A case report of neuronal intranuclear inclusion disease and literature review

Abstract

Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disease with a characteristic pathological feature of eosinophilic hyaluronan inclusions in the nervous system and internal organs. The identification of GGC-repeat expansions in the Notch 2 N-terminal like C (NOTCH2NLC) gene facilitates the accurate diagnosis of NIID. Due to its rareness and high clinical heterogeneity, the diagnosis of NIID is often delayed or missed. Here, we report a case of NIID mimicking autoimmune encephalitis. A 55-year-old Chinese man presented with fever, headache, recurrent seizures, and weakness in the upper and lower left limbs. Brain MRI revealed diffuse T2/ FLAIR-hyperintense lesions in the bilateral basal ganglia, corpus callosum, and periventricular white matter, with swelling of the right temporal, frontal, and parietal cortices accompanied by meningeal enhancement. Abnormally high signal lesions were observed in the corticomedullary junction in diffusion-weighted imaging (DWI). The infectious or autoimmune disease screening of central nervous system using CSF was normal. The test of GGC-repeat expansion in the NOTCH2NLC gene by capillary electrophoresis indicated GGC repeats (48 and 110 GGC repeats), which supported the diagnosis of NIID. After treatment with glucocorticoid, the clinical symptoms of this patient improved significantly. In the literature, 12 cases of NIID presenting with encephalitis-like attacks were identified, most of which were recurrent, accompanied by progressive symptoms such as dementia, Parkinsonism symptoms, migraine, or dysuria. In this case, there was a single encephalitis-like episode without other progressive symptoms. In patients with encephalitis-like symptoms, NIID should be considered, especially when no other evidence of infection is found, as demonstrated in this case. In addition, long-term monitoring of disease progression is also very important.

Background

NIID is a rare progressive neurodegenerative disease with a characteristic pathological feature of eosinophilic hyaluronan inclusions in the nervous system and internal organs. But the mechanisms underlying its formation and its precise correlation with neuronal degeneration remain unclear. After the description of typical pathological findings in skin biopsy and the discovery of GGC-repeat expansions in the NOTCH2NLC gene associated with NIID, an increasing number of cases were confirmed. With the deeper investigation of the clinical cohort and cases, it is found that the manifestations of NIID exhibit significant heterogeneity. Yun et al. [1] summarized the clinical features of 247 patients with NIID, and the common manifestations in their cohort included paroxysmal symptoms, autonomic dysfunction, movement disorders, cognitive impairment, and muscle weakness. The division of NIID into four subgroups was determined by the patients’ initial and main clinical manifestations, which were dementia-dominant, movement disorder-dominant, muscle weakness-dominant, and paroxysmal symptom-dominant types. White matter intensity signals, including periventricular, frontal subcortical and deep white matter, as well as the corpus callosum and external capsule, has been reported as one of the radiographic alterations in NIID, while the most characteristic and typical radiographic finding is the high signal intensity at the corticomedullary junction on diffusion-weighted imaging (DWI). However, it can also be absent in 3.4–18.2% of NIID patients especially in patients with muscle weakness [1,2,3,4]. The diagnosis of NIID can be delayed or missed due to its rare nature and high clinical heterogeneity [5, 6].

According to previous research and case reports, the most common manifestations were paroxysmal symptoms including encephalitic episodes. Although NIID lacks a precise treatment approach, glucocorticoids may be a treatment option, particularly for those with encephalitic symptoms, cortical edema and enhanced MRI findings [1]. Here, we report a case of NIID mimicking autoimmune encephalitis that responded well to glucocorticoid therapy. In addition, we performed a comprehensive literature review to characterize NIID and its patients exhibiting encephalitis-like symptoms, aiming to more effectively differentiate NIID from encephalitis.

Methods

Demographic data, clinical presentations, physical examinations, imaging data, laboratory results, lumbar puncture findings, and the prognosis of the patient were recorded. Written informed consent was obtained from patient and his family members. A review of the literature was conducted on PubMed using the following research terms: ((NIID) OR (neuronal intranuclear inclusion disease)) AND ((encephalitis) OR (cerebral edema) OR (leukoencephalopathy) OR (cortical enhancement)). According to the clinical criteria for autoimmune encephalitis (AE) proposed by Graus et al. in 2016 [7], the characteristic symptoms of encephalitis were defined as acute or subacute onset of symptoms including fever, headache, vomiting, disturbance of consciousness, seizure, or focal neurological deficits. MRI could reveal focal lesions, cortical edema, and gadolinium enhancement.

Results

Case presentation

A 55-year-old Chinese male was admitted to the Department of Neurology of Peking University Shenzhen Hospital, with a history of fever and headache for three days. During hospitalization, the patient experienced recurrent epileptic seizures. His past medical history was unremarkable, with no relevant medical history of encephalitis, epilepsy, cognitive impairment, or muscle weakness in his family. Neurological examination revealed drowsiness, left-sided central facial and tongue paralysis, motor weakness affecting the left upper and lower limbs with slightly increased muscle tone, while Babinski and Chaddock signs were positive. Upon admission, the scores for the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) [8] were 26 and 22, respectively.

Brain MRI revealed diffuse T2/ FLAIR-hyperintense lesions in the bilateral basal ganglia, corpus callosum, and periventricular white matter, with edema of the right temporal, frontal, and parietal cortices accompanied by meningeal enhancement. The lesions were asymmetric, with more significant involvement of the right cerebral hemisphere. In addition, abnormally high signal lesions were observed in the corticomedullary junction in diffusion-weighted imaging (DWI), reminiscent of NIID (Fig. 1). Routine serum screening including blood routine, liver and kidney function, electrolytes, blood lipids, and homocysteine was unremarkable. The routine urine screening, which includes urine glucose and urine protein, revealed no significant abnormalities. The serum autoimmune screening, including anti-nuclear antibodies (ANA), anti-extractable nuclear antigen (ENA), anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies and anti-phospholipid antibodies, were negative. Infection-related indicators such as IgM against herpes simplex virus type I (HSV-I) and type II (HSV-II), and cytomegalovirus (CMV) were normal. Tests based on the cell-based assessment (CBA) for autoimmune encephalitis antibodies (NMDA, LGI1, CASPR2, AMPA receptors 1, AMPA receptors 2, and GABAB receptors) and IgG of AQP4, GFAP and MOG were all negative in serum and CSF. During the lumbar puncture, it was observed that there was a pressure of 220 mmH₂O, WBC of 9 × 10⁶/L (normal range: 0–8 × 10⁶/L), slightly elevated protein content of 72 mg/dL (normal range: 12–60 mg/dL) with glucose being normal. An infectious disease screening of the central nervous system using CSF included IgG and IgM against cytomegalovirus and herpes simplex virus type I and II, Gram and acid-fast stains, and the metagenomic testing results for pathogenic microorganisms were all normal, indicating no current infection. While CSF and serum Ig electrophoresis revealed intrathecal IgG oligoclonal bands.

Fig. 1

A-D The cranial MRI showed diffuse hyperintense lesion in bilateral white matter in T2WI. E-H High signal band changes were observed in the corticomedullary junction in DWI imaging. I-L Post-contrast MRI revealed meningeal enhancement

Diagnosis of NIID was suspected due to the characteristic paroxysmal symptoms and radiology changes. Therefore, a test for GGC-repeat expansion in the NOTCH2NLC gene was performed. Gene test by capillary electrophoresis indicated 48 and 110 GGC repeats, respectively, which supported the diagnosis of NIID. However, due to the possible similarity between the clinical manifestations and radiological changes of NIID and meningoencephalitis (acute fever, headache, consciousness disorders, cognitive impairment, and epileptic seizures accompanied by white matter encephalopathy and cortical swelling), the diagnosis of immune-mediated meningoencephalitis (especially autoimmune encephalitis) is not completely ruled out until NIID’s genetic testing results are positive in the early stages of the disease. Therefore, the patient was administered methylprednisolone 1000 mg intravenously for two days, 500 mg for two days, and 250 mg for two days, followed by oral prednisone 60 mg for treatment. After glucocorticoid treatment, symptoms such as headache, fever, and epilepsy gradually improved.

Literature review

Seventy-six articles in PubMed have been identified through searching. All identified articles were screened and evaluated. Articles written in English with NIID case showing encephalitis-like episode with detailed clinical information were recorded. 12 cases from 9 articles have been selected (Fig. 2). The detailed information including age, gender, race, clinical manifestations, neurological symptoms, NOTCH2NLC GGC repeats, treatment and prognosis was recorded [9,10,11,12,13,14,15,16,17]. Table 1 presents a summary of 13 NIID cases (including our case from Peking University Shenzhen Hospital) presenting with encephalitis-like seizures.

Fig. 2

Summary of literature search and screening

Table 1 The summary of the 13 cases of NIID case showing encephalitis-like episode

Discussion

In 1968, the first case of NIID was reported, in a 28-year-old white male with intellectual disability. Autopsy revealed the widespread presence of eosinophilic inclusion bodies throughout the entire brain and internal organs [18]. Since then, some autopsy reports have shown similar eosinophilic inclusion bodies, but the underlying mechanisms remained unclear at that time. In 2003, Takahashi-Fujigasaki and colleges [19] summarized the reported cases diagnosed by pathological results and categorized the cases into three clinical subgroups according to age of onset and disease duration: infantile, juvenile, and adult. The infantile form patients typically exhibit symptoms during their infancy, commonly manifesting as cerebellar ataxia and/or dysarthria, which may be accompanied by involuntary motor seizures, hyporeflexia and autonomic nervous system dysfunction. The infantile form patients show a relatively short clinical course which not exceeding 10 years. Since 2003, the majority cases were juvenile onset form, showing more varied phenotypes than infantile form patients, and the most characteristic symptom are personality change and learning difficulties. Other manifestations include pyramidal signs, parkinsonism, involuntary movements, cerebellar signs, and other progressive multiple-system degeneration [19, 20]. Juvenile onset form patients ultimately become bedridden and die from repeated bouts of pneumonia 10–20 years after onset [19]. Given the rarity of reported adult-onset cases prior to 2003, the variations in symptoms were less pronounced compared to juvenile-onset patients, primarily presenting with memory loss, cognitive dysfunction, and disorientation.

In addition to autopsy examination, some studies indicated that biopsy of visceral organs (including biopsy of skin, kidney, gastrointestinal tract, or sural nerve) could reveal the similar characteristic eosinophilic inclusions. The study of Sone et al. [21, 22] in 2011 proved the intranuclear inclusions could be observed in adipocytes, fibroblasts, and sweat gland cells through skin biopsy, indicating the relative non-invasive skin biopsy examination could contribute to the antemortem diagnosis. With this advance finding, more and more cases of NIID were confirmed, especially those of adult-onset form. Sone et al. [4] summarized 57 cases of adult-onset form that were confirmed by skin biopsy or autopsy in 2016. Their results found the high heterogeneity of NIID, with varied presentations including dementia, autonomic dysfunction, ataxia, disturbance of consciousness, muscle weakness.

In 2019, an abnormal expansion of GGC repeat of in the 5’ region of NOTCH2NLC gene was found to be associated with NIID [23, 24]. Tian and colleagues summarized 247 patients diagnosed by abnormal expanded GGC repeats (> 65 repeats) within NOTCH2HLC gene, and their results divided NIID patients into four subgroups according to the initial and dominant manifestations: dementia dominant, movement disorder dominant, paroxysmal symptom dominant and muscle weakness dominant. It is noteworthy that more and more patients with atypical presentation were confirmed by gene test. For example, patients clinically diagnosed with Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, essential tremor, and amyotrophic lateral sclerosis were identified with abnormal expansion GGC repeats in NOTCH2NLC gene and thus diagnosed with NIID. The atypical cases proved NIID is a kind of disease with highly variable clinical manifestations with multiple systematic involvements. Therefore, Tian and his colleges [24] raised the concept of “NOTCH2NLC-related NIID”. NOTCH2NLC is one of the three human-specific NOTCH2-derived genes involved in the development of the human brain [25, 26]. There were some possible mechanisms have been discussed in previous studies, such as toxic polyG protein, toxic repeat RNA. However, the underlying mechanism and the role of intranuclear inclusions play in NIID remain unclear [17, 27,28,29,30]. For example, pathology study of Takahashi-Fujigasaki indicated that intranuclear inclusions contained the small ubiquitin modifier-1 (SUMO-1) and the SUMO acylation substrates promyelocytic leukaemia protein (PML) and histone deacetylase 4 (HDAC4), suggesting that transcriptional activity regulated by histone acetylation might contribute to the disease process in NIID [17]. To better understand the pathophysiology of NIID, increasing studies have been conducted to verify the relationship between mutation and clinical phenotype or pathological finding. Tian and his colleges’ study revealed that the number of GGC repeats might correlated to the muscle weakness and negatively correlated with paroxysmal symptoms, while patients with dominant muscle weakness type have significantly higher GGC repeat sizes [1]. However, evidence about genotype-phenotype relationship is too limited, and further investigation is required.

NIID patients with encephalitis-like episodes accounted a significant portion of all patients. According to a study conducted by Tian and his colleges [24], paroxysmal symptoms are the most common manifestations in their cohort, with nearly 23.5% of their patients experiencing encephalitic episodes symptoms. Sone and colleges [4] summarized 57 adult-onset NIID diagnosed by pathological evidence (autopsy or ante-mortem skin biopsy), while their result revealed 21% (8/38) sporadic cases and 5.3% (1/19) familiar cases showed characteristic clinical manifestation of encephalitic episodes. A study by Liu et al. [2] in Taiwan indicated that 32.4% of cases presenting with nonvascular leukoencephalopathies were NIID patients with encephalitis-like episodes. The most recent study of Tai and colleges [3] indicated that 14.3% (32/223) of their NIID patients show encephalitic episodes.

Our study reviewed the previous cases with encephalitic symptoms. Among all 13 cases, with the exception of one Chinese Canadian, the rest are all Asians. While most cases were sporadic (12/13, 92.3%), except one patient whose mother had dementia and similar encephalopathy episodes. As for the radiological changes, 84.6% (11/13) patients revealed hyperintense lesions in white matter, while 30.7% (4/13) showed cortical edema and 46.2% (6/13, some articles didn’t mentioned results of post-contrast MRI) showed enhancement. There were no abnormalities in DWI imaging in only one case (1/13, 7.7%) [10]. The aforementioned radiographic changes are consistent with prior research findings. However, it is noteworthy that hyperintensity and enhancement in MRI was reversible and may be associated with the acute episode of encephalopathy [13]. According to previous studies and case reports, encephalitic symptoms could improve with the steroid treatment. Interestingly, our review indicated that some cases (4/11, 36.4%) spontaneously improved without specific treatment [10, 12, 14]. Steroid treatment is effective in reducing symptoms of a brain attack, but progressive symptoms, such as dementia and Parkinson’s, can progressively worsen [6]. In addition, most cases have experienced recurrent episodes of encephalitis-like attacks, accompanied by progressive symptoms like dementia, Parkinsonism symptoms, migraines, or dysuria. Thus, it is rare that the case from our hospital experienced single encephalitis-like episode, without signs of other progressive symptoms. We believe it is essential to keep long-term follow up for the patient.

According to our experience, it is necessary to consider fully differential diagnosis of some cases showing encephalitic symptoms. Due to the high clinical heterogeneity of some genetic diseases, some patients could also present with acute or subacute onset of symptoms mimicking autoimmune encephalitis. Caldarazzo Ienco have reported a case of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS syndrome) mimicking the clinical and neuroimaging features of infective encephalitis [31]. Early-onset Alzheimer disease (AD) associated with the pathogenic variants in presenilin 1 (PSEN1) can present with psychiatric manifestations, seizures, myoclonus, and focal presentation. Because PSEN1 can occur in young patients who lack a family history of neurologic disorders, and these symptoms are also frequent in autoimmune encephalitis (AE), diagnosis may be overlooked [32]. Other genetic diseases including Fragile X Syndrome [33] and Methylmalonic Acidemia [34, 35] could mimic autoimmune encephalitis. Therefore, we report an atypical case of NIID to emphasize the importance of considering genetic disorders, especially NIID, in cases mimicking autoimmune encephalitis.

Conclusion

We report a case of NIID with encephalopathic presentation. Genetic testing for a NOTCH2NLC-related disorder and typical radiological findings confirmed the diagnosis of NIID. In addition, we conducted a literature review of previous reported NIID cases showing encephalitis-like episode, which suggested some characteristic clinical features such as more frequent occurrence of hyperintense lesion in T2 or DWI imaging, could accompanied by cortical edema and enhancement. Encephalitis-like symptoms may be relived with steroid treatment, however some progressive symptoms such as dementia and parkinsonism may continue to deteriorate slowly.