Clinicopathological features of adult-onset neuronal intranuclear inclusion disease

Abstract

Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous system, and also in the visceral organs. NIID has been considered to be a heterogeneous disease because of the highly variable clinical manifestations, and ante-mortem diagnosis has been difficult. However, since we reported the usefulness of skin biopsy for the diagnosis of NIID, the number of NIID diagnoses has increased, in particular adult-onset NIID. In this study, we studied 57 cases of adult-onset NIID and described their clinical and pathological features. We analysed both NIID cases diagnosed by post-mortem dissection and by ante-mortem skin biopsy based on the presence of characteristic eosinophilic, hyaline and ubiquitin-positive intanuclear inclusion: 38 sporadic cases and 19 familial cases, from six families. In the sporadic NIID cases with onset age from 51 to 76, dementia was the most prominent initial symptom (94.7%) as designated 'dementia dominant group', followed by miosis, ataxia and unconsciousness. Muscle weakness and sensory disturbance were also observed. It was observed that, in familial NIID cases with onset age less than 40 years, muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia. In familial cases with more than 40 years of onset age, dementia was most prominent (100%). Elevated cerebrospinal fluid protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases. Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis. All of the dementia dominant cases presented with this type of leukoencephalopathy on head magnetic resonance imaging. Both sporadic and familial NIID cases presented with a decline in Mini-Mental State Examination and Frontal Assessment Battery scores. Based on these clinicopathological features, we proposed a diagnosis flow chart of adult-onset NIID. Our study suggested that the prevalence rate of adult-onset NIID may be higher than previously thought, and that NIID may be underdiagnosed. We should take NIID into account for differential diagnosis of leukoencephalopathy and neuropathy.

Keywords: dementia; diffusion-weighted image; intranuclear inclusion; leukoencephalopathy; skin biopsy.

Figure 1

Family trees and major clinical phenotype of familial NIID.

Figure 2

Histopathological findings of NIID cases. (A–H) Sporadic NIID cases. (I–P) Familial NIID cases. (A and I) Haematoxylin and eosin stain of sympathetic ganglion of Subject S-31(A) and spinal cord motor neuron of Subject F2-1 (I). (B, C, E, F, J and M–O) Immunostained samples with anti-ubiquitin antibody of temporal cortex neuron of Subject S-31 (B), cingulate gyrus astrocyte of Subject S-5 (C), dorsal root Schwann cells of Subject S-31 (E), renal tubule cells of Subject S-5 (F), Perkinje cell of Subject F1-2 (J), myenteric plexus neuron of Subject F1-1 (M), renal tubule cells of Subject F2-1 (N), adipocyte of Subject F3-1 (O). (G and K) Immunostained samples with anti-p62 antibody of adipocyte of Subject S-1 (G) and astrocytes of Subject F1-2 (K). (D, H, L and P) Electron microscopic images of astrocyte of Subject S-31 (D), skin fibroblast of Subject S-31 (H), astrocyte of Subject F1-2 (L), and skin fibroblast of Subject F5-1(P). Scale bars in A–C, E–G, I–K and M–O = 10 μm; in D, H, L and P = 1 μm.

Figure 3

Frequency of intranuclear inclusion in the NIID brain. (A–C) Sporadic NIID Subject S-5. (D–F) Familial NIID case Subject F1-2. (A and D) Klüver-Barrera stain of coronal section of cerebral hemisphere. White matter of frontal lobe in both samples showed evident demyelination. (B, C, E and F) Schematic diagrams of frequency and distribution of intranuclear inclusion of neurons (B and E) and astrocytes (C and F) in cerebral cortex, basal ganglia and hippocampus. Frequencies were assessed in serial section of Klüver-Barrera slide with immunohistochemistry with anti-p62 antibody. In Subject F1-2, hippocampus was not included in large coronal section, we analysed frequencies with other hippocampus slide separately. (G and H) p62 immunostaining of cerebral cortex of frontal lobe of Subjects S-5 (G) and F1-2 (H). Green arrow shows intranuclear inclusion positive neuron and red arrowhead shows intranuclear inclusion positive astrocyte. Scale bar = 50 μm.

Figure 4

The results of NIID head MRI and SPECT. Head MRI findings of Subject S-31 (sporadic NIID) (A–D), Subject S-25 (sporadic NIID) (E–H), Subject F3-1 (familial NIID) (I–L) and Subject F5-2 (familial NIID) (M–P). (A and M) T₁-weighted image. (B, E and N) T₂-weighted image. (C, F, I–K and O) FLAIR image. (D, G, L and P) DWI image. (H) Gadolinium-enhanced T₁-weighted image. (A–D) Head MRI findings of Subject S-31 at age 72 years, almost akinetic mutism state. Prominent leukoencephalopathy, DWI high intensity signal in corticomedurally junction and ventricular distention were observed (D). (E–H) Head MRI findings at the presence of encephalitic symptom of Subject S-25. On T₂ (E) and FLAIR (F) image, brain oedema is observed (blue arrowhead). On DWI, oedematous portion showed slightly high intensity but weaker than corticomedurally junction high intensity signal (yellow arrow) (G). Oedematous portion showed high intensity on gadolinium enhanced T₁ image (red arrow head) (H). (I–L) Progress of leukoencephalopathy in familial NIID Subject F3-1 at age 53 (I), age 58 (J) and age 64 (K and L). High intensity area of FLAIR image extended remarkably. (M–P) Head MRI findings of familial NIID Subject F5-2 presented dementia dominantly. Findings are almost identical to sporadic case. (Q and R) The results of easy Z-score imaging system (eZIS) analysed data of ^99mTc-ECD SPECT. Subject S-9 showed severe regional cerebral blood flow decline and Subject F2-2 eZIS data showed light regional cerebral blood flow decline.

Figure 5

Sporadic and familial NIID and phenotypic subgroup.

Figure 6

Proposed flowchart of adult-onset NIID diagnosis. DWI = diffusion-weighted imaging; FAP = familial amyloid polyneuropathy; NCV = nerve conduction velocity.