迟发性单纯小脑共济失调:鉴别有和无可识别突变的患者

Late onset cerebellar ataxia can be caused by several genetic mutations but a large percentage of patients remain undiagnosed. Thirty-eight patients with onset of slowly progressive, pure cerebellar ataxia ≥40 years-of-age were identi fied from a large ataxia database. Their clinical findings and quantitative ocul omotor tests were reviewed; all were screened for SCA1, SCA2, SCA3, SCA6, SCA8, SCA14, and the Fragile X premutation (FMR1). All 47 exons of CACNA1A were screen ed for mutations. Genetic analysis uncovered a mutation in 11 patients. The SCA6 mutation was present in 8 patients (repeats 22-23). Three additional genetic m utations were found: SCA1 (42 repeats), SCA3 (66 repeats), and SCA8 (121 repeats ). Patients without identified genetic mutations were characterized by 1) a late r age of onset, 2) truncal without extremity ataxia, 3) and down beat nystagmus. Although only a third of these idiopathic late onset ataxia patients had a posi tive family history, this homogeneous syndrome probably represents a yet to be i dentified genetic disorder.

具有灾难性抗磷脂综合征病史患者经氟伐他汀治疗后的局灶性癫痫发作

We report a 36-year-old woman with the occurrence of painful focal seizures of her left hand and the left leg. She also had focal motor seizures at the left corner of her mouth. The duration and frequency of the episodes increased over four days from a few seconds once a day to frequent intervals lasting more than four hours at a time. The symptoms appeared one day after start of the treatment with fluvastatin (40 mg) administered in order to diminish the endothelial activation induced by antiphospholipid antibo dies (aPL). The patient suffered from severe manifestations of the antiphospholi pid syndrome (APS)including Catastrophic Antiphospholipid Syndrome (CAPS, Ashers on’s syndrome). In this case a single 40 mg dose of oral fluvastatin was linked to seizures. After discontinuation of this treatment, the seizures immediately disappeared and the patient fully recovered without evidence of permanent neurol ogical damage. This data links statins to seizures in patients with compromised blood brain barrier such as APS.

利用质子MR波谱分析研究丛集性头痛患者的下丘脑代谢

The authors used 1H-MRS to investigate hypothalamic metabolism in 26 patients with cluster headache (CH) and 12 healthy subjects. Hypothalamic N-acetylaspartate/creatine was reduced in patients with CH vs controls (p < 0.01). Dividing the patients into episodic CH outside-and in-cluster periods and chronic CH, the hypothalamic N-acetylaspartate/creatine in all three subgroups of patients was reduced. The reduction of the neuronal marker N-acetylaspartate is consistent with hypothalamic neuronal dysfunction in patients with CH.

干扰素β-1b对多发性硬化症患者黑洞的影响:每月评估1次为期6年的试验结果

Background: Chronic, hypointense black holes (BHs) are recognized as a sign of permanent damage in patients with multiple sclerosis. Although the effects of interferon beta-1b in reducing the formation of new BHs are established, it is not clear whether the drug may reduce BH duration after these lesions are formed. Objective: To analyze the effects of interferon beta-1b in reducing the duration of T1 BHs in patients with multiple sclerosis. Design: Patients were clinically assessed and imaged monthly over a 36-month natural history phase and 36-month therapy phase. Numbers of contrast-enhanced lesions and newly formed BHs were counted on each scan. Each BH was counted until it was no longer seen. Setting: Outpatient service of the Neuroimmunology Branch at the National Institutes of Health, Bethesda, Md. Patients: Six patients with relapsing-remitting multiple sclerosis were included. One patient did not form any BHs during the therapy phase. Analyses were performed on the remaining 5 individuals. Interventions: Interferon beta-1b at the dosage of 8 million international units every other day. Main Outcome Measures: Number and duration (in months) of newly formed BHs. Res ults: Rate of BH accumulation decreased with treatment (P=.01), but Kaplan-Meier models revealed that the duration of BHs did not shorten (=2.47, P=.12). Conclusions: Interferon beta-1b reduces the frequency of new BH formation but does not appear to decrease their duration in time. Analyses with larger patient cohorts are needed to confirm these preliminary findings.

疑似多发性硬化症的临床孤立综合征患者的磁化传递直方图

In established multiple sclerosis, magnetization transfer ratio (MTR) histograms reveal abnormalities of normal-appearing white matter (NAWM) and grey matter (NAGM). The aim of this study was to investigate for such abnormalities in a large cohort of patients presenting with clinically isolated syndromes suggestive of multiple sclerosis. Magnetization transfer imaging was performed on 100 patients (67 women, 33 men, median age 32 years) a mean of 19 weeks (SD 3.8, range 12-33 weeks) after symptom onset with a clinically isolated syndrome and in 50 healthy controls (34 women, 16 men, median age 32.5 years). SPM99 software was used to generate segmented NAWM and NAGM MTR maps. The volumes of T2 lesions, white matter and grey matter were calculated. Eighty-one patients were followed up clinically and with conventional MRI after 3 years (n = 61) or until they developed multiple sclerosis if this occurred sooner (n = 20). Multiple regression analysis was used to investigate differences between patients and controls with age, gender and volume measures as covariates to control for potential confounding effects. The MTR histograms for both NAWM and NAGM showed a reduction in the mean (NAWM, 38.14 versus 38.33, P = 0.001; NAGM 32.29 versus 32.50, P = 0.009; units in pu) and peak location, with a left shift in the histogram. Mean NAWM and NAG M MTR were also reduced in the patients who developed clinically definite multiple sclerosis and multiple sclerosis according to the McDonald criteria but not in the 24 patients with normal T 2-weighted brain magnetic resonance imaging (MRI). MTR abnormalities occur in the NAWM and NAGM at the earliest clinical stages of multiple sclerosis.

1例CPT缺乏、mtDNA同质性突变和粗红纤维的肌肉活检病例

A 45-year-old male patient had an episode of acute renal failure with myoglobinuria, myalgias, weakness, and markedly increased serum CK levels. Similar episodes had occurred in the past. Carnitine palmitoyl-transferase II (CPT II) deficiency was documented both biochemically and genetically. Interestingly, muscle biopsy also showed some ragged red fibers (RRF)and complete mitochondrial DNA (mtDNA) sequence disclosed a homoplasmic T3394C point mutation. This mutation is described in Leber’s hereditary optic neuropathy (LHON) or in patients with diabetes mellitus.

抗Yo阳性伴副瘤性小脑变性患者原发性肿瘤的检出策略

In patients with anti-Yo associated paraneoplastic cerebellar degeneration (P CD) neurological symptoms precede the diagnosis of the underlying cancer in abou t 60%. Ovarian carcinoma, breast cancer and other gynaecological malignancies a re most frequently found as causative malignancies. Antitumour treatment should be applied in an early stage of disease. The identification of the tumour is a d iagnostic challenge in many of these patients. In the first of two patients repo rted here a pelvic tumour was suggested after detection of a pathological lymph node and elevated tumour markers. The intraoperative findings appeared macroscop ically normal during ovariectomy with adnexectomy. Not until microscopic examina tion of the resected tissue was performed was a tubal adenocarcinoma found. If i ntrapelvic gynaecological tumours are suspected a deliberate surgical exploratio n seems to be justified, but only after an intensive diagnostic investigation. T o search for the underlying cancer in patients with paraneoplastic neurological disorders successive CT and[18F]-FDG-PET are widely recommended. Instead of th is in the second reported patient whole-body dualmodality PET/CT was performed revealing enhanced uptake in three regions of the left thorax. By combining func tion and anatomy PET/CT was able to localise the lesions and characterise them a s lymph node metastases of breast cancer. Diagnosis could be confirmed by subseq uently executed needle biopsy. PET/CT seems to be highly applicable in the inves tigation of paraneoplastic disorders with unknown primary cancer. It may help in guidance of needle biopsy or to optimise the results of deliberate surgery and it provides whole-body tumour staging in a single session with higher diagnosti c accuracy than PET alone.

接受冠状动脉旁路移植手术时年龄因素对于老年男性双生子认知状态改变的影响

Background: Research regarding long-term cognitive outcome following corona ry artery bypass graft (CABG) is inconsistent, which may be due in part to diffe rential genetic and environmental influences within most study samples. Methods: The authors examined the effect of CABG on cognitive status change scores in me mbers of the National Academy of Sciences-National Research Council Twins Regi stry of World War II veterans. Subjects were administered the modified Telephone Interview for Cognitive Status (TICS-m) at approximately 3-year intervals b etween 1990 and 2002 as part of an epidemiologic study of dementia. Results: Bas ed on co-twin control analyses using a repeated-measures analysis of varianc e matching twins discordant for CABG within the pair (n = 464 individuals) acros s three age categories (63 to 70, 71 to 73, 74 to 83), the authors found at foll ow-up that men who had CABG between ages 63 and 70 showed an increase in TICS -m scores and performed better than their co-twin who did not have the proce dure. No significant differences were found within twin pairs for the older two age groups following CABG surgery. This age effect was replicated when comparing individuals positive for CABG surgery with nonfamilial, age-and education-m atched controls who were negative for CABG. Conclusions: In this study of twin p airs who share many genetic and environmental risks for cerebrovascular problems , the results suggest that timing of the CABG procedure may be important to pred icting positive cognitive outcomes.

长时间经鼻持续气道正压治疗后的非典型头痛

We report a case of atraumatic pneumocephalus associated with prolonged use o f nasal continuous positive airway pressure. Initial symptoms included headache, ataxia, vertigo, and a “ gurgling” sensation in the head; and a CT image sho wed small air bubbles along the falx of cerebrum and adjacent to the temporal ep idural spaces bilaterally. Although no evidence of cerebrospinal fluid (CSF) lea k was either reported by the patient or found at initial clinical examination, s ubsequent nasal discharge tested positive for β 2- transferrin, a finding cons istent with CSF leak in the paranasal sinus region or through the cribriform pla te. To try to prevent infection from an open communication between the paranasal sinuses and intracranial structures, an attempt should be made to localize the anatomic defect.

超声溶栓治疗rt-PA禁忌的急性缺血性卒中患者

The authors studied the effect of transcranial ultrasound on patients with acu te middle cerebral artery occlusion and contraindications for thrombolysis. Fift een consecutive subjects were randomized for insonation over 1 hour or for inclusion in a control group. By day 4, recanalization and neurologic improvem ent occurred more frequently in the target group. Ultrasound-induced accelerati on of clot dissolution may be an option for patients with contraindications for recombinant tissue plasminogen activator.

可进展为多发性硬化的临床横断综合征患者颈髓磁转移磁共振研究

Cervical cord magnetization transfer ratio (MTR) histograms were obtained from 45 patients at presentation with clinically isolated syndromes (CIS) suggestive ofmultiple sclerosis (MS). The mean values of MTR histogram derived metrics were not different between CIS patients and healthy control subjects or between patients with and without evidence of disease dissemination in time. Only three patients showed significantly lower cord MTR values than control subjects. These findings suggest the absence of intrinsic structural damage of the cervical cord soon after the onset of CIS suggestive of MS, even in those patients with an early evolution to MS.

潘生丁对于缺血性卒中的复发和其他血管病变的预防作用:随机对照试验中个体患者资料的荟萃分析

Background and Purpose - Results from randomized controlled trials of dipyridamole, given with or without aspirin, for secondary prevention after ischemic stroke or transient ischemic attack (TIA) have given conflicting results. We performed a meta- analysis using individual patient data from relevant randomized controlled trials. Methods - Randomized controlled trials involving dipyridamole in patients with previous ischemic stroke or TIA were sought from searches of the Cochrane Library, other electronic databases, references lists, earlier reviews, and contact with the manufacturer of dipyridamole. Individual patient data were merged from 5 of 7 relevant trials involving 11 459 patients. Results were adjusted for age, gender, qualifying event, and history of previous hypertension. Results- Recurrent stroke was reduced by dipyridamole as compared with control (OR, 0.82; 95% CI, 0.68 to 1.00), and by combined aspirin and dipyridamole versus aspirin alone (OR, 0.78; 95% CI, 0.65 to 0.93), dipyridamole alone (OR, 0.74; 95% CI, 0.60 to 0.90), or control (OR, 0.61; 95% CI, 0.51 to 0.71). The point estimates obtained for the comparisons of aspirin and dipyridamole versus control (OR, 0.63; significant) or versus aspirin (OR, 0.88; nonsignificant) were similar if the data from the largest trial, ESPS II (which provided 57% of data), were excluded. Similar findings were observed for nonfatal stroke. The combination of aspirin and dipyridamole also significantly reduced the composite outcome of nonfatal stroke, nonfatal myocardial infarction, and vascular death as compared with aspirin alone (OR, 0.84; 95% CI, 0.72 to 0.97), dipyridamole alone (OR, 0.76; 95% CI, 0.64 to 0.90), or control (OR, 0.66; 95% CI, 0.57 to 0.75). Vascular death was not altered in any group. Conclusions - Dipyridamole, given alone or with aspirin, reduces stroke recurrence in patients with previous ischemic cerebrovascular disease. The combination of aspirin and dipyridamole also reduces the composite of nonfatal stroke, nonfatal myocardial infarction, and vascular death as compared with aspirin alone.

职业特点与阿尔茨海默病

Objective: To investigate the association between Alzheimer disease (AD) and worker functions and traits associated with occupations. Background: Studies have reported that occupational attainment is related to AD. However, most have not identified specific worker functions and traits (i.e., occupational demands) of occupations that may explain the association, nor have they accounted for changing occupational demands over time. Methods: Within and between group differences in mental, motor, physical, and social occupational demands of 122 AD cases and 235 control subjects were compared across four decades of life (20s, 30s, 40s, and 50s) using repeatedmeasures analyses of covariance adjusted for race, gender, year of birth, and education. Results: Overall, mental occupational demands were significantly lower and physical occupational demands were significantly higher for cases than for control subjects. Case/control differences in mental demand scores were not found in their 20s but only in later decades. Differences in physical demands were found in all decades but their 30s. Social and motor demands did not differ between cases and control subjects. Among cases only, there were no signifi cant occupational demand score differences across decades. In contrast, mental and social demand scores of control subjects increased in later decades, and motor demand scores declined. Like cases, physical demand scores of control subjects remained stable across the decades. Conclusions: The authors’ results may indicate a relatively early influence of Alzheimer disease neuropathology on capacity to pursue mentally demanding occupations. However, results also are consistent with the notion that mentally demanding occupations have a direct influence on Alzheimer disease neuropathology.

女性中等量酒精摄入对认知功能的影响

BACKGROUND: The adverse effects of excess alcohol intake on cognitive function are well established, but the effect of moderate consumption is uncertain. METHODS: Between 1995 and 2001, we evaluated cognitive function in 12,480 participants in the Nurses’ Health Study who were 70 to 81 years old, with follow- up assessments in 11,102 two years later. The level of alcohol consumption was ascertained regularly beginning in 1980. We calculated multivariate- adjusted mean cognitive scores and multivariate- adjusted risks of cognitive impairment (defined as the lowest 10 percent of the scores) and a substantial decline in cognitive function over time (defined as a change that was in the worst 10 percent of the distribution of the decline). We also stratified analyses according to the apolipoprotein E genotype in a subgroup of women. RESULTS: After multivariate adjustment, moderate drinkers (those who consumed less than 15.0 g of alcohol per day [about one drink]) had better mean cognitive scores than nondrinkers. Among moderate drinkers, as compared with nondrinkers, the relative risk of impairment was 0.77 on our test of general cognition (95 percent confidence interval, 0.67 to 0.88) and 0.81 on the basis of a global cognitive score combining the results of all tests (95 percent confidence interval, 0.70 to 0.93). The results for cognitive decline were similar; for example, on our test of general cognition, the relative risk of a substantial decline in performance over a two- year period was 0.85 (95 percent confidence interval, 0.74 to 0.98) among moderate drinkers, as compared with nondrinkers. There were no significant associations between higher levels of drinking (15.0 to 30.0 g per day) and the risk of cognitive impairment or decline. There were no significant differences in risks according to the beverage (e.g., wine or beer) and no interaction with the apolipoprotein E genotype. CONCLUSIONS: Our data suggest that in women, up to one drink per day does not impair cognitive function and may actually decrease the risk of cognitive decline.

荟萃分析:糖尿病患者糖基化血红蛋白与心血管疾病的关系

Background: In persons with diabetes, chronic hyperglycemia (assessed by glyco sylated hemoglobin level) is related to the development of microvascular disease ; however, the relation of glycosylated hemoglobin to macrovascular disease is l ess clear. Purpose: To conduct a meta analysis of observational studies of the association between glycosylated hemoglobin and cardiovascular disease in diabet ic persons. Data Sources: Search of the MEDLINE database by using Medical Subjec t Heading search terms and keywords related to glycosylated hemoglobin, diabete s, and cardiovascular disease. Study Selection: Prospective cohort studies with data on glycosylated hemoglobin levels and incident cardiovascular disease. Data Extraction: Relative risk estimates were derived or abstracted from each cohort study that met the inclusion criteria. Data Synthesis: Adjusted relative risk e stimates for glycosylated hemoglobin (total glycosylated hemoglobin, hemoglobin A1, or hemoglobin A1c levels) and cardiovascular disease events (coronary heart disease and stroke) were pooled by using random ef fects models. Three studies involved persons with type 1 diabetes (n = 1688), and 10 studies involved perso ns with type 2 diabetes (n = 7435). The pooled relative risk for cardiovascular disease was 1.18; this represented a 1 percentage point increase in glycosylate d hemoglobin level (95%CI, 1.10 to 1.26) in persons with type 2 diabetes. Resul ts in persons with type 1 diabetes were similar but had a wider CI (pooled relat ive risk, 1.15 [CI, 0.92 to 1.43]). Limitations: This review largely reflects th e limitations of the literature. Important concerns were residual confounding, t he possibility of publication bias, the small number of studies, and the heterog eneity of study results. Conclusions: Pending confirmation from large, ongoing c linical trials, this analysis shows that observational studies are consistent wi th limited clinical trial data and suggests that chronic hyperglycemia is associ ated with an increased risk for cardiovascular disease in persons with diabetes.

特定DWI病损形式预测MCA供血区域急性缺血性卒中的预后

Background: Apart from diffusion-weighted imaging (DWI)- lesion volume and diffusion-perfusion mismatching, there is limited information about neuroradiological predictors of early prognosis after an ischaemic stroke. This study sought to identify specific DWI lesion patterns that would help prediction of early prognosis of three different endpoints: unstable hospital course, recurrence of stroke, and poor neurological outcome at 90 days after ischaemic stroke. Methods: A total of 426 patients with acute cerebral infarcts within the middle cerebral artery territory were prospectively studied. Using the DWI data the patients were divided into six groups (territorial, other cortical, small superficial, internal border zone, small deep, and other deep infarcts), and any recurrent strokes and prognosis over the following 90 days were recorded. Results: DWI lesion pattern was a stronger and more consistent independent outcome predictor than DWI lesion volume. The specific DWI lesion patterns associated with each endpoint differed. An unstable hospital course was frequently observed in patients with internal border zone infarcts, whereas recurrent strokes after the index stroke were commoner in those who had small superficial infarcts (p < 0.05 in both cases). Similarly, poor outcome after stroke was associated with older age, severe neurological deficits at admission, and a DWI lesion pattern showing internal border zone infarcts. Conclusions: The results of the present study indicate that the DWI lesion pattern may help in recognition of the likely differences in the early prognostic endpoints after ischaemic stroke, and DWI analysis may guide targeted interventions to prevent negative outcomes.

先兆性偏头痛亚型患者在视觉刺激时磁共振波谱成像的改变

Migraine pathophysiology possibly involves deficient mitochondrial energy res erve and diminished cortical habituation. Using functional magnetic resonance sp ectroscopic imaging (fMRSI), we studied cortical lactate changes during prolonge d visual stimulation to search for different pathophysiological mechanisms in cl inically distinct subgroups of migraine with aura. Eleven healthy volunteers (HV ) and 10 migraine patients were investigated interictally: five with visual aura (MA) and five with visual symptoms and at least one of the following: paraesthe sia, paresis or dysphasia (MAplus). Using MRSI (Philips, 1.5 T) 1H- spectra wer e repeatedly obtained from a 25 mm- thick slice covering visual and non- visua l cortex, with the first and fifth measurements in darkness and the second to fo urth with 8- Hz checkerboard stimulation. In MAplus lactate increased only duri ng stimulation, only in visual cortex; in MA resting lactate was high in visual cortex, without further increase during stimulation. This is compatible with an abnormal metabolic strain during stimulation in MAplus, possibly due to dishabit uation, and a predominant mitochondrial dysfunction in MA.

显性遗传的听觉前庭综合征的颞骨组织病理学

Objective: To describe the clinical and pathologic features of a new dominantly inherited audiovestibular syndrome. Methods: History, examination, and audiometric testing in the proband, brother, and son; quantitative rotational testing in the proband and son; histopathology of the cochlea and vestibular labyrinth in the proband; sequencing candidate genes COCH and MYO7A in the brother and son. Results: Affected family members developed slowly progressive hearing loss beginning in their late 30s and progressive imbalance in their early 70s. Three of four affected had brief (minutes) episodes of vertigo typically occurring a few times per year. Auditory and vestibular function testing documented a slowly progressive loss of auditory and vestibular function. Postmortem examination showed a loss of hair cells in the cochlea and vestibular receptor organs. There were no cellular infiltrates or acidophilic deposits. No mutations were found in the COCH or MYO7A genes. Conclusions: This dominantly inherited audiovestibular syndrome results in a selective loss of hair cells in the auditory and vestibular end organs. Finding the causative gene could have important implications for understanding the pathophysiology of presbycusis and dysequilibrium of aging.

曾经有过短暂性脑缺血发作或卒中的患者应用叶酸、维生素B_(12)和维生素B_6降低高半胱氨酸的治疗不能降低血管炎症、内皮功能异常或高凝的血液学标记物:VITATOPS试验的随机亚研究

Background and Purpose - Epidemiological and laboratory studies suggest that increasing concentrations of plasma homocysteine (total homocysteine [tHcy]) accelerate cardiovascular disease by promoting vascular inflammation, endothelial dysfunction, and hypercoagulability. Methods - We conducted a randomized controlled trial in 285 patients with recent transient ischemic attack or stroke to examine the effect of lowering tHcy with folic acid 2 mg, vitamin B12 0.5 mg, and vitamin B6 25 mg compared with placebo on laboratory markers of vascular inflammation, endothelial dysfunction, and hypercoagulability. Results - At 6 months after randomization, there was no significant difference in blood concentrations of markers of vascular inflammation (high- sensitivity C- reactive protein [P=0.32]; soluble CD40L [P=0.33]; IL- 6 [P=0.77]), endothelial dysfunction (vascular cell adhesion molecule- 1 [P=0.27]; intercellular adhesion molecule- 1 [P=0.08]; von Willebrand factor [P=0.92]), and hypercoagulability (P- selectin [P=0.33]; prothrombin fragment 1 and 2 [P=0.81]; D- dimer [P=0.88]) among patients assigned vitamin therapy compared with placebo despite a 3.7- μ mol/L (95% CI, 2.7 to 4.7) reduction in total homocysteine (tHcy). Conclusions - Lowering tHcy by 3.7 μ mol/L with folic acidbased multivitamin therapy does not significantly reduce blood concentrations of the biomarkers of inflammation, endothelial dysfunction, or hypercoagulability measured in our study. The possible explanations for our findings are: (1) these biomarkers are not sensitive to the effects of lowering tHcy (eg, multiple risk factor interventions may be required); (2) elevated tHcy causes cardiovascular disease by mechanisms other than the biomarkers measured; or (3) elevated tHcy is a noncausal marker of increased vascular risk.

脑神经胶质瘤病首选化疗:替莫唑胺的疗效

The optimal therapy for gliomatosis cerebri is unclear, and the rate of response to chemotherapy is not known. Eleven radiotherapy naive patients received a median number of 10 treatment cycles of temozolomide. An objective response was documented in 45% , and the median time to tumor progression was 13 months with a progression free survival of 55% at 12 months. These results indicate that radiotherapy to extensive brain regions can be deferred until progressive disease is observed.