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Background and Purpose: Patients with episodic ataxia type 2 (EA2) suffer from recurrent paroxysmal episodes of vertigo and oscillopsia. Pathophysiologically, altered neuronal excitability has been suspected. Vestibular excitability in 22 EA2 patients and 22 age-matched healthy participants was compared., Methods: Galvanic vestibular stimulation (GVS) was used to assess vestibular excitability by vestibular motion perception thresholds and mean postural sway velocity during various visual and proprioceptive conditions in the two groups. Control stimuli using sham and no GVS were established to identify the specificity of GVS-induced postural sway., Results: In the baseline condition, EA2 patients showed larger postural instability. However, motion perception thresholds and the increase in mean postural sway velocity during vestibular stimulation (stimulation ratio) did not differ between groups. Postural sway during suprathreshold GVS increased with the vestibular motion perception threshold in EA2 patients, in contrast to healthy participants., Conclusions: The larger postural unsteadiness of EA2 patients probably reflects their progressive cerebellar degeneration. It is not related to abnormal visual (Romberg's ratio) or proprioceptive control of stance. Postural unsteadiness during vestibular stimulation does not indicate altered vestibular excitability in EA2 patients. However, vestibular stimulation increasingly destabilized postural control of EA2 patients with higher motion perception thresholds when proprioceptive information was diminished. This conclusion, however, is restricted to the postural control of EA2 patients in the interval between the vestibulo-cerebellar episodes., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

With many viable strategies in the therapeutic pipeline, upcoming clinical trials in hereditary and sporadic degenerative ataxias will benefit from non-invasive MRI biomarkers for patient stratification and the evaluation of therapies. The MRI Biomarkers Working Group of the Ataxia Global Initiative therefore devised guidelines to facilitate harmonized MRI data acquisition in clinical research and trials in ataxias. Recommendations are provided for a basic structural MRI protocol that can be used for clinical care and for an advanced multi-modal MRI protocol relevant for research and trial settings. The advanced protocol consists of modalities with demonstrated utility for tracking brain changes in degenerative ataxias and includes structural MRI, magnetic resonance spectroscopy, diffusion MRI, quantitative susceptibility mapping, and resting-state functional MRI. Acceptable ranges of acquisition parameters are provided to accommodate diverse scanner hardware in research and clinical contexts while maintaining a minimum standard of data quality. Important technical considerations in setting up an advanced multi-modal protocol are outlined, including the order of pulse sequences, and example software packages commonly used for data analysis are provided. Outcome measures most relevant for ataxias are highlighted with use cases from recent ataxia literature. Finally, to facilitate access to the recommendations by the ataxia clinical and research community, examples of datasets collected with the recommended parameters are provided and platform-specific protocols are shared via the Open Science Framework., (© 2023. The Author(s).)

Ataxias are a heterogeneous group of diseases. They can occur at any age and have various causes. Most ataxias are rare diseases and many are genetic disorders. A large and steadily increasing number of underlying gene defects are known. The path to the correct diagnosis is often challenging. This overview summarizes the typical findings for the most important acquired, hereditary and non-hereditary degenerative ataxias. The focus is on ataxias with adult onset., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: ja, von einer anderen Institution; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: ja, Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen Andreas Thieme ist Mitglied in der Deutschen Gesellschaft für Neurologie (DGN).Dagmar Timmann ist im ärztlichen Beirat der der Deutschen Heredoataxie Gesellschaft (DHAG) und sie ist Mitglied in der DGN und in der Deutschen Gesellschaft für Klinische Neurophysiologie und funktionelle Bildgebung (DGKN)., (Thieme. All rights reserved.)

Background: Mutations in the mitochondrial DNA polymerase gamma are causing a wide phenotypic spectrum including ataxia as one of the most common presentations., Objective: The objective of this study was to determine the course of disease of polymerase gamma-related ataxia., Methods: In a prospective natural history study, we assessed 24 adult ataxia patients with biallelic polymerase gamma mutations for (1) severity of cerebellar dysfunction using the Scale for the Assessment and Rating of Ataxia score, (2) presence of nonataxia signs using the Inventory of Non-Ataxia Symptoms, (3) gray- and white-matter changes in brain MRI, and (4) findings in nerve conduction studies., Results: Assessment included follow-up visits up to 11.6 years. The Scale for the Assessment and Rating of Ataxia showed a mean annual increase of 1.02 ± 0.78 points/year. Disease progression was faster in patients with age at onset ≤ 30 years (1.5 Scale for the Assessment and Rating of Ataxia points/year) than with later onset (0.5 points/year); P = 0.008. The Inventory of Non-Ataxia Symptoms count increased by 0.30 ± 0.4 points/year. External ophthalmoplegia, brain stem oculomotor signs, areflexia, and sensory deficits were the most common nonataxic features. On MRI cerebellar atrophy was mild. T2 signal alterations affected mostly cerebellar white matter, middle cerebellar peduncles, thalamus, brain stem, and occipital and frontal white matter. Within 4 years, progression was primarily observed in the context of repeated epileptic seizures. Nerve conduction studies revealed axonal sensory peripheral neuropathy with mild motor nerve involvement. Exploratory sample size calculation implied 38 patients per arm as sufficient to detect a reduction of progression by 50% in hypothetical interventions within a 1-year trial., Conclusion: The results recommend the Scale for the Assessment and Rating of Ataxia as a primary outcome measure for future interventional trials in polymerase gamma-related ataxia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations., Methods: The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing., Results: The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 ± 0.74, p < 0.0001) and disease duration (0.22 ± 0.06 per additional year, p = 0.0007) were associated with a higher SARA score. Forty-eight participants who did not fulfill MSA-C criteria and had a disease duration of >10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 ± 6.0 vs 16.0 ± 5.8, p = 0.0200) and a slower annual SARA increase (1.1 ± 2.3 vs 3.3 ± 3.2, p = 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made., Conclusions: Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort., Clinicaltrialsgov Registration: NCT02701036., (© 2017 American Academy of Neurology.)

Ataxia with ocular apraxia type 2 (AOA2) is an autosomal recessive, early onset ataxia caused by mutations in the senataxin (SETX) gene. Ocular apraxia and increased levels of alpha-fetoprotein are characteristic but not obligate markers of the disease. AOA2 is allelic with ALS4, a motor neuron disorder of early onset and autosomal dominant inheritance. We observed a two generation family with ataxia which started at age 14 and 17 in two sibs and at age 23 in their paternal uncle.Oculomotor disturbances included strabismus, saccadic pursuit and gaze evoked nystagmus. MRI revealed severe cerebellar atrophy. All patients presented pronounced peripheral neuropathy with wasting of hand and leg muscles resembling distal motor neuronopathy. Increased alphafetoprotein levels triggered genetic analyses of SETX. We found the sib pair to be compound heterozygous for a single base deletion c.2835delC, resulting in a frameshift mutation and causing nonsense related mRNA decay, and a base exchange c.6106G > A, resulting in abnormal splicing and skipping of exon 15. The similarly affected uncle was homozygous for the c.6106G > A mutation probably due to distant consanguinity in the paternal branch of the family. Pseudodominant occurrence in two generations has not been described before in AOA2 and led, in this family, to false categorization as dominant ataxia before SETX mutations were detected. Clinically this family presented with a phenotype combining typical features of AOA2 and ALS4; thus extending the phenotypic spectrum of SETX mutations.

To evaluate the therapies for cerebellar diseases appropriate neurological assessment methods to measure severity of ataxia are required. Reliability and validity of the semiquantitative International Cooperative Ataxia Rating Scale (ICARS) has recently been examined in patients with degenerative ataxias. We evaluated reliability (internal consistency), criterion-related validity and internal construct validity of ICARS for the first time in patients with focal cerebellar lesions (68 patients with surgical lesions and 68 patients with ischemic lesions). For comparison 45 patients with degenerative cerebellar ataxia were included. We found an excellent Cronbach's alpha as a measurement for internal consistency which was independent from underlying disease. Criterion-related validity was high. Total ICARS score mirrored clearly the immediate postsurgical worsening and the improvement during the first 3 months after focal surgical and ischemic lesions, whereas in chronic state of focal and degenerative cerebellar disorders ICARS score remained nearly unchanged. Principal component analysis in patients with focal lesions revealed five distinct and clinically meaningful factors which corresponded to the four ICARS subscores and reflected the laterality of kinetic functions. In degenerative disorders, however, the items for the subscore "kinetic function" loaded to more than one factor. Total ICARS score seems to be a useful and valid measurement to describe the time course of ataxia in patients with focal and degenerative disorders affecting primarily the cerebellum. Validity of subscores however is good in focal, but not in degenerative disorders., ((c) 2007 Movement Disorder Society.)

The objective of this study was to test the reliability and validity of the Scale for the Assessment and Rating of Ataxia (SARA) in ataxia patients not suffering from autosomal dominant spinocerebellar ataxia (SCA). To this end, 64 patients with various ataxia disorders or stable cerebellar lesions were rated independently by two investigators. In addition to SARA, the following assessment instruments were applied: ataxia disease stage, Barthel index and part IV (functional assessment) of the Unified Huntington's Disease Rating scale (UHDRS-IV). Eighteen patients were rated twice. Inter-rater and intrarater reliability were very high with ICCs of 0.98 and 0.99. Internal consistency was high indicated by Cronbach's alpha of 0.97. Factorial analysis revealed that the rating results were mainly determined by one major factor with an eigenvalue of 6.34 which explained 52.8% of the variance. SARA score increased with disease stage (P<0.0001) and was closely correlated with Barthel index (r=-0.63, P<0.0001) and UHDRS-IV (r=-0.62, P<0.0001), but only weakly correlated with disease duration (r=0.44, P<0.001). The results suggest that SARA is a reliable and valid measure of ataxia in non-SCA ataxia patients., (Copyright (c) 2007 Movement Disorder Society.)

To elucidate whether the cerebellar cortex may contribute to trace eyeblink conditioning in humans, eight patients with degenerative cerebellar disorders (four with sporadic adult onset ataxia, three with autosomal dominant cerebellar ataxia type III and one with spinocerebellar ataxia type 6) and eight age- and sex-matched healthy control subjects were investigated. Individual high resolution three-dimensional MRI data sets were acquired. As revealed by volumetric measurements of the cerebellum using ECCET software, patients showed cerebellar atrophy to various degrees. No abnormalities were observed in the control subjects. Eyeblink conditioning was performed twice using a tone of 40 ms as conditioned stimulus, followed by a short (400 ms) and a long (1,000 ms) trace interval and an air-puff of 100 ms as unconditioned stimulus. Using the short trace interval, eyeblink conditioning was significantly impaired in cerebellar patients compared to controls, even in those who fulfilled criteria of awareness. Using the long trace interval no significant group differences could be observed. The present findings of impaired trace eyeblink acquisition in patients with cortical cerebellar degeneration suggest that the cerebellar cortex in humans, in addition to the interposed nucleus, is involved in trace eyeblink conditioning, if the trace interval is relatively short. Using a long trace interval, the cerebellum appears to be less important. [ABSTRACT FROM AUTHOR]

Delay eyeblink conditioning was examined in patients with genetically-defined heredoataxias and age-matched control subjects. 24 patients with spinocerebellar ataxia type 6 (SCA6), type 3 (SCA3), and Friedreich’s ataxia (FRDA) participated. SCA6 affects primarily the cerebellum, whereas extracerebellar involvement is common in SCA3 and FRDA. Testing was performed in three sessions six months apart. Severity of ataxia was defined based on the International Ataxia Cooperative Rating Scale (ICARS). As expected, cerebellar patients were significantly impaired in eyeblink conditioning compared to controls. Signs of retention and further learning across sessions were present in controls, but not in the cerebellar patients. In addition, findings of disturbed timing of conditioned responses were observed. Both onsets and peaks of the conditioned responses (CRs) occurred significantly earlier in cerebellar patients. Shortened CR responses were most prominent in patients with primarily cerebellar cortical disease (SCA6). In the group of all cerebellar patients, the SCA3 and the FRDA group correlations between learning deficits and clinical findings were weak. Moderate-to-strong correlations were found in the SCA6 patients. There was no significant change, however, in clinical ataxia scores and CR incidence across the three sessions. In summary, impaired learning of conditioned eyeblink responses is a stable finding across multiple sessions in patients with degenerative cerebellar disorders. Eyeblink conditioning may be a useful measure of cerebellar impairment in patients with hereditary ataxias that primarily affect the cerebellum (such as SCA6). In other heredoataxias (such as SCA3 and FRDA), extracerebellar involvement not assessed by ICARS likely contributes to eyeblink conditioning abnormalities. [ABSTRACT FROM AUTHOR]

Although ataxias of stance and gait are frequent manifestations of cerebellar disease, the number of human studies examining stance or gait in cerebellar subjects is limited. In the present study, we examined whether anticipatory postural adjustments were impaired in cerebellar subjects during perturbed and unperturbed step initiation. The first aim was to show possible abnormalities in timing, force and kinematic parameters of anticipatory postural adjustments in unperturbed stepping in cerebellar subjects. Second, we examined the ability of cerebellar subjects to modify anticipatory postural adjustments associated with step initiation in response to a backward translation. Finally, we asked whether cerebellar subjects (and controls) make use of predictive knowledge of perturbation amplitude in perturbed stepping. Only few abnormalities of anticipatory postural adjustments were found in cerebellar subjects compared to controls. Both in the unperturbed and perturbed step conditions, force production as well as step length and step velocity were reduced in cerebellar subjects compared to controls, suggesting compensatory slowing. Cerebellar subjects also appeared to be less able to use predictive information of perturbation amplitude to scale anticipatory postural adjustments than control subjects. Nevertheless, in unperturbed steps, temporal parameters of anticipatory postural adjustments were preserved in cerebellar subjects. When subjects voluntarily initiated a step in response to the surface translation, both control and cerebellar subjects adapted by executing the anticipatory postural adjustments for step more rapidly. Furthermore, both control and cerebellar subjects were able to use online information regarding perturbation amplitude to scale parameters of step initiation in perturbed stepping. Overall, our findings suggest that the cerebellum is neither critical for the basic motor program underlying unperturbed step initiation nor for many adaptive changes occurring during perturbed step initiation. Like its role in predictive scaling of automatic postural responses to external perturbations, the cerebellum appears to be important for predictive adaptation of anticipatory postural adjustments during step initiation. [ABSTRACT FROM AUTHOR]

Cerebellar patients throw inaccurately in the left-right direction but the cause of this multijoint ataxia is unclear. We tested whether it was due, as originally proposed, to variable left-right directions of the hand path, or, alternatively, to variable timing of ball release occurring on a right to left curved hand path. We also examined the cause of the variability in hand path direction per se. Six right-handed cerebellar patients and six control subjects were instructed to throw tennis balls at a slow, medium and fast speed from a seated position while angular positions in 3D of five arm segments were recorded at 1000 Hz with the search-coil technique. Compared to controls, cerebellar patients threw slower and less accurately, had more variable timing of ball release occurring on a right to left curved hand path and had more variable left-right directions of hand paths at a fixed point in front of the sternum. In all cerebellar patients, ball left-right inaccuracy was related both to timing of ball release and to hand path direction at the fixed point. The cause of the increased variability in hand path direction varied between patients and could not be explained by disorder in a single joint rotation. No evidence was found that it resulted from variable stabilization at the shoulder during elbow extension. Instead, the more variable left-right direction of the hand path was related to the initial pattern of joint rotations occurring early in the throw before the onset of elbow extension, and to the amplitudes of radioulnar pronation and wrist abduction occurring late in the throw. The results emphasize that in the presence of a cerebellar lesion, ball left-right inaccuracy in overarm throws cannot be explained by a single disorder. Rather ball inaccuracy was likely due to disorders in central commands to proximal joint rotations that produced the hand path and in central commands to distal joints that controlled the timing of finger opening. [ABSTRACT FROM AUTHOR]

Abstract: As yet, human cerebellar lesion studies have not taken advantage of direct magnetic resonance imaging (MRI) of the cerebellar nuclei in individual patients. In the present study, susceptibility weighted imaging (SWI) was used to visualize lesions of the dentate nuclei in patients with chronic focal lesions. Fifteen patients with cerebellar lesions either due to stroke or tumor surgery underwent SWI imaging using a 1.5T MRI scanner. Dentate nuclei were seen as hypointensities in all patients. Three of the patients underwent additional SWI imaging at 3T and 7T. Compared to 1.5T, corrugation of the dentate wall was seen with greater precision and the dorsal, iron-poorer part was seen more fully. Lesion-symptom mapping was performed based on the 1.5T MR images. Patients were divided into two groups with and without upper limb ataxia. A region-of-interest-(ROI)-driven normalization technique was used which had initially been developed by Diedrichsen et al. (2011) for functional MRI (fMRI) of the dentate nuclei. Compared to conventional normalization of the cerebellum, overlap of dentate lesions improved and lead to increased sensitivity of lesion-symptom maps. Subtraction analysis revealed that the more dorsal and rostral parts of the dentate nuclei were related to upper limb ataxia. Findings were in good accordance with the dentate hand area shown in recent fMRI studies. These data provide evidence that direct identification of dentate lesions together with the ROI-driven normalization technique allows for improved lesion-symptom mapping at the level of the cerebellar nuclei already at conventional 1.5T MRI field strength. [Copyright &y& Elsevier]

Abstract: In a recent study using voxel based lesion symptom mapping (VLSM) in cerebellar patients following stroke we found associations of prehensile deficits to lesions of the cerebellar cortex and dentate nucleus (DN). Associations to lesions of the interposed nucleus (IN), which has been shown to contribute to prehension in monkeys, could not be established. One possible reason was that the IN was largely unaffected in the stroke patients. To further address the question of IN involvement in prehension we performed VLSM in patients with surgical cerebellar lesions (n =20), exhibiting high lesion overlap in the medial and intermediate cerebellum including the IN. Prehensile deficits were quantified by analyses of movement kinematics and finger forces. In the patient population prehensile deficits comprised lower movement velocity in reaching and increased lift-off time in grasping. These were associated with lesions of the intermediate and lateral cerebellar cortex together with their output nuclei. Specifically, IN lesions were linked to increased lift-off time in grasping and not to slower reaching movements. Thus, our data support IN contribution particularly for the fluent production of grip forces during dexterous prehension in humans. [Copyright &y& Elsevier]

Abstract: Objective: This study established the relationship between kinematic and grip force parameters in prehension tasks, disease severity and cerebellar atrophy in patients with cerebellar degeneration. Methods: Prehension was tested in a condition during which the hand reached out, grasped, and lifted an object. Task complexity was modified by limiting the transport component to a single-joint movement, and introducing a bimanual condition. Results: Compared to controls the cerebellar patients showed disturbances in hand transport, in hand shaping and the most pronounced in time to peak grip force and the grip/load force coupling. Task-dependent changes did not differ between groups. Ataxia scores revealed significant correlations with hand transport and shaping measures only. Ataxia subscores correlated with volume reduction of appropriate longitudinal cerebellar zones. Volume reduction of the intermediate zone was associated with grip force coordination deficits. Conclusions: Results indicate that the cerebellum may have a more general role in motor control of grasping independent of task complexity. Temporal and coordinative measures of grip force appear to be most useful to assess the severity of grasping deficits in patients with cerebellar degeneration not detectable by clinical ataxia scales. Significance: To assess the severity and course of cerebellar disease grip force control in a standard prehension task is a sensitive quantitative measure. [Copyright &y& Elsevier]

Abstract: The aim of the present study was to examine somatotopy in the cerebellar cortex and a possible differential role of the cerebellar cortex and nuclei in functional outcome. Clinical findings and 3D MRI-based cerebellar lesions site were compared in a group of 90 patients with focal cerebellar lesion using International Cooperative Ataxia Rating Scale (ICARS) and voxel-based lesion–symptom mapping (VLSM). Separate analysis was performed in patients with acute and chronic ischemic lesions (n = 43) and patients with acute and chronic surgical lesions (n = 47). Thirty-eight patients were included after resection of a cerebellar tumor in childhood or adolescence. The most significant lesion symptom correlations were observed in the subgroup with acute ischemic lesions. Limb ataxia was significantly correlated with lesions of the interposed (NI) and part of the dentate nuclei (ND), ataxia of posture and gait with lesions of the fastigial nuclei (NF) including NI. Correlations with cortical lesions were less significant and present in the superior cerebellum only. Upper limb ataxia was correlated with lesions of vermal, paravermal and hemispheral lobules IV–V and VI, lower limb ataxia with lesions of vermal, paravermal and hemispheral lobules III and VI, dysarthria with lesions of paravermal and hemispheral lobules V and VI and ataxia of posture and gait with lesions of vermal and paravermal lobules II, III and IV. In the subgroups with chronic focal lesions, similar correlations were observed with lesions of the cerebellar nuclei, but significantly less correlations with lesions of the cerebellar cortex. Functional localization based on VLSM backs findings in previous animal and functional brain images studies in healthy human subjects. The lesion site appears to be critical for motor recovery. Lesions affecting the cerebellar nuclei are not fully compensated at any age and independent of the pathology in humans. [Copyright &y& Elsevier]