Sorenson, Eric J.

Importance Tofersen is a disease-modifying antisense oligonucleotide therapeutic for people living with SOD1 –amyotrophic lateral sclerosis ( SOD1 -ALS). Autopsy tissue donors have provided the first opportunity to study the distribution of intrathecally administered tofersen in human central nervous system tissues. Objectives To determine the tissue distribution of tofersen and to provide the first estimates of SOD1 reduction in human somatic motor systems tissues. Design, Setting, and Participants This was a cross-sectional autopsy tissue case series conducted between 2018 and 2026. Autopsies were performed at 3 US academic medical institutions. Tissue samples from 8 deceased patients who lived with SOD1 -ALS, participated in tofersen clinical trials (ClinicalTrials.gov Identifiers NCT02623699 [An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)] and NCT03070119 [Long-Term Evaluation of BIIB067 (Tofersen)]) or the Expanded Access Program, and whose families authorized autopsies were eligible for this study. All autopsy tissue donors known at the time of this study were included (none were excluded). Analyses were conducted between August 2020 and January 2026. Exposures Participants received multiple intrathecal 20- to 100-mg tofersen doses. Main Outcomes and Measures Tofersen tissue concentrations were measured using hybridization enzyme-linked immunosorbent assay (ELISA). SOD1 messenger RNA (mRNA) and protein reduction estimates, defined as percentage SOD1 levels in this study’s recently treated autopsy tissue donors compared to a cohort of samples from tofersen-naive SOD1 -ALS autopsy tissue donors, were measured using quantitative reverse transcription polymerase chain reaction (PCR) and ELISA. Histological localization of tofersen and SOD1 transcripts were studied using immunohistochemistry and in situ hybridization assays. Results In 8 tofersen-treated autopsy tissue donors (5 male and 3 female donors; age range, 42-66 years), spinal cord and motor cortical tissue tofersen concentrations strongly correlated with predictions based on individual dosing histories and a preclinical pharmacokinetic model. For 3 recently treated autopsy tissue donors, reductions in lumbar spinal cord tissue SOD1 mRNA and protein levels ranged from 45% to 84% despite not having been administered 1 to 2 scheduled doses before autopsy. Residual somatic motor neurons demonstrated tofersen transduction and low SOD1 mRNA probe hybridization. Misfolded SOD1 protein inclusions were detected in residual motor neurons of tofersen-naive SOD1- ALS tissue donor controls and tofersen-treated tissue donors. Meningeal and perivascular lymphocytic immune responses were observed in 5 recently treated tissue donors but were not apparent in tissue donors with remote final tofersen doses. Conclusions and Relevance This case series presents the first emerging autopsy tissue data confirming the predicted distribution of tofersen and robust SOD1 protein reduction in human somatic motor systems tissues.

Purpose: Neuromuscular ultrasound, including cross-sectional area measurements, adds diagnostic value to the clinical and electrodiagnosis evaluation of ulnar neuropathy at the elbow. Previously published reference values for ulnar nerve size vary widely. Our objective was to establish age-specific reference values for ulnar nerve cross-sectional area at multiple sites in asymptomatic adults for our laboratory. Methods: Healthy adult subjects without neuromuscular symptoms or disease were recruited from our tertiary referral electromyogram laboratory and staff. Ulnar nerve cross-sectional area measurements were made in short axis at the wrist, forearm, cubital tunnel, retrocondylar groove, 2 cm proximal to the medial epicondyle, and mid-upper arm with the elbow flexed to 90°. Dynamic neuromuscular ultrasound evaluated for subluxation and dislocation at the medial epicondyle. Results were stratified by age group (younger than 40, 40–60, and older than 60 years) with at least 20 subjects per sex per group, as well as by sex, body mass index, and handedness. The upper limit of normal was established as two standard deviations above the mean. Results: One hundred forty-two subjects (ages 18–84, mean 47.7 years) were included. Cross-sectional area significantly increased with age at all sites except the wrist. Cross-sectional area cut-offs at the retrocondylar groove were 10.0, 10.9, and 11.4 mm 2 , respectively, by age group. Ratios comparing retrocondylar groove and cubital tunnel to arm and forearm were calculated. Thirty-two percent had subluxation or dislocation in at least one limb. Conclusions: Age-specific cross-sectional area cut-offs and ratios may facilitate a more nuanced interpretation and diagnostic value when used in conjunction with clinical and electrodiagnosis evaluation of ulnar neuropathy at the elbow.

ABSTRACT Background Primary lateral sclerosis (PLS) is an ultrarare upper motor neuron syndrome with a prognosis unique from classical ALS. The study of PLS is complicated by its rarity and the difficulty distinguishing PLS from ALS. We present data from a 1‐year prospective follow‐up study on PLS and efforts to distinguish it from ALS. Methods Seventy‐six PLS participants enrolled in this prospective natural history study. EMG studies, blood neurofilament light chain levels (NfLs), and demographic characteristics were obtained at baseline. At 1‐year follow‐up, repeat EMG studies were conducted to determine which participants fulfilled criteria for ALS. Baseline characteristics were then compared to determine features that predict reclassification. Results Seventy participants completed 1‐year follow‐up. Five of the 70 were reclassified to ALS (7.1%). Those reclassified had higher trends in baseline blood NfL levels (91.4 vs. 34.0 pg/mL, p = 0.13) and shorter symptom duration (39 vs. 69 months in the PLS group, p = 0.15). Reclassification was noted in both probable and definite PLS participants. All cases with a symptomatic duration of less than 2 years retained the PLS phenotype (5 of 5). NfL levels over 90 pg/mL predicted reclassification with 94% specificity and 60% sensitivity. No other features predicted reclassification to ALS. Conclusions In our population, reclassification of PLS to ALS occurred at a low frequency at 1 year follow‐up (7.1%). Baseline NfL was the strongest predictor in differentiating UMN dominant ALS from PLS at 1‐year follow‐up. Based on our data, we propose EMG and NfL criteria for enrollment in future PLS trials.

Objective The primary lateral sclerosis ( PLS ) consensus diagnostic criteria and functional rating scale ( PLSFRS ) were recently established to facilitate and optimize future PLS clinical trials. We examined the trajectory of the PLSFRS and other functional outcome measures and biomarkers in the PLS Natural History Study ( PLS NHS ) to understand their performance in this prospective cohort. Methods The PLS NHS is a prospective, longitudinal, multicenter study of people living with PLS in different diagnostic categories: early (disease duration <2 years); probable (2–4 years); and definite PLS (4–15 years). PLSFRS scores and other functional outcome measures were collected at baseline, 3‐, 6‐, 9‐, and 12‐month follow‐up visits. Baseline characteristics were compared between the groups. The slopes of the PLSFRS and other functional outcome measures over 12 months were examined in the overall cohort and subgroups using linear mixed‐effect models. The associations between baseline characteristics and the rate of PLSFRS decline were analyzed with linear regression models. Results A total of 76 participants were included: early (n = 6); probable (n = 26); and definite (n = 44) PLS . Baseline PLSFRS total scores were highest in the early PLS group, followed by the probable and definite PLS groups. In the overall cohort, the PLSFRS total score declined by 0.33 points/month (95% confidence interval [0.27–0.39], adjusted p < 0.05). The rate of decline was steepest in the early PLS group, followed by the probable and definite PLS groups. Baseline neurofilament light chain level was associated with the rate of PLSFRS decline over 1 year ( p = 0.001). Interpretation In PLS, the rate of functional decline, as measured by the PLSFRS total score, is faster during the early phase of the disease. Neurofilament light might serve as a prognostic biomarker in PLS. ANN NEUROL 2026;99:418–428

Neurologic complications associated with regional anesthesia and pain medicine practice are extremely rare. The ASRA Practice Advisory on Neurologic Complications in Regional Anesthesia and Pain Medicine addresses the etiology, differential diagnosis, prevention, and treatment of these complications. This Advisory does not focus on hemorrhagic and infectious complications, because they have been addressed by other recent ASRA Practice Advisories. The current Practice Advisory offers recommendations to aid in the understanding and potential limitation of neurologic complications that may arise during the practice of regional anesthesia and pain medicine.

ABSTRACTIntroduction/AimsNeuromuscular ultrasound (NMUS), initially performed by physicians, is increasingly performed by technicians in many electrodiagnostic (EDX) laboratories for certain studies under physician supervision. The aims of this study were to determine: (1) the reproducibility of nonphysician sonographers' assessments of the median nerve and (2) the need for ongoing training to maintain the reproducibility and reliability of median nerve ultrasound assessments.MethodsThe median nerve was examined sonographically in a healthy volunteer by 12 nonphysicians on 3 separate occasions: Day 1 and then 2 weeks (Day 2) and 4 months (Day 3) later. Cross‐sectional area (CSA) and wrist‐to‐forearm ratios (WFRs) were calculated each time. Sonographers were retrained prior to Day 2. Reproducibility and reliability were determined using coefficients of variation calculated for each characteristic for each day and each nonphysician sonographer, comparing performance across the 3 time points.ResultsThere was overall less variation for each characteristic (wrist CSA, forearm CSA, and WFR) on Day 2 compared to Day 1 (coefficients of variation 3.0%, 5.4%, and 5.7% vs. 8.8%, 15.5%, and 11.3%, respectively), both when viewed at the group and individual levels, indicating an improvement in reproducibility and reliability after the retraining session. The improvement was similar for Day 3.DiscussionThis study demonstrates the need for training and subsequent retraining sessions to ensure the reproducibility and reliability of NMUS measurements in the median nerve.