Hille Koppen

Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial

BACKGROUND Calcitonin gene-related peptide (CGRP) probably has a role in migraine pathophysiology, and antagonism of its receptors might provide treatment without the vasoconstrictor effects of triptans. We aimed to assess the clinical profile of MK-0974 (telcagepant), an orally bioavailable antagonist of CGRP receptor. METHODS In a randomised, parallel-treatment, placebo-controlled, double-blind, trial at 81 sites in the Europe and the USA, adults with migraine diagnosed by International Headache Society criteria treated moderate or severe attacks with either oral telcagepant 150 mg or 300 mg, zolmitriptan 5 mg, or placebo. The five co-primary endpoints were pain freedom, pain relief, or absence of photophobia, phonophobia, or nausea at 2 h after treatment. Analysis was by the full analysis set and multiplicity was controlled for with a step-down closed-testing procedure. This trial is registered with ClinicalTrials.gov, number NCT00442936. FINDINGS 1380 patients were randomly assigned to receive telcagepant 150 mg (n=333) or 300 mg (354), zolmitriptan (345), or placebo (348). Telcagepant 300 mg was more effective than placebo for pain freedom (95 [27%] of 353 patients vs 33 [10%] of 343 [p<0.0001]), pain relief (194 [55%] of 353 vs 95 [28%] of 343 [p<0.0001]), and absences of phonophobia (204 [58%] of 353 vs 126 [37%] of 342 [p<0.0001]), photophobia (180 [51%] of 353 vs 99 [29%] of 342 [p<0.0001]), and nausea (229 [65%] of 352 vs 189 [55%] of 342 [p=0.0061]). Efficacy of telcagepant 300 mg and zolmitriptan 5 mg were much the same, and both were more effective than telcagepant 150 mg. Adverse events were recorded for 31% taking telcagepant 150 mg, 37% taking telcagepant 300 mg, 51% taking zolmitriptan 5 mg, and 32% taking placebo. INTERPRETATION Telcagepant 300 mg is effective as an acute treatment for migraine with efficacy comparable to that of zolmitriptan 5 mg, but with fewer associated adverse effects. FUNDING Merck Research Laboratories.

Structural Brain Changes in Migraine

CONTEXT A previous cross-sectional study showed an association of migraine with a higher prevalence of magnetic resonance imaging (MRI)-measured ischemic lesions in the brain. OBJECTIVE To determine whether women or men with migraine (with and without aura) have a higher incidence of brain lesions 9 years after initial MRI, whether migraine frequency was associated with progression of brain lesions, and whether progression of brain lesions was associated with cognitive decline. DESIGN, SETTING, AND PARTICIPANTS In a follow-up of the 2000 Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis cohort, a prospective population-based observational study of Dutch participants with migraine and an age- and sex-matched control group, 203 of the 295 baseline participants in the migraine group and 83 of 140 in the control group underwent MRI scan in 2009 to identify progression of MRI-measured brain lesions. Comparisons were adjusted for age, sex, hypertension, diabetes, and educational level. The participants in the migraine group were a mean 57 years (range, 43-72 years), and 71% were women. Those in the control group were a mean 55 years (range, 44-71 years), and 69% were women. MAIN OUTCOME MEASURES Progression of MRI-measured cerebral deep white matter hyperintensities, infratentorial hyperintensities, and posterior circulation territory infarctlike lesions. Change in cognition was also measured. RESULTS Of the 145 women in the migraine group, 112 (77%) vs 33 of 55 women (60%) in the control group had progression of deep white matter hyperintensities (adjusted odds ratio [OR], 2.1; 95%CI, 1.0-4.1; P = .04). There were no significant associations of migraine with progression of infratentorial hyperintensities: 21 participants (15%) in the migraine group and 1 of 57 participants (2%) in the control group showed progression (adjusted OR, 7.7; 95% CI, 1.0-59.5; P = .05) or new posterior circulation territory infarctlike lesions: 10 of 203 participants (5%) in the migraine group but none of 83 in the control group (P = .07). There was no association of number or frequency of migraine headaches with progression of lesions. There was no significant association of high vs nonhigh deep white matter hyperintensity load with change in cognitive scores (-3.7 in the migraine group vs 1.4 in the control group; 95% CI, -4.4 to 0.2; adjusted P = .07). CONCLUSIONS In a community-based cohort followed up after 9 years, women with migraine had a higher incidence of deep white matter hyperintensities but did not have significantly higher progression of other MRI-measured brain changes. There was no association of migraine with progression of any MRI-measured brain lesions in men.

Severe unilateral headache caused by skull bone infarction with epidural haematoma in a patient with sickle cell disease

Background: The clinical manifestations of sickle cell disease (SCD) vary, but may be attributed to vaso-occlusion, chronic hemolytic anemia, and infections as a result of functional asplenia. We report a case of a man who presented with severe headache caused by an uncommon complication of SCD. Case: A 19-year-old Surinamer man presented to the emergency department with severe headache. The progressive headache started one day previously. The headache was located frontotemporally on the right side. It was pulsating with paroxysms of fierce pain. There was no nausea or vomiting. The medical history reported sickle cell disease of the HbSC type. The physical and neurological examination was normal. He was afebrile with a blood pressure of 118/72 mmHg. Blood tests and CSF investigation showed no abnormalities. CT-scan of the head was normal. The headache disappeared after two days. Eight days later he presented again, with a relapsing severe headache. Physical, neurological examination and blood investigations were normal. MRI now showed infarction located in the parietal skull bone, with a small adjacent epidural hematoma. The headache disappeared gradually over 8 days. Repeat MRI one month later showed complete disappearance of the epidural hematoma. The first headache episode was thought to be due to the initial skull bone infarction as no epidural hematoma had been present initially. The second headache episode was thought to be due to the development of the epidural hematoma. Discussion: A skull bone infarction is an uncommon complication of SCD, as typically these are located in the long bones. Even more uncommon is a epidural hematoma which was probably the result of the altered bone and vesselwall structure following the skull bone infarction. To our knowledge this is the first case reporting a skull-bone infarction with adjacent spontaneous epidural hematoma in an adult with sickle cell disease of the HbSC type. Our case emphasizes the need to recognize skull infarction and a concomitant spontaneous epidural hematoma as a possible complication of SCD.

Effect of Cardiac Resynchronization Therapy on Cerebral Blood Flow

Decreased cerebral blood flow is frequently observed in patients with heart failure, and this could be the result of impaired cardiac systolic function. Cardiac resynchronization therapy (CRT) improves cardiac function and heart failure symptoms in selected patients. The effects of CRT on cerebral blood flow have not been previously evaluated. In the present study, left ventricular systolic function and cerebral blood flow were assessed in 35 patients with heart failure, before and 6 months after CRT. Additionally, 15 patients with heart failure, who were not candidates for CRT, were included as a control group. The peak systolic velocity, end-diastolic velocity, mean velocity, and pulsatility index ([peak systolic velocity--end-diastolic velocity]/mean velocity) were obtained using transcranial Doppler from the right middle cerebral artery from the temporal window in all subjects. Response to CRT was defined as a reduction in the left ventricular end-systolic volume of > or =15%. At 6 months of follow-up, the peak systolic velocity had significantly increased from 83 +/- 20 cm/s to 100 +/- 20 cm/s (p = 0.001), the end-diastolic velocity had increased from 29 +/- 7 cm/s to 37 +/- 8 cm/s (p <0.001), and the mean velocity had increased from 47 +/- 10 cm/s to 58 +/- 11 cm/s (p <0.001) only in the responders to CRT. In contrast, no significant changes in cerebral blood flow were observed in the nonresponders and the controls. In conclusion, CRT induced an increase in cerebral blood flow in patients with heart failure. This increase in cerebral blood flow was related to the improvement in left ventricular systolic function.

The impact of a migraine attack and its after-effects on perceptual organization, attention, and working memory

Introduction: Many migraine patients report cognitive complaints during the first hours or days following a migraine attack. The aim of this study was to assess whether and which cognitive (perceptual, attentional, or memory) processes are impaired during the first 48 hours after a migraine attack. Methods: Three different cognitive tasks (global-local task, the attentional network task, and N-back task) were administered to 16 migraine patients (13 migraine without aura; mean age 58 years, 15 female) and 18 controls (59 years, 15 female), matched on age, gender, and educational level. Tasks were administered at three time points; during the first headache free day following a migraine attack (first session), 24 hours later (second session), and 12 days after the attack (third session). Results: The attentional network and N-back tasks showed no significant differences between migraineurs and controls. In the global-local task, controls showed faster reaction times to global than to local stimuli, which is the standard global-precedence effect. This effect was absent in the migraineurs in all three sessions, especially if they used prophylaxis. Conclusion: Migraineurs had no impaired attentional or working-memory functioning in the 2 days after an attack. They did show impairments in the processing of global visual features compared with controls, both between and immediately after an attack.

Systemic right-to-left shunts, ischemic brain lesions, and persistent migraine activity

Objective: To assess whether migraine in the general population is associated with increased risk of systemic right-to-left shunts (RLS) and whether RLS are associated with increased prevalence of brain infarcts and persistent recurrence of migraine attacks at older age. Methods: Brain MRI and transcranial Doppler with air contrast in 166 unselected migraineurs (mean age ± SD 56 ± 7.7 years; 70% women; n = 96 migraine with aura) and 69 controls (mean age ± SD 55 ± 7.6 years; 65% women) from the general population. Results: Participants with migraine with aura more frequently had Valsalva-induced RLS (60%), in particular large-sized, compared to controls (42%; odds ratio [OR] 2.1; 95% confidence interval [CI] 1.1–3.9; p = 0.02) and participants with migraine without aura (40%; OR 2.3; 95% CI 1.2–4.3; p = 0.01). They also more frequently had spontaneous RLS (35%) than participants with migraine without aura (17%; OR 2.6; 95% CI 1.3–5.6; p = 0.01) but not compared to controls (26%; OR 1.6; 95% CI 0.8–3.1; p = 0.2). Participants with migraine with aura and spontaneous RLS more frequently had persistent migraine activity (85%) than participants with migraine without spontaneous RLS (63%; OR 3.4; 95% CI 1.2–10.1; p = 0.03). Nine percent of participants with RLS had silent posterior circulation infarcts compared to 3% of participants without RLS (OR 2.8; 95% CI 0.9–9.3; p = 0.08), independent of migraine status. RLS were not associated with white matter lesions. Conclusions: RLS are more prevalent in migraineurs with aura but do not explain the increased prevalence of silent posterior circulation infarcts or white matter lesions in migraineurs. Spontaneous RLS are associated with persistent migraine.

Volumetric brain changes in migraineurs from the general population

Objective: To assess volumetric brain changes in migraineurs from the general population compared with controls. Methods: Structural brain changes in migraineurs from the general population-based MRI Cerebral Abnormalities in Migraine, an Epidemiologic Risk Analysis (CAMERA)-2 observational cohort study were assessed by state-of-the-art voxel-based morphometry. T1-weighted MRIs of 84 migraineurs (52 with aura, 32 without aura) and 35 headache-free controls were evaluated. Regional volumes were compared voxelwise, corrected for age, sex, and total intracranial volume, with region-of-interest and whole-brain analyses. Results: In region-of-interest analyses, migraineurs showed decreased gray matter volume in the visual areas V3 and V5 of the right occipital cortex compared to controls (p < 0.05, familywise error correction). Post hoc analyses revealed that similar changes were present regardless of migraine aura status, disease activity (>1 year attack-free [inactive] vs ≥1 attack within the last year [active] and attack frequency [≤1 (low) vs ≥1 attack per month [high]). In exploratory whole-brain analyses (p < 0.001, uncorrected for multiple comparisons), we identified additional structural differences in migraineurs in other cortical and subcortical areas, including white matter tracts, that are particularly involved in visual processing. Conclusions: Migraineurs from the general population showed small volumetric brain changes, mainly in cortical areas involved in visual motion processing, compared to controls. The presence of morphologic changes regardless of the presence of migraine aura or disease activity suggests that migraines with and without aura share common pathophysiologic pathways and suggests that these changes are (partially) irreversible or might have been present throughout life.

Cerebellar function and ischemic brain lesions in migraine patients from the general population

Objective The objective of this article is to obtain detailed quantitative assessment of cerebellar function and structure in unselected migraine patients and controls from the general population. Methods A total of 282 clinically well-defined participants (migraine with aura n = 111; migraine without aura n = 89; non-migraine controls n = 82; age range 43–72; 72% female) from a population-based study were subjected to a range of sensitive and validated cerebellar tests that cover functions of all main parts of the cerebellar cortex, including cerebrocerebellum, spinocerebellum, and vestibulocerebellum. In addition, all participants underwent magnetic resonance imaging (MRI) of the brain to screen for cerebellar lesions. As a positive control, the same cerebellar tests were conducted in 13 patients with familial hemiplegic migraine type 1 (FHM1; age range 19–64; 69% female) all carrying a CACNA1A mutation known to affect cerebellar function. Results MRI revealed cerebellar ischemic lesions in 17/196 (8.5%) migraine patients and 3/79 (4%) controls, which were always located in the posterior lobe except for one control. With regard to the cerebellar tests, there were no differences between migraine patients with aura, migraine patients without aura, and controls for the: (i) Purdue-pegboard test for fine motor skills (assembly scores p = 0.1); (ii) block-design test for visuospatial ability (mean scaled scores p = 0.2); (iii) prism-adaptation task for limb learning (shift scores p = 0.8); (iv) eyeblink-conditioning task for learning-dependent timing (peak-time p = 0.1); and (v) body-sway test for balance capabilities (pitch velocity score under two-legs stance condition p = 0.5). Among migraine patients, those with cerebellar ischaemic lesions performed worse than those without lesions on the assembly scores of the pegboard task (p < 0.005), but not on the primary outcome measures of the other tasks. Compared with controls and non-hemiplegic migraine patients, FHM1 patients showed substantially more deficits on all primary outcomes, including Purdue-peg assembly (p < 0.05), block-design scaled score (p < 0.001), shift in prism-adaptation (p < 0.001), peak-time of conditioned eyeblink responses (p < 0.05) and pitch-velocity score during stance-sway test (p < 0.001). Conclusions Unselected migraine patients from the general population show normal cerebellar functions despite having increased prevalence of ischaemic lesions in the cerebellar posterior lobe. Except for an impaired pegboard test revealing deficits in fine motor skills, these lesions appear to have little functional impact. In contrast, all cerebellar functions were significantly impaired in participants with FHM1.

Postural sway in migraine patients and controls, results from a population based CAMERA-2 study

Methods Trunk sway in the medio-lateral (roll) and anterior-posterior (pitch) plane was measured using two digital angular velocity transducers attached to the lower back. Subjects completed three different trials. All tests were done interictally and investigators were blinded for all participant characteristics. Outcomes are given as trunksway angles and angular velocity in both the roll and pitch plane.

Migraine and vascular disease biomarkers: A population-based case-control study

Background The underpinnings of the migraine-stroke association remain uncertain, but endothelial activation is a potential mechanism. We evaluated the association of migraine and vascular disease biomarkers in a community-based population. Methods Participants (300 women, 117 men) were recruited as a part of the Dutch CAMERA 1 (Cerebral Abnormalities in Migraine, an Epidemiologic Risk Analysis) study. Participants were aged 30–60 (mean 48) years, 155 migraine had with aura (MA), 128 migraine without aura (MO), and 134 were controls with no severe headaches. Plasma concentrations of fibrinogen, Factor II, D-dimer, high sensitivity C-reactive protein (hs-CRP), and von Willebrand factor antigen were compared between groups, also stratifying by sex. Results Fibrinogen and hs-CRP were elevated in migraineurs compared to controls. In logistic regression analyses, MO and MA had increased likelihood of elevated fibrinogen, and MA had increased likelihood of elevated Factor II and hs-CRP. Fibrinogen and Factor II were associated with MA in women but not men. In the migraine subgroup, the total number of years of aura, but not headache, predicted elevated hs-CRP, and the average number of aura, but not headache, attacks predicted all biomarkers but Factor II. Conclusions Elevated vascular biomarkers were associated with migraine, particularly MA, as well as with years of aura and number of aura attacks.