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J Neurol Neurosurg Psychiatry. 2019 Feb;90(2):141-147. doi: 10.1136/jnnp-2018-318788. Epub 2018 Aug 3.

Cognitive and behavioural changes in PLS and PMA:challenging the concept of restricted phenotypes.

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Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Center of Excellence for Rehabilitation Medicine, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University and De Hoogstraat Rehabilitation, Utrecht, The Netherlands.
Ecare4you, Amersfoort, The Netherlands.
Department of Experimental Psychology, Helmholtz Institute, Utrecht University, Utrecht, The Netherlands.
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands



Cognitive and behavioural changes within the spectrum of frontotemporal dementia (FTD) are observed frequently in patients with amyotrophic lateral sclerosis (ALS). Whether these changes also occur in other forms of motor neuron disease (MND) is not well studied. We therefore systemically screened a large cohort of patients with primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA) for cognitive and behavioural changes, and subsequently compared our findings with a cohort of patients with ALS.


Using a set of screening instruments (Edinburgh Cognitive and Behavioural ALS Screen, ALS and Frontotemporal Dementia Questionnaire, Frontal Assessment Battery, and Hospital Anxiety and Depression Scale), the presence of cognitive and behavioural changes as well as anxiety and depression in 277 patients with ALS, 75 patients with PLS and 143 patients with PMA was evaluated retrospectively.


We found a high frequency of cognitive and behavioural abnormalities with similar profiles in all three groups. Subjects with behavioural variant FTD were identified in all groups.


The percentage of patients with PLS and PMA with cognitive dysfunction was similar to patients with ALS, emphasising the importance for cognitive screening as part of routine clinical care in all three patient groups. With a similar cognitive profile, in line with genetic and clinical overlap between the MNDs, the view of PLS as an MND exclusively affecting upper motor neurons and PMA exclusively affecting lower motor neurons cannot be held. Therefore, our findings are in contrast to the recently revised El Escorial criteria of 2015, where PLS and PMA are described as restricted phenotypes. Our study favours a view of PLS and PMA as multidomain diseases similar to ALS.


Conflict of interest statement

Competing interests: MAvE serves on the UK Motor Neurone Disease Association Biomedical Research Advisory Panel, has consulted for Biogen and has received travel grants from Shire (formerly Baxalta). LHvdB reports grants from Netherlands ALS Foundation, grants from Prinses Beatrix Spierfonds, grants from Netherlands Organization for Health Research and Development (Vici scheme), and grants from European Community’s Health Seventh Framework Programme (FP7/2007-2013) (grant agreement no 259867), during the conduct of the study; and personal fees from Baxter for scientific advisory board and travel grant, and personal fees from Scientific Advisory Board, Biogen Idec, outside the submitted work. The other authors declare that they have no conflict of interest.

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