Journal Article

DZNE-2024-01417

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Diagnosing primary lateral sclerosis: a clinico-pathological study.

de Boer, E. M. J. ; de Vries, B. S. ; Van Hecke, W. ; Mühlebner, A. ; Vincken, K. L. ; Mol, C. P. ; van Rheenen, W. ; Westeneng, H.-J. ; Veldink, J. H. ; Höglinger, G. U.DZNE* ; Morris, H. R. ; Litvan, I. ; Raaphorst, J. ; Ticozzi, N. ; Corcia, P. ; Vandenberghe, W. ; Pijnenburg, Y. A. L. ; Seelaar, H. ; Ingre, C. ; Van Damme, P. ; van den Berg, L. H. ; van de Warrenburg, B. P. C. ; van Es, M. A.

2025
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00415-024-12816-0

Abstract: Primary lateral sclerosis (PLS) is a rare motor neuron disease characterized by upper motor neuron degeneration, diagnosed clinically due to the absence of a (neuropathological) gold standard. Post-mortem studies, particularly TDP-43 pathology analysis, are limited.This study reports on 5 cases in which the diagnostic criteria for PLS were met, but in which neuropathology findings showed (partially) conflicting results. These discrepancies prompted us to perform a clinico-pathology study focussing on diagnostic challenges and accuracy in PLS. To this end, all cases were reviewed by an international panel of 11 experts using an e-module and structured questionnaires.Autopsy exhibited neuropathological findings consistent with amyotrophic lateral sclerosis (ALS) in one case, while two cases exhibited similar, but more limited lower motor neuron involvement, hinting at PLS or ALS overlap. Another case displayed tau-pathology indicative of progressive supranuclear palsy. The final case displayed extensive myelin loss without a proteinopathy or a clear diagnosis. The expert panel identified 24 different ancillary investigations lacking across cases (e.g. genetic testing, DAT scans, neuropsychological evaluation), listed 28 differential diagnoses, and identified 13 different conditions as the most likely diagnosis. Autopsy results led panel members to change their final diagnosis in 42% of the cases.This study underscores the diagnostic challenges posed by diverse underlying pathologies resulting in upper motor neuron phenotypes. Despite adhering to the same diagnostic criteria, consensus amongst experts was limited. Ensuring the diagnostic consistency is crucial for advancing understanding and treatment of PLS. Explicit guidelines for excluding potential mimics along with a neuropathological gold standard are imperative.

Keyword(s): Humans (MeSH) ; Male (MeSH) ; Aged (MeSH) ; Female (MeSH) ; Middle Aged (MeSH) ; Motor Neuron Disease: diagnosis (MeSH) ; Motor Neuron Disease: pathology (MeSH) ; Autopsy (MeSH) ; Amyotrophic Lateral Sclerosis: diagnosis (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Diagnosis, Differential (MeSH) ; Aged, 80 and over (MeSH) ; Brain: pathology (MeSH) ; Brain: diagnostic imaging (MeSH) ; DNA-Binding Proteins (MeSH) ; Amyotrophic lateral sclerosis ; Neuropathology ; Primary lateral sclerosis ; TDP-43 ; Tau ; TARDBP protein, human ; DNA-Binding Proteins

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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