Neuronal intranuclear inclusion disease ... - Wiley Online Library

doi:10.1111/ncn3.12016

CASE REPORT

Neuronal intranuclear inclusion disease manifesting with new-onset epilepsy in the elderly Tomoko Toyota,1 Zhe Huang,1 Souhei Nohara,1 Kazumasa Okada,1 Shingo Kakeda,2 Yukunori Korogi,2 Toshiyuki Nakayama,3 Jun Sone,4 Gen Sobue4 and Hiroaki Adachi1 1

Department of Neurology, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Fukuoka, 2 Departments of Radiology, 3 Pathology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, and 4Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan

Key words adult form, epilepsy, intranuclear inclusions, neuronal intranuclear inclusion disease, skin biopsy. Accepted for publication 14 June 2015. Correspondence Hiroaki Adachi Department of Neurology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. Email: [email protected]

Abstract We report the case of a 72-year-old woman with a first epileptic seizure at the age of 70 years. Neuronal intranuclear inclusion disease was subsequently diagnosed based on characteristic magnetic resonance imaging findings and intranuclear inclusions on skin biopsy histology. Neuronal intranuclear inclusion disease is a rare neurodegenerative disease with a diverse range of clinical manifestations, including epilepsy. It is categorized into three categories: infantile, juvenile and adult forms. Epileptic seizure is the third most common neurological disorder in the elderly after stroke and dementia. To our knowledge, this is the first case of a patient presenting with epileptic seizures as a manifestation of the adult form of neuronal intranuclear inclusion disease. We further showed intranuclear inclusions in keratinocytes by skin biopsy histology. We report neuronal intranuclear inclusion disease as a cause of new-onset epilepsy in the elderly.

Introduction Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder with a diverse range of clinical manifestations, including pyramidal and extrapyramidal symptoms, cerebellar ataxia, dementia, epileptic seizure, neuropathy, and autonomic dysfunction. Fujigasaki proposed classifying NIID into three categories based on age at onset: infantile, juvenile and adult forms.1 Epileptic seizures in both infantile and juvenile forms, but rarely in the adult form, have been previously reported.1–4 We report the case of a patient with the adult form of NIID presenting with epilepsy.

Case report A 70-year-old Japanese woman with medication-controlled atrial fibrillation lost consciousness while walking alone, suffering a bleeding jaw wound and abrasions involving the whole body. The patient remained confused over the next hour. She had no family history of neurological disease. She attended the Department of Cardiology at the University of Occupational Health School of Medicine, Kitakyusyhu where syncope was excluded based on medical history and long-term recorded electrocardiography. She was then referred to the Department of Neurology. Her first interictal electroencephalogram showed a right mid-temporal spike (Fig. 1a), and treatment with levetiracetam (250 mg/day)

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was initiated. Her second electroencephalogram showed sharp waves in the left central electrodes, and levetiracetam dosing was increased to 500 mg/day. She arbitrarily ceased attending our institution and the use of levetiracetam at 3 months after the initial epileptic episode. Two years later, she lost her consciousness again. A neighbor witnessed her fall and called an ambulance. The patient was subsequently unable to clearly recall the ambulance ride. She was referred to the Neurology Department at our hospital 10 days later, and levetiracetam 500 mg/day was restarted. Neurological examination revealed an action tremor affecting the upper limbs and mild frontal cognitive impairment with decreased Frontal Assessment Battery score (13/18). Snout reflex, forced grasping, cerebellar ataxia, sensory disturbance and autonomic dysfunction were not observed. Her Mini-Mental State Examination score was normal (29/30). Brain magnetic resonance imaging showed a hyperintense corticomedullary junction on diffusionweighted imaging (Fig. 1b) and diffuse leukoaraiosis on T2weighted imaging/fluid-attenuated inversion recovery (Fig. 1c). Cerebrospinal fluid examination showed a normal cell count (2/lL) and slightly elevated protein concentration (49.4 mg/dL). Interictal electroencephalogram showed left frontal and central spikes (Fig. 1d). Nerve conduction studies showed mildly delayed sensory conduction velocity in bilateral sural nerves. A 5-mm diameter punch biopsy specimen of the thigh was obtained and fixed in 10% formalin.

Neurology and Clinical Neuroscience 3 (2015) 238–240 ª 2015 Japanese Society of Neurology and Wiley Publishing Asia Pty Ltd

T Toyota et al.

NIID with epilepsy in the elderly

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T Toyota et al.

NIID with epilepsy in the elderly

Figure 1 Interictal electroencephalography and magnetic resolution imaging findings. (a) Initial interictal electroencephalography showed a right mid-temporal spike. (b) Diffusion-weighted imaging showed the high intensity of the corticomedullary junction. (c) Fluid-attenuated inversion recovery imaging showed diffuse leukoaraiosis. (d) A left central sharp wave was detected in the third record. (e–g) Pathological sections at skin biopsy. Immunohistochemical analysis with the anti-ubiquitin antibody (1:5000) using the diaminobenzidine (DAB) technique showed intranuclear inclusions in the (e) keratinocytes, (f) sweat gland cells and (f) fibroblasts. The inset shows a magnified image in the square box. Arrows and insets indicate intranuclear inclusions. Bar (e), 20 lm; (f,g) 10 lm.

Immunohistochemical analysis was carried out (anti-ubiquitin antibody; Santa Cruz, Dallas, TX, USA). Nuclear inclusions (NI) were identified in keratinocytes, sweat gland cells and fibroblasts using a BZ-X700 system (Keyence, Osaka, Japan; Fig. 1e–g). NIID was diagnosed according to skin biopsy pathology and characteristic magnetic resonance imaging findings. There were no neurological findings suggestive of other diseases with NI.

Discussion This is the first report of a case of the adult form of NIID presenting as epilepsy. All previously reported cases presenting with seizures involved infantile or juvenile forms.1–4 Although non-lesional epilepsy is the most frequent new-onset epilepsy in the elderly, NIID should be considered as a differential diagnosis.5 NIID is conventionally diagnosed by post-mortem histopathological findings characterized by eosinophilic hyaline NI in neuronal and visceral organ cells. Recently, NIID can be diagnosed by characteristic magnetic resonance imaging findings and skin biopsy, showing the presence of NI in adipocytes, fibroblasts and sweat gland cells.6,7 In the present case, NI were also detected in keratinocytes, although its diagnostic significance was not determined. Autopsy findings from patients with triplet repeat diseases and Unverricht–Lundborg disease,8 the most common form of progressive myoclonic epilepsy, included the presence of ubiquitin-positive NI; however, the prevalence of epilepsy varies widely in patients affected by these diseases. Accumulating evidence suggests oligomeric forms of mutant proteins, not NI, are the major pathogenic species, suggesting the abnormal nuclear accumulation of aggregate-prone proteins is a major manifestation of epilepsy pathogenesis.9 Elucidating NI components could enhance our understanding of epilepsy pathophysiology.

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Acknowledgments The authors declare no conflict of interest.

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