•Cerebellar nuclei are discernible on susceptibility maps (QSM) acquired at 3 Tesla in healthy subjects and patients with SCA6.•The QSM-based volume of the dentate nuclei in adults is independent of ...age.•Dentate nuclei are significantly atrophied in SCA6.•The amount of iron of the dentate nuclei is reduced in SCA6.•Volume and iron concentration of the dentate nuclei did not show reliable changes in SCA6 patients within one year.
Understanding cerebellar alterations due to healthy aging provides a reference point against which pathological findings in late-onset disease, for example spinocerebellar ataxia type 6 (SCA6), can be contrasted. In the present study, we investigated the impact of aging on the cerebellar nuclei and cerebellar cortex in 109 healthy controls (age range: 16 – 78 years) using 3 Tesla magnetic resonance imaging (MRI). Findings were compared with 25 SCA6 patients (age range: 38 – 78 years). A subset of 16 SCA6 (included: 14) patients and 50 controls (included: 45) received an additional MRI scan at 7 Tesla and were re-scanned after one year. MRI included T1-weighted, T2-weighted FLAIR, and multi-echo T2*-weighted imaging. The T2*-weighted phase images were converted to quantitative susceptibility maps (QSM). Since the cerebellar nuclei are characterized by elevated iron content with respect to their surroundings, two independent raters manually outlined them on the susceptibility maps. T1-weighted images acquired at 3T were utilized to automatically identify the cerebellar gray matter (GM) volume. Linear correlations revealed significant atrophy of the cerebellum due to tissue loss of cerebellar cortical GM in healthy controls with increasing age. Reduction of the cerebellar GM was substantially stronger in SCA6 patients. The volume of the dentate nuclei did not exhibit a significant relationship with age, at least in the age range between 18 and 78 years, whereas mean susceptibilities of the dentate nuclei increased with age. As previously shown, the dentate nuclei volumes were smaller and magnetic susceptibilities were lower in SCA6 patients compared to age- and sex-matched controls. The significant dentate volume loss in SCA6 patients could also be confirmed with 7T MRI. Linear mixed effects models and individual paired t-tests accounting for multiple comparisons revealed no statistical significant change in volume and susceptibility of the dentate nuclei after one year in neither patients nor controls. Importantly, dentate volumes were more sensitive to differentiate between SCA6 (Cohen's d = 3.02) and matched controls than the cerebellar cortex volume (d = 2.04). In addition to age-related decline of the cerebellar cortex and atrophy in SCA6 patients, age-related increase of susceptibility of the dentate nuclei was found in controls, whereas dentate volume and susceptibility was significantly decreased in SCA6 patients. Because no significant changes of any of these parameters was found at follow-up, these measures do not allow to monitor disease progression at short intervals.
Display omitted
Objective
To investigate the safety and efficacy of
N
-acetyl-
l
-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann–Pick disease type C (NPC) ...patients.
Methods
In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6–12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments.
Results
33 subjects aged 7–64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75,
p
= 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred.
Conclusions
NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC.
Clinicaltrials.gov identifier
NCT03759639.
OBJECTIVE:Downbeat nystagmus (DBN) is the most frequent form of acquired persisting fixation nystagmus with different symptoms such as unsteadiness of gait, postural instability, and blurred vision ...with reduced visual acuity (VA) and oscillopsia. However, different symptomatic therapeutic principles are required, such as 3,4-diaminopyridine and 4-aminopyridine, that effectively suppress DBN. Chlorzoxazone (CHZ) is a nonselective activator of small conductance calcium-activated potassium (SK) channels that modifies the activity of cerebellar Purkinje cells. We evaluated the effects of this agent on DBN in an observational proof-of-concept pilot study.
METHODS:Ten patients received CHZ 500 mg 3 times a day for 1 or 2 weeks. Slow-phase velocity of DBN, VA, postural sway, and the drugʼs side effects were evaluated. Recordings were conducted at baseline, 90 minutes after first administration, and after 1 or 2 weeks.
RESULTS:Mean slow-phase velocity significantly decreased from a baseline of 2.74°/s ± 2.00 to 2.29°/s ± 2.12 (mean ± SD) 90 minutes after first administration and to 2.04°/s ± 2.24 (p < 0.001; post hoc both p = 0.024) after long-term treatment. VA significantly increased and postural sway in posturography showed a tendency to decrease on medication. Fifty percent of patients did not report any side effects. The most common reported side effect was abdominal discomfort and dizziness.
CONCLUSIONS:The treatment with the SK-channel activator CHZ is a potentially new therapeutic agent for the symptomatic treatment of DBN.
CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that CHZ 500 mg 3 times a day may improve eye movements and visual fixation in patients with DBN.
OBJECTIVEAnimal experiments have demonstrated that aminopyridines increase Purkinje cell excitability, and in clinical studies, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP) improved ...downbeat nystagmus. In this double-blind, prospective, crossover study, the effects of equivalent doses of 4-AP and 3,4-DAP on the slow-phase velocity (SPV) of downbeat nystagmus were compared.
METHODSEight patients with downbeat nystagmus due to different etiologies (cerebellar degeneration n = 1, bilateral vestibulopathy n = 1, bilateral vestibulopathy and cerebellar degeneration n = 1, Arnold-Chiari I malformation and cerebellar ataxia n = 1, cryptogenic cerebellar ataxia n = 4) were included. They were randomly assigned to receiving a single capsule of 10 mg of 3,4-DAP or 4-AP followed by 6 days with no medication. One week later, the treatment was switched, that is, 1 single capsule (10 mg) of the other agent. Recordings with 3-dimensional video-oculography were performed before and 45 and 90 minutes after drug administration.
RESULTSBoth medications had a significant effect throughout time (pre vs post 45 vs post 90) (F() = 8.876; P < 0.01). Following the administration of 3,4-DAP, mean slow velocity decreased from −5.68°/s (pre) to −3.29°/s (post 45) to −2.96°/s (post 90) (pre vs post 45/post 90 P < 0.01). In 4-AP, the mean SPV decreased from −6.04°/s (pre) to −1.58°/s (post 45) to −1.21°/s (post 90) (pre vs post 45/post 90 P < 0.00001). Both after 45 and after 90, the mean SPVs were significantly lower for 4-AP than for 3,4-DAP (P < 0.05). None of the patients reported serious side effects.
CONCLUSIONBased on these results, 10-mg doses of 4-AP lead to a more pronounced decrease of the SPV of downbeat nystagmus than do equivalent doses of 3,4-DAP.
Previous studies have shown that cerebellar transcranial direct current stimulation (tDCS) leads to faster adaptation of arm reaching movements to visuomotor rotation and force field perturbations in ...healthy subjects. The first aim of the present study was to confirm a stimulation-dependent effect on motor adaptation. Secondly, we investigated whether tDCS effects differ depending on onset, that is prior to or at the beginning of the adaptation phase. A total of 120 healthy and right-handed subjects (60 females, mean age 23.2 ±2.7 years, range 18-31 years) were tested. Subjects moved a cursor with a manipulandum to one of eight targets presented on a vertically orientated screen. Three baseline blocks were followed by one adaptation block and three washout blocks. 60 subjects did a force field adaptation task (FF), and 60 subjects a visuomotor adaptation task (VM). Equal numbers of subjects received anodal, cathodal or sham cerebellar tDCS beginning either in the third baseline block or at the start of the adaptation block. In FF and VM, tDCS and the onset of tDCS did not show a significant effect on motor adaptation (all p values > 0.05). We were unable to support previous findings of modulatory cerebellar tDCS effects in reaching adaptation tasks in healthy subjects. Prior possible application in patients with cerebellar disease, future experiments are needed to determine which tDCS and task parameters lead to robust tDCS effects.
GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) are rare, autosomal recessive, neurodegenerative diseases with no available symptomatic or disease-modifying treatments. This clinical trial ...investigated N-acetyl-l-leucine (NALL), an orally administered, modified amino acid in pediatric (≥6 years) and adult patients with GM2 gangliosidoses.
In this phase IIb, multinational, open-label, rater-blinded study (IB1001-202), male and female patients aged ≥6 years with a genetically confirmed diagnosis of GM2 gangliosidoses received orally administered NALL for a 6-week treatment period (4 g/d in patients ≥13 years, weight-tiered doses for patients 6-12 years), followed by a 6-week posttreatment washout period. For the primary Clinical Impression of Change in Severity analysis, patient performance on a predetermined primary anchor test (the 8-Meter Walk Test or the 9-Hole Peg Test) at baseline, after 6 weeks on NALL, and again after a 6-week washout period was videoed and evaluated centrally by blinded raters. Secondary outcomes included assessments of ataxia, clinical global impression, and quality of life.
Thirty patients between the age of 6 and 55 years were enrolled. Twenty-nine had an on-treatment assessment and were included in the primary modified intention-to-treat analysis. The study met its CI-CS primary end point (mean difference 0.71, SD = 2.09, 90% CI 0.00, 1.50,
= 0.039), as well as secondary measures of ataxia and global impression. NALL was safe and well tolerated, with no serious adverse reactions.
Treatment with NALL was associated with statistically significant and clinically relevant changes in functioning and quality of life in patients with GM2 gangliosidosis. NALL was safe and well tolerated, contributing to an overall favorable risk:benefit profile. NALL is a promising, easily administered (oral) therapeutic option for these rare, debilitating diseases with immense unmet medical needs.
The trial is registered with ClinicalTrials.gov (NCT03759665; registered on November 30, 2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled on June 7, 2019.
This study provides Class IV evidence that NALL improves outcomes for patients with GM2 gangliosidoses.
The effects of 4-aminopyridine (4-AP) on downbeat nystagmus (DBN) were analysed in terms of slow-phase velocity (SPV), stance, locomotion, visual acuity (VA), patient satisfaction and side effects ...using standardised questionnaires.
Twenty-seven patients with DBN received 5 mg 4-AP four times a day or placebo for 3 days and 10 mg 4-AP four times a day or placebo for 4 days. Recordings were done before the first, 60 min after the first and 60 min after the last drug administration.
SPV decreased from 2.42 deg/s at baseline to 1.38 deg/s with 5 mg 4-AP and to 2.03 deg/s with 10 mg 4-AP (p<0.05; post hoc: 5 mg 4-AP: p=0.04). The rate of responders was 57%. Increasing age correlated with a 4-AP-related decrease in SPV (p<0.05). Patients improved in the 'get-up-and-go test' with 4-AP (p<0.001; post hoc: 5 mg: p=0.025; 10 mg: p<0.001). Tandem-walk time (both p<0.01) and tandem-walk error (4-AP: p=0.054; placebo: p=0.059) improved under 4-AP and placebo. Posturography showed that some patients improved with the 5 mg 4-AP dose, particularly older patients. Near VA increased from 0.59 at baseline to 0.66 with 5 mg 4-AP (p<0.05). Patients with idiopathic DBN had the greatest benefit from 4-AP. There were no differences between 4-AP and placebo regarding patient satisfaction and side effects.
4-AP reduced SPV of DBN, improved near VA and some locomotor parameters. 4-AP is a useful medication for DBN syndrome, older patients in particular benefit from the effects of 5 mg 4-AP on nystagmus and postural stability.
PDF
