Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease caused by GGC repeat expansion in the 5′ region of the notch 2 N‐terminal like C (NOTCH2NLC) gene. 1 NIID is characterized by eosinophilic hyaline intranuclear inclusions in the nervous system and visceral organs. 2 Although patients with NIID present with various manifestations, 2 subgroups with core symptoms have been reported: 1 with dementia and another with limb weakness attributed to peripheral neuropathy or myopathy. 2 Moreover, various types of movement disorders, including tremor or levodopa‐responsive parkinsonism, have been reported in patients with NIID. 2 , 3 , 4 , 5 However, insufficient information is available on deep brain stimulation (DBS) effects in such cases.
Herein we describe a case of NIID with intractable tremor that had significantly improved after thalamic DBS but showed subsequent cognitive decline.
Case Report
A 58‐year‐old Japanese woman with no family history of neurological diseases presented with a 5‐year history of bilateral hand tremor. On examination, she exhibited 3.0‐Hz right‐dominant intention and postural tremor affecting both distal upper extremities with worsening of large‐amplitude oscillations during target‐directed movements. Dystonia, ataxia, and parkinsonism were not noted. Neuropsychological screening revealed normal cognitive function. Fluid‐attenuated inversion recovery brain magnetic resonance imaging (MRI) showed lateral ventricle dilation, diffuse cerebral atrophy, and high‐intensity areas in the cerebral white matter (Fig. 1A). Diffusion‐weighted imaging showed high‐intensity signals in the corticomedullary junction (Fig. 1B). Skin biopsy and genetic analysis confirmed NIID diagnosis (Fig. 1D–H). Brain perfusion single‐photon computed emission tomography using technetium‐99 m‐L, L‐ethyl cysteinate dimer; dopamine transporter scintigraphy using 123I‐ioflupane, and 123I‐metaiodobenzylguanidine myocardial scintigraphy showed no specific findings.
FIG. 1.
(A) Fluid‐attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) on the first visit showing lateral ventricle dilation, diffuse cerebral atrophy, and high‐intensity areas in the cerebral white matter. (B) Diffusion‐weighted MRI on the first visit showing a high‐intensity signal in the corticomedullary junction. (C) Postoperative FLAIR MRI images showing implantation of deep brain stimulation (DBS) electrodes in the ventral medial intermediate nucleus (Vim) and progression of cerebral atrophy involving the cerebellum and pons. (D, E) Sweat gland tissue skin biopsy specimens and (F, G) adipose tissue skin biopsy specimens. Hematoxylin and eosin stains of sweat showing eosinophilic intranuclear inclusions in sweat gland cell (arrow; D) and adipose cells (arrows; F). Immunostaining indicating p62‐immunoreactive intranuclear inclusions in a sweat gland cell (E; arrow), fibroblasts (E; arrowheads), and adipocytes (G; arrows). (H) Repeat‐primed polymerase chain reaction assays. Electropherogram showing a saw‐tooth pattern, identifying a GGC repeat expansion in the notch 2 N‐terminal like C (NOTCH2NLC) gene. The repeat number of GGC repeat expansion was calculated using fluorescence amplicon length analysis to 130 and 9 repeats in the mutation and normal allele (data not shown; normal, 5–44 repeats). (I) Tremor electromyograms from the left upper limb recorded under Vim DBS OFF and ON. Coarse tremor appears under Vim DBS OFF when the patient lifts her left arm, but the tremor gradually diminishes after DBS ON and disappears 4 seconds later.
The patient's tremor developed proximally in the bilateral upper extremities accompanied by mild ataxic gait and was unresponsive to intensive drug therapies. Because the tremor interfered with activities of daily living (ADL), the patient required assistance. At the age of 61, DBS of the thalamic ventral medial intermediate nucleus (Vim) was performed using a quadripolar electrode, Activa SC37603 (Medtronic Inc., Minneapolis, MN). The tremor markedly decreased using monopolar stimulation (130 Hz, 60‐μs pulse width, and 4.5 and 4.0 V on the left and right Vim, respectively; Video 1), as shown in the surface electromyogram of the right arm (Fig. 1I). The total Fahn–Tolosa–Marin Clinical Rating Scale for Tremor score improved from 64/144 to 19/144 after DBS. Postoperative MRI confirmed DBS electrode implantation in the Vim and progression of cerebral atrophy involving the cerebellum and pons (Fig. 1C). The patient no longer required assistance with ADL. However, 4 months after DBS, the patient developed cognitive impairments including memory, orientation, attention, and executive function. Her neuropsychological scores worsened compared with those on the first visit: scores of the Mini‐Mental State Examination, Frontal Assessment Battery, and perseverative errors/nonperseverative errors/achievement categories assessed by the Wisconsin Card Sorting Test changed from 29 to 17 (preoperative evaluation: 28), 17 to 7, and 3/0/5 to 20/20/1, respectively. This patient is currently living in a nursing home and generally performing ADL independently.
VIDEO 1.
The video shows the state of the tremor with stimulation ON and OFF a month after surgery. Scene 1: the patient holds her left arm forward. A coarse postural tremor appears during ventral medial intermediate nucleus (Vim) deep brain stimulation (DBS) OFF and ameliorates during Vim DBS ON. Scene 2: the patient tries to draw a circle, but the manipulation is impossible because of coarse postural and action tremors during Vim DBS OFF. The tremor dramatically improves, and she can draw a circle during Vim DBS ON.
Discussion
The tremor features in this case were intention and postural; frequency <5 Hz, involvement of both distal and proximal upper extremities, and mild ataxic gait, cerebellar tremor characteristic, suggesting cerebellothalamic dysfunction. 6 , 7 Although essential tremor (ET) and parkinsonian tremor have been reported in patients with NIID, 5 cerebellar tremor has been rarely reported.
Regarding DBS for NIID, there has been 1 reported patient with juvenile levodopa‐responsive parkinsonism who underwent subthalamic nucleus stimulation and showed improvement in motor symptoms only during the first 2 weeks. 3 Our case is novel: Vim stimulation was performed and showed sustained effects on tremor.
Substantial cognitive decline after Vim DBS is rare in patients with idiopathic ET, although subtle decline can occur, particularly in verbal memory. 8 In contrast, there is virtually no knowledge of the impact of Vim DBS on cognitive function in patients with NIID. In our case, although cognitive declines might have been considered part of the natural course, they appeared shortly after surgery and might have been accelerated by DBS or surgical invasion into the fragile brain. Our experience suggests that indication for DBS would not be strongly recommended at this time, even in patients with NIID without overt cognitive impairment.
GGC repeat expansion in NOTCH2NLC has recently been implicated in various diseases, such as familial ET, multiple system atrophy, and Parkinson's disease, mainly in Asia. 5 The length of GGC expansion and type and frequency of interruption sequence in the GGC expansion may be related to these phenotypes. Therefore, the concept of NOTCH2NLC‐associated GGC repeat elongation disease (NRED) has been proposed as a comprehensive disease spectrum. 5 In China, GGC repeat expansion in NOTCH2NLC has been reported in patients with familial ET. Long‐term follow‐up did not reveal cognitive impairment or brain MRI abnormalities in many patients and showed pure ET presentation. However, some patients with ET developed the NIID phenotype. 4 , 5 , 9 , 10 Our case suggests that DBS impacts on cognitive function should be considered even in patients with the pure ET phenotype of NRED.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
K.F.:1A, 1B, 1C, 2A, 2B
T.H.: 1C, 2A, 2B
T.Y.: 1C, 2B
A.N.: 1A, 1B, 1C, 2B
K.O.: 1C, 2B
R.H.: 1A, 1C, 2B
J.S.: 1C, 2B
Y.T.: 1A, 1B, 2B
Disclosures
Ethical Compliance Statement: The authors confirm that the approval by an institutional review board was not required for this work. The patient and her daughter provided a written informed consent for the publication of the report and video. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest: This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant JP12345678) from the Japan Society for the Promotion of Science, Japan, and the MHLW Policy Planning and Evaluation for Rare and Intractable Diseases Program (Grants JPMH19189624 and JPMH21445246) from the Ministry of Public Health, Labour and Welfare, Japan. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.
Acknowledgments
We thank Dr. Hiroko Itagaki and Dr. Koh Nakazawa (both from the Department of Diagnostic Pathology, National Hospital Organization Matsumoto Medical Center) for the pathological evaluation of this case. We thank Dr. Fuyuko Arakura (Department of Dermatology, National Hospital Organization Matsumoto Medical Center) for performing the skin biopsy in this case. We express our gratitude to Dr. Chisato Tamai (Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University) for performing the genetic analysis in this case.
Relevant disclosures and conflicts of interest are listed at the end of this article.
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