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
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
This thesis is about the role of spreading depolarization (SD) in subarachnoid hemorrhage (SAH) as explained in Chapter 1.Chapters 2 and 3 use a rat model of SAH, SD induction and SD-inhibitor... Show moreThis thesis is about the role of spreading depolarization (SD) in subarachnoid hemorrhage (SAH) as explained in Chapter 1.Chapters 2 and 3 use a rat model of SAH, SD induction and SD-inhibitor valproate. They suggest a direct association between SD and lesion growth after experimental SAH, which can be counteracted by valproate.Chapter 4 explores the application of MRI techniques to monitor SD induced in rats. Balanced-steady-state-free-precession (b-SSFP) captures more detail than gradient-echo MRI. Diffusion-weighted multi-spin-echo (DT2) scans allowed for simultaneous recording of hemodynamic and diffusion changes.Chapter 5 describes a trend towards less DCI in SAH patients using SD-inhibiting drugs, but that did not result in a better clinical outcome. This suggests a possible protective effect of SD-inhibition on DCI but an unclear possible detrimental effect on other factors that affect clinical outcome.Chapter 6 found, in an ischemic stroke cohort, no statistically significant differences in the percentage of incomplete circles of Willis between migraine and non-migraine patients.Chapter 7 provides a general discussion of the findings from chapter 2-6. Show less
The research described in this thesis was aimed at identifying and understanding biological mechanisms and molecular pathways involved in the pathophysiology of stroke and migraine, including the... Show moreThe research described in this thesis was aimed at identifying and understanding biological mechanisms and molecular pathways involved in the pathophysiology of stroke and migraine, including the detrimental connection between them. The thesis consists of two parts. Part 1 describes multiple experimental stroke research projects in mice in which we set out to: (I) improve the methodology of stroke research, and (II) unravel the stroke-migraine connection using diff erent research strategies, methods, and transgenic mouse models. The mouse models express human pathogenic mutations found in CADASIL, RVCL-S and FHM1 and represent the clinical spectrum of monogenic disorders linking ischemic stroke and migraine. Part 2 includes multiple clinical projects in which we set out to study a large cohort of ischemic stroke patients with and without migraine in search for means to investigate stroke characteristics and vascular pathology. Show less
The premonitory phase and early phase of both spontaneous and nitroglycerin-triggered migraine attacks were explored in this thesis, in association with clinical modulators and trigger factors.... Show moreThe premonitory phase and early phase of both spontaneous and nitroglycerin-triggered migraine attacks were explored in this thesis, in association with clinical modulators and trigger factors. Clinical research strategies, experimental designs, neuroimaging techniques and biochemical methods have revealed clinical risk factors, biochemical modulators and pharmacological triggers. Furthermore, newly discovered hypothalamus-specific alterations in metabolism and perfusion in the early phases of the migraine attack were described. Taken together, these results suggest that each migraine attack starts well before the initiation of the headache phase. The hypothalamus is postulated to have a pivotal role in the early phases of the migraine attack, and possibly affects attack susceptibility interictally as well. Show less
This thesis is about the relation between pain and language and focuses on migraine, a specific type of headache that comes in attacks. The first conclusion is that migraine is a signifier without... Show moreThis thesis is about the relation between pain and language and focuses on migraine, a specific type of headache that comes in attacks. The first conclusion is that migraine is a signifier without signified. A diagnosis of migraine only depends on the words of the patients by applying internationally agreed on criteria which form a discourse and artificially exclude ‘non-migraine headaches’. Further research-questions are whether so-defined migraine can destroy language and what is the role of time in its existence. The answers to these questions will be applied to selected novels that include protagonists with migraine. The aim of these analyses is not how migraine is being described, but how it is performed in and through these texts. The overall goal of this thesis is to come to a better understanding of the relation between migraine and language and vice versa, on the one hand by seeing the patient as text and on the other by seeing the text as patient. 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
Migraine is a severe headache syndrome, affecting approximately 33% of females and 13% of males. Patients suffer from recurring headache episodes in combination with nausea, vomiting, phono and... Show moreMigraine is a severe headache syndrome, affecting approximately 33% of females and 13% of males. Patients suffer from recurring headache episodes in combination with nausea, vomiting, phono and photophobia. It is a paroxysmal disorder for which several several trigger factors have been identified by patients. This thesis has focused on the relation between i) psychosocial stress, ii) nitroglycerin and iii) hypoxia and the occurrence of a migraine attack, as well as the mechanism of action. The first conclusion is that, in contrast to previous studies, we could not detect a correlation between psychosocial stress and migraine. The second conclusion is that normobaric hypoxia might be a trigger factor for migraine possibly through the development of mild cerebral edema. The third conclusion is that migraine can be triggered by nitroglycerin through a vascular effect without any indication of vasodilation in cerebral or meningeal arteries during the delayed provoked attack. Show less
