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

Abstract

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.

Figure 1. Sleep recording in patient 1 with continuous positive airway pressure (index case)

A. Hypnogram; B. Arousals, dissociations and periodic movements; C. Density Spectral Array (DSA) showing the power spectrum of electroencephalographic frequencies (0–17 Hz) in electrode C3 referenced to electrode O2. Warmer colors indicate more dominant frequencies. Abbreviations: Rems: Rapid eye movements; RBD: REM sleep behavior disorder; PLM: Periodic limb movements; RPLM: Rapid periodic leg movements.

Figure 2. Polysomnograhic epochs illustrative of each sleep state in patient 1 (index case)

See also figure 1. A:Sleep onset characterized by undifferentiated NREM sleep with diffuse theta activity and rapid periodic leg movements that were particularly prominent at the left AT EMG channel; B:N2 sleep with chain of four consecutive K complexes (arrows) with frequent muscular phasic activity in EMG surface of the limbs that correlate with vocalizations and finalistic movements; C: REM sleep with typical rapid eye movements and EEG features with excessive phasic and tonic muscular activity and body jerks typical of REM sleep behavior disorder; D: N3 with diffuse delta activity and well defined sleep spindles at 13 Hz (arrows) without body/limb movements. Abbreviations: EEG: electroencephalogram; EMG: electromyogram; EOG: electrooculogram; Chin: electromyography of mentalis muscle; EKG: electrocardiogram; FDS: flexor digitorumsuperficialis muscle left (L) and right (R); EDB: extensor digitorumbrevis muscle left (L) and right (R); AT: anterior tibialis left (L) and right (R); NAS: nasal air flow; THO: thoracic respiratory movement; ABD: abdominal respiratory movement. Note the calibration mark for time / EEG voltage.

Figure 3. Reactivity of patient’s antibodies with rat brain and cultures of hippocampal neurons

(A) Sagittal section of rat brain immunostained with a patient’s CSF: there is a diffuse staining of the neuropil, which is not seen when rat brain sections are incubated with a control CSF (B). Immunoreactivity was particularly robust in the cerebellum (C) where there was diffuse staining of the molecular layer and synaptic glomerula of the granular cell layer (D, counterstained with hematoxylin). (E) Culture of rat hippocampal neurons incubated (non-permeabilized) with a patient’s serum showing intense reactivity with a cell surface antigen. Scale bars in A and B=1000 µm, C=200 µm, D=50 µm and E=20 µm

Figure 4. Detection of IgLON5 antibodies using a HEK293 cell based assay

HEK293 cells were transfected to express green fluorescent protein (GFP)-tagged IgLON5 and incubated live, not permeabilized, with a patient’s (A–C) or control (D–F) serum. Patient’s serum, but not control serum, stained the cell surface of cells (red) that specifically express IgLON5, as demonstrated by the GFP fluorescence (green). Both reactivities are shown merged in C. Nuclei counterstained with DAPI. Scale bar=20 µm

Figure 5. Distribution of tau pathology

Panels A1-F1 correspond to patient 2, and panels A2-F2 correspond to patient 7. Moderate amounts of AT8 immunoreactive neuropil threads and neurofibrillary tangles are detected in hypothalamic nuclei (B1, A2. posterior hypothalamic nucleus; example of score ++) and anterior thalamus (A1, B2: left figure), but are completely absent in lateral and posterior thalamic neurons of both cases (A1, B2, right figure; example of score 0). While the pontinetegmentum is mildly (D2; example of score +) and moderately (C1) affected in Patients 7 and 2, respectively, neurons of n. propii of basis pontis show extensive Tau-pathology mainly in form of pretangles(D1; example of score +++), which is not observed in patient 7 (C2). In contrast, prominent pathology in n. ambiguus is detected in patient 7 (F2; example of score +++), and less in case 2 (E1) and to a lesser extent in magnocellular nuclei of formatioreticularis in both cases (F1, E2).