Understanding anti-IgLON5 disease

The unambiguous characterization of antibodies against neural antigens has been critical to understand the interplay between the immune system and the brain, allowing in some instances the discovery of clinical entities that had been previously unrecognized or lumped with other syndromes under generic names.1 The best example is anti-NMDA receptor encephalitis, a relatively common disease that before the discovery of NMDA receptor antibodies was unrecognized or defined with nonspecific terms, such as non–herpetic encephalitis, or confused with Hashimoto encephalopathy or encephalitis lethargica.2 A similar scenario applies to anti-IgLON5 disease in which the identification of antibodies against IgLON5, a neural cell adhesion molecule of unknown function, has led to the characterization of a new disorder.3 Before the discovery of IgLON5 antibodies, the disease of these patients was defined with descriptive terms or labeled as “atypical early progressive supranuclear palsy (PSP)” or “brainstem tauopathy”(for review, see reference 4), indicating that it could not be classified among well-defined CNS disorders. However, the comprehensive evaluation of the initial patients with IgLON5 antibodies disclosed a common clinical core of symptoms that included a complex sleep disorder with abnormal behaviors and vocalizations during non-REM and REM sleep along with sleep-disordered breathing, gait instability, more typical of disequilibrium than cerebellar ataxia, and bulbar symptoms such as stridor, dysphagia, or central hypoventilation.3 These symptoms were found to evolve over months to years, and unlike other CNS disorders associated with antibodies against neural surface antigens, patients with IgLON5 disease did not respond to common immunotherapies. With the identification of more patients, 4 clinical presentations were characterized according to predominant symptoms: prominent sleep disorder, progressive bulbar dysfunction, gait instability with abnormal eye movements reminiscent, but not typical of PSP, and cognitive deterioration sometimes associated with chorea. Independently of the form of presentation, most patients described a sleep disorder when directly questioned about symptoms of sleep apnea and other alterations of sleep or when they were studied with video-polysomnography (V-PSG).5