreceptive input and manifests with autonomic stimulation-induced surges in blood pressure and heart rate accompanied by distinct signs, including thunderclap headache, diaphoresis, and emotional instability. Although the adult literature includes cases of severe headache in baroreflex failure,(1) (,) (2) we present the first case of a child with recurrent thunderclap headache and cerebral vasospasm with baroreflex failure secondary to vascular complications of a rare genetic connective tissue disorder.

Polymorphisms of the SCN1A gene in children and adolescents with primary headache and idiopathic or cryptogenic epilepsy: is there a linkage?

The purpose of this study was to evaluate the distribution of the polymorphisms of the SCN1A gene in a series of children and adolescents with primary headache and idiopathic or cryptogenic epilepsy compared to controls. Five non-synonymous exonic polymorphisms (1748A > T, 2656T > C, 3199A > G, 5771G > A, 5864T > C) of the SCN1A gene were selected and their genotyping was performed, by high resolution melting (HRM), in 49 cases and 100 controls. We found that among the five polymorphisms, only 3199A > G was a true polymorphism. We did not find a statistically significant difference between distribution of 3199A > G genotypes between cases and controls. We excluded the role of the SCN1A gene in the pathogenesis of comorbidity between headache (especially migraine) and epilepsy. The SCN1A gene is a major gene in different epilepsies and epilepsy syndromes; the HRM could be the new methodology, more rapid and efficacious, for molecular analysis of the SCN1A gene.

Alexithymia in juvenile primary headache sufferers: a pilot study.

Starting in the 1990s, there has been accumulating evidence of alexithymic characteristics in adult patients with primary headache. Little research has been conducted, however, on the relationship between alexithymia and primary headache in developmental age. In their research on alexithymia in the formative years, the authors identified one of the most promising prospects for research, as discussed here. The aim of this study was to verify whether there is: (a) a link between tension-type headache and alexithymia in childhood and early adolescence; and (b) a correlation between alexithymia in children/preadolescents and their mothers. This study was based on an experimental group of 32 patients (26 females and 6 males, aged from 8 to 15 years, mean 11.2 ± 2.0) suffering from tension-type headache and 32 control subjects (26 females and 6 males, aged from 8 to 15 years, mean 11.8 ± 1.6). Tension-type headache was diagnosed by applying the International Headache Classification (ICHD-II, 2004). The alexithymic construct was measured using an Italian version of the Alexithymia Questionnaire for Children in the case of the juvenile patients and the Toronto Alexithymia Scale (TAS-20) for their mothers. Higher rates of alexithymia were observed in the children/preadolescents in the experimental group (EG) than in the control group; in the EG there was no significant correlation between the alexithymia rates in the children/preadolescents and in their mothers.

The primary headaches as a reflection of genetic darwinian adaptive behavioral responses.

OBJECTIVE: The objective of this study is to present a view of the primary headaches as genetically determined behavioral responses consistent with sickness behavior and defense reaction, respectively. BACKGROUND AND DESIGN: A review of the literature bearing on the behavioral, humoral, and functional imaging aspects of the primary headaches shows that migraine and cluster headache (CH) are pain conditions characterized by different behaviors during the attacks. Here it is postulated that the behavioral responses to migraine and CH are evolutionary conserved reactions consistent with sickness behavior and defense reaction. RESULTS: The sickness behavior observed during migraine attacks is a pan-mammalian adaptive response to internal and external stressors, characterized by withdrawal and motor quiescence, sympatho-inhibition and lethargy, in which visceral pain signals a homeostatic imbalance of the body and/or brain. In contrast, the defense reaction in CH consists of a fight-or-flight reaction, with motor restlessness and agitation, in which pain is exteroceptive in kind. CONCLUSION: These different behavioral responses are thus specific to different kinds of pain, distinguished by the behavioral significance of the pain (visceral pain in migraine vs exteroceptive pain in CH), and imply brain matrices involving different networks in the brainstem, hypothalamus, and forebrain regions that engender evolutionarily conserved adaptive genetic responses. Cytokines play an important role in their development. Predictions and limitations of the hypothesis are discussed together with implications for genetic studies on headaches.

Familial occurrence of signs of temporomandibular disorders in headache children and their mothers.

OBJECTIVE: Earlier studies have provided evidence of genetic inheritance of headache, especially migraine, but no familial occurrence has been found regarding temporomandibular disorders (TMD). In adults, headache and TMD have been found to be associated with each other, but studies on children are few. The aim of the present study was to test the hypothesis that there is no association between signs of TMD in 13-year-old headache children and their mothers. MATERIAL AND METHODS: The study population was a nested case-control study of the population-based Finnish Family Competence Study originally consisting of over 1000 families. A structured questionnaire was sent to the families of 6-year-old children. A clinical examination was performed in 96 children with headache and 96 pairwise controls. At the age of 13 years, 75 of these same 96 children with headache and 79 of 96 headache-free controls participated in pediatric and stomatognathic examinations. Moreover, the mothers (n=154) filled in a structured headache questionnaire and participated in the stomatognathic examination. RESULTS: No association between mother's and child's TMD signs was found. There was a significant association between signs of TMD and both migraine and tension-type headache in children. In mothers, the association was significant only between migraine and TMD signs. CONCLUSIONS: Familial occurrence of signs of TMD cannot be found in headache children and their mothers.

Novel therapeutic targets.

The need for novel therapeutic strategies for the treatment of migraine and other primary headaches is well recognised. Although the underlying mechanism(s) and the molecular targets that should be tackled by novel medicines are still uncertain, significant improvements have been made in the last decade in the treatment of migraine. Strong evidence in experimental animal models and clinical investigation focus on drugs that limit the phenomena promoted by activation of neurons of the trigeminal ganglion at the level of both their central and peripheral perivascular endings. Identification of compounds that abort the migraine attack by precisely targeting different mechanisms should also help to recompose the puzzle of migraine pathogenesis.

Etiology of primary headaches: the importance of genes and environment.

Results from twin studies show that genes play an important role for susceptibility to migraine. The propensity for migraine to run in some families but not in others arises predominantly from alleles shared by family members and not the shared family environment, and that environmental influences on migraine are unique to the affected family member. The main genetic and environmental architecture for the other two major primary headaches, tension-type and cluster, remains to be elucidated. This review focuses on recent advances in twin studies of primary headaches and the future prospects are outlined.