Elsevier

The Lancet Neurology

Volume 13, Issue 6, June 2014, Pages 575-586
The Lancet Neurology

Articles
A 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

https://doi.org/10.1016/S1474-4422(14)70051-1Get rights and content

Summary

Background

Autoimmunity might be associated with or implicated in sleep and neurodegenerative disorders. We aimed to describe the features of a novel neurological syndrome associated with prominent sleep dysfunction and antibodies to a neuronal antigen.

Methods

In this observational study, we used clinical and video polysomnography to identify a novel sleep disorder in three patients referred to the Sleep Unit of Hospital Clinic, University of Barcelona, Spain, for abnormal sleep behaviours and obstructive sleep apnoea. These patients had antibodies against a neuronal surface antigen, which were also present in five additional patients referred to our laboratory for antibody studies. These five patients had been assessed with polysomnography, which was done in our sleep unit in one patient and the recording reviewed in a second patient. Two patients underwent post-mortem brain examination. Immunoprecipitation and mass spectrometry were used to characterise the antigen and develop an assay for antibody testing. Serum or CSF from 298 patients with neurodegenerative, sleep, or autoimmune disorders served as control samples.

Findings

All eight patients (five women; median age at disease onset 59 years [range 52–76]) had abnormal sleep movements and behaviours and obstructive sleep apnoea, as confirmed by polysomnography. Six patients had chronic progression with a median duration from symptom onset to death or last visit of 5 years (range 2–12); in four the sleep disorder was the initial and most prominent feature, and in two it was preceded by gait instability followed by dysarthria, dysphagia, ataxia, or chorea. Two patients had a rapid progression with disequilibrium, dysarthria, dysphagia, and central hypoventilation, and died 2 months and 6 months, respectively, after symptom onset. In five of five patients, video polysomnography showed features of obstructive sleep apnoea, stridor, and abnormal sleep architecture (undifferentiated non-rapid-eye-movement [non-REM] sleep or poorly structured stage N2, simple movements and finalistic behaviours, normalisation of non-REM sleep by the end of the night, and, in the four patients with REM sleep recorded, REM sleep behaviour disorder). Four of four patients had HLA-DRB1*1001 and HLA-DQB1*0501 alleles. All patients had antibodies (mainly IgG4) against IgLON5, a neuronal cell adhesion molecule. Only one of the 298 controls, who had progressive supranuclear palsy, had IgLON5 antibodies. Neuropathology showed neuronal loss and extensive deposits of hyperphosphorylated tau mainly involving the tegmentum of the brainstem and hypothalamus in the two patients studied.

Interpretation

IgLON5 antibodies identify a unique non-REM and REM parasomnia with sleep breathing dysfunction and pathological features suggesting a tauopathy.

Funding

Fondo de Investigaciones Sanitarias, Centros de Investigación Biomédica en Red de enfermedades neurodegenerativas (CIBERNED) and Respiratorias (CIBERES), Ministerio de Economía y Competitividad, Fundació la Marató TV3, and the National Institutes of Health.

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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