This thesis explores biochemical and genetical changes associated with migraine and cluster headache. This research aims to increase knowledge of the pathophysiology and signaling pathways involved... Show moreThis thesis explores biochemical and genetical changes associated with migraine and cluster headache. This research aims to increase knowledge of the pathophysiology and signaling pathways involved in migraine and cluster headache, thereby identifying new targets for treatment. Uncovering the biological mechanisms on how patients differ from those without disease leads to a better understanding of the pathophysiology of primary headache disorders. The biological systems in our body are related to each other, and are based on the genomic blueprint and lead via epigenetics, transcription and translation to proteins and biomolecules. The first part of the dissertation focuses on the examination of biomolecules in body fluids (blood and cerebrospinal fluid) in migraineurs. Several studies showed that biomolecule concentrations differed between people with and without migraine for lipids, amino acids and metabolites of glucose metabolism. These results indicate a general disruption of the metabolic profile in migraineurs. For other substances, no differences were found. The second part of the thesis looked at the genetic blueprint of various headache disorders. There a genetic difference between people with migraine and people without migraine was found. In addition, a genetic difference between people with and without cluster headache was found. Show less
In this thesis, the role of migraine as a cardiovascular risk factor is investigated in different populations with a varying medical history, including stroke and polycystic ovary syndrome (PCOS).... Show moreIn this thesis, the role of migraine as a cardiovascular risk factor is investigated in different populations with a varying medical history, including stroke and polycystic ovary syndrome (PCOS). We focused primarily on women and sex-specific features, exploring both conventional and novel measures for vascular health. This thesis was written in the context of the CREW consortium. The aim of the CREW consortium, a cooperation of major medical centers in the Netherlands and commissioned by the Dutch Heart Institute, was to study female-specific cardiovascular pathophysiology. The CREW-MIST (Cardiovascular Riskprofile in Women – MIcrovascular STatus) project, which was part of this consortium, focused on migraine in relation to stroke in women. Female-specific factors such as sex hormone- and pregnancy-related disorders were included in our studies and we explored microvascular health through heart- and brain imaging and functional measurements of the vasculature. Show less
Stroke is one of the leading causes of disability and death worldwide. Prevention of stroke is therefore essential. Effective prevention should be tailored to the clinical characteristics,... Show moreStroke is one of the leading causes of disability and death worldwide. Prevention of stroke is therefore essential. Effective prevention should be tailored to the clinical characteristics, lifestyle, and environment of the individual, among others. This is also known as precision prevention. An important example illustrating the need for precision prevention is the existence of sex differences in stroke occurrence. In practice, for predicting stroke risk, only traditional risk factors (such as smoking and hypertension) are included, and women-specific risk factors are not yet routinely included. As a result, women with an increased risk of stroke may be missed, which also prevents timely initiation of preventive treatments. In this thesis, I tried to lay the foundation for precision prevention of stroke in women.Part I discussed the pathophysiology underlying women-specific risk factors for stroke, and gender differences in the clinical presentation of stroke. I found that the mechanisms underlying the relationship between women-specific risk factors and stroke, in particular the relationship between migraine and cerebral infarctions, seem to be particularly significant in the childbearing phase of life.In Part II, I described how health data from the EHR can be used to develop prediction models for the risk of myocardial infarction or stroke specifically for women under 50 years of age, and found that women-specific risk factors can add value in the predictions. However, there is still a long way to go to actually implement these models in practice, such as testing them on new datasets, and complying with current laws and regulations for safe application. Show less
We developed an easy and semi-automated way to collect large numbers of cluster headache patients for large scale genetic-epidemiologic studies which we called the LUCA program. Cluster headache is... Show moreWe developed an easy and semi-automated way to collect large numbers of cluster headache patients for large scale genetic-epidemiologic studies which we called the LUCA program. Cluster headache is associated with three times higher odds for lifetime depression compared to controls. About one third of cluster headache patients report allodynia during attacks. The term cluster-tic should be avoided as it, incorrectly, suggests a separate clinically entity, with an innate pathophysiological mechanism and treatment. Cluster headache and epilepsy are comorbid disorders which supports the hypothesis that cortical hyperexcitability may play a role in cluster headache. The ICON study will determine if occipital nerve stimulation is an effective preventive treatment for patients suffering medically intractable chronic cluster headache. Show less
This thesis explores clinical phenotypes and the pathophysiology of rare monogenic models of migraine with the ultimate goal to identify novel treatment targets for these disorders, as well as for... Show moreThis thesis explores clinical phenotypes and the pathophysiology of rare monogenic models of migraine with the ultimate goal to identify novel treatment targets for these disorders, as well as for the common types of migraine. The research is divided in two parts: part one describes studies on hemiplegic migraine (HM), a monogenic form of migraine, part two describes studies on Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S), a monogenic vascular syndrome hypothesised to be associated with migraine. Show less
Room for improvement is present in the treatment of migraine in primary care. However, inviting all patients who receive prescriptions for __2 triptans each month to have an evaluation consultation... Show moreRoom for improvement is present in the treatment of migraine in primary care. However, inviting all patients who receive prescriptions for __2 triptans each month to have an evaluation consultation with their general practitioner (GP), produces insufficient effect on headache outcomes and costs. However, it remains important to stay alert on patients who are candidate for preventive treatment. When discussing the possibility of preventive treatment, GPs should keep in mind possible barriers in patients. Also, GPs have to ask themselves if they do not deny patients a possibly effective treatment because of their own negative ideas towards preventive medication. Also, we learned that when designing pragmatic studies in primary care, there are methodological issues that make it harder to prove the effectiveness of an intervention. First, the outcomes of pragmatic studies in primary care can negatively affected by changes in the behaviour of GPs and patients in the control group. Second, the quality of life outcome measures that are often used in this type of research are harder to validate and to interpret than the more robust outcome measures that are used in clinical trials Show less
CADASIL is a hereditary cerebral small vessel disease, caused by a mutation in the NOTCH3 gene, leading to migraine with aura, cerebrovascular accidents and cognitive decline at young to middle... Show moreCADASIL is a hereditary cerebral small vessel disease, caused by a mutation in the NOTCH3 gene, leading to migraine with aura, cerebrovascular accidents and cognitive decline at young to middle adult age. MRI scans of the brain may show lacunar infarcts, white matter lesions and microbleeds. In this thesis MRI scans of the brains are used to investigate the disease course in CADASIL. It is shown that lacunar infarcts, white matter lesions and microbleeds are progressive in CADASIL patients. Vascular risk factors are not associated with rate of progression of these MRI abnormalities. However, the rate of disease progression can be predicted by measuring the amount of MRI abnormalities at baseline. Lacunar infarcts, microbleeds and increased white ventricular volume are strongly associated with cognitive decline in CADASIL. Progression of white matter hyperintensities can be predicted by measurements of cerebrovascular reactivity. Using high-field MRI we demonstrated that luminal diameters of lenticulostriate arteries are normal in CADASIL, and that lacunar infarcts in CADASIL are not the result of luminal narrowing of these vessels. High-field MRI also showed that CADASIL patients have an increased diffuse iron deposition in the putamen and caudate nucleus of the brain. Show less
The research in this thesis was aimed at identifying and characterizing novel migraine gene mutations and pathways. Several FHM and non-FHM genes were investigated in patients with monogenic... Show moreThe research in this thesis was aimed at identifying and characterizing novel migraine gene mutations and pathways. Several FHM and non-FHM genes were investigated in patients with monogenic familial hemiplegic migraine or other monogenic disorders in which migraine can be prevalent. Functional consequences of these mutations and the clinical phenotypes associated with them were investigated. Common migraine with a complex genetic background was studied using a genome-wide association analysis in an isolated population and with a meta-analysis study. Furthermore, FHM1 mice were used to study expression profiles in brain tissues that are relevant for the induction of cortical spreading depression ___ underlying the migraine aura - (i.e., the occipital cortex) and cerebellar ataxia (i.e., the cerebellum). These studies will further our insight in the molecular pathophysiology of migraine. Show less
The objective of this thesis was to elucidate whether migraine is a true and independent risk factor for brain lesions. We summarized migraine symptoms, diagnostic criteria, epidemiologic data, and... Show moreThe objective of this thesis was to elucidate whether migraine is a true and independent risk factor for brain lesions. We summarized migraine symptoms, diagnostic criteria, epidemiologic data, and assumed pathophysiology. We described the existing literature on the relationship between migraine and ischemic stroke and cerebral white matter lesions (WML). The findings of the population-based CAMERA MRI-study are reported. Posterior circulation (cerebellar) infarcts occurred in 8% of migraineurs with aura (adjusted-OR 13.7). Female migraineurs were at increased risk of high-deep-WML-load (OR 2.0). Risks increased with attack frequency, suggestive of a causal relationship. We detailed on the infarcts and other infratentorial lesions. Findings of higher iron-concentration in deep brain nuclei in younger migraineurs suggest that repeated migraine attacks are associated with changes in regions known to be involved in central pain processing and migraine pathophysiology. In addition, we showed that migraineurs had more syncope-related autonomic-nervous-system symptoms, and we identified frequent syncope and orthostatic insufficiency as independent risk factors for high-DWML-load. With these data, there is now strong evidence that migraine is indeed an independent risk factor for silent brain lesions. The real extent of brain injury in migraine patients in the general population is likely underestimated. Show less
