Monoclonal antibodies blocking CGRP transmission: An update on their added value in migraine prevention.

The avenue of effective migraine therapies blocking calcitonin gene-related peptide (CGRP) transmission is the successful outcome of 35 years of translational research. Developed after short-acting, the small antagonists of the CGRP receptor (the "gepants"), the monoclonal antibodies blocking CGRP or its receptor (CGRP/rec mAbs) have changed the paradigm in migraine treatment. Contrary to the classical acute medications like triptans or nonsteroidal anti-inflammatory drugs (NSAIDs) with a transient effect, they act for long durations exclusively in the peripheral portion of the trigeminovascular system and can thus be assimilated to a durable attack treatment, unlike the classical preventives that chiefly act upstream on the central facets of migraine pathophysiology. Randomized controlled trials (RCT) of eptinezumab, erenumab, fremanezumab and galcanezumab have included collectively several thousands of patients, making them the most extensively studied class of preventive migraine treatments. Their results clearly indicate that CGRP/rec mAbs are significantly superior to placebo and have been comprehensively reviewed by Dodick [Cephalalgia 2019;39(3):445-458]. In this review we will briefly summarize the placebo-subtracted outcomes and number-needed-to-treat (NNT) of these pivotal RCTs and analyze new and post-hoc studies published afterwards focusing on effect size, effect onset and sustainability, response in subgroups of patients, safety and tolerability, and cost-effectiveness. We will also summarize our limited real-world experience with one of the CGRP/rec mAbs. Although methodological differences and lack of direct comparative trials preclude any reliable comparison, the overall impression is that there are only minor differences in efficacy and tolerability profiles between the four monoclonals: the average placebo-subtracted 50% responder rates for reduction in migraine headaches are 21.4% in episodic migraine (NNTs: 4-5), 17.4% in chronic migraine (NNTs: 4-8). Patients with an improvement exceeding 50% are rare, chronic migraineurs with continuous headache are unlikely to be responders and migraine auras are not improved. The effect starts within the first week after administration and is quasi maximal at one month. It is sustained for long time periods and may last for several months after treatment termination. CGRP/rec mAbs are effective even after prior preventive treatment failures and in patients with medication overuse, but the effect size might be smaller. They significantly reduce disability and health care resource utilization. The adverse effect profile of CGRP/rec mAbs is close to that of placebo with few minor exceptions and despite concerns related to the safeguarding role of CGRP in ischemia, no treatment-related vascular adverse events have been reported to date. Putting the CGRP/rec mAbs in perspective with available preventive migraine drug treatments, their major advantage seems not to be chiefly their superior efficacy but their unprecedented efficacy over adverse event ratio. Regarding cost-effectiveness, preliminary pharmaco-economic analyses of erenumab suggest that it is cost-effective for chronic migraine compared to no treatment or to onabotulinumtoxinA, but likely not for episodic migraine unless attack frequency is high, indirect costs are considered and its price is lowered.

Desencadenantes migrañosos y habituación del potencial evocado visual. Definiendo subgrupos de pacientes / Migraine triggers and habituation of visual evoked potentials. Defining subset of patient

Identificar subgrupos específicos de pacientes dentro del espectro clínico de la migraña podría ayudar a personalizar el tratamiento de la misma. Definir perfiles de pacientes según su relación entre las características clínicas y los biomarcadores neurofisiológicos sería de suma importancia y es en gran medida un ámbito inexplorado. Los ataques de migraña pueden ser desencadenados por distintos factores, entre los cuales el estrés, los cambios hormonales, el ayuno y la falta de sueño son los mayormente asociados. Los desencadenantes de la migraña no forman parte de los criterios diagnósticos, pero pueden caracterizar subgrupos de pacientes. La deficiente habituación a los estímulos visuales repetidos es una característica neurofisiológica comúnmente encontrada en las cohortes de migraña, sin embargo, no se puede demostrar en todos los pacientes y no se ha reproducido en todos los estudios. Se puede suponer que los pacientes con diferentes perfiles de habituación pueden diferir por rasgos fenotípicos, como los desencadenantes de las crisis. Por ello nos propusimos estudiar qué asociación existe entre los desencadenantes del ataque de migraña y la habituación de los potenciales evocados visuales (PEV). (AU)

Identifying specific subsets of patients within the widespread clinical spectrum of migraine could help in developing a beneficial migraine treatment approach. The possibility of such categorization combining clinical features with accessible para-clinical tests remains quasi unexplored. Migraine attacks can be triggered by different factors, among which stress, hormonal changes, fasting, and lack of sleep are the most frequently referenced.1 Migraine triggers are not part of the diagnostic criteria for migraine, but they may characterize subgroups of patients. Also, deficient habituation to repeated stimulations is a neurophysiological feature commonly found in migraine cohorts, however it cannot be demonstrated in all patients and has not been reproduced in all studies. One may thus assume that patients with different habituation profiles might differ by phenotypic features, such as attack triggers. Therefore, we analyzed the visual evoked potentials habituation (VEP)4 profile in relation to the report of migraine triggers during a head-to-head, semi-structured interview, which preceded the neurophysiological recordings. (AU)

One-year prevalence of migraine using a validated extended French version of the ID Migraine™: A Belgian population-based study.

BACKGROUND: Country-specific prevalence data on migraine and comorbidities are vital to assess the public health burden of migraine and the corresponding resources required for proper management. Considering the absence of reliable statistics, this study aimed to estimate the one-year prevalence of migraine in Wallonia (Belgium) in relation to socio-demographic factors and several health indicators. METHODS: Among the 1071 people aged 20-69 years who participated in the NESCaV survey, 751 (70.1%) were screened for one-year migraine attacks using the "ef-ID Migraine", a validated, extended French version of the self-administered ID Migraine™ questionnaire. Socio-demographic and health data were collected with a self-administered questionnaire and a physical examination. RESULTS: The overall one-year prevalence of migraine was 25.8%; 40.8% of migraineurs reported visual symptoms compatible with an aura. The prevalence was higher in women than in men (33.9% vs. 17.9%, P<0.0001) and declined markedly after the age of 50 (P=0.005). Importantly, migraine was associated with the subjective feeling of poorer health (P=0.0004). No other socio-demographic factor or health indicator studied was significantly correlated with migraine. CONCLUSIONS: High prevalence of migraine and strong association with feeling of poor health should incite health authorities to institute more active public health and management policies with regards to the migraine problem.

Analysis and clinical correlates of 20 Hz photic driving on routine EEG in migraine.

Enhanced photic driving (PD) during high-frequency flicker stimulation, the so-called H response, is a classical feature of migraine patients between attacks, but is thought to be of poor clinical utility. Visual inspection of the EEG for its detection may not be reliable, however, data on its possible correlations with clinical features and migraine pathophysiology are scarce. We have compared visual inspection and EEG spectral analysis to detect abnormal PD in 280 consecutive migraine patients of our headache clinic (episodic migraine without aura, n = 171; chronic migraine, n = 48; migraine with aura, n = 61) and in a group of 24 non-migrainous neurological controls. Spectral frequency analyses were performed blindly by one of us (YF). On visual inspection, 50.4 % of migraineurs were thought to have increased 20 Hz PD. After spectral analysis, only 62.4 % of them had PD power superior to the mean + 95 % CI of the control group. Sensitivity of visually identified PD was 82.24 %, specificity 69.36 %. Increased PD on spectral analysis was more prevalent in episodic migraine than in chronic migraine, in patients with low attack frequency, in those with ictal autonomic symptoms in addition to nausea and in those with a strong family history of migraine. We confirm therefore that 20 Hz photic driving is of little diagnostic utility and its prevalence in migraine overestimated on visual inspection. Its presence on spectral analysis of the EEG, however, might be of pathophysiological interest, as it identifies subgroups of migraineurs of whom the common denominator could be lack of habituation of cortical responses during repetitive stimulation.

Brain functional connectivity and morphology changes in medication-overuse headache: Clue for dependence-related processes?

BACKGROUND: Several imaging studies have identified localized anatomical and functional brain changes in medication-overuse headache (MOH). OBJECTIVE: The objective of this article is to evaluate whole-brain functional connectivity at rest together with voxel-based morphometry in MOH patients, in comparison with episodic migraine (EM) patients and healthy controls (HCs). METHODS: Anatomical MRI and resting-state functional MRI scans were obtained in MOH patients (n = 17 and 9, respectively), EM patients (n = 18 and 15, respectively) and HCs (n = 17 and 17). SPM8 was used to analyze voxel-based morphometry and seed (left precuneus) to voxel connectivity data in the whole brain. RESULTS: Functional connectivity at rest was altered in MOH patients. Connectivity was decreased between precuneus and regions of the default-mode network (frontal and parietal cortices), but increased between precuneus and hippocampal/temporal areas. These functional modifications were not accompanied by significant gross morphological changes. Furthermore, connectivity between precuneus and frontal areas in MOH was negatively correlated with migraine duration and positively correlated with self-evaluation of medication dependence. Gray matter volumes of frontal regions, precuneus and hippocampus were also negatively related to migraine duration. Functional connectivity within the default-mode network appeared to predict anxiety scores of MOH patients while gray matter volumes in this network predicted their depression scores. CONCLUSIONS: Our data suggest that MOH is associated with functional alterations within intrinsic brain networks rather than with macrostructural changes. They also support the view that dependence-related processes might play a prominent role in its development and maintenance.

[Migraine: from genetics to environment]. / Les migraines: des gènes à l'environnement.

Migraine is a frequent neurological syndrome with a heterogenous clinical presentation. Its pathophysiology remains poorly understood but a genetic aetiology has been suspected for a long time, as well as a significant influence of the environment. Familial hemiplegic migraine belongs to monogenic migraines, which are very rare entities with an autosomal dominant transmission. In that type of migraine, environment has a minor role, even if some attack triggering factors have been identified. The common forms of migraines, with and without aura, episodic or chronic, are polygenic and the results of genetic studies concerning these migraines are rather disappointing. The recent use of genome-wide approaches (linkage analyses and genome wide association studies) opened new perspectives and more convincing results are eagerly awaited in the next years. The environmental contribution (endogenous or exogenous) is much more pronounced in the common forms of migraine, with the identification of numerous predisposing or triggering factors, among which only some can be avoided. Finally, a recent behavioural hypothesis coming from adaptative darwinian theories has proposed a genetic-environment integrative model for common migraine. The latter would result of hereditary physiological adaptative defence mechanisms which would be progressively impaired by repeated brain homeostasis imbalances due to the environment.

[Neurostimulation: which place in the treatment of refractory headaches?]. / La neurostimulation: quelle place dans les céphalées réfractaires?

The management of refractory headaches (migraine or cluster headache) is often challenging in clinical practice. Most of the time, these patients are "desperate" and have already tried all existing medications. Many progresses have recently been made in the therapeutic approach of these diseases, especially with the advent of neurostimulation techniques. In this review of the literature, we describe various neurostimulation methods which have been studied in clinical trials or case reports of refractory headaches. The most effective and best studied methods are occipital nerve stimulation (ONS) and hypothalamic deep brain stimulation (DBS), the latter being however at higher surgical risk. Hence, there is a new hope for patients with refractory headaches. Various clinical trials are still underway.

Habituation of evoked responses is greater in patients with familial hemiplegic migraine than in controls: a contrast with the common forms of migraine.

BACKGROUND: Familial hemiplegic migraine (FHM) is a rare, dominantly inherited subtype of migraine with transient hemiplegia during the aura phase. Mutations in at least three different genes can produce the FHM phenotype. The mutated FHM genes code for ion transport proteins that animal and cellular studies have associated with disturbed ion homeostasis, altered cellular excitability, neurotransmitter release, and decreased threshold for cortical spreading depression. The common forms of migraine are characterized interictally by a habituation deficit of cortical and subcortical evoked responses that has been attributed to neuronal dysexcitability. FHM and the common forms of migraine are thought to belong to a spectrum of migraine phenotypes with similar pathophysiology, and we therefore examined whether an abnormal habituation pattern would also be found in FHM patients. METHODS: In a group of genotyped FHM patients (five FHM-1, four FHM-2), we measured habituation of visual evoked potentials (VEP), auditory evoked potentials including intensity dependence (IDAP), the nociception-specific blink reflex (nsBR) and compared the results to a group of healthy volunteers (HV). RESULTS: FHM patients had a more pronounced habituation during VEP (P=0.025) and nsBR recordings (P=0.023) than HV. There was no difference for IDAP, but the slope tended to be steeper in FHM. CONCLUSION: Contrary to the common forms of migraine, FHM patients are not characterized by a deficient, but rather by an increased habituation in cortical/brain stem evoked activities. These results suggest differences between FHM and the common forms of migraine, as far as central neuronal processing is concerned.

Neurophysiological tests and neuroimaging procedures in non-acute headache (2nd edition).

BACKGROUND AND PURPOSE: A large number of instrumental investigations are used in patients with non-acute headache in both research and clinical fields. Although the literature has shown that most of these tools contributed greatly to increasing understanding of the pathogenesis of primary headache, they are of little or no value in the clinical setting. METHODS: This paper provides an update of the 2004 EFNS guidelines and recommendations for the use of neurophysiological tools and neuroimaging procedures in non-acute headache (first edition). Even though the period since the publication of the first edition has seen an increase in the number of published papers dealing with this topic, the updated guidelines contain only minimal changes in the levels of evidence and grades of recommendation. RESULTS: (i) Interictal EEG is not routinely indicated in the diagnostic evaluation of patients with headache. Interictal EEG is, however, indicated if the clinical history suggests a possible diagnosis of epilepsy (differential diagnosis). Ictal EEG could be useful in certain patients suffering from hemiplegic or basilar migraine. (ii) Recording evoked potentials is not recommended for the diagnosis of headache disorders. (iii) There is no evidence warranting recommendation of reflex responses or autonomic tests for the routine clinical examination of patients with headache. (iv) Manual palpation of pericranial muscles, with standardized palpation pressure, can be recommended for subdividing patient groups but not for diagnosis. Pain threshold measurements and EMG are not recommended as clinical diagnostic tests. (v) In adult and pediatric patients with migraine, with no recent change in attack pattern, no history of seizures, and no other focal neurological symptoms or signs, the routine use of neuroimaging is not warranted. In patients with trigeminal autonomic cephalalgia, neuroimaging should be carefully considered and may necessitate additional scanning of intracranial/cervical vasculature and/or the sellar/orbital/(para)nasal region. In patients with atypical headache patterns, a history of seizures and/or focal neurological symptoms or signs, MRI may be indicated. (vi) If attacks can be fully accounted for by the standard headache classification (IHS), a PET or SPECT scan will normally be of no further diagnostic value. Nuclear medical examinations of the cerebral circulation and metabolism can be carried out in subgroups of patients with headache for the diagnosis and evaluation of complications, when patients experience unusually severe attacks or when the quality or severity of attacks has changed. (vii) Transcranial Doppler examination is not helpful in headache diagnosis. CONCLUSION: Although many of the examinations described in the present guidelines are of little or no value in the clinical setting, most of the tools, including thermal pain thresholds and transcranial magnetic stimulation, have considerable potential for differential diagnostic evaluation as well as for the further exploration of headache pathophysiology and the effects of pharmacological treatment.

Post-mortem assessment of rat spinal cord injury and white matter sparing using inversion recovery-supported proton density magnetic resonance imaging.

STUDY DESIGN: This was an experimental study. OBJECTIVES: White matter sparing influences locomotor recovery after traumatic spinal cord injury (SCI). The objective of the present post-mortem magnetic resonance imaging (MRI) investigation was to assess the potential of a simple inversion recovery (IR) sequence in combination with high-resolution proton density (PD) images to selectively depict spared white matter after experimental SCI in the rat. SETTING: This study was conducted at University of Liège and Centre Hospitalier Universitaire, Liège, Belgium and Hasselt University, Diepenbeek, Belgium. METHODS: Post-mortem 9.4 tesla (T) MRI was obtained from five excised rat spines 2 months after compressive SCI. The locomotor recovery had been followed weekly using the standardized Basso-Beattie-Bresnahan scale. IR MRI was used to depict normal white matter as very hypo-intense. Preserved white matter, cord atrophy and lesion volume were assessed, and histology was used to confirm MRI data. RESULTS: MRI showed lesion severity and white matter sparing in accordance with the degree of locomotor recovery. IR MRI enhanced detection of spared and injured white matter by selectively altering the signal of spared white matter. Even subtle white matter changes could be detected, increasing diagnostic accuracy as compared to PD alone. MRI accuracy was confirmed by histology. CONCLUSION: High-resolution IR-supported PD MRI provides useful micro-anatomical information about white matter damage and sparing in the post-mortem assessment of chronic rat SCI.

EFNS guideline on the treatment of tension-type headache - report of an EFNS task force.

BACKGROUND: Tension-type headache (TTH) is the most prevalent headache type and is causing a high degree of disability. Treatment of frequent TTH is often difficult. OBJECTIVES: To give evidence-based or expert recommendations for the different treatment procedures in TTH based on a literature search and the consensus of an expert panel. METHODS: All available medical reference systems were screened for the range of clinical studies on TTH. The findings in these studies were evaluated according to the recommendations of the EFNS resulting in level A, B or C recommendations and good practice points. RECOMMENDATIONS: Non-drug management should always be considered although the scientific basis is limited. Information, reassurance and identification of trigger factors may be rewarding. Electromyography (EMG) biofeedback has a documented effect in TTH, whilst cognitive-behavioural therapy and relaxation training most likely are effective. Physical therapy and acupuncture may be valuable options for patients with frequent TTH, but there is no robust scientific evidence for efficacy. Simple analgesics and non-steroidal anti-inflammatory drugs are recommended for the treatment of episodic TTH. Combination analgesics containing caffeine are drugs of second choice. Triptans, muscle relaxants and opioids should not be used. It is crucial to avoid frequent and excessive use of analgesics to prevent the development of medication-overuse headache. The tricyclic antidepressant amitriptyline is drug of first choice for the prophylactic treatment of chronic TTH. Mirtazapine and venlafaxine are drugs of second choice. The efficacy of the prophylactic drugs is often limited, and treatment may be hampered by side effects.

[The anatomical laboratory: a tool for the trial of the new therapeutic procedures]. / Le laboratoire d'anatomie: un banc d'essai des nouvelles technologies.

Since September 2009, the new anatomical department is located on the CHU building. This modern anatomical laboratory is an effective tool to design the new therapeutic procedures and to teach these procedures to practitioners.

Tonabersat, a gap-junction modulator: efficacy and safety in two randomized, placebo-controlled, dose-ranging studies of acute migraine.

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.

Proposals for new standardized general diagnostic criteria for the secondary headaches.

Headache classification is a dynamic process through clinical testing and re-testing of current and proposed criteria. After publication of the second edition of the International Classification of Headache Disorders (ICHD-II), need arose for revisions in the classification of medication overuse headache and chronic migraine. These changes made apparent a further need for broader revisions to the standard formulation of diagnostic criteria for the secondary headaches. Currently, the fourth criterion makes impossible the definitive diagnosis of a secondary headache until the underlying cause has resolved or been cured or greatly ameliorated by therapy, at which time the headache may no longer be present. Given that the main purpose of diagnostic criteria is to enable a diagnosis at the onset of a disease in order to guide treatment, this is unhelpful in clinical practice. In the present paper we propose maintaining a standard approach to the secondary headaches using a set of four criteria A, B, C and D, but we construct these so that the requirement for resolution or successful treatment is removed. The proposal for general diagnostic criteria for the secondary headaches will be entered into the internet-based version of the appendix of ICHD-II. During 2009 the Classification Committee will apply the general criteria to all the specific types of secondary headaches. These, and other changes, will be included in a revision of the entire classification entitled ICHD-IIR, expected to be published in 2010. ICHD-IIR will be printed and posted on the website and will be the official classification of the International Headache Society. Unfortunately, it will be necessary to translate ICHD-IIR into the many languages of the world, but the good news is that no major changes to the headache classification are then foreseen for the next 10 years. Until the printing of ICHD-IIR, the printed ICHD-II criteria remain in place for all other purposes. We issue a plea to the headache community to use and study these proposed general criteria for the secondary headaches in order to provide more evidence for their utility-before their incorporation in the main body of the classification.

Glossopharyngeal neuralgia triggered by non-noxious stimuli at multiple cephalic and extracephalic sites.

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.

Implementation and evaluation of existing guidelines on the use of neurophysiological tests in non-acute migraine patients: a questionnaire survey of neurologists and primary care physicians.

BACKGROUND AND PURPOSE: The main aims of this study were to evaluate: the diffusion, use and perception of the usefulness of the 2004 EFNS guidelines on neurophysiological testing in non-acute headache patients; the frequency with which the different neurophysiological tests were recommended in non-acute migraine patients by physicians aware or unaware of the guidelines; and the appropriateness of the reasons given for recommending neurophysiological tests. METHODS: One hundred and fifty physicians selected amongst the members of the Italian societies of general practitioner (GPs), neurologists and headache specialists were contacted via e-mail and invited to fill in a questionnaire specially created for the study. RESULTS: Ninety-two percent of the headache specialists, 8.6% of the neurologists and 0% of the GPs were already aware of the EFNS guidelines. A significantly higher proportion of headache specialists had not recommended any neurophysiological tests to the migraine patients they had seen in the previous 3 months, whereas these tests had frequently been prescribed by the GPs and neurologists. Overall, 80%, 42% and 42.6% of the reasons given by headache specialists, neurologists and GPs, respectively, for recommending neurophysiological testing in their migraine patients were appropriate (P < 0.01). CONCLUSIONS: The diffusion of the EFNS guidelines on neurophysiological tests and neuroimaging procedures was found to be very limited amongst neurologists and GPs. The physicians aware of the EFNS guidelines recommended neurophysiological tests to migraine patients less frequently and more appropriately than physicians who were not aware of them. The most frequent misconceptions regarding neurophysiological tests concerned their perceived capacity to discriminate between migraine and secondary headaches or between migraine and other primary headaches.

Mitochondrial DNA haplogroups influence the therapeutic response to riboflavin in migraineurs.

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.

[Secondary amenorrhea and cerebral ventriculomegaly]. / Aménorrhée secondaire et ventriculomégalie cérébrale.

Cerebral ventriculomegaly and hydrocephalus are not frequently associated with endocrine disorders of the gonadotropic axis. The mechanism of this association is not clarified. The most probable cause is however a partial hypothalamic dysfunction. The examination of the few reported cases is in favour of this explanation. We present the case of a young woman with a cerebral ventriculomegaly and suffering from secondary amenorrhea. Shunt was not necessary from the neurological point of view, the problem of secondary amenorrhea and anovulatory infertility was solved by clomiphen citrate therapy.