Journal of Neurological Sciences 345: 118-124, 2014. PMCID: PMC4177937
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 motil-ity, cerebellar, extrapyramidal and autonomic functioning. Relative to those without ALS-Plus, cognitive impair-ment (8.0% vs 2.9%, p = 0.029), bulbar-onset (49.3% vs 23.2%, p b 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 signif-icantly 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.