Publications by authors named "Alain Vighetto"

78 Publications

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

Pheochromocytoma, paragangliomas, and pituitary adenoma: An unusual association in a patient with an SDHD mutation. Case report.

Medicine (Baltimore) 2019 Jul;98(30):e16594

Department of Endocrinology, Hospices Civils de Lyon, Fédération d'Endocrinologie.

Rationale: Pituitary adenomas and paragangliomas are both rare endocrine diseases. Paragangliomas (PGL)/pheochromocytomas (PHEO) are part of an inherited syndrome in about 30% to 40% of cases. Among familial cases, mutations of the succinate dehydrogenase (SDH) subunit genes (succinate dehydrogenase subunit [SDH]B, SDHC, SDHD, succinate dehydrogenase subunit AF2 [SDHAF2] , and SDHA) are the most common cause.

Patient Concerns: We here report a 31-year-old patient with a known SDHD mutation whose disease has been revealed by a left PHEO during childhood and who presented at age 29 years a large paraganglioma of the right jugular foramen, a concomitant PHEO of the left adrenal and 2 retroperitoneal paragangliomas. A pituitary incidentaloma was found during investigations on a fluorodeoxyglucose (FDG)-positron emission tomography (PET) (FDG-PET).

Diagnosis: A pituitary magnetic resonance imaging (MRI) confirmed the presence of a 14 mm pituitary macroadenoma. The pituitary function was normal except for hypogonadotropic hypogonadism. On examination of the fundus, a diagnosis of Pseudo Foster-Kennedy syndrome was made due to a venous compression of the right jugular vein caused by the paraganglioma (PGL). The pituitary adenoma was not compressive to the optic chiasm.

Interventions: A treatment with acetazolamide was started in order to improve intracranial hypertension. The patient couldn't benefit of a surgical approach for the paraganglioma of the right jugular foramen; the patient has been treated with stereotactic radiosurgery (Gamma Knife).

Outcomes: The most recent MRI revealed that the right jugular foramen PGL is stable and the latest visual assessment demonstrated stability despite a recent reduction in acetazolamide dosage. A surveillance by MRI of the pituitary adenoma has been planned.

Lessons: The association of a pituitary adenoma to paragangliomas within a same patient is very uncommon and raises the question of related physiopathological mechanisms.
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http://dx.doi.org/10.1097/MD.0000000000016594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708967PMC
July 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

Isotopic Evidence for Disrupted Copper Metabolism in Amyotrophic Lateral Sclerosis.

iScience 2018 Aug 1;6:264-271. Epub 2018 Aug 1.

Université de Lyon, ENS de Lyon, CNRS, LGL-TPE, 69007 Lyon, France. Electronic address:

Redox-active metals are thought to be implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). To address this point, we measured the concentrations of 12 elements and, for the first time, the stable isotope compositions of copper (redox-active) and zinc (redox-inactive) in human cerebrospinal fluids of 31 patients with ALS, 11 age-matched controls (CTRL), and 14 patients with Alzheimer disease. We first show that metal concentrations weakly discriminate patients with ALS from the two other groups. We then report that zinc isotopic compositions are similar in the three groups, but that patients with ALS have significantly 65copper-enriched isotopic compositions relative to CTRL and patients with AD. This result unambiguously demonstrates that copper is implicated in ALS. We suggest that this copper isotopic signature may result from abnormal protein aggregation in the brain parenchyma, and propose that isotopic analysis is a potential tool that may help unraveling the molecular mechanisms at work in ALS.
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http://dx.doi.org/10.1016/j.isci.2018.07.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137708PMC
August 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

MD1003 (High-Dose Pharmaceutical-Grade Biotin) for the Treatment of Chronic Visual Loss Related to Optic Neuritis in Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Study.

CNS Drugs 2018 07;32(7):661-672

Department of Ophthalmology, Faculty of Medicine, CHU de Reims, URCA, Reims, France.

Background: Chronic visual loss is a disabling feature in patients with multiple sclerosis (MS). It was recently shown that MD1003 (high-dose pharmaceutical-grade biotin or hdPB) may improve disability in patients with progressive MS.

Objective: The aim of this study was to evaluate whether MD1003 improves vision compared with placebo in MS patients with chronic visual loss.

Methods: The MS-ON was a 6-month, randomized, double-blind, placebo-controlled study with a 6-month open-label extension phase. Adult patients with MS-related chronic visual loss of at least one eye [visual acuity (VA) below 0.5 decimal chart] were randomized 2:1 to oral MD1003 300 mg/day or placebo. The selected eye had to show worsening of VA within the past 3 years following either acute optic neuritis (AON) or slowly progressive optic neuropathy (PON). The primary endpoint was the mean change from baseline to month 6 in VA measured in logarithm of the minimum angle of resolution (logMAR) at 100% contrast of the selected eye. Visually evoked potentials, visual field, retinal nerve fiber layer (RNFL) thickness, and health outcomes were also assessed.

Results: Ninety-three patients received MD1003 (n = 65) or placebo (n = 28). The study did not meet its primary endpoint, as the mean change in the primary endpoint was nonsignificantly larger (p = 0.66) with MD1003 (- 0.061 logMAR, + 3.1 letters) than with placebo (- 0.036 logMAR, + 1.8 letters). Pre-planned subgroup analyses showed that 100% contrast VA improved by a mean of + 2.8 letters (- 0.058 logMAR) with MD1003 and worsened by - 1.5 letters (+ 0.029 logMAR) with placebo (p = 0.45) in the subgroup of patients with PON. MD1003-treated patients also had nonsignificant improvement in logMAR at 5% contrast and in RNFL thickness and health outcome scores when compared with placebo-treated patients. There was no superiority of MD1003 vs placebo in patients with AON. The safety profile of MD1003 was similar to that of placebo.

Conclusions: MD1003 did not significantly improve VA compared with placebo in patients with MS experiencing chronic visual loss. An interesting trend favoring MD1003 was observed in the subgroup of patients with PON. Treatment was overall well tolerated.

Trial Registration: EudraCT identifier 2013-002112-27. ClinicalTrials.gov Identifier: NCT02220244 FUNDING: MedDay Pharmaceuticals.
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http://dx.doi.org/10.1007/s40263-018-0528-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061426PMC
July 2018

Efficacy and safety of infliximab therapy in refractory upper respiratory tract sarcoidosis: experience from the STAT registry.

Sarcoidosis Vasc Diffuse Lung Dis 2017 28;34(4):343-351. Epub 2017 Apr 28.

Département de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.

Upper respiratory tract (URT) involvement in sarcoidosis may be refractory to corticosteroids and immunosuppressants. Whether TNF-antagonists are efficient and safe in such phenotype is unknown. STAT is a French national drug registry including patients presenting sarcoidosis treated with TNF alpha antagonists. All cases of biopsy-proven sinonasal and laryngeal sarcoidosis were extracted and retrospectively analyzed from July 2014 to July 2015. Twelve patients presenting biopsy-proven sarcoidosis with URT involvement were included in the STAT registry. Infliximab appeared effective in decreasing URT symptoms, as assessed by a significant decrease of the e-POST (extra-pulmonary Physician Organ Severity Tool) (1.5 [0-2] vs 5 [1.5-5], p=0.03) and a corticosteroids-sparing effect (7.5mg per day [5-10] vs 17.5 mg per day [7.5-20], p=0.04) at the end of follow-up. TNF-antagonists may be an efficient treatment of refractory URT manifestations and should be discussed when prolonged or high dosages of corticosteroids despite immunosuppressive therapy are required. .
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http://dx.doi.org/10.36141/svdld.v34i4.5817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170073PMC
April 2017

Reduced Regional Cortical Thickness Rate of Change in Donepezil-Treated Subjects With Suspected Prodromal Alzheimer's Disease.

J Clin Psychiatry 2016 Dec;77(12):e1631-e1638

Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.

Objective: Cortical thinning, previously identified during prodromal stages of Alzheimer's disease (AD), is a "candidate" biomarker implemented in AD clinical therapy trials. We investigated the effect of donepezil treatment on cortical thickness in mild cognitively impaired subjects with the amnestic syndrome of the hippocampal type, a prodromal at-risk group for progression to AD dementia.

Methods: Data were from a longitudinal analysis of a community-based multicenter suspected prodromal AD cohort diagnosed by the Free and Cued Selective Reminding Test (81 donepezil vs 92 placebo) enrolled in a double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day). The study started in November 2006 and concluded in August 2010. All subjects underwent 2 brain structural magnetic resonance imaging (MRI) scans, at baseline and at the end of the trial. Structural MRI images had been processed using the automated pipeline for longitudinal segmentation and surface reconstruction implemented in FreeSurfer. The primary outcome measure of this post hoc study was the annualized percentage change (APC) of cortical thickness.

Results: The donepezil group exhibited reduced APC cortical thinning compared to placebo in the rostral anterior cingulate (right: P = .048; left: P = .032), the orbitofrontal (right: P = .012; left: P < .048), and the right inferior frontal (P = .022) cortices and in the right insula (P = .010). These results were not statistically significant after Bonferroni correction likely due to insufficient power for cortical thickness measurements in the study group powered for the predefined hippocampus outcome.

Conclusions: Our findings support the hypothesis that cortical thickness is a reliable candidate surrogate outcome in early predementia AD trials. In addition, donepezil treatment may have an impact on cortical structure/morphology in areas innervated by the medial and lateral cholinergic pathways.

Trial Registration: ClinicalTrials.gov identifier: NCT00403520.
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http://dx.doi.org/10.4088/JCP.15m10413DOI Listing
December 2016

A New Symptom, 'Palinendophonia', Associated with Pure Verbal Palinacousis Induced by a Right Inferior Temporal Lesion.

Eur Neurol 2015 27;74(3-4):219-21. Epub 2015 Nov 27.

Department of Neurology, Memory Resources and Research Centre (CMRR), CHU Besanx00E7;on, Besanx00E7;on, France.

We describe the case of a patient with pure verbal palinacousis and perseveration of inner speech after a right inferior temporal lesion. The superior temporal lobe, including the superior temporal sulcus and the interhemispheric connection between the 2 superior temporal lobes, explored by tractography, were preserved. These regions are involved in voice processing, verbal short-term memory and inner speech. It can then be hypothesised that abnormal activity in this network has occurred. Palinacousis and 'palinendophonia', a term proposed for this symptom not previously reported, may be due to common cognitive processes disorders involved in both voice hearing and inner speech.
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http://dx.doi.org/10.1159/000441974DOI Listing
July 2016

Neuro-ophthalmologic exploration in non-functioning pituitary adenoma.

Ann Endocrinol (Paris) 2015 Jul 10;76(3):210-9. Epub 2015 Jun 10.

Clinique Mathilde, 4, rue Lessard, 76100 Rouen, France.

Non-functioning pituitary adenoma may lead to blindness and causes visual impairment in 58% of cases and, more rarely, ocular motor disorder. Patients are slow to become aware of their visual dysfunction, vision in one eye compensating the deficit in the other. Assessment of visual function, comprising visual acuity and visual field evaluation and fundus examination, should be performed regularly according to the severity of impairment. Optic nerve optical coherence tomography (OCT) can quantify optic atrophy reproducibly, and is of prognostic value for postoperative visual recovery. Diplopia most often involves decompensation of heterophoria, visual field fusion being hampered by the visual field defect; such diplopia without ocular motor deficit is known as "hemifield slide". Diplopia associated with ocular motor palsy is caused by tumoral invasion of the cavernous sinus (IIIrd, IVth or VIth nerve palsy); in large impairment, restricted eye movement is easily observed; milder palsies require neuro-ophthalmologic assessment and/or Lancaster test. Pituitary apoplexy induces ocular motor impairment in 70% of cases, strongly guiding diagnosis. Visual impairment is associated in 75% of cases. The degree of neuro-ophthalmologic (visual and ocular motor) impairment is one of the main criteria guiding treatment of pituitary apoplexy (conservative medical and/or surgical treatment) and follow-up.
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http://dx.doi.org/10.1016/j.ando.2015.04.006DOI Listing
July 2015

Isolated oculomotor nerve palsy revealing infectious mononucleosis.

Acta Ophthalmol 2015 Sep 9;93(6):e518-9. Epub 2015 Mar 9.

Neuro-Ophthalmology Unit, Lyon Civil Hospitals, Neurological Hospital, Lyon 1 University, Bron Cedex, France.

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http://dx.doi.org/10.1111/aos.12636DOI Listing
September 2015

Combination of attentional and spatial working memory deficits in Bálint-Holmes syndrome.

Ann N Y Acad Sci 2015 Mar 23;1339:165-75. Epub 2015 Feb 23.

Lyon Neuroscience Research Center (CRNL), ImpAct, INSERM U1028, CNRS UMR5292, Lyon University and Neurological Hospital L. Wertheimer, Bron, France.

This study aims to investigate whether attention and spatiotemporal integration deficits are dissociated in patients with bilateral posterior cortical atrophy (PCA), and whether it is their combination that leads to a severe clinical handicap. We recorded performance and ocular behavior of four PCA patients and four age-matched controls in visual search and counting tasks. We measured the percentage of targets detected and the mean detection time in a "pop-out" search. We also compared counting ability when a set of dots is presented briefly (in healthy individuals, the automatic deployment of attention over space allows a fast estimation of quantity) or for unlimited duration (favoring sequential counting, hence spatiotemporal integration). All patients showed reduced deployment of attention over space (simultanagnosia), resulting in increased visual search times and underestimations of the number of briefly presented dots. Only two patients showed ocular revisiting behavior that caused frequent omissions in visual search and overestimations of the number of dots presented for unlimited duration. The impairment to deploy attention is considered here as a bilateral covert attention deficit. Disorganized ocular exploration appears to be independent and is hypothesized to result from processes maintaining a salience map over time (spatial working memory) and especially across saccades.
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http://dx.doi.org/10.1111/nyas.12731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418412PMC
March 2015

Donepezil decreases annual rate of hippocampal atrophy in suspected prodromal Alzheimer's disease.

Alzheimers Dement 2015 Sep 14;11(9):1041-9. Epub 2015 Jan 14.

INSERM, CNRS, UMR-S975, Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie-Paris 6, Paris, France; Neuroradiology Department, Hôpital de la Salpêtrière, Paris, France.

Introduction: The purpose of this study was to study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD).

Methods: A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method.

Results: Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = -1.89%) compared with the placebo group (APC = -3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups.

Discussion: A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo.
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http://dx.doi.org/10.1016/j.jalz.2014.10.003DOI Listing
September 2015

Association of cerebrospinal fluid prion protein levels and the distinction between Alzheimer disease and Creutzfeldt-Jakob disease.

JAMA Neurol 2015 Mar;72(3):267-75

Hospices Civils de Lyon, Groupement Hospitalier Est, Department of Biochemistry, Neurochemistry Unit, Lyon, France6Lyon 1 University, Lyon Neuroscience Research Center, Bron Cedex, France.

Importance: Although typical forms of Alzheimer disease (AD) and Creutzfeldt-Jakob disease (CJD) are clinically distinguishable, atypical AD phenotypes may pose a diagnostic challenge. The major biological diagnostic biomarker for identifying CJD, 14-3-3 protein in cerebrospinal fluid (CSF), unfortunately lacks specificity when confronting a rapid dementia presentation.

Objective: To assess the relevance of total CSF prion protein (t-PrP) levels in the differential biological diagnosis between atypical AD phenotypes and CJD.

Design, Setting, And Participants: A retrospective study in an autopsy-confirmed cohort of 82 patients was performed to evaluate the relevance of CSF t-PrP to distinguish 30 definite cases of AD from 52 definite cases of CJD. Next, CSF t-PrP concentration was measured in a cohort of 104 patients including 55 patients with probable AD, 26 with probable sporadic CJD, and 23 control patients for whom 14-3-3 protein, total tau, phosphorylated tau 181 (P-tau181), and Aβ1-42 were available. We investigated 46 patients diagnosed as having probable AD who presented atypical phenotypes. A diagnosis strategy was proposed to classify atypical AD phenotypes with suspicion of CJD based on a decision tree combining CSF biomarkers.

Main Outcomes And Measures: We determined CSF t-PrP levels for all patients. We calculated the ratio of total tau and P-tau181 and determined the diagnostic accuracy of each biomarker alone or in combination. We calculated the misclassification rate for each biomarker that corresponded to the percentage of patients within the group of atypical AD phenotypes wrongly classified as CJD.

Results: In patients with CJD, CSF t-PrP concentrations were decreased compared with control participants and patients with AD. When considering the differential diagnosis of CJD compared with atypical AD phenotypes, CSF t-PrP determination reached 82.1% sensitivity and 91.3% specificity. The misclassification rate of atypical AD phenotypes decreased from 43.5%, obtained when using the CSF 14-3-3 protein determination alone, to only 4.3% when calculating the ratio total tau/(P-tau181 × t-PrP). The proposed classification tree permitted correct classification of 98.4% of the patients.

Conclusions And Relevance: For unusual phenotypes of AD, especially cases presenting with a biological ambiguity suggesting CJD, determination of CSF t-PrP levels increased diagnostic accuracy. The use of CSF t-PrP levels may be beneficial in clinical practice in addition to the current classic biomarkers.
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http://dx.doi.org/10.1001/jamaneurol.2014.4068DOI Listing
March 2015

Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion.

J Neurol Neurosurg Psychiatry 2015 Sep 4;86(9):986-95. Epub 2014 Dec 4.

Sorbonne Universités, Université Pierre et Marie Curie - Paris 06, UMR_S1127, Paris, France Inserm, U1127, Paris, France Cnrs, UMR 7225, Paris, France AP-HP, Groupe Hospitalier Pitié-Salpêtriére, Departement of Genetics and Cytogenetics, Paris, France.

Objective: Spinocerebellar ataxia 36 (SCA36) is an autosomal-dominant neurodegenerative disorder caused by a large (>650) hexanucleotide GGCCTG repeat expansion in the first intron of the NOP56 gene. The aim of this study is to clarify the prevalence, clinical and genetic features of SCA36.

Methods: The expansion was tested in 676 unrelated SCA index cases and 727 controls from France, Germany and Japan. Clinical and neuropathological features were investigated in available family members.

Results: Normal alleles ranged between 5 and 14 hexanucleotide repeats. Expansions were detected in 12 families in France (prevalence: 1.9% of all French SCAs) including one family each with Spanish, Portuguese or Chinese ancestry, in five families in Japan (1.5% of all Japanese SCAs), but were absent in German patients. All the 17 SCA36 families shared one common haplotype for a 7.5 kb pairs region flanking the expansion. While 27 individuals had typically long expansions, three affected individuals harboured small hexanucleotide expansions of 25, 30 and 31 hexanucleotide repeat-units, demonstrating that such a small expansion could cause the disease. All patients showed slowly progressive cerebellar ataxia frequently accompanied by hearing and cognitive impairments, tremor, ptosis and reduced vibration sense, with the age at onset ranging between 39 and 65 years, and clinical features were indistinguishable between individuals with short and typically long expansions. Neuropathology in a presymptomatic case disclosed that Purkinje cells and hypoglossal neurons are affected.

Conclusions: SCA36 is rare with a worldwide distribution. It can be caused by a short GGCCTG expansion and associates various extracerebellar symptoms.
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http://dx.doi.org/10.1136/jnnp-2014-309153DOI Listing
September 2015

Pontine infarction responsible for wall-eyed bilateral internuclear ophthalmoplegia syndrome.

Neurol Clin Pract 2014 Dec;4(6):524-525

Department of Ophthalmology (TM), Croix Rousse Hospital; Departments of Neuro-oncology (FD), Neurology, and Neuro-ophthalmology (CT, AV, DB), Hôpital Neurologique Pierre Wertheimer; and Université de Lyon 1-Université Claude Bernard (CT, AV, DB), Lyon, France.

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http://dx.doi.org/10.1212/CPJ.0000000000000063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759983PMC
December 2014

Clinical reasoning: A young woman with rapid mental deterioration and leukoencephalopathy: a treatable cause.

Neurology 2014 Nov;83(21):e182-6

From the Departments of Neurology (D.B., M.E.-M., C.T., A.V.) and Neuro-ophthalmology (D.B., C.T., A.V.), Hôpital Neurologique Pierre Wertheimer, Lyon; Université de Lyon 1 (D.B., C.T., A.V.), Université Claude Bernard; Department of Neurology (E.D.), Centre Hospitalier de Vienne; Service des Maladies Héréditaires du Métabolisme et Centre de Référence des Maladies Héréditaires du Métabolisme (C.A., N.G.), HFME, Lyon; Service de Biochimie-Hormonologie (J.-F.B.), APHP-Hôpital Robert Debré, Paris; and Service de Neurologie (P.L.), CHRU Gui-de-Chauliac, Montpellier, France.

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http://dx.doi.org/10.1212/WNL.0000000000001006DOI Listing
November 2014

Endoscopic endonasal optic nerve and orbital apex decompression for nontraumatic optic neuropathy: surgical nuances and review of the literature.

Neurosurg Focus 2014 ;37(4):E19

Skull Base Surgery Unit, Department of Neurosurgery B, Pierre Wertheimer Neurological and Neurosurgical Hospital, Hospices Civils de Lyon.

Object: While several approaches have been described for optic nerve decompression, the endoscopic endonasal route is gaining favor because it provides excellent exposure of the optic canal and the orbital apex in a minimally invasive manner. Very few studies have detailed the experience with nontraumatic optic nerve decompressions, whereas traumatic cases have been widely documented. Herein, the authors describe their preliminary experience with endoscopic endonasal decompression for nontraumatic optic neuropathies (NONs) to determine the procedure's efficacy and delineate its potential indications and limits.

Methods: The medical reports of patients who had undergone endoscopic endonasal optic nerve and orbital apex decompression for NONs at the Lyon University Neurosurgical Hospital in the period from January 2012 to March 2014 were reviewed. For all cases, clinical and imaging data on the underlying pathology and the patient, including demographics, preoperative and 6-month postoperative ophthalmological assessment results, symptom duration, operative details with video debriefing, as well as the immediate and delayed postoperative course, were collected from the medical records.

Results: Eleven patients underwent endoscopic endonasal decompression for NON in the multidisciplinary skull base surgery unit of the Lyon University Neurosurgical Hospital during the 27-month study period. The mean patient age was 53.4 years, and there was a clear female predominance (8 females and 3 males). Among the underlying pathologies were 4 sphenoorbital meningiomas (36%), 3 optic nerve meningiomas (27%), and 1 each of trigeminal neuroma (9%), orbital apex meningioma (9%), ossifying fibroma (9%), and inflammatory pseudotumor of the orbit (9%). Fifty-four percent of the patients had improved visual acuity at the 6-month follow-up. Only 1 patient whose sphenoorbital meningioma had been treated at the optic nerve atrophy stage continued to worsen despite surgical decompression. The 2 patients presenting with preoperative papilledema totally recovered. One case of postoperative epistaxis was successfully treated using balloon inflation, and 1 case of air swelling of the orbit spontaneously resolved.

Conclusions: Endoscopic endonasal optic nerve decompression is a safe, effective, and minimally invasive technique affording the restoration of visual function in patients with nontraumatic compressive processes of the orbital apex and optic nerve. The timing of decompression remains crucial, and patients should undergo such a procedure early in the disease course before optic atrophy.
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http://dx.doi.org/10.3171/2014.7.FOCUS14303DOI Listing
June 2015

Initial memory deficit profiles in patients with a cerebrospinal fluid Alzheimer's disease signature.

J Alzheimers Dis 2014 ;41(4):1109-16

Research and Resources Memory Center of Lyon, Hôpital des Charpennes, Hospices Civils de Lyon, Lyon, France University Lyon I, Lyon, France INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Lyon, France.

Background: Alzheimer's disease (AD) clinical onset is usually characterized by a memory complaint and a progressive memory deficit. The proportion of typical medial-temporal amnesia revealing AD remains unknown.

Objective: The present study explores the episodic memory impairment profiles by the Free and Cued Selective Recall Reminding Test (FCSRT) in patients with initial memory complaint and a cerebrospinal fluid (CSF) biomarker signature of AD.

Methods: Seventy-three patients referred for memory complaint to the Centers for Memory, Resource and Research of Lyon and Montpellier (France) were included consecutively. All patients underwent an extensive neuropsychological examination and had a Mini-Mental State Examination (MMSE) score ≥20 and a positive CSF AD signature. The patients were classified as having mild dementia or prodromal AD. Verbal episodic memory was assessed using the French version of the FCSRT exploring encoding, storage/consolidation, and cued delayed retrieval phases of memorization. Three different memory profiles were identified according to the results of FCSRT.

Results: The median age was 72 year-old [interquartiles: 65-76]. The median MMSE score was 23 [interquartiles: 21-25]. 88% of the patients (n = 64) presented with a medial temporal amnesia profile. The dysexecutive amnesia and normal verbal episodic memory profiles represented respectively 5% (n = 4) and 7% (n = 5). There were no significant differences in term of age, gender, and MMSE score between the three profile groups.

Conclusion: In a population initially presenting with memory complaints and depicting a CSF AD signature, a high proportion of medial temporal amnesia is disclosed as expected, but also a proportion of dysexecutive amnesia and normal FCSRT.
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http://dx.doi.org/10.3233/JAD-131916DOI Listing
March 2015

Decoupled visually-guided reaching in optic ataxia: differences in motor control between canonical and non-canonical orientations in space.

PLoS One 2013 31;8(12):e86138. Epub 2013 Dec 31.

School of Kinesiology and Health Science, Centre for Vision Research, York University, Toronto, Ontario, Canada.

Guiding a limb often involves situations in which the spatial location of the target for gaze and limb movement are not congruent (i.e. have been decoupled). Such decoupled situations involve both the implementation of a cognitive rule (i.e. strategic control) and the online monitoring of the limb position relative to gaze and target (i.e. sensorimotor recalibration). To further understand the neural mechanisms underlying these different types of visuomotor control, we tested patient IG who has bilateral caudal superior parietal lobule (SPL) damage resulting in optic ataxia (OA), and compared her performance with six age-matched controls on a series of center-out reaching tasks. The tasks comprised 1) directing a cursor that had been rotated (180° or 90°) within the same spatial plane as the visual display, or 2) moving the hand along a different spatial plane than the visual display (horizontal or para-sagittal). Importantly, all conditions were performed towards visual targets located along either the horizontal axis (left and right; which can be guided from strategic control) or the diagonal axes (top-left and top-right; which require on-line trajectory elaboration and updating by sensorimotor recalibration). The bilateral OA patient performed much better in decoupled visuomotor control towards the horizontal targets, a canonical situation in which well-categorized allocentric cues could be utilized (i.e. guiding cursor direction perpendicular to computer monitor border). Relative to neurologically intact adults, IG's performance suffered towards diagonal targets, a non-canonical situation in which only less-categorized allocentric cues were available (i.e. guiding cursor direction at an off-axis angle to computer monitor border), and she was therefore required to rely on sensorimotor recalibration of her decoupled limb. We propose that an intact caudal SPL is crucial for any decoupled visuomotor control, particularly when relying on the realignment between vision and proprioception without reliable allocentric cues towards non-canonical orientations in space.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086138PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877394PMC
August 2014

Increased cerebrospinal fluid tau levels in logopenic variant of Alzheimer's disease.

J Alzheimers Dis 2014 ;39(3):611-6

Research Memory Center (CMRR), CHU Besançon, Besançon, France.

Background: Patients with logopenic variant of primary progressive aphasia (lvPPA) display neuropathological differences from typical amnestic Alzheimer's disease (AD).

Objective: The aim of the study was to compare cerebrospinal fluid (CSF) biomarker levels between patients with lvPPA due to AD (lvPPA-AD), non-logopenic forms of AD (nlAD), and amnestic mild cognitive impairment due to AD (aMCI-AD).

Methods: CSF biomarker concentrations were assessed in 124 patients divided into three groups matched for age, level of education, center, and disease duration: lvPPA-AD (n = 30), nlAD (n = 67). and aMCI-AD (n = 27).

Results: p-Tau181 levels were higher in the lvPPA-AD group than in the aMCI-AD group (p < 0.05). Total tau levels were higher in the lvPPA-AD group versus those in the nlAD (p < 0.05) and aMCI-AD (p < 0.001) groups.

Conclusions: These results suggest a more pronounced involvement of a taupathy in lvPPA-AD compared to aMCI-AD and a more important neuronal death in lvPPA-AD than in nlAD or aMCI-AD.
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http://dx.doi.org/10.3233/JAD-131382DOI Listing
October 2014

MRI findings in AOA2: Cerebellar atrophy and abnormal iron detection in dentate nucleus.

Neuroimage Clin 2013 10;2:542-8. Epub 2013 Apr 10.

Hospices Civils de Lyon, Neuro-ophtalmology Unit and Neurology D, Neurological and Neurosurgical Hospital P. Wertheimer, Lyon F-69000, France.

Ataxia with Oculomotor Apraxia type 2 (AOA2) is one of the most frequent types of autosomal degenerative cerebellar ataxia. The first objective of this work was to identify specific cerebellar atrophy using MRI in patients with AOA2. Since increased iron deposits have been reported in degenerative diseases, our second objective was to report iron deposits signals in the dentate nuclei in AOA2. Five patients with AOA2 and 5 age-matched controls were subjects in a 3T MRI experiment that included a 3D turbo field echo T1-weighted sequence. The normalized volumes of twenty-eight cerebellar lobules and the percentage of atrophy (relative to controls) of the 4 main cerebellar regions (flocculo-nodular, vermis, anterior and posterior) were measured. The dentate nucleus signals using 3D fast field echo sequence for susceptibility-weighted images (SWI) were reported, as a measure of iron content. We found that all patients had a significant atrophy of all cerebellar lobules as compared to controls. The percentage of atrophy was the highest for the vermis, consistent with patients' oculomotor presentation, and for the anterior lobe, consistent with kinetic limb ataxia. We also describe an absence of hypointensity of the iron signal on SWI in the dentate nucleus of all patients compared to control subjects. This study suggests that patients with Ataxia with Oculomotor Apraxia type 2 present MRI patterns consistent with their clinical presentation. The absence of SWI hypointensity in dentate nucleus is a new radiological sign which was identified in all patients. The specificity of this absence of signal must be further determined in AOA2.
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http://dx.doi.org/10.1016/j.nicl.2013.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777765PMC
November 2013

Relapsing optic neuritis: a multicentre study of 62 patients.

Mult Scler 2014 06 31;20(7):848-53. Epub 2013 Oct 31.

University Hospital, France Clinical Investigation Centre, INSERM 10002, France.

Background: Optic neuritis (ON) may be the first symptom of a central nervous system demyelinating, systemic or infectious disease but few patients experience recurrent episodes and have a negative workup.

Objective: This disorder, named relapsing optic neuritis (RON), is poorly described in the literature and still presents a particular challenge in diagnosis and management.

Methods: We describe the clinical, laboratory, magnetic resonance imaging (MRI) and disability course of RON in a French cohort of 62 patients, based on a multicentre, retrospective, observational study.

Results: In our cohort, we identified two distinct groups of RON patients. The first is characterised by relapsing inflammatory optic neuritis (RION, 68%), which is non-progressive, whereas the second presented as a chronic relapsing inflammatory optic neuritis (CRION, 32%), which is progressive. We have noted more cases with steroid dependence in the CRION group than the RION group (42% vs 10%). The long-term visual prognosis was more severe in CRION patients and neuromyelitis optica-immunoglobulin G (NMO-IgG)-positive patients.

Conclusion: RON is likely a separate entity corresponding to an autoimmune disease that differs from multiple sclerosis (MS), NMO and vasculitis. We provide a new classification system based on a better understanding of RON which could allow an improved management by early treatment of poor prognosis forms.
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http://dx.doi.org/10.1177/1352458513510223DOI Listing
June 2014

Teaching neuroimages: chiasmal enlargement and enhancement in Leber hereditary optic neuropathy.

Neurology 2013 Oct;81(17):e126-7

From the Departments of Neurology (E.O., D.B., C.T., A.V.), Neuro-ophthalmology (D.B., L.A., C.T., A.V.), and Radiology (G.L.-T.), Hôpital Neurologique Pierre Wertheimer, Lyon; and Université de Lyon 1-Université Claude Bernard (D.B., L.A., C.T., A.V.), Lyon, France.

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http://dx.doi.org/10.1212/WNL.0b013e3182a95698DOI Listing
October 2013

Optic neuritis as a possible phenotype of anti-GQ1b/GT1a antibody syndrome.

J Neurol 2013 Nov 6;260(11):2890-1. Epub 2013 Sep 6.

Departments of Neurology and Neuro-ophthalmology, Hôpital Neurologique Pierre Wertheimer, 59 boulevard Pinel, 69394, Lyon, France,

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http://dx.doi.org/10.1007/s00415-013-7094-9DOI Listing
November 2013

Images in clinical medicine. Upper limb clonus.

N Engl J Med 2013 Sep;369(10):e12

Hôpital Neurologique Pierre Wertheimer, Lyon, France.

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http://dx.doi.org/10.1056/NEJMicm1206994DOI Listing
September 2013