Ute A. Kopp

Cognitive deficits following anti-NMDA receptor encephalitis

Background Anti-NMDA receptor (NMDAR) encephalitis is a recently characterised autoimmune disorder mainly affecting young women. Although the clinical features of the acute disease are well characterised, cognitive long-term outcome has not been examined in detail. Methods The authors investigated cognitive performance in nine patients with proven anti-NMDAR encephalitis after recovery from the acute disease period (median 43 months after disease onset, range 23 to 69). Patients underwent a comprehensive neuropsychological assessment, including memory tasks that have previously been shown to be sensitive for hippocampal dysfunction. Results Substantial persistent cognitive impairments were observed in eight out of nine patients that mainly consisted of deficits in executive functions and memory. The severity of these deficits varied inter-individually. Patients with early immunotherapy performed significantly better. The most severe deficits were observed with inefficient or delayed initial treatment. Conclusion Our results suggest that cognitive deficits constitute a major long-term morbidity of anti-NMDAR encephalitis. These deficits relate to the distribution of NMDARs in the human brain and their functional role in normal cognition. Good cognitive long-term outcome may depend on early and aggressive treatment.

Long-term effects of pallidal deep brain stimulation in tardive dystonia

Objective: High-frequency stimulation of the globus pallidus internus (GPi) is a highly effective therapy in primary dystonia. Recent reports have also demonstrated almost immediate improvement of motor symptoms in patients with tardive dystonia after pallidal deep brain stimulation (DBS). Here, we show the long-term effect of continuous bilateral GPi DBS in tardive dystonia on motor function, quality of life (QoL), and mood. Methods: Nine consecutive patients undergoing DBS for tardive dystonia were assessed during continuous DBS at 3 time points: 1 week, 3 to 6 months, and last follow-up at the mean of 41 (range 18–80) months after surgery using established and validated movement disorder and neuropsychological scales. Clinical assessment was performed by a neurologist not blinded to the stimulation settings. Results: One week and 3 to 6 months after pallidal DBS, Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) motor scores were ameliorated by 56.4 ± 26.7% and 74.1 ± 15.8%, BFMDRS disability scores by 62.5 ± 21.0% and 88.9 ± 10.3%, and Abnormal Involuntary Movement Scale (AIMS) scores by 52.3 ± 24.1% and 69.5 ± 27.6%, respectively. At last follow-up, this improvement compared with the presurgical assessment was maintained as reflected by a reduction of BFMDRS motor scores by 83.0 ± 12.2%, BFMDRS disability scores by 67.7 ± 28.0%, and AIMS scores by 78.7 ± 19.9%. QoL improved significantly in physical components, and there was a significant improvement in affective state. Furthermore, cognitive functions remained unchanged compared with presurgical status in the long-term follow-up. No permanent adverse effects were observed. Conclusion: Pallidal deep brain stimulation is a safe and effective long-term treatment in patients with medically refractory tardive dystonia.

Pallidal stimulation in dystonia: effects on cognition, mood, and quality of life.

Bilateral deep brain stimulation (DBS) of the globus pallidus internus (GPi) alleviates symptoms in patients with dystonia but its effects on cognition, neuropsychiatric status, and quality of life have not been examined. This is a case series report of 15 consecutive patients with different forms of dystonia who underwent bilateral implantation of DBS electrodes in the GPi. The patients were evaluated preoperatively and after 3–12 months of DBS with tests of cognition (Mattis Dementia Rating Scale, Stroop Test, Trail Making Test, Phonemic and Category Word Fluency, Digit Span, Rey Auditory Verbal Learning Test, Tonic and Phasic Alertness), neuropsychiatric status (Beck Depression and Anxiety Inventories, Montgomery Asberg Depression Rating Scale, Snaith–Hamilton Pleasure Scale, Brief Psychiatric Rating Scale), quality of life, and motor functions. GPi DBS significantly improved dystonic symptoms, functional abilities, and quality of life allowing for a significant reduction of antidystonic medications. No deterioration was observed in cognitive scores and neuropsychiatric measures. The present case series report thus provides preliminary evidence for the safety of GPi DBS regarding cognitive and neuropsychiatric functions in patients with dystonia.

Pallidal and thalamic deep brain stimulation in myoclonus-dystonia.

Deep brain stimulation (DBS) of the internal globus pallidus (GPi) and ventral intermediate thalamic nucleus (VIM) are established treatment options in primary dystonia and tremor syndromes and have been reported anecdotally to be efficacious in myoclonus‐dystonia (MD). We investigated short‐ and long‐term effects on motor function, cognition, affective state, and quality of life (QoL) of GPi‐ and VIM‐DBS in MD. Ten MD‐patients (nine ε‐sarcoglycan‐mutation‐positive) were evaluated pre‐ and post‐surgically following continuous bilateral GPi‐ and VIM‐DBS at four time points: presurgical, 6, 12, and as a last follow‐up at a mean of 62.3 months postsurgically, and in OFF‐, GPi‐, VIM‐, and GPi‐VIM‐DBS conditions by validated motor [unified myoclonus rating scale (UMRS), TSUI Score, Burke‐Fahn‐Marsden dystonia rating scale (BFMDRS)], cognitive, affective, and QoL‐scores. MD‐symptoms significantly improved at 6 months post‐surgery (UMRS: 61.5%, TSUI Score: 36.5%, BFMDRS: 47.3%). Beneficial effects were sustained at long‐term evaluation post‐surgery (UMRS: 65.5%, TSUI Score: 35.1%, BFMDRS: 48.2%). QoL was significantly ameliorated; affective status and cognition remained unchanged postsurgically irrespective of the stimulation conditions. No serious long‐lasting stimulation‐related adverse events (AEs) were observed. Both GPi‐ and VIM‐DBS offer equally effective and safe treatment options for MD. With respect to fewer adverse, stimulation‐induced events of GPi‐DBS in comparison with VIM‐DBS, GPi‐DBS seems to be preferable. Combined GPi‐VIM‐DBS can be useful in cases of incapaciting myoclonus, refractory to GPi‐DBS alone.

Planning and realisation of complex intentions in patients with Parkinson’s disease

Background: There is some evidence that patients with Parkinson’s disease may impaired in prospective memory performance (planning and self initiated realisation of delayed intentions). Little is known about the effect of the disease on distinct phases of prospective memory and the potential mechanisms underlying these effects. Objective: To investigate intention formation, intention retention, intention initiation, and intention execution of patients with Parkinson’s disease and test for the mediating influence of working memory, inhibition, short term retrospective memory, and divided attention. Methods: 16 patients with Parkinson’s disease and 16 age and education matched normal controls were given a complex event based prospective memory task which differentiates four phases of prospective remembering. In addition, participants completed tasks assessing potential cognitive mediators. Results: On the prospective remembering task, Parkinson patients were impaired in the intention formation phase and showed a trend towards impairment in the intention initiation. In contrast, there were no impairments of retrospective intention retention or the fidelity with which the patients executed their previously developed plan. The group effects were related to interindividual differences in working memory span. Conclusions: The results suggest that the planning phase of prospective remembering is specifically impaired in Parkinson’s disease, and that the impairment is related to working memory deficit. In contrast, even when complex intentions have to be remembered, the retrospective storage of intentions to be performed is not impaired.

Functional and structural brain changes in anti-N-methyl-D-aspartate receptor encephalitis.

Anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis with a characteristic neuropsychiatric syndrome and severe and prolonged clinical courses. In contrast, standard clinical magnetic resonance imaging (MRI) remains normal in the majority of patients. Here, we investigated structural and functional brain changes in a cohort of patients with anti‐NMDAR encephalitis.

The human hippocampal formation mediates short-term memory of colour–location associations

The medial temporal lobe (MTL) has long been considered essential for declarative long-term memory, whereas the fronto-parietal cortex is generally seen as the anatomical substrate of short-term memory. This traditional dichotomy is questioned by recent studies suggesting a possible role of the MTL for short-term memory. In addition, there is no consensus on a possible specialization of MTL sub-regions for memory of associative information. Here, we investigated short-term memory for single features and feature associations in three humans with post-surgical lesions affecting the right hippocampal formation and in 10 healthy controls. We used three delayed-match-to-sample tasks with two delays (900/5000 ms) and three set sizes (2/4/6 items). Subjects were instructed to remember either colours, locations or colour-location associations. In colour-only and location-only conditions, performance of patients did not differ from controls. By contrast, a significant group difference was found in the association condition at 5000 ms delay. This difference was largely independent of set size, thus suggesting that it cannot be explained by the increased complexity of the association condition. These findings show that the hippocampal formation plays a significant role for short-term memory of simple visuo-spatial associations, and suggest a specialization of MTL sub-regions for associative memory.

Role of working memory components in planning performance of individuals with Parkinson's disease

The current study investigated the involvement of all four components of Baddeleys [Baddeley, A. D. (2000). The episodic buffer: A new component of working memory? Trends in Cognitive Sciences, 4, 417-423] revised working memory model in deficits of planning accompanying Parkinsons disease (PD). PD resulted in poorer formulation and execution of plans, as measured by the Tower of London task. PD also reduced the efficiency of the episodic buffer and central executive components of working memory, but did not influence storage of verbal or visuospatial information. Planning deficits in PD were particularly linked to problems in integrating multimodal short-term information with long-term memory (episodic buffer). These results emphasize the importance of integrative and executive processing in cognitive problems in PD, rather than simple memory deficits.

Structural Hippocampal Damage Following Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

BACKGROUND The majority of patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis suffer from persistent memory impairment despite unremarkable routine clinical magnetic resonance imaging. With improved acute care in these patients, neurocognitive impairment represents the major contributor to long-term morbidity and has thus become a focus of attention. METHODS Forty patients with anti-NMDAR encephalitis after the acute disease stage and 25 healthy control subjects underwent multimodal structural imaging that combined volumetry of hippocampal subfields with analysis of hippocampal microstructural integrity. Verbal and visuospatial memory performance was assessed in all patients and correlation and mediation analyses were performed to examine associations between hippocampal structural integrity, memory performance, and disease severity. RESULTS Hippocampal volumes were significantly reduced in patients and hippocampal subfield analysis revealed bilateral atrophy of the input and output regions of the hippocampal circuit. Microstructural integrity was impaired in both hippocampi in patients. Importantly, hippocampal volumetric and microstructural integrity measures correlated with memory performance and disease severity and duration. Mediation analysis revealed that hippocampal microstructure mediated the effect of disease severity on memory performance. CONCLUSIONS Data from this largest cohort of anti-NMDAR encephalitis patients that underwent extensive multimodal magnetic resonance imaging demonstrate that structural hippocampal damage and associated memory deficits are important long-term sequelae of the encephalitis. Correlation with disease duration and severity highlights the need for rapid diagnosis and adequate immunotherapy to prevent persistent damage to the hippocampus. Advanced imaging protocols may allow a more detailed analysis of structural damage to assess disease progression in clinical routine examinations and for therapy evaluation in prospective trials.

Subthalamic stimulation differentially modulates declarative and nondeclarative memory

Declarative memory has been reported to rely on the medial temporal lobe system, whereas non-declarative memory depends on basal ganglia structures. We investigated the functional role of the subthalamic nucleus (STN), a structure closely connected with the basal ganglia for both types of memory. Via deep brain high frequency stimulation (DBS) we manipulated neural activity of the STN in humans. We found that DBS-STN differentially modulated memory performance: declarative memory was impaired, whereas non-declarative memory was improved in the presence of STN-DBS indicating a specific role of the STN in the activation of memory systems.