Limbic Encephalitis Research Articles

32. Facio-brachial dystonic seizures in LGI1 Limbic Encephalitis: Analysis of video EEG monitoring in a small group of patients

Leucine-rich glioma inactivated 1(LGI1) antibodies are frequently associated with a common form of limbic encephalitis (LE) presenting with cognitive impairment, tonic-clonic and distinctive facio-brachial dystonic seizures (FBDS), not related with a specific EEG pattern. We describe clinical-EEG features of three patients with LGl1-LE with different response to immunotherapy. Three pts, admitted to our Neurology department for LE with positive test for LGI1 antibodies, performed video-EEG monitoring and immunotherapy. Video and still images showed frequently (3–40 episodes/day) paroxysmal brief events characterized by facial grimacing and sometimes dystonic arm posturing, with alternating side, suggestive for FBDS. We observed electrodecremental events (EDEs) or a contralateral slow-wave before “dystonic seizures” but not a clear ictal-EEG pattern. In all of the patients interictal EEG was normal. Furthermore, Video-EEG monitoring revealed multiple daily electrographic temporal seizures. Immunotherapy were associated with control of FBDS in two of three presented patients, with different latency. Video-EEG monitoring of our LGI1-LE patients showed frequent FBDS and bilateral temporal seizures. The lack of a clear ictal-EEG pattern for FBDS and the positive response to immunotherapy, support the hypothesis that dystonic episodes does not have a cortical origin, but are rather related to a possible basal ganglionic dysfunction.

Application of the 2016 diagnostic approach for autoimmune encephalitis from Lancet Neurology to Chinese patients

BackgroundA unified clinical approach to diagnose autoimmune encephalitis was published in Lancet Neurology in 2016. Purpose of our study is to examine the feasibility and reasonability of the 2016 “A clinical approach to diagnosis of autoimmune encephalitis” in China with a retrospective study.MethodsWe retrospectively collected 95 cases of autoimmune encephalitis and non autoimmune encephalitis cases with detailed clinical data from Beijing Tongren Hospital and the China National Knowledge Infrastructure (CNKI). All cases were analysed stepwise according to the approach in Lancet Neurology to compare the new diagnosis with the final clinical diagnosis.ResultsThe disease course of these 95 cases ranged from 2 to 540 days. Initial symptoms include fever, headache, seizure, mental and behavioral disorders, memory deterioration and illusion. Based on symptoms and signs when the patient came to the hospital, the sensitivity and specificity of criteria were as follows: possible autoimmune encephalitis (pAE) 84% and 94%, definite autoimmune limbic encephalitis (dALE) 38% and 96%, probable anti-N-methyl-D-aspartate receptor encephalitis (prNMDARE) 49% and 98%. The sensitivities of the above three criteria and the specificity of pAE were low during early disease stage, while the specificities of dALE and prNMDAER remained relatively high in different time periods.ConclusionsThis new autoimmune encephalitis diagnostic approach can recognize possible autoimmune encephalitis. The chances of a case being autoimmune-mediated following classification as autoimmune encephalitis with the new criteria are high. The flowchart is recommended to use as a whole. At the early disease stage, criteria with low sensitivity and high specificity, such as dALE and prNMDARE, lead most cases to enter subsequent diagnosis steps, namely autoantibody detection in the flowchart. Final diagnoses can only be made by autoantibody tests. These factors may make it challenging for clinicians to make diagnosis promptly and to begin immune-modulating therapy immediately. Moreover, the criteria for patients with paraneoplastic syndromes (PNSs) should be considered to avoid diagnosis omission. For Chinese patients, a multi-centre, prospective study on the clinical manifestations, laboratory diagnostic technology, therapy, and prognosis is greatly needed.

P2.15-012 Analysis of Small Cell Lung Cancer with Paraneoplastic Limbic Encephalitis

Not applicable. The clinical data of 15 patients with small cell lung cancer (SCLC) combined with paraneoplastic limbic encephalitis (PLE) from 1980 to 2017 were collected from Peking Union medical college hospital. Their symptoms and laboratory data were analyzed and the prognosis of the patients was followed. 1. PLE is a rare disease, the incidence rate in small cell lung cancer is about 0.842%. The data may be underestimated because of misdiagnose or missed diagnosis. 2. High incidence crowd of the disease is the middle-aged male smoker. The TNM stages of them are later than others. 3. Typical neurological symptoms include varying degrees of short-term memory loss, seizures and varying degrees of mental disorders; neurological symptoms usually occur before the onset of cancer or respiratory symptoms appear, an average of about 2 months be taken from onset to diagnosis. 4. Serum antibody (anti-Hu, GABA-R-Ab), cerebrospinal fluid, head MRI and EEG of the patients has abnormalities; Videography, especially CT is a good means of screening the primary tumor, pathology diagnosis mainly rely on bronchoscopy. 5. The treatment of primary tumors can be more effective in alleviating the nervous system symptoms than immunotherapy. Paraneoplastic limbic encephalitis is a rare paraneoplastic syndrome in nervous system caused by malignant neoplasms often characterized by facial neurological symptoms. The disease is usually associated with lung cancer (especially small cell lung cancer). Its nervous system symptoms occur earlier than the tumor diagnosis. Early diagnosis and treatment for primary tumors will increase the benefit.

Autoimmune encephalitis and sleep disorders

Research shows that autoimmune encephalitis is associated with sleep disorders. Paraneoplastic neurological syndrome (PNS) with Ma2 antibodies can cause sleep disorders, particularly narcolepsy and rapid eye movement sleep behavior disorder (RBD). Limbic encephalitis (LE) and Morvan syndrome, associated with voltage - gated potassium channel (VGKC)-complex antibodies, which include leucine-rich glioma-inactivated 1 (LGI1) antibody and contactin-associated protein 2 (Caspr2), can result in profound insomnia and other sleep disorders. Central neurogenic hypoventilation are found in patients with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, whereas obstructive sleep apnea (OSA), stridor and parasomnia are prominent features of encephalopathy associated with IgLON5 antibodies. Sleep disorders are cardinal manifestations in patients with autoimmune encephalitis. Immunotherapy possiblely can improve clinical symptoms and prognosis in a positive way. DOI: 10.3969/j.issn.1672-6731.2017.10.004

Selective Limbic Blood-Brain Barrier Breakdown in a Feline Model of Limbic Encephalitis with LGI1 Antibodies.

Human leucine-rich glioma-inactivated protein 1 encephalitis (LGI1) is an autoimmune limbic encephalitis in which serum and cerebrospinal fluid contain antibodies targeting LGI1, a protein of the voltage gated potassium channel (VGKC) complex. Recently, we showed that a feline model of limbic encephalitis with LGI1 antibodies, called feline complex partial seizures with orofacial involvement (FEPSO), is highly comparable to human LGI1 encephalitis. In human LGI1 encephalitis, neuropathological investigations are difficult because very little material is available. Taking advantage of this natural animal model to study pathological mechanisms will, therefore, contribute to a better understanding of its human counterpart. Here, we present a brain-wide histopathological analysis of FEPSO. We discovered that blood–brain barrier (BBB) leakage was present not only in all regions of the hippocampus but also in other limbic structures such as the subiculum, amygdale, and piriform lobe. However, in other regions, such as the cerebellum, no leakage was observed. In addition, this brain-region-specific immunoglobulin leakage was associated with the breakdown of endothelial tight junctions. Brain areas affected by BBB dysfunction also revealed immunoglobulin and complement deposition as well as neuronal cell death. These neuropathological findings were supported by magnetic resonance imaging showing signal and volume increase in the amygdala and the piriform lobe. Importantly, we could show that BBB disturbance in LGI1 encephalitis does not depend on T cell infiltrates, which were present brain-wide. This finding points toward another, so far unknown, mechanism of opening the BBB. The limbic predilection sites of immunoglobulin antibody leakage into the brain may explain why most patients with LGI1 antibodies have a limbic phenotype even though LGI1, the target protein, is ubiquitously distributed across the central nervous system.

Seizure semiology in leucine-rich glioma-inactivated protein 1 antibody-associated limbic encephalitis

ObjectiveThe objective of this study was to advance the characterization of seizure semiology in leucine-rich glioma-inactivated protein 1 (LGI1) antibody-associated limbic encephalitis (LE). MethodsEighteen patients diagnosed with LGI1 LE were identified. Seizure semiology, demographic features, MRI and fluorodeoxyglucose positron emission tomography (FDG-PET), electroencephalograms, and outcomes following immunotherapy were evaluated. ResultsPatients were divided into the following groups based on seizure semiology: faciobrachial dystonic seizure only (FBDS-only, n=4), epileptic seizure without FBDS (Non-FBDS, n=6), and FBDS plus epileptic seizure (FBDS+, n=8). In the group with Non-FBDS, the majority of patients (5/6) manifested mesial temporal lobe epilepsy (MTLE) like semiology (i.e., fear, epigastric rising, staring, and automatisms) with a frequency of 7±5 times per day and a duration of 15.3±14.3s. In the group with FBDS+, the distinctive symptom was FBDS followed by epileptic events, especially automatisms (7/8), with a frequency of 16±12 times per day and a duration of 13.0±8.0s. In these cases, 67% and 50% of the patients showed abnormalities on MRI and FDG-PET, respectively, and the mesial temporal lobe structures were most often involved. Ictal discharges were observed in 0/4, 6/6, and 8/8 of the patients in the groups with FBDS only, Non-FBDS, and FBDS+, respectively. The temporal lobe was mainly affected. Immunotherapy had favorable therapeutic effects. SignificanceThe LGI1 LE should be considered as one disease syndrome with a series of clinical manifestation. Identifying types of unique semiology features will facilitate the early diagnosis and the timely initiation of immunotherapy.

Chapter 20 - Immune-mediated disorders

Paraneoplastic and autoimmune encephalitis comprise a group of immune-mediated disorders that are associated with different immune effector mechanisms. Classic paraneoplastic neurologic syndromes are triggered by an antitumor immune response. The disease is considered to result from a T-cell response; in addition, patients harbour high titers of autoantibodies against intracellular antigens that are considered as epiphenomenon but are useful diagnostic markers. Neuropathology consists of T-cell-dominated inflammation, marked neuronal loss, and microglial activation with upregulation of HLA-DR. In the last decade, an increasing number of diseases associated with autoantibodies against neuronal surface antigens have been described. There is strong evidence that these autoantibodies are pathogenic and the associated syndromes are generally termed as antineuronal autoimmune encephalitis. Patients typically present with limbic, multifocal, or diffuse encephalitis and respond to immunotherapy. Neuropathologic descriptions are restricted to few biopsy and autopsy specimens and show mild inflammatory infiltrates and microglial activation, together with reduced expression of the respective target antigens, immunoglobulin deposits, and a variable degree of complement activation. Other putative autoimmune disorders of the central nervous system include, among others, Rasmussen encephalitis, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), acute cerebellitis, Susac syndrome, and Hashimoto encephalitis. While pathologic studies suggest an immune-mediated disease for Rasmussen encephalitis, CLIPPERS, acute cerebellitis, and Susac syndrome, neuropathologic descriptions of Hashimoto encephalitis are rare and the pathogenesis deserves further study.

The Elephant in the Room: GABAB Receptor Autoantibody-Associated Paraneoplastic Neurological Syndrome Masquerading as Small Cell Lung Cancer

SESSION TITLE: Lung Cancer 3 SESSION TYPE: Affiliate Case Report Slide PRESENTED ON: Wednesday, November 1, 2017 at 11:00 AM - 12:15 PM INTRODUCTION: Paraneoplastic neurological syndrome (PNS) is rare in daily clinical practice, and may be the heralding sign of malignancy. Early recognition can lead to prompt diagnosis and potential reversal of neurologic manifestations with treatment of the underlying cancer. We describe a woman who initially presented with Limbic Encephalitis (LE) and was subsequently diagnosed with small cell lung cancer (SCLC). CASE PRESENTATION: A 64-year-old woman with an 80-pack-year smoking history presented with acute onset seizures, confusion, and memory loss. On physical exam, she was oriented to person only. CT Head demonstrated encephalomalacia of the right temporal and frontal lobe, and an MRI brain confirmed the same. An EEG showed continuous diffuse mixed theta and alpha slowing of the background suggestive of mild diffuse cerebral dysfunction. A lumbar puncture was performed demonstrating 6 WBC (85% lymphocytes), 49 protein, 61 glucose. CSF studies were negative for cytology, VDRL, EBV, and HSV. Autoimmune serologies were also negative, but CSF subsequently returned positive for GABAB receptor autoantibody (GABAB R Ab). PET CT (Fig.1) showed increased FDG uptake in enlarged left hilar and subcarinal lymph nodes, without a primary lung mass. An EBUS-TBNA of the hilar lymph node confirmed SCLC. (Fig.2) DISCUSSION: GABAB R Ab resulting in paraneoplastic LE is a relatively recent clinical entity first described in 20111. In a group of 3989 patients with suspected autoimmune encephalopathy, the incidence of GABAB R Ab was 0.2%1. Most of these patients had SCLC and showed improvement of neurologic symptoms with treatment. Most recently, a case series of patients with anti-GABAB R Ab LE emphasized the typical triad of clinical presentation, including memory alteration, seizures, and SCLC2. CONCLUSIONS: Although a rare clinical entity, GABAB R Ab is closely associated with LE and SCLC. The misdiagnosis rate of anti-GABAB receptor encephalitis is high as testing is not always readily available. GABAB R Ab LE with concomitant SCLC is associated with a median survival of less than one year. The diagnosis requires strong clinical suspicion, and prompt treatment for improved outcomes. Reference #1: Jefferey et al. GABAB receptor autoantibody frequency in service serologic evaluation. Neurology 2013. 81;882-7. Reference #2: Liu KQ, Yan SQ, Lou M. Gamma-aminobutyric-acid-B receptor antibodies in limbic encephalitis with small cell lung cancer. Neuroimmunol Neuroinflammation 2015;2(3):187-9. DISCLOSURE: The following authors have nothing to disclose: Nikita Desai, Marina Mosunjac, Munish Luthra No Product/Research Disclosure Information

Neurologic disorders associated with anti-glutamic acid decarboxylase antibodies: Comparison of anti-GAD antibodies titer and time-dependent changes between neurologic disease and type I diabetes mellitus

Background: Anti-Glutamic acid decarboxylase (GAD) antibodies are associated with neurological disorders, such as Stiff-person syndrome (SPS), cerebellarataxia, epilepsy, limbic encephalitis.

Contactin-2 associated protein (CASPR2) autoimmune neurological conditions: Detailed clinical phenotype and antibody quantification

Background: Contactin-2 association protein (CASPR2) antibodies are associated with neurological symptoms peripherally (neuromyotonia), centrally (limbic encephalitis) and combinations of both (Morvan’s Syndrome).

Limbic encephalitis: Clinical experience of a large serie of patients from Latin America

Limbic encephalitis: Clinical experience of a large serie of patients from Latin America

Autoimmune and Epilepsy

The recent discovery of autoimmune antibodies to the neuronal cell surface membrane and extra- or intra-cellular proteins, such as NMDAR and LGI1, shed light on a proposed new etiology of epilepsy, namely, "autoimmune epilepsy". A large part of this entity most likely belongs to a forme fruste of autoimmune (limbic) encephalitis. Seizures are usually subacute in onset and refractory to antiepileptic medications. Patients occasionally manifest multiple seizure semiologies, such as autonomic or faciobrachial dystonic seizures. They may develop other symptoms of autoimmune encephalitis to variable degrees. Clinical diagnosis of autoimmune epilepsy should be considered even before the results of antibody testing, when objective evidence of CNS inflammation, such as abnormal MRI (amygdala/hippocampal enlargement), FDG-PET (hypermetabolism), EEG (bitemporal spikes or subclinical seizure patterns) and/or CSF findings, are present. Early intensive immunotherapy could cure seizures and prevent the full-blown clinical manifestation of encephalitis. Some patients present with relatively mild clinical symptoms and/or MRI findings, and can have a smoldering course lasting years. Establishment of the biomarkers of the ongoing CNS inflammation, especially for the smoldering and the suspected autoantibody-negative cases, is warranted for tailored immunotherapy for both the subacute and chronic phases of the disease.

Autoimmune limbic encephalitis associated with anti-NAE antibodies as a clinical subtype of Hashimoto’s encephalopathy

Autoimmune limbic encephalitis associated with anti-NAE antibodies as a clinical subtype of Hashimoto’s encephalopathy

Gaba B receptor encephalitis: Unexplored association with pulmonary tuberculosis

Background: GABA B encephalitis refers to limbic encephalitis caused by autoantibodies to the Ƴ - aminobutyric acid receptor (subtype B), can be paraneoplastic up to 35% of cases.

Clinical profile and treatment outcome of patients with anti LGI-1 encephalitis: A disease of jerks and confusion

Background: Encephalitis with antibodies against the leucine-rich, glioma inactivated 1 protein (LGI1) of the VGKC-complex is a rare form of limbic encephalitis with distinct clinical presentation.

Anti-VGKC-antibody mediated limbic encephalitis in a Sudanese patient: Rarity in sub Saharan Africa

Anti-VGKC-antibody mediated limbic encephalitis in a Sudanese patient: Rarity in sub Saharan Africa

Comprehensive and Methodical: Diagnostic and Management Approaches to Rapidly Progressive Dementia.

Purpose of review The sudden emergence of a change in cognitive abilities or behavior is an important symptom that warrants medical evaluation and may represent the early stages of a rapidly progressive dementia (RPD). To correctly ascertain the cause of RPD in a given patient, the clinician must be methodical and knowledgeable about the range of potential causes and must move forward with supportive treatment, and in some cases empiric treatment, based on clinical features alone. Recent findings Significant advances in prion disease biomarkers, the molecular features of rapidly progressive Alzheimer's disease, and new detection of autoimmune limbic encephalitis disease entities have caused a shift in the diagnostic and treatment framework of RPD. Additionally, in the past decade, emerging retrospective data have led to suggested treatments in autoimmune encephalitis that, if instituted early, can protect patients against residual deficits and disease relapse. Summary Here, we provide an integrative clinical and diagnostic treatment approach that is applicable to the various forms of RPD. We have highlighted the clinical features of selected types of RPD that have experienced advances in the last 10-15years.

Clinical analysis of paraneoplastic neurological syndrome associated with thymoma

Objectives: To investigate the clinical features, diagnosis and treatment of antibody mediated paraneoplastic neurological syndrome associated with thymoma. Methods: From 2012 to 2017, the paraneoplastic antibody and neuron antibody were tested from both blood and cerebrospinal fluid (CSF) in consecutive patients clinically suspected with neurological paraneoplastic syndromes/unknown encephalitis in Peking Union Medical College Hospital.The clinical data, lab results, electrophysiological examinations, imaging features, treatment and clinical prognosis were collected.In this study, the patients who met the diagnostic criteria of both thymoma and neurological paraneoplastic syndrome were retrospectively analyzed.The functional severity was assessed by modified Rankin score(mRS). Results: Six patients (4 female and 2 male) were included for the analysis.Of them, 4 patients presented with limbic encephalitis, 1 with peripheral neuropathy accompanying with myasthenia gravis and 1 with spinal and cerebella degeneration.Three patients were in severe condition (mRS=5). Positive α-amino-3-hydroxy-5-methyl-4-iso xazolepropionic acid receptor, antibody (AMPAR) was identified in 3 patients(2 in blood and CSF, 1 in blood), CV2 plus acetylcholine receptor antibody (ACH-Ab) positive in blood was seen in 1 patient and positive N-methyl-D-aspartate receptor (NMDAR) in blood and CSF in 1 patient. Brain MRI showed abnormalities in 2 patients.The CT scan revealed thymoma in all 6 patients.All patients received intravenous immunogloblin (IVIG) and/or glucocorticoid immediately after diagnosis.Furthermore, thymectomy was performed in 5 patients. All the patients were remarkably improved with mRS 0-1 at discharge.Five patients were clinical stable within follow-up of 1-2.5 years.However, one patient who refused thymectomy experienced several clinical recurrencs. Conclusions: Antibodies mediated paraneoplastic neurological syndrome/autoimmune encephalitis can occur in patients with thymoma with typical characteristics. The correlated antibody test and chest CT might be important in patients clinically suspected with neurological paraneoplastic syndrome or encephalitis with unknown reason. Surgical thymectomy combining with active immunological treatment may play a role in the favorable prognosis, even in those clinical severe patients.

Claustrum hyperintensities: A potential clue to autoimmune epilepsy.

SummaryIn a cohort of 34 patients with autoimmune limbic encephalitis and/or epilepsy, we identified 4 patients exhibiting claustrum fluid‐attenuated inversion recovery (FLAIR) hyperintensities. All 4 patients presented with explosive onset of seizures and developed medically intractable epilepsy, and 2 exhibited a marked response to immunotherapy. Associated features included cognitive and behavioral disturbances (4/4), cerebrospinal fluid (CSF) lymphocytic pleocytosis (3/4), and a neural autoantibody (2/4). Electroencephalogram (EEG) features consisted of slow wave activity and epileptiform discharges in frontal and parasagittal regions, where ictal patterns were captured in 1 patient. In 1 patient, magnetoencephalographic source imaging of interictal spikes revealed dipole sources in anterior insular or subinsular localizations, mirroring claustrum FLAIR hyperintensities, which developed after a short lag from presentation and resolved in all but 1 patient. These MRI abnormalities were isolated (2/4) or associated with mesial temporal hyperintensities (2/4). Claustrum FLAIR hyperintensities may be a useful MRI marker of autoimmune epilepsy.

P 81 Voiding disorder – almond or walnut?

Introduction Limbic encephalitis is an inflammatory disease of the central nervous system. The subacute development of short-term memory deficit is typical of this disease, as are psychiatric symptoms and seizures. Limbic encephalitis is caused by auto -immunity and is associated with cancer in about 60 per cent of cases. Since 1999, several antibodies associated with limbic encephalitis have been identified. Case report A 74-year-old patient was referred to our hospital because of urinary retention (residual urine volume: 840 ml) and disorientation. In the previous 4 months, he had developed short-term memory deficit and gait disturbance. A neurological examination, showed, ataxic gait, dysmetria of the right arm and leg, light paresis for the ab-/adduction of the fingers and dorsal flexion of the foot, and pallanesthesia of the malleolus. Neurological nerve conduction studies, electromyography and ultrasound revealed signs of neuropathy with axonal and demyelinating damage. After prostate resection the urinary retention did not improve. The spinal MRI did not show any significant cervical or lumbar stenosis. Cerebrospinal fluid showed a monocytic pleocytosis and an elevated protein. Also, positive oligoclonal bands GABA-B-Rezepor antibodies were detected isolated in the cerebrospinal fluid. A diagnostic search for cancer including imaging (PET-CT) and various tumor markers was negative. After treatment with metylprednisolone (500 mg for 5 days) and prednisolone (1 mg per kg with tapering doses), and IVIG (2 g per kg body weight over 5 days and 1 g per kg body weight over 2 days every four weeks), there was a rapid improvement of the voiding disorder to restored normal urine flow. Also, a slow improvement of the short-term memory deficit and a stabilization of the gait disturbance. Summary In conclusion, we diagnosed a GABAB receptor positive limbic encephalitis with polyneuropathy and possible transverse myelitis. In our opinion, this has not been described before.