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See detailOccipital nerve stimulation for drug-resistant chronic cluster headache: long term follow-up up to 3 years
Gérardy, Pierre-Yves ULg; Magis, Delphine ULg; Allena, M. et al

in Cephalalgia : An International Journal of Headache (2009, January), 29(1),

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See detailMitochondrial DNA haplogroups influence response to Riboflavin in Migraineurs
Di Lorenzo, C.; Coppola, G.; Santorelli, F. et al

in Cephalalgia : An International Journal of Headache (2009, January), 29(1),

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See detailMitochondrial DNA haplogroups influence the therapeutic response to riboflavin in migraineurs.
Di Lorenzo, C.; Pierelli, F.; Coppola, G. et al

in Neurology (2009), 72(18), 1588-94

OBJECTIVES: In migraine, an interictal reduction of mitochondrial energy metabolism and a preventive effect of high-dose riboflavin were reported. To explore the relation between the two, we tested if the ... [more ▼]

OBJECTIVES: In migraine, an interictal reduction of mitochondrial energy metabolism and a preventive effect of high-dose riboflavin were reported. To explore the relation between the two, we tested if the therapeutic response to riboflavin is associated with specific mitochondrial DNA (mtDNA) haplogroups. We focused our attention on haplogroup H, which is known to differ from others in terms of energy metabolism. METHODS: Sixty-four migraineurs completed a 4-month open trial with riboflavin (400 mg QD) and were genotyped blindly for mtDNA haplogroups. RESULTS: Forty patients responded to riboflavin treatment and 24 were nonresponders. The mtDNA haplogroup H was found in 29 subjects (20 migraine without aura, 9 migraine with aura). Riboflavin responders were more numerous in the non-H group (67.5%). Conversely, nonresponders were mostly H (66.7%). The difference between the two groups was significant (chi(2) = 7.07; p = 0.01). The presence of aura had no influence on riboflavin's effectiveness (chi(2) = 0.113; p = 0.74) and was not associated with a particular haplogroup (chi(2) = 0.55; p = 0.46). CONCLUSIONS: In this pharmacogenetic study, riboflavin appears to be more effective in patients with migraine with non-H mitochondrial DNA haplotypes. The underlying mechanisms are unknown, but could be related to the association of haplogroup H with increased activity in complex I, which is a major target for riboflavin. Our results may have ethnic implications, since haplogroup H is chiefly found in the European population. [less ▲]

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See detailNitroglycerin sensitises in healthy subjects CNS structures involved in migraine pathophysiology: evidence from a study of nociceptive blink reflexes and visual evoked potentials.
Di Clemente, Laura; Coppola, Gianluca; Magis, Delphine ULg et al

in Pain (2009), 144(1-2), 156-61

Nitroglycerin (NTG), a NO donor, induces an attack in migraine patients approximately 4-6 h after administration. The causative mechanisms are not known, but the long delay leaves room for a central ... [more ▼]

Nitroglycerin (NTG), a NO donor, induces an attack in migraine patients approximately 4-6 h after administration. The causative mechanisms are not known, but the long delay leaves room for a central effect, such as a change in neuronal excitability and synaptic transmission of various CNS areas involved in pain and behaviour including trigeminal nucleus caudalis and monoaminergic brain stem nuclei. To explore the central action of NTG, we have studied its effects on amplitude and habituation of the nociceptive blink reflex (nBR) and the visual evoked potential (VEP) before, 1 h and 4 h after administration of NTG (1.2 mg sublingual) or placebo (vehicle sublingual) in two groups of 10 healthy volunteers. We found a significant decrease in nBR pain and reflex thresholds both 1 and 4 h post-NTG. At the 4 h time point R2 latency was shorter (p=0.04) and R2 response area increased (p<0.01) after NTG but not after placebo. Habituation tended to become more pronounced after both NTG and placebo administration. There was a significant amplitude increase in the 5th VEP block (p=0.03) at 1h after NTG and in the 1st block (p=0.04) at 4 h. VEP habituation was replaced by potentiation at both delays after NTG; the change in habituation slope was significant at 1h (p=0.02). There were no significant VEP changes in subjects who received sublingual placebo. In conclusion, we found that in healthy subjects sublingual NTG, but not its vehicle, induces changes in a trigeminal nociceptive reflex and an evoked cortical response which are comparable to those found immediately before and during an attack of migraine. These changes could be relevant for the attack-triggering effect of NTG in migraineurs. [less ▲]

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See detailMetabolic correlates of clinical heterogeneity in questionable Alzheimer’s disease
Salmon, Eric ULg; Lekeu, Françoise ULg; Garraux, Gaëtan ULg et al

in Neurobiology of Aging (2008), 29

Thirty-four subjects with questionable Alzheimer's disease (QAD) were included in a 3-year prospective study and underwent neuropsychological testing and measurement of brain metabolism using FDG-PET at ... [more ▼]

Thirty-four subjects with questionable Alzheimer's disease (QAD) were included in a 3-year prospective study and underwent neuropsychological testing and measurement of brain metabolism using FDG-PET at entry. Seventeen patients (50%) did not convert to AD during the follow-up period. Compared to elderly controls of similar age, the cerebral activity of non-converters was reduced in the dorsolateral prefrontal cortex. Moreover, the variability of metabolism in the posterior cingulate cortex was related to their visuospatial memory performance, while disparity in parietal activity was related to their verbal memory performance. These results demonstrate the cerebral metabolic heterogeneity of patients with QAD. Initial functional images of converters showed that activity was already impaired in the posterior cingulate, lateral temporal cortex, anterior cingulate and orbitofrontal cortex. This metabolic pattern is consistent with a pre-dementia stage of AD, and highlights the fact that significant frontal metabolic involvement may be associated with impaired activity in posterior associative cortices in very early AD. [less ▲]

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See detailNeurostimulation in chronic cluster headache.
Magis, Delphine ULg; Schoenen, Jean ULg

in Current Pain and Headache Reports (2008), 12(2), 145-53

About 1% of all chronic cluster headache patients become intractable (iCCH; ie, they are refractory to adequate regimens of all established preventive drugs). Various lesional interventions have been ... [more ▼]

About 1% of all chronic cluster headache patients become intractable (iCCH; ie, they are refractory to adequate regimens of all established preventive drugs). Various lesional interventions have been attempted in these patients, none with lasting benefits. In recent years, nondestructive neurostimulation methods have raised new hope. Hypothalamic deep brain stimulation (hDBS) acts rather rapidly and has durable efficacy, but it is not without risk. Occipital nerve stimulation (ONS) was studied in two trials that included 17 iCCH patients. Clinical efficacy was found to be very satisfactory by most patients and investigators. Although slightly less efficacious than hDBS, ONS has the advantage of being harmless and reversible. At this stage, it should be the preferred first-line invasive therapy for iCCH. Recent case reports mention efficacy of supraorbital and vagus nerve stimulation. Whether these neurostimulation methods have a place in the management of iCCH patients remains to be determined. [less ▲]

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See detailInterictal abnormalities of gamma band activity in visual evoked responses in migraine: an indication of thalamocortical dysrhythmia?
Coppola, G.; Ambrosini, Anna; Di Clemente, L. et al

in Cephalalgia : An International Journal of Headache (2007), 27(12), 1360-1367

Between attacks, migraineurs lack habituation in standard visual evoked potentials (VEPs). Visual stimuli also evoke high-frequency oscillations in the gamma band range (GBOs, 20-35 Hz) assumed to be ... [more ▼]

Between attacks, migraineurs lack habituation in standard visual evoked potentials (VEPs). Visual stimuli also evoke high-frequency oscillations in the gamma band range (GBOs, 20-35 Hz) assumed to be generated both at subcortical (early GBOs) and cortical levels (late GBOs). The consecutive peaks of GBOs were analysed regarding amplitude and habituation in six successive blocks of 100 averaged pattern reversal (PR)-VEPs in healthy volunteers and interictally in migraine with (MA) or without aura patients. Amplitude of the two early GBO components in the first PR-VEP block was significantly increased in MA patients. There was a significant habituation deficit of the late GBO peaks in migraineurs. The increased amplitude of early GBOs could be related to the increased interictal visual discomfort reported by patients. We hypothesize that the hypofunctioning serotonergic pathways may cause, in line with the thalamocortical dysrhythmia theory, a functional disconnection of the thalamus leading to decreased intracortical lateral inhibition, which can induce dishabituation. [less ▲]

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See detailEvaluation and proposal for optimization of neurophysiological tests in migraine: Part 2 - neuroimaging and the nitroglycerin test
Magis, Delphine ULg; Bendtsen, L.; Goadsby, P. J. et al

in Cephalalgia : An International Journal of Headache (2007), 27(12), 1339-1359

Neuroimaging methods have been widely used in headache and migraine research. They have provided invaluable information on brain perfusion, metabolism and structure during and outside of migraine attacks ... [more ▼]

Neuroimaging methods have been widely used in headache and migraine research. They have provided invaluable information on brain perfusion, metabolism and structure during and outside of migraine attacks, contributing to an improved understanding of the pathophysiology of the disorder. Human models of migraine attacks are indispensable tools in pathophysiological and therapeutic research. This review of neuroimaging methods and the attack-provoking nitroglycerin test is part an initiative by a task force within the EUROHEAD project (EU Strep LSHM-CT-2004-5044837-Workpackage 9) with the objective of critically evaluating neurophysiological tests used in migraine. The first part, presented in a companion paper, is devoted to electrophysiological methods, this second part to neuroimaging methods such as functional magnetic resonance imaging, positron emission tomography and voxel-based morphometry, as well as the nitroglycerin test. For each of these methods, we summarize the results, analyse the methodological limitations and propose recommendations for improved methodology and standardization of research protocols. [less ▲]

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See detailEvaluation and proposal for optimalization of neurophysiological tests in migraine: Part 1 - electrophysiological tests
Magis, Delphine ULg; Ambrosini, Anna; Bendtsen, L. et al

in Cephalalgia : An International Journal of Headache (2007), 27(12), 1323-1338

Neurophysiological testing has become a valuable tool for investigating brain excitability and nociceptive systems in headache disorders. Previous reviews have suggested that most neurophysiological tests ... [more ▼]

Neurophysiological testing has become a valuable tool for investigating brain excitability and nociceptive systems in headache disorders. Previous reviews have suggested that most neurophysiological tests have limited value for headache diagnosis, but a vast potential for exploring the pathophysiology of headaches, the central effects of certain pharmacological treatments and phenotype-genotype correlations. Many protocols, however, lack standardization. This meta-analytical review of neurophysiological methods in migraine was initiated by a task force within the EUROHEAD project (EU Strep LSHM-CT-2004-5044837-Workpackage 9). Most of the neurophysiological approaches that have been used in headache patients are reviewed, i.e. evoked potentials, nociception-specific blink reflex, single-fibre electromyography, neuroimaging methods (functional MRI, PET, and voxel-based morphometry) and the nitroglycerin attack-provoking test. For each of them, we summarize the results, analyse the methodological limitations and propose recommendations for improved methodology and standardization of research protocols. The first part is devoted to electrophysiological methods, the second to neuroimaging techniques and the NTG test. [less ▲]

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See detailThe vestibulo-collic reflex is abnormal in migraine
Allena, M.; Magis, Delphine ULg; De Pasqua, Victor ULg et al

in Cephalalgia : An International Journal of Headache (2007), 27(10), 1150-1155

Interictal evoked central nervous system responses are characterized in migraineurs by a deficit of habituation, at both cortical and subcortical levels. The click-evoked vestibulo-collic reflex (VCR ... [more ▼]

Interictal evoked central nervous system responses are characterized in migraineurs by a deficit of habituation, at both cortical and subcortical levels. The click-evoked vestibulo-collic reflex (VCR) allows the assessment of otolith function and an oligosynaptic pathway linking receptors in the saccular macula to motoneurons of neck muscles. Three blocks of 75 averaged responses to monaural 95-dB normal hearing level 3-Hz clicks were recorded over the contracted ipsilateral sternocleidomastoid muscle in 25 migraineurs between attacks and 20 healthy subjects, without vestibular symptoms. Amplitudes, raw and corrected for baseline electromyography, were significantly smaller in migraine patients. Whereas in healthy volunteers the VCR habituated during stimulus repetition (-4.96% +/- 14.3), potentiation was found in migraineurs (4.34% +/- 15.3; P = 0.04). The combination with a reduced mean amplitude does not favour vestibular hyperexcitability as an explanation for the habituation deficit in migraine, but rather an abnormal processing of repeated stimuli in the reflex circuit. [less ▲]

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See detailSearch for correlations between genotypes and electrophysiological patterns in migraine: the MTHFR C677T polymorphism and visual evoked potentials
Magis, Delphine ULg; Allena, M.; Coppola, G. et al

in Cephalalgia : An International Journal of Headache (2007), 27(10), 1142-1149

Interictally, migraineurs have on average a reduction in habituation of pattern-reversal visual evoked potentials (PR-VEP) and in mitochondrial energy reserve. 5,10-Methylenetetrahydrofolate reductase ... [more ▼]

Interictally, migraineurs have on average a reduction in habituation of pattern-reversal visual evoked potentials (PR-VEP) and in mitochondrial energy reserve. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and its C677T polymorphism may be more prevalent in migraine. The aim of this study was to search in migraineurs for a correlation between the MTHFR C677T polymorphism and the PR-VEP profile. PR-VEP were recorded in 52 genotyped migraine patients: 40 female, 24 without (MoA), 28 with aura (MA). Among them 21 had a normal genotype (CC), 18 were heterozygous (CT) and 13 homozygous (TT) for the MTHFR C677T polymorphism. Mean PR-VEP N1-P1 amplitude was significantly lower in CT compared with CC, and tended to be lower in TT with increasing age. The habituation deficit was significantly greater in CC compared with TT subjects. The correlation between the cortical preactivation level, as reflected by the VEP amplitude in the first block of averages, and habituation was stronger in CC than in CT or TT. The MTHFR C677T polymorphism could thus have an ambiguous role in migraine. On one hand, the better VEP habituation which is associated with its homozygosity, and possibly mediated by homocysteine derivatives increasing serotoninergic transmission, may protect the brain against overstimulation. On the other hand, MTHFR C677T homozygosity is linked to a reduction of grand average VEP amplitude with illness duration, which has been attributed to brain damage. [less ▲]

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See detailConditioning by high frequency visual stimuli of the visual evoked potential in healthy volunteers and migraineurs
Bolla, M.; Magis, Delphine ULg; Gerardy, P. et al

Poster (2007, August)

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See detailInhibition of the nociceptive R2 blink reflex after supraorbital or index finger stimulation is normal in migraine without aura between attacks
Coppola, G.; Di Clemente, L.; Fumal, Arnaud ULg et al

in Cephalalgia : An International Journal of Headache (2007), 27(7), 803-808

Coppola G, Di Clemente L, Fumal A, Magis D, De Pasqua V, Pierelli F & Schoenen J. Inhibition of the nociceptive R2 blink reflex after supraorbital or index finger stimulation is normal in migraine without ... [more ▼]

Coppola G, Di Clemente L, Fumal A, Magis D, De Pasqua V, Pierelli F & Schoenen J. Inhibition of the nociceptive R2 blink reflex after supraorbital or index finger stimulation is normal in migraine without aura between attacks. Cephalalgia 2007; 27:803-808. London. ISSN 0333-1024 In order to explore possible interictal brainstem dysfunctions in migraine, we have studied the R2 component of the nociceptive specific blink reflex (nBR) after conditioning by supraorbital or index finger stimuli in 14 untreated migraine without aura patients (MO) between attacks and in 15 healthy volunteers. We determined the R2 recovery curve at increasing inter-stimulus intervals between 50 and 600 ms. The nBR was conditioned by a paired supraorbital stimulus and, in another session, by an ipsilateral electrical shock delivered to the index finger. The R2 nBR recovery curves were normal in MO patients for both the supraorbital and peripheral conditioning. These results do not favour persistent interictal sensitization in the spinal trigeminal sensory system. They also suggest that the control exerted by descending brainstem pathways on medullary R2 interneurones is normal in migraine between attacks. [less ▲]

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See detailSearch for correlations between the therapeutic response to riboavin and migraine mitochondrial abnormalities
Coppola, Gianluca; Di Lorenzo, Cherubino; Magis, Delphine ULg et al

in Cephalalgia : An International Journal of Headache (2007, June), 27(6), 590

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See detailPrevalence of patent foramen ovale and MRI white matter lesions in migraine with aura
Schoenen, Jean ULg; Magis, Delphine ULg; Fumal, Arnaud ULg et al

in Cephalalgia : An International Journal of Headache (2007, June), 27(6), 577-578

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See detailTranscutaneous temporal electrotherapy in chronic migraine: a pilot study of short term efficacy and mode of action
Bolla, M.; De Pasqua, Victor ULg; Gérardy, Pierre-Yves ULg et al

in Cephalalgia : An International Journal of Headache (2007, June), 27(6), 743-744

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See detailInterictal cognition in migraineurs: a study correlating psychometric and neurophysiological tests
Magis, Delphine ULg; Coppola, G.; Di Clemente, L. et al

in Cephalalgia : An International Journal of Headache (2007, June), 27(6), 714

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See detailOccipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study
Magis, Delphine ULg; Allena, Marta; Bolla, Monica et al

in Lancet Neurology (2007), 6(4), 314-321

Background Drug-resistant chronic duster headache (drCCH) is a devastating disorder for which various destructive procedures have been tried unsuccessfully. Occipital nerve stimulation (ONS) is a new ... [more ▼]

Background Drug-resistant chronic duster headache (drCCH) is a devastating disorder for which various destructive procedures have been tried unsuccessfully. Occipital nerve stimulation (ONS) is a new, safe strategy for intractable headaches. We undertook a prospective pilot trial of ONS in drCCH to assess clinical efficacy and pain perception. Methods Eight patients with drCCH had a suboccipital neurostimulator implanted on the side of the headache and were asked to record details of frequency, intensity, and symptomatic treatment for their attacks in a diary before and after Continuous ONS. To detect changes in cephalic and extracephalic pain processing we measured electrical and pressure pain thresholds and the nociceptive blink reflex. Findings Two patients were pain free after a follow-up of 16 and 22 months; one of them still had occasional autonomic attacks. Three patients had around a 90% reduction in attack frequency. Two patients, one of whom had had the implant for only 3 months, had improvement of around 40%. Mean follow-up was 15.1 months (SD 9.5, range 3-22). Intensity of attacks tends to decrease earlier than frequency during ONS and, on average, is improved by 50% in remaining attacks. All but one patient were able to substantially reduce their preventive drug treatment. Interruption of ONS by switching off the stimulator or because of an empty battery was followed within days by recurrence and increase of attacks in all improved patients. ONS did not significantly modify pain thresholds. The amplitude of the nociceptive blink reflex increased with longer durations of ONS. There were no serious adverse events. Interpretation ONS could be an efficient treatment for drCCH and could be safer than deep hypothalamic stimulation. The delay of 2 months or more between implantation and significant clinical improvement suggests that the procedure ads via slow neuromodulatory processes at the level of upper brain stem or diencephalic centres. [less ▲]

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See detailInterictal habituation deficit of the nociceptive blink reflex: an endophenotypic marker for presymptomatic migraine?
Di Clemente, L.; Coppola, G.; Magis, Delphine ULg et al

in Brain : A Journal of Neurology (2007), 130(Pt 3), 765-770

Habituation of the nociception-specific blink reflex (nBR) is reduced interictally in migraine patients. This could be related to the habituation deficit of evoked cortical responses, a reproducible ... [more ▼]

Habituation of the nociception-specific blink reflex (nBR) is reduced interictally in migraine patients. This could be related to the habituation deficit of evoked cortical responses, a reproducible abnormality in migraine which has a familial character, or to central trigeminal sensitization due to repeated attacks. We compared nBR habituation in healthy volunteers devoid of personal or family history of migraine (HV), in migraine without aura patients (MO) and in healthy volunteers with a family history of migraine in first degree relatives (HV-F). We elicited the nBR by stimulating the right supraorbital region with a custom-built electrode in 16 MO between attacks, 15 HV and 14 HV-F. Habituation was measured as the percentage area-under-the-curve decrease in 10 consecutive blocks of five averaged rectified responses. nBR habituation was clearly reduced in MO and HV-F compared to HV. Percentage area under the curve decreased between the 1st and the 10th block by 55.01% in HV, 25.71% in MO (P = 0.001) and 26.73% in HV-F (P = 0.043). HV-F had the most pronounced abnormality with potentiation instead of habituation in the second block. We found a positive intraindividual correlation between attack frequency and habituation in MO (r = 0.621; P = 0.010). Migraine patients have interictally a deficient habituation of the nBR which is inversely related to attack frequency, suggesting that it is not due to trigeminal sensitization. Surprisingly, the most pronounced habituation deficit is found in asymptomatic individuals with a family history of migraine. Deficient nBR habituation could thus be a trait marker for the genetic predisposition to migraine. [less ▲]

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See detailA randomized double-blind placebo-controlled trial of thioctic acid in migraine prophylaxis
Magis, Delphine ULg; Ambrosini, Anna; Sandor, Peter et al

in Headache (2007), 47(1), 52-57

BACKGROUND: Impaired mitochondrial phosphorylation potential may play a role in migraine pathogenesis. Metabolic enhancers, such as riboflavin or coenzyme Q, are effective in migraine prophylaxis and ... [more ▼]

BACKGROUND: Impaired mitochondrial phosphorylation potential may play a role in migraine pathogenesis. Metabolic enhancers, such as riboflavin or coenzyme Q, are effective in migraine prophylaxis and quasi-devoid of adverse effects. Thioctic acid (-lipoic acid) is another substance known to enhance energy metabolism in mitochondria and to be beneficial in diabetic neuropathy. OBJECTIVE: After an open pilot study suggesting its therapeutic antimigraine potentials, we embarked therefore in a randomized controlled trial of thioctic acid (Thioctacid) in migraine prophylaxis steered by the Belgian Headache Society. METHODS: Five Belgian centers recruited 54 migraineurs (43 migraine without aura, 11 with aura; mean age 38 +/- 8 years; 7 males). After a 1-month single-blinded run-in period, 44 patients received either placebo (n = 18) or thioctic acid 600 mg p.o./day (n = 26) for 3 months. RESULTS: Statistical analysis was carried out on an intention-to-treat basis. Monthly attack frequency tended to be reduced between run-in and the 3rd month of treatment in the thioctic acid group compared to placebo (P= .06). The proportion of 50% responders was not significantly different between thioctic acid (30.8%) and placebo (27.8%). Within-group analyses showed a significant reduction of attack frequency (P= .005), headache days (P= .009), and headache severity (P= .03) in patients treated with thioctic acid for 3 months, while these outcome measures remained unchanged in the placebo group. No adverse effects were reported. For logistical reasons this trial was interrupted before the planned 80 patients were enrolled. CONCLUSION: Albeit underpowered, this study tends to indicate that thioctic acid may be beneficial in migraine prophylaxis. Before any firm conclusion can be drawn, however, a large multicenter trial is necessary. [less ▲]

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