崎山 快夫

Sanayama H, Namekawa M, Sakiyama Y, et al. (March 22, 2024) Herpes Zoster Ophthalmicus Initially Diagnosed As Cluster Headache, Complicated by Delayed Eruption. Cureus 16(3): e56698. doi:10.7759/cureus.56698

BACKGROUND: Fabry disease (FD) is an inherited lysosomal storage disease caused by deficiency of α-galactosidase A (α-Gal A) encoded by the GLA gene. The symptoms of FD occur as a result of the accumulation of globotriaosylceramide (Gb3), comprising a substrate of α-Gal A, in the organs. Adeno-associated virus (AAV)-mediated gene therapy is a promising treatment for FD. METHODS: α-Gal A knockout (GLAko) mice were injected intravenously with AAV2 (1 × 1011 viral genomes [vg]) or AAV9 (1 × 1011 or 2 × 1012 vg) vectors carrying human GLA (AAV-hGLA), and plasma, brain, heart, liver and kidney were tested for α-Gal A activity. The vector genome copy numbers (VGCNs) and Gb3 content in each organ were also examined. RESULTS: The plasma α-Gal A enzymatic activity was three-fold higher in the AAV9 2 × 1012 vg group than wild-type (WT) controls, which was maintained for up to 8 weeks after injection. In the AAV9 2 × 1012 vg group, the level of α-Gal A expression was high in the heart and liver, intermediate in the kidney, and low in the brain. VGCNs in the all organs of the AAV9 2 × 1012 vg group significantly increased compared to the phosphate-buffered-saline (PBS) group. Although Gb3 in the heart, liver and kidney of the AAV9 2 × 1012 vg was reduced compared to PBS group and AAV2 group, and the amount of Gb3 in the brain was not reduced. CONCLUSIONS: Systemic injection of AAV9-hGLA resulted in α-Gal A expression and Gb3 reduction in the organs of GLAko mice. To expect a higher expression of α-Gal A in the brain, the injection dosage, administration route and the timing of injection should be reconsidered.

Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher (p = 0.002) and the spermine/spermidine ratio was lower (p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression. Additionally, when the odds ratio was analyzed with spermine/spermidine instead of polyamine concentrations, only for spermine/spermidine, the odds ratio values varied in parallel with the progression of sarcopenia. Based on the present data, we believe that the blood spermine/spermidine ratio may be a diagnostic indicator of risk for sarcopenia.

Several mechanisms strictly regulate polyamine concentration, and blood polyamines are excreted in urine. This indicates polyamine accumulation in renal dysfunction, and studies have shown increased blood polyamine concentrations in patients with renal failure. Hemodialysis (HD) may compensate for polyamine excretion; however, little is known about polyamine excretion. We measured whole-blood polyamine levels in patients on HD and examined the relationship between polyamine concentrations and indicators associated with health status. Study participants were 59 hemodialysis patients (median age: 70.0 years) at Minami-Uonuma City Hospital and 26 healthy volunteers (median age: 44.5 years). Whole-blood spermidine levels were higher and spermine/spermidine ratio (SPM/SPD) was lower in hemodialysis patients. Hemodialysis showed SPD efflux into the dialysate; however, blood polyamine levels were not altered by hemodialysis and appeared to be minimally excreted. The skeletal muscle mass index (SMI), which was positively correlated with hand grip strength and serum albumin level, was positively correlated with SPM/SPD. Given that sarcopenia and low serum albumin levels are reported risk factors for poor prognosis in HD patients, whole blood SPM/SPD in hemodialysis patients may be a new indicator of the prognosis and health status of HD patients.

症例は25歳女性で、発熱、頭痛、めまい、左半身のしびれをきたし、当院に救急搬送された。20歳時に両側感音難聴を発症し、他院で突発性難聴と診断された。その後、右補聴器を使用していたが、難聴が進行したため24歳時に人工内耳植込術を施行され、術後経過は良好であった。若年発症で血管支配域に一致しない頭部CT低吸収域があり、脳卒中様発作を考え、低身長、両側感音難聴があることを併せてMELASを疑い加療を開始した。エダラボンを開始したが意識レベルの低下をきたし、第5病日に経鼻胃管を挿入し、L-アルギニン、タウリン、ユビデカレノン、レボカルニチンの4剤の経管投与を開始した。第10病日に撮影した頭部CT検査で後頭葉への低吸収域の拡大を確認し、浮腫の軽減効果を期待してグリセリンを投与、左半側空間無視、着衣失行は残存するが自立歩行可能となり、第41病日に自宅退院した。

小児の神経系疾患に対する治療の向上や社会的支援体制の整備に伴い,多くの神経系疾患患者が成人を迎えることが可能となった.そのため,小児から成人期までの生涯医療が必要になった.2020年7月に日本神経学会小児-成人移行医療対策特別委員会が発足し,小児-成人移行医療の現状と課題を検討した.小児神経科医と脳神経内科医の双方がより良い小児-成人移行医療を構築するための問題意識を持っていた.しかし,医療体制には改善すべき課題があることが認識された.日本神経学会と日本小児神経学会が協力し,小児-成人移行医療への理解の促進や診療報酬上の評価に向けた働き掛けに取り組む.(著者抄録)

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.

症例は49歳男性で、複視と右眼瞼下垂を自覚した。構音障害、下肢脱力、続いて嚥下障害が出現した。筋力低下は進行して歩行困難となり、緊急入院となった。重症筋無力症の悪化と考えピリドスチグミン、プレドニゾロン内服を開始した。筋力は改善傾向を呈し歩行も可能となったが、第7病日未明に脱衣し病棟を徘徊、聴取困難な1独語や意思疎通困難となる異常言動が出現した。次第に呼吸状態が悪化したため気管挿管しICU管理とした。重症筋無力症クリーゼとして単純血漿交換療法3日間、ステロイドパルス療法、ガンマグロブリン大量静注療法(IVIg)による治療を開始した。また発熱と発汗、流涎が顕著であったことから、セロトニン症候群が疑われ、並行してプロポフォールによる鎮静とシプロヘプタジン投与を開始した。複数の医療機関から多種・多剤の抗精神病薬を処方され薬物依存状態にあったことが判明した。治療継続により症状改善が得られ、第49病日に自宅退院とした。

症例は89歳女性。立位時の膝と体幹の震えを主訴に来院。表面筋電図で4Hzの下肢、体幹筋の振戦を認めた。Orthostatic tremorは13-18Hz程度であるが、本例では周波数が低く、Pseudo-orthostatic tremorの概念に当てはまると判断した。リズムジェネレーターの存在部位は小脳や視床、パーキンソン病の振戦のネットワークの一部、長い伸張反射ループを考えたが特定には至らなかった。アルツハイマー病が進行すると基底核障害を生じることがあるが、本例に合併したアルツハイマー病との関与は不明であった。クロナゼパムとガバペンチンが部分的に有効であった。(著者抄録)

Diagnosing clinical progressive supranuclear palsy (PSP) is challenging. We hypothesize that there are more cases of pathological PSP than have been clinically identified, but its diagnosis is challenging because the initial lesions and progression of PSP have not yet been clarified. The purpose of our study was to clarify the incidence of PSP in consecutive autopsy cases and identify pathological characteristics of early PSP. We investigated 324 consecutive autopsy patients from a general geriatric hospital (age, mean SD=82.5 +/- 8.7 years). Paraffin sections of the midbrain were immunostained with anti 4-repeat tau antibodies (RD4). We selected cases showing RD4-positive neurofibrillary tangles and tufted astrocytes in the midbrain sections. Then, we used anti-phosphorylated tau antibody to immunostain sections from the basal ganglia, subthalamic nucleus, midbrain, pons, medulla, and cerebellum. Of the 324 patients, 35 had RD4-positive structures in the midbrain. From these 35 cases, we excluded those for which autopsies confirmed definite PSP (n=5) and cases of corticobasal degeneration (n=1), Alzheimer's disease (n=11), dementia of grain (n=10), and neurofibrillary tangles predominant forms of senile dementia (n=2), leaving 8 cases. We diagnosed these 8 cases as pure PSP-type tauopathy. Pure PSP-type tauopathy was detected in 2.5% of the consecutive autopsy cases, and this incidence was 1.6 times greater than that of neuropathologically definite PSP. This pure PSP-type tauopathy likely indicates preclinical stages of PSP. Furthermore, the novel neuropathological finding, which we term "pre clinical PSP," is unique and has not previously been reported. In order to elucidate the causes and pathological mechanisms of PSP, preclinical PSP should be investigated further.

Diagnosing clinical progressive supranuclear palsy (PSP) is challenging. We hypothesize that there are more cases of pathological PSP than have been clinically identified, but its diagnosis is challenging because the initial lesions and progression of PSP have not yet been clarified. The purpose of our study was to clarify the incidence of PSP in consecutive autopsy cases and identify pathological characteristics of early PSP. We investigated 324 consecutive autopsy patients from a general geriatric hospital (age, mean SD=82.5 +/- 8.7 years). Paraffin sections of the midbrain were immunostained with anti 4-repeat tau antibodies (RD4). We selected cases showing RD4-positive neurofibrillary tangles and tufted astrocytes in the midbrain sections. Then, we used anti-phosphorylated tau antibody to immunostain sections from the basal ganglia, subthalamic nucleus, midbrain, pons, medulla, and cerebellum. Of the 324 patients, 35 had RD4-positive structures in the midbrain. From these 35 cases, we excluded those for which autopsies confirmed definite PSP (n=5) and cases of corticobasal degeneration (n=1), Alzheimer's disease (n=11), dementia of grain (n=10), and neurofibrillary tangles predominant forms of senile dementia (n=2), leaving 8 cases. We diagnosed these 8 cases as pure PSP-type tauopathy. Pure PSP-type tauopathy was detected in 2.5% of the consecutive autopsy cases, and this incidence was 1.6 times greater than that of neuropathologically definite PSP. This pure PSP-type tauopathy likely indicates preclinical stages of PSP. Furthermore, the novel neuropathological finding, which we term "pre clinical PSP," is unique and has not previously been reported. In order to elucidate the causes and pathological mechanisms of PSP, preclinical PSP should be investigated further.

59歳男。まぶしさや見え難さを自覚し、構音障害・ふらつきが加わり受診したが、頭部MRIに異常なく、陳旧性脳梗塞の影響と判断され、帰宅した。その後、車椅子移動となり、幻視や被害妄想が出現した。うつ病の診断で精神科に入院予定であったが、自力で動くことが困難となり、救急搬送された。入院時現症は、疎通性低下、体幹失調のため歩行困難であった。MRI拡散強調画像で大脳皮質の広範囲と両側尾状核・被殻に高信号を認め、脳波では周期性同期性放電、脳脊髄液14-3-3蛋白異常高値、プリオン蛋白遺伝子検査では遺伝子プリオンは否定的で、孤発性クロイツフェルト・ヤコブ病と診断した。経管栄養を導入し転院予定であったが、誤嚥性肺炎から非ケトン性高血糖性昏睡、多臓器不全を併発し、第43病日に死亡した。

症例は73歳女性、右利き。以前より軽度の記銘力低下があったが、生活は自立していた。既往に大動脈弁置換と心房細動があったが、ワーファリンを怠薬していた。ふらつきと視覚異常を主訴に来院した。上方水平半盲、色覚異常、体幹失調を認め、頭部MRIで両側後頭葉下部と左小脳虫部に梗塞像を認めた。保存的加療で体幹失調と色覚異常は改善した。第8病日よりリハビリテーション室で歩行訓練を開始したが、一人で帰室できなかった。高次脳機能評価で相貌失認を伴わない街並失認が示唆された。街並失認が改善するまでの外出時付き添いを家族に指導したところ、退院後6ヵ月で自宅付近では独歩可能となった。街並失認はベッドサイド診察で気付くのは困難であり、特に軽度記銘力低下例では見過ごされている可能性がある。右後頭葉病変を有する患者では積極的にその存在を疑い、適切な評価と助言を行うことが重要である。(著者抄録)

Diagnosing clinical progressive supranuclear palsy (PSP) is challenging. We hypothesize that there are more cases of pathological PSP than have been clinically identified, but its diagnosis is challenging because the initial lesions and progression of PSP have not yet been clarified. The purpose of our study was to clarify the incidence of PSP in consecutive autopsy cases and identify pathological characteristics of early PSP. We investigated 324 consecutive autopsy patients from a general geriatric hospital (age, mean±SD=82.5±8.7 years). Paraffin sections of the midbrain were immunostained with anti 4-repeat tau antibodies (RD4). We selected cases showing RD4-positive neurofibrillary tangles and tufted astrocytes in the midbrain sections. Then, we used anti-phosphorylated tau antibody to immunostain sections from the basal ganglia, subthalamic nucleus, midbrain, pons, medulla, and cerebellum. Of the 324 patients, 35 had RD4-positive structures in the midbrain. From these 35 cases, we excluded those for which autopsies confirmed definite PSP (n=5) and cases of corticobasal degeneration (n=1), Alzheimer's disease (n=11), dementia of grain (n=10), and neurofibrillary tangles predominant forms of senile dementia (n=2), leaving 8 cases. We diagnosed these 8 cases as pure PSP-type tauopathy. Pure PSP-type tauopathy was detected in 2.5% of the consecutive autopsy cases, and this incidence was 1.6 times greater than that of neuropathologically definite PSP. This pure PSP-type tauopathy likely indicates preclinical stages of PSP. Furthermore, the novel neuropathological finding, which we term "preclinical PSP," is unique and has not previously been reported. In order to elucidate the causes and pathological mechanisms of PSP, preclinical PSP should be investigated further.

Diagnosing clinical progressive supranuclear palsy (PSP) is challenging. We hypothesize that there are more cases of pathological PSP than have been clinically identified, but its diagnosis is challenging because the initial lesions and progression of PSP have not yet been clarified. The purpose of our study was to clarify the incidence of PSP in consecutive autopsy cases and identify pathological characteristics of early PSP. We investigated 324 consecutive autopsy patients from a general geriatric hospital (age, mean±SD=82.5±8.7 years). Paraffin sections of the midbrain were immunostained with anti 4-repeat tau antibodies (RD4). We selected cases showing RD4-positive neurofibrillary tangles and tufted astrocytes in the midbrain sections. Then, we used anti-phosphorylated tau antibody to immunostain sections from the basal ganglia, subthalamic nucleus, midbrain, pons, medulla, and cerebellum. Of the 324 patients, 35 had RD4-positive structures in the midbrain. From these 35 cases, we excluded those for which autopsies confirmed definite PSP (n=5) and cases of corticobasal degeneration (n=1), Alzheimer's disease (n=11), dementia of grain (n=10), and neurofibrillary tangles predominant forms of senile dementia (n=2), leaving 8 cases. We diagnosed these 8 cases as pure PSP-type tauopathy. Pure PSP-type tauopathy was detected in 2.5% of the consecutive autopsy cases, and this incidence was 1.6 times greater than that of neuropathologically definite PSP. This pure PSP-type tauopathy likely indicates preclinical stages of PSP. Furthermore, the novel neuropathological finding, which we term "preclinical PSP," is unique and has not previously been reported. In order to elucidate the causes and pathological mechanisms of PSP, preclinical PSP should be investigated further.

Diagnosing clinical progressive supranuclear palsy (PSP) is challenging. We hypothesize that there are more cases of pathological PSP than have been clinically identified, but its diagnosis is challenging because the initial lesions and progression of PSP have not yet been clarified. The purpose of our study was to clarify the incidence of PSP in consecutive autopsy cases and identify pathological

The patient was a 53-year-old male. He showed steppage gait at the age of 11 and equinus foot at 13. He walked unaided with shoe-insoles to support his heels. Atrial fibrillation and cardiac hypertrophy were found in his 30s, and ventricular tachycardia (VT) was observed at the age of 48. Electrophysiological studies were performed, but VT was not sustained, symptomatic, or showed signs of infra-Hisian block, and a pacemaker was not indicated. At 53, he was introduced to a neurologist because of tetraplegia after the first episode of syncope. A spinal MR showed ossification of posterior longitudinal ligament (OPLL) and central cervical cord injury. Furthermore, he presented not only contracture in his shoulder, elbow, and ankles but also atrophy in his scapulohumeral and gastrocnemius muscles. In accordance with a diagnosis of Emery-Dreifuss muscular dystrophy (EDMD), provocative testing of VT was carried out, and a cardiac resynchronization therapy defibrillator (CRT-D) was implanted. Later, a mutation analysis of the LMNA gene disclosed a known missense mutation of p.Arg377His, and we diagnosed him as EDMD2 (laminopathy). Contractures could be the clue to diagnose EDMD and indicate the need for pacemakers and defibrillators in patients with cardiac conduction disorders.

Clinical phenotype of individuals with spinocerebellar ataxia 2 (SCA2) is characterised by cerebellar ataxia and cognitive impairment. Although L-dopa-responsive Parkinsonism is considered as a rare clinical presentation in SCA2, it has been brought to the attention of many neurologists in several studies. The authors report an autopsy case of SCA2 with Parkinsonism from a Japanese family using archival materials of our Brain Bank to describe unique neuropathologic findings. The individual clinically showed Parkinsonism as a predominant phenotype instead of cerebellar ataxia. Besides the classic SCA2 neuropathologic alterations, Lewy bodies and Lewy neurites were present in the brainstem nuclei. Genetic analysis revealed shorter abnormal expansion of CAG repeats (less than 39). In contrast, the authors could not find α-synuclein pathology in two SCA2 cases without Parkinsonism. The present case will provide a neuropathologic evidence of correlation between α-synucleinopathy and Parkinsonism of SCA2 as well as shed light on understanding the pathomechanism of Parkinsonism in SCA2. Copyright 2011 BMJ Publishing Group. All rights reserved.

This is the first autopsy case of SCA2 with parkinsonian phenotype. At the age of 46, the patient got symptoms of parkinsonism to which anti-parkinsonian drugs were effective. He had mosaic 38, 40 CAG repeat expansions on chromosome 12q23-24. being diagnosed as SCA2, and his mother and his son also had CAG expansions on the same locus. In addition to parkinsonism, he also exhibited autonomic disturbance, dementia, and mild cerebellar ataxia. Brain images revealed severe atrophy of pons and medulla oblongata, resembling MSA-C. HVA and 5-HIAA were reduced in the cerebrospinal fluid, and the heart-mediastinum (H/M) ratio in myocardial 123I-MIBG cintigram was decreased, which suggested Lewy body pathology. He died at the age of 75 and the autopsy revealed atrophy of the olivo-ponto-cerebellar (OPC) system and substantia nigra which was compatible to SCA2, although the OPC system atrophy was less severe than formerly reported SCA2 cases. The degrees of atrophy of the OPC system and substantia nigra might explain the predominancy of clinical symptoms. Anti-lC2 positive inclusions in the pontine nuclei, inferior olive nuclei, cerebellum and substantia nigra confirmed a polyglutamine disease. In addition, there were the anti-phosphorylated α-synuclein positive. Lewy body related pathological changes in the substantia nigra, the locus ceruleus, the dorsal motor nuclei of vagus, and the sympathetic nerve in the myocardium. Major genetic abnormalities related to Parkinson disease were not detected. As another case of SCA2 with Lewy body pathology was reported in Japan, the coexistence of SCA2 and Lewy body pathology may not be accidental. Since myocardial MIBG scincigram can predict Lewy body pathology, we should seek more clinical cases of SCA2 with Lewy body pathology.

We investigated the incidence and extent of Lewy body (LB)-related alpha-synucleinopathy (LBAS) in the olfactory bulb (OB) in 320 consecutive autopsy patients from a general geriatric hospital (mean aged 81.5 +/- 8.5 years). Paraffin sections were immunostained with anti-phosphorylated alpha-synuclein, tyrosine hydroxylase, phosphorylated tau, and amyloid beta antibodies. LBAS was found in 102 patients (31.9%) in the central nervous system, including the spinal cord; the OB was involved in 85 (26.6%). Among these 85 patients, 2 had LBAS only in the anterior olfactory nucleus, 14 in the peripheral OB only, and 69 in both areas. In 5 patients, Lewy bodies were found only in the OB by hematoxylin and eosin stain;, 3 of these patients had Alzheimer disease, and all had LBAS. Very few tyrosine hydroxylase-immunoreactive periglomerular cells exhibited LBAS. All 35 LBAS patients with pigmentation loss in the substantia nigra had LBAS in the OB. LBAS in the amygdala was more strongly correlated with LBAS in the anterior olfactory nucleus than with that in the OB periphery. LBAS did not correlate with systemic tauopathy or amyloid beta amyloidosis. These results indicate a high incidence of LBAS in the aging human OB; they also suggest that LBAS extends from the periphery to the anterior olfactory nucleus and results in clinical manifestations of LB disease.