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

• Published in: Journal of the neurological sciences 2014-10, Vol.345 (1), p.118-124
• Main Authors: McCluskey, Leo, Vandriel, Shannon, Elman, Lauren, Van Deerlin, Vivianna M, Powers, John, Boller, Ashley, Wood, Elisabeth McCarty, Woo, John, McMillan, Corey T, Rascovsky, Katya, Grossman, Murray
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases; Adult; Aged; Aged, 80 and over; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - complications; Amyotrophic Lateral Sclerosis - diagnosis; Amyotrophic Lateral Sclerosis - genetics; C9orf72 Protein; Cell Cycle Proteins; Cognition Disorders - etiology; Cognition Disorders - genetics; Cognitive; Cohort Studies; DNA-Binding Proteins; Female; Genetic Testing; Genetics; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Mutation - genetics; Neurology; Non-neuromuscular; Proteins - genetics; Superoxide Dismutase - genetics; Superoxide Dismutase-1; Survival; Syndrome; Valosin Containing Protein
• ISSN: 0022-510X; 1878-5883
• DOI: 10.1016/j.jns.2014.07.022

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.