Neuronal intranuclear inclusion disease with subtle imaging findings: a case report and literature review

Abstract

Introduction

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder. Hyperintense signals on diffusion-weighted imaging (DWI) at the corticomedullary junction are key diagnostic features. Early manifestations are often overlooked, leading to misdiagnoses. Here, we report a case of adult-onset NIID with DWI hyperintensities at the corticomedullary junction.

Case presentation

A 72-year-old woman presented with progressive memory deterioration starting 9 years ago. In the third year, MRI showed extensive white matter lesions and brain atrophy, with focal high signal intensity in the corticomedullary junction of the frontal lobe; however, this was overlooked. The patient was clinically diagnosed with Alzheimer’s disease. In the seventh year, the patient gradually developed emotional instability, bradykinesia and urinary incontinence. In the eighth year, MRI revealed a remarkable curvilinear DWI hyperintense signal at the corticomedullary junction. Further genetic testing identified 105 GGC repeats in the NOTCH2NLC gene. Skin biopsy revealed intranuclear inclusions in P62 and ubiquitin-positive fibroblasts, confirming the NIID diagnosis.

Conclusions

Patients with NIID show characteristic DWI hyperintensity at the corticomedullary junction during symptoms. This early imaging finding is subtle and often overlooked. For patients with dementia and episodic encephalopathy, observing radiological changes, along with genetic and skin biopsies, is indispensable.

Introduction

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease characterised by eosinophilic and translucent inclusions in neuronal nuclei of the central and peripheral nervous system. Histopathological biopsies reveal these intranuclear inclusions,¹ and the disease results from GGC repeat expansion in the 5'-untranslated region of the NOTCH2NLC gene.²

NIID is classified into infantile, juvenile and adult forms, based on the age of onset. Adult NIID manifests as a complex constellation of symptoms, including episodic encephalopathy, limb tremors, ataxia, epileptic seizures, Parkinsonism, peripheral neuropathy and autonomic dysfunction.³ A characteristic imaging feature of adult NIID is the curvilinear diffusion-weighted imaging (DWI) hyperintensity signal at the corticomedullary junction, known as the ‘ribbon sign’. This imaging signature reflects pathophysiological processes of NIID and serves as a crucial diagnostic criterion for clinicians and researchers.⁴

However, recent studies show NIID may have absent, delayed, subtle or variable DWI findings. Thus, assessing corticomedullary junction hyperintensities is crucial in suspected cases. We report a case of NIID with subtle imaging signs. The patient showed memory decline and episodic encephalopathy with subtle prefrontal hyperintense signals, which clinicians and radiologists initially overlooked.

Case presentations

A 72-year-old woman with hypertension developed gradual short-term memory impairment 9 years prior to presentation. This cognitive decline manifested through frequent misplacement of belongings, suggesting insidious onset of her neurodegenerative disorder. During cognitive decline, the patient showed characteristic neuropsychiatric symptoms, including delusions (false accusations of abandonment and theft) and auditory hallucinations. The symptom profile, particularly visuospatial disorientation and complex delusions, indicated right hemispheric involvement in the disease process. Auditory hallucinations of insults directed at the patient were reported, indicating paranoid symptoms. These episodes led to her inability to find her way home, showing advancing cognitive impairment.

6 years prior, brain MRI revealed ‘bilateral cerebral white matter lesions and brain atrophy’. The patient scored 22 on the Mini–Mental State Examination and was diagnosed with mixed-type Alzheimer’s disease (AD). Treatment with 5 mg/night donepezil hydrochloride was initiated to improve memory but proved ineffective. 3 years prior, the patient showed unstable emotions, irritability, shouting, depressive mood, poor sleep, unstable gait, frequent falls and urinary incontinence. Multiple hospital visits led to a diagnosis of AD and depression. Treatment with 10 mg/night of memantine, 5 mg/night of donepezil, 10 mg/morning of paroxetine and 0.5 tablets/night of lorazepam failed to improve her condition. The patient visited our hospital in March 2023.

The patient remained conscious and cooperative, with normal orientation to time, space, and person. A decline was observed in memory and computational abilities, manifesting as inability to perform simple subtraction. Deficits in judgement and naming were apparent, including inability to distinguish chickens from ducks. These cognitive deficits indicate deteriorating condition consistent with NIID. No auditory or other hallucinations were elicited, no delusions of persecution or paranoia were detected, and only partial insight was present. Broad-based gait, difficulty initiating movement, unsteady gait, left foot eversion and negative cranial nerve findings. Muscle strength was grade V in upper limbs and grade IV in lower limbs, with increased muscle tone, normal tendon reflexes bilaterally, and no abnormalities in deep or superficial sensation. The finger-to-nose test was unsteady, with positive Romberg’s sign, inability to perform straight-line walking and negative bilateral pathological reflex.

Blood test results were normal. Electroencephalography showed mild-to-moderate abnormalities. The Social Dysfunction Screening Scale scored 9 points. DWI sequences in March 2023 showed hyperintense signal abnormalities progressing from the right frontal lobe corticomedullary junction to the corpus callosum and external capsule (figure 1). A 2019 DWI review revealed a subtle hyperintensity at the frontal corticomedullary junction, with no diffusion restriction in the ADC. These findings were extremely suggestive of NIID; however, these findings were not identified during the initial evaluation. Genetic testing revealed 105 GGC repeats in the NOTCH2NLC gene (online supplemental figure 1). Skin biopsy showed intranuclear inclusions in fibroblasts positive for P62 and ubiquitin (online supplemental figure 2), confirming NIID diagnosis. The patient had no family history, and her daughters tested negative for GGC repeat expansion.

Figure 1. Brain MRI findings taken in 2019 and 2023. DWI, diffusion-weighted imaging. ADC, apparent diffusion coefficient; FLAIR, fluid attenuated inversion recovery.

Discussion and conclusions

In brain imaging research, hyperintense signals at the bilateral corticomedullary junction on DWI are characteristic of NIID, though also seen in toxic and metabolic brain disorders. DWI hyperintensity signals start at the anterior frontal and parietal lobes, sometimes originating from the corpus callosum and spreading to posterior regions, showing the ‘ribbon sign’. Our case demonstrates this. This DWI hyperintense signal lesion is a specific early NIID marker, though these subtle imaging changes are often missed initially.

Current research suggests that hyperintensity signals on DWI in patients with NIID may result from ubiquitination of nuclear inclusions causing protein deposition in nucleosomes, leading to spongiform changes in subcortical white matter of proximal U-fibres.⁵ Tachin K et al⁶ reported a patient who developed typical hyperintensity signals at the corticomedullary junction 6 years after NIID diagnosis, which disappeared 8 years postdiagnosis. Chen et al described a 5-year NIID case where DWI abnormalities appeared in the third year, progressed along the corticomedullary junction, and resolved in the occipital lobe by the fifth year.⁷ In our case, the patient presented with memory impairment and episodic encephalopathy, with subtle initial corticomedullary junction hyperintensities becoming apparent only as symptoms worsened.

Notably, negative imaging findings do not exclude NIID, as early-stage changes at the corticomedullary junction can be subtle and easily overlooked even when typical imaging is lacking. Ni Y et al reported two NIID patients with recurrent encephalitis and apathy, showing only reversible cortical swelling, progressive white matter lesions, and brain atrophy, with no typical NIID imaging features during follow-up.⁸ Dong et al reported NIID with only progressive white matter changes and atrophy.⁹ Cupidi et al described mild leukoaraiosis with no DWI abnormalities due to minimal U-fibre involvement.¹⁰ Cerebral white matter lesions are a major NIID imaging manifestation, typically showing bilateral symmetrical diffusion affecting frontal lobe white matter tracts.¹¹ This correlates with leucoencephalopathy-related dementia in NIID patients.³ Our case series shows progressive white matter lesion expansion parallel to cognitive decline in all NIID patients. For patients with leukoencephalopathy showing diffusion restriction, cognitive decline and motor symptoms, consider adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and alanyl-tRNA synthetase gene (AARS2-L) in differential diagnosis. Both show asymmetric periventricular and deep white matter changes, with possible pyramidal tract or basal ganglia involvement. ALSP shows persistent punctate diffusion restriction, while AARS2-L presents more confluent lesions.^{12 13} In our case, white matter lesions were symmetrically distributed around lateral ventricles with mild DWI hyperintensity and characteristic corticomedullary junction signal. The absence of fragile X-associated tremor/ataxia syndrome findings, such as symmetric T2 hyperintensity in middle cerebellar peduncle,² supports differential diagnostic features. However, this report has limitations as cerebrospinal fluid Aβ, T-tau and positron emission tomography-computed tomography(PET-CT) were not performed, and coexisting AD dermatitis cannot be ruled out.

Our case showed the patient initially presented with memory deterioration and episodic encephalopathy. Hyperintensities at the corticomedullary junction were visible on early imaging but disregarded. This highlights the diagnostic challenge of early NIID, where imaging findings may precede clinical symptoms and are often missed. For patients without DWI abnormalities, paroxysmal encephalopathy should raise suspicion of NIID, requiring genetic testing and skin biopsy.

The funder was involved in the study design, data collection and data analysis. The funder had no role in the interpretation of data, writing of the report, or the decision to submit the article for publication.

Data availability statement

Data are available on reasonable request.