Antibody-associated Limbic Encephalitis Research Articles

Paraneoplastic Kelch-like protein 11 antibody-associated cerebellar and limbic encephalitis caused by metastatic “burned-out” seminoma – A scar(r)y phenomenon

IntroductionThe diagnosis of paraneoplastic neurologic syndromes is challenging when the primary tumor masquerades as scar tissue (i.e. “burned-out”). MethodsCase report. ResultsA 45-year-old male patient presented with progressive cerebellar symptoms and hearing loss. Initial screening for malignancy and extensive testing of paraneoplastic and autoimmune neuronal antibodies gave negative results. Repeated whole-body FDG-PET CT revealed a single paraaortic lymphadenopathy, metastasis of a regressed testicular seminoma. Anti-Kelch-like protein-11 (KLHL11) encephalitis was finally diagnosed. ConclusionOur case highlights the importance of continued efforts to find an often burned-out testicular cancer in patients with a highly unique clinical presentation of KLHL11 encephalitis.

Long-term evolution and prognostic factors of epilepsy in limbic encephalitis with LGI1 antibodies.

To characterize the evolution of epilepsy in patients with leucine-rich glioma inactivated 1 antibody-associated (LGI1ab) limbic encephalitis, including factors associated with drug-resistant epilepsy (DRE). Retrospective analysis of patients with LGI1 encephalitis managed at two tertiary epilepsy centers between 2005 and 2019 and whose samples were confirmed by the French Reference Center of Paraneoplastic Neurological Syndromes. Raw clinical, biological, EEG, and MRI data were reviewed. Two endpoints were defined: (i) Epilepsy remission: patients seizure free and in whom anti-seizure medications (ASM) have been stopped for at least 1year at the last follow-up visit (ii) DRE: patients with persistent seizures at the last follow-up despite at least two ASM used at efficacious daily dose. 39 patients with LGI1 encephalitis were included with a median follow-up duration of 42months (range 13-169). All of them reported seizures at the acute phase, with faciobrachial dystonic seizures (FBDS) in 23 (59%) and other focal seizures in 38 (97%), including 4 patients (10%) with de novo status epilepticus. At the last follow-up visit, 11 patients (28%) achieved epilepsy remission. Among the 28 patients with persistent epilepsy, eight (29%) fulfilled criteria of DRE. The only factor significantly associated with epilepsy remission was the time from clinical onset of the encephalitis to initiation of the first immunomodulatory treatment, with longer delay in patients with persistent epilepsy (7.5 ± 8.9 vs 2.4 ± 1.7months, p = 0.006). Evolution to DRE was only driven by MRI evolution. Eight of the 15 patients (53%) who developed hippocampal atrophy (p = 0.007) also suffered from drug-resistant seizures at the last follow-up. In patients with LGI1 encephalitis, rapid initiation of immunomodulatory treatment favors long-term epilepsy remission. Evolution to DRE might primarily reflect the anatomical lesion of limbic structures. Determining what modalities of immune treatment may alter these outcomes requires prospective studies with long-term follow-up.

A Case of Antiglutamic Acid Decarboxylase and Voltage-Gated Potassium Channel Antibody-Associated Limbic Encephalitis With Temporal Lobe Epilepsy

A Case of Antiglutamic Acid Decarboxylase and Voltage-Gated Potassium Channel Antibody-Associated Limbic Encephalitis With Temporal Lobe Epilepsy

Rituximab as a treatment for limbic encephalitis associated with leucine-richglioma inactivated-1: A case report and literature review.

Leucine-rich glioma-inactivated-1 (LGI1) protein antibody-associated limbic encephalitis (LE) is a treatable autoimmune disease. This report is about the administration of rituximab in two patients with LGI1 antibody-associated LE. Both patients had progressive confusion, behavioral alteration, memory impairment and temporal lobe seizures. Treatment included steroids, intravenous immunoglobulin (IVIG) and rituximab. Patients showed a positive response to the therapy. Both patients satisfactorily tolerated rituximab and neither experienced side effects. We also reviewed the recommended treatments for the LGI1 LE. Based on the recent reports, rituximab has the potential to become one of the treatment options for LE. Nevertheless, more evidence is necessary in order to accurately evaluate its efficacy.

Pre- and long-term postoperative courses of hippocampus-associated memory impairment in epilepsy patients with antibody-associated limbic encephalitis and selective amygdalohippocampectomy

ObjectiveLimbic encephalitis (LE) is defined by mesiotemporal lobe structure abnormalities, seizures, memory, and psychiatric disturbances. This study aimed to identify the long-term clinical and neuropsychological outcome of selective amygdalohippocampectomy (sAH) in drug-resistant patients with temporal lobe epilepsy due to known or later diagnosed subacute LE not responding to immunotherapy associated with neuronal autoantibodies. MethodsIn seven patients with temporal lobe epilepsy due to antibody positive LE (glutamic acid decarboxylase (GAD65): n=5; voltage-gated potassium channel complex (VGKC), N-methyl d-aspartate receptor (NMDAR): n=1; Ma-2/Ta: n=1) sAH (6 left, 1 right) was performed. Those patients underwent repeated electroencephalography (EEG) recordings, magnetic resonance imaging (MRI) volumetry of the amygdala and hippocampus, and neuropsychological examinations and were followed up for 6–7years on average. ResultsVerbal memory and figural memory were affected in 57% of patients at baseline and 71% at the last follow-up. At the last follow-up, 14% of the patients had declined in verbal memory and figural memory. We observed improved memory in 43% of patients regarding figural memory, but not in a single patient regarding verbal memory. Repeated evaluations across the individual courses reveal cognitive and MRI dynamics that appear to be unrelated to surgery and drug treatment. Three of the seven patients with LE with different antibodies (NMDAR: n=1, Ma-2/Ta: n=1 and GAD65: n=1) achieved persistent seizure freedom along with no accelerated memory decline after surgery. Two of the five GAD65-antibody patients positive with LE showed progressive memory decline and a long-term tendency to contralateral hippocampus atrophy. ConclusionsWhile memory demonstrated some decline in the long run, what is most important is that a progressive decline in memory is seldom found after sAH in patients with LE. Moreover, the dynamics in performance and MRI before and after surgery reveal disease dynamics independent of surgery. Selective amygdalohippocampectomy can lead to seizure freedom, but should be considered as a last resort treatment option for drug-resistant patients with temporal lobe epilepsy due to LE. Particular caution is recommended in patients with GAD65-LE.

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.

GAD antibody-associated limbic encephalitis in a young woman with APECED.

The autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome is a genetic disorder caused by a mutation in the autoimmune regulator (AIRE) gene. Immune deficiency, hypoparathyroidism and Addison’s disease due to autoimmune dysfunction are the major clinical signs of APECED. We report on a 21-year-old female APECED patient with two inactivating mutations in the AIRE gene. She presented with sudden onset of periodic nausea. Adrenal insufficiency was diagnosed by means of the ACTH stimulation test. Despite initiation of hormone replacement therapy with hydrocortisone and fludrocortisone, nausea persisted and the patient developed cognitive deficits and a loss of interest which led to the diagnosis of depression. She was admitted to the psychiatric department for further diagnostic assessment. An EEG showed a focal epileptic pattern. Glutamic acid decarboxylase (GAD) antibodies, which had been negative eight years earlier, were now elevated in serum and in the cerebrospinal fluid. Oligoclonal bands were positive indicating an inflammatory process with intrathecal antibody production in the central nervous system (CNS). The periodic nausea was identified as dialeptic seizures, which clinically presented as gastrointestinal aura followed by episodes of reduced consciousness that occurred about 3–4 times per day. GAD antibody-associated limbic encephalitis (LE) was diagnosed. Besides antiepileptic therapy, an immunosuppressive treatment with corticosteroids was initiated followed by azathioprine. The presence of nausea and vomiting in endocrine patients with autoimmune disorders is indicative of adrenal insufficiency. However, our case report shows that episodic nausea may be a symptom of epileptic seizures due to GAD antibodies-associated LE in patients with APECED.Learning points:Episodic nausea cannot only be a sign of Addison’s disease, but can also be caused by epileptic seizures with gastrointestinal aura due to limbic encephalitis.GAD antibodies are not only found in diabetes mellitus type 1, but they are also associated with autoimmune limbic encephalitis and can appear over time.Limbic encephalitis can be another manifestation of autoimmune disease in patients with APECED/APS-1 that presents over the time course of the disease.

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

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

Editorial: Limbic Encephalitis: Autoimmune Impact on Inhibitory GABAergic Neuronal Pathways in Temporal Lobe Epilepsy.

The Editorial on the Research Topic Limbic Encephalitis: Autoimmune Impact on Inhibitory GABAergic Neuronal Pathways in Temporal Lobe Epilepsy Mesial temporal lobe epilepsy (mTLE), a common adult epilepsy syndrome, is generally acquired. Recent data have demonstrated autoimmune inflammation predominantly affecting the limbic structures of the brain as a cause of adult mTLE development (1–3). Patients usually present with mesial temporal lobe seizures with interictal temporal epileptiform activity and slowing, episodic memory disturbance, and a variety of other behavioral, emotional, and cognitive changes. Magnetic resonance imaging typically exhibits volume and signal changes of the amygdala and hippocampus, and specific anti-neuronal antibodies binding to either intracellular or plasma membrane neuronal antigens can be detected in sera and cerebrospinal fluid. Glutamic acid decarboxylase (GAD) (4) and γ-aminobutyric acid (GABA)-B receptors (5) have recently been identified as distinct neuronal antigens in limbic encephalitis. This suggests a possible involvement of disturbed inhibitory GABAergic signaling in the etiology of seizures and neuropsychiatric symptoms characterizing this form of autoimmune epilepsy. Due to restricted access to their target antigen, autoantibodies directed toward intracellular GAD are believed to bear limited pathogenic potential, and neurons may be affected by autoreactive T cells instead (1). In contrast, autoantibodies against plasma membrane GABA-B receptors have been suggested to exert direct pathogenic effects (6), and the role of autoreactive T cells in these disorders is unclear at present (1). In the Frontiers in Neurology Research Topic “Limbic Encephalitis: Autoimmune Impact on Inhibitory GABAergic Neuronal Pathways in Temporal Lobe Epilepsy,” authors provide a survey on clinical and scientific aspects of autoimmune inflammation in mTLE. Ehling et al. review and discuss the role of CD8+ T cells–neuron interactions, whereas Seebohm et al. summarize the current knowledge and discuss technical approaches to study the autoantibody–receptor interactions in limbic encephalitis. Haselmann et al. present a methodical approach to investigate the impact of stereotactically injected human IgG fractions on GABAergic signaling in intact murine hippocampal network ex vivo. Stemmler et al. could not detect any effect of serum of a patient with confirmed GAD antibody-associated limbic encephalitis on GABAergic neurotransmission in murine cultured hippocampal networks, challenging the view that the presence of such autoantibodies compromise inhibitory network function. Widman et al. report a correlation of the CD8+ T cells in the cerebrospinal fluid with clinical and paraclinical measures of disease activity together with an unambiguous response to treatment with basiliximab, a chimeric mouse–human monoclonal antibody to the α-chain of the interleukin-2 receptor (CD25) on T cells in a patient with GAD antibody-associated limbic encephalitis. This strongly argues in favor of a pathogenic role of CD8+ T cells in this form of autoimmune temporal lobe epilepsy. The amygdala is central for the generation of adequate homoeostatic behavioral responses to emotionally significant external stimuli following processing in a variety of parallel neuronal circuits. Melzer et al. hypothesize that adaptive cellular and humoral autoimmunity may target and modulate distinct inhibitory or excitatory neuronal networks within the amygdala and thereby strongly impact processing of emotional stimuli and corresponding behavioral responses in patients with limbic encephalitis. Indeed, Schroder et al. show defective modulation of sympathetic ­autonomic responses during emotional stimulation in limbic encephalitis probably due to impaired functioning of the amygdala. Witt et al. present a case of GAD antibody-associated limbic encephalitis with predominant involvement of the left amygdala that presented with retrograde episodic memory impairment, characterized by loss of emotional attachment and autonoetic awareness of usually highly emotional autobiographical memories consistent with the known role of the amygdala as part of the basolateral limbic circuit relevant for emotional valence of memories. Furthermore, a special form of anterograde episodic memory impairment was present called accelerated long-term forgetting, consisting of accelerated loss or impaired access to newly encoded episodes. These cognitive and emotional disturbances occurred in the absence of overt epileptic seizures, suggesting a direct causal role of autoimmune inflammation within temporomesial structures.

Limbic Encephalitis Associated with Anti-γ-aminobutyric Acid B Receptor Antibodies: A Case Series from China.

Background:Autoimmune encephalitis associated with antibodies against γ-aminobutyric acid B receptor (GABAB R) in patients with limbic encephalitis (LE) was first described in 2010. We present a series of Han Chinese patients for further clinical refinement.Methods:Serum and cerebrospinal fluid (CSF) samples from patients referred to the program of encephalitis and paraneoplastic syndrome of Peking Union Medical College Hospital were tested with indirect immunofluorescence. Clinical information of patients with anti-GABAB R antibody positivity was retrospectively reviewed, and descriptive statistical analysis was performed.Results:All eighteen anti-GABAB R antibody-positive cases had limbic syndromes, and electroencephalogram (EEG) or neuroimaging evidence fulfilled the diagnostic criteria of LE. Four patients had additional antibodies against Hu in serum and one had anti-N-methyl-d-aspartate receptor antibody in both sera and CSF. Seventeen (17/18) patients presented with new-onset refractory seizure or status epileptics. Twelve (12/18) patients had memory deficits, 11 (11/18) patients had personality change, 7 (7/18) patients had disturbance of consciousness, and 3 (3/18) patients showed cerebellar dysfunction. One patient with LE had progressive motor and sensory polyneuropathy. Lung cancer was detected in 6 (6/18) patients. Ten (10/18) patients showed abnormality in bilateral or unilateral mediotemporal region on magnetic resonance imaging. Ten (10/18) patients had temporal lobe epileptic activity with or without general slowing on EEG. Seventeen patients received immunotherapy and 15 of them showed neurological improvement. Four patients with lung cancer died within 1–12 months due to neoplastic complications.Conclusions:Our study demonstrates that most Han Chinese patients with anti-GABAB R antibody-associated LE have prominent refractory epilepsy and show neurological improvement on immunotherapy. Patients with underlying lung tumor have a relatively poor prognosis. Testing for anti-GABAB R antibodies is necessary for patients with possible LE or new-onset epilepsy with unknown etiology.

Serum from a Patient with GAD65 Antibody-Associated Limbic Encephalitis Did Not Alter GABAergic Neurotransmission in Cultured Hippocampal Networks

Glutamate decarboxylase is an intracellular enzyme converting glutamate into GABA. Antibodies (abs) to its isoform GAD65 were described in limbic encephalitis and other neurological conditions. The significance of GAD65 abs for epilepsy is unclear, but alterations of inhibitory GABAergic neurotransmission may be involved. Here, we investigated the effects of the serum of a female patient suffering from GAD65 ab-associated LE on GABAA currents in cultured hippocampal networks. Spontaneous or evoked post-synaptic GABAA currents were measured in cultured hippocampal neurons prepared from embryonic mice after 11-21 days in vitro using the patch-clamp technique in the whole-cell mode after incubation with serum of a healthy control or the LE-patient at a final concentration of 1% for 5-8 h. Properties of miniature inhibitory post-synaptic currents were not different in cultures treated with control and LE-serum. Likewise, paired-pulse ratio of evoked GABAA currents as a measure of release probability was not different in both conditions. Evoked GABAA currents were significantly depressed during 10 Hz stimulation without significant differences between control and LE-serum treated cultures. In our experimental paradigms, serum of a patient with confirmed GAD65 ab-associated LE had no apparent effect on GABAergic neurotransmission in murine-cultured hippocampal networks. These results challenge the view that the presence of GAD65 abs invariably compromise inhibitory network function.

Treating a GAD65 Antibody-Associated Limbic Encephalitis with Basiliximab: A Case Study.

Antibodies (ABs) against the 65-kDa isoform of the intracellular enzyme glutamate decarboxylase (GAD65) have been found in limbic encephalitis (LE) and other neurological conditions. The direct significance of anti-GAD65-ABs for epilepsy is unclear. However, in histological preparations from biopsies of resective epilepsy surgeries, predominantly cytotoxic T-lymphocytes were detected making close contacts to neurons. Activated T-lymphocytes can, in turn, be selectively controlled by therapeutic interleukin-2 receptor Abs, such as basiliximab. We report of a 25-year-old male patient with epilepsy since the age of 18 and displaying clinical signs of LE and a high titer of GAD65 ABs in cerebrospinal fluid (CSF) and serum. Monthly, repetitive, intravenous cortisone pulse therapies that were initially administered for 6 months failed to improve his condition. Subsequent flow-cytometry analysis of CSF showed especially an increased fraction of activated HLA-DR(+) CD8(+) T-lymphocytes (fCD8(+)TL) when compared to controls. Thus, a second, intravenous cortisone pulse therapy with an additional basiliximab dose of 20 mg/month was started. After 3 months, the fCD8(+)TL in the CSF normalized; after 6 months, the psychological impulse-control deficits normalized; and after 11 months the patient was seizure free. However, 7 weeks later, seizures and, later on, psychological deficits recurred and fCD8(+)TL was once again present in the CSF. Flumazenil PET, magnetic resonance imaging-volumetry, and neuropsychological changes during therapy are described. The correlation of the fCD8(+)TL in the CSF with clinical and paraclinical measures of disease activity combined with the unambiguous response to basiliximab strongly argues in favor of the putative pathogenic role fCD8(+)TL in anti-GAD65 LE. The clinical relapse at the end of the observation period might be due to the formation of human anti-drug ABs, a well-known complication of therapy with chimeric ABs.

Early and chronic gray matter volume changes in limbic encephalitis revealed by voxel-based morphometry.

Antibody-associated limbic encephalitis (LE) is an increasingly recognized cause of mostly adult-onset temporal lobe epilepsy. Magnetic resonance imaging (MRI) typically shows volume and signal changes of the mesiotemporal structures. However, recent studies indicate that imaging characteristics depend on the type of the associated antibody. The aim of the present study was to investigate early and chronic gray matter (GM) volume changes in LE by means of voxel-based morphometry (VBM). Optimized VBM analysis was applied to altogether 73 MRI volumes of 55 patients with antibody-associated LE. Based on the time point of MRI acquisition, patients were split into two separate groups to enable the evaluation of early (≤2 years after LE onset) and chronic (>2 years after LE onset) GM volume changes. In addition, separate analyses for the two most common LE subtypes in our study cohort, that is, glutamic acid decarboxylase (GAD)-associated LE and voltage-gated potassium channel (VGKC)-complex-associated LE were performed. Age- and gender-matched healthy subjects served as controls. Referring to the entire LE group, VBM revealed bi-amygdalar GM volume increase in the early disease stage. In the chronic disease stage, amygdala enlargement had resolved and we found GM volume reduction in the right cerebellar hemisphere. In the subgroup analysis, VBM showed corresponding bi-amygdalar GM volume increase in VGKC-complex-associated LE on early MRI, whereas no changes were found in GAD-associated LE. In the chronic disease stage, VBM revealed left frontal GM volume increase in VGKC-complex-associated LE and right frontoparietal GM volume reduction in GAD-associated LE. The present study provides further evidence of a predominant affection of the amygdala in the early disease stage of LE, which resolves during the later course of the disease. Furthermore, our results show that LE features distinct imaging characteristics depending on the associated antibody and thus may contribute to a better pathophysiologic understanding of this disease.

Anti-vgkc Antibody-associated Limbic Encephalitis Presenting with Recurrent Catatonia

Limbic encephalitis is an inflammatory disorder, commonly characterized by psychiatric features and cognitive impairment. It used to be considered a rare disease, usually paraneoplastic, with poor prognosis. Recent findings of membrane-surface directed antibodies, including anti-VGKC (Voltage-Gated Potassium Channels) antibodies, showed a substantial proportion of cases with no association with any malignancy and better prognosis. A 56-year-old woman was admitted to the psychiatric ward in Nov/2007, with an acute onset of psychomotor retardation and agitation periods, apathy and nihilistic symptoms. She improved very slowly with lorazepam, clomipramine and quetiapine. In Jun/2014, she was admitted again to the psychiatric ward with acute onset of intense headache, confusion, insomnia, agitation and prejudice ideas. There was a clinical deterioration with mnesic deficits, catatonic stupor, autonomic dysfunction and seizures. Complementary exams revealed: ESR>120mm; hyponatraemia; acelular CSF with slightly elevated protein; EEG with slow base activity; Brain MRI with diffuse cortical atrophy and multiples subcortical hyperintensities of frontoparietal regions on FLAIR and T2 sequences; and positive anti-VGKC antibodies. Initially there was a poor transitory improvement with high-dose steroids and intravenous immunoglobulins. After 5 months, she did plasmapheresis with relevant clinical improvement. About 80% of anti-VGKC encephalitis patients have clinical improvement following prompt treatment. In this case, there was not as good improvement as initially expected probably because of the prolonged duration of disease prior to effective treatment. Given the good prognostic outcome with prompt initiation of immunotherapy, early recognition and diagnosis of this rare neuropsychiatric syndrome is crucial.

Automated volumetry of the mesiotemporal structures in antibody-associated limbic encephalitis

ObjectiveLimbic encephalitis (LE) is an autoimmune mediated disease leading to temporal lobe epilepsy, mnestic and psychiatric symptoms. In recent years, several LE subforms defined by serum antibody findings have been...

The Face (and Arm) of Treatment for Seizures in VGKC/LGI1 Antibody-Associated Limbic Encephalitis.

The Face (and Arm) of Treatment for Seizures in VGKC/LGI1 Antibody-Associated Limbic Encephalitis.

Quantitative FLAIR analysis indicates predominant affection of the amygdala in antibody‐associated limbic encephalitis

Limbic encephalitis is an autoimmune-mediated disease leading to temporal lobe epilepsy, mnestic deficits, and affective disturbances. Magnetic resonance imaging (MRI) usually shows signal and volume changes of the temporomesial structures. However, these abnormalities may be subtle, thereby hampering the diagnosis by conventional visual assessment. In the present study we evaluated the diagnostic value of a fully automated MRI postprocessing technique in limbic encephalitis and hippocampal sclerosis. The MRI postprocessing was based largely on a recently described method allowing for an observer-independent quantification of the fluid-attenuated inversion recovery (FLAIR) signal intensities of amygdala and hippocampus. A 95% confidence region was calculated from the FLAIR intensities of 100 healthy controls. We applied this analysis to the MRI data of 39 patients with antibody-associated limbic encephalitis and 63 patients with hippocampal sclerosis. Moreover, the results were compared to those of visual assessment by an experienced neuroradiologist. The method detected limbic encephalitis and hippocampal sclerosis with a high sensitivity of 85% and 95%, respectively. The detection rate of the automated approach in limbic encephalitis was significantly superior to visual analysis (85% vs. 51%; p = 0.001), whereas no statistically significant difference for the detection rate in hippocampal sclerosis was found. Patients with limbic encephalitis had significantly higher absolute intensity values of the amygdala and a significantly higher percentage fell outside of the amygdalar confidence region compared to those with hippocampal sclerosis (79% vs. 27%; p < 0.001), whereas we found opposite results in the hippocampal analysis (38% vs. 95%; p < 0.001). The FLAIR analysis applied in this study is a powerful tool to quantify signal changes of the amygdala and hippocampus in limbic encephalitis and hippocampal sclerosis. It significantly increases the diagnostic sensitivity in limbic encephalitis in comparison to conventional visual analysis. Furthermore, the method provides an interesting insight into the distinct properties of these two disease entities on MRI, indicating a predominant affection of the amygdala in limbic encephalitis, whereas the affection of the hippocampus is far less pronounced when compared to hippocampal sclerosis.

Binding deficits in memory following medial temporal lobe damage in patients with voltage-gated potassium channel complex antibody-associated limbic encephalitis

Some prominent studies have claimed that the medial temporal lobe is not involved in retention of information over brief intervals of just a few seconds. However, in the last decade several investigations have reported that patients with medial temporal lobe damage exhibit an abnormally large number of errors when required to remember visual information over brief intervals. But the nature of the deficit and the type of error associated with medial temporal lobe lesions remains to be fully established. Voltage-gated potassium channel complex antibody-associated limbic encephalitis has recently been recognized as a form of treatable autoimmune encephalitis, frequently associated with imaging changes in the medial temporal lobe. Here, we tested a group of these patients using two newly developed visual short-term memory tasks with a sensitive, continuous measure of report. These tests enabled us to study the nature of reporting errors, rather than only their frequency. On both paradigms, voltage-gated potassium channel complex antibody patients exhibited larger errors specifically when several items had to be remembered, but not for a single item. Crucially, their errors were strongly associated with an increased tendency to report the property of the wrong item stored in memory, rather than simple degradation of memory precision. Thus, memory for isolated aspects of items was normal, but patients were impaired at binding together the different properties belonging to an item, e.g. spatial location and object identity, or colour and orientation. This occurred regardless of whether objects were shown simultaneously or sequentially. Binding errors support the view that the medial temporal lobe is involved in linking together different types of information, potentially represented in different parts of the brain, regardless of memory duration. Our novel behavioural measures also have the potential to assist in monitoring response to treatment in patients with memory disorders, such as those with voltage-gated potassium channel complex antibody limbic encephalitis.

Autoimmune epilepsy in children: Case series and proposed guidelines for identification

Antibodies against neuronal surface proteins are increasingly recognized in autoimmune central nervous system (CNS) disorders in which seizures are the main or an important feature. The disorders include antibody-associated limbic encephalitis and N-methyl-D-aspartate receptor (NMDAR) encephalitis; however, seizures of autoimmune etiology may exist beyond the spectrum of these recognized syndromes. Because these seizures are potentially treatable with immune therapy, guidelines are needed to help in their early recognition. We describe 13 representative children seen at our tertiary institution over a period of 3.5 years with suspected autoimmune epilepsy. Autoimmune epilepsy was suspected clinically when there was any of the following: (1) recognizable syndromes such as NMDAR encephalitis or limbic encephalitis, (2) evidence of CNS inflammation in cerebrospinal fluid or on magnetic resonance imaging (MRI), (3) the presence of other autoimmune diseases, or (4) positive response to immunotherapy. We tested these patients for neuronal surface antibodies (voltage gated potassium channel [VGKC]-complex, leucine rich glioma inactivated 1 [LGI1], contactin-associated protein-like 2 [CASPR2], and NMDAR) and glutamic acid decarboxylase (GAD) antibodies. We modified the J Neurol Neurosurg Psychiatry, 83, 2012, 638 guidelines that were designed to classify adults with neuronal surface antibody syndromes (NSAS), to be more appropriate for children with suspected autoimmune epilepsy. Using the modified guidelines, the 13 patients were classified into definite, probable, possible, unlikely, or unknown autoimmune epilepsy according to the presence of neuronal surface or GAD antibodies, and the response to immune therapy when given. Of the 13 patients, 11 were females, and the mean age was 6 years (range 1-13 years). Three patients had classical NMDAR encephalitis, two had VGKC encephalitis, two had limbic encephalitis with negative antibodies, three had epilepsy with other autoimmune diseases (one with high titer GAD antibodies), two had fever-induced refractory epileptic encephalopathy in school-aged children (FIRES), and one epileptic encephalopathy associated with VGKC antibodies. Seven patients of the 13 children with suspected autoimmune epilepsy were positive for neuronal surface antibodies (NMDAR, n = 3; VGKC-complex, n = 3; and GAD, n = 1). Immunotherapy was given to nine cases, and a positive response was more common in patients with positive neuronal surface antibodies (5/5) compared to those with negative antibodies (2/4). Applying the proposed guidelines, the classification of autoimmune epilepsy was definite in five, probable in one, possible in three, unlikely in two, and unknown in two patients. Neuronal surface antibodies and GAD antibodies are present in a proportion of children with suspected autoimmune epilepsy and may define a treatable subgroup of childhood epilepsy. The proposed guidelines can be useful in the recognition of children with seizures of autoimmune etiology.

Clinical study on antibody-associated limbic encephalitis

In recent years, the antibody-associated limbic encephalitis (LE) has attracted attentions of more and more clinicians. The associated antibodies mainly act on neuronal cell surface antigens, including the N-methyl-D-aspartate (NMDA) receptor, the α-amino-3 -hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, the γ-aminobutyric acid B (GABA B ) receptor, leucine-rich glioma⁃ inactivated 1 (LGI1) and contactin-associated protein-like 2 (Caspr2) and so on. The clinical manifestation is primarily defined by the subacute onset of short ⁃ term memory loss, seizures, confusion and psychiatric symptoms suggesting the involvement of the limbic system. These severe and protracted disorders can affect children and young adults, occurring with or without tumor association. Routine detection of serum and cerebrospinal fluid (CSF) and imaging tests show no specificity, but associated antibodies can be detected in serum and (or) CSF. The patients respond well to tumor resection and immunotherapies, including corticosteroids, intravenous immunoglobulin (IVIg), plasma exchange or combination of them, but may relapse. This article aims to study the clinical features and treatment of antibody-associated limbic encephalitis and to improve the diagnosis and prognosis of these diseases.