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
Dit proefschrift beschrijft de effectiviteit en veiligheid van monoclonale antilichamen gericht tegen CGRP (fremanezumab) en de CGRP receptor (erenumab) als preventieve behandeling van... Show moreDit proefschrift beschrijft de effectiviteit en veiligheid van monoclonale antilichamen gericht tegen CGRP (fremanezumab) en de CGRP receptor (erenumab) als preventieve behandeling van migrainepatiënten in een ‘real world’ setting. Daarnaast bespreekt het factoren die voorspellend zijn voor de mate van de klinische response op deze medicatie. 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
The aim of this thesis was to identify functional biomarkers for migraine attack prediction based on neurophysiological readout parameters. The main focus of this work was on the development of... Show moreThe aim of this thesis was to identify functional biomarkers for migraine attack prediction based on neurophysiological readout parameters. The main focus of this work was on the development of methodologies to measure brain excitability over the migraine cycle, with special emphasis on identifying changes in excitability of the visual system and the occipital cortex. Applying such measures over the course of a migraine cycle could help elucidate factors that initiate the migraine attack, and might lead to better (or better timing of) preventive measures. The research described in this thesis is divided into two parts. The first part reports on the development and application of several methodologies to measure excitability of the visual system including the cortex in migraine patients and a migraine mouse model. The second part consists of two studies employing transcranial magnetic stimulation (TMS) in combination with concurrent electroencephalography (EEG) recordings to provide direct measures of cortical excitability in migraine and epilepsy. Show less
This thesis aimed to explore biochemical processes related to migraine outside (interictal) and during upcoming attacks. Chapter 2 describes the biochemical profiling of plasma samples from... Show moreThis thesis aimed to explore biochemical processes related to migraine outside (interictal) and during upcoming attacks. Chapter 2 describes the biochemical profiling of plasma samples from interictal migraine patients and healthy controls from eight Dutch cohorts with a proton nuclear magnetic resonance based metabolomics platform. In Chapter 3 cerebrospinal fluid (CSF) and plasma samples from interictal migraine with and without aura patients and healthy volunteers, were profiled using an ultra-performance liquid chromatography mass spectrometry (UPLC-MS) platform for amine measurements, as multiple amines have been implicated in migraine pathophysiology. Alcoholic beverages are frequently reported migraine triggers. Chapter 4 assessed the potential of various alcohol beverages as a migraine attack trigger using a questionnaire study in a large cohort of migraine patients. In Chapter 5, the frequently used pharmacological migraine trigger glyceryl trinitrate (GTN) was studied in migraine patients and healthy controls to investigate whether previously reported premonitory symptoms are indeed specific to migraine patients. In Chapter 6 glutamate, glutamine, and GABA were assed in the visual cortex of migraine patients before and over the course of a GTN-provoked attack to detect possible involvement of the glutamatergic system in the onset of attacks using proton magnetic resonance spectroscopy. Show less
The research in this thesis is divided into two parts. Part I consists of biochemical studies in migraine, a paroxysmal brain disorder where visual disturbances may form a part of the migraine... Show moreThe research in this thesis is divided into two parts. Part I consists of biochemical studies in migraine, a paroxysmal brain disorder where visual disturbances may form a part of the migraine attack. The main objective was quantification of amine neurotransmitters and other amine molecules in cerebrospinal fluid and plasma of migraine patients, and compare these concentrations with those from healthy controls. Part II describes the clinical relation between migraine and visual snow, a brain disorder with continuous visual disturbances and that is possibly associated with migraine. Since not much is known about this relationship this thesis presents observational studies on the incidence of comorbid migraine in visual snow. Show less
Chronic migraine is a highly disabling and difficult to treat form of migraine. In this thesis, various clinical aspects and the management of chronic migraine are investigated, in order to enhance... Show moreChronic migraine is a highly disabling and difficult to treat form of migraine. In this thesis, various clinical aspects and the management of chronic migraine are investigated, in order to enhance prevention and treatment of chronic migraine. Important risk factors for chronic migraine are depression, anxiety, cutaneous allodynia and especially overuse of acute anti-headache medication. The studies in this thesis conform that withdrawal of the overused medication results into a meaningful improvement in many patients. A double-blind randomised controlled trial did not show any additional benefit of treatment with Botulinum toxin A adjacent to acute withdrawal. Another double-blind randomised controlled trial did suggest effectiveness of a behavioural intervention during acute withdrawal on the reduction of medication intake during and shortly after withdrawal. Cutaneous allodynia (the perception of pain upon a non-painful stimuli) is a clinical marker of central sensitisation, an important mechanism in the pathophysiology of chronic migraine. The presence of cutaneous allodynia in general, and the extent of allodynia symptoms, appear to be a predictor for response to withdrawal therapy. Show less
This thesis describes several studies on migraine and cluster headache which associate these primary headache syndromes with macrostructural and microstructural changes. Some of these brain changes... Show moreThis thesis describes several studies on migraine and cluster headache which associate these primary headache syndromes with macrostructural and microstructural changes. Some of these brain changes may be congenital, some may represent reversible or irreversible neuroplastic changes as a response of the brain to adapt to external stimuli and others should be considered as brain damage associated with these primary headache syndromes. Cluster headache patients have larger anterior hypothalamic volumes and wider skulls, observations that oppose previous neuroimaging findings and pathophysiological theories. Migraine is associated with microstructural changes in particularly visual processing areas in both cortical and subcortical grey matter and in white matter tracts connecting these structures. These changes might in part be irreversible or mSome migraineurs are also at increased risk of visually detectable changes on MRI, such as infratentorial microbleeds, and in male migraineurs, infratentorial hypertensities. Some migraineurs are also at increased risk of visually detectable changes on MRI, such as infratentorial microbleeds and, in male migraineurs, infratentorial hyperintensities. The underlying etiology of these types of cerebrovascular damage remains elusive and is probably the consequence of a multifactorial process. 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
This thesis describes the longitudinal population-based CAMERA-study on the association between migraine and brain changes (e.g. white matter hyperintensities, infarct-like and other lesions) and... Show moreThis thesis describes the longitudinal population-based CAMERA-study on the association between migraine and brain changes (e.g. white matter hyperintensities, infarct-like and other lesions) and possible causes and consequences of those brain changes. Women with migraine showed higher incidence of deep white matter hyperintensities after nine years of follow-up. Infratentorial hyperintensities were also found more often among migraine women compared to controls. Migraine severity characteristics were not associated with progression of lesions. By using voxel based morphometry region-of-interest analyses, migraineurs showed decreased grey matter volume in visual areas of the right occipital cortex compared to controls. The occurrence of ischemia during attacks seems a logical explanation for the development of lesions. One other possible explanation for brain lesions is recurrent paradoxical (micro-)emboli as a result of right-to-left shunting (RLS). In our study, RLS are also more prevalent among migraineurs than among controls. As for the possible consequences: migraine patients and controls showed similar performance on all cerebellar functioning tests. In addition, cognitive functioning was similar for migraine patients and controls, deep white matter hyperintensities were not related to impaired cognitive performance, and migraine had no influence on this association. Our findings are reassuring for migraine patients and their doctors. Show less
Hoewel voorheen al onderzoek is verschenen naar verschillende onderdelen van de migrainedriehoek: chronificatie, depressie, en medicatieafhankelijkheid, waren er nog altijd ontbrekende stukken van... Show moreHoewel voorheen al onderzoek is verschenen naar verschillende onderdelen van de migrainedriehoek: chronificatie, depressie, en medicatieafhankelijkheid, waren er nog altijd ontbrekende stukken van de puzzel. Dit proefschrift onderzocht verschillende aspecten van deze driehoeksrelatie, waarbij wij ons richtten op:• klinische determinanten van depressie in migrainepatiënten (hoofdstuk 2 en 3),• de associatie van depressie met migraine aanvalsfrequentie, zowel in dwarsdoorsnede onderzoek (hoofdstuk 2) als in longitudinale studieopzet (hoofdstuk 3),• de rol van allodynie van de huid in zowel de comorbiditeit met depressie alsook migraine chronificatie (hoofdstuk 2 en 3),• symptoomdimensies van affectieve stoornissen in migrainepatiënten, in vergelijking met personen zonder migraine met en zonder affectieve aandoeningen (hoofdstuk 5),• de comorbiditeit van depressie in hemiplegische migraine, als een monogenetisch migraine fenotype (hoofdstuk 4),• genetische factoren die betrokken zijn bij migraine chronificatie (hoofdstuk 7),• de comorbiditeit van depressie in clusterhoofdpijn, als een ernstige episodische primaire hoofdpijnvorm anders dan migraine (hoofdstuk 8), en• de behandeling van medicatieafhankelijke hoofdpijn. Show less
The comorbidities of epilepsy include those conditions, somatic and psychiatric, that are associated with epilepsy. These associations with epilepsy may be direct and indirect, causal and spurious.... Show moreThe comorbidities of epilepsy include those conditions, somatic and psychiatric, that are associated with epilepsy. These associations with epilepsy may be direct and indirect, causal and spurious. The comorbidities of epilepsy are relevant in that they provide an opportunity to improve our understanding of the pathophysiology of epilepsy, as well as allow us to better understand factors determinant of outcome. This PhD thesis examines the comorbidities of epilepsy, as a general construct, delving into particular examples, and finally demonstrating its impact on premature mortality in epilepsy. Show less
Het doel van dit proefschrift was daarom de onderliggende biochemische processen gerelateerd aan migraine te onderzoeken. Het eerste gedeelte (Hoofdstukken 2 en 3) beschrijft twee onderzoeken... Show moreHet doel van dit proefschrift was daarom de onderliggende biochemische processen gerelateerd aan migraine te onderzoeken. Het eerste gedeelte (Hoofdstukken 2 en 3) beschrijft twee onderzoeken waarin gekeken is naar de biochemische constitutie van de hersenen van migraine patiënten door middel van proton magnetische resonantie spectroscopie (1H-MRS) en diffusie gewogen spectroscopie (DWS). In het tweede gedeelte (Hoofdstukken 4 en 5) wordt een systematische review met meta-analyse beschreven om een overzicht te geven van eerdere inspanningen om in verschillende lichaamsvloeistoffen biochemische verschillen te detecteren die relevant zijn voor migraine. Daarnaast wordt er een studie beschreven waarin is gekeken naar biochemische verschillen in liquor van migraine patiënten en gezonde controles. In het derde gedeelte worden twee methodologische studies beschreven waarin (Hoofdstukken 6 en 7) de biochemische stabiliteit van liquor en het effect van vervuiling met ethanol werden onderzocht. Show less
The research in this thesis was aimed at investigating the central hypothesis that susceptibility to SD determines both the susceptibility to migraine with aura and the susceptibility to... Show moreThe research in this thesis was aimed at investigating the central hypothesis that susceptibility to SD determines both the susceptibility to migraine with aura and the susceptibility to hypoxic/ischemic injury in the same direction. We envisage that factors that enhance the susceptibility to SD increase the likelihood of migraine with aura as well as ischemic stroke. To this end we assess to what extent genetic, hormonal and pharmacological modulators of SD susceptibility will influence the susceptible to ischemic injury. Thus we will unravel underlying mechanisms of SD susceptibility and susceptibility to ischemic injury. Central to this research is the use of two transgenic mouse models of migraine that carry migraine-relevant FHM1 gene mutations in voltage-gated CaV2.1 Ca2+ channels. Show less
The research in this thesis was aimed at identifying and understanding mechanisms underlying modulating factors for and consequences of cortical spreading depression (CSD), the pathophysiological... Show moreThe research in this thesis was aimed at identifying and understanding mechanisms underlying modulating factors for and consequences of cortical spreading depression (CSD), the pathophysiological substrate for migraine aura that occurs in one-third of migraine patients. In this thesis, experimental studies on CSD were performed in wild-type (WT) and transgenic migraine mice, which express CaV2.1 Ca2+ channels with a mutated _1 subunit that contains the R192Q missense mutation. The R192Q mutation was previously identified in patients with familial hemiplegic migraine type 1 (FHM1) and causes gain-of-function effects in terms of neuronal Ca2+ influx, neurotransmission, and susceptibility to experimentally induced CSD. Using various experimental strategies, in this thesis, the FHM1 R192Q mouse model was used to study pathophysiological mechanisms of the initiation and modulation of CSD as well as of neurobiological and molecular changes that accompany CSD events. Show less
Migraine and cluster headache are disabling brain disorders. Current treatment is ineffective in many patients. The research performed in this thesis aimed at elucidating some of the molecular... Show moreMigraine and cluster headache are disabling brain disorders. Current treatment is ineffective in many patients. The research performed in this thesis aimed at elucidating some of the molecular genetic mechanisms in these two headache disorders by means of clinical and genetic studies in complex and/or monogenic forms of these diseases and related disorders. Knowledge from studies like these could be used to the benefit of patients by improving clinical diagnoses and/or by providing useful drug targets for future drug development strategies. Show less
This thesis is about migraine. Three elements are discussed. First element is preventive treatment, second element is attack treatment and the third part focuses on medication overuse headache. The... Show moreThis thesis is about migraine. Three elements are discussed. First element is preventive treatment, second element is attack treatment and the third part focuses on medication overuse headache. The preventive treatment of migraine is a valuable intervention in primary care. If preventive treatment is applied, usually only one attempt with one type of medication is performed. A number of considerations hinder GPs to address preventive treatment of migraine. Also several patient-related aspects cause that the GP differ from national guidelines. The decision to start preventive treatment is based on a complex of considerations from the patient. For example, experienced suffering from migraine and interaction with family, colleagues and general practitioner. Interest in preventive therapy increases with increased concerns about migraine symptoms. In attack treatment of migraine, most patients had a clear preference for one of both treatments. Preference correlated only moderately with the commonly used "two-hour pain-free score." Multi-attack, crossover, 'patient preference' studies are well able to detect clinically relevant differences between existing treatments. Overuse of triptans, resulting in chronic headaches is common and causes unnecessary costs. The common thread through this thesis is what patients want in migraine and which interventions they prefer: patients' preference in migraine. Show less
In this dissertation clinical genetic investigations on migraine, related syndromes and comorbid conditions are described. The first migraine syndrome studied is Familial Hemiplegic Migraine (FHM),... Show moreIn this dissertation clinical genetic investigations on migraine, related syndromes and comorbid conditions are described. The first migraine syndrome studied is Familial Hemiplegic Migraine (FHM), a monogenic migraine variant. The clinical spectrum of FHM1-3 and the relation with closely related diseases such as Alternating hemiplegia of Chilhood, Early Seizures and Cerebral Edema after Trivial Head Trauma, epilepsy and episodic ataxia were investigated. The second monogenic migraine syndrome studied is Retinal Vasculopathy with Cerebral Leukodystrophy (later renamed CHARIOT), where common migraine is part of the clinical spectrum. The identification of TREX1 as the causal gene for RVCL is described. Investigation of the clinical spectrum showed retinal, cerebral and internal organ involvement, without an apparent genotype-phenotype correlation. Endothelial dysfunction of large arteries was shown in RVCL patients and is proposed as a possible disease mechanism. Lastly, migraine patients were identified in a Dutch genetic isolate and the relation with depression and atherosclerosis was assessed. For depression it was shown that shared genetic factors, at least partly, underlie the comorbidity with migraine, in particular migraine with aura. These studies improve our insight in genetic factors and pathofysiological mechanisms involved in migraine, which may ultimately contribute to better treatment options for migraine patients Show less
