Neuropsychiatric symptoms and metamemory across the life span: psychometric properties of the German Multifactorial Memory Questionnaire (MMQ).

OBJECTIVE: We assessed the psychometric properties, established normative data for the German Multifactorial Memory Questionnaire (MMQ), and analyzed its association with neuropsychiatric factors across the life span to provide a validated metamemory assessment for a German-speaking population. METHODS: The three MMQ scales (memory satisfaction, self-rated ability, and strategy application) were translated into German, considering cultural, linguistic, and conceptual aspects. To validate the MMQ and assess associations with neuropsychiatric factors, the Complainer Profile Identification, Geriatric Depression Scale, Beck Anxiety Inventory, Pittsburgh Sleep Quality Index, and Short-Form-Health Survey were applied in an online study in 336 healthy participants with follow-up after 8 months. RESULTS: Psychometric evaluation of the German MMQ showed normal distribution of all scales and good to excellent validity, internal consistency, and retest reliability. We provide percentiles and normative data for z-score conversion. Importantly, even subclinically elevated scores in depressiveness and anxiety were associated with decreased memory satisfaction and self-rated ability. Furthermore, although the influence of age on the German MMQ scales was minimal, effects of neuropsychiatric factors such as sleep quality, anxiety, and depressiveness on MMQ Satisfaction and Ability varied across the life span. CONCLUSIONS: Our study provides a validated German translation of the MMQ with normative data and reliability measures, including reliable change scores. We show the impact of neuropsychiatric factors on the MMQ scales across the life span and emphasize the relevance of a multifactorial approach to metamemory as a measure of individualized everyday functionality and the importance of including neuropsychiatric factors into both research and clinical assessments of metamemory.

Cognitive decline in post-COVID-19 syndrome does not correspond with persisting neuronal or astrocytic damage.

Cognitive impairment is the most frequent symptom reported in post-COVID-19 syndrome (PCS). Aetiology of cognitive impairment in PCS is still to be determined. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are increased in acute COVID-19. Their role as biomarkers in other neurological disorders is under debate. We analysed serum levels of NfL and GFAP as markers for neuronal and astrocytic damage in 53 patients presenting to a PCS Neurology outpatient clinic. Only individuals with self-reported cognitive complaints were included. In these individuals, cognitive complaints were further assessed by comprehensive neuropsychological assessment (NPA). Patients were categorized into subgroups of subjective cognitive decline, single domain impairment, or multi-domain impairment. Serum NfL was in normal range, however an increase of serum GFAP was detected in 4% of patients. Serum NfL and GFAP levels correlated with each other, even when adjusting for patient age (r = 0.347, p = 0.012). NPA showed deficits in 70%; 40% showing impairment in several tested domains. No significant differences were found between serum NfL- and GFAP-levels comparing patients with subjective cognitive decline, single domain impairment, or multi-domain impairment. Persistent neuronal or astrocytic damage did not correlate with cognitive impairment in PCS.

Characteristic functional connectome related to Post-COVID-19 syndrome.

Post-COVID-19 syndrome is a serious complication following SARS-CoV-2 infection, characterized primarily by fatigue and cognitive complaints. Although first metabolic and structural imaging alterations in Post-COVID-19 syndrome have been identified, their functional consequences remain unknown. Thus, we explored the impact of Post-COVID-19 syndrome on the functional connectome of the brain providing a deeper understanding of pathophysiological mechanisms. In a cross-sectional observational study, resting-state functional magnetic resonance imaging data of 66 patients with Post-COVID-19 syndrome after mild infection (mean age 42.3 years, 57 female) and 57 healthy controls (mean age 42.1 years, 38 female) with a mean time of seven months after acute COVID-19 were analysed using a graph theoretical approach. Network features were quantified using measures including mean distance, nodal degree, betweenness and Katz centrality, and compared between both groups. Graph measures were correlated with clinical measures quantifying fatigue, cognitive function, affective symptoms and sleep disturbances. Alterations were mainly found in the brainstem, olfactory cortex, cingulate cortex, thalamus and cerebellum on average seven months after SARS-CoV-2 infection. Additionally, strong correlations between fatigue severity, cognitive functioning and daytime sleepiness from clinical scales and graph measures were observed. Our study confirms functional relevance of brain imaging changes in Post-COVID-19 syndrome as mediating factors for persistent symptoms and improves our pathophysiological understanding.

The T1-weighted/T2-weighted ratio as a biomarker of anti-NMDA receptor encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis rarely causes visible lesions in conventional MRI, yet advanced imaging detects extensive white matter damage. To improve prognostic capabilities, we evaluate the T1-weighted/T2-weighted (T1w/T2w) ratio, a measure of white matter integrity computable from clinical MRI sequences, in NMDAR encephalitis and examine its associations with cognitive impairment. METHODS: T1-weighted and T2-weighted MRI were acquired cross-sectionally at 3 Tesla in 53 patients with NMDAR encephalitis (81% women, mean age 29 years) and 53 matched healthy controls. Quantitative and voxel-wise group differences in T1w/T2w ratios and associations with clinical and neuropsychological outcomes were assessed. P-values were false discovery rate (FDR) adjusted where multiple tests were conducted. RESULTS: Patients with NMDAR encephalitis had significantly lower T1w/T2w ratios across normal appearing white matter (p=0.009, Hedges' g=-0.51), which was associated with worse verbal episodic memory performance (r=0.39, p=0.005, p(FDR)=0.026). White matter integrity loss was observed in the corticospinal tract, superior longitudinal fascicle, optic radiation and callosal body with medium to large effects (Cohen's d=[0.42-1.17]). In addition, patients showed decreased T1w/T2w ratios in the hippocampus (p=0.002, p(FDR)=0.005, Hedges' g=-0.62), amygdala (p=0.002, p(FDR)=0.005, Hedges' g=-0.63) and thalamus (p=0.010, p(FDR)=0.019, Hedges' g=-0.51). CONCLUSIONS: The T1w/T2w ratio detects microstructural changes in grey and white matter of patients with NMDAR encephalitis that correlate with cognitive performance. Computable from conventional clinical MRI sequences, this measure shows promise in bridging the clinico-radiological dissociation in NMDAR encephalitis and could serve as an imaging outcome measure in clinical trials.

Severe Hippocampal Atrophy in a Patient With Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy.

This case report describes a patient who presented with headache, fever, quadriparesis, and reduced visual acuity in the left eye and 6 months later presented with persistent quadriparesis and new-onset cognitive deficits.

Structural brain changes in patients with post-COVID fatigue: a prospective observational study.

Background: Post-COVID syndrome is a severe long-term complication of COVID-19. Although fatigue and cognitive complaints are the most prominent symptoms, it is unclear whether they have structural correlates in the brain. We therefore explored the clinical characteristics of post-COVID fatigue, describe associated structural imaging changes, and determine what influences fatigue severity. Methods: We prospectively recruited 50 patients from neurological post-COVID outpatient clinics (age 18-69 years, 39f/8m) and matched non-COVID healthy controls between April 15 and December 31, 2021. Assessments included diffusion and volumetric MR imaging, neuropsychiatric, and cognitive testing. At 7.5 months (median, IQR 6.5-9.2) after the acute SARS-CoV-2 infection, moderate or severe fatigue was identified in 47/50 patients with post-COVID syndrome who were included in the analyses. As a clinical control group, we included 47 matched multiple sclerosis patients with fatigue. Findings: Our diffusion imaging analyses revealed aberrant fractional anisotropy of the thalamus. Diffusion markers correlated with fatigue severity, such as physical fatigue, fatigue-related impairment in everyday life (Bell score) and daytime sleepiness. Moreover, we observed shape deformations and decreased volumes of the left thalamus, putamen, and pallidum. These overlapped with the more extensive subcortical changes in MS and were associated with impaired short-term memory. While fatigue severity was not related to COVID-19 disease courses (6/47 hospitalised, 2/47 with ICU treatment), post-acute sleep quality and depressiveness emerged as associated factors and were accompanied by increased levels of anxiety and daytime sleepiness. Interpretation: Characteristic structural imaging changes of the thalamus and basal ganglia underlie the persistent fatigue experienced by patients with post-COVID syndrome. Evidence for pathological changes to these subcortical motor and cognitive hubs provides a key to the understanding of post-COVID fatigue and related neuropsychiatric complications. Funding: Deutsche Forschungsgemeinschaft (DFG) and German Ministry of Education and Research (BMBF).

Association of cerebrospinal fluid brain-binding autoantibodies with cognitive impairment in post-COVID-19 syndrome.

BACKGROUND: Neurological symptoms, in particular cognitive deficits, are common in post-COVID-19 syndrome (PCS). There is no approved therapy available, and the underlying disease mechanisms are largely unknown. Besides others, autoimmune processes may play a key role. DESIGN: We here present data of a prospective study conducted between September 2020 and December 2021 and performed at two German University hospitals with specialized Neurology outpatient clinics. Fifty patients with self-reported cognitive deficits as main complaint of PCS and available serum and CSF samples were included. Cell-based assays and indirect immunofluorescence on murine brain sections were used to detect autoantibodies against intracellular and surface antigens in serum and CSF and analyzed for associations with cognitive screening assessment. RESULTS: Clearly abnormal cognitive status (MoCA ≤ 25/30 points) was only seen in 18/50 patients with self-reported cognitive deficits. Most patients (46/50) had normal routine CSF parameters. anti-neuronal autoantibodies were found in 52 % of all patients: n = 9 in serum only, n = 3 in CSF only and n = 14 in both, including those against myelin, Yo, Ma2/Ta, GAD65 and NMDA receptor, but also a variety of undetermined epitopes on brain sections. These included cerebral vessel endothelium, Purkinje neurons, granule cells, axon initial segments, astrocytic proteins and neuropil of basal ganglia or hippocampus as well as a formerly unknown perinuclear rim pattern. Pathological MoCA results were associated with the presence of anti-neuronal antibodies in CSF (p = 0.0004). CONCLUSIONS: Autoantibodies targeting brain epitopes are common in PCS patients and strongly associate with pathological cognitive screening tests, in particular when found in CSF. Several underlying autoantigens still await experimental identification. Further research is needed to inform on the clinical relevance of these autoantibodies, including controlled studies that explore the potential efficacy of antibody-depleting immunotherapy in PCS.

Reduced resilience of brain state transitions in anti-N-methyl-D-aspartate receptor encephalitis.

Patients with anti-N-methyl-aspartate receptor (NMDA) receptor encephalitis suffer from a severe neuropsychiatric syndrome, yet most patients show no abnormalities in routine magnetic resonance imaging. In contrast, advanced neuroimaging studies have consistently identified disrupted functional connectivity in these patients, with recent work suggesting increased volatility of functional state dynamics. Here, we investigate these network dynamics through the spatiotemporal trajectory of meta-state transitions, yielding a time-resolved account of brain state exploration in anti-NMDA receptor encephalitis. To this end, resting-state functional magnetic resonance imaging data were acquired in 73 patients with anti-NMDA receptor encephalitis and 73 age- and sex-matched healthy controls. Time-resolved functional connectivity was clustered into brain meta-states, giving rise to a time-resolved transition network graph with states as nodes and transitions between brain meta-states as weighted, directed edges. Network topology, robustness and transition cost of these transition networks were compared between groups. Transition networks of patients showed significantly lower local efficiency (t = -2.41, pFDR  = .029), lower robustness (t = -2.01, pFDR  = .048) and higher leap size (t = 2.18, pFDR  = .037) compared with controls. Furthermore, the ratio of within-to-between module transitions and state similarity was significantly lower in patients. Importantly, alterations of brain state transitions correlated with disease severity. Together, these findings reveal systematic alterations of transition networks in patients, suggesting that anti-NMDA receptor encephalitis is characterized by reduced stability of brain state transitions and that this reduced resilience of transition networks plays a clinically relevant role in the manifestation of the disease.

[Autoimmune encephalitis-An update]. / Autoimmunenzephalitis ­ ein Update.

Detection of autoantibodies against neurons and glia cells has brought about the early and specific diagnosis of autoimmune encephalitis in patients with variable neurological and psychiatric symptoms. Growing knowledge not only resulted in profound changes in treatment algorithms including immunotherapy but also in the understanding of disease mechanisms and etiological factors. The still increasing numbers of new autoantibodies calls for continuous updates on the state of the art in antibody diagnostics, frequencies of associated tumors and the clinical spectrum linked to each antibody, which can range from mood changes, cognitive impairment and epileptic seizures to abnormal movements, autonomic dysfunction and impaired levels of consciousness. This article summarizes the recent developments in the predominant clinical presentations of autoimmune encephalitis patients in imaging and cerebrospinal fluid diagnostics and also in prognostic markers, in the establishment of innovative immunotherapies, in the use of diagnostic pathways even before the results of the antibody tests are available and the understanding of the autoimmune etiology.

State-dependent signatures of anti-N-methyl-d-aspartate receptor encephalitis.

Traditional static functional connectivity analyses have shown distinct functional network alterations in patients with anti-N-methyl-d-aspartate receptor encephalitis. Here, we use a dynamic functional connectivity approach that increases the temporal resolution of connectivity analyses from minutes to seconds. We hereby explore the spatiotemporal variability of large-scale brain network activity in anti-N-methyl-d-aspartate receptor encephalitis and assess the discriminatory power of functional brain states in a supervised classification approach. We included resting-state functional magnetic resonance imaging data from 57 patients and 61 controls to extract four discrete connectivity states and assess state-wise group differences in functional connectivity, dwell time, transition frequency, fraction time and occurrence rate. Additionally, for each state, logistic regression models with embedded feature selection were trained to predict group status in a leave-one-out cross-validation scheme. Compared to controls, patients exhibited diverging dynamic functional connectivity patterns in three out of four states mainly encompassing the default-mode network and frontal areas. This was accompanied by a characteristic shift in the dwell time pattern and higher volatility of state transitions in patients. Moreover, dynamic functional connectivity measures were associated with disease severity and positive and negative schizophrenia-like symptoms. Predictive power was highest in dynamic functional connectivity models and outperformed static analyses, reaching up to 78.6% classification accuracy. By applying time-resolved analyses, we disentangle state-specific functional connectivity impairments and characteristic changes in temporal dynamics not detected in static analyses, offering new perspectives on the functional reorganization underlying anti-N-methyl-d-aspartate receptor encephalitis. Finally, the correlation of dynamic functional connectivity measures with disease symptoms and severity demonstrates a clinical relevance of spatiotemporal connectivity dynamics in anti-N-methyl-d-aspartate receptor encephalitis.

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.

Distinct Functional Connectivity Signatures of Impaired Social Cognition in Multiple Sclerosis.

Objective: Multiple sclerosis (MS) is characterized by impairments in basic cognitive functions such as information processing speed as well as in more complex, higher-order domains such as social cognition. However, as these deficits often co-occur, it has remained challenging to determine whether they have a specific pathological basis or are driven by shared biology. Methods: To identify neural signatures of social cognition deficits in MS, data were analyzed from n = 29 patients with relapsing-remitting MS and n = 29 healthy controls matched for age, sex, and education. We used neuropsychological assessments of information processing speed, attention, learning, working memory, and relevant aspects of social cognition (theory of mind, emotion recognition (ER), empathy) and employed neuroimaging of CNS networks using resting-state functional connectivity. Results: MS patients showed significant deficits in verbal learning and memory, as well as implicit ER. Performance in these domains was uncorrelated. Functional connectivity analysis identified a distinct network characterized by significant associations between poorer ER and lower connectivity of the fusiform gyrus (FFG) with the right lateral occipital cortex, which also showed lower connectivity in patients compared to controls. Moreover, while ER was correlated with MS symptoms such as fatigue and motor/sensory functioning on a behavioral level, FFG connectivity signatures of social cognition deficits showed no overlap with these symptoms. Conclusions: Our analyses identify distinct functional connectivity signatures of social cognition deficits in MS, indicating that these alterations may occur independently from those in other neuropsychological functions.

Transdiagnostic hippocampal damage patterns in neuroimmunological disorders.

Hippocampal damage and associated cognitive deficits are frequently observed in neuroimmunological disorders, but comparative analyses to identify shared hippocampal damage patterns are missing. Here, we adopted a transdiagnostic analytical approach and investigated hippocampal shape deformations and associated cognitive deficits in four neuroimmunological diseases. We studied 120 patients (n = 30 in each group), including patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), anti-NMDAR and anti-LGI1 encephalitis. A control group was matched to each patient sample from a pool of 79 healthy participants. We performed an MRI-based vertex-wise hippocampal shape analysis, extracted hippocampal volume estimates and scalar projection values as a measure of surface displacement. Cognitive testing included assessment of verbal memory and semantic fluency performance. Our cross-sectional analyses revealed characteristic patterns of bilateral inward deformations covering up to 32% of the hippocampal surface in MS, anti-NMDAR encephalitis, and anti-LGI1 encephalitis, whereas NMOSD patients showed no deformations compared to controls. Significant inversions were noted mainly on the hippocampal head, were accompanied by volume loss, and correlated with semantic fluency scores and verbal episodic memory in autoimmune encephalitis and MS. A deformation overlap analysis across disorders revealed a convergence zone on the left anterior hippocampus that corresponds to the CA1 subfield. This convergence zone indicates a shared downstream substrate of immune-mediated damage that appears to be particularly vulnerable to neuroinflammatory processes. Our transdiagnostic morphological view sheds light on mutual pathophysiologic pathways of cognitive deficits in neuroimmunological diseases and stimulates further research into the mechanisms of increased susceptibility of the hippocampus to autoimmunity.

Computerized Cognitive Training in Multiple Sclerosis: A Systematic Review and Meta-analysis.

Background. Cognitive impairments are common in people with multiple sclerosis (MS). Systematic reviews reported promising evidence for various cognitive interventions in this population. Computerized cognitive training (CCT) has strong evidence for safety and efficacy in several populations, but its effects in MS have yet to be specified. Objective. We aimed to synthesize the evidence from randomized controlled trials (RCTs) investigating the effects of CCT on cognitive, psychosocial, and functional outcomes in adults with MS. Method. We searched MEDLINE, EMBASE, PsycINFO, CINAHL, and CENTRAL from inception to March 2019. We calculated standardized mean difference (Hedges' g) of change from baseline in untrained measures of cognition, individual domains, psychosocial functioning, and daily function between CCT and control groups using a random-effects model. Results. A total of 20 RCTs encompassing 982 participants (78% with relapsing-remitting MS) were included. The overall cognitive effect size was moderate (g = 0.30; 95% CI = 0.18-0.43), with no evidence of small-study effect or between-study heterogeneity (prediction interval = 0.17-0.44). Small to moderate effect sizes were found for attention/processing speed, executive functions, and verbal and visuospatial memory. Evidence for working memory, fatigue, and psychosocial and daily functioning were inconclusive. Cognitive effects waned without further training. Conclusions. CCT is efficacious for overall and key cognitive domains in adults with MS, but efficacy on other outcomes and in progressive subtypes remains unclear. Long-term and well-powered trials with diverse cohorts are needed to optimize and maintain the efficacy of CCT, investigate transfer to daily living, and determine who can benefit and whether CCT is a cost-effective strategy to attenuate cognitive decline in MS.

Multiple sclerosis-related fatigue: Altered resting-state functional connectivity of the ventral striatum and dorsolateral prefrontal cortex.

OBJECTIVE: Since recent studies suggested a role of the striatum and prefrontal cortex for multiple sclerosis (MS)-related fatigue, we investigated resting-state functional connectivity alterations of striatal subdivisions and the dorsolateral prefrontal cortex (dlPFC). METHODS: Resting-state functional magnetic resonance imaging was acquired in 77 relapsing-remitting MS patients (38 fatigued (F-MS), 39 non-fatigued (NF-MS)) and 41 matched healthy controls (HC). Fatigue severity was assessed using the fatigue severity scale. Seed-based connectivity analyses were performed using subregions of the striatum and the dlPFC as regions of interest applying non-parametric permutation testing. RESULTS: Compared to HC and NF-MS patients, F-MS patients showed reduced caudate nucleus and ventral striatum functional connectivity with the sensorimotor cortex (SMC) and frontal, parietal, and temporal cortex regions. Fatigue severity correlated negatively with functional connectivity of the caudate nucleus and ventral striatum with the SMC and positively with functional connectivity of the dlPFC with the rostral inferior parietal gyrus and SMC. CONCLUSION: MS-related fatigue is associated with reduced functional connectivity between the striatum and sensorimotor as well as attention and reward networks, in which the ventral striatum might be a key integration hub. Together with increased connectivity between the dlPFC and sensory cortical areas, these connectivity alterations shed light on the mechanisms of MS-related fatigue.

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.

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.

Immunoadsorption or plasma exchange in the treatment of autoimmune encephalitis: a pilot study.

Therapeutic apheresis has emerged as a major treatment option for autoantibody-associated inflammatory diseases of the nervous system. This includes patients with autoimmune encephalitides caused by antibodies against neuronal proteins. Plasma exchange (PE) and immunoadsorption (IA) constitute two possibilities to eliminate pathogenic antibodies from patients' plasma, but their efficacy and safety has not been prospectively assessed in larger patient groups of autoimmune encephalitides. In a prospective observational case control study, we, therefore, investigated the disease courses and treatment effects of 21 patients with autoimmune encephalitis associated with NMDAR, LGI1, CASPR2, GAD, mGluR5 and Hu antibodies. Patients were randomly assigned to receive PE (n = 11) or IA (n = 10). Symptoms were evaluated using the modified Rankin Scale (mRS). Side effects or adverse events were recorded. Both interventions, IA (p = 0.014) and PE (p = 0.01), resulted in significant reduction of the median mRS. With IA, 60 % of the patients improved clinically by at least 1 mRS score, none worsened. PE led to a comparable symptom reduction in 67 % of the cases. During 83 PE sessions, three adverse events were documented, while no side effects occurred under IA. Symptom improvement was significantly associated with younger age (r = -0.58), but not with disease duration. Therapeutic apheresis was most effective for neuronal surface antigens (83.3 %), followed by intracellular-synaptic antigens (66.7 %). Both IA and PE resulted in moderate to marked clinical improvement, with a low rate of adverse events. Apheresis is well tolerated and effective also as first-line therapy in autoimmune encephalitis, particularly in patients with antibodies targeting neuronal surfaces.

Normal volumes and microstructural integrity of deep gray matter structures in AQP4+ NMOSD.

OBJECTIVE: To assess volumes and microstructural integrity of deep gray matter structures in a homogeneous cohort of patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: This was a cross-sectional study including 36 aquaporin-4 antibody-positive (AQP4 Ab-positive) Caucasian patients with NMOSD and healthy controls matched for age, sex, and education. Volumetry of deep gray matter structures (DGM; thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens) was performed using 2 independent automated methods. Microstructural integrity was assessed based on diffusion tensor imaging. RESULTS: Both volumetric analysis methods consistently revealed similar volumes of DGM structures in patients and controls without significant group differences. Moreover, no differences in DGM microstructural integrity were observed between groups. CONCLUSIONS: Deep gray matter structures are not affected in AQP4 Ab-positive Caucasian patients with NMOSD. NMOSD imaging studies should be interpreted with respect to Ab status, educational background, and ethnicity of included patients.