NOTCH2NLC mutation-positive neuronal intranuclear inclusion disease with retinal dystrophy: A case report and literature review.

INTRODUCTION: Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that produces a broad spectrum of clinical conditions such as dementia, upper motor neuron involvement, extrapyramidal symptoms, and neuropathy. Some studies have reported ophthalmological conditions associated with the disease; however, the details of these conditions remain unclear. PATIENT CONCERNS: We report a 63-year-old Japanese female with cognitive decline, blurred vision, photophobia, and color blindness at 52 years of age who was diagnosed with cone dystrophy. She also had anxiety, insomnia, depression, delusions, hallucinations, a wide-based gait with short steps, and urinary incontinence. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Magnetic resonance imaging revealed diffuse cerebral white matter changes and subcortical hyperintensity on diffusion-weighted imaging. Skin biopsy showed p62-positive intranuclear inclusions in sweat glands. NOTCH2NLC gene analysis revealed abnormal GGC expansion; therefore, NIID was diagnosed. CONCLUSION: NOTCH2NLC mutation-positive NIID may be associated with retinal dystrophy. Brain magnetic resonance imaging and skin biopsy are helpful diagnostic clues, and gene analysis is crucial for accurate diagnosis and appropriate management.

[A case of neurolymphomatosis that was diagnosed by acoustic nerve biopsy].

A 58-year-old female was admitted to our hospital because of recurrent multiple cranial neuropathy (right facial palsy followed by involvement of the left trigeminal, facial, acoustic, pharyngeal, and vagal nerves and the right abducens nerve). Brain MRI showed gadolinium enhancement of the right abducens, bilateral facial/acoustic, and left pharyngeal/vagal nerves, and 18F-Fluorodeoxyglucose (FDG)-positron emission tomography revealed abnormal FDG uptake in the right facial, acoustic, pharyngeal, and vagal nerves and the left cervical lymph nodes. Blood and biochemical analyses did not show any abnormalities, including in the patient's lactate dehydrogenase and soluble interleukin-2 receptor (sIL2R) levels. A cerebrospinal fluid (CSF) examination showed gradual increases in the patient's cell counts and protein, ß2-microglobulin, and sIL2R levels, but no malignant cells were detected. A thorough investigation involving repeated CSF examinations, whole-body computed tomography, bone marrow aspiration, random skin biopsies, and cervical lymph node aspiration biopsy examinations did not result in any definitive conclusions. Steroid therapy was ineffective, and the patient developed deafness in her left ear. Therefore, we performed a biopsy examination of the left acoustic nerve, which resulted in the patient being diagnosed with diffuse large B-cell lymphoma. High-dose MTX following the intrathecal administration of MTX, cytarabine, and prednisolone partially improved her symptoms, but she died after several episodes of clinical recurrence. Acoustic nerve biopsy may help diagnose neurolymphomatosis in carefully selected cases.

Biopsy-proven case of Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system.

A 75-year-old woman was admitted to our hospital with rapidly deteriorating consciousness disturbance. She had a 7-year history of rheumatoid arthritis (RA), which had been treated with methotrexate (MTX) and prednisolone. Brain T2-weighted MRI showed diffuse high-intensity lesions in the cerebral subcortical and deep white matter, bilateral basal ganglia and thalamus. A cerebrospinal fluid examination revealed elevated protein levels and positive Epstein-Barr virus (EBV) DNA. Human immunodeficiency virus was negative. Brain biopsy showed perivascular lymphocytic infiltration in the parenchyma and meninx with EBV-encoded small RNA (EBER). Since this case did not fulfill the criteria for chronic active EBV infection (CAEBV), she was diagnosed with Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system. High-dose methylprednisolone, acyclovir, ganciclovir and foscarnet were not effective. Although EBV is a causative agent of infectious mononucleosis (IM), lymphomas and nasopharyngeal carcinomas, vasculitic pathology of the central nervous system with EBV reactivation in the elderly is rare. Immunosuppressive drugs such as steroids and MTX are widely used to treat autoimmune disorders, but may exacerbate the reactivation of EBV. This is the first case of biopsy-proven EBV-positive/HIV-negative vasculitis during the treatment of RA with MTX and steroids. This case indicates that EBV-associated vasculitis needs to be considered as a differential diagnosis of CNS vasculitis.

A Sporadic Case of Fabry Disease Involving Repeated Fever, Psychiatric Symptoms, Headache, and Ischemic Stroke in an Adult Japanese Woman.

Fabry disease can cause various neurological manifestations. We describe the case of a Japanese woman with Fabry disease who presented with ischemic stroke, aseptic meningitis, and psychiatric symptoms. The patient had a mutation in intron 4 of her α-galactosidase A gene, which was not detected in her family. This case suggests that Fabry disease should be considered in young patients who exhibit central nervous system symptoms such as ischemic stroke, even if there is no family history of the condition. The episodes of aseptic meningitis and stroke experienced by our patient suggest that persistent inflammation might be the mechanism underlying Fabry disease.

Non-vitamin k antagonist oral anticoagulants do not increase cerebral microbleeds.

BACKGROUND: Atrial fibrillation (AF) is a cardiac arrhythmia that frequently induces ischemic strokes. Nowadays, non-vitamin K antagonist oral anticoagulants (NOACs) have come into widespread use for cardiogenic embolism prevention in place of warfarin. Recently, cerebral microbleeds (CMBs) have been noticed for their potential implication in cerebral small vessel disease. We hypothesized that NOACs do not have an unfavorable influence over cerebral small vessels and investigated whether NOACs increase CMBs in AF patients in a prospective manner. METHODS: We performed baseline magnetic resonance imaging (MRI) examinations on the 69 enrolled AF patients and re-examined second round of MRI 1 year later. The enrolled patients continued the same anticoagulation therapy during the meantime. RESULTS: CMBs did not develop in the 23 patients with NOACs for 1 year. Nine patients with antiplatelets also did not develop CMBs. On the other hand, 3 of 21 patients continued on warfarin and 3 of 9 with warfarin and antiplatelets had CMBs. When divided into 2 groups according to whether the CMBs developed, significant differences in the incidence of using NOACs were observed between the 2 groups (P = .02). A multivariate regression analysis showed that warfarin was independently related to the new development of CMBs (hazard ratio, 10.75; 95% confidence interval, 1.22-94.99; P = .03). CONCLUSIONS: This is the first report to clarify that NOACs do not increase CMBs in AF patients longitudinally in 1 year. Further consideration will be continued with a much longer follow-up in large samples.

Combination therapy for segmental craniocervical dystonia (Meige syndrome) with aripiprazole, trihexyphenidyl, and botulinum toxin: three cases reports.

Segmental craniocervical dystonia is characterized by blephalospasm and oromandibular dystonia and is also called Meige syndrome. The current treatment strategy including botulinum toxin (BTX) injections has not yet attained an acceptable level. We describe a long-term favorable response of a novel combination therapy with aripiprazole (ARP), trihexyphenidyl (THP), and BTX in three patients with segmental craniocervical dystonia. The symptoms of three patients responded promptly to the combination therapy with ARP 3-6 mg daily, THP 2-8 mg daily, and BTX. Although the patients were required to receive a BTX 50-100 IU injection every 3-6 months, their symptoms were kept in a satisfactory condition for up to 2 years without any adverse effects. ARP possesses the potential for dramatically improving dystonia. THP has the possibility to enhance the efficacy of ARP and prolong the effective period of BTX. It may be an important requisite to give all three agents together for a successful treatment. The combination therapy with ARP, THP, and BTX was well-tolerated and useful in controlling the symptoms of segmental craniocervical dystonia, however, the reason why this combination therapy succeeded is unknown. A further long-term follow-up is required to monitor the delayed neurological adverse effects.

A case of pathology-proven neuromyelitis optica spectrum disorder with Sjögren syndrome manifesting aphasia and apraxia due to a localized cerebral white matter lesion.

A woman with Sjögren syndrome manifesting as aphasia with a left deep cerebral white matter lesion tested positive for anti-aquaporin 4 (AQP4) antibody. Open biopsy of the lesion revealed active demyelination with edematous changes and the preservation of most axons, indicating a non-necrotic demyelinating lesion. Immunostaining for AQP4 was diffusely lost, whereas the loss of glial fibrillary acidic protein immunostaining was limited but with highly degenerated astrocytic foot processes in perivascular areas. These results suggested neuromyelitis optica spectrum disorder (NMOSD) pathology rather than Sjögren-related vasculitis. Only cerebral cortical symptoms with a cerebral white matter lesion could be observed in NMOSDs.

Cerebral microbleeds and asymptomatic cerebral infarctions in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a cardiac arrhythmia that does not infrequently induce ischemic strokes; however, little research has been reported on focal cerebral microangiopathic lesions in patients with AF. Recently cerebral microbleeds (CMBs) have been noticed for their potential implication in cerebral small vessel disease. Therefore, we had 2 goals in the present study: (1) to compare the prevalence of CMBs in patients with AF with that in patients without AF, and (2) to prove that CMBs could be a clinical predictive factor for the development of future cerebral microangiopathy in patients with AF without a history of symptomatic cerebral infarction in a prospective manner. METHODS: We performed yearly brain magnetic resonance imaging (MRI) assessments for a maximum of 5 years in 131 patients with AF and 112 control patients. Seventy-seven patients with AF underwent more than 3 yearly MRI scans. RESULTS: The Kaplan-Meier curve showed that the development of an asymptomatic cerebral infarction (ACI) was associated with the baseline presence of a CMB (P=.004). A multivariate Cox regression analysis revealed that the CMBs at baseline were significantly associated with an increment in not only the occurrence of ACIs (hazard ratio [HR], 5.414; 95% confidence interval [CI], 1.03-28.43; P=.046) but also in the consecutive development of CMBs (HR, 6.274; 95% CI, 1.43-27.56; P=.015). CONCLUSIONS: Patients with AF had a significantly higher prevalence of CMBs. The presence of CMBs in the baseline MRI may predict the consequent onset of an ACI and increase in CMBs in patients with AF.

[A case of myasthenia gravis following sarcoidosis and rheumatoid arthritis].

We report an elderly woman with sarcoidosis and rheumatoid arthritis who subsequently developed myasthenia gravis. She was given a diagnose of rheumatoid arthritis at the age of 65 years and sarcoidosis, proved by multiple lymphadenopathy with noncaseating granuloma at the age of 67. Prednisolone, methotrexate, and etanercept had been administrated for rheumatoid arthritis. She consulted our hospital because of bilateral ptosis with diurnal fluctuation at the age of 72. Myasthenia gravis was confirmed by an elevated serum anti-acetylcholine receptor antibody titer (1,100 nmol/l, normal <0.2) and a positive edrophonium test. A chest CT showed a small granular structure in the anterior mediastinum, suggesting thymic hyperplasia. This is the first reported case of myasthenia gravis complicated by sarcoidosis and rheumatoid arthritis. Administration of etanercept may be involved in the onset of myasthenia gravis.