Primary Lateral Sclerosis: Implications for Diagnostic Criteria From a Natural History Study in the Netherlands

Abstract

Background and objectives: Primary lateral sclerosis (PLS) is a rare disease characterized by upper motor neuron (UMN) degeneration. We aimed to elucidate the natural history in patients with UMN syndromes suggestive of PLS and validate the most recent diagnostic (consensus) criteria.

Methods: A validation study of a long-term follow-up cohort was conducted, including adults with UMN syndromes and disease durations ≥6 months. Patients were assessed at baseline (T1), at 3 years (T2), and when possible after 13 years (T3). Diagnostic categorization followed the 2020 PLS consensus criteria. Main outcomes included diagnostic classification at follow-up and survival.

Results: The study comprised 86 patients (34 women [40%], mean age 58.9 ± 10.1 years), of whom 43 met the PLS consensus criteria at baseline (6 probable, 37 definite). Eight patients had a disease duration <2 years, and 35 patients presented with UMN symptoms localized to 1 region (1 bulbar, 34 legs). Change of initial diagnosis occurred in 14% of patients with PLS, and 49% of patients presenting with UMN symptoms in 1 region progressed to PLS. Seven patients developed amyotrophic lateral sclerosis (ALS), and for 7 patients, diagnosis was revised to hereditary spastic paraplegia (HSP). Survival was shorter for patients with a disease duration <4 years. In the probable PLS group, 33% converted to ALS. Converters had a steeper Amyotrophic Lateral Sclerosis Functional Rating Scale slope (p = 0.023) and shorter symptom duration (p < 0.001) at inclusion. Of patients presenting with leg symptoms, diagnosis was revised between T2 and T3 in 29%. Introducing a 4-year minimal disease duration for PLS diagnosis and categorization based on regions involved resulted in 86% of PLS diagnoses remaining within the PLS category, 5% transitioning to ALS (slow variant), and 9% to HSP. Survival was longest for patients presenting with symptoms confined to arms and legs or legs only, followed by those with bulbar involvement at baseline, while patients with disease durations between 6 months and 4 years exhibited the shortest survival.

Discussion: Our findings suggest that a diagnosis of PLS should be deferred until 4 years after symptom onset because shorter durations correlate with higher ALS conversion rates and shorter survival. Categorization by regional involvement may facilitate more effective monitoring of patients with UMN syndromes.

Figure 1. Diagnosis at Each Time Point Based on the 2020 Consensus Criteria for PLS

The numbers represent the number of patients per category at each time point. T1 = baseline; T2 = 3 years of follow-up; T3 = approximately 13 years of follow-up. ALS = amyotrophic lateral sclerosis; HSP = hereditary spastic paraplegia; PLS = primary lateral sclerosis.

Figure 2. Diagnosis at Each Time Point Based on the Adapted Criteria

The numbers represent the number of patients per category at each time point. T1 = baseline; T2 = 3 years of follow-up; T3 = approximately 13 years of follow-up. ALS = amyotrophic lateral sclerosis; HSP = hereditary spastic paraplegia; PLS = primary lateral sclerosis.

Figure 3. Survival Curves According to 2020 PLS Consensus Criteria and Regional Categorization

(A) Kaplan-Meier curves for the different diagnostic groups included in this study according to the current consensus criteria. There is a statistically significant shorter survival for the P-PLS and undetermined groups compared with the D-PLS and lower limbs only groups. There is no difference between P-PLS and the undetermined groups or between the D-PLS and lower limbs only groups. Because there was only 1 patient with bulbar involvement restricted to the bulbar region, this case was not included in the figure. (B) Kaplan-Meier curves for the different diagnostic groups when categorized according to the adapted regional criteria. This results in 3 distinct survival curves for the undetermined group, PLS with bulbar involvement group, and spastic paraplegia group. The PLS with lower and upper limb involvement group shows a similarly long survival distinct from the undetermined group. *The tables with number at risk are affected by missing follow-up data. D-PLS = definite PLS; PLS = primary lateral sclerosis; P-PLS = probable PLS.