Intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis type I, a randomized, open-label, controlled pilot study.

Central nervous system manifestations of mucopolysaccharidosis type I (MPS I) such as cognitive impairment, hydrocephalus, and spinal cord compression are inadequately treated by intravenously-administered enzyme replacement therapy with laronidase (recombinant human alpha-L-iduronidase). While hematopoietic stem cell transplantation treats neurological symptoms, this therapy is not generally offered to attenuated MPS I patients. This study is a randomized, open-label, controlled pilot study of intrathecal laronidase in eight attenuated MPS I patients with cognitive impairment. Subjects ranged between 12 years and 50 years old with a median age of 18 years. All subjects had received intravenous laronidase prior to the study over a range of 4 to 10 years, with a mean of 7.75 years. Weekly intravenous laronidase was continued throughout the duration of the study. The randomization period was one year, during which control subjects attended all study visits and assessments, but did not receive any intrathecal laronidase. After the first year, all eight subjects received treatment for one additional year. There was no significant difference in neuropsychological assessment scores between control or treatment groups, either over the one-year randomized period or at 18 or 24 months. However, there was no significant decline in scores in the control group either. Adverse events included pain (injection site, back, groin), headache, neck spasm, and transient blurry vision. There were seven serious adverse events, one judged as possibly related (headache requiring hospitalization). There was no significant effect of intrathecal laronidase on cognitive impairment in older, attenuated MPS I patients over a two-year treatment period. A five-year open-label extension study is underway.

White matter measures correlate with essential tremor severity-A pilot diffusion tensor imaging study.

BACKGROUND: An evolving pathophysiological concept of essential tremor (ET) points to diffuse brain network involvement, which emphasizes the need to investigate white matter (WM) changes associated with motor symptoms of ET. OBJECTIVES: To investigate ET-related WM changes and WM correlates of tremor severity using tremor clinical rating scales and accelerometry. METHODS: Tract-based spatial statistics (TBSS) approach was utilized to compare 3 Tesla diffusion tensor imaging (DTI) data from 12 ET patients and 10 age- and gender-matched healthy individuals. Clinical scales, tremor frequency and amplitude as measured by accelerometry were correlated with DTI data. RESULTS: ET patients demonstrated mean (MD) and radial diffusivity (RD) abnormalities in tracts involved in primary and associative motor functions such as bilateral corticospinal tracts, the superior longitudinal fascicles, and the corpus callosum but also in nonmotor regions including the inferior fronto-occipital and longitudinal fascicles, cingulum bundles, anterior thalamic radiations, and uncinate fascicles. A combined tremor frequency and amplitude score correlated with RD and MD in extensive WM areas, which partially overlapped the regions that were associated with tremor frequency. No significant relationship was found between DTI measures and clinical rating scales scores. CONCLUSIONS: The results show that ET-related diffusion WM changes and their correlates with tremor severity are preferentially located in the primary and associative motor areas. In contrast, a relationship between WM was not detected with clinical rating scales. Accelerometry parameters may, therefore, serve as a potentially useful clinical measures that relate to WM deficits in ET.

Intrathecal enzyme replacement therapy reverses cognitive decline in mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disease that seriously affects the brain. Severity of neurocognitive symptoms in attenuated MPS subtype (MPS IA) broadly varies partially, due to restricted permeability of blood-brain barrier (BBB) which limits treatment effects of intravenously applied α-L-iduronidase (rhIDU) enzyme. Intrathecal (IT) rhIDU application as a possible solution to circumvent BBB improved brain outcomes in canine models; therefore, our study quantifies effects of IT rhIDU on brain structure and function in an MPS IA patient with previous progressive cognitive decline. Neuropsychological testing and MRIs were performed twice prior (baseline, at 1 year) and twice after initiating IT rhIDU (at 2nd and 3rd years). The difference between pre- and post-treatment means was evaluated as a percentage of the change. Neurocognitive performance improved particularly in memory tests and resulted in improved school performance after IT rhIDU treatment. White matter (WM) integrity improved together with an increase of WM and corpus callosum volumes. Hippocampal and gray matter volume decreased which may either parallel reduction of glycosaminoglycan storage or reflect typical longitudinal brain changes in early adulthood. In conclusion, our outcomes suggest neurological benefits of IT rhIDU compared to the intravenous administration on brain structure and function in a single MPS IA patient.© 2017 Wiley Periodicals, Inc.