Anti-IgLON5 Disease: A Case With 11-Year Clinical Course and Review of the Literature

Abstract

Background: Anti-IgLON5 disease is a novel disorder with a complex interplay between inflammation and neurodegeneration. Patients develop antibodies against IgLON5 but also deposition of neuronal tau protein. Symptoms often have an insidious onset, slow progression and mimic other neurological disorders. Here we report a case with severely prolonged 11-year disease course and provide a review of current reported cases with focus on presentation, work-up, treatment, and outcome. Method: All reported cases of anti-IgLON5 disease were evaluated. Cases reported twice (in case series and as single case reports), were carefully excluded. Results: Most patients display a characteristic sleep disorder with severe insomnia, non rapid eye movement (NREM) parasomnia, with finalistic movements and sleep disordered breathing (stridor and obstructive sleep apnea). Other symptoms are bulbar involvement, gait instability, movement disorders, oculomotor abnormalities, dysautonomia, and peripheral symptoms. Antibodies are present in both serum and CSF and there is a strong correlation with human leukocyte antigen (HLA) DRB1^*10:01 and HLA-DQB1^*05:01. Neuropathological examination reveals neurodegeneration with neuronal tau deposits in regions that correlate with the clinical presentation (e.g., predominantly hypothalamus and tegmentum of the brain stem). Majority of cases respond partially to immunotherapy. Cases, who received no treatment or treatment with IV corticosteroids alone, had a higher mortality than cases treated with more potent immunotherapy. Conclusion: The clinical spectrum of Anti-IgLON5 disease continues to expand. Further studies are needed to elucidate the pathophysiology, therapeutic strategies and outcome in this novel disorder. Aggressive immunotherapy seems to increase survival.

Keywords: IgLON5; autoimmune encephalitis; immunology; inflammation; tau.

Figure 1

Connections between different symptom groups in anti-IgLON5 disease. Each symptom group is represented by a fragment of the outer circular layout. Arcs represent connection and flow between groups. Fragments and arch sizes are equal to percentage of overall symptoms/flow between symptom groups. (A) Shows the combination of all symptoms. Majority of cases experienced sleep disorder and bulbar symptoms, but almost all patients have three symptoms or more. (B) When focusing on patients with sleep disorder, most cases also display bulbar symptoms followed by gait impairment, while association with peripheral symptoms is the rarest combination. (C) Patients with bulbar symptoms mainly have sleep disorder, followed by gait impairment, oculomotor abnormalities and neuropsychiatric symptoms. (D) Patients with movement disorders (mainly chorea and parkinsonism) have associative sleep disorder and bulbar symptoms, but also gait impairment. (E) Oculomotor abnormalities were associated with sleep disorder, bulbar symptoms, and gait impairment. (F) Patients with gait impairment were also found to have mainly sleep disorder, bulbar symptoms, but also neuropsychiatric symptoms. (G) Neuropsychiatric symptoms were associated with mainly sleep disorder, bulbar symptoms, and gait impairment. (H) Dysautonomia was also associated to with these features.

Figure 2

Treatment strategies and survival outcome in anti-IgLON5 disease. Patients receiving no therapy or CS monotherapy had a higher mortality than patients treated with a combination of 1. line therapy (CS+IVIg or TPE or IVIg/TPE alone) and a steroid sparing agent. Similarly, addition of 2. line therapy with Rituximab or cyclophosphamide improved survival. (A) Kaplan-Meier survival curve showing the difference in survival between no therapy and/or CS alone (green line) and 1. or 2. line therapy (blue line). It should be noted that follow-up time differed from case to case, resulting in a high number of censored data (black dot) within an already small population (n = 27, p = 0.064). (B) Outcome between different treatment strategies n = 36. CS, corticosteroids; IVIg, intravenous immunoglobulin; TPE, therapeutic plasma exchange; Aza, Azathioprine; MM, Mycophenolate Mofetil; Rtx, Rituximab; Cyc, Cyclophosphamide.