Christine Daniels

Neuropsychological and psychiatric changes after deep brain stimulation for Parkinson's disease: a randomised, multicentre study.

BACKGROUND Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces motor symptoms in patients with Parkinsons disease (PD) and improves their quality of life; however, the effect of DBS on cognitive functions and its psychiatric side-effects are still controversial. To assess the neuropsychiatric consequences of DBS in patients with PD we did an ancillary protocol as part of a randomised study that compared DBS with the best medical treatment. METHODS 156 patients with advanced Parkinsons disease and motor fluctuations were randomly assigned to have DBS of the STN or the best medical treatment for PD according to the German Society of Neurology guidelines. 123 patients had neuropsychological and psychiatric examinations to assess the changes between baseline and after 6 months. The primary outcome was the comparison of the effect of DBS with the best medical treatment on overall cognitive functioning (Mattis dementia rating scale). Secondary outcomes were the effects on executive function, depression, anxiety, psychiatric status, manic symptoms, and quality of life. Analysis was per protocol. The study is registered at ClinicalTrials.gov, number NCT00196911. FINDINGS 60 patients were randomly assigned to receive STN-DBS and 63 patients to have best medical treatment. After 6 months, impairments were seen in executive function (difference of changes [DBS-best medical treatment] in verbal fluency [semantic] -4.50 points, 95% CI -8.07 to -0.93, Cohens d=-;0.4; verbal fluency [phonemic] -3.06 points, -5.50 to -0.62, -0.5; Stroop 2 naming colour error rate -0.37 points, -0.73 to 0.00, -0.4; Stroop 3 word reading time -5.17 s, -8.82 to -1.52, -0.5; Stroop 4 colour naming time -13.00 s, -25.12 to -0.89, -0.4), irrespective of the improvement in quality of life (difference of changes in PDQ-39 10.16 points, 5.45 to 14.87, 0.6; SF-36 physical 16.55 points, 10.89 to 22.21, 0.9; SF-36 psychological 9.74 points, 2.18 to 17.29, 0.5). Anxiety was reduced in the DBS group compared with the medication group (difference of changes in Beck anxiety inventory 10.43 points, 6.08 to 14.78, 0.8). Ten patients in the DBS group and eight patients in the best medical treatment group had severe psychiatric adverse events. INTERPRETATION DBS of the STN does not reduce overall cognition or affectivity, although there is a selective decrease in frontal cognitive functions and an improvement in anxiety in patients after the treatment. These changes do not affect improvements in quality of life. DBS of the STN is safe with respect to neuropsychological and psychiatric effects in carefully selected patients during a 6-month follow-up period. FUNDING German Federal Ministry of Education and Research (01GI0201).

Presentation, diagnosis, and management of multiple system atrophy in Europe: Final analysis of the European multiple system atrophy registry†

Multiple system atrophy (MSA) is a Parkinsons Disease (PD)‐like α‐synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four‐hundred thirty‐seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA‐P) and 32% as cerebellar type (MSA‐C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas.

Red Flags for Multiple System Atrophy

The clinical diagnosis of multiple system atrophy (MSA) is fraught with difficulty and there are no pathognomonic features to discriminate the parkinsonian variant (MSA‐P) from Parkinsons disease (PD). Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs (ataxia) or autonomic failure as major diagnostic criteria, certain other clinical features known as “red flags” or warning signs may raise the clinical suspicion of MSA. To study the diagnostic role of these features in MSA‐P versus PD patients, a standardized red flag check list (RFCL) developed by the European MSA Study Group (EMSA‐SG) was administered to 57 patients with probable MSA‐P and 116 patients with probable PD diagnosed according to established criteria. Those red flags with a specifity over 95% were selected for further analysis. Factor analysis was applied to reduce the number of red flags. The resulting set was then applied to 17 patients with possible MSA‐P who on follow‐up fulfilled criteria of probable MSA‐P. Red flags were grouped into related categories. With two or more of six red flag categories present specificity was 98.3% and sensitivity was 84.2% in our cohort. When applying these criteria to patients with possible MSA‐P, 76.5% of them would have been correctly diagnosed as probable MSA‐P 15.9 (±7.0) months earlier than with the Consensus criteria alone. We propose a combination of two out of six red flag categories as additional diagnostic criteria for probable MSA‐P.

Minocycline 1‐year therapy in multiple‐system‐atrophy: Effect on clinical symptoms and [11C] (R)‐PK11195 PET (MEMSA‐trial)

The aim of the study was to investigate the efficacy of the antibiotic minocycline as a drug treatment in patients with Multiple‐System‐Atrophy Parkinson‐type (MSA‐P). Sixty‐three patients were randomized to minocycline 200 mg/d (n = 32) or a matching placebo (n = 31). The primary outcome variable was the change in the value of the motor score of the Unified Multiple‐System‐Atrophy Rating‐Scale (UMSARSII) from baseline to 48 weeks. Secondary outcome variables included subscores and individual Parkinsonian symptoms as determined by the UMSARS and the Unified‐Parkinsons‐Disease Rating‐Scale (UPDRS). Health‐related quality of life (HrQoL) was assessed using the EQ‐5D and SF‐12. “Progression rate” was assumed to be reflected in the change in motor function over 48 weeks. At 24 weeks and 48 weeks of follow‐up, there was a significant deterioration in motor scores in both groups, but neither the change in UMSARSII nor in UPDRSIII differed significantly between treatment groups, i.e. “progression rate” was considered to be similar in both treatment arms. HrQoL did not differ among the two treatment arms. In a small subgroup of patients (n = 8; minocycline = 3, placebo = 5)[11C](R)‐PK11195‐PET was performed. The three patients in the minocycline group had an attenuated mean increase in microglial activation as compared to the placebo group (P = 0.07) and in two of them individually showed decreased [11C](R)‐PK11195 binding actually decreased. These preliminary PET‐data suggest that minocycline may interfere with microglial activation. The relevance of this observation requires further investigation. This prospective, 48 week, randomized, double‐blind, multinational study failed to show a clinical effect of minocycline on symptom severity as assessed by clinical motor function.

Progression of multiple system atrophy (MSA): A prospective natural history study by the European MSA study group (EMSA SG)

The disease‐specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed recently and validated for assessing disease severity in multiple system atrophy (MSA). Here, we aimed at (1) assessing rates of disease progression in MSA and (2) validating UMSARS for sensitivity to change over time. Impairment was assessed at two time points 12 months apart using UMSARS Part I (historical review), UMSARS Part II (motor examination), as well as measures of global disease severity, including UMSARS Part IV, Hoehn and Yahr (HY) Parkinsons disease staging, Schwab England Activities of Daily Living (SE ADL), and a three‐point global Severity Scale (SS3). Fifty patients (male:female ratio, 1:0.9; possible MSA, 16%; probable MSA, 84%; MSA‐parkinsonian, 58%; MSA‐cerebellar, 42%) were assessed twice with an interval of 12.3 months. UMSARS II scores progressed by 57.3% (P < 0.0001) and UMSARS I scores by 35.6% (P < 0.0001) in relation to the respective baseline scores with no differences between motor subtypes, diagnostic categories and gender. Significant inverse correlations between (1) UMSARS I or UMSARS II progression and (2) baseline disability measures (i.e., the respective UMSARS or SS3 scores) and disease duration were found. Furthermore, the increases in HY staging, SE ADL and SS3 correlated significantly with UMSARS I, UMSARS II, and UMSARS IV progression. This report is the first prospective study showing rapid annual UMSARS rates of decline in MSA. Our data contribute to the ongoing validation process of UMSARS, and they facilitate the planning and implementation of future neuroprotective intervention trials.

Relation of lead trajectory and electrode position to neuropsychological outcomes of subthalamic neurostimulation in Parkinson’s disease: results from a randomized trial

Deep brain stimulation of the subthalamic nucleus improves motor functions in patients suffering from advanced Parkinsons disease but in some patients, it is also associated with a mild decline in cognitive functioning about one standard deviation from the preoperative state. We assessed the impact of the cortical lead entry point, the subcortical electrode path and the position of the active electrode contacts on neuropsychological changes after subthalamic nucleus-deep brain stimulation compared to a control group of patients receiving best medical treatment. Sixty-eight patients with advanced Parkinsons disease were randomly assigned to have subthalamic nucleus-deep brain stimulation or best medical treatment for Parkinsons disease. All patients had a blinded standardized neuropsychological exam (Mattis Dementia Rating scale, backward digit span, verbal fluency and Stroop task performance) at baseline and after 6 months of treatment. Patients with subthalamic nucleus-deep brain stimulation were defined as impaired according to a mild decline of one or more standard deviations compared to patients in the best medical treatment group. The cortical entry point of the electrodes, the electrode trajectories and the position of the active electrode contact were transferred into a normalized brain volume by an automated, non-linear registration algorithm to allow accurate statistical group analysis using pre- and postoperative magnetic resonance imaging data. Data of 31 patients of the subthalamic nucleus-deep brain stimulation group and 31 patients of the best medical treatment group were analysed. The subthalamic nucleus-deep brain stimulation group showed impaired semantic fluency compared with the best medical treatment group 6 months after surgery (P = 0.02). Electrode trajectories intersecting with caudate nuclei increased the risk of a decline in global cognition and working memory performance. Statistically, for every 0.1 ml overlap with a caudate nucleus, the odds for a decline >1 standard deviation increased by a factor of 37.4 (odds ratio, confidence interval 2.1-371.8) for the Mattis Dementia Rating Scale and by a factor of 8.8 (odds ratio, confidence interval 1.0-70.9) for the backward digit span task. Patients with subthalamic nucleus-deep brain stimulation who declined in semantic verbal fluency, Stroop task and the backward digit span task performance showed a position of the active electrode outside the volume built by the active electrodes of stable performers. Passage of the chronic stimulation lead through the head of the caudate increases the risk of global cognitive decline and working memory performance after subthalamic nucleus-deep brain stimulation in Parkinsons disease. Therefore the electrode path should be planned outside the caudate nuclei, whenever possible. This study also stresses the importance of precise positioning of the active stimulating contact within the subthalamic volume to avoid adverse effects on semantic verbal fluency and response inhibition.

The European Multiple System Atrophy-Study Group (EMSA-SG)

Summary.Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson’s Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and – to a lesser degree – of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.

Risk factors for executive dysfunction after subthalamic nucleus stimulation in Parkinson's disease.

A slight decline in cognitive functions and especially in executive functioning after deep brain stimulation (DBS) of the nucleus subthalamicus (STN) in patients with Parkinsons disease (PD) has been described. This study evaluated baseline parameters that contribute to a deterioration of cognitive functioning after DBS. We analyzed data from the neuropsychological protocol in a randomized controlled study comparing DBS with best medical treatment (BMT). Change scores were calculated for the cognitive domains “global cognitive functioning,” “memory,” “working memory,” “attention,” and “executive function.” These domain‐specific change scores were correlated with previously defined preoperative parameters. Compared with the BMT group (63 patients), the STN‐DBS group (60 patients) showed a significant decline only in the domain executive function 6 months after DBS, which was significantly correlated with age, levodopa‐equivalence dosage (LED) and axial subscore of the UPDRS in the off‐medication state at baseline. Multiple regression analysis showed that these three factors explained, however, only about 23% of the variance. Patients with higher age, higher baseline LED, and/or higher axial subscore of the UPDRS at baseline have an increased risk for worsening of executive function after STN‐DBS. High scores of these factors might reflect an advanced stage of disease progression. As these baseline factors explained the variance of the change score executive function only to a minor proportion, other factors including the surgical procedure, the exact placement of the electrode or postsurgical management might be more relevant for a decline in executive functioning after STN‐DBS.

Rate dependency of the human cortical network subserving executive functions during generation of random number series – a functional magnetic resonance imaging study

In a random number generation (RNG) task subjects are instructed to generate the numbers 1-10 in a random fashion. RNG performance is assumed to involve executive functions, as it requires controlled response generation and suppression of habitual responses. To investigate cerebral structures involved in RNG associated executive functions we investigated functional magnetic resonance imaging in eight healthy subjects while performing an RNG task at two different response rates (1 and 2 Hz). During the 1 Hz condition an activation was detected bilaterally in the dorsolateral prefrontal cortex (BA 9/46), the lateral premotor cortex (BA 6), the anterior cingulate (BA 32), the inferior and superior parietal cortex (BA 7/40) and the cerebellar hemispheres. In the 2 Hz condition behavioural data showed higher counting tendencies reflecting poorer executive control. In parallel, a homogenous diminution of the activity in the involved cortical areas was obtained. This finding would support the theory of a cortical network involved in executive functions consisting of distinct brain regions working together rather than a distinct fronto-cortical functional localisation.

Neuropsychological consequences of endarterectomy and endovascular angioplasty with stent placement for treatment of symptomatic carotid stenosis : A prospective randomised study

Background and purposePrevious studies compared carotid endarterectomy (CEA) and carotid artery stent placement (CAS) for treatment of symptomatic carotid artery stenosis. Whereas most previous studies showed both treatment modalities to be associated with a comparable risk of periprocedural cerebrovascular complications, these previous studies have shown significantly more microemboli and significantly more lesions in diffusion-weighted MR imaging after CAS compared to CEA. The clinical relevance of these differences remains unknown.We therefore compared the neuropsychological consequences of CAS and CEA and additionally measured the S100β protein, a marker of cerebral damage.MethodsA total of 48 patients with symptomatic carotid artery stenosis greater than 70 % (according to ECST criteria) were enrolled and 45 patients participated in the follow-up. The patients were randomly assigned for CEA (24 patients) or CAS (21 patients). S100β protein values were evaluated 2 hours before the procedure, as well as one and two hours thereafter. Patients were assessed before treatment, and again 6 and 30 days after treatment using a comprehensive neuropsychological test battery.ResultsPatients of the CAS and the CEA groups did not significantly differ in terms of age, gender, education, degree of carotid artery stenosis, cerebrovascular symptoms and vascular risk factors. Following previously used criteria, a cognitive change in patients was assumed to have occurred when there was a decline of more than one standard deviation in two or more tests assessing various cognitive domains. Six days and 30 days after the treatment both groups showed a comparable number of patients with cognitive changes compared to baseline. There were no significant differences in S100β protein values.ConclusionThese results provide some reassurance that CAS is not associated with greater cognitive deterioration than CEA is.