Takayuki Katayama

TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2

Both the appearance of cytoplasmic inclusions containing phosphorylated TAR DNA-binding protein (TDP-43) and inefficient RNA editing at the GluR2 Q/R site are molecular abnormalities observed specifically in motor neurons of patients with sporadic amyotrophic lateral sclerosis (ALS). The purpose of this study is to determine whether a link exists between these two specific molecular changes in ALS spinal motor neurons. We immunohistochemically examined the expression of adenosine deaminase acting on RNA 2 (ADAR2), the enzyme that specifically catalyzes GluR2 Q/R site-editing, and the expression of phosphorylated and non-phosphorylated TDP-43 in the spinal motor neurons of patients with sporadic ALS. We found that all motor neurons were ADAR2-positive in the control cases, whereas more than half of them were ADAR2-negative in the ALS cases. All ADAR2-negative neurons had cytoplasmic inclusions that were immunoreactive to phosphorylated TDP-43, but lacked non-phosphorylated TDP-43 in the nucleus. Our results suggest a molecular link between reduced ADAR2 activity and TDP-43 pathology.

Anti–N-methyl-D-aspartate Receptor Encephalitis During Pregnancy

OBJECTIVE To report 3 patients who developed anti-N-methyl-d-aspartate receptor encephalitis during pregnancy. DESIGN Case reports. SETTING University hospitals. Patients Three young women developed at 14, 8, and 17 weeks of gestation acute change of behavior, prominent psychiatric symptoms, progressive decrease of consciousness, seizures, dyskinesias, and autonomic dysfunction. MAIN OUTCOME MEASURES Clinical, radiological, and immunological findings. RESULTS The 3 patients had cerebrospinal fluid pleocytosis, normal magnetic resonance imaging, and electroencephalogram showing slow activity. All had higher antibody titers in cerebrospinal fluid than in serum and 2 had ovarian teratomas that were removed. The pregnancy was terminated in 1 patient with recurrent bilateral teratomas. All patients had substantial neurological recoveries, and the 2 newborns were normal. Results of extensive antibody testing in 1 of the babies were negative. CONCLUSION The current study shows that anti-NMDAR encephalitis during pregnancy can have a good outcome for the mother and newborn.

Prevalence of multiple sclerosis in Asahikawa, a city in northern Japan

Twenty-two years after the first survey, a follow-up study was performed on the prevalence of multiple sclerosis (MS) in Asahikawa, a city in northern Japan. The crude prevalence of MS rose from 2.5/100,000 (in 1975) to 10.2/100,000 (in 2002). The clinical diagnosis was established using the Poser diagnostic criteria, and the degree of physical disability was determined using the Expanded Disability Status Scale (EDSS). The distribution of patients according to the clinical form of MS was 65% with relapsing-remitting MS, 19% with secondary chronic progressive MS and 16% with the primary chronic progressive forms of MS. Symptoms at onset in the present study less often affected optic nerves (3%) than previously reported in Japan and was more like that seen in western MS series. Although prevalence of MS increase four-fold in Japan over the last two decades, it remains uncertain whether this apparent increase is real or reflects better ascertainment.

Nineteen CAG repeats of the SCA6 gene in a Japanese patient presenting with ataxia.

Sirs: Spinocerebellar ataxia type 6 (SCA6), an autosomal dominant neurodegenerative disease characterized by slowly progressive cerebellar ataxia, has been shown to be due to expansion of the number of CAG repeats in the human α1A voltagedependent calcium channel subunit gene on chromosome 19p13 [11]. The increases in the CAG repetitions within the SCA6 gene are small and close to those of normal subjects. According to previous reports, the pathological range of CAG repeats in the SCA6 gene is 20 or more, and the normal range is 18 or less [1, 2, 4–10]. Interestingly, four individuals who were 70–75 years of age with 19 CAG repeats of SCA6 gene have been reported as neurologically normal [3]. We present a 50-year-old patient with 19/7 CAG repeats of the SCA6 gene who showed ataxia. He began to stagger and slur his words at the age of 48 years. Before that time he had no history of vertigo or episodic ataxia. Subsequently he developed progressive gait disturbance, dysarthria, dysuria, constipation, and impotence. Two years later he was admitted to our hospital. His pulse was 76 and blood pressure 136/86 mmHg. He did not show orthostatic hypotension, and the blood pressure response to standing was normal. Neurological examination revealed slurred speech, moderate ataxia of limbs and trunk, bilateral hyperreflexia in the lower extremities, and bilateral Babinski sign. Muscular strength and sensory modalities were normal. He has no family history of neurological illness. Routine laboratory tests were normal except for hypercholesterolemia and hypertriglyceridemia. Magnetic resonance imaging of the brain showed slight atrophy of the cerebellar vermis and hemispheres and a few lacunar infarcts in the basal ganglia and pons (Fig. 1). We concluded that the ataxia was due to cerebellar degeneration rather than the lacunae in the pons because of the progression of the ataxia and the size of the pontine lesions. Blood samples were obtained from the patient with informed consent. Gene analysis was performed by a modification of the method originally reported [11]. The primers used to amplify the CAG repeat region were: 5′-CAC GTG TCC TAT TCC CCT GTG ATC C–3′ and 5′TGG GTA CCT CCG AGG GCC GCT GGT G–3′. Polymerase chain reaction (PCR) was performed in a total volume of 50 μl, containing 100 ng genomic DNA, 15 pmol each primer, 10 mM Tris-HCl (pH 8.8), 50 mM KCl, 1.5 mM MgCl, 0.1% Triton X–100, 0.2 mM dNTP, and 1.25 U Taq DNA polymerase. The amplification procedure consisted of an initial denaturation at 96°C for 3 min, followed by 35 cycles of denaturation at 96°C for 1 min, annealing at 62°C for 1 min, and extension at 72°C for 1 min in a thermal cycler. The sample was electrophoresed through 4% agarose gel. The sizes of the PCR products were determined by comparing them to a ladder marker. We detected an expanded allele in the SCA6 gene (Fig. 2). To determine the CAG repeat length in the SCA6 gene the PCR products were purified from the gels and sequenced using an automated DNA sequencer (Applied Biosystems, ABI Prism 310 Genetic Analyzer). Direct sequencing revealed 19/7 CAG repeats in the gene. To exclude other forms of hereditary cerebellar ataxia we performed additional gene analysis for SCA1, SCA2, SCA3, SCA7, SCA8, and dentatorubral pallidoluysian atrophy. No abnormally expanded alleles for these genes were detected. Unfortunately, gene analysis could not be performed for his family members. The pathological range of CAG repeats in the SCA6 gene has been reported to be 20 or more [1, 2, 4–10]. In these reports 20 CAG LETTER TO THE EDITORS

A case of spinocerebellar ataxia type 6 mimicking olivopontocerebellar atrophy

Abstract Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant, slowly progressive cerebellar ataxia without multisystem involvement. We report a 57-year-old woman with genetically confirmed SCA6 who showed clinical features of olivopontocerebellar atrophy. Conventional T2-weighted and FLAIR MRI demonstrated high signal in the middle cerebellar peduncles, in addition to mild atrophy of the pons and cerebellum.

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.

Lesion of the Nucleus Intercalatus in Primary Position Upbeat Nystagmus

Primary position upbeat nystagmus (PPUN) is an upward vertical nystagmus that is rarely observed in brainstem disorders. The lesion responsible for PPUN was considered to be in either the ventral tegmental tract in pons or caudal medulla. To date, PPUN has been reported in 3 cases with medullary lesions. The lesion in our case was localized in the overlapped region described in 2 articles by Munro et al and Hirose et al. The lesion in our case was confined to an extremely small area of part of the most dorsal medulla, and its location corresponded to the location of the nucleus intercalatus according to several microscopic anatomical charts. The lesion in the present case was located in a more dorsal portion of the medulla than those described by Munro et al and Hirose et al. Therefore, our case seems to be the most convincing evidence to date that a lesion of the intercalatus nucleus is a candidate for PPUN. Janssen et al also described a case with PPUN. His lesion existed in the dorsal paramedial caudal medulla, which encompassed the nucleus intercalatus. PierrotDeseilligny and Milea illustrated the neural circuit and explained why a lesion in the posterior caudal medulla produces primary position upbeat nystagmus (Figure 2). When the nucleus intercalatus is invaded, the superior rectus responds with impaired functioning and, eventually, the eyeball continually moves downward. Consequently, upbeat nystagmus appears. To confirm the lesion in the medulla responsible for PPUN, accumulation of similar cases is needed. Accepted for Publication: February 9, 2010. Correspondence: Dr Saito, Division of Neurology, Department of Internal Medicine, Asahikawa Medical College, Asahikawa, Hokkaido 078-8510, Japan (tsukasa @asahikawa-med.ac.jp). Author Contributions: Study concept and design: Saito, Aizawa, and Hasebe. Acquisition of data: Saito and Sawada. Analysis and interpretation of data: Saito, Aizawa, and Katayama. Drafting of the manuscript: Saito. Critical revision of the manuscript for important intellectual content: Saito, Aizawa, Sawada, Katayama, and Hasebe. Administrative, technical, or material support: Katayama. Study supervision: Aizawa, Katayama, and Hasebe. Financial Disclosure: None reported. Online-onlyMaterial:A video is available at http://www.archneurol.com.

Cortical silent period in the tongue induced by transcranial magnetic stimulation

Cortical silent period (SP) of the limb muscles is thought to reflect the cortical excitability. However, the lingual SP has not been examined precisely even in normal subjects. We investigated SP in the tongue induced by transcranial magnetic stimulation (TMS) in 18 controls. Surface electrodes were placed on the lingual dorsum using a bipolar technique. A round coil (13.5 cm in outer diameter) connected with Magstim 200 stimulator was placed on the motor cortex of the tongue, and the intensity of the stimulation was increased stepwise to maximum. SP was detected in all subjects especially at the contralateral side to the stimulated side, without contamination of peripheral SP. The duration of SP depended on the stimulus intensity, while the degrees of muscle contraction did not influence SP. SP of the tongue showed similar characteristics to that of limb muscles. This suggests that SP of lingual muscles can be clinically useful for the evaluation of corticobulbar excitability.

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 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.