Dodick, David W.

Abstract Migraine and functional neurological disorder (FND) are two of the most common conditions in neurological practice. It is assumed that the two conditions have distinct underlying mechanisms. However, it can be clinically challenging to disentangle their relative contributions to a patient's symptoms. In addition, apart from the relationship between persistent postural perceptual dizziness (PPPD) and migraine, the frequency of co-occurrence has not been characterized in detail. Contemporary conceptualizations of FND have driven a re-evaluation of its relationship to other neurological disorders, including migraine. We carried out a narrative review of the literature examining the co-occurrence of migraine and FND. We also explored their comorbidities, aetiological risk factors and mechanisms, focusing especially on areas of potential overlap. Our review suggests increased frequency of migraine in people with functional seizures compared to epilepsy, but data from people with functional motor symptoms is mixed. Robust epidemiological studies evaluating the frequency of FND in migraine are lacking. Similar to other neurological disorders, migraine is an established trigger of FND. Female gender, adverse childhood experiences and comorbid psychiatric and functional disorders, such as irritable bowel syndrome and fibromyalgia, are more common in both conditions than in controls, but perhaps more so in FND. Mechanistic research in both conditions highlights converging frameworks of dysregulated allostatic/stress responses in the context of predictive processing models of the brain. This has implications for pharmaceutical and rehabilitation treatments. The relationship between migraine and FND is poorly studied. An overview of their overlap offers a model of non-dualistic thinking within a clinical neuroscience framework for future studies.

Recent reports support the startling conclusion that peripheral nociceptors, the first link in pain transmission, are sexually dimorphic. The mechanisms promoting pain in men and women are therefore likely to be different, suggesting the need to consider patient sex as a factor in managing pain and painful conditions such as migraine. Many patients do not achieve sufficient benefit from available therapies and migraine therefore remains a major unmet medical need. The concept of sexual dimorphism in pain mechanism reveals previously unrecognized gaps in knowledge of migraine pathophysiology and in treatment outcomes. As migraine is highly female prevalent, our knowledge is based on studies conducted predominately in women. Data from these studies have rarely been analyzed and reported based on sex, limiting our interpretation of the occurrence, timing and severity of disease symptoms as well as possible differences in treatment efficacy in men. Inclusion of a higher proportion of men in both mechanistic investigations and clinical trials is therefore needed. Advancing our knowledge and improving therapeutic outcomes will require both preclinical and clinical investigations that address the contribution of sex in headache pain and other non-painful symptoms of migraine that impact the quality of life for patients. This viewpoint highlights the importance of considering sex as a variable in advancing our understanding of migraine pathophysiology and therapy. Consideration of patient sex could influence current clinical practice and the design of clinical studies.

Abstract Objective To estimate the real‐world risk of cardiovascular events among patients with migraine treated with erenumab and other migraine preventive medications. Background Migraine preventive treatment with calcitonin gene‐related peptide (CGRP) pathway inhibitors, such as erenumab and others, may theoretically result in cardiovascular effects due to a lack of compensatory vasodilation with CGRP pathway inhibition. Methods In this retrospective observational cohort study, we estimated the unadjusted cumulative risk (CR) of new‐onset hypertension, acute myocardial infarction (MI), or stroke among patients with migraine newly treated with erenumab, other anti‐CGRP pathway monoclonal antibodies (mAbs), standard oral preventive medications, and onabotulinumtoxinA using data from the MarketScan® Commercial and Medicare Supplemental medical claims database. Comparative analyses to assess the relative risk (RR) of vascular events were gated on the comparability of treatment groups with respect to baseline demographics and clinical characteristics. Potential bias due to unmeasured confounding was evaluated via negative control outcome (NCO) analyses. Confounding based on measured covariates and differential informative censoring were addressed with inverse probability weights. Results A total of 108,019 new users of migraine preventive medications were included. Unadjusted CR (95% confidence interval [CI]) of hypertension at 12 months of treatment was: erenumab, 9.34% (8.79–9.89%); other anti‐CGRP pathway mAbs, 9.42% (8.92–9.92%); standard oral preventive medications, 9.09% (8.77–9.41%); and onabotulinumtoxinA, 9.10% (8.39–9.81%). NCO analyses identified minimal concerns related to unmeasured confounding in erenumab versus other mAbs and erenumab versus onabotulinumtoxinA comparisons. Adjusted RRs (95% CIs) of acute MI and stroke, respectively, at 36 months of treatment were 1.02 (0.45–1.59) and 0.90 (0.56–1.25) for erenumab versus other mAbs and 0.87 (0.19–1.55) and 0.97 (0.42–1.52) for erenumab versus onabotulinumtoxinA. Conclusions In this analysis of the MarketScan medical claims database, we found no difference in the risk of vascular events in patients treated with erenumab versus other anti‐CGRP pathway mAbs or onabotulinumtoxinA.

Background Traumatic brain injury (TBI) commonly elicits acute (APTH) and/or persistent (PPTH) post-traumatic headache. Calcitonin gene related peptide (CGRP) has been implicated as a contributor to PTH pathophysiology. We explored the possibility of sexual dimorphism in the effects of CGRP receptor (CGRP-R) blockade in a preclinical model of PTH induced by a mild TBI (mTBI) in male or female mice. Methods Mice were lightly anesthetized and placed on a tissue paper stage prior to receiving a sham procedure or mTBI resulting from a closed-head weight drop injury. Behavioral responses to periorbital and hindpaw tactile (von Frey filaments) or thermal (hot plate) stimuli over the first 14 days post-mTBI were evaluated as measures of APTH. The PPTH phase was studied following the resolution of mTBI-induced APTH at days 14 and 28. PPTH was precipitated by exposure to bright lights (i.e., bright light stress, BLS). Olcegepant was delivered subcutaneously either repeatedly beginning 2 h after mTBI to produce a sustained block of CGRP-R signaling across the APTH phase, or as a single administration on days 14 or 28 post-mTBI to evaluate possible effects during the PPTH phase. Results mTBI, but not sham-procedure, produced periorbital and hindpaw tactile allodynia, as well as thermal hypersensitivity in mice of both sexes. APTH-related hypersensitivity was transient and resolved by day 14 post-injury. No sex differences were observed in the magnitude or duration of APTH-related pain behaviors. Sustained CGRP-R blockade was, however, significantly more effective in female than male mice in inhibiting pain behaviors in the APTH phase and in preventing the emergence of BLS-induced PPTH. CGRP-R blockade following the resolution of mTBI-induced APTH pain behaviors, on either day 14 or 28, minimally altered BLS-induced PPTH in either sex. Conclusions Sustained CGRP-R blockade starting soon after mTBI significantly inhibited APTH and prevented the expression of PPTH with greater analgesic effects in females compared to males. Delayed CGRP-R blockade beginning after resolution of APTH phase was minimally effective in preventing expression of PPTH in either sex. These data are consistent with previous observations that CGRP induces pain behaviors preferentially in females. Early and continuous CGRP blockade following mTBI may represent a viable treatment option for PTH treatment and the prevention of PTH persistence, especially in females.

Background Acute therapies targeting calcitonin gene-related peptide (CGRP) for episodic migraine (EM) demonstrate efficacy in women, but evidence of efficacy in men remains to be established. By contrast, CGRP targeting therapies for migraine prevention are effective in both men and women with frequent EM or chronic migraine (CM). Preclinical studies have shown that supradural application of CGRP preferentially produces migraine-like pain behaviors in female rodents. We hypothesized that, in male mice, increased frequency of migraine-like pain may sensitize to nociceptive effects of CGRP and this might be associated with altered expression of CGRP in trigeminal ganglion (TG) neurons and/or in their dural projections. Methods CM was modeled in male and female mice by repeated administration of nitroglycerin (NTG). Medication overuse headache (MOH), a form of CM, was modeled by repeated daily administration of sumatriptan. Following resolution of transient cutaneous allodynia (CA) elicited by NTG or sumatriptan, mice received a sex specific subthreshold dose of supradural CGRP that does not elicit CA in naïve male or female mice, and CA was evaluated. CGRP-positive cell bodies in the ophthalmic V1 region of the trigeminal ganglion (TGV1) and CGRP-positive nerve fibers innervating the dura mater were assessed. Results Supradural administration of 1 pg of CGRP produced migraine-like pain behaviors in female, but not male, mice; a ten-fold lower dose was established as subthreshold in naïve female mice. Repeated NTG or sumatriptan produced transient CA in both female and male mice that resolved within 8–11 days after treatment cessation. Following resolution of CA, previously subthreshold doses of CGRP elicited CA in CM and MOH models in mice of both sexes, with no effects observed in vehicle treated controls. A higher number of CGRP-positive neurons in the TGV1 was found in naïve female compared to male mice. The number of CGRP-positive TGV1 neurons was increased in both sexes following repeated NTG. Similar nerve fiber density was observed in the dura mater of male and female mice and no differences were detected following repeated NTG. Conclusions As previously reported, CGRP produced female-selective migraine-like pain behaviors in naïve mice. Consistent with behavioral effects, female mice demonstrated a higher number of CGRP-positive cells in the TGV1. These findings appear relevant to clinical observations of female efficacy of CGRP-receptor antagonists for acute treatment in EM patients. In models of CM or MOH that are characterized by increased frequency of migraine-like pain, previously subthreshold doses of supradural CGRP now elicited migraine-like nociceptive behaviors in mice of both sexes. The increased pain responses were accompanied by increased number CGRP positive TGV1 cells in the NTG model in both female and male mice. These data suggest that increased frequency of migraine promotes physiological changes including increased expression of TGV1 CGRP along with sensitization to CGRP-induced nociception in both males and females. Thus, as EM transforms to CM, CGRP-dependent mechanisms may become increasingly important, consistent with observations of efficacy of CGRP targeting therapies for migraine prevention in both men and women. Our results also suggest the possibility of enhanced efficacy of CGRP-receptor antagonists for the acute treatment of migraine in men as migraine frequency increases.