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Bilateral cerebral peduncles are rarely simultaneously infarcted unless the basilar artery is involved. A 60-year-old man developed locked-in syndrome because of bilateral cerebral peduncle infarctions with right intracranial vertebral artery occlusion. Dysarthria occurred a day before admission. His neurological condition rapidly deteriorated, and he subsequently became quadriplegic. His left vertebral artery showed a posterior inferior cerebellar artery end pattern, and anastomosis between the anterior and posterior circulations through the hypoplastic right P1 and fine left posterior communicating artery was insufficient; therefore, severe hypoperfusion and multiple infarctions in the distribution of the posterior circulation were induced by right intracranial vertebral artery occlusion. These findings highlight the fact that large-artery atherosclerosis represents an important cause of mesencephalic infarctions. Several neurological manifestations are caused by intracranial vertebral artery occlusion, and when collateral flow to the posterior circulation is insufficient, intracranial vertebral artery occlusion results in bilateral cerebral peduncle infarctions and locked-in syndrome without basilar artery occlusion.

The aim of this study was to investigate corticobasal syndrome with respect to underlying pathologies, the ability of current clinical criteria to detect early stages of disease, and symptoms and signs predicting background pathologies. We retrospectively analyzed the clinicopathological findings from patients with corticobasal syndrome. We also analyzed whether those findings fulfilled the diagnostic criteria for corticobasal degeneration (CBD). Finally, we investigated characteristic clinical features that are specific to each background pathology. Of 10 consecutive autopsied patients who had corticobasal syndrome (mean age ± standard deviation, 67.9 ± 9.3 years; male:female ratio, 6:4), three had corticobasal degeneration pathology, three had progressive supranuclear palsy, three had Alzheimer's disease, and one had atypical four-repeat tauopathy. Nine patients fulfilled Mayo criteria, and all 10 patients fulfilled modified Cambridge criteria at the later stage, but only two patients fulfilled either clinical criteria within 2 years of disease onset. Five patients fulfilled the clinical criteria for possible CBD (p-CBD), and one patient fulfilled the clinical research criteria for probable sporadic CBD (cr-CBD) at the later stage. Only two patients fulfilled the criteria for either p-CBD or cr-CBD within 2 years of disease onset. Although we could not find any predictive characteristic clinical features that were specific to CBD pathology, only patients with progressive supranuclear palsy developed apraxia of eyelid opening and cerebellar ataxia. Myoclonus and memory impairment, especially if they appear at an early stage of the disease, may predict Alzheimer's disease pathology. Sensitivity of the available clinical criteria for corticobasal syndrome was poor within 2 years of disease onset.

Here, we describe a therapeutic strategy for attenuating hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment for acute ischemic stroke. Recent studies have shown that tPA treatment is beneficial within 4.5 h of onset for patients with acute ischemic stroke. However, the risk of serious or fatal symptomatic hemorrhage increases with delayed initiation of treatment. HT is considered to be caused by ischemic/reperfusion injury, as well as the toxicity of tPA itself. Therapeutic strategies to attenuate HT after tPA treatment might involve (i) identification of risk factors for HT after tPA treatment and (ii) the development of thrombolytic drugs, which are less likely to cause bleeding, or drugs that can be concomitantly administered for vascular protection. Several studies have shown that matrix metalloproteinases and free radicals are potential therapeutic targets. In addition, we recently showed that inhibition of the vascular endothelial growth factor (VEGF) signaling pathway might be a promising therapeutic strategy for attenuating HT after tPA treatment. Further studies are required to link the results obtained in experimental animal models to human clinical trials.

Aim To investigate the frequency of calcification in the basal ganglia and the dentate nuclei in the cerebellum, and compare the difference in age and area, we examined the brain computed tomography (CT) images of all patients in two representative university hospitals in Japan. Methods We examined the brain CT images of 2526 patients in Gifu University Hospital (UH) and 2573 patients in Niigata UH. These patients were examined in these hospitals from October 2009 to September 2010. Results Punctate calcification of the basal ganglia was observed in 435 of 2526 patients (17.2%) in Gifu UH and 530 of 2573 patients (20.6%) in Niigata UH. The frequency of calcification increased with age. Patchy calcification of the basal ganglia was observed in 32 (1.3%) and 50 patients (1.9%) in Gifu UH and Niigata UH, respectively. Among patients aged over 65 years, 24 (2.1%) and 34 (3.1%) patients showed patchy calcification in Gifu UH and Niigata UH, respectively. Calcification of the cerebellar dentate nuclei was detected in just seven and four patients in Gifu UH and Niigata UH, respectively. Conclusion Compared with previous reports, the frequency of calcification of the basal ganglia in this study markedly increased. This might be because of the increased number of older adults and the increased sensitivity of CT. Geriatr Gerontol Int 2013; 13: 706–710.

Background: The purpose of this study was to investigate whether heart rate variability parameters can be useful for evaluating cardiac autonomic dysfunction in multiple system atrophy patients. Methods: Both the time and frequency domains of heart rate variability were investigated among 17 multiple system atrophy patients and 27 normal control subjects. Results: All time- and frequency-domain measures, except the low- to high-frequency ratio, were significantly lower in multiple system atrophy patients than in controls. In multiple system atrophy patients, there were significant inverse correlations between heart rate variability parameters and disease duration, as well as disease severity, but heart rate variability parameters were not affected by other autonomic dysfunctions. Conclusions: The cardiac autonomic state of multiple system atrophy was characterized by decreases in both sympathetic and parasympathetic tones. Because heart rate variability parameters were not affected by other autonomic dysfunctions, this may be a useful method for evaluating cardiac autonomic dysfunction in multiple system atrophy. © 2012 Movement Disorder Society

Two Japanese families with benign hereditary chorea (BHC) 2 have recently been reported. BHC 2 is characterized by adult-onset non-progressive chorea, and by genetic abnormality in the locus of chromosome 8q21.3-q23.3. This differs from the genetic abnormality previously reported in BHC. Here we report the first autopsied case of a member of one of two known families with BHC 2. A normally developed woman recognized choreiform movements of her bilateral upper extremities beginning approximately at age 40. The movements had slowly spread to her trunk and lower extremities by approximately age 60. Generalized muscular hypotonia was also observed. The symptoms persisted until her death at the age 83, but had not worsened. Neuropathological examination revealed mild to moderate neuronal loss and astrocytosis in the striatum and decreased volume of cerebral white matter with astrocytosis bilaterally. Additionally, sparse but widely distributed neurofibrillary tangles and argyrophilic threads as well as scattered tufted astrocytes immunoreactive for 4-repeat isoform of tau were observed in the cerebrum, brainstem and cerebellum, showing 4-repeat tauopathy similar to that of progressive supranuclear palsy (PSP). Unique neuronal cytoplasmic inclusions were observed in the oculomotor nuclei; however, any specific immunoreactivities (e.g. ubiquitin and p62) were not detected, suggesting the presence of previously undescribed protein intracellular inclusions. Clinicopathologically, chorea accompanied with generalized muscular hypotonia seemed to be associated with mild degeneration of the striatum and cerebral white matter. The significance of PSP-like changes in the pathogenesis of BHC 2 remains to be elucidated.

Background: The aim of this study was to find biomarkers of disease severity in multiple system atrophy of cerebellar type by imaging disease specific regions using proton magnetic resonance spectroscopy on a 3.0 T system. Methods: We performed proton magnetic resonance spectroscopy separately in the pons and medulla on 12 multiple system atrophy of cerebellar type patients and 12 age and gender matched control subjects. The metabolite concentrations were estimated from single-voxel proton magnetic resonance spectra measured by point resolved spectroscopy, which were then correlated with clinical severity using Part I, II, and IV of the unified multiple system atrophy rating scale. Results: Proton magnetic resonance spectroscopy showed that myo-inositol concentrations in both the pons and medulla were significantly higher in multiple system atrophy of cerebellar type patients compared to those of the control subjects (P < 0.05). By contrast, total N-acetylaspartate (the sum of N-acetylaspartate and N-acetylaspartylglutamate) and total choline compounds concentrations in both the pons and medulla were significantly lower in multiple system atrophy of cerebellar type patients compared to control subjects (P < 0.05). Creatine concentration in the pons was significantly higher in multiple system atrophy of cerebellar type patients compared to the control subjects (P < 0.05). Furthermore, a significant correlation was found between the myo-inositol/creatine ratio in the pons and clinical severity, defined by the sum score of unified multiple system atrophy rating scale (I+II+IV) (r = 0.76, P < 0.01). Conclusion: Proton magnetic resonance spectroscopy, in conjunction with a 3.0 T system, can be feasible to detect part of pathological changes in the brainstem, such as gliosis and neuronal cell loss, and the metabolites can be used as biomarkers of clinical severity in multiple system atrophy of cerebellar type patients. © 2011 Movement Disorder Society

Nuclear factor TAR DNA-binding protein-43 (TDP-43) is considered to play roles in pathogenesis of human neurodegenerative diseases, so-called TDP-43 proteinopathy, via its proteolytic cleavage, abnormal phosphorylation, subcellular redistribution, and insolubilization generating TDP-43-positive neuronal intracellular inclusions. The purpose of this study was to elucidate biochemical and histopathological alternations in TDP-43 specific to acute ischemic stroke. Adult male rats were subjected to a 90-min middle cerebral artery occlusion. We examined the proteolytic cleavage, phosphorylation, subcellular localization, and solubility of TDP-43 by immunoblottings and histopathological examinations using the ischemic and sham-operated cortex. The level of full-length TDP-43 (43 kDa) decreased and that of the 25-kDa C-terminal fragment increased after acute ischemic stroke, which can be explained by proteolytic cleavage of TDP-43. Cytoplasmic redistribution and altered nuclear distribution of TDP-43 was observed after acute ischemic stroke, whereas abnormal phosphorylation and insolubilization of TDP-43 as well as formation of intracellular inclusions were not observed. Ischemic neurons with the cytoplasmic redistribution of TDP-43 expressed ubiquitin and activated caspase 3 and were terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling-positive. In conclusion, biochemical and histopathological alterations in TDP-43 were identified in rats after acute ischemic stroke, although there was very less similarity between TDP-43 alterations observed in acute ischemic stroke and those observed in TDP-43 proteinopathy.

A 79-year-old patient with diabetes mellitus was diagnosed with cryptococcal meningitis based on detection of Cryptococcus neoformans from cerebrospinal fluid culture. After administration of liposomal amphotericin B, the patient promptly developed acute renal failure as a side-effect. We therefore switched treatment to voriconazole with low-dose liposomal amphotericin B. Cerebrospinal fluid cultures and antigen titer for Cryptococcus became negative 266 days after initiating voriconazole. The present case suggests that voriconazole might be useful as induction therapy to reduce the risk of renal insufficiency and achieve successful outcomes.

To determine whether tremulous arytenoid movements predict the severity of glottic stenosis in patients with multiple system atrophy (MSA), 28 MSA patients and 14 age-matched controls underwent fiberoptic laryngoscopy with video monitoring during wakefulness and under anesthesia induced by intravenous injection of propofol. Presence or absence of tremulous arytenoid movements was recorded during wakefulness. The ratio of glottic stenosis (%), which represents the extent of airway narrowing under anesthesia, was obtained by measuring the inspiratory glottic angle during wakefulness and under anesthesia. The median ratio of glottic stenosis was significantly higher in patients with MSA (57.5%) than in control subjects (0.5%). Tremulous arytenoid movements were characterized by shaking movements of the arytenoid region including the vocal folds, which are most apparent in the arytenoid cartilage. In this study, tremulous arytenoid movements were observed in 18 (64.2%) of 28 patients with MSA, who displayed a significantly higher median ratio of glottic stenosis (71.2%) than other patients (34.9%). None of the control subjects exhibited tremulous arytenoid movements. A clear correlation existed between the ratio of glottic stenosis and disease duration. Our observations indicate that tremulous arytenoid movements are a marker of the severity of glottic stenosis, which confers an increased risk of upper airway obstruction in patients with MSA.

The clinical heterogeneity of progressive supranuclear palsy (PSP), which is classified as classic Richardson's syndrome (RS) and PSP-Parkinsonism (PSP-P), has been previously discussed. We retrospectively analyzed 22 consecutive Japanese patients with pathologically proven PSP to investigate the clinicopathological heterogeneity. We investigated the clinical features both early in and at any time during the disease course. The pathological severities of neuronal loss with gliosis and tau pathology were also evaluated. On the basis of the clinical features, 10 patients were categorized as having RS, and 8 were categorized as having PSP-P. Four patients presenting with cerebellar ataxia or cerebral cortical signs were categorized as having unclassifiable PSP. Among them, 3 developed cerebellar ataxia as the initial and principal symptom. Notably, tau-positive inclusion bodies in Purkinje cells were significantly more frequently observed in the patients with cerebellar ataxia than in those without cerebellar ataxia. All the patients with cerebellar ataxia exhibited more neuronal loss with gliosis and higher densities of coiled bodies in the cerebellar dentate nucleus than those without cerebellar ataxia. This study confirms the wide spectrum of clinicopathological manifestations associated with PSP regardless of different ethnic origin, and demonstrates that PSP patients manifest cerebellar ataxia.

Huntington's Disease-like 2 (HDL2) is a progressive, autosomal dominant, neurodegenerative disorder with marked clinical and pathological similarities to Huntington's disease (HD). The causal mutation is a CTG/CAG expansion mutation on chromosome 16q24.3, in a variably spliced exon of junctophilin-3. The frequency of HDL2 was determined in nine independent series of patients referred for HD testing or selected for the presence of an HD-like phenotype in North America or Japan. The repeat length, ancestry, and age of onset of all North American HDL2 cases were determined. The results show that HDL2 is very rare, with a frequency of 0 to 15% among patients in the nine case series with an HD-like presentation who do not have the HD mutation. HDL2 is predominantly, and perhaps exclusively, found in individuals of African ancestry. Repeat expansions ranged from 44 to 57 triplets, with length instability in maternal transmission detected in a repeat of r2=0.29, p=0.0098). The results further support the evidence that the repeat expansion at the chromosome 16q24.3 locus is the direct cause of HDL2 and provide preliminary guidelines for the genetic testing of patients with an HD-like phenotype.

Polyglutamine (polyQ) aggregate bodies are a hallmark of dentatorubral-pallidoluysian atrophy and related neurodegenerative disorders, although the relationship between aggregate body formation and cell death is not clear. We analyzed the kinetics of polyQ aggregate formation and the time intervals for cell death, tracking individual cells using fluorescence video microscopy, for the first time. Expanded polyQ tracts of atrophin-1 with or without nuclear localization signal (NLS) labeled with green fluorescent protein (GFP) were constructed, Q57NLS/GFP and Q56/GFP, respectively. All of the Q57NLS/GFP aggregate bodies were in nuclei, and all of the Q56/GFP aggregate bodies were in cytoplasm. Aggregates of Q56/GFP were larger than those of Q57NLS/GFP. Surprisingly, a kinetic analysis showed that the latter grew 5.37 times faster than the former. The time interval between transfection and cell death was shorter in Q57NLS/GFP, but the time between the end of the rapid growing phase of aggregation and the start of the cell death process did not show a significant difference. Aggregate growth was confirmed to correspond to the accumulated free polyQ by the time of starting aggregation. These findings suggest that aggregate body formation induced by expanded polyQ stretches is a self-limiting process and is enhanced by factor(s) in nuclei, whereas it is not tightly bound to the cell death process. © 2002 Wiley-Liss, Inc.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion. In the present study of DRPLA, we have demonstrated immunohistochemically that diffuse accumulation of mutant atrophin-1 in the neuronal nuclei, rather than the formation of neuronal intranuclear inclusions (NIIs), was the predominant pathologic condition and involved a wide range of central nervous system regions far beyond the systems previously reported to be affected. In the neuronal nuclei harboring NIIs, promyelocytic leukemia protein (PML) nuclear bodies were redistributed into a single NII, and the CREB (cAMP-responsive element-binding protein)-binding protein was also recruited into NIIs. The results suggest that the novel lesion distribution revealed by the diffuse nuclear labeling may be responsible for a variety of clinical features, such as dementia and epilepsy in DRPLA, and that certain transcriptional abnormalities may be induced secondarily in neuronal nuclei with the formation of NIIs.

At least eight inherited neurodegenerative diseases are known to be caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches have been suggested, the molecular mechanisms of neurodegeneration remain unclear. The nuclear translocation of mutant proteins containing expanded polyQ stretches has been demonstrated as a prerequisite for the expression of their cytotoxicity. Hypothesizing that nuclear proteins that interact with mutant proteins, particularly, those that bind to the expanded polyQ stretches, are involved in the pathogenetic mechanisms underlying neurodegeneration, nuclear proteins were screened for their capability of binding to expanded polyQ stretches. It was found that expanded polyQ stretches preferentially bind to TAF(II)130, a coactivator involved in cAMP-responsive element-binding protein (CREB)-dependent transcriptional activation. The binding of TAF(II)130 with expanded polyQ stretches strongly suppresses CREB-dependent transcriptional activation, suggesting that interference with transcription due to the binding of expanded polyQ stretches with TAF(II)130 and redistribution of TAF(II)130 are involved in the pathogenetic mechanisms underlying neurodegeneration.

Pregabalin has favorable effects on several types of neurological pain, but can cause side-effects including dizziness, somnolence and delirium. Delirium presents as two variants in terms of psychomotor disturbance: the hyperactive type, showing agitation and vigilance; and the hypoactive type, showing lethargy and decreased motor activity. Patients with delirium associated with pregabalin therapy have been reported to experience hyperactive delirium. Here, we report the case of a 68-year-old patient with insidious hypoactive delirium caused by pregabalin therapy for postherpetic neuralgia. Delirium improved after discontinuation of pregabalin. Hypoactive delirium is considered to be more common than the hyperactive type in older adults, and is likely to be overlooked. Attention should thus be paid to latent cases of hypoactive delirium associated with pregabalin therapy in elderly individuals.

Objectives: Multiple system atrophy (MSA) is a chronic neurological disorder characterized by atypical parkinsonism and autonomic dysfunction. Sudden death during sleep is common among MSA patients. Sleep laryngoscopy demonstrates the restriction of abduction of vocal cords with a markedly reduced size of the glottic chink. Vocal cord abductor paralysis (VCAP) is considered to be an important predisposing factor of sudden death in MSA. The aim of this study was to elucidate the effects of VCAP on sleep and the utility of awake and sleep laryngoscopy in MSA. Methods: We recruited 14 patients with MSA presenting with snoring (4 men and 10 women; mean age, 54.6 years; disease duration, 4.2 years; International Cooperative Ataxia Rating Scale [ICARS], 46.9). After performing arterial blood gas analysis, spirometry, and polysomnography (PSG), awake and sleep laryngoscopy were performed. Results: Sleep laryngoscopy revealed that 7 patients exhibited VCAP and 7 patients did not. Between these 2 groups, there were no significant difference in the following findings: sex, disease duration, ICARS, findings of daytime blood gas analysis and PSG findings (mean SpO2 during sleep, AI, AHI and arousal index). Five of 7 patients who exhibited VCAP also showed bilateral arytenoidal tremor on awake laryngoscopy. Conclusion: These findings suggest that MSA should be followed by sleep laryngoscopy, however, it is difficult to perform sleep laryngoscopy as a routine evaluation. Since early diagnosis of VCAP is difficult to make on awake laryngoscopy, arytenoidal tremor may be useful as a sign to predict VCAP.

We investigated the incidence and clinical features of patients with myasthenia gravis (MG) associated with autoimmune diseases. Associated autoimmune diseases were found in 28 of 142 consecutive Japanese MG patients (19.7%), amongst which Graves' disease (7.7%) and Hashimoto's thyroiditis (4.2%) were predominant. The clinical features of MG patients with Graves' disease were different from those of MG patients without autoimmune diseases in terms of age at onset of MG symptoms (35.5 +/- 4.0 years and 49.0 +/- 1.7 years; P < 0.05), positivity for the anti-acetylcholine receptor antibody (44.4% and 89.8%; P < 0.05), and association with thymic hyperplasia (72.7 and 17.9%; P < 0.05). The therapeutic outcome of MG patients with Graves' disease and that of those without autoimmune diseases were not significantly different. Further studies should be performed to investigate whether MG associated with Graves' disease is a distinct subtype of MG.