First described in 2014, anti-IgLON5-related disorder represents an intriguing neurological syndrome characterized by autoimmunity and neurodegeneration, the latter in the form of neuronal deposits of hyperphosphorylated tau. This disorder spans a diverse clinical spectrum—notable for non-REM and REM parasomnias, sleep apnea, and progressive neurological symptoms—that is often refractory to treatment, with resultant high morbidity and mortality.

A 61-year-old male presented with progressive encephalopathy, which had started 2.5 years prior to presentation with insomnia and abnormal sleep behaviors. One year following onset, he started developing visual hallucinations, stereotyped hyperkinetic movements, cognitive impairment, gait imbalance with recurrent falls, dysarthria, dysphagia with associated weight loss, and dysautonomic symptoms. Initial exam was remarkable for dysarthria, stereotyped choreiform movements, generalized fasciculations, hyperreflexia, and gait ataxia. 

MRI brain showed leukoaraiotic changes. Malignancy workup was negative. EMG revealed fibrillation potentials and chronic neurogenic changes in the left tibialis anterior and first dorsal interosseous muscles. EEG showed poorly-sustained posterior dominant rhythm with preservation of normal sleep architectures. Huntington gene testing was negative. Routine CSF analysis was unremarkable.

The patient was treated with high-dose IV methylprednisolone and plasmapheresis. At one-month follow-up, he reported some improvement of gait, balance, and dysarthria. Autoimmune panel, sent during the hospitalization, was positive for anti-IgLON5 antibodies in both serum and CSF. He was started on rituximab for chronic immunotherapy. 

We described a rare case of anti-IgLON5-related disease, presenting with a diverse set of slowly progressive neurological symptoms. This disorder remains a diagnostic challenge given the often nonspecific or normal imaging and laboratory findings, as noted in our case. A high index of suspicion for underlying autoimmune disease is warranted in the appropriate patient population.