Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies

Ataxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia. The gene APTX, which encodes aprataxin, has been identified recently. We studied a large series of 158 families with non‐Friedreich progressive ARCA. We identified 14 patients (nine families) with five different missense or truncating mutations in the aprataxin gene (W279X, A198V, D267G, W279R, IVS5+1), four of which were new. We determined the relative frequency of AOA1 which is 5%. Mutation carriers underwent detailed neurological, neuropsychological, electrophysiological, oculographic and biological examinations, as well as brain imaging. The mean age at onset was 6.8± 4.8 years (range 2-18 years). Cerebellar ataxia with cerebellar atrophy on MRI and severe axonal sensorimotor neuropathy were present in all patients. In contrast, oculomotor apraxia (86%), hypoalbuminaemia (83%) and hypercholesterolaemia (75%) were variable. Choreic movements were frequent at onset (79%), but disappeared in the course of the disease in most cases. However, a remarkably severe and persistent choreic phenotype was associated with one of the mutations (A198V). Cognitive impairment was always present. Ocular saccade initiation was normal, but their duration was increased by the succession of multiple hypometric saccades that could clinically be confused with ‘slow saccades'. We emphasize the phenotypic variability over the course of the disease. Cerebellar ataxia and/or chorea predominate at onset, but later on they are often partially masked by severe neuropathy, which is the most typical symptom in young adults. The presence of chorea, sensorimotor neuropathy, oculomotor anomalies, biological abnormalities, cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich's ataxia on a clinical basis. The frequency of chorea at onset suggests that this diagnosis should also be considered in children with chorea who do not carry the IT15 mutation responsible for Huntington's diseas

Physiopathologie de l'hypersensibilité intercritique aux odeurs dans la migraine

Ce travail de thèse vise à préciser les mécanismes physiopathologiques de l hypersensibilité intercritique aux odeurs décrite par les patients migraineux entre les crises. Notre première étude consiste à évaluer les capacités olfactives chez des patients migraineux pendant les périodes libres de crise grâce à l utilisation de tests olfactifs. Ce travail montre que les patients migraineux hypersensibles aux odeurs présentent une altération du jugement hédonique, suggérant une modification du traitement de l information olfactive au niveau du système nerveux central. L objectif de notre seconde étude est d explorer les régions cérébrales sous-tendant cette anomalie, en recherchant des anomalies des débits sanguins cérébraux au repos et lors de stimulations olfactives en tomographie par émission de positons (TEP). Nous observons chez les migraineux hypersensibles aux odeurs un hyperdébit localisé au niveau du cortex piriforme et du gyrus temporal antéro-supérieur gauches en condition de repos. Nous émettons l hypothèse que le cortex piriforme joue un rôle important dans les modifications du jugement hédonique et dans l activation du système trigémino-vasculaire chez les migraineux. Lors des stimulations olfactives, une perte de l activation physiologique est observée dans différentes régions corticales et sous-corticales, notamment le locus coeruleus qui joue un rôle important dans la physiopathologie de la crise migraineuse. Notre troisième étude a pour objectif d explorer la neurotransmission sérotoninergique chez les mêmes patients que ceux de l étude précédente, grâce à la TEP au [18F]MPPF marquant sélectivement les récepteurs 5-HT1A. Aucune anomalie n est retrouvée en période inter-critique, mais les quatre patients ayant présenté une crise de migraine déclenchée par les stimulations olfactives au cours de l examen présentent des anomalies des récepteurs 5-HT1A au niveau pontique, suggérant l implication de ces derniers dans les mécanismes conduisant au développement de la crise, possiblement via leur rôle neuromodulateur sur le système trigéminalThis thesis presents an original work that focuses on the pathophysiology of interictal olfactory hypersensitivity (OHS) in migraine patients. In the first study, we evaluate olfactory performances in migraineurs and control subjects and show that patients with OHS judge odours less pleasant than non-OHS patients and control subjects, suggesting an alteration of central olfactory processes. Our second study aims to determine brain areas involved in interictal OHS using a H215O-Positron Emission Tomography (PET) study. During both olfactory and non-olfactory stimulations, we observe an hyperperfusion localized in the left piriform cortex (PC) and anterior superior temporal gyrus in migraineurs with OHS compared to control subjects. We hypothesize that PC is particularly involved in the hedonic alteration observed in migraineurs with OHS between attacks and in activation of trigemino-vascular system in odour-triggered attacks. During olfactory stimulation, we observe a lack of normal activation in several cortical and sub-cortical areas, such as the right locus coeruleus. The aim of our third study is to evaluate brain serotonin distribution in the same subgroup of OHS migraineurs using PET with a selective 5-HT1A antagonist, the [18F]MPPF. No significant interictal [18F]MPPF BP change is observed between headache-free migraineurs and controls. Conversely, in four patients who present a migraine attack without aura during the PET study, analyses show a [18F]MPPF binding potential (BP) increase in the pontine raphe when compared to headache-free migraineurs and control subjects. These results highlight the role of 5HT1A receptors dependent neuromodulation in the pontine raphe nuclei during migraine attacks, possibly through their inhibitory descending projections on the trigeminal systemLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Migraine with brainstem aura: Why not a cortical origin?

International audienceBackground Migraine with brainstem aura is defined as a migraine with aura including at least two of the following symptoms: dysarthria, vertigo, tinnitus, hypacusis, diplopia, ataxia and/or decreased level of consciousness. Aim The aim of this study is to review data coming from clinical observations and functional mapping that support the role of the cerebral cortex in the initiation of brainstem aura symptoms. Results Vertigo can result from a vestibular cortex dysfunction, while tinnitus and hypacusis can originate within the auditory cortex. Diplopia can reflect a parieto-occipital involvement. Dysarthria can be caused by dysfunctions located in precentral gyri. Ataxia can reflect abnormal processing of vestibular, sensory, or visual inputs by the parietal lobe. Alteration of consciousness can be caused by abnormal neural activation within specific consciousness networks that include prefrontal and posterior parietal cortices. Conclusion Any symptom of so-called brainstem aura can originate within the cortex. Based on these data, we suggest that brainstem aura could have a cortical origin. This hypothesis would explain the co-occurrence of typical and brainstem aura during attacks and would fit with the theory of cortical spreading depression. We propose that migraine with brainstem aura should be classified as a typical migraine aura

Attention orienting dysfunction with preserved automatic auditory change detection in migraine.

International audienceOBJECTIVE:To investigate automatic event-related potentials (ERPs) to an auditory change in migraine patients.METHODS:Auditory ERPs were recorded in 22 female patients suffering from menstrually-related migraine and in 20 age-matched control subjects, in three sessions: in the middle of the menstrual cycle, before and during menses. In each session, 200 trains of tone-bursts each including two duration deviants were presented in a passive listening condition.RESULTS:In all sessions, duration deviance elicited a mismatch negativity (MMN) showing no difference between the two groups. However, migraine patients showed an increased N1 orienting component to all incoming stimuli and a prolonged N2b to deviance. They also presented a different modulation of P3a amplitude along the menstrual cycle, which tended to normalise during migraine attacks. None of the studied ERP components showed a default of habituation.CONCLUSIONS:This passive paradigm highlighted increased automatic attention orienting to auditory changes but normal auditory sensory processing in migraineurs.SIGNIFICANCE:Our observations suggest normal auditory processing up to attention triggering but enhanced activation of attention-related frontal networks in migraineurs

Is Migraine Associated to Brain Anatomical Alterations? New Data and Coordinate-Based Meta-analysis

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Top-down inhibition of irrelevant information indexed by alpha rhythms is disrupted in migraine

There is growing evidence that migraine is associated with attentional abnormalities, both during and outside migraine attacks, which would impact the cognitive processing of sensory stimulation. However, these attention alterations are poorly characterized and their neurophysiological basis is still unclear. Nineteen migraineurs without aura and nineteen healthy participants were recruited to perform a task which used visually-cued auditory targets and distracting sounds to evaluate conjointly top-down and bottom-up attention mechanisms. Magnetoencephalography (MEG) signals were recorded. We investigated anticipatory alpha activity (power increase and decrease) and distractor-induced gamma activity as markers for top-down (inhibition and facilitation) and bottom-up attention, respectively. Compared to healthy participants, migraineurs presented a significantly less prominent alpha power increase in visual areas in anticipation of the auditory target, indexing a reduced inhibition of task-irrelevant visual areas. However, there was no significant group difference regarding the alpha power decrease in the relevant auditory cortices in anticipation of the target, nor regarding the distractor-induced gamma power increase in the ventral attention network. These results in the alpha band suggest that top-down inhibitory processes in the visual cortices are deficient in migraine but there is no clear evidence supporting a disruption of top-down facilitatory attentional processes. This relative inability to suppress irrelevant sensory information may be underlying the self-reported increased distractibility and contribute to sensory disturbances in migraine

Self-perceived attention difficulties are associated with sensory hypersensitivity in migraine

Objectives: The aim of the study was to investigate potential interactions between sensory hypersensitivity and attentional difficulties in migraineurs. Methods: Forty-six episodic migraineurs without aura and 46 healthy controls filled out questionnaires on self-perceived attention difficulties and self-reported sensitivity to visual, auditory and olfactory stimulations. Results: Compared to controls, migraineurs reported significantly higher levels of attention difficulty and sensory sensitivity. Sensory hypersensitivity correlated significantly with attentional difficulties in migraineurs (p=0.002), but not with migraine disability or levels of anxiety or depression. Ictal and interictal sensory sensitivity were significantly correlated in migraineurs within visual (p<.001), auditory (p<.001) and olfactory (p=.001) modalities. Conclusion: Self-reported attentional difficulties, multimodal sensory hypersensitivity and the association between both may reflect the fact that external stimuli engage attention in an exacerbated manner in migraineurs, yielding distraction

Facial pain as first manifestation of anti-Hu paraneoplastic syndrome

The diagnosis of anti-Hu-associated encephalomyelitis/sensory neuropathy may be particularly difficult when cranial nerve involvement represents the first clinical manifestation of the disease. We report a case of a patient who presented with facial pain as the first manifestation of an anti-Hu paraneoplastic syndrome, which needs a rapid detection and treatment of the underlying tumour. We suggest that paraneoplastic neuropathy should be considered during the management of trigeminal neuropathic pain, especially when brain imagery is normal

Auditory attention alterations in migraine: A behavioral and MEG/EEG study

International audienceObjectives: To evaluate alterations of top-down and/or bottom-up attention in migraine and their cortical underpinnings.Methods: 19 migraineurs between attacks and 19 matched control participants performed a task evaluating jointly top-down and bottom-up attention, using visually-cued target sounds and unexpected task-irrelevant distracting sounds. Behavioral responses and magneto- and electro-encephalography signals were recorded. Event-related potentials and fields were processed and source reconstruction was applied to event-related fields.Results: At the behavioral level, neither top-down nor bottom-up attentional processes appeared to be altered in migraine. However, migraineurs presented heightened evoked responses following distracting sounds (orienting component of the N1 and Re-Orienting Negativity, RON) and following target sounds (orienting component of the N1), concomitant to an increased recruitment of the right temporo-parietal junction. They also displayed an increased effect of the cue informational value on target processing resulting in the elicitation of a negative difference (Nd).Conclusions: Migraineurs appear to display increased bottom-up orienting response to all incoming sounds, and an enhanced recruitment of top-down attention.Significance: The interictal state in migraine is characterized by an exacerbation of the orienting response to attended and unattended sounds. These attentional alterations might participate to the peculiar vulnerability of the migraine brain to all incoming stimuli