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Downbeat nystagmus (DBN) is the most common form of acquired central vestibular nystagmus. Gravity perception in patients with DBN has previously been investigated by means of subjective visual straight ahead (SVA) and subjective visual vertical (SVV) in the pitch and roll planes only during whole-body tilts. To our knowledge, the effect of head tilt in the roll plane on the SVV and on DBN has not yet been systematically studied in patients. In this study, we investigated static and dynamic graviceptive function in the roll-plane in patients with DBN (patients) and healthy-controls (controls) by assessment of the Subjective Visual Vertical (SVV) and the modulation of slow-phase-velocity (SPV) of DBN. SPV of DBN and SVV were tested at different head-on trunk-tilt positions in the roll-plane (0°,30° clockwise (cw) and 30° counterclockwise (ccw)) in 26 patients suffering from DBN and 13 controls. In patients, SPV of DBN did not show significant modulations at different head-tilt angles in the roll-plane. SVV ratings did not differ significantly between DBN patients vs. controls, however patients with DBN exhibited a higher variability in mean SVV estimates than controls. Our results show that the DBN does not exhibit any modulation in the roll-plane, in contrast to the pitch-plane. Furthermore, patients with DBN show a higher uncertainty in the perception of verticality in the roll-plane in form of a higher variability of responses. [ABSTRACT FROM AUTHOR]

The cerebellum is important for motor adaptation. Lesions to the vestibulo-cerebellum selectively cause gait ataxia. Here we investigate how such damage affects locomotor adaptation when performing the 'broken escalator' paradigm. Following an auditory cue, participants were required to step from the fixed surface onto a moving platform (akin to an airport travellator). The experiment included three conditions: 10 stationary (BEFORE), 15 moving (MOVING) and 10 stationary (AFTER) trials. We assessed both behavioural (gait approach velocity and trunk sway after stepping onto the moving platform) and neuromuscular outcomes (lower leg muscle activity, EMG). Unlike controls, cerebellar patients showed reduced after-effects (AFTER trials) with respect to gait approach velocity and leg EMG activity. However, patients with cerebellar damage maintain the ability to learn the trunk movement required to maximise stability after stepping onto the moving platform (i.e., reactive postural behaviours). Importantly, our findings reveal that these patients could even initiate these behaviours in a feedforward manner, leading to an after-effect. These findings reveal that the cerebellum is crucial for feedforward locomotor control, but that adaptive locomotor behaviours learned via feedback (i.e., reactive) mechanisms may be preserved following cerebellum damage. [ABSTRACT FROM AUTHOR]

Downbeat nystagmus (DBN) is a neuro-otological finding frequently encountered by clinicians dealing with patients with vertigo. Since DBN is a finding that should be understood because of central vestibular dysfunction, it is necessary to know how to frame it promptly to suggest the correct diagnostic-therapeutic pathway to the patient. As knowledge of its pathophysiology has progressed, the importance of this clinical sign has been increasingly understood. At the same time, clinical diagnostic knowledge has increased, and it has been recognized that this sign may occur sporadically or in association with others within defined clinical syndromes. Thus, in many cases, different therapeutic solutions have become possible. In our work, we have attempted to systematize current knowledge about the origin of this finding, the clinical presentation and current treatment options, to provide an overview that can be used at different levels, from the general practitioner to the specialist neurologist or neurotologist. [ABSTRACT FROM AUTHOR]

Objective: To investigate the topical diagnosis, possible etiology and mechanism of spontaneous downbeat nystagmus (sDBN) patients with dizziness/vertigo. Methods: The clinical features of dizziness/vertigo patients accompanied with DBN were retrospectively reviewed in the Vertigo Center of our hospital from January 2018 to March 2021. The clinical features of dizziness/vertigo patients accompanied with DBN were reviewed. Comprehensive VNG, bithermal caloric testing, video-head-impulse test (vHIT), vestibular-evoked myogenic potentials (VEMP), head magnetic resonance imaging (MRI), three-dimensional fluidattenuated incersion recovery magnetic resonance imaging (3D-FLAIR MRI) in the inner ear, serum immunology and other examinations were to determine the lesion site, and analyze its possible etiology and mechanism. Results: A total of 54 patients were included. Among them, 70.4% (n = 38) of DBN patients were diagnosed with episodic vestibular syndrome (EVS), 22.2% (n = 12) with chronic vestibular syndrome (CVS), and 7.4% (n = 4) with acute vestibular syndrome (AVS). Among all the patients, 51.9% of DBN patients had clear etiology, with central lesions of 29.6% and peripheral diseases of 22.2%. The most common diseases in DBN patients were cerebellar lesions (13.0%, n = 7) and vestibular migraine (13.0%, n = 7), followed by benign positional paroxysmal vertigo (7.4%, n = 4) and drug-related dizziness/vertigo (5.6%, n = 3). The other 48.1% of the patients had unknown etiology. 53.8% (14/26) of patients with idiopathic DBN had decreased semicircular canal function, with 42.9% (6/14) decreased posterior semicircular canal function. The posterior semicircular canal gain in DBN patients decreased compared to the anterior semicircular canal in the same conjugate plane. Patients with peripheral DBN were more prone to horizontal/torsional nystagmus during positional testing. Conclusion: In our study, DBN patients have a relative decrease in posterior semicircular canal gain, which is possibly a particular result found in a subset of downbeat nystagmus patients. The changes in nystagmus during positional testing may be helpful in distinguishing between peripheral and central causes. [ABSTRACT FROM AUTHOR]

Downbeat nystagmus (DBN) is a neuro-otological finding frequently encountered by clinicians dealing with patients with vertigo. Since DBN is a finding that should be understood because of central vestibular dysfunction, it is necessary to know how to frame it promptly to suggest the correct diagnostic-therapeutic pathway to the patient. As knowledge of its pathophysiology has progressed, the importance of this clinical sign has been increasingly understood. At the same time, clinical diagnostic knowledge has increased, and it has been recognized that this sign may occur sporadically or in association with others within defined clinical syndromes. Thus, in many cases, different therapeutic solutions have become possible. In our work, we have attempted to systematize current knowledge about the origin of this finding, the clinical presentation and current treatment options, to provide an overview that can be used at different levels, from the general practitioner to the specialist neurologist or neurotologist.

Summary: Background: GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA)≥250 expansions in the fibroblast growth factor 14 (FGF14) gene, but its phenotypic spectrum, pathogenic threshold, and evidence-based treatability remain to be established. We report on the frequency of FGF14 (GAA)≥250 and (GAA)200-249 expansions in a large cohort of patients with idiopathic downbeat nystagmus (DBN) and their response to 4-aminopyridine. Methods: Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial. Findings: Frequency of FGF14 (GAA)≥250 expansions was 48% (82/170) in patients with idiopathic DBN. Additional cerebellar ocular motor signs were observed in 100% (82/82) and cerebellar ataxia in 43% (35/82) of patients carrying an FGF14 (GAA)≥250 expansion. FGF14 (GAA)200-249 alleles were enriched in patients with DBN (12%; 20/170) compared to controls (0.87%; 19/2191; OR, 15.20; 95% CI, 7.52–30.80; p

Neuromyelitis optica (NMO), an autoimmune disease, typically presents with loss of vision and myelopathic signs. NMO may be associated with antibodies selective for aquaporin-4 (AQP4), a water channel located within the optic nerves and spinal cord.AQP4 is distributed in the periventricular region, corpus callosum, magnocellular nuclei of the hypothalamus, and brain stem.Downbeat nystagmus (DBN) is associated with structural, metabolic, and autoimmune disorders, but is rarely reported in NMO.We treated a 33-year-old female with known AQP4-positive NMO who presented with new-onset DBN. We review the literature and discuss possible mechanisms and lesion locations hypothetically responsible for the symptoms and signs., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Canut et al.)

Background: GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA) ≥250 expansions in the fibroblast growth factor 14 (FGF14) gene, but its phenotypic spectrum, pathogenic threshold, and evidence-based treatability remain to be established. We report on the frequency of FGF14 (GAA) ≥250 and (GAA) 200-249 expansions in a large cohort of patients with idiopathic downbeat nystagmus (DBN) and their response to 4-aminopyridine., Methods: Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial., Findings: Frequency of FGF14 (GAA) ≥250 expansions was 48% (82/170) in patients with idiopathic DBN. Additional cerebellar ocular motor signs were observed in 100% (82/82) and cerebellar ataxia in 43% (35/82) of patients carrying an FGF14 (GAA) ≥250 expansion. FGF14 (GAA) 200-249 alleles were enriched in patients with DBN (12%; 20/170) compared to controls (0.87%; 19/2191; OR, 15.20; 95% CI, 7.52-30.80; p < 0.0001). The phenotype of patients carrying a (GAA) 200-249 allele closely mirrored that of patients carrying a (GAA) ≥250 allele. Patients carrying a (GAA) ≥250 or a (GAA) 200-249 allele had a significantly greater clinician-reported (80%, 33/41 vs 31%, 5/16; RR, 2.58; 95% CI, 1.23-5.41; Fisher's exact test, p = 0.0011) and self-reported (59%, 32/54 vs 11%, 2/19; RR, 5.63; 95% CI, 1.49-21.27; Fisher's exact test, p = 0.00033) response to 4-aminopyridine treatment compared to patients carrying a (GAA) <200 allele. Placebo-controlled video-oculography data, available for four patients carrying an FGF14 (GAA) ≥250 expansion, showed a significant decrease in slow phase velocity of DBN with 4-aminopyridine, but not placebo., Interpretation: This study confirms that FGF14 GAA expansions are a frequent cause of DBN syndromes. It provides preliminary evidence that (GAA) 200-249 alleles might be pathogenic. Finally, it provides large real-world and preliminary piloting placebo-controlled evidence for the efficacy of 4-aminopyridine in GAA-FGF14 disease., Funding: This work was supported by the Clinician Scientist program "PRECISE.net" funded by the Else Kröner-Fresenius-Stiftung (to CW, AT, and MSy), the grant 779257 "Solve-RD" from the European's Union Horizon 2020 research and innovation program (to MSy), and the grant 01EO 1401 by the German Federal Ministry of Education and Research (BMBF) (to MSt). This work was also supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) N° 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N° 825575 (to MSy, BB and-as associated partner-SZ), the NIH National Institute of Neurological Disorders and Stroke (grant 2R01NS072248-11A1 to SZ), the Fondation Groupe Monaco (to BB), and the Montreal General Hospital Foundation (grant PT79418 to BB). The Care4Rare Canada Consortium is funded in part by Genome Canada and the Ontario Genomics Institute (OGI-147 to KMB), the Canadian Institutes of Health Research (CIHR GP1-155867 to KMB), Ontario Research Foundation, Genome Quebec, and the Children's Hospital of Eastern Ontario Foundation. The funders had no role in the conduct of this study., Competing Interests: Declaration of interests DP, FH, CW, MCD, AT, CA, MJD, AC, GDG, KMB, JC, AMH, and BB report no disclosures. DR has received grant/research support from Janssen and Lundbeck; he has served as a consultant or on advisory boards for AC Immune, Janssen, Roche and Rovi and he has served on speakers bureaus of Janssen and Pharmagenetix. He also received honoraria from Gerot Lannacher, Janssen and Pharmagenetix, and travel support from Angelini and Janssen, all unrelated to the present manuscript. SZ has received consultancy honoraria from Neurogene, Aeglea BioTherapeutics, Applied Therapeutics, and is an unpaid officer of the TGP foundation, all unrelated to the present manuscript. MSt is Joint Chief Editor of the Journal of Neurology, Editor in Chief of Frontiers of Neuro-otology and Section Editor of F1000. He has received speakers honoraria from Abbott, Auris Medical, Biogen, Eisai, Grünenthal, GSK, Henning Pharma, Interacoustics, J&J, MSD, NeuroUpdate, Otometrics, Pierre-Fabre, TEVA, UCB, and Viatris. He receives support for clinical studies from Decibel, U.S.A., Cure within Reach, U.S.A. and Heel, Germany. He distributes M-glasses and Positional vertigo App. He acts as a consultant for Abbott, AurisMedical, Bulbitec, Heel, IntraBio, Sensorion and Vertify. He is an investor and share-holder of IntraBio. All are unrelated to the present manuscript. MSy has received consultancy honoraria from Janssen, Ionis, Orphazyme, Servier, Reata, Biohaven, Zevra, Lilly, GenOrph, and AviadoBio, all unrelated to the present manuscript. MSy is planning a treatment trial of 4-AP in GAA-FGF14 disease together with Solaxa Inc. as a sponsor, but has not received any type of honoraria or funding from Solaxa., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the topical diagnosis, possible etiology and mechanism of spontaneous downbeat nystagmus (sDBN) patients with dizziness/vertigo., Methods: The clinical features of dizziness/vertigo patients accompanied with DBN were retrospectively reviewed in the Vertigo Center of our hospital from January 2018 to March 2021. The clinical features of dizziness/vertigo patients accompanied with DBN were reviewed. Comprehensive VNG, bithermal caloric testing, video-head-impulse test (vHIT), vestibular-evoked myogenic potentials (VEMP), head magnetic resonance imaging (MRI), three-dimensional fluid-attenuated incersion recovery magnetic resonance imaging (3D-FLAIR MRI) in the inner ear, serum immunology and other examinations were to determine the lesion site, and analyze its possible etiology and mechanism., Results: A total of 54 patients were included. Among them, 70.4% ( n  = 38) of DBN patients were diagnosed with episodic vestibular syndrome (EVS), 22.2% ( n  = 12) with chronic vestibular syndrome (CVS), and 7.4% ( n  = 4) with acute vestibular syndrome (AVS). Among all the patients, 51.9% of DBN patients had clear etiology, with central lesions of 29.6% and peripheral diseases of 22.2%. The most common diseases in DBN patients were cerebellar lesions (13.0%, n  = 7) and vestibular migraine (13.0%, n  = 7), followed by benign positional paroxysmal vertigo (7.4%, n  = 4) and drug-related dizziness/vertigo (5.6%, n  = 3). The other 48.1% of the patients had unknown etiology. 53.8% (14/26) of patients with idiopathic DBN had decreased semicircular canal function, with 42.9% (6/14) decreased posterior semicircular canal function. The posterior semicircular canal gain in DBN patients decreased compared to the anterior semicircular canal in the same conjugate plane. Patients with peripheral DBN were more prone to horizontal/torsional nystagmus during positional testing., Conclusion: In our study, DBN patients have a relative decrease in posterior semicircular canal gain, which is possibly a particular result found in a subset of downbeat nystagmus patients. The changes in nystagmus during positional testing may be helpful in distinguishing between peripheral and central causes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Lang, Wang, Wu, Yan, Zhang, Li, Liu, Hao, Yang and Gu.)