Long-term event monitoring study of fluvastatin in Japanese patients with hypercholesterolemia: Efficacy and incidence of cardiac and other events in elderly patients (≥ 65 years old).

OBJECTIVE: This long-term event monitoring (LEM) study was designed to evaluate the long-term lipid-lowering efficacy and safety of fluvastatin (Lochol®, Novartis A.G.) along with the incidence of cardiac and other events, and safety of fluvastatin in Japanese patients with hypercholesterolemia. METHODS: Patients (n = 21,139) who started fluvastatin between April 1, 2000 and March 31, 2002, across 2563 centers in Japan were prospectively registered and followed up for 3 years (secondary prevention cohort) or 5 years (primary prevention cohort). RESULTS: Of the patients registered, 19,084 were included in this analysis. Levels of low-density lipoprotein-cholesterol (LDL-C) and total cholesterol (TC) decreased significantly in the primary (-27.1% and -18.8%) and secondary (-25.3% and -18.4%) prevention cohorts. Reductions in LDL-C (-22.1 vs. -18.2%, p < 0.0001) and TC (-16.1 vs. -13.1%, p < 0.0001) levels were significantly greater among patients aged ≥ 65 than < 65 years old. Overall, 1.7% (146/8563) and 1.1% (93/8563) of patients aged ≥ 65 years old experienced confirmed cardiac and cerebral events, compared with 1.1% (112/10,517) and 0.3% (28/10,517) of patients aged < 65 years old (p = 0.0002 and < 0.0001, respectively). Incidence of cardiac and cerebral events was lowest in patients aged < 65 years old in the primary prevention cohort and highest among patients aged ≥ 65 years old in the secondary prevention cohort. Adverse events were reported in 7.9% (1501/19,084) of patients. CONCLUSION: This large-scale, prospective, uncontrolled study confirmed the lipid-lowering efficacy and safety of long-term fluvastatin treatment for hypercholesterolemia in Japanese patients aged ≥ 65 years old. The higher incidence of cardiac and cerebral events in patients aged ≥ 65 years old in the secondary prevention cohort reflects a high-risk clinical profile with multiple classic risk factors warranting multifactorial interventions.

Antiplatelet cilostazol is beneficial in diabetic and/or hypertensive ischemic stroke patients. Subgroup analysis of the cilostazol stroke prevention study.

BACKGROUND AND PURPOSE: Although antiplatelets are known to be effective for secondary prevention of cerebral infarction, the number needed to treat is rather large and the effects in stroke patients with complications such as hypertension or diabetes are inadequately defined. This study was conducted to examine the effect of such complications on recurrence of cerebral infarction, and to assess the effect of cilostazol, an antiplatelet agent, in these high-risk subjects. METHODS: A post hoc subgroup analysis of the already reported Cilostazol Stroke Prevention Study, which was a placebo-controlled double-blind trial, has been carried out to clarify the influence of various complications on recurrence in the placebo group and the effects of cilostazol in 1,095 patients with noncardioembolic ischemic cerebrovascular disease. Treatment continued for an average of 1.8 +/- 1.3 years (maximum 4.8 years). RESULTS: The recurrence rate of the diabetic stroke patients was significantly higher compared with the nondiabetics in the placebo group (9.4 vs. 4.7%/year, p = 0.01). Furthermore, our study showed that the relative risk reduction (RRR) for recurrence of infarction was 41.7% with cilostazol. This treatment provided a significant benefit in patients with lacunar infarction (RRR 43.4%, p = 0.04), with diabetes (RRR 64.4%, p = 0.008), or with hypertension (RRR 58.0%, p = 0.003). CONCLUSIONS: Diabetic patients are particularly at risk for recurrence of cerebral infarction. Cilostazol is useful for the prevention of the recurrence of vascular events in patients with lacunar infarction, and is probably effective in high-risk patients with diabetes and/or hypertension.

Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction (S-ACCESS): A randomized, double-blind, aspirin-controlled trial.

BACKGROUND AND PURPOSE: The antiplatelet agent sarpogrelate is a selective inhibitor of 5-hydroxytryptamine receptors. The purpose of this study was to compare the efficacy and safety of sarpogrelate with those of aspirin in Japanese ischemic stroke patients. METHODS: In total, 1510 patients with recent cerebral infarction (1 week to 6 months after onset) were randomly assigned to receive either sarpogrelate (100 mg TID) or aspirin (81 mg/d). Mean follow-up period was 1.59 years. The primary efficacy end point was recurrence of cerebral infarction. Clusters of serious vascular events (stroke, acute coronary syndrome, or vascular event-related death) were selected as secondary end points. The aim of the primary efficacy analysis was to demonstrate the noninferiority of sarpogrelate with respect to aspirin, with the criterion that the upper limit of the 95% CI of the hazard ratio (sarpogrelate vs aspirin) for recurrence of cerebral infarction should not exceed 1.33. RESULTS: Cerebral infarction recurred in 72 patients (6.09%/y) in the sarpogrelate group and in 58 (4.86%/y) in the aspirin group (hazard ratio=1.25; 95% CI, 0.89 to 1.77; P=0.19). A serious vascular event occurred in 90 (7.61%/y) and in 85 (7.12%/y) patients, respectively (hazard ratio=1.07; 95% CI, 0.80 to 1.44; P=0.65). The overall incidences of bleeding events were 89 (11.9%) and 131 (17.3%), respectively (P<0.01). CONCLUSIONS: Sarpogrelate was not noninferior to aspirin for prevention of recurrence of cerebral infarction. Bleeding events were significantly fewer with sarpogrelate than aspirin. The effect of aspirin in Japanese patients was similar to that in Western studies.

Effect of the Ca antagonist nilvadipine on stroke occurrence or recurrence and extension of asymptomatic cerebral infarction in hypertensive patients with or without history of stroke (PICA Study). 1. Design and results at enrollment.

BACKGROUND: We examined the effect of a Ca antagonist (nilvadipine) on the occurrence or recurrence of symptomatic stroke in hypertensive patients with MRI-defined asymptomatic cerebral infarction (ACI), periventricular hyperintensity (PVH), and deep and subcortical white matter hyperintensity (DSWMH), with or without a history of stroke, and evaluated the effect of long-term treatment on the lesions. METHODS: Patients with hypertension and incidental ACI were divided into those with (group B, 235 patients) or without (group A, 181 patients) a history of symptomatic stroke, and were given nilvadipine 4-8 mg/day for 3 years. Primary evaluation points were occurrence of symptomatic ischemic stroke and development or extension of asymptomatic ischemic lesions. RESULTS: Male sex, hyperuricemia, diabetes, maximum diameter of infarction and PVH severity were stronger risk factors for group B. Numbers of cerebral infarctions were 31 +/- 28 (group A) and 42 +/- 32 (group B) at enrollment (p < 0.001). Infarctions were larger and located more frequently on the internal capsule, putamen, thalamus and brainstem in group B. The severity of PVH and DSWMH paralleled the number of cerebral infarctions in both groups. CONCLUSION: The study design and status of asymptomatic ischemic brain lesions in hypertensive subjects at enrollment are presented.

Genetic analysis of the cystatin C gene in familial and sporadic ALS patients.

Bunina bodies, small eosinophilic intraneuronal inclusions, stain positive for cystatin C and are the only specific pathological hallmark of amyotrophic lateral sclerosis (ALS). We screened the cystatin C gene (CST3) for mutations in 57 sporadic ALS patients and 12 familial ALS cases that did not possess a SOD1 mutation. We detected the known polymorphism in exon 1, a G/A transition at +73, in both familial and sporadic ALS patients. However, the allelic and genotypic frequencies of the +73 G/A polymorphism did not differ between ALS patients and control samples. No other mutation was detected in the ALS patients. The results reported here indicate that there may not be a direct genetic link between cystatin C and ALS, and it may be that deficits occur in proteins that interact with cystatin C.

Effects of fasudil in acute ischemic stroke: results of a prospective placebo-controlled double-blind trial.

BACKGROUND: A multicenter, double-blind, placebo-controlled study was conducted to assess the efficacy and safety of fasudil, a Rho-kinase inhibitor (RKI), in the treatment of acute ischemic stroke. METHODS: A total of 160 patients, who were able to receive drug treatment within 48 h of acute ischemic stroke onset were enrolled. Patients received either 60 mg fasudil or a placebo (saline) by intravenous injection over 60 min, twice daily for 14 days. The primary end points were neurological status at 2 weeks after the start of treatment, and clinical outcome at 1 month after the onset of symptoms. RESULTS: Fasudil treatment resulted in significantly greater improvements in both neurological functions (p=0.0013), and clinical outcome (p=0.0015). There were no serious adverse events reported in the fasudil group. The average trough value (12 h values) of active metabolite hydroxyfasudil, another RKI, in healthy elderly volunteers receiving 60 mg of fasudil was 0.077 microM-a concentration well above that needed to inhibit Rho-kinase (0.025-0.05 microM). CONCLUSION: Treatment with fasudil within 48 h of acute ischemic stroke onset significantly improved the patient's clinical outcome. This study found fasudil to be a useful and safe drug for patients with acute ischemic stroke. Further evaluations, for example, 3-month functional outcomes in a larger clinical trial, may help to define the efficacy of fasudil in acute ischemic stroke.

Recurrence of acute disseminated encephalomyelitis after a 12-year symptom-free interval.

We report a patient with recurrent acute meningoencephalitis who had three episodes of headache, fever and unconsciousness; the first episode was at age 6 and the second, at age 7. After a 12-year symptom-free interval, she had a relapse, exhibiting the same symptoms as those in the previous two episodes. Head magnetic resonance imaging also revealed the recurrence of lesions in the basal ganglia and medial portion of the temporal lobe. The occurrences of stereotyped symptoms with meningoencephalitis and the same lesions in the basal ganglia observed in each episode favor the diagnosis of recurrent acute disseminated encephalomyelitis (ADEM) rather than multiple sclerosis or multiphasic disseminated encephalomyelitis. The occurrence of this rare case suggests that ADEM can relapse after a very long symptom-free interval.

Link between linear hyperintensity objects in cerebral white matter and hypertensive intracerebral hemorrhage.

BACKGROUND: We retrospectively studied the relationship between linear hyperintensity objects (LHOs) on T(2)-weighted magnetic resonance images (MRI) in the cerebral white matter and the occurrence of hypertensive intracerebral hemorrhage (HIH). METHODS: Forty-nine hypertensive patients with a fixed imaging condition MRI were classified into three groups: HIH (n = 17), ischemic stroke due to hypertensive vasculopathy (n = 19), and hypertension only (n = 13). After assessing clinical and radiological background information among these groups and the reliability of LHO measurements, polynomial logistic regression analysis was used to identify the factors relating to HIH. RESULTS: HIH had a significantly higher LHO number (p = 0.002) and larger diameter (p = 0.007). The LHO number showed an excellent interrater (kappa = 0.91, 95% CI = 0.87-0.94, SEM = 6.2%) and intrarater reliability (kappa = 0.95, 95% CI= 0.92-0.97, SEM = 4.8%), and was the most significant independent indicator of HIH (OR = 1.29, 95% CI = 1.05-1.60, p = 0.017). The number of microbleeds was an additional indicator (OR = 3.73, 95% CI = 1.10-12.65, p = 0.034). CONCLUSIONS: LHOs are closely linked to HIH. A prospective, longitudinal study is needed to clarify whether LHOs can predict HIH.

Soluble Abeta homeostasis in AD and DS: impairment of anti-amyloidogenic protection by lipoproteins.

In order to assess whether lipoproteins are physiologically able to balance and modulate the sAbeta homeostasis in vivo, soluble Abeta levels in lipoprotein-depleted plasma were measured as a function of age in normal controls, Alzheimer's disease (AD) patients, and Down's syndrome (DS) cases. The reshaping of sAbeta homeostasis, in particular the sAbeta42-lipoprotein interaction, takes place over normal-60's, whereas mild AD patients appear to have impaired this anti-amyloidogenic mechanism resulting in a significant increase of lipoprotein-free sAbeta42. Similar loss of function takes place in Down's syndrome patients. Lipoprotein-free sAbeta remains significantly elevated from the pre-symptomatic through the symptomatic stages of the disease, and declines with the progression of the AD-like pathology. The dissociation of sAbeta from lipoprotein-particles also occurs in brain parenchyma and the presence of soluble dimeric lipoprotein-free Abeta prior to its parenchymal deposition in AD brains would support the hypothesis that functionally declined lipoproteins may be major determinants in the production of metabolic conditions leading to higher levels of sAbeta species and cerebral amyloidosis.

[A case of agnosia for streets without visual memory disturbance].

A 70-year-old, right-handed man was admitted to our hospital for his sudden-onset topographical disorientation. He failed to find his way to familiar places, but he knew distance and direction to the places. Neurological examination revealed homonymous left-upper quadrantanopsia on Goldmann perimeter and hypoesthesia over the left side of his body. Magnetic resonance imaging showed an abnormal intensity area at the right medial temporo-occipital region, due to the infarct of the right posterior cerebral arterial territory. The neuropsychological examination revealed agnosia for streets, and prosopagnosia without any other disturbance of visual perception. Both visual and topographical memories were intact. It is suggested that, in this case, the agnosia for streets was caused by impairment of recognizing familiar streets and houses or disconnection between their recognition and memory.

Cerebral blood flow and oxygen metabolism in patients with progressive dementia and amyotrophic lateral sclerosis.

We examined regional cerebral blood flow (rCBF) and oxygen metabolism (rCMRO2) in 10 patients with progressive dementia and amyotrophic lateral sclerosis (DALS), in 21 patients with classical amyotrophic lateral sclerosis without dementia (ALS), and in 17 controls. The mean rCBF and rCMRO2, especially in the anterior cerebral hemispheres, decreased significantly in patients with DALS. Patients with only ALS showed very mild changes in rCBF and rCMRO2 which were not significant except for the reductions in the sensorimotor area. Some rCBF and rCMRO2 values in ALS showed a significant correlation with some neurological signs indicating upper motor neuron involvement. These data suggest that hypoperfusion and oxygen hypometabolism in the anterior cerebral hemispheres have an etiological relationship with the deterioration of intellect in patients with progressive dementia and ALS. The metabolic and perfusional changes in the cerebral cortex of ALS patients are likely to depend on upper motor neuron involvement, but they are not confined to the neurons of the corticospinal tract.

Central retinal artery Doppler flow parameters reflect the severity of cerebral small-vessel disease.

BACKGROUND AND PURPOSE: We investigated the usefulness of central retinal artery (CRA) Doppler flowmetry in patients with cerebral small-vessel disease (SVD). METHODS: CRA Doppler flowmetry was performed in 103 SVD patients who underwent MRI. Sixty-four adjusted control subjects were also registered. We assessed average CRA flow parameter values for both eyes with the clinical and MRI findings. RESULTS: Each Doppler flowmetry was performed within 5 minutes. Patients with SVD had significantly lower end-diastolic and mean velocities of the CRA than control subjects; they also had higher pulsatility and resistive indexes. Multivariate analysis showed that the number of small infarcts was an independent predictor of peak systolic and mean velocities. Grade of periventricular hyperintensities was an additional independent predictor of peak systolic and mean velocities, whereas the number of small infarcts was predictive of end-diastolic velocity. CONCLUSIONS: Flow parameters may be useful for the quantitative assessment of SVD severity.

Heterogeneity of nigral and cortical Lewy bodies differentiated by amplified triple-labeling for alpha-synuclein, ubiquitin, and thiazin red.

Alpha-synuclein(alpha-S) and ubiquitin(Ub) are constituents of the Lewy bodies (LBs), composed of fibrillary structures. To clarify morphological heterogeneity of LBs, we looked for localization of these epitopes in relation to fibrillary structure possibly detectable by a fluorochrome, thiazin red (TR). On the sections of the substantia nigra (SN) and the cingulate gyrus (CG) obtained from Parkinson's disease brains, double amplification by CARD fluorescent immunohistochemistry with anti-alpha-S monoclonal (LB509) and anti-Ub polyclonal antibodies was performed, followed by staining with TR. These triple-labeled images were captured by a confocal laser microscope and subsequently stained with Campbell-Switzer method, a silver staining specific for LBs. Staining profiles of LBs were different between those in the SN and in the CG. Immunolabeling either with the anti-alpha-S or anti-Ub antibody was diffuse without halo structure in LBs of CG. In addition to this diffuse staining, a lot of LBs of SN exhibited a halo structure immunopositive for alpha-S and Ub, probably representing later stages of LB evolution. Irrespective of the presence of this halo structure, the TR signal was always concentrated in the center of LBs, as the silver-stained material was, suggesting that fibrillary components in the central portion of LBs undergo some conformational changes detectable by TR and the silver-staining. This technique reveals different epitopes in relation to LB evolution in vivo. Heterogeneity in staining profile of LBs, as clarified by this method, may represent evolutional changes of LBs, related to conformational states of their constituents.

Motor cortical disinhibition in the unaffected hemisphere after unilateral cortical stroke.

Following a hemispheric stroke, various degrees of neuronal reorganization around the lesion occur immediately after disease onset and thereafter up to several months. These include transcallosal excitability, changes of the intact motor cortex and ipsilateral motor responses after transcranial magnetic stimulation (TMS) on the intact hemisphere. To elucidate the relationship between lesion localization and motor cortex excitability (intracortical inhibition; ICI) in the intact hemisphere, we applied a paired conditioning-test TMS paradigm in 12 patients with unilateral cortical stroke (cortical group) and nine patients with subcortical stroke caudal to the corpus callosum (subcortical group), with interstimulus intervals varying from 1 to 10 ms. All patients exhibited unilateral complete hand palsy. ICI was significantly less in the cortical group than in age-matched healthy control subjects. It was especially more marked in the cortical group patients with a disease duration of less than 4 months after onset. Patients in the cortical group with a duration longer than 4 months showed a tendency for ICI to be normalized, and there was a significant correlation between ICI and disease duration. Patients in the subcortical group showed normal excitability curves. All patients in the cortical group showed no transcallosal inhibition (TCI) in the active unaffected hand muscle after TMS of the affected motor cortex, whereas all the subcortical patients showed some TCI. No ipsilateral motor responses were elicited in the paretic hand in any of the patients. The reduced ICI in the cortical group might have been a result of disruption of TCI. The normalization of ICI in the patients with longer disease duration and the normal ICI in the subcortical group patients do not support the functional significance of motor cortex hyperexcitability in the unaffected hemisphere, at least in a patient population with poor motor recovery.

Different mechanism of vocal cord paralysis between spinocerebellar ataxia (SCA 1 and SCA 3) and multiple system atrophy.

While multiple system atrophy (MSA) is frequently associated with vocal cord paralysis (VCP) causing severe respiratory failure, it is still unknown whether hereditary types of spinocerebellar degeneration develop similar laryngeal paralysis. We analyzed the laryngeal function from the viewpoints of fiberoptic laryngoscopy and laryngeal myopathology and then attempted to clarify the difference of the mechanism of VCP among the patients with spinocerebellar ataxia type 1 (SCA 1), type 3 (SCA 3), and MSA. Seven patients with SCA 1, nineteen with SCA 3, and eleven with MSA were studied. Vocal cord movement was analyzed by fiberoptic laryngoscopy during wakefulness and diazepam-induced sleep (sleep load test). Paraffin-embedded sections or cryosections of the intrinsic laryngeal muscles from five autopsied cases (one with SCA 1 and four with SCA 3) were histologically examined. VCP was found in two of the seven SCA 1 patients (29%), three of the nineteen SCA 3 patients (16%), and in nine of the eleven MSA patients (82%). VCP observed in SCA 1 and SCA 3 was various in the severity and showed no exacerbation on sleep load test in all of the eight patients but one SCA 3 patient. In this patient, the findings of fiberoptic laryngoscopy were quite similar to those found in MSA. All the intrinsic laryngeal muscles including cricothyroid (CT), interarytenoid (IA), and posterior cricoarytenoid (PCA) muscles showed neurogenic atrophy in one autopsied SCA 1 and four SCA 3 patients. Our conclusion is that VCP in SCA 1 and SCA 3 contrasts with that in MSA in its occurrence, response to the sleep load test, and the distribution of the neurogenic abnormalities among the intrinsic laryngeal muscles.