Phd in CLINICAL EXPERIMENTAL NEUROSCIENCE AND PSYCHIATRY

Thesis title: Riluzole treatment in two families with Spinocerebellar Ataxia type 7: A long-term follow-up.

Background: Spinocerebellar Ataxias (SCAs) is an eterogeneous group of inherited autosomal dominant progressive ataxias. Currently no curative treatment exist for SCAs. Riluzole has demonstrated promising results as symptomatic treatment in different types of cerebellar ataxia. However, the effectivness in individual subtypes of disease is still unclear and under debate. The aim of our pilot study was to test riluzole in two families with spinocerebellar ataxia type 7 (SCA7). Methods: The study cohort included five patients of Peruvian origin belonging to the same family recruited at the Robert Hollman Foundation (RHF, Italy), and two American sisters recruited at the Ophthalmological Department of Tampa (USA). All patients were administered Riluzole 100 mg (50 mg twice) daily based on a compassionate use program in a period ranging from three to five years. We collected neurological data, through the Scale for the Assessment and Rating of Ataxia (SARA), and ophthalmological data, through Visual acuity (VA) with logarithmic Snellen chart (logMAR notation used); Vistech electronic optotype, Ishihara pseudoisocromatic colour plates and colour vision test Roth 28, computerized threshold 30° visual field testing, full-field ERG, multi-focal ERG, visual evoked potential by flash and pattern-reversal stimuli, ocular motility and fixation, macular optical coherence tomography (OCT) and fundus photography, before and after Riluzole treatment. Electrocardiogram and laboratory profile for drug safety were performed every three months. Results: Riluzole treatment was started at a mean age of 36.4 years (range 11.5-68) and lasted for a mean of 4.8 years (range 3.5-9). It showed no effect on visual function in two patients with an advanced retinal damage (PII-1 and PII-3). Improvement occurred in four patients (PI-1, PII-2, S1 and S2). In these four cases a stability in visual function was observed up to 5 years after the start of the treatment. One patient (PII-2) had an overall stabilization of visual deterioration without neurological impairment and he was the only one treated before the onset of ataxia. Two patients (PII-1 and PII-3) showed a less steep deterioration of cerebellar ataxia after treatment compared to pre-treatment, during the first 2,5 years of therapy. PI-1 showed soon after therapy an improvement of the SARA score, as well as an overall stability lasting 3,5 years and followed by ataxia worsening. It shows that PII-2 had an overall stabilization of visual deterioration without neurological impairment (no ataxia occurred until the last visit after 3,5 years of follow-up). He was the only one treated before ataxia onset, and, though he had the same triplet number as PIII-1, his disease course was apparently impacted by the start of the drug. S1 and S2 showed an improvement of SARA scores soon after therapy, and an overall stability lasting respectively 5 and 3 years. No adverse event was registered during the observation period demonstrating the substantial safety of the drug. Discussion: This pilot study suggest a possible beneficial and action of Riluzole in SCA7 and supply a detailed description of the ophthalmologic profile of these patients. A randomized, controlled trial with a delayed-start study design (NCT03660917) is ongoing to confirm a symptomatic effect of riluzole in this form of cerebellar ataxia, as well as to support the possibility that this drug may represent a possible disease-modifying approach.