Severe and refractory autonomic failure in diffusion- weighted imaging-negative neuronal intranuclear inclusion disease: A case with progressive leukoencephalopathy

Abstract

Neuronal intranuclear inclusion disease (NIID) is a heterogeneous neurodegenerative disorder most commonly associated with GGC repeat expansions in the NOTCH2NLC gene. Although curvilinear hyperintensity along the corticomedullary junction on diffusion-weighted imaging (DWI) is considered a hallmark diagnostic feature, a proportion of patients present without this characteristic finding. The clinical course and disease activity of DWI-negative NIID remain poorly defined. We describe a 55-year-old man with genetically and pathologically confirmed NIID who exhibited a markedly aggressive autonomic phenotype. After a six-year history of nonspecific dizziness, he developed acute, severe, and refractory autonomic failure, characterized by catheter-dependent urinary retention, pharmacoresistant constipation, and generalized hyperhidrosis. Despite the persistent absence of typical DWI abnormalities, serial brain MRI over a 12-month period demonstrated progressive confluent white matter hyperintensities accompanied by worsening cerebral atrophy. In conclusion, this case highlights that DWI-negative NIID can present with severe, rapidly progressive autonomic dysfunction alongside active structural neurodegeneration. Clinicians should maintain a high suspicion for NIID in patients with atypical leukoencephalopathy and prominent autonomic failure, even in the absence of characteristic DWI findings, to facilitate prompt genetic diagnosis.