Paroxysmal Cerebral Disorders

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Neurology.

Aim and focus

Paroxysmal Cerebral Disorders (PaCD) consists of four, strongly (inter-)related translational research lines on “Episodic Brain Disorders”:
  1. Migraine, cluster headache, and related episodic headache syndromes (Ferrari, Terwindt, van den Maagdenberg, Tolner, Wermer, Fronczek)
  2. Stroke and Cerebral Hereditary Angiopathies (CHA) (Wermer, Terwindt, van den Maagdenberg, Ferrari, Kruyt)
  3. Syncope (transient global cerebral hypoperfusion) and other autonomic disorders (van Dijk, Thijs)
  4. Narcolepsy and other excessive daytime sleepiness disorders (Lammers, van Dijk, Fronczek)
In each research line we study the clinical features, diagnosis, epidemiology, socio-economic impact, structural and functional cerebral consequences, pathophysiology, and treatment of highly disabling and mechanistically-related brain disorders that primarily are characterised by recurring attacks of disabling acute transient cerebral dysfunction. In stroke, there may only be a single episode with permanent rather than transient loss of brain function.

Project-specific aims include:

Migraine, cluster headache, and related episodic headache syndromes
  • To unravel the pathogenesis of migraine and cluster headache, and to dissect molecular and neurobiological mechanisms and role of hypothalamus for the triggering, initiation, recurrence and chronification of attacks
  • To identify and validate treatment targets for the acute and prophylactic treatment of attacks and chronification
  • To decipher the underlying mechanisms for the bidirectional comorbidity of migraine, depression, and epilepsy
  • To uncover the mechanisms and to test novel treatment modalities for migraine-related cerebral ischaemia
Stroke and CHA
  • To unravel pathogenetic mechanisms for ischaemic stroke, in particular migraine- and female-specific mechanisms
  • To uncover mechanisms for amyloid-related intracerebral haemorrhage (Cerebral Amyloid Angiopathy; CAA) and CHA: Retinal Vasculopathy with Cerebral Leucoencephalopathy and Systemic Manifestations (RVCL-S), Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy (CADASIL), and Hereditary Cerebral hemorrhage with Amyloidosis - Dutch type (HCHWA-D)
  • To identify and validate novel treatment targets for Stroke, CAA and CHA
  • To improve clinical outcome in stroke by optimizing patient selection and logistics throughout the acute stroke chain
  • To improve clinical outcome in stroke caused by large artery occlusion by investigating thrombectomy in new target groups by radiological patient selection and extending the window of treatment
Syncope

  • To delineate the clinical spectrum and to unravel the role of the autonomic nervous system in reflex syncope, pure autonomic failure, psychogenic pseudo-syncope, “sudden unexpected death in epilepsy” (SUDEP), and sleep disorders
  • To unravel the mechanisms for how orthostatic hypotension may lead to brain dysfunction and damage
  • To improve the diagnosis and clinical care of patients with “transient loss of consciousness” (TLOC)
Narcolepsy and other excessive daytime sleepiness disorders
  • To unravel the aetiology and pathophysiology of narcolepsy, with a focus on autoimmune aspects
  • To validate easy-to-perform objective measurements of vigilance as a marker for disease severity
  • To assess the impact of sleep disturbance on metabolic and endocrine function, using narcolepsy as a model
  • To study the borderland of narcolepsy, including behaviourally-induced sleep complaints     

Position in international context

The PaCD research lines perform internationally very well as evidenced by the excellent results in the CWTS citation analysis. The Mean Normalized Citation Score (MNCS) for PaCD = 3.36 (i.e. more than thrice the world average). The PaCD PI’s act at the forefront of the international scientific arena within their respective fields and are regularly invited for prestigious lectures, congress programme committees, and advisory boards of pharmaceutical & medical device companies. They are leading participants in major international scientific consortia & professional organizations, have extensive scientific & clinical collaborations with prestigious biomedical institutes world-wide, including Harvard, MIT, Stanford, Cambridge, University College & Kings College London, University of California San Francisco & Los Angeles, University & ETH of Zurich, Charité Berlin, Max Planck Cologne, and the Universities of Lausanne, Bern, Munich, Hamburg & Copenhagen, and regularly publish in high-impact Journals.

The LUMC Headache Group is the only academic headache research and referral centre in The Netherlands and is globally recognized as one of the premier headache groups for genetics, molecular biology, neuroimaging, and clinical assessment of new treatments. Comparable headache groups are Harvard (Burstein, Ayata), Kings College London/UC San Francisco (Goadsby) and Copenhagen (Olesen, Ashina). Main assets are extensive local & (inter)national collaborations between clinical & fundamental research groups, with ample access to state-of-the-art technology platforms (genetics, transgenic animal models, stem cell generation & differentiation, neuroimaging, bioinformatics) and some of the world largest and best pheno- and genotyped patient cohorts for migraine (> 8,000), monogenic migraine-subtype syndromes (> 600), and cluster headache (> 2000). The Group is well embedded within major National Consortia (Centre for Medical Systems Biology, Biobanking & Biomolecular Research Infrastructure, Gravity 2017 Netherlands Organs on Chip Initiative [NOCI]).

The three PI’s have leading (inter-)national positions. Ferrari (> 600 publications, H=84) is/has been PI of leading international research consortia (EU-FP6 EUROHEAD, EU-FP7 EUROHEADPAIN, NIH CAMERA, and Gravity 2017 Brain-on-a-Chip/NOCI). He holds/has held many prominent international positions (President IHS, Chair IHS Scientific Committee, Member IHS Clinical Trial Guideline Committee, Chair IHS World Congress, Vice President Serotonin Club, Dutch Neurology Association Headache Representative to EAN & WFN, and Chair/ Member Scientific Programme Committees of IHS, EHF, IASP, Neurology, Pharmacology and Methodology Congresses). Ferrari has received many prestigious (inter-)national accolades & awards, incl. Spinoza & Vici (NWO), Hartmann Muller Prize for Biomedical Research (Zurich University), >10 awards from International Scientific Societies, Elected Fellow British Royal Society of Physicians (FRCP) & American Neurological Association (FANA), and Honorary Member of the International, Italian & Danish Headache Societies. He ranks 3rd as leading global scientist in the field of “Migraine & Vascular Headaches” and 6th in Pain (Thomson Essential Science Indicators). His professional profile was highlighted in Lancet Neurol 2015. Terwindt (> 240 publications, H=41) is on the IHS Executive Board and Classification Committee, Scientific Programme Co-Chair IHS World Congress 2019, and Chair Migraine Treatment Guideline Committee of the Dutch Neurology Association. She ranks 22 in Pain. Van den Maagdenberg (> 250 publications, H=40) is on the Steering Board of the European Network for Research on Alternating Hemiplegia and the Scientific Advisory Committees for the EU- FP7 Non-coding RNAs in Neurogenic & Neuropathic Pain Project and American Registry for Migraine Research, Genetic Study Coordinator of the International Consortium for Research on Alternating Hemiplegia of Childhood, Co-Chair of the International Headache Genetics Consortium (IHGC) Publication Committee, and Research Coordinator of EUROHEADPAIN. He is also the “Father” of 6 transgenic migraine mouse models which are extensively used world-wide. He ranks 20th in Pain. All three PI’s are associate editor of Cephalalgia, the scientific Journal of IHS.

Stroke and CHA is a rapidly growing and maturing new and highly productive research line, which only started in 2011. In the Netherlands, it is the only group studying the clinical and pathophysiological relation between migraine, stroke and CAA.

Terwindt is heading the only national CAA referral centre. LUMC has a leading international position thanks to its close vicinity to Katwijk, with world’s largest and best characterized HCHWA-D population. Wermer (> 125 publications, H: 25) is on the scientific advisory board of the International CAA Foundation and fellow of the European Stroke Organisation (FESO).

Kruyt (> 35 publications, H: 13) has joined the Stroke group since 2014 and focuses on improving acute stroke care. All three PI’s have published in high impact Journals.

The Syncope Group has been instrumental in developing the international classification of 'transient loss of consciousness'. There are strong links with the international cardiological and neurological communities. Van Dijk (> 285 publications, H: 42; Expertscape: # 12) is member of the European Society of Cardiology Syncope Guidelines group, while Thijs (> 85 publications, H: 18; Expertscape: # 8) serves as the secretary of the European Federation of Autonomic Societies.

The Narcolepsy Group has access to one of the largest and clinically best characterised narcolepsy patient cohorts in the world. They were instrumental in the seminal discoveries that narcolepsy is caused by loss of hypocretin/orexin cells in the hypothalamus and that this might be triggered by immunological processes. Lammers (> 160 publications, H=39) is co- founding father and past-president of the European Narcolepsy Network and Fronczek (> 55 publications, H=16) is current board member. Both participate in important consensus meetings (e.g. European Guidelines for Narcolepsy)..  

Content / highlights / achievements

Migraine, cluster headache, and related episodic brain syndromes

Genetics and molecular neurobiology
  • Identification and functional analysis of pathogenic mutations in (the first) four genes for monogenic subtypes of migraine: Familial Hemiplegic Migraine type 1 (FHM1; Ophoff RA, et al. Cell 1996), FHM2 (Vanmolkot KR, et al. Ann Neurol 2003), FHM3 (Dichgans M, et al. Lancet 2005), and RVCL-S (former RVCL) (Richards A, et al. Nat Genet 2007)
  • Identification of pathogenic mutations in CACNA1A for Episodic Ataxia type 2 (Ophoff RA, et al. Cell 1996)
  • Generation and characterisation of six transgenic migraine mouse models each harbouring different human pathogenic migraine gene mutations. Main findings include (Ferrari MD, et al. Lancet Neurol 2015):
  • The mice faithfully display migraine-associated features, including transient hemiparesis, high susceptibility to jet lag, and headache and photophobia, uniquely responding to migraine-specific treatment with triptans; these characteristics validate the clinical relevance and use of these mice as models to study migraine mechanisms (e.g. Langford DJ, et al. Nat Methods 2010; van Oosterhout F, et al Ann Neurol 2008; Chanda ML, et al. Pain 2013)
  • Demonstration that the migraine brain is hyperexcitable due to increased release of glutamate and that this ultimately leads to enhanced susceptibility to (sub-)cortical spreading depolarisation (e.g. van den Maagdenberg AMJM, et al. Neuron 2004 & Ann Neurol 2010; Eikermann-Haerter K, et al. J Clin Invest 2009 & J Neurosci 2011; Tottene A, et al. Neuron 2009; Kahlig KM et al. PNAS 2008)
  • The mouse models, like migraine patients, show increased susceptibility to cerebral ischaemia,  which was shown to be due to increased incidence of peri-infarct depolarisations (Eikermann-Haerter K, et al. Circulation 2012), providing a possible explanation for why migraine is a risk factor for stroke
  • All of the above effects on the brain are enhanced by female hormones and mitigated by male hormones, offering a likely explanation for why migraine is so much more common among females (Eikermann-Haerter K, et al. J Clin Invest 2009; Ann Neurol 2009; Circulation 2012)
  • Identification, in collaboration with the IHGC, of in total 44 gene variants for the common multifactorial forms of migraine (Anttila V, et al. Nat Genet 2010 & 2013; Chasman D, et al, Nat Genet 2011; Freilinger T, et al. Nat Genet 2012; Gormley P, et al. Nat Genet 2016). These genetic findings support both neuronal (hyperexcitability) and vascular pathways in migraine pathogenesis, well in line with findings in the migraine mouse models
  • Demonstration with MRS of enhanced glutamate in the visual cortex of migraineurs supporting the hypothesis that the migraine brain is hyperexcitable (Zielman R, et al. Brain 2017)
  • Identification of genes for Alternating Hemiplegia of Childhood (Heinzen EL, et al. Nat Genet 2012) and focal epilepsy (Dibbens LM, et al. Nat Genet 2013), using next generation sequencing
  • Sampling and genotyping of DNA from > 8000 clinically well-characterised migraine and > 860 cluster headache patients
  • First complete description of a new monogenic migraine syndrome, “Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations” (Stam A, et al. Brain 2016)
  • Demonstration that patients with mutations in one of the three known genes for FHM have a predictably different phenotype than patients with genetically complex FHM without a mutation in FHM1,2,3 and that most likely there is no FHM4 gene (Pelzer N, et al. Neurology 2017)
Treatment, mechanisms of action of antimigraine agents, and pathophysiolocal mechanisms
  • Demonstration of deranged serotonin (5HT) & glutamate homeostasis in migraine (Ferrari, et al. Neurology 1989 & 1990)
  • Demonstration that triptans, a novel class of selective 5HT1B/1D/1F receptor agonists, are effective and well tolerated in the acute treatment of migraine attacks (Ferrari MD, et al, New Eng J Med 1991)
  • Clinical comparison and pharmacological and mechanistic evaluation of 7 different triptans resulting in evidence-based acute migraine treatment protocols and unravelling of migraine headache mechanisms (Ferrari MD. Lancet 1998; Ferrari MD, et al. Lancet 2001; Goadsby PJ, et al. New Eng J Med 2002)
  • Demonstration that inhibition of neurogenic inflammation (Roon K, et al. Ann Neurol 2000) and vasoconstriction (Schoonman GC, et al. Brain 2008) are redundant pharmacological effects of triptans and that agents without potentially hazardous vasoconstrictor activity such as selective 5HT1F receptor agonists (Goldstein DJ, et al. Lancet 2001) and CGRP receptor antagonists (Ho T, et al. Lancet 2008) are also effective in migraine but safer
  • Demonstration of cutaneous allodynia as risk factors for migraine chronification (Louter M, et al. Brain 2013)
  • Sampling and detailed biochemical characterisation with “omics technologies” of cerebrospinal fluid of > 400 patients with various types of migraine and > 100 age- and sex-matched healthy controls without headache history
  • Identification of distinct amine profile in CSF of 200 interictal migraineurs versus 100 controls (in prep) 
Epidemiology, impact and neuroimaging
  • Demonstration prevalence of migraine and that migraine severely affects quality of life (Launer L, et al. Neurology 1999 and Terwindt GM et al, Neurology 2000) and may cause ischaemic brain lesions (Kruit MC, et al. JAMA 2004, Brain 2005, and Stroke 2006; Meinders I, et al. JAMA 2012).
  • Development and implementation of a validated web-based recruiting system (www.lumc.nl/hoofdpijn) through which up to now more than 7000 patients with migraine have been enrolled for genetic studies, cerebrospinal fluid sampling, and various other forms of clinical studies
  • First description of “Space Headache” (Vein AA, et al. Cephalalgia 2009; van Oosterhout WV, et al. Cephalalgia 2014)
  • Cutaneous allodynia as a predictor of migraine chronification. Louter MA, et al. Brain 2013;136:3489-96
  • Demonstration with MRS of enhanced glutamate in the visual cortex of migraineurs (Zielman R, et al. Brain 2017)
Cluster headache
  • Setting up of the world-wide largest and clinically best documented data-base of patients with cluster headache (> 3000)
  • Designing and conducting the world’s first and largest, prospective, randomised, sham-controlled clinical trial on the prophylactic efficacy and tolerability of neuromodulation in medically intractable cluster headache (in progress)
  • Delineating the frequently atypical clinical presentation of cluster headache in women (van Vliet JA, et al. JNNP 2003)
  • Showing the efficacy of intranasal sumatriptan in cluster headache (van Vliet JA, et al. Neurology 2003)
  • Demonstration that cluster headache may be caused by treatable brain lesions (Favier I, et al Arch Neurol 2007)
  • Efficacy of non-invasive vagus nerve stimulation as acute treatment of attacks of cluster headache (Submitted 2017)  
Stroke and CHA
  • Patients with headache during stroke have a better long-term prognosis with fewer cardiovascular events than patients who do not experience headache (Maino A, et al. Stroke 2013)
  • Persons with hereditary subarachnoid haemorrhage have high risk of new aneurysm formation and therefore need long term follow-up (Bor AS, et al. Lancet Neurol 2014)
  • Thrombectomy is effective for ischaemic stroke (Berkhemer OA, et al. N Engl J Med 2015)
  • Certain anatomical variations are risk factors for aneurysm growth (Bor AS, et al. Stroke 2015)
  • Blood pressure-lowering facilitates access to thrombolytics (Dirks M, et al. Neurology 2015)
  • Recurrent hemorrhage risk and mortality in hereditary and sporadic cerebral amyloid angiopathy (van Etten et al. Neurology 2016)
  • Cerebrovascular reactivity is affected in presymptomatic and symptomatic individuals with hereditary cerebral amyloid angiopathy (van Opstal et al. Lancet Neurol 2017)
  • β-Amyloid in CSF as a biomarker for preclinical cerebral amyloid angiopathy (van Etten et al. Neurology 2017)
  • Migraine is not associated with excess atherosclerosis in large vessels in patients with acute ischemic stroke (van Os et al, Stroke 2017)
  • Spreading depolarizations increase delayed brain injury in a rat model of subarachnoid hemorrhage and that Valproate can reverse this damage (Hamming et al, JCBFM 2016 and Stroke 2017)
  • Circulating endothelial markers in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (Pelzer N, et al. Stroke 2017)
  • Development of PHASES prediction score for rupture of intracranial aneurysms (Greving JP, et al. Lancet Neurol 2014)
  • Development and implementation of the LUMC String of Pearls Stroke Biobank (N > 700 blood samples)
Syncope
  • Detailed clinical and EEG description of syncope and differential diagnosis versus other conditions with transient loss of consciousness (Wieling W, et al Brain 2009; van Dijk JG, et al. Nat Rev Neurology 2009 & Brain 2014)
  • Demonstration that white matter lesions are prevalent in frequent syncope patients (Kruit MC, et al. Neurology 2013) 
  • Syncope guideline development in the context of the  European Society of Cardiology  and  in “Definition of Orthostatic Hypotension, Neurally Mediated Syncope, and Postural Tachycardia” (Moya A, et al. Eur Heart J 2009; Freeman R, et al. Autonom Neurosci 2011)
  • Improved understanding of psychogenic pseudo-syncope (Tannemaat MR, et al. Neurology 2013) and the clinical overlap with reflex syncope (Blad et al, Neurology 2015)
  • First long term follow-up study in psychogenic pseudo-syncope (Saal D, et al. Neurology 2016)
  • Detailed analysis of the autonomic features of Sudden Unexpected Death in Epilepsy (SUDEP; Surges, et al. Nat Rev Neurology 2009; Lamberts RJ, et al. Epilepsia 2013 & Neurology 2013; van der Lende JNNP 2016)
  • Demonstration that epilepsy is a risk factor for sudden cardiac arrest and that sudden cardiac arrest and SUDEP are partially overlapping conditions (Bardai, et al., PLos One 2012; Lamberts et al, Neurology 2015)
  • Detailing the dynamics of convulsive seizure termination and postictal EEG depression, a SUDEP risk marker (Bauer et al, Brain 2016)
Narcolepsy
  • Identification of hypocretin deficiency as cause for narcolepsy (Nishino S, et al. Lancet 2000)
  • Validation of low cerebrospinal fluid hypocretin as diagnostic test for narcolepsy (Mignot E, et al. Arch Neurol 2002)
  • Demonstration that hypocretin deficiency is a risk factor for obesity (Kok SW, et al. Obes Res 2003)
  • Demonstration that “Weak with laughter” is a measurable phenomenon (Overeem S, et al. Lancet. 1999)
  • Unravelling the role of hypocretin in Parkinson’s and Alzheimer’s Disease (Overeem S, et al. Neurology 2002; Fronczek R, et al. Brain 2007; Donga E, et al. J Clin Endocrinol Metab 2010; Fronczek R, et al. Neurobiol Aging 2012)
  • Demonstration that gammahydroxybutyrate is effective in narcolepsy (Lammers GJ, et al. Sleep 1993)
  • Establishing the European Narcolepsy Network and largest prospective international narcolepsy patient Database
  • Development (Fronczek R, et al. Sleep 2006 & van der Heide A, et al. Sleep 2015, van Schie M, et al J Sleep res 2016) and successful implementation in clinical trials (Dauvilliers Y, et al. Lancet Neurol 2013) of the quantitative “Sustained Attention to Response Task (SART)” to measure vigilance as most important marker of disease severity in narcolepsy and other hypersomnia’s
  • Introduction of narcolepsy as a model to study the relation between sleep disturbance and endocrine/metabolic derangements and the effect of pharmacological improvement of sleep hereupon (Donjacour CE, et al. Sleep 2014)
  • Established that changes in skin temperature patterns predict sleep episodes in narcolepsy (Fronczek R, et al, Sleep 2006, Sleep 2008, J Neurol Neurosurg Psychiatry. 2008; van der Heide A, et al, J Sleep Res 2015, Sleep 2016)
  • Demonstration that T-cell mediated, autoimmune mechanisms are involved in the pathophysiology of narcolepsy (Tafti M, et al. Sleep 2014; Faraco J, et al. PLoS Genet 2013; Poli F, et al. Vaccine 2013, van der Heide A, et al, Immunogenetics. 2015)

Future themes

Migraine, cluster headache, epilepsy, and related episodic brain syndromes
  • Expanding our DNA database of patients with migraine and cluster headache for further genetic analyses
  • Neurophysiology, MR Spectroscopy, and cerebrospinal fluid & blood sampling outside, shortly before, during and immediately after spontaneous and provoked migraine attacks to assess brain changes throughout the attack cycle
  • Assessing the role of “critical slowing down of cerebral compensatory mechanisms, predictably leading to critical neuronal transitions and cerebral network tipping points” in the onset of migraine attacks (Spinoza 2009 Trio Project) as well as attacks of epilepsy and related mortality in mouse models and patients (Netherlands Epilepsy Fund)
  • Optimisation and implementation of “Omics” and Magnetic Resonance Spectroscopy strategies for biochemical assessment of brain and cerebrospinal fluid of migraine patients and mouse models in collaboration with the LUMC Department of Radiology, the Biomolecular Mass Spectrometry Unit, and the Netherlands Metabolomics Centre
  • Next generation sequencing of DNA from patients with various forms or combinations of epilepsy and migraine
  • Generation and functional characterisation of novel transgenic mouse models for PaCD
  • Generation and functional characterisation of human induced pluripotent stem cell (hiPSC) lines derived from patients with monogenic and common multifactorial forms of migraine and/or epilepsy
  • Generation and functional characterisation of hiPSC-based Brain on a Chip from patients with monogenic and common multifactorial forms of migraine and/or epilepsy
  • Expansion and improved integration of platforms for functional characterisation of animal, tissue, and cell models for migraine and epilepsy, incl. molecular, in vivo awake and under anaesthesia electrophysiological, and behavioural characterisation, non-invasive in vivo light-triggered selective activation and inhibition of neuronal functions using optogenetics systems, biochemical profiling using “omics” technology, functional neuroimaging, and MR spectroscopy
  • Uncovering mechanisms for comorbidity of migraine with depression, epilepsy and stroke in patients & mouse models
  • Deciphering the effects of stress, sleep, and female sex hormones on migraine attack triggering & chronification
  • Unraveling the relationship of cluster headache attacks and the biological clock
  • Dissecting migraine- and female-specific pathogenetic mechanisms and factors for ischaemic stroke
  • Testing the prophylactic efficacy and deciphering the mechanisms of action of neuromodulation and novel CRGP and CGRP-receptor antibodies in patients with and animal models for migraine and cluster headache
  • Unraveling the pathogenetic role of depression and overuse of acute headache medication in migraine chronification and studying the structural and functional effects of chronification on the brain
  • Testing the effectiveness of study nurses in the clinical management of headache patients
  • Establishing an international clinical and scientific research centre of excellence for PaCD in partnership with Stichting Epilepsie Instellingen Nederland (SEIN) and University College London (UCL)
  • Studying hormonal influences and female gender specific factors, and the modulation thereof, on migraine activity and its relation to stroke in females (2 ZonMW Gender & Health Grants 2017)
  • Generation, differentiation and analysis of induced pluripotent stem cell lines and iPSC-based “Brain-on-a-Chip” derived from patients with various monogenic and complex forms of migraine, cluster headache and/or epilepsy (Zwaartekracht - Gravity Premium 2017)
Stroke and CHA
  • Dissecting migraine- and female-specific pathogenetic mechanisms and factors for ischaemic stroke (NWO/ZonMw VIDI)
  • Identification of biomarkers for disease progression in Cerebral Hereditary Angiopathies (CHA)
  • Identifying biomarkers and triggers for cerebral amyloid angiopathy-related intracranial haemorrhage in a large follow-up study of patients with 1) sporadic and 2) Hereditary Cerebral Haemorrhage with Amyloidosis - Dutch type (HCHWA-D) (Netherlands Heart Foundation)
  • Identifying biomarkers and triggers in a follow-up study of patients with  Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S)
  • Identifying female specific risk factors for stroke, with a focus on migraine but also including reproductive disorders, gestational hypertensive complications, early menopause (CREW consortium, Hartstichting)
  • Investigate the influence of female hormones on the outcome after ischemic stroke in different transgenic migraine-stroke models (NWO/ZonMw VIDI)
  • Investigate the effect of nervus vagus stimulation in acute ischemic stroke (NWO/ZonMw VIDI)
  • Investigate blue tooth technology to improve treatment times in acute ischemic stroke (Hersenstichting, Innovatiefonds)
  • Biomarkers for cognitive impairment due to CAA (BIONlC) (Memorabel Grant ZonMW)
Syncope (most themes are currently in progress)
  • Mechanisms and consequences of reflex syncope and its relation with  migraine
  • Uncovering clinical and pathophysiological links between syncope, cardiac arrhythmia, epileptic seizures, and SUDEP
  • Establishing the temporal hemodynamic patterns in relation to loss of consciousness in vasovagal syncope
  • Determining  the effects of implementation of syncope algorithms on diagnostic yield, health care costs and quality of life in a nationwide study (ZonMW health care efficiency programme)
  • Detailing the long term follow-up in autonomic failure (NIH collaboration NYU)
  • Developing the 'Leiden Brugada Index'(quantification dynamic ECG changes over time in Brugada syndrome)
  • Studying cerebral perfusion in Duchenne syndrome (with paediatric neurology and Fontan syndrome (with paediatric cardiology)
Narcolepsy
  • Furthering the understanding of the aetiology of narcolepsy, with a focus on autoimmune aspects
  • Identification of new treatment targets for narcolepsy
  • Testing usefulness of SART in the evaluation of disease severity in treatment trials and assessment of fitness to drive
  • Identification of the cerebral substrate for the vigilance impairment in narcolepsy by performing combined SART/EEG/ fMRI studies
  • To unravel the role of hypocretin in the metabolism of brown fat in humans
  • Strategies to prevent obesity and diabetes by modulating sleep disturbances and its metabolic and hormonal effects
  • Studying the borderland of narcolepsy by using the large prospective database of the EU-Network on Narcolepsy
  • To study the influence of opiates on hypocretin cells
  • Development of European Guidelines for Narcolepsy and its borderland

Cohesion within LUMC

Neurology research lines PaCD (30702) and Neuromotor Disorders (NMD, 30703), together with Human Genetics research line 50104, are the leading research programmes of the medical research profile “Translational Neuroscience” (TN). All research efforts of TN are clustered within two themes: PaCD and NMD. Ferrari & van der Maarel (Human Genetics) are chair and co-chair of TN. PaCD is also well embedded within Leiden University priority research profile “Brain function and dysfunction over the lifespan” (Ferrari is member of its management team) and the generic research profile “Biomedical Imaging”, with many flourishing collaborations, in particular on migraine, cluster headache, CHA, and Stroke.

Many PaCD researchers (in particular Headache, Stroke and Syncope) also participate in various research projects of the medical research profile “Vascular & Regenerative Medicine”. PaCD is main partner of the LUMC-wide hiPSC generation and differentiation platform and is coordinating the Gravity 2017 hiPSC-based Brain-on-a-Chip Initiative (PI Ferrari) as part of the Gravity 2017 Netherlands Organs-on-a-Chip Initiative (NOCI, PI Prof. Mummery). Narcolepsy has a research collaboration with the medical research profile “Immunity, Infection and Tolerance”, focussing on the role of HLA and T-cells in Narcolepsy pathogenesis. There are extensive clinical and scientific collaborations with many LUMC departments, in particular Human Genetics and Radiology, but also Molecular Cell Biology, Center for Proteomics and Metabolomics (CPM; Ferrari is member of the CPM supervisory board), Public Health, Psychiatry, Bioinformatics, Clinical Genetics, Vascular Medicine, Nephrology, Thrombosis and Hemostasis, Anaesthesiology, Rheumatology, Immunohematology, Clinical Epidemiology, and Blood Bank.

Clinically, PaCD is also very well embedded within LUMC. Headaches, CHA, Stroke, Syncope, and Narcolepsy have all five been selected as National Clinical Referral Centre (TRF), and “Rare Headache Syndromes” (i.e. Hemiplegic Migraine and Trigeminal Autonomic Cephalgia’s such as cluster headache) and CHA have been identified by the NFU as National Expert Centres for Rare Disorders.