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筋萎縮性側索硬化症(amyotrophic lateral sclerosis;ALS)の診断は,厚生労働省の診断基準に基づいて臨床症候,電気生理学的所見,病理学的所見などを基に総合的に判定して得られる.近年では,頭部核磁気共鳴画像(magnetic resonance imaging;MRI)上,内包後脚を中心として錐体路に一致して出現するT2高信号域が異常所見として報告されている.一方,筋MRIにおける筋内信号強度の上昇は,炎症および浮腫性変化を反映していると考えられている.非典型的なALSでは臨床症候と検査所見からだけでは他の疾患との鑑別が困難なこともあるため,今回我々は,ALS患者の下腿筋MRIについて検討した.対象は,ALS患者10例で男性7例,女性3例からなり,平均年齢は,68.6±11.2歳(49～87歳)である.発病初期より球症状が顕著な症例が1例,筋力低下が上肢に強い症例が3例,下肢に強い症例が6例あった.9例に下腿筋MRI,10例に針筋電図と末梢神経伝導検査を施行した.発病初期の筋力低下が下肢に強い6例の筋MRI・T2強調画像において筋内信号強度の上昇を認めた.それに対して筋力低下が上肢に強い症例や球症状の顕著な症例では,筋MRIの筋内信号強度は正常であった.また,筋内信号が上昇していた6例のうち5例における腓骨神経電気刺激で,複合筋活動電位の著明な振幅低下を認めた.ALS患者における筋MRI・T2強調画像の信号強度上昇は,脱神経後の浮腫性変化を反映していると考えられるため,ALS患者の病期判定や他疾患との鑑別が困難な場合の補助検査のひとつとして筋MRIは有用である., Various objective measurements can be used to diagnose amyotrophic lateral sclerosis (ALS). T2-weighted brain MRI images revealed high signal areas at the posterior limb of the internal capsules in ALS patients. Recently, muscle MRI proved useful to evaluate abnormalities of the muscle in myositis patients. Therefore, in the present study, we examined muscle MRI of leg muscles in ALS patients, and correlated MRI with functional measurements, such as muscle strength, and compound muscle action potential amplitude of the tibialis anterior (TA) after stimulation of the peroneal nerve. The subjects consisted of 10 ALS patients (7 males and 3 females), ranging in age from 49 to 87. Neurologic symptoms at the onset of ALS consisted of bulbar dysfunction in one patient, upper extremity involvement in three patients, and lower extremity involvement in six patients. Muscle MRI of the legs was performed in 9 (ALS patients. A peripheral nerve conduction study was performed on the peroneal nerve, with the recording electrode over the TA. The T2-weighted muscle MRI images revealed high signal aeras in the muscle in six ALS patients, whose muscle weakness existed predominantly in the lower extremities. Extracellular fluid accumulation has been proposed to be responsible for the signal increase of denervated muscles on T2-weighted muscle MRI images. We assume that muscle MRI is useful to demonstrate the distribution of muscle involvement in ALS patients and to assess the disease's stage.

筋生検・ミトコンドリアDNA遺伝子診断などによりMELASと診断され,脳卒中様発作を繰り返し,頭部MRIで病変が確認された成人MELAS5症例に,少量のジクロロ酢酸を含むLiverall^を投与し,脳卒中様発作を抑制できるか臨床経過を検討した.内服開始後は,全例で頭部MRI画像上病変を認める脳卒中様発作は生じなかった.従来小児科領域で報告されていた必要量よりも少量で発作を抑制できる可能性があると考えられた.しかし,血清中の乳酸・ピルビン酸は異常値を示す場合もあり,痙攣発作やイレウスなどの合併症状を呈する症例も2例あり,今後の検討が必要と考えられた.本論文の要旨は,第44回日本神経学会総会(横浜,2003年5月)において発表した., In five adult patients with MELAS, we evaluated clinical symptoms, FLAIR and DWI brain MRI, and serum level of lactate and pyruvic acid, to assess whether stroke-like episodes in MELAS are suppressed by small dose of dichloroacetate. After beginning oral therapy of Liverall^ for MELAS, none of the five cases showed any occurrence of the stroke-like episodes associated with brain MRI lesions. We noticed that the stroke-like episodes were suppressed by using a smaller dose of dichloroacetate, compared with the dose required for therapy of pediatric patients with MELAS. In spite of favorable effect of Liverall^ for MELAS in symptomatic and MRI evaluations, the serum level of lactate and pyruvic acid continued to show abnormal values and convulsive seizures or ileus occurred in a few cases. Further investigations are required to know whether Liverall^ is a useful therapeutic drug.

1970年代以降,静岡,山梨両県の富士川流域にCreutzfeldt-Jakob病(CJD)が多いことは知られていたが,筆者らは同地域に位置する共立蒲原総合病院で1999年の1年間に3例のCJD患者を経験したことから,静岡,山梨両県の36施設に対し,1990年から1999年の10年間にわたるCJD患者についてのアンケート調査を行なった.36施設中26施設から文献例を含む合計34例のCJD患者が確認された.症例は男性16例,女性18例で,平均発症年齢は62.5±10.7歳であった.遺伝子変異が10/34例(29.4%)にみられ,全例がcodon 200の変異(CJD^)であり,そのうち2家系に家族内発症を認めた.臨床所見では高率にミオクローヌス(95.7%)と脳波上の周期性同期性放電(periodic synchronous discharge,PSD)(95.7%)を認め,従来の孤発例やCJD^の特徴と一致していた.過去10年間では富士川中流地区に,1999年の1年間では下流地区に,それぞれCJD患者の有為な集積が確認された(ボアソン分析でpの10例のうち8例が富士川流域(7例が中流～下流地区)の出身であったことから,同地区がCJD^の主たる集積地区と考えられた.また周辺の静岡市から三島市にかけても症例(CJD^2例を含む)が散見され,同地区まで含めた範囲をCJD関連地域として注目すべきと考えた., An epidemiological study of Creutzfeldt-Jakob disease (CJD) was carried out during the period between 1990 and 1999. A total of 34 cases with CJD was collected from the information provided by neurologists, psychiatrists, and neurosurgeons in Shizuoka and Yamanashi Prefecture. There was no significant difference between males and females. The average age of onset was 62.5 years, with high occurrence seen in patients in their fifties, sixties, and seventies. The mean duration of CJD was 7.3 months. There were no cases with a cadaveric dural graft. There were two families with CJD patients having codon 200 mutations. Myoclonus occurred in 95.7% of cases and there were electroencephalographic (EEG) tracings with periodic synchronous discharges (PSD) in 95.7% of the cases. Ten patients had a mutation at codon 200 of prion protein gene (CJD^) . In the middle reaches of the Fuji River basin (Yamanashi Prefecture), the retrospective incidence of CJD between 1990 and 1999 was 5.77 cases/million/annum; highly significant clustering (p = 0.01) was confirmed in this area. The point prevalence rate in 1999 at the lower reaches of the Fuji River (eastern part of Shizuoka Prefecture) was 9.78 cases/million/annum. These results demonstrated significant clusters of CJD patients at the middle and lower reaches of the Fuji River. The incidence of CJD^ appeared to be much higher in these areas than other areas in Japan.

Nuclear aggregates of enhanced green fluorescent protein and nuclear localization signal-fused truncated N-terminal huntingtin containing 150 repeats of glutamine residue were purified from ecdysine-inducible mutant neuro2A cell line by sequential extraction of nuclear soluble proteins. To analyze the aggregate-interacting proteins, we subjected the nuclear aggregates to high performance liquid chromatography–mass spectrometry analysis. The resulting data revealed the presence of three new putative aggregate-interacting proteins: ubiquilin 1, ubiquilin 2 and Tollip. These proteins also associated with neuronal intranuclear inclusions in a mouse model of Huntington disease (HD). These aggregate-interacting proteins contain ubiquitin-interacting motifs, suggesting that they are recruited to the aggregates where they may lose their normal function.

To study the human brain activity correlated with illusory perception, we chose a physically flat plane figure which looks like a convex figure. We studied visual evoked potential (VEP) changes, which reflect perceptual properties of illusory perception. We defined two paradigms, an illusory paradigm (IP) and a control paradigm (CP). Two stimuli, A and B, were randomly presented in the IP, while stimuli C and D were randomly presented in the CP. Stimulus A was the only figure which looked like a convex figure. A three-way analysis of variance was applied to the VEP components in each paradigm, with three factors: figures, electrodes, and sessions. Different configuration patterns between the two paradigms explained different grand mean VEP waveforms between the two paradigms; a greater N1 for the CP, a greater P1 for the IP, and marked attenuation of the N3 and P3 components for the IP. Significant main effects of figures only for the IP were found on P1 and P1N2 amplitude and P2 latency, which are assumed to reflect perceptual properties of stereoscopical illusory perception.

Vertical eye deviation in hypoxic coma is considered to be rare. In contrast, we found that in a consecutive series of 50 postresuscitation comatose patients, 28 (56.0%) developed tonic upward or downward eye deviation. We suggest that both the upward and the downward deviations resulted from diffuse cerebrocerebellar damage sparing the brainstem. Upward deviation is an early sign, whereas downward deviation appears later and generally implies a transition to the vegetative state.

Neuronal progenitor cells (NPCs) may provide dopaminergic neurons for the treatment of Parkinson's disease (PD). However, transplantation of NPCs into the striatum by current methods has had limited success. It is possible to reverse the symptoms of PD in model rats but difficult to reverse them in humans because the number of dopaminergic neurons generated from NPCs is low. We transduced the von Hippel-Lindau (VHL) gene into NPCs isolated from embryonic rat brain. The NPCs with the transduced VHL gene efficiently differentiated into tyrosine hydroxylase-positive neurons in vitro. NPCs with the transduced VHL gene, which were labeled in advance with bromodeoxyuridine, were transplanted into the striatum of a rat model of PD. Numerous bromodeoxyuridine-tyrosine hydroxylase double-labeled cells were seen close to the transplant site, showing that the transplanted cells efficiently generated new dopaminergic neurons within the host striatum. Moreover, all of the animals with NPCs with VHL showed a remarkable decrease in apomorphine-induced rotations. These findings show that NPCs with the VHL gene can efficiently generate dopaminergic neurons and that a sufficient number of dopaminergic neurons can develop from them to reverse the symptoms of PD in humans. VHL gene transduction provides a new therapeutic approach for treatment of PD.

A 37-year-old man developed an acute encephalitic condition after respiratory infection. His condition rapidly deteriorated, and he experienced ophthalmoplegia, tetraplegia, loss of brainstem reflexes and deep tendon reflexes, and deep coma. Electrophysiological evaluations indicated involvement of the peripheral nerve as well as the brainstem. Follow-up studies found acute progression of peripheral nerve damage. Serum anti-GQ1b IgG antibody was present. The initial condition was diagnosed as Bickerstaff's brainstem encephalitis, and subsequent overlapping of Guillain-Barré syndrome probably was responsible for the clinical deterioration. When unusual worsening is observed in clinically suspected encephalitis, neurologists must take into account the possibility of associated Guillain-Barré syndrome and related disorders.

After an episode of vasodilator-induced systemic hypotension, a 75-year-old man developed ocular lateropulsion to the right, left-side-dominant quadriparesis, loss of superficial sensation below C4 dermatome level, and anuresis. Magnetic resonance imaging (MRI) showed infarcts in the right cerebellar hemisphere (posterior inferior cerebellar artery territory) and the upper cervical cord (anterior spinal artery territory); the combination of posterior inferior cerebellar artery (PICA) and anterior spinal artery (ASA) infarcts has not been reported previously. Angiography revealed severe stenosis in the bilateral vertebral arteries. Hemodynamic hypoperfusion of the stenotic vertebral arteries may cause this unusual combination.

In amyotrophic lateral sclerosis (ALS) patients, dysphagia eventually occurs independent of time of onset. We studied dysphagia conditions in the early stage of ALS, principally at the oral phase. Videofluoroscopic and manometric studies were conducted on 11 patients (5 males and 6 females, age range = 47-82 years) who were diagnosed at our Neurology Clinic as having ALS. All patients were able to ingest orally. Swallowing scores on the ALS severity scale were from 10 to 5. In the oral phase of swallowing, abnormal movements of the anterior and/or posterior tongue were recognized in 8 cases. Dysphagia severity tended to be particularly influenced by dysfunction of the posterior tongue. Manometric studies were almost normal in all cases except one. These results suggested that the early stage of dysphagia in ALS was mainly caused by oral dysfunction, and the oral phase disorders began in some cases with a decreased function of bolus transport at the anterior part of the tongue, and in other cases with a deteriorated function of holding the bolus at the posterior part of the tongue. In conclusion, the tongue function of holding the bolus in the oral cavity mainly affects the severity of the early stage of dysphagia in ALS.

We investigated the visual event-related potentials (ERPs) in two subtypes of multisystem atrophy (MSA) in 15 MSA-C patients, 12 MSA-P patients, and 21 normal control (NC) subjects. We used a visual oddball task to elicit ERPs. No significant changes were seen in N1 or N2 latency, in either MSA-C or MSA-P, compared with the NC group. An early stage of visual information process related to N1 and a visual discrimination process related to N2 might be preserved in both MSA-C and MSA-P. The P3a peak was more frequently undetectable in MSA than in the NC group. Significant P3a amplitude reduction in both MSA-C and MSA-P suggests impairment of the automatic cognitive processing in both MSA-C and MSA-P. Significant difference was found in P3b latency and P3b amplitude only in MSA-C, compared with the NC group. The result suggests the impairment of the controlled cognitive processing after the visual discrimination process in the MSA-C group. We further investigated the correlation between visual ERP changes and magnetic resonance imaging (MRI) data. Quantitative MRI measurements showed reduced size of the pons, cerebellum, perisylvian cerebral area, and deep cerebral gray matter in both MSA-C and MSA-P, and of the corpus callosum only in MSA-P, as compared to NC group. In both MSA-C and MSA-P, P3b latency was significantly correlated with the size on MRI of the pons and the cerebellum. P3b latency in the whole MSA group was also significantly correlated with the size of the pons and the cerebellum. These results indicate that P3b latency changes in parallel with the volume of the pons and the cerebellum in both MSA-C and MSA-P.

Visual event-related potentials (ERPs) during oddball paradigms with button pressing, silent counting and movement imagery tasks were recorded in right-handed subjects from 32 scalp electrodes. By incorporating the knowledge deduced from the task relevance of the P300 into equivalent current dipole source localization (ECDL), stable multiple ECD solutions with goodness-of-fit (GOF) of more than 90% and confidence limits (CLs) of less than 1 mm were estimated for all the three target P300s. The obtained frontal dipoles were discussed in terms of visual working memory, sustained attention and higher motor control in reference to the previous PET, fMRI and MEG studies. The distributed multiple ECDs may suggest that P300 should be interpreted as being the embodiment of the cortico-limbic-thalamic network accomplishing various cognitive functions.

Visual event-related potentials during an oddball paradigm with movement imagery tasks were recorded in 10 right-handed subjects from 32 scalp electrodes. Rare targets and non-targets elicited early (P3e) and late (P31) P300 components. In the P3e there was no difference between the rare target and non-target. In the right-imagery task the rare target P31 amplitude was larger than the rare non-target one, whereas the rare non-target P31 amplitude was larger than the rare target one in the left-imagery task. Some of the 4 equivalent current dipole (ECD) sources were located at the subcortical regions, the cerebellum and the cingulate cortex, common to the P3e and the P31. Moreover, another P3e dipole was localized to the parietal regions, while that of the P31 dipoles to the contralateral premotor cortex. This difference between the P3e and P31 dipoles might reflect two different neural networks related with the transformation of coordinates from visual to motor space.

The electroencephalographic finding of periodic synchronous discharges (PSDs) is a basic clue for the diagnosis of Creutzfeldt-Jacob disease (CJD). We proposed grading of PSDs. We defined grade A as typical PSDs, grade B as PSDs of relatively longer periodic intervals, grade C as PSDs of relatively rare appearance, grade D as PSDs of rudimentary appearance, and grade E as absent PSDs. The occurrence rate of PSDs in Japanese CJD surveillance was 62% in total CJD (490/794), 72% in sporadic CJD (441/610), 24% in genetic CJD (41/171), and 61% in dura CJD patients (8/13). Among 171 genetic CJD patients, the occurrence rate of PSDs was 0% in P105L mutation CJD (0/2), 3% in V180I mutation CJD (3/90), 14% in P102L mutation CJD (4/29), 70% in E200K mutation CJD (16/23), and 71% in M232R mutation CJD patients (17/24). The occurrence rate of MRI changes in both cortical and basal ganglia was significantly higher in the s-CJD group with PSDs than in the s-CJD group without PSDs. The occurrence rate of PSDs in non-CJD patients who needed differential diagnosis of CJD was 10% (37/355). Non-CJD diseases associated with PSDs were status epilepticus, diffuse Lewy disease, Hashimoto encephalopathy, Wernicke encephalopathy and uremic encephalopathy.

Spinocerebellar degeneration (SCD) is a progressive neurodegenerative disorder in which cerebellar ataxia causes motor disability. There are no widely applicable methods for objective evaluation of ataxia in SCD. An objective system to evaluate ataxia is necessary for use in clinical trials of newly developed medication and rehabilitation. The aim of this study was to develop a simple method to quantify the degree of upper-limb ataxia. Forty-nine patients with SCD participated in this study. Patients were instructed to trace an Archimedean spiral template, and the gap between the template spiral and the drawn spiral (gap area; GA) was measured using Image J software. Ataxia was rated using the Scale for the Assessment and Rating of Ataxia (SARA) and cerebellar volume was evaluated in 37 patients using an axial cross-section of magnetic resonance images that were obtained within 6 months of clinical evaluation. Regression analysis was performed to assess the relation between GA and patient age, disease duration, SARA score, and cerebellar volume. GA was significantly related to total SARA score (r = 0.660, p < 0.001), the posture and gait (r = 0.551, p < 0.001), speech (r = 0.527, p < 0.001), hand movements (r = 0.553, p < 0.001), and heel-shin slide (r = 0.367, p = 0.036) SARA subscores, and cerebellar volume (r = 0.577, p < 0.001) but was not related to patient age (r = 0.176, p = 0.227) or disease duration (r = 0.236, p = 0.103). GA is a simple, useful method to objectively quantify the degree of cerebellar ataxia, especially upper-limb ataxia, and can be widely adopted in various settings, including clinical trials.

Spinocerebellar ataxia type 2 (SCA2) is a hereditary neurodegenerative disorder caused by the expansion of the trinucleotide CAG repeats encoding elongated polyglutamine tract in ataxin‐2, the SCA2 gene product. Polyglutamine diseases comprise nine genetic entities, including seven different forms of spinocerebellar ataxias, Huntington's disease, and spinal and bulbar muscular atrophy. These are pathologically characterized by neuronal loss and intranuclear aggregates or inclusions of mutant proteins including expanded polyglutamine in selected neuronal groups. Previously, we examined immunolocalization of ubiquitin, expanded polyglutamine (probed by 1C2 antibody), and ataxin‐2 in genetically confirmed SCA2 patients. In the present study, we expanded this approach by distinguishing different patterns of subcellular 1C2 immunoreactivity (“granular cytoplasmic,” “cytoplasmic and nuclear” and “nuclear with inclusions.”) and by quantifying their regional frequencies in three autopsied SCA2 brains at different stage of the disease. Comparison with neuronal loss and gliosis revealed that overall 1C2 immunoreactivity was paralleled with their severity. Furthermore, appearance of granular cytoplasmic pattern corresponded to early stage, cytoplasmic and nuclear pattern to active stage, and nuclear with inclusions pattern to final stage. We conclude that this 1C2‐immunoreactive typing may be useful for evaluating the overall severity and extent of affected regions and estimating the neuropathological stage of SCA2.

In order to cope with the non-uniqueness of multiple equivalent current dipole source (ECD) solutions, a priori knowledge about P300 generators of visual event-related potentials (ERPs) during an oddball paradigm with silent counting task was incorporated into the multiple ECD localization method. Four-ECD solutions for the target P300 were selected which had the left frontal ECD. The rest of the ECDs were localized to the inferior parietal lobule, the hippocampal formation and subcortical region. By comparing the present results with those on the visual ERPs with button-pressing task, the P300 dipoles common to both the tasks were located at the frontal cortices, the hippocampal formation and the thalamus, suggesting that these structures are the main P300 generators.

Neuronal intranuclear inclusions (NIIs) are the pathological hallmark of polyglutamine (polyQ) diseases. We previously found that the RNA-binding protein FUS/TLS is the major component of nuclear polyQ aggregates of a cellular model of Huntington disease. In this study, we revealed that FUS/TLS binds to NIIs in the human brains from patients with spinocerebellar ataxia type 1, 2, 3, and dentatorubral-pallidoluysian atrophy. Recent reports have revealed that mutations in FUS/TLS gene are responsible for familial amyotrophic lateral sclerosis 6 (ALS6). Our results indicated that changing FUS/TLS to an insoluble form may be a common process in polyQ diseases and ALS6.

We studied scalp visual evoked potentials (VEPs) during a simple visual attention paradigm using a dot stimulus, which was presented every 1600 ms, at the center of a screen. The visual attention paradigm consisted of three tasks: task R, task L and task N. The subjects were instructed to press a button either with the right hand (task R) or with the left hand (task L) after seeing the dot. They were also instructed just to look at a dot, without pressing the button (task N). We defined N1 as a negative wave with a latency of 50–130 ms, P1 as a positive wave with a latency of 110–150 ms and N2 as a negative wave with a latency of 130–210 ms. During task R, P1–N2 amplitude at T6 was significantly greater than that at T5. The N1–P1 and N2 amplitudes at O2 were significantly greater than those at O1. During task L, the waveforms at T6 and O2 were more clearly detected than those at T5 and O1. We conclude that there is a functional dominance of the right cerebral hemisphere in our simple visual reaction tasks.

Event-related potentials (ERPs) during a visual oddball paradigm with button-pressing responses were recorded in 12 right-handed subjects from 32 scalp electrodes. The single equivalent current dipole (ECD) of the target C1 (weak occipito-parietal negativity from 30-80ms) was consistently located at the primary visual cortex. From the 4-ECD localization of the target P1/N1 (temporally coincident frontal positivity and occipito-temporal negativity), it was suggested that this complex reflected activities from distributed sources along both dorsal occipito-parietal and ventral occipito-temporal areas. The stable multiple ECD solutions for the target P3b were chosen as those including the left primary motor and/or sensorimotor dipole and satisfying goodness-of-fit (GOF) of more than 98% and confidence limit (CL) of less than 1mm. The obtained frontal dipoles were discussed in terms of visual working memory and sustained attention in reference to the previous PET, fMRI and MEG studies. The distributed multiple ECDs may suggest that P3 should be interpreted as being the embodiment of the cortico-limbic-thalamic network which involves Halgren and Marinkovic's emotional and behavioral model and Mesulam's attentional circuit.

OBJECTIVE—Visual event related potentials (ERPs) were studied during an oddball paradigm, to testify whether cognitive slowing in Parkinson's disease exists and to investigate whether cognitive information processing can be influenced by different interstimulus intervals (ISIs) of an oddball task in patients with Parkinson's disease and normal subjects. METHODS—ERPs and reaction time were measured in 38 non-demented patients with Parkinson's disease and 24 healthy elderly subjects. A visual oddball paradigm was employed to evoke ERPs, at three different interstimulus (ISI) intervals: ISI(S), 1600 ms; ISI(M), 3100 ms; and ISI(L), 5100 ms. The effect of ISIs on ERPs and reaction time was investigated. RESULTS—Compared with the normal subjects, P300 latency at Cz and Pz was significantly delayed after rare target stimuli in patients with Parkinson's disease only at ISI(L). Reaction time was prolonged in patients at all the three ISIs, compared with the normal controls. There was also significantly delayed N200 and reduced P300 amplitude at Cz and/or Pz to rare non-target stimuli in patients at the three ISIs, compared with the normal controls. During rare target visual stimulation, P300 latency and reaction time in the patients with Parkinson's disease and reaction time in the normal subjects were gradually prolonged as the ISI increased. CONCLUSION—Prolonged N200 latency to rare non-target stimuli might indicate that automatic cognitive processing was slowed in Parkinson's disease. Cognitive processing reflected by P300 latency to rare target stimuli was influenced by longer ISI in patients with Parkinson's disease.

A visual oddball paradigm and an S1–S2 paradigm were employed to evoke event-related potentials (ERPs) in 38 nondemented Parkinson’s disease (PD) patients and 24 healthy elderly subjects. Delayed N200 and reduced P300 amplitude in the whole PD sample were only found in the S1–S2 paradigm. Delayed N200 and reaction time in PD with short duration of illness were found only after the S1–S2 paradigm, which might be an early sign of cognitive changes in PD. This is the first study to apply an S1–S2 paradigm for a visual P300 test in PD and proved the value of this paradigm for detecting minor cognitive abnormalities. ERP changes were correlated with clinical features. Reduced P300 amplitude for the S1–S2 paradigm was significantly correlated with WAIS-R scores and gait disturbance. The correlation between P300 amplitude and clinical scores has rarely been discussed before. P300 latency during the oddball paradigm in PD was influenced by age at test, age at onset, and duration of illness. This may explain why P300 results in nondemented PD have varied among previous authors.

A coma patient was diagnosed with tuberculous meningitis by the detection of ESAT-6-specific gamma interferon-secreting cells in the patient's cerebrospinal fluid by enzyme-linked immunospot assay prior to the identification of the pathogen in a culture of the cerebrospinal fluid.

An unusual combination of downgaze palsy and bilateral ptosis occurred in a patient with central nervous system lymphoma involving bilateral thalamus and midbrain tegmentum. Following treatment with corticosteroids, the transition from total paralysis of downgaze to the supranuclear form was noted, along with alleviation of ptosis, followed by complete resolution of both. The results of serial magnetic resonance images were consistent with our interpretation that his initial eye signs were caused by the combined involvement of the bilateral rostral interstitial nucleus of the medial longitudinal fasciculus (supranuclear downgaze palsy) and the oculomotor subnuclei (nuclear palsy of the inferior recti and levator palpebrae muscles).

Background and Purpose —Pure hemisensory syndrome can be caused by small strokes occurring in a number of regions, including the thalamus and pons. Differentiation of the pontine sensory syndrome from the thalamic sensory syndrome has generally been made on the basis of distribution of sensory loss and involvement of specific sensory modalities but not without uncertainties and difficulties. Because the pontine tegmentum plays a pivotal role in generating horizontal eye movement, we attempted to discriminate these 2 syndromes by analyzing horizontal eye movements in stroke patients with pure hemisensory syndrome. Methods —Horizontal saccade, pursuit, vestibulo-ocular reflex (VOR), and VOR cancellation (VORC) were evaluated using electro-oculography in 6 patients with hemisensory syndromes, 3 due to pontine stroke and 3 due to thalamic stroke, and all were verified by MRI or CT. In addition, somatosensory evoked potentials (SEPs) were recorded. Results —Smooth pursuit and VORC directed toward the side of the lesion were impaired unilaterally in patients with pontine sensory stroke, whereas those 2 movements were intact bilaterally in patients with thalamic sensory stroke. Saccade and VOR were preserved in all patients. SEPs were normal in all patients with pontine and thalamic sensory strokes. No difference was found in the pattern of sensory disturbance between the 2 types of stroke patients. Conclusions —Ipsilateral impairment of the smooth pursuit system may be a sign of a pontine lesion in patients with hemisensory stroke.

A 32-year-old Japanese woman with headache, anorexia and malaise, just after travelling cities of the altitude of over 4,000 m by a long-distance coach is described. Her magnetic resonance imaging (MRI) demonstrated strikingly increased T2 signal in the corpus callosum, particularly in the splenium, and MR angiography (MRA) revealed widespread vasospasm. These abnormalities resolved on subsequent MRI studies. We diagnosed her as high altitude cerebral edema (HACE), considered to be the end stage of acute mountain sickness (AMS).

In 12 patients with the clinical characteristics of Marinesco-Sjögren syndrome including an autosomal recessive inheritance, congenital cataracts, mental retardation, cerebellar ataxia and progressive muscle weakness, the most common pathological finding was rimmed vacuole formation comprising from 0.1% to 10% of fibers in their muscle biopsy samples. The nuclear changes varied from condensed chromatin granules to vacuolation with amorphous inclusions which were predominantly seen in younger patients with prominent rimmed vacuoles, suggesting a close relationship between nuclear change and rimmed vacuole formation. From the severe destructive changes in nuclei, we speculated that the nuclear changes in Marinesco-Sjögren syndrome play a primary role in muscle degeneration resulting in myofibrillar disorganization and rimmed vacuole formation. In 2 patients, the TUNEL method demonstrated scattered myonuclei with fragmented DNA, but "ladder formation" was not found, probably because of the small numbers of nuclei with fragmented DNA. Nuclear degeneration with focal myofibrillar degeneration seen in these muscle samples suggests that the apoptotic process may occur in muscle disorders, especially in diseases with rimmed vacuole formation.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by degeneration of both upper and lower motor neurons. Neuropathologically, degeneration of the corticospinal tracts is evident and may be associated with loss of motor neurons in the motor cortex. The data from a recently developed imaging technology, the diffusion tensor imaging method of MRI have suggested that white matter in the corpus callosum (CC) is lost in patients with ALS. However, the specific neuropathologic changes of the commissural fibers remain unclear. To investigate the pathologic changes of the CC in ALS, we analyzed midsagittal sections of the CC from eight individuals with ALS and eight controls by using conventional staining and immunohistochemistry with antibodies against CD68, GFAP and phosphorylated neurofilament (SMI-31). The CC was divided into seven areas. The number of CD68-immunoreactive macrophages/microglia and GFAP-immunoreactive astrocytes was significantly higher in individuals with ALS than in controls in all areas of the CC except the rostrum. Among the patients with ALS, the number of macrophages/microglia and astrocytes was significantly higher in the posterior midbody and isthmus than in the rostrum. There was no significant difference in number of SMI-31 immunoreactive axons between ALS and control group as well as among each area of the CC. These findings suggest that pathologic changes in the CC in ALS are present in the posterior midbody and isthmus, where callosal motor fibers may traverse between the two hemispheres. CD68 and GFAP immunohistochemistry are sensitive methods to detect those pathologic changes in routine paraffin-embedded specimens.

Multiple sclerosis (MS) is a demyelinating disease of the CNS that is presumably mediated by CD4+ autoimmune T cells. Although both Th1 and Th17 cells have the potential to cause inflammatory CNS pathology in rodents, the identity of pathogenic T cells remains unclear in human MS. Given that each Th cell subset preferentially expresses specific chemokine receptors, we were interested to know whether T cells defined by a particular chemokine receptor profile play an active role in the pathogenesis of MS. In this article, we report that CCR2+CCR5+ T cells constitute a unique population selectively enriched in the cerebrospinal fluid of MS patients during relapse but not in patients with other neurologic diseases. After polyclonal stimulation, the CCR2+CCR5+ T cells exhibited a distinct ability to produce matrix metalloproteinase-9 and osteopontin, which are involved in the CNS pathology of MS. Furthermore, after TCR stimulation, the CCR2+CCR5+ T cells showed a higher invasive potential across an in vitro blood–brain barrier model compared with other T cells. Of note, the CCR2+CCR5+ T cells from MS patients in relapse are reactive to myelin basic protein, as assessed by production of IFN-γ. We also demonstrated that the CCR6−, but not the CCR6+, population within CCR2+CCR5+ T cells was highly enriched in the cerebrospinal fluid during MS relapse (p < 0.0005) and expressed higher levels of IFN-γ and matrix metalloproteinase-9. Taken together, we propose that autoimmune CCR2+CCR5+CCR6− Th1 cells play a crucial role in the pathogenesis of MS.

失神患者を診た時には,まず主訴,現病歴から意識を失う直前の前駆症状,意識障害の発症形式,意識障害の深さ,持続,頻度,意識障害の回復過程などについて情報を得る.ついで既往歴・家族歴をチェックして診察を行う.発作時には皮膚の色,呼吸,皮下静脈の状態,心拍などの診察が必須である.病歴と診察から失神の原因疾患を推定し,さらに必要な臨床検査を行い,原因鑑別をすすめる.

Malnutrition in the early stage has been reported as an independent predictor of survival in amyotrophic lateral sclerosis (ALS). We analyzed retrospectively the effect of variation of body mass index (BMI) on survival in ALS patients. In total, 77 consecutive ALS patients were enrolled from nine hospitals in Japan. Reduction rate of BMI was calculated from BMI before the disease onset and at the time of the first visit to each hospital. We analyzed the correlation between BMI reduction rate and total disease duration. Results showed that the median BMI reduction rate was 2.5 per year (interquartile range 1.3-3.8). The BMI reduction rate was significantly correlated with survival length (p

Cervical angina is defined as chest pain resembling true cardiac angina but originating from disorders of the cervical spine. Cervical angina is caused by cervical spondylosis in most cases. A 66-year-old man presented with bilateral arm palsy after chest pain resembling angina pectoris. Neurological examination revealed motor and sensory disturbances of the C7 to T1 level, and magnetic resonance imaging showed a hyperintense spinal cord lesion on T2-weighted imaging. Spinal cord infarction was diagnosed. Severe sinus bradycardia was identified on admission, and improved over the course of 5 weeks. Sympathetic afferent fibers from the heart and coronary arteries generally have their cell bodies in the dorsal root ganglia of the C8 to T9 spinal segments. Electrical stimulation of cardiopulmonary afferent fibers excites spinothalamic tract cells in the T1 to T6 segments of the spinal cord. Spinal cord injury can result in the loss of supraspinal control of the sympathetic system and can cause bradycardia, as commonly seen in patients with severe lesions of the cervical or high-thoracic (T6 or above) spinal cord. Bradycardia in the present case suggested impairment of the sympathetic system at the cervical and thoracic levels. These findings indicated that cervical angina in this case was mediated through the sympathetic nervous system. This represents only the second report of cervical angina caused by spinal cord infarction.

In English- and German-speaking countries, ataxic speech is often described as showing scanning based on acoustic impressions. Although the term 'scanning' is generally considered to represent abnormal speech features including prosodic excess or insufficiency, any precise acoustic analysis of ataxic speech has not been performed in Japanese-speaking patients. This raises the question of what is the most dominant acoustic characteristic of ataxic speech in Japanese subjects, particularly related to the perceptual impression of 'scanning'.The study was designed to investigate the nature of speech characteristics of Japanese ataxic subjects, particularly 'scanning', by means of acoustic analysis.The study comprised 20 Japanese cases with spinocerebellar degeneration diagnosed to have a perceptual impression of scanning by neurologists (ataxic group) and 20 age-matched normal healthy subjects (control group). Recordings of speech samples of Japanese test sentences were obtained from each subject. The recorded and digitized acoustic samples were analysed using 'Acoustic Core-8' (Arcadia Inc.).Sentence duration was significantly longer in the ataxic group as compared with the control group, indicating that the speaking rate was slower in the ataxic subjects. Segment duration remained consistent in both vowels and consonants in the control group as compared with the ataxic group. In particular, the duration of vowel segments, i.e. the nucleus of Japanese mora, was significantly invariable in the control group regardless of differences between subjects as well as in segments compared with the ataxic group. In addition, the duration of phonemically long Japanese vowels was significantly shorter in the ataxic group.The results indicate that the perceptual impression of 'scanning' in Japanese ataxic cases derives mainly from the breakdown of isochrony in terms of difficulty in keeping the length of vowel segments of Japanese invariable during speech production. In addition, the tendency toward irregular shortening of the length of phonemically long Japanese vowels is thought to reinforce the impression of 'scanning' in ataxic speech in Japanese cases.

The intramembranous particle (IMP), orthogonal array (OA) and orthogonal array subunit particle (OASP) densities in skeletal muscle plasma membranes from eight patients with Becker's muscular dystrophy (BMD) were analysed by the freeze-fracture technique. The results showed almost normal IMP density with the significant decrease of OA and OASP densities in BMD. The group mean densities +/- SE of IMPs on the protoplasmic faces with and without OASPs, and on extracellular faces/microns 2 were 2137 +/- 207, 1839 +/- 68 and 895 +/- 108, respectively in controls; whereas those of BMD were 1989 +/- 259, 1837 +/- 203 and 900 +/- 239, respectively (P > 0.1 by two-tailed t-test). The group median density of OAs and their pits/microns 2 was 4.89 with mid-ranges (25-75% values of the counts) of 2.66-10.18 in controls; whereas that in BMD was 2.15 with mid-ranges of 1.14-4.31 (P < 0.01 by Wilcoxon rank-sum test). The group mean density +/- SE of OASPs in controls was 15.99 +/- 1.83; whereas that in BMD was 13.47 +/- 1.07 (P < 0.01 by two-tailed t-test). However, the diminution of OA and OASP densities in BMD muscle plasma membranes was not as severe as in Duchenne's muscular dystrophy. There was a relationship between OA density and clinical severity in BMD patients; the decrease of OA density in a severe BMD patient was more marked than that in mildly affected BMD patients. Therefore, it seems that marked depletion of OA density may lead to the severe disability in muscular dystrophies.

T. Hirai, Y. Iguchi, M. Uchiyama, Y. Kuroiwa, I. Nakamura, S. Yokota, K. Nishioka Department of Neurology, The Jikei University School of Medicine Department of Radiology, The Jikei University School of Medicine Department of Neurology and Stroke Center, Mizonokuchi Hospital, Teikyo University School of Medicine Japan Medical Research Foundation, Yokohama City University Department of Pediatrics, Yokohama City University Institute of Medical Science, Tokyo Medical University, Japan

Degeneration of cerebellar cortex is one of the principal features of hereditary ataxias linked to expansion of CAG repeat. In an attempt to clarify possible correlation between neuronal depletion and neuronal intranuclear inclusions, both triggered by the pathological expansion of CAG repeat, cerebellar sections from SCA1, SCA2, SCA3, and DRPLA cases were immunostained with anti-ubiquitin or anti-expanded polyglutamine antibody (1C2) and were screened for the presence of neuronal intranuclear inclusions. Although the degree of cerebellar degeneration varied greatly, cerebellar Purkinje cells were uniformly characterised by the absence of neuronal intranuclear inclusion. Complete absence of neuronal intranuclear inclusion in Purkinje cells is apparently paradoxical and hardly explained if neuronal intranuclear inclusion formation is positively correlated to a mechanism accelerating neuronal death. It may, otherwise, suggest an intrinsic link between neuronal intranuclear inclusion formation and neurodegeneration in opposite directions in human Purkinje cells, more or less affected in these CAG repeat disorders.

A 41 year old man with parkinsonism and pyramidal signs is described. He was non-responsive to levodopa and dopamine receptor agonists but dramatically responded to trihexyphenidyl. In this patient, brain MRI showed bilateral hyperintensities along the corticospinal tracts on T2 weighted images. PET studies showed a decrease in (18)F-6-fluorodopa uptake in the putamen contralateral to the more affected limbs and normal D(2) receptor binding in the putamen. The PET and MRI findings and responsiveness to antiparkinsonian agents suggested degeneration of nigrostriatal dopaminergic neurons, striatal output pathways, and corticospinal tracts.

Chronic dizziness is frequently reported by patients in the chronic stage after ischemic stroke. The aim of this study was to determine the efficacy of cilostazol versus that of aspirin for the chronic dizziness that follows ischemic stroke.We performed a prospective, randomized, open-label, blinded endpoint trial. One hundred six patients who suffered supratentorial ischemic stroke within the previous 1-6 months and subsequently complained of persistent dizziness without other obvious sequelae were enrolled. Patients were randomly given cilostazol (200mg/day) or aspirin (100mg/day) for 6 months. Rates of improvement in the dizziness were then evaluated. Changes in fixation suppression of the vestibulo-ocular reflex (an indicator of cerebral control over the brainstem reflex related to balance), regional cerebral blood flow (CBF) in the cerebrum, cerebellum, and brainstem; and the Zung Self-Rating Depression Scale (SDS) were also evaluated.Dizziness was significantly improved in the cilostazol group versus the aspirin group (P0.0001) after the 6-month therapy. The capacity for fixation suppression of the vestibulo-ocular reflex was improved (P0.0001), and regional CBF in the cerebrum (relative to that in the brainstem [P=0.003] and to that in the cerebello-brainstem [P=0.012]) was increased only in the cilostazol group. There was no statistical difference in the change in SDS scores between the two groups.Cilostazol improves the chronic dizziness that follows ischemic stroke and increases supratentorial CBF and cerebral function for adaptation of the brainstem reflex related to the sense of balance.

During early postnatal brain development, experience-driven delivery of AMPA receptors to synapses participates in the initial organization of cortical function. By combining virus-mediated in vivo gene delivery with in vitro whole cell recordings, we identified a subunit-specific developmental program of experience-driven AMPA receptor delivery to synapses in rat barrel cortex. We expressed green fluorescent protein (GFP)-tagged AMPA receptors (GFP-GluR1, or GFP-GluR4) into layer 2/3 pyramidal neurons at two distinct developmental periods, postnatal day (P)8–P10 and P12–P14. Two days after viral infection, acute brain slices were prepared, and synaptic transmission from layer 4 to layer 2/3 was analyzed by whole cell recordings. We found that whisker experience drives GluR4 but not GluR1 into these synapses early in postnatal development (P8–P10). However, at P12–14, GluR1 but not GluR4 is delivered into synapses by whisker experience. This precise developmental plan suggests unique plasticity properties endowed in different AMPA receptor subunits which shape the initial experience-driven organization of cortical function.

The Social Insurance Union of Societies Related to Internal Medicine and the Social Insurance Union of Societies Related to Surgical Medicine have pushed for revisions of the medical service fee against the Medical Economics Division of Insurance Department, Ministry of Health, Labor and Welfare. About neurological diseases, Japanese Society of Neurology, Japanese Society of Neurological Therapeutics, Japanese Society of Clinical Neurolphysiology, and Japanese Society of Child Neurology are involved in this movement. The examination fee of the electrical encephalography and the nerve conduction study was accepted. I review the process of the comprehensive medicine, and the revision of DPC (Diagnosis Procedure Combination) and medical service fee.

Autosomal-recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous disorders associated with diverse neurological and nonneurological features that occur before the age of 20. Currently, mutations in more than 20 genes have been identified, but approximately half of the ARCA patients remain genetically unresolved. In this report, we describe a Japanese family in which two siblings have slow progression of a type of ARCA with psychomotor retardation. Using whole-exome sequencing combined with homozygosity mapping, we identified a homozygous missense mutation in SYT14, encoding synaptotagmin XIV (SYT14). Expression analysis of the mRNA of SYT14 by a TaqMan assay confirmed that SYT14 mRNA was highly expressed in human fetal and adult brain tissue as well as in the mouse brain (especially in the cerebellum). In an in vitro overexpression system, the mutant SYT14 showed intracellular localization different from that of the wild-type. An immunohistochemical analysis clearly showed that SYT14 is specifically localized to Purkinje cells of the cerebellum in humans and mice. Synaptotagmins are associated with exocytosis of secretory vesicles (including synaptic vesicles), indicating that the alteration of the membrane-trafficking machinery by the SYT14 mutation may represent a distinct pathomechanism associated with human neurodegenerative disorders.