ALS-Plus syndrome: Non-pyramidal features in a large ALS cohort

https://doi.org/10.1016/j.jns.2014.07.022Get rights and content

Highlights

  • ALS-Plus syndrome encompasses non-pyramidal, non-neuromuscular deficits in ALS.

  • 13.6% of 550 ALS patients demonstrated features of ALS-Plus syndrome.

  • ALS-Plus syndrome is associated with increased risk of genetic mutation.

  • ALS-Plus syndrome is associated with poorer survival.

Abstract

Objective

Autopsy studies show widespread pathology in amyotrophic lateral sclerosis (ALS), but clinical surveys of multisystem disease in ALS are rare. We investigated ALS-Plus syndrome, an understudied group of patients with clinical features extending beyond pyramidal and neuromuscular systems with or without cognitive/behavioral deficits.

Methods

In a large, consecutively-ascertained cohort of 550 patients with ALS, we documented atypical clinical manifestations. Genetic screening for C9orf72 hexanucleotide expansions was performed in 343 patients, and SOD1, TARDBP, and VCP were tested in the subgroup of patients with a family history of ALS. Gray matter and white matter imaging was available in a subgroup of 30 patients.

Results

Seventy-five (13.6%) patients were identified with ALS-Plus syndrome. We found disorders of ocular motility, cerebellar, extrapyramidal and autonomic functioning. Relative to those without ALS-Plus, cognitive impairment (8.0% vs 2.9%, p = 0.029), bulbar-onset (49.3% vs 23.2%, p < 0.001), and pathogenic mutations (20.0% vs 8.4%, p = 0.015) were more than twice as common in ALS-Plus. Survival was significantly shorter in ALS-Plus (29.66 months vs 42.50 months, p = 0.02), regardless of bulbar-onset or mutation status. Imaging revealed significantly greater cerebellar and cerebral disease in ALS-Plus compared to those without ALS-Plus.

Conclusions

ALS-Plus syndrome is not uncommon, and the presence of these atypical features is consistent with neuropathological observations that ALS is a multisystem disorder. ALS-Plus syndrome is associated with increased risk for poor survival and the presence of a pathogenic mutation.

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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    This work was supported in part by grants from NIH (AG032953, AG017586, AG038490, NS044266, NS053488 and NS043503), the ALS Association, and the Wyncote Foundation.

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