Beate Schoch

Genome-wide association study of intracranial aneurysm identifies three new risk loci

Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with ∼832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 × 10−12), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 × 10−9) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 × 10−9). We also confirmed prior associations near SOX17 (8q11.23–q12.1; OR = 1.28, P = 1.3 × 10−12) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 × 10−22). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.

Functional localization in the human cerebellum based on voxelwise statistical analysis: a study of 90 patients.

The aim of the present study was to examine somatotopy in the cerebellar cortex and a possible differential role of the cerebellar cortex and nuclei in functional outcome. Clinical findings and 3D MRI-based cerebellar lesions site were compared in a group of 90 patients with focal cerebellar lesion using International Cooperative Ataxia Rating Scale (ICARS) and voxel-based lesion-symptom mapping (VLSM). Separate analysis was performed in patients with acute and chronic ischemic lesions (n=43) and patients with acute and chronic surgical lesions (n=47). Thirty-eight patients were included after resection of a cerebellar tumor in childhood or adolescence. The most significant lesion symptom correlations were observed in the subgroup with acute ischemic lesions. Limb ataxia was significantly correlated with lesions of the interposed (NI) and part of the dentate nuclei (ND), ataxia of posture and gait with lesions of the fastigial nuclei (NF) including NI. Correlations with cortical lesions were less significant and present in the superior cerebellum only. Upper limb ataxia was correlated with lesions of vermal, paravermal and hemispheral lobules IV-V and VI, lower limb ataxia with lesions of vermal, paravermal and hemispheral lobules III and VI, dysarthria with lesions of paravermal and hemispheral lobules V and VI and ataxia of posture and gait with lesions of vermal and paravermal lobules II, III and IV. In the subgroups with chronic focal lesions, similar correlations were observed with lesions of the cerebellar nuclei, but significantly less correlations with lesions of the cerebellar cortex. Functional localization based on VLSM backs findings in previous animal and functional brain images studies in healthy human subjects. The lesion site appears to be critical for motor recovery. Lesions affecting the cerebellar nuclei are not fully compensated at any age and independent of the pathology in humans.

The influence of focal cerebellar lesions on the control and adaptation of gait

Cerebellar ataxic gait is influenced greatly by balance disorders, most likely caused by lesions of the medial zone of the cerebellum. The contributions of the intermediate and lateral zone to the control of limb dynamics for gait and the adaptation of locomotor patterns are less well understood. In this study, we analysed locomotion and goal-directed leg movements in 12 patients with chronic focal lesions after resection of benign cerebellar tumours. The extent of the cortical lesion and possible involvement of the cerebellar nuclei was determined by 3D-MR imaging. The subjects (age range 13-39 years, mean 20.3; seven female; ICARS score: mean 5.7, SD 6.3) performed three tasks: goal-directed leg placement, walking and walking with additional weights on the shanks. Based on the performance on the first two tasks, patients were categorized as impaired or unimpaired for leg placement and for dynamic balance control in gait. The subgroup with impaired leg placement but not the subgroup with impaired balance showed abnormalities in the adaptation of locomotion to additional loads. A detailed analysis revealed specific abnormalities in the temporal aspects of intra-limb coordination for leg placement and adaptive locomotion. These findings indicate that common neural substrates could be responsible for intra-limb coordination in both tasks. Lesion-based MRI subtraction analysis revealed that the interposed and the adjacent dentate nuclei were more frequently affected in patients with impaired compared to unimpaired leg placement, whereas the fastigial nuclei (and to a lesser degree the interposed nuclei) were more frequently affected in patients with impaired compared with unimpaired dynamic balance control. The intermediate zone appears thus to be of particular importance for multi-joint limb control in both goal-directed leg movements and in locomotion. For locomotion, our results indicate an influence of the intermediate zone on dynamic balance control as well as on the adaptation to changes in limb dynamics.

Reliability and validity of the scale for the assessment and rating of ataxia: a study in 64 ataxia patients.

The objective of this study was to test the reliability and validity of the Scale for the Assessment and Rating of Ataxia (SARA) in ataxia patients not suffering from autosomal dominant spinocerebellar ataxia (SCA). To this end, 64 patients with various ataxia disorders or stable cerebellar lesions were rated independently by two investigators. In addition to SARA, the following assessment instruments were applied: ataxia disease stage, Barthel index and part IV (functional assessment) of the Unified Huntingtons Disease Rating scale (UHDRS‐IV). Eighteen patients were rated twice. Inter‐rater and intrarater reliability were very high with ICCs of 0.98 and 0.99. Internal consistency was high indicated by Cronbachs α of 0.97. Factorial analysis revealed that the rating results were mainly determined by one major factor with an eigenvalue of 6.34 which explained 52.8% of the variance. SARA score increased with disease stage (P < 0.0001) and was closely correlated with Barthel index (r = −0.63, P < 0.0001) and UHDRS‐IV (r = −0.62, P < 0.0001), but only weakly correlated with disease duration (r = 0.44, P < 0.001). The results suggest that SARA is a reliable and valid measure of ataxia in non‐SCA ataxia patients.

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

Abstract.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.

Postural and gait performance in children with attention deficit/hyperactivity disorder

Up to 50% of children and adolescents with attention deficit/hyperactivity disorder (ADHD) exhibit motor abnormalities including altered balance. Results from brain imaging studies indicate that these balance deficits could be of cerebellar origin as ADHD children may show atrophy in those regions of the cerebellum associated with gait and balance control. To address this question, this study investigated postural and gait abilities in ADHD children and compared their static and dynamic balance with children with known lesions in the cerebellum. Children diagnosed with ADHD according to DSM IV-TR diagnostic criteria were compared with children with chronic surgical cerebellar lesions and age-matched controls. A movement coordination test was used to assess differences in motor development. Postural and gait abilities were assessed using posturography, treadmill walking and a paced stepping task. Volumes of the cerebellum and the cerebrum were assessed on the basis of 3D magnetic resonance images (MRI). Children with cerebellar lesions showed significant performance decrements in all tasks compared with the controls, particularly in the movement coordination test and paced stepping task. During dynamic posturography ADHD-participants showed mild balance problems which correlated with findings in cerebellar children. ADHD children showed abnormalities in a backward walking task and minor abnormalities in the paced stepping test. They did not differ in treadmill walking from the controls. These findings support the notion that cerebellar dysfunction may contribute to the postural deficits seen in ADHD children. However, the observed abnormalities were minor. It needs to be examined whether balance problems become more pronounced in ADHD children exhibiting more prominent signs of clumsiness.

Cerebellar regions involved in adaptation to force field and visuomotor perturbation

Studies with patients and functional magnetic resonance imaging investigations have demonstrated that the cerebellum plays an essential role in adaptation to visuomotor rotation and force field perturbation. To identify cerebellar structures involved in the two tasks, we studied 19 patients with focal lesions after cerebellar infarction. Focal lesions were manually traced on magnetic resonance images and normalized using a new spatially unbiased template of the cerebellum. In addition, we reanalyzed data from 14 patients with cerebellar degeneration using voxel-based morphometry. We found that adjacent regions with only little overlap in the anterior arm area (lobules IV to VI) are important for adaptation in both tasks. Although adaptation to the force field task lay more anteriorly (lobules IV and V), lobule VI was more important for the visuomotor task. In addition, regions in the posterolateral cerebellum (Crus I and II) contributed to both tasks. No consistent involvement of the posterior arm region (lobule VIII) was found. Independence of the two kinds of adaptation is further supported by findings that performance in one task did not correlate to performance in the other task. Our results show that the anterior arm area of the cerebellum is functionally divided into a more posterior part of lobule VI, extending into lobule V, related to visuomotor adaption, and a more anterior part including lobules IV and V, related to force field adaption. The posterolateral cerebellum may process common aspects of both tasks.

Analysis of intrathecal interleukin-6 as a potential predictive factor for vasospasm in subarachnoid hemorrhage

OBJECTIVEInflammatory response seems to be one of the relevant pathophysiological aspects for developing vasospasm in subarachnoid hemorrhage. The probable diagnostic value of intrathecal proinflammatory markers is still unclear and is assessed in this study. METHODSWe analyzed daily clinical data and laboratory tests of the cerebrospinal fluid (CSF) of 64 patients with mostly poor-grade subarachnoid hemorrhage during a period of 14 days. Special attention was given to the relationship between the development of vasospasm and the time course of the intrathecal interleukin (IL)-6 concentrations in CSF (IL-6CSF). The potential power of IL-6CSF for predicting vasospasm was studied. RESULTSVasospasm developed in 28.1% of the patients, with a mean onset of 6.4 days after bleeding, and was detected by conventional methods. Patients with vasospasm demonstrated statistically significant higher median values of IL-6CSF on Days 4 and 5 (P < 0.05). Most importantly, the increase of IL-6CSF preceded the conventional signs of vasospasm. A cut-off value of IL-6CSF of at least 2000 pg/ml on Day 4 yielded an 11.72-fold higher relative risk (95% confidence interval, 2.93–46.60) of developing vasospasm, predicting vasospasm with a sensitivity of 88.9% and a specificity of 78.3%. We found a statistically significant correlation between IL-6CSF and delayed cerebral ischemia for Day 7 (P = 0.03). However, there was no correlation with IL-6CSF on any other day and outcome. CONCLUSIONIL-6CSF seems to be a reliable early marker for predicting vasospasm after subarachnoid hemorrhage on Days 4 and 5 before clinical onset.

Clipping versus coiling: neuropsychological follow up after aneurysmal subarachnoid haemorrhage (SAH).

ABSTRACT Patients treated with microsurgical clipping of ruptured intracranial aneurysms often suffer from neuropsychological deficits in spite of a good neurological outcome. The purpose of this study was to explore if the deficits are related to the type of therapy. Two groups of 16 patients each suffering from aneurysmal SAH, matched for sex, age, aneurysm-site and Hunt and Hess score, and 16 control subjects were examined with a battery of neuropsychological tests including memory, attention, and executive function. Depression, mood, and quality of life were also assessed. One patient group had been treated with surgical clipping, the other with endovascular coiling. Both patient groups showed deficits in verbal and visual memory. Clipped patients were slightly more impaired than coiled patients, especially on measures of affect and on a self-assessment measure of executive function. The pattern of results suggests that the neuropsychological outcome after aneurysmal SAH is affected by both the severity of the bleeding and the type of therapy.

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 lesionsymptom 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.