Episodic encephalopathy in NOTCH2NLC-related neuronal intranuclear inclusion disease: Clinical spectrum and a proposed classification framework.

OBJECTIVE

Episodic encephalopathy is an important yet underexplored manifestation of NOTCH2NLC-related neuronal intranuclear inclusion disease (NIID). Current studies are limited by small sample sizes and a lack of long-term follow-up, hindering a comprehensive understanding of its clinical and radiological features, which this study aims to address.

METHODS

Patients diagnosed as NOTCH2NLC-related NIID were evaluated retrospectively and categorized into episodic encephalopathy-positive group (NIID-EP) and episodic encephalopathy-negative group (NIID-EN) depending on the presence of persistent disturbances of consciousness. Clinical information was collected and compared between the groups.

RESULTS

This study evaluated 65 NIID patients, with a median onset age of 63 years and comprising 27 NIID-EP patients. Compared to NIID-EN, NIID-EP patients exhibited higher incidence of fever (p = 0.000), bladder dysfunction (p = 0.002), and abnormal behaviors (p = 0.001), and brainstem hyperintensities on MRI (p = 0.024). Focal imaging lesions such as cerebral edema, hyperperfusion, and cortical laminar necrosis were found in 5 patients that were classified as MELAS-like episodic encephalopathy and exhibited transhemispheric distribution and longitudinal changes of lactate peaks on magnetic resonance spectroscopy. Three NIID-EP patients were found to have hyperammonemia and ammonia-lowering therapy alleviated conscious disturbance rapidly. NIID-EP patients experienced more complications, prolonged hospitalizations, and worse modified Rankin Scale outcomes. A refined classification framework was proposed for paroxysmal events in NIID.

SIGNIFICANCE: Episodic encephalopathy is a frequent, heterogeneous, and prognostically significant manifestation in NIID, driven by mechanisms such as inflammation, mitochondrial dysfunction, hyperammonemia, and may represent a shared clinical phenotype of genetic leukoencephalopathies with corticomedullary junction DWI hyperintensities.