Search

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.

Background and ObjectiveGM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) are rare, inherited neurodegenerative disorders with no available symptomatic or disease modifying treatments. This clinical trial aimed to investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms of pediatric (≥ 6 years) and adult patients with GM2 gangliosidosis.Methods\We conducted an 8-center, multi-national, open-label, rater-blinded Phase IIb study (IB1001-201). Patients with a genetically confirmed diagnosis of GM2 gangliosidosis 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 rating scales (namely Scale for the Assessment and Rating of Ataxia), clinical global impression, and quality of life assessments.Results30 patients aged 6 to 55 years with a confirmed diagnosis of GM2 gangliosidosis (Tay-Sachs or Sandhoff’s disease) were enrolled. 29 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.71, SD=2.09, 90% CI 0.00, 1.50, p=0.044), as well as secondary endpoints. No treatment-related serious adverse events occurred.ConclusionsThis study showed NALL led to a statistically significant improvement in symptoms, functioning, and quality of life in patients with GM2 gangliosidosis. It is a safe, well-tolerated, easily administered oral therapy, therefore offering a favorable risk/benefit profile for this serious, debilitating disorder. NALL is a new therapeutic option for the treatment of this rare disease that has no other approved therapies worldwide.Classification of EvidenceThis study provides Class IV evidence NALL is safe, well-tolerated, and improves neurological symptoms and quality of life in patients with GM2 gangliosidosis.Trial Registration InformationThe trial is registered with ClinicalTrials.gov (NCT03759665; registered 30-Nov-2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled 07-June-2019.

BackgroundNiemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative disorder characterized by symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in observational case studies and animal and cellular models of NPC. Therefore, the effects of the active L-enantiomer, N-acetyl-L-leucine (NALL, Sponsor Code IB1001) were evaluated in paediatric and adult patients with NPC.MethodsWe conducted a 9-center, multinational, open-label, rater-blinded Phase 2 study to assess the safety and efficacy of NALL for the treatment of pediatric (≥ 6 years) and adult patients with NPC (IB1001-201 clinical trial). Eligible patients were assessed during three study phases: a baseline period (with or without a study run-in), a 6-week treatment period (dosage of NALL 4 g/d in patients aged ≥13 years; weight tiered doses for patients aged 6-12 years based on approximately 0.1 g/kg/day), and a 6-week post-treatment washout period. The primary outcome was based on the Clinical Impression of Change in Severity (CI-CS) assessment (assessed on a 7-point Likert scale) performed by blinded, centralized raters who compared videos of patients performing a pre-defined primary anchor test (either the 8-Meter Walk Test (8MWT) or 9-Hole Peg Test of the Dominant Hand (9HPT-D)) at different study periods. Secondary outcomes included the cerebellar function evaluations, namely the Scale for Assessment and Rating of Ataxia (SARA), the Spinocerebellar Ataxia Functional Index (SCAFI), and the Clinical Global Impression Scales (CGI) as well as the EuroQol-5D/VAS.ResultsThirty-three subjects aged 7 to 64 years with a confirmed diagnosis of NPC were enrolled according to the trial protocol between 04 September 2019 and 30 January 2020. Thirty-two patients were included in the modified intention-to-treat analysis. IB1001 met its CI-CS primary endpoint (mean difference 0.86 ((90% CI 0.25,1.75, p=0.029). IB1001 also met secondary endpoints, including improvement during treatment on the SARA scale (mean difference −1.19 (90% CI −1.8, −0.5, p=0.001)), investigator’s CGI-C assessment (mean difference from baseline to the end of treatment 0.6 (90% CI 0.5, 1.0, pp=0.002)) and investigator’s CGI-C assessment (washout mean difference −0.5 (90% CI −1.0, 0.0, p=0.006). IB1001 was well-tolerated with no treatment related serious adverse reactions occurring.ConclusionsConsistent with its pharmacological action, IB1001 rapidly improved symptoms, functioning, and quality of life in 6-weeks, the clinical effect of which was lost after the 6-week, post-treatment washout period. High consistency and statistical significance between the primary and secondary endpoints demonstrate a clear, clinically meaningful improvement with IB1001. IB1001 was well-tolerated and no drug-related serious adverse events were reported, demonstrating a favorable risk/benefit profile for the treatment of NPC (Funded by IntraBio; ClinicalTrials.gov number, NCT03759639; EudraCT number 2018-004331-71).

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. Context dependency of extinction can be demonstrated by the renewal effect. When CR acquisition takes place in context A and is extinguished in context B, renewal refers to the recovery of the CR in context A (A-B-A paradigm). In the present study acquisition, extinction and renewal of classically conditioned eyeblink responses were tested in 18 patients with subacute focal cerebellar lesions and 18 age- and sex-matched healthy controls. Standard delay eyeblink conditioning was performed using an A-B-A paradigm. All cerebellar patients underwent a high-resolution T1-weighted brain MRI scan to perform lesion-symptom mapping. CR acquisition was not significantly different between cerebellar and control participants allowing to draw conclusions on extinction. CR extinction was significantly less in cerebellar patients. Reduction of CR extinction tended to be more likely in patients with lesions in the lateral parts of lobule VI and Crus I. A significant renewal effect was present in controls only. The present data provide further evidence that the cerebellum contributes to extinction of conditioned eyeblink responses. Because acquisition was preserved and extinction took place in another context than acquisition, more lateral parts of the cerebellar hemisphere may contribute to context-related processes. Furthermore, lack of renewal in cerebellar patients suggest a contribution of the cerebellum to context-related processes.

Chronic pain disorders are extremely common, including chronic back pain and headaches, but also chronic visceral pain disorders, such as irritable bowel syndrome. Treatment is notoriously difficult. A detailed understanding of the neural pain circuitry is a prerequisite for the development of new treatment options. The cerebellum has become an interesting target for non-invasive and invasive brain stimulations in a wide range of brain disorders and may be a future option in treating chronic pain. The possible contribution of the cerebellum to the pathophysiology of chronic pain has become of interest only recently.1 Although the cerebellum has frequently been shown to respond to painful stimuli, knowledge about the specific contributions of the cerebellum to pain processing remains elusive. Electrophysiological studies in rodents provide evidence that the cerebellum receives afferent input coming from cutaneous and visceral nociceptors.2 Our group and others have found that neural processing of somatic and visceral pain is partly overlapping but reveals also significant differences.3 As yet, however, it is unknown to what extent cerebellar responses differ between visceral and somatic pain. To address this question, we compared pain-related activations of the cerebellum between carefully matched rectal distensions and cutaneous heat stimuli. Functional MRI (fMRI) data were acquired in 22 healthy female participants as part of a previous study.3 fMRI data were reanalysed using a normalising method optimised for the cerebellum. Participants were on average 24.4±0.6 years old with a mean body mass index of 21.9±0.5. Questionnaires confirmed lack …

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. Second, we investigated whether tDCS effects differ depending on onset, that is, before or at the beginning of the adaptation phase. A total of 120 healthy and right-handed subjects (60 women, mean age 23.2 ± SD 2.7 yr, range 18–31 yr) 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. Sixty subjects did a force field adaptation task (FF), and 60 subjects did 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 to possible application in patients with cerebellar disease, future experiments are needed to determine which tDCS and task parameters lead to robust tDCS effects. NEW & NOTEWORTHY Transcranial direct current stimulation (tDCS) is a promising tool to improve motor learning. We investigated whether cerebellar tDCS improves motor learning in force field and visuomotor tasks in healthy subjects and what influence the onset of stimulation has. We did not find stimulation effects of tDCS or an effect of onset of stimulation. A reevaluation of cerebellar tDCS in healthy subjects and at the end of the clinical potential in cerebellar patients is demanded.

Resting in an upright position during daytime decreases downbeat nystagmus (DBN). When measured in brightness only, that is, without intermitting exposure to darkness, it does not make a significant difference whether patients have previously rested in brightness or in darkness. In real-world scenarios, people are often exposed to brightness and darkness intermittently. The aim of this study was to analyze whether resting in brightness or resting in darkness was associated with a lower post-resting DBN after intermitting exposures to brightness and darkness. Eight patients were recorded with three-dimensional video-oculography in brightness and darkness conditions, each following two 2-h resting intervals under either brightness or darkness resting conditions. The dependent variable was DBN intensity, measured in mean slow phase velocity. A repeated measures ANOVA with the factors measurement condition (brightness vs. darkness), resting condition (brightness vs. darkness), and time (after first vs. second resting interval) showed a significant effect for the factor resting condition, where previous resting in darkness was associated with a significantly lower DBN relative to previous resting in brightness (P < 0.01). The clinical relevance is to advise patients with DBN to rest in darkness.

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 drug's 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.

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 (p0.05; 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 (p0.05). Patients improved in the 'get-up-and-go test' with 4-AP (p0.001; post hoc: 5 mg: p=0.025; 10 mg: p0.001). Tandem-walk time (both p0.01) 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 (p0.05). 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.

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. Mean SPV decreased from a baseline of 2.12 deg/s ± 1.72 (mean ± SD) to 0.51 deg/s ± 1.00 180 min after first administration of dalfampridine 10 mg and to 0.89 deg/s ± 0.75 after 2 weeks of treatment with dalfampridine (p < 0.05; post hoc both: p < 0.05). After a wash-out period of 1 week, mean SPV increased to 2.30 deg/s ± 1.6 (p < 0.05; post hoc both: p < 0.05). The VA significantly improved during treatment with dalfampridine. Also, 50 % of patients did not report any side effects. The most common reported side effects were abdominal discomfort and dizziness. Dalfampridine is an effective treatment for DBN in terms of SPV. It was well-tolerated in all patients.

There is evidence to support a role of the cerebellum in emotional learning processes, which are demonstrably altered in patients with chronic pain. We tested if cerebellar activation is altered during visceral pain-related fear conditioning and extinction in irritable bowel syndrome (IBS). Cerebellar blood oxygenation level-dependent (BOLD) data from N = 17 IBS patients and N = 21 healthy controls, collected as part of a previous fMRI study, was reanalyzed utilizing an advanced normalizing method of the cerebellum. The differential fear conditioning paradigm consisted of acquisition, extinction, and reinstatement phases. During acquisition, two visual conditioned stimuli (CS) were presented either paired (CS+) or unpaired (CS-) with painful rectal distension as unconditioned stimulus (US). In the extinction phase, the CS+ and CS- were presented without US. For reinstatement, unpaired US presentations were followed by unpaired CS+ and CS- presentations. Group differences in cerebellar activation were analyzed for the contrasts CS+ CS- and CS- CS+. During acquisition, IBS patients revealed significantly enhanced cerebellar BOLD responses to pain-predictive (CS+) and safety (CS-) cues compared to controls (p 0.05, family-wise error corrected). Increased activation was found in three main clusters, including the vermis (maximum in vermal lobule VI), intermediate cerebellum (maximum in lobule VIII), and the posterolateral cerebellar hemisphere (maximum in lobule VI). Areas overlapped for the contrasts CS+ CS- and CS- CS+. Group differences were most prominent in the contrast CS- CS+. During extinction and reinstatement, no significant group differences were found. During visceral pain-related fear conditioning, IBS patients showed increased activations in circumscribed areas of the medial, intermediate, and lateral cerebellum. These areas are involved in autonomic, somatosensory, and cognitive functions and likely contribute to the different aspects of pain-related fear. The cerebellum contributes to altered pain-related fear learning in IBS.

Cerebellar ataxia (CA) is a frequent and often disabling condition that impairs motor functioning and impacts on quality of life (QoL). No medication has yet been proven effective for the symptomatic or even causative treatment of hereditary or non-hereditary, non-acquired CA. So far, the only treatment recommendation is physiotherapy. Therefore, new therapeutic options are needed. Based on three observational studies, the primary objective of the acetyl-DL-leucine on ataxia (ALCAT) trial is to examine the efficacy and tolerability of a symptomatic therapy with acetyl-DL-leucine compared to placebo on motor function measured by the Scale for the Assessment and Rating of Ataxia (SARA) in patients with CA. An investigator-initiated, multicenter, European, randomized, double-blind, placebo-controlled, 2-treatment 2-period crossover phase III trial will be carried out. In total, 108 adult patients who meet the clinical criteria of CA of different etiologies (hereditary or non-hereditary, non-acquired) presenting with a SARA total score of at least 3 points will be randomly assigned in a 1:1 ratio to one of two different treatment sequences, either acetyl-DL-leucine (up to 5 g per day) followed by placebo or vice versa. Each sequence consists of two 6-week treatment periods, separated by a 4-week wash-out period. A follow-up examination is scheduled 4 weeks after the end of treatment. The primary efficacy outcome is the absolute change in the SARA total score. Secondary objectives are to demonstrate that acetyl-DL-leucine is effective in improving (1) motor function measured by the Spinocerebellar Ataxia Functional Index (SCAFI) and SARA subscore items and (2) QoL (EuroQoL 5 dimensions and 5 level version, EQ-5D-5 L), depression (Beck Depression Inventory, BDI-II) and fatigue (Fatigue Severity Score, FSS). Furthermore, the incidence of adverse events will be investigated. The results of this trial will inform whether symptomatic treatment with the modified amino-acid acetyl-DL-leucine is a worthy candidate for a new drug therapy to relieve ataxia symptoms and to improve patient care. If superiority of the experimental drug to placebo can be established it will also be re-purposing of an agent that has been previously used for the symptomatic treatment of dizziness. The trial was prospectively registered at www.clinicaltrialsregister.eu (EudraCT no. 2015–000460–34) and at https://www.germanctr.de (DRKS-ID: DRKS00009733 ).

Resting in an upright position during daytime decreases downbeat nystagmus (DBN). When measured in brightness only, that is, without intermitting exposure to darkness, it does not make a significant difference whether patients have previously rested in brightness or in darkness. In real-world scenarios, people are often exposed to brightness and darkness intermittently. The aim of this study was to analyze whether resting in brightness or resting in darkness was associated with a lower post-resting DBN after intermitting exposures to brightness and darkness. Eight patients were recorded with three-dimensional video-oculography in brightness and darkness conditions, each following two 2-h resting intervals under either brightness or darkness resting conditions. The dependent variable was DBN intensity, measured in mean slow phase velocity. A repeated measures ANOVA with the factors measurement condition (brightness vs. darkness), resting condition (brightness vs. darkness), and time (after first vs. second resting interval) showed a significant effect for the factor resting condition, where previous resting in darkness was associated with a significantly lower DBN relative to previous resting in brightness (P0.01). The clinical relevance is to advise patients with DBN to rest in darkness.

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. 18 young healthy participants were examined in this coherent threshold paradigm. Motion coherence thresholds were significantly lower when position and motion were congruent with gravity independent of motion velocity (p=0.024). In the other conditions higher motion coherence thresholds (MCT) were found at lower velocities and vice versa (p

Sir, We recently reported in Brain a large multi-centre study suggesting that truncating SYNE1 mutations are a recurrent cause of recessive ataxia also outside Quebec (23/434 = 5.3% of patients with unexplained early-onset ataxia) (Synofzik et al. , 2016). Moreover, this study indicated that SYNE1 ataxia might commonly present with complex multisystemic phenotypes rather than pure cerebellar ataxia, including in particular motor neuron and brainstem dysfunction (Synofzik et al. , 2016). However, confirmation of both the frequency estimate and the complex phenotypic spectrum is still lacking, raising the question whether these findings indeed represent systematic results rather than just exceptional or coincidental associations. Here, we now report the mutational and phenotypic findings on SYNE1 from a second, independent ataxia series of 116 patients. These findings not only confirm the high frequency of SYNE1 ataxia and extend both the mutational spectrum (seven novel index patients, 12 novel SYNE1 mutations) and the multisystemic phenotypic spectrum, including amyotrophic lateral sclerosis (ALS)-like motor neuron features, they also indicate that muscle immunohistochemistry might provide a valuable diagnostic biomarker for clarifying the pathogenic contribution of SYNE1 missense variants. This observation may have consequences for clinical SYNE1 diagnostics, as diagnostic tests are urgently needed for clarifying the role of the ubiquitous SYNE1 missense variants with unknown clinical significance (VUS), which are frequently found in neurological and non-neurological patients and controls (Synofzik et al. , 2016). Index subjects ( n = 116) with unexplained degenerative ataxia compatible with autosomal recessive inheritance (no ataxia in the parental generation) and negative for trinucleotide repeat expansions causing Friedreich’s ataxia (FRDA) were compiled from three sources: the Early Onset Ataxia Consortium ( n = 88), the ataxia centre Antwerp, Belgium ( n = 9), and the ataxia centre Milano, Italy ( n = 19). All subjects originated from European, Middle East or Mediterranean countries. This …

Context dependency of extinction is well known and has extensively been studied in fear conditioning, but has rarely been assessed in eyeblink conditioning. One way to demonstrate context dependency of extinction is the renewal effect. ABA paradigms are most commonly used to show the renewal effect of extinguished learned fear: if acquisition takes place in context A, and extinction takes place in context B (extinction phase), learned responses will recover in subsequent extinction trials presented in context A (renewal phase). The renewal effect of the visual threat eyeblink response (VTER), a conditioned eyeblink response, which is naturally acquired in early infancy, was examined in a total of 48 young and healthy participants with two experiments using an ABA paradigm. Twenty paired trials were performed in context A (baseline trials), followed by 50 extinction trials in context B (extinction phase) and 50 extinction trials in context A (renewal phase). In 24 participants, contexts A and B were two different rooms, and in the other 24 participants, two different background colors (orange and blue) and noises were used. To rule out spontaneous recovery, an AAA design was used for comparison. There were significant effects of extinction in both experiments. No significant renewal effects were observed. In experiment 2, however, extinction was significantly less using orange background during extinction compared to the blue background. The present findings suggest that extinction of conditioned eyeblinks depends on the physical context. Findings add to the animal literature that context can play a role in the acquisition of classically conditioned eyeblink responses. Future studies, however, need to be performed to confirm the present findings. Lack of renewal effect may be explained by the highly overlearned character of the VTER.

Objective: The therapeutic effects of 4-aminopyridine (4AP) were investigated in a randomized, double-blind, crossover trial in 10 subjects with familial episodic ataxia with nystagmus. Methods: After randomization, placebo or 4AP (5 mg 3 times daily) was administered for 2 3-month-long treatment periods separated by a 1-month-long washout period. The primary outcome measure was the number of ataxia attacks per month; the secondary outcome measures were the attack duration and patient-reported quality of life (Vestibular Disorders Activities of Daily Living Scale [VDADL]). Nonparametric tests and a random-effects model were used for statistical analysis. Results: The diagnosis of episodic ataxia type 2 (EA2) was genetically confirmed in 7 subjects. Patients receiving placebo had a median monthly attack frequency of 6.50, whereas patients taking 4AP had a frequency of 1.65 ( p = 0.03). Median monthly attack duration decreased from 13.65 hours with placebo to 4.45 hours with 4AP ( p = 0.08). The VDADL score decreased from 6.00 to 1.50 ( p = 0.02). 4AP was well-tolerated. Conclusions: This controlled trial on EA2 and familial episodic ataxia with nystagmus demonstrated that 4AP decreases attack frequency and improves quality of life. Level of evidence: This crossover study provides Class II evidence that 4AP decreases attack frequency and improves the patient-reported quality of life in patients with episodic ataxia and related familial ataxias.

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. To this aim, we objectified rigidity measurements via surface EMG recordings of the Mm. biceps (bic) and triceps brachii (tric) in patients treated with chronic stimulation of the STN. We show that cessation and initiation of DBS have effects on the EMG profile during standardized extension and flexion movements in the elbow joint. These data correlate significantly with clinical ratings. Thus, EMG recordings of the Mm. bic and tric during this standardized extension-flexion movement can be used to objectively measure rigidity and to monitor its course over time. In view of its low technical requirements, this technique lends itself to use during DBS implantation surgery and in the clinical environment.

A 60-year-old man had a 3-year history of cerebellar ataxia and dementia, without a family history. T1-weighted MRI showed cerebellar atrophy (figure, A). Susceptibility-weighted images (SWI) revealed hypointensities of the basal ganglia and mesencephalic and cerebellar nuclei (figure, B, a–c), suggesting neurodegeneration with brain iron accumulation.1 Serum copper, iron, ferritin, transferrin, and ceruloplasmin levels were normal. Genetic testing revealed a CAG/CAA repeat expansion of 1 allele with 44 repeats (normal range 25–42), within the reduced penetrance range (43–48 repeats) in the TATA box binding protein ( TBP ) gene.2 In patients with cerebellar atrophy with hypointensities of subcortical and cerebellar nuclei in SWI or gradient echo imaging, diagnostic considerations should include spinocerebellar ataxia 17.

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. 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. RESULTS: Both 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. CONCLUSION: Based 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.

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. The authors now examine motion coherence tasks, which have two advantages: (1) the task is associated with the functions of the middle temporal area; and (2) it affords testing at low and high motion velocities, as relevant for patients with oscillopsia due to BVF.Nine BVF patients and nine healthy control subjects were examined with a random dot pattern with variable percentages of dots moving in the target direction. Participants were asked to indicate in which of two possible directions they perceived the coherent motion. Horizontal and vertical planes were tested at speeds from 0.156 to 40°/s.Motion coherence thresholds were lower at higher speeds in both groups (p0.0001). BVF patients had raised motion coherence thresholds (p=0.002) across all velocities as compared with the control subject group.In a motion coherence paradigm, BVF patients show raised thresholds. This is the first demonstration of diminished visual motion processing at high velocities, supporting the view that the changes allow BVF patients to partly compensate for the oscillopsia. The findings are interpreted as an adaptive process likely to involve the middle temporal visual motion processing areas.

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. To this aim, we objectified rigidity measurements via surface EMG recordings of the Mm. biceps (bic) and triceps brachii (tric) in patients treated with chronic stimulation of the STN. We show that cessation and initiation of DBS have effects on the EMG profile during standardized extension and flexion movements in the elbow joint. These data correlate significantly with clinical ratings. Thus, EMG recordings of the Mm. bic and tric during this standardized extension-flexion movement can be used to objectively measure rigidity and to monitor its course over time. In view of its low technical requirements, this technique lends itself to use during DBS implantation surgery and in the clinical environment.

{#article-title-2} “A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias”1 follows this group's preliminary report on how 4-aminopyridine (4-AP) is one of few compounds that effectively blocks attacks in EA2 patients.1,2 The authors convincingly demonstrate that 4-AP reduces the frequency of attacks, but it would be interesting to know if it modified the severity or duration of the attacks. A …