Objective: To clarify clinicopathologic features of pathologically-confirmed primary lateral sclerosis (PLS).

Background: PLS is a neurodegenerative disorder characterized by slowly progressive upper motor neuron signs with minimal or no lower motor neuron signs. TDP-43 was identified as the pathological protein accumulating in most cases of frontotemporal lobar degeneration (FTLD) and sporadic amyotrophic lateral sclerosis. The pathology of PLS is most often associated with TDP-43 positive neuronal and glial inclusions; however, studies of clinicopathologic features of PLS are sparse. We report a series of patients with pathologically-confirmed PLS who were clinically thought to have atypical parkinsonism.

Method: We reviewed 24 patients with PLS with TDP-43 pathology with or without FTLD. We also reviewed the medical records of patients with pathologically confirmed corticobasal degeneration (CBD) with a final clinical diagnosis of corticobasal syndrome (CBS-CBD; n = 10) and progressive supranuclear palsy who had received a final clinical diagnosis of progressive supranuclear palsy-Richardson syndrome (PSPS-PSP; n = 10).

Results: The average age at death in PLS patients was 64 years, and disease duration was 5 years. Twenty PLS patients had a clinical diagnosis of an atypical parkinsonian disorder (11 CBS; CBS-PLS, 8 progressive supranuclear palsy syndrome; PSPS-PLS, 1 multiple systemic atrophy). Only two PLS patients were diagnosed with motor neuron disease, and two were diagnosed with frontotemporal dementia. The PLS was classified into two types (i.e., limited and extended) based on the severity and distribution of neuronal loss. In the extended type, all patients had cognitive dysfunction. Comparing CBS-PLS and CBS-CBD, limb apraxia was more frequent in CBS-CBD than CBS-PLS. The cases that met the diagnostic criteria for possible or probable CBS were more frequent in CBS-CBD than in CBS-PLS. Similarly, more cases of PSPS-PSP met criteria for probable PSP than PSPS-PLS. Oculomotor dysfunction typical of PSPS was also more frequent in PSPS-PSP than in PSPS-PLS.

Conclusion: PLS with TDP-43 pathology can clinically mimic atypical parkinsonism, especially CBS and PSP; therefore, PLS should be considered in the differential diagnosis of patients with atypical parkinsonism who do not have apraxia or vertical gaze palsy. Our findings emphasize the need for further clinical and biomarker studies of PLS.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinicopathologic-features-of-primary-lateral-sclerosis-with-tdp-43-presenting-as-atypical-parkinsonism/