No / Two different theories of migraine aura exist: In the vascular theory of Wolff, intracerebral vasoconstriction causes migraine aura via energy deficiency, whereas in the neuronal theory of Leão and Morison, spreading depression (SD) initiates the aura. Recently, it has been shown that the cerebrovascular constrictor endothelin-1 (ET-1) elicits SD when applied to the cortical surface, a finding that could provide a bridge between the vascular and the neuronal theories of migraine aura. Several arguments support the notion that ET-1¿induced SD results from local vasoconstriction, but definite proof is missing. If ET-1 induces SD via vasoconstriction/ischemia, then neuronal damage is likely to occur, contrasting with the fact that SD in the otherwise normal cortex is not associated with any lesion. To test this hypothesis, we have performed a comprehensive histologic study of the effects of ET-1 when applied topically to the cerebral cortex of halothane-anesthetized rats. Our assessment included histologic stainings and immunohistochemistry for glial fibrillary acidic protein, heat shock protein 70, and transferase dUTP nick-end labeling assay. During ET-1 application, we recorded (i) subarachnoid direct current (DC) electroencephalogram, (ii) local cerebral blood flow by laser-Doppler flowmetry, and (iii) changes of oxyhemoglobin and deoxyhemoglobin by spectroscopy. At an ET-1 concentration of 1 µM, at which only 6 of 12 animals generated SD, a microarea with selective neuronal death was found only in those animals demonstrating SD. In another five selected animals, which had not shown SD in response to ET-1, SD was triggered at a second cranial window by KCl and propagated from there to the window exposed to ET-1. This treatment also resulted in a microarea of neuronal damage. In contrast, SD invading from outside did not induce neuronal damage in the absence of ET-1 (n = 4) or in the presence of ET-1 if ET-1 was coapplied with BQ-123, an ETA receptor antagonist (n = 4). In conclusion, SD in presence of ET-1 induced a microarea of selective neuronal necrosis no matter where the SD originated. This effect of ET-1 appears to be mediated by the ETA receptor.

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)

Background: Patent Foramen Ovale (PFO), a remnant of the foetal circulation, is emerging as a new cause of disease. It has been found to be associated with cryptogenic stroke in young adults, peripheral arterial embolism and neurological decompression sickness in divers. The detection of PFO remains a diagnostic challenge; transoesophageal echocardiogram being currently considered the ‘gold standard’. The development of a non-invasive technique is crucial for the identification of a venous-to-arterial shunt (v-aCS) which may permit paradoxical embolism. Little is known about the genetic basis of PFO and our limited knowledge is based on animal studies and gene mutations detected in patients with other cardiac septal defects. Methods: Study 1: PFO Detection and Evaluation: This study was designed to evaluate transcranial Doppler (TCD), transthoracic echocardiogram (TTE) and transoesophageal echocardiogram (TOE) with administration of contrast via arm and femoral veins. We then developed a standardized protocol for PFO detection and quantification using TCD. Study 2: PFO and Migraine: The PFO detection protocol developed from the first study formed the diagnostic technique to detect v-aCS in an adequately powered matched case control study to explore the association between PFO and migraine. Study 3: The Genetic basis of PFO: This study was designed to explore the genetic basis of a PFO using a candidate gene approach. Results: Study 1 - PFO Detection Study: When compared with TOE with femoral vein contrast injection as the ‘gold standard’, TCD with arm vein contrast was 100% sensitive and 97.4% specific for detecting a PFO. We defined a PFO positive (+ve) study on TCD as > 15 microbubbles entering the cerebral circulation, on TCD following arm vein injection and >16 microbubbles with a femoral contrast injection. A ‘major’ PFO+ve v-aCS was defined as >35 microbubbles with arm vein injection or >90 microbubbles with femoral vein injection. We then developed a new diagnostic pathway for PFO detection in clinical practice. Study 2 - PFO Migraine study: A significant difference in prevalence of v-aCS between migraine with aura M+A) and their matched controls was demonstrated with adjusted OR=3.72 (1.48-9.38) p=0.005 for a PFO+ve v-aCS, and a highly significant difference between M+A and controls for a ‘major’ PFO+ve v-aCS with adjusted OR = 6.38 (1.89 – 21.48) p = 0.003. There was significant association with APC resistance and migraine on thrombophilia screen. Study 3 - The PFO Genetics Study: This study detected mutations of GATA4 and NKX2-5 in both PFO+ve cases and PFO-ve controls. Two novel non synonymous mutations of GATA4, c.461T>A and c.994G>A were found only in PFO positive individuals and may be associated with a PFO. All the PFO+ve cases with a GATA4 gene mutation had a major PFO+ve v-aCSConclusion:TCD detects PFO with a sensitivity of 100% and specificity of 92.3% and is the most reliable non-invasive technique for PFO detection. When arm vein injections are used both cough and valsalva provocation is essential. There was a highly significant association between PFO+ve v- aCS and M+A, especially with a ‘major’ PFO+ve v-aCS. GATA 4 mutations though infrequent were found PFO+ve cases and all had major v-aCS.