Cognitive functioning in allogeneic hematopoietic stem cell transplantation recipients and its medical correlates: a prospective multicenter study.

BACKGROUND: Owing to its neurotoxicity, allogeneic hematopoietic stem cell transplantation (HSCT) carries risks for cognitive impairment. In this multicenter study, we prospectively evaluated cognitive functioning and its medical and demographic correlates in patients undergoing allogeneic HSCT. METHODS: A total of 102 patients were consecutively assessed prior to (T0 ), 100 ± 20 days (T1 ) after, and 12 ± 1 months (T2 ) after HSCT (61% men, 41% acute myeloid leukemia). A comprehensive neuropsychological test battery was applied to evaluate attention, memory, executive function, and fine motor function, summing up into 14 test scores. RESULTS: Before and after HSCT, patients performed below test norms in up to 50% of the test scores. Patients were mostly impaired on word fluency (24%, T0 ), fine motor function, and verbal delayed recall (19% each, T2 ). Impairment on ≥ 1/5 cognitive domains occurred in 47% (T0 ) and 41% (T2 ) of the patients. Performance (mean z-scores) partially improved over time (i.e., visual span forward, verbal learning, and word fluency). However, from baseline to T2 , 16% of the patients showed reliable decline on ≥ 3/14 test scores (reliable change index method). For the majority of neuropsychological subtests, no associations with conditioning intensity, total body irradiation, graft-versus-host disease, cyclosporine treatment, and length of hospital stay were found. Age and premorbid intelligence level were consistently associated with cognition. CONCLUSIONS: Below average cognitive performance is common in this patient group. In addition, a subgroup shows reliable cognitive decline after allogeneic HSCT. Healthcare professionals should be aware of these treatment-related cognitive side effects.

Exposure to high-field MRI does not affect cognitive function.

PURPOSE: To assess potential cognitive deficits under the influence of static magnetic fields at various field strengths some studies already exist. These studies were not focused on attention as the most vulnerable cognitive function. Additionally, mostly no magnetic resonance imaging (MRI) sequences were performed. MATERIALS AND METHODS: In all, 25 right-handed men were enrolled in this study. All subjects underwent one MRI examination of 63 minutes at 1.5 T and one at 7 T within an interval of 10 to 30 days. The order of the examinations was randomized. Subjects were referred to six standardized neuropsychological tests strictly focused on attention immediately before and after each MRI examination. Differences in neuropsychological variables between the timepoints before and after each MRI examination were assessed and P-values were calculated RESULTS: Only six subtests revealed significant differences between pre- and post-MRI. In these tests the subjects achieved better results in post-MRI testing than in pre-MRI testing (P = 0.013-0.032). The other tests revealed no significant results. CONCLUSION: The improvement in post-MRI testing is only explicable as a result of learning effects. MRI examinations, even in ultrahigh-field scanners, do not seem to have any persisting influence on the attention networks of human cognition immediately after exposure.

Cognitive functions in patients with MR-defined chronic focal cerebellar lesions.

The aim of the present study was to examine cognitive functions in a group of chronic patients with focal cerebellar lesions. Both effects of localization (anterior vs. posterior lobe) and side (left vs. right cerebellar hemisphere) were of interest. Fourteen patients with infarctions within the territory of the posterior inferior cerebellar artery (PICA) and seven patients with infarctions within the territory of the superior cerebellar artery (SCA) participated. The affected lobules and nuclei were assessed based on 3D MR imaging. The right cerebellar hemisphere was affected in eight PICA and two SCA patients, the left hemisphere in six PICA and four SCA patients. One SCA patient revealed a bilateral lesion. In order to study possible lateralization of functions, subjects performed a language task as well as standard neglect and extinction tests. Moreover, two tests of executive functions were applied. There were no significant group differences apart from a verbal fluency task, in which all cerebellar patients - but especially those with right-sided lesions - were impaired. Voxel-based lesion-symptom mapping (VLSM) revealed that a lesion of the right hemispheric lobule Crus II was associated with impaired performance in the verbal fluency task. In sum, the results showed preserved cognitive abilities in chronic cerebellar patients apart from impairments of verbal fluency in patients with right-cerebellar lesions. The latter findings are in line with the assumption that the right posterolateral cerebellar hemisphere supports functions associated with verbal fluency.

Transcranial sonography of the third ventricle and cognitive dysfunction in HIV patients.

BACKGROUND: Although the incidence and prevalence of dementia associated with human immunodeficiency virus (HIV) infection has decreased since the introduction of highly active antiretroviral therapy, cognitive dysfunction remains one of the most prevalent factors severely affecting quality of life in patients with HIV. Previous magnetic resonance imaging (MRI) studies showed a correlation between brain atrophy, enlargement of the ventricles and cognitive impairment in HIV patients. OBJECTIVE: To investigate the usefulness of transcranial sonographic (TCS) measurement of the third ventricle in detection of brain atrophy in HIV patients and the correlation with neuropsychological deficits. METHODS: We examined 47 HIV patients and 40 healthy age-matched controls with TCS, neuroimaging (cranial MRI or computed tomography) and a neuropsychological test battery. RESULTS: The third ventricle was significantly larger in patients than in healthy controls and correlated significantly with duration of HIV, Center of Disease Control (CDC) stage, CD4 lymphocytes and distinct cognitive and motor deficits. CONCLUSION: TCS cannot replace neuroimaging but is a valuable method in the detection of brain atrophy and follow-up of HIV patients at risk or with a recent diagnosis of HIV encephalopathy.

Small ischemic brain lesions after cardiac valve replacement detected by diffusion-weighted magnetic resonance imaging: relation to neurocognitive function.

OBJECTIVE: Following coronary artery bypass graft surgery, some studies using magnetic resonance imaging (MRI) have demonstrated new small ischemic brain lesions in patients without apparent neurological deficits. We aimed to prospectively evaluate brain injury after cardiac valve replacement using MRI and to determine the relationship to neurocognitive function. METHODS: Thirty patients with a mean age of 64.9+/-9.8 years (range, 32-82, 12 female) receiving cardiac valve replacement (aortic valve replacement [AVR], n = 24; mitral valve replacement [MVR], n = 2; AVR and MVR, n = 2; AVR and mitral valve repair, n = 2) were investigated. Study protocol included neurological examination, comprehensive neuropsychological assessment and diffusion-weighted (DW) MRI. The investigations were performed before surgery and 5 days and 4 months after surgery. RESULTS: Postoperative DW MRI detected new focal brain lesions in 14 patients (47%). No patient revealed a focal neurological deficit. Six patients (43%) had multiple (> or = 3) lesions (range, 1-7). Lesion volume ranged from 50-500 mm3 except 1 territorial infarct of 1900 mm3. Of a total of 41 lesions, 27 (66%) were located in the right hemisphere and 32 in a subcortical location. By 5 days postoperatively, significant neurocognitive decline was observed in 5 of 13 tests affecting memory, attention and rate of information processing. By 4 months, dysfunction had recovered in all cognitive areas. The presence of new ischemic lesions was not associated with neurocognitive decline at discharge. There was also no significant correlation between clinical and operative variables and the presence of new DW lesions or neuropsychological outcome. CONCLUSIONS: Following cardiac valve replacement, new small ischemic brain lesions were detected by diffusion-weighted MRI. Neurocognitive decline was present early after operation, but resolved within 4 months. A correlation of new ischemic lesions to postoperative cognitive dysfunction or clinical variables was not found.

Clinical outcome and neuropsychological deficits after right decompressive hemicraniectomy in MCA infarction.

BACKGROUND AND PURPOSE: The purpose of this study was to analyse in detail the functional outcome and the neuropsychological deficits in patients with space-occupying infarction of the non-dominant hemisphere one year after surgery. METHODS: Postoperative complications and retrospective consent to surgery were assessed in a semi-structured interview in 26 patients. Functional outcome was measured with the Barthel-Index (BI) and Rankin-Scale. Neuropsychological tests in 14 patients focused on visuo-spatial and visuo-constructive abilities, attention, spatial span and self-rated mood. RESULTS: The one-year survival rate was 69 % (18 of 26). The functional outcome was good (BI >/= 90) in 3 patients, fairly good (BI 75-85) in 6, moderate (BI 30-70) in 6, and poor (BI 0-25) in 3 patients. Age was an independent predictor of outcome, patients above 52 years had a BI of 50 or below. Neuropsychological tests (14 of 18) showed profound attention deficits in all patients, and visuo-spatial and visuo-constructive deficits in patients with lower formal education. Retrospectively, 4 of 18 patients would not give consent to surgery again, mostly because of the bad quality of life postoperatively. CONCLUSION: Older patients do not seem to benefit from decompressive hemicraniectomy; more than half of the surviving younger patients have a good outcome and live independently. Attention deficits are prominent in all patients; visuo-spatial and constructive deficits are less pronounced in patients with higher formal education. Retrospective agreement to decompressive hemicraniectomy is high in patients with good functional outcome.

Evaluation of brain injury after coronary artery bypass grafting. A prospective study using neuropsychological assessment and diffusion-weighted magnetic resonance imaging.

OBJECTIVE: Neurocognitive dysfunction is a common complication after cardiac surgery with cardiopulmonary bypass (CPB). Studies using magnetic resonance imaging (MRI) have demonstrated that new focal brain lesions can occur after coronary artery bypass grafting (CABG), even in patients without apparent neurological deficits. Diffusion-weighted MRI is superior to conventional MRI and allows for sensitive and early detection of ischemic brain lesions. We prospectively investigated cerebral injury early and 3 months after CABG using diffusion-weighted MRI and related the findings to clinical data and neurocognitive functions. METHODS: Twenty-nine patients [67.6+/-8.6 (52-85) years, 5 females] undergoing elective CABG with CPB were examined before surgery, at discharge and 3 months after surgery. A battery of standardized neuropsychological tests and questionnaires on depression and mood were administered. Conventional and diffusion-weighted MRI of the brain was performed and new lesions were analyzed. Clinical characteristics, neuropsychological test performance and radiographic data were collected and compared. RESULTS: There was no major neurological complication after CABG. Thirteen patients (45%) exhibited 32 new ischemic lesions on postoperative diffusion-weighted MRI. The lesions were small, rounded and equally dispersed in both hemispheres. Eight patients had at least two lesions. At discharge, significant deterioration of neuropsychological performance was observed in 6 of the 13 tests compared to baseline assessment. By 3 months postoperatively, 5 of the 6 tests returned to preoperative levels. Verbal learning ability, however, remained impaired. The presence of new focal brain lesions was not associated with impaired neuropsychological performance. There was also no correlation between clinical variables, intraoperative parameters and postoperative complications and MRI findings. CONCLUSIONS: Although neurocognitive decline after CABG is mostly transient, memory impairment can persist for months. New ischemic brain lesions on postoperative diffusion-weighted MRI do not appear to account for the persistent neurocognitive decline.

ARTA: AT1-receptor blocker therapy in patients undergoing coronary artery bypass grafting.

BACKGROUND: Decline in renal and cognitive function may complicate early recovery after coronary-artery bypass grafting. AT(1)-receptor antagonists have been demonstrated to be neuro- and renoprotective. Aim of ARTA, a prospective, double-blind, randomised and placebo controlled study, was to detect whether preoperative treatment with candesartan influences postoperative cognitive and renal function. STUDY PROTOCOL: One hundred and five patients eligible for coronary artery bypass graft surgery (65-85 years old, all suffering from hypertension and coronary artery disease, with stable kidney function) were randomized to candesartan (8 mg od) or placebo for between 8 and 11 days prior to surgery. Existing ACE-inhibitor/angiotensin receptor antagonist-therapy had to be stopped prior to the study. Validated cognitive function tests (trail making, Horn's perfomance III und VI, divided attention and change of reaction, memory - immediate and delayed recall, digit span) were performed preoperatively, 1 week and 3 months after surgery. Renal function was assessed by creatinine clearance on the day before, 1 week and 3 months after surgery. RESULTS: Eighty-seven patients (n = 43 Candesartan, n = 44 placebo) were included in the ITT-population for analysis. Drug treatment had no adverse effect on perioperative blood pressure. Only five patients experienced a period of hypotension during introduction of anaesthesia (Candesartan 1/44, placebo 4/44). One week as well as three months after surgery, there were no differences in relevant cognitive function parameters compared to the status prior to surgery, independent from treatment. Creatinine clearance showed a clear decrease one week after surgery with a minor further reduction observed 3 months after surgery, but there was no difference between Candesartan and placebo treated patients. Between both groups, there were no significant differences in the number of adverse events and number of patients with adverse events nor in the incidence of renal failure with consecutive dialysis and cerebral strokes (candesartan 2, placebo 5) and possibly drug related severe adverse events. CONCLUSION: This randomised placebo-controlled and prospective study in elderly patients does not support previous reports suggesting a substantial impairment of cognitive function after coronary artery bypass graft surgery. Preservation of cognitive and renal function was independent of pre-surgical administration of candesartan.

Cognitive outcomes three years after coronary artery bypass surgery: relation to diffusion-weighted magnetic resonance imaging.

BACKGROUND: Cognitive decline is well recognized early after coronary artery bypass graft surgery (CABG), but controversy exists regarding the degree and duration of these changes. We investigated the course of cognitive performance during 3 years after surgery and determined whether ischemic brain injury detected by diffusion-weighted magnetic resonance imaging was related to cognitive decline. METHODS: Thirty-nine patients undergoing on-pump CABG completed preoperative neuropsychologic examination and were followed up prospectively at discharge, 3 months, and 3 years after surgery. Cognitive performance was assessed with a battery of 11 standardized psychometric tests assessing 7 cognitive domains. Cognitive outcome was analyzed by determining (1) mean changes in within-patient scores over time (identifying cognitive functions with decline), and (2) the incidence of cognitive deficit for each individual (identifying patients with decline). Objective evidence of acute cerebral ischemia was obtained by diffusion-weighted magnetic resonance imaging. Prospectively collected data were used to identify predictors of cognitive deficits. RESULTS: From baseline to discharge, cognitive test scores significantly declined in 7 measures. Most tests improved by 3 months. Between 3 months and 3 years, late decline was observed in 2 measures with persistent deterioration in 1 measure (verbal memory) relative to baseline. Postoperative cognitive deficits (drop of > or = 1 SD in scores on > or = 3 tests) were observed in 56% of patients at discharge, 23% at 3 months and 31% at 3 years. On postoperative diffusion-weighted magnetic resonance imaging, there were new ischemic cerebral lesions in 51% of patients. The presence of cognitive deficit at discharge was a significant univariate predictor of late cognitive decline (p = 0.025). A relation between the presence of new diffusion-weighted magnetic resonance imaging detected lesions and cognitive decline, however, was not found. CONCLUSIONS: Longitudinal cognitive performance of patients with CABG showed a two-stage course with early improvement followed by later decline. Long-term cognitive deficit was predicted by early cognitive decline, but not by ischemic brain lesions on magnetic resonance imaging.

Patients with chronic focal cerebellar lesions show no cognitive abnormalities in a bedside test.

The aim of the present study was to show whether cognitive deficits are present in chronic cerebellar patients using a self-developed, validated bedside screening test. Twenty-one adults with a history of infarction within the territory of the posterior-inferior (PICA) or the superior cerebellar artery (SCA), and 25 age-, sex-, and education-matched healthy controls participated. Lesion localization was based on individual 3D MRI scans. The test took 10-12 min including subtests of naming, executive functions, attention, figural and verbal memory, reading, long-term memory, mental arithmetic, higher order motor control, and spatial functions. Though individual patients tended to make more errors than controls, neither total error score nor subscores revealed significant group differences. No obvious cognitive deficits appeared to be present in chronic cerebellar patients as assessed by a bedside screening test.

Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial.

PURPOSE: To investigate the role of prophylactic cranial irradiation (PCI) within a trimodality protocol (chemotherapy, chemoradiotherapy, surgery) for patients with operable stage IIIA non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: After mediastinoscopic staging, patients with operable stage IIIA NSCLC were enrolled to a German multicenter trial and randomly assigned to receive either primary resection followed by adjuvant thoracic radiation therapy (50 to 60 Gy; arm A) or preoperative chemotherapy (cisplatin/etoposide [PE]; three cycles) followed by concurrent chemoradiotherapy (PE plus 45 Gy; 1.5 Gy twice per day) and definitive surgery (arm B), respectively. Patients in arm B were scheduled to receive PCI (30 Gy; 2 Gy daily fractions). RESULTS: One hundred twelve patients were randomly assigned between November 1994 and July 2001. One hundred six patients were eligible (arm A: 51, arm B: 55), 90 males and 16 females, 50 with squamous cell, 16 with large cell, five with adenosquamous, and 35 with adenocarcenoma (median age, 57 years; range, 37 to 71 years). Forty-three patients received PCI as scheduled in arm B. Eleven long-term survivors (arm A: four; arm B: seven) underwent a comprehensive neuropsychological examination. PCI significantly reduced the probability of brain metastases as first site of failure (7.8% at 5 years v 34.7%; P = .02), the overall brain relapse rate was reduced comparably (9.1% at 5 years v 27.2%; P = .04). A slightly reduced neurocognitive performance in comparison with the age-matched normal population was found for patients in both treatment groups. No significant difference between patients who were treated with or without PCI could be noted. CONCLUSION: PCI is effective in preventing brain metastases following this aggressive trimodality approach. Neurocognitive late effects are not significantly different between patients treated with or without PCI.

Carotid intima-media thickness in HIV-infected individuals: relationship of premature atherosclerosis to neuropsychological deficits?

BACKGROUND: Intima-media thickness (IMT) measured by extracranial duplex sonography is a surrogate marker for atherosclerosis. It is well known that IMT is greater in HIV patients than in age-matched healthy controls due to HIV- induced endothelial damage and metabolic side-effects of antiretroviral therapy. However, it remains unclear whether atherosclerosis has an additional impact on cognitive function in HIV patients. Therefore, the objective of this study was to investigate the correlation between IMT and neuropsychological deficits in HIV patients. METHODS: 47 HIV patients and 40 age-matched healthy controls were examined by extracranial ultrasound 2 and 3 cm before the flow divider to evaluate differences in IMT. Possible neuropsychological deficits in HIV patients were assessed using a battery of 10 neuropsychological tests. Results of neuropsychological tests and markers of disease severity were correlated with IMT in HIV patients. RESULTS: IMT was significantly greater in patients than in healthy controls (p < 0.001). However, none of the neuropsychological tests correlated significantly with IMT measurements in HIV patients. There was only a weak correlation between deficits in attention and IMT in HIV patients (r = 0.44; p = 0.005), which was non-significant after correction for multiple comparisons. Markers of disease severity (CD4 cell count, HIV load in plasma, duration of HIV disease) did not correlate with IMT either. CONCLUSION: IMT was greater in HIV patients compared to age-matched controls but it appears that premature atherosclerosis has no additional impact on the evolution of neuropsychological deficits in HIV patients. IMT did not correlate with the severity of immunodeficiency.

Attention and memory dysfunctions in mild multiple sclerosis.

This study investigated the relationship between clinical symptoms and cognitive dysfunction in multiple sclerosis. Cognitive dysfunction and visual evoked potentials (VEPs) were studied in patients free of physical disability and mildly to moderately disabled patients with multiple sclerosis (MS). Disability-free patients (EDSS < or = 1.5; n = 13), mildly to moderately disabled patients (EDSS ranging from 2 to 6; n = 13) and a healthy matched control group (n = 16) were examined with respect to attention, verbal and nonverbal memory and early visual processing (VEPs). Disability-free patients showed mild impairments on phasic alertness and divided attention. Deficits were more pronounced in mildly to moderately disabled patients who were additionally impaired with respect to non-verbal memory. Despite adequate visual acuity, one half of all patients showed abnormal VEP latencies for both eyes at the same time. The findings suggest that cognitive deficits are already present in multiple sclerosis even in the absence of physical disability. Even with normal visual acuity, perceptual impairments should be considered as part of the CNS affection.

Long-term survival following radiotherapy and cytarabine chemotherapy for sporadic primary central nervous system lymphoma.

PURPOSE: To analyze the long-term results following whole brain radiotherapy (WBRT) with sequential intrathecal (i.th.) cytosine arabinoside (Ara-C) +/- intravenous (i.v.) Ara-C in patients with primary central nervous system lymphoma (PCNSL). PATIENTS AND METHODS: 14 patients were treated between July 1987 and August 1995. All had sporadic PCNSL with proven histology of high-grade CNS lymphoma (twelve diffuse large-cell B-lymphomas, one lymphoblastic lymphoma, one large T-cell lymphoma). Patients were treated with two to four cycles of induction chemotherapy (40 mg/m2 Ara-C i.th.), four patients received additional Ara-C i.v. (150 mg/m2, d1-4). WBRT was administered using 1.8-Gy fractions. Intrathecal chemotherapy was planned afterwards in 4-week intervals for 6 months. Posttreatment neurocognitive evaluations were performed in two long-term survivors. RESULTS: Two of four patients who received i.v. and i.th. induction chemotherapy showed progressive disease, and irradiation was started immediately. Six of 14 patients received 50.4 Gy WBRT, four patients had WBRT up to 39.6 Gy followed by a 10.8-Gy boost. Five patients died early during therapy either due to a decline of the general medical condition or progressive disease. Median survival was 41 months (95% confidence interval: 6-79 months), survival at 3 and 5 years was 59% and 42%, respectively. Six patients survived for 3 years, two younger patients are still alive (> 12 years). They show only slightly impaired neurocognitive functions without clinical relevance. CONCLUSION: This WBRT-based protocol with i.th. meningeal prophylaxis using Ara-C +/- i.v. Ara-C yields substantial long-term survival with moderate toxicity. The value of i.v. chemotherapy is currently being investigated in prospective studies.