- Case report
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Coexistence of neuronal intranuclear inclusion disease and amyotrophic lateral sclerosis: an autopsy case
BMC Neurology volume 21, Article number: 273 (2021)
Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. Pathologically, it is characterized by eosinophilic hyaline intranuclear inclusions in the cells of the visceral organs as well as central, peripheral, and autonomic nervous system cells. Recently, a GGC repeat expansion in the NOTCH2NLC gene has been identified as the etiopathological agent of NIID. Interestingly, this GGC repeat expansion was also reported in some patients with a clinical diagnosis of amyotrophic lateral sclerosis (ALS). However, there are no autopsy-confirmed cases of concurrent NIID and ALS.
A 60-year-old Taiwanese woman reported a four-month history of progressive weakness beginning in the right foot that spread to all four extremities. She was diagnosed with ALS because she met the revised El Escorial diagnostic criteria for definite ALS with upper and lower motor neuron involvement in the cervical, thoracic, and lumbosacral regions. She died of respiratory failure at 22 months from ALS onset, at the age of 62 years. Brain magnetic resonance imaging (MRI) revealed lesions in the medial part of the cerebellar hemisphere, right beside the vermis (paravermal lesions). The subclinical neuropathy, indicated by a nerve conduction study (NCS), prompted a potential diagnosis of NIID. Antemortem skin biopsy and autopsy confirmed the coexistence of pathology consistent with both ALS and NIID. We observed neither eccentric distribution of p62-positive intranuclear inclusions in the areas with abundant large motor neurons nor cytopathological coexistence of ALS and NIID pathology in motor neurons. This finding suggested that ALS and NIID developed independently in this patient.
We describe a case of concurrent NIID and ALS discovered during an autopsy. Abnormal brain MRI findings, including paravermal lesions, could indicate the coexistence of NIID even in patients with ALS showing characteristic clinical phenotypes.
Neuronal intranuclear inclusion disease (NIID), a rare neurodegenerative disease, is pathologically characterized by eosinophilic hyaline intranuclear inclusions in the cells of the visceral organs as well as central, peripheral, and autonomic nervous system cells [1, 2]. NIID’s clinical manifestations vary and include cerebellar ataxia, pyramidal and extrapyramidal symptoms, peripheral neuropathy, autonomic dysfunction, cognitive dysfunction, and retinopathy [1, 2]. It appears in both familial and sporadic forms, and onset can occur at any age [1, 2].
Recently, techniques such as long-read sequencing [3, 4] and direct identification by short-read analysis  have confirmed a GGC repeat expansion in the NOTCH2NLC gene as NIID’s underlying etiopathology. This abnormal GGC repeat expansion in the NOTCH2NLC gene is reportedly associated with essential tremor and leukoencephalopathy [6, 7]. Moreover, this GGC repeat expansion in the NOTCH2NLC gene has appeared in 4 out of 545 patients with a clinical diagnosis of amyotrophic lateral sclerosis (ALS) . These observations suggest the following hypotheses: (i) ALS might be a special NIID phenotype, and the GGC repeat expansion might modify the clinical manifestations of ALS, or (ii) NIID and ALS might share part(s) of the pathophysiology and can, therefore, coexist. Interestingly, no autopsy-confirmed cases of concurrent NIID and ALS were previously reported.
Here, we describe a case wherein the main clinical features were consistent with ALS diagnosis, but an autopsy confirmed the coexistence of both NIID and ALS.
A 60-year-old Taiwanese woman presented to the Chiba University Hospital with a four-month history of progressive weakness beginning in the right foot and spreading to all four extremities. Her medical history was unremarkable except for cough-variant asthma, and there was no family history of neuromuscular or neurodegenerative disorders.
A neurological examination showed no abnormality of the cranial nerves except for slight dysarthria. However, reduced muscle strength in all four extremities, especially in the right foot, with wasting, was observed. Fasciculations were noted in both arms. Deep tendon reflexes were brisk with a positive Trömner sign on the right, and bilateral plantar reflexes were extensor. Abdominal skin reflexes were absent bilaterally, whereas abdominal muscle reflex was enhanced. There were no signs of cerebellar dysfunction. The sensation was also intact to all modalities used for testing. The patient scored 28/30 on the Mini-Mental State Examination (MMSE) as she lost points for recall and following a command. She scored 16/18 on the Frontal Assessment Battery (FAB) where she lost points for similarities and lexical fluency. The overall score of Addenbrooke’s Cognitive Examination III was 83 out of 100, with subscores of 18/18 for attention and orientation, 15/26 for memory, 9/14 for fluency, 25/26 for language, and 16/16 for visuospatial skills.
Needle electromyography demonstrated active and chronic denervation potentials in her biceps brachii, first dorsal interosseous, thoracic paraspinal muscles, tibialis anterior, and vastus lateralis. Nerve conduction studies (NCS) in the right upper and lower limbs revealed reduced conduction velocities and prolonged distal latencies in all tested motor nerves (Table 1). Decreased compound muscle action potential was observed in the ulnar, the peroneal, and the tibial nerves. Sensory studies revealed reduced conduction velocities and decreased sensory nerve action potential in the ulnar nerve. Brain magnetic resonance imaging (MRI) revealed bilateral subcortical high-intensity lesions in the precentral gyri and abnormal high-intensity signals along the corticospinal tracts on T2-weighted (T2WI) and fluid-attenuated inversion recovery (FLAIR) images (Fig. 1). High-intensity signals in the medial part of the cerebellar hemisphere, right beside the vermis (paravermal lesions), were also seen in FLAIR images (Fig. 1).
The patient met the El Escorial diagnostic criteria for definite ALS with upper and lower motor neuron involvement in the cervical, thoracic, and lumbosacral regions . On the other hand, paravermal lesions on brain MRI and NCS findings that indicated demyelinating and axonal neuropathy prompted a diagnosis of NIID. A skin biopsy revealed eosinophilic, p62-positive, ubiquitin-positive, intranuclear inclusions in adipocytes, sweat gland cells, fibroblasts, and Schwann cells of the endoneurium and the perineurium. Electron microscopy showed that they consisted of tubule-filamentous material (Fig. 2). Based on these results, we considered the following possible diagnoses, namely, (i) coexistence of ALS and NIID or (ii) an ALS phenotype of NIID; however, a definitive diagnosis was difficult to establish at that time.
Subsequently, clinical signs of upper and lower motor neuron involvement in the bulbar lesion became evident. The patient underwent a gastrostomy eight months after ALS onset and died 22 months after onset, at 62 years of age, due to respiratory failure.
The patient’s family provided informed consent for postmortem analyses, and an autopsy was performed. Appropriate brain areas were dissected and embedded in paraffin, 5 μm-thick serial sections were stained with hematoxylin and eosin and Klüver-Barrera (KB), and then immunostained against phosphorylated transactivation response DNA-binding protein (TARDBP) 43 kDa (pTDP-43) (pS409/410–2, polyclonal, rabbit, Cosmo Bio, Tokyo, Japan, 1:3,000), TDP-43 (clone 3H8, monoclonal, mouse, Novus Biologicals, Centennial, CO, 1:3,000) and p62 (SQSTM1, polyclonal, rabbit, MBL, Nagoya, Japan).
At autopsy, the brain weighed 1,020 g. The pia mater, particularly on the central regions’ surface, appeared cloudy, suggesting cortical atrophy in these areas (Fig. 3). The precentral cortex appeared more brown than usual and displayed an ill-defined corticomedullary boundary, which was in contrast to the other cortices (Fig. 3). The spinal cord was atrophic with clear evidence of thinning in its anterior roots. Microscopic examination was remarkable for gliosis and loss of spinal motor neurons. Bunina bodies and TDP-43-positive cytoplasmic inclusions were occasionally identified in the remaining motor neurons of the anterior spinal horn and in the hypoglossal nucleus (Fig. 3). TDP-43-positive cytoplasmic inclusions were absent from the neocortex, limbic areas, and subcortical gray matter, including in the striatum, pallidum, and thalamus. Precentral gyrus thinning was corroborated by severe neuronal loss and gliosis, and the precentral subcortical white matter showed severe gliosis and the presence of several vacuoles (Fig. 3). Vacuolar degeneration, accompanied by macrophage infiltration, occurred throughout the corticospinal tracts, such as in the posterior limb of the internal capsule, the cerebral peduncle, the pyramid of the medulla oblongata, and the lateral funiculus of the spinal cord (Fig. 3). We also observed that significant quantities of p62-positive intranuclear inclusions were widely distributed across different central nervous system areas, including the neocortex, the limbic regions, basal ganglia, brainstem, cerebellum, and the spinal cord (Fig. 4). Most inclusions appeared to be present in the glial cells (astrocytes, oligodendrocytes, and ependymal cells), were well-defined and round, and appeared eosinophilic with hyaline-like features on hematoxylin–eosin staining. A small number of p62-positive inclusions were localized to the nuclei of motor neurons, and they were plotted on a brain map at × 200 magnification using a VS120 virtual slide system (Olympus, Tokyo, Japan) to investigate an association, if any, between the distribution of p62-positive intranuclear inclusions and neuronal degeneration (Fig. 5). We found no eccentric distribution of these inclusions in areas with abundant large motor neurons, such as in the spinal cord’s anterior horn and the deep Betz cell layer of the precentral gyrus. Additionally, double immunohistochemical evaluation using antibodies against p62 and TDP-43 on five different sections at the fourth level of the lumbar cord to determine the cytopathological coexistence of motoneuronal p62-positive intranuclear inclusions (NIID pathology) and pTDP-43-positive cytoplasmic inclusions with native TDP-43 loss from the nucleus (ALS pathology) did not show any motor neuron overlap between NIID and ALS pathology (Fig. 6). These results indicated that, in the present case, ALS pathology might have occurred independently of NIID pathology.
We observed abundant p62-positive intranuclear inclusions in the cerebellar glial cells, particularly in the Purkinje and the granular cell layers and in the periventricular ependymal region (Fig. 4). Inclusions were also occasionally identified in cerebellar cortical neurons, such as in the Purkinje and granular cells; however, neurons harboring p62-positive intranuclear inclusions in the dentate nucleus were rare. The distribution of intranuclear inclusions in the glia varied across different areas of white matter. These inclusions were more abundant in the paravermis’ white matter than in the hemispheric white matter (Fig. 5). Interestingly, the p62-positive nuclear inclusions in the paravermal white matter were accompanied by focal demyelination (Fig. 4). This lesion appeared to correspond with paravermal high-intensity lesions observed on MR images (Fig. 1).
Discussion and conclusions
The patient presented with a clinical course consistent with limb-onset ALS and met the El Escorial diagnostic criteria for a definite antemortem ALS diagnosis. Paravermal lesions in the medial part of the cerebellar hemisphere as seen in the brain MRI prompted a diagnosis of NIID, and both antemortem skin biopsy and postmortem autopsy confirmed the coexistence of ALS and NIID. Further, the absence of an eccentric distribution of p62-positive intranuclear inclusions in areas with abundant large motor neurons and no evidence of cytopathological coexistence of ALS and NIID pathology in the motor neurons suggests that ALS and NIID developed independently in this patient.
ALS and NIID may share underlying etiologic factors but coexist independently in an individual. Intranuclear inclusions positive for ubiquitin and p62 have been reported in both ALS and NIID [1, 2, 10]. Further, GGC repeat expansion in the NOTCH2NLC gene, which is etiopathological of NIID, has been observed in 4 out of 545 patients with a clinical diagnosis of ALS . While the previous report did not describe the definitive pathological diagnoses in these four patients, they reported eosinophilic, p62-positive, ubiquitin-positive intranuclear inclusions in skin biopsies in two of them . Unfortunately, we could not perform genetic analysis of the NOTCH2NLC gene for this case; nevertheless, the autopsy confirmed the coexistence of pathology consistent with both ALS and NIID. Moreover, the distribution of p62-positive intranuclear inclusions and double immunohistochemical staining against p62 and TDP-43 suggested that ALS and NIID had developed independently in our patient. While ALS and NIID’s coincidental coexistence cannot be completely ruled out, the very low prevalence of these two conditions precludes any assessment of the probability of such an occurrence.
It is possible that paravermal lesions in the medial part of the cerebellar hemisphere are the sole radiological clue for diagnosing NIID because, in our case, although the brain MRI revealed abnormal signals in the paravermal areas, findings typical of NIID, such as high-intensity signals along the corticomedullary junction on diffusion-weighted imaging (DWI) or diffuse high-intensity signals in cerebral white matter on FLAIR [2, 11], were absent. The autopsy also revealed focal demyelination with abundant p62-positive nuclear inclusions in the white matter of the paravermis, which appeared to correspond to the paravermal lesions in the MRI. Further, paravermal lesions have been described as features of adult-onset NIID . Interestingly, observations similar to our case, i.e., paravermal lesions without apparent DWI abnormality along the corticomedullary junction on MRI, at the time of onset, have been previously described . In addition to these paravermal lesions, MRI also revealed abnormal signals in the precentral subcortical white matter and along the corticospinal tract. These lesions appeared to correspond to vacuolar degeneration seen during autopsy pathology. Consistent with our observations, previous studies associated vacuolar degeneration with abnormal MRI signals in the precentral subcortical white matter and along the corticospinal tract .
The results of NCS in our case may be interpreted as a mixture of NIID-associated subclinical peripheral neuropathy and ALS-related changes. Motor and peripheral sensory neuropathy is a common symptom in patients with NIID  and can be the predominant symptom in some NIID patients . Slower conduction in both motor and sensory nerves has been reported to be frequently observed in patients with NIID , and prolonged distal latencies in motor nerves, along with slower conduction in sensory nerves, as seen in our case, might be associated with NIID. The revised El Escorial criteria for ALS diagnosis allow abnormal sensory NCS only in the presence of entrapment syndrome or coexisting peripheral nerve disease. While normal sensory NCS has been shown in ALS patients [9, 15], motor or sensory nerve conduction abnormalities do occur in some ALS patients [16,17,18].
This case report’s limitations are that the GGC repeat length of the NOTCH2NLC gene and CGG repeat length of the FMR1 gene could not be determined. Similarities in clinical, radiological, and pathological findings between NIID and fragile X- associated tremor/ataxia syndrome (FXTAS) have been reported [19, 20], and genetic testing is recommended to discriminate between these entities [2, 21]. However, pathological differences between NIID and FXTAS have also been reported , and the non-ALS pathologic findings were attributed to NIID rather than FXTAS, based on the following points. First, intranuclear inclusions were observed in oligodendrocytes, but such inclusions are not observed in FXTAS . Second, there were intranuclear inclusions in adipocytes, sweat gland cells, and fibroblasts. The usefulness of skin biopsies has been reported in NIID but not in FXTAS [23, 24].
In conclusion, we describe a case of coexisting NIID and ALS diagnosed at autopsy. Abnormal brain MRI findings, including paravermal lesions, could indicate the coexistence of NIID even in patients with ALS showing a typical clinical phenotype.
Availability of data and materials
The complete data are available from the corresponding author on reasonable request.
Neuronal intranuclear inclusion disease
Amyotrophic lateral sclerosis
Mini-Mental State Examination
Frontal Assessment Battery
Nerve conduction study
Magnetic resonance imaging
Fluid-attenuated inversion recovery
Transactivation response DNA-binding protein 43 kDa
Fragile X- associated tremor/ataxia syndrome
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We would like to thank the patient for her participation in this study. We are grateful to the pathological team and Mrs. Yuriko Ogawa at National Hospital Organization Chibahigashi National Hospital for their excellent technical assistance.
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Sugiyama, A., Takeda, T., Koide, M. et al. Coexistence of neuronal intranuclear inclusion disease and amyotrophic lateral sclerosis: an autopsy case. BMC Neurol 21, 273 (2021). https://doi.org/10.1186/s12883-021-02306-5
- Neuronal intranuclear inclusion disease
- Amyotrophic lateral sclerosis
- Magnetic resonance imaging
- Paravermal lesion
- Case report