Publications by authors named "Caroline Tilikete"

71 Publications

Cranial Nerve Disorders Associated With Immune Checkpoint Inhibitors.

Neurology 2021 02 14;96(6):e866-e875. Epub 2020 Dec 14.

From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France.

Objective: To describe the spectrum, treatment, and outcome of cranial nerve disorders associated with immune checkpoint inhibitor (Cn-ICI).

Methods: This nationwide retrospective cohort study on Cn-ICI (2015-2019) was conducted using the database of the French Refence Center. In addition, a systematic review of the literature (MEDLINE, Scopus, and Web of Science) for records published between 2010 and 2019 was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the search terms cranial nerve or neuropathy or palsy and immune checkpoint inhibitors.

Results: Among 67 cases with ICI-related neurologic toxicities diagnosed in our reference center, 9 patients with Cn-ICI were identified (7 men, 78%, median age 62 years [range 26-82 years]). Patients were receiving a combination of anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed cell death 1 (PD-1)/PD-1 ligand (n = 5, 56%) or anti-PD-1 antibodies alone (n = 4, 44%). Cn-ICI involved optic (n = 3), vestibulocochlear (n = 3), abducens (n = 2), facial (n = 2), and oculomotor (n = 1) nerves. Two patients had involvement of 2 different cranial nerves. Treatment comprised corticosteroids (n = 8, 89%), ICI permanent discontinuation (n = 7, 78%), plasma exchange (n = 2, 22%), and IV immunoglobulin (n = 1, 11%). Median follow-up was 11 months (range 1-41 months). In 3 cases (33%), neurologic deficit persisted/worsened despite treatment: 2 optic and 1 vestibulocochlear. Among cases from the literature and the present series combined (n = 39), the most commonly affected cranial nerves were facial (n = 13, 33%), vestibulocochlear (n = 8, 21%), optic (n = 7, 18%), and abducens (n = 4, 10%). Trigeminal, oculomotor, and glossopharyngeal nerves were less frequently affected (total n = 7).

Conclusion: Cranial nerve disorders can complicate treatment with ICIs. Approximately one-third of the patients had persisting deficits, most frequently involving hearing and vision loss.
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http://dx.doi.org/10.1212/WNL.0000000000011340DOI Listing
February 2021

The role of the vestibular system in value attribution to positive and negative reinforcers.

Cortex 2020 Dec 2;133:215-235. Epub 2020 Oct 2.

Integrative Multisensory Perception Action & Cognition Team (ImpAct), INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center (CRNL), Lyon, France; University of Lyon, Lyon, France. Electronic address:

Somatic inputs originating from bioregulatory processes can guide cognition and behavior. One such bodily signal, mostly overlooked so far, is represented by visuo-vestibular coupling and its alteration, which in extreme cases may result in motion sickness. We argued that the inherently perturbed interoceptive state that follows can be a powerful determinant of human motivated behavior, resulting in a blunted response to appetitive stimuli and an exaggerated response to noxious ones. We sought to assess such differential impact of visuo-vestibular mismatches on value through a task involving conflict monitoring. We therefore administered to 42 healthy participants a modified version of the Flankers task, in which distractors (arrows, pointing in either a congruent or incongruent direction) signaled the availability of monetary incentives (gains, losses, or neutral trials). While performing the task, participants received either galvanic vestibular stimulation (GVS), or sham stimulation. We have found impaired behavioral performances when value, which was attached to task-irrelevant information, was at stake. Gains and losses, interestingly, dissociated, and only the latter caused enhanced interference costs in the task, suggesting that negative incentives may be more effective in capturing human attention than positive ones. Finally, we have found some weak evidence for GVS to further increase the processing of losses, as suggested by even larger interference costs in this condition. Results were, however, overall ambiguous, and suggest that much more research is needed to better understand the link between the vestibular system and motivation.
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http://dx.doi.org/10.1016/j.cortex.2020.09.004DOI Listing
December 2020

Cohort profile: a collaborative multicentre study of retinal optical coherence tomography in 539 patients with neuromyelitis optica spectrum disorders (CROCTINO).

BMJ Open 2020 10 29;10(10):e035397. Epub 2020 Oct 29.

Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

Purpose: Optical coherence tomography (OCT) captures retinal damage in neuromyelitis optica spectrum disorders (NMOSD). Previous studies investigating OCT in NMOSD have been limited by the rareness and heterogeneity of the disease. The goal of this study was to establish an image repository platform, which will facilitate neuroimaging studies in NMOSD. Here we summarise the profile of the Collaborative OCT in NMOSD repository as the initial effort in establishing this platform. This repository should prove invaluable for studies using OCT to investigate NMOSD.

Participants: The current cohort includes data from 539 patients with NMOSD and 114 healthy controls. These were collected at 22 participating centres from North and South America, Asia and Europe. The dataset consists of demographic details, diagnosis, antibody status, clinical disability, visual function, history of optic neuritis and other NMOSD defining attacks, and OCT source data from three different OCT devices.

Findings To Date: The cohort informs similar demographic and clinical characteristics as those of previously published NMOSD cohorts. The image repository platform and centre network continue to be available for future prospective neuroimaging studies in NMOSD. For the conduct of the study, we have refined OCT image quality criteria and developed a cross-device intraretinal segmentation pipeline.

Future Plans: We are pursuing several scientific projects based on the repository, such as analysing retinal layer thickness measurements, in this cohort in an attempt to identify differences between distinct disease phenotypes, demographics and ethnicities. The dataset will be available for further projects to interested, qualified parties, such as those using specialised image analysis or artificial intelligence applications.
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http://dx.doi.org/10.1136/bmjopen-2019-035397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597491PMC
October 2020

Outcomes of coronavirus disease 2019 in patients with neuromyelitis optica and associated disorders.

Eur J Neurol 2020 Oct 26. Epub 2020 Oct 26.

Service de Neurologie and CIC INSERM 1434, CHU de Strasbourg, Strasbourg, France.

Background: Outcomes of coronavirus disease 2019 (COVID-19) in patients with neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), often treated with immunosuppressive therapies, are still unknown.

Methods: We conducted a multicenter, retrospective, observational cohort study among all French expert centers for neuromyelitis optica and related disorders. Patients with NMOSD or MOGAD included in the study received a confirmed or highly suspected diagnosis of COVID-19 between 1 March 2020 and 30 June 2020. Main outcome was COVID-19 severity score assessed on a seven-point ordinal scale ranging from 1 (not hospitalized with no limitations on activities) to 7 (death).

Results: Fifteen cases (mean [SD] age: 39.3 [14.3] years, 11 female) were included. Five patients (33.3%) were hospitalized, all receiving rituximab. A 24-year-old patient with positive aquaporine-4 antibody, with obesity as comorbidity, needed mechanical ventilation. Outpatients were receiving anti-CD20 (5), mycophenolate mofetil (3) or azathioprine (3). They were younger (mean [SD] age: 37.0 [13.4] years), with a longer disease duration (mean [SD]: 8.3 [6.3] years) and had a lower expanded disability severity score (EDSS) score (median [range] EDSS: 2.5 [0-4]) relative to patients requiring hospitalization (mean [SD] age: 44.0 [16.4] years, mean [SD] disease duration: 5.8 [5.5] years, median [range] EDSS: 4 [0-6.5]).

Conclusions: COVID-19 outcome was overall favorable in this cohort. Larger international studies are needed to identify risk factors of severe COVID-19; however, we recommend personal protective measures to reduce risk of SARS-CoV-2 infection in this immunocompromised population.
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http://dx.doi.org/10.1111/ene.14612DOI Listing
October 2020

A key role for conservative treatment in the management of pituitary apoplexy.

Endocrine 2021 Jan 21;71(1):168-177. Epub 2020 Sep 21.

Hospices Civils de Lyon, Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, 59 Pinel Boulevard, 69677, Bron, France.

Purpose: The management of pituitary apoplexy, a rare emergency neuroendocrine condition, is controversial. The aim of the present study is to compare the outcomes of patients with pituitary apoplexy managed either by a conservative or surgical approach.

Methods: A retrospective cohort study including patients diagnosed between 2007 and 2018 in a tertiary French university hospital. Pituitary Apoplexy Score (PAS) was retrospectively applied in the perspective of therapeutic decision support.

Results: Forty-six patients were treated for pituitary apoplexy either with conservative management (n = 27) or surgery (n = 19). At initial evaluation, visual field defects (VFD) and visual acuity impairment were more frequent in patients from the surgery group. At 1 year there were no statistical differences in the rates of complete/near-complete resolution of VFD (100 vs. 91.7%), visual acuity impairment (100 vs. 87.5%), and cranial nerve palsies (83.3 vs. 100%), between conservative and surgical treatment groups. There were more endocrine deficits at 1 year in the surgical group (p = 0.029). PAS (n = 41) was 3.4 on average in the early surgery group and 1.3 in the conservative treatment/delayed surgery group. Among patients with a score < 4, 31.3% were operated at first line and did not present better outcomes than patients managed conservatively. In all, 88.9% of patients with a score ≥ 4 underwent surgery.

Conclusions: PAS may be a reliable parameter for defining therapeutic strategy. Patients with non-severe and nonprogressive neuro-ophthalmological deficits can be managed conservatively without negative impact on outcomes, thus surgery should be reserved only for those patients with a PAS ≥ 4.
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http://dx.doi.org/10.1007/s12020-020-02499-8DOI Listing
January 2021

Consensus on Virtual Management of Vestibular Disorders: Urgent Versus Expedited Care.

Cerebellum 2021 Feb;20(1):4-8

Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

The virtual practice has made major advances in the way that we care for patients in the modern era. The culture of virtual practice, consulting, and telemedicine, which had started several years ago, took an accelerated leap as humankind was challenged by the novel coronavirus pandemic (COVID19). The social distancing measures and lockdowns imposed in many countries left medical care providers with limited options in evaluating ambulatory patients, pushing the rapid transition to assessments via virtual platforms. In this novel arena of medical practice, which may form new norms beyond the current pandemic crisis, we found it critical to define guidelines on the recommended practice in neurotology, including remote methods in examining the vestibular and eye movement function. The proposed remote examination methods aim to reliably diagnose acute and subacute diseases of the inner-ear, brainstem, and the cerebellum. A key aim was to triage patients into those requiring urgent emergency room assessment versus non-urgent but expedited outpatient management. Physicians who had expertise in managing patients with vestibular disorders were invited to participate in the taskforce. The focus was on two topics: (1) an adequate eye movement and vestibular examination strategy using virtual platforms and (2) a decision pathway providing guidance about which patient should seek urgent medical care and which patient should have non-urgent but expedited outpatient management.
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http://dx.doi.org/10.1007/s12311-020-01178-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426203PMC
February 2021

Ocular Sarcoidosis.

Semin Respir Crit Care Med 2020 Oct 10;41(5):673-688. Epub 2020 Aug 10.

Department of Internal Medicine, Hopital de la Croix-Rousse, Université Claude Bernard Lyon I, Lyon, France.

Sarcoidosis is one of the leading causes of inflammatory eye disease. Any part of the eye and its adnexal tissues can be involved. Uveitis and optic neuropathy are the main manifestations, which may require systemic treatment. Two groups of patients with sarcoid uveitis can be distinguished: one of either sex and any ethnicity in which ophthalmological findings are various and another group of elderly Caucasian women with mostly chronic posterior uveitis. Clinically isolated uveitis revealing sarcoidosis remains a strictly ocular condition in a large majority of cases. Although it can be a serious condition involving functional prognosis, early recognition in addition to a growing therapeutic arsenal (including intravitreal implant) has improved the visual prognosis of the disease in recent years. Systemic corticosteroids are indicated when uveitis does not respond to topical corticosteroids or when there is bilateral posterior involvement, especially macular edema. In up to 30% of the cases that require an unacceptable dosage of corticosteroids to maintain remission, additional immunosuppression is used, especially methotrexate. As with other forms of severe noninfectious uveitis, monoclonal antibodies against tumor necrosis factor-α have been used. However, only very rarely does sarcoid uveitis fail to respond to combined corticosteroids and methotrexate therapy, a situation that should suggest either poor adherence or another granulomatous disease. Optic neuropathy often affects women of African and Caribbean origins. Some authors recommend that patients should be treated with high-dose of corticosteroids and concurrent immunosuppression from the onset of this manifestation, which is associated with a poorer outcome.
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http://dx.doi.org/10.1055/s-0040-1710536DOI Listing
October 2020

Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis.

JAMA Neurol 2020 09;77(9):1079-1088

Service de Neurologie, Clinical Investigation Center Institut National de la Santé et de la Recherche Médicale 1434, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France.

Importance: Risk factors associated with the severity of coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (MS) are unknown. Disease-modifying therapies (DMTs) may modify the risk of developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities.

Objective: To describe the clinical characteristics and outcomes in patients with MS and COVID-19 and identify factors associated with COVID-19 severity.

Design, Setting, And Participants: The Covisep registry is a multicenter, retrospective, observational cohort study conducted in MS expert centers and general hospitals and with neurologists collaborating with MS expert centers and members of the Société Francophone de la Sclérose en Plaques. The study included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020, and May 21, 2020.

Exposures: COVID-19 diagnosed with a polymerase chain reaction test on a nasopharyngeal swab, thoracic computed tomography, or typical symptoms.

Main Outcomes And Measures: The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1 [not hospitalized with no limitations on activities] to 7 [death]) with a cutoff at 3 (hospitalized and not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Scale score (EDSS; ranging from 0 to 10, with cutoffs at 3 and 6), comorbidities, COVID-19 characteristics, and outcomes. Univariate and multivariate logistic regression models were used to estimate the association of collected variables with COVID-19 outcomes.

Results: A total of 347 patients (mean [SD] age, 44.6 [12.8] years, 249 women; mean [SD] disease duration, 13.5 [10.0] years) were analyzed. Seventy-three patients (21.0%) had a COVID-19 severity score of 3 or more, and 12 patients (3.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 284 patients (81.8%) were receiving DMT. There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients with no DMT relative to patients receiving DMTs (46.0% vs 15.5%; P < .001). Multivariate logistic regression models determined that age (odds ratio per 10 years: 1.9 [95% CI, 1.4-2.5]), EDSS (OR for EDSS ≥6, 6.3 [95% CI. 2.8-14.4]), and obesity (OR, 3.0 [95% CI, 1.0-8.7]) were independent risk factors for a COVID-19 severity score of 3 or more (indicating hospitalization or higher severity). The EDSS was associated with the highest variability of COVID-19 severe outcome (R2, 0.2), followed by age (R2, 0.06) and obesity (R2, 0.01).

Conclusions And Relevance: In this registry-based cohort study of patients with MS, age, EDSS, and obesity were independent risk factors for severe COVID-19; there was no association found between DMTs exposure and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of patients with MS during the COVID-19 pandemic.
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http://dx.doi.org/10.1001/jamaneurol.2020.2581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320356PMC
September 2020

Visual Outcome Improvement in Tacrolimus-Related Bilateral Optic Neuropathy.

J Neuroophthalmol 2021 Mar;41(1):e22-e24

Hospices Civils de Lyon (MD, KT-ST, SR, VD, AV, CT), Neuro-Ophthalmology and Neuro-Cognitive Unit, Hôpital Neurologique Pierre Wertheimer, Bron, France; Lyon I University (VD, AV, CT), Lyon, France; and CRNL INSERM U1028 CNRS UMR5292 (AV, CT), ImpAct Team, Bron, France.

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http://dx.doi.org/10.1097/WNO.0000000000000859DOI Listing
March 2021

A Spatial Decision Eye-Tracking Task in Patients with Prodromal and Mild Alzheimer's Disease.

J Alzheimers Dis 2019 08;71(2):613-621

Université de Bordeaux, CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.

Background/objective: Performances on spatial decision eye-tracking tasks are known to be impaired in patients with moderate Alzheimer's disease (AD), but the clinical relevance of this deficit during earlier stages of AD remains unclear.

Methods: This study recruited patients with amnestic mild cognitive impairment (aMCI, prodromal AD), patients with mild AD, and age-matched controls from three French memory clinics. Participants' ability to make spatial judgments and decisions was assessed with an eye-tracking system, and cognitive performance on conventional neuropsychological tests was evaluated.

Results: We enrolled 26 controls, 25 aMCI patients (median Mini-Mental State Exam [MMSE] 26), and 23 mild-AD patients (median MMSE 23). Patients with mild AD had higher error rates on the spatial decision task than aMCI patients and controls (32.4% versus 23.5%; p < 0.01 and 32.4% versus 22.2%; p < 0.05, respectively), but there were no differences among the groups in anticipation rate or the percentage of express saccades. Additionally, error rates on the spatial decision task were inversely correlated with performance on visual memory tests (immediate and delayed recall on the DMS- 48: r =-0.44, p = 0.0019 and r =-0.43, p = 0.0020, respectively), semantic fluency (r =-0.44, p = 0.0016), and global cognition (MMSE: r =-0.44, p = 0.0019). Performance on the spatial decision task was not correlated with anti-saccades, processing speed, or attentional performance.

Conclusions: Patients with mild AD made more errors on a spatial decision task than aMCI patients and controls. We hypothesize that impaired visuospatial judgment may explain these results and distinguish aMCI patients from mild AD patients.
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http://dx.doi.org/10.3233/JAD-190549DOI Listing
August 2019

Gabapentin and Memantine for Treatment of Acquired Pendular Nystagmus: Effects on Visual Outcomes.

J Neuroophthalmol 2020 06;40(2):198-206

Hospices Civils de Lyon (EN, LA, FP-V, A-LV, AV, CT), Neuro-Ophthalmology and Neuro-Cognition Unit, Hôpital Neurologique Pierre Wertheimer, Bron, France; Lyon I University (EN, SV, JB, AV, CT), Lyon, France; Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Hôpital Neurologique Pierre Wertheimer, Bron, France; INSERM U1028 CNRS UMR5292 Lyon Neuroscience Center, Team ImpAct (AV, CT) and Observatoire Français de la Sclérose en Plaques (SV), Bron, France; Hospices Civils de Lyon (JB), Pôle Information Médicale Evaluation Recherche Unit, Equipe d'Accueil 4129, Bron, France; and Hospices Civils de Lyon (BC), Pharmacie Department, Hôpital Neurologique Pierre Wertheimer, Bron, France.

Background: The most common causes of acquired pendular nystagmus (APN) are multiple sclerosis (MS) and oculopalatal tremor (OPT), both of which result in poor visual quality of life. The objective of our study was to evaluate the effects of memantine and gabapentin treatments on visual function. We also sought to correlate visual outcomes with ocular motor measures and to describe the side effects of our treatments.

Methods: This study was single-center cross-over trial. A total of 16 patients with chronic pendular nystagmus, 10 with MS and 6 with OPT were enrolled. Visual acuity (in logarithm of the minimum angle of resolution [LogMAR]), oscillopsia amplitude and direction, eye movement recordings, and visual function questionnaires (25-Item National Eye Institute Visual Functioning Questionnaire [NEI-VFQ-25]) were performed before and during the treatments (gabapentin: 300 mg 4 times a day and memantine: 10 mg 4 times a day).

Results: A total of 29 eyes with nystagmus were evaluated. Median near monocular visual acuity improved in both treatment arms, by 0.18 LogMAR on memantine and 0.12 LogMAR on gabapentin. Distance oscillopsia improved on memantine and on gabapentin. Median near oscillopsia did not significantly change on memantine or gabapentin. Significant improvement in ocular motor parameters was observed on both treatments. Because of side effects, 18.8% of patients discontinued memantine treatment-one of them for a serious adverse event. Only 6.7% of patients discontinued gabapentin. Baseline near oscillopsia was greater among those with higher nystagmus amplitude and velocity.

Conclusions: This study demonstrated that both memantine and gabapentin reduce APN, improving functional visual outcomes. Gabapentin showed a better tolerability, suggesting that this agent should be used as a first-line agent for APN. Data from our investigation emphasize the importance of visual functional outcome evaluations in clinical trials for APN.
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http://dx.doi.org/10.1097/WNO.0000000000000807DOI Listing
June 2020

A new MRI marker of ataxia with oculomotor apraxia.

Eur J Radiol 2019 Jan 29;110:187-192. Epub 2018 Nov 29.

Hospices Civils de Lyon, Neurology D and Neuro-Ophthalmology Unit, Hôpital Neurologique Pierre Wertheimer, Bron, F-69677, France; Université de Lyon, Lyon 1 University, Lyon, F-69373, France; Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292, Team ImpAct, Bron, F-69676, France. Electronic address:

Purpose: Evaluate the specificity and sensitivity of disappearance of susceptibility weighted imaging (SWI) dentate nuclei (DN) hypointensity in oculomotor apraxia patients (AOA).

Method: In this prospective study, 27 patients with autosomal genetic ataxia (AOA (n = 11), Friedreich ataxia and ataxia with vitamin E deficit (n = 4), and dominant genetic ataxia (n = 12)) were included along with fifteen healthy controls. MRIs were qualitatively classified for the presence or absence of DN hypointensity on FLAIR and SWI sequences. The MRIs were then quantitatively studied, with measurement of a ratio of DN over brainstem white matter signal intensity through manual delineation. The institutional review board approved this study, and written informed consent was obtained. In the cross-sectional analysis, the Mann-Whitney test was applied.

Results: Qualitatively, the eleven AOA patients presented absence of both DN SWI and FLAIR hyposignals; three dominant genetic ataxia patients had moderate SWI DN hyposignal and absent FLAIR hyposignal; the thirteen remaining subjects presented normal SWI and FLAIR DN hyposignal. Absence of DN SWI hypointensity was 100% sensitive and specific to AOA. Quantitative signal intensity ratio (mean ± standard deviation) of the AOA group (98·96 ± 5·37%) was significantly higher than in control subjects group (76.40 ± 8.34%; p < 0.001), dominant genetic ataxia group (81·15 ± 9·94%; p < 0·001), and Friedreich ataxia and ataxia with vitamin E deficit group (87·56 ± 2·78%; p < 0·02).

Conclusion: This small study shows that loss of the normal hypointensity in the dentate nucleus on both SWI and FLAIR imaging at 3 T is a highly sensitive and specific biomarker for AOA.
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http://dx.doi.org/10.1016/j.ejrad.2018.11.035DOI Listing
January 2019

Balint syndrome in anti-NMDA receptor encephalitis.

Neurol Neuroimmunol Neuroinflamm 2019 01 13;6(1):e532. Epub 2018 Dec 13.

Service de neuro-ophtalmologie et neuro-cognition (A.M., A.V., C.T., V.D.), Hospices Civils de Lyon, hôpital neurologique Pierre Wertheimer; IMPACT-Integrative, Multisensory (L.P., A.V., C.T.), Perception, Action and Cognition Team, Centre de recherche des Neurosciences de Lyon (CRNL); Université Claude Bernard Lyon 1 (A.V., B.J., J.H., C.T., V.D.); Centre de référence français des syndromes paranéoplasiques (B.J., J.H.), Hospices Civils de Lyon, hôpital neurologique Pierre Wertheimer; and Institut NeuroMyoGene INSERM U1217/CNRS UMR 5310 (B.J., J.H., V.D.), équipe synaptopathies et anticorps (SYNATAC), Lyon, France.

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http://dx.doi.org/10.1212/NXI.0000000000000532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299677PMC
January 2019

Recurrent vertigo is a predictor of stroke in a large cohort of hypertensive patients.

J Hypertens 2019 05;37(5):942-948

Cardiology Department, European Society of Hypertension Excellence Center, Hôpital de la Croix-Rousse et Hôpital Lyon Sud, Hospices Civils de Lyon, Lyon.

Objective: Dizziness is associated with hypertension but there are numerous other causes. The aims of the present study were to describe the characteristics and the clinical correlates of dizziness in a large cohort of hypertensive patients, and to test its prognostic value for all-cause, cardiovascular, and stroke mortality.

Methods: A total of 1716 individuals from the OLD-HTA Lyon's cohort of hypertensive patients recruited in the 1970s were categorized according to the absence or the presence of dizziness. The dizziness group was subdivided into vertigo and other dizziness excluding vertigo.

Results: Multiple regression analysis demonstrated that presence of dizziness was predicted by age, female sex, coronary artery disease, and the absence of microalbuminuria. During 30 years of follow-up, we observed 956 deaths, 508 of which with a cardiovascular cause, and 114 fatal acute strokes. In the multivariate Cox regression model, the presence of dizziness had no impact on the risk for all-cause mortality [hazard ratio 0.91; 95% CI (0.78-1.06)], cardiovascular mortality [hazard ratio 0.86; 95% CI (0.70-1.05)], or stroke mortality [hazard ratio 1.27; 95% CI (0.85-1.90)]. In an analysis of the different subgroups of dizziness, only vertigo had a prognostic impact. The increased risk was particularly marked on stroke death with a hazard ratio of 2.43 (95% CI 1.33-4.46) vs. patients without dizziness and 2.22 (95% CI 1.21-4.06) vs. patients with dizziness excluding vertigo.

Conclusion: Hypertensive patients with dizziness did not have a high-risk profile at baseline, but those with vertigo must be carefully followed over years because of the higher stroke mortality.
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http://dx.doi.org/10.1097/HJH.0000000000001978DOI Listing
May 2019

Adult Niemann-Pick disease type C in France: clinical phenotypes and long-term miglustat treatment effect.

Orphanet J Rare Dis 2018 10 1;13(1):175. Epub 2018 Oct 1.

Reference Centre for Lysosomal Diseases (CRML), Department of Pediatric Neurology, and Sorbonne Université, GRC n°19, Pathologies Congénitales du Cervelet-LeucoDystrophies, AP-HP, Hôpital Armand Trousseau, F-75012, Paris, France.

Background: Niemann-Pick disease type C (NP-C) is a neurodegenerative lysosomal lipid storage disease caused by autosomal recessive mutations in the NPC1 or NPC2 genes. The clinical presentation and evolution of NP-C and the effect of miglustat treatment are described in the largest cohort of patients with adolescent/adult-onset NP-C studied to date.

Methods: Observational study based on clinical chart data from adult patients with NP-C (> 18 year old) diagnosed in France between 1990 and 2015. Retrospective data from patients at diagnosis, onset of miglustat therapy (if applicable), and last follow up were analysed.

Results: In France, patients with an adolescent-adult neurological form constituted approximately 25% of all NP-C cases diagnosed during the study period. Forty-seven patients (46 with NP-C1 and one with NP-C2; 53% female) were included. Mean ± SD (range) ages at neurological onset and diagnosis were 23.9 ± 12.5 (8-56) years and 34 ± 13.5 (15-65) years, respectively. At presentation, patients mainly had 1) impaired gait due to cerebellar ataxia and/or dystonia, 2) and/or cognitive/behavioural manifestations, 3) and/or psychotic signs. Initially, almost half of patients had only one of the above three neuro-psychiatric manifestations. Vertical supranuclear gaze palsy, usually occurring without patient complaint, was only detected on careful clinical examination and was recorded in most patients (93%) at the time of diagnosis, several years after neurological onset. Thirty-seven patients (79%) received miglustat, among whom seventeen (46%) continued beyond 2 years (at last follow up) to a maximum of 9.8 years. Eight patients (22%) discontinued treatment early due to side effects (n = 3) or perceived lack of efficacy (n = 5).Miglustat treatment duration correlated significantly with reduced neurological worsening (p < 0.001). Treatment for≥2 years was associated with improved patient survival (p = 0.029). Good responses to miglustat were associated with less severe neurological disability at the start of miglustat treatment (p = 0.02).

Conclusion: The proportion of adolescent/adult-onset NP-C cases diagnosed in France increased 2.5-fold since 2009 compared with the 2000-2008 period due to improved awareness. Adolescent/adult-onset NP-C frequently presented initially with a non-specific isolated neuro-psychiatric manifestation (motor, cognitive or psychotic). Patients with less severe neurological disability responded better to miglustat therapy.
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http://dx.doi.org/10.1186/s13023-018-0913-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167825PMC
October 2018

Prodromal Alzheimer's Disease Demonstrates Increased Errors at a Simple and Automated Anti-Saccade Task.

J Alzheimers Dis 2018 ;65(4):1209-1223

Institute for Neurodegenerative Diseases, Clinical Branch, University and University Hospital of Bordeaux, Bordeaux, France.

Saccade alterations are potential early signs of Alzheimer's disease. However, uncertainty persists in how early and reliably automated saccade recording systems detect impairments. This multicenter pathophysiological case-control transversal study explored saccade execution in carefully diagnosed amnestic mild cognitive impairment patients fulfilling research criteria for prodromal Alzheimer's disease (n = 29), as compared to both aged-matched mild Alzheimer's disease patients (n = 23) and controls (n = 27). Auto-coded saccades from horizontal (gap) vertical (step) stimulus elicited pro-saccades, and anti-saccade (gap) tasks were compared across the 3 groups. Mild cognitive impairment patients committed significantly more anti-saccade errors compared to controls (46.9 versus 24.3%, p < 0.001). Conventional analyses of the auto-coded stimulus elicited saccades parameters did not distinguish the amnestic mild cognitive impairment from controls or the mild Alzheimer's disease group. However, an offline analysis of manually coded saccade latencies, using resampling statistics did reveal subtle differences among the groups. Analysis of the manually coded data revealed that the mild Alzheimer's disease group had a reliably larger self-corrected error-rate than in amnestic mild cognitive impairment and controls (p = 0.003). Analysis of the manually coded saccade latencies, using more sensitive lognormal bootstrap analysis revealed a continuum, from amnestic mild cognitive impairment to mild Alzheimer's disease, of an increased severity of impaired inhibition of stimulus elicited saccades and correct voluntary saccade initiation. Anti-saccade error rates and psychometric measures of executive and several other cognitive functions were moderately and negatively correlated. Overall, inhibitory impairments in stimulus elicited saccades, characteristic of Alzheimer's disease, may be detected early in presumed prodromal patients using a simple, automated anti-saccade task.
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http://dx.doi.org/10.3233/JAD-180082DOI Listing
August 2019

Bilateral Vestibulopathy: Vestibular Function, Dynamic Visual Acuity and Functional Impact.

Front Neurol 2018 10;9:555. Epub 2018 Jul 10.

INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Equipe IMPACT, Lyon, France.

Patients suffering from bilateral vestibular hypofunction (BVH) often experience ataxia as well as visual instability. Even though progress has been made in vestibular testing, insights regarding vestibular deficit in BVH remain incomplete since no method allows evaluation of frequency ranges of vestibular sensors in a continuous way. The aim of our study was to give a detailed description of the level of vestibular deficit in different ranges of vestibular stimulation and an exhaustive evaluation of the functional impact including dynamic visual acuity (DVA) in a cohort of BVH patients in different etiologies. We prospectively included 20 patients with chronic BVH. All patients underwent clinical evaluation and functional assessment including evaluation of their symptoms related to BVH, quality of life questionnaire and DVA in the horizontal and vertical plane. Patients underwent vestibulo-ocular reflex (VOR) testing using rotatory chair, caloric stimulation and video head impulse (vHIT) in the plane of the 6 canals, and cervical and ocular Vestibular evoked myogenic potentials. Mean rotatory VOR gain was 0.07 ( = 0.07). Mean rotatory VOR gain during vHIT for the lateral, anterior and posterior canals was respectively < 0.28, < 0.34, and < 0.20. Mean loss of DVA in the 4 directions was >0.30 LogMAR. In our population fall frequency was significantly higher in patients with lower UniPedal Stance Test (UPST), higher Dizziness Handicap Inventory and Ataxia Numeric Scale (ANS) scores, as well as greater loss of upwards DVA. Patients with ototoxic BVH had a significantly higher residual VOR gain during vHIT in the anterior canal plane and lower DHI than other patients. In the general population anterior canal function was significantly higher than lateral or posterior canal function. This study gives extensive descriptive results of residual vestibular function, DVA and quality of life in a population of patients suffering from severe BVH. UPST and ANS are good indicators for fall risk in case of BVH. Gentamicin induced BVH seems to have a lesser impact on quality of life than other etiologies.Anterior semi-circular canal function seems less deteriorated than lateral and posterior function.
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http://dx.doi.org/10.3389/fneur.2018.00555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048872PMC
July 2018

Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: The MOGADOR study.

Neurology 2018 05 25;90(21):e1858-e1869. Epub 2018 Apr 25.

Objective: To describe clinical and radiologic features associated with myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) in a large French nationwide adult cohort, to assess baseline prognostic features of MOG-Ab-associated diseases after a first acute demyelinating syndrome, and to evaluate the clinical value of MOG-Ab longitudinal analysis.

Methods: Clinical data were obtained from 197 MOG-Ab-positive patients ≥18 years of age. Complete imaging data were available in 108, and 54 serum samples were eligible for longitudinal evaluation. For survival analysis comparison, 169 aquaporin-4 antibody (AQP4-Ab)-positive patients from the NOMADMUS database were included.

Results: Median age at onset was 36.46 (range 18.0-76.8) years, and patients were predominantly white (92.9%) with male:female ratio, 1.1. Clinical phenotype at onset included optic neuritis or myelitis in 90.86%, isolated brainstem or encephalopathy syndromes in 6.6%, and a combination of syndromes in 2.5%. Distinctive brain MRI findings in MOG-Ab-positive patients were thalamic and pontine lesions. Cortical and leptomeningeal lesions were found in 16.3% and 6.1%, respectively. The probability of reaching a first relapse after 2 and 5 years was 44.8% and 61.8%, respectively. MOG-Ab-positive patients were at lower risk at presentation of further clinical relapse (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.26-0.79) compared to AQP4-Ab-positive individuals. MOG-Ab-positive individuals had a lower risk of reaching Disability Status Scale score of 3.0 (HR 0.46, 95% CI 0.22-0.94) and visual acuity of 20/100 (HR 0.23, 95% CI 0.07-0.72). Finally, MOG-Ab titers were higher at relapse than in remission ( = 0.009).

Conclusion: In adults, MOG-Ab-associated disease extends beyond clinical and radiologic abnormalities in the optic nerve and spinal cord. Despite the relapsing course, the overall visual and motor outcome is better compared with AQP4-Ab-positive patients.
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http://dx.doi.org/10.1212/WNL.0000000000005560DOI Listing
May 2018

Probing the role of the vestibular system in motivation and reward-based attention.

Cortex 2018 06 27;103:82-99. Epub 2018 Feb 27.

Integrative Multisensory Perception Action & Cognition Team (ImpAct), INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center (CRNL), Lyon, France; University of Lyon 1, Lyon, France. Electronic address:

The vestibular system has widespread connections in the central nervous system. Several activation loci following vestibular stimulations have been notably reported in deep, limbic areas that are otherwise difficult to reach and modulate in healthy subjects. Following preliminary evidence, suggesting that such stimulations might affect mood and affective processing, we wondered whether the vestibular system is also involved in motivation. Evolutionary accounts suggest that visuo-vestibular mismatches might have a role in preventing the search for and exploitation of goods that previously resulted in aversive reactions, as they would be a fine warning signal which follows the contact with or ingestion of noxious neurotoxins. The first question was thus whether vestibular stimulation alters sensitivity to reward. Secondly, we sought to assess whether attention is allocated in space differently when cued by highly motivational stimuli, and if this interplay is further modulated by the vestibular system. In order to evaluate both motivational and attentional assets, we administered a Posner-like cueing task to 30 healthy subjects concurrently receiving sham or galvanic vestibular stimulation (GVS; Left-Anodal and Right-Anodal configurations). The participants had to discriminate targets appearing in either exogenously cued or uncued locations (50% validity); cues predicted the amount of points (0, 2, or 10) and thus money that they could earn for a correct response. The results highlight a robust inhibition of return (IOR) (faster responses for invalidly-cued targets) which was not modulated by different levels of reward or GVS. Across all stimulation sessions, rewards exerted a powerful beneficial effect over performance: reaction times were faster when rewards were at stake. However, this effect was largest in sham, but greatly reduced in GVS conditions, most notably with the Right-Anodal configuration. This is the first evidence for a decreased sensitivity to rewards causally induced by a perturbation of the vestibular system. While future studies will shed light on its neural underpinnings and clinical implications, here we argue that GVS could be a safe and promising way to enrich our understanding of reward processes and eventually tackle the management of patients with aberrant sensitivity to rewards.
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http://dx.doi.org/10.1016/j.cortex.2018.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002611PMC
June 2018

Cyclosporine A does not prevent second-eye involvement in Leber's hereditary optic neuropathy.

Orphanet J Rare Dis 2018 02 17;13(1):33. Epub 2018 Feb 17.

Service d'Ophtalmologie, CHU Angers, 49000, Angers, France.

Backrground: Evaluation of the efficacy of oral cyclosporine A as a prophylactic agent in preventing second-eye involvement in Leber's hereditary optic neuropathy (LHON) in a prospective, open-label, non-randomized, multicenter pilot study. Only LHON patients aged 18 years or more, with confirmed primary mitochondrial DNA mutations and strictly unilateral optic neuropathy occurring within 6 months prior to enrolment, were included in the study. All these patients, receiving treatment with oral cyclosporine (Neoral®, Novartis) at 2.5 mg/kg/day, were examined at three-month intervals for a year. The primary endpoint was the best corrected visual acuity in the unaffected eye; the secondary endpoints were the best corrected visual acuity in the first eye affected, the mean visual field defect on automated perimetry, the thickness of the perifoveal retinal ganglion cell inner plexiform layer, and the thickness of the peripapillary retinal nerve fiber layer in both eyes.

Results: Among the 24 patients referred to our institution with genetically confirmed LHON, between July 2011 and April 2014, only five patients, four males and one female, fulfilled the inclusion criteria. Age at enrolment ranged from 19 to 42 years (mean: 27.2 years; median: 26 years), four patients harbored the m.11778G > A pathogenic variant, and one the m.14484 T > C pathogenic variant. The time-interval between the onset of symptoms and inclusion in the study ranged from 7 to 17 weeks (mean: 11.8 weeks; median: 9 weeks). Despite treatment with oral cyclosporine A, all patients eventually experienced bilateral eye involvement, occurring within 11-65 weeks after the initiation of treatment. Over the study time period, the average best corrected visual acuity worsened in the first eye affected; by the end of the study, both eyes were equally affected.

Conclusions: Oral cyclosporine, at 2.5 mg/kg/day, did not prevent second-eye involvement in patients with strictly unilateral Leber's hereditary optic neuropathy.

Trial Registration: ClinicalTrials.gov Identifier: NCT02176733 . Registrated June 25, 2014.
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http://dx.doi.org/10.1186/s13023-018-0773-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816422PMC
February 2018

Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1.

JAMA Neurol 2018 04;75(4):495-502

Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Importance: Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels.

Objectives: To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations.

Design, Setting, And Participants: This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016.

Main Outcomes And Measures: The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations.

Results: The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P < .01). Decreased albumin levels (ρ = -0.532) and elevated AFP levels (ρ = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001).

Conclusions And Relevance: The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.
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http://dx.doi.org/10.1001/jamaneurol.2017.4373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933354PMC
April 2018

Brain volumetric analysis and cortical thickness in adults with saccadic intrusions (ocular flutter or opsoclonus-myoclonus syndrome).

Clin Neurol Neurosurg 2017 Dec 31;163:167-172. Epub 2017 Oct 31.

Department of Neurology 2, Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris (AP-HP), 75013, Paris, France; Sorbonne Universités, Université Pierre et Marie Curie, Université Paris VI, 75013, Paris, France; Institut du Cerveau et de la Moelle Epinière, INSERM U1127 and Centre National de la Recherche Scientifique, Unité de Recherche Mixte, 7225, Paris, France. Electronic address:

Objectives: Ocular flutter (OF) and opsoclonus are considered a continuum with a similar pathogenesis. Due to the rarity of this disease in the adult population, little is known about the brain morphological changes in the chronic phase of the disease.

Patients And Methods: Six magnetic resonance imaging from adults with previous history of OF/Opsoclonus and 12 healthy patients (paired by age and sex) were analyzed in order to identify the long term cortical thickness pattern in this rare disease by using Freesurfer.

Results: Patients with OF/Opsoclonus showed reduced cerebellum cortical volume with a subsequent diminution in total cerebellar volume. White mater cerebellum volume was not modified. In addition, we have also identified a significant supratentorial gray matter volume decrease in OF/Opsoclonus patients, involving both the cortical and the subcortical gray matter.

Conclusions: OF/Opsoclonus in adults may be associated with cortical and subcortical gray matter atrophy, as well as decreased cerebellar cortical volume. Further larger prospective studies are necessary to confirm these results.
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http://dx.doi.org/10.1016/j.clineuro.2017.10.028DOI Listing
December 2017

Hypertrophic Olivary Degeneration and Palatal or Oculopalatal Tremor.

Front Neurol 2017 29;8:302. Epub 2017 Jun 29.

Neuro-Ophthalmology and Neurocognition, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France.

Hypertrophic degeneration of the inferior olive is mainly observed in patients developing palatal tremor (PT) or oculopalatal tremor (OPT). This syndrome manifests as a synchronous tremor of the palate (PT) and/or eyes (OPT) that may also involve other muscles from the branchial arches. It is associated with hypertrophic inferior olivary degeneration that is characterized by enlarged and vacuolated neurons, increased number and size of astrocytes, severe fibrillary gliosis, and demyelination. It appears on MRI as an increased T2/FLAIR signal intensity and enlargement of the inferior olive. There are two main conditions in which hypertrophic degeneration of the inferior olive occurs. The most frequent, studied, and reported condition is the development of PT/OPT and hypertrophic degeneration of the inferior olive in the weeks or months following a structural brainstem or cerebellar lesion. This "symptomatic" condition requires a destructive lesion in the Guillain-Mollaret pathway, which spans from the contralateral dentate nucleus the brachium conjunctivum and the ipsilateral central tegmental tract innervating the inferior olive. The most frequent etiologies of destructive lesion are stroke (hemorrhagic more often than ischemic), brain trauma, brainstem tumors, and surgical or gamma knife treatment of brainstem cavernoma. The most accepted explanation for this symptomatic PT/OPT is that denervated olivary neurons released from inhibitory inputs enlarge and develop sustained synchronized oscillations. The cerebellum then modulates/accentuates this signal resulting in abnormal motor output in the branchial arches. In a second condition, PT/OPT and progressive cerebellar ataxia occurs in patients without structural brainstem or cerebellar lesion, other than cerebellar atrophy. This syndrome of progressive ataxia and palatal tremor may be sporadic or familial. In the familial form, where hypertrophic degeneration of the inferior olive may not occur (or not reported), the main reported etiologies are Alexander disease, polymerase gamma mutation, and spinocerebellar ataxia type 20. Whether or not these are associated with specific degeneration of the dentato-olivary pathway remain to be determined. The most symptomatic consequence of OPT is eye oscillations. Therapeutic trials suggest gabapentin or memantine as valuable drugs to treat eye oscillations in OPT.
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http://dx.doi.org/10.3389/fneur.2017.00302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490180PMC
June 2017

Ocular Motor Manifestations of Multiple Sclerosis.

J Neuroophthalmol 2017 09;37(3):332-340

Hospices Civils de Lyon (EN, CT), Neuro-Ophthalmology and Neurology D, Hôpital Neurologique Pierre Wertheimer, Bron, France; Lyon I University (EN, CT), Lyon Est Medical School, Lyon, France; and CRNL (CT), INSERM U1028, CNRS UMR5292, ImpAct Team, Bron, France.

Background: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system leading to disability, especially in young patients. Acute or chronic lesions of MS within the brainstem and the cerebellum frequently result in ocular motor disorders.

Evidence Acquisition: This review encompasses the spectrum of ocular motor disorders in patients with MS emphasizing prevalence, examination findings, diagnostic features, functional consequences, classification of MS course, and management of these disturbances of ocular motility.

Results: Ocular motor manifestations of MS can occur acutely in relapse or chronically, the latter as a consequence of previous relapses or as a chronic course of the disease. The most frequent and specific acute ocular motor manifestation is uni- or bilateral internuclear ophthalmoplegia (INO). The most frequent chronic manifestations include INO and cerebellar ocular motor disorders such as gaze-evoked nystagmus, saccadic hypermetria, and lack of vestibulo-ocular reflex inhibition. The most disabling syndrome is pendular nystagmus.

Conclusions: The high prevalence of ocular motor manifestations emphasizes the importance of neuro-ophthalmological examination among patients with MS. Because chronic manifestations may cause minimal or no symptoms, a systematic investigation of the most common manifestations should be performed in daily practice. Appropriate treatment may improve visual outcome in some of these ocular motor disorders.
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http://dx.doi.org/10.1097/WNO.0000000000000507DOI Listing
September 2017

Teaching Video NeuroImages: Bilateral complete horizontal gaze palsy with preserved convergence: The 1 + 1 syndrome.

Neurology 2016 09;87(11):e117-8

From Pole des Neurosciences (D.B.), B4 Neurology Unit, Hôpital Pierre-Paul-Riquet, CHU Purpan, Toulouse; and Neuro-ophthalmology Unit (C.T.), Hôpital Neurologique, Hospices Civils de Lyon, Bron, France.

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http://dx.doi.org/10.1212/WNL.0000000000003096DOI Listing
September 2016

Influence of the referential framework in the human pursuit coding system.

Neurology 2016 10 2;87(14):1517-1518. Epub 2016 Sep 2.

From the UMR 7152 (P.L., A.B., J.B.), CNRS-Collège de France, Laboratoire de Physiologie de la Perception et de l'Action, Paris; Clinique Ophtalmologique (P.L.), CHU Hôtel Dieu (P.K., J.B.), Nantes; Université Grenoble Alpes, Grenoble; INSERM U836 (P.K., J.B.), Grenoble Institut des Neurosciences, Grenoble; Neurology Department (P.K.), Michallon Hospital, Grenoble; Lyon Neuroscience Research Center (J.-P.L.), Brain Dynamics and Cognition Team, CRNL, INSERM U1028, CNRS UMR5292, Lyon; University Lyon 1 (J.-P.L.), Lyon; Hospices Civils de Lyon (C.T.), Neuro-ophthalmology Unit and Neurology D, Hôpital P Wertheimer, Lyon; INSERM U1028 (C.T.), CNRS UMR5292, IMPACT Team, Lyon Neuroscience Research Center, Lyon, France; Laboratorium voor Neuro-en Psychofysiologie (G.A.O.), K.U. Leuven Medical School, Leuven, Belgium; and Department of Neuroscience (G.A.O.), University of Parma, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000003172DOI Listing
October 2016

Adaptation of Saccadic Sequences with and without Remapping.

Front Hum Neurosci 2016 22;10:359. Epub 2016 Jul 22.

Centre de Recherche en Neurosciences de Lyon (CRNL), ImpAct team, Inserm U1028, CNRS UMR 5292, Lyon1 University Bron, France.

It is relatively easy to adapt visually-guided saccades because the visual vector and the saccade vector match. The retinal error at the saccade landing position is compared to the prediction error, based on target location and efference copy. If these errors do not match, planning processes at the level(s) of the visual and/or motor vector processing are assumed to be inaccurate and the saccadic response is adjusted. In the case of a sequence of two saccades, the final error can be attributed to the last saccade vector or to the entire saccadic displacement. Here, we asked whether and how adaptation can occur in the case of remapped saccades, such as during the classic double-step saccade paradigm, where the visual and motor vectors of the second saccade do not coincide and so the attribution of error is ambiguous. Participants performed saccades sequences to two targets briefly presented prior to first saccade onset. The second saccade target was either briefly re-illuminated (sequential visually-guided task) or not (remapping task) upon first saccade offset. To drive adaptation, the second target was presented at a displaced location (backward or forward jump condition or control-no jump) at the end of the second saccade. Pre- and post-adaptation trials were identical, without the re-appearance of the target after the second saccade. For the 1st saccade endpoints, there was no change as a function of adaptation. For the 2nd saccade, there was a similar increase in gain in the forward jump condition (52% and 61% of target jump) in the two tasks, whereas the gain decrease in the backward condition was much smaller for the remapping task than for the sequential visually-guided task (41% vs. 94%). In other words, the absolute gain change was similar between backward and forward adaptation for remapped saccades. In conclusion, we show that remapped saccades can be adapted, suggesting that the error is attributed to the visuo-motor transformation of the remapped visual vector. The mechanisms by which adaptation takes place for remapped saccades may be similar to those of forward sequential visually-guided saccades, unlike those involved in adaptation for backward sequential visually-guided saccades.
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http://dx.doi.org/10.3389/fnhum.2016.00359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956671PMC
August 2016

Spontaneous ocular positioning during visual imagery in patients with hemianopia and/or hemineglect.

Neuropsychologia 2016 06 26;86:141-52. Epub 2016 Apr 26.

INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center, ImpAct, 16 Avenue du Doyen Lépine, 69676 Bron cedex, France; Université Lyon1, Villeurbanne, France.

Spontaneous eye movements during imagery are not random and can be used to study and reveal mental visualization processes (Fourtassi et al., 2013; Johansson et al. 2006). For example, we previously showed that during memory recall of French towns via imagery healthy individuals looks straight ahead when recalling Paris and their subsequent gaze positions are significantly correlated with the real GPS coordinates of the recalled towns. This correlation suggests that memory retrieval is done via depictive representations as it is never found when the towns are recalled using verbal fluency. In the present paper we added to this finding by showing that the mental image is spontaneously centered on the head or body midline. In order to investigate the capacities of visual imagery in patients, and by extension, the role of primary visual cortex and fronto-parietal cortex in spatial visual imagery, we recorded gaze positions during memory recall of French towns in an imagery task, a non-imagery task (verbal fluency), and a visually-guided task in five patients with left or right hemianopia and in four patients with hemineglect (two with left hemianopia and two without). The correlation between gaze position and real GPS coordinates of the recalled towns was significant in all hemianopic patients, but in patients with hemineglect this was only the case for towns located on the right half of the map of France. This suggests hemianopic patients can perform spatially consistent mental imagery despite direct or indirect unilateral lesions of the primary visual cortex. In contrast, the left-sided towns recalled by hemineglect patients, revealed that they have some spatial inconsistency or representational difficulty. Hemianopic patients positioned and maintained their gaze in their contralesional hemispace, suggesting that their mental map was not centered on their head or body midline. This contralesional gaze positioning appeared to be a general compensation strategy and was not observed in patients with neglect (with or without hemianopia). Instead, neglect patients positioned their gaze in their ipsilesional hemispace and only when performing the visual imagery task. These findings are discussed in the context of the role of occipital and fronto-parietal cortices in the neuroanatomical model of visual imagery developed by Kosslyn et al. (2006).
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http://dx.doi.org/10.1016/j.neuropsychologia.2016.04.024DOI Listing
June 2016

The Effects of Short-Lasting Anti-Saccade Training in Homonymous Hemianopia with and without Saccadic Adaptation.

Front Behav Neurosci 2015 5;9:332. Epub 2016 Jan 5.

Neuroscience Research Center - Institut National de la Santé et de la Recherche Médicale U 1028 - Centre National de la Recherche Scientifique UMR 5292Bron, France; Unité de Neuro-ophtalmologie, Hospices Civils de Lyon, Hôpital Neurologique Pierre WertheimerBron, France; University Lyon 1Lyon, France.

Homonymous Visual Field Defects (HVFD) are common following stroke and can be highly debilitating for visual perception and higher level cognitive functions such as exploring visual scene or reading a text. Rehabilitation using oculomotor compensatory methods with automatic training over a short duration (~15 days) have been shown as efficient as longer voluntary training methods (>1 month). Here, we propose to evaluate and compare the effect of an original HVFD rehabilitation method based on a single 15 min voluntary anti-saccades task (AS) toward the blind hemifield, with automatic sensorimotor adaptation to increase AS amplitude. In order to distinguish between adaptation and training effect, 14 left- or right-HVFD patients were exposed, 1 month apart, to three trainings, two isolated AS task (Delayed-shift and No-shift paradigm), and one combined with AS adaptation (Adaptation paradigm). A quality of life questionnaire (NEI-VFQ 25) and functional measurements (reading speed, visual exploration time in pop-out and serial tasks) as well as oculomotor measurements were assessed before and after each training. We could not demonstrate significant adaptation at the group level, but we identified a group of nine adapted patients. While AS training itself proved to demonstrate significant functional improvements in the overall patient group, we could also demonstrate in the sub-group of adapted patients and specifically following the adaptation training, an increase of saccade amplitude during the reading task (left-HVFD patients) and the Serial exploration task, and improvement of the visual quality of life. We conclude that short-lasting AS training combined with adaptation could be implemented in rehabilitation methods of cognitive dysfunctions following HVFD. Indeed, both voluntary and automatic processes have shown interesting effects on the control of visually guided saccades in different cognitive tasks.
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http://dx.doi.org/10.3389/fnbeh.2015.00332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700208PMC
January 2016

Consensus Paper: Revisiting the Symptoms and Signs of Cerebellar Syndrome.

Cerebellum 2016 Jun;15(3):369-91

Department of Neurology and Memory Clinic, ZNA Middelheim General Hospital, Antwerp, Belgium.

The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of recent advances in our understanding of cerebellar operations. The key symptoms and signs of cerebellar dysfunction, often grouped under the generic term of ataxia, are discussed. Vertigo, dizziness, and imbalance are associated with lesions of the vestibulo-cerebellar, vestibulo-spinal, or cerebellar ocular motor systems. The cerebellum plays a major role in the online to long-term control of eye movements (control of calibration, reduction of eye instability, maintenance of ocular alignment). Ocular instability, nystagmus, saccadic intrusions, impaired smooth pursuit, impaired vestibulo-ocular reflex (VOR), and ocular misalignment are at the core of oculomotor cerebellar deficits. As a motor speech disorder, ataxic dysarthria is highly suggestive of cerebellar pathology. Regarding motor control of limbs, hypotonia, a- or dysdiadochokinesia, dysmetria, grasping deficits and various tremor phenomenologies are observed in cerebellar disorders to varying degrees. There is clear evidence that the cerebellum participates in force perception and proprioceptive sense during active movements. Gait is staggering with a wide base, and tandem gait is very often impaired in cerebellar disorders. In terms of cognitive and affective operations, impairments are found in executive functions, visual-spatial processing, linguistic function, and affective regulation (Schmahmann's syndrome). Nonmotor linguistic deficits including disruption of articulatory and graphomotor planning, language dynamics, verbal fluency, phonological, and semantic word retrieval, expressive and receptive syntax, and various aspects of reading and writing may be impaired after cerebellar damage. The cerebellum is organized into (a) a primary sensorimotor region in the anterior lobe and adjacent part of lobule VI, (b) a second sensorimotor region in lobule VIII, and (c) cognitive and limbic regions located in the posterior lobe (lobule VI, lobule VIIA which includes crus I and crus II, and lobule VIIB). The limbic cerebellum is mainly represented in the posterior vermis. The cortico-ponto-cerebellar and cerebello-thalamo-cortical loops establish close functional connections between the cerebellum and the supratentorial motor, paralimbic and association cortices, and cerebellar symptoms are associated with a disruption of these loops.
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http://dx.doi.org/10.1007/s12311-015-0687-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565264PMC
June 2016