Friedreich ataxia (FRDA), the commonest of the inherited ataxias, is a multisystem neurodegenerative condition that affects ocular motor function. We assessed eye movement abnormalities in 20 individuals with genetically confirmed FRDA and compared these results to clinical measures. All subjects were assessed with infrared oculography. Fifteen individuals underwent a full protocol of eye movement recordings. Ten subjects were analysed using two-dimensional scleral coil equipment and five using three-dimensional scleral coil recording equipment. We also recorded visual quality of life, Sloan low contrast letter acuity and Friedreich Ataxia Rating Scale scores to compare to the visual measures. Whilst saccadic velocity was essentially normal, saccadic latency was prolonged. The latency correlated with clinical measures of disease severity, including the scores for the Friedreich Ataxia Rating Scale and the Sloan low contrast letter acuity tests. Fixation abnormalities consisting of square wave jerks and ocular flutter were common, and included rare examples of vertical square wave jerks. Vestibular abnormalities were also evident in the group, with markedly reduced vestibulo-ocular reflex gain and prolonged latency. The range of eye movement abnormalities suggest that neurological dysfunction in FRDA includes brainstem, cortical and vestibular pathways. Severe vestibulopathy with essentially normal saccadic velocity are hallmarks of FRDA and differentiate it from a number of the dominant spinocerebellar ataxias. The correlation of saccadic latency with FARS score raises the possibility of its use as a biomarker for FRDA clinical trials.

Objective: To elucidate the neuropathology in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS), a novel cerebellar ataxia comprised of the triad of cerebellar impairment, bilateral vestibular hypofunction, and a peripheral sensory deficit.Method: Brain and spinal neuropathology in 2 patients with CANVAS, together with brain and otopathology in another patient with CANVAS, were examined postmortem.Results: Spinal cord pathology demonstrated a marked dorsal root ganglionopathy with secondary tract degeneration. Cerebellar pathology showed loss of Purkinje cells, predominantly in the vermis. Conclusion:The likely underlying sensory pathology in CANVAS is loss of neurons from the dorsal root and V, VII, and VIII cranial nerve ganglia-in other words, it is a "neuronopathy" rather than a "neuropathy." Clinically, CANVAS is a differential diagnosis for both spinocerebellar ataxia type 3 (or Machado-Joseph disease) and Friedreich ataxia. In addition, there are 6 sets of sibling pairs, implying that CANVAS is likely to be a late-onset recessive or autosomal dominant with reduced penetrance disorder, and identification of the culprit gene is currently a target of investigation. An abnormal visually enhanced vestibulo-ocular reflex (VVOR) represents a compound impairment of the 3 key corrective oculomotor reflexes, namely, smooth pursuit, the vestibulo-ocular reflex (VOR), and the opticokinetic reflex. We refer the reader to our earlier work for details of the VVOR.1 While the initial description of a syndrome of cerebellar ataxia and bilateral vestibulopathy noted the presence of a peripheral neuropathy in 3 of the 4 index cases, we later showed that in 18 patients a peripheral nerve disease was an integral component of the syndrome we renamed cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS).2 At this time, we noted that a neuronopathy (ganglionopathy) could not be definitively excluded. Subsequently, temporal bone histopathology 1 revealed a vestibular, facial, and trigeminal sensory neuronopathy. In an effort to unify the underlying pathology in CANVAS, we speculated that the peripheral sensory deficit, invariably seen in this syndrome, was more likely to be a neuronopathy than a neuropathy. Our efforts at testing this hypothesis were initially limited by the difficulty in differentiating these 2 entities with conventional neurophysiologic protocols. On obtaining the first spinal cord postmortem samples in cases of diagnosed CANVAS, it appears that the peripheral sensory deficit in CANVAS may be due to a dorsal root ganglionopathy. We hope to develop neurophysiologic protocols that may be used to identify this pathology in the living patient.