Abstract Details

Natural history studies are essential for informing therapeutic trial design in rare diseases. As a relatively slowly progressing motor neuron disease, longitudinal studies of PLS have relied on retrospective designs which are subject to inherent biases.

To evaluate functional decline, mortality, and transition to ALS in a large primary lateral sclerosis (PLS) cohort. An additional objective is to explore the relationship between individual symptom duration and progression rate in PLS.

Patients meeting consensus diagnostic criteria for PLS were recruited to a prospective  study. Standardised clinical assessments including functional rating scores (ALSFRS), finger-tapping speeds and upper motor neuron (UMN) burden scores were performed at regular intervals and progression rates were calculated. Additionally, patients were regularly assessed for lower motor neuron signs, to indicate an emerging ALS phenotype. 

Forty-three patients with PLS were enrolled. The mean age was 63 years and median symptom duration was 8 years (range 1- 25). No subject was lost to follow-up over a median 2-year evaluation period. No deaths occurred and no patient developed features of ALS.

The annual decrease in ALSFRS-R was 2.0 (SD 0.2). However, individual progression rates were strongly influenced by total symptom duration, being much faster in patients with shorter symptom duration i.e. below the group median (2.8 vs 1.2 per year, p<.05). Although 38 patients (88%) showed signs and symptoms of pseudobulbar palsy, none developed anarthria or required gastrostomy. Nevertheless, most patients experienced a meaningful functional decline (65%). A clinically significant increase in UMN burden score was observed in 67% of subjects. 

This study indicates that transition to ALS is rarer than retrospective studies have suggested. Functional decline was significantly faster earlier in the course of the disease followed by a relative slowing or plateau. This finding has implications therapeutic trials design and highlights the imperative of earlier diagnosis in PLS.