To compare the efficacy of the Sémont maneuver (SM) with the new "SémontPLUS maneuver" (SM+) in patients with posterior canal BPPV canalolithiasis (pcBPPVcan).
In a prospective trinational (Germany, ...Italy, and Belgium) randomized trial, patients with pcBPPVcan were randomly assigned to SM or SM+; SM+ means overextension of the head by 60+° below earth horizontal line during the movement of the patient toward the affected side. The first maneuver was done by the physician, and the subsequent maneuvers by the patients 9 times/day on their own. Each morning the patient documented whether vertigo could be induced. The primary endpoints were: "How long (in days) does it take until no attacks can be induced?" and "What is the efficacy of a single SM/SM+?"
In the 194 patients analyzed (96 SM, 98 SM+), it took 2 days (median, range 1-21 days, mean 3.6 days) for recovery with SM and 1 day (median, range 1-8 days, mean 1.8 days) with SM+ (
= 0.001, Mann-Whitney
-test). There was no difference in the second primary endpoint (chi
-test,
= 0.39).
This prospective trial shows that SM+ is more effective than SM when repeated therapeutic maneuvers are performed but not when a single maneuver is performed. It also supports the hypothesis of the biophysical model: overextension of the head during step 2 brings the clot of otoconia beyond the vertex of the canal, which increases the effectivity.
This study provides Class I evidence that SM+ is superior to SM for multiple treatment maneuvers of pcBPPVcan.
Background and purpose
The scientific literature on COVID‐19 is increasingly growing.
Methods
In this paper, we review the literature on movement disorders in the context of the COVID‐19 pandemic.
...Results
First, there are a variety of transient movement disorders that may manifest in the acute phase of COVID‐19, most often myoclonus, with more than 50 patients described in the literature. New onset parkinsonism, chorea, and tic‐like behaviours have also been reported. Movement disorders as a side effect after COVID‐19 vaccination are rare, occurring with a frequency of 0.00002–0.0002 depending on the product used, mostly manifesting with tremor. Current evidence for potential long‐term manifestations, for example, long COVID parkinsonism, is separately discussed. Second, the pandemic has also had an impact on patients with pre‐existing movement disorder syndromes, with negative effects on clinical status and overall well‐being, and reduced access to medication and health care. In many parts, the pandemic has led to reorganization of the medical system, including the development of new digital solutions. The movement disorder‐related evidence for this is reviewed and discussed.
Conclusions
The pandemic and the associated preventive measures have had a negative impact on the clinical status, access to health care, and overall well‐being of patients with pre‐existing movement disorders.
New onset movement disorders may occur in the acute phase of an infection with Sars‐CoV‐2, whereas movement disorders as an adverse event after vaccination are rare according to large drug safety report databases. There is concern that Sars‐CoV‐2 may trigger a hit‐and‐run mechanism and predispose to the development of neurodegenerative disorders, similar to what was observed after the Spanish flu in 1918 and the subsequent wave of encephalitis lethargica. The pandemic and the associated preventive measures have had a negative impact on the clinical status, access to health care, and overall well‐being of patients with pre‐existing movement disorders.
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.
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.
Purpose
Late-onset Tay-Sachs disease (LOTS) is a form of GM2 gangliosidosis, an autosomal recessive neurodegenerative disorder characterized by slowly progressive cerebellar ataxia, lower motor ...neuron disease, and psychiatric impairment due to mutations in the
HEXA
gene. The aim of our work was to identify the characteristic brain MRI findings in this presumably underdiagnosed disease.
Methods
Clinical data and MRI findings from 16 patients (10F/6 M) with LOTS from two centers were independently assessed by two readers and compared to 16 age- and sex-related controls.
Results
Lower motor neuron disease (94%), psychiatric symptoms—psychosis (31%), cognitive impairment (38%) and depression (25%)—and symptoms of cerebellar impairment including dysarthria (94%), ataxia (81%) and tremor (69%), were the most common clinical features. On MRI, pontocerebellar atrophy was a constant finding. Compared to controls, LOTS patients had smaller mean middle cerebellar peduncle diameter (
p
< 0.0001), mean superior cerebellar peduncle diameter (
p
= 0.0002), mesencephalon sagittal area (
p
= 0.0002), pons sagittal area (
p
< 0.0001), and larger 4
th
ventricle transversal diameter (
p
< 0.0001). Mild corpus callosum thinning (37.5%), mild cortical atrophy (18.8%), and white matter T2 hyperintensities (12.5%) were also present.
Conclusion
Given the characteristic clinical course and MRI findings of the pontocerebellar atrophy, late-onset Tay-Sachs disease should be considered in the differential diagnosis of adult-onset cerebellar ataxias.
Objective: To compare the efficacy of the Sémont maneuver (SM) with the new “SémontPLUS maneuver” (SM+) in patients with posterior canal BPPV canalolithiasis (pcBPPVcan).
Methods and Patients: In a ...prospective trinational (Germany, Italy, and Belgium) randomized trial, patients with pcBPPVcan were randomly assigned to SM or SM+; SM+ means overextension of the head by 60+° below earth horizontal line during the movement of the patient toward the affected side. The first maneuver was done by the physician, and the subsequent maneuvers by the patients 9 times/day on their own. Each morning the patient documented whether vertigo could be induced. The primary endpoints were: “How long (in days) does it take until no attacks can be induced?” and “What is the efficacy of a single SM/SM+?”
Results: In the 194 patients analyzed (96 SM, 98 SM+), it took 2 days (median, range 1–21 days, mean 3.6 days) for recovery with SM and 1 day (median, range 1-8 days, mean 1.8 days) with SM+ (p = 0.001, Mann-Whitney U-test). There was no difference in the second primary endpoint (chi2-test, p = 0.39).
Interpretation: This prospective trial shows that SM+ is more effective than SM when repeated therapeutic maneuvers are performed but not when a single maneuver is performed. It also supports the hypothesis of the biophysical model: overextension of the head during step 2 brings the clot of otoconia beyond the vertex of the canal, which increases the effectivity.
Classification of Evidence: This study provides Class I evidence that SM+ is superior to SM for multiple treatment maneuvers of pcBPPVcan.
An important channel of cell-to-cell communication is direct contact. The immune synapse is a paradigmatic example of such type of interaction: it forms upon engagement of antigen receptors in ...lymphocytes by antigen-presenting cells and allows the local exchange of molecules and information. Although mechanics has been shown to play an important role in this process, how forces organize and impact on synapse function is unknown. We find that mechanical forces are spatio-temporally patterned at the immune synapse: global pulsatile myosin II-driven tangential forces are observed at the synapse periphery while localised forces generated by invadosome-like F-actin protrusions are detected at its centre. Noticeably, we observe that these force-producing actin protrusions constitute the main site of antigen extraction and endocytosis and require myosin II contractility to form. The interplay between global and local forces dictated by the organization of the actomyosin cytoskeleton therefore controls endocytosis at the immune synapse.
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