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A clinical scale fully dedicated to evaluating ocular motor abnormalities is required for now. We investigated the utility of a recently developed Scale for Ocular motor Disorders in Ataxia (SODA) in patients with multiple system atrophy (MSA). We prospectively assessed SODA in consecutive patients with MSA between August 2021 and August 2023 at the Korea University Medical Center. The results of the clinical exam-based SODA were compared with those measured using video-oculography (VOG-guided SODA). We also compared the findings with other established clinical scales targeting patients with MSA, including the Unified Multiple System Atrophy Rating Scale (UMSARS) I-II, Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor part (UPDRS-III), Scale for Assessment of Rating of Ataxia (SARA), Composite Autonomic Symptom Score-31 (COMPASS-31), and Composite Autonomic Severity Score (CASS). Twenty patients were enrolled in our study (17 with cerebellar-type MSA and three with Parkinson-type MSA). Scores ranged from 1 to 14 (median [interquartile range (IQR)] = 8 [5−10]). Among the subscales, saccades had a median score of 2.5 (IQR = 1–3), followed by ocular pursuit (1 [0–1]), nystagmus (1 [0–2]), saccadic intrusions (1 [0–1]), vestibulo-ocular reflex (VOR) (0.5 [0–1]), ocular alignment (0 [0–1]), and VOR cancellation (1 [0–1]). The clinical-exam-based SODA (p = 0.020) and VOG-guided SODA (p = 0.034) positively correlated with disease duration. No correlation was found between clinical exam-based SODA and other scales. Skew deviation, gaze-evoked nystagmus, VOR cancellation, and smooth pursuit had the highest precision among the items. Ocular misalignment and spontaneous and positional nystagmus were frequently false positive and were poorly detected with clinical exam-based SODA. Six patients with repeated evaluation exhibited higher scores, along with deterioration documented on other clinical scales. The SODA can reliably predict neurodegeneration as an additional clinical surrogate in MSA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The diagnosis of spinocerebellar ataxia (SCA) currently depends upon genetic testing. Although genetic testing for SCA is highly specific, clinical parameters for the differentiation of SCAs are still insufficient. We aimed to assess the vestibulo-ocular reflex (VOR) parameters of various SCA subtypes to determine whether they have substantial value in differential diagnosis. We consecutively enrolled 33 genetically confirmed SCA patients (SCA2 = 8, SCA3 = 6, SCA6 = 10, SCA7 = 9). Normative data were obtained from 36 age- and gender-matched healthy controls. Quantitative indicators of VOR were measured using video head impulse test (HIT) and combined ocular motor dysfunctions were investigated using video-oculography. Compared with the control group, the VOR gains in SCA2 were relatively spared, but were markedly decreased for all six canals in SCA3. The VOR gains for the posterior canals (PCs) were significantly decreased in SCA6, and for both vertical canals were decreased in SCA7. The VOR gains for the horizontal canals in SCA3 were negatively correlated with disease severity (R = -0.900, p = 0.037). Abnormal catch-up saccades were common in SCA3 and SCA6, rare in SCA7 and absent in SCA2. Spontaneous, headshaking-induced, and positional nystagmus were only documented in SCA6. SCA3 and SCA6 commonly showed horizontal gaze-evoked nystagmus, but SCA2 and SCA7 had characteristic saccadic slowing without gaze-evoked nystagmus. VOR impairments are common in SCAs, but their patterns vary depending on subtype. In addition to ocular motor characteristics, distinctive VOR performance for each subtype using video HIT may aid the differential diagnosis of the SCA genotypes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) presents an unpredictable and uneven clinical development of cerebellar ataxia, neuropathy, and vestibular areflexia. The aim of this study is to report the variability of vestibular test results in genetically confirmed patients with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome. METHODS: Caloric testing, video head impulse test (vHIT), and rotatory chair testing were performed in 7 patients who presented pathogenic repeat expansions in the replication factor complex unit 1 gene related to cerebellar ataxia, neuropathy, and vestibular areflexia syndrome. RESULTS: Reduced vestibulo-ocular reflex (VOR) gain was observed in 100% of the patients in rotatory chair testing. Three of them had bilateral areflexia in caloric testing while 2 showed unilateral hypofunction and 2 had no alterations in the test. Only 1 patient had bilateral abnormal vHIT with gains under 0.6 in both ears. CONCLUSION: Genetic testing allows an early diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, whereby the vestibular system may be affected to different degrees. Rotatory chair testing has a higher sensitivity for the detection of vestibular hypofunction in these patients. Caloric testing can provide additional information. vHIT might underdiagnose patients with mild-to-moderate vestibulopathy. [ABSTRACT FROM AUTHOR]

The patient with CANVAS has a decreased VVOR gain and multiple compensatory (catch-up) refixation saccades; VORS is paradoxically normal (low gain) as there is no VOR to suppress. If the eye movement reflex is inadequate, the patient will be unable to keep their eyes steady on the target as the eyes move together with the head, and they will need to generate refixation saccades. ARCA3, due to a mutation in the I ANO10 i gene, was first identified in 3 Dutch siblings with ataxia and down-beat nystagmus [[7]] though the latter feature is not universal [[8]]; a subsequent case series has also found mild restriction of vertical eye movements in some patients [[8]]. An examiner, while moving the patients head quickly (VOR) or slowly (VVOR), observes the patients' eyes for refixation saccades as they attempt to fixate on a stationary, earth-referenced target. [Extracted from the article]

Spinocerebellar Ataxia Type 6 (SCA6) is a mid-life onset neurodegenerative disease characterized by progressive ataxia, dysarthria, and eye movement impairment. This autosomal dominant disease is caused by the expansion of a CAG repeat tract in the CACNA1A gene that encodes the α1A subunit of the P/Q type voltage-gated Ca2+ channel. Mouse models of SCA6 demonstrate impaired locomotive function and reduced firing precision of cerebellar Purkinje in the anterior vermis. Here, to further assess deficits in other cerebellar-dependent behaviors, we characterized the oculomotor phenotype of a knock-in mouse model with hyper-expanded polyQ repeats (SCA684Q). We found a reduction in the efficacy of the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) in SCA6 mutant mice, without a change in phase, compared to their litter-matched controls. Additionally, VOR motor learning was significantly impaired in SCA684Q mice. Given that the floccular lobe of the cerebellum plays a vital role in the generation of OKR and VOR calibration and motor learning, we investigated the firing behavior and morphology of floccular cerebellar Purkinje cells. Overall, we found a reduction in the firing precision of floccular lobe Purkinje cells but no morphological difference between SCA684Q and wild-type mice. Taken together, our findings establish that gaze stabilization and motor learning are impaired in SCA684Q mice and suggest that altered cerebellar output contributes to these deficits. [ABSTRACT FROM AUTHOR]

Long-term depression at parallel fibers-Purkinje cells (PF-PC LTD) is essential for cerebellar motor learning and motor control. Recent progress in ataxiology has identified dysregulation of PF-PC LTD in the pathophysiology of certain types of immune-mediated cerebellar ataxias (IMCAs). Auto-antibodies towards voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta) induce dysfunction of PF-PC LTD, resulting in the development of cerebellar ataxias (CAs). These disorders show a good response to immunotherapies in non-paraneoplastic conditions but are sometimes followed by cell death in paraneoplastic conditions. On the other hand, in some types of spinocerebellar ataxia (SCA), dysfunction in PF-PC LTD, and impairments of PF-PC LTD-related adaptive behaviors (including vestibulo-ocular reflex (VOR) and prism adaptation) appear during the prodromal stage, well before the manifestations of obvious CAs and cerebellar atrophy. Based on these findings and taking into account the findings of animal studies, we re-assessed the clinical concept of LTDpathy. LTDpathy can be defined as a clinical spectrum comprising etiologies associated with a functional disturbance of PF-PC LTD with concomitant impairment of related adaptative behaviors, including VOR, blink reflex, and prism adaptation. In IMCAs or degenerative CAs characterized by persistent impairment of a wide range of molecular mechanisms, these disorders are initially functional and are followed subsequently by degenerative cell processes. In such cases, adaptive disorders associated with PF-PC LTD manifest clinically with subtle symptoms and can be prodromal. Our hypothesis underlines for the first time a potential role of LTD dysfunction in the pathogenesis of the prodromal symptoms of CAs. This hypothesis opens perspectives to block the course of CAs at a very early stage. [ABSTRACT FROM AUTHOR]

1 Schematic diagram of the pathophysiological mechanisms underlying anti-VGCC, anti-mGluR1, and anti-GluR delta-associated cerebellar ataxias ("LTDpathies"). Basal synaptic transmission is impaired not only by anti-VGCC Abs but also by anti-mGluR1 and GluR delta Abs [[24]]. These studies suggest that anti-VGCC, anti-mGluR1, and anti-GluR delta Abs-associated cerebellar ataxias share one common pathophysiological mechanism, the deregulated PF-PC LTD. In IMCAs, various synaptic proteins, such as glutamic acid decarboxylase 65 (GAD65), voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta), are targets of auto-immunity [[14]-[16]]. [Extracted from the article]

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recently described slowly progressive ataxia with severe imbalance due to the compromise of three of the four sensory inputs for balance, leaving only vision unaffected. Bilateral vestibulopathy is present but saccular and utricular function, measured by vestibular evoked myogenic potentials (VEMPs), has not been widely studied in these patients. Dysautonomia has been reported but is not among the diagnostic criteria. We performed a database analysis to identify patients evaluated between 2003 and 2019 with probable diagnosis of CANVAS by using key words "bilateral vestibulopathy and/or cerebellar ataxia and/or sensory polyneuropathy." Five out of 842 met all conditions. Patients underwent neurological/neurootological exam, brain MRI, visually enhanced vestibulo-ocular reflex (VVOR) exam by high-speed video-oculography using video-Head Impulse Test (vHIT), VEMPs, neurophysiological studies, and genetic tests to exclude other causes of ataxia. Dysautonomia was addressed by the standardized survey of autonomic symptoms. All patients had clinically definite CANVAS as brain MRI showed vermal cerebellar atrophy, neurophysiological studies showed a sensory neuronopathy pattern (absent sensory action potentials), VVOR was abnormal bilaterally, and genetic tests ruled out other causes of ataxia including SCA 3 and Friedreich ataxia. Patients had at least 3 dysautonomic symptoms, including xerostomia/xerophthalmia (5/5). VEMP results varied among patients, ranging from normal to completely abnormal. We found inconsistent results with VEMPs. The utilization of VEMPs in more CANVAS cases will determine its utility in this syndrome. Dysautonomia may be included in the diagnostic criteria. [ABSTRACT FROM AUTHOR]

The data show that while the gentamicin toxicity patient had a normal VVOR even at 60 deg/s peak stimulus velocity, all 3 CANVAS patients had impaired VVOR even at 10 deg/s with the impairment was most marked at 60 deg/s. Figure 2 plots this graphically. Figure 1 shows this VVOR test in (A) normal subject, (B) in a gentamicin vestibulotoxicity patient and (C, D, E) in 3 CANVAS patients with increasing disease duration (4, 12 and 20 years) and severity of imbalance. In contrast, the VVOR was impaired, highlighted by clinically observable catch-up saccades, at all stimulus velocities, in all 3 CANVAS patients, most severely in patient (E) who had the disease for the longest and had the worst balance. [Extracted from the article]

Spinocerebellar ataxia (SCA) 27B, first reported in late 2022, is caused by the abnormal expansion of GAA repeats in the first intron of the FGF14 gene, which encodes the fibroblast growth factor 14. We present two late-onset cases, each manifesting mild cerebellar ataxia accompanied by omnidirectional downbeat nystagmus, which was enhanced in a suspended head position. None of the patients exhibited impaired head impulse or caloric tests. Repeat-primed PCR and targeted long-read nanopore sequence analysis of the FGF14 GAA repeat site identified more than 250 repeats, leading to the diagnosis of SCA27B. Downbeat nystagmus is reported to be associated with disturbances in the suppression of the vestibulo-ocular reflex (VOR). Our patients with SCA27B demonstrated downbeat nystagmus, likely due to a disruption of the VOR at the level of the cerebellar cortex, a potentially characteristic clinical feature of SCA27B. We have included video footages of eye movements recorded using Frenzel goggles for these cases. Omnidirectional downbeat nystagmus may be a distinctive clinical feature of SCA27B. • We report 2 cases of SCA27B accompanied by omnidirectional downbeat nystagmus. • Omnidirectional downbeat nystagmus emerges as potential distinctive marker for SCA27B diagnosis. • We present utilizing Frenzel goggles captures characteristic eye movements, validating downbeat nystagmus in SCA27B. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxias (SCAs) are a group of autosomal dominant neurodegenerative diseases that are characterized by cerebellar ataxia. The most common types of SCAs are caused by polyglutamine (polyQ)-encoding cytosine-adenine-guanine repeat expansions. Autosomal dominant SCAs share similar pathophysiological mechanisms. The cerebellum plays an important role in the generation and control of eye movement, and neuropathological findings indicate that cerebellar degeneration is commonly present in polyQ-SCAs. As a result, various patterns of oculomotor impairment are present in most SCA subtypes. The present review summarizes the visual oculomotor abnormalities and vestibulo-ocular reflex dynamics of the most common polyQ-SCAs, as well as their genetic, clinical and neuropathological features. In conclusion, the systemic evaluation of eye movement features is useful in the differential diagnosis of polyQ-SCAs. [ABSTRACT FROM AUTHOR]