GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort.

Background: GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA) expansions in the fibroblast growth factor 14 (FGF14) gene, but its phenotypic spectrum, pathogenic threshold, and evidence-based treatability remain to be established. We report on the frequency of FGF14 (GAA) and (GAA) expansions in a large cohort of patients with idiopathic downbeat nystagmus (DBN) and their response to 4-aminopyridine.

Methods: Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial.

Age-related differences of cerebellar cortex and nuclei: MRI findings in healthy controls and its application to spinocerebellar ataxia (SCA6) patients.

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).

Efficacy and Safety of N-Acetyl-l-Leucine in Children and Adults With GM2 Gangliosidoses.

Background And Objectives: 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.

Methods: 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.

Efficacy and safety of N-acetyl-L-leucine in Niemann-Pick disease type C.

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.

Extinction and Renewal of Conditioned Eyeblink Responses in Focal Cerebellar Disease.

Extinction of conditioned aversive responses (CR) has been shown to be context-dependent. The hippocampus and prefrontal cortex are of particular importance. The cerebellum may contribute to context-related processes because of its known connections with the hippocampus and prefrontal cortex.

Gravity matters: Motion perceptions modified by direction and body position.

Motion coherence thresholds are consistently higher at lower velocities. In this study we analysed the influence of the position and direction of moving objects on their perception and thereby the influence of gravity. This paradigm allows a differentiation to be made between coherent and randomly moving objects in an upright and a reclining position with a horizontal or vertical axis of motion.

Effect of chlorzoxazone in patients with downbeat nystagmus: a pilot trial.

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.

A randomised double-blind, cross-over trial of 4-aminopyridine for downbeat nystagmus--effects on slowphase eye velocity, postural stability, locomotion and symptoms.

Objective: 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.

Methods: 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.

Dalfampridine in patients with downbeat nystagmus--an observational study.

We investigated the effects of dalfampridine, the sustained-release form of 4-aminopyridine, on slow phase velocity (SPV) and visual acuity (VA) in patients with downbeat nystagmus (DBN) and the side effects of the drug. In this proof-of-principle observational study, ten patients received dalfampridine 10 mg bid for 2 weeks. Recordings were conducted at baseline, 180 min after first administration, after 2 weeks of treatment and after 4 weeks of wash-out.

Preventing road injuries in children by applying feedback devices.

Objective: The objective of this article is to determine how to prevent road injuries in schoolchildren by reducing the prevalence of speeding.

Methods: On a busy road in the neighborhood of a preschool and two secondary schools in Oberhaching (greater Munich, Germany), a board was mounted next to the road (visible to the drivers as well as the pedestrians). The board consisted of a picture of a smiling child.

Comparison of 10-mg doses of 4-aminopyridine and 3,4-diaminopyridine for the treatment of downbeat nystagmus.

Objective: Animal 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.

Methods: Eight 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.

Adaptive motion processing in bilateral vestibular failure.

Background: Patients with bilateral vestibular failure (BVF) suffer from oscillopsia during head movements. This is secondary to the loss of the vestibulo-ocular reflex which is responsible for stabilising retinal images during head movements of high frequency or velocity. Previous studies documented decreased visual motion sensitivity in such patients at low velocities.

Objective measurement of muscle rigidity in Parkinsonian patients treated with subthalamic stimulation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to be an effective treatment for Parkinson's disease (PD). The intraoperative positioning of DBS electrodes and postoperative adjustment of the stimulation parameters, however, require continuous, precise evaluation. Moreover, ambulatory measurements of the symptoms would also help to evaluate changes in the progression of PD in these patients.