Gotowa bibliografia na temat „Migraine without aura”

Data from the Prolonged Migraine Prevention (PROMPT) with Topiramate trial were evaluated post hoc to determine whether topiramate could prevent migraine auras, and whether its efficacy in preventing migraine headaches was similar in patients with (MA; n = 269) and without (MoA; n = 542) aura. Migraines and auras were recorded during prospective baseline, 6-month open-label (OL) topiramate and 6-month double-blind (DB), placebo-controlled phases. In the last 28 OL days, migraines without aura and migraine auras decreased by 43.1% and 54.1%, respectively, in MA patients. MoA patients experienced a 44.3% reduction in migraines. In the DB phase, increases in migraines with placebo vs. topiramate were similar to the full study, but were generally not statistically significant, probably due to lack of power in the subgroup analysis. Similarly, there were no statistically significant changes in number of auras between groups. Thus, topiramate appears to reduce migraine auras in parallel with headache reductions, which are similar in patients with and without aura.

Background: Migraines are a broad spectrum of disorders classified by the type of aura with some requiring attentive treatment. Vasoconstrictors, including triptans, should be avoided in the acute phase of migraines with brainstem aura, in hemiplegic migraine, and in retinal migraine. This study investigated the characteristics and burden of these migraines. Methods: Medical charts of 278 Japanese pediatric patients with migraines were retrospectively reviewed. Migraine burden of migraines with brainstem aura, hemiplegic migraines, and retinal migraine was assessed using the Headache Impact Test-6™ (HIT-6) and the Pediatric Migraine Disability Assessment scale (PedMIDAS). Results: Of 278 patients screened, 12 (4.3%) patients with migraines with brainstem aura (n = 5), hemiplegic migraines (n = 2), and retinal migraine (n = 5) were enrolled in the study. All patients had migraine with/without typical aura, whereas some patients had coexisting migraine with another type of headache (chronic tension-type headache in 3 patients, and 1 each with frequent episodic tension-type headache, headache owing to medication overuse, and chronic migraine). Migraines with brainstem aura, hemiplegic migraines, and retinal migraine patients with coexisting headaches had higher HIT-6 or PedMIDAS scores, whereas migraines with brainstem aura, hemiplegic migraines, and retinal migraine patients without coexisting headache did not show high HIT-6 or PedMIDAS scores. Conclusion: All migraines with brainstem aura, hemiplegic migraines, and retinal migraine patients experienced migraine with or without typical aura, and some patients having other coexisting headaches also had high PedMIDAS and HIT-6 scores. PedMIDAS and HIT-6 should not be considered diagnostic indicators of migraines with brainstem aura, hemiplegic migraines, or retinal migraine. In clinical practice for headaches in children, careful history taking and proactive assessment of the aura are needed for accurate diagnosis of migraines with brainstem aura, hemiplegic migraines, and retinal migraine.

Purpose: Different types of migraine may be studied separately to understand their epidemiology and pathophysiology better. No studies have investigated patients with associated factors of anxiety severity in migraine without auras. Therefore, in this study, anxiety and its associated factors were investigated in a sample of Saudi Arabian patients with migraine without aura. Methods: A cross-sectional study of 122 conveniently sampled migraine patients at Madinah hospitals, Saudi Arabia, completed the Generalized anxiety disorder-7 scale (GAD-7), and a tool for social, demographics, and clinical information. Results: The majority of patients who did not have an aura with their migraine were female (67.2%); many did not report participating in sports activities (58.2%), or have a family history of migraine-headaches (74.6%). Anxiety severity was higher in migraine-without-aura patients, and those undergoing treatment for co-morbid conditions (β = .547, p = .042), those without family history of migraine/chronic headache (β = .016, p = .016), and patients with high frequency of migraine medication use (β = .009, p = .009). Discussion: The correlation of the anxiety severity level in patients who have migraines without aura may have important clinical, and epidemiological implications. females with their change in hormonal stat have a higher prevalence of migraine without aura, those with no habitual sport activity, and family history of migraine may indicate the need for targeted screening for migraine in these groups. Keywords: migraine; headache; sports; family history; trauma; GAD

Previous studies have revealed highly reproducible patterns of temporally lagged brain activity in healthy human adults. However, it is unknown whether temporal organization of intrinsic activity is altered in migraines or if it relates to migraine chronification. In this resting-state functional magnetic resonance imaging study, temporal features of intrinsic activity were investigated using resting-state lag analysis, and 39 episodic migraine patients, 17 chronic migraine patients, and 35 healthy controls were assessed. Temporally earlier intrinsic activity in the hippocampal complex was revealed in the chronic migraine group relative to the other two groups. We also found earlier intrinsic activity in the medial prefrontal cortex in chronic compared with episodic migraines. Both migraine groups showed earlier intrinsic activity in the lateral temporal cortex and sensorimotor cortex compared with the healthy control group. Across all patients, headache frequency negatively correlated with temporal lag of the medial prefrontal cortex and hippocampal complex. Disrupted propagation of intrinsic activity in regions involved in sensory, cognitive and affective processing of pain may contribute to abnormal brain function during migraines. Decreased time latency in the lateral temporal cortex and sensorimotor cortex may be common manifestations in episodic and chronic migraines. The temporal features of the medial prefrontal cortex and hippocampal complex were associated with migraine chronification.

The familial occurrence and mode of inheritance were analysed in families with migraine without aura (MO) and migraine with aura (MA). The probands were found among 4000 persons from the general population. All persons with MA were included as probands, and an equivalent number of probands with MO was selected as a random sample among those with MO. Spouses and first-degree relatives were blindly interviewed. All interviews were performed by one neurological research fellow. The distinct familial patterns indicate that MO and MA have a different aetiology. Compared with the general population, the first-degree relatives of probands with MO had a 1.9-fold increased risk of MO while spouses had a 1.5-fold increased risk of MO, indicating that both genetic and environmental factors are important in MO. The first-degree relatives of probands with MA had a four-fold increased risk of MA while spouses had no increased risk of MA, indicating that MA is determined largely by genetic factors. The complex segregation analysis indicate that both MO and MA have multifactorial inheritance without generational difference.

In a cross-sectional study of headache disorders in a representative general population of 1,000 persons the epidemiology of migraine with aura (MA) and migraine without aura (MO) was analysed in relation to sex and age distribution, symptomatology and precipitants. The headache disorders were classified on the basis of a clinical interview as well as a physical and a neurological examination using the operational diagnostic criteria of the International Headache Society (IHS). Lifetime prevalence of MA was 5%, male:female ratio 1:2. Lifetime prevalence of MO was 8%, M:F ratio 1:7. Women, but not men, were significantly more likely to have MO than MA. Neither MA nor MO showed correlation to age in the studied age interval (25–64 years). Premonitory symptoms occurred in 16% of subjects with MA and in 12% with MO. One or more precipitating factor was present in 61% with MA and in 90% with MO. In both MA and MO the most conspicuous precipitating factor was stress and mental tension. Visual disturbances were the most common aura phenomenon occurring in 90% of subjects with MA. Aura symptoms of sensory, motor or speech disturbances rarely occurred without coexisting visual disturbances. The pain phase of MA fulfilled the criteria for MO of the IHS. Headache was, however, less severe and shorter lasting in MA than in MO. Onset at menarche, menstrual precipitation, menstrual problems, influence of pregnancy and use of oral contraceptives all showed some relationship with the presence of MO and less with MA. The present findings suggest that MA and MO share the pain phase. Among subjects with MA and MO, 50% and 62%, respectively, had consulted their general practitioner because of migraine. Selection bias in previous clinical studies is demonstrated by comparisons with the present unselected sample.

Studies of twins, spouses and familial aggregation strongly suggest that migraine without aura (MO) and migraine with aura (MA) are genetically determined. The mode of inheritance is most likely multifactorial in both MO and MA. However, autosomal dominant inheritance with reduced penetrance cannot be excluded in either MO or MA. At present the only evidence for genetic heterogeneity of MA is familial hemiplegic migraine with slowly progressive ataxia. This phenomenon can also be explained by linkage of different genes. All existing studies have been characterized by one or more of the following methodologic shortcomings: selection of probands from clinic populations, information obtained by questionnaire, family history obtained through probands, insufficient description of the attacks, lack of distinction between MO and MA. Useful strategies for future studies of migraine genetics are discussed.

We present a diagnostic aura diary for prospective recordings of migraine with aura. Three questionnaires are supplemented with sheets for drawings and plottings of visual and sensory auras. Twenty patients recorded 54 attacks of migraine with aura and 2 attacks of migraine aura without headache. The visual and sensory aura were usually gradually progressive, reaching maximum development in 15 and 25 min (median) respectively and had a total duration of 20 and 55 min (median) respectively. Approximately 13% of the attacks had acute onset of visual aura associated with other features more typical of migraine. The visual and sensory auras always preceded typical migraine headache, and headache occurring before aura symptoms was always of the tension type, The migraine headache was milder than in attacks of migraine without aura and often did not have migraine characteristics. In attacks with unilateral head pain, headache and aura symptoms were contralateral in 90% and ipsilateral in 10%.

Migraine is a painful neurological disease that affects at least 12% of the Australian population. It is generally characterized by recurrent head pain usually accompanied by nausea, vomiting, neurological disturbance, photo-and phonophobia. Migraine has been classified by the international headache society (IHS) into two most common types, migraine with aura (MA) and migraine without aura (MO). The underlying pathophysiology of this debilitating disease is still partially understood and there are no known diagnostic markers for these common types of migraine. Current diagnosis of migraine is based on patient reported symptoms. Studies have shown several health conditions such as epilepsy, depression and stroke to be co-morbid with migraine. Current migraine treatments work with varying efficacy and often have adverse side effects. A greater understanding of this debilitating and painful disease is thus pertinent for developing new and improved migraine treatment. Both familial clustering and twin studies have shown evidence for significant genetic mechanisms to underlie migraine pathogenesis. Migraine is thus currently defined as a complex multifactorial disorder which involves an interaction between genetic and environmental factors. We have not yet identified all migraine genes but a number of genes, causative mutations and susceptibility variants have been identified and are already of significant clinical relevance. Currently the detection of 3 rare subtypes of migraine (Familial Hemiplegic Migraine 1, 2 and 3) and several related conditions with symptom overlap (Episodic Ataxia 2, Spinocerebellar Ataxia Type 6 and Cerebral Autosomal Dominant Arteriopathy with Sub cortical Infarcts and leucoencephalopathy (CADASIL) is undertaken by sequencing, with susceptibility variants for common types of migraine detected by sequencing or genotyping.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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Migraine is a serious neurological disorder that affects the central nervous system causing painful attacks of headache. Attacks of head pain vary widely in intensity, frequency and duration lasting from anywhere between 4-72 hours and are often accompanied by further symptoms of nausea, vomiting, photo- and phonophobia. In 1988, a group of world leaders in the diagnosis of migraine formed the International Headache Society (IHS) and compiled and published a consensus set of diagnostic criteria known as International Classification of Headache Disorders, ICHD-I 1988. This was the first classification system and was subsequently updated in 2004, ICHD-II 2004 and more recently a 3rd Edition beta version has been released (ICHD-3rd Ed Beta Version) and is the gold standard for diagnosing headache disorders. Migraine displays two main subtypes termed migraine with or without aura (MA and MO respectively). The two forms are distinguished from each other based on the development of aura, a period of variable and diverse neurological symptoms that precede the headache phase.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Science, Environment, Engineering and Technology
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Migraine is a painful temporarily incapacitating disorder that affects an estimated 12% of the general population including 18% of adult women and 6% of adult men. The disorder involves two main subtypes termed migraine with or without aura (MA and MO respectively). Migraine can present with a variety of symptoms that vary between individuals and between episodes experienced by a single individual. This disorder causes significant social and economic burden and alarmingly is often poorly treated. A direct cause of this is a lack of understanding of the underlying pathology of migraine. Migraine is believed to be a neurogenic disorder that involves temporary disruption of pathways that receive and respond to sensory signals. While numerous environmental triggers may have been identified the exact mechanisms that cause the disruption are still largely unknown. However, familial aggregation of migraine suggests significant genetic contributors.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
Full Text

This research was conducted to expand the understanding of the role of the X chromosome in common and familial typical migraine. The primary objective of this study was to identify new X chromosomal genetic targets that cause migraine. Overall this research has identified nine genetic targets of interest. Various obstacles were encountered throughout this study, but the knowledge gained for overcoming these obstacles are invaluable for implementation and improvement of future genetic studies investigating the X chromosome.

Migraine is a common, debilitating neurovascular disease charactensed by severe recurrent headache, nausea and vomiting, photophobia and phonophobia. It is clinically diagnosed based on criteria specified by the International Headache Society (IHS), defining two major classes of migraine: migraine with aura (MA) and migraine without aura (MO) MA sufferers experience neurovascular disturbances that precede the headache phase of an attack. Although migraine is partly influenced by environmental determinants, there is a significant genetic component, with disease heritability estimated to be up to 60% and mode of transmission multifactorial. The disorder is common with a large Dutch study reporting lifetime prevalence estimates of 33% in women and 13.3% in men, with an earlier study estimating 24% of women and 12% of men in the overall population. Mutations in various ion channel genes are responsible for neuromuscular and other neurological disorders. Inherited ion channel mutations or 'channelopathies' are increasingly found to be the cause of various neurological disorders in humans. In familial hemiplegic migraine (FHM), a rare subtype of migraine with aura, mutations in the CACNA1A gene (localised at C19p13) have been fbund (FHM1). This gene codes for the alphalA subunit of the neuronal voltage-dependent P/Q-type calcium channel. Recently a second gene, ATP1A2 (FHM2) (localised at C1q23), was implicated in some EHM families. The ATP1A2 ion channel gene, codes for the alpha2 subunit of the Na+, K+ ion ATPase pump. These findings of mutations in these genes have focused attention on central nervous system ionic channels and helped to better understand EHM pathophysiology, where the best genetic evidence providing molecular insight into migraine still comes flom the mutations detected in the rare form of migraine with aura; FHM. Migraine family studies, at the Genomic Research Centre (GRC), have utilised linkage analysis methods in providing results that have indicated suggestive linkage to the FHM1-CACNA1A region on l9p13, in a large multigenerational family (Migraine Family 1; MEl) affected with typical migraine. Also linkage studies conducted within the GRC have implicated an additional susceptibility region on chromosome 1q31, but still not ruling out a second susceptibility region on C1q23, with the possibility of there being two distinct loci, on the chromosome lq region. The focus of research in this thesis is on two main chromosomal regions, which were tested for migraine susceptibility on chromosome 1 and chromosome 19. The research involved a cross-disciplinary approach utilising association, linkage and mutation screening approaches. Allelic candidate gene studies can provide a suitable method for locating genes of small effect that contribute to complex genetic disorders, such as migraine. Family linkage studies are useful for detection of chromosomal susceptibility regions and association studies are powerful when a plausible candidate gene and a sequence variant with potential functional relevance is examined. Mutation screening studies can indicate a direct cause of disorders such as migraine, where possible sequence variants may alter the translation of proteins in genes, causing the disease. The first gene exanted on chromosome 19 was that of the Low Density Lipoprotein Receptor (LDLR) gene. The LDLR gene is a cell surface receptor that plays an important role in cholesterol homeostasis. We investigated the (TA)n polymorphism in exon 18 of the LDLR gene on chromosome l9pl3.2 performing an association analysis in 244 typical migraine affected patients, 151 suffering from migraine with aura, 96 with migraine without aura and 244 unaffected controls. The populations consisted of Caucasians only and controls were age and sex matched. The results showed no significant difference between groups for allele frequency distributions of the (TA)n polymorphism even after separation of the migraine affected individuals into subgroups of MA and MO affected patients. This is in contradiction to Mochi et al, 2003 who found a positive association of this variant with MO. Our study discusses possible differences between the two studies and extends this research by investigating circulating cholesterol levels in a migraine affected genetically-isolated population. Another gene examined on chromosome l9pl3 was the insulin receptor gene (1NSR). The aim of this study was to investigate through direct sequencing the INSR gene in DNA samples from a migraine affected family previously showing linkage to chromosome l9pl3 in an attempt to detect disease associated mutations. The insulin receptor gene (INSR) on chromosome 19pl3.3-13.2 is a gene of interest since a number of SNPs located within the gene have been implicated in migraine with (MA) and without aura (MO). Six DNA samples obtained from non-founding migraine affected members of migraine family one (MF 1) were used in this study. Genomic DNA was sequenced for the 1NSR gene in exons 1-22 and the promoter region. In the six migraine family member samples, previously reported single nucleotide polymorphisms (SNP5) were detected within two exonic DNA coding regions of the INSR gene. These SNPs, in exon 13 and 17, do not alter the normal INSR polypeptide sequence. In addition, intron 7 also revealed a DNA base sequence variation. For the 5' untranslated promoter region of the gene, no mutations were detected. In conclusion, this study detected no INSR mutations in affected members of a chromosome 19 linked migraine pedigree. Hence, migraine linkage to this chromosomal region may involve other candidate genes. The NOTCH3 gene on C19p13.2-p13.l has previously been shown to be a gene involved in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and may also be implicated in migraine as there are some symptom similarities between the two disorders. The TNFSF7 gene localised on Cl9pl3 is homologous to the ligands of the TNF receptor family, including TNF-alpha and TNF-beta, genes that have both been previously associated with migraine. This study investigated the migraine susceptibility locus at Cl9p13 studying two genes that may be involved in the disorder. The NOTCH3 gene was analysed by sequencing all exons with known CADASIL mutations in a family (MF1) that has previously been shown to be linked to Cl9pl3. The sequencing results for affected members of this pedigree proved to be negative for all known sequence variants giving rise to mutation causing amino acid changes for CADASIL. The direct sequencing results displayed that of a normal coding sequence for the NOTCH3 gene F or the TNFSF7 gene, this was investigated through SNP association analysis using a matched case-control migraine diagnosed population. Chi-square results showed non-significant P values across all populations tested against controls except for the MO subgroup which displayed a weak association with the TNFSF7 SNP (genotype, allele analysis P = 0.036, P = 0 017 respectively). Our results suggest that common migraine is not caused by any known CADASIL mutations in the NOTCH3 gene of interest however, the TNFSF7 gene displayed signs of involvement in a MO affected population, but, further studies are needed to confirm these results and to further explore a TNF receptor - migraine potential interaction. A final examination on chromosome 19 involved a case report of an extremely rare and severe form of migraine. As stated earlier Familial Hemiplegic Migraine (FHM) is a severe rare sub-type of migraine and gene mutations on chromosome 19 have been identified in the calcium channel gene CACNA1A (Cl9pl3) fOr FHM. Recently a gene mutation (S218L) for a dramatic syndrome originating from FHM, commonly named 'migraine coma', has implicated exon 5 of the CACNA1A gene. The occurrence of trivial head trauma, in FHM patients, may also be complicated by severe, sometimes even fatal, cerebral edema and coma occurring after a lucid interval. Hemiplegic migraine has also been found to be sporadic in which both forms share a similar spectrum of clinical presentations and genetic heterogeneity. The case report presented in this study enhances the involvement of the S218L CACNA1A mutation in the extremely rare disorder of minor head trauma induced migraine coma. It not only proves to be a powerful diagnostic tool in detecting cases of FHM head trauma induced coma but also for sporadic hemiplegic migraine (SHM) coma subjects. We conclude from this case study that the S218L mutation, in the CACNA1A calcium channel subunit gene, is involved in sporadic hemiplegic migraine (SHM), delayed cerebral edema and coma after minor head trauma. This thesis also involved analysis of chromosome 1 for migraine susceptibility, where FHM studies provided a foundation fOr common migraine research on chromosome 1. Studies have suggested that mutations in the CACNA1A gene on chromosome l9p cause FHM in only approximately 50% of affected pedigrees. The CACNAIA gene has previously been tested, within the Genomics Research Centre, in the common forms of migraine; however no new mutations or the FHM mutations were detected in these MA/MO affected samples. A second FHM susceptibility locus maps to chromosome 1q23 and mutations in the ATP1A2 gene have recently been implicated in two Cl-linked FHM pedigrees. As FHM is considered a rare and severe form of MA, it is possible that the chromosome 1q23 locus, and the ATP1A2 gene, may be involved in the common forms of migraine with (MA) and possibly without aura (MO). Also, we have previously reported evidence of linkage to microsatellite markers on chromosome 1q31 in a large pedigree affected predominately with MA, which suggests the possibility that there are two distinct loci for migraine susceptibility on chromosome 1. The objectives of this study were to extend our linkage analysis of chromosome lq microsatellite markers in predominantly migraine with aura pedigrees. Also, our aim was to test the novel FHM-2 ATP1A2 gene for involvement in these migraine affected pedigrees and a previous pedigree (Migraine Family 14; MF 14) showing evidence of linkage of markers to Clq31. This was performed by a chromosome 1 scan (31 markers) in 21 multiplex pedigrees affected mainly with MA. Also, the known FHM-2 ATP1A2 gene mutations were tested, by sequencing, fOr involvement in MA and MO in these pedigrees. Mutation screening by direct sequencing was also performed throughout the coding areas of the ATP1A2 gene in 3 MA individuals fiom MF14. The results of this study detected evidence for linkage in our migraine pedigrees at chromosome 1q23, to microsatellite markers spanning the ATP1A2 (FHM-2) gene. However testing of the known ATP1A2 gene mutations (for FHM) in migraine probands of pedigrees showing excess allele sharing was negative, with no mutations detected in these migraineurs. Sequencing of the entire coding areas of the gene through 3 MA affecteds from MF14, a pedigree showing significant linkage to this region, was also negative for mutations. In conclusion, this study reported that microsatellite markers on chromosome 1q23 show evidence of excess allele sharing in MA and some MO pedigrees, suggesting linkage to the common forms of migraine and the presence of a susceptibility gene in this region. The new FHM-2 (ATPIA2 gene) mutations reported by Fusco et al, 2003 do not cause migraine in probands of affected pedigrees showing excess allele sharing to markers in this genomic region. Also no mutations were detected in all exons of the ATP1A2 gene in 3 MA affected individuals from a large pedigree (MF14) showing linkage to this region. Investigation in this thesis continued on chromosome 1, with other genes being examined on C1q23, as well as the C1q31 region for a migraine susceptibility locus or gene. Previously in our laboratory, evidence for linkage was shown to migraine at C1q31 in one family predominantly affected with MA, with microsatellite markers in this region. The initial Cl study (above; ATP1A2 gene) has also provided evidence for linkage to the chromosome 1 locus 1q23, with evidence for excess allele sharing of markers in predominantly MA affected pedigrees. To further investigate both chromosome I loci, an investigation with six candidate genes that lie within the C1q23 and 1q31 regions through association analysis was undertaken. The results from this study reported non-significant chi-square results, showing P values greater than 0.05 across all SNPs (and a CA rpt) tested. An exception was the rs704326 SNP from exon 43 of the CACNA1E gene on C1q31. P values significantly less than 0.001 were obtained in the total migraine population and the MA subgroup, with similar frequency comparisons ascertained in both genotype and allele analysis. Examination through contingency table analysis of the CACNA1E flequency data indicated that the risk allele (A) was over-represented in the migraine group compared to the control group. Further comparison of the genotype data indicated a difference in frequency distributions (P less than 0 0001). Stratified analyses of migraine subtypes indicated that this association was specifically attributed to the MA subtype group. Odds ratios produced an OR of 4.14 with a 95% CI of 2.36 - 7.26 (P less than 0.0001). The positive association results obtained within the CACNA1E gene are interesting in the fact that FHM is considered to be a rare and severe form of migraine with aura (MA) and FHM-1 is caused by mutations contained within the calcium channel gene CACNA1A (localized at Cl9p13). The idea that FHM and specifically an FHM gene in the C1q31 genomic region may also contribute to susceptibility to the more common forms of migraine i e. migraine with aura, strongly supports and reinforces the idea that a common defective gene may be influencing both FHM and typical migraine. In conclusion, this thesis undertook a cross-disciplinary approach to genetic research of a complex disorder. The research involved linkage, association and mutation analysis strategies of migraine. This research implicated a specific variant on chromosome 1 and further supported the heterogeneic nature of migraine. Future directions into migraine research should involve further investigation of this specific variant and this genomic region. Such studies may aid in the development of more precise diagnosis and treatment methods for this complex disorder.

Migraine is a common, debilitating neurovascular disease charactensed by severe recurrent headache, nausea and vomiting, photophobia and phonophobia. It is clinically diagnosed based on criteria specified by the International Headache Society (IHS), defining two major classes of migraine: migraine with aura (MA) and migraine without aura (MO) MA sufferers experience neurovascular disturbances that precede the headache phase of an attack. Although migraine is partly influenced by environmental determinants, there is a significant genetic component, with disease heritability estimated to be up to 60% and mode of transmission multifactorial. The disorder is common with a large Dutch study reporting lifetime prevalence estimates of 33% in women and 13.3% in men, with an earlier study estimating 24% of women and 12% of men in the overall population. Mutations in various ion channel genes are responsible for neuromuscular and other neurological disorders. Inherited ion channel mutations or 'channelopathies' are increasingly found to be the cause of various neurological disorders in humans. In familial hemiplegic migraine (FHM), a rare subtype of migraine with aura, mutations in the CACNA1A gene (localised at C19p13) have been fbund (FHM1). This gene codes for the alphalA subunit of the neuronal voltage-dependent P/Q-type calcium channel. Recently a second gene, ATP1A2 (FHM2) (localised at C1q23), was implicated in some EHM families. The ATP1A2 ion channel gene, codes for the alpha2 subunit of the Na+, K+ ion ATPase pump. These findings of mutations in these genes have focused attention on central nervous system ionic channels and helped to better understand EHM pathophysiology, where the best genetic evidence providing molecular insight into migraine still comes flom the mutations detected in the rare form of migraine with aura; FHM. Migraine family studies, at the Genomic Research Centre (GRC), have utilised linkage analysis methods in providing results that have indicated suggestive linkage to the FHM1-CACNA1A region on l9p13, in a large multigenerational family (Migraine Family 1; MEl) affected with typical migraine. Also linkage studies conducted within the GRC have implicated an additional susceptibility region on chromosome 1q31, but still not ruling out a second susceptibility region on C1q23, with the possibility of there being two distinct loci, on the chromosome lq region. The focus of research in this thesis is on two main chromosomal regions, which were tested for migraine susceptibility on chromosome 1 and chromosome 19. The research involved a cross-disciplinary approach utilising association, linkage and mutation screening approaches. This research implicated a specific variant on chromosome 1 and further supported the heterogeneic nature of migraine. Future directions into migraine research should involve further investigation of this specific variant and this genomic region. Such studies may aid in the development of more precise diagnosis and treatment methods for this complex disorder.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Full Text

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Doctors belonging to a Medical Services Cooperative in Campina Grande were interviewed with the objective to determine their diagnostic accuracy when faced with clinical cases of primary headache, and also to appreciate the amplitude of their knowledge about headache classification and procedures concerning exams prescriptions and therapeutic indications. Methodology. The method of extensive direct observation through the application of a questionnaire was used. The doctors were presented with three fictitious clinical histories which represented situations of frequent primary migraines such as: migraine with aura (MA), migraine without aura (MO) and chronic tensional-type headache (CTTH) according to criteria established on International Headache Classification, second edition (IHCD-II), 2003, by the Headache Classification Subcommittee as part of the International Headache Society (IHS). 173 out of 462 doctors members of the Cooperative were contacted and 91 of these accepted to take part in the study. Results. In the group of 91 doctors interviewed, 51 (56%) were male, 35 (38,5%) were female and five (5,5%) refused to answer. Their age varied from 27 to 70 years old (44,8 + 09 years old). Their experience as doctors varied from three to 46 years (21,4 + 8,2 years). 67 (73.6%) stated to have been in a medical internship. The doctors interviewed were doctors of several areas. About the accuracy of the diagnostic test, concerning MO, 60 participants (66%) identified the case as migraine, only two (2,2%) identified the MO subtype and two (2,2%) suggested it was a case of mere headache. For the clinical case of MA, 25 doctors (27,5%) said it was a case of migraine and only one (1,1%) identified it as MA. About the diagnostic of CTTH, 12 doctors (13,2%) acknowledged it as tensional headache and there was not any reference to the CTTH subgroup. Among other possibilities of diagnostic, the most mentioned ones were migraine 36 (39,6%), secondary headache to systemic arterial hypertension 12 (13,2%) and headaches caused by brain expansive process 06 (6,6%). For the three clinical cases, most of the doctors researched 79 (86,8%) in the example of MO, 74 (81,3%) in the cases of MA and 71 (78%) in the example of CTTH wouldn´t prescribe complementary exams. Regarding treatment 77 (84,6%) in the case of MO, 80 (87,9%) in the case of MA and 67 (73,6%) in the case of CTTH decided not to treat it. Among those who forwarded the case to a neurologist, we have 67 (73,6%) for MO, 78 (85,7%) for MA and 59 (64,8%) for CTTH. 65 (71,4%) doctors who were interviewed said to be unaware of the IHS diagnostic criteria for primary headaches. Conclusion. Migraine was the most common initial diagnosis for any kind of headache without any identification of the subgroups. The CTTH was subdiagnosed being frequently misidentified as migraine cases despite it is the most prevailing kind of primary headache. Most of the doctors interviewed (p<0,05) does not prescribe complementary exams for headache patients and prefer to forward them to a specialist, choosing not to treat them. These results show the lack of information found in the doctors interviewed about the diagnostic criteria for the several kinds of primary headaches.
Foram entrevistados médicos pertencentes a uma Cooperativa de Serviços Médicos, na cidade de Campina Grande, com o objetivo de investigar a acurácia diagnóstica desses profissionais frente a casos clínicos de cefaléia primária, além de apreciar seus conhecimentos sobre a classificação das cefaléias e condutas quanto à solicitação de exames e indicações terapêuticas. Metodologia: Utilizou-se o método de observação direta extensiva através da aplicação de questionário. Foram apresentadas a todos os médicos entrevistados três histórias clínicas, fictícias, reproduzindo quadros de cefaléias primárias freqüentes, a saber: migrânea com aura (MCA), migrânea sem aura (MSA) e cefaléia do tipo tensional crônica (CTTC), seguindo os critérios da Classificação Internacional das Cefaléias, 2ª. Edição (IHCD-II), em 2003, elaborados pelo Subcomitê de Classificação das Cefaléias da Sociedade Internacional de Cefaléia (IHS). Foram contatados 173 médicos, de um total de 462 cooperados, dos quais 91 aceitaram participar do estudo. Resultados: Eles eram 51 homens (56%) e 35 mulheres (38,5%), cinco (5,5%) não identificaram o gênero. A idade variou entre 27 e 70 anos (44,8 + 09 anos). Eles tinham entre três e 46 anos de formados (21,4 + 8,2 anos). 67 (73,6%) afirmaram ter feito residência médica. Os médicos entrevistados atuavam nas mais diversas especialidades. Em relação ao índice de acerto diagnóstico, no exemplo de MSA, 60 participantes (66,2%) identificaram o quadro como migrânea, enquanto apenas dois (2,2%) identificaram o subtipo MSA e dois (2,2 %) sugeriram tratar-se apenas de cefaléia. No caso clínico de MCA, 25 (27,5%) disseram tratar-se de quadro de migrânea e apenas um (1,1%) respondeu ser MCA. Quanto ao diagnóstico de CTTC, 12 (13,2%) reconheceram tratar-se de cefaléia tensional, não houve acerto diagnóstico no subgrupo CTTC, e dentre outras possibilidades diagnósticas as mais citadas foram: migrânea 36 (39.6%), cefaléia secundária a hipertensão arterial sistêmica 12 (13,2%) e cefaléias ocasionadas por processo expansivo cerebral seis (6,6%). Nos três casos clínicos, a maior parte dos profissionais pesquisados 79 (86,8%) no exemplo de MSA, 74 (81,3%) nos casos de MCA e 71 (78%) no exemplo de CTTC - não solicitaria exames complementares. Quanto ao tratamento: 77 médicos (84,6%) no caso de MSA, 80 (87,9%) no caso de MCA e 67 (73,6%) no caso de CTTC, optaram por não tratar. Preferiram encaminhar ao neurologista: 67 médicos (73,6%) para MSA, 78 (85,7%) para MCA e 59 (64,8%) para CTTC. 65 (71,4%) dos entrevistados afirmaram desconhecer os critérios diagnósticos da IHS para cefaléias primárias. Conclusão: O diagnóstico inicial mais freqüente foi migrânea, comumente usado para identificar qualquer tipo de cefaléia, sem, contudo identificar seus subgrupos. A cefaléia do tipo tensional foi subdiagnosticada, freqüentemente sendo confundida com quadros de migrânea, a despeito de ser o tipo mais prevalente de cefaléia primária. A maioria (p<0,05) dos médicos não solicita exames complementares para portadores de cefaléia e prefere encaminhá-los ao especialista, optando por não tratar. Esses resultados demonstram a falta de informações por parte dos médicos entrevistados sobre os critérios diagnósticos para os diversos tipos de cefaléias primárias.

Migraine - with or without aura - is an enervating primary headache disorder that represents a heavy economic and social burden. The health-related quality of life of migraineurs is poor. The aim of this research was to investigate the health-related quality of life of migraine without aura sufferers. As the thesis was approached from a biopsychosocial perspective, potential determinants were chosen for investigation from the molecular, individual, interpersonal and wider societal levels. The research was executed in two phases: Phase 1 data (N = 341) were gathered using a survey of health-related quality of life (Short Form 6), temperament (the Tridimensional Personality Questionnaire), catastrophizing as a pain coping strategy (the four-item Pain Coping Scale) and the amount of perceived social support (the six-item Social Support Questionnaire). For phase 2, participants were requested to provide blood specimens for ELISA serum quantification of glutamate (n = 66) and gene expression analysis of the main glutamate transporter gene SLC1A2 on real-time reverse-transcription polymerase chain reaction (n = 20). Of the 341 adult residents of Gauteng Province, South Africa that participated in the survey, 94 (28%) met the criteria for migraine without aura and a further 60 (18%) suffer from possible migraine without aura, using the International Classification of Headache Diagnosis (2nd edition) criteria. This indicates that migraine without aura is a significant burden for South Africa. Health-related quality of life was significantly poorer for migraineurs versus those without migraine (p < .001), and is in fact comparable to that of liver transplant, cardiac bypass and elderly populations. This raises concerns about the severe burden of the disease on the mental and physical well-being of South African sufferers. Investigation of the predictors of health-related quality of life yielded two significant variables when controlling for sex, head and neck injury and language - Harm Avoidance and vii Catastrophizing. The regression model accounts for 29% of the variance in health-related quality of life. A reciprocal relationship likely exists between Harm Avoidance and Catastrophizing, in which a harm avoidant migraineur interprets the headache pain as a catastrophic event to be avoided – even at high cost to the self. Though there have been calls for more biopsychosocial studies of migraine, this thesis did not find added understanding of health-related quality of life through the combination of biological and psychosocial data. The implication is that the role of glutamate in migraine without aura still requires further investigation. Further study is also required with regard to which biological factors may influence the sufferer’s quality of life. The thesis indicates a key role for psychological intervention in aiding migraineurs to live a life of quality. The inclusion of interventions for the psychological aspects of migraine may yield improved outcomes for patients. However, Gauteng residents suffering from MO are potentially unaware of their diagnosis and therefore of potential management for their disorder. Awareness around migraine needs to be the first step in limiting this disorder’s devastating impact on individuals, their relationships and their potential to contribute meaningfully to society.
Psychology
D.Litt. et Phil. (Psychology)

Cloninger’s Psychobiological Theory of Personality proposes four temperament dimensions, each underpinned by a different neurotransmitter system. The serotonergic system is purportedly linked to Harm Avoidance (HA). The aim of this study was to explore the relationship between HA and serotonin in migraine without aura (MO). A second aim was to explore the personality profile of MO patients. Sixty-six participants completed an online questionnaire and donated blood samples. Results indicated no significant association between HA and serotonin and a significant relationship between MO and HA. This study indicates that both Cloninger’s Psychobiological Theory of Personality and the Tridimensional Personality Questionnaire used for its assessment have value in South African personality research. In addition, the findings of the study reveal support for personality influences on the processes involved in migraine. This not only produces worthwhile avenues of research but also an alternative perspective for clinical practice.
Psychology
M.A. (Psychology (Research Consultation))

This case is illustrative of migraine during pregnancy. In pregnancy, due to changes in the level of estrogen, migraines are often more frequent in the first trimester. The natural history for migraine, especially migraine without aura, is that 70% get better by the second trimester. A general strategy for management of migraines during pregnancy is illustrated. In general, prophylactic medications are not used during pregnancy, and migraines are treated symptomatically. Tables of the usual migraine medications to treat both the acute headache and to prevent migraine are included, along with their pregnancy classification and breast feeding safety. The chapter is meant to be a practical guide to migraine management during pregnancy and postpartum.

In most cases, women with headache disorders have normal pregnancy and delivery outcomes and should not be discouraged from becoming pregnant. Pre-pregnancy planning includes weaning of contraindicated medications. Most women with migraine without aura improve during pregnancy. Although there are limitations, various acute and preventive treatments may be employed, including non-pharmacologic options. Anti-epileptic medications should be avoided. For pseudotumor cerebri, the mainstay of treatment includes diuretics and therapeutic lumbar punctures, avoiding topiramate. Surgical treatment may be necessary if vision is threatened. Close monitoring and collaboration between an ophthalmologist, neurologist and obstetrician are critical. New-onset pseudotumor cerebri requires an investigation for secondary causes such as cerebral venous thrombosis. In the absence of a pre-existing primary headache disorder, new headaches in the postnatal period warrant evaluation for secondary headache disorders, including post-dural puncture headache, stroke, cerebral venous thrombosis, pre-eclampsia, eclampsia, reversible cerebral vasoconstriction syndrome (RCVS), and pituitary apoplexy.

Introduction: The increased use of devices during the SARS-CoV-2 pandemic is noteworthy. The democratization of technological products caused a significant increase an its use by the population across the globe. This has caused a consistent increase in the appearance of some diseases among users of those devices. Thus, a concern arises about the student context and its high workload online during the pandemic. Objective: Analyze the association between the use of digital devices and the incidence of headache among students during the pandemic. Design and setting: A literature review was conducted on the topic. Methods: We included 15 original articles in English and Portuguese from MEDLINE, Pubmed, and Google Academic databases, selected from 2011 to 2021. Results: In cross-sectional studies, reports of headache were higher in individuals who use digital devices frequently compared to those who do not use them, and migraine attacks with aura and use of analgesics were more recurrent in the first group. Several causal mechanisms between headache and the use of digital devices have already been proposed, such as exposure to electromagnetic fields, neck posture, stress and sleep alterations without, however, having any evidence. Conclusion: We conclude that the excessive use of electronic devices can increase the incidence and duration of headache. However, the literature on the subject is still limited. Therefore, there is an urgent need for research that controls exposure to digital devices in order to analyze the causal relationship between electronic devices and headache.