Patterns of symptom development in patients with motor neuron disease

Renée Walhout, Esther Verstraete, Martijn P. van den Heuvel, Jan H. Veldink, Leonard H. van den Berg*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


Objective: To investigate whether symptom development in motor neuron disease (MND) is a random or organized process. Methods: Six hundred patients with amyotrophic lateral sclerosis (ALS), upper motor neuron (UMN) or lower motor neuron (LMN) phenotypes were invited for a questionnaire concerning symptom development. A binomial test was used to examine distribution of symptoms from site of onset. Development of symptoms over time was evaluated by Kaplan-Meier analysis. Results: There were 470 respondents (ALS = 254; LMN = 100; UMN = 116). Subsequent symptoms were more often in the contralateral limb following unilateral limb onset (ALS: arms p = 1.05 × 10−8, legs p < 2.86 × 10−15; LMN phenotype: arms p = 6.74 × 10−9, legs p = 6.26 × 10−6; UMN phenotype: legs p = 4.07 × 10−14). In patients with limb onset, symptoms occurred significantly faster in the contralateral limb, followed by the other limbs and lastly by the bulbar region. Patterns of non-contiguous symptom development were also reported: leg symptoms followed bulbar onset in 30%, and bulbar symptoms followed leg onset in 11% of ALS patients. Conclusions: Preferred spread of symptoms from one limb to the contralateral limb, and to adjacent sites appears to be a characteristic of MND phenotypes, suggesting that symptom spread is organized, possibly involving axonal connectivity. Non-contiguous symptom development, however, is not uncommon, and may involve other factors.

Original languageEnglish
Pages (from-to)21-28
Number of pages8
JournalAmyotrophic lateral sclerosis and frontotemporal degeneration
Issue number1-2
Publication statusPublished - 2 Jan 2018
Externally publishedYes


This study was supported by the ALS Foundation Netherlands, Prinses Beatrix Spierfonds, the European Community’s Health Seventh Framework Programme (grant agreement n° 259867), and the SOPHIA project (funded through the EU Joint Programme – Neurodegenerative Disease Research, JPND). R. Walhout reports no disclosures. E. Verstraete received a consultancy fee from Biogen Idec. MPvdH received a grant from The Netherlands Organization for Health Research and Development (Veni scheme), from the ALS Foundation Netherlands and from MQ. J.H. Veldink reports no disclosures. LHvdB received a grant from The Netherlands Organization for Health Research and Development (Vici scheme), travel grants and consultancy fees from Baxalta; serves on scientific advisory boards for Prinses Beatrix Spierfonds, Thierry Latran Foundation, Cytokinetics and Biogen.

FundersFunder number
Netherlands Organization for Health Research and Development
Fondation Thierry Latran
EU Joint Programme – Neurodegenerative Disease Research
European Commission
Prinses Beatrix Spierfonds
Seventh Framework Programme259867


    • amyotrophic lateral sclerosis
    • lower motor neuron
    • Motor neuron disease
    • symptom development
    • upper motor neuron


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