Rozprawy doktorskie na temat „Headache”

Application of advanced magnetic resonance imaging techniques to better understand the pathophysiology of migraine and other primary headache disorders, such as cluster headache.
Application of advanced magnetic resonance imaging techniques to better understand the pathophysiology of migraine and other primary headache disorders, such as cluster headache.

Consumption of monosodium glutamate (MSG) can induce headache in young healthy individuals and migraine-like headache in migraineurs. Blood plasma levels of glutamate are also elevated in migraineurs, but it is unknown how elevated levels of glutamate contribute to headache. The current study was undertaken to investigate the hypothesis that monosodium glutamate induces headache through activation of peripheral glutamate receptors. To test the hypothesis, we combined in vivo electrophysiology, laser Doppler recordings of dural vasculature, and immunohistochemistry to investigate the effect of systemic administration of MSG on the trigeminovascular pathway. Immunohistochemical analysis of the dura, determined that the nerve fibres innervating dural blood vessels express NMDA, AMPA, kainate and mGlur5 receptors. The glutamate transporter EAAT2, but not EAAT1 or 3, is expressed by dural blood vessels. Systemic administration of 50mg/kg MSG induced a 24.5 and 20.6 percent increase in dural blood flow in male and female rats, respectively, as measured by laser Doppler flowmetry. Dural blood flow returned to baseline values by a mean of 170 seconds. In in vivo extracellular recordings of spinal trigeminal subnucleus caudalis (SpVc) neurons with dural receptive fields, intravenously administered MSG evoked an increase in neuronal discharge in 5/6 neurons in both male and female rats. MSG also induced mechanical sensitization in both sexes. When the NMDA receptor selective antagonist APV (5, 50mg/kg) was co-administered with MSG, it attenuated both the MSG evoked activation and mechanical sensitization of SpVc neurons. My results suggest that MSG induced headache is mediated, in part, through activation of the peripheral NMDA receptor.
Pharmaceutical Sciences, Faculty of
Graduate

Headache pain impacts most of the population at some point in life, at an enormous cost to day-to-day functioning. Determination of the variables that are associated with prevalence and severity of headaches has been inconsistent. One area that deserves more attention is the relationship between headaches and sleep. For instance, several sleep parameters may precipitate or exacerbate headaches, but previous research often used inconsistent and limited assessments of both headaches and sleep, making results difficult to interpret and compare. The current study seeks to extend previous research by using more comprehensive and empirically validated assessment techniques to study the relationship between sleep and headaches in a healthy sample. Greater self-reported sleep quality is related to lower headache frequency and severity, and lower self-reported sleep quality is characteristic of individuals having migraine-type headaches. Greater sleep efficiency is related to lower headache severity and shorter headache duration. Greater sleep onset latency is related to longer headache duration and greater headache severity. Greater number of nighttime awakenings is related to greater headache severity and is characteristic of individuals having a diagnosable headache disorder (either tension-type or migraine-type). Stress appeared to be a partial mediator between self-reported sleep quality and headache severity. Further experimental studies may clarify causality between sleep and headache.

Typical migraine, comprised of migraine with aura (MA) and migraine without aura (MO), is a chronic, painful and debilitating neurovascular disease which is generally characterised by recurrent attacks of severe headache usually accompanied by nausea, vomiting, photo and phonophobia. Migraine has been shown to affect a large proportion of Caucasian populations with a recent comprehensive study indicating that around 25% of women and 8% of men suffer from the disease. Strong familial aggregation of typical migraine and an increased concordance for the disease in MZ twins over DZ twins, suggests that it has a significant genetic component. Heritability estimates are calculated to be between 40% and 60%, indicating that disease variation, in part, is explained by environmental determinants. The mode of transmission of typical migraine is not clear but is most likely multifactorial. Although the MA and MO subtypes exhibit some clinical heterogeneity, segregation analysis has suggested that there may be a common genetic aetiology for MA and MO, and a major gene contributing to typical migraine pathogenesis. This idea is substantiated by the fact that both subtypes of migraine can occur within the same family and even within the same individual, with up to 33% of sufferers experiencing both types of the disease. In addition, migraine prophylactics have been shown to result in similar effects in patients treated for both types of migraine. However, whether the two subtypes are truly separate entities or not remains unclear. At present, the type and number of genes involved in typical migraine is not known. Despite this, several studies into Familial Hemiplegic Migraine (FHM), a very severe subtype of MA, have led to the discovery that mutations in a brain specific calcium channel subunit gene (CACNA1A) located on chromosome 19, cause FHM in about 50% of affected families. FHM is a rare disease and is distinguished from typical migraine by its association with hemiparesis and clear autosomal dominant mode of inheritance. However, certain clinical features are common to both FHM and typical migraine including similarities in headache characteristics and triggers. Hence, FHM genetic studies provide a valuable model for investigating the genes involved in the more prevalent types of migraine with and without aura. For this reason the Genomics Research Centre has been conducting linkage studies utilising large Australian migraine pedigrees with a focus on the known FHM (CACNA1A) gene region on chromosome 19p13. Our results to date have indicated suggestive linkage to the FHM region on 19p13 in a large multigenerational pedigree (MF1) affected with typical migraine, with a maximum parametric LOD score of 1.92 (P = 0.001) obtained for a triplet repeat polymorphism situated in exon 47 of the CACNA1A gene. Expansion of this repeat was not observed, but is possible that mutations elsewhere in the CACNA1A gene may be responsible for migraine in this pedigree. To investigate this possibility, the current research involved sequencing two patients carrying the critical susceptibility haplotype surrounding the CACNA1A gene. The results of this mutation screen revealed no disease causing mutations or polymorphisms in any of the 47 exons screened. To determine whether the CACNA1A genomic region was implicated in typical migraine susceptibility in the general Caucasian population, 82 independent pedigrees and a large case-control group were also analysed using highly polymorphic microsatellite markers. There was no linkage or association detected in these groups and thus, it was concluded that if CACNA1A plays a role in typical migraine it does not confer a major effect on the disease. However, subsequent case-control studies of SNPs in the INSR gene, which is located ~15cM telomeric from CACNA1A, provided evidence of association to typical migraine. Thus, the INSR gene may now emerge as the new migraine susceptibility gene in this genomic region on chromosome 19. Family linkage studies conducted by Gardner et al have implicated an additional FHM susceptibility region on chromsome 1q31. Furthermore, independent research carried out by Ducros et al. has indicated a second FHM locus at 1q21-23, which is ~ 30cM centromeric to the region reported by Gardner et al. At this stage it is not clear whether there is a single locus, or two distinct loci, on the chromosome 1q region. This research also involved a family-based linkage and association approach to investigating the FHM susceptibility region on chromosome 1q31 for involvement in typical migraine susceptibility in affected Australian pedigrees. Initial multipoint ALLEGRO analysis provided strong evidence for linkage of Chr1q31 markers to typical migraine in a large multigenerational pedigree. The 1-LOD* unit support interval for suggestive linkage spanned ~18cM with a maximum allele sharing LOD* score of 3.36 obtained for marker D1S2782, P = 0.00004. Subsequent analysis of an independent sample of 82 affected pedigrees added support to the initial findings with a maximum LOD* of 1.24 (P = 0.008). Utilising the independent sample of 82 pedigrees we also performed a family-based association test. Results of this analysis indicated distortion of allele transmission at marker D1S249 (global c2(5) of 15.00, P = 0.010) in these pedigrees. These positive linkage and association results will need further confirmation by independent researchers, but overall they provide good evidence for the existence of a typical migraine locus near these markers on Chr1q31, and reinforce the idea that an FHM gene in this genomic region may also contribute to susceptibility to the more common forms of migraine. The serotonergic system has long been implicated in the pathophysiology of migraine. Researchers have therefore focused on the serotonin receptors and the genes that code for them when investigating this disease. Although serotonin receptor agonists have proven to be effective in the treatment of migraine, there has been little evidence of a serotonin receptor gene being associated with the disorder. However, in 1998, Ogilvie et al reported that a VNTR in the serotonin transporter gene (SERT) showed altered allelic distributions in a Danish migraine population. In addition to serotonin, there has been renewed interest in the involvement of the dopaminergic pathways in migraine. This interest has gained impetus since the study of Peroutka et al who reported an allelic association between the dopamine receptor gene DRD2 and migraine with aura. Another dopamine related gene, the dopamine beta-hydroxylase gene (DBH), has been localised to Chr 9q34 and codes for the enzyme that catalyses the conversion of dopamine to norepinephrine. It therefore plays an important role in dopaminergic and noradrenergic neurotransmission. Serum levels of DbH enzyme have been reported to be elevated in migrainous patients during the headache phase of an attack. Also, significantly increased DbH enzyme activity has been observed in migraine patients during the headache-free interval. Thus, the DBH gene is another good candidate for involvement in migraine pathophysiology and, to our knowledge, has not been previously implicated in this disease. Candidate gene studies may be useful strategies for identifying genes involved in complex diseases such as migraine, especially if the gene being examined contributes only a minor effect to the overall phenotype. This research also involved a linkage and association approach to investigating neurotransmitter related migraine candidate genes. Specifically, polymorphisms within the serotonin transporter gene (SERT), the dopamine receptor gene (DRD2) and the dopamine beta-hydroxylase (DBH) gene were tested in unrelated Caucasian migraineurs and non-migraine control individuals. In addition, an independent sample of 82 families affected with migraine were examined. Unrelated case-control association analysis of a DBH intragenic dinucleotide polymorphism indicated altered allelic distribution between migraine and control groups (c2 = 16.53, P = 0.019). Furthermore, the transmission/disequilibrium test (TDT) which was implemented on the family data also indicated distortion of allele transmission for the same DBH marker (c2 = 4.44, P = 0.035). Together, these results provide evidence for allelic association of the DBH gene with typical migraine susceptibility (Fisher's Combined P-value = 0.006) and indicate that further research into the role of the DBH gene in migraine aetiology is warranted. Nitric oxide (NO) is emerging as a key molecule affecting the pain associated with migraine. Since nitric oxide synthase (NOS) enzymes catalyse the synthesis of NO, the genes that code for these enzymes are good candidates for migraine molecular genetic analysis. This research involved investigating the role of a functionally relevant bi-allelic tetranucleotide polymorphism located in the promoter region of the human inducible nitric oxide synthase (iNOS) gene in migraine aetiology. A large group of migraine affected individuals were genotyped and compared to an age and sex matched group of unaffected controls. Results of a chi-squared analysis indicated that allele distributions for both migraine cases and controls were not significantly different (c2 = 1.93, P = 0.16). These findings offer no evidence for an allelic association of the tested iNOS polymorphism with the common forms of the disease and therefore do not support a role for this gene in migraine pathogenesis. In summary, this research involved linkage and association analysis of migraine candidate genes and genomic susceptibility regions. Whilst, the known FHM gene (CACNA1A) was excluded for significant involvement in typical migraine the adjacent INSR gene has been associated. Migraine is genetically heterogeneous and the results of this research also provide good evidence that the DBH gene is involved in disease predisposition, whilst the DRD2, SERT and INOS gene were not shown to be implicated. An additional susceptibility region for typical migraine is also likely to localise to chromosome 1q31. Overall, the results presented in this thesis have contributed valuable data to the understanding of the molecular genetics of migraine with and without aura. Future research into the molecular pathophysiological mechanisms of migraine will greatly facilitate the development of more effective diagnosis and treatment strategies.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Health Sciences
Full Text

Aim: The aim of this study was to investigate the patients' perspective of migraine and chronic daily headache (CDH) management. Methods: The study used a combination of qualitative (Phase 1) and quantitative methods (Phase 2). Both phases were conducted in the UK in adults (aged 18-65), who suffered either from migraine according to the International Headache Society criteria or from CDH. Phase 1 used semi-structured interviews (n=13) that were analysed according to the grounded theory methodology. Phase 2 was based on a postal survey that was administered to migraine, migraine with aura and CDH patients (n=438), who were members of the Migraine Action Association (UK). Findings: The qualitative findings revealed the patients' decision-making to treat and prevent headaches, their perceptions of headache and headache management and the holistic set of strategies used for headache management. Patients were highly involved in their headache care and perceived themselves as a key resource to management. The survey showed that a high proportion of headache patients use strategies from 4 areas of management including health care consultations, medication use, general management and social support. The survey also showed that the use of some strategies differs between different types of headaches. Overall, it was generally the CDH patients, who were more active in their headache management than migraine and migraine with aura patients, and some of these findings were statistically significant. Conclusion: Both the qualitative and quantitative findings of this study showed the patients' high level of involvement in their headache care. Combining the two methodologies helped to confirm and reinforce the findings. The results of this study can be used to identify headache patients as a key resource to management. Their high level of activity in this study shows the patients' willingness to be involved in their own headache care. However, since headache patients still report considerable suffering, it may be necessary to educate headache patients to maximise the outcome of their management efforts.

Proefschrift Universiteit Maastricht.
Omslagtitel: Headache, pain coping and quality of life in children. - Auteursnaam op omslag: Inez Bandell-Hoekstra. Met lit. opg. - Met samenvatting in het Nederlands.

Psychological stress triggers headaches, but how this happens is unclear. To explore this, 38 episodic migraine sufferers, 28 with tension-type headache (T-TH) and 20 controls rated nausea, negative affect, task-expectancies and headache at 5-minute intervals during an unpredictable and uncontrollable 25-minute mental arithmetic task with a non-contingent failure rate. Blood pressure and pulse rate were measured every 3 minutes and salivary cortisol was sampled before and after the task. Trigeminal activation was measured by nociceptive blink reflex measures during each of the three experimental phases. Multiple regression analyses indicated that negative affect (NA) was the strongest predictor of headache intensity during the task. Increases in stress-headache were unrelated to consistent changes in cardiovascular activity but were related to declines in cortisol and increased post-task trigeminal activity. In repeated measures ANOVAs, participants who developed headache had higher nausea, NA and self-efficacy expectancies than those with no-or-low headache (p <.05 to p <.001). In further multiple regression analyses to identify which aspects of the stress process contributed to the high NA preceding headache, discouragement, anxiety, irritation and tension mediated the relationship between headache intensity during the stressful task and primary and secondary appraisal processes (stressor exposure and stressor reactivity). Avoidant coping, perceived inability to decrease pain, and outcome expectancy independently predicted headache intensity during the stressful task. Anxiety mediated the relationship between headache intensity and the coping tactics of wishful thinking, self-criticism, pain catastrophizing and praying/hoping. Attachment anxiety and the personality traits of openness, agreeableness and conscientiousness moderated the relationship between stress appraisals and headache. Results were discussed using the model of stress-headache as allostatic load. Findings suggest that headache developed when participants overextended themselves during a stressful task, adopting an information processing style which impeded emotional adjustment to changing situational demands. Learning to modify perceptions of threat and adopting a more flexible, less outcome-dependent processing style which avoids response conflict might help to prevent headache from spiralling upward.

Typical migraine, comprised of migraine with aura (MA) and migraine without aura (MO), is a chronic, painful and debilitating neurovascular disease which is generally characterised by recurrent attacks of severe headache usually accompanied by nausea, vomiting, photo and phonophobia. Migraine has been shown to affect a large proportion of Caucasian populations with a recent comprehensive study indicating that around 25% of women and 8% of men suffer from the disease. Strong familial aggregation of typical migraine and an increased concordance for the disease in MZ twins over DZ twins, suggests that it has a significant genetic component. Heritability estimates are calculated to be between 40% and 60%, indicating that disease variation, in part, is explained by environmental determinants. The mode of transmission of typical migraine is not clear but is most likely multifactorial. Although the MA and MO subtypes exhibit some clinical heterogeneity, segregation analysis has suggested that there may be a common genetic aetiology for MA and MO, and a major gene contributing to typical migraine pathogenesis. This idea is substantiated by the fact that both subtypes of migraine can occur within the same family and even within the same individual, with up to 33% of sufferers experiencing both types of the disease. In addition, migraine prophylactics have been shown to result in similar effects in patients treated for both types of migraine. However, whether the two subtypes are truly separate entities or not remains unclear. At present, the type and number of genes involved in typical migraine is not known. Despite this, several studies into Familial Hemiplegic Migraine (FHM), a very severe subtype of MA, have led to the discovery that mutations in a brain specific calcium channel subunit gene (CACNA1A) located on chromosome 19, cause FHM in about 50% of affected families. FHM is a rare disease and is distinguished from typical migraine by its association with hemiparesis and clear autosomal dominant mode of inheritance. However, certain clinical features are common to both FHM and typical migraine including similarities in headache characteristics and triggers. Hence, FHM genetic studies provide a valuable model for investigating the genes involved in the more prevalent types of migraine with and without aura. For this reason the Genomics Research Centre has been conducting linkage studies utilising large Australian migraine pedigrees with a focus on the known FHM (CACNA1A) gene region on chromosome 19p13. Our results to date have indicated suggestive linkage to the FHM region on 19p13 in a large multigenerational pedigree (MF1) affected with typical migraine, with a maximum parametric LOD score of 1.92 (P = 0.001) obtained for a triplet repeat polymorphism situated in exon 47 of the CACNA1A gene. Expansion of this repeat was not observed, but is possible that mutations elsewhere in the CACNA1A gene may be responsible for migraine in this pedigree. To investigate this possibility, the current research involved sequencing two patients carrying the critical susceptibility haplotype surrounding the CACNA1A gene. The results of this mutation screen revealed no disease causing mutations or polymorphisms in any of the 47 exons screened. To determine whether the CACNA1A genomic region was implicated in typical migraine susceptibility in the general Caucasian population, 82 independent pedigrees and a large case-control group were also analysed using highly polymorphic microsatellite markers. There was no linkage or association detected in these groups and thus, it was concluded that if CACNA1A plays a role in typical migraine it does not confer a major effect on the disease. However, subsequent case-control studies of SNPs in the INSR gene, which is located ~15cM telomeric from CACNA1A, provided evidence of association to typical migraine. Thus, the INSR gene may now emerge as the new migraine susceptibility gene in this genomic region on chromosome 19. Family linkage studies conducted by Gardner et al have implicated an additional FHM susceptibility region on chromsome 1q31. Furthermore, independent research carried out by Ducros et al. has indicated a second FHM locus at 1q21-23, which is ~ 30cM centromeric to the region reported by Gardner et al. At this stage it is not clear whether there is a single locus, or two distinct loci, on the chromosome 1q region. This research also involved a family-based linkage and association approach to investigating the FHM susceptibility region on chromosome 1q31 for involvement in typical migraine susceptibility in affected Australian pedigrees. Initial multipoint ALLEGRO analysis provided strong evidence for linkage of Chr1q31 markers to typical migraine in a large multigenerational pedigree. The 1-LOD* unit support interval for suggestive linkage spanned ~18cM with a maximum allele sharing LOD* score of 3.36 obtained for marker D1S2782, P = 0.00004. Subsequent analysis of an independent sample of 82 affected pedigrees added support to the initial findings with a maximum LOD* of 1.24 (P = 0.008). Utilising the independent sample of 82 pedigrees we also performed a family-based association test. Results of this analysis indicated distortion of allele transmission at marker D1S249 (global c2(5) of 15.00, P = 0.010) in these pedigrees. These positive linkage and association results will need further confirmation by independent researchers, but overall they provide good evidence for the existence of a typical migraine locus near these markers on Chr1q31, and reinforce the idea that an FHM gene in this genomic region may also contribute to susceptibility to the more common forms of migraine. The serotonergic system has long been implicated in the pathophysiology of migraine. Researchers have therefore focused on the serotonin receptors and the genes that code for them when investigating this disease. Although serotonin receptor agonists have proven to be effective in the treatment of migraine, there has been little evidence of a serotonin receptor gene being associated with the disorder. However, in 1998, Ogilvie et al reported that a VNTR in the serotonin transporter gene (SERT) showed altered allelic distributions in a Danish migraine population. In addition to serotonin, there has been renewed interest in the involvement of the dopaminergic pathways in migraine. This interest has gained impetus since the study of Peroutka et al who reported an allelic association between the dopamine receptor gene DRD2 and migraine with aura. Another dopamine related gene, the dopamine beta-hydroxylase gene (DBH), has been localised to Chr 9q34 and codes for the enzyme that catalyses the conversion of dopamine to norepinephrine. It therefore plays an important role in dopaminergic and noradrenergic neurotransmission. Serum levels of DbH enzyme have been reported to be elevated in migrainous patients during the headache phase of an attack. Also, significantly increased DbH enzyme activity has been observed in migraine patients during the headache-free interval. Thus, the DBH gene is another good candidate for involvement in migraine pathophysiology and, to our knowledge, has not been previously implicated in this disease. Candidate gene studies may be useful strategies for identifying genes involved in complex diseases such as migraine, especially if the gene being examined contributes only a minor effect to the overall phenotype. This research also involved a linkage and association approach to investigating neurotransmitter related migraine candidate genes. Specifically, polymorphisms within the serotonin transporter gene (SERT), the dopamine receptor gene (DRD2) and the dopamine beta-hydroxylase (DBH) gene were tested in unrelated Caucasian migraineurs and non-migraine control individuals. In addition, an independent sample of 82 families affected with migraine were examined. Unrelated case-control association analysis of a DBH intragenic dinucleotide polymorphism indicated altered allelic distribution between migraine and control groups (c2 = 16.53, P = 0.019). Furthermore, the transmission/disequilibrium test (TDT) which was implemented on the family data also indicated distortion of allele transmission for the same DBH marker (c2 = 4.44, P = 0.035). Together, these results provide evidence for allelic association of the DBH gene with typical migraine susceptibility (Fisher's Combined P-value = 0.006) and indicate that further research into the role of the DBH gene in migraine aetiology is warranted. Nitric oxide (NO) is emerging as a key molecule affecting the pain associated with migraine. Since nitric oxide synthase (NOS) enzymes catalyse the synthesis of NO, the genes that code for these enzymes are good candidates for migraine molecular genetic analysis. This research involved investigating the role of a functionally relevant bi-allelic tetranucleotide polymorphism located in the promoter region of the human inducible nitric oxide synthase (iNOS) gene in migraine aetiology. A large group of migraine affected individuals were genotyped and compared to an age and sex matched group of unaffected controls. Results of a chi-squared analysis indicated that allele distributions for both migraine cases and controls were not significantly different (c2 = 1.93, P = 0.16). These findings offer no evidence for an allelic association of the tested iNOS polymorphism with the common forms of the disease and therefore do not support a role for this gene in migraine pathogenesis. In summary, this research involved linkage and association analysis of migraine candidate genes and genomic susceptibility regions. Whilst, the known FHM gene (CACNA1A) was excluded for significant involvement in typical migraine the adjacent INSR gene has been associated. Migraine is genetically heterogeneous and the results of this research also provide good evidence that the DBH gene is involved in disease predisposition, whilst the DRD2, SERT and INOS gene were not shown to be implicated. An additional susceptibility region for typical migraine is also likely to localise to chromosome 1q31. Overall, the results presented in this thesis have contributed valuable data to the understanding of the molecular genetics of migraine with and without aura. Future research into the molecular pathophysiological mechanisms of migraine will greatly facilitate the development of more effective diagnosis and treatment strategies.

Migraine, comprised of migraine with aura (MA) and migraine without aura (MO), is a painful neurovascular disease, affecting approximately 16% of the general population. It is characterised by a wide variety of symptoms including headache, nausea and vomiting, and photo- and phonophobia. The disorder is complex involving not only multiple genes, but also specific environmental factors, which can induce attacks in genetically predisposed individuals. Hyperhomocysteinaemia is a known risk factor for cerebrovascular, peripheral vascular and coronary heart disease. The Methylenetetrahydrofolate Reductase (MTHFR) enzyme is involved in homocysteine metabolism. Furthermore, it has been reported that a homozygous mutation (677C to T; Ala to Val) in the 5,10-MTHFR gene is associated with an elevation in plasma homocysteine levels (Frosst et al., 1995). This common mutation in the MTHFR gene has recently been associated with migraine with aura in a Japanese cohort (Kowa et al., 2000). The present study was designed to determine the prevalence of the MTHFR C677T mutation in Australian patients with migraine and to determine whether this mutation is associated with the disease in Caucasians. A large case-control study, consisting of 270 patients with migraine (167 with aura and 103 without aura), and 270 normal matched controls was investigated. Genotypic results indicated that the prevalence of the homozygous (T/T) genotype in migraine sufferers (15%) was higher than that of controls (9%) (P = 0.084). Furthermore, the frequency of the mutant (T/T) genotype in individuals with MA (19%) was significantly higher than in controls (9%) (P = 0.006). Interestingly, the risk of MA was ~2.5-fold higher in suffers possessing the homozygous variant (OR = 2.52, CI: 1.42 - 4.47, P = 0.0012). To confirm the MTHFR allelic association with MA, family-based tests were performed in an independent pedigrees group, where only those with MA were considered affected. Results from both the Pedigree Disequilibrium Test (PDT) and Family-Based Association Test (FBAT) analysis revealed slight, although not significant (PDT test, P = 132; and FBAT test, P = 0.390), over-transmission of the mutant allele (T) from parents to affected offspring. However, despite the MTHFR variant having a high heterozygosity (0.48), there were a limited number of informative transmissions for the MTHFR variant in the pedigree group resulting in reduced power for these tests. In conclusion, our results support the trends reported in the Japanese migraine study and suggest that the homozygous 677T gene variant causing mild hyperhomocysteinaemia, is a genetic risk factor for migraine, and indicate that further studies investigating the role of this gene are warranted. Mutations in various ion channel genes are responsible for neurovascular and other neurological disorders. Inherited ion channel mutations or "channelopathies" are increasingly found to be the cause of various neurological disorders in humans. Wittekindt and colleagues (1998) reported that the calcium-activated potassium channel (hKCa3) gene is a good candidate for schizophrenia and bipolar disorder (BD), as well as for other neurological disorders such as migraine. The hKCa3 gene is a neuronal small conductance calcium-activated potassium channel, which contains a polyglutamine tract, encoded by a polymorphic CAG repeat in the gene. The hKCa3 gene encodes a protein of 731 amino acids containing two adjacent polyglutamine sequences in its N-terminal domain separated by 25 amino acids. The C-terminal polyglutamine sequence is highly polymorphic in length (Austin et al., 1999). hKCa3 plays a critical role in determining the firing pattern of neurons via the generation of slow after-polarization pulses and the regulation of intracellular calcium channels (Kohler et al., 1996). Three distinct mutations in the a1 calcium channel gene have been shown to cause SCA-6, episodic ataxia-2 and familial hemiplegic migraine (FHM) (Ophoff et al., 1996). The hKCa3 gene contains a highly polymorphic CAG repeat that was initially mapped (Chandy et al., 1997) to a schizophrenia locus on chromosome 22 (Pulver et al., 1994). Recently Austin et al (1999) re-mapped hKCa3 and found it to reside on chromosome 1q21, a region that has been linked to FHM (Austin et al., 1999), a rare subtype of MA (Ducros et al., 1997; Gardner et al., 1998), and a region recently showing genetic linkage to typical migraine (Lea et al., 2002). The hKCa3 polymorphism results in small variations in polyglutamine number, similar to those that occur in the calcium channel a1a subunit gene (CACNA1A), which is encoded by CAG expansions and thought to cause Spinocerebellar Ataxia Type 6 via loss of channel function (Austin et al., 1999). Given the recent linkage of FHM to the region of chromosome 1q21, to which hKCa3 resides, and also linkage of typical migraine to this region, a large case-control study investigating this hKCa3 CAG marker and consisting of 270 migraine and 270 stringently matched healthy controls was undertaken. Our results indicated that there was no statistically significant difference in allele distributions for this marker between migraine and non-migraine patients (P >0.05). No significant difference in the allelic distribution was observed in the MA or MO groups when compared to controls (P >0.05) and there was no significant difference in CAG repeat length distribution between the migraine group and controls (P = 0.92), or between the MA and MO groups (P = 0.72) collectively. Hence, the CAG repeat in this gene does not show expansion in migraine. Overall, our results provide no genetic evidence to suggest that the hKCa3 CAG repeat polymorphism is involved in migraine aetiology in Australian Caucasians. Thus the involvement of the hKCa3 gene in migraine is not likely, although the hKCa3 gene remains an important candidate for other neurological disorders that may be linked to the 1q21.3 chromosomal region.

Migraine, comprised of migraine with aura (MA) and migraine without aura (MO), is a painful neurovascular disease, affecting approximately 16% of the general population. It is characterised by a wide variety of symptoms including headache, nausea and vomiting, and photo- and phonophobia. The disorder is complex involving not only multiple genes, but also specific environmental factors, which can induce attacks in genetically predisposed individuals. Hyperhomocysteinaemia is a known risk factor for cerebrovascular, peripheral vascular and coronary heart disease. The Methylenetetrahydrofolate Reductase (MTHFR) enzyme is involved in homocysteine metabolism. Furthermore, it has been reported that a homozygous mutation (677C to T; Ala to Val) in the 5,10-MTHFR gene is associated with an elevation in plasma homocysteine levels (Frosst et al., 1995). This common mutation in the MTHFR gene has recently been associated with migraine with aura in a Japanese cohort (Kowa et al., 2000). The present study was designed to determine the prevalence of the MTHFR C677T mutation in Australian patients with migraine and to determine whether this mutation is associated with the disease in Caucasians. A large case-control study, consisting of 270 patients with migraine (167 with aura and 103 without aura), and 270 normal matched controls was investigated. Genotypic results indicated that the prevalence of the homozygous (T/T) genotype in migraine sufferers (15%) was higher than that of controls (9%) (P = 0.084). Furthermore, the frequency of the mutant (T/T) genotype in individuals with MA (19%) was significantly higher than in controls (9%) (P = 0.006). Interestingly, the risk of MA was ~2.5-fold higher in suffers possessing the homozygous variant (OR = 2.52, CI: 1.42 - 4.47, P = 0.0012). To confirm the MTHFR allelic association with MA, family-based tests were performed in an independent pedigrees group, where only those with MA were considered affected. Results from both the Pedigree Disequilibrium Test (PDT) and Family-Based Association Test (FBAT) analysis revealed slight, although not significant (PDT test, P = 132; and FBAT test, P = 0.390), over-transmission of the mutant allele (T) from parents to affected offspring. However, despite the MTHFR variant having a high heterozygosity (0.48), there were a limited number of informative transmissions for the MTHFR variant in the pedigree group resulting in reduced power for these tests. In conclusion, our results support the trends reported in the Japanese migraine study and suggest that the homozygous 677T gene variant causing mild hyperhomocysteinaemia, is a genetic risk factor for migraine, and indicate that further studies investigating the role of this gene are warranted. Mutations in various ion channel genes are responsible for neurovascular and other neurological disorders. Inherited ion channel mutations or "channelopathies" are increasingly found to be the cause of various neurological disorders in humans. Wittekindt and colleagues (1998) reported that the calcium-activated potassium channel (hKCa3) gene is a good candidate for schizophrenia and bipolar disorder (BD), as well as for other neurological disorders such as migraine. The hKCa3 gene is a neuronal small conductance calcium-activated potassium channel, which contains a polyglutamine tract, encoded by a polymorphic CAG repeat in the gene. The hKCa3 gene encodes a protein of 731 amino acids containing two adjacent polyglutamine sequences in its N-terminal domain separated by 25 amino acids. The C-terminal polyglutamine sequence is highly polymorphic in length (Austin et al., 1999). hKCa3 plays a critical role in determining the firing pattern of neurons via the generation of slow after-polarization pulses and the regulation of intracellular calcium channels (Kohler et al., 1996). Three distinct mutations in the a1 calcium channel gene have been shown to cause SCA-6, episodic ataxia-2 and familial hemiplegic migraine (FHM) (Ophoff et al., 1996). The hKCa3 gene contains a highly polymorphic CAG repeat that was initially mapped (Chandy et al., 1997) to a schizophrenia locus on chromosome 22 (Pulver et al., 1994). Recently Austin et al (1999) re-mapped hKCa3 and found it to reside on chromosome 1q21, a region that has been linked to FHM (Austin et al., 1999), a rare subtype of MA (Ducros et al., 1997; Gardner et al., 1998), and a region recently showing genetic linkage to typical migraine (Lea et al., 2002). The hKCa3 polymorphism results in small variations in polyglutamine number, similar to those that occur in the calcium channel a1a subunit gene (CACNA1A), which is encoded by CAG expansions and thought to cause Spinocerebellar Ataxia Type 6 via loss of channel function (Austin et al., 1999). Given the recent linkage of FHM to the region of chromosome 1q21, to which hKCa3 resides, and also linkage of typical migraine to this region, a large case-control study investigating this hKCa3 CAG marker and consisting of 270 migraine and 270 stringently matched healthy controls was undertaken. Our results indicated that there was no statistically significant difference in allele distributions for this marker between migraine and non-migraine patients (P >0.05). No significant difference in the allelic distribution was observed in the MA or MO groups when compared to controls (P >0.05) and there was no significant difference in CAG repeat length distribution between the migraine group and controls (P = 0.92), or between the MA and MO groups (P = 0.72) collectively. Hence, the CAG repeat in this gene does not show expansion in migraine. Overall, our results provide no genetic evidence to suggest that the hKCa3 CAG repeat polymorphism is involved in migraine aetiology in Australian Caucasians. Thus the involvement of the hKCa3 gene in migraine is not likely, although the hKCa3 gene remains an important candidate for other neurological disorders that may be linked to the 1q21.3 chromosomal region.
Thesis (Masters)
Master of Philosophy (MPhil)
School of Health Sciences
Full Text

Headache is the most frequently reported pain in children and is associated with missed schooldays, anxiety, depressive symptoms and various physical symptoms. A secular trend of increasing headache prevalence has been suggested. Few studies have focused on tension-type headache among children from the general population.

The aims of this thesis were to describe the prevalence, incidence and prognosis of tension-type headache, migraine and overall headache in schoolchildren, to identify medical, psychological and social factors associated with these headache types, and to determine whether the prevalence of headache has increased over the last decades.

In 1997, 1850 schoolchildren aged 7-15 years from the city of Uppsala participated in a questionnaire study and 1371 (74.1%) responded. Out of these, a randomly selected, stratified sample of 131 children and their parents were interviewed. Three years later, 122 children from the interview sample replied to an identical headache questionnaire.

Compared with a similar study in 1955, a significantly lower proportion of schoolchildren reported no headache. The prevalence of tension-type headache increased with age and was significantly higher in girls than boys after the age of twelve. Similar age and gender differences were obtained for migraine. A higher proportion of girls reported frequent headache than boys. Children with headache, especially those with migraine, as well as their first-degree relatives suffered from other pains and physical symptoms more frequently than headache-free children and their first-degree relatives. Although the likelihood of experiencing the same headache diagnosis and symptoms at follow-up was high, about one fifth of children with migraine developed tension-type headache and vice versa. Female gender was a predictor of migraine and frequent headache a predictor of overall headache at follow-up. The estimated annual incidence for tension-type headache, migraine and overall headache was 81, 65 and 131 per 1000 children, respectively.

In conclusion, the results indicate that headache has become increasingly common among schoolchildren over the last decades. Prevention and treatment of headache is particularly important for girls since they have high prevalence of headache, frequent headache episodes and a poor outcome. In children with headache, diagnoses and treatment should be reassessed regularly and other pains should be asked about and treated as well.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.
Response to prophylactic treatment of migraine with Onabotulinumtoxin A (BTX-A) has been noted to be significantly correlated to the perceived direction of headache pain, namely imploding vs. exploding subtype. This study analyzed 3 methods of assessing migraine directionality in comparison to a 30-day headache log; pictorial representation, written description, and physician assessment. Each of these assessment types was shown to have poor agreement with the headache log at the initial visit. However, all 3 assessments displayed excellent agreement at the return visit, as well as significantly improved confidence in patient ability to determine headache directionality.

This thesis investigates the hypothesis that dysfunction of the hypothalamo-pituitary axis is important in headache in patients with pituitary disorders. The observation that patients with small functional pituitary tumours may suffer with severe headache syndromes, and the dramatic analgesic effect that may be seen with somatostatin analogues, are central to the thesis. In the first study, I showed that there was no correlation between pituitary volume or cavernous sinus invasion with headache in pituitary tumours. In this study, prolactinomas and growth hormone- secreting tumours were found to be associated with the highest degree of headache, suggesting that biochemical mechanisms may be more important than structural ones in the pathophysiology of pituitary tumour-associated headache. In the second study, the presence of potentially nociceptive peptides CGRP and substance P within pituitary tumours was investigated there was no association between the presence of these peptides and headache. In the third study, the clinical characteristics of pituitary tumour-associated headache were investigated. The commonest presentation of headache was migraine. The rare primary headache, Short lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT), was exclusively associated with acromegaly or prolactinoma. In the fourth study, the possibility that cessation of somatostatin infusion could be a useful non-vascular way of triggering headache was investigated the headache induction was not reliable. In the final study, the potential use of octreotide in the management of primary headache was investigated. Octreotide was unhelpful for migraine, but was efficacious in the acute treatment of cluster headache. The findings suggest that functional disturbances in the hypothalamo-pituitary axis may have a pathophysiological role in some headache types.

Paroxysmal hemicrania and hemicrania continua are primary headache syndromes characterized by exquisite response to indometacin. Migrainous features such as phonophobia and photophobia occur in hemicrania continua and the differential diagnosis with unilateral chronic migraine can be challenging. This thesis explores the phenotypical aspects of paroxysmal hemicrania, hemicrania continua and unilateral chronic migraine, revisits the current criteria for the identification of paroxysmal hemicrania and hemicrania continua, and identifies clinical markers that can be used to differentiate hemicrania continua from unilateral chronic migraine. The study of thirty-one patients with paroxysmal hemicrania shows the pain is in a wider area of the head and face and a full range of cranial autonomic features occurs with the attacks. The study of thirty-nine patients with hemicrania continua shows 92% of patients have side-locked pain. Ninety-five per cent of patients have at least one autonomic feature and a wider range of autonomic features occurs with severe pain. The study comparing twenty-seven patients with hemicrania continua and twenty-seven patients with indometacin negative unilateral chronic migraine shows that both syndromes share several clinical characteristics. However, cranial autonomic features and phonophobia and photophobia tend to be lateralized to the same side of the pain in hemicrania continua. The thesis concludes that the International Headache Society criteria for paroxysmal hemicrania and hemicrania continua should be revised. The results suggest to remove specification of attack site, and to include the full range of autonomic features in paroxysmal hemicrania; to allow side-swift of the pain, to include a more extensive range of autonomic features, and to consider the occurrence of autonomic features as an important but not an essential criterion in hemicrania continua. In addition, unilateral cranial autonomic features and phonophobia and photophobia may be helpful during the differential diagnosis between hemicrania continua and chronic migraine.

An underlying disorder in the migraine condition is an apparent subclinical sensitization of the trigemino cervical nucleus (TCN) indicated, for example, by an interictal deficient habituation of the nociceptive blink reflex (nBR). This has ramifications for tension-type headache (TTH), as there is considerable support for a pathogenesis of TTH which overlaps with that of migraine. The aim of this thesis was to investigate the upper cervical (C1-3) afferents as a potential sensitising source of the TCN in migraine and TTH, thereby addressing the hypothesis that upper cervical afferents evoke sensitisation of the TCN in migraine and TTH. Firstly, manual examination of the upper cervical (atlanto-occipital and C2-3) joints was performed in 20 migraineurs, 14 TTH patients and 14 controls. The reproduction of customary head pain in 100 and 95 per cent of TTH patients and migraineurs, respectively, supports a role of the upper cervical spine in primary headache, perhaps involving sensitization of the TCN. The second study employed the nociceptive blink reflex (nBR) to assess processing of trigeminal nociceptive information during reproduction and resolution of customary head pain (as the examination technique was sustained) in 15 migraineurs interictally. Reproduction and resolution of head pain was repeated over four 90 second trials; each trial was separated by 30 seconds. Migraineurs reported significant lessening of reproduction and increasing resolution of customary head pain over the four trials. In parallel was a significant increase in latency and decrease in amplitude of the nBR. The desensitizing effect of this examination technique on head pain implies that modulation of cervical afferent information may benefit migraineurs during manual cervical reproduction of customary head pain. Whiplash of the neck is considered a musculo skeletal event and subsequent headache implies involvement of upper cervical (C1-3) afferents. The symptomatic profile of chronic whiplash associated headache (CWAH) mirrors that of primary headache, inviting speculation that CWAH shares a pathophysiology similar to that of primary headache. This prompted us to assess trigeminal nociceptive processing in CWAH patients in the third study. The symptomatic profile of 22 CWAH patients confirmed previous studies demonstrating similar profiles to primary headache. Furthermore, when compared to controls (n=25), CWAH patients had significant photophobia and allodynia. In addition, analysis of the nBR revealed hyperexcitability in central nociceptive pathways in CWAH patients, thus reinforcing the hypothesis that CWAH could be driven by central sensitization from upper cervical afferents. Together, these studies support the view that upper cervical (C1-3) nociceptive information may contribute to sensitising the TCN in primary headache. Thus, therapeutic strategies that aim to alleviate aberrant discharge of cervical afferents may play a role in the management of primary headache.

Congenital Heart Disease (CHD) is one of the most common birth defects. It is the single most modifiable cause of infant mortality under one year of age. Therefore, the causes of CHD have been extensively researched in the past but the etiology remains largely unknown. Environmental risks, particularly maternal risk factors for congenital cardiac malformation have been evaluated in the original BWIS previously. However, in this research we examined one of the additional risk factors. We sought to determine whether maternal headache during six months prior to conception and throughout gestation until birth is a risk factor for CHD in the BWIS dataset. Among 3274 singleton cases and 3519 controls, a maternal report of headache was found to be associated with a nearly 20% increase in the risk of a congenital heart defect (OR= 1.2 p=0.001). Moreover, any medications use for headache 1-6 months prior to conception increased the risk of abnormal cardiac development by 1.3 fold (OR = 1.3, p=0.0004). Aspirin or aspirin containing analgesics were found to increase the risk for CHD at the defined risk period. According to subgroup analysis, aspirin or aspirin containing analgesics and acetaminophen or acetaminophen containing analgesics were found to be the risk factor for CTD i.e. Conotruncal defects. Furthermore, aspirin or aspirin containing analgesics increased the risk for PVSD i.e. Peri-membranous Ventricular Defect in offspring when the mother uses these drugs 1-6 months prior to conception. Additionally, the risk for CVD i.e. critical valve disease were found to be increased when women were exposed to aspirin or aspirin containing analgesics during third trimester after pregnancy. In conclusion, maternal headache increased the risk for CHD by 20% and the use of headache medications specifically pain relievers during 1-6 months prior to conception modulated type of defect was observed.

This thesis studies the effect of hypoxia (at rest and during exercise) on the arterial and venous cerebral circulation, investigating the venous system role in high altitude headache. Methods: 1) Hypobaric hypoxic studies investigated 198 trekkers and 24 Investigators to 5300m, 14 to 6400m and 8 to 8848m. 2) Normobaric hypoxic studies used Magnetic Resonance Imaging (MRI)) at sea-level. Four domains were addressed: i. Arterial: Hypobaric hypoxia: (n=24) Transcranial Doppler (TCD) measured middle cerebral artery diameter (MCAD) and blood velocity (MCAv). Sea-Level normobaric hypoxia: (n=7) A hypoxicator (FiO2 = 11%) for 3 hours with a 3Tesla MRI scan measured MCAD and MCAv. ii. Brain Oxygenation: Near Infrared Spectroscopy (NIRS) monitored Regional Brain Oxygenation (rSO2). iii. Venous: Retinal imaging at altitude and MRI at sea-level assessed the venous system. iv. Headache: A daily diary recorded headache burden. Results: Arterial: Hypobaric and normobaric hypoxia induced MCA dilatation. Mean (±(SEM)) MCAD increased in hypoxia (from 5.23(±0.23)mm (at 5300m) to 9.34(±0.88)mm (at 7950m)(p<0.001) (TCD). At sea-level, (after 3 hours FiO2 = 11%) MCAD increased from 3.04(±0.13)mm to 3.27(±0.13)mm (MRI). Brain Oxygenation: rSO2 decreased more than peripheral arterial saturation (SaO2), especially during exercise. The relative percentage reduction in resting SaO2 and rSO2 from 75m to 5300m was -22.23 ±0.56% and -30.61 ±1.28% (p<0.001) respectively. Venous: Hypoxia induced retinal and cerebral venous distension. Twenty-three of 24 subjects exhibited retinal venous distension (range 5 to 44%). Degree of distension correlated with headache (r = 0.553, p=0.005). Possession of a narrow transverse sinus strongly related to retinal and cerebral venous distension and headache. Headache: Headache Severity Index (HSI) (headache score x duration) correlated inversely to both lateral and third ventricular volumes summed (r = -0.5, p = 0.005) and pericerebellar CSF volume (r = -0.56, p = 0.03). Conclusions: Large cerebral arteries dilate and veins distend with hypoxia. This suggests an important influence of cerebral venous anatomy and physiology on headache, with implications for pathophysiological states and their management.

Cluster headache is a primary headache disorder that can be highly disabling. In this thesis we look at the treatment landscape of cluster headache with a scoping review of preventive and acute therapies for cluster headache as identified in randomized controlled trials and two-arm observational studies. We subsequently compare these therapies where data are available using network meta-analysis of randomized trials, and we attempt subgroup analyses again where data are available for acute treatments of episodic and chronic cluster. We identify the ranking of treatments for acute cluster headache, and certain acute therapies that may be beneficial in episodic and chronic cluster headache. Based on our findings, we also identify future directions for cluster headache trials.

Abstract

This is a qualitative study on what motivates personnel to apply for middle management positions within the Värmland County Police Department. This study also looks at whether or not there are differences in motivation between men and women in regards to applying for middle management positions.

The study has been conducted through in-depth interviews with 17 employees of the Police Department. The material collected was analysed using the Empirical Phenomenological Method (EPP). 29 categories were generated which were then divided into four themes.

The result showed that motivation can be achieved by having a more structured middle management roll whereby, for example, there are clear guidelines on the responsibility and authority you have. Support and encouragement were also named as motivating factors. With regards to differences in motivation between the sexes when applying for middle management positions it was found that there are differences. The main one being that women are more likely to degrade themselves when considering applying, thus convincing themselves that they have not got the competence that is being sought, while men are more likely never to consider the possibility that they are not suitable.

Keywords: Gender, Leadership, Motivation and Organisations culture

Sammanfattning

Denna kvalitativa studie avser att undersöka vad som motiverar personalen att söka enhetschefspositioner inom Polismyndigheten Värmland, samt att granska om det finns skillnader mellan män och kvinnor i relation till motivation för att bli chef.

Studien baseras av med djupintervjuer med 17 respondenter inom Polismyndigheten Värmland. Analysen av det insamlade materialet skedde genom Empirical Phenomenological Metod. Resultatet genererar totalt 29 kategorier vilka senare delades upp i fyra teman. Slutsatser som kan dras av studien är att medarbetarna kan motiveras genom att få stöd och uppmuntran, samt att enhetschefsrollen blir mer tydligt förklarad med hänsyn, till exempel, till ansvar och befogenhet. Socialt stöd och stöttning framkommer också som bra motivationsfaktorer. Resultatet visar att det finns skillnader i motivation mellan män och kvinnor när de ska söka cheftjänster. Det är mer sannolikt att kvinnor nedvärderar sig själva medan män övervärderar sig.

Nyckelord: genus, ledarskap, motivation och organisationskultur.

SUNCT (Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing) and SUNA (Short-lasting Unilateral Neuralgiform headache attacks with cranial Autonomic symptoms) are rare primary headache syndromes, classified with the Trigeminal Autonomic Cephalgias (TACs). Hypothalamic involvement in SUNCT and other TACs has been suggested by functional imaging data and clinically with successful deep brain stimulation. This thesis studies 52 patients (43 SUNCT, 9 SUNA). It addresses the clinical phenotype of these conditions and response to medications. A functional imaging study explores activation of the posterior hypothalamus in attacks of SUNCT and SUNA, and looks for structural changes in this region on voxel-based morphometry. The clinical study characterises SUNCT and SUNA in terms of epidemiology of the syndromes, phenotype and clinical characteristics. A double-blind trial of topiramate in SUNCT showed a 40% response rate, although a similar trial in lamotrigine was less successful. Indomethacin is ineffective in these conditions on single-blind testing. Intravenous lidocaine was effective in all cases. Open- label trials showed the effectiveness of lamotrigine, topiramate and gabapentin. On functional imaging there was activation bilaterally in the posterior hypothalamus in 5/9 SUNCT patients, and contralaterally in two patients. Two SUNCT patients had ipsilateral negative activation. In SUNA the activation was bilaterally negative. Group analysis showed bilateral activation, although there was no such activation on whole brain analysis. There was no structural change in this region on voxel-based morphometry. The thesis concludes that there should be revised classification for SUNCT and SUNA, with an increased range of attack duration and frequency, cutaneous triggering of attacks, and a lack of refractory period. The concept of 'attack load' is introduced. The lack of response to indomethacin, and the response to intravenous lidocaine, are useful in diagnostic and therapeutic measures respectively. Preventive treatments include lamotrigine, gabapentin and topiramate. Hypothalamic activation is discussed in light of the imaging and methodological issues. Finally the role of hypothalamic involvement in SUNCT and SUNA as TACs is considered.

Primary headache disorders are the most common complaints worldwide. The socioeconomic and personal impact of headache disorders is enormous, as it is the leading cause of workplace absence. Headache patients’ consultations are increasing as the population has increased in size, live longer and many people have multiple conditions, however, access to specialist services across the UK is currently inequitable because the numbers of trained consultant neurologists in the UK are 10 times lower than other European countries. Additionally, more than two third of headache cases presented to primary care were labelled with unspecified headache. Therefore, an alternative pathway to diagnose and manage patients with primary headache could be crucial to reducing the need for specialist assessment and increase capacity within the current service model. Several recent studies have targeted this issue through the development of clinical decision support systems, which can help non-specialist doctors and general practitioners to diagnose patients with primary headache disorders in primary clinics. However, the majority of these studies were following a rule-based system style, in which the rules were summarised and expressed by a computer engineer. This style carries many downsides, and we will discuss them later on in this dissertation. In this study, we are adopting a completely different approach. The use of machine learning is recruited for the classification of primary headache disorders, for which a dataset of 832 records of patients with primary headaches was considered, originating from three medical centres located in Turkey. Three main types of primary headaches were derived from the data set including Tension Type Headache in both episodic and chronic forms, Migraine with and without Aura, followed by Trigeminal Autonomic Cephalalgia that further subdivided into Cluster headache, paroxysmal hemicrania and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. Six popular machine-learning based classifiers, including linear and non-linear ensemble learning, in addition to one regression based procedure, have been evaluated for the classification of primary headaches within a supervised learning setting, achieving highest aggregate performance outcomes of AUC 0.923, sensitivity 0.897, and overall classification accuracy of 0.843. This study also introduces the proposed HydroApp system, which is an M-health based personalised application for the follow-up of patients with long-term conditions such as chronic headache and hydrocephalus. We managed to develop this system with the supervision of headache specialists at Ashford hospital, London, and neurology experts at Walton Centre and Alder Hey hospital Liverpool. We have successfully investigated the acceptance of using such an M-health based system via an online questionnaire, where 86% of paediatric patients and 60% of adult patients were interested in using HydroApp system to manage their conditions. Features and functions offered by HydroApp system such as recording headache score, recording of general health and well-being as well as alerting the treating team, have been perceived as very or extremely important aspects from patients’ point of view. The study concludes that the advances in intelligent systems and M-health applications represent a promising atmosphere through which to identify alternative solutions, which in turn increases the capacity in the current service model and improves diagnostic capability in the primary headache domain and beyond.