Christina Sjöstrand

Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke

BACKGROUND The efficacy of closure of a patent foramen ovale (PFO) in the prevention of recurrent stroke after cryptogenic stroke is uncertain. We investigated the effect of PFO closure combined with antiplatelet therapy versus antiplatelet therapy alone on the risks of recurrent stroke and new brain infarctions. METHODS In this multinational trial involving patients with a PFO who had had a cryptogenic stroke, we randomly assigned patients, in a 2:1 ratio, to undergo PFO closure plus antiplatelet therapy (PFO closure group) or to receive antiplatelet therapy alone (antiplatelet‐only group). Imaging of the brain was performed at the baseline screening and at 24 months. The coprimary end points were freedom from clinical evidence of ischemic stroke (reported here as the percentage of patients who had a recurrence of stroke) through at least 24 months after randomization and the 24‐month incidence of new brain infarction, which was a composite of clinical ischemic stroke or silent brain infarction detected on imaging. RESULTS We enrolled 664 patients (mean age, 45.2 years), of whom 81% had moderate or large interatrial shunts. During a median follow‐up of 3.2 years, clinical ischemic stroke occurred in 6 of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet‐only group (hazard ratio, 0.23; 95% confidence interval [CI], 0.09 to 0.62; P=0.002). The incidence of new brain infarctions was significantly lower in the PFO closure group than in the antiplatelet‐only group (22 patients [5.7%] vs. 20 patients [11.3%]; relative risk, 0.51; 95% CI, 0.29 to 0.91; P=0.04), but the incidence of silent brain infarction did not differ significantly between the study groups (P=0.97). Serious adverse events occurred in 23.1% of the patients in the PFO closure group and in 27.8% of the patients in the antiplatelet‐only group (P=0.22). Serious device‐related adverse events occurred in 6 patients (1.4%) in the PFO closure group, and atrial fibrillation occurred in 29 patients (6.6%) after PFO closure. CONCLUSIONS Among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, PFO closure was associated with higher rates of device complications and atrial fibrillation. (Funded by W.L. Gore and Associates; Gore REDUCE ClinicalTrials.gov number, NCT00738894.)

A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort.

Objective: To investigate the molecular genetic basis of cluster headache (CH), using a genome-wide scan and candidate gene strategy. Methods: Northern European CH families and a case-control cohort of Danish, Swedish, and British origin (total n = 259 sporadic CH patients), including 267 control subjects matched for ancestry, participated in the study. A genome-wide genetic screen using approximately 400 microsatellite markers was performed for five informative Danish CH families. Additional markers were typed for those loci generating statistical evidence suggestive of linkage, together with genotypes for 111 individuals from further Danish and Italian kindreds. Sporadic CH patients and controls were investigated by association analysis for variation in the candidate gene, HCRTR2. Finally, complete HCRTR2 sequencing was undertaken for eight independent probands. Results: Potential linkage was identified at four possible disease loci in Danish kindreds, yet no single chromosome location generated a lod or NPL score of recognized significance. No deleterious sequence variants of the HCRTR2 gene were detected by comparison to wild-type sequence. Association of the HCRTR2 gene was not replicated in this large dataset, even when the data were stratified into distinct populations. Conclusions: Cluster headache is a complex genetic disorder, with possible phenotypic and genetic heterogeneity compounding attempts at gene identification.

Higher Prehospital Priority Level of Stroke Improves Thrombolysis Frequency and Time to Stroke Unit The Hyper Acute STroke Alarm (HASTA) Study

Background and Purpose— Early initiated treatment of stroke increases the chances of a good recovery. This randomized controlled study evaluates how an increased priority level for patients with stroke, from level 2 to 1, from the Emergency Medical Communication Center influences thrombolysis frequency, time to stroke unit, and whether other medical emergencies reported negative consequences. Methods— Patients aged 18 to 85 years in Stockholm, Sweden, with symptoms of stroke within 6 hours were randomized from the Emergency Medical Communication Center or emergency medical services to an intervention group, priority level 1, immediate call of an ambulance, or to a control group with standard priority level, that is, priority level 2 (within 30 minutes). Before study start, an educational program on identification of stroke and importance of early initiated treatment was directed to all medical dispatchers and ambulance and emergency department personnel. Results— During 2008, 942 patients were randomized of which 53% (n=496) had a final stroke/transient ischemic attack diagnosis. Patients in the Emergency Medical Communication Center randomized intervention group reached the stroke unit 26 minutes earlier than the control group (P<0.001) after the emergency call. Thrombolysis was given to 24% of the patients in the intervention group compared with 10% of the control subjects (P<0.001). The higher priority level showed no negative effect on other critical ill patients requiring priority level 1 prehospital attention. Conclusion— This randomized study shows negligible harm to other medical emergencies, a significant increase in thrombolysis frequency, and a shorter time to the stroke unit for patients with stroke upgraded to priority level 1 from the Emergency Medical Communication Center and through the acute chain of stroke care.

Migraine and Olfactory Stimuli

Migraine patients often report intolerance to odours. Migraineurs report odours may trigger attacks, that they experience osmophobia during attacks, and olfactory hypersensitivity between attacks. In this paper we discuss olfactory mechanisms in migraine. We also present data from a pilot questionnaire study in a group of young women diagnosed with migraine. The study results confirm that hypersensitivity to odour is a common feature in women with migraine. Migraine pathophysiology likely explains this particular vulnerability. We discuss these pathophysiologic mechanisms and hypotheses relating odour intolerances and migraine.

CACNA1A gene polymorphisms in cluster headache

Cluster headache (CH) is a primary headache disorder where the aetiological and pathophysiological mechanisms still are largely unknown. An increased risk of CH in first- and second-degree relatives suggests the importance of genetic factors. Mutations of the P/Q type calcium channel alpha 1 subunit (CACNA1A) gene on chromosome 19p13 have been shown to cause several neurological disorders with a wide clinical spectrum, mainly episodic diseases. Missence mutations of the gene cause familial hemiplegic migraine (FHM) and it is also likely to be involved in the more common forms of migraine. The CACNA1A gene is thus a promising candidate gene for CH. In this study we performed an association analysis of an intragenic polymorphic (CA)n-repeat with marker D19S1150 and a (CAG)n-repeat in the 3′UTR region, in 75 patients with CH according to IHS criteria and 108 matched controls. Genotypes and allele frequencies were similarly distributed in patients and controls. Linkage disequilibrium between the two markers was similar in patients and controls. We conclude that an importance of the CACNA1A gene in sporadic CH is unlikely.

Analysis of Nitric Oxide Synthase Genes in Cluster Headache

The aetiology of cluster headache is still not yet completely understood, but the potential relevance of genetic factors has been recognized during recent years. Nitric oxide (NO) plays a critical role in the regulation of vasodilation, neurotransmission, inflammation and many other events throughout the body. NO also appears to be an important mediator of vascular headache pathophysiology. In this study we have performed an association analysis of five polymorphic micro-satellite markers in the three different NO synthase (NOS) genes; nNOS (NOS1), iNOS (NOS2A) and eNOS (NOS3). Ninety-one cluster headache patients diagnosed according to International Headache Society criteria and 111 matched controls were studied. Phenotype and allele frequencies were similarly distributed in patients and controls except for an iNOS (NOS2A) pentanucleotide repeat allele which was significantly more common in controls. We observed a higher phenotype frequency of this allele in our control group compared with rates in control groups of other studies, whereas the frequency in our patients was similar to that in controls from previous reports. Thus, we conclude that it is unlikely that genetic variations within the NOS genes contribute greatly to cluster headache susceptibility.

A Follow-Up Study of 60 Patients After an Assumed First Period of Cluster Headache

During 1981–96 a series of 60 consecutive out-patients was examined in relation to an assumed first period of cluster headache (CH). On follow up in 1998 we found that six were deceased at a mean age of 56.5 years (range 45–74 years), of whom one had a definitive CH diagnosis and five had one documented headache period only. Six patients were lost to follow up because they could not be reached. In the final group for evaluation (n = 49) it was found that 13 (26.5%) patients had had one cluster period only during a mean observation time of 8.9 years. Out of 36 patients with a definitive CH diagnosis according to International Headache Society (IHS) criteria, 31 patients had episodic CH, four patients had primary chronic CH and one patient had secondary chronic CH. Of the patients with a definitive CH diagnosis, 83% on follow up had had a recurrence of a second period of CH within 3 years or continuous attacks (chronic/semichronic CH) from the onset. Evidently some patients may suffer from one cluster period only. In our patient material only 17% had a second cluster period after 3 years.

Gene Expression Profiling in Cluster Headache: A Pilot Microarray Study

Background.—Cluster headache (CH) is a primary neurovascular headache disorder characterized by attacks of excruciating pain accompanied by ipsilateral autonomic symptoms. CH pathophysiology is presumed to involve an activation of hypothalamic and trigeminovascular systems, but inflammation and immunological mechanisms have also been hypothesized to be of importance.

Ischemic stroke and patent foramen ovale: risk factors and genetic profile.

BACKGROUND Patent foramen ovale (PFO) is considered to be a risk factor for ischemic cerebrovascular disease (ICVD), especially in young people. However, the potential pathophysiological relevance in ischemic stroke is controversial and in need of further investigation. In this study, we examined the conventional risk factors and the distribution of 100 polymorphisms in 47 suspected susceptibility genes for ICVD in stroke patients with or without a PFO. METHODS In the South Stockholm Ischemic Stroke Study, 928 ICVD patients and 602 controls were genotyped for 100 different gene polymorphisms. The stroke patients also underwent relevant investigation and standardized blood tests. Patients who underwent transeosophageal echocardiography as part of their investigation were divided into groups that either had or did not have a PFO. RESULTS There were no significant differences in the 2 groups with regard to conventional risk factors or blood analyses. Three different polymorphisms located in the prothrombin, F2 (20210G/A), and apolipoprotein-C3 (-641A/C and -455T/A) genes were significantly associated with ICVD and PFO. The strongest association was found for F2 (P = .0049; odds ratio 26.4). CONCLUSIONS We found that F2, which previously has been described as being a possible link between PFO and ICVD, was significantly associated with ICVD and PFO. There was also a trend toward an association between 2 other polymorphisms in the APO-CIII gene and PFO and ICVD.

Interleukin‐2 gene expression in different phases of episodic cluster headache – a pilot study

Steinberg A, Sjöstrand C, Sominanda A, Fogdell‐Hahn A, Nilsson Remahl AIM. Interleukin‐2 gene expression in different phases of episodic cluster headache – a pilot study.
Acta Neurol Scand: 2011: 124: 130–134.
© 2010 John Wiley & Sons A/S.