Clinical analysis of adult-onset neuronal intranuclear inclusion disease

Abstract

Neuronal intranuclear inclusion disease (NIID) is characterized by eosinophilic nuclear inclusions (NI) in the nervous systems and the visceral organs. Ante-mortem diagnoses have been made by NI identification in skin biopsy samples based on characteristic corticomedullary junction (CMJ) high intensity in brain diffusion-weighted imaging (DWI). However, the clinical symptoms of NIID are variable. We analyzed 14 (10 sporadic, 4 familial) adult-onset NIID patients with clinical examination, electrophysiological study, brain MRI, cerebrospinal fluid (CSF) biomarker, and skin biopsy. The mean onset-age was 63.8 years. Initial symptoms were consciousness disturbance, memory impairment, gait disturbance, etc. The mean scores of MMSE, Japanese version of Montreal Cognitive Assessment and Frontal Assessment Battery were 20.7/30, 14.2/30 and 9.2/18, respectively. Neurological examination demonstrated hypo-areflexia, miosis and urinary dysfunction. All patients showed abnormal nerve conduction. Thirteen of 14 patients revealed high intensities of CMJ in DWI and leukoencephalopathy with ventricular dilatation and brain atrophy in MRI FLAIR images. In one patient with leukoencephalopathy, DWI high intensity was not detected. The levels of total Tau in CSF were increased in accordance with the grade of DWI high intensity. Skin biopsies from all patients demonstrated that NI immunostained with anti-ubiquitin and anti-p62 antibodies in the sweat gland cells, adipocytes and fibroblasts, were composed of filamentous structure without limiting membrane by electron microscopy. In patients with miosis and hyporeflexia with leukoencephalopathy, NIID should be considered for differential diagnosis even when DWI high intensity is negative. Total Tau in CSF will be a biomarker for progression of NIID.