Long-Term Cognitive Outcome in Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

OBJECTIVE: Cognitive dysfunction is a core symptom of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, but detailed studies on prevalence, characteristics of cognitive deficits, and the potential for recovery are missing. Here, we performed a prospective longitudinal study to assess cognitive long-term outcome and identify clinical predictors. METHODS: Standardized comprehensive neuropsychological assessments were performed in 43 patients with NMDAR encephalitis 2.3 years and 4.9 years (median) after disease onset. Cognitive assessments covered executive function, working memory, verbal/visual episodic memory, attention, subjective complaints, and depression and anxiety levels. Cognitive performance of patients was compared to that of 30 healthy participants matched for age, sex, and education. RESULTS: All patients had persistent cognitive deficits 2.3 years after onset, with moderate or severe impairment in >80% of patients. Core deficits included memory and executive function. After 4.9 years, significant improvement of cognitive function was observed, but moderate to severe deficits persisted in two thirds of patients, despite favorable functional neurological outcomes (median modified Rankin Scale = 1). Delayed treatment, higher disease severity, and longer duration of the acute phase were predictors for impaired cognitive outcome. The recovery process was time dependent, with greater gains earlier after the acute phase, although improvements were possible for several years after disease onset. INTERPRETATION: Cognitive deficits are the main contributor to long-term morbidity in NMDAR encephalitis and persist beyond functional neurological recovery. Nonetheless, cognitive improvement is possible for several years after the acute phase and should be supported by continued cognitive rehabilitation. Cognition should be included as an outcome measure in future clinical studies. ANN NEUROL 2021;90:949-961.

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult-onset disorder.

OBJECTIVES: Genetic variant classification is a challenge in rare adult-onset disorders as in SCA-PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA-PRKCG a comprehensive phenotype description from a German multi-center cohort, including standardized 3D MR imaging. METHODS: This cross-sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS). RESULTS: Our sample included 25 cases confirmed as SCA-PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA-PRKCG included slowly progressive ataxia (onset at 4-50 years), preceded in some by early-onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive-affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA-PRKCG cases but in none of the controls. INTERPRETATION: In this largest cohort to date, SCA-PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non-ataxia movement disorders and cognitive-affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA-PRKCG.

Bortezomib at therapeutic doses poorly passes the blood-brain barrier and does not impair cognition.

The 26S proteasome inhibitor bortezomib is currently used to treat multiple myeloma but also is effective in the treatment of antibody-mediated autoimmune disorders. One clinical concern is bortezomib's toxicity towards the (central) nervous system. We used standardized neuropsychological testing to assess cognitive function in six patients with myasthenia gravis and systemic lupus erythematodes before and after treatment with a mean cumulative dose of 9.4 mg m-2 bortezomib. In addition, cognitive performance was measured in adult C57Bl/6 mice after treatment with a human equivalent cumulative dose of 15.6 mg m-2. Bortezomib concentrations were analysed in the human CSF as well as the brain tissue and serum of adult C57Bl/6 mice at various time points after the injection of 1.3 mg m-2 bortezomib with liquid chromatography-tandem mass spectrometry. Neither patients nor mice showed signs of cognitive impairment after bortezomib therapy. Bortezomib concentrations in the human CSF and murine brain tissue reached only 5-7% of serum concentrations with comparable concentrations measured in the hippocampus and the neocortex. Five-fold higher concentrations were needed to damage neuronal cells in vitro. In conclusion, penetration of the intact blood-brain barrier by bortezomib is low. Overall, our data show that bortezomib is a safe medication in terms of central nervous system toxicity.

Impact of atrial fibrillation burden on cognitive function after left atrial ablation - Results of the MACPAF study.

Atrial fibrillation (AF) is associated with cognitive decline and dementia irrespective of AF-related ischemic stroke. We investigated whether AF burden after ablation in patients with symptomatic paroxysmal AF has an impact on cognitive function. After enrolment to the prospective MACPAF study, study patients received an insertable loop recorder (ILR) and underwent serial neurological/cognitive assessment. To compare cognitive function, the delta of baseline and six months test results (Δpre/post) and a score to assess overall cognitive performance were computed. Thirty patients (median age 65 years (IQR 57-69), 40% female) were divided into groups according to median AF burden (<0.5% vs. ≥0.5%) after ablation. Overall cognitive performance did not differ in patients with an AF burden < 0.5% (median 120% [IQR 100-150]) vs. ≥0.5% (median 120% [IQR 100-160]) within six months after ablation (p = 0.74). Comparing Δpre/post, patients with an AF burden ≥ 0.5% showed significantly better results in the digit-span backwards test (median + 1 [IQR 0 - +2 points]) compared to patients with an AF burden < 0.5% (median 0 [IQR -1-+1]) six months after ablation (p = 0.03). In patients with an AF burden < 0.5%, there was a statistical trend towards better results in the RAVLT test (median + 3 [IQR 0-+4]; p = 0.08) and the ROC test (median + 3 [IQR -1-+5; p = 0.07) compared to patients with an AF burden ≥ 0.5% (median -1 [IQR -3-+2] words and median -1 [IQR -5-+2] points, respectively). Therefore, AF burden had no significant impact on cognitive performance within six months after ablation. Clinical Trial Registration: clinicaltrials.gov NCT01061931.

Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)-study protocol for a randomized controlled trial.

BACKGROUND: Given the global increase in the aging population and age-related diseases, the promotion of healthy aging is one of the most crucial public health issues. This trial aims to contribute to the establishment of effective approaches to promote cognitive and brain health in older individuals with subjective cognitive decline (SCD). Presence of SCD is known to increase the risk of objective cognitive decline and progression to dementia due to Alzheimer's disease. Therefore, it is our primary goal to determine whether spermidine supplementation has a positive impact on memory performance in this at-risk group, as compared with placebo. The secondary goal is to examine the effects of spermidine intake on other neuropsychological, behavioral, and physiological parameters. METHODS: The SmartAge trial is a monocentric, randomized, double-blind, placebo-controlled phase IIb trial. The study will investigate 12 months of intervention with spermidine-based nutritional supplementation (target intervention) compared with 12 months of placebo intake (control intervention). We plan to recruit 100 cognitively normal older individuals with SCD from memory clinics, neurologists and general practitioners in private practice, and the general population. Participants will be allocated to one of the two study arms using blockwise randomization stratified by age and sex with a 1:1 allocation ratio. The primary outcome is the change in memory performance between baseline and post-intervention visits (12 months after baseline). Secondary outcomes include the change in memory performance from baseline to follow-up assessment (18 months after baseline), as well as changes in neurocognitive, behavioral, and physiological parameters (including blood and neuroimaging biomarkers), assessed at baseline and post-intervention. DISCUSSION: The SmartAge trial aims to provide evidence of the impact of spermidine supplementation on memory performance in older individuals with SCD. In addition, we will identify possible neurophysiological mechanisms of action underlying the anticipated cognitive benefits. Overall, this trial will contribute to the establishment of nutrition intervention in the prevention of Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03094546 . Registered 29 March 2017-retrospectively registered. PROTOCOL VERSION: Based on EA1/250/16 version 1.5.

Musical memory and hippocampus revisited: Evidence from a musical layperson with highly selective hippocampal damage.

The role of the human hippocampus for musical memory is still unclear. While imaging studies in healthy humans have repeatedly shown hippocampal activation in musical memory tasks, studies in musicians with chronic bilateral medial temporal lobe damage and in non-musicians suffering from neuro-degenerative diseases suggest that musical memory may at least partly be independent of hippocampal integrity. Here, we report on a musical layperson who acutely developed an amnesic syndrome in the context of autoimmune encephalitis. Structural and resting state functional MRI revealed exceptionally selective bilateral lesions of the hippocampi and altered functional connectivity with retrosplenial cortex and precuneus. Neuropsychological testing showed a severe global amnesic syndrome. Perception and processing of scales, melodic contours, intervals, rhythms and meter were unaffected. Most notably, the patient performed completely normally on tests of recognition memory for unfamiliar melodies and excerpts of complex musical material, while recognition memory for visual and verbal information was severely impaired. Likewise, emotional evaluation of musical excerpts did not differ from controls. We infer that integrity of musical processing and recognition memory in patients with hippocampal dysfunction does not result from training-induced or post-lesional brain plasticity, but rather reflects integrity of brain networks outside the hippocampi and presumably also outside retrosplenial cortex and precuneus. Our findings suggest major differences in the neural substrates of musical and non-musical recognition memory.

Longterm outcome of cognition, affective state, and quality of life following subthalamic deep brain stimulation in Parkinson's disease.

Normal cognition is an established selection criteria for subthalamic (STN) deep brain stimulation (DBS) in Parkinson's disease (PD), while concern has been raised as to aggravated cognitive decline in PD patients following STN-DBS. The present longterm study investigates cognitive status in all patients (n = 104) suffering from PD, who were treated via continuous bilateral STN-DBS between 1997 and 2006 in a single institution. Preoperative neuropsychological results were available in 79/104 of the patients. Thirty-seven of these patients were additionally assessed after 6.3 ± 2.2 years (range 3.6-10.5 years) postsurgery via neuropsychological and motor test batteries, classifying cognitive conditions according to established criteria. At DBS-surgery patients, available for longterm follow-up (n = 37; mean age 67.6 ± 6.9 years, mean disease duration 11.3 ± 4.1 years), showed no (24.3%; 9/37) or mild preoperative cognitive impairment (MCI, 75.7%; 28/37). Postoperatively (mean disease duration: 17.1 ± 5.1 years), 19% of the patients (7/37) had no cognitive impairment, while 41% of the patients presented with either MCI or dementia (15/37, respectively). Preoperative MCI correlated with conversion to dementia by trend. Overall, STN-DBS-treated patients deteriorated by 1.6/140 points/year in the Mattis dementia rating scale. Disease duration, but not age, at DBS-surgery negatively correlated with postoperative cognitive decline and positively correlated with conversion to dementia. This observational, "real-life" study provides longterm results of cognitive decline in STN-DBS-treated patients with presurgical MCI possibly predicting the conversion to dementia. Although, the present data is lacking a control group of medically treated PD patients, comparison with other studies on cognition and PD do not support a disease-modifying effect of STN-DBS on cognitive domains.

Beyond the limbic system: disruption and functional compensation of large-scale brain networks in patients with anti-LGI1 encephalitis.

OBJECTIVE: Hippocampal inflammation in anti-LGI1 encephalitis causes memory deficits, seizures and behavioural abnormalities. Recent findings suggest that extralimbic brain areas are additionally affected and that patients also suffer from non-limbic cognitive symptoms. Moreover, up to 60% of patients show no structural MRI abnormalities in the acute disease stage. We therefore investigated whether functional connectivity analyses can identify brain network changes underlying disease-related symptoms. METHODS: We studied 27 patients and a matched healthy control group using structural and functional MRI. Intrinsic functional networks were analysed using Independent Component Analysis and Dual Regression. Cognitive testing covered working memory, episodic memory, attention and executive function. RESULTS: Our analysis revealed functional connectivity alterations in several large-scale networks, including the default mode network (DMN) which showed an aberrant structure-function relationship with the damaged hippocampus. In addition, connectivity in the sensorimotor, salience and higher visual networks was impaired independent of hippocampal damage. Increased connectivity in ventral and dorsal DMN regions significantly correlated with better memory performance. In contrast, stronger connectivity of the insula with the salience network and DMN was linked to impaired memory function. CONCLUSIONS: Anti-LGI1 encephalitis is associated with a characteristic pattern of widespread functional network alterations. Increased DMN connectivity seems to represent a compensatory mechanism for memory impairment induced by hippocampal damage. Network analyses may provide a key to the understanding of clinical symptoms in autoimmune encephalitis and reveal changes of brain function beyond apparent structural damage.

Interferon-free therapy in hepatitis C virus (HCV) monoinfected and HCV/HIV coinfected patients: effect on cognitive function, fatigue, and mental health.

The efficacy and safety of interferon-free therapies for hepatitis C virus (HCV) infection have been reported. Considering the accumulating evidence for a direct central nervous system infection by HCV, we aim to evaluate the effect of direct acting antivirals (DAA) therapy on cognitive function in HCV patients. We conducted a longitudinal analysis of the cognitive performance of 22 patients (8 HCV+, 14 HCV+/HIV+) who completed neuropsychological testing at baseline and at week 12 after DAA therapy. In 20 patients, we analyzed specific attention parameters derived from an experimental testing based on the Theory of Visual Attention (TVA). Depression, fatigue, and mental health were assessed as patient reported outcomes. At baseline, 54.5% of the patients met the criteria for cognitive impairment and 40% showed impairment in TVA parameters. Follow-up analysis revealed significant improvements in the domains of visual memory/learning, executive functions, verbal fluency, processing speed, and motor skills but not in verbal learning and attention/working memory. We did not observe significant improvement in visual attention measured by TVA. Fatigue and mental health significantly improved at follow-up. Our findings indicate that successful DAA treatment leads to cognitive improvements in several domains measured by standard neuropsychological testing. The absence of improvement in TVA parameters and of significant improvement in the domain of attention/working memory might reflect the persistence of specific cognitive deficits after HCV eradication. In summary, DAA treatment seems to have a positive effect on some cognitive domains and leads to an improvement in mental health and fatigue in HCV-infected patients.

Evaluation of Cognitive Deficits and Structural Hippocampal Damage in Encephalitis With Leucine-Rich, Glioma-Inactivated 1 Antibodies.

IMPORTANCE: Limbic encephalitis with leucine-rich, glioma-inactivated 1 (LGI1) antibodies is one of the most frequent variants of autoimmune encephalitis with antibodies targeting neuronal surface antigens. However, the neuroimaging pattern and long-term cognitive outcome are not well understood. OBJECTIVE: To study cognitive outcome and structural magnetic resonance imaging (MRI) alterations in patients with anti-LGI1 encephalitis. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study was conducted at the Departments of Neurology at Charité-Universitätsmedizin Berlin and University Hospital Schleswig-Holstein, Kiel, Germany. Data on 30 patients with anti-LGI1 encephalitis and 27 healthy control individuals matched for age, sex, and educational level were collected from June 1, 2013, through February 28, 2015. MAIN OUTCOMES AND MEASURES: Clinical assessment, cognitive testing, and high-resolution MRI data, including whole-brain, hippocampal and basal ganglia volumetry; white matter integrity (diffusion tensor imaging); gray matter density (voxel-based morphometry); and hippocampal microstructural integrity (mean diffusivity and fractional anisotropy). RESULTS: Of the 30 patients included in the study, 19 were male (63%); mean (SD) age was 65.7 (12.3) years. Patients with anti-LGI1 encephalitis had incomplete recovery with significant and persisting verbal (mean [SE] Rey Auditory Verbal Learning Test [RAVLT], delayed recall: patients, 6.52 [1.05]; controls, 11.78 [0.56], P < .001) and visuospatial (Rey-Osterrieth Complex Figure Test [ROCF], delayed recall: patients, 16.0 [1.96]; controls, 25.86 [1.24]; P < .001) memory deficits. These deficits were accompanied by pronounced hippocampal atrophy, including subfields cornu ammonis 2/3 (CA2/3) and CA4/dentate gyrus (DG), as well as impaired hippocampal microstructural integrity. Higher disease severity correlated with larger verbal memory deficits (RAVLT delayed recall, r = -0.40; P = .049), decreased volumes of left hippocampus (r = -0.47; P = .02) and left CA2/3 (r = -0.41; P = .04) and CA4/DG (r = -0.43; P = .03) subfields, and impaired left hippocampal microstructural integrity (r = 0.47; P = .01). In turn, decreased volume of the left CA2/3 subfield (RAVLT delayed recall, r = 0.40; P = .047) and impaired left hippocampal microstructural integrity (RAVLT recognition, r = -0.41; P = .04) correlated with verbal memory deficits. Basal ganglia MRI signal abnormalities were observed in only 1 patient, but a longer duration of faciobrachial dystonic seizures correlated with a reduction of pallidum volume (r = -0.71; P = .03). In contrast, no abnormalities of cortical gray matter or white matter were found. The latency between disease onset and initiation of immunotherapy was significantly correlated with verbal (RAVLT recall after interference, r = -0.48; P = .02) and visuospatial (ROCF delayed recall, r = -0.46; P = .03) memory deficits. CONCLUSIONS AND RELEVANCE: Anti-LGI1 encephalitis is associated with cognitive deficits and disability as a result of structural damage to the hippocampal memory system. This damage might be prevented by early immunotherapy.

Validation of the International HIV Dementia Scale as a Screening Tool for HIV-Associated Neurocognitive Disorders in a German-Speaking HIV Outpatient Clinic.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) are widely present among people living with HIV. Especially its milder forms, asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND), remain highly prevalent worldwide. Diagnosing these conditions is subject to a time and resource consuming neuropsychological assessment. Selecting patients at a higher risk of cognitive impairment by using a simple but effective screening tool helps to organise access to further neuropsychological diagnosis. The International HIV Dementia Scale (IHDS) has until now been a well-established screening tool in African and American countries, however these populations' demographics defer significantly from ours, so using the same parameters could be ineffective. OBJECTIVES: To calculate the prevalence of this condition among people attending an HIV outpatient clinic in Berlin and to validate the use of the IHDS as a screening tool for HAND in a German-speaking population. METHODS: We screened 480 HIV-infected patients using the IHDS, 89% of them were on a stable antiretroviral treatment. Ninety of them completed a standardised neuropsychological battery of tests and a specific cognitive complaints questionnaire. The same procedure was applied to a control group of 30 HIV-negative participants. HAND diagnosis was established according to the Frascati criteria. RESULTS: The overall prevalence of HAND in our cohort was 43% (20% ANI, 17% MND and 6% HIV-associated dementia). The optimal cut-off on the IHDS for detecting HAND cases was set at 11 and achieved both a sensitivity and a specificity of 80%. When specifically screening for the more severe form of HAND, HIV-associated dementia, a cut-off value of 10 offered an increase in both sensitivity (94%) and specificity (86%). The Youden Index for diagnostic accuracy was 0.6 and 0.8, respectively. CONCLUSIONS: The prevalence of HAND was comparable to the reported by recent studies performed in countries with a similar economic development. The study confirms the IHDS to be a useful HAND screening tool in primary care settings and establishes new recommendations for its use in German-speaking countries.

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.

Severe cognitive impairment associated with intrathecal antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor in a patient with multiple sclerosis.

IMPORTANCE: Some patients with multiple sclerosis (MS) can either present with or develop severe cognitive impairment during the course of their disease. However, the mechanisms underlying severe cognitive dysfunction in MS are not well understood. OBSERVATIONS: We report on a woman who was diagnosed as having MS at age 33 years and who after giving birth at age 37 years developed cognitive impairment with severe memory dysfunction as the leading symptom. Treatment with different immunotherapies, including cyclophosphamide and natalizumab, did not improve her cognitive deficits, necessitating admission to a nursing home at age 39 years. During a thorough reevaluation at age 43 years, analysis of current and stored cerebrospinal fluid and serum samples demonstrated an intrathecal synthesis of IgG antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor, that is, the characteristic laboratory finding of anti-N-methyl-D-aspartate receptor encephalitis. Although the patient initially stabilized under therapy with corticosteroids, plasma exchange, and mitoxantrone, severe cognitive impairment persisted and she eventually died from the sequelae of her disease. CONCLUSIONS AND RELEVANCE: This report suggests that the occasional occurrence of severe cognitive impairment in patients with MS may, in some cases, be related to a superimposed antibody-mediated autoimmune encephalitis.

An object location memory paradigm for older adults with and without mild cognitive impairment.

BACKGROUND: Object-location memory is critical in every-day life and known to deteriorate early in the course of neurodegenerative disease. NEW METHOD: We adapted the previously established learning paradigm "LOCATO" for use in healthy older adults and patients with mild cognitive impairment (MCI). Pictures of real-life buildings were associated with positions on a two-dimensional street map by repetitions of "correct" object-location pairings over the course of five training blocks, followed by a recall task. Correct/incorrect associations were indicated by button presses. The original two 45-item sets were reduced to 15 item-sets, and tested in healthy older adults and MCI for learning curve, recall, and re-test effects. RESULTS: The two 15-item versions showed comparable learning curves and recall scores within each group. While learning curves increased linearly in both groups, MCI patients performed significantly worse on learning and recall compared to healthy controls. Re-testing after 6 month showed small practice effects only. COMPARISON WITH EXISTING METHODS: LOCATO is a simple standardized task that overcomes several limitation of previously employed visuospatial task by using real-life stimuli, minimizing verbal encoding, avoiding fine motor responses, combining explicit and implicit statistical learning, and allowing to assess learning curve in addition to recall. CONCLUSIONS: Results show that the shortened version of LOCATO meets the requirements for a robust and ecologically meaningful assessment of object-location memory in older adults with and without MCI. It can now be used to systematically assess acquisition of object-location memory and its modulation through adjuvant therapies like pharmacological or non-invasive brain stimulation.

Levodopa inhibits habit-learning in Parkinson's disease.

Mixed dopaminergic medication, comprising dopamine agonists and levodopa, may affect habit-learning in patients with Parkinson's disease (PD). However, the specific impact of levodopa on this effect is unknown. We assessed habit-learning in 20 non-demented PD-patients both with and without levodopa. We observed intact habit-learning in PD-patients OFF-medication. In contrast, the administration of 200 mg of levodopa impaired habit-learning. We conclude that potential deficits in habit-learning in PD may be attributed to the intake of levodopa.

Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study.

BACKGROUND: MRI-detected brain lesions are common after left atrial catheter ablation for symptomatic atrial fibrillation. The clinical relevance of these acute ischemic lesions is not fully understood, but ablation-related cerebral injury could contribute to cognitive dysfunction. METHODS AND RESULTS: In the prospective Mesh Ablator versus Cryoballoon Pulmonary Vein Ablation of Symptomatic Paroxysmal Atrial Fibrillation (MACPAF) study, serial 3-T brain MRIs and neuropsychological assessment were performed to analyze the rate of ablation-related brain lesions and their effect on cognitive function. Thirty-seven patients with paroxysmal atrial fibrillation (median age, 63.0 [interquartile range, 57-68] years; 41% female; median CHA2DS2VASc score 2 [interquartile range, 1-3]) underwent 41 ablation procedures according to study criteria. None of these patients had overt neurological deficits after ablation. High-resolution diffusion-weighted imaging, performed within 48 hours after ablation, showed that new brain lesions (range, 1-17) were present in 16 (43.2%) patients after 18 (43.9%) left atrial catheter ablation procedures. Follow-up MRI at 6 months (median, 6.5; interquartile range, 6-7) revealed that 7 (12.5%) of the 56 total acute brain lesions after ablation formed a persistent glial scar in 5 (31.3%) patients. Large diffusion-weighted imaging lesions and a corresponding fluid-attenuated inversion recovery lesion 48 hours after ablation predicted lesion persistence on 6-month follow-up. Neither persistent brain lesions nor the ablation procedure itself had a significant effect on attention or executive functions, short-term memory, or verbal and nonverbal learning after 6 months. CONCLUSIONS: Ablation-related acute ischemic brain lesions persist to some extent but do not cause cognitive impairment 6 months after the ablation procedure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01061931.

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

OBJECTIVE: 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. METHODS: Twenty-four patients with established diagnosis of anti-NMDAR encephalitis and age- and gender-matched controls underwent neuropsychological testing and multimodal MRI, including T1w/T2w structural imaging, analysis of resting state functional connectivity, analysis of white matter using diffusion tensor imaging, and analysis of gray matter using voxel-based morphometry. RESULTS: Patients showed significantly reduced functional connectivity of the left and right hippocampus with the anterior default mode network. Connectivity of both hippocampi predicted memory performance in patients. Diffusion tensor imaging revealed extensive white matter changes, which were most prominent in the cingulum and which correlated with disease severity. In contrast, no differences in T1w/T2w structural imaging and gray matter morphology were observed between patients and controls. INTERPRETATION: Anti-NMDAR encephalitis is associated with characteristic alterations of functional connectivity and widespread changes of white matter integrity despite normal findings in routine clinical MRI. These results may help to explain the clinicoradiological paradox in anti-NMDAR encephalitis and advance the pathophysiological understanding of the disease. Correlation of imaging abnormalities with disease symptoms and severity suggests that these changes play an important role in the symptomatology of anti-NMDAR encephalitis.

3 Tesla MRI-detected brain lesions after pulmonary vein isolation for atrial fibrillation: results of the MACPAF study.

BACKGROUND: Left atrial catheter ablation (LACA) is an established therapeutic approach to abolish symptomatic atrial fibrillation (AF). OBJECTIVE: Based on the prospective MACPAF study (clinicaltrials.gov NCT01061931) we report the rate of ischemic brain lesions postablation and their impact on cognitive function. METHODS: Patients with symptomatic paroxysmal AF were randomized to LACA using the Arctic Front® or the HD Mesh Ablator® catheter. All patients underwent brain MRI at 3 Tesla, neurological, and neuropsychological examinations within 48 hours prior and after the ablation procedure. RESULTS: There was no clinically evident stroke in 37 patients (mean age 62.4 ± 8.4 years; 41% female; median CHADS2 score 1 [IQR 0-2]) after LACA but high-resolution diffusion-weighted imaging (DWI) detected new ischemic lesions in 15 (41%) patients after LACA. Four (27%) of the HD Mesh Ablator® patients and 11 (50%) of the Arctic Front® patients suffered a silent ischemic lesion (P = 0.19). In these 15 patients, there was a nonsignificant trend toward lower cardiac ejection fraction (P = 0.07) and AF episodes during LACA (P = 0.09), while activated clotting time levels, number of energy applications, periprocedural electrocardioversion or CHADS(2) score had no impact. Lesion volumes varied from 5 to 150 mm(3) and 1 to 5 lesions were detected per patient. However, acute brain lesions had no effect on cognitive performance immediately after LACA. Of the DWI lesions postablation 82% were not detectable on FLAIR images 6-9 months postablation. CONCLUSIONS: According to 3 Tesla high-resolution DWI, ischemic brain lesions after LACA were common but not associated with impaired cognitive function after the ablation procedure.