Genetics of migraine: where are we now?

Migraine is a complex brain disorder explained by the interaction of genetic and environmental factors. In monogenic migraines, including familial hemiplegic migraine and migraine with aura associated with hereditary small-vessel disorders, the identified genes code for proteins expressed in neurons, glial cells, or vessels, all of which increase susceptibility to cortical spreading depression. The study of monogenic migraines has shown that the neurovascular unit plays a prominent role in migraine. Genome-wide association studies have identified numerous susceptibility variants that each result in only a small increase in overall migraine risk. The more than 180 known variants belong to several complex networks of "pro-migraine" molecular abnormalities, which are mainly neuronal or vascular. Genetics has also highlighted the importance of shared genetic factors between migraine and its major co-morbidities, including depression and high blood pressure. Further studies are still needed to map all of the susceptibility loci for migraine and then to understand how these genomic variants lead to migraine cell phenotypes.

Circulating microRNAs Associated With Reversible Cerebral Vasoconstriction Syndrome.

OBJECTIVE: The purpose of this study was to investigate the significance of circulating micro RNAs (miRNAs) in the pathogenesis of reversible cerebral vasoconstriction syndrome (RCVS). METHODS: We prospectively recruited 3 independent cohorts of patients with RCVS and age-matched and sex-matched controls in a single medical center. Next-generation small RNA sequencing followed by quantitative polymerase chain reaction (PCR) was used to identify and validate differentially expressed miRNAs, which was cross-validated in migraine patients in ictal stage or interictal stage. Computational analysis was used to predict the target genes of miRNAs, followed by in vitro functional analysis. RESULTS: We identified a panel of miRNAs including miR-130a-3p, miR-130b-3p, let-7a-5p, let-7b-5p, and let-7f-5p that well differentiated patients with RCVS from controls (area under the receiver operating characteristics curve [AUC] was 0.906, 0.890, and 0.867 in the 3 cohorts, respectively). The abundance of let-7a-5p, let-7b-5p, and let-7f-5p, but not miR-130a-3p nor miR-130b-3p, was significantly higher in patients with ictal migraine compared with that of controls and patients with interictal migraine. Target prediction and pathway enrichment analysis suggested that the transforming growth factor-ß signaling pathway and endothelin-1 responsible for vasomotor control might link these miRNAs to RCVS pathogenesis, which was confirmed in vitro by transfecting miRNAs mimics or incubating the patients' cerebrospinal fluid (CSF) in 3 different vascular endothelial cells. Moreover, miR-130a-3p was associated with imaging-proven disruption of the blood-brain barrier (BBB) in patients with RCVS and its overexpression led to reduced transendothelial electrical resistance (ie, increased permeability) in in vitro human BBB model. INTERPRETATION: We identified the circulating miRNA signatures associated with RCVS, which may be functionally linked to its headache, BBB integrity, and vasomotor function. ANN NEUROL 2021;89:459-473.

Effectiveness of onabotulinumtoxinA (BOTOX®) for the preventive treatment of chronic migraine: A meta-analysis on 10 years of real-world data.

BACKGROUND: This meta-analysis evaluated the real-world effectiveness of onabotulinumtoxinA (BOTOX®), the first preventive treatment FDA-approved specifically for chronic migraine in 2010. METHODS: We systematically reviewed onabotulinumtoxinA observational data in chronic migraine published between 1 January 2010 and 31 March 2021. Random-effects models evaluated available data for primary and secondary endpoints defined in onabotulinumtoxinA pivotal trials at approximately 24 weeks and 52 weeks. RESULTS: Of the 44 full-text eligible studies (29 prospective; 13 retrospective; 2 other), seven evaluated change from baseline (mean[confidence interval]) at ∼24 weeks and ∼52 weeks, respectively, for onabotulinumtoxinA in: number of headache days/month: (-10.64 [-12.31, -8.97]; -10.32 [-14.92, -5.73]); number of days of acute headache pain medication intake per month (-7.40 [-13.04, -1.77]; overlapping CIs at 52 weeks); total Headache Impact Test-6 score (-11.70 [-13.86, -9.54]); -11.80 [14.70, -8.90]); and Migraine-Specific Quality-of-Life v2.1 score (MSQ; 23.60 [CI: 21.56, 25.64]; 30.90 [CI: 28.29, 33.51]). At ∼24 weeks onabotulinumtoxinA showed total Migraine Disability Assessment score of 44.74 [28.50, 60.99] and ≥50% reduction in migraine days response rate of 46.57% [29.50%, 63.65%]. A sensitivity analysis at study-end suggested durability of onabotulinumtoxinA effectiveness on MSQ. CONCLUSION: The meta-analysis reflecting real-world practice broadly corroborated with evidence from pivotal and long-term open-label studies of onabotulinumtoxinA in chronic migraine preventive treatment.

Diagnostic utility of T2*-weighted GRE in migraine with aura attack. The cortical veins sign.

OBJECTIVE: To evaluate the frequency, distribution, and clinical associations of the dilated appearance of cerebral cortical veins, termed cortical veins sign on T2*-weighted gradient recalled-echo (T2*-GRE) in the acute setting of migraine with aura attack in adult patients. METHODS: We conducted a retrospective analysis of 60 consecutive patients admitted for acute neurological symptoms with a final diagnosis of migraine with aura (42%) or probable migraine with aura (58%) who underwent emergency brain magnetic resonance imaging and 60 non-migrainous control adults. The cortical veins sign was defined as a marked hypo-intensity and/or an apparent increased diameter of at least one cortical vein. We examined the prevalence, the spatial distribution, and the associations of cortical veins sign with clinical characteristics of migraine with aura. RESULTS: We detected the cortical veins sign in 25 patients (42%) with migraine with aura, compared to none in the control group (p < 0.0001). The spatial distribution of cortical veins sign was characterised by the predominantly bilateral and posterior location. Presence of cortical veins sign was associated with increased severity of aura (p = 0.05), and shorter delay to MRI (p = 0.02). CONCLUSION: In the setting of acute neurological symptoms, the presence of cortical veins sign is frequent in patients with migraine with aura and can be detected with good reliability. This imaging marker may help clinicians identify underlying migraine with aura.

Type of headache at onset and risk for complications in reversible cerebral vasoconstriction syndrome.

BACKGROUND: In a recent Italian study, 30% of patients with reversible cerebral vasoconstriction syndrome (RCVS) presented without thunderclap headache (TCH), and tended to present more severe forms of RCVS than patients with TCH. We aimed to analyze the risk for complications of RCVS in patients with and without TCH at onset. METHODS: In a pooled cohort of 345 French patients with RCVS, we compared patients with and without TCH at onset regarding rates of neurological complications, and the functional outcome at 3 months. RESULTS: As compared to the 281 patients with TCH at onset, the 64 patients without TCH had a higher risk for any neurological complication (61% vs. 24%, OR 4.9, 95% CI 2.8-8.7, p < 0.001). The association was strongest for cervical artery dissections (28% vs. 5%, OR 8.1, 95% CI 3.7-17.6, p < 0.001), followed by posterior reversible encephalopathy syndrome (17% vs. 3%, OR 7.1, 95% CI 2.7-18.4, p < 0.001), seizures (9% vs. 2.5%, OR 4.1, 95% CI 1.3-12.5, p = 0.019), and subarachnoid hemorrhage (41% vs. 16%, OR 3.5, 95% CI 1.9-6.3, p < 0.001). In multivariable analysis, the risk for any neurological complication remained significantly elevated in the absence of TCH (OR 3.5, 95% CI 1.8-6.8, p < 0.001). The functional outcome was equal in both groups, with a modified Rankin scale score of 0-1 in ≥90% of patients. CONCLUSIONS: Absence of TCH at onset might predict a higher risk of complications in RCVS. Our results warrant further multicentric studies to prove this finding.

The teaching of headache medicine in France: A questionnaire-based study.

BACKGROUND: The treatment of patients with headache represents an important part of a neurologist's activity. It requires sufficient training for neurology residents. In France, residents in neurology can complete this training by attending specialized consultations or by participating in a postgraduate training program called "Diplôme Inter-Universitaire Migraine et Céphalées" (DIUMC). OBJECTIVE: The objective of this cross-sectional study was to investigate the French residents' knowledge in headache medicine and the impact of different types of training in headache medicine that are available in France. METHODS: An anonymous survey was carried out among 548 French residents in neurology. RESULTS: The questionnaires of 121 residents (22.1%) were analyzed. Among them, 54.5% (66/121) had no complementary training apart from the internship (Group 1), 21.5% (26/121) had attended only specialized consultations (Group 2), and 24% (29/121) had participated in the DIUMC (Group 3). There was no difference between all groups regarding the knowledge of the prevalence of primary or chronic headaches. There was almost no difference between the groups in the management of episodic migraine. In contrast, the management of tension-type headache and chronic headache was better known by residents of Group 3 than residents of Group 1. In these two diseases, residents of Group 3 offered prophylactic treatment more often. Almost 29% of the residents (35/121) had read the French guidelines for the diagnosis and management of migraine. In Group 3, residents had read them significantly more often (1.6% in Group 1, 38.5% in Group 2 and 62.1% in Group 3, p < 0.001). CONCLUSION: This study shows the lack of knowledge among French neurology residents regarding headache medicine. It highlights the interest of specific training programs that could improve the practical and theoretical knowledge of future neurologists.

Outcomes among patients with primary angiitis of the CNS: A Nationwide United States analysis.

BACKGROUND: Primary angiitis of the central nervous system (PACNS) is a relapsing-remitting disease with a heterogeneous course. Case series have delineated the long-term disease course but not acute outcomes or their determinants. The national United States hospital burden of PACNS has not been quantified. METHODS: Analysis of the United States Nationwide Readmissions Database (2016-2018) to characterize the frequency of PACNS hospitalizations, demographic features, inpatient mortality, and discharge outcomes. RESULTS: During the 3-year study period, unweighted 1843 (weighted 3409) patients with PACNS were admitted to the 1078 Healthcare Cost and Utilization Project HCUP participating hospitals; with weighting, this value indicates that 1136 patients were admitted each year to US hospitals, representing yearly 0.01 cases per 100 000 national hospitalizations. The majority of patients were hospitalized in metropolitan teaching hospitals (81.6%). The median age at admission was 54.9 (IQR: 44.0-66.5) years and 59.4% were women. Neurologic manifestations included ischemic stroke in 38.2%, transient ischemic attack in 20.2%, seizure disorder in 22.8%, and intracranial hemorrhage in 13.0%. Overall, 60.0% of patients were discharged home, 35.0% discharged to a rehabilitation facility or nursing home and 5.0% died before discharge. Patient features independently associated with the discharge to another facility or death included older age (odds ratio [OR], 1.03 [95% CI, [1.03-1.04]]), male sex (OR, 1.22 [1.04-1.43]), intraparenchymal hemorrhage (OR, 1.41 [1.08-1.84]), ischemic stroke (OR, 2.79 [2.38-3.28]), and seizure disorder (OR, 1.57 [1.31-1.89]). CONCLUSION: Our study showed PACNS is still a rare inflammatory disorder of the blood vessels of the central nervous system suggesting an annual hospitalization of 5.1 cases per 1,000,000 person-years in the more diverse and contemporary US population. Overall, 4 in 10 had unfavorable discharge outcome, being unable to be discharged home, and 1 in 20 died before discharge.

European Headache Federation (EHF) consensus on the definition of effective treatment of a migraine attack and of triptan failure.

BACKGROUND: Triptans are migraine-specific acute treatments. A well-accepted definition of triptan failure is needed in clinical practice and for research. The primary aim of the present Consensus was to provide a definition of triptan failure. To develop this definition, we deemed necessary to develop as first a consensus definition of effective treatment of an acute migraine attack and of triptan-responder. MAIN BODY: The Consensus process included a preliminary literature review, a Delphi round and a subsequent open discussion. According to the Consensus Panel, effective treatment of a migraine attack is to be defined on patient well-being featured by a) improvement of headache, b) relief of non-pain symptoms and c) absence of adverse events. An attack is considered effectively treated if patient's well-being, as defined above, is restored within 2 hours and for at least 24 hours. An individual with migraine is considered as triptan-responder when the given triptan leads to effective acute attack treatment in at least three out of four migraine attacks. On the other hand, an individual with migraine is considered triptan non-responder in the presence of failure of a single triptan (not matching the definition of triptan-responder). The Consensus Panel defined an individual with migraine as triptan-resistant in the presence of failure of at least 2 triptans; triptan refractory, in the presence of failure to at least 3 triptans, including subcutaneous formulation; triptan ineligibile in the presence of an acknowledged contraindication to triptan use, as specified in the summary of product characteristics. CONCLUSIONS: The novel definitions can be useful in clinical practice for the assessment of acute attack treatments patients with migraine. They may be helpful in identifying people not responding to triptans and in need for novel acute migraine treatments. The definitions will also be of help in standardizing research on migraine acute care.

Outcomes Among Patients With Reversible Cerebral Vasoconstriction Syndrome: A Nationwide United States Analysis.

BACKGROUND AND PURPOSE: Reversible cerebral vasoconstriction syndrome (RCVS) is a well-established cause of stroke, but its demographics and outcomes have not been well delineated. METHODS: Analysis of the United States Nationwide Inpatient Sample database (2016-2017) to characterize the frequency of hospitalizations for RCVS, demographic features, inpatient mortality, and discharge outcomes. RESULTS: During the 2-year study period, 2020 patients with RCVS were admitted to Nationwide Inpatient Sample hospitals, representing 0.02 cases per 100 000 national hospitalizations. The mean age at admission was 47.6 years, with 85% under 65 years of age, and 75.5% women. Concomitant neurological diagnoses during hospitalization included ischemic stroke (17.1%), intracerebral hemorrhage (11.0%), subarachnoid hemorrhage (32.7%), seizure disorders (6.7%), and reversible brain edema (13.6%). Overall, 70% of patients were discharged home, 29.7% discharged to a rehabilitation facility or nursing home and 0.3% died before discharge. Patient features independently associated with the poor outcome of discharge to another facility or death were advanced age (odds ratio [OR], 1.04 [95% CI, 1.03-1.04]), being a woman (OR, 2.45 [1.82-3.34]), intracerebral hemorrhage (OR, 2.91 [1.96-4.31]), ischemic stroke (OR, 5.72 [4.32-7.58]), seizure disorders (OR, 2.61 [1.70-4.00]), reversible brain edema (OR, 6.26 [4.41-8.89]), atrial fibrillation (OR, 2.97 [1.83-4.81]), and chronic kidney disease (OR, 3.43 [2.19-5.36]). CONCLUSIONS: Projected to the entire US population, >1000 patients with RCVS are hospitalized each year, with the majority being middle-aged women, and about 300 required at least some rehabilitation or nursing home care after discharge. RCVS-related inpatient mortality is rare.

Severe migraine and its control: A proposal for definitions and consequences for care.

Currently many patients with severe migraine do not receive appropriate treatment and are never referred to specialist headache centres. On the other hand, specialist headache centres are frequently attended by patients whose migraines could be managed adequately in the community. One reason for this may be the absence of standardised definitions of migraine severity and control and of a treatment algorithm for orientating difficult-to-treat patients to specialist headache centres. Based on a review of the relevant literature and consensus meetings, proposals have been made for these items. We propose that migraine should be considered severe if headache frequency is at least eight migraine days per month or, if headaches are less frequent, the HIT-6 score is ≥60 or ≥50% of headaches require complete interruption of activity. The proposed definition of migraine control is defined on the basis of appropriate response to acute headache therapy and to preventative therapy. A treatment algorithm is proposed to assess migraine control regularly and to adapt therapy accordingly. These proposals may contribute to developing and testing strategies for management of severe disease with appropriate and effective preventive treatment strategies. With the anticipated introduction of new possibilities for migraine prevention in the near future, the time is ripe for a holistic approach to migraine management.

Burden and attitude to resistant and refractory migraine: a survey from the European Headache Federation with the endorsement of the European Migraine & Headache Alliance.

BACKGROUND: New treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts). The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions. METHODS: We conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care. RESULTS: There were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care. CONCLUSIONS: This report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities.

Long-Term Outcomes After Reversible Cerebral Vasoconstriction Syndrome.

Background and Purpose- We aimed to further investigate the long-term outcomes after reversible cerebral vasoconstriction syndrome (RCVS). Methods- A longitudinal follow-up study was conducted in 173 RCVS patients. Results- Of the 172 patients who completed a mean follow-up of 9.2±3.3 years, 10 had a recurrent RCVS that was benign in all. Independent predictors of relapse were having a history of migraine and having exercise as a trigger for thunderclap headache during initial RCVS. After new delivery, the rate of postpartum RCVS was 9%. Conclusions- Overall, long-term outcome after RCVS is excellent.

European headache federation consensus on the definition of resistant and refractory migraine : Developed with the endorsement of the European Migraine & Headache Alliance (EMHA).

INTRODUCTION: Despite advances in the management of headache disorders, some patients with migraine do not experience adequate pain relief with acute and preventive treatments. It is the aim of the present document to provide a definition of those migraines which are difficult-to-treat, to create awareness of existence of this group of patients, to help Healthcare Authorities in understanding the implications, and to create a basis to develop a better pathophysiological understanding and to support further therapeutic advances. MAIN BODY: Definitions were established with a consensus process using the Delphi method. Patients with migraine with or without aura or with chronic migraine can be defined as having resistant migraine and refractory migraine according to previous preventative failures. Resistant migraine is defined by having failed at least 3 classes of migraine preventatives and suffer from at least 8 debilitating headache days per month for at least 3 consecutive months without improvement; definition can be based on review of medical charts. Refractory migraine is defined by having failed all of the available preventatives and suffer from at least 8 debilitating headache days per month for at least 6 consecutive months. Drug failure may include lack of efficacy or lack of tolerability. Debilitating headache is defined as headache causing serious impairment to conduct activities of daily living despite the use of pain-relief drugs with established efficacy at the recommended dose and taken early during the attack; failure of at least two different triptans is required. CONCLUSIONS: We hope, that the updated EHF definition will be able to solve the conflicts that have limited the use of definitions which have been put forward in the past. Only with a widely accepted definition, progresses in difficult-to-treat migraine can be achieved. This new definition has also the aim to increase the understanding of the impact of the migraine as a disease with all of its social, legal and healthcare implications. It is the hope of the EHF Expert Consensus Group that the proposed criteria will stimulate further clinical, scientific and social attention to patients who suffer from migraine which is difficult-to-treat.

A Clinico-Radiological Study of Cerebral Amyloid Angiopathy-Related Inflammation.

OBJECTIVE: To describe the clinico-radiological features and long-term prognosis in patients with cerebral amyloid angiopathy-related inflammation (CAA-ri). METHODS: Twenty-eight CAA-ri patients were recruited retrospectively from 6 neurological centers. We recorded the clinico-radiological and biological data, at baseline and during follow-up. Baseline characteristics associated with relapse risk and prognosis were assessed. RESULTS: Five patients had pathologically confirmed CAA-ri whereas 23 had probable (n = 21) or possible (n = 2) CAA-ri. The mean age was 72 years; main clinical symptoms included confusion (54%), hemiparesis (36%), and aphasia (29%). Cerebral MRI disclosed a brain parenchymal lesion (89%), which was usually multifocal (82%) and bilateral (89%). It was associated with gadolinium enhancement (84%), small ischemic lesions (39%), cortical superficial siderosis (CSS; 50%), and a high number of microbleeds (mean 240 ± 277). An isolated leptomeningeal involvement was observed in 3 patients with pathological confirmation. Despite a favorable initial evolution after treatment, we observed a 42% risk of relapse, mostly within the first year (83%). After a mean follow-up of 2 years, 29% died and 25% had a marked disability. Disseminated CSS was associated with death. CONCLUSION: Despite an apparently favorable initial evolution, CAA-ri is characterized by a poor prognosis. Diagnostic criteria should consider patients with isolated leptomeningeal involvement.

Migraine with brainstem aura: Why not a cortical origin?

Background Migraine with brainstem aura is defined as a migraine with aura including at least two of the following symptoms: dysarthria, vertigo, tinnitus, hypacusis, diplopia, ataxia and/or decreased level of consciousness. Aim The aim of this study is to review data coming from clinical observations and functional mapping that support the role of the cerebral cortex in the initiation of brainstem aura symptoms. Results Vertigo can result from a vestibular cortex dysfunction, while tinnitus and hypacusis can originate within the auditory cortex. Diplopia can reflect a parieto-occipital involvement. Dysarthria can be caused by dysfunctions located in precentral gyri. Ataxia can reflect abnormal processing of vestibular, sensory, or visual inputs by the parietal lobe. Alteration of consciousness can be caused by abnormal neural activation within specific consciousness networks that include prefrontal and posterior parietal cortices. Conclusion Any symptom of so-called brainstem aura can originate within the cortex. Based on these data, we suggest that brainstem aura could have a cortical origin. This hypothesis would explain the co-occurrence of typical and brainstem aura during attacks and would fit with the theory of cortical spreading depression. We propose that migraine with brainstem aura should be classified as a typical migraine aura.

Reversible cerebral vasoconstriction syndrome in the context of recent cerebral venous thrombosis: Report of a case.

INTRODUCTION: Reversible cerebral constriction syndrome and cerebral venous thrombosis are two rare conditions. Reversible cerebral constriction syndrome affects the cerebral arteries and the pathology is still largely unknown. To date, no physiological link with cerebral venous thrombosis has been reported. CASE RESULTS: We report here the case of a 24-year-old woman who presented a reversible cerebral constriction syndrome in the setting of a cerebral venous thrombosis. Cerebral venous thrombosis had developed in her left lateral venous sinus, within the stent placed one year before, in order to treat an idiopathic intracranial hypertension. DISCUSSION: The co-occurrence of cerebral venous thrombosis and reversible cerebral constriction syndrome in the same patient raises the issue of a potential link between them. We discuss the potential common trigger factors in this case: recent hormonal therapy; intracranial hypotension iatrogenically induced by lumbar puncture.

The Typical Thunderclap Headache of Reversible Cerebral Vasoconstriction Syndrome and its Various Triggers.

During the last 10 years, reversible cerebral vasoconstriction syndrome (RCVS) has emerged as the most frequent cause of thunderclap headache (TCH) in patients without aneurysmal subarachnoid hemorrhage, and as the most frequent cause of recurrent TCHs. The typical TCHs of RCVS are multiple, recurring over a few days to weeks, excruciating, short-lived, and brought up by exertion, sexual activities, emotion, Valsalva maneuvers, or bathing, among other triggers. All these triggers induce sympathetic activation. In a minority of cases with RCVS, TCH heralds stroke and rarely death. Early diagnosis of RCVS in patients who present with isolated headache enables proper management and might reduce the risk of eventual stroke. This review describes the characteristics, triggers, diagnosis, and management of TCH in RCVS. One aim is to underline that the TCH pattern of RCVS is so typical that it enables, according to the 2013 revision of the International Classification of Headache Disorders, the diagnosis of "probable RCVS" in patients with such a headache pattern, normal cerebral angiography, and no other cause. Another objective is to discuss the role of physical and emotional stress in RCVS and in other related conditions involving similar triggers.

Reversible Cerebral Vasoconstriction Syndrome Without Typical Thunderclap Headache.

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe headache and diffuse segmental intracranial arterial constriction that resolve within three months. Stroke, which is the major complication of RCVS, can result in persistent neurological disability, and rarely causes death. Diagnosis of RCVS early in the clinical course might improve outcomes. Although recurrent thunderclap headache is the clinical hallmark of RCVS, the absence of such a pattern should not lead to discard the diagnosis. Our literature review shows that RCVS can also manifest as an unspecific headache, such as a single severe headache episode, a mild or a progressive headache. Moreover, a subset of patients with severe RCVS presents without any headache, but frequently with seizures, focal neurological deficits, confusion or coma, in the setting of stroke or posterior reversible encephalopathy syndrome. These patients may be aphasic or in comatose state, explaining their inability to give their own medical history. They may have forgotten the headache they had a few days before more dramatic symptoms, or may have a variant of the classical RCVS. By consequence, an RCVS should be suspected in patients with any unusual headache, whether thunderclap or not, and in patients with cryptogenic stroke or convexity subarachnoid hemorrhage, whether the patient also has headache or not. Diagnosis in such cases relies on the demonstration of reversible multifocal intracranial arterial stenosis and the exclusion of other causes.

The Link Between Migraine, Reversible Cerebral Vasoconstriction Syndrome and Cervical Artery Dissection.

Headache is the common thread of migraine, reversible cerebral vasoconstriction syndrome (RCVS) and cervical artery dissection (CeAD), three medical conditions that otherwise appear to be very different. However, epidemiological, clinical and genetic data suggest that these conditions share common and complex features and are, at least partly, linked. The purpose of this manuscript is to review existing evidence for an association between migraine, RCVS and CeAD and discuss the potential underlying mechanisms.