Discussion

To the best of our knowledge, only few studies of adults-onset NIID have previously been discussed in the literature in China, and most studies are case reports. ^{Reference Cao, Wu and Yue6–Reference Wang, Ma and Shi8} Herein, we summarized the clinical manifestations, pathological, and imaging features of 17 patients. NIID similarly affected patients of both sexes in our cohort. The average age of onset for symptoms was 60.18 years and the average time from onset of symptom to diagnosis was 4.06 years. Compared with the age of onset in the literature, our patients have symptoms at a relatively young age (60.18 versus 63.4). ^{Reference Zhang, Wu, Zhu, Ni and Zhang9}

Jia’s team found that dementia is the most common initial symptom of adult-onset NIID. ^{Reference Wang, Ma and Shi8} Most patients with sporadic NIID present with dementia as the initial and main clinical manifestation. However, in our retrospective study, we found that tremor was the most common symptom. Patient 8 had progressive resting tremor in the right hand accompanied by bradykinesia. He was initially misdiagnosed with Parkinson’s disease. Kitagawa reported a 73-year-old woman with NIID who presented with slowly progressive resting tremor in both hands. Levodopa and trihexyphenidyl were ineffective against the tremor. ^{Reference Kitagawa, Sone, Sobue, Kuroda and Sakurai10} O’Sullivan reported juvenile parkinsonism in a patient with NIID. The patient showed asymmetric arm tremor and bulbar symptoms. Widespread hyaline intranuclear inclusions and neuronal depletion in the substantia nigra were observed at autopsy. ^{Reference O’Sullivan, Hanagasi, Daniel, Tidswell, Davies and Lees11} In addition, some of our patients had postural tremor and were initially misdiagnosed with essential tremor. Similarly, in our patients, drugs did not effectively treat tremors. We suggest that NIID should be suspected if tremor is severe and is poorly responsive to drug treatment. In our retrospective study, the age at onset of patients with tremor was lower than that of patients without tremor. Cognitive impairment occurred in 7 of the 11 patients with tremor, who presented with very mild cognitive decline.

In addition to tremor and cognitive impairment, the patients with NIID in our cohort had several other clinical manifestations. Li reported a patient with NIID who had multiple reversible encephalitic attacks and remained stable and nonprogressive for 7 years. ^{Reference Li, Li and Li12} However, we found that five patients with multiple encephalitic episodes progressively deteriorated. Compared with patients without encephalitic episodes, patients with encephalitis were more likely to have fever, nausea and vomiting, confusion, and incontinence. The imaging feature of patients with encephalitic episodes was focal cortical swelling. Based on our long-term follow-up, encephalitic episodes followed by reversible asymmetric leukoencephalopathy, which were seen in our patients, may be a new indication for disease. Furthermore, cerebral atrophy may occur after encephalitic episodes. We speculate that each attack may aggravate cerebral atrophy. We suggest that NIID should be suspected in patients with encephalitic episodes followed by leukoencephalopathy. ^{Reference Zhou, Luan, Chen and Liu13}

Although NIID most commonly affects the nervous system and most pathological evidence has been observed in brain tissues, NIID occasionally involves multiple systems. Here, we present a case of NIID in which severe renal failure occurred previously. P62-positive eosinophilic hyaline intranuclear inclusions were found not only in fibroblast cells but also in renal tubular cells. Interestingly, the patient’s renal insufficiency preceded her CNS symptoms by 5 years. We speculated that this renal insufficiency was associated with NIID. Motoki reported that eosinophilic intranuclear inclusions can occur in renal tubular cells 12 years before diagnosis. ^{Reference Motoki, Nakajima, Sato, Tada, Kakita and Arawaka14} Horino first reported a case of NIID associated with lupus nephritis-like nephropathy. ^{Reference Horino, Matsumoto, Inoue, Ichii and Terada15} The patient was treated with steroids and angiotensin-converting enzyme inhibitors and his proteinuria improved. However, our patient eventually developed renal failure during long-term follow-up. Therefore, our case suggested NIID may cause severe renal insufficiency, and we need more cases to study the causal relationship between renal insufficiency and NIID.

The MRI features of our patients including high-intensity U-fiber signals on DWI, brain atrophy, leukoencephalopathy, cortical swelling and enlarged ventricles, cerebral sulci, and gyri. There are other specific MRI features not yet seen in our patients but reported in other literature including T2 hyperintensities in the bilateral paravermal regions and/or bilateral middle cerebellar peduncles. ^{Reference Pang, Yang and Yuan16,Reference Chen, Lu and Wang17} Sone reported that high-intensity signals in the corticomedullary junction on DWI are highly characteristic of NIID. ^{Reference Sone, Mori and Inagaki1} This abnormal hyperintense signal usually first appears in the frontal lobe and then develops in the parietal and occipital lobes. ^{Reference Yokoi, Yasui and Hasegawa18} This continuous and linear high-intensity signal on DWI can also extend into the deep white matter. ^{Reference Sugiyama, Sato and Kimura19} Interestingly, in our center, 14 patients showed high-intensity signals on DWI. One patient without high-intensity U-fiber signals on DWI had recurrent episodes of encephalitis, focal leukoencephalopathy, and progressive brain atrophy. We followed up with this patient for 4 years, and typical hyperintensity at the corticomedullary junction was still absent. Like the patient mentioned above, another patient at our center did not show a high-intensity signal on DWI at the first visit (patient 11, Figure 2, B–D). During long-term follow-up and after several encephalitic episodes, high-intensity signals on DWI appeared. To date, there have been few reports on the longitudinal course of hyperintensity on DWI. We suggest that although abnormal high-intensity DWI signals are indicative of NIID, negative findings do not exclude the diagnosis. We speculate that imaging examinations show dynamic changes as the disease progresses. ^{Reference Raza, Singh and Rai20}

In recent studies, the presence of repeat expansions in the 5’UTR of the NOTCH2NLC gene was shown to aid the diagnosis of NIID. One limitation of our study is that the CGG repeat length of the NOTCH2NLC gene was not analyzed. Skin biopsy and imaging results confirmed our diagnosis of NIID.

In summary, we analyzed the clinical characteristics of NIID patients who were diagnosed through skin biopsy and MRI. The prevalence of tremor in Chinese patients with NIID is likely to be higher than that reported in previous studies. Although MRI findings play an important role in the diagnosis of NIID, we should be aware that not all patients show the typical high-intensity signals on DWI in the corticomedullary junction at all times.