IGLON5 Frequency in Idiopathic REM Sleep Behavior Disorder: A Multicenter Study
Ronald Postuma1, Nisa Vorasoot1, Erik K St Louis1
1From the Montreal Neurological Institute and Department of Neurology and Neurosurgery (R.P.), Montréal, McGill University; Center for Advanced Research in Sleep Medicine (R.P., A.P., J.-F.G.), Hôpital du Sacré-Coeur de Montréal; Research Institute of the McGill University Health Centre (R.P., A.P., Z.G.-O.), Montreal, Quebec, Canada; Neurology and Medicine (N.V., L.K.F., J.A.F., O.A.R., W.S., B.F.B., A.M.), Mayo Clinic, Rochester, MN; Division of Neurology (N.V., E.K.S.L.), Department of Medicine, Faculty of Medicine, Khon Kaen University, Thailand; Department of Neurology (M.M.L., J.E.), Oregon Health & Science University; Department of Behavioral Neuroscience (M.M.L.); Department of Pulmonary and Critical Care Medicine; Oregon Institute of Occupational Health Sciences; Mental Illness Research Education and Clinical Center (M.M.L.); Neurology; National Center for Rehabilitative Auditory Research; Research Service (M.M.L., J.E.), VA Portland Health Care System, OR; Département of Psychology (J.-F.G.), Université du Québec à Montréal; Department of Human Genetics (Z.G.-O.), McGill University, Montréal, Québec, Canada; Neurology (D.E.H., D.L.B.), Emory University, Atlanta, GA; Neurology (A.Y.A.), Sleep Disorders Center, University of California, Los Angeles; Minnesota Regional Sleep Disorders Center (M.H., C.H.S.), and Departments of Psychiatry, Hennepin County Medical Center, and University of Minnesota Medical School; Minnesota Regional Sleep Disorders Center (M.H.), Hennepin County Medical Center, Minneapolis, MN; Washington University School of Medicine (J.M., A.A.D., Y.-E.S.J.), Saint Louis, MO; Barrow Neurological Institute (S.R.C.), Phoenix, AZ; Movement Disorders Unit (A.V.), Division of Sleep Medicine, Massachusetts General Hospital; Neurological Clinical Research Institute (A.V.), Harvard Medical School, Boston, MA; Psychiatry and Behavioral Sciences (E.H.D., M.G.M.), Stanford University, Redwood City, CA; Neurology and Neurological Sciences (E.H.D., M.G.M.), Stanford University, Palo Alto, CA; and Neurology (E.H.D.), Mt. Sinai School of Medicine, New York.
Background And Objectives:
Idiopathic/isolated REM sleep behavior disorder (iRBD) has been strongly linked to neurodegenerative synucleinopathies such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. However, there have been increasing reports of RBD as a presenting feature of serious and treatable autoimmune syndromes, particularly IGLON5. This study's objective was to investigate the frequency of autoantibodies in a large cohort of participants with iRBD.
Methods:
Participants were enrolled in the North American Prodromal Synucleinopathy cohort with polysomnography-confirmed iRBD, free of parkinsonism and dementia. Plasma samples were systematically screened for the autoantibodies IGLON5, DPPX, LGI1, and CASPR2 using plasma IgG cell-based assay. Positive or equivocal results were confirmed by repeat testing, plus tissue-based indirect immunofluorescence assay for IGLON5.
Results:
Of 339 samples analyzed, 3 participants (0.9%) had confirmed positive IGLON5 autoantibodies in the cell-based assay, which were confirmed by the tissue-based assay. An additional participant was positive for CASPR2 with low titer by cell-based assay only (of lower clinical certainty). These cases exhibited a variety of symptoms including dream enactment, cognitive decline, autonomic dysfunction, and motor symptoms. In 1 IGLON5 case and the CASPR2 case, evolution was suggestive of typical synucleinopathy, suggesting the possibility that findings were incidental. However, 2 participants with IGLON5 died before diagnosis was clinically suspected, with a final clinical picture highly suggestive of autoimmune disease.
Discussion:
Our finding that nearly 1% of a large iRBD cohort may have a serious but potentially treatable autoantibody syndrome has important clinical implications. In particular, it raises the question of whether autoantibody testing for IGLON-5-IgG should be widely implemented for participants with iRBD, considering the difficulty in diagnosis of autoimmune diseases, their response to treatment, and the potential for rapid disease progression. However, any routine testing protocol will also have to consider costs and potential adverse effects of false-positive findings.
Trial Registration Information:
NCT03623672.
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