Cerebral Amyloid Angiopathy-Related Inflammation and Biopsy-Positive Primary Angiitis of the CNS: A Comparative Study.

BACKGROUND AND OBJECTIVES: Cerebral amyloid angiopathy-related inflammation (CAA-RI) and biopsy-positive primary angiitis of the CNS (BP-PACNS) have overlapping clinicoradiologic presentations. It is unknown whether clinical and radiologic features can differentiate CAA-RI from BP-PACNS and whether both diseases have different relapse rates. The objectives of this study were to compare clinicoradiologic presentations and relapse rates in patients with CAA-RI vs BP-PACNS. METHODS: Patients with CAA-RI and BP-PACNS were enrolled from 2 retrospective multicenter cohorts. Patients with CAA-RI were biopsy-positive or met probable clinicoradiologic criteria. Patients with BP-PACNS had histopathologic confirmation of CNS angiitis, with no secondary etiology. A neuroradiologist read brain MRIs, blinded to the diagnosis of CAA-RI or BP-PACNS. Clinicoradiologic features were compared using univariable logistic regression models. Relapse rates were compared using a univariable Fine-Gray subdistribution hazard model, with death as a competing risk. RESULTS: This study enrolled 104 patients with CAA-RI (mean age 73 years, 48% female sex) and 52 patients with BP-PACNS (mean age 45 years, 48% female sex). Patients with CAA-RI more often had white matter hyperintense lesions meeting the probable CAA-RI criteria (93% vs 51%, p < 0.001), acute subarachnoid hemorrhage (15% vs 2%, p = 0.02), cortical superficial siderosis (27% vs 4%, p < 0.001), ≥1 lobar microbleed (94% vs 26%, p < 0.001), past intracerebral hemorrhage (17% vs 4%, p = 0.04), ≥21 visible centrum semiovale perivascular spaces (34% vs 4%, p < 0.01), and leptomeningeal enhancement (70% vs 27%, p < 0.001). Patients with BP-PACNS more often had headaches (56% vs 31%, p < 0.01), motor deficits (56% vs 36%, p = 0.02), and nonischemic parenchymal gadolinium enhancement (82% vs 16%, p < 0.001). The prevalence of acute ischemic lesions was 18% in CAA-RI and 22% in BP-PACNS (p = 0.57). The features with the highest specificity for CAA-RI were acute subarachnoid hemorrhage (98%), cortical superficial siderosis (96%), past intracerebral hemorrhage (96%), and ≥21 visible centrum semiovale perivascular spaces (96%). The probable CAA-RI criteria had a 71% sensitivity (95% CI 44%-90%) and 91% specificity (95% CI 79%-98%) in differentiating biopsy-positive CAA-RI from BP-PACNS. The rate of relapse in the first 2 years after remission was lower in CAA-RI than in BP-PACNS (hazard ratio 0.46, 95% CI 0.22-0.96, p = 0.04). CONCLUSION: Clinicoradiologic features differed between patients with CAA-RI and those with BP-PACNS. Specific markers for CAA-RI were hemorrhagic signs of subarachnoid involvement, past intracerebral hemorrhage, ≥21 visible centrum semiovale perivascular spaces, and the probable CAA-RI criteria. A biopsy remains necessary for diagnosis in some cases of CAA-RI. The rate of relapse in the first 2 years after disease remission was lower in CAA-RI than in BP-PACNS.

An AluYa5 Insertion in the 3'UTR of COL4A1 and Cerebral Small Vessel Disease.

Importance: Cerebral small vessel diseases (CSVDs) account for one-fifth of stroke cases. Numerous familial cases remain unresolved after routine screening of known CSVD genes. Objective: To identify novel genes and mechanisms associated with familial CSVD. Design, Setting, and Participants: This 2-stage study involved linkage analysis and a case-control study; linkage analysis and whole exome and genome sequencing were used to identify candidate gene variants in 2 large families with CSVD (9 patients with CSVD). Then, a case-control analysis was conducted on 246 unrelated probands, including probands from these 2 families and 244 additional probands. All probands (clinical onset

Mode and site of action of therapies targeting CGRP signaling.

Targeting CGRP has proved to be efficacious, tolerable, and safe to treat migraine; however, many patients with migraine do not benefit from drugs that antagonize the CGRPergic system. Therefore, this review focuses on summarizing the general pharmacology of the different types of treatments currently available, which target directly or indirectly the CGRP receptor or its ligand. Moreover, the latest evidence regarding the selectivity and site of action of CGRP small molecule antagonists (gepants) and monoclonal antibodies is critically discussed. Finally, the reasons behind non-responders to anti-CGRP drugs and rationale for combining and/or switching between these therapies are addressed.

Future targets for migraine treatment beyond CGRP.

BACKGROUND: Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides a comprehensive overview of the pathophysiological role of these possible non-CGRP targets in migraine. FINDINGS: We covered targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphodiesterase-3 (PDE3) and -5 (PDE5)), and ion channels (potassium, calcium, transient receptor potential (TRP), and acid-sensing ion channels (ASIC)). The majority of non-CGRP targets were able to induce migraine-like attacks, except for (i) calcium channels, as it is not yet possible to directly target channels to elucidate their precise involvement in migraine; (ii) TRP channels, activation of which can induce non-migraine headache; and (iii) ASICs, as their potential in inducing migraine attacks has not been investigated thus far. Drugs that target its receptors exist for PACAP, NO, and the potassium, TRP, and ASIC channels. No selective drugs exist for the other targets, however, some existing (migraine) treatments appear to indirectly antagonize responses to amylin, adrenomedullin, and calcium channels. Drugs against PACAP, NO, potassium channels, TRP channels, and only a PAC1 antibody have been tested for migraine treatment, albeit with ambiguous results. CONCLUSION: While current research on these non-CGRP drug targets has not yet led to the development of efficacious therapies, human provocation studies using these targets have provided valuable insight into underlying mechanisms of migraine headaches and auras. Further studies are needed on these alternative therapies in non-responders of CGRP(-receptor) targeted therapies with the ultimate aim to pave the way towards a headache-free future for all migraine patients.

Stroke phenotype in cannabis users among young adults with ischemic stroke.

BACKGROUND AND PURPOSE: Incidence of ischemic stroke in young adults has been steadily increasing over the past 20 years. One hypothesis to explain this phenomenon is the increase in the use of illicit drugs, including cannabis. However, the mechanisms and the clinical presentation of ischemic stroke associated with cannabis use are unclear. The objective of this study was to describe the phenotype of ischemic stroke in cannabis users compared to nonusers among a population of young adults with a first-ever ischemic stroke. METHODS: Patients aged 18-54 years consecutively hospitalized in a university department of neurology for a first-ever ischemic stroke from January 2017 to July 2021 were included. Drug use over the past year was assessed by a semistructured interview, and the stroke phenotype was described using the ASCOD classification. RESULTS: A total of 691 patients, including 78 of 691 (11.3%) cannabis users, were included. Cannabis use was independently associated with potential A1 (odds ratio [OR] = 3.30, 95% confidence interval [CI] = 1.45-7.5, p = 0.004) and uncertain A2 (OR = 13.1, 95% CI = 2.89-59.4, p < 0.001) atherosclerotic cause of stroke after adjustment for vascular risk factors including tobacco and other drug use. Moreover, the association of atherosclerosis and cannabis use was significant for frequent (OR = 3.13, 95% CI = 1.07-8.6, p = 0.030) and daily cannabis use (OR = 4.43, 95% CI = 1.40-13.4, p = 0.008), but not for occasional use. CONCLUSIONS: We found a significant, independent, and graded association of cannabis use with the atherosclerotic stroke phenotype.

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.

The premonitory phase of migraine is due to hypothalamic dysfunction: revisiting the evidence.

OBJECTIVE: To critically appraise the evidence for and against premonitory symptoms in migraine being due to hypothalamic dysfunction. DISCUSSION: Some premonitory symptoms (e.g. fatigue, mood changes, yawning, and food craving) are associated with the physiologic effects of neurotransmitters such as orexins, neuropeptide Y, and dopamine; all of which are expressed in hypothalamic neurons. In rodents, electrophysiologic recordings have shown that these neurotransmitters modulate nociceptive transmission at the level of second-order neurons in the trigeminocervical complex (TCC). Additional insights have been gained from neuroimaging studies that report hypothalamic activation during the premonitory phase of migraine. However, the available evidence is limited by methodologic issues, inconsistent reporting, and a lack of adherence to ICHD definitions of premonitory symptoms (or prodromes) in human experimental studies. CONCLUSIONS: The current trend to accept that premonitory symptoms are due to hypothalamic dysfunction might be premature. More rigorously designed studies are needed to ascertain whether the neurobiologic basis of premonitory symptoms is due to hypothalamic dysfunction or rather reflects modulatory input to the trigeminovascular system from several cortical and subcortical areas. On a final note, the available epidemiologic data raises questions as to whether the existence of premonitory symptoms and even more so a distinct premonitory phase is a true migraine phenomenon. Video recording of the debate held at the 1st International Conference on Advances in Migraine Sciences (ICAMS 2022, Copenhagen, Denmark) is available at: https://www.youtube.com/watch?v=d4Y2x0Hr4Q8 .

Insular functional connectivity in migraine with aura.

INTRODUCTION: Insula plays an integrating role in sensory, affective, emotional, cognitive and autonomic functions in migraine, especially in migraine with aura (MA). Insula is functionally divided into 3 subregions, the dorsoanterior, the ventroanterior and the posterior insula respectively related to cognition, emotion, and somatosensory functions. This study aimed at investigating functional connectivity of insula subregions in MA. METHODS: Twenty-one interictal patients with MA were compared to 18 healthy controls (HC) and 12 interictal patients with migraine without aura (MO) and were scanned with functional MRI during the resting state. Functional coupling of the insula was comprehensively tested with 12 seeds located in the right and left, dorsal, middle, ventral, anterior and posterior insula, by using a seed-to-voxel analysis. RESULTS: Seed-to-voxel analysis revealed, in MA, a strong functional coupling of the right and left antero-dorsal insula with clusters located in the upper cerebellum. The overlap of these cerebellar clusters corresponded to the vermis VI. These functional couplings were not correlated to duration of MA, frequency of MA attacks nor time since last MA attack, and were not found in MO. DISCUSSION: The anterior insula and superior cerebellum, including vermis VI, are components of the central Autonomic Nervous System (ANS) network. As these regions are involved in the control of cardiovascular parasympathetic tone, we hypothesize that this connectivity may reflect the cardiovascular features of MA. CONCLUSION: The anterior dorsal insula is connected with vermis VI in MA patients in the resting state. This connectivity may reflect the cardiovascular features of MA. TRIAL REGISTRATION: NCT02708797.

Ultrasound characteristics of carotid web.

BACKGROUND AND PURPOSE: Carotid web (CaW) is a cause of recurrent ischemic stroke that remains underdiagnosed using Duplex ultrasound (DUS). Improved methods and description of its ultrasound's features could allow better detection of CaW. Ultrasound microflow imaging (MFI) is a blood flow imaging technique sensitive to slow flow that could increase CaW detection. This study aimed to describe ultrasound features of CaW using B-mode imaging and MFI. METHODS: In a retrospective monocentric study, patients with CaW on CT angiography who underwent DUS examination of carotid arteries were included. DUS was performed by two nonblinded experienced neurosonologists. The specificity of CaW ultrasound features was evaluated using a group of patients with carotid atherosclerotic plaque (AP). RESULTS: Twenty-four patients with CaW were included. Mean age (standard deviation) was 48 years (11). Seventeen (71%) were females. Fifteen (63%) CaWs were symptomatic. MFI was available for 22 patients. B-mode imaging demonstrated the characteristic CaW appearance in 19/24 (79%) patients as a protruding triangular iso-hypoechoic lesion on longitudinal view. CaW were detected on axial view in only 9/24 (38%) patients. MFI displayed slow blood flow above CaW during systole and allowed it delineation, appearing as a thin triangular endoluminal defect in 18/22 (82%) cases. Based on MFI and B-mode, 21/22 (95%) CaWs were visible, including three CaWs only with MFI. These ultrasound features were not found among 24 patients with AP. CONCLUSION: We report the ultrasound features from a series of 24 CaW. The use of MFI in addition to B-mode imaging improved the detection rate of CaW.

Imaging the inflammatory phenotype in migraine.

Several preclinical and clinical lines of evidence suggest a role of neuroinflammation in migraine. Neuroimaging offers the possibility to investigate and localize neuroinflammation in vivo in patients with migraine, and to characterize specific inflammatory constituents, such as vascular permeability, and macrophage or microglia activity. Despite all imaging data accumulated on neuroinflammation across the past three decades, an overview of the imaging evidence of neuroinflammation in migraine is still missing.We conducted a systematic review in the Pubmed and Embase databases to evaluate existing imaging data on inflammation in migraine, and to identify gaps in the literature. We included 20 studies investigating migraine without aura (N = 4), migraine with aura (N = 8), both migraine with and without aura (N = 3), or hemiplegic migraine (N = 5).In migraine without aura, macrophage activation was not evident. In migraine with aura, imaging evidence suggested microglial and parameningeal inflammatory activity. Increased vascular permeability was mostly found in hemiplegic migraine, and was atypical in migraine with and without aura. Based on the weight of existing and emerging data, we show that most studies have concentrated on demonstrating increased vascular permeability as a marker of neuroinflammation, with tools that may not have been optimal. In the future, novel, more sensitive techniques, as well as imaging tracers delineating specific inflammatory pathways may further bridge the gap between preclinical and clinical findings.

Functional MRI in migraine.

PURPOSE OF REVIEW: The underlying mechanisms of migraine are complex and heterogenous. Advances in neuroimaging techniques during the past few decades have contributed to our understanding of migraine pathophysiology. Brain function in migraine patients has been widely explored using functional MRI (fMRI). This review will highlight the major fMRI findings that characterize the different phases of migraine. RECENT FINDINGS: The migraine attack starts with hypothalamic hyperexcitability and early reorganization of the common ascending pain and central trigeminovascular pathways. Moreover, the visual cortex becomes hyperexcitable during the aura phase. During the headache phase, further disruptions of the pontine, thalamic, sensorimotor and visual networks occur, although the hypothalamic activity and connectivity normalizes. The visual cortex remains hyperexcitable during the postdromal phase. Asymptomatic migraine patients can also experience functional alternations of pain and visual processing brain areas. At present, the heterogeneity of the asymptomatic phase and fMRI findings make it difficult to find common denominator. SUMMARY: fMRI studies have captured functional brain changes associated with migraine phases, leading to an improvement of our understanding of migraine pathophysiology. Further MRI studies are needed to disclose whether the migraine attack is triggered by intrinsic brain dysfunction or external factors.

Cryptogenic Ischemic Stroke in Migraine: Role of Patent Foramen Ovale.

Introduction: Migraine with aura (MWA) has been associated with cryptogenic ischemic stroke (CIS) after adjustment for the presence of a patent foramen ovale (PFO) assessed by a transcranial Doppler. This study aimed at evaluating the association of MWA with causal PFO assessed by Transesophageal echocardiography (TEE) in CIS. Methods: Patients aged 18-54 years consecutively treated for first acute ischemic stroke in a university hospital stroke unit, between January 2017 and December 2019, were included in this cross-sectional study. Associations between migraine subtypes and PFO were tested for all PFO, possibly causal PFO (PFO with large shunt and/or atrial septal aneurysm [ASA]), and the probably causal PFO subset (large shunt and/or ASA, plus risk of paradoxical embolism [RoPE] score ≥ 7). We adjusted the association between migraine subtypes and possibly causal PFO, which included the probably causal subset for age, sex, large artery atherosclerosis, and small vessel disease. Results: A total of two hundred and two patients with CIS were included, of whom 42/202 (20%) had MWA, 32/202 (15%) had migraine without aura, and 128/202 (63%) had no migraine. MWA was associated with possibly causal PFO (OR = 4.0, 95%CI [1.78-9.3], P < 0.001) and with probably causal PFO (OR = 5.4, 95%CI [2.37-13], P < 0.001). In a multinomial logistic regression analysis, MWA remained associated with possibly causal PFO (OR = 3.24, 95% CI [1.45-7.2], P = 0.004). Conclusion: In a young adult population with CIS, MWA was strongly associated with possibly causal PFO, i.e., with a large shunt or combined with an interatrial septal aneurysm.

Migraine and large artery atherosclerosis in young adults with ischemic stroke.

INTRODUCTION: Migraine is a risk factor for ischemic stroke, but the mechanisms of stroke associated with migraine are debated. The aim of this study was to investigate the association between migraine and large artery atherosclerosis (LAA) in young adults with ischemic stroke. METHODS: Patients aged between 18 and 54 years consecutively treated for first acute ischemic stroke in a university hospital stroke unit between January 2017 and December 2019 were included in this cross-sectional study. Migraine status was systematically assessed by the same headache specialist. Stenotic and nonstenotic LAA of extracranial and intracranial cerebral arteries were evaluated and graded using the ASCOD (atherosclerosis, small-vessel disease, cardiac pathology, other causes, dissection) criteria. We adjusted the association between migraine and LAA for traditional risk factors. RESULTS: A total of 415 patients were included (mean age [standard deviation], 43.9 [8.7] years; 258/415 [62.2%] men). Migraine with aura (MWA) was diagnosed in 76 patients, and migraine without aura (MWoA) in 68 patients. Patients with migraine had fewer traditional cardiovascular risk factors. Stenotic LAA (10/144 [6.9%] vs. 42/271 [15.5%]; p < 0.001) and LAA of any grade (35/144 [24.3%] vs. 138/271 [50.9%]; p < 0.001) were significantly less frequent in patients with migraine than in patients without migraine, respectively. Multivariable analysis adjusting for age, sex, overweight, tobacco use, hypertension, diabetes, and hyperlipidemia showed a negative association between migraine and LAA of any grade (odds ratio [OR] = 0.44, 95% confidence interval [CI: 0.254-0.78], p = 0.005). This negative association was found for both MWoA (OR = 0.42, 95% CI [0.204-0.88], p = 0.020) and MWA (OR = 0.47, 95% CI [0.228-0.96], p = 0.037) compared to no migraine. CONCLUSION: In this study of young adults with ischemic stroke, migraine had a negative association with LAA. This negative association was independent of traditional vascular risk factors and was found for both MWA and MWoA.

Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.

Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease (CSVD) whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known CSVD genes, including HTRA1, in 3853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 mRNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases: gnomAD v3.1.1 [P = 3.12 × 10-17, odds ratio (OR) = 21.9], TOPMed freeze 5 (P = 7.6 × 10-18, OR = 27.1) and 1000 Genomes (P = 1.5 × 10-5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counselling.

Atrial fibrillation and migraine with aura in young adults with ischemic stroke.

BACKGROUND: Migraine is associated with an increased risk of ischemic stroke. The associations are stronger in migraine with aura than in migraine without aura, in women than in men, and in younger subjects. However, the mechanisms by which migraine might increase the risk of ischemic stroke are debated. METHODS: We analysed the associations between migraine without aura and migraine with aura and the causes of ischemic stroke in patients aged 18-54 years treated consecutively in a university hospital stroke center. RESULTS: A total of 339 patients (mean/SD age 43.8/8.8 years, 62.83% male) were included. Migraine with aura was diagnosed in 58 patients, and migraine without aura in 54 patients. Patients with migraine with aura were younger and had fewer traditional cardiovascular risk factors than patients with no migraine. Migraine with aura was strongly associated with atrial fibrillation (odds ratio, 5.08; 95% confidence interval, 1.24-21.92; p = 0.011) and negatively associated with atherosclerosis (odds ratio, 0.29; 95% confidence interval, 0.05-0.97; p = 0.033) and small vessel disease (odds ratio, 0.13; 95% confidence interval, 0.00-0.87; p = 0.022). No other cause of stroke was significantly associated with migraine. The most common cause of stroke was atherosclerosis in no-migraine patients, dissection in migraine without aura patients and patent foramen ovale in migraine with aura patients. Atrial fibrillation was, together with dissection, the second leading cause of stroke in migraine with aura patients, accounting for 10.34% of cases in this subgroup. CONCLUSION: We showed that atrial fibrillation was a common cause of ischemic stroke in young adults with migraine with aura.