Citations

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

ABSTRACTIntroduction/AimsMuscle cramps are a common symptom in amyotrophic lateral sclerosis (ALS). Ameliorating muscle cramps may improve quality of life in devastating diseases like ALS. A traditional Japanese medicine (Kampo, TJ‐68) is widely prescribed in Japan for muscle cramps. However, it is not available in the USA. This study evaluated the safety, tolerability, and efficacy of TJ‐68 in ALS.MethodsThis study was a double‐blind, randomized, placebo‐controlled crossover trial, consisting of four periods, conducted at three centers in the USA. Safety was evaluated using multiple measures. The primary efficacy outcome was the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity (item #5 of the Muscle Cramp Scale (MCS)). The secondary outcomes included the remaining items of the MCS and the Clinical Global Impression of Changes (CGIC), among others. The study was planned to enroll 22 participants with ALS within 2 years.ResultsThe enrollment was slow and was completed with 11 participants. There were no serious safety issues and TJ‐68 was well tolerated. Although the primary outcome measure did not reach statistical significance (p = 0.35), several secondary measures showed significant results: MCS #1 triggering of cramps (p = 0.01), MCS #2 cramp frequency (p = 0.03), MCS Additional 1 change of motor behaviors (p = 0.02), and CGIC assessed by the evaluator (p = 0.009). Other outcome measures did not reach statistical significance.DiscussionThe study revealed that N‐of‐1 trial design can detect changes in a small sample size, and TJ‐68 appeared to be safe. Larger studies are needed to confirm the efficacy of TJ‐68.

Abstract Introduction/Aims: Muscle cramps are a common and often disabling symptom in Amyotrophic Lateral Sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in this patient population may sustain quality of life longer. A traditional Japanese medicine, shakuyakukanzoto (TJ-68) is widely prescribed in Japan for managing muscle cramps in a variety of conditions. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, this clinical trial is designed to test the safety and efficacy of TJ-68 in participants with ALS reporting serious muscle cramps using a personalized N-of-1 approach. If successful, we can introduce TJ-68 for muscle cramps in ALS to Western medicine. Methods: With FDA-IND approval, we are conducting a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study was sized to detect a one-point shift on the Columbia Muscle Cramp Scale (MCS) item #5 with 85% power under a four-period crossover design.The secondary assessment includes the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R). Discussion: The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate MCS in rare disorders. If TJ-68 proves safe and efficacious, we will work to introduce this product to Western medicine for treatment of patients with ALS and disabling muscle cramps. Trial Registration: This clinical trial has been registered with ClinicalTrials.gov (NCT04998305).

AbstractIntroduction/AimsALS is a heterogeneous disease that may be complicated or in part driven by inflammation. NP001, a regulator of macrophage activation, was associated with slowing disease progression in those with higher levels of the plasma inflammatory marker C‐reactive protein (CRP) in phase 2A studies in ALS. Here, we evaluate the effects of NP001 in a phase 2B trial, and perform a post hoc analysis with combined data from the preceding phase 2A trial.MethodsThe phase 2B trial enrolled 138 participants within 3 y of symptom onset and with plasma hs‐CRP values >1.13 mg/L. They were randomized 1:1 to receive either placebo or NP001 for 6 mo. Change from baseline ALSFRS‐R scores was the primary efficacy endpoint. Secondary endpoints included vital capacity (VC) change from baseline and percentage of participants showing no decline of ALSFRS‐R score over 6 mo (non‐progressor).ResultsThe phase 2B study did not show significant differences between placebo and active treatment with respect to change in ALSFRS‐R scores, or VC. The drug was safe and well tolerated. A post hoc analysis identified a 40‐ to 65‐y‐old subset in which NP001‐treated patients demonstrated slower declines in ALSFRS‐R score by 36% and VC loss by 51% compared with placebo. A greater number of non‐progressors were NP001‐treated compared with placebo (p = .004).DiscussionAlthough the phase 2B trial failed to meet its primary endpoints, post hoc analyses identified a subgroup whose decline in ALSFRS‐R and VC scores were significantly slower than placebo. Further studies will be required to validate these findings.