ArticleLiterature Review

Autoantibodies associated with diseases of the CNS: New developments and future challenges

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Abstract

Several CNS disorders associated with specific antibodies to ion channels, receptors, and other synaptic proteins have been recognised over the past 10 years, and can be often successfully treated with immunotherapies. Antibodies to components of voltage-gated potassium channel complexes (VGKCs), NMDA receptors (NMDARs), AMPA receptors (AMPARs), GABA type B receptors (GABA(B)Rs), and glycine receptors (GlyRs) can be identified in patients and are associated with various clinical presentations, such as limbic encephalitis and complex and diffuse encephalopathies. These diseases can be associated with tumours, but they are more often non-paraneoplastic, and antibody assays can help with diagnosis. The new specialty of immunotherapy-responsive CNS disorders is likely to expand further as more antibody targets are discovered. Recent findings raise many questions about the classification of these diseases, the relation between antibodies and specific clinical phenotypes, the relative pathological roles of serum and intrathecal antibodies, the mechanisms of autoantibody generation, and the development of optimum treatment strategies.

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... Early on, we identified this area as having potential for improving test utilization. Based on the literature, most antibodies associated with AErelated disorders are higher in serum than in CSF (15,(17)(18)(19). Furthermore, not all antibodies may be detected in CSF, as is the case with VGKC (voltage-gated potassium channel)-complex and LG-1 (17). ...
... Based on the literature, most antibodies associated with AErelated disorders are higher in serum than in CSF (15,(17)(18)(19). Furthermore, not all antibodies may be detected in CSF, as is the case with VGKC (voltage-gated potassium channel)-complex and LG-1 (17). We also wanted to understand the clinical utility of each different body fluid based on sensitivity and specificity, but data are limited. ...
... We also wanted to understand the clinical utility of each different body fluid based on sensitivity and specificity, but data are limited. A clear understanding of the utility of both body fluids simultaneously is still under debate (17,19). In a study by Gresa-Arribas et al. (19), use of serum for detecting anti-NMDA receptor antibodies had sensitivity of 85%, but this sensitivity was calculated based on whether or not the antibody was detected in CSF. ...
Article
Background For many laboratories, autoimmune encephalopathy (AE) panels are send-out tests. These tests are expensive, and ordering patterns vary greatly. There is also a lack of consensus on which panel to order and poor understanding of the clinical utility of these panels. These challenges were presented to our newly formed, multidisciplinary, diagnostic stewardship committee (DSC). Through this collaboration, we developed an algorithm for ordering AE panels; combining diagnostic criteria with practice guidelines. Methods We analyzed test-ordering patterns in 2018 and calculated a true-positive rate based on clinical presentation and panel interpretation. An evidence-based approach was combined with input from the Department of Neurology to synthesize our algorithm. Efficacy of the algorithm (number of panels ordered, cost, and true positives) was assessed before and after implementation. Results In 2018, 77 AE-related panels were ordered, costing $137 510. The true-positive rate was 10%, although ordering multiple, similar panels for the same patient was common. Before implementing the algorithm (January 1–July 31, 2019), 55 panels were ordered, costing $105 120. The total true-positive rate was 3.6%. After implementation, 23 tests were ordered in a 5-month period, totaling $50 220. The true-positive rate was 13%. Conclusion With the DSC-directed mandate, we developed an algorithm for ordering AE panels. Comparison of pre- and postimplementation data showed a higher true-positive rate, indicating that our algorithm was able to successfully identify the at-risk population for AE disorders. This was met with a 43% decrease in the number of tests ordered, with total cost savings of $25 000 over 5 months.
... -Syndrome paranéoplasique Les encéphalites à anti LGI1 sont associées à une tumeur dans moins de 10 % des cas, et de nature variée [193]. Diverses tumeurs semblent être associées, mais le thymome et le cancer du poumon sont probablement les plus courants. ...
... Contrairement à la neuromyotonie ou au syndrome de Morvan, les encéphalites limbiques pures à anti CASPR2 étaient rarement associées à un cancer (16,7%), ce qui a été constaté Pour les encéphalites à anti-LGI-1, notre série n'a pas détecté aussi de néoplasie, d'autant plus que ce type d'encéphalite a été rarement associé à une tumeur, selon la littérature, car elles ne n'ont été détectées que dans 0% à 11% des cas, couramment à type de thymome ou le cancer du poumon [94,114,189,193]. ...
Thesis
Introduction: Les encéphalites autoimmunes sont des entités récentes et méconnues, ciblant les antigènes du SNC, réalisant souvent une encéphalite limbique inflammatoire, dont l’immunothérapie est souvent efficace.Objectifs de l’étude: Déterminer les caractéristiques cliniques et para cliniques des encéphalites à anti NMDAr, à anti CASPR2 et à anti LGI1.Matériels et méthodes: C’est une étude descriptive, prospective et rétrospective, de janvier 2016 à décembre 2018.Résultats: Nous avons recensé 30 patients (âge moyen de 44 ± 18,05 ans). Le tableau clinique était souvent aigu (73,3%), avec des troubles psychiatriques, des troubles de la vigilance, de crises d’épilepsie, et des troubles mnésiques, voir de la dysautonomie. Un hyper signal temporal (± extra limbique) a été souvent retrouvé à l’IRM, des anomalies aspécifiques à l’EEG, et un LCR inflammatoire. Les FBDS, les dyskinésies, et la neuromyotonie était les signes discriminatifs. Une néoplasie a été retrouvée chez 16,7% des cas. L’immunothérapie a conduit à une bonne évolution.Conclusion: Cette étude a pour objectif de savoir diagnostiquer ces entités dans notre pays et d’instaurer un traitement précoce et efficace. Une étude avec de grands échantillons serait plus bénéfique.
... Approximately, 70% of the patients had presymptomatic headaches, Disease Markers fever, vomiting, diarrhea, and upper respiratory tract infections. The typical manifestation is the neuropsychiatric symptoms in the early stage [6,7], followed by progressive worsening of cognitive dysfunction and confusion [5,8,9]. There was the presence of partial or complete seizures during the disease (even status epilepticus), which might be refractory epilepsy [10], and the antiepileptic drugs were generally ineffective but the response improved after receiving immunotherapy. ...
... There was the presence of partial or complete seizures during the disease (even status epilepticus), which might be refractory epilepsy [10], and the antiepileptic drugs were generally ineffective but the response improved after receiving immunotherapy. The seizures also manifested as autonomic dysfunction and required intensive care when the patient experienced coma central hypopnea [5,7,9]. In this study, out of the 13 patients, 6 had anti-NMDA encephalitis, with an average age of 40 years. ...
Article
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Objective: To investigate the clinical manifestations, laboratory and imaging examinations, and the treatment outcomes of autoimmune encephalitis (AE). Methods: The clinical data of 13 patients with autoimmune encephalitis who were hospitalized in the department of neurology, Liaocheng People's Hospital from July 2016 to August 2018 were retrospectively analyzed. Results: The average age of onset of the 13 patients was 45 years, including 6 cases (46%) of anti-NMDAR encephalitis, 3 cases (23%) of anti-GABAB receptor encephalitis, and 4 cases (30%) of anti-LG11 encephalitis, and 4 of them showed abnormal signals of brain MRI (30%). 13 patients (100%) had cognitive impairment and psychiatric symptoms; seizures occurred in 12 patients (92%); lung cancer was found in 1 patient (7%). One case was given up because of the treatment of lung cancer, the other was controlled obviously in epilepsy, and cognitive impairment and abnormal mental behavior were also significantly improved. Conclusion: Patients with AE still need to be diagnosed early to avoid missed diagnosis and receive early immunosuppressive therapy, which could effectively reduce mortality and morbidity. A detailed history, clinical manifestations, and positive results for specific NSAbs tests can confirm the diagnosis, and the treatment is mainly done by immunosuppressive therapy.
... Several mechanisms have been proposed for the pathogenesis of onchocerciasisrelated epilepsy. However, one of the most identified mechanisms is the O. volvulusinduced immune response via an inflammatory process or autoantibodies against neuron surface proteins such as the voltage-gated potassium channel complex (VGKC), the N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), gamma-aminobutyric acid (GABA)A, GABAB, and glycine receptors which are recognized causes of severe epileptic disorders [33]. ...
Chapter
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Epilepsy is a neurological disorder affecting over 50 million people worldwide. Global epilepsy prevalence has been reported to be the greatest in Africa, prevalent among children living in resource-poor areas compared with all other continents. In West Africa, a meta-analysis of epilepsy prevalence was quoted to be 13-15 per 1000 persons. As a result of the lack of specialists and electroencephalographic facilities, the type of seizures that are more likely reported in rural areas is generalized tonic-clonic seizures. A high prevalence of epilepsy in low-and middle-income countries has been identified with CNS infections due to viral, bacterial, and parasitic infections. Parasitic infections including malaria, onchocerciasis, cysticercosis, and toxocariasis are believed to account for up to 27% of pediatric epilepsy cases reported in Sub-Saharan Africa, of which onchocerciasis has been more documented as a parasitic cause of epilepsy in most of west Africa. The management of epilepsy in West Africa centers around the administration of anti-seizure medications when available, and an onchocerciasis control program that has reduced onchocerciasis-associated epilepsy in these countries. However, several management options put in place still seem insufficient to curb the disease prevalence, hence improved strategy for effective control of parasite-induced epilepsy in West Africa.
... The clinical spectrum of autoimmune encephalitis (AE) consists of AE with neuronal surface antibodies (nsAb) in which autoreactive antibodies directly induce brain dysfunction with often good response to immunotherapy [1,2]. Classic AE with onconeuronal antibodies is accompanied by structural brain damage mediated by dysregulated T-cells. ...
Article
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Background: To investigate severe autoimmune encephalitis (AE) on the intensive care unit (ICU) with regard to standard treatment in responsive patients and additional escalation therapies for treatment-refractory cases. Methods: This retrospective, single-center study analyzed medical records of ICU-dependent AE patients for clinical characteristics, treatments, prognostic factors and neurological outcome as quantified by modified Rankin Scale (mRS) and Clinical Assessment Scale for Autoimmune Encephalitis (CASE). Results: From 40 enrolled patients (median age 52 years, range: 16-89) with AE mediated by neuronal surface antibodies (nsAb; 90%) and AE with onconeuronal antibodies (10%) 98% received first-line therapy. Thereof, 62% obtained additional second-line therapy and 33% escalation therapy with bortezomib and/or daratumumab. Good neurological outcome defined as mRS=0-2 was observed in 47% of AE with nsAb (CASE: 5), 77% of NMDAR-encephalitis patients (CASE: 1), whereas AE patients with onconeuronal antibodies had the poorest outcome (mRS=6: 100%). Treatment-refractory AE patients with nsAb requiring escalation therapy achieved similar good recovery (mRS=0-2: 39%; CASE: 3) as patients improving without (mRS=0-2: 54%; CASE: 4) although they presented a higher disease severity at disease maximum (mRS=5 100% versus 68%; CASE: 24 versus 17; p=0.0036), had longer ICU stays (97 versus 23 days; p=0.0002) and a higher survival propability during follow-up (p=0.0203). Prognostic factors for good recovery were younger age (p=0.025) and lack of preexisting comorbidities (p=0.011). Conclusions: Our findings suggest that apparently treatment-refractory AE patients with nsAb on ICU can reach similarly good outcomes after plasma cell-depleting escalation therapy as patients already responding to standard first- and/or second-line therapies.
... Mirror OCBs indicate the presence of OCBs in serum and CSF. Recent studies have demonstrated that autoimmune-related CNS disease antibodies are produced in the peripheral circulation (131,132). Therefore, mirror OCBs should not be ignored, as they may be an important biomarker of inflammatory CNS diseases. ...
Article
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Autoimmune encephalitis (AE) is a severe inflammatory disease of the brain. Patients with AE demonstrate amnesia, seizures, and psychosis. Recent studies have identified numerous associated autoantibodies (e.g., against NMDA receptors (NMDARs), LGI1, etc.) involved in the pathogenesis of AE, and the levels of diagnosis and treatment are thus improved dramatically. However, there are drawbacks of clinical diagnosis and treatment based solely on antibody levels, and thus the application of additional biomarkers is urgently needed. Considering the important role of immune mechanisms in AE development, we summarize the relevant research progress in identifying cerebrospinal fluid (CSF) biomarkers with a focus on cytokines/chemokines, demyelination, and nerve damage.
... So, this approach can be navigated and studied further for developing an efficient transport medium for immunotherapeutic vaccines (Yu et al. 2019). Also, we need to equally look into the clearance mechanism of these antibodies from the CNS after they bind to the target protein, as they may lead to the release of some inflammatory mediators that may affect the normal functioning of healthy cells, so we need to keep a check on the adversities caused due to this too (Vincent et al. 2011). ...
Chapter
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Dementia is a syndrome that marks a significant cognitive decline with an estimated 50 million populations being affected by this globally and addition of ten million cases every year predicting a compelling threat to society. It commonly involves the neuronal accumulation of proteins leading to protein toxicity, transmission interruptions, cognitive dysfunction, and eventually neuronal death. Currently, novel techniques using different protocols for early theragnostic and prognosis of this age-related disorder have been analyzed to develop efficient and reproducible combinatorial and biologically viable options. Subsequently, immunotherapies have gained much importance among the researchers with promising leads to control and avert the dementing process, while specifically targeting the senile plaques and protein accumulation to control neurotoxicity in neurodegenerative disorders (NDDs). Therefore, in this chapter authors have explored all the reported and possible immunologically applicable options for improving the further cognitive decline in dementia.
... This crossover may further lead to the generation of CNS protein-targeting autoantibodies that, upon subsequent injury, may enter the CNS and damage nerve cells. [54][55][56] Figure 1. Representation of the pathophysiological manifestations associated with primary (left) and secondary (right) phases of TBI. ...
Article
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Traumatic brain injury (TBI) is not a single disease state but describes an array of conditions associated with insult or injury to the brain. While some individuals with TBI recover within a few days or months, others present with persistent symptoms that can cause disability, neuropsychological trauma, and even death. Understanding, diagnosing, and treating TBI is extremely complex for many reasons, including the variable biomechanics of head impact, differences in severity and location of injury, and individual patient characteristics. Because of these confounding factors, the development of reliable diagnostics and targeted treatments for brain injury remains elusive. We argue that the development of effective diagnostic and therapeutic strategies for TBI requires a deep understanding of human neurophysiology at the molecular level and that the framework of multiomics may provide some effective solutions for the diagnosis and treatment of this challenging condition. To this end, we present here a comprehensive review of TBI biomarker candidates from across the multiomic disciplines and compare them with known signatures associated with other neuropsychological conditions, including Alzheimer’s disease and Parkinson’s disease. We believe that this integrated view will facilitate a deeper understanding of the pathophysiology of TBI and its potential links to other neurological diseases.
... The voltage-gated potassium channel (VGKC) complex consists of leucine-rich gliomainactivated 1 (LGI1), contactin-associated protein-like-2 (CASPR2), and contactin-2. LGI1 constitutes 70% of the complex [26]. Some patients with high titers of LGI1 antibodies may develop dystonic seizures of the face and arms (faciobrachial dystonic seizures) before temporal lobe seizures or other typical LE symptoms. ...
Article
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Introduction: The concept of "autoimmune epilepsy" (AE) has been emphasized more frequently through the recent increase in recognition of various autoantibodies specific to neuronal proteins. Aims: To evaluate the attitudes of neurologists in regard to AE, to review the differential diagnosis, treatment options, and to reveal the effect of COVID-19 on this matter. Methods: A detailed questionnaire prepared for AE was sent to neurologists via social media and WhatsApp after the approval of the Ethics Committee. The responses of 245 respondents working in different settings were analyzed, and the group with 15 years or less experience in neurology was statistically compared to the group with more than 15 years of experience. Results: Awareness and knowledge levels on AE seemed high in all groups, while 11% had never thought about AE during the differential diagnosis in real life. Before starting treatment, 20% thought that the autoantibody result should definitely support it, and 77.6% reported that they did not recognize AE well. Participants stated that satisfactory guidelines for diagnosis and treatment (88.2%) and widespread laboratory support (83.7%) were lacking. Neurologists with less experience and those working outside of training hospitals get more often consultation from an experienced clinician while diagnosing and conduct more detailed investigations at the diagnosis stage (p = 0.0025, p = 0.0001). Conclusion: This first survey study conducted in a large group of neurologists on the attitudes for the concept of AE suggested that postgraduate education, and diagnostic and treatment guidelines should be organized and antibody screening tests need to be better disseminated.
... The circulating neuronal cell surface antibodies are aimed at extracellular proteins which have a direct pathogenic effect by influencing the antigen function or causing antigen internalization in the absence of cell destruction [10][11][12][13]. By counteracting the autoimmune response with immunosuppressive drugs, most patients, even those who are severely ill, make a substantial improvement [1,5,14,15]. ...
Article
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Autoimmune encephalitis (AE) comprises a heterogeneous group of disorders in which the host immune system targets self-antigens expressed in the central nervous system. The most conspicuous example is an anti- N -methyl- d -aspartate receptor encephalitis linked to a complex neuropsychiatric syndrome. Current treatment of AE is based on immunotherapy and has been established according to clinical experience and along the concept of a B cell-mediated pathology induced by highly specific antibodies to neuronal surface antigens. In general, immunotherapy for AE follows an escalating approach. When first-line therapy with steroids, immunoglobulins, and/or plasma exchange fails, one converts to second-line immunotherapy. Alkylating agents could be the first choice in this stage. However, due to their side effect profile, most clinicians give preference to monoclonal antibodies (mAbs) directed at B cells such as rituximab. Newer mAbs might be added as a third-line therapy in the future, or be given even earlier if shown effective. In this chapter, we will discuss mAbs targeting B cells (rituximab, ocrelizumab, inebulizumab, daratumumab), IL-6 (tocilizumab, satralizumab), the neonatal Fc receptor (FCRn) (efgartigimod, rozanolixizumab), and the complement cascade (eculizumab).
... Anti-LGI1 AE is characterized by cognitive impairment or rapid progressive dementia, psychiatric disorders, faciobrachial dystonic seizures (FBDS) and refractory hyponatremia (1)(2)(3)(4). It is also considered as a subtype of limbic encephalitis usually occurring without any detectable paraneoplastic cause (5,6). It is responsive to immunotherapy treatment including steroids, intravenous immunoglobulin (IVIG) and other immunosuppressive agents (7). ...
Article
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Anti-leucine rich glioma inactivated 1 (LGI1) autoimmune encephalitis (AE) is characterized by cognitive impairment or rapid progressive dementia, psychiatric disorders, faciobrachial dystonic seizures (FBDS) and refractory hyponatremia. Since December 2020, millions of people worldwide have been vaccinated against COVID-19. Several soft neurological symptoms like pain, headache, dizziness, or muscle spasms are common and self-limited adverse effects after receiving the COVID-19 vaccine. However, several major neurological complications, despite the unproven causality, have been reported since the introduction of the COVID-19 vaccine. Herein, we describe a 48 years old man presenting with rapidly progressive cognitive decline and hyponatremia diagnosed with anti LGI1 AE, occurring shortly after the second dose of mRNA COVID -19 vaccine and possibly representing a severe adverse event related to the vaccination. Response to high dose steroid therapy was favorable. As millions of people worldwide are currently receiving COVID-19 vaccinations, this case should serve to increase the awareness for possible rare autoimmune reactions following this novel vaccination in general, and particularly of anti-LGI1 AE.
... Hepatic disease, renal insufficiency, migraine, or depression may affect the choice of ASM, while autoimmune diseases associated with seizures may be treated with immunotherapy. 6,59 Second, determination of the medication regimen to treat comorbidities requires consideration of the effect of these on seizure susceptibility. 60 For example, some antipsychotics increase the risk of seizures. ...
Article
Purpose of review: Comorbidities are a common feature in epilepsy, but neither the entire spectrum nor the significance of such comorbidities has been fully explored. We review comorbidities associated with epilepsy and their associated burden, provide an overview of relationships, and discuss a new conceptualization of the comorbidities. Recent findings: The epidemiology of the comorbidities of epilepsy and effects on health outcomes, healthcare use, and healthcare expenditures have been partly delineated. Distinct mechanisms of the associations have been suggested but not entirely ascertained. Movement from conceptualizing epilepsy as a condition to a symptom-complex has occurred. Summary: Comorbidities are common among people with epilepsy and are associated with poorer clinical outcomes and quality of life, greater use of health resources, and increased expenditure. Becoming aware of the associated mechanisms and their uncertainty is central to understanding the relationships between epilepsy and comorbid health conditions, which have implications for diagnosis and screening, medical management, and surgical management. Conceptualizing comorbidities of epilepsy as precipitating factors and epilepsy as the symptom will improve the understanding of epilepsy and catalyze research and improvements in clinical practice.
... LGI1 is most specific for LE while CASPR2 is more specific to neuromyotonia [50]. ...
Article
Limbic encephalitis is an autoimmune cause of encephalitis. In addition to the usual symptoms of encephalitis such as altered consciousness, fever, and focal neurological deficits, limbic encephalitis can present with neuropsychiatric manifestations and seizures. Making a formal diagnosis involves a difficult and prolonged workup phase. The purpose of this review is to help readers delineate limbic encephalitis from other illnesses. This is done by presenting a spectrum of potential organic differential diagnoses and pertinent findings that distinguish them from limbic encephalitis. Instead of presenting a variety of psychiatric differential diagnoses, the authors present a review of psychiatric manifestations known to be associated with limbic encephalitis, as naturally, any psychiatric disorder could be a potential comorbid disease.
... As more related cases have been identified in the past 10 years, there has been increasing interest in the pathogenesis and clinical features of AE, especially in patients with Abs to cell-surface proteins expressed in neurons, including antibodies against synaptic receptors and antibodies targeting ion channels and cell-surface proteins, who have an effective response to immunosuppressive therapies and who respond well to immunosuppressive therapies (4). Abs to N-methyl-D-aspartate receptor (NMDAR), gamma-aminobutyric acid A receptor (GABAAR), gamma-aminobutyric acid B receptor (GABABR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), metabotropic glutamate receptor 5 (mGluR5), dopamine 2 receptor, leucine-rich gliomainactivated 1 (LGI1), contactin-associated protein-like 2 (Caspr2), and dipeptidyl-peptidase-like protein 6 (DPPX) were identified in patients and were associated with various clinical manifestations (5). ...
Article
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Objective: Autoimmune encephalitis (AE) is a severe but treatable autoimmune disorder that is diagnosed by antibody (Ab) testing. However, it is unrealistic to obtain an early diagnosis in some areas since the Ab status cannot be immediately determined due to time and technology restrictions. In our study, we aimed to validate the Antibody Prevalence in Epilepsy and Encephalopathy (APE ² ) score among patients diagnosed with possible AE as a predictive model to screen AE patients with antibodies to cell-surface proteins expressed in neurons. Methods: A total of 180 inpatients were recruited, and antibodies were detected through serological and/or cerebrospinal fluid (CSF) evaluations. The APE ² score was used to validate the predictive models of AE with autoantibodies. Results: The mean APE ² score in the Ab-positive cases was 7.25, whereas the mean APE ² score in the Ab-negative cases was 3.18 ( P < 0.001). The APE ² score had a receiver operating characteristic (ROC) area under the curve of 0.924 [ P < 0.0001, 95% confidence interval (CI) = 0.875–0.973]. With a cutoff score of 5, the APE ² score had the best psychometric properties, with a sensitivity of 0.875 and a specificity of 0.791. Conclusion: The APE ² score is a predictive model for AE with autoantibodies to cell-surface proteins expressed in neurons and was validated and shown to have high sensitivity and specificity in our study. We suggest that such a model should be used in patients with a suspected diagnosis of AE, which could increase the detection rate of Abs, reduce testing costs, and help patients to benefit from treatment quickly.
... In the past two decades, a subset of epilepsies, particularly temporal lobe epilepsy (TLE), has been recognized as an antibody-mediated autoimmune disorder. The most common phenotypes are non-paraneoplastic and paraneoplastic limbic encephalitis (1). The diagnostic criteria (2) include subacute onset seizures, neurocognitive changes, cerebral magnetic resonance imaging changes suggestive of encephalitis with FLAIR hyperintensities of the temporal lobes and/or other cortical areas, and cerebrospinal fluid (CSF) pleocytosis. ...
Article
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Introduction: Our goal was to investigate whether biomarkers of cerebral damage are found in autoimmune-mediated epilepsy (AIE) and whether these can differentiate AIE from other seizure disorders. Methods: We retrospectively searched our cerebrospinal fluid (CSF) database for patients with definite AIE, hippocampal sclerosis due to other causes (HS), genetic generalized epilepsy (GGE), and psychogenic, non-epileptic seizures (PNES). We measured serum and CSF tau, neurofilament 1 (NFL), glial fibrillary acid protein (GFAP), and ubiquitin-carboxy-terminal hydrolase L1 with a single-molecule array. Results: We identified suitable samples from patients with AIE ( n = 13) with different antibodies and compared them to HS ( n = 13), GGE ( n = 7), and PNES ( n = 8). The NFL levels were significantly elevated in the serum ( p = 0.0009) and CSF ( p < 0.0019) of AIE patients. The AIE group was significantly older, while the disease duration was significantly shorter than in the control groups. NFL correlated significantly with age in all groups, and the NFL levels of AIE patients were hardly higher than those of healthy elderly people published elsewhere. Conclusions: Our data indicate that the elevated NFL levels in AIE patients are most likely due to the higher age in this group and not due to the underlying inflammation. Unless larger prospective studies with intra-individual, longitudinal analyses and treatment responses would contradict our findings, NFL in serum might yet become a biomarker for disease activity and differential diagnosis.
... These antibodies can result in seizures, loss of skills, (sometimes a dramatic loss), behavioral changes and even psychosis. Effective immunotherapy can, in at least some cases, reverse all these changes [107,108]. This is an area which requires further consideration. ...
Chapter
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ASD and epilepsy, two common co-occurrent conditions, may appear in a developing brain in various genetic and non- genetic syndromes. The fact that multiple genetic and epigenetic factors, metabolic diseases, environmental factors and epileptic encephalopathies are related to the causation of both ASD and epilepsy indicate the presence of some common underlying pathophysiologic mechanisms. Although many questions are yet to be answered, recent studies suggest that synaptic aberrant connectivity and disruption of the delicate balance between neuronal excitation and inhibition (E/I imbalance) leads to various aspects of neuronal dysfunction. The presence of intellectual disability increases the likelihood of co-morbid ASD and epilepsy and all these associations greatly affect the quality of life of these children as well as their families. Therefore, understanding the genetic, cellular and molecular basis of relationship between these common co-morbid conditions is fundamental in planning appropriate and prompt management of these children. Future researches will as such continue to address the pathophysiology underlying the genetic, chromosomal, metabolic-mitochondrial disorders and environmental factors related to these co-morbidities as well as preventing them. Thus, it will lay the base of focused investigations and targeted management in this field.
... As differential diagnoses, primarily infectious encephalitis (e.g., HSV encephalitis) [112,113] as well as various autoimmune etiologies with neuropsychiatric manifestations must be taken into consideration. The latter include encephalitis with classical paraneoplastic autoantibodies (against intracellular onconeural antigens: Hu, Ma, CV2, amphiphysin), neuropsychiatric lupus, Sj ö gren ' s syndrome, Hashimoto' s encephalopathy, antiphospholipid syndrome, metabolic encephalopathy, Korsakoff ' s syndrome, primary angiitis of the CNS and others [2,3,61,62,114] . Occasionally, the symptoms give rise to a diagnosis of a suspected drug-induced psychosis (e.g., neuroleptic malignant syndrome). ...
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Recently, several novel autoantibodies have been identified which are closely associated with different subtypes of autoimmune encephalitis. These antibodies are directed against structures located on the neuronal cell surface: glutamate receptors (types NMDA and AMPA), GABA B receptors, as well as the voltage-gated potassium channel-associated proteins LGI1 and CASPR2. They are much more common than the classical paraneoplastic antibodies (anti-Hu, -Yo, -Ri, -Ma, -CV2, -amphiphysin), less frequently associated with a tumor, and the corresponding clinical syndromes respond significantly better to immunotherapy. Monospecific detection of these autoantibodies in the serum or cerebrospinal fluid of patients is primarily performed by indirect immunofluorescence using transfected HEK293 cell lines recombinantly expressing the membrane-associated target antigens. Owing to the symptom overlap of the respective disorders, it is highly appropriate to determine these parameters in parallel for each patient (autoantibody profiles). Early diagnosis (substantially supported by the serological laboratory), the immediate initiation of immunotherapeutic intervention and, in cases of paraneoplastic etiology, tumor resection are crucial for prognosis. In our own investigations, antibodies against glutamate receptors (type NMDA) are most frequently found among the newly identified forms of autoimmune encephalitis, accounting for 42% of cases. In laboratory practice, one-third of positive reactions were caused by an autoantibody whose determination was not requested by the clinician. Considering the urgency for therapeutic measures in positive cases, these findings substantiate the need to implement multiparametric serological test systems in this diagnostic area.
... autoimmune encephalitis | GABA-A-receptor encephalitis | autoantibody | paraneoplastic encephalitis | epilepsy A shared feature of autoimmune encephalitis syndromes are autoantibodies recognizing either intracellular antigens or extracellular epitopes of cell-surface antigens (1)(2)(3)(4)(5). Intracellular antigens are primarily released by cellular immune responses and later bound by autoantibodies, whereas cell surface antigens are assumed to be targets of direct humoral immune responses. ...
Article
Significance Antibodies recognizing the neuronal gamma-aminobutyric acid A receptor (GABA A -R) cause severe encephalitis by triggering internalization of the antibody–receptor complexes in inhibitory synapses, which leads to hyperexcitability and dysfunction of neuronal networks. From the cerebrospinal fluid of a patient with GABA A -R encephalitis we cloned a highly expressed antibody and showed that it binds the GABA A -R and influences signal transduction in neurons, explaining clinical symptoms. Using several experimental techniques, we confirmed that the antibody cross-reacts to an oncoprotein which is known to be involved in several malignancies. We showed that cross-reactivity to this oncoprotein may also be detected in two other GABA A -R patients, suggesting that such cross-reactivity is presumably a key event in the pathogenesis of GABA A -R encephalitis.
... Other clinical reports have been published showing effective utilization of immunomodulatory treatment for autoimmune encephalitis based upon the presence of antineuronal antibodies directed against NMDA receptor (Dalmau et al., 2017), voltage-gated potassium channel-complex (VGKC) (Vincent et al., 2011), leucine-rich glioma inactivated-1 (LGI1), astrocyte aquaporin-4 (AQP4) (Zekeridou and Lennon, 2015), glutamic acid decarboxylase (GAD65), gamma-aminobutyric acid-B receptor (GABAB), and others (Mader et al., 2017;Platt et al., 2017;Mohammad and Dale, 2018;Lancaster, 2016;Dale et al., 2017). It is plausible there could be additional antineuronal antibody targets that lead to symptoms of autoimmune encephalitis. ...
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Objective: This retrospective study examined whether changes in patient pre-and post-treatment symptoms correlated with changes in anti-neuronal autoantibody titers and the neuronal cell stimulation assay in the Cunningham Panel in patients with Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection (PANDAS), and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). Methods: In an analysis of all tests consecutively performed in Moleculera Labs' clinical laboratory from April 22, 2013 to December 31, 2016, we identified 206 patients who were prescribed at least one panel prior to and following treatment, and who met the PANDAS/PANS diagnostic criteria. Patient follow-up was performed to collect symptoms and treatment or medical intervention. Of the 206 patients, 58 met the inclusion criteria of providing informed consent/assent and documented pre-and post-treatment symptoms. Clinician and parent-reported symptoms after treatment or medical intervention were categorized as "Improved/Resolved" (n = 34) or "Not-Improved/Worsened" (n = 24). These were analyzed for any association between changes in clinical status and changes in Cunningham panel test results. Clinical assay performance was also evaluated for re-producibility and reliability. Results: Comparison of pre-and post-treatment status revealed that the Cunningham Panel results correlated with changes in patient's neuropsychiatric symptoms. Based upon the change in the number of positive tests, the overall accuracy was 86%, the sensitivity and specificity were 88% and 83% respectively, and the Area Under the Curve (AUC) was 93.4%. When evaluated by changes in autoantibody levels, we observed an overall accuracy of 90%, a sensitivity of 88%, a specificity of 92% and an AUC of 95.7%. Assay reproducibility for the calcium/calmodulin-dependent protein kinase II (CaMKII) revealed a correlation coefficient of 0.90 10 −6) and the ELISA assays demonstrated test-retest reproducibility comparable with other ELISA assays. Conclusion: This study revealed a strong positive association between changes in neuropsychiatric symptoms and changes in the level of anti-neuronal antibodies and antibody-mediated CaMKII human neuronal cell activation. These results suggest there may be clinical utility in monitoring autoantibody levels and stimulatory activity against these five neuronal antigen targets as an aid in the diagnosis and treatment of infection-triggered autoimmune neuropsychiatric disorders. Future prospective studies should examine the feasibility of predicting antimicrobial and immunotherapy responses with the Cunningham Panel.
Article
Autoimmune Encephalitis (AE) spans a group of non-infectious inflammatory conditions of the central nervous system due to an imbalanced immune response. Aiming to elucidate the pathophysiological mechanisms of AE, we applied an unsupervised proteomic approach to analyze the cerebrospinal fluid (CSF) protein profile of AE patients with autoantibodies against N-methyl-d-aspartate receptor (NMDAR) (n = 9), leucine-rich glioma-inactivated protein 1 (LGI1) (n = 9), or glutamate decarboxylase 65 (GAD65) (n = 8) compared to 9 patients with relapsing-remitting multiple sclerosis as inflammatory controls, and 10 patients with somatic symptom disorder as non-inflammatory controls. We found a dysregulation of the complement system, a disbalance between pro-inflammatory and anti-inflammatory proteins on the one hand, and dysregulation of proteins involved in synaptic transmission, synaptogenesis, brain connectivity, and neurodegeneration on the other hand to a different extent in all AE subtypes compared to non-inflammatory controls. Furthermore, elevated levels of several proteases and reduction in protease inhibitors could be detected in all AE subtypes compared to non-inflammatory controls. Moreover, the different AE subtypes showed distinct protein profiles compared to each other and inflammatory controls which may facilitate future identification of disease-specific biomarkers. Overall, CSF proteomics provides insights into the complex pathophysiological mechanisms of AE, including immune dysregulation, neuronal dysfunction, neurodegeneration, and altered protease function.
Article
Autoimmune encephalitis, diseases where the immune system attacks the brain, have become a fast-moving field of study in recent years. The authors, Drs Josep Dalmau and Francesc Graus, have played pivotal roles in the discovery of these diseases. Here, they provide a comprehensive clinical guide to the differential diagnosis of these disorders, illustrated with over 200 figures, 30 videos and numerous clinical vignettes, many from their own practice. Clinical descriptions are straightforward, emphasizing distinctive diagnostic clues for each disease. The strengths and weaknesses of diagnostic tests and clinical criteria are discussed extensively, as well as the best evidence supporting the use of available treatments. There is an up-to-date description of immunological triggers and comorbidities, and well-illustrated and clearly summarized pathogenic mechanisms and disease models. Gain full HTML access of the whole book, including supplementary videos, via a scratch-off code inside the cover.
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Antibody-mediated encephalitides constitute a group of inflammatory brain diseases that are characterized by prominent neuropsychiatric symptoms and are associated with antibodies against neuronal cell-surface proteins, ion channels, or receptors. Common clinical features include a change in behavior, psychosis, seizures, memory and cognitive deficits, abnormal movements, dysautonomia, and a decreased level of consciousness. The estimated annual incidence of all types of encephalitis is approximately 5 to 8 cases per 100,000 persons, and in 40 to 50% of the cases, the cause cannot be established. A prospective, multicenter, population-based study suggests that autoimmune disorders are the third most common cause of encephalitis, after infections, usually viral, and acute disseminated encephalomyelitis, which is typically a postinfectious disorder. The frequency of the most common form of autoimmune encephalitis, the type with antibodies against the N-methyl-d-aspartate receptor (NMDAR), surpasses the frequency of any individual viral cause of encephalitis in young persons, and in one retrospective study, anti-NMDAR encephalitis accounted for 1% of all admissions of young adults to an intensive care unit. The patient discussed here is a 47-year old male who presented to our casualty as a case of fever and abnormal behaviour which started suddenly. Patient was evaluated thoroughly and the diagnosis of anti-NMDA antibody encephalitis was made. Patient was treated with IV methylprednisolone 1g for 5 days after which he didn't improve much. An alternative therapy with IVIGs was made after which patient improved significantly. A 47 year old male with no known comorbidities, presented to casualty with 3 day history of fever and abnormal behaviour. Patient had started with low grade fever which gradually worsened over some hours and was followed by abnormal behaviour in the form of irrelevant talking, abusive language and disorientation. There was no history of weakness of any side of body, history suggestive of cranial nerve palsies or bowel or bladder involvement. Patient's past history was medically insignificant. Patient was admitted and clinical examination revealed a GCS of 14/15 (E4V4M6), pulse of 102 beats/minute, temperature of 101 F. There was no pallor, icterus,
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Clinical case studies have long been recognized as a useful adjunct to problem-based learning and continuing professional development. They emphasize the need for clinical reasoning, integrative thinking, problem-solving, communication, teamwork and self-directed learning - all desirable generic skills for health care professionals. Epilepsy is amongst the most frequently encountered of neurological disorders. There are important emerging clinical management issues (e.g., first seizure, therapy-resistant seizures, ICU, pregnancy) but also differential diagnosis of non-epileptic seizures (syncopy, pseudo-seizure, paroxysmal dystonic syndromes, sleep disorders, psychosis, inborn errors of metabolism, etc.). This selection of epilepsy case studies will inform and challenge clinicians at all stages in their careers. Including both common and uncommon cases, Case Studies in Epilepsy reinforces the diagnostic skills and treatment decision-making processes necessary to treat epilepsy and other seizures confidently. Written by leading experts, the cases and discussions work through differential diagnoses, treatments and social consequences in pediatric and adult patients.
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Clinical case studies have long been recognized as a useful adjunct to problem-based learning and continuing professional development. They emphasize the need for clinical reasoning, integrative thinking, problem-solving, communication, teamwork and self-directed learning - all desirable generic skills for health care professionals. Epilepsy is amongst the most frequently encountered of neurological disorders. There are important emerging clinical management issues (e.g., first seizure, therapy-resistant seizures, ICU, pregnancy) but also differential diagnosis of non-epileptic seizures (syncopy, pseudo-seizure, paroxysmal dystonic syndromes, sleep disorders, psychosis, inborn errors of metabolism, etc.). This selection of epilepsy case studies will inform and challenge clinicians at all stages in their careers. Including both common and uncommon cases, Case Studies in Epilepsy reinforces the diagnostic skills and treatment decision-making processes necessary to treat epilepsy and other seizures confidently. Written by leading experts, the cases and discussions work through differential diagnoses, treatments and social consequences in pediatric and adult patients.
Chapter
Clinical case studies have long been recognized as a useful adjunct to problem-based learning and continuing professional development. They emphasize the need for clinical reasoning, integrative thinking, problem-solving, communication, teamwork and self-directed learning - all desirable generic skills for health care professionals. Epilepsy is amongst the most frequently encountered of neurological disorders. There are important emerging clinical management issues (e.g., first seizure, therapy-resistant seizures, ICU, pregnancy) but also differential diagnosis of non-epileptic seizures (syncopy, pseudo-seizure, paroxysmal dystonic syndromes, sleep disorders, psychosis, inborn errors of metabolism, etc.). This selection of epilepsy case studies will inform and challenge clinicians at all stages in their careers. Including both common and uncommon cases, Case Studies in Epilepsy reinforces the diagnostic skills and treatment decision-making processes necessary to treat epilepsy and other seizures confidently. Written by leading experts, the cases and discussions work through differential diagnoses, treatments and social consequences in pediatric and adult patients.
Chapter
Clinical case studies have long been recognized as a useful adjunct to problem-based learning and continuing professional development. They emphasize the need for clinical reasoning, integrative thinking, problem-solving, communication, teamwork and self-directed learning - all desirable generic skills for health care professionals. Epilepsy is amongst the most frequently encountered of neurological disorders. There are important emerging clinical management issues (e.g., first seizure, therapy-resistant seizures, ICU, pregnancy) but also differential diagnosis of non-epileptic seizures (syncopy, pseudo-seizure, paroxysmal dystonic syndromes, sleep disorders, psychosis, inborn errors of metabolism, etc.). This selection of epilepsy case studies will inform and challenge clinicians at all stages in their careers. Including both common and uncommon cases, Case Studies in Epilepsy reinforces the diagnostic skills and treatment decision-making processes necessary to treat epilepsy and other seizures confidently. Written by leading experts, the cases and discussions work through differential diagnoses, treatments and social consequences in pediatric and adult patients.
Chapter
Clinical case studies have long been recognized as a useful adjunct to problem-based learning and continuing professional development. They emphasize the need for clinical reasoning, integrative thinking, problem-solving, communication, teamwork and self-directed learning - all desirable generic skills for health care professionals. Epilepsy is amongst the most frequently encountered of neurological disorders. There are important emerging clinical management issues (e.g., first seizure, therapy-resistant seizures, ICU, pregnancy) but also differential diagnosis of non-epileptic seizures (syncopy, pseudo-seizure, paroxysmal dystonic syndromes, sleep disorders, psychosis, inborn errors of metabolism, etc.). This selection of epilepsy case studies will inform and challenge clinicians at all stages in their careers. Including both common and uncommon cases, Case Studies in Epilepsy reinforces the diagnostic skills and treatment decision-making processes necessary to treat epilepsy and other seizures confidently. Written by leading experts, the cases and discussions work through differential diagnoses, treatments and social consequences in pediatric and adult patients.
Chapter
Clinical case studies have long been recognized as a useful adjunct to problem-based learning and continuing professional development. They emphasize the need for clinical reasoning, integrative thinking, problem-solving, communication, teamwork and self-directed learning - all desirable generic skills for health care professionals. Epilepsy is amongst the most frequently encountered of neurological disorders. There are important emerging clinical management issues (e.g., first seizure, therapy-resistant seizures, ICU, pregnancy) but also differential diagnosis of non-epileptic seizures (syncopy, pseudo-seizure, paroxysmal dystonic syndromes, sleep disorders, psychosis, inborn errors of metabolism, etc.). This selection of epilepsy case studies will inform and challenge clinicians at all stages in their careers. Including both common and uncommon cases, Case Studies in Epilepsy reinforces the diagnostic skills and treatment decision-making processes necessary to treat epilepsy and other seizures confidently. Written by leading experts, the cases and discussions work through differential diagnoses, treatments and social consequences in pediatric and adult patients.
Chapter
Clinical case studies have long been recognized as a useful adjunct to problem-based learning and continuing professional development. They emphasize the need for clinical reasoning, integrative thinking, problem-solving, communication, teamwork and self-directed learning - all desirable generic skills for health care professionals. Epilepsy is amongst the most frequently encountered of neurological disorders. There are important emerging clinical management issues (e.g., first seizure, therapy-resistant seizures, ICU, pregnancy) but also differential diagnosis of non-epileptic seizures (syncopy, pseudo-seizure, paroxysmal dystonic syndromes, sleep disorders, psychosis, inborn errors of metabolism, etc.). This selection of epilepsy case studies will inform and challenge clinicians at all stages in their careers. Including both common and uncommon cases, Case Studies in Epilepsy reinforces the diagnostic skills and treatment decision-making processes necessary to treat epilepsy and other seizures confidently. Written by leading experts, the cases and discussions work through differential diagnoses, treatments and social consequences in pediatric and adult patients.
Chapter
Clinical case studies have long been recognized as a useful adjunct to problem-based learning and continuing professional development. They emphasize the need for clinical reasoning, integrative thinking, problem-solving, communication, teamwork and self-directed learning - all desirable generic skills for health care professionals. Epilepsy is amongst the most frequently encountered of neurological disorders. There are important emerging clinical management issues (e.g., first seizure, therapy-resistant seizures, ICU, pregnancy) but also differential diagnosis of non-epileptic seizures (syncopy, pseudo-seizure, paroxysmal dystonic syndromes, sleep disorders, psychosis, inborn errors of metabolism, etc.). This selection of epilepsy case studies will inform and challenge clinicians at all stages in their careers. Including both common and uncommon cases, Case Studies in Epilepsy reinforces the diagnostic skills and treatment decision-making processes necessary to treat epilepsy and other seizures confidently. Written by leading experts, the cases and discussions work through differential diagnoses, treatments and social consequences in pediatric and adult patients.
Chapter
Clinical case studies have long been recognized as a useful adjunct to problem-based learning and continuing professional development. They emphasize the need for clinical reasoning, integrative thinking, problem-solving, communication, teamwork and self-directed learning - all desirable generic skills for health care professionals. Epilepsy is amongst the most frequently encountered of neurological disorders. There are important emerging clinical management issues (e.g., first seizure, therapy-resistant seizures, ICU, pregnancy) but also differential diagnosis of non-epileptic seizures (syncopy, pseudo-seizure, paroxysmal dystonic syndromes, sleep disorders, psychosis, inborn errors of metabolism, etc.). This selection of epilepsy case studies will inform and challenge clinicians at all stages in their careers. Including both common and uncommon cases, Case Studies in Epilepsy reinforces the diagnostic skills and treatment decision-making processes necessary to treat epilepsy and other seizures confidently. Written by leading experts, the cases and discussions work through differential diagnoses, treatments and social consequences in pediatric and adult patients.
Chapter
Clinical case studies have long been recognized as a useful adjunct to problem-based learning and continuing professional development. They emphasize the need for clinical reasoning, integrative thinking, problem-solving, communication, teamwork and self-directed learning - all desirable generic skills for health care professionals. Epilepsy is amongst the most frequently encountered of neurological disorders. There are important emerging clinical management issues (e.g., first seizure, therapy-resistant seizures, ICU, pregnancy) but also differential diagnosis of non-epileptic seizures (syncopy, pseudo-seizure, paroxysmal dystonic syndromes, sleep disorders, psychosis, inborn errors of metabolism, etc.). This selection of epilepsy case studies will inform and challenge clinicians at all stages in their careers. Including both common and uncommon cases, Case Studies in Epilepsy reinforces the diagnostic skills and treatment decision-making processes necessary to treat epilepsy and other seizures confidently. Written by leading experts, the cases and discussions work through differential diagnoses, treatments and social consequences in pediatric and adult patients.
Chapter
Clinical case studies have long been recognized as a useful adjunct to problem-based learning and continuing professional development. They emphasize the need for clinical reasoning, integrative thinking, problem-solving, communication, teamwork and self-directed learning - all desirable generic skills for health care professionals. Epilepsy is amongst the most frequently encountered of neurological disorders. There are important emerging clinical management issues (e.g., first seizure, therapy-resistant seizures, ICU, pregnancy) but also differential diagnosis of non-epileptic seizures (syncopy, pseudo-seizure, paroxysmal dystonic syndromes, sleep disorders, psychosis, inborn errors of metabolism, etc.). This selection of epilepsy case studies will inform and challenge clinicians at all stages in their careers. Including both common and uncommon cases, Case Studies in Epilepsy reinforces the diagnostic skills and treatment decision-making processes necessary to treat epilepsy and other seizures confidently. Written by leading experts, the cases and discussions work through differential diagnoses, treatments and social consequences in pediatric and adult patients.
Chapter
Clinical case studies have long been recognized as a useful adjunct to problem-based learning and continuing professional development. They emphasize the need for clinical reasoning, integrative thinking, problem-solving, communication, teamwork and self-directed learning - all desirable generic skills for health care professionals. Epilepsy is amongst the most frequently encountered of neurological disorders. There are important emerging clinical management issues (e.g., first seizure, therapy-resistant seizures, ICU, pregnancy) but also differential diagnosis of non-epileptic seizures (syncopy, pseudo-seizure, paroxysmal dystonic syndromes, sleep disorders, psychosis, inborn errors of metabolism, etc.). This selection of epilepsy case studies will inform and challenge clinicians at all stages in their careers. Including both common and uncommon cases, Case Studies in Epilepsy reinforces the diagnostic skills and treatment decision-making processes necessary to treat epilepsy and other seizures confidently. Written by leading experts, the cases and discussions work through differential diagnoses, treatments and social consequences in pediatric and adult patients.
Article
Rasmussen's encephalitis (RE) is a rare condition of unknown etiology that causes a severe chronically neurological disorder with mostly affecting children. The main clinical feature of RE includes frequent seizures with drug‐resistant, unilateral hemispheric atrophy, and progressive neurological deficits. In this review, we summarized five pathogenesis on the basis of the current research including virus infection, antibody‐mediated degeneration, cell‐mediated immunity, microglia‐induced degeneration, and genetic mutations. So far, no exact virus in RE brain tissue or definite antigen in humoral immune system was confirmed as the determined etiology. The importance of cytotoxic CD8+ T lymphocytes and activated microglial and the role of their immune mechanism in RE development are gradually emerging with the deep study. Genetic researches support the notion that the pathogenesis of RE is probably associated with single nucleotide polymorphisms on immune‐related genes, which is driven by affecting inherent antiretroviral innate immunity. Recent advances in treatment suggest immunotherapy could partially slows down the progression of RE according to the histopathology and clinical presentation, which aimed at the initial damage to the brain by T cells and microglia in the early stage. However, the cerebral hemispherectomy is an effective means to controlling the intractable seizure, which is accompanied by neurological complications inevitably. So, the optimal timing for surgical intervention is still a challenge for RE patient. On the contrary, exploration on other aspects of pathogenesis such as dysfunction of adenosine system may offer a new therapeutic option for the treatment of RE in future.
Article
Background: Autoimmune limbic encephalitis in children occurs most frequently in those with antibodies against the N-methyl-D-aspartate glutamatergic receptor. We report the case of a 14-year-old girl who was diagnosed with antileucine-rich glioma-inactivated protein 1 limbic encephalitis. Case: A fourteen years old, previously healthy girl applied to the emergency department with suspicion of dystonic seizure, ataxia, gait disturbance and speech disorders. Serum sample of the patient was positive for leucine-rich glioma inactivated protein 1 IgG. Conclusions: Although it is a rare disease in childhood, in the presence of new onset psychotic symptoms or altered mental state, concomittant hyponatremia and unique type of seizures, anti leucine-rich glioma inactivated protein 1encephalitis should be considered in differential diagnosis.
Article
Accurate serologic evaluation of autoantibodies in patients with autoimmune diseases is critical. In the present study, we established a live cell-based assay for simultaneous detection of multiple autoantibodies in a single serum sample. Autoantibody seropositivity was determined by 3-color flow cytometry using live Chinese hamster ovary cells transiently expressing a target protein of interest fused to enhanced green fluorescent protein and labeled with Alexa Fluor 647 and Hoechst 33342. As a representative example, we applied the strategy for simultaneous detection of 2 recently established biomarkers for central nervous system autoimmune inflammatory demyelinating disorders, anti-aquaporin-4 autoantibody and anti-myelin oligodendrocyte glycoprotein autoantibody, in a single serum sample. This analysis revealed the coexistence of these 2 autoantibodies. We demonstrated that this assay can simultaneously detect 3 different autoantibodies. We propose a quadrant gating strategy of flow cytometry contour plots to clearly distinguish seropositive sera from seronegative sera regardless of the extent of the background signal level or the autoantibody titer. This novel and practical method using a combination of fluorescent proteins and fluorochromes to simultaneously detect multiple autoantibodies improves the efficiency of evaluating serum samples, and therefore provides significant benefits to both the patient and the healthcare professionals performing autoantibody testing.
Article
Seronegative autoimmune limbic encephalitis is a rare clinical syndrome defined by a rapid onset of cognitive impairment with neuropsychiatric features and an absence of associated autoantibodies that often lead to diagnostic uncertainty, delayed treatment and ultimately, poor prognosis. Here a case is presented that highlights the benefits of implementing a multidisciplinary approach to treating the psychiatric manifestations, including a cautious use of therapeutic home leave for patients where the clinical course is prolonged.
Article
We investigated the immunological outcome predictors in patients with antibody-mediated autoimmune encephalitis. A severe disability on admission, a low lymphocyte count, including T, B, and T + B + NK (TBNK) cells, an elevated neutrophil (%) and neutrophil to lymphocyte ratio (NLR) could predict poor prognoses. The increased neutrophils (%) and NLR with the decreased eosinophil percent and count were sensitive (>0.8) in predicting severe disabilities, while the declined total T cell count, lymphocyte percent and count were specific (>0.9). TBNK cell count had a balanced sensitivity and specificity (both>0.8). Patients with autoimmune encephalitis with poor outcomes are immunologically distinct from those with good recoveries.
Article
Objective: The investigators aimed to explore the clinical characteristics, immunotherapy, and outcomes of patients with antileucine-rich glioma-inactivated-1 (anti-LGI1) encephalitis. Methods: Data on participants' clinical characteristics, laboratory findings, radiological and electroencephalogram (EEG) features, treatment, and outcomes from January 2012 to December 2016 were collected. Statistical analysis was conducted to assess the factors associated with patient functional outcome. Forty-three patients were enrolled in the study, with a predominance of males (65.1%). The median age at onset was 57 years (interquartile range [IQR]: 44.0-65.0). The median time from onset to diagnosis was 60 days (IQR: 37.0-127.0). Results: The main clinical manifestations included epilepsy (100%), faciobrachial dystonic seizures (FBDS; 44.2%), cognitive dysfunction (95.3%), neuropsychiatric disturbances (76.7%), sleep disorders (58.1%), and disturbance of consciousness (48.8%). Twenty-two patients (51.2%) had hyponatremia, 31 (72.1%) had abnormal EEG results, and 30 (69.8%) had abnormal brain MRI scans, mainly involving the hippocampus (76.7%) or temporal lobe (40%). Twenty of 34 patients (58.8%) in a follow-up MRI examination exhibited hippocampal atrophy. Twenty-five patients (58.2%) were administered corticosteroids and intravenous immunoglobulin, whereas 17 patients were treated only with corticosteroids. Forty-one patients (95.3%) had favorable outcomes after a median of 21.5 months (IQR: 7-43) of follow-up. Serum sodium level was a factor associated with a disabled status (odds ratio=0.81, 95% CI=0.66, 0.98, p=0.03). Anti-LGI1 encephalitis patients were characterized by seizures, FBDS, cognitive deficits, neuropsychiatric disturbances, and hyponatremia. Conclusions: Most patients with anti-LGI1 encephalitis are nonparaneoplastic, have low recurrence rates, and have favorable prognostic outcomes. Rapid evaluation, prompt immunotherapy, and long-term follow-up are essential in the care of anti-LGI1 encephalitis patients.
Article
Epilepsy is one of the most frequent chronic neurological disorder extremely threatening the life and good health. More than 70 million individuals suffering from epilepsy worldwide and it required long-term therapy. Many epileptic patients not fully satisfied with currently available treatment likewise, frequent drugs have shown a lack of efficacy, side effects, and drug interaction. Therefore, the search for antiepileptics with greater selectivity and lesser toxicity continues to be the focus and task in medicinal chemistry. Quinazoline represents a distinct class of biologically active nitrogen heterocyclic nucleus with great anticonvulsants potential. In the past few years, persistent medicinal chemistry efforts have developed diverse structurally functionalized potential quinazoline derivatives for anticonvulsant potential. This work report covers most current efforts taken in the design, development, and anticonvulsant efficacy of quinazoline analogs from 2015 to 2020.
Article
Autoimmune encephalitis represented by anti‐NMDA receptor antibody positive encephalitis is a type of non‐herpetic limbic encephalitis, and it is well known that emotional and memory disorders manifest as limbic symptoms. However, it should be noted that autonomic dysfunction is also an important symptom of limbic system dysfunction. Autonomic manifestations of autoimmune encephalitis include not only general physical symptoms such as high fever, sweating, and bladder and rectal disorders, but also life‐threatening symptoms such as large fluctuations in blood pressure and pulse, and central apnea, which require treatment in the intensive care unit. This review outlines autoimmune encephalitis with autonomic symptoms and summarizes reports on each antibody that causes autoimmune encephalitis.
Article
Objective To evaluate the cognitive and neurofunctional outcomes in patients with anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis. Methods A cohort follow-up study was performed after a median of 33 months (range 6–78) from disease onset to the last follow-up in patients diagnosed with anti-LGI1 encephalitis, to assess the neurofunctional outcomes using modified Rankin Scale (mRS), activities of daily living (ADL), neuropsychiatric inventory (NPI) and modified telephone interview for cognitive status (TICS-M). Remote symptomatic seizure and clinical relapses were also recorded. The clinical, laboratory features, and treatment responses that characterize the disability were analyzed. Results The results showed that 81 of 86 (94.2%) patients with anti-LGI1 encephalitis were successfully followed up, while eight (9.9%) died after discharge. Among the 73 survivors, clinical relapses occurred in 18 (24.7%) patients, and those with relapses were at a higher risk of developing remote symptomatic seizure (p = .019). Although 85.2% of the patients became functionally independent (mRS ≤2), the sequelae of symptomatic seizure, neuropsychiatric symptoms, and cognitive deficits were found in 11.0%, 21.9%, and 39.7% of the patients, respectively. Residual cognitive deficits primarily occurred in the elderly subjects as well as those with symptoms of memory deficit, psychiatric disorders, sleep disturbance, disturbance of consciousness at diagnosis, and higher CSF protein levels. Conclusions Although most patients survived and became functionally independent, a subset of patients could not return to all premorbid activities. They may have clinical relapses or suffer from remote symptomatic seizure, neuropsychiatric symptoms, and cognitive impairment.
Article
The emerging paradigm of childhood autoimmune neurological disorders has exploded in recent times due to reliable diagnostic methods and their ease of availability, well-defined diagnostic criteria, and universal awareness about these disorders. The most important aspect of these disorders is a considerable recovery in response to early targeted immunotherapy. If left untreated and/or ill-treated, these can lead to mortality or lifelong morbidity. Autoantibodies can target any part of the central nervous system (CNS), ranging from superficial structures like myelin to deep intracellular ion channels like voltage-gated potassium channels, resulting in contrasting and at times overlapping symptomatology. Though neuroimaging characteristics and serological tests confirm these disorders’ diagnosis, it is essential to suspect them clinically and start management before the reports are available for minimizing morbidity and mortality. In the pediatric age group, several metabolic conditions, like mitochondrial disorders and enzyme deficiencies like HMG-CoA-lyase deficiency, can develop neuroimaging patterns similar to those seen in childhood CNS autoimmune disorders and may also show a favorable response to steroids in acute phases. Hence, the clinician must suspect and work up the index patient appropriately. Here, we briefly discuss the pathophysiology, clinical clues, and potential therapeutic targets related to pediatric CNS autoimmune disorders.
Chapter
The discovery of anti-N-methyl-D-aspartate receptor (NMDAR) autoimmune encephalitis (AE) in 2007 has paved the path for the discovery of multiple other neuronal antibodies causing AE. A correct diagnosis in these patients is vital, because treatment with immunosuppressive drugs leads to a substantial improvement of eventual clinical outcome in most AE patients, even in those who are initially severely affected by the disease. In the acute phase, first-line immunotherapy is installed, most often with a combination of high-dose steroids and immunoglobulins. An alternative first-line treatment strategy is plasmapheresis. When first-line therapy fails, one converts to second-line immunotherapy consisting of rituximab or cyclophosphamide or a combination of both. In patients with a reasonable relapse risk, there is a need for maintenance therapy with immunosuppressants with the so-called steroid-sparing agents, such as azathioprine and mycophenolate mofetil.
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Autoimmune inflammatory disorders are often marked by subacute development of new or worsening symptoms. These relapses reflect active inflammation and should be promptly recognized for early treatment and optimization of chronic immunomodulating or immunosuppressing therapies to avoid disability accumulation over time. Detection of subclinical activity using paraclinical testing also warrants a change in treatment and should be part of the monitoring approach of most disorders. Differentiating pseudorelapses or fluctuating symptoms from true relapses is important for appropriate management. Depending on the disease, oral or intravenous corticosteroids at low or high dosages, intravenous immunoglobulin, and plasmapheresis can be used to halt the inflammatory process and increase the chances of tissue recovery. Optimal symptom management is essential to improve functional outcomes and to complement the beneficial effect of long-term maintenance therapies. Management is limited by the lack of evidence-based guidelines for the monitoring and treatment of most disorders, with the exception of multiple sclerosis. Because of the difficulty to perform randomized controlled trials in autoimmune neurology, future work should aim at increasing knowledge from real-world cohorts and optimizing monitoring tools of disease activity.
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Ion channel drug discovery is a rapidly evolving field fuelled by recent, but significant, advances in our understanding of ion channel function combined with enabling technologies such as automated electrophysiology. The resurgent interest in this target class by both pharmaceutical and academic scientists was clearly highlighted by the over-subscribed RSC/BPS 'Ion Channels as Therapeutic Targets' symposium in February 2009. This book builds on the platform created by that meeting, covering themes including advances in screening technology, ion channel structure and modelling and up-to-date case histories of the discovery of modulators of a range of channels, both voltage-gated and non-voltage-gated channels. The editors have built an extensive network of contacts in the field through their first-hand scientific experience, collaborations and conference participation and the organisation of the meeting at Novartis, Horsham, increased the network enabling the editors to draw on the experience of eminent researchers in the field. Interest and investment in ion channel modulation in both industrial and academic settings continues to grow as new therapeutic opportunities are identified and realised for ion channel modulation. This book provides a reference text by covering a combination of recent advances in the field, from technological and medicinal chemistry perspectives, as well as providing an introduction to the new 'ion channel drug discoverer'. The book has contributions from highly respected academic researchers, industrial researchers at the cutting edge of drug discovery and experts in enabling technology. This combination provides a complete picture of the field of interest to a wide range of readers.
Article
Epilepsy and autism frequently co-occur. Epilepsy confers an increased risk of autism and autism confers an increased risk of epilepsy. Specific epilepsy syndromes, intellectual disability, and female gender present a particular risk of autism in individuals with epilepsy. Epilepsy and autism are likely to share common etiologies, which predispose individuals to either or both conditions. Genetic factors, metabolic disorders, mitochondrial disorders, and immune dysfunction all can be implicated.
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Paraneoplastic neurological disorder (PND) syndromes are disorders that occur physically remote from and commonly develop before the detection of a primary malignancy or metastases. They are thought to be the by-product of systemic immune responses to cancer. PND syndromes may potentially affect any part of the central, peripheral, or autonomic nervous systems individually or in combination. Their diagnosis may be challenging because of the lack of a diagnostic consensus and familiarity among physicians. Patient management centers on the recognition and treatment of the tumor as well as concomitant immunosuppressant and symptomatic therapy.
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Voltage gated potassium channel antibody encephalopathy, a rare cause of limbic encephalopathy, typically presents with sub-acute memory impairment and seizures. However, psychiatric symptoms have not been emphasised in the literature. Here we describe a 58-year-old businessman who presented with panic attacks and 'pseudoseizures', and who later developed delusions and hallucinations. Following investigation, he was found to have antibodies to voltage gated potassium channels. Treatment with immuno-modulatory therapy resulted in almost complete recovery.
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The precise knowledge of the subunit assembly process of NMDA receptors (NMDA-Rs) is essential to understand the receptor architecture and underlying mechanism of channel function. Because NMDA-Rs are obligatory heterotetramers requiring the GluN1 subunit, it is critical to investigate how GluN1 and GluN2 type subunits coassemble into tetramers. By combining approaches in cell biology, biochemistry, single particle electron microscopy, and x-ray crystallography, we report the mechanisms and phenotypes of mutant GluN1 subunits that are defective in receptor maturation. The T110A mutation in the N-terminal domain (NTD) of the GluN1 promotes heterodimerization between the NTDs of GluN1 and GluN2, whereas the Y109C mutation in the adjacent residue stabilizes the homodimer of the NTD of GluN1. The crystal structure of the NTD of GluN1 revealed the mechanism underlying the biochemical properties of these mutants. Effects of these mutations on the maturation of heteromeric NMDA-Rs were investigated using a receptor trafficking assay. Our results suggest that the NTDs of the GluN1 subunit initially form homodimers and the subsequent dimer dissociation is critical for forming heterotetrameric NMDA-Rs containing GluN2 subunits, defining a molecular determinant for receptor assembly. The domain arrangement of the dimeric NTD of GluN1 is unique among the ionotropic glutamate receptors and predicts that the structure and mechanism around the NTDs of NMDA-Rs are different from those of the homologous AMPA and kainate receptors.
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Since its discovery in 2007, the encephalitis associated with antibodies against the N-methyl-D-aspartate receptor (NMDAR) has entered the mainstream of neurology and other disciplines. Most patients with anti-NMDAR encephalitis develop a multistage illness that progresses from psychosis, memory deficits, seizures, and language disintegration into a state of unresponsiveness with catatonic features often associated with abnormal movements, and autonomic and breathing instability. The disorder predominantly affects children and young adults, occurs with or without tumour association, and responds to treatment but can relapse. The presence of a tumour (usually an ovarian teratoma) is dependent on age, sex, and ethnicity, being more frequent in women older than 18 years, and slightly more predominant in black women than it is in white women. Patients treated with tumour resection and immunotherapy (corticosteroids, intravenous immunoglobulin, or plasma exchange) respond faster to treatment and less frequently need second-line immunotherapy (cyclophosphamide or rituximab, or both) than do patients without a tumour who receive similar initial immunotherapy. More than 75% of all patients have substantial recovery that occurs in inverse order of symptom development and is associated with a decline of antibody titres. Patients' antibodies cause a titre-dependent, reversible decrease of synaptic NMDAR by a mechanism of crosslinking and internalisation. On the basis of models of pharmacological or genetic disruption of NMDAR, these antibody effects reveal a probable pathogenic relation between the depletion of receptors and the clinical features of anti-NMDAR encephalitis.
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Limbic encephalitis is rare in people <18 years of age and rarely given a formal diagnosis. Retrospective study on presentation and outcome of children and adolescents with the clinico-radiological syndrome of limbic encephalitis tested for specific neuronal autoantibodies (Abs) over 3.5 years. Assessment, diagnosis, treatment and follow-up at 12 neuropaediatric and neurological departments in Europe, with Abs determined in Bonn, Germany and Oxford, UK. Ten patients <18 years of age who presented with a disorder mainly affecting the limbic areas of <5 years' duration with MRI evidence of mediotemporal encephalitis (hyperintense T2/FLAIR signal, resolving over time). Median age at disease onset was 14 years (range 3-17). Eight patients had defined Abs: one each with Hu or Ma1/2 Abs, four with high titre glutamic acid decarboxylase (GAD) Abs, two of whom had low voltage-gated potassium channel (VGKC) Abs and two with only low titre VGKC Abs. A tumour was only found in the patient with Hu Abs (a neuroblastoma). After a median follow-up of 15 months with corticosteroid or intravenous immunoglobulin treatment, starting after a median of 4 months, two patients recovered, eight remained impaired and one died. Limbic encephalitis is a disease that can occur in childhood or adolescence with many of the hallmarks of the adult disorder, suggesting that both result from similar pathogenic processes. Since most of the cases were non-paraneoplastic, as now also recognised in adults, more systematic and aggressive immunotherapies should be evaluated in order to improve outcomes.
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Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with encephalitis in England. Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. We identified 203 patients with encephalitis. Median age was 30 years (range 0-87). 86 patients (42%, 95% CI 35-49) had infectious causes, including 38 (19%, 14-25) herpes simplex virus, ten (5%, 2-9) varicella zoster virus, and ten (5%, 2-9) Mycobacterium tuberculosis; 75 (37%, 30-44) had unknown causes. 42 patients (21%, 15-27) had acute immune-mediated encephalitis. 24 patients (12%, 8-17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7-65) and varicella zoster virus (two patients; 20%, 2-56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups-nine (56%, 30-80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR = 3·44). Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. The Policy Research Programme, Department of Health, UK.
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Antibodies that immunoprecipitate (125)I-alpha-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan's syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with (125)I-alpha-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan's syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.
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Mutations of the LGI1 (leucine-rich, glioma-inactivated 1) gene underlie autosomal dominant lateral temporal lobe epilepsy, a focal idiopathic inherited epilepsy syndrome. The LGI1 gene encodes a protein secreted by neurons, one of the only non-ion channel genes implicated in idiopathic familial epilepsy. While mutations probably result in a loss of function, the role of LGI1 in the pathophysiology of epilepsy remains unclear. Here we generated a germline knockout mouse for LGI1 and examined spontaneous seizure characteristics, changes in threshold for induced seizures and hippocampal pathology. Frequent spontaneous seizures emerged in homozygous LGI1(-/-) mice during the second postnatal week. Properties of these spontaneous events were examined in a simultaneous video and intracranial electroencephalographic recording. Their mean duration was 120 +/- 12 s, and behavioural correlates consisted of an initial immobility, automatisms, sometimes followed by wild running and tonic and/or clonic movements. Electroencephalographic monitoring indicated that seizures originated earlier in the hippocampus than in the cortex. LGI1(-/-) mice did not survive beyond postnatal day 20, probably due to seizures and failure to feed. While no major developmental abnormalities were observed, after recurrent seizures we detected neuronal loss, mossy fibre sprouting, astrocyte reactivity and granule cell dispersion in the hippocampus of LGI1(-/-) mice. In contrast, heterozygous LGI1(+/-) littermates displayed no spontaneous behavioural epileptic seizures, but auditory stimuli induced seizures at a lower threshold, reflecting the human pathology of sound-triggered seizures in some patients. We conclude that LGI1(+/-) and LGI1(-/-) mice may provide useful models for lateral temporal lobe epilepsy, and more generally idiopathic focal epilepsy.
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A severe subacute encephalitis associated with auto-antibodies to the NMDA receptor (NMDA-R) has been reported in humans. These antibodies are directed to NR1/NR2 heteromers of the NMDA receptor. We studied the effects of patients' cerebrospinal fluid (CSF) injected in rFr2 (the prefrontal area) on the afferent facilitation in a conditioning paradigm for corticomotor responses. The afferent facilitation was assessed in forelimbs and hindlimbs of rats, before and after application of trains of high-frequency stimulation (HFS) which are known to modulate the excitability of M1. Before HFS, patients' CSF did not modify afferent facilitation. After HFS, the amplitudes of corticomotor responses before conditioning were significantly larger in forelimbs and hindlimbs. There was an increase of the afferent facilitation in forelimbs. The same effect was observed after injection of purified IgGs from patients' sera. Our results highlight that IgGs of patients with NMDA-R antibodies induce a state of corticomotor hyperexcitability following application of HFS over the prefrontal area.
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Antibodies to the N-methyl-d-aspartate subtype of glutamate receptor have been associated with a newly-described encephalopathy that has been mainly identified in young females with ovarian tumours. However, the full clinical spectrum and treatment responses are not yet clear. We established a sensitive cell-based assay for detection of N-methyl-d-aspartate receptor antibodies in serum or cerebrospinal fluid, and a quantitative fluorescent immunoprecipitation assay for serial studies. Although there was marked intrathecal synthesis of N-methyl-d-aspartate receptor antibodies, the absolute levels of N-methyl-d-aspartate receptor antibodies were higher in serum than in cerebrospinal fluid. N-methyl-d-aspartate receptor antibodies were of the immunoglobulin G1 subclass and were able to activate complement on N-methyl d-aspartate receptor-expressing human embryonic kidney cells. From questionnaires returned on 44 N-methyl-d-aspartate receptor antibody-positive patients, we identified a high proportion without a detected tumour (35/44, 80%: follow-up 3.6-121 months, median 16 months). Among the latter were 15 adult females (43%), 10 adult males (29%) and 10 children (29%), with four in the first decade of life. Overall, there was a high proportion (29%) of non-Caucasians. Good clinical outcomes, as defined by reductions in modified Rankin scores, correlated with decreased N-methyl-d-aspartate receptor antibody levels and were associated with early (<40 days) administration of immunotherapies in non-paraneoplastic patients (P < 0.0001) and earlier tumour removal in paraneoplastic patients (P = 0.02). Ten patients (23%) who were first diagnosed during relapses had no evidence of tumours but had received minimal or no immunotherapy during earlier episodes. Temporal analysis of the onset of the neurological features suggested progression through two main stages. The time of onset of the early features, characterized by neuropsychiatric symptoms and seizures preceded by a median of 10-20 days, the onset of movement disorders, reduction in consciousness and dysautonomia. This temporal dichotomy was also seen in the timing of cerebrospinal fluid, electroencephalographic and in the rather infrequent cerebral imaging changes. Overall, our data support a model in which the early features are associated with cerebrospinal fluid lymphocytosis, and the later features with appearance of oligoclonal bands. The immunological events and neuronal mechanisms underlying these observations need to be explored further, but one possibility is that the early stage represents diffusion of serum antibodies into the cortical grey matter, whereas the later stage results from secondary expansion of the immunological repertoire within the intrathecal compartment acting on subcortical neurons. Four patients, who only had temporal lobe epilepsy without oligoclonal bands, may represent restriction to the first stage.
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We recently described a severe, potentially lethal, but treatment-responsive encephalitis that associates with autoantibodies to the NMDA receptor (NMDAR) and results in behavioral symptoms similar to those obtained with models of genetic or pharmacologic attenuation of NMDAR function. Here, we demonstrate that patients' NMDAR antibodies cause a selective and reversible decrease in NMDAR surface density and synaptic localization that correlates with patients' antibody titers. The mechanism of this decrease is selective antibody-mediated capping and internalization of surface NMDARs, as Fab fragments prepared from patients' antibodies did not decrease surface receptor density, but subsequent cross-linking with anti-Fab antibodies recapitulated the decrease caused by intact patient NMDAR antibodies. Moreover, whole-cell patch-clamp recordings of miniature EPSCs in cultured rat hippocampal neurons showed that patients' antibodies specifically decreased synaptic NMDAR-mediated currents, without affecting AMPA receptor-mediated currents. In contrast to these profound effects on NMDARs, patients' antibodies did not alter the localization or expression of other glutamate receptors or synaptic proteins, number of synapses, dendritic spines, dendritic complexity, or cell survival. In addition, NMDAR density was dramatically reduced in the hippocampus of female Lewis rats infused with patients' antibodies, similar to the decrease observed in the hippocampus of autopsied patients. These studies establish the cellular mechanisms through which antibodies of patients with anti-NMDAR encephalitis cause a specific, titer-dependent, and reversible loss of NMDARs. The loss of this subtype of glutamate receptors eliminates NMDAR-mediated synaptic function, resulting in the learning, memory, and other behavioral deficits observed in patients with anti-NMDAR encephalitis.
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Epilepsy is a devastating and poorly understood disease. Mutations in a secreted neuronal protein, leucine-rich glioma inactivated 1 (LGI1), were reported in patients with an inherited form of human epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF). Here, we report an essential role of LGI1 as an antiepileptogenic ligand. We find that loss of LGI1 in mice (LGI1(-/-)) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3. Moreover, heterozygous mice for the LGI1 mutation (LGI1(+/-)) show lowered seizure thresholds. Extracellularly secreted LGI1 links two epilepsy-related receptors, ADAM22 and ADAM23, in the brain and organizes a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus. Thus, LGI1 may serve as a major determinant of brain excitation, and the LGI1 gene-targeted mouse provides a good model for human epilepsy.
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Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis has been recently reported as autoimmune/paraneoplastic encephalitis, affecting mostly young females. To describe opsoclonus-myoclonus syndrome in association with anti-NMDAR antibodies. Case report. Geneva University Hospital. Patient A 23-year-old woman with opsoclonus-myoclonus syndrome. Two weeks after an episode of gastroenteritis, the patient developed symptoms of depression associated with psychomotor slowing, progressive gait instability, and opsoclonus-myoclonus. Cerebrospinal fluid examination showed mild lymphocytic pleocytosis and intrathecal IgG synthesis with oligoclonal bands. The patient's condition worsened rapidly to an akinetic mutism, followed by a period of agitation, delirium, and hallucinations. These gradually subsided; however, a frontal behavior and executive dysfunction persisted 5 months after symptom presentation. No tumor was found. Anti-NMDAR antibodies were found in the cerebrospinal fluid. Opsoclonus-myoclonus may occur in patients with anti-NMDAR encephalitis. Prompt diagnosis of this disorder is important because after tumor removal and immunomodulatory therapies it has a relatively good prognosis.
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Some encephalitides or seizure disorders once thought idiopathic now seem to be immune mediated. We aimed to describe the clinical features of one such disorder and to identify the autoantigen involved. 15 patients who were suspected to have paraneoplastic or immune-mediated limbic encephalitis were clinically assessed. Confocal microscopy, immunoprecipitation, and mass spectrometry were used to characterise the autoantigen. An assay of HEK293 cells transfected with rodent GABA(B1) or GABA(B2) receptor subunits was used as a serological test. 91 patients with encephalitis suspected to be paraneoplastic or immune mediated and 13 individuals with syndromes associated with antibodies to glutamic acid decarboxylase 65 were used as controls. All patients presented with early or prominent seizures; other symptoms, MRI, and electroencephalography findings were consistent with predominant limbic dysfunction. All patients had antibodies (mainly IgG1) against a neuronal cell-surface antigen; in three patients antibodies were detected only in CSF. Immunoprecipitation and mass spectrometry showed that the antibodies recognise the B1 subunit of the GABA(B) receptor, an inhibitory receptor that has been associated with seizures and memory dysfunction when disrupted. Confocal microscopy showed colocalisation of the antibody with GABA(B) receptors. Seven of 15 patients had tumours, five of which were small-cell lung cancer, and seven patients had non-neuronal autoantibodies. Although nine of ten patients who received immunotherapy and cancer treatment (when a tumour was found) showed neurological improvement, none of the four patients who were not similarly treated improved (p=0.005). Low levels of GABA(B1) receptor antibodies were identified in two of 104 controls (p<0.0001). GABA(B) receptor autoimmune encephalitis is a potentially treatable disorder characterised by seizures and, in some patients, associated with small-cell lung cancer and with other autoantibodies. National Institutes of Health.
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This report concerns a 26-year-old Italian woman who was given the diagnosis of anti-NMDAR encephalitis after the incidental identification of an ovarian tumour. Neuropsychiatric symptoms and hyperkinetic movements are very commonly seen as initial symptoms of paraneoplastic encephalitis. Interestingly, our patient showed stereotypical movements predominantly located to lower limbs, mimicking a psychogenic seizure. This latter feature further extends the clinical spectrum of dyskinetic movements of anti-NMDAR encephalitis.
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A subset of central glutamatergic synapses are coordinately pruned and matured by unresolved mechanisms during postnatal development. We report that the human epilepsy gene LGI1, encoding leucine-rich, glioma-inactivated protein-1 and mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTE), mediates this process in hippocampus. We created transgenic mice either expressing a truncated mutant LGI1 (835delC) found in ADLTE or overexpressing a wild-type LGI1. We discovered that the normal postnatal maturation of presynaptic and postsynaptic functions was arrested by the 835delC mutant LGI1, and contrastingly, was magnified by excess wild-type LGI1. Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission. Inhibitory transmission, by contrast, was unaffected. Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial gamma-aminobutyric acid(A) (GABA(A)) receptor blockade. Thus, LGI1 represents a human gene mutated to promote epilepsy through impaired postnatal development of glutamatergic circuits.
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We report the immunopathological analysis of the brain and tumor of two patients who died of anti-NMDAR-associated encephalitis, and of the tumor of nine patients who recovered. Findings included prominent microgliosis and deposits of IgG with rare inflammatory infiltrates in the hippocampus, forebrain, basal ganglia, and spinal cord. Detection of cells expressing markers of cytotoxicity (TIA, granzyme B, perforin and Fas/Fas ligand) was extremely uncommon. All tumors showed NMDAR-expressing neurons and inflammatory infiltrates. All patients’ NMDAR antibodies were IgG1, IgG2, or IgG3. No complement deposits were observed in any of the central nervous system regions examined. Overall, these findings coupled with recently reported in vitro data showing that antibodies downregulate the levels of NMDA receptors suggest that the antibody immune-response is more relevant than cytotoxic T-cell mechanisms in the pathogenesis of anti-NMDAR-associated encephalitis.
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Neuromuscular hyperexcitability is a characteristic of Isaacs' syndrome. Autoantibodies specific for voltage-gated potassium channels (VGKC) or ganglionic nicotinic acetylcholine receptors (AChR) are markers of this disorder. To determine the frequency of these ion channel antibodies and of related neuron- and muscle-specific antibodies in patients with acquired neuromuscular hyperexcitability, we tested serum specimens from 77 affected patients (35 neuromyotonia, 32 cramp-fasciculation syndrome, 5 rippling muscle syndrome, and 5 focal neuromuscular hyperexcitability) and 85 control subjects. Among study patients, 14% had coexisting myasthenia gravis, and 16% had an associated neoplasm. We found that 35% had VGKC antibodies, 12% ganglionic AChR antibodies, 16% muscle AChR antibodies, and 10% striational antibodies. Overall, 55% had serological evidence of neurological autoimmunity compared to 2% of control subjects. Patients with neuromyotonia were more frequently seropositive (71%) than patients with cramp-fasciculation syndrome (31%). We conclude that acquired neuromuscular hyperexcitability consists of a continuum of clinical disorders with a common autoimmune pathogenesis. © 2002 Wiley Periodicals, Inc. Muscle Nerve 26: 702–707, 2002
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Stiff person syndrome (SPS) is a rare disorder, characterised by fluctuating rigidity and stiffness of the axial and proximal lower limb muscles, with superimposed painful spasms and continuous motor unit activity on electromyography. Although rare in general neurology practice, once observed it is unforgettable. The general neurologist may see only one or two cases during his or her career and as such it remains underdiagnosed. Left untreated, SPS symptoms can progress to cause significant disability. Patients have a poor quality of life and an excess rate of comorbidity and mortality. The severity of symptoms and lack of public awareness of the condition create anxiety and uncertainty for people with the disease. This review aims to raise awareness of SPS and to improve the likelihood of its earlier diagnosis and treatment.
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Antibodies to potassium channels (VGKC-Ab) were first associated with acquired neuromyotonia and its variant with CNS involvement, Morvan's syndrome. Recently, VGKC-Ab were found in patients with non-paraneoplastic limbic encephalitis (LE), characterised by personality changes, seizures and memory impairment. These patients may respond to immunotherapies. Thus the association of VGKC-Ab and non-paraneoplastic LE established the concept of a potentially reversible autoimmune encephalopathy. We describe a patient with startle syndrome and VGKC-Ab, without neuromyotonia or LE, who responded dramatically to plasma exchange (PE) and immunosuppression, adding to the spectrum of disorders associated with VGKC-Ab.
Article
Voltage-gated potassium channel antibodies (VGKC Ab) are associated with limbic encephalitis and neuromyotonia in adults. There have been no systematic investigations in children to date. We looked for antibodies that are associated with CNS syndromes in adults including antibodies to VGKCs, NMDARs, glutamic acid decarboxylase (GAD), and glycine receptor (GlyR) in the stored acute serum from 10 children with unexplained encephalitis presenting with encephalopathy and status epilepticus. We also looked for antibodies to leucine-rich glioma-inactivated 1 (Lgi1) and contactin-associated protein-like 2 (Caspr2), which are now known to be tightly complexed with VGKCs in vivo. Sixty-nine pediatric controls were used for comparison. An elevated VGKC Ab (>100 pM) was detected in 4/10 patients with encephalitis compared to only 1/69 controls (p < 0.001). The outcome in the 4 VGKC Ab-positive patients with encephalitis was variable including good recovery (n = 1), cognitive impairment (n = 3), temporal lobe epilepsy (n = 2), and mesial temporal sclerosis (n = 1). No other antibodies were detected, including those to Lgi1 and Caspr2. Encephalitis associated with VGKC Ab occurs in children and presents with status epilepticus and focal epilepsy. These antibodies are not directed against Lgi1 or Caspr2.
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To describe a distinctive seizure semiology that closely associates with voltage-gated potassium channel (VGKC)-complex/Lgi1 antibodies and commonly precedes the onset of limbic encephalitis (LE). Twenty-nine patients were identified by the authors (n = 15) or referring clinicians (n = 14). The temporal progression of clinical features and serum sodium, brain magnetic resonance imaging (MRI), positron emission tomography/single photon emission computed tomography, and VGKC-complex antibodies was studied. Videos and still images showed a distinctive adult-onset, frequent, brief dystonic seizure semiology that predominantly affected the arm and ipsilateral face. We have termed these faciobrachial dystonic seizures (FBDS). All patients tested during their illness had antibodies to VGKC complexes; the specific antigenic target was Lgi1 in 89%. Whereas 3 patients never developed LE, 20 of the remaining 26 (77%) experienced FBDS prior to the development of the amnesia and confusion that characterize LE. During the prodrome of FBDS alone, patients had normal sodium and brain MRIs, but electroencephalography demonstrated ictal epileptiform activity in 7 patients (24%). Following development of LE, the patients often developed other seizure semiologies, including typical mesial temporal lobe seizures. At this stage, investigations commonly showed hyponatremia and MRI hippocampal high T2 signal; functional brain imaging showed evidence of basal ganglia involvement in 5/8. Antiepileptic drugs (AEDs) were generally ineffective and in 41% were associated with cutaneous reactions that were often severe. By contrast, immunotherapies produced a clear, and often dramatic, reduction in FBDS frequency. Recognition of FBDS should prompt testing for VGKC-complex/Lgi1 antibodies. AEDs often produce adverse effects; treatment with immunotherapies may prevent the development of LE with its potential for cerebral atrophy and cognitive impairment.
Article
Glycine receptor antibodies (GlyR-ab) were reported in a patient with progressive encephalomyelitis with rigidity and myoclonus (PERM). Three additional patients were clinically described. GlyR-ab was detected with a cell-based assay of HEK293 cells transfected with the α1 subunit of the GyR. A 33-year-old woman presented with diplopia, dysphagia and gait ataxia that improved in 5 weeks. Then, she developed a typical stiff-person syndrome (SPS) that resolved with corticosteroids, but relapsed 17 months later with a stiff limb syndrome. After treatment with intravenous immunoglobulins (IVIG), she has been asymptomatic for 8 years. A 60-year-old man developed, dysphagia, diplopia, left facial palsy and right trigeminal hypoaesthesia in a few days, followed by muscular rigidity, corticospinal signs, myoclonic jerks and severe dysautonomia. He developed seizures and suffered a cardiac arrest that left him in a persistent vegetative state. A 48-year-old man presented with leg rigidity and frequent spells of trismus, muscle spasms followed by opisthotonus and diaphoresis. The symptoms were antedated by pruritus of the left scapulae, right arm and T11-T12 dermatome. At the same time he became progressively more aggressive with emotional irritability. He also developed dysgeusia (metallic taste) and severe concurrent behavioural changes and diurnal hypersomnia. Only the rigidity and the spasms improved after therapy. The clinical picture associated with GlyR-ab is wider than the classical view of PERM. GlyR-ab should be examined in patients with core symptoms of muscle rigidity and spasms atypical for SPS.
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Anti-NMDA-receptor (NMDAR) encephalitis is a severe disorder that occurs in association with antibodies to the NR1 subunit of the NMDAR and results in a characteristic syndrome. To determine in a single institution setting whether patients previously diagnosed with encephalitis of unknown origin had anti-NMDAR encephalitis. Charts of 505 patients aged 18 to 35 years admitted to the intensive care unit (ICU) during a 5-year period were retrospectively reviewed for criteria of encephalitis of unknown etiology. These included encephalitic signs with psychiatric symptoms (agitation, paranoid thoughts, irritability, or hallucinations); seizures; CSF inflammation; and exclusion of viral or bacterial infection. Archived serum and CSF samples of patients fulfilling these criteria were examined for NMDAR antibodies. Follow-up visits allowed the analysis of the natural disease course and estimation of prognosis. Seven patients (all women) fulfilled the indicated criteria; 6 of them had NMDAR antibodies. Ovarian teratomas were detected in 2 patients, in one 3 years after the onset of encephalitis. Outcome was favorable in all patients. One patient without teratoma improved spontaneously along with disappearance of NMDAR antibodies. Anti-NMDAR encephalitis represented 1% of all young patients' admissions to the ICU. Six of 7 cases with the indicated clinical criteria had anti-NMDAR encephalitis. NMDAR antibodies should be tested in all patients with encephalitis who fulfill these criteria.
Article
Limbic encephalitis (LE) is a central nervous system (CNS) disease characterized by subacute onset of memory loss and epileptic seizures. A well-recognized form of LE is associated with voltage-gated potassium channel complex antibodies (VGKC-Abs) in the patients' sera. We aimed to test the hypothesis that purified immunoglobulin G (IgG) from a VGKC-Ab LE serum would excite hippocampal CA3 pyramidal cells by reducing VGKC function at mossy-fiber (MF)-CA3 pyramidal cell synapses. We compared the effects of LE and healthy control IgG by whole-cell patch-clamp and extracellular recordings from CA3 pyramidal cells of rat hippocampal acute slices. We found that the LE IgG induced epileptiform activity at a population level, since synaptic stimulation elicited multiple population spikes extracellularly recorded in the CA3 area. Moreover, the LE IgG increased the rate of tonic firing and strengthened the MF-evoked synaptic responses. The synaptic failure of evoked excitatory postsynaptic currents (EPSCs) was significantly lower in the presence of the LE IgG compared to the control IgG. This suggests that the LE IgG increased the release probability on MF-CA3 pyramidal cell synapses compared to the control IgG. Interestingly, α-dendrotoxin (120 nm), a selective Kv1.1, 1.2, and 1.6 subunit antagonist of VGKC, mimicked the LE IgG-mediated effects. This is the first functional demonstration that LE IgGs reduce VGKC function at CNS synapses and increase cell excitability.
Article
Myasthenia gravis is the best known autoimmune disease associated with thymomas, but other conditions can be found in patients with thymic tumors, including some that affect the central nervous system (CNS). We have become particularly interested in patients who have acquired neuromyotonia, the rare Morvan disease, or limbic encephalitis. Neuromyotonia mainly involves the peripheral nerves, Morvan disease affects both the peripheral nervous system and CNS, and limbic encephalitis is specific to the CNS. Many of these patients have voltage-gated potassium channel autoantibodies. All three conditions can be associated with thymomas and may respond to surgical removal of the underlying tumor together with immunotherapies and symptomatic treatments. Herein, we review the results of our recent studies that show that voltage-gated potassium channel autoantibodies are not principally directed against the potassium channels themselves but in some patients are directed against a protein that is complexed with potassium channels in both the peripheral nervous system and CNS, contactin-2 associated protein (Caspr2). These antibodies are common in the subgroup of patients with thymic malignancies.
Article
A young girl with antibodies to the N-methyl-D-aspartate receptor presented with a clinical syndrome suggestive of dyskinetic encephalitis lethargica with neuropsychiatric features at presentation, movement disorder, mutism, sleep disorder, and seizures. Persistent lesions in the white matter and pons were observed in magnetic resonance imaging of the brain, findings that have not been described previously in N-methyl-D-aspartate receptor antibody encephalitis.
Article
Limbic encephalitis (LE) is characterised by seizures and impairment of short-term memory as well as behavioural and psychiatric symptoms such as anxiety, depression, personality change and hallucinations. Onset of these symptoms is typically subacute over a few weeks or months but may also evolve over a few days. In many patients, limbic encephalitis is a paraneoplastic syndrome usually preceding diagnosis of the malignancy. Associated tumours are most commonly small-cell lung cancer (SCLC), breast cancer, testicular tumour, teratoma, Hodgkin lymphoma and thymoma.1 Antineuronal autoantibodies can be detected in the sera of about 60% of patients. These autoantibodies are classically directed to intracellular antigens (eg, anti-Hu, anti-Ma1/2, anti-CRMP5/CV2, anti-amphiphysin). However, LE is now being recognised frequently in the absence of malignancy and can be associated with antibodies to voltage-gated potassium channel (VGKC-ab). More recently, a new type of immunotherapy-responsive severe LE was described by Dalmau and colleagues that is associated with antibodies to the n -methyl-d-aspartate-receptor (NMDAR) and ovarian teratoma. In rare instances, these NMDAR-ab also occur in men with testicular teratoma or SCLC.2 3 For the first time, we describe a male patient with non-paraneoplastic limbic encephalitis and with serum antibodies to both NMDAR and VGKC. This previously healthy 56-year-old man reported the first signs of disease …
Article
A form of encephalitis associated with anti– N -methyl-d-aspartate receptor (anti–NMDA-R) antibodies has recently been described.1 Reported patients are mainly young women, presenting with severe encephalitis and additional distinctive neurological features. Around 60% have an ovarian teratoma.1 The severe course of the disease does not rule out favourable prognosis. Immunotherapy is advocated1–3 and appears to be associated with improved outcome. We present a patient with anti–NMDA-R encephalitis and serial [18F]-fluorodeoxyglucose–positron emission tomography (FDG-PET) examinations showing markedly increased activity in the basal ganglia as compared with that in the cortex when extrapyramidal features were prominent, which normalised after improvement of this movement disorder. A 25-year old woman developed language difficulties, followed by repeated complex-partial seizures with rare secondary generalisations. On admission 3 weeks later (day 0), the patient had developed fluctuating obtundation, mutism and episodic laughter with dysautonomia (bilateral mydriasis, tachycardia and facial flush), catatonia and progressive limb rigidity with plantar flexor response. The findings of an extended etiological workup (blood cell counts; routine serum chemical analysis and cerebrospinal fluid analysis of infectious, inflammatory, metabolic and paraneoplastic parameters) and a body computed tomographic …
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Voltage-gated potassium channels are thought to be the target of antibodies associated with limbic encephalitis. However, antibody testing using cells expressing voltage-gated potassium channels is negative; hence, we aimed to identify the real autoantigen associated with limbic encephalitis. We analysed sera and CSF of 57 patients with limbic encephalitis and antibodies attributed to voltage-gated potassium channels and 148 control individuals who had other disorders with or without antibodies against voltage-gated potassium channels. Immunohistochemistry, immunoprecipitation, and mass spectrometry were used to characterise the antigen. An assay with HEK293 cells transfected with leucine-rich, glioma-inactivated 1 (LGI1) and disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) or ADAM23 was used as a serological test. The identity of the autoantigen was confirmed by immunoabsorption studies and immunostaining of Lgi1-null mice. Immunoprecipitation and mass spectrometry analyses showed that antibodies from patients with limbic encephalitis previously attributed to voltage-gated potassium channels recognise LGI1, a neuronal secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22. Immunostaining of HEK293 cells transfected with LGI1 showed that sera or CSF from patients, but not those from control individuals, recognised LGI1. Co-transfection of LGI1 with its receptors, ADAM22 or ADAM23, changed the pattern of reactivity and improved detection. LGI1 was confirmed as the autoantigen by specific abrogation of reactivity of sera and CSF from patients after immunoabsorption with LGI1-expressing cells and by comparative immunostaining of wild-type and Lgi1-null mice, which showed selective lack of reactivity in brains of Lgi1-null mice. One patient with limbic encephalitis and antibodies against LGI1 also had antibodies against CASPR2, an autoantigen we identified in some patients with encephalitis and seizures, Morvan's syndrome, and neuromyotonia. LGI1 is the autoantigen associated with limbic encephalitis previously attributed to voltage-gated potassium channels. The term limbic encephalitis associated with antibodies against voltage-gated potassium channels should be changed to limbic encephalitis associated with LGI1 antibodies, and this disorder should be classed as an autoimmune synaptic encephalopathy. National Institutes of Health, National Cancer Institute, and Euroimmun.
Article
Antibodies to glutamic acid decarboxylase (GAD) have been described in a few patients with temporal lobe epilepsies consistent with limbic encephalitis (LE). We studied a cohort of patients with recent-onset temporal lobe epilepsy caused by LE to test for GAD antibody positivity and response to immunotherapies. Over a period of 3.75 years, 138 patients aged >or=18 years investigated at the Department of Epileptology, University of Bonn, for recent-onset epilepsy were prospectively collected and studied for cliniconeuroradiological features of LE, autoantibodies, and treatment responses. Fifty-three adult patients fulfilled the criteria for LE: (1) limbic signs and symptoms for <or=5 years and (2) brain MRI revealing mediotemporal encephalitis (T2/fluid attenuated inversion recovery hyperintensity without atrophy). Nine had high-titer GAD antibodies; 10 had voltage-gated potassium channel (VGKC) antibodies. Patients with GAD antibodies were younger (median age, 23 years; range, 17-66 years) (p = 0.003) and presented with seizures only, whereas polymorphic limbic features were more common in the VGKC antibody-positive group (p < 0.001). None had tumors. Patients with GAD antibodies more frequently had cerebrospinal fluid oligoclonal bands (p = 0.009) and intrathecal secretion of the specific antibody (p = 0.01). Following monthly intravenous methylprednisolone pulses, GAD antibodies remained highly elevated in 6/6 patients, whereas VGKC antibodies normalized in 6/9 patients (p = 0.03). Despite more intense anticonvulsive treatment in the GAD antibody-positive group (p = 0.01), none of these patients became seizure free, unlike all of the patients with VGKC antibodies (p < 0.001). High-titer GAD antibodies define a form of nonparaneoplastic LE. This is a chronic, nonremitting disorder and should be included in the differential diagnosis of patients with TLE and mediotemporal encephalitis. Therapeutic trials of other immunotherapies should be undertaken.
Article
A new category of treatment-responsive encephalitis has been proposed in association with antibodies to neuronal cell membrane antigens, including voltage-gated potassium channel (VGKC), N-methyl-D-aspartic acid receptor (NMDAR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), gamma-aminobutyric acid (GABA) B receptor and other antigens that have not yet been characterized. Among the forms of encephalitis under this category, anti-NMDAR encephalitis is a distinct disorder characterized by the predictable sequential development of symptoms; prodromal symptoms are initially noted, followed by prominent psychiatric symptoms, seizures, an unresponsive/catatonic state, hypoventilation, and involuntary orofacial-limb movements. This disorder usually affects young women with ovarian teratoma but may also affect women of any age or even men. A recent study revealed that the main epitope targeted by anti-NMDAR antibodies lies in the extracellular N-terminal domain of the NR1 subunit (25-380 amino-acid residues); the NR2B subunit is not necessarily involved. The antibodies are shown to produce selectively and reversibly reduce postsynaptic NMDARs clusters without complement activation. Considering the symptomatology of anti-NMDAR encephalitis and the results of cell culture analysis, we speculate that the overall antibody-mediated inhibition of NMDARs expressed on GABAergic interneurons, glutamatergic neurons and dopaminergic neurons may cause neuropsychiatric symptoms and dyskinesias via dopamine and glutamate dysregulation. We also hypothesize that these antibodies affect not only trafficking/localization/clustering of postsynaptic NMDARs, but also the expression of other receptors including AMPAR and dopamine receptors, by including a chronic state of exposure to excessive or decreased neurotransmitters release. The establishment of an animal model is awaited to resolve these issues. Anecdotal reports have revealed that recovery may be spontaneous without tumor resection but early tumor resection along with aggressive immunotherapy facilitates early functional recovery. In a recent case, a microscopic teratoma was detected on autopsy; therefore exploratory laparotomy may be considered in severe refractory cases.