Headache Highlights 2016: Junior Editors’ Choice

Over the past two decades, research on primary headache disorders, and migraine in particular, has considerably increased our understanding of the disease pathobiology and advanced treatment opportunities. This is particularly remarkable as despite the high prevalence and disease burden, headache research is hampered by limited financial support from public funding agencies and the private sector compared to other research areas in neurology. In this article, we highlight just a few of the articles published between the end of 2015 and year to date 2016 that have advanced our understanding of headache and its treatment.

Preclinical and clinical studies on mechanism of action

Photophobia is a typical feature of migraine, but despite its commonness the underlying pathophysiology is far from being entirely understood. Noseda et al. have shown in the past that intrinsically photosensitive retinal ganglion cells (ipRGC) that connect to dura-sensitive thalamic neurons and represent an essential element of the non-image-forming visual pathway may be crucial in the perception of photophobia (1). The same group has now continued to dissect these mechanisms even further in an extensive study with an experimental paradigm in migraineurs and an in vivo rodent model (2). The study reveals that exacerbation of migraine pain occurs predominantly under exposure to blue, white, amber or red light, whereas green light may reduce headache intensity in some patients. These findings are in line with the performed in vivo experiments on rats which confirm these findings on dura- and light-sensitive thalamic neurons. In the context of the preceding studies (1), the findings suggest that the neuronal activation underlying photophobia in migraine may originate in cone-driven retinal pathways and is then transmitted via ipRGC to light-sensitive trigeminovascular thalamic neurons where fine-tuning of the signal may occur prior to its transmission to the cortex.

The mechanisms leading to the initiation of a migraine attack have been debated for decades. Existing studies are commonly hampered by the fact that the initiation of a migraine attack is difficult to investigate in spontaneous migraine attacks as it may precede headache onset by up to 48 h. Schulte and May elegantly circumvented this problem performing functional magnetic resonance imaging (fMRI) in one patient at a given time over 30 consecutive days (3) and thereby obtaining fMRI data of three attacks including their pro- and postdromal phases. The study reveals that the hypothalamus shows an increased activity and an enhanced functional coupling with the spinal trigeminal nuclei in the 24 h preceding migraine headache which shifts to the dorsal rostral pons during the headache phase. The results strongly support the hypothesis that the initiation of a migraine attack takes place within the hypothalamus. Despite being a study on a single patient, the results show that there is a vast potential in studying the mechanisms underlying the initiation and the resolution of spontaneous migraine attacks.

Much has been speculated about the mechanism of action of onabotulinumtoxin A for the preventive treatment of chronic migraine. In particular, it remained unclear how the peripherally administered neurotoxin may exert its effect on a disorder which is thought to originate mainly in the brain. Zhang et al. addressed this issue in a series of in vivo experiments (4) which show that the extracranial administration of onabotulinumtoxin A inhibits the responses of meningeal nociceptors to transient receptor potential vanilloid channel 1 (TRPV1) activation, which is thought to play an important role in the chronification of migraine and in the preventive action of onabotulinumtoxin A. As TRPV1 channel activation induces the release of calcitonin gene-related peptide (CGRP) into the peripheral circulation, this finding may also explain why responders to onabotulinumtoxin A treatment show a marked decrease in serum CGRP levels after treatment while this effect is not observed in non-responders (5). Interestingly, the study by Zhang et al. also revealed that the effect of onabotulinumtoxin A is enhanced if the injection is additionally performed along the cranial suture lines. Based on this finding it may be speculated that an injection along the cranial suture lines may potentially enhance clinical efficacy.

Advances in the genetics of headache disorders

That there is a genetic influence on migraine pathophysiology is evidenced by data from family and twin studies. Yet, aside from familial hemiplegic forms of migraine, there are few identified variants associated with polygenic forms of migraine. In the largest genetic study of migraine to date, Gormley et al. published a meta-analysis of 59,674 migraine patients and 316,078 controls of European descent from 22 genome-wide association studies (GWAS) (6). The authors were able to identify 44 migraine-risk associated single nucleotide polymorphisms and 38 gene loci. Most loci found in this study were not previously associated with migraine. While the authors implicate signalling in vascular tissue and visceral smooth muscle tissue based on gene expression patterns as potentially involved in migraine pathogenesis, the results are really more hypothesis-generating than explanatory of any unified mechanism involved in migraine pathogenesis. In fact, the genes identified are expressed in a number of different tissue types and their change in expression based on disease state remains unclear. Nonetheless, the authors take advantage of the statistical power in combining data from various GWAS and reveal the genes of protein products whose involvement in migraine pathobiology may be the subject of future bench research.

The treatment of headache: What is on the horizon?

There have been significant advances in the treatment of migraine headaches that leverage pre-existing preclinical data. Peptidergic nociceptive trigeminovascular afferent activation and resultant central sensitisation is an important step in the initiation of migraine pain. Consequently, CGRP antagonists and antibodies have reached phase IIb and phase III clinical trials. In late 2015, Bigal et al. published the results of two multicentre randomised double-blind placebo-controlled phase IIb clinical trials of TEV-48125, a subcutaneously administered monoclonal anti-CGRP antibody, for the preventive treatment of episodic and chronic migraine (7,8). For episodic migraine, the investigators demonstrated that during the third cycle (weeks 9–12), there was a significant difference between the reduction in migraine headache days in the group receiving the study drug as compared to placebo of 2.8 days in patients given 225 mg and 2.6 days in patients given 675 mg of TEV-48125 when the drug was given once a month for three months. Other exploratory analyses and secondary endpoints were in favour of the CGRP antibody. Similar to the trial for episodic migraine, for chronic migraineurs, TEV-48125 appears to reduce the number of headache-hours when given as a dose of 675 mg in the first of three treatment cycles and 225 mg in the second and third treatment cycle over three months or 900 mg in three treatment cycles over three months. The advent of CGRP antibodies has the potential to impact our treatment of migraine and is reflective of how our understanding of pathobiology can germinate new therapeutic targets for preventive therapies.

While new drugs are on the horizon, previously prescribed preventive medications face questions of efficacy in the paediatric population. The Childhood and Adolescent Migraine Prevention (CHAMP) trial investigators, Powers et al., recently published a trial of amitriptyline, topiramate and placebo for paediatric migraine in the New England Journal of Medicine (9). The trial was a multicentre randomised double-blind placebo-controlled trial including patients aged 8 to17 years with episodic migraine. Cessation of the trial occurred following an interim analysis that revealed no difference between groups and futility of trial continuation. The conclusion was that there are no differences in the reduction of headache frequency or disability in children and adolescents treated with amitriptyline or topiramate as compared with placebo. Taken in the context of the limited available preventive treatments for migraine in the paediatric population, the negative results of the CHAMPS study are noteworthy and highlight the importance of considering non-pharmacological approaches to headache management in children. Moreover, the results from this trial and others will likely inform the framework for future guidelines in the management of headache disorders in paediatric patients which is earnestly needed. There are, however, lingering questions about the selection and efficacy of preventive agents for the treatment of paediatric migraine that remain unanswered. One such question is whether older adolescents should be studied separately from pre-pubertal children to account for possible age-related differences in the influence of gender, body composition, drug metabolism and hormones on response to drug therapy. It should be emphasised that changes in the clinical practice based on a single negative study may be premature. Nonetheless, clinicians who treat paediatric migraine will still have to reconcile the results of this most recent trial with that of clinical practice. The disparity in clinical efficacy of migraine preventive medications based on age forms a compelling argument for additional data and re-evaluation of medications for paediatric migraine that may not have strong evidence in the adult population.

From side effects to headache treatment, and the foundation, headache classification, historical perspective

Buettner et al. published in Annals of Neurology results from a randomised, double-blind, placebo-controlled study on a combination of simvastatin 20 mg and vitamin D3 1000 IU each twice daily, as a preventive treatment for migraine in 57 adults with episodic migraine. A reduction in number of migraine days was observed over a 24-week period of eight days for those on treatment (–8.0 days interquartile range [IQR], 15.0 to –2.0) but those receiving placebo had an increase of one day (+1 day IQR, –1.0 to +6.0) (10).

This study follows a cross-sectional population-based study of 5938 US individuals where statin use was associated with lower prevalence of severe headache (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.46–0.98; P = 0.04) (11). When the participants were dichotomised on serum 25-hydroxy vitamin D (25(OH)D) levels, ≤ or >57 nmol/L, a significant interaction with statin use was found (P = 0.005). Participants with a level >57 nmol/L and receiving statins had further reduced odds of having severe headache or migraine 0.48 (95% CI, 0.32–0.71; P = 0.001). Preceding these two studies are case reports (12,13) where statins are proposed as a potential preventive medication for migraine. The process described above from case reports to epidemiological studies to trials is an important one as it relies on the observant clinician to spot potential effects of medication used for diseases other than migraine and writing the case up for publication. If the clinician’s hunch proves right it may end up in a trial and a new treatment option for migraine. There are several such examples, such as botulinum toxin, candesartan, ACE inhibitors and beta-blockers, all medications that have ended up being useful to some headache sufferers.

Ottar Sjaastad published a paper in Cephalalgia this year titled “The International Headache Society: The history of its founding” (14). One may wonder how this paper can be the highlight of this year’s studies? But when going through numerous studies on headache and migraine that have been published, one starts to wonder how it is possible to compare the results from all these studies given the numerous differences in their characteristics. These studies include cohorts, cases and controls from different continents where vast differences exist in so many aspects including culture, demographics, nutrition, lifestyle, etc. The main reason for that being possible is the existence of classification criteria of headache disorders that has been constructed through a collaborative effort of headache researchers from all corners of the globe. The paper by Sjaastad highlights the birth of the International Headache Society (IHS) which preceded the creation of the 1988 IHS criteria (15). The creation of the IHS, and the subsequent creation of the International Classification on Headache Disorders (ICHD), all three versions, is a great feat. The ICHD has enabled researchers to conduct standardised clinical trials, systematic reviews and meta-analyses on headache studies which would not have been possible without standardised diagnostic criteria. A marked increase in publications of case-control and cohort studies on migraine headache can be seen in PubMed since the beginning of the 1990s to this date, and a great deal of that increase can be attributed to the ICHD. Since then, the second and third versions have been published in 2004 and 2013, respectively, with considerable improvements with each new version. Numerous diagnostic challenges remain, for example how to diagnose migraine aura symptoms using a questionnaire, but these challenges are more likely to be beaten through an international collective effort.

A closing remark from the Junior Editors

In 2015–2016, the understanding of primary headaches and their potential treatment options advanced significantly. Despite their significance to the field, the abovementioned manuscripts represent only a small excerpt as many other exceptional contributions have been published and widely discussed at headache conferences during that time. We are looking forward with excitement to the next 12 months as we anticipate that many findings, in particular treatment options, will be published, and that these findings may have a sustained clinical impact in our field.