Anna Steinberg

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.

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.

Expression of messenger molecules and receptors in rat and human sphenopalatine ganglion indicating therapeutic targets

BackgroundMigraine and Cluster Headache (CH) are two primary headaches with severe disease burden. The disease expression and the mechanisms involved are poorly known. In some attacks of migraine and in most attacks of CH, there is a release of vasoactive intestinal peptide (VIP) originating from parasympathetic cranial ganglia such as the sphenopalatine ganglion (SPG). Patients suffering from these diseases are often deprived of effective drugs. The aim of the study was to examine the localization of the botulinum toxin receptor element synaptic vesicle glycoprotein 2A (SV-2A) and the vesicular docking protein synaptosomal-associated protein 25 (SNAP25) in human and rat SPG. Additionally the expression of the neurotransmitters pituitary adenylate cyclase activating polypeptide (PACAP-38), nitric oxide synthase (nNOS), VIP and 5-hydroxttryptamine subtype receptors (5-HT1B,1D,1F) were examined.MethodsSPG from adult male rats and from humans, the later removed at autopsy, were prepared for immunohistochemistry using specific antibodies against neurotransmitters, 5-HT1B,1D,1F receptors, and botulinum toxin receptor elements.ResultsWe found that the selected neurotransmitters and 5-HT receptors were expressed in rat and human SPG. In addition, we found SV2-A and SNAP25 expression in both rat and human SPG. We report that all three 5-HT receptors studied occur in neurons and satellite glial cells (SGCs) of the SPG. 5-HT1B receptors were in addition found in the walls of intraganglionic blood vessels.ConclusionsRecent focus on the SPG has emphasized the role of parasympathetic mechanisms in the pathophysiology of mainly CH. The development of next generation’s drugs and treatment of cranial parasympathetic symptoms, mediated through the SPG, can be modulated by treatment with BoNT-A and 5-HT receptor agonists.

Neuroendocrinal, Neurodevelopmental, and Embryotoxic Effects of Recombinant Tissue Plasminogen Activator Treatment for Pregnant Women with Acute Ischemic Stroke.

Thrombolysis with recombinant tissue plasminogen activator (rTPA) was the first evidence-based treatment approved for acute stroke. Ischemic stroke is relatively uncommon in fertile women but treatment is often delayed or not given. In randomized trials, pregnancy has been an exclusion criterion for thrombolysis. Physiologic TPA has been shown to have neuroendocrine effects namely in vasopressin secretion. Important TPA effects in brain function and development include neurite outgrowth, migration of cerebellar granular neurons and promotion of long-term potentiation, among others. Until now, no neuroendocrine side-effects have been reported in pregnant women treated with rTPA. The effects of rTPA exposure in the fetus following intravenous thrombolysis in pregnant women are still poorly understood. This depends on low case frequency, short-duration of exposure and the fact that rTPA molecule is too large to pass the placenta. rTPA has a short half-life of 4–5 min, with only 10% of its concentration remaining in circulation after 20 min, which may explain its safety at therapeutically doses. Ischemic stroke during pregnancy occurs most often in the third trimester. Complication rates of rTPA in pregnant women treated for thromboembolic conditions and ischemic stroke were found to be similar when compared to non-pregnant women (7–9% mortality). In embryos of animal models so far, no indications of a teratogenic or mutagenic potential were found. Pregnancy is still considered a relative contraindication when treating acute ischemic stroke with rTPA, however, treatment risk must be balanced against the potential of maternal disability and/or death.

A genetic CLOCK variant associated with cluster headache causing increased mRNA levels

Background Cluster headache is characterized by recurrent unilateral headache attacks of severe intensity. One of the main features in a majority of patients is a striking rhythmicity of attacks. The CLOCK (Circadian Locomotor Output Cycles Kaput) gene encodes a transcription factor that serves as a basic driving force for circadian rhythm in humans and is therefore particularly interesting as a candidate gene for cluster headache. Methods We performed an association study on a large Swedish cluster headache case-control sample (449 patients and 677 controls) screening for three single nucleotide polymorphisms (SNPs) in the CLOCK gene implicated in diurnal preference (rs1801260) or sleep duration (rs11932595 and rs12649507), respectively. We further wanted to investigate the effect of identified associated SNPs on CLOCK gene expression. Results We found a significant association with rs12649507 and cluster headache (p = 0.0069) and this data was strengthened when stratifying for reported diurnal rhythmicity of attacks (p = 0.0009). We investigated the effect of rs12649507 on CLOCK gene expression in human primary fibroblast cultures and identified a significant increase in CLOCK mRNA expression (p = 0.0232). Conclusions Our results strengthen the hypothesis of the involvement of circadian rhythm in cluster headache.

Role of Nitric Oxide in Cluster Headache

Nitric oxide (NO) is an important molecule in headache pathophysiology. NO regulates vascular tone and acts as a potent vasodilator, and thus participates in regulating blood flow. NO is also considered to play a role in processing sensory information and pain sensitization. In this article, we review the role of NO in one of the primary headache disorders, cluster headache (CH). The pathophysiology of CH is still not completely understood. A multifactorial genesis where NO is likely to be involved is probable. The level of NO production has been shown to correlate with disease activity in several inflammatory disorders, such as cystitis, multiple sclerosis, and cerebral lupus erythematosus. In this article, the issue of whether similar circumstances apply for CH and also the role of NO in the pathophysiology of CH in a wider perspective are discussed.

Cluster headache – clinical pattern and a new severity scale in a Swedish cohort

Background The aim of this study was to investigate clinical features of a cluster headache cohort in Sweden and to construct and test a new scale for grading severity. Methods Subjects were identified by screening medical records for the ICD 10 code G44.0, that is, cluster headache. Five hundred participating research subjects filled in a questionnaire including personal, demographic and medical aspects. We constructed a novel scale for grading cluster headache in this cohort: The Cluster Headache Severity Scale, which included number of attacks per day, attack and period duration. The lowest total score was three and the highest 12, and we used the Cluster Headache Severity Scale to grade subjects suffering from cluster headache. We further implemented the scale by defining a cluster headache maximum severity subgroup with a high Cluster Headache Severity Scale score ≥ 9. Results A majority (66.7%) of the patients reported that attacks appear at certain time intervals. In addition, cluster headache patients who were current tobacco users or had a history of tobacco consumption had a later age of disease onset (31.7 years) compared to non-tobacco users (28.5 years). The Cluster Headache Severity Scale score was higher in the patient group reporting sporadic or no alcohol intake than in the groups reporting an alcohol consumption of three to four standard units per week or more. Maximum severity cluster headache patients were characterised by higher age at disease onset, greater use of prophylactic medication, reduced hours of sleep, and lower alcohol consumption compared to the non-cluster headache maximum severity group. Conclusion There was a wide variation of severity grade among cluster headache patients, with a very marked impact on daily living for the most profoundly affected.

Screening of Two ADH4 Variations in a Swedish Cluster Headache Case–Control Material

Cluster headache (CH) is a severe neurovascular disorder and an increasing amount of evidence points to a genetic contribution to this disease. When CH was first described, it was observed that alcohol may precipitate an attack during the active phase of the disease. The alcohol dehydrogenase 4 (ADH4) gene encodes an enzyme which contributes to the metabolization of alcohol and is, therefore, an interesting candidate gene for CH. Two Italian groups have reported association of the single nucleotide polymorphism (SNP) rs1126671 located in the ADH4 gene with an increased risk of CH in Italy. In addition, one of the groups found an association between the ADH4 SNP rs1800759 and CH.

White blood cell SPECT during active period of cluster headache and in remission.

Background and purpose:  Cluster headache (CH) is an episodic headache disorder characterized by recurrent, unilateral attacks of excruciating pain in the temporal/orbital region. The pathophysiology of CH is largely unknown although involvement of immunological mechanisms has been suggested. The aim of our study was to investigate whether patients with CH show signs of intracranial inflammation, when using white blood cell single‐photon emission computer tomography (WBC‐SPECT).

Levels of nitric oxide metabolites in cerebrospinal fluid in cluster headache

The pathophysiology of cluster headache (CH) is only partly understood. Nitric oxide (NO), a potent vasodilator, has been suggested to be involved, and increased plasma levels of nitrite, a stable product on NO degradation, have been identified in the active period and in remission. The aim of our study was to investigate the role of NO in CH by measuring its oxidation products, nitrite and nitrate, in the cerebrospinal fluid (CSF), a biological compartment closer to the supposed focus of the disorder. We collected CSF from 14 episodic CH patients. Lumbar puncture (LP) was performed at two occasions: in active period between headache attacks, and in remission, not earlier than three weeks after the last CH attack. Eleven healthy volunteers served as controls. To estimate NO production, we determined the levels of NO-oxidation end products (NOx), that is, the sum of nitrite and nitrate, by using capillary electrophoresis. CH patients in the active period had significantly increased NOx levels (mean 9.3, 95% confidence interval [CI] 8.5–10.1) compared with those in remission (mean 7.6, 95% CI 6.9–8.2; p < 001) and control subjects (mean 6.2, 95% CI 4.9–7.5; p < 0.001). CH patients also had statistically significant enhanced NOx levels in remission compared with those of control subjects (p = 0.034). CSF was also analysed with regard to inflammatory parameters and protein content. CSF showed signs of pleocytosis or oligoclonal bands or albumin increase in 43% of CH patients although these results were not conclusive. We suggest that CH patients have a generally raised NO tonus, both in the active period and in remission. We interpret these results as indications of a basal hyperfunction of the L-arginine-NO pathway, possibly as an expression of inflammatory activity, and sensitization of pain pathways. This is the first study analysing NOx in CSF in CH, and the results support NO involvement in the pathogenesis of CH.