1389 Progressive Neurocognitive Decline and Insomnia: A Case of Fatal Familial Insomnia in a Patient with Corticobasal Syndrome

Abstract Introduction Fatal familial insomnia (FFI) is a rare, autosomal dominant prion disease characterized by progressive, treatment-refractory insomnia, cognitive decline, motor dysfunction, and autonomic instability. Diagnosis is challenging due to heterogenous presentations and overlap with other neurodegenerative disorders. Report of case(s) A 45-year-old male developed progressive cognitive impairment, memory loss, gait imbalance, right hemiparesis, apraxia, visual changes, behavioral disturbances, urinary frequency, and severe insomnia over the course of three years. By year two, insomnia became profound and refractory to quetiapine, ramelteon, zolpidem, clonazepam, suvorexant, with total sleep time < 5 hours nightly. Daytime napping was absent. Without sedative medications, the patient was unable to sleep. He exhibited rapid functional decline with frequent falls and inability to perform ADLs, requiring total care. No family history of sleep disorders was reported. Extensive evaluation revealed asymmetric cortical atrophy on MRI, hypometabolism in the left frontal and parietal lobes and right precuneus on FDG-PET, and reduced dopamine transporter activity on (DaT) scan. EEG showed moderate encephalopathy with bitemporal dysfunction on EEG, and CSF studies notable for negative RT-QuIC, elevated 14-3-3 gamma, and normal t-Tau. Skin biopsy was negative for alpha-synucleinopathy. Neuropsychological testing confirmed major neurocognitive disorder. Workup for autoimmune, metabolic, paraneoplastic, and infectious etiologies was unremarkable. An empiric trial of steroids and IVIG did not provide any objective benefit. The clinical course was initially attributed to CBD based on asymmetric cortical atrophy, parkinsonism, and apraxia; however, the rapid emergence of profound insomnia, autonomic dysfunction, and progressive decline – combined with negative evaluation for alternative etiologies - raised strong suspicion for FFI, even without a family history. Conclusion This case highlights the diagnostic challenge of distinguishing FFI from neurodegenerative disorders, as both can present with overlapping motor, cognitive, and neuropsychiatric features, while standard imaging and laboratory studies may be inconclusive. Recognition of the distinctive sleep-autonomic signature of FFI is critical, and genetic testing for PRNP mutations should be pursued when clinical suspicion persists, even in the absence of a family history. Support (if any)