Randomized assessment of imatinib in patients with acute ischaemic stroke treated with intravenous thrombolysis.

BACKGROUND: Imatinib, a tyrosine kinase inhibitor, has been shown to restore blood-brain barrier integrity and reduce infarct size, haemorrhagic transformation and cerebral oedema in stroke models treated with tissue plasminogen activator. We evaluated the safety of imatinib, based on clinical and neuroradiological data, and its potential influence on neurological and functional outcomes. METHODS: A phase II randomized trial was performed in patients with acute ischaemic stroke treated with intravenous thrombolysis. A total of 60 patients were randomly assigned to four groups [3 (active): 1 (control)]; the active treatment groups received oral imatinib for 6 days at three dose levels (400, 600 and 800 mg). Primary outcome was any adverse event; secondary outcomes were haemorrhagic transformation, cerebral oedema, neurological severity on the National Institutes of Health Stroke Scale (NIHSS) at 7 days and at 3 months and functional outcomes on the modified Rankin scale (mRS). RESULTS: Four serious adverse events were reported, which resulted in three deaths (one in the control group and two in the 400-mg dose group; one patient in the latter group did not receive active treatment and the other received two doses). Nonserious adverse events were mostly mild, resulting in full recovery. Imatinib ameliorated neurological outcomes with an improvement of 0.6 NIHSS points per 100 mg imatinib (P = 0.02). For the 800-mg group, the mean unadjusted and adjusted NIHSS improvements were 4 (P = 0.037) and 5 points (P = 0.012), respectively, versus controls. Functional independence (mRS 0-2) increased by 18% versus controls (61 vs. 79; P = 0.296). CONCLUSION: This phase II study showed that imatinib is safe and tolerable and may reduce neurological disability in patients treated with intravenous thrombolysis after ischaemic stroke. A confirmatory randomized trial is currently underway.

Intracranial vessel wall MRI.

There are many different methods of imaging the intracranial arteries; however, the vast majority of currently used techniques are based on luminal imaging. Although this is useful, it does have limitations as many different pathological processes can produce the same appearance. Therefore, directly imaging the site of the pathology - the vessel wall itself - offers the hope of discriminating between different disease processes. In this review, we will discuss the current status of vessel wall magnetic resonance imaging alongside its potential usefulness in differentiating between various disease entities.

Prevalence of migraine headache in an in-patient stroke population.

INTRODUCTION: Migraine, especially with aura, is a risk factor for ischemic stroke. In this study, we investigated descriptive data and prevalence of migraine in an in-patient stroke population. MATERIALS AND METHODS: Patients with acute cerebrovascular disease (CVD) admitted to the stroke unit during a 6-month period were recruited. Prevalence of migraine was assessed using a structured questionnaire. Additional clinical data regarding risk factors for CVD were evaluated for all responding patients. RESULTS: A total of 229 patients received a questionnaire and 175 answers were collected (response frequency of 76.4%). Responders matched the initial cohort regarding distribution of age, sex, and type of stroke. Thirty-six cases (20.6%) fulfilled the criteria for migraine or probable migraine according to the 2nd edition of the International Headache Classification (ICHD-2). Sixty percent of migraine patients had migraine with aura. Stroke patients with migraine were younger (P = 0.007), the presence of patent foramen ovale (PFO) was significantly increased (P = 0.008), and atrial fibrillation was less common (P = 0.048). There were no other differences between patients with and without migraine headache regarding conventional risk factors. CONCLUSIONS: The prevalence of migraine in this hospital-based stroke cohort was comparable to the estimated prevalence of migraine usually described in population studies. In our study population, the prevalence of migraine with aura was higher than expected. The increased prevalence of PFO in patients with migraine headache corresponds well to previous population studies.

Migraine-related ischemic stroke?

INTRODUCTION: Migraine, especially migraine with aura, has been described to be associated with an increased risk for ischemic stroke. An increased incidence of silent lesions in the posterior circulation has also been described. METHOD: Six cases with migraine and stroke in close relation over time were retrospectively reviewed. RESULTS: All patients had previously known MA or MO and suffered from a stroke within the first 24-hour period after an acute migraine attack. None of the patients fulfilled the IHS criteria for migrainous infarction. Four out of these six patients had a patent foramen ovale (PFO) or an atrial septal defect (ASD). DISCUSSION: None of these cases can be categorized as migrainous infarctions according to IHS. However, the migraine attack might have been involved in the mechanisms for the development of the infarctions.

Interleukin-2 gene expression in different phases of episodic cluster headache--a pilot study.

BACKGROUND: The pathophysiology of cluster headache (CH) is still largely unknown. Immunological mechanisms have been suggested to be of importance. AIM: This study aimed to investigate cytokine interleukin-2 (IL-2) as a possible marker of immune system involvement in the pathophysiology of CH. METHODS: Eight episodic patients with CH and 16 healthy headache-free control subjects matched for age and gender were studied. Venous blood samples were drawn from the patients with CH on three occasions; during active period between headache attacks, during an attack and in remission. Venous blood samples were drawn once from each control subject. We analysed IL-2 gene expression, using quantitative real-time polymerase chain reaction. RESULTS: Patients with CH had significantly increased relative IL-2 gene expression levels between headache attacks during active CH period (median 9.9 IL-2 cDNA/glyceraldehyde-3-phosphate dehydrogenase cDNA; IQR 6.2-10.3) compared to during attacks (median 2.8; IQR 0.7-3.2, P = 0.012), remission (median 1.6; IQR 0.9-1.8, P = 0.017) and controls (median 0.9; IQR 0.6-1.9, P = 0.0001). CONCLUSION: The increment of IL-2 found during the active CH period may support a role for this cytokine and subsequently for the immune system in the pathophysiology of CH. An expansion of this study to a broader group of cytokines and a larger patient cohort is warranted.

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.

Familial cluster headache. Is atypical cluster headache in family members part of the clinical spectrum?

Familial cluster headache (CH) was analysed in 21 Swedish families. Diagnosis was made according to The International Classification of Headache Disorders 2004. We identified 55 affected, of whom 42 had episodic or chronic CH, one had probable CH and 12 had atypical symptoms. The atypical cases did not fulfil the diagnostic criteria for CH, but had clinical symptoms with more resemblance to CH than to migraine or other trigeminal autonomic cephalgia syndromes. The overall male : female ratio was 1.8:1. The overall mean age at onset was significantly lower in the second/third generation than in the first generation (mean age at onset 22 vs. 31 years, SD +/- 7 vs. 13 years; P < 0.01). This may be anticipation or selection bias, since individuals with late age at onset from the second/third generation may not yet have symptoms. The prevalence of migraine was 24% (13/55), i.e. similar to the prevalence in the general population. The high incidence of atypical CH cases in the Swedish families with other members affected with CH may suggest that the spectrum of CH is broader than previously thought. We suggest that atypical CH in CH families may represent an expanded spectrum of the disease with a common aetiology, i.e. a common genetic background.

Periods of cluster headache induced by nitrate therapy and spontaneous remission of angina pectoris during active clusters.

Glyceryl trinitrate (GTN) is known to induce single extra attacks of cluster headache (CH) during active cluster periods, most probably via actions of nitric oxide (NO). Induction of whole periods of CH by organic nitrates has, however, attracted little attention in the literature. We report on eight patients with episodic CH and coexistent effort-induced angina pectoris. Cases 1-6 had been free of their headaches for many years but got recurrence of CH within a few weeks after the administration of long-acting organic nitrates (isosorbide-dinitrate, isosorbide-5-mononitrate or slow-release GTN) aimed at treating their chest pains. These nitrate-induced headache periods were more severe and had a longer duration than the previous spontaneous ones. Furthermore, one of the subjects and two additional cases experienced a marked reduction of their anginal attacks during successive CH periods. Exercise time to effort-induced angina was increased in all three patients and one of them revealed a markedly elevated threshold for eliciting ischaemic cardiac symptoms by standardized physical exercise on a cycle ergometer. We hypothesize whether extra CH periods elicited by sustained nitrate therapy and remission of angina pectoris during active clusters are caused by central mechanisms involving inhibition of sympathetic tone and effects on both cranial vessels and cardiac functions.

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 microsatellite 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.

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. Missense 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.

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.