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.

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.

Clinical dynamic visual acuity in patients with cerebellar ataxia and vestibulopathy.

Deterioration of dynamic visual acuity (DVA) as a result of impaired vestibulo-ocular reflex (VOR) has been well described in peripheral vestibulopathies, however, changes in DVA in patients with degenerative cerebellar ataxias (CA) and its relation to VOR impairment in these patients has not yet been evaluated. Our aim was to assess the alterations of DVA in CA and to evaluate its relation to vestibular function. 32 patients with CA and 3 control groups: 13 patients with unilateral and 13 with bilateral vestibulopathy and 21 age matched healthy volunteers were examined by clinical DVA test, VOR was assessed by video Head Impulse Test and caloric irrigation. The severity of ataxia in CA was assessed by Scale for the assessment and rating of ataxia (SARA). Relationship between DVA and vestibular function in CA patients was examined by linear regressions. DVA impairment was highly prevalent in CA patients (84%) and its severity did not differ between CA and bilateral vestibulopathy patients. The severity of DVA impairment in CA was linked mainly to VOR impairment and only marginally to the degree of ataxia. However, DVA impairment was present also in CA patients without significant vestibular lesion showing that central mechanisms such as impairment of central adaptation of VOR are involved. We suggest that the evaluation of DVA should be a standard part of clinical evaluation in patients with progressive CA, as this information can help to target vestibular and oculomotor rehabilitation.

3 Hz postural tremor: A specific and sensitive sign of cerebellar dysfunction in patients with cerebellar ataxia.

OBJECTIVE: 3 Hz postural tremor was described in patients with anterior cerebellar lobe atrophy, however sensitivity and specificity of this sign in degenerative cerebellar diseases has not yet been evaluated. Our aim was to assess the 3 Hz tremor in patients with cerebellar ataxia, compare its sensitivity and specificity with other posturography parameters and to find out a correlation of intensity of 3 Hz tremor with ataxia severity. METHODS: 30 patients with degenerative cerebellar ataxia, a control group of 30 patients with compensated peripheral vestibulopathy and 40 healthy volunteers were examined by posturography. 3 Hz tremor was assessed both qualitatively and quantitatively, its sensitivity and specificity were compared with other standard posturography parameters. RESULTS: 3 Hz postural tremor was detected in 90% of patients with cerebellar ataxia, with 100% specificity and 90% sensitivity. The sensitivity and specificity of quantitative analysis of 3 Hz tremor was largely superior to standard posturography parameters when differentiating patients with cerebellar ataxia from vestibular impairment and healthy controls. CONCLUSION: 3 Hz postural tremor is highly sensitive and specific sign of cerebellar impairment in patients with cerebellar ataxia. SIGNIFICANCE: Evaluation of 3 Hz postural tremor should be a standard part of posturography examination when considering a cerebellar impairment.

Lanthanide Complexes of the alpha-1 Isomer of the [P(2)W(17)O(61)](10-) Heteropolytungstate: Preparation, Stoichiometry, and Structural Characterization by (183)W and (31)P NMR Spectroscopy and Europium(III) Luminescence Spectroscopy.

The alpha-1 and alpha-2 [P(2)W(17)O(61)](10)(-) isomers, derivatives of the Wells-Dawson molecule, [alpha-P(2)W(18)O(62)](6)(-), may be useful ligands for stabilizing high-valent metal ions and lanthanides and actinides. However, the potential utility of the [alpha1-P(2)W(17)O(61)](10)(-) ligand has not been realized. Specifically, for the lanthanides, the stoichiometry, structure, and purity of the lanthanide complexes of the [alpha1-P(2)W(17)O(61)](10)(-) isomer are ambiguous. We have prepared lanthanide (Ln) complexes of the [alpha1-P(2)W(17)O(61)](10)(-) isomer in >/=98% isomeric purity, according to (31)P NMR data. (183)W NMR data clearly showed, for the first time, that the C(1) symmetry of the [alpha1-P(2)W(17)O(61)](10)(-) lanthanide complexes was maintained in solution. We determined the stoichiometry of the lanthanide complexes of the [alpha1-P(2)W(17)O(61)](10)(-) isomer in solution by two different methods: a complexometric titration method and excited state lifetime measurements and luminescence titrations for the europium(III) analogue. All experiments show a 1:1 Ln:[alpha1-P(2)W(17)O(61)](10)(-) ratio. The (31)P NMR data showed that the lanthanides with smaller ionic radii (higher charge-size ratio) form stable complexes, even surviving crystallization from hot water. On the other hand, the lanthanum analogues were not stable in solutions of high lithium content. The tetrabutylammonium salt of the [Lu(alpha1-P(2)W(17)O(61))](7)(-) complex showed >/=98% isomeric purity and the C(1) symmetry required for a derivative of [alpha1-P(2)W(17)O(61)](10)(-). Also the tetrabutylammonium cation stabilized the [Lu(alpha1-P(2)W(17)O(61))](7)(-) complex; a mixed tetrabutylammonium, lithium salt was stable in water for weeks according to (31)P NMR spectroscopy.

Lanthanide complexes of [alpha-2-P2W17O61]10-: solid state and solution studies.

We have isolated the 1:1 Ln:[alpha-2-P2W17O61]10- complexes for a series of lanthanides. The single-crystal X-ray structure of the Eu3+ analogue reveals two identical [Eu(H2O)3(alpha-2-P2W17O61)]7- moieties connected through two Eu-O-W bonds, one from each polyoxometalate unit. An inversion center relates the two polyoxometalate units. The Eu(III) ion is substituted for a [WO]4+ unit in the "cap" region of the tungsten-oxygen framework of the parent Wells-Dawson ion. The point group of the dimeric molecule is Ci. The extended structure is composed of the [Eu(H2O)3(alpha-2-P2W17O61)]214- anions linked together by surface-bound potassium cations. The space group is P, a = 12.7214(5) A, b = 14.7402(7) A, c = 22.6724(9) A, alpha = 71.550(3), beta = 84.019(3)degrees, gamma = 74.383(3), V = 3883.2(3) A3, Z = 1. The solution studies, including 183W NMR spectroscopy and luminescence lifetime measurements, show that the molecules dissociate in solution to form monomeric [Ln(H2O)4(alpha-2-P2W17O61)]7- species.