Early detection of familial Creutzfeldt-Jakob disease on diffusion-weighted imaging before symptom onset.

Familial Creutzfeldt-Jakob disease (CJD) with V180I shows different clinical characteristics from classical CJD and is difficult to diagnose in the early stage. We report a CJD180 patient in whom results of diffusion-weighted imaging (DWI) led us to suspect CJD before symptoms started. A 68-year-old woman presented to our hospital with headache and nausea and underwent magnetic resonance imaging. DWI showed cortical hyperintensity. Three months later, cognitive function started to decline and CJD180 was diagnosed following genetic examination. In the early stage, ADC values were not decreased and single positron emission computed tomography demonstrated a decreased pattern like Alzheimer disease.


Voltage-gated potassium channel complex antibodies in Creutzfeldt-Jakob disease.


Efficacy of zolpidem for dystonia: a study among different subtypes

Although there are some newly developed options to treat dystonia, its medical treatment is not always satisfactory. Zolpidem, an imidazopyridine agonist with a high affinity on benzodiazepine subtype receptor BZ1 (ω1), was found to improve clinical symptoms of dystonia in a limited number of case reports. To investigate what subtype of dystonia is responsive to the therapy, we conducted an open label study to assess the efficacy of zolpidem (5-20 mg) in 34 patients suffering from miscellaneous types of dystonia using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). Patients were entered into the study if they had been refractory to other medications as evaluated by BFMDRS (no change in the previous two successive visits). After zolpidem therapy, the scores in the patients as a whole were decreased from 7.2 ± 7.9 to 5.5 ± 5.0 (P = 0.042). Patients with generalized dystonia, Meige syndrome/blepharospasm, and hand dystonia improved in the scale by 27.8, 17.8, and 31.0%, respectively, whereas no improvement was found in cervical dystonia patients. Overall response rate among patients were comparable to that of trihexyphenidyl. Zolpidem may be a therapeutic option for generalized dystonia, Meige syndrome, and hand dystonia including musician's. Drowsiness was the dose-limiting factor.


Parkin interacts with Klokin1 for mitochondrial import and maintenance of membrane potential

Parkin is a multifunctional protein, including maintaining mitochondrial homeostasis. Recent evidence suggests that Parkin is recruited from the cytoplasm to damaged mitochondria with low membrane potential. We found that intracellular localization of Parkin changed with cellular growth phase. Parkin was preferentially localized in the mitochondria of cultured cells. The mitochondria with large amounts of Parkin showed preserved membrane potentials even during treatment with carbonyl cyanide m-chlorophenylhydrazone. Here we report a novel protein named Klokin 1 that transports Parkin to the mitochondria. Klokin 1 was localized to the mitochondria and enhanced mitochondrial expression of Parkin. Klokin 1 enhanced cell viability in Parkin-silenced cells. Klokin 1 expression was enhanced in the brains of Parkin-deficient mice but not in an autopsied PARK2 brain. Our findings indicate that mitochondrial Parkin prevents mitochondrial depolarization and that Klokin 1 may compensate for Parkin deficiency.


Nuclear factor B expression in patients with sporadic amyotrophic lateral sclerosis and hereditary amyotrophic lateral sclerosis with optineurin mutations

Nuclear factor κ B (NF-κB) is involved in the pathogenesis of a number of neurodegenerative disorders with neuroinflammation. In order to clarify the role of NF-κB in ALS, immunohistochemical studies with an antibody that recognizes the p65 subunit of NF-κB were performed on the spinal anterior horn of 4 patients with sporadic ALS (sALS), 1 patient with optineurin-mutated ALS (OPTN-ALS), and 3 normal controls (NC). In patients with sALS or OPTN-ALS, the expression pattern of NF-κB was altered when compared to that of NC; NF-κB immunoreactivity tended to be absent from neuronal nucleus and was increased in microglia. The down-regulation of NF-κB in neuronal nucleus might contribute to a loss of neuroprotection, or neurons with nuclear NF-κB might be lost immediately after its activation. The microglial induction of NF-κB might contribute to neuroinflammation. In conclusion, NF-κB signaling pathway could have a key role in the pathomechanism of ALS.


行政的な「高次脳機能障害」の診断

Diagnostic criteria of the administrative higher brain dysfunction are defined. Young people between the period of entering school and starting work occasionally suffer from brain damage. Although the patient may seem to recover, memory and attention disturbances may continue. As a result, higher brain dysfunction may interfere with return to school, and reinstatement is difficult.Patients diagnosed with higher brain dysfunction by these diagnostic criteria can continue rehabilitation and achieve functional restoration. In the Tokushima University Hospital, many patients with cerebrovascular disease, brain tumor, or traffic injury(in that order)consulted about higher brain dysfunction.


A case of enlargement of the right atrium associated with myositis detected by muscle ultrasonography

筋エコーにより筋炎の関与が判明した右房拡張症の一例

A 45-year-old woman was admitted to the hospital because of general malaise since 2005. She have not remarkable disease in the past history. In the family history, one of her older sister died of ulcerative colitis, another one suffers from systemic lupus erythematosis, and her older brother affected of Behçet's disease. On electrocardiogram examination, atrial fibrillation was revealed associated with remarkable dilation of the right atrium in echocardiogram, but any abnormal finding is not seen both ventricles. The ultrasonographic findings of the biceps brachi showed remarkable myopathic pattern. A biopsy specimen obtained from the biceps brachi, these muscles revealed degeneration and necrosis of muscle fibers, interstitial infiltration with monocytes, and perivascular infiltrates of inflammatory cells. In the magnetic resonance imaging of the heart showed, not only remarkable dilatation of right atria, but also diffuse high intensity areas in left ventricle under T2-intensified conditions. We diagnosed generalized myositis involved with myocarditis, and treated with steroid. One year later, she still takes steroid, and her symptoms improvement continuously.If one of cardiac atrium or ventricle enlarged, there is possibility of the cardiac myositis or systemic myositis. In these cases, skeletal muscle ultrasonography may be non-invasive and useful method of differential diagnosis.

症例は45歳女性で，全身倦怠感を主訴にした．42歳時に動悸症状を自覚し，44歳時に全身倦怠感を強く自覚し，近医の心電図で心房細動を指摘された．聴診では心雑音や過剰心音はなく，肺音は清，頸動脈雑音を認めなかった．頸部，四肢近位部にごく軽度の筋力低下を認め，Gowers徴候は明らかでなかった．24時間心電図検査で頻発する発作性心房細動を認め，モニター心電図で最大約7秒の洞停止を確認した．心エコーでは右房の著明な拡張，左房の軽度拡張を認めた．三尖弁に軽度逆流を認めたが，逆流の程度からは右房拡張の直接原因とは考え難かった．僧帽弁に異常は認めず，左室収縮能は保たれていた．膠原病関連疾患としての筋炎，サルコイドーシスなどの鑑別目的に筋エコー検査を施行した．特発性右房拡張症中に，全身性筋炎を伴う心筋炎を原因とした一群の存在の可能性があり，スクリーニング検査として，筋エコー検査は侵襲性が少なく，簡便で，またペースメーカー導入後も使用でき有用であった．


Temporal evolution of sporadic Creutzfeldt-Jakob disease monitored by 3-Tesla MR spectroscopy.


Incidence and clinical correlation of intracranial hemorrhages observed by 3-tesla gradient echo T2*-weighted images following intravenous thrombolysis with recombinant tissue plasminogen activator

The purpose of this study was to determine the incidence and clinical correlation of intracranial hemorrhages (ICHs) detected by 3-tesla gradient echo T(2)*-weighted images after intravenous recombinant tissue plasminogen activator (rt-PA) administration. We included 43 consecutive patients with anterior-circulation ischemia who underwent MRI studies before and after thrombolysis. Each hemorrhage was classified as a hemorrhagic infarction (HI) or parenchymal hemorrhage (PH) according to the European Cooperative Acute Stroke Study definition. The clinical outcome was defined as an improvement (> or =4-point reduction) or deterioration (> or =4-point increase) based on a comparison between the initial and the 30-day NIHSS scores. The incidence of ICHs was 58%, and the HI rate was 52%; both were higher than the rates reported in the literature. Most of the patients with HI improved clinically, and these patients had second MRAs that showed recanalization. None of the patients with PH demonstrated improvement. Three-tesla MRI may reveal a higher frequency of HI type hemorrhages than lower-field MRIs, and HI may be a predictor of good recovery by reflecting the presence of recanalization. The rate of PH in our study was low compared to other studies, probably due to the lower dosage of rt-PA.


Neurological manifestations in hereditary hemorrhagic telangiectasia type 1: a familial case in Japan


脳死様状態を呈した劇症型GBSの症例を救命しえた．GBSの中に，急性に脳死様状態を呈し，α昏睡をきたす劇症型GBSの一群の存在が示唆された．脳死様状態を呈する劇症型GBSでは死亡症例も多く，厳重な全身管理が必要である．(著者抄録)


A case of cryptococcal meningitis successfully treated with liposomal amphotericin-B, Fulcytosine, and Voriconazole

クリプトコッカス性髄膜炎の59歳男性症例について検討した．発熱と頭痛を主訴とし，風邪と診断さたが，嘔吐，意識障害，歩行困難の症状が出現し，発症から16日目に入院となった．入院時に意識障害と強い傾眠傾向が認められた．右眼の対光反射が鈍く，瞳孔径の左右差が認められた．顕著な頸部硬直も認められた．ウイルス関連抗原抗体は陰性であった．脳脊髄液はキサントクロミーを呈しており，脳脊髄液圧，脳脊髄液中の細胞数と蛋白濃度の上昇，脳脊髄液中の糖濃度低下が認められた．May-Giemsa染色および墨汁染色では莢膜を有する菌体が多数確認された．Cryptococcus抗原の256倍上昇が示された．頭部のガドリニウム造影MRI検査で脳溝に沿った造影像を認めた．クリプトコッカス性髄膜炎と診断し，liposomal amphotericin-Bおよびfulcytosineによる2剤療法を開始した．臨床検査結果および脳脊髄液検査結果は徐々に改善したが，入院45日目に左顔面麻痺が出現した．MRI検査から新しい病変が確認され，造影MRI検査で造影病変の拡大を認めた．Voriconazole追加による3剤療法を開始した．脳脊髄液検査結果および臨床症状の改善を示し，入院180日目に退院となった．左顔面麻痺も徐々に改善した．


Diagnosis and Treatment in Stroke Center of Tokushima University Hospital : Efficacy of 3 Tesla Stroke MRI(<Topic> Stroke Care Unit, Stroke Center)

徳島大学病院stroke centerでの脳卒中医療の現状 -特にstroke MRIの有用性-

After the stroke care unit of Tokushima University hospital was established in November 1999, stroke MRI (diffusion-, perfusion-weighted image, MRA) was performed to initially evaluate stroke patients, except for SAH. Since April 2004, 3 tesla MRI has been used for stroke MRI, and T2^* weighted image was added to routine study of stroke MRI. 3 tesla stroke MRI can reduce examination time and also take functional MR images, which yield important information for diagnosis and treatment decisions. The combination of our stroke center and rehabilitation hospital is a key factor in improving patients' outcomes for acute rehabilitation and improving quality of life.


3 Tesla T2^*-weighted MRI demonstrating an intra-MCA embolus in a young adult with cerebral embolism

3 Tesla T2 *強調MRIで中大脳動脈内塞栓子を呈した若年性脳塞栓症の1例


健常者に発症し治療に難渋したクリプトコッカス髄膜脳炎の1例

健常者に発症し治療に難渋したクリプトコッカス髄膜脳炎の1例


A single nucleotide polymorphism of dopamine transporter gene is associated with Parkinson's disease.

We identified two polymorphisms out of all coding regions of the dopamine transporter gene. One existed in exon 9 (1215A/G) and another in exon 15 (1898T/C). The 1215G was significantly less frequent among patients with Parkinson's disease than the controls. Although the polymorphism caused no amino acid substitution, we concluded that it was associated with decreasing the susceptibility to Parkinson's disease through mechanisms other than the protein function of dopamine transporter.


Japanese Journal of Geriatric Psychiatry


筋萎縮性側索硬化症の病態解明・治療法開発への試み

筋萎縮性側索硬化症の病態解明・治療法開発への試み

I graduated from Tokushima University in 1995 and trained at Hiroshima University and Sumitomo Hospital. In2000, Professor Ryuji Kaji was appointed as the first professor of the Department of Neurology, Tokushima University. In 2001, I graduated from Hiroshima University Graduate School and returned to Tokushima University. At the Department of Neurology, Tokushima University, we have been investigating natural history, neurophysiology including neuromuscular sonology, MRI, liquid biomarkers, genes, neuropathology, iPS cells, and new treatments as research on amyotrophic lateral sclerosis(ALS)(Tokushima ALS Research). We have examined the effect of methylcobalamin on ALS as a new therapeutic candidate. A phase Ⅲ study, Japanese Early-stage Trial of ultra-high dose methylcobalamin for ALS(JETALS), was carried out. Patients with ALS diagnosed within1year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after12‐week observation were eligible for randomization :1- or 2-point decrease in ALS Functional Rating Scale Revised (ALSFRS-R)total score, a percent forced vital capacity over 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulant. Methylcobalamin 50 mg or placebo was intramuscularly injected twice weekly for 16 weeks. The primary endpoint was change in ALSFRS-R total score from baseline to week 16. As a result, the least-squares mean difference in ALSFRS-R total score at week 16 of the randomized period was 1．97 points greater with methylcobalamin than placebo. The incidence of adverse events was similar between the two groups. In the future, we plan to work on elucidating the pathophysiology of ALS, developing more powerful treatments for ALS, and dealing with non-motor symptoms of ALS.


【ALS 2019】メコバラミン

【ALS 2019】メコバラミン


CIDPにおける頸部脊髄神経根内のHiS sign

CIDPにおける頸部脊髄神経根内のHiS sign


進行性に増悪をきたし血管内治療を施行した右内頸動脈閉塞の1例

進行性に増悪をきたし血管内治療を施行した右内頸動脈閉塞の1例


Utility of recovery cycle with two conditioning pulses for detection of impaired axonal slow potassium current in ALS.

Slow potassium current (I(Ks)) is important in controlling nerve excitability and its impairment is known in various neurological diseases, including amyotrophic lateral sclerosis (ALS). I(Ks) gives rise to the late subexcitability phase of the recovery cycle, which can be amplified by the use of multiple conditioning pulses. The clinical utility of this technique has not previously been explored.


「徳島治験ネットワーク」における治験の共同実施について 国際共同治験実施の現状

「徳島治験ネットワーク」における治験の共同実施について 国際共同治験実施の現状


Usefulness of skeletal muscle ultrasound as a screening test for sarcopenia in patients with rheumatoid arthritis

International Journal of Rheumatic Diseases


On-period unified Parkinson's disease rating scale before surgery correlates with differences in outcomes between pallidal and subthalamic stimulation: a meta-analysis.


Lack of C9orf72 expansion in 406 sporadic and familial cases of idiopathic dystonia in Japan.


DYT6 in Japan-genetic screening and clinical characteristics of the patients.


A new CSF1R mutation presenting with an extensive white matter lesion mimicking primary progressive multiple sclerosis.

HDLS (Hereditary Diffuse Leukodystrophy with Spheroids) is a hereditary leukodystrophy whose main clinical manifestations include parkinsonism, spasticity, and ataxia. Genetic defects in the colony-stimulating factor 1 receptor (CSF1R) gene have been reported in many HDLS cases. The present report describes a new missense mutation Arg777Gln involving exon 18 of the CSF1R gene in a sporadic patient presenting with tumor-like lesions mimicking primary progressive multiple sclerosis. The patient was initially diagnosed with a progressive variant of multiple sclerosis and received inadequate treatments. Although most HDLS cases have a positive family history, this disease should also be suspected in sporadic patients showing unusual white matter lesions at MRI.


精神発育遅滞を伴う家族性小脳変性症の臨床遺伝学的研究の具体的事例

精神発育遅滞を伴う家族性小脳変性症の臨床遺伝学的研究の具体的事例


Brainstem and spinal cord motor neuron involvement with optineurin inclusions in proximal-dominant hereditary motor and sensory neuropathy

Journal of Neurology, Neurosurgery, and Psychiatry


Mutations of optineurin in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) has its onset in middle age and is a progressive disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord. Most cases of ALS are sporadic, but about 10% are familial. Genes known to cause classic familial ALS (FALS) are superoxide dismutase 1 (SOD1), ANG encoding angiogenin, TARDP encoding transactive response (TAR) DNA-binding protein TDP-43 (ref. 4) and fused in sarcoma/translated in liposarcoma (FUS, also known as TLS). However, these genetic defects occur in only about 20-30% of cases of FALS, and most genes causing FALS are unknown. Here we show that there are mutations in the gene encoding optineurin (OPTN), earlier reported to be a causative gene of primary open-angle glaucoma (POAG), in patients with ALS. We found three types of mutation of OPTN: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Analysis of cell transfection showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B (NF-kappaB), and the E478G mutation revealed a cytoplasmic distribution different from that of the wild type or a POAG mutation. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also noticeably immunolabelled by anti-OPTN antibodies. Our findings strongly suggest that OPTN is involved in the pathogenesis of ALS. They also indicate that NF-kappaB inhibitors could be used to treat ALS and that transgenic mice bearing various mutations of OPTN will be relevant in developing new drugs for this disorder.