Structural brain and spinal cord damage in symptomatic and pre-symptomatic VAPB-related ALS.

INTRODUCTION: The VAPB gene is associated with fALS (fALS 8). This disease presents a variable phenotype and no study sought to characterize its neuroanatomical abnormalities until now. This study aims to evaluate structural brain and spinal cord abnormalities in symptomatic and pre-symptomatic VAPB-related ALS. METHODS: This cohort included 10 presymptomatic and 20 symptomatic carriers of the Pro56Ser VAPB variant as well as 30 matched controls and 20 individuals with sporadic ALS. They underwent detailed clinical evaluation and MRI in a 3 T scanner. Using volumetric T1 sequence, we computed cerebral cortical thickness (FreeSurfer), basal ganglia volumetry (T1 Multi-atlas) and SC morphometry (SpineSeg). DTI was used to assess white matter integrity (DTI Multi-atlas). Groups were compared using a generalized linear model with Bonferroni-corrected p values<0.05. We also plotted VAPB brain expression map using Allen Human Brain Atlas to compare with imaging findings. RESULTS: Mean age of presymptomatic and symptomatic subjects were 43.2 and 51.9 years, respectively. Most patients had a predominant lower motor neuron phenotype (16/20). Sleep complaints and tremor were the most frequent additional manifestations. Compared to controls, symptomatic subjects had pallidal, brainstem and SC atrophy, whereas presymptomatic only had SC atrophy. This pattern also contrasted with the sALS group that presented motor cortex and corticospinal abnormalities. Brain structural damage and VAPB expression maps were highly overlapping. CONCLUSION: VAPB-related ALS has a distinctive structural signature that targets the basal ganglia, brainstem and SC, which are regions with high VAPB expression. Neuroanatomical SC changes are evident before clinical onset of the disease.

Randomized Trial of Botulinum Toxin Type A in Hereditary Spastic Paraplegia - The SPASTOX Trial.

BACKGROUND: Hereditary spastic paraplegia presents spasticity as the main clinical manifestation, reducing gait quality and producing incapacity. Management with botulinum toxin type A (BoNT-A) is not well elucidated. The objective of the current study was to evaluate the efficacy and safety of BoNT-A in patients with hereditary spastic paraplegias. METHODS: This was a double-blind, randomized, placebo-controlled crossover trial. Each participant was randomly assigned to receive 1 injection session of either BoNT-A (100 IU/2 mL of Prosigne in each adductor magnus and each triceps surae) or saline 0.9% (2 mL). The primary outcome measure was change from baseline in maximal gait velocity, and secondary outcome measures included changes in gait at self-selected velocity, spasticity, muscle strength, Spastic Paraplegia Rating Scale, pain, fatigue, and subjective perception of improvement. We also looked at adverse events reported by the patients. RESULTS: We enrolled 55 patients, 36 of whom were men and 41 with the pure phenotype. Mean age was 43 ± 13.4 years (range, 19-72 years), mean age of onset waws 27 ± 13.1 years (range, <1 to 55 yars), and mean disease duration was 17 ± 12.7 years (range, 1-62 years). Compared with baseline, we did not find significant differences between groups in primary and secondary outcomes, except for reduction in adductor tone (P = 0.01). The adverse events were transient and tolerable, and their incidence did not significantly differ between treatments (P = 0.17). CONCLUSIONS: BoNT-A was safe in patients with hereditary spastic paraplegias and reduced the adductor tone, but it was not able to produce functional improvement considering the doses, injection protocol, measures, and instruments used. © 2021 International Parkinson and Movement Disorder Society.

Sensory ataxia rating scale: Development and validation of a functional scale for patients with sensory neuronopathies.

Sensory neuronopathies (SN) result from dorsal root ganglia damage and manifest with a combination of sensory deficits and proprioceptive ataxia. Characterization of the natural history and development of therapeutic trials are hampered by the lack of clinical scales that capture the whole spectrum of SN-related manifestations. We propose and validate a rating instrument for SN. Three experienced neuromuscular specialists developed items to rate SN. The resultant instrument was later validated by the assessment of the intra-class correlation coefficient, for inter-rater validity in 48 SN patients, and later in a smaller subset of 16 patients to assess its intra-rater validity. Standardized Crombach's alpha and Oblimin rotation analysis were performed to verify internal consistency and items' relationship, respectively. Evaluation of Sensory Ataxia Rating Scale (SEARS)'s external validity was performed by comparison to: scale for the assessment and rating of ataxia (SARA), Beck balance scale (BBS), and INCAT sensory sum score (ISS). A 10-item scale with an intra-class correlation coefficient >0.95 for intra- and inter-rating measurements with a good internal consistency (standardized Cronbach's alpha of 0.83) were observed. There was a normal distribution of the scores without a floor or ceiling effect. A moderate to good correlation between SEARS and SARA, BBS, and ISS was observed. SEARS is a reliable, easy-to-perform and consistent instrument to rate SN. Larger cohorts and multicenter studies are needed to validate its usefulness towards possible treatment trials.

Electrophysiology of Cranial Nerve Testing: Cranial Nerves IX and X.

The cranial nerves IX and X emerge from medulla oblongata and have motor, sensory, and parasympathetic functions. Some of these are amenable to neurophysiological assessment. It is often hard to separate the individual contribution of each nerve; in fact, some of the techniques are indeed a composite functional measure of both nerves. The main methods are the evaluation of the swallowing function (combined IX and X), laryngeal electromyogram (predominant motor vagal function), and heart rate variability (predominant parasympathetic vagal function). This review describes, therefore, the techniques that best evaluate the major symptoms presented in IX and X cranial nerve disturbance: dysphagia, dysphonia, and autonomic parasympathetic dysfunction.