Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1.
; ; et al
in Nature Genetics (2010), 42(10), 869-73
Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular ... [more ▼]
Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 x 10, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 x 10(1)(1) (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 x 10, permuted threshold for genome-wide significance 7.7 x 10. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine. [less ▲]Detailed reference viewed: 72 (2 ULg)
Abnormal cortical responses to somatosensory stimulation in medication-overuse headache.
; ; et al
in BMC neurology (2010), 10
BACKGROUND: Medication-overuse headache (MOH) is a frequent, disabling disorder. Despite a controversial pathophysiology convincing evidence attributes a pivotal role to central sensitization. Most ... [more ▼]
BACKGROUND: Medication-overuse headache (MOH) is a frequent, disabling disorder. Despite a controversial pathophysiology convincing evidence attributes a pivotal role to central sensitization. Most patients with MOH initially have episodic migraine without aura (MOA) characterized interictally by an absent amplitude decrease in cortical evoked potentials to repetitive stimuli (habituation deficit), despite a normal initial amplitude (lack of sensitization). Whether central sensitization alters this electrophysiological profile is unknown. We therefore sought differences in somatosensory evoked potential (SEP) sensitization and habituation in patients with MOH and episodic MOA. METHODS: We recorded median-nerve SEPs (3 blocks of 100 sweeps) in 29 patients with MOH, 64 with MOA and 42 controls. Episodic migraineurs were studied during and between attacks. We measured N20-P25 amplitudes from 3 blocks of 100 sweeps, and assessed sensitization from block 1 amplitude, and habituation from amplitude changes between the 3 sequential blocks. RESULTS: In episodic migraineurs, interictal SEP amplitudes were normal in block 1, but thereafter failed to habituate. Ictal SEP amplitudes increased in block 1, then habituated normally. Patients with MOH had larger-amplitude block 1 SEPs than controls, and also lacked SEP habituation. SEP amplitudes were smaller in triptan overusers than in patients overusing nonsteroidal anti-inflammatory drugs (NSAIDs) or both medications combined, lowest in patients with the longest migraine history, and highest in those with the longest-lasting headache chronification. CONCLUSIONS: In patients with MOH, especially those overusing NSAIDs, the somatosensory cortex becomes increasingly sensitized. Sensory sensitization might add to the behavioral sensitization that favors compulsive drug intake, and may reflect drug-induced changes in central serotoninergic transmission. [less ▲]Detailed reference viewed: 52 (1 ULg)
Sustained efficacy of occipital nerve stimulation in drug-resistant chronic cluster headache after up to 5 years treatment
Magis, Delphine ; ; et al
in Journal of Headache & Pain (2010), 11(Suppl 1), 15
Background. Drug-resistant chronic cluster headache (drCCH) is a devastating condition for which various invasive procedures have been tempted without any satisfactory effect. Our prospective pilot study ... [more ▼]
Background. Drug-resistant chronic cluster headache (drCCH) is a devastating condition for which various invasive procedures have been tempted without any satisfactory effect. Our prospective pilot study of great occipital nerve stimulation (ONS) in 8 drCCH patients showed encouraging results at 15 months (1). Methods. We recruited 15 patients with drCCH according to the previously published criteria of intractability (2). They were implanted with suboccipital stimulators on the side of their headache. Long-term follow-up was achieved by questionnaires administered during a headache consultation and/or by telephone interviews. Results. One patient had an immediate post operative infection of the material. Mean time with ONS was 28.8 months (range 3-60 months). Nine of the 14 remaining patients were totally pain-free (64%), 2 patients had an improvement in frequency exceeding 90% and one patient a 89% amelioration. Two patients did not respond or described mild improvement. Intensity of residual attacks was not improved by ONS. Four patients (29%) were able to reduce their prophylaxis. Common technical problems were battery depletion (N=8/14, 57%) and material infection (N=3/15, 20%). Recurrent battery replacement (until 2/ year in one patient) is now avoided by the availability of rechargeable batteries. Clinical peculiarities associated with ONS were occurrence of infrequent contralateral attacks (N=5/14, 36%), and/or isolated ispilateral autonomic attacks (N=5/14, 36%). Rapid attack recurrence after stimulator switch off was reported by 7/12 improved patients (58%). Two patients found ONS-related paresthesias unbearable; one had his stimulator removed, the other switched it off though he was objectively ameliorated. Subjectively, nine patients are very satisfied by ONS and one patient moderately satisfied. Conclusions. Our long-term follow-up confirms the efficacy of ONS in drCCH, which remains a safe and well-tolerated technique. The occurrence of contralateral attacks and isolated autonomic attacks in nearly 50% of ONS responders may have therapeutic and pathophysiological implications. [less ▲]Detailed reference viewed: 65 (4 ULg)
Central neuromodulation in cluster headache patients treated with occipital nerve stimulators: A PET study
Magis, Delphine ; Bruno, Marie-Aurélie ; Fumal, Arnaud et al
in Acta Neurologica Belgica (2010), 110(Suppl 1), 17
OBJECTIVES: Use functional brain imaging to explore activity changes in centres involved in trigeminal pain processing and control before and after occipital neurostimulation in drug-resistant chronic ... [more ▼]
OBJECTIVES: Use functional brain imaging to explore activity changes in centres involved in trigeminal pain processing and control before and after occipital neurostimulation in drug-resistant chronic cluster headache patients. BACKGROUND: Occipital nerve stimulation (ONS) provides relief to about 60% of patients suffering from drug-resistant chronic cluster headache (drCCH). Its mode of action, however, remains elusive, but the long latency to meaningful effect suggests that ONS induces slow neuromodulation. METHODS: Ten drCCH patients underwent an 18FDG-PET scan after ONS durations varying between 0 and 30 months. All were scanned with ongoing ONS (ON) and with the stimulator switched OFF. RESULTS: After 6-30 months of ONS, 3 patients were pain free and 4 had a ≥ 90% reduction of attack frequency (responders). In patients overall compared to controls, several areas of the pain matrix were hypermetabolic: ipsilateral hypothalamus, midbrain and ipsilateral lower pons. All normalized after ONS, except the hypothalamus. Switching ON or OFF the stimulator had little influence on brain glucose metabolism. The perigenual anterior cingulate cortex (PACC) was hyperactive in ONS responders compared to non-responders. INTERPRETATION AND CONCLUSIONS: Metabolic normalization in the pain neuromatrix and lack of short-term changes induced by the stimulation support the hypothesis that ONS acts in drCCH through slow neuromodulatory processes. Selective activation in responders of PACC, a pivotal structure in the endogenous opioid system, suggests that ONS may restore balance within dysfunctioning pain control centres. That ONS is nothing but a symptomatic treatment might be illustrated by the persistent hypothalamic hypermetabolism which could explain why autonomic attacks may persist despite pain relief and why cluster attacks recur shortly after stimulator arrest. [less ▲]Detailed reference viewed: 68 (4 ULg)
Neurostimulation therapy in intractable headaches.
Schoenen, Jean ; ; Magis, Delphine
in Handbook of clinical neurology / edited by P.J. Vinken and G.W. Bruyn (2010), 97
A proportion of chronic headache patients become refractory to medical treatment and severely disabled. In such patients various neurostimulation methods have been proposed, ranging from invasive ... [more ▼]
A proportion of chronic headache patients become refractory to medical treatment and severely disabled. In such patients various neurostimulation methods have been proposed, ranging from invasive procedures such as deep-brain stimulation to minimally invasive ones like occipital nerve stimulation. They have been applied in single cases or small series of patients affected with varying headache disorders: cervicogenic headache, hemicrania continua, posttraumatic headache, chronic migraine, and cluster headache. Although favorable results were reported overall, it is premature to consider neurostimulation as a treatment with established utility in refractory headaches. At present, the most detailed clinical studies have been performed in intractable chronic cluster headache (iCCH) patients, who represent about 1% of all chronic cluster headache (CCH) patients. Various lesional interventions have been attempted in these patients, none with lasting benefits. In recent years, non-destructive neurostimulation methods have raised new hope. Hypothalamic deep-brain stimulation (hDBS) acts rapidly and has lasting efficacy, but is not without risk. Occipital nerve stimulation (ONS) was studied in two trials on a total of 17 iCCH patients. Clinical efficacy was found to be very satisfactory by most patients and by the investigators. Although slightly less efficacious than hDBS, ONS has the advantage of being rather harmless and reversible. At this stage, it should be preferred as first-line invasive therapy for iCCH. Recent case reports mention the efficacy of supraorbital (SNS) and vagal (VNS) nerve stimulation. Whether these neurostimulation methods have a place in the management of iCCH patients remains to be determined. [less ▲]Detailed reference viewed: 40 (4 ULg)
Migraine - clinical neurophysiology.
; Magis, Delphine ; Schoenen, Jean
in Nappi, G.; Moskowitz, M. (Eds.) Headache (2010)
Central nervous system (CNS) dysfunction is thought to be pivotal in migraine, and could occur at several levels: the brain (the cortex and its connections with subcortical nuclei), the brainstem, and ... [more ▼]
Central nervous system (CNS) dysfunction is thought to be pivotal in migraine, and could occur at several levels: the brain (the cortex and its connections with subcortical nuclei), the brainstem, and even peripheral structures (e.g., trigeminal ganglion and nerve). As it is particularly suited to functional evaluation of various components of the nervous system, neurophysiological testing has become a valuable tool for investigating migraine pathophysiology and the effects of pharmacological treatment. However it has limited value for migraine diagnosis because of a high interindividual variability. In this chapter, we critically review and summarize the available published literature on neurophysiological approaches in migraine, i.e., electroencephalography, evoked and event-related potentials, transcranial magnetic stimulation (TMS), electromyography, and cerebellar testing. The most relevant techniques for understanding migraine pathophysiological mechanisms are highlighted. [less ▲]Detailed reference viewed: 62 (5 ULg)
Gender-Dependant Effect of Acute Dietary Tryptophan Depletion on Sensitivity to Cortical Spreading Depression in Rats
Chauvel, Virginie ; Multon, Sylvie ; Schoenen, Jean
Poster (2009, September)Detailed reference viewed: 19 (1 ULg)
Expression and role of Placental Growth Factor (PLGF) in the inflammatory context resulting from nerve injury, the Wallerian Degeneration.
Chaballe, Linda ; Wouters, Murielle ; Fanielle, Julien et al
Poster (2009, May 11)Detailed reference viewed: 26 (4 ULg)
Is hypoxia-inducible factor 1 an actor in migraine pathogenesis?
TRUONG, Julie ; ; Schoenen, Jean et al
Poster (2009, May)Detailed reference viewed: 29 (0 ULg)
Gender-Dependant Effect of Acute Dietary Tryptophan Depletion on Sensitivity to Cortical Spreading Depression in Rats
Chauvel, Virginie ; Multon, Sylvie ; et al
Poster (2009, May)Detailed reference viewed: 18 (0 ULg)
Occipital nerve stimulation for drug-resistant chronic cluster headache: long term follow-up up to 3 years
Gérardy, Pierre-Yves ; Magis, Delphine ; et al
in Cephalalgia : An International Journal of Headache (2009, January), 29(1),Detailed reference viewed: 92 (19 ULg)
Mitochondrial DNA haplogroups influence response to Riboflavin in Migraineurs
; ; et al
in Cephalalgia : An International Journal of Headache (2009, January), 29(1),Detailed reference viewed: 34 (5 ULg)
NG2 and phosphacan are present in the astroglial scar after human traumatic spinal cord injury.
; ; et al
in BMC Neurology (2009), 9
BACKGROUND: A major class of axon growth-repulsive molecules associated with CNS scar tissue is the family of chondroitin sulphate proteoglycans (CSPGs). Experimental spinal cord injury (SCI) has ... [more ▼]
BACKGROUND: A major class of axon growth-repulsive molecules associated with CNS scar tissue is the family of chondroitin sulphate proteoglycans (CSPGs). Experimental spinal cord injury (SCI) has demonstrated rapid re-expression of CSPGs at and around the lesion site. The pharmacological digestion of CSPGs in such lesion models results in substantially enhanced axonal regeneration and a significant functional recovery. The potential therapeutic relevance of interfering with CSPG expression or function following experimental injuries seems clear, however, the spatio-temporal pattern of expression of individual members of the CSPG family following human spinal cord injury is only poorly defined. In the present correlative investigation, the expression pattern of CSPG family members NG2, neurocan, versican and phosphacan was studied in the human spinal cord. METHODS: An immunohistochemical investigation in post mortem samples of control and lesioned human spinal cords was performed. All patients with traumatic SCI had been clinically diagnosed as having "complete" injuries and presented lesions of the maceration type. RESULTS: In sections from control spinal cord, NG2 immunoreactivity was restricted to stellate-shaped cells corresponding to oligodendrocyte precursor cells. The distribution patterns of phosphacan, neurocan and versican in control human spinal cord parenchyma were similar, with a fine reticular pattern being observed in white matter (but also located in gray matter for phosphacan). Neurocan staining was also associated with blood vessel walls. Furthermore, phosphacan, neurocan and versican were present in the myelin sheaths of ventral and dorsal nerve roots axons. After human SCI, NG2 and phosphacan were both detected in the evolving astroglial scar. Neurocan and versican were detected exclusively in the lesion epicentre, being associated with infiltrating Schwann cells in the myelin sheaths of invading peripheral nerve fibres from lesioned dorsal roots. CONCLUSION: NG2 and phosphacan were both present in the evolving astroglial scar and, therefore, might play an important role in the blockade of successful CNS regeneration. Neurocan and versican, however, were located at the lesion epicentre, associated with Schwann cell myelin on regenerating peripheral nerve fibres, a distribution that was unlikely to contribute to failed CNS axon regeneration. The present data points to the importance of such correlative investigations for demonstrating the clinical relevance of experimental data. [less ▲]Detailed reference viewed: 17 (2 ULg)
Tonabersat, a gap-junction modulator: efficacy and safety in two randomized, placebo-controlled, dose-ranging studies of acute migraine.
; Schoenen, Jean ; et al
in Cephalalgia : An International Journal of Headache (2009), 29 Suppl 2
Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of ... [more ▼]
Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis. [less ▲]Detailed reference viewed: 32 (1 ULg)
Glossopharyngeal neuralgia triggered by non-noxious stimuli at multiple cephalic and extracephalic sites.
; ; Schoenen, Jean
in Cephalalgia : An International Journal of Headache (2009), 29(11), 1174-9
Glossopharyngeal neuralgia (GN) triggered by non-noxious stimuli at multiple cephalic and extracephalic sites with positron emission tomography (PET) evidence for involvement of the upper brainstem has ... [more ▼]
Glossopharyngeal neuralgia (GN) triggered by non-noxious stimuli at multiple cephalic and extracephalic sites with positron emission tomography (PET) evidence for involvement of the upper brainstem has never been reported. We present such a patient, a 73-year-old man who since the age of 50 had suffered from GN with a high recurrence rate and very severe unilateral, non-familial GN episodes with very easy trigger zones widely extending beyond the n IX territory. Extensive neuroimaging and neurophysiological tests detected no precise underlying cause. PET scan revealed activation in the upper brainstem on extracephalic triggers. Single-fibre electromyography data will be discussed. We hypothesize that deficient inhibition as seen in trigeminal nociceptive reflexes on the level of brainstem interneurons, a functional lesion in the primary somatosensory cortex-sensory thalamic nuclei circuit and the dorsal column-thalamic pathway both activated by light touch may in part be involved in the extracephalic triggering. [less ▲]Detailed reference viewed: 66 (0 ULg)
Chronic tension-type headache: what is new?
; Schoenen, Jean
in Current Opinion in Neurology (2009), 22(3), 254-61
PURPOSE OF REVIEW: This review discusses current data on nosological boundaries related to diagnosis, pathophysiology and therapeutic strategies in chronic tension-type headache (CTTH). RECENT FINDINGS ... [more ▼]
PURPOSE OF REVIEW: This review discusses current data on nosological boundaries related to diagnosis, pathophysiology and therapeutic strategies in chronic tension-type headache (CTTH). RECENT FINDINGS: Diagnostic criteria of CTTH should be adapted to improve its sensitivity against migraine. It seems that mechanical pain sensitivity is a consequence and not a causative factor of CTTH. Recent evidence is modifying previous knowledge about relationships between muscle tissues and CTTH, suggesting a potential role of muscle trigger points in the genesis of pain. An updated pain model suggests that headache perception can be explained by referred pain from trigger points in the craniocervical muscles, mediated through the spinal cord and the trigeminal nucleus caudalis rather than only tenderness of the muscles themselves. Different therapeutic strategies, pharmacological, physical therapy, psychological and acupuncture, are generally used. The therapeutic efficacy of nonsteroidal anti-inflammatory drugs remains incomplete. The tricyclic antidepressants are the most used first-line therapeutic agents for CTTH. Surprisingly, few controlled studies have been performed and not all of them have found an efficacy superior to placebo. Further, there is insufficient evidence to support/refute the efficacy of physical therapy in CTTH. SUMMARY: Although there is an increasing scientific interest in CTTH, future studies incorporating subgroups of patients who will likely to benefit from a specific treatment (clinical prediction rules) should be conducted. [less ▲]Detailed reference viewed: 73 (3 ULg)
Mitochondrial DNA haplogroups influence the therapeutic response to riboflavin in migraineurs.
; ; 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 ▲]Detailed reference viewed: 55 (3 ULg)
Nitroglycerin sensitises in healthy subjects CNS structures involved in migraine pathophysiology: evidence from a study of nociceptive blink reflexes and visual evoked potentials.
; ; Magis, Delphine 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 ▲]Detailed reference viewed: 37 (1 ULg)
Habituation and migraine.
; ; Schoenen, Jean
in Neurobiology of Learning & Memory (2009), 92(2), 249-59
The most reproducible and ubiquitous interictal abnormality of the migraineurs' brain is lack of habituation in neuronal information processing. The underlying mechanisms are uncertain. Increased neuronal ... [more ▼]
The most reproducible and ubiquitous interictal abnormality of the migraineurs' brain is lack of habituation in neuronal information processing. The underlying mechanisms are uncertain. Increased neuronal excitability, decreased inhibition or decreased pre-activation levels have all been proposed as possible culprits. The present review summarizes the available data on habituation in migraine patients obtained with different methodological approaches. We will discuss the change of habituation level over the migraine cycle and we will show that these data congruently indicate that the sensory cortices of migraineurs react excessively to repetitive, but not to a small series of stimuli. Although the precise cellular and molecular mechanisms of this hyper-responsivity must still be determined, we will describe experimental data suggesting that a dysrhythmic thalamo-cortical activity due to inadequate monoaminergic control might be a plausible explanation. [less ▲]Detailed reference viewed: 35 (3 ULg)