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 10days. 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 14days, the patient was symptom-free and discharged home. Follow-up after 30days showed normal neurological status. Our observation confirms and reinforces the comborbidity 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.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SIGNIFICANCE: The generator of 14 & 6Hz positive spikes may still persist despite the presence of severe structural and epileptogenic lesions in the same hemisphere.

Mutations in three different genes have been implicated in familial hemiplegic migraine (FHM), two of them code for neuronal voltage-gated cation channels, CACNA1A and SCN1A, while the third encodes ATP1A2, the alpha(2)-isoform of the Na(+)/K(+)-ATPase's catalytic subunit, thus classifying FHM as an ion channel/ion transporter disorder. The Na(+)/K(+)-ATPase maintains the physiological gradients for Na(+) and K(+) ions and is therefore critical for the activity of ion channels and transporters involved in neurotransmitter uptake or Ca(2+) signaling. Diverse functional abnormalities have been identified for disease-linked ATP1A2 mutations, which reach far beyond simple loss-of-function. We have shown recently that ATP1A2 mutations frequently lead to changes in the enzyme's voltage-dependent properties, kinetics or apparent cation affinities. Here, we present functional data on a so far uncharacterized set of ATP1A2 mutations (G301R, R908Q and P979L) upon expression in Xenopus oocytes and HEK293FT cells, and provide evidence for a novel pathophysiological mechanism. Whereas the G301R mutant was inactive, no functional changes were observed for mutants R908Q and P979L in the oocyte expression system. However, the R908Q mutant was less effectively expressed in the plasma membrane of oocytes, making it the first missense mutation to result in defective plasma membrane targeting. Notably, the P979L mutant exhibited the same cellular expression profile as the wild-type protein, both in Xenopus oocytes and in transfected HEK293FT cells grown at 28 degrees C, but much less P979L protein was found upon cell growth at 37 degrees C, showing for the first time that temperature-sensitive effects on protein stability can underlie ATP1A2 loss-of-function.

Cortical ischemic stroke affecting the precentral "hand knob" area is a rare but well known stroke entity. To date, little is known about the underlying stroke mechanisms and the prognosis. Twenty-nine patients admitted to our service between 2003 and 2007 were included in the study on the basis of an acute ischemic infarct of the cortical "hand knob" area confirmed by diffusion-weighted magnetic resonance imaging with contralateral hand paresis. For all patients clinical, epidemiological as well as imaging data at the time point of admission were analysed retrospectively and follow-up data on all patients was obtained. The majority (n = 21/72%) had an isolated infarct of the cortical "hand knob" area. In 23 (79%) patients it was a first ever stroke. Ten patients (34%) had ipsilateral extracranial stenosis of the internal carotid artery (ICA), whereas potential cardiac embolic sources were less frequent (n = 4/14%). No patient exhibited ipsilateral MCA stenosis. All but two patients (93%) had marked atherosclerotic alterations of the ICA. Hypertension was the most prevalent vascular risk factor (n = 23/79%). At follow-up (mean 25.0 months, range 0.4-47.4 months) no patient had died and only one (3%) experienced a recurrent stroke. The majority of patients (79%) reported improvement of hand paresis, 17 (59%) were asymptomatic (modified Rankin score = 0). Only one patient was significantly disabled due to a recurrent stroke. In conclusion, ischemic infarcts affecting the cortical "hand knob" area are frequently associated with atherosclerotic changes of the carotid artery, suggesting an arterio-arterial thrombembolic stroke mechanism. It mostly reflects first ever ischemic stroke, and follow-up data suggest a rather benign course.

Mitochondrial dysfunction is a hypothesized component in the multifactorial pathogenesis of migraine without aura (MoA,'common migraine') and the related condition of cyclic vomiting syndrome (CVS). In this study, the entire mitochondrial genome was sequenced in 20 haplogroup-H CVS patients, a subject group studied because of greater genotypic and phenotypic homogeneity. Sequences were compared against haplogroup-H controls. Polymorphisms of interest were tested in 10 additional CVS subjects and in 112 haplogroup-H adults with MoA. The 16519C-->T polymorphism was found to be highly disease associated: 21/30 CVS subjects [70%, odds ratio (OR) 6.2] and 58/112 migraineurs (52%, OR 3.6) vs. 63/231 controls (27%). A second polymorphism, 3010G-->A, was found to be highly disease associated in those subjects with 16519T: 6/21 CVS subjects (29%, OR 17) and 15/58 migraineurs (26%, OR 15) vs. 1/63 controls (1.6%). Our data suggest that these polymorphisms constitute a substantial proportion of the genetic factor in migraine pathogenesis, and strengthen the hypothesis that there is a component of mitochondrial dysfunction in migraine.

BACKGROUND AND PURPOSE: Several genes involved in the lymphotoxin-alpha cascade (LTA, LGALS2, and PSMA6) have been linked with the risk of myocardial infarction. Here, we present a comprehensive analysis of these genes in patients with ischemic stroke (IS). METHODS: Twenty-three single nucleotide polymorphisms (SNPs) from LTA, LGALS2, and PSMA6 were genotyped in 601 German IS patients and 736 matched controls. SNPs and haplotypes were tested for association with overall IS, large vessel stroke, and cardioembolic stroke. Significant associations were replicated in an independent sample of 843 IS cases and 933 controls from the UK. RESULTS: Only one SNP (rs1048990 in PSMA6) showed association with overall IS, but this was not replicated in the UK sample. Three SNPs showed significant associations with stroke subtypes (P<0.05), but none of these associations could be replicated in the UK population. CONCLUSIONS: Genetic variation in the lymphotoxin-alpha cascade (LTA, LGALS2, and PSMA6) is not a major risk factor for IS.

Mutations in ATP1A2, the gene coding for the Na(+)/K(+)-ATPase alpha(2)-subunit, are associated with both familial hemiplegic migraine (FHM) and sporadic cases of hemiplegic migraine (SHM). In this study, we examined the functional properties of 11 ATP1A2 mutations associated with FHM or SHM, including missense mutations (T263M, T376M, R383H, A606T, R763H, M829R, R834Q, R937P, X1021R), a deletion mutant (del(K935-S940)ins(I)), and a frameshift mutation (S966fs). According to the Na(+)/K(+)-ATPase crystal structure, a subset of the mutated residues (A606, R763, M829, and R834) is involved in important inter-domain H-bond networks, and the enzyme's carboxy-terminus, which is elongated by the X1021R mutation, has been implicated in voltage dependence and formation of a third Na(+) binding site. Upon heterologous expression in Xenopus oocytes the analysis of electrogenic transport properties, Rb(+) uptake, and protein expression revealed pronounced and markedly diverse functional alterations in all ATP1A2 mutants. Abnormalities included a complete loss of function (T376M), impaired plasma membrane expression (del(K935-S940)ins(I), S966fs), and altered apparent affinities for extracellular cations or reduced enzyme turnover (R383H, A606T, R763H, R834Q, and X1021R). In addition, changes in the voltage dependence of pump currents and increased rate constants of the voltage jump-induced redistribution between E(1)P and E(2)P states were observed. Thus, mutations that disrupt distinct inter-domain H-bond patterns can cause abnormal conformational flexibility and exert long-range consequences on apparent cation affinities or voltage dependence. Of interest, the X1021R mutation severely impaired voltage dependence and kinetics of Na(+)-translocating partial reactions, corroborating the critical role of the Na(+)/K(+)-ATPase's carboxy-terminus in these processes.

The clinical overlap between monogenic Familial Hemiplegic Migraine (FHM) and common migraine subtypes, and the fact that all three FHM genes are involved in the transport of ions, suggest that ion transport genes may underlie susceptibility to common forms of migraine. To test this leading hypothesis, we examined common variation in 155 ion transport genes using 5,257 single nucleotide polymorphisms (SNPs) in a Finnish sample of 841 unrelated migraine with aura cases and 884 unrelated non-migraine controls. The top signals were then tested for replication in four independent migraine case-control samples from the Netherlands, Germany and Australia, totalling 2,835 unrelated migraine cases and 2,740 unrelated controls. SNPs within 12 genes (KCNB2, KCNQ3, CLIC5, ATP2C2, CACNA1E, CACNB2, KCNE2, KCNK12, KCNK2, KCNS3, SCN5A and SCN9A) with promising nominal association (0.00041 < P < 0.005) in the Finnish sample were selected for replication. Although no variant remained significant after adjusting for multiple testing nor produced consistent evidence for association across all cohorts, a significant epistatic interaction between KCNB2 SNP rs1431656 (chromosome 8q13.3) and CACNB2 SNP rs7076100 (chromosome 10p12.33)(pointwise P = 0.00002; global P = 0.02) was observed in the Finnish case-control sample. We conclude that common variants of moderate effect size in ion transport genes do not play a major role in susceptibility to common migraine within these European populations, although there is some evidence for epistatic interaction between potassium and calcium channel genes KCNB2 and CACNB2. Multiple rare variants or trans regulatory elements of these genes are not ruled out.

Familial hemiplegic migraine type 3 (FHM3) is a severe autosomal dominant migraine disorder caused by mutations in the voltage-gated sodium channel Na(V)1.1 encoded by SCN1A. We determined the functional consequences of three mutations linked to FHM3 (L263V, Q1489K, and L1649Q) in an effort to identify molecular defects that underlie this inherited migraine disorder. Only L263V and Q1489K generated quantifiable sodium currents when coexpressed in tsA201 cells with the human beta(1) and beta(2) accessory subunits. The third mutant, L1649Q, failed to generate measurable whole-cell current because of markedly reduced cell surface expression. Compared to WT-Na(V)1.1, Q1489K exhibited increased persistent current but also enhanced entry into slow inactivation as well as delayed recovery from fast and slow inactivation, thus resulting in a predominantly loss-of-function phenotype further demonstrated by a greater loss of channel availability during repetitive stimulation. In contrast, L263V exhibited gain-of-function features, including delayed entry into, as well as accelerated recovery from, fast inactivation; depolarizing shifts in the steady-state voltage dependence of fast and slow inactivation; increased persistent current; and delayed entry into slow inactivation. Notably, the two mutations (Q1489K and L1649Q) that exhibited partial or complete loss of function are linked to typical FHM, whereas the gain-of-function mutation L263V occurred in a family having both FHM and a high incidence of generalized epilepsy. We infer from these data that a complex spectrum of Na(V)1.1 defects can cause FHM3. Our results also emphasize the complex relationship between migraine and epilepsy and provide further evidence that both disorders may share common molecular mechanisms.

BACKGROUND : Mutations in the Notch3 gene are the cause of CADASIL, a hereditary small vessel disease leading to stroke and vascular dementia. The disease is characterized by ultrastructural granular deposits within small arterial vessels and degeneration of vascular smooth muscle cells. Yet, little is known about endothelial function in CADASIL. Vasoreactivity induced by L-arginine, which is the substrate for endothelial nitric oxide synthase, is a parameter of endothelial function and has been shown to be altered in patients with cerebrovascular disease. METHODS : To assess endothelial function in CADASIL, L-arginineinduced vasoreactivity was studied in 25 CADASIL subjects and 24 non-CADASIL control subjects without previous history of cerebrovascular disease by transcranial Doppler sonography of the middle cerebral artery. RESULTS : Resting mean flow velocity was significantly reduced in patients (43.7 +/- 14.5 cm/s) compared to controls (57.0 +/- 10.4 cm/s)[p < 0.001]. Patients exhibited a significantly higher pulsatility index (PI = 0.94 +/- 0.19) than control subjects (PI = 0.79 +/- 0.11)[p < 0.01]. L-arginine-induced vasoreactivity was significantly increased in patients (36.1 +/- 15.5 %) versus controls (27.9 +/- 8.5 %)[p < 0.05]. In patients, there was a significant reduction of the PI following L-arginine application (PI = 0.86 +/- 0.13) compared to resting PI [p < 0.01]. CONCLUSIONS : Our results may indicate a pathogenic role of impaired cerebral hemodynamics and endothelial dysfunction in CADASIL. Our finding of enhanced L-arginine vasoreactivity might have therapeutic implications for CADASIL and sporadic small vessel disease.