[Integrating new migraine treatments into clinical practice (part 1) : management of acute migraine attack]. / Intégration des nouveaux anti-migraineux dans notre pratique clinique . Partie 1 : traitement de la crise de migraine.

Although migraine is one of the most common chronic diseases and is the subject of numerous studies, there is still a considerable proportion of patients who are not satisfied with their acute treatment. Left without any real new therapeutic option to offer patients since sumatriptan was introduced on the Belgian market 30 years ago, neurologists have recently seen a change in the therapeutic landscape with the advent of new specific acute treatments for migraine: gepants and ditans. Being the only ones currently available in Belgium, gepants (including the newly marketed rimegepant) bring added value to traditional treatments such as non-steroidal anti-inflammatory drugs and triptans. This is why it seemed useful to review the different therapeutic options available in Belgium today by including these new treatments and to propose a rational pharmacological approach to relieve acute migraine attack.

Bien que la migraine soit une des maladies chroniques les plus fréquentes et fasse l'objet de nombreuses recherches, il existe malheureusement encore une proportion importante de patients insatisfaits de leur traitement anti-douleur. Sans nouvelle vraie option thérapeutique à proposer aux patients depuis la mise sur le marché belge du sumatriptan voici 30 ans, le neurologue a vu récemment le paysage thérapeutique se modifier avec l'arrivée de nouveaux traitements spécifiques de la crise de migraine : les gépants et les ditans. Seuls disponibles pour le moment en Belgique, les gépants (avec notamment le rimégépant nouvellement commercialisé) apportent une plus-value aux traitements traditionnels que sont les anti-inflammatoires non stéroïdiens et les triptans. C'est la raison pour laquelle il nous a semblé utile de refaire le point sur les différentes options thérapeutiques disponibles aujourd'hui en Belgique en intégrant ces nouveaux traitements et de proposer une approche pharmacologique rationnelle pour soulager la douleur de la crise de migraine.

TMS of the occipital cortex induces tactile sensations in the fingers of blind Braille readers.

Various non-visual inputs produce cross-modal responses in the visual cortex of early blind subjects. In order to determine the qualitative experience associated with these occipital activations, we systematically stimulated the entire occipital cortex using single pulse transcranial magnetic stimulation (TMS) in early blind subjects and in blindfolded seeing controls. Whereas blindfolded seeing controls reported only phosphenes following occipital cortex stimulation, some of the blind subjects reported tactile sensations in the fingers that were somatotopically organized onto the visual cortex. The number of cortical sites inducing tactile sensations appeared to be related to the number of hours of Braille reading per day, Braille reading speed and dexterity. These data, taken in conjunction with previous anatomical, behavioural and functional imaging results, suggest the presence of a polysynaptic cortical pathway between the somatosensory cortex and the visual cortex in early blind subjects. These results also add new evidence that the activity of the occipital lobe in the blind takes its qualitative expression from the character of its new input source, therefore supporting the cortical deference hypothesis.

Interictal habituation deficit of the nociceptive blink reflex: an endophenotypic marker for presymptomatic migraine?

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.

[Epidemiology and economic repercussion of headache: an inquiery among the administrative and technical personnel of the Liège University]. / Epidémiologie et répercussions économiques des céphalées: une enquête parmi le personnel administratif, technique et ouvrier (PATO) de l'Université de Liège.

Headache is an important individual and societal burden. Despite an important prevalence, migraine remains an underdiagnosed and undertreated disease. Large population-based epidemiological studies are available in many countries, but not in Belgium. We decided to assess 1 year prevalence and loss of productivity due to headaches in a sample of workers representative of the active Belgian population, the employees and workers of Liège University (ULg). A structured questionnaire based on the diagnostic criteria of the International Headache Society (IHS) was sent to the 1467 members of the ULg personnel in 2002. Among them, 212 (14.5%) had suffered of at least one headache in the previous 12 months ; 163 (77%) fulfilled the criteria for migraine, 49 (23%) had other headache types. One year-prevalence was 13% for migraine, 3.9% for other headaches. Among migraineurs there were 83% females, 19% had migraine with aura and the majority (49%) had 1-2 attacks per month. Acute anti-migraine treatment was taken by 98% of migraineurs, among whom only 9% used triptans. Intake of acute treatment more than twice per week, which tends to chronify headaches, was mentioned by 29% of migraineurs. Although 35% of subjets reported more than 2 attacks per month, only 13% were taking preventive anti-migraine treatment. The correct diagnosis of migraine was known to 51% of migraineurs, while 28% of non-migraineurs thought they were suffering from migraine. During the 3 months preceding the survey, 60% of migraineurs had to reduce (48%) or totally interrupt work (12%) at ULg for at least 1 day. Taking into account the mean salary at the ULg, the cost due to lost productivity was estimated at 300,000 Euro per year. This cost could be more than halved by an adequate anti-migraine treatment.

[Migraine management: current trends and future prospects]. / Actualités thérapeutiques dans la migraine.

Despite its high prevalence and individual as well as societal burden, migraine remains underdiagnosed and undertreated. In recent years, the options for the management of migraine patients have greatly expanded. A number of drugs belonging to various pharmacological classes and deliverable by several routes are now available both for the acute and the preventive treatments of migraine. Nevertheless, disability and satisfaction remain low in many subjects because treatments are not accessible, not optimized, not effective or simply not tolerated. There is thus still considerable room for better education and for more efficient therapies. In spite of useful internationally accepted guidelines, anti-migraine treatment has to be individually tailored to each patient taking into account the migraine subtype, the ensuing disability, the patient's previous history and present expectations, and the comorbid disorders. In this article we will summarize the phenotypic presentations of migraine and review recommendations for acute and preventive treatment, highlighting recent advances which are relevant for clinical practice in terms of both diagnosis and management.

[Therapeutic potential of repetitive transcranial magnetic stimulation in brain disorders]. / La stimulation magnétique transcrânienne répétitive: thérapeutique d'avenir dans les pathologies cérébrales?

Transcranial magnetic stimulation (TMS), a non-invasive means of electrically stimulating neurons in the human cerebral cortex, is able to modify neuronal activity locally and at distant sites when delivered in series or trains of pulses (repetitive TMS). Research into clinical applications for TMS is very active and has the potential to provide useful data, but, to date, the results of blinded, sham-controlled trials do not provide clear evidence of beneficial effects that replace or even match the effectiveness of conventional treatments in any disorder. In this review, we discuss the clinical and scientific bases for the therapeutic use of TMS, and review the results of trials in psychiatric and neurological disorders to date.

Interictal abnormalities of gamma band activity in visual evoked responses in migraine: an indication of thalamocortical dysrhythmia?

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.

[Rhabdomyolysis and hypothyroidism]. / Le cas clinique du mois. Rhabdomyolyse et hypothyroïdie.

We describe the case of a 29 year old patient who presented severe myalgias and asthenia for 3 months. First biological assessment revealed muscular lysis and raised transaminases. The following complementary screening showed major hypothyroidism with the presence of anti-microsomes antibodies, a carpian canal syndrome and a left ventricular systolic dysfunction. A diagnosis of hypothyroidic rhabdomyolysis consecutive to a Hashimoto disease was then mash. Patient was treated by hormonal thyroid substitution with a progressive improvement of muscular symptoms to complete recovery, and a concomitant normalization of cardiac and thyroid functions.

Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and mode of action.

We enrolled six patients suffering from refractory chronic cluster headache in a pilot trial of neurostimulation of the ipsilateral ventroposterior hypothalamus using the stereotactic coordinates published previously. After the varying durations needed to determine optimal stimulation parameters and a mean follow-up of 14.5 months, the clinical outcome is excellent in three patients (two are pain-free; one has fewer than three attacks per month), but unsatisfactory in one patient, who only has had transient remissions. Mean voltage is 3.28 V, diplopia being the major factor limiting its increase. When the stimulator was switched off in one pain-free patient, attacks resumed after 3 months until it was turned on again. In one patient the implantation procedure had to be interrupted because of a panic attack with autonomic disturbances. Another patient died from an intracerebral haemorrhage that developed along the lead tract several hours after surgery; there were no other vascular changes on post-mortem examination. After 1 month, the hypothalamic stimulation induced resistance against the attack-triggering agent nitroglycerin and tended to increase pain thresholds at extracephalic, but not at cephalic, sites. It had no detectable effect on neurohypophyseal hormones or melatonin excretion. We conclude that hypothalamic stimulation has remarkable efficacy in most, but not all, patients with treatment-resistant chronic cluster headache. Its efficacy is not due to a simple analgesic effect or to hormonal changes. Intracerebral haemorrhage cannot be neglected in the risk evaluation of the procedure. Whether it might be more prevalent than in deep-brain stimulation for movement disorders remains to be determined.

[Medication overuse headache]. / Les céphalées par abus d'antalgiques. et d'anti-migraineux.

Medication overuse headache (MOH) insidiously evolves from episodic migraine or tension-type headache because of overconsumption of analgesics, ergotamine or triptans. It affects 1-2% of the general population, but 15-20% of patients attending specialized headache centers. The precise neurobiologic mechanisms underlying this complication of episodic headaches are not well understood. Abnormalities of central monoaminergic systems have been suggested and substance dependence is more frequent in personal and family histories of affected subjects. In a recent FDG-PET study of 16 migraineurs with MOH before and after analgesics withdrawal we found a persistent hypometabolism of the medial orbitofrontal cortex, comparable to the one described after withdrawal in substance abuse. The orbitofrontal cortex plays a pivotal role in drive, decision-making and drug dependence. We postulate that its hypoactivity predisposes certain migraineurs to MOH and to relapse after withdrawal. There is no unique management strategy for these patients, but medication withdrawal is a prerequisite for the effectiveness of preventive treatments and headache improvement.

[Tension-type headache]. / Céphalées de tension.

The diagnosis of tension-type headache (TTH), a heterogeneous syndrome, is mainly based on the absence of typical features found in other headaches such as migraine. However TTH is the most common headache as about 80 percent of the general population suffer from episodic TTH and 3 percent have chronic TTH (CTTH). The underlying pathophysiology is complex. The present consensus is that peripheral pain mechanisms most likely play a role in infrequent and frequent episodic TTH whereas central pain mechanisms play a more important role in CTTH. Ibuprofen (800 mg) is currently the leading choice for the treatment of acute TTH because of its very good gastro-intestinal tolerance, followed by sodium naproxen (825 mg). Tricyclic antidepressants are the most widely used first-line therapeutic agents for CTTH (amitriptyline is the most widely used). Other preventive treatments such as relaxation, muscular biofeedback and behavioural (cognitive) techniques have also showed efficacy. It is demonstrated that the combination of stress management therapy and a tricyclic is more effective in CTTH than either behavioral or drug treatment alone.

Motor and phosphene thresholds to transcranial magnetic stimuli: a reproducibility study.

OBJECTIVES: As repetitive transcranial magnetic stimulation (rTMS) is often applied on different days, it is of interest to know whether motor (MT) and phosphene (PT) thresholds are reproducible across time and whether the intensity determined on the first day can be used in subsequent sessions. METHODS: We studied MT and PT over 5 separate recordings in 10 healthy volunteers using a focal coil and a Magstim(Rapid stimulator. After the initial recording (session 1), the others (2 to 5) were performed respectively after 1 day, 7 days, 1 month and 4 months. RESULTS: Mean MT at rest were 65.30 +/- 5.54%, 65.7 +/- 7.18%, 60.4 +/- 4.27%, 61.8 +/- 4.34%, and 63 +/- 9.1% at sessions 1 to 5. Mean PT were 71.43 +/- 6.68%, 66.29 +/- 10.67%, 60.71 +/- 8.64%, 60.57 +/- 8.08%, and 68.71 +/- 15.48% at sessions 1 to 5. MT and PT were reproducible (ANOVA analysis), however, as shown by coefficients of variation, variability between the first 3 sessions exceeded 10% for MT in 3 subjects and in 4 subjects for PT. CONCLUSIONS: It seems preferable to determine thresholds and adapt output intensity of the stimulator at each rTMS session.

[Genetics of migraines: from ionic channels to single nucleotide polymorphisms?]. / La génétique des migraines: des canaux ioniques aux polymorphismes de nucléotide ?

Our knowledge about migraine pathogenesis has increased exponentially over the last decade and this greatly due to the advances in genetics. In familial hemiplegic migraine (FHM), the findings of mutations in the CACNA1A gene (19p13), coding for the pore-forming subunit (alpha1A) of neuronal voltage-dependent P/Q-type calcium channels (FHM1), and in the ATP1A2 gene (1q21-23), encoding the alpha2-subunit of the Na+, K+ ATPase ionic pump (FHM2) have focused attention on central nervous system ionic channels and helped to better understand FHM pathophysiology. A dysfunction of these channels modifies neuronal excitability (favouring spreading depression), chemical neurotransmission and, indirectly, neuronal metabolism. These channels may represent targets for novel anti-migraine drugs, which underscores their importance for the frequent forms of migraine (without or with aura). Studies of gene associations, neuromuscular transmission, cerebellar functions, neuronal excitability and metabolism and certain drug effects suggest indeed that ionic channels play a pathogenic role in migraine with aura patients. However, in the majority of patients they are probably not the sole culprit, since most of the frequent forms of migraine seem to have a more complex genetic predisposition based on a number of single nucleotide polymorphisms. The challenge for the next decade is to establish correlations between the geno- and the phenotype of migraine patients which needs more frequent and focused genetic studies and a more precise phenotype, based on clinical as well as on neurophysiologic and metabolic data.

[Neuroborreliosis]. / La neuroborréliose.

Lyme disease, or borreliosis, is an endemic affection in Belgium. It is transmitted by a spirochete, Borrelia burgdorferi. The particularity of the infecting genomic group, Borrelia garinii, implies that half of the reported cases of Lyme disease in our country have neurologic manifestations. Due to the marked clinical heterogeneity and the difficult serologic diagnosis, neuroborreliosis is often part of the differential diagnosis in neurology. The antibiotic treatment is necessary because it decreases the risk of more advanced stages of the disease. We hope that a vaccination will soon be available in Belgium.

[Clinical case of the month. Report of a case of antiphospholipid syndrome]. / Le cas clinique du mois. A propos d'un cas de syndrome des antiphospholipides.

This article reports a case of Anton-Babinski syndrome, due to right middle cerebral artery thrombosis and attributed to a likely primary antiphospholipid syndrome. It is always difficult to diagnose the latter, especially in the case of our patient who had a past history of multiple venous thromboses but also a heterozygosity for the mutation of the factor V of Leyden. We reviewed the literature dedicated to the prothrombotic events linked to the presence of these antiphospholipid antibodies: the lupus anticoagulant and the anticardiolipin antibodies.

Inhibition of the nociceptive R2 blink reflex after supraorbital or index finger stimulation is normal in migraine without aura between attacks.

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.

rTMS of the occipital cortex abolishes Braille reading and repetition priming in blind subjects.

To study the functional involvement of the visual cortex in Braille reading, we applied repetitive transcranial magnetic stimulation (rTMS) over midoccipital (MOC) and primary somatosensory (SI) cortex in blind subjects. After rTMS of MOC, but not SI, subjects made significantly more errors and showed an abolishment of the improvement in reading speed following repetitive presentation of the same word list, suggesting a role of the visual cortex in repetition priming in the blind.

Induction of long-lasting changes of visual cortex excitability by five daily sessions of repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers and migraine patients.

We have shown that in healthy volunteers (HV) one session of 1 Hz repetitive transcranial magnetic stimulation (rTMS) over the visual cortex induces dishabituation of visual evoked potentials (VEPs) on average for 30 min, while in migraineurs one session of 10 Hz rTMS replaces the abnormal VEP potentiation by a normal habituation for 9 min. In the present study, we investigated whether repeated rTMS sessions (1 Hz in eight HV; 10 Hz in eight migraineurs) on 5 consecutive days can modify VEPs for longer periods. In all eight HV, the 1 Hz rTMS-induced dishabituation increased in duration over consecutive sessions and persisted between several hours (n=4) and several weeks (n=4) after the fifth session. In six out eight migraineurs, the normalization of VEP habituation by 10 Hz rTMS lasted longer after each daily stimulation but did not exceed several hours after the last session, except in two patients, where it persisted for 2 days and 1 week. Daily rTMS can thus induce long-lasting changes in cortical excitability and VEP habituation pattern. Whether this effect may be useful in preventative migraine therapy remains to be determined.