ArticlesA novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study
Introduction
Various and well characterised sleep disorders have been noted in patients with neurodegenerative diseases or autoimmune encephalitis.1, 2, 3 The immune system has been implicated in pathological processes of neurodegeneration, but the exact mechanisms involved and whether they have a primary or secondary role are unclear.4 Some patients with neurodegenerative diseases develop antibodies against neuronal proteins, although the intracellular location of the target antigens suggests they are not pathogenic.5 By contrast, in a category of rapidly progressive disorders named autoimmune encephalitis, disruption of sleep patterns can be prominent, the target antigens are known, and highly specific (probably pathogenic) antibodies against cell-surface or synaptic proteins can be used as disease biomarkers.6 For example, patients with limbic encephalitis and antibodies against leucine-rich glioma-inactivated 1 (LGI1) often develop rapid-eye-movement (REM) sleep behaviour disorder (RBD),7 and patients with Morvan's syndrome and antibodies against contactin-associated protein-related 2 (Caspr2) develop severe insomnia with abnormal sleep-related motor activation (agrypnia excitata).8, 9
In clinical practice, identification of antibodies to cell-surface or synaptic proteins is increasingly being considered in patients with rapidly progressing encephalitis of unclear cause, but is rarely done in those with protracted neurological deficits suggestive of a neurodegenerative disease, including those with prominent sleep abnormalities. In such clinical scenarios, the potential detection of highly specific antibodies against a neuronal cell-surface protein would provide a link between immune mechanisms, neurodegeneration, and sleep dysfunction.
In this observational study, we assessed the clinical features and detailed video polysomnography of eight patients with a novel sleep disorder. We describe the target neuronal cell-surface antigen recognised by antibodies present in all patients' serum and CSF, and the neuropathological findings in two cases.
Section snippets
Participants
In 2010, we observed a 59-year-old man (patient one; table 1) with an insidiously progressive atypical sleep disorder in our multidisciplinary sleep disorders unit (Hospital Clinic, University of Barcelona, Spain). Although the patient's clinical features were different from those of Morvan's syndrome, the presence of dysautonomic features led us to investigate his serum and CSF for antibodies against Caspr2. We did not find such antibodies or those against other neuronal surface antigens
Results
The eight patients (five women; median age at disease onset 59 years [range 52–76]) had a sleep disorder characterised by abnormal sleep movements and behaviours, and obstructive sleep apnoea identified by polysomnography. The three index patients had initial polysomnography without synchronised audiovisual recording in other hospitals, and were misdiagnosed with isolated obstructive sleep apnoea. The clinical features are described in detail in table 1 and the appendix. Patients one to six (
Discussion
We report findings for eight patients with a neurological disorder characterised by a unique non-REM and REM parasomnia with sleep breathing dysfunction, variable features of gait instability and brainstem symptoms, and autoantibodies against IgLON5, a neuronal cell adhesion protein. Several findings establish this disorder as a new parasomnia: first, the characteristic sleep disorder identified in the first three patients by investigators in the Sleep Disorders Unit who were masked to
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These authors contributed equally