ALS-Plus syndrome: Non-pyramidal features in a large ALS cohort☆
Introduction
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with survival of 3–5 years [1]. Phenotypic classification has been based on clinical observations such as site of onset and pattern of weakness involving upper and lower motor neurons [2]. However, recent observations have emphasized considerable heterogeneity in clinical presentation. Single cases and small series of patients with atypical features have been reported [3], including ocular motility abnormalities [4], [5], [6], cerebellar [7], [8] and extrapyramidal signs [9], [10], [11], [12], [13], [14], [15], and autonomic dysfunction [16], [17]. While this has been long recognized [18], consensus criteria for the diagnosis of ALS more recently encompass these atypical clinical manifestations in a phenotype known as ALS-Plus syndrome [2]. This clinical heterogeneity is consistent with the widespread pathology found in ALS at autopsy, extending beyond the pyramidal and neuromuscular motor systems into other brain areas [19], [20], and supports the characterization of ALS as a multisystem disorder [21]. However, the frequency of these findings and their clinical consequences are not well documented.
Here we assess the frequency of ALS-Plus syndrome features in a large, consecutively-ascertained series of 550 ALS patients. We demonstrate that ALS-Plus syndrome may not be as uncommon as previously thought, and appears to be associated with poorer survival and increased risk for an inherited disorder. These observations are consistent with the hypothesis that ALS is a multisystem disorder, and provide clinical validation of pathologic observations suggesting widespread disease in ALS.
Section snippets
Participants
We identified a consecutively-ascertained series of 550 patients clinically diagnosed with ALS using a query report from an integrated clinical database at the University of Pennsylvania. All patients were assessed by a neurologist with expertise in neuromuscular diseases (LM, LE). Patients were diagnosed according to El Escorial-revised criteria and assigned to a diagnostic category when first seen [2]. Patients with isolated upper or lower motor neuron disease were included in the cohort. All
Clinical characteristics of ALS-Plus
Seventy-five patients were identified with ALS-Plus syndrome, representing 13.6% of 550 cases (Table 1). The most common ALS-Plus feature was an ocular motility abnormality, found in 63 (84%) of ALS-Plus patients. This was present more commonly than an extrapyramidal abnormality (n = 17, 22.7%), autonomic dysfunction (n = 4, 5.3%) and cerebellar disorder (n = 1, 1.3%) [p < 0.01 for each contrast]. The median number of plus features per patient was four (range 1–11). PBA [χ2 = 19.20; p < 0.001] and
Discussion
In a large cohort of ALS patients, we found a substantial number of individuals who have ALS-Plus syndrome. This is consistent with pathologic observations suggesting that ALS is a multisystem disorder. The presence of non-pyramidal features appears to be a marker of several important clinical characteristics, including poorer prognosis and increased probability of a pathogenic mutation.
Informal estimates suggest that ALS-Plus syndrome is rare [2], but ascertainment in this large cohort
Conflict of interest
The authors declare no conflicts of interest.
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