BackgroundWe demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and... Show moreBackgroundWe demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and effective. In L-ICON we prospectively evaluate its long-term effectiveness and safety.MethodsICON participants were enrolled in L-ICON immediately after completing ICON. Therefore, earlier ICON participants could be followed longer than later ones. L-ICON inclusion was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years by completing six-monthly questionnaires on attack frequency, side effects, subjective improvement and whether they would recommend ONS to others. Primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study compared to baseline. Missing values for log-transformed attack-frequency were imputed for up to 5 years of follow-up. Descriptive analyses are presented as (pooled) geometric or arithmetic means and 95% confidence intervals.FindingsOf 103 eligible participants, 88 (85%) gave informed consent and 73 (83%) were followed for ≥2 year, 61 (69%) ≥ 3 year, 33 (38%) ≥ 5 years and 3 (3%) ≥ 8.5 years. Mean (±SD) follow-up was 4.2 ± 2.2 years for a total of 370 person years (84% of potentially 442 years). The pooled geometric mean (95% CI) weekly attack frequency remained considerably lower after one (4.2; 2.8–6.3), two (5.1; 3.5–7.6) and five years (4.1; 3.0–5.5) compared to baseline (16.2; 14.4–18.3). Of the 49/88 (56%) ICON ≥50% responders, 35/49 (71%) retained this response and 15/39 (38%) ICON non-responders still became a ≥50% responder for at least half the follow-up period. Most participants (69/88; 78% [0.68–0.86]) reported a subjective improvement from baseline at last follow-up and 70/88 (81% [0.70–0.87]) would recommend ONS to others. Hardware-related surgery was required in 44/88 (50%) participants in 112/122 (92%) events (0.35 person-year−1 [0.28–0.41]). We didn't find predictive factors for effectiveness. Show less
Background and ObjectivesFemale-specific factors and psychosocial factors may be important in the prediction of strokebut are not included in prediction models that are currently used. We... Show moreBackground and ObjectivesFemale-specific factors and psychosocial factors may be important in the prediction of strokebut are not included in prediction models that are currently used. We investigated whetheraddition of these factors would improve the performance of prediction models for the risk ofstroke in women younger than 50 years.MethodsWe used data from the Stichting Informatievoorziening voor Zorg en Onderzoek, population-based, primary care database of women aged 20–49 years without a history of cardiovasculardisease. Analyses were stratified by 10-year age intervals at cohort entry. Cox proportionalhazards models to predict stroke risk were developed, including traditional cardiovascularfactors, and compared with models that additionally included female-specific and psychosocialfactors. We compared the risk models using the c-statistic and slope of the calibration curve at afollow-up of 10 years. We developed an age-specific stroke risk prediction tool that may helpcommunicating the risk of stroke in clinical practice.ResultsWe included 409,026 women with a total of 3,990,185 person-years of follow-up. Strokeoccurred in 2,751 women (incidence rate 6.9 [95% CI 6.6–7.2] per 10,000 person-years).Models with only traditional cardiovascular factors performed poorly to moderately in all agegroups: 20–29 years: c-statistic: 0.617 (95% CI 0.592–0.639); 30–39 years: c-statistic: 0.615(95% CI 0.596–0.634); and 40–49 years: c-statistic: 0.585 (95% CI 0.573–0.597). After addingthe female-specific and psychosocial risk factors to the reference models, the model discrimi-nation increased moderately, especially in the age groups 30–39 (Dc-statistic: 0.019) and 40–49years (Dc-statistic: 0.029) compared with the reference models, respectively.DiscussionThe addition of female-specific factors and psychosocial risk factors improves the discrimina-tory performance of prediction models for stroke in women younger than 50 years. Show less
Migraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability... Show moreMigraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability can be directly assessed by combining transcranial magnetic stimulation with electroencephalography (TMS-EEG). We measured TMS evoked potential (TEP) amplitude and response consistency as these measures have been linked to cortical excitability but were not yet reported in migraine.We recorded 64-channel EEG during single-pulse TMS on the vertex interictally in 10 people with migraine with aura and 10 healthy controls matched for age, sex and resting motor threshold. On average 160 pulses around resting motor threshold were delivered through a circular coil in clockwise and counterclockwise direction. Trial-averaged TEP responses, frequency spectra and phase clustering (over the entire scalp as well as in frontal, central and occipital midline electrode clusters) were compared between groups, including comparison to sham-stimulation evoked responses.Migraine and control groups had a similar distribution of TEP waveforms over the scalp. In migraine with aura, TEP responses showed reduced amplitude around the frontal and occipital N100 peaks. For the migraine and control groups, responses over the scalp were affected by current direction for the primary motor cortex, somatosensory cortex and sensory association areas, but not for frontal, central or occipital midline clusters.This study provides evidence of altered TEP responses in-between attacks in migraine with aura. Decreased TEP responses around the N100 peak may be indicative of reduced cortical GABA-mediated inhibition and expand observations on enhanced cortical excitability from earlier migraine studies using more indirect measurements. Show less
Migraine is a common, chronic, disorder that is typically characterized by recurrent disabling attacks of headache and accompanying symptoms, including aura. The aetiology is multifactorial with... Show moreMigraine is a common, chronic, disorder that is typically characterized by recurrent disabling attacks of headache and accompanying symptoms, including aura. The aetiology is multifactorial with rare monogenic variants. Depression, epilepsy, stroke and myocardial infarction are comorbid diseases. Spreading depolarization probably causes aura and possibly also triggers trigeminal sensory activation, the underlying mechanism for the headache. Despite earlier beliefs, vasodilation is only a secondary phenomenon and vasoconstriction is not essential for antimigraine efficacy. Management includes analgesics or NSAIDs for mild attacks, and, for moderate or severe attacks, triptans or 5HT1B/1D receptor agonists. Because of cardiovascular safety concerns, unreliable efficacy and tolerability issues, use of ergots to abort attacks has nearly vanished in most countries. CGRP receptor antagonists (gepants) and lasmiditan, a selective 5HT1F receptor agonist, have emerged as effective acute treatments. Intramuscular onabotulinumtoxinA may be helpful in chronic migraine (migraine on ≥15 days per month) and monoclonal antibodies targeting CGRP or its receptor, as well as two gepants, have proven effective and well tolerated for the preventive treatment of migraine. Several neuromodulation modalities have been approved for acute and/or preventive migraine treatment. The emergence of new treatment targets and therapies illustrates the bright future for migraine management. Show less
Metabolic profiling of cerebrospinal fluid (CSF) is a promising technique for studying brain diseases. Measurements should reflect the in vivo situation, so ex vivo metabolism should be avoided. To... Show moreMetabolic profiling of cerebrospinal fluid (CSF) is a promising technique for studying brain diseases. Measurements should reflect the in vivo situation, so ex vivo metabolism should be avoided. To investigate the effects of temperature (room temperature vs. 4 °C), centrifugation and ethanol, as anti-enzymatic additive during CSF sampling on concentrations of glutamic acid, glutamine and other endogenous amines. CSF samples from 21 individuals were processed using five different protocols. Isotopically-labeled alanine, isoleucine, glutamine, glutamic acid and dopamine were added prior to sampling to trace any degradation. Metabolomics analysis of endogenous amines, isotopically-labeled compounds and degradation products was performed with a validated LC-MS method. -phosphoethanolamine concentrations were also lower when ethanol was added. Degradation of isotopically-labeled compounds (e.g. glutamine to glutamic acid) was minor with no differences between protocols. Most amines can be considered stable during sampling, provided that samples are cooled immediately to 4 °C, centrifuged, and stored at - 80 °C within 2 h. The effect of ethanol addition for more unstable metabolites needs further investigation. This was the first time that labeled compounds were used to monitor ex vivo metabolism during sampling. This is a useful strategy to study the stability of other metabolites of interest. Show less
Endocannabinoids, a class of lipid messengers, have emerged as crucial regulators of synaptic communication in the central nervous system (CNS). Dysregulation of these compounds has been... Show moreEndocannabinoids, a class of lipid messengers, have emerged as crucial regulators of synaptic communication in the central nervous system (CNS). Dysregulation of these compounds has been implicated in many brain disorders. Although some studies have identified and quantified a limited number of target compounds, a method that provides comprehensive quantitative information on endocannabinoids and related N-acylethanolamines (NAEs) in CSF is currently lacking as measurements are challenging due to low concentrations under normal physiological conditions. Here we developed and validated a high-throughput nano liquid chromatography-electrospray ionization mass spectrometry (nano LC-ESI-MS/MS) platform for the simultaneous quantification of endocannabinoids (anandamide (AEA), 2-arachidonoyl glycerol (2-AG)), ten related NAEs and eight additional putatively annotated NAEs in human CSF. Requiring only 200 μL of CSF our method has limits of detection from 0.28 to 61.2 pM with precisions of RSD <15% for most compounds. We applied our method to CSF from 45 healthy humans and demonstrated potential age and gender effects on concentrations of endocannabinoids and NAEs. Notably, our results show that docosahexaenoyl ethanolamide (DHEA) concentrations increase with age in males. Our method may offer new opportunities to gain insight into regulatory functions of endocannabinoids in the context of (ab)normal brain function. Show less
Eising, E.; Shyti, R.; Hoen, P.A.C. 't; Vijfhuizen, L.S.; Huisman, S.M.H.; Broos, L.A.M.; ... ; Maagdenberg, A.M.J.M. van den 2017
Familial hemiplegic migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in CACNA1A that encodes the alpha(1A) subunit of voltage-gated Ca(V)2.1 calcium... Show moreFamilial hemiplegic migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in CACNA1A that encodes the alpha(1A) subunit of voltage-gated Ca(V)2.1 calcium channels. Transgenic knock-in mice that carry the human FHM1 R192Q missense mutation ('FHM1 R192Q mice') exhibit an increased susceptibility to cortical spreading depression (CSD), the mechanism underlying migraine aura. Here, we analysed gene expression profiles from isolated cortical tissue of FHM1 R192Q mice 24 h after experimentally induced CSD in order to identify molecular pathways affected by CSD. Gene expression profiles were generated using deep serial analysis of gene expression sequencing. Our data reveal a signature of inflammatory signalling upon CSD in the cortex of both mutant and wild-type mice. However, only in the brains of FHM1 R192Q mice specific genes are up-regulated in response to CSD that are implicated in interferon-related inflammatory signalling. Our findings show that CSD modulates inflammatory processes in both wild-type and mutant brains, but that an additional unique inflammatory signature becomes expressed after CSD in a relevant mouse model of migraine. Show less
Maassen van den Brink, A.; Meijer, J.; Villalon, C.M.; Ferrari, M.D. 2016
Migraine is a common brain disorder characterized by recurrent attacks of severe headaches and other neurological symptoms. In one-third of patients headaches are accompanied by auras, which... Show moreMigraine is a common brain disorder characterized by recurrent attacks of severe headaches and other neurological symptoms. In one-third of patients headaches are accompanied by auras, which consist of transient visual and sensory disturbances, believed to be caused by cortical spreading depression (CSD). CSD is characterized by a wave of neuronal and glial depolarization with concomitant changes in metabolite concentrations in the brain and cerebrospinal fluid. It remains unknown whether CSD-induced brain metabolic changes can be captured outside the central nervous system, i.e., in peripheral fluids. This study investigated plasma metabolic changes in transgenic mice that harbor a gene mutation in voltage-gated CaV2.1 Ca(2+) channels previously identified in patients with familial hemiplegic migraine, a subtype of migraine with auras. The use of a mouse model allows investigation of molecular changes occurring shortly after CSD, which is notoriously difficult in patients. Capillary electrophoresis - mass spectrometry was used for the analysis of plasma samples to obtain, for the first time, a comprehensive view of molecular changes immediately after experimentally induced CSD. Multivariate data analysis showed a clear distinction between profiles of transgenic and wild-type animals after CSD. Two metabolites considered important for this discrimination were tentatively identified as being lysine and its by-product pipecolic acid with additional evidence provided by hydrophilic interaction chromatography combined with tandem mass spectrometry. The changed metabolites suggest a compensatory increase in GABAergic neurotransmission upon enhanced excitatory neurotransmission. These results show that CSD induces metabolic remodeling in transgenic migraine mice that can be captured and measured in plasma. Show less
