Regional spreading pattern is associated with clinical phenotype in amyotrophic lateral sclerosis

Abstract

Increasing evidence shows that disease spreading in amyotrophic lateral sclerosis (ALS) follows a preferential pattern with more frequent involvement of contiguous regions from the site of symptom onset. The aim of our study was to assess if: (i) the burden of upper (UMN) and lower motor neuron (LMN) involvement influences directionality of disease spreading; (ii) specific patterns of disease progression are associated with motor and neuropsychological features of different ALS subtypes (classic, bulbar, primary lateral sclerosis, UMN-predominant, progressive muscular atrophy, flail arm, flail leg); and (iii) specific clinical features may help identify ALS subtypes, which remain localized to the site of onset for a prolonged time (regionally entrenching ALS). A single-centre, retrospective cohort of 913 Italian ALS patients was evaluated to assess correlations between directionality of the disease process after symptom onset and motor/neuropsychological phenotype. All patients underwent an extensive evaluation including the following clinical scales: Penn Upper Motor Neuron Score (PUMNS), MRC Scale for Muscle Strength and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The most frequent initial spreading pattern was that towards adjacent horizontal regions (77.3%), which occurred preferentially in patients with lower MRC scores (P = 0.038), while vertical diffusion (21.1%) was associated with higher PUMNS (P < 0.001) and with reduced survival (P < 0.001). Non-contiguous disease spreading was associated with more severe UMN impairment (P = 0.003), while contiguous disease pattern with lower MRC scores. Furthermore, non-contiguous disease spreading was associated with more severe cognitive impairment in both executive and visuospatial ECAS domains. Individuals with regionally entrenching ALS were more frequently female (45.6% versus 36.9%; P = 0.028) and had higher frequencies of symmetric disease onset (40.3% versus 19.7%; P < 0.001) and bulbar phenotype (38.5% versus 16.4%; P < 0.001). Our study suggests that motor phenotypes characterized by a predominant UMN involvement are associated with a vertical pattern of disease progression reflecting ipsilateral spreading within the motor cortex, while those with predominant LMN involvement display more frequently a horizontal spreading from one side of the spinal cord to the other. These observations raise the hypothesis that one of the mechanisms underlying disease spreading in ALS pathology is represented by diffusion of toxic factors in the neuron microenvironment. Finally, it is possible that in our cohort, regionally entrenching ALS forms are mainly observed in patients with atypical bulbar phenotypes, characterized by a slowly progressive course and relatively benign prognosis.

Keywords: amyotrophic lateral sclerosis (ALS); disease progression; motor neuron disease (MND); motor phenotype; site of onset; somatotopic organization of motor system.

Figure 1

Summary of pattern of disease progression. Classification of site of disease onset and patterns of disease progression.

Figure 2

Flow chart of patients analysed for each pattern of disease progression. Flow chart describing number of patients for whom it was possible to define specific patterns of disease progression. ALS = amyotrophic lateral sclerosis; re-ALS = regionally entrenching ALS; d-ALS = disseminating ALS.

Figure 3

Kruskal-Wallis analysis to compare motor features among different patterns of disease progression. Distribution of upper motor neuron involvement using the Penn Upper Motor Neuron Score (PUMNS) and lower motor neuron involvement using the Medical Research Council Muscle Scale (MRC) in patients with vertical versus horizontal (A and B) and contiguous versus non-contiguous (C and D) pattern of disease progression from site of onset. Kruskal-Wallis test for independent samples. For each group, the bold horizontal line shows the median, the grey box includes the middle 50% of the data and whiskers show the minimum and maximum values. Empty circles represent outliers (above Q3 + 1.5 IQR and below Q1 − 1.5 IQR, respectively).

Figure 4

Survival analysis in patients with horizontal/vertical pattern of disease progression. Kaplan-Meyer curves of survival probabilities: patients with horizontal disease progression (light blue line) had significantly prolonged survival when compared to patients with vertical spreading (green line) (log-rank: χ² = 11.083; P < 0.001).

Figure 5

Distribution of d-ALS and re-ALS individuals among successive quintiles of time to first visit. Per cent distribution of d-ALS and re-ALS individuals among successive quintiles of time to first visit. The quintile distribution was as follows: 1° from 1.1 to 6.9 months; 2° from 6.9 to 11.1 months; 3° from 11.1 to 17.4 months; 4° from 17.4 to 30.3 months; 5° more than 30.3 months. ALS = amyotrophic lateral sclerosis; d-ALS = disseminating ALS; re-ALS = regionally entrenching ALS.