Anti-IgLON5 Disease 10 Years Later: What We Know and What We Do Not Know

Abstract

Anti-IgLON5 disease was identified 10 years ago, thanks to the discovery of IgLON5 antibodies and the joint effort of specialists in sleep medicine, neuroimmunology, and neuropathology. Without this collaboration, it would have been impossible to untangle fundamental aspects of this disease. After the seminal description in 2014, today there is growing evidence that most patients present a chronic progressive course with gait instability, abnormal movements, bulbar dysfunction, and a sleep disorder characterized by nonrapid eye movement and REM parasomnias, and obstructive sleep apnea with stridor. Unlike other autoimmune encephalitides, the response to immunotherapy is suboptimal. Neuropathologic studies in patients with a prolonged clinical course showed a novel 3-repeat and 4-repeat neuronal tauopathy mainly involving the hypothalamus and tegmentum of the brainstem. The absence of tau deposits in the brain of patients who died early, the demonstration that IgLON5 antibodies cause an irreversible decrease in cell-surface levels of IgLON5, and a disorganization of the neuronal cytoskeleton suggest that the disease is primarily autoimmune and the tauopathy a secondary event. After a decade, we now know the disease much better, but important issues still need to be addressed. We have to gather more information on the natural course of the disease, develop better treatments, and identify robust predictors of outcome. More basic research is needed on the physiology of IgLON5, how antibodies disrupt its function, and the downstream effects leading to neurodegeneration. Finally, better designed passive transfer and active immunization models are needed to confirm the pathogenic effect of IgLON5 antibodies.

Figure 1. Reason for Consultation in 98 Patients With Anti-IgLON5 Disease

Figure 2. Neuropathologic Findings

(A) Representative overview section through the medulla oblongata stained with antibodies against phosphorylated tau (AT8) (brown signal, counterstained with hematoxylin). There is abundant deposition of tau in the tegmental region involving multiple nuclei such as the motor nucleus of the hypoglossus (XII), the dorsal motor nucleus of the vagal nerve (DMNV), the solitary nucleus (S), the nucleus ambiguus (A), the reticular formation (RF), and the dorsal raphe, among others. The inferior olivary (IO) nucleus shows only minimal pathology. (B and C). At higher magnification, the accumulation is mainly observed within the neuronal bodies (neurofibrillary tangles and pretangles) and neuronal processes (neuropil threads and neurites). IV = fourth ventricle; PC = choroid plexus; MLF = medial longitudinal fasciculus. Scale bars: A: 4 mm, B: 160 μm, and C: 50 μm.

Figure 3. Effects of IgLON5 Antibodies on Rat Hippocampal Neurons in Culture

(A). Immunofluorescence on live hippocampal neurons treated with control IgG (B) or IgLON5 antibodies (C). IgLON5 antibodies cause a decrease in IgLON5 clusters (C) that do not recover after removing the antibodies from the culture media (E). This effect is different from that observed with other antibodies against surface antigens, such as NMDAR, in which the reduction of antigen clusters is reversible (D and G). The intracellular staining of neurofilaments (H) revealed a disorganization of the cytoskeleton when neurons were treated with IgLON5 antibodies (J) but not with NMDAR antibodies (K). Figure generated from data of experiments reported in reference. DIV = days in vitro. Scale bars: G: 5 µm, H: 20 µm, and K: 3 µm.