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Brain. 2016 Dec;139(Pt 12):3170-3186. Epub 2016 Oct 25.

Clinicopathological features of adult-onset neuronal intranuclear inclusion disease.

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1 Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
2 Department of Therapeutics for Intractable Neurological Disorders, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
3 Department of Neurology, Oyamada Memorial Spa Hospital, Yokkaichi, Mie, Japan.
4 Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
5 Department of Neurology, Ibaraki Prefectural University of Health Sciences, Ami, Ibaraki, Japan.
6 Department of Neurology, National Hospital Organization Kure Medical Centre, Kure, Hiroshima, Japan.
7 Department of Neurology, Ota Memorial Hospital, Fukuyama, Hiroshima, Japan.
8 Department of Neurology, University of Yamanashi, Kofu, Yamanashi, Japan.
9 Department of Neurology, Kosei Chuo General Hospital, Tokyo, Japan.
10 Department of Neurology, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan.
11 Department of Neurology, Tottori Prefectural Central Hospital, Tottori, Japan.
12 Department of Neurology, National Hospital Organization Utano Hospital, Kyoto, Japan.
13 Department of Neurology, Kanto Central Hospital, Tokyo, Japan.
14 Department of Neurology, Dokkyo Medical University, Tochigi, Japan.
15 Department of Neurology, Nagaoka Red Cross Hospital, Nagaoka, Niigata, Japan.
16 Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
17 Department of Neuropathology, Institute for Medical Sciences of Aging, Aichi Medical University, Nagakute, Aichi, Japan.
1 Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
18 Brain and Mind Research Center, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.


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.


dementia; diffusion-weighted image; intranuclear inclusion; leukoencephalopathy; skin biopsy

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