Patient-Related Outcome Measures for Oculomotor Symptoms in the Cerebellar Ataxias: Insights from Non-Cerebellar Disorders.

In patients with cerebellar ataxia (CA), symptoms related to oculomotor dysfunction significantly affect quality of life (QoL). This study aimed to analyze the literature on patient-related outcome measures (PROMs) assessing QoL impacts of vestibular and cerebellar oculomotor abnormalities in patients with CA to identify the strengths and limitations of existing scales and highlight any areas of unmet need. A systematic review was conducted (Medline, Embase) of English-language original articles reporting on QoL measures in patients with vertigo, dizziness or CA. Pre-specified parameters were retrieved, including diseases studied, scales applied and conclusions drawn. Our search yielded 3671 articles of which 467 studies (n = 111,606 participants) were deemed relevant. The most frequently studied disease entities were (a) non-specific dizziness/gait imbalance (114 studies; 54,581 participants), (b) vestibular schwannomas (66; 15,360), and (c) vestibular disorders not further specified (66; 10,259). The Dizziness Handicap Inventory (DHI) was the most frequently used PROM to assess QoL (n = 91,851), followed by the Penn Acoustic Neuroma Quality-of-Life Scale (n = 12,027) and the Activities-Specific Balance Confidence Scale (n = 2'471). QoL-scores capturing symptoms related to oculomotor abnormalities in CA were rare, focused on visual impairments (e.g., National-Eye-Institute Visual Function Questionnaire, Oscillopsia Functional Impact, oscillopsia severity score) and were unvalidated. The DHI remains the most widely used and versatile scale for evaluating dizziness. A lack of well-established PROMs for assessing the impact of oculomotor-related symptoms on QoL in CA was noted, emphasizing the need for developing and validating a new QoL-score dedicated to the oculomotor domain for individuals with CA.

Quantitative Oculomotor Assessment in Hereditary Ataxia: Discriminatory Power, Correlation with Severity Measures, and Recommended Parameters for Specific Genotypes.

Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.

What is the current status of care by neuro-otology specialists in Switzerland-A national survey.

Background: Vertigo and dizziness are frequent presenting symptoms in the emergency department and in outpatient centers. While the majority of dizzy patients are evaluated by primary care physicians, specialists are often involved in the diagnostic workup. We aimed to gain more insights into the role of specialists in the care of dizzy patients. Materials and methods: Board-certified neurologists and ear-nose-throat (ENT) physicians working in Switzerland were invited to participate in an online survey. Descriptive statistical analyses were performed, and prospectively defined hypotheses were assessed using correlation analyses. Results: All 111 participating specialists (neurologists = 62; ENT specialists = 49) were familiar with testing for posterior canal benign paroxysmal positional vertigo (BPPV), and 66% regularly applied provocation maneuvers for suspected lateral canal BPPV. Reposition maneuvers for posterior (99%) and lateral (68%) canals were frequently performed. ENT physicians were familiar with lateral canal BPPV repositioning maneuvers significantly more often than neurologists (84 vs. 56%, p ≤ 0.012). Specialists strongly agreed that performing the head impulse test (86%) and looking for deficient eccentric gaze holding (82%) are important. Compared to neurologists, significantly fewer ENT physicians indicated ordering brain MRI in acutely dizzy patients (OR = 0.33 [0.16-0.067], p = 0.002) and physical therapy in patients with acute (50 vs. 20%, p = 0.005) or episodic/chronic dizziness (78 vs. 50%, p = 0.003). Conclusion: We found substantial differences in the care of dizzy patients by neurologists and ENT physicians. This underlines the need for a standardized, guideline-oriented diagnostic workup and treatment across specialties. Dedicated training for performing lateral canal BPPV repositioning maneuvers should be prioritized for neurologists. Similarly, physical therapy should be considered more often by ENT physicians.

What's in a Name? Chronic Vestibular Migraine or Persistent Postural Perceptual Dizziness?

Current consensus diagnostic criteria for vestibular migraine (VM) describes this as an episodic disorder. However, a minority of patients report prolonged (>72 h duration) or even persistent VM symptoms, prompting whether a chronic variant of vestibular migraine (CVM) should be introduced to the current classification and how best to define it. Here we summarize current evidence of such a potential chronic variant of VM and critically review proposed definitions for CVM. Potential approaches to establish a diagnostic framework for CVM include (a) following the distinction between episodic and chronic migraine headaches, namely, frequent and/or prolonged episodes of VM (but not persistent vertigo or dizziness) in the context of chronic migraine headaches or (b) daily dizzy spells over more than 6 months that responded well to prophylactic anti-migraine therapy. A key challenge when defining diagnostic criteria for CVM is how to distinguish it from other chronic vestibular syndromes such as motion sickness, persistent postural-perceptual dizziness (PPPD), and mal de débarquement syndrome. Indeed, more than 50% of patients with PPPD and up to 46% with mal de débarquement syndrome fulfil diagnostic criteria for episodic migraine headaches, suggesting these disorders may all lie along a spectrum. We propose that when VM becomes persistent, it is best classified as PPPD but that VM and PPPD are not mutually exclusive, such that patients with PPPD need not have features of VM, and the triggering event for persistent dizziness may be independent of migraine. However, further research is needed to better characterize the spectrum of clinical phenotypes in patients with chronic dizziness, migraine headaches and anxiety, to define whether a chronic variant of VM sufficiently differs from current persistent dizziness definitions.

What is the current status of primary care in the diagnosis and treatment of patients with vertigo and dizziness in Switzerland? A national survey.

Background: Vertigo and dizziness are among the most frequent presenting symptoms in the primary care physicians' (PCPs) office. With patients facing difficulties in describing their complaints and clinical findings often being subtle and transient, the diagnostic workup of the dizzy patient remains challenging. We aimed to gain more insights into the current state of practice in order to identify the limitations and needs of the PCPs and define strategies to continuously improve their knowledge in the care of the dizzy patient. Materials and methods: Board-certified PCPs working in Switzerland were invited to participate in an online survey. A descriptive statistical analysis was performed, and prospectively defined hypotheses were assessed using regression analyses. Results: A vast majority of participating PCPs (n = 152) were familiar with the key questions when taking the dizzy patient's history and with performing provocation/repositioning maneuvers when posterior-canal benign paroxysmal positional vertigo (BPPV) was suspected (91%). In contrast, strong agreement that performing the alternating cover test (21%), looking for a spontaneous nystagmus with fixation removed (42%), and performing the head-impulse test (47%) were important was considerably lower, and only 19% of PCPs were familiar with lateral-canal BPPV treatment. No specific diagnosis could be reached in substantial fractions of patients with acute (35% [25; 50%], median [inter-quartile range]) and episodic/chronic (50% [40; 65.8%]) dizziness/vertigo. Referral to specialists was higher in patients with episodic/chronic dizziness than in acutely dizzy patients (50% [20.3; 75] vs. 30% [20; 50]), with younger PCPs (aged 30-40 years) demonstrating significantly increased odds of referral to specialists (odds ratio = 2.20 [1.01-4.81], p = 0.048). Conclusion: The assessment of dizzy patients takes longer than that of average patients in most primary care practices. Many dizzy patients remain undiagnosed even after a thorough examination, highlighting the challenges faced by PCPs and potentially leading to frequent referrals to specialists. To address this, it is crucial to promote state-of-the-art neuro-otological examination and treatment techniques that are currently neglected by most PCPs, such as "HINTS" and lateral-canal BPPV treatment. This can help reduce referral rates allowing more targeted treatment and referrals.

Bedside Testing in Acute Vestibular Syndrome-Evaluating HINTS Plus and Beyond-A Critical Review.

Acute vertigo and dizziness are frequent presenting symptoms in patients in the emergency department. These symptoms, which can be subtle and transient, present diagnostic challenges because they can be caused by a broad range of conditions that cut across many specialties and organ systems. Previous work has emphasized the value of combining structured history taking and a targeted examination focusing on subtle oculomotor signs. In this review, we discuss various diagnostic bedside algorithms proposed for the acutely dizzy patient. We analyzed these different approaches by calculating their area-under-the-curve (ROC) characteristics and sensitivity/specificity. We found that the algorithms that incorporated structured history taking and the use of subtle oculomotor signs had the highest diagnostic accuracy. In fact, both the HINTS+ bedside exam and the STANDING algorithm can more accurately diagnose acute strokes than early (<24 to 48 h after symptom onset) MRI with diffusion-weighted imaging (DWI). An important caveat is that HINTS and STANDING require moderate training to achieve this accuracy. Therefore, for physicians who have not undergone adequate training, other approaches are needed. These other approaches (e.g., ABCD2 score, PCI score, and TriAGe+ score) rely on vascular risk factors, clinical symptoms, and focal neurologic findings. While these other scores are easier for frontline providers to use, their diagnostic accuracy is far lower than HINTS+ or STANDING. Therefore, a focus on providing dedicated training in HINTS+ or STANDING techniques to frontline clinicians will be key to improving diagnostic accuracy and avoiding unnecessary brain imaging.

Ischaemic stroke despite antiplatelet therapy: Causes and outcomes.

BACKGROUND: Ischaemic stroke may occur despite antiplatelet therapy (APT). We aimed to investigate frequency, potential causes and outcomes in patients with ischaemic stroke despite APT. METHODS: In this cohort study, we enrolled patients with imaging-confirmed ischaemic stroke from the Swiss Stroke Registry (01/2014-07/2022). We determined the frequency of prior APT, assessed stroke aetiology (modified TOAST classification) and determined the association of prior APT with unfavourable functional outcome (modified Rankin Scale score 3-6) and recurrent ischaemic stroke at 3 months using regression models. RESULTS: Among 53,352 patients, 27,484 (51.5%) had no prior antithrombotic treatment, 17,760 (33.3%) were on APT, 7039 (13.2%) on anticoagulation and 1069 (2.0%) were on APT + anticoagulation. In patients with a history of ischaemic stroke/TIA (n = 11,948; 22.4%), 2401 (20.1%) had no prior antithrombotic therapy, 6594 (55.2%) were on APT, 2489 (20.8%) on anticoagulation and 464 (3.9%) on APT + anticoagulation. Amongst patients with ischaemic stroke despite APT, aetiology was large artery atherosclerosis in 19.8% (n = 3416), cardiac embolism in 23.6% (n = 4059), small vessel disease in 11.7% (n = 2011), other causes in 7.4% (n = 1267), more than one cause in 6.3% (n = 1078) and unknown cause in 31.3% (n = 5388). Prior APT was not independently associated with unfavourable outcome (aOR = 1.06; 95% CI: 0.98-1.14; p = 0.135) or death (aOR = 1.10; 95% CI: 0.99-1.21; p = 0.059) at 3-months but with increased odds of recurrent stroke (6.0% vs 4.3%; aOR 1.26; 95% CI: 1.11-1.44; p < 0.001). CONCLUSIONS: One-third of ischaemic strokes occurred despite APT and 20% of patients with a history of ischaemic stroke had no antithrombotic therapy when having stroke recurrence. Aetiology of breakthrough strokes despite APT is heterogeneous and these patients are at increased risk of recurrent stroke.

Impact of Clinician Training Background and Stroke Location on Bedside Diagnostic Test Accuracy in the Acute Vestibular Syndrome - A Meta-Analysis.

OBJECTIVE: Acute dizziness/vertigo is usually due to benign inner-ear causes but is occasionally due to dangerous neurologic ones, particularly stroke. Because symptoms and signs overlap, misdiagnosis is frequent and overuse of neuroimaging is common. We assessed the accuracy of bedside findings to differentiate peripheral vestibular from central neurologic causes. METHODS: We performed a systematic search (MEDLINE and Embase) to identify studies reporting on diagnostic accuracy of physical examination in adults with acute, prolonged dizziness/vertigo ("acute vestibular syndrome" [AVS]). Diagnostic test properties were calculated for findings. Results were stratified by examiner type and stroke location. RESULTS: We identified 6,089 citations and included 14 articles representing 10 study cohorts (n = 800). The Head Impulse, Nystagmus, Test of Skew (HINTS) eye movement battery had high sensitivity 95.3% (95% confidence interval [CI] = 92.5-98.1) and specificity 92.6% (95% CI = 88.6-96.5). Sensitivity was similar by examiner type (subspecialists 94.3% [95% CI = 88.2-100.0] vs non-subspecialists 95.0% [95% CI = 91.2-98.9], p = 0.55), but specificity was higher among subspecialists (97.6% [95% CI = 94.9-100.0] vs 89.1% [95% CI = 83.0-95.2], p = 0.007). HINTS sensitivity was lower in anterior cerebellar artery (AICA) than posterior inferior cerebellar artery (PICA) strokes (84.0% [95% CI = 65.3-93.6] vs 97.7% [95% CI = 93.3-99.2], p = 0.014) but was "rescued" by the addition of bedside hearing tests (HINTS+). Severe (grade 3) gait/truncal instability had high specificity 99.2% (95% CI = 97.8-100.0) but low sensitivity 35.8% (95% CI = 5.2-66.5). Early magnetic resonance imaging (MRI)-diffusion-weighted imaging (DWI; within 24-48 hours) was falsely negative in 15% of strokes (sensitivity 85.1% [95% CI = 79.2-91.0]). INTERPRETATION: In AVS, HINTS examination by appropriately trained clinicians can differentiate peripheral from central causes and has higher diagnostic accuracy for stroke than MRI-DWI in the first 24-48 hours. These techniques should be disseminated to all clinicians evaluating dizziness/vertigo. ANN NEUROL 2023;94:295-308.

Quantitative Oculomotor Assessment in Hereditary Ataxia: Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital-motor Biomarkers.

Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia. MEDLINE was searched for articles reporting on oculomotor/vestibular properties in ataxia patients and a study-tailored quality-assessment was performed. One-hundred-and-seventeen articles reporting on subjects with genetically confirmed (n=1134) or suspected hereditary ataxia (n=198), and degenerative ataxias with sporadic presentation (n=480) were included and subject to data extraction. Based on robust discrimination from controls, correlation with disease-severity, sensitivity to change, and feasibility in international multicenter settings as prerequisite for clinical trials, we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex. We provide detailed guidelines for their acquisition, and recommendations on the quantitative parameters to extract. Limitations include low study quality, heterogeneity in patient populations, and lack of longitudinal studies. Standardization of quantitative oculomotor assessments will facilitate their implementation, interpretation, and validation in clinical trials, and ultimately advance our understanding of the evolution of oculomotor network dysfunction in hereditary ataxias.

Central Retinal Artery Occlusion: Current Practice, Awareness and Prehospital Delays in Switzerland.

Background and Purpose: Central retinal artery occlusion (CRAO) often leads to permanent monocular blindness. Hence, early recognition and rapid re-perfusion is of paramount importance. This study aims to describe prehospital pathways in CRAO compared to stroke and study the knowledge about CRAO. Methods: (1) Description of baseline characteristics, prehospital pathways/delays, and acute treatment (thrombolysis/thrombectomy vs. standard of care) of patients with CRAO and ischemic stroke registered in the Swiss Stroke Registry. (2) Online survey about CRAO knowledge amongst population, general practitioners (GPs) and ophthalmologists in Eastern Switzerland. Results: Three hundred and ninety seven CRAO and 32,816 ischemic stroke cases were registered from 2014 until 2019 in 20 Stroke Centers/Units in Switzerland. In CRAO, 25.6% arrived at the hospital within 4 h of symptom onset and had a lower rate of emergency referrals. Hence, the symptom-to-door time was significantly longer in CRAO compared to stroke (852 min. vs. 300 min). The thrombolysis/thrombectomy rate was 13.2% in CRAO and 30.9% in stroke. 28.6% of the surveyed population recognized CRAO-symptoms, 55.4% of which would present directly to the emergency department in contrast to 90.0% with stroke symptoms. Almost 100% of the ophthalmologist and general practitioners recognized CRAO as a medical emergency and 1/3 of them considered IV thrombolysis a potentially beneficial therapy. Conclusions: CRAO awareness of the general population and physician awareness about the treatment options as well as the non-standardized prehospital organization, seems to be the main reason for the prehospital delays and impedes treating CRAO patients. Educational efforts should be undertaken to improve awareness about CRAO.

Ischemic stroke in COVID-19 patients: Mechanisms, treatment, and outcomes in a consecutive Swiss Stroke Registry analysis.

BACKGROUND: Most case series of patients with ischemic stroke (IS) and COVID-19 are limited to selected centers or lack 3-month outcomes. The aim of this study was to describe the frequency, clinical and radiological features, and 3-month outcomes of patients with IS and COVID-19 in a nationwide stroke registry. METHODS: From the Swiss Stroke Registry (SSR), we included all consecutive IS patients ≥18 years admitted to Swiss Stroke Centers or Stroke Units during the first wave of COVID-19 (25 February to 8 June 2020). We compared baseline features, etiology, and 3-month outcome of SARS-CoV-2 polymerase chain reaction-positive (PCR+) IS patients to SARS-CoV-2 PCR- and/or asymptomatic non-tested IS patients. RESULTS: Of the 2341 IS patients registered in the SSR during the study period, 36 (1.5%) had confirmed COVID-19 infection, of which 33 were within 1 month before or after stroke onset. In multivariate analysis, COVID+ patients had more lesions in multiple vascular territories (OR 2.35, 95% CI 1.08-5.14, p = 0.032) and fewer cryptogenic strokes (OR 0.37, 95% CI 0.14-0.99, p = 0.049). COVID-19 was judged the likely principal cause of stroke in 8 patients (24%), a contributing/triggering factor in 12 (36%), and likely not contributing to stroke in 13 patients (40%). There was a strong trend towards worse functional outcome in COVID+ patients after propensity score (PS) adjustment for age, stroke severity, and revascularization treatments (PS-adjusted common OR for shift towards higher modified Rankin Scale (mRS) = 1.85, 95% CI 0.96-3.58, p = 0.07). CONCLUSIONS: In this nationwide analysis of consecutive ischemic strokes, concomitant COVID-19 was relatively rare. COVID+ patients more often had multi-territory stroke and less often cryptogenic stroke, and their 3-month functional outcome tended to be worse.

Association of the COVID-19 outbreak with acute stroke care in Switzerland.

BACKGROUND AND PURPOSE: In Switzerland, the COVID-19 incidence during the first pandemic wave was high. Our aim was to assess the association of the outbreak with acute stroke care in Switzerland in spring 2020. METHODS: This was a retrospective analysis based on the Swiss Stroke Registry, which includes consecutive patients with acute cerebrovascular events admitted to Swiss Stroke Units and Stroke Centers. A linear model was fitted to the weekly admission from 2018 and 2019 and was used to quantify deviations from the expected weekly admissions from 13 March to 26 April 2020 (the "lockdown period"). Characteristics and 3-month outcome of patients admitted during the lockdown period were compared with patients admitted during the same calendar period of 2018 and 2019. RESULTS: In all, 28,310 patients admitted between 1 January 2018 and 26 April 2020 were included. Of these, 4491 (15.9%) were admitted in the periods March 13-April 26 of the years 2018-2020. During the lockdown in 2020, the weekly admissions dropped by up to 22% compared to rates expected from 2018 and 2019. During three consecutive weeks, weekly admissions fell below the 5% quantile (likelihood 0.38%). The proportion of intracerebral hemorrhage amongst all registered admissions increased from 7.1% to 9.3% (p = 0.006), and numerically less severe strokes were observed (median National Institutes of Health Stroke Scale from 3 to 2, p = 0.07). CONCLUSIONS: Admissions and clinical severity of acute cerebrovascular events decreased substantially during the lockdown in Switzerland. Delivery and quality of acute stroke care were maintained.

Pre-habilitation Before Vestibular Schwannoma Surgery-Impact of Intratympanal Gentamicin Application on the Vestibulo-Ocular Reflex.

Background: Patients with vestibular schwannoma that show residual peripheral-vestibular function before surgery may experience sudden and substantial vestibular loss of function after surgical resection. To alleviate the sudden loss of peripheral-vestibular function after vestibular-schwannoma (VS) resection, pre-surgical intratympanic gentamicin application was proposed. Objective: We hypothesized that this approach allows for a controlled reduction of peripheral-vestibular function before surgery but that resulting peripheral-vestibular deficits may be canal-specific with anterior-canal sparing as observed previously in systemic gentamicin application. Methods: Thirty-four patients (age-range = 27-70 y) with unilateral VS (size = 2-50 mm) were included in this retrospective single-center trial. The angular vestibulo-ocular reflex (aVOR) was quantified before and after (29.7 ± 18.7 d, mean ± 1SD) a single or two sequential intratympanic gentamicin applications by use of video-head-impulse testing. Both aVOR gains, cumulative saccadic amplitudes, and overall aVOR function were retrieved. Statistical analysis was done using a generalized linear model. Results: At baseline, loss of function of the horizontal (20/34) and posterior (21/34) canal was significantly (p < 0.001) more frequent than that of the anterior canal (5/34). After gentamicin application, loss of function of the horizontal (32/34) or posterior (31/34) canal remained significantly (p ≤ 0.003) more frequent than that of the anterior canal (18/34). For all ipsilesional canals, significant aVOR-gain reductions and cumulative-saccadic-amplitude increases were noted after gentamicin. For the horizontal canal, loss of function was significantly larger (increase in cumulative-saccadic-amplitude: 1.6 ± 2.0 vs. 0.8 ± 1.2, p = 0.007) or showed a trend to larger changes (decrease in aVOR-gain: 0.24 ± 0.22 vs. 0.13 ± 0.29, p = 0.069) than for the anterior canal. Conclusions: Intratympanic gentamicin application resulted in a substantial reduction in peripheral-vestibular function in all three ipsilesional canals. Relative sparing of anterior-canal function noted at baseline was preserved after gentamicin treatment. Thus, pre-surgical intratympanic gentamicin is a suitable preparatory procedure for reducing the drop in peripheral-vestibular function after VS-resection. The reasons for relative sparing of the anterior canal remain unclear.

Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease.

OBJECTIVE: To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). METHODS: Multimodal RFC1 repeat screening (PCR, Southern blot, whole-exome/genome sequencing-based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia. RESULTS: Prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C-like progression (SARA points 2.5-5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression. CONCLUSIONS: RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.

Cerebellar Rebound Nystagmus Explained as Gaze-Evoked Nystagmus Relative to an Eccentric Set Point: Implications for the Clinical Examination.

A brain stem/cerebellar neural integrator enables stable eccentric gaze. Cerebellar loss-of-function can cause an inability to maintain gaze eccentrically (gaze-evoked nystagmus). Moreover, after returning gaze to straight ahead, the eyes may drift toward the prior eye position (rebound nystagmus). Typically, gaze-evoked nystagmus decays during continuously held eccentric gaze. We hypothesized this adaptive behavior to be prerequisite for rebound nystagmus and thus predicted a correlation between the velocity decay of gaze-evoked nystagmus and the initial velocity of rebound nystagmus. Using video-oculography, eye position was measured in 11 patients with cerebellar degeneration at nine horizontal gaze angles (15° nasal to 25° temporal) before (baseline), during, and after attempted eccentric gaze at ± 30° for 20 s. We determined the decrease of slow-phase velocity at eccentric gaze and the slow-phase velocity of the subsequent rebound nystagmus relative to the baseline. During sustained eccentric gaze, eye drift velocity of gaze-evoked nystagmus decreased by 2.40 ± 1.47°/s. Thereafter, a uniform change of initial eye drift velocity relative to the baseline (2.40 ± 1.35°/s) occurred at all gaze eccentricities. The velocity decrease during eccentric gaze and the subsequent uniform change of eye drift were highly correlated (R2 = 0.80, p < 0.001, slope = 1.09). Rebound nystagmus can be explained as gaze-evoked nystagmus relative to a set point (position with least eye drift) away from straight-ahead eye position. To improve detection at the bedside, we suggest testing rebound nystagmus not at straight-ahead eye position but at an eccentric position opposite of prior eccentric gaze (e.g., 10°), ideally using quantitative video-oculography to facilitate diagnosis of cerebellar loss-of-function.

Prior Anticoagulation in Patients with Ischemic Stroke and Atrial Fibrillation.

OBJECTIVE: The aim was to evaluate, in patients with atrial fibrillation (AF) and acute ischemic stroke, the association of prior anticoagulation with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) with stroke severity, utilization of intravenous thrombolysis (IVT), safety of IVT, and 3-month outcomes. METHODS: This was a cohort study of consecutive patients (2014-2019) on anticoagulation versus those without (controls) with regard to stroke severity, rates of IVT/mechanical thrombectomy, symptomatic intracranial hemorrhage (sICH), and favorable outcome (modified Rankin Scale score 0-2) at 3 months. RESULTS: Of 8,179 patients (mean [SD] age, 79.8 [9.6] years; 49% women), 1,486 (18%) were on VKA treatment, 1,634 (20%) on DOAC treatment at stroke onset, and 5,059 controls. Stroke severity was lower in patients on DOACs (median National Institutes of Health Stroke Scale 4, [interquartile range 2-11]) compared with VKA (6, [2-14]) and controls (7, [3-15], p < 0.001; quantile regression: ß -2.1, 95% confidence interval [CI] -2.6 to -1.7). The IVT rate in potentially eligible patients was significantly lower in patients on VKA (156 of 247 [63%]; adjusted odds ratio [aOR] 0.67; 95% CI 0.50-0.90) and particularly in patients on DOACs (69 of 464 [15%]; aOR 0.06; 95% CI 0.05-0.08) compared with controls (1,544 of 2,504 [74%]). sICH after IVT occurred in 3.6% (2.6-4.7%) of controls, 9 of 195 (4.6%; 1.9-9.2%; aOR 0.93; 95% CI 0.46-1.90) patients on VKA and 2 of 65 (3.1%; 0.4-10.8%, aOR 0.56; 95% CI 0.28-1.12) of those on DOACs. After adjustments for prognostic confounders, DOAC pretreatment was associated with a favorable 3-month outcome (aOR 1.24; 1.01-1.51). INTERPRETATION: Prior DOAC therapy in patients with AF was associated with decreased admission stroke severity at onset and a remarkably low rate of IVT. Overall, patients on DOAC might have better functional outcome at 3 months. Further research is needed to overcome potential restrictions for IVT in patients taking DOACs. ANN NEUROL 2021;89:42-53.

Asymmetry in Gaze-Holding Impairment in Acute Unilateral Ischemic Cerebellar Lesions Critically Depends on the Involvement of the Caudal Vermis and the Dentate Nucleus.

Stabilizing the eyes in space when looking at a target is provided by a brainstem/cerebellar gaze-holding network, including the flocculus/paraflocculus complex (non-human primate studies) and the caudal vermis, biventer, and inferior semilunar lobule (human studies). Previous research suggests that acute lateralized cerebellar lesions preferentially lead to gaze-evoked nystagmus (GEN) on ipsilesional gaze. Here, we further characterize the effect of unilateral cerebellar lesions on gaze-holding and hypothesize that the side-specific magnitude of gaze-holding impairment depends on the lesion location. Nine patients (age range = 31-62 years) with acute/subacute (≤ 10 days old) MRI-confirmed unilateral cerebellar stroke were included. Horizontal gaze holding was quantified while looking at a slowly moving (0.5°/s) flashing target (gaze angle = ±40°). Asymmetry in eye-drift velocity was calculated and compared with the different MRI patterns of cerebellar lesions. Individual peak eye-drift velocities (range = 1.7-8.8°/s) occurred at the most eccentric eye positions (gaze angle = 28-38°). We found significantly asymmetric eye-drift velocity (EDV) in eight out of nine patients. The four patients with MRI-confirmed involvement of the caudal vermis and the dentate nucleus all presented with ipsilesionally-predominant EDV, while in the five patients with lesions restricted to the cerebellar hemisphere, EDV was stronger on contralesional gaze in three out of four found with an asymmetric EDV. Involvement of the caudal vermis and the dentate nucleus is critical for determining the directional GEN asymmetry in unilateral cerebellar lesions. Thus, our findings support the occurrence of GEN without floccular/parafloccular lesions and suggest that the EDV asymmetry in relation to the side of the lesion provides information about the involvement of specific structures.

Prolonged Static Whole-Body Roll-Tilt and Optokinetic Stimulation Significantly Bias the Subjective Postural Vertical in Healthy Human Subjects.

Background: Prolonged static whole-body roll-tilt has been shown to bias estimates of the direction of gravity when assessed by static paradigms such as the subjective visual vertical and the subjective haptic vertical. Objective: We hypothesized that these shifts are paradigm-independent and thus predicted a post-tilt bias as well for self-adjustments along perceived vertical (subjective postural vertical, SPV). Likewise, rotatory optokinetic stimuli, which have been shown to shift the SPV when presented at the time of adjustments, may have an lasting effect on the SPV, predicting a shift in the perceived direction of gravity in the direction of the optokinetic rotatory stimulation. Methods: Self-adjustments along perceived vertical by use of a motorized turntable were recorded at baseline and after 5 min of static whole-body roll-tilt (orientation = ±90°, adaptation period) in 10 healthy human subjects. During adaptation subjects were either in darkness (no OKN stimulation) or were presented a full-field rotatory optokinetic stimulus (velocity = ±60°/s). Statistical analysis of adjustment errors for the different conditions was performed using a generalized linear model. Results: After 5 min of static whole-body roll-tilt in darkness, we observed significant (p < 0.001) shifts in the SPV averaging -2.8° (adaptation position: -90°) and 3.1° (+90°), respectively. Adding an optokinetic rotatory stimulus resulted in an additional, significant shift of SPV adjustments toward the direction of the previously presented optokinetic rotation (optokinetic clockwise rotation: 1.4°, p = 0.034; optokinetic counter-clockwise rotation: -1.3°, p = 0.037). Trial-to-trial variability of turntable adjustments was not significantly affected by adaptation. Conclusions: Prolonged static roll-tilt results in a significant post-tilt bias of the perceived direction of gravity when assessed by the SPV, confirming previous findings from other vision-dependent and vision-independent paradigms. This finding emphasizes the impact of recent whole-body roll orientations relative to gravity. Such adaptational shifts in verticality estimates may be explained in the context of Bayesian optimal observer theory with a bias of prior knowledge (i.e., expectation biased by experience). Our findings also have clinical implications, as the observed post-tilt bias may contribute to postural instability when standing up in the morning with an increasing risk for falls and fall-related injuries in humans with preexisting balance disorders.