INTRODUCTION Primary lateral sclerosis is a rare neurodegenerative disorder of the upper motor neurons. Diagnostic criteria have changed considerably over the years, and the recent consensus criteria introduced 'probable PLS' for patients with a symptom duration of 2-4 years. The objective of this study is the systematic evaluation of clinical and neuroimaging characteristics in early PLS by studying a group of 'probable PLS patients' in comparison to a cohort of established PLS patients. METHODS In a prospective neuroimaging study, thirty-nine patients were stratified by the new consensus criteria into 'probable' (symptom duration 2-4 years) or 'definite' PLS (symptom duration >4 years). Patients were evaluated with a standardised battery of clinical instruments (ALSFRS-r, Penn upper motor neuron score, the modified Ashworth spasticity scale), whole genome sequencing, and underwent structural and diffusion MRI. The imaging profile of the two PLS cohorts were contrasted to a dataset of 100 healthy controls. All 'probable PLS' patients subsequently fulfilled criteria for 'definite' PLS on longitudinal follow-up and none transitioned to develop ALS. RESULTS PLS patients tested negative for known ALS- or HSP-associated mutations on whole genome sequencing. Despite their shorter symptom duration, 'probable PLS' patients already exhibited considerable functional disability, upper motor neuron disease burden and the majority of them required walking aids for safe ambulation. Their ALSFRS-r, UMN and modified Ashworth score means were 83%, 98% and 85% of the 'definite' group respectively. Motor cortex thickness was significantly reduced in both PLS groups in comparison to controls, but cortical changes were less widespread in 'probable' PLS on morphometric analyses. Corticospinal tract and corpus callosum metrics were relatively well preserved in the 'probable' group in contrast to the widespread white matter degeneration observed in the 'definite' group. CONCLUSIONS Our clinical and radiological analyses support the recent introduction of the 'probable' PLS category, as this cohort already exhibits considerable disability and cerebral changes consistent with established PLS. Before the publication of the new consensus criteria, these patients would have not been diagnosed with PLS on the basis of their symptom duration despite their significant functional impairment and motor cortex atrophy. The introduction of this new category will facilitate earlier recruitment into clinical trials, and shorten the protracted diagnostic uncertainty the majority of PLS patients face.

中文翻译：

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原发性侧索硬化的不断发展的诊断标准：“可能的 PLS”的临床和放射学基础

引言 原发性侧索硬化症是一种罕见的上运动神经元神经退行性疾病。多年来，诊断标准发生了很大变化，最近的共识标准为症状持续时间为 2-4 年的患者引入了“可能的 PLS”。本研究的目的是通过研究一组“可能的 PLS 患者”与一组已建立的 PLS 患者，对早期 PLS 的临床和神经影像学特征进行系统评估。方法 在一项前瞻性神经影像学研究中，根据新的共识标准将 39 名患者分为“可能”（症状持续时间 2-4 年）或“确定”PLS（症状持续时间 >4 年）。使用一组标准化的临床仪器（ALSFRS-r、Penn 上运动神经元评分、改良的 Ashworth 痉挛量表）、全基因组测序，并接受了结构和扩散 MRI。将两个 PLS 队列的成像特征与 100 名健康对照的数据集进行对比。随后，所有“可能的 PLS”患者在纵向随访中都符合“确定”PLS 的标准，并且没有人转变为发展为 ALS。结果 PLS 患者在全基因组测序中检测出已知的 ALS 或 HSP 相关突变阴性。尽管他们的症状持续时间较短，“可能的 PLS”患者已经表现出相当大的功能障碍、上运动神经元疾病负担，并且他们中的大多数人需要助行器才能安全行走。他们的 ALSFRS-r、UMN 和改良 Ashworth 评分平均值分别为“确定”组的 83%、98% 和 85%。与对照组相比，两个 PLS 组的运动皮层厚度均显着降低，但在形态测量分析中，“可能的”PLS 的皮层变化不那么普遍。与在“确定”组中观察到的广泛的白质变性相比，“可能”组的皮质脊髓束和胼胝体指标相对完好。结论我们的临床和放射学分析支持最近引入的“可能”PLS 类别，因为该队列已经表现出与已建立的 PLS 一致的相当大的残疾和大脑变化。在新的共识标准发布之前，尽管这些患者有明显的功能障碍和运动皮层萎缩，但不会根据症状持续时间被诊断为 PLS。