Clinical and genetic aspects on cluster headache

Sammanfattning: Cluster headache (CH), a primary neurovascular headache syndrome, is characterized by recurrent, unilateral, short-lasting attacks of excruciating pain in the temporal region. The pain is considered one of the most severe pain conditions known to humans. This thesis has focused on studies of the clinical picture, especially in relation to headache classification criteria, studies of the genetic background and a search for pathophysiological mechanisms through gene expression analysis. In Study I we prospectively evaluated the prognosis after one typical cluster period. We found that 13 (26.5%) had had one cluster period only during a mean observation time of 8.9 years, and conclude that some patients may suffer from one cluster period only. In the new IHS classification (2004) only one period is required for a CH diagnosis. In Study II we identified 55 affected in 21 different CH families of whom 12 had atypical symptoms. The atypical cases did not fulfil the IHS (2004) diagnostic criteria for CH, but had clinical symptoms resembling CH. We suggest that the clinical spectrum of familial CH may be broader than previously thought and that these atypical cases in CH families may represent an expanded spectrum of the disease. Mutations of the CACNA1A gene have shown to cause several, mainly episodic, neurological disorders. In Study III we studied the impact of the CACNA1A gene on CH by performing an association analysis of two polymorphic markers in 75 sporadic CH patients and 108 matched controls. We found no significant differences between the patients and controls and we conclude that a great importance of the CACNA 1 A gene in our sporadic CH patients is unlikely. Nitric oxide (NO) has been regarded as an important mediator in vascular headache pathophysiology. In Study IV we analyzed five polymorphic markers of the three different NOS genes (NOS1, NOS2a and NOS3 coding for iNOS, nNOS and eNOS respectively) in 91 CH patients and 111 matched controls. However, this study offers no support for an association between these markers and our CH patients. In Study V, an international collaboration, a genome wide scan of extended CH pedigrees was performed, without identifying a single disease locus for CH. An association analysis of two polymorphisms of the HCRTR2 gene in a Danish, Swedish and British sporadic case-control cohort could not confirm a recently reported association of CH to this gene. Complete HCRTR2 sequencing in 8 independent familial CH cases could not detect any mutaitons. Genetic predisposition to CH is likely to be complex and compounded by heterogeneity. Finally, in Study VI, by using Affymetrix microarray technology, we obtained gene expression profiles from peripheral blood from 3 CH patients during attacks, between attacks and in remission, and from 3 matched controls. An upregulation of several S 100 proteins was seen during the active phase of the disease compared to remission, which could be confirmed for the calcium-binding S100P gene with quantitative RT-PCR in 6 CH patients. These findings might indicate an inflammatory process during the active phase of CH.