Gravity-Dependent Modulation of Downbeat Nystagmus and Subjective Visual Vertical in the Roll Plane.

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.

Dissociated cerebellar contributions to feedforward gait adaptation.

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.

Vestibulo-spatial navigation: pathways and sense of direction.

Aims of the present article are: 1) assessing vestibular contribution to spatial navigation, 2) exploring how age, global positioning systems (GPS) use, and vestibular navigation contribute to subjective sense of direction (SOD), 3) evaluating vestibular navigation in patients with lesions of the vestibular-cerebellum (patients with downbeat nystagmus, DBN) that could inform on the signals carried by vestibulo-cerebellar-cortical pathways. We applied two navigation tasks on a rotating chair in the dark: return-to-start (RTS), where subjects drive the chair back to the origin after discrete angular displacement stimuli (path reversal), and complete-the-circle (CTC) where subjects drive the chair on, all the way round to origin (path completion). We examined 24 normal controls (20-83 yr), five patients with DBN (62-77 yr) and, as proof of principle, two patients with early dementia (84 and 76 yr). We found a relationship between SOD, assessed by Santa Barbara Sense of Direction Scale, and subject's age (positive), GPS use (negative), and CTC-vestibular-navigation-task (positive). Age-related decline in vestibular navigation was observed with the RTS task but not with the complex CTC task. Vestibular navigation was normal in patients with vestibulo-cerebellar dysfunction but abnormal, particularly CTC, in the demented patients. We conclude that vestibular navigation skills contribute to the build-up of our SOD. Unexpectedly, perceived SOD in the elderly is not inferior, possibly explained by increased GPS use by the young. Preserved vestibular navigation in cerebellar patients suggests that ascending vestibular-cerebellar projections carry velocity (not position) signals. The abnormalities in the cognitively impaired patients suggest that their vestibulo-spatial navigation is disrupted.NEW & NOTEWORTHY Our subjective sense-of-direction is influenced by how good we are at spatial navigation using vestibular cues. Global positioning systems (GPS) may inhibit sense of direction. Increased use of GPS by the young may explain why the elderly's sense of direction is not worse than the young's. Patients with vestibulo-cerebellar dysfunction (downbeat nystagmus syndrome) display normal vestibular navigation, suggesting that ascending vestibulo-cerebellar-cortical pathways carry velocity rather than position signals. Pilot data indicate that dementia disrupts vestibular navigation.

Vestibular seizures and spontaneous downbeat nystagmus of ganglioglioma origin: a case report.

BACKGROUND: Low-grade gangliogliomas (GGs) are typically epileptogenic intracranial neoplasms. Yet, the presentation of simplex vertiginous experience and spontaneous downbeat nystagmus (DBN) has not been reported to date. CASE PRESENTATION: We present the case of a 26-year-old male with focal onset impaired awareness seizures, characterized by vertigo due to right temporal lobe epilepsy caused by ganglioglioma. As rare presentations, a spontaneous, consistent DBN in the absence of vertiginous experience was noticed. MRI suggested lesion in the right temporal pole. Twenty-four-hour continuous electroencephalogram (EEG) monitoring recorded periodic sharp and slow waves, originating from the right temporal lobe. The patient was completely relieved of the symptoms after surgical removal of the tumor, which was histologically confirmed as Grade I Ganglioglioma. CONCLUSIONS: Asides from the cortical pathogenesis of epileptic vertigo, this case also provides insight into the DBN secondary to tumor of the temporal lobe. Moreover, the 24-h EEG is advantageous to recognize vestibular seizures and localize the ictal onset areas.

Downbeat Nystagmus as a Presenting Manifestation of Neurolisteriosis in a Pregnant Woman.

Listeria monocytogenes has tropism towards two immunologically "privileged" sites, the fetoplacental unit in pregnant women and the central nervous system (neurolisteriosis) in immunocompromised individuals. We report a case of neurolisteriosis in a previously asymptomatic pregnant woman from rural West Bengal, India, who presented with a subacute onset febrile illness with features of rhombencephalitis and a predominantly midline-cerebellopathy (slow and dysmetric saccades, florid downbeat nystagmus, horizontal nystagmus, and ataxia). With timely detection and the institution of prolonged intravenous antibiotic therapy, both the mother and the fetus were saved uneventfully.

Episodic Vestibular Syndrome with Hyperventilation-Induced Downbeat Nystagmus.

Hyperventilation-induced downbeat nystagmus (HV-DBN) has been reported in cerebellar disorders and explained by a loss of the inhibitory cerebellar output via a metabolic effect on cerebellar Ca2+ channels. The aim of this study was to determine the clinical characteristics and underlying pathogenesis of episodic vestibular syndrome (EVS) with HV-DBN. Of 667 patients with EVS, we recruited 22 with HV-DBN and assessed their clinical characteristics, video-oculographic findings, and the results of molecular genetic analyses. The age at symptom onset was 47.5 ± 13.0 years (mean ± SD), and there was a female preponderance (n = 15, 68%). The duration of vertigo/dizziness attacks ranged from minutes to a few days, and 11 patients (50%) fulfilled the diagnostic criteria for vestibular migraine. HV-induced new-onset DBN in 8 patients, while the remaining 14 showed augmentation of spontaneous DBN by HV. The maximum slow-phase velocity of HV-DBN ranged from 2.2 to 11.9°/s, which showed a statistical difference with that of spontaneous DBN (median = 4.95, IQR = 3.68-6.55 vs. median = 1.25, IQR = 0.20-2.15, p < 0.001). HV-DBN was either purely downbeat (n = 11) or accompanied with small horizontal components (n = 11). Other neuro-otologic findings included perverted head-shaking nystagmus (n = 11), central positional nystagmus (n = 7), saccadic pursuit (n = 3), and horizontal gaze-evoked nystagmus (n = 1). Gene expression profiling with a bioinformatics analysis identified 43 upregulated and 49 downregulated differentially expressed genes (DEGs) in patients with EVS and HV-DBN and revealed that the downregulated DEGs were significantly enriched in terms related to the ribosome pathway. Our results suggest that the underlying cerebellar dysfunction would be responsible for paroxysmal attacks of vertigo in patients with EVS and HV-DBN.

The fixation suppression test can uncover vertical nystagmus of central origin in some patients with dizziness.

BACKGROUND: Identifying dangerous causes of dizziness is a challenging task for neurologists, as it requires interpretation of subtle bedside exam findings, which become even more subtle with time. Nystagmus can be instrumental in differentiating peripheral from central vestibular disorders. Conventional teaching is that peripheral vestibular nystagmus is accentuated by removal of visual fixation. We sought to systematically test the hypothesis that, in some cases, vertical nystagmus due to central vestibular disorders may also be easier to identify when fixation is removed. METHODS: To identify patients with vertical nystagmus, we retrospectively reviewed clinical, MRI, and VNG data of consecutive patients undergoing VNG in our vestibular clinic over a 9-month period. We analyzed clinical features, bedside neuro-otological examination, MRI results, and VNG findings in fixation as well as those with fixation removed. RESULTS: Two hundred and fourteen charts were reviewed. Twenty-six patients had vertical nystagmus with fixation removed on VNG. Only three (11.5%) of these patients had vertical nystagmus apparent with fixation (and only two had nystagmus observed clearly at the bedside with the unaided eye). Thirteen (50%) of the patients had posterior fossa lesions on MRI and eight of the rest (30.8%) were diagnosed with central vestibular disorders. Of the 13 patients with MRI-confirmed lesions, 3 patients (23.1%) had no neurological signs or conventional bedside oculomotor signs; in these cases, vertical nystagmus without fixation was the only sign of a central lesion. CONCLUSIONS: Our findings go against conventional teaching and show that removing fixation can uncover subtle vertical nystagmus due to central vestibular disease, particularly from focal or chronic lesions.

The Use of Video-Head Impulse Test in Different Head Positions in Vertical Nystagmus and Ataxia Associated with Probable Thiamine Deficiency.

Upward and downward bias of eye movement signals in the semicircular canals (SCC)- and/or otolith-related central pathways have been proposed to explain the occurrence of vertical nystagmus (downbeat nystagmus [DBN] and upbeat nystagmus [UBN]) and its frequent modulation with head position. Video-head impulse test (VHIT), usually performed in upright position, is a recent development for measuring SCC function. We performed longitudinal nystagmus and VHIT assessments in different head positions in a patient with probable thiamine deficiency, in order to explore a possible relationship between the positional behavior of vertical nystagmus and SCC function. Initially, UBN in upright position changed to DBN in prone position and remained relatively unchanged in supine position. This was associated with both anterior and posterior SCC hyperactive responses in upright position, and a relative enhancement of the anterior SCC responses in prone position and the posterior SCC responses in supine position. Over 1 year, in prone position, change from UBN to DBN and the enhancement of anterior SCC responses remained, while in supine position, UBN either decreased or changed to DBN, when compared to upright position. This was associated with a relative enhancement of the anterior SCC responses in supine position, albeit inconsistently, and the presence of posterior SCC hypoactive responses in all positions, including prone. While not contradicting a primary otolithic dysfunction in the genesis of UBN change to DBN with head position, we provide evidence for positional modulation of SCC function in thiamine deficiency and a possible relationship with nystagmus positional behavior.

A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study.

Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (p < 5 × 10-8) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (p < 1 × 10-05) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs).

Perverted Downward Corrective Saccades During Horizontal Head Impulses in Chiari Malformation.

The mechanism of perverted vertical responses during horizontal head impulse tests (HITs) requires further elucidation. A 47-year-old woman with a Chiari malformation showed alternating skew deviation, downbeat nystagmus with an increasing slow phase velocity, impaired smooth pursuit, and upward ocular deviation during horizontal HITs and corrective downward saccades in the presence of normal bithermal caloric tests and intact tilt suppressions of the post-rotatory nystagmus. These findings suggest dysfunction of the inferior cerebellum including the tonsil, nodulus, and uvula. We propose that disruption of signals from the medial part of the vestibulocerebellum, which normally inhibits the lateral and anterior canal pathways, may elicit an upward misdirection of the eye velocity during rapid horizontal head rotation. Otherwise, the Chiari malformation may have directly affected the brainstem structures involved in the direction matrix of the vestibulo-ocular reflex.

Finger extension weakness and downbeat nystagmus motor neuron disease syndrome: A novel motor neuron disorder?

INTRODUCTION: Disturbances of eye movements are infrequently encountered in motor neuron diseases (MNDs) or motor neuropathies, and there is no known syndrome that combines progressive muscle weakness with downbeat nystagmus. METHODS: To describe the core clinical features of a syndrome of MND associated with downbeat nystagmus, clinical features were collected from 6 patients. RESULTS: All patients had slowly progressive muscle weakness and wasting in combination with downbeat nystagmus, which was clinically most obvious in downward and lateral gaze. Onset was in the second to fourth decade with finger extension weakness, progressing to other distal and sometimes more proximal muscles. Visual complaints were not always present. Electrodiagnostic testing showed signs of regional motor axonal loss in all patients. DISCUSSION: The etiology of this syndrome remains elusive. Because finger extension weakness and downbeat nystagmus are the discriminating clinical features of this MND, we propose the name FEWDON-MND syndrome. Muscle Nerve 56: 1164-1168, 2017.

Perverted Head-Shaking and Positional Downbeat Nystagmus in Essential Tremor.

Even though the pathophysiology is not completely understood, cerebellar dysfunction has been invoked in essential tremor (ET). We evaluated cerebellar dysfunction in ET with the presence of perverted head-shaking (pHSN) and positional downbeat nystagmus (pDBN) which are known to reflect cerebellar dysfunction. First, we reviewed the videooculography (VOG) of 185 patients with ET from March 2007 to April 2010. Seventeen of 28 patients with pHSN and pDBN were followed up for at least a 1.8-year interval from baseline to determine the clinical course. And then, we recruited 52 consecutive patients with ET and compared their ocular motor findings with 51 normal controls using VOG. Among the 185 patients with ET, 28 (15.1 %) showed pHSN (n = 23, 12.4 %) or pDBN (n = 8, 4.3 %). Seventeen of them who were followed up did not develop Parkinsonism or other neurologic deficits during the observation period. The subsequent case-control study showed a higher prevalence of pHSN or pDBN (11/52, 21.2 %, pHSN in nine and pDBN in five) in patients with ET than in the normal controls (2/51, 3.9 %, pHSN only, P = 0.015). The tremor rating scale or involved body sites did not differ between the patients with and without pHSN/pDBN. pHSN and pDBN were more common in patients with ET than in the normal controls. This result supports that cerebellar dysfunction is associated with ET.

Update on the Pharmacotherapy of Cerebellar Ataxia and Nystagmus.

Pharmacological treatment of cerebellar ataxias and cerebellar nystagmus still remains difficult. The efficacy of most of the agents recommended in the past for symptomatic or even causative therapy could not be proven in larger state-of-the art clinical trials. Exceptions are (a) 4-aminopyridine (4-AP) for episodic ataxia type 2 (EA2): one observational and one randomized controlled trial showed a significant effect on the number of attacks of ataxia and quality of life; (b) aminopyridines in cerebellar downbeat nystagmus (DBN): two randomized controlled trials and several observational studies demonstrate a significant improvement of the intensity of DBN, visual acuity, and postural imbalance. In both diseases the sustained-release form is evidently also efficient; (c) 4-AP in cerebellar gait ataxia: evidence comes from two observational studies. (d) chlorzoxazone in DBN which, however, was so far demonstrated in only one observational study; (e) the modified amino acid acetyl-DL-leucine: evidently effective in cerebellar ataxias, shown in three observational studies, one on patients with Niemann-Pick type C; its mode of action has to be evaluated in animal models and on a cellular/electrophysiological level. There are ongoing randomized placebo-controlled trials on EA2 with 4-AP versus acetazolamide (EAT-2-TREAT), cerebellar gait ataxia with 4-AP (FACEG), and a multinational trial on cerebellar ataxia with acetyl-DL-leucine (ALCAT).

Downbeat nystagmus: evidence for enhancement of utriculo-ocular pathways by ocular vestibular evoked myogenic potentials?

Downbeat nystagmus (DBN) is caused by an impairment of Purkinje cells in the flocculus. The decreased cerebellar inhibitory input affects otolith pathways. Since ocular and cervical vestibular evoked myogenic potentials (o-/cVEMP) test the otoliths, the VEMP were measured in DBN patients and in controls. Sixteen patients with DBN, 14 cerebellar oculomotor disorder patients without DBN (COMD), and 16 healthy controls were examined with o-/cVEMP. Computational modeling was used to predict VEMP differences between groups. DBN patients had significantly higher oVEMP peak-to-peak (PP) amplitudes than COMD patients without DBN and controls. Cervical VEMP did not differ. The computational model of DBN predicted a twofold oVEMP increase for DBN patients. These findings suggest an enhancement of the utriculo-ocular response. The unchanged cVEMP indicate no effect on the otolith-cervical reflex in DBN. Computational modeling suggests that the utriculo-ocular enhancement is caused by an impaired vertical neural integrator resulting in the increased influence of utricular signals. This also explains the gravitational dependence of DBN.

New treatment of vertigo caused by jugular bulb abnormalities.

OBJECTIVE: Jugular bulb abnormalities can induce tinnitus, hearing loss, or vertigo. Vertigo can be very disabling and may need surgical treatments with risk of hearing loss, major bleeding or facial palsy. Hence, we have developed a new treatment for vertigo caused by jugular bulb anomalies, using an endovascular technique. PATIENTS: Three patients presented with severe vertigos mostly induced by high venous pressure. One patient showed downbeat vertical nystagmus during the Valsalva maneuver. The temporal-bone computed tomography scan showed a high rising jugular bulb or a jugular bulb diverticulum with dehiscence and compression of the vestibular aqueduct in all cases. INTERVENTION: We plugged the upper part of the bulb with coils, and we used a stent to maintain the coils and preserving the venous permeability. RESULTS: After 12- to 24-month follow-up, those patients experienced no more vertigo, allowing return to work. The 3-month arteriographs showed good permeability of the sigmoid sinus and jugular bulb through the stent, with complete obstruction of the upper part of the bulb in all cases. CONCLUSION: Disabling vertigo induced by jugular bulb abnormalities can be effectively treated by an endovascular technique. This technique is minimally invasive with a probable greater benefit/risk ratio compare with surgery.

Downbeat nystagmus: a clinical and pathophysiological review.

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.

Analysis of etiology and clinical features of spontaneous downbeat nystagmus: a retrospective study.

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.

GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort.

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.