Pathogenesis, clinical features and treatment of anti-IgLON5 disease

Anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease is an autoimmune encephalitis that targets the cell adhesion molecule, IgLON5. The disease presents with various clinical features, including sleep disorders, bulbar palsy, movement disorders, cognitive dysfunction and neuromuscular manifestations. Sleep disorders are characterized by parasomnias and sleep-disordered breathing (stridor and sleep apnea). Bulbar palsy includes dysarthria, dysphagia, vocal cord paralysis and stridor. Movement disorders include a variety of symptoms and signs, such as chorea, dystonia, rigidity, tremor, myoclonus and myorhythmia. Cognitive dysfunction includes executive dysfunction, impairment of attention, and verbal and visual memory dysfunction. Neuromuscular manifestations include fasciculations in the tongue and peripheral muscles, limb weakness, and muscle atrophy. Some patients resemble those with neurodegenerative diseases, such as progressive supranuclear palsy or amyotrophic lateral sclerosis. On video polysomnography, undifferentiated non-rapid eye movement sleep and poorly structured N2 sleep are characteristic. Brain magnetic resonance imaging and cerebrospinal fluid studies are often normal or non-specific. Human leukocyte antigen testing shows that HLA-DRB1*10:01-DQB1*05:01 is highly associated with the disease. Pathologically, neuronal deposition of both hyperphosphorylated 3-repeat and 4-repeat tau isoforms, neuronal loss, and gliosis in the hypothalamus, brainstem tegmentum, and upper cervical cord are observed. Some patients are responsive to immunotherapies, such as steroids, intravenous immunoglobulin, plasma exchange therapy and rituximab. Factors associated with a favorable response to immunotherapies include early initiation of treatment, cerebrospinal fluid inflammation and immunoglobulin G1 (IgG1) predominance of IgLON5 antibody compared with immunoglobulin G4 (IgG4). Anti-IgLON5 disease should be suspected in patients with atypical movement disorders complicated by sleep disturbances.