MR Imaging Features of the Cerebellum in Adult-Onset Neuronal Intranuclear Inclusion Disease: 8 Cases

Discussion

We have presented the MR imaging features of the cerebellum in 8 patients with pathologically confirmed adult-onset NIID. We observed abnormal FLAIR high-intensity signal in the paravermal area and middle cerebellar peduncle as characteristic MR imaging findings of the cerebellum in NIID. Although cerebellar atrophy in NIID has been described in several cases,^3,9,10 there is no report focusing on the distribution of abnormal signals in the cerebellum.

Previous studies have demonstrated that remarkable diffuse high-intensity signal of the cerebral white matter and DWI high-intensity signal along the corticomedullary junction are characteristic MR imaging findings of patients with NIID.^3,5 The DWI finding of high-intensity signal along the corticomedullary junction could thus be a strong indicator of the diagnosis of NIID. According to a study comparing MR imaging and pathologic findings in NIID, DWI high-intensity signal along the corticomedullary junction and FLAIR high-intensity signal in the white matter correlated with pathologic spongiotic changes and diffuse myelin pallor without spongiosis, respectively.¹¹ The spongiotic changes were restricted to the subcortical lesions proximal to the U-fibers, and these changes might induce an inactivation of water diffusion.

That report¹¹ also described a remarkable loss of glial fibrillary acidic protein–positive astrocytes compared with relatively mild axonal loss in the subcortical lesions, and astrocyte dysfunction has been considered a possible cause of white matter damage that ranges from myelin pallor to spongiotic change. These MR imaging findings extend predominantly into the frontal lobe and are thought to be related to white matter dementia, which is more easily detectable by the FAB than the MMSE.⁵ Consistent with this previously reported finding, most of our patients showed a decreased FAB score. Although it was not observed in our patients, transient focal brain edema with gadolinium enhancement has also been reported in patients with NIID during subacute encephalic episodes.⁵

In accordance with previous reports,^3,9,10 all 8 of our patients with NIID presented with cerebellar atrophy. In addition, an abnormal signal in the medial part of the cerebellar hemisphere right beside the vermis, which we defined as the paravermal area, was observed at a high frequency in our patient series. The paravermal area is included in the intermediate part of the cerebellar hemisphere that receives somatosensory input from the limbs and projects via the interposed nucleus to the lateral corticospinal and rubrospinal systems.¹² A previous investigation revealed that lesions in this intermediate part induced impaired gait balance control.¹³

In the present study, the relationship between the extent of the lesion and the severity of ataxia could not be assessed, but all 3 patients with ataxia presented with an abnormal signal in the paravermal area. It is possible that the lesions in the paravermal area observed in our patients influence the ataxic gait in NIID. In our patients, the second most frequent abnormal signal in the cerebellum was the middle cerebellar peduncle lesion. Although we could not determine the pathologic background of these abnormal signals in the cerebellum in our patients, in previous reports describing the cerebellar pathology of NIID, a loss of myelin in the white matter of the cerebellum was described.^9,14,15

The paravermal abnormal signal observed in our patients might be a specific finding for NIID. Another lesion in the medial part of the cerebellar hemisphere, in the peridentate white matter with and without a middle cerebellar peduncle lesion, has been described in several disorders, such as fragile X–associated tremor/ataxia syndrome (FXTAS),^16,17 Erdheim-Chester disease,¹⁸ neurofibromatosis,¹⁹ and progressive multifocal leukoencephalopathy.²⁰ However, the distribution of the lesions in the peridentate white matter observed in these disorders is different from that in the lesions in the paravermal area found in our cases. Although the term “paravermal” has been used in a case with brain infarction,²¹ it has never been used to describe a lesion of a neurodegenerative disorder, to our knowledge.

The paravermal abnormal signal observed in our patients has a unique distribution, and it could be an indicator of the diagnosis of NIID, along with the DWI finding of a high-intensity signal along the corticomedullary junction. The middle cerebellar peduncle lesion is also considered a characteristic finding of NIID, though it can be found in other neurodegenerative disorders such as FXTAS, multiple system atrophy, and spinocerebellar ataxia and diseases due to other etiologies (neoplasm, metabolic, cerebrovascular, inflammatory, and demyelinating diseases).²² Like the high-intensity signal along the corticomedullary junction on DWI, this lesion may also help clinicians distinguish between NIID and clinically similar diseases such as gelsolin amyloidosis, which can present with neuropathy, ataxia, and dementia.²³

The limitation of this study was that in no patients was brain pathology obtained. However, in both sporadic and familial cases of NIID, it was reported that nuclear inclusions detected by skin biopsy are morphologically and immunohistochemically identical to those reported for NIID inclusions in neuronal cells.^3,4 Moreover, in cases of NIID diagnosed by both postmortem dissection and skin biopsy, the histopathologic features of the inclusions in the skin and central nervous system tissues were identical.⁵ We therefore think that the absence of postmortem cases of NIID does not limit the validity of our findings. On the other hand, as in our patients, a skin biopsy has been performed, with the abnormal findings on DWI as a trigger for most cases reported in recent years.⁵ The frequency of an abnormal signal along the corticomedullary junction on DWI may be overestimated in NIID.

Another limitation of our study is that the CGG repeat length of the FMR1 gene was not analyzed. In FXTAS, which is caused by permutation alleles of the FMR1 gene, eosinophilic ubiquitin–positive intranuclear inclusions, similar to those reported in NIID, were observed in neurons and glial cells.^24,25 However, whereas the core clinical features of FXTAS are progressive tremor and gait ataxia, the core clinical feature of adult-onset NIID in our patients was dementia.^5,26 There was no family history of symptoms or medical history that suggested FXTAS in any of our patients. In addition, in a study of 27 cases of NIID with the analyzed FMR1 gene, all cases showed a normal range of CGG repeats.⁵ The possibility that FXTAS was present among our patients thus seems to be extremely low.