[show abstract][hide abstract] ABSTRACT: Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P < 5 x 10(-8)). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: To determine if black-blood 3 T cardiovascular magnetic resonance (bb-CMR) can depict differences between symptomatic and asymptomatic carotid atherosclerotic plaques in acute ischemic stroke patients. METHODS: In this prospective monocentric observational study 34 patients (24 males; 70 +/-9.3 years) with symptomatic carotid disease defined as ischemic brain lesions in one internal carotid artery territory on diffusion weighted images underwent a carotid bb-CMR at 3 T with fat-saturated pre- and post-contrast T1w-, PDw-, T2w- and TOF images using surface coils and Parallel Imaging techniques (PAT factor = 2) within 10 days after symptom onset. All patients underwent extensive clinical workup (lab, brain MR, duplex sonography, 24-hour ECG, transesophageal echocardiography) to exclude other causes of ischemic stroke. Prevalence of American Heart Association lesion type VI (AHA-LT6), status of the fibrous cap, presence of hemorrhage/thrombus and area measurements of calcification, necrotic core and hemorrhage were determined in both carotid arteries in consensus by two reviewers who were blinded to clinical information. McNemar and Wilcoxon's signed rank tests were use for statistical comparison. A p-value <0.05 was considered statistically significant. RESULTS: Symptomatic plaques showed a higher prevalence of AHA-LT6 (67.7% vs. 11.8%; p < 0.001; odds ratio = 12.5), ruptured fibrous caps (44.1% vs. 2.9%; p < 0.001; odds ratio = 15.0), juxtaluminal thrombus (26.5 vs. 0%; p < 0.01; odds ratio = 7.3) and intraplaque hemorrhage (58.6% vs. 11.8%; p = 0.01; odds ratio = 3.8). Necrotic core and hemorrhage areas were greater in symptomatic plaques (14.1 mm2 vs. 5.5 mm2 and 13.6 mm2 vs. 5.3 mm2; p < 0.01, respectively). CONCLUSION: 3 T bb-CMR is able to differentiate between symptomatic and asymptomatic carotid plaques, demonstrating the potential of bb-CMR to differentiate between stable and vulnerable lesions and ultimately to identify patients with low versus high risk for cardiovascular complications. Best predictors of the symptomatic side were a ruptured fibrous cap, AHA-LT 6, juxtaluminal hemorrhage/thrombus, and intraplaque hemorrhage.
Journal of Cardiovascular Magnetic Resonance 05/2013; 15(1):44. · 4.44 Impact Factor
[show abstract][hide abstract] ABSTRACT: Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10(-5) for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10(-4); combined P = 7.06 × 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 × 10(-4); combined P = 1.17 × 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10(-8) and P = 0.02; combined P = 3.86 × 10(-8), respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.
[show abstract][hide abstract] ABSTRACT: Our goal was to assess the prevalence of complicated American Heart Association (AHA) lesion type VI plaques in the carotid arteries of patients with cryptogenic stroke.
In up to 40% of ischemic stroke patients, no definite cause can be established despite extensive workup (i.e., cryptogenic stroke). To test the hypothesis if nonstenosing complicated carotid plaques may be the underlying etiology in some of these patients, we used high-resolution black-blood carotid magnetic resonance imaging (MRI), which can quantitatively assess plaque composition and morphology with good correlation to histopathology. Specifically, we focused on AHA type VI plaques, which are characterized by hemorrhage, thrombus, or fibrous cap rupture.
Thirty-two consecutive patients (22 male; mean age 71.7 ± 11.9 years) with cryptogenic stroke and nonstenosing (<50%) eccentric carotid plaques were recruited from a single stroke unit. All patients underwent extensive clinical workup (brain MRI, duplex sonography, electrocardiography and Holter monitoring, transthoracic and transesophageal echocardiography, and laboratory investigations) to exclude other causes of stroke. All patients received a black-blood carotid MRI at 3-T with fat-saturated pre- and post-contrast T-1-, proton density-, and T-2-weighted and time-of-flight images using surface coils and parallel imaging techniques. Prevalence of AHA type VI plaque was determined in both carotid arteries on the basis of previously published MRI criteria.
AHA type VI plaques were found in 12 of 32 arteries (37.5%) ipsilateral to the stroke, whereas there were no AHA type VI plaques contralateral to the stroke (p = 0.001). The most common diagnostic feature of AHA type VI plaques was intraplaque hemorrhage (75%), followed by fibrous plaque rupture (50%) and luminal thrombus (33%).
This pilot study suggests that arterio-arterial embolism from complicated, nonstenosing carotid atherosclerotic plaques may play a role in a subgroup of patients previously diagnosed with cryptogenic stroke. To further evaluate the significance of AHA type VI plaques in cryptogenic stroke, future studies will have to analyze both clinical and imaging follow-up data, including event rates for secondary strokes.
[show abstract][hide abstract] ABSTRACT: Cervical artery dissection (CAD) is an important etiology of stroke in young adults. Its etiology is incompletely understood. Here, we report a young woman who presented with acute ischemic stroke in the setting of internal carotid artery (ICA) dissection and essential thrombocythemia (ET). We present a review of previous cases with comorbidity of CAD and ET and discuss the pathophysiological implications of this co-occurrence. In particular, we speculate that ET may increase the susceptibility of cervical vessels to spontaneous dissection, for example, by disturbing the microcirculation within the vessel wall.
Clinical and Applied Thrombosis/Hemostasis 11/2011; 17(6):E138-40. · 1.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: The therapeutic effects of 4-aminopyridine (4AP) were investigated in a randomized, double-blind, crossover trial in 10 subjects with familial episodic ataxia with nystagmus.
After randomization, placebo or 4AP (5 mg 3 times daily) was administered for 2 3-month-long treatment periods separated by a 1-month-long washout period. The primary outcome measure was the number of ataxia attacks per month; the secondary outcome measures were the attack duration and patient-reported quality of life (Vestibular Disorders Activities of Daily Living Scale [VDADL]). Nonparametric tests and a random-effects model were used for statistical analysis.
The diagnosis of episodic ataxia type 2 (EA2) was genetically confirmed in 7 subjects. Patients receiving placebo had a median monthly attack frequency of 6.50, whereas patients taking 4AP had a frequency of 1.65 (p = 0.03). Median monthly attack duration decreased from 13.65 hours with placebo to 4.45 hours with 4AP (p = 0.08). The VDADL score decreased from 6.00 to 1.50 (p = 0.02). 4AP was well-tolerated.
This controlled trial on EA2 and familial episodic ataxia with nystagmus demonstrated that 4AP decreases attack frequency and improves quality of life. Level of evidence: This crossover study provides Class II evidence that 4AP decreases attack frequency and improves the patient-reported quality of life in patients with episodic ataxia and related familial ataxias.
[show abstract][hide abstract] ABSTRACT: Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.
[show abstract][hide abstract] ABSTRACT: Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10⁻⁹, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10⁻¹¹ (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10⁻⁵, permuted threshold for genome-wide significance 7.7 × 10⁻⁵. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.
[show abstract][hide abstract] ABSTRACT: Hemiplegic migraine (HM) is a rare and severe subtype of migraine with aura, characterized by some degree of hemiparesis and other aura symptoms. Mutations in three genes (CACNA1A, ATP1A2 and SCN1A) have been detected in familial and, more rarely, in sporadic cases. The disease can be complicated by permanent neurological deficits, the most frequent one being a cerebellar syndrome; in addition, mental retardation has been recognized as part of the phenotypic spectrum. Here, we report a Caucasian male with a novel CACNA1A mutation and an unusual clinical phenotype: the patient, who had had a history of only two HM attacks, sought medical advice at age 49 primarily because of increasing cognitive decline accompanied by cerebellar dysfunction. While common neurodegenerative causes were excluded, neuropsychological evaluation revealed a distinct profile of deficits of a subcortico-prefrontal type as previously reported in patients with cerebellar dysfunction. This suggests a possible causal link between cerebellar and cognitive disturbances in this patient; in addition to these pathophysiological aspects, we review of the role of the cerebellum in cognition.
Journal of the neurological sciences 10/2010; 300(1-2):160-3. · 2.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: Reversible cerebral vasoconstriction syndrome (RCVS) comprises a heterogeneous group of acute neurological diseases which are characterized by thunderclap headache and evidence of reversible multifocal constriction of cerebral arteries. A number of precipitating factors have been described in the literature, including recent childbirth and use of vasoactive substances.
Here we present the case of a female patient with RCVS which occurred in the setting of hormonal ovarian stimulation for intrauterine insemination.
This case possibly contributes to the understanding of the pathophysiological mechanisms underlying reversible cerebral vasoconstriction.
[show abstract][hide abstract] ABSTRACT: Stiff-person syndrome (SPS), a rare neuroimmunological disorder, is characterized by symmetrical rigidity and muscle stiffness, particularly of axial and proximal limb muscles. Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a variant of SPS which includes additional clinical features (e.g. sensory symptoms, brain stem signs and pathological CSF findings). An association of both SPS and PERM with (solid) malignancies has been previously reported. Beyond this, there have been single reports of SPS in the setting of Hodgkin's lymphoma (HL). Here, we present a case of PERM associated with HL, with PERM preceding occurrence of lymphoma by more than seven months. Our observation has obvious implications for the management and, in particular, diagnostic evaluation of patients with PERM.
Journal of the neurological sciences 04/2010; 291(1-2):118-20. · 2.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hemiplegic migraine (HM) in the setting of Sturge-Weber syndrome (SWS) has been previously described. Here, we report clinical and multimodal imaging data on a 21-year-old man with SWS and HM, who presented during an acute HM attack with a dense left-hemispheric syndrome (expressive aphasia and right sensorimotor hemiplegia), lasting for more than 10 days. Repeated EEGs were without evidence of status epilepticus. Consistent with previous findings in prolonged migraine aura, perfusion computed tomography demonstrated left-hemispheric hyperperfusion on day 7. 18F-FDG positron emission tomography (day 7) revealed left-hemispheric hypermetabolism. After 14 days, the patient was symptom-free and discharged home. Follow-up after 30 days showed normal neurological status. Our observation confirms and reinforces the comorbidity of SWS and HM and shows that prolonged HM attacks are associated with complex changes of both cerebral perfusion and glucose metabolism. A pathophysiological model explaining both the association between SWS/HM and the observed imaging changes is presented.
Journal of the neurological sciences 10/2009; 287(1-2):271-4. · 2.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: We describe the coincidence of 14 & 6Hz positive spikes with PLEDs in a patient with clonic status epilepticus of the left upper extremity and the persistence of 14 & 6Hz positive spikes after cessation of status.
Digital video-EEG recordings were performed using 32-channel EEG equipment (XLTEK, Canada) with all electrodes of the international 10-20 system and additional anterior temporal electrodes in a patient during clonic status epilepticus and 2 months later after cessation of status.
The initial EEG during clonic status epilepticus showed right hemispheric PLEDs and right lateral temporal 14 & 6Hz positive spikes in between the PLEDs. Follow up EEG recording 2 months later after cessation of status revealed an absence of PLEDs, a continuous slowing over the right hemisphere and the occipital background of 7Hz. Right lateral temporal 14 & 6Hz positive spikes were recorded in the same frequency and the same localization as in the previous status EEG.
This case demonstrates that a hemisphere which is in a status epilepticus as clinically reflected by clonic status of the left hand and PLEDs in the EEG is still capable to produce a benign variant pattern like 14 & 6Hz positive spikes.
The generator of 14 & 6Hz positive spikes may still persist despite the presence of severe structural and epileptogenic lesions in the same hemisphere.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 08/2009; 120(8):1489-91. · 3.12 Impact Factor