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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.

SUBMITTER: Sone J

PROVIDER: S-EPMC5382941 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Amyotrophic lateral sclerosis (ALS) is one of the differential diagnoses of diseases that occur in adulthood and lead to progressive generalized muscle weakness. Neuronal intranuclear inclusion disease (NIID) is a disease in which histopathologically eosinophilic nuclear inclusion bodies are found in various systems. Both familial and sporadic forms of the disease have been reported. Most cases of sporadic NIID are of the dementia type, in which the main symptom is dementia at the first onset. Familial NIID is more diverse, with the main dominant symptoms being muscle weakness (NIID-M), dementia (NIID-D), and parkinsonism (NIID-P). Furthermore, recently, a GGC-repeat expansion in the Notch 2 N-terminal like C (NOTCH2NLC) gene, which produces a toxic polyglycine-containing protein (uN2CpolyG) in patients with NIID, has been associated with the pathogenesis of ALS. These results suggest that sporadic NIIDs may have more diverse forms. To date, no autopsy cases of NIID patients with an ALS phenotype have been reported. Here, we describe the first autopsy case report of a patient with sporadic NIID who had been clinically diagnosed with ALS. A 65-year-old Japanese man with no family history of neuromuscular disease developed progressive muscle atrophy and weakness in all limbs. The patient was diagnosed with ALS (El Escoriral diagnostic criteria: probable ALS, laboratory-supported ALS). He had no cognitive dysfunction or neuropathies suggestive of NIID. He required respiratory assistance 48 months after onset. He died of pneumonia at the age of 79 years. Postmortem examinations revealed neuronal loss in the spinal anterior horns and motor cortex. In these affected regions, eosinophilic, round neuronal intranuclear inclusions were evident, which were immunopositive for ubiquitin, p62, and uN2CpolyG. No Bunina bodies or TDP-43-positive inclusions were observed in the brain or spinal cord. Our findings suggest that a small proportion of patients with NIID can manifest a clinical phenotype of ALS. Although skin biopsy is commonly used for the clinical diagnosis of NIID, it may also be useful to identify cases of NIID masquerading as ALS.

Project description:Neuronal intranuclear inclusion disease is a neurodegenerative disorder with a wide phenotypic spectrum, including peripheral neuropathy. This study aims to characterize the nerve conduction features and proposes an electrophysiological criterion to assist the diagnosis of neuronal intranuclear inclusion disease. In this study, nerve conduction studies were performed in 50 genetically confirmed neuronal intranuclear inclusion disease patients, 200 age- and sex-matched healthy controls and 40 patients with genetically unsolved leukoencephalopathy. Abnormal electrophysiological parameters were defined as mean values plus or minus two standardized deviations of the healthy controls or failure to evoke a response on the examined nerves. Compared to controls, neuronal intranuclear inclusion disease patients had significantly slower motor and sensory nerve conduction velocities, as well as lower amplitudes of compound motor action potentials and sensory nerve action potentials in all tested nerves (P < 0.05). Forty-eight of the 50 neuronal intranuclear inclusion disease patients (96%) had at least one abnormal electrophysiological parameter, with slowing of motor nerve conduction velocities being the most prevalent characteristic. The motor nerve conduction velocities of median, ulnar, peroneal and tibial nerves were 44.2 ± 5.5, 45.3 ± 6.1, 37.3 ± 5.3 and 35.6 ± 5.1 m/s, respectively, which were 12.4-13.6 m/s slower than those of the controls. The electrophysiological features were similar between neuronal intranuclear inclusion disease patients manifesting with CNS symptoms and those with PNS-predominant presentations. Thirteen of the 14 patients (93%) who underwent nerve conduction study within the first year of symptom onset exhibited abnormal findings, indicating that clinical or subclinical peripheral neuropathy is an early disease marker of neuronal intranuclear inclusion disease. We then assessed the feasibility of using motor nerve conduction velocity as a diagnostic tool of neuronal intranuclear inclusion disease and evaluated the diagnostic performance of various combinations of nerve conduction parameters using receiver operating characteristic curve analysis. The criterion of having at least two nerves with motor nerve conduction velocity ranging from 35 to 50 m/s in median/ulnar nerves and 30-40 m/s in tibial/peroneal nerves demonstrated high sensitivity (90%) and specificity (99%), with an area under the curve of 0.95, to distinguish neuronal intranuclear inclusion disease patients from healthy controls. The criterion's diagnostic performance was validated on an independent cohort of 56 literature reported neuronal intranuclear inclusion disease cases (area under the curve = 0.93, sensitivity = 87.5%, specificity = 99.0%), and in distinguishing neuronal intranuclear inclusion disease from genetically unresolved leukoencephalopathy cases (sensitivity = 90.0%, specificity = 80.0%). In conclusion, mildly to moderately decreased motor nerve conduction velocity in multiple nerves is a significant electrophysiological hallmark assisting the diagnosis of neuronal intranuclear inclusion disease, regardless of CNS- or PNS-predominant manifestations.

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Clinicopathological features of adult-onset neuronal intranuclear inclusion disease.

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