Diagnostic criteria for Susac syndrome.

BACKGROUND: Susac syndrome is characterised by the triad of encephalopathy with or without focal neurological signs, branch retinal artery occlusions and hearing loss. Establishment of the diagnosis is often delayed because the triad is complete only in a minority of patients at disease onset. This leads to a critical delay in the initiation of appropriate treatment. Our objective was to establish criteria for diagnosis of either definite or probable Susac syndrome. METHOD: The establishment of diagnostic criteria was based on the following three steps: (1) Definition of a reference group of 32 patients with an unambiguous diagnosis of Susac syndrome as assessed by all interdisciplinary experts of the European Susac Consortium (EuSaC) team (EuSaC cohort); (2) selection of diagnostic criteria, based on common clinical and paraclinical findings in the EuSaC cohort and on a review of the literature; and (3) validation of the proposed criteria in the previously published cohort of all Susac cases reported until 2012. RESULTS: Integrating the clinical presentation and paraclinical findings, we propose formal criteria and recommend a diagnostic workup to facilitate the diagnosis of Susac syndrome. More than 90% of the cases in the literature fulfilled the proposed criteria for probable or definite Susac syndrome. We surmise that more patients could have been diagnosed with the recommended diagnostic workup. CONCLUSIONS: We propose diagnostic criteria for Susac syndrome that may help both experts and physicians not familiar with Susac syndrome to make a correct diagnosis and to prevent delayed treatment initiation.

Apraxia profile differentiates behavioural variant frontotemporal from Alzheimer's dementia in mild disease stages.

OBJECTIVE: Despite refined criteria for behavioural variant frontotemporal dementia (bvFTD), its differentiation from Alzheimer's dementia (AD) remains difficult at early clinical presentation. Apraxia is not considered as a supportive feature for the diagnosis of bvFTD, but for AD. However, only few studies have quantified praxis disturbances in mild disease stages and their specificity for AD compared with bvFTD remains indistinct. We explore apraxia in bvFTD and investigate the differential validity of apraxia screening tests to distinguish between AD, bvFTD and healthy controls (HC). METHODS: We compared composite apraxia scores assessed with standardised neuropsychological screening tests as well as performance in praxis subdomains in patients who fulfil current clinical criteria for AD (N=20), bvFTD (N=20), and in HC (N=20). RESULTS: Composite scores of apraxia screening tests provided high diagnostic accuracy for detecting mild stages of both neurodegenerative disorders compared with HC (sensitivity: 75-95%; specificity: 70-90%). Both patient groups showed pronounced impairments in limb praxis, especially in imitation of hand and finger postures (bvFTD: 71.7%; AD: 55.5%; HC: 86.7%) and pantomime of object use (bvFTD: 88.6%; AD: 81.4%; HC: 97.5%). Beyond that, patients with bvFTD displayed a unique profile of deficits for imitating face postures (bvFTD: 69%; AD: 88%; HC: 95.5%). CONCLUSIONS: Praxis disturbances are important but under-represented diagnostic features in mild stages of AD and bvFTD. Apraxia screening tests are easily applicable diagnostic tools, which may support clinical diagnoses of both neurodegenerative diseases. The analysis of individual apraxia profiles can effectively facilitate differential diagnosis of AD and bvFTD.

Executive performance is related to regional gray matter volume in healthy older individuals.

Individual differences in executive functioning and brain morphology are considerable. In this study, we investigated their interrelation in a large sample of healthy older individuals. Digit span, trail-making, and Stroop tasks were used to assess different executive subfunctions in 367 nondemented community-dwelling individuals (50-81 years). Task performance was analyzed relative to brain structure using voxel-based morphometry, corrected for age and sex. Improved task performance was associated with increased local gray matter volume in task-specific patterns that showed partial, but not complete overlap with known task-specific functional imaging patterns. While all three tasks showed associations with prefrontal gray matter volume as expected for executive functioning, the strongest overlap between the three tasks was found in insular cortex, suggesting that it has a previously underestimated role for executive functions. The association between the insular cortex and executive functioning was corroborated using stereological region-of-interest measurement of insular volume in a subgroup of 93 subjects. Quantitatively, the volume of the single most strongly related region explained 2.4 ± 1.1% of the variance in executive performance over and above the variance explained by age, which amounted to 7.4 ± 4.1%. The age-independent peak associations between executive performance and gray matter described here occurred in regions that were also strongly affected by age-related gray matter atrophy, consistent with the hypothesis that age-related regional brain volume loss and age-related cognitive changes are linked.

Presurgical functional transcranial Doppler sonography (fTCD) with intravenous echo enhancing agent SonoVue enables determination of language lateralization in epilepsy patients with poor temporal bone windows.

Presurgical determination of language lateralization is important for planning and outcome estimation of neurosurgical interventions in patients with drug-refractory epilepsy. Functional transcranial Doppler sonography (fTCD) provides an established measure for language lateralization using the temporal bone windows for continuous recording of the cerebral blood flow velocity (CBFV) in both middle cerebral arteries (MCAs). However, because of insufficient temporal bone windows, fTCD cannot be applied properly in every patient. Here, we established stable and sufficient CBFV signals in both MCAs using continuous intravenous application of echo-enhancing agent SonoVue in 7 of 10 patients with poor temporal bone windows and were thus able to determine language lateralization. We conclude that the application of SonoVue can solve one principal disadvantage of fTCD and improves the applicability of the technique as a presurgical functional language lateralization procedure.

A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects.

Hereditary spastic paraplegias (HSP) are genetically and clinically heterogeneous neurodegenerative disorders. The purpose of this study was to assess the genotype and phenotype in a family with a complicated form of autosomal recessive hereditary spastic paraplegia (ARHSP). Neurological and neuropsychological evaluation, neurophysiologic studies, fiberoptic endoscopic evaluation of swallowing (FEES), neuroimaging analysis including diffusion tensor imaging (DTI), and mutation analysis of SPG4 and SPG7 gene were performed. The index case (mother) was affected by an adult-onset form of complicated ARHSP due to the homozygous splice site mutation c.1552+1 G>T in the SPG7 gene. This mutation leads to an abnormally spliced mRNA lacking exon 11. Additional clinical features were bilateral ptosis and subtle deficits in executive function. All three asymptomatic daughters carried the sequence variation c.1552+1 G>T in heterozygous state. DTI of the mother revealed disturbance of white matter (WM) integrity in the left frontal lobe, the left corticospinal tract and both sides of the brainstem. DTI of the daughters showed subtle WM alteration in the frontal corpus callosum. The novel mutation is the first splice site mutation found in the SPG7 gene. It removes part of the AAA domain of paraplegin protein, probably leading to a loss-of-function of the paraplegin-AFG3L2 complex in the mitochondrial inner membrane. The pattern of WM damage in the homozygote index case may be specific for SPG7-HSP. The detection of cerebral WM alterations in the corpus callosum of asymptomatic heterozygote carriers confirms this brain region as the most prominent and early location of fiber damage in ARHSP.

Endoscopic characteristics and levodopa responsiveness of swallowing function in progressive supranuclear palsy.

Dysphagia is a frequent and early symptom in progressive supranuclear palsy (PSP) predisposing patients to aspiration pneumonia. Fiberoptic endoscopic evaluation of swallowing (FEES) has emerged as a valuable apparative tool for objective evaluation of neurogenic dysphagia. This is the first study using FEES to investigate the nature of swallowing impairment in PSP. Eighteen consecutive PSP patients (mean age 69.7 +/- 9.0 years) were included. The salient findings of FEES in PSP patients were compared with those of 15 patients with Parkinson's disease (PD). In 7 PSP patients, a standardized FEES protocol was performed to explore levodopa (L-dopa) responsiveness of dysphagia. Most frequent abnormalities detected by FEES were bolus leakage, delayed swallowing reflex, and residues in valleculae and piriformes. Aspiration events with at least one food consistency occurred in nearly 30% of PSP patients. Significant pharyngeal saliva pooling was observed in 4 PSP patients. We found no difference of salient endoscopic findings between PSP and PD patients. Endoscopic dysphagia severity in PSP correlated positively with disease duration, clinical disability, and cognitive impairment. No correlation was found with dysarthria severity. In early PSP patients, swallowing dysfunction was solely characterized by liquid leakage with the risk of predeglutitive aspiration during the oral phase of swallowing. Two PSP patients showed relevant improvement of swallowing function after L-dopa challenge. Chin tuck-maneuver, hard swallow, and modification of food consistency were identified as the most effective therapeutic interventions. In conclusion, FEES assessment can deliver important findings for the diagnosis and refined therapy of dysphagia in PSP patients.

Specific pattern of early white-matter changes in pure hereditary spastic paraplegia.

Hereditary spastic paraplegias (HSP) are genetically and clinically heterogeneous neurodegenerative disorders. Most MR studies on HSP include very heterogeneous samples of patients, and findings were inconsistent. Here, we examined six patients with pure HSP and SPG4 mutations by clinical evaluation, detailed neuropsychological testing, and neuroimaging analyses, including conventional MRI, diffusion tensor imaging (DTI), and brain volumetry. Differences of voxel-wise statistics and ROI-based analysis of DTI data between patients and 32 healthy volunteers were evaluated. Although conventional MRI and brain volumetry were normal, DTI revealed widespread disturbance of white matter (WM) integrity (P < 0.001), mainly affecting the corticospinal tract. With longer disease duration, frontal regions were also involved. The WM changes were also present in subclinical subjects harbouring the pathogenic mutation. These subtle WM abnormalities have functional relevance because they correlated with clinical symptoms. Thus, early alterations of nerve fibres, which can be detected by DTI, might serve as a biological marker in HSP, in particular with respect to future longitudinal studies.

Imaging short- and long-term training success in chronic aphasia.

BACKGROUND: To date, functional imaging studies of treatment-induced recovery from chronic aphasia only assessed short-term treatment effects after intensive language training. In the present study, we show with functional magnetic resonance imaging (fMRI), that different brain regions may be involved in immediate versus long-term success of intensive language training in chronic post-stroke aphasia patients. RESULTS: Eight patients were trained daily for three hours over a period of two weeks in naming of concrete objects. Prior to, immediately after, and eight months after training, patients overtly named trained and untrained objects during event-related fMRI. On average the patients improved from zero (at baseline) to 64.4% correct naming responses immediately after training, and treatment success remained highly stable at follow-up. Regression analyses showed that the degree of short-term treatment success was predicted by increased activity (compared to the pretraining scan) bilaterally in the hippocampal formation, the right precuneus and cingulate gyrus, and bilaterally in the fusiform gyri. A different picture emerged for long-term training success, which was best predicted by activity increases in the right-sided Wernicke's homologue and to a lesser degree in perilesional temporal areas. CONCLUSION: The results show for the first time that treatment-induced language recovery in the chronic stage after stroke is a dynamic process. Initially, brain regions involved in memory encoding, attention, and multimodal integration mediated treatment success. In contrast, long-term treatment success was predicted mainly by activity increases in the so-called 'classical' language regions. The results suggest that besides perilesional and homologue language-associated regions, functional integrity of domain-unspecific memory structures may be a prerequisite for successful (intensive) language interventions.

Atrial fibrillation in stroke-free patients is associated with memory impairment and hippocampal atrophy.

AIMS: To determine whether atrial fibrillation (AF) in stroke-free patients is associated with impaired cognition and structural abnormalities of the brain. AF contributes to stroke and secondary cognitive decline. In the absence of manifest stroke, AF can activate coagulation and cause cerebral microembolism which could damage the brain. METHODS AND RESULTS: We cross-sectionally evaluated 122 stroke-free individuals with AF recruited locally within the German Competence Network on AF. As comparator, we recruited 563 individuals aged 37-84 years without AF from the same community. Subjects underwent 3 T magnetic resonance imaging to assess covert territorial brain infarction, white matter lesions, and brain volume measures. Subjects with evidence for stroke, dementia, or depression were excluded. Cognitive function was assessed by an extensive neuropsychological test battery covering the domains learning and memory, attention and executive functions, working memory, and visuospatial skills. Cognitive scores and radiographic measures were compared across individuals with and without AF by stepwise multiple regression models. Stroke-free individuals with AF performed significantly worse in tasks of learning and memory (ß = -0.115, P < 0.01) as well as attention and executive functions (ß = -0.105, P < 0.01) compared with subjects without AF. There was also a trend (P = 0.062) towards worse performance in learning and memory tasks in patients with chronic as compared with paroxysmal AF. Corresponding to the memory impairment, hippocampal volume was reduced in patients with AF. Other radiographic measures did not differ between groups. CONCLUSION: Even in the absence of manifest stroke, AF is a risk factor for cognitive impairment and hippocampal atrophy. Therefore, cognition and measures of structural brain integrity should be considered in the evaluation of novel treatments for AF.

Accelerated long-term forgetting in focal epilepsies with special consideration given to patients with diagnosed and suspected limbic encephalitis.

RATIONALE: Accelerated long-term forgetting (ALF) is a phenomenon found in late onset epilepsy and in transient epileptic amnesia (TEA). Here we evaluated ALF in patients with focal epilepsies and limbic encephalitis (LE) in particular. METHODS: ALF was assessed in 36 patients with focal epilepsy and 154 healthy subjects using an extended version of the Verbal Learning and Memory Test (VLMT), with free recall after 30 min and again after one week. From these patients, 89% had temporal lobe epilepsy; 42% left-lateralized; 39% right; 19% bilateral; 17% were diagnosed with hippocampal sclerosis; 64% displayed features indicating LE; 52% with amygdala pathology, and 61% were antibody positive. ALF was defined as either having unimpaired free recall after 30 min and impaired recall after a week (A) or as a loss in recall exceeding the absolute (B) and percentage loss (C) in the interval of the 30 min and one week recall seen in controls by more than one standard deviation. RESULTS: Repeated measures analysis revealed an association between LE and ALF. Depending on its definition (A, B, or C), ALF was evident in 31%, 42%, or 67% of the patients. Poor verbal memory and ALF (C) were prominent in left-lateralized epilepsies. ALF (A) appeared more frequently in auto-antibody negative patients with LE, ALF (B) less frequently with hippocampal sclerosis. Seizures during the interval did not explain ALF. CONCLUSION: Depending on its definition, ALF is seen in patients with normal or impaired memory at ½ h. ALF seems related to LE but might as well be the first sign of memory impairment in patients with milder epilepsies and not yet definite structural temporal lobe pathology. Longitudinal assessment would be essential for discerning when ALF becomes evident, whether conditions exist in which ALF precedes short-term forgetting, and whether ALF responds to treatment.

Lifestyle and memory in the elderly.

BACKGROUND: Healthy lifestyle has been associated with a decreased risk of developing cardiovascular disease, but its relationship with memory functions is still inconclusive. This study aims to analyze the association between a composite lifestyle index and memory performance. METHODS: In this cross-sectional survey, 198 healthy individuals (aged 65-84 years) underwent tests of verbal episodic memory. A composite lifestyle index was calculated that included the following lifestyle dimensions: physical exercise, dietary habits, BMI, smoking and alcohol consumption. The healthiest behavior was defined as: a BMI <22; a diet high in fruits, vegetables, wholemeal/low-fat foods and unsaturated fatty acids; energy expenditure through physical activity >13,000 kcal/week; a history of never smoking; an alcohol consumption of 4-10 drinks per week. RESULTS: Linear regression analysis revealed that a high lifestyle index score was associated with a better memory score (after adjusting for age, sex, education and blood pressure). The composite index had a stronger relationship with memory scores than single factors. CONCLUSIONS: This cross-sectional study revealed that a healthy lifestyle, assessed by a simple composite index, is related to better memory performance in healthy elderly individuals. Our findings point to the importance of a comprehensive modulation of lifestyle factors when finding ways to preserve memory functions in the elderly.

Can cognitive assessment really discriminate early stages of Alzheimer's and behavioural variant frontotemporal dementia at initial clinical presentation?

BACKGROUND: Neuropsychological testing is considered crucial for differential diagnosis of Alzheimer's disease (AD) and behavioural variant frontotemporal dementia (bvFTD). In-depth neuropsychological assessment revealed specific dysfunctions in the two dementia syndromes. However, a significant overlap of cognitive impairments exists in early disease stages. We questioned whether a standard neuropsychological assessment at initial clinical presentation can delineate patients with AD versus bvFTD. METHODS: In a retrospective approach, we evaluated and compared how cognitive profiles assessed at initial clinical presentation predicted the diagnosis of later verified AD (n = 43) and bvFTD (n = 26). Additionally, the neuropsychological standard domains memory, language, visuospatial skills, executive functions, praxis and social cognition were subjected to stepwise discriminant analysis to compare their differential contribution to diagnosis. RESULTS: Regardless of diagnosis, a percentage of patients presented with major deterioration in a wide range of cognitive domains when compared with age-matched normative data. Only few significant differences were detected on the group level: Patients with AD were relatively more impaired in the verbal recall, verbal recognition, figure copy, and surprisingly in the executive subdomains, set shifting and processing speed whereas bvFTD was characterised by more deficits in imitation of face postures. A combination of tests for verbal recall, imitation of limb and face postures, and figure copy showed the greatest discriminatory power. CONCLUSIONS: Our results imply that the contribution of a standard neuropsychological assessment is limited for differential diagnosis of AD and bvFTD at initial presentation. In contrast to current clinical guidelines, executive functions are neither particularly nor exclusively impaired in patients with bvFTD when assessed within a standard clinical neuropsychological test battery. The significant overlap of bvFTD and AD concerning the profile of cognitive impairments questions current neuropsychological diagnostic criteria and calls for revision, regarding both the degree and the profile of cognitive deficits.

Alemtuzumab Improves Cognitive Processing Speed in Active Multiple Sclerosis-A Longitudinal Observational Study.

BACKGROUND: Several disease-modifying drugs have shown promising effects on cognitive impairment in multiple sclerosis (MS). Alemtuzumab, a humanized monoclonal antibody, is effective in controlling disease activity, however, has not been evaluated for its effects on cognition in detail so far. OBJECTIVE: To explore the influence of alemtuzumab on cognitive impairment in active relapsing-remitting MS (RRMS) as well as possible clinical and neuroimaging predictors of cognitive changes during the first year of therapy. METHODS: Extensive neuropsychological assessment was administered to 21 patients with active RRMS at baseline and again after the second treatment with alemtuzumab (mean time span: 15.05 months). Clinical and routine structural neuroimaging markers were explored for their capacity to predict individual courses of cognitive change. RESULTS: Overall cognitive functioning remained stable or improved during the observational period of alemtuzumab treatment on average. Scores on two neuropsychological tests of processing speed significantly improved and clinically relevant individual gains of processing speed were seen in the majority of patients. Linear regression models showed that clinical and routine neuroimaging measures of disease activity could not fully account for these cognitive changes. CONCLUSION: Results suggest that alemtuzumab treatment in active RRMS stabilizes overall cognitive functioning and furthermore positively affects cognitive processing speed. Changes in processing speed were independent from clinical and structural neuroimaging parameters of disease activity and may thus represent an underrated and independent outcome measure to evaluate treatment effects.

Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration.

OBJECTIVE: To report on a novel neuronal target antigen in 3 patients with autoimmune cerebellar degeneration. METHODS: Three patients with subacute to chronic cerebellar ataxia and controls underwent detailed clinical and neuropsychological assessment together with quantitative high-resolution structural MRI. Sera and CSF were subjected to comprehensive autoantibody screening by indirect immunofluorescence assay (IFA) and immunoblot. Immunoprecipitation with lysates of hippocampus and cerebellum combined with mass spectrometric analysis was used to identify the autoantigen, which was verified by recombinant expression in HEK293 cells and use in several immunoassays. Multiparameter flow cytometry was performed on peripheral blood and CSF, and peripheral blood was subjected to T-cell receptor spectratyping. RESULTS: Patients presented with a subacute to chronic cerebellar and brainstem syndrome. MRI was consistent with cortical and cerebellar gray matter atrophy associated with subsequent neuroaxonal degeneration. IFA screening revealed strong immunoglobulin G1 reactivity in sera and CSF with hippocampal and cerebellar molecular and granular layers, but not with a panel of 30 recombinantly expressed established neural autoantigens. Neurochondrin was subsequently identified as the target antigen, verified by IFA and immunoblot with HEK293 cells expressing human neurochondrin as well as the ability of recombinant neurochondrin to neutralize the autoantibodies' tissue reaction. Immune phenotyping revealed intrathecal accumulation and activation of B and T cells during the acute but not chronic phase of the disease. T-cell receptor spectratyping suggested an antigen-specific T-cell response accompanying the formation of antineurochondrin autoantibodies. No such neurochondrin reactivity was found in control cohorts of various neural autoantibody-associated neurologic syndromes, relapsing-remitting multiple sclerosis, cerebellar type of multiple system atrophy, hereditary cerebellar ataxias, other neurologic disorders, or healthy donors. CONCLUSION: Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration.

Shared neural correlates of limb apraxia in early stages of Alzheimer's dementia and behavioural variant frontotemporal dementia.

Limb apraxia denotes a cognitive impairment of gesture production. Lesion studies in patients with stroke point towards distinct neural processing streams for limb imitation and object-pantomime within left parietal and temporal cortex, respectively. Despite its frequent occurrence as an early symptom in both, Alzheimer's dementia (AD) and behavioural variant frontotemporal dementia (bvFTD), neural correlates of limb apraxia within these patient groups remain unexplored. Using voxel-based morphometry and multiple regression models, associations between limb apraxia and gray matter (GM) volume were investigated in 36 dementia patients (18 AD, 18 bvFTD) in early disease stages. Both dementia subtypes showed a comparable degree of limb apraxia. Although the patient groups showed distinct atrophy patterns with significantly more severe frontal GM loss in bvFTD, we found similar neural correlates of limb apraxia within posterior brain regions for both dementia subtypes: limb-imitation was associated with bilateral atrophy of superior, inferior and medial parietal cortex. Object-pantomime showed associations with GM volume in right middle temporal and angular gyrus. Our results argue for shared neural correlates of limb apraxia in AD and bvFTD and validate the syndrome as an important neuropsychological feature across different etiologies. Moreover, our results are compatible with neural models derived from patients with stroke, suggesting partly distinct neural representations of imitation and pantomime. Compared to patients with stroke however, AD and bvFTD showed more bilateral or even right lateralized neural representations of limb apraxia, proposing a greater influence of visuospatial impairments and spatial body representation deficits on praxis performance.

Dementia Apraxia Test (DATE): A Brief Tool to Differentiate Behavioral Variant Frontotemporal Dementia from Alzheimer's Dementia Based on Apraxia Profiles.

BACKGROUND: Standardized praxis assessments with modern, empirically validated screening tests have substantially improved clinical evaluation of apraxia in patients with stroke. Although apraxia may contribute to early differential diagnosis of Alzheimer's dementia (AD) and behavioral variant frontotemporal dementia (bvFTD), no comparable test is readily available to clinicians for this purpose to date. OBJECTIVE: To design a clinically useful apraxia test for the differentiation of AD and bvFTD. METHODS: 84 test items pertaining to twelve praxis subdomains were evaluated for their efficacy to discriminate between patients with bvFTD (n = 24), AD (n = 28), and elderly healthy controls (HC; n = 35). Items were then selected based on discriminative value and psychometric properties. RESULTS: Items indicative of mild AD comprised spatially complex imitation of hand and finger postures and to a lesser degree, pantomime of common object-use. Buccofacial apraxia including imitation of face postures, emblematic face postures, and repetition of multisyllabic pseudowords differentiated bvFTD from HC and AD. The final test version consisting of 20 items proved highly efficient for the discrimination of biologically confirmed dementia patients from HC (sensitivity 91% , specificity 71%) but also for differential diagnosis of bvFTD and AD (sensitivity 74% , specificity 93%). CONCLUSIONS: Assessment of praxis profiles effectively contributes to diagnosis and differential diagnosis of AD and bvFTD. The Dementia Apraxia Test (DATE) is a brief and easy to administer cognitive tool for dementia assessment, has a high inter-rater reliability (Cohen's κ= 0.885) and demonstrates content validity.

Immunoadsorption therapy in autoimmune encephalitides.

OBJECTIVE: It was hypothesized that in encephalitides with autoantibodies directed to CNS surface antigens an antibody-removing intervention might speed up recovery. METHODS: The outcome of autoimmune encephalitis in 19 patients with antibodies against surface antigens (leucine-rich, glioma inactivated 1 [LGI1], n = 3; contactin-associated protein-2 [CASPR2], n = 4; NMDA receptor [NMDAR], n = 7) and intracellular antigens (glutamic acid decarboxylase [GAD], n = 5) after immunoadsorption in addition to corticosteroid therapy was evaluated retrospectively. Modified Rankin scale (mRS) scores and data on seizures, memory, and antibody titers directly after immunoadsorption (early follow-up) and after a median of 4 months (late follow-up) were compiled. RESULTS: Immediately after immunoadsorption, 9 of 14 patients with antibodies against LGI1, CASPR2, or NMDAR (64%), but none with GAD antibodies, had improved by at least one mRS point. Five of the 7 patients with LGI1 or CASRP2 antibodies had become seizure-free, and 2 patients with NMDAR antibodies had a memory improvement of more than 1 SD of a normal control population. At late follow-up, 12 of 14 patients with surface antibodies had improved (86%), and none of the patients with GAD antibodies. CONCLUSIONS: It is suggested that addition of immunoadsorption to immunosuppression therapy in patients with surface antibodies may accelerate recovery. This supports the pathogenic role of surface antibodies. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that immunoadsorption combined with immunosuppression therapy is effective in patients with autoimmune encephalitis with surface antibodies.

Evidence of a pathogenic role for CD8(+) T cells in anti-GABAB receptor limbic encephalitis.

OBJECTIVES: To characterize the cellular autoimmune response in patients with γ-aminobutyric acid (GABA)B receptor antibody-associated limbic encephalitis (GABAB-R LE). METHODS: Patients underwent MRI, extensive neuropsychological assessment, and multiparameter flow cytometry of peripheral blood and CSF. RESULTS: We identified a series of 3 cases of nonparaneoplastic GABAB-R LE and one case of paraneoplastic GABAB-R LE associated with small cell lung cancer. All patients exhibited temporal lobe epilepsy, neuropsychological deficits, and MRI findings typical of LE. Absolute numbers of CD19(+) B cells, CD138(+) CD19(+) plasma cells, CD4(+) T cells, activated HLADR(+) CD4(+) T cells, as well as CD8(+) T cells and HLADR(+) CD8(+) T cells did not differ in peripheral blood but were elevated in CSF of patients with GABAB-R LE compared to controls. Augmented absolute numbers of CD138(+) CD19(+) plasma cells and activated HLADR(+) CD8(+) T cells in CSF corresponded to higher overall neuropsychological and memory deficits in patients with GABAB-R LE. A histologic specimen of one patient following selective amygdalohippocampectomy revealed perivascular infiltrates of CD138(+) plasma cells and CD4(+) T cells, whereas cytotoxic CD8(+) T cells were detected within the brain parenchyma in close contact to neurons. CONCLUSION: Our data suggest a pathogenic role for CD8(+) T cells in addition to the established role of plasma cell-derived autoantibodies in GABAB-R LE.

Impaired Autonomic Responses to Emotional Stimuli in Autoimmune Limbic Encephalitis.

Limbic encephalitis (LE) is an autoimmune-mediated disorder that affects structures of the limbic system, in particular, the amygdala. The amygdala constitutes a brain area substantial for processing of emotional, especially fear-related signals. The amygdala is also involved in neuroendocrine and autonomic functions, including skin conductance responses (SCRs) to emotionally arousing stimuli. This study investigates behavioral and autonomic responses to discrete emotion evoking and neutral film clips in a patient suffering from LE associated with contactin-associated protein-2 (CASPR2) antibodies as compared to a healthy control group. Results show a lack of SCRs in the patient while watching the film clips, with significant differences compared to healthy controls in the case of fear-inducing videos. There was no comparable impairment in behavioral data (emotion report, valence, and arousal ratings). The results point to a defective modulation of sympathetic responses during emotional stimulation in patients with LE, probably due to impaired functioning of the amygdala.

Neurocognitive decline in HIV patients is associated with ongoing T-cell activation in the cerebrospinal fluid.

OBJECTIVE: HIV-associated neurocognitive disorders (HAND) remain a challenge despite combination antiretroviral therapy (cART). Immune cell activation has been implicated to play a major role in the development of HAND. METHODS: In this study, we used multicolor flow cytometry on peripheral blood (PB) and cerebrospinal fluid (CSF) samples to determine the expression of HLA-DR and programmed death-1 (PD-1) on CD4+ and CD8+ T cells in patients with chronic HIV infection. Expression levels were correlated with HI virus load in PB and CSF, classification of HAND and severity of magnetic resonance imaging (MRI) signal abnormalities. RESULTS: In a cohort of 86 HIV patients we found that the grade of neurocognitive impairment and the severity of MRI signal abnormalities correlated with decreasing CD4/CD8-ratios and increased frequencies of HLA-DR expressing CD4+ and CD8+ T cells reaching the highest values in the CSF samples. Importantly, HLA-DR upregulation was still detectable in virologically suppressed HIV patients. Further, T-cell subpopulation analysis of 40 HIV patients showed a significant shift from naïve to effector memory (EM) T cells that was negatively correlated with the grade of neurocognitive impairment in the PB samples. Moreover, PD-1 was significantly increased on CD4+ memory T cells with highest levels on EM T cells in HIV patients with mild or severe neurocognitive alterations. INTERPRETATION: The CD4/CD8 ratio, the proportion of EM to naïve T cells and the immune activation profile of CD4+ and CD8+ T cells in PB and CSF might be useful parameters to monitor the efficacy of cART and to identify HIV patients at risk of further neurocognitive deterioration.