The spectrum of autoimmune encephalopathies

Dubey, Divyanshu; Sawhney, Anshudha; Greenberg, Benjamin; Lowden, Andrea; Warnack, Worthy; Khemani, Pravin; Stüve, Olaf; Vernino, Steven

doi:10.1016/j.jneuroim.2015.08.014

Cited by 40 publications

(49 citation statements)

References 15 publications

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“…These autoantibodies may target intracellular proteins (e.g., Hu and Ma-2) and serve as markers of autoimmunity rather than play a pathogenic role, whereas others are thought to target cell surface proteins (e.g., leucine-rich glioma-inactivated 1, NMDAR) and play an important role in syndrome pathogenesis (2,(40)(41)(42). Some of these autoantibodies are thought to be paraneoplastic, particularly those targeting intracellular proteins.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Value of¹⁸F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis

et al. 2017

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Diagnosis of autoimmune encephalitis presents some challenges in the clinical setting because of varied clinical presentations and delay in obtaining antibody panel results. We examined the role of neuroimaging in the setting of autoimmune encephalitides, comparing the utility of 18 F-FDG PET/CT versus conventional brain imaging with MRI. Methods: A retrospective study was performed assessing the positivity rate of MRI versus 18 F-FDG PET/CT during the initial workup of 23 patients proven to have antibody-positive autoimmune encephalitis. 18 F-FDG PET/CT studies were analyzed both qualitatively and semiquantitatively. Areas of cortical lobar hypo (hyper)-metabolism in the cerebrum that were 2 SDx from the mean were recorded as abnormal. Results: On visual inspection, all patients were identified as having an abnormal pattern of 18 F-FDG uptake. In semiquantitative analysis, at least 1 region of interest with metabolic change was identified in 22 of 23 (95.6%) patients using a discriminating z score of 2. Overall, 18 F-FDG PET/ CT was more often abnormal during the diagnostic period than MRI (10/23, 43% of patients). The predominant finding on brain 18 F-FDG PET/CT imaging was lobar hypometabolism, being observed in 21 of 23 (91.3%) patients. Hypometabolism was most commonly observed in the parietal lobe followed by the occipital lobe. An entire subset of antibody-positive patients, anti-N-methyl-D-aspartate receptor (5 patients), had normal MRI results and abnormal 18 F-FDG PET/CT findings whereas the other subsets demonstrated a greater heterogeneity. Conclusion: Brain 18 F-FDG PET/CT may play a significant role in the initial evaluation of patients with clinically suspected antibody-mediated autoimmune encephalitis. Given that it is more often abnormal when compared with MRI in the acute setting, this molecular imaging technique may be better positioned as an early biomarker of disease so that treatment may be initiated earlier, resulting in improved patient outcomes.

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Section: Discussionmentioning

confidence: 99%

Diagnostic Value of¹⁸F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis

et al. 2017

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“…AE has also been linked to various infectious triggers, including bacteria, viruses, fungi, and other parasites. However, an underlying infection is the causative agent for only a small fraction of all AE cases; in many cases, the triggers are either unknown or unidentified infectious agents (4, 5). While the evidence supporting various microbial triggers is scant, some autoimmune encephalopathies have well-established infectious links.…”

Section: Introductionmentioning

confidence: 99%

“…For example, untreated Group A Streptococcus ( S. pyogenes ) infections cause autoimmune sequela in many target tissues such as the heart or CNS, manifested as either rheumatic fever or Sydenham’s chorea (SC), respectively (6–8). Several recent reviews have highlighted the clinical and mechanistic features for many of these currently accepted autoimmune encephalitides and the aberrant autoimmunity/CNS axis (4, 5, 9–15). Here, we review infectious and non-infectious triggers for AE and discuss findings from animal models of AE related to blood–brain barrier (BBB) integrity, immune cell infiltration into the CNS, and neuronal circuit dysfunction that provide useful avenues to improve diagnosis (e.g., clinical assays and imaging techniques).…”

Section: Introductionmentioning

confidence: 99%

Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis

2017

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Antibodies against neuronal receptors and synaptic proteins are associated with autoimmune encephalitides (AE) that produce movement and psychiatric disorders. In order to exert their pathological effects on neural circuits, autoantibodies against central nervous system (CNS) targets must gain access to the brain and spinal cord by crossing the blood–brain barrier (BBB), a tightly regulated gateway formed by endothelial cells lining CNS blood vessels. To date, the pathogenic mechanisms that underlie autoantibody-triggered encephalitic syndromes are poorly understood, and how autoantibodies breach the barrier remains obscure for almost all AE syndromes. The relative importance of cellular versus humoral immune mechanisms for disease pathogenesis also remains largely unexplored. Here, we review the proposed triggers for various autoimmune encephalopathies and their animal models, as well as basic structural features of the BBB and how they differ among various CNS regions, a feature that likely underlies some regional aspects of autoimmune encephalitis pathogenesis. We then discuss the routes that antibodies and immune cells employ to enter the CNS and their implications for AE. Finally, we explore future therapeutic strategies that may either preserve or restore barrier function and thereby limit immune cell and autoantibody infiltration into the CNS. Recent mechanistic insights into CNS autoantibody entry indicate promising future directions for therapeutic intervention beyond current, short-lived therapies that eliminate circulating autoantibodies.

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“…It has been postulated that these antibodies may have a direct etiopathogenic role in these encephalitis syndromes, whereas immune-mediated syndromes associated with antibodies directed against intraneuronal antigens (such as anti-Hu, anti-Yo, anti-Ri, anti-Tr, and anti-CV2/CRMP5 antibodies) are hypothesized to be mediated by cytotoxic T-cells, (an epiphenomena secondary to antigenic release following T-cell-mediated neuronal cytotoxicity) [Dubey et al 2015b;Gultekin et al 2000;Dubey, 2016]. As supported by our study, cell-surface antigen-mediated antibody syndromes are considered to be more responsive to immunomodulation.…”

Section: Discussionmentioning

confidence: 99%

“…Studies which did not quantify seizure frequency or document change in seizure frequency were excluded. We were careful to avoid including patients twice when they were included in more than one publication [Dubey et al 2015a[Dubey et al , 2015b. Demographic/clinical variables (sex, age, race, clinical presentation, type of antibody, localization of antigen [intra-neuronal or cell surface], cerebrospinal fluid [CSF] protein, CSF pleocytosis, epilepsy focus, magnetic resonance imaging [MRI] characteristics, number of ASMs used, underlying malignancy, time to diagnosis and initiation of immunomodulatory therapy, and type of immunomodulatory therapy) were compared between two outcome groups (responders and nonresponders).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of positive and negative predictors of seizure outcomes among patients with immune-mediated epilepsy: a meta-analysis

Dubey

Farzal

Hays

et al. 2016

Ther Adv Neurol Disord

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Background: The objective of this study was to analyze published literature on autoimmune epilepsy and assess predictors of seizure outcome. Methods: From PubMed and EMBASE databases, two reviewers independently identified publications reporting clinical presentations, management and outcomes of patients with autoimmune epilepsy. A meta-analysis of 46 selected studies was performed. Demographic/ clinical variables (sex, age, clinical presentation, epilepsy focus, magnetic resonance imaging [MRI] characteristics, time to diagnosis and initiation of immunomodulatory therapy, and type of immunomodulatory therapy) were compared between two outcome groups (responders and nonresponders). Clinical response was defined as >50% reduction in seizure frequency. Unstandardized effect sizes were collected for the studies for responder and nonresponder groups. Sample size was used as the weight in the meta-analysis. The random effects model was used to account for heterogeneity in the studies. Results: The 46 reports included 186 and 96 patients in responder and nonresponder groups respectively. Mean age of the responders and nonresponders was 43 and 31 years (p < 0.01). Responders were more likely to have cell-surface antibodies (68% versus 39%, p < 0.05), particularly voltage-gated potassium channel complex antibodies (p < 0.01). Mean duration from symptom onset to diagnosis, and symptom onset to initiation of immunomodulation was significantly lower among the responders (75 versus 431 days, p < 0.05, and 80 versus 554, p < 0.01, respectively). There was no outcome difference based on gender, MRI characteristics, seizure type, type of acute immunomodulatory therapy, or use of chronic immunomodulation. Conclusions: Among published cases to date, older age, presence of cell-surface antibodies, early diagnosis and immunomodulatory treatment are associated with better seizure outcomes among patients with autoimmune epilepsy.

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The spectrum of autoimmune encephalopathies

Cited by 40 publications

References 15 publications

Diagnostic Value of¹⁸F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis

Diagnostic Value of¹⁸F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis

Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis

Evaluation of positive and negative predictors of seizure outcomes among patients with immune-mediated epilepsy: a meta-analysis

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The spectrum of autoimmune encephalopathies

Cited by 40 publications

References 15 publications

Diagnostic Value of18F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis

Diagnostic Value of18F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis

Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis

Evaluation of positive and negative predictors of seizure outcomes among patients with immune-mediated epilepsy: a meta-analysis

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Diagnostic Value of¹⁸F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis

Diagnostic Value of¹⁸F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis