Clinical features, investigations, and outcomes of pediatric limbic encephalitis: A multicenter study.

OBJECTIVES: To describe the clinical presentation, investigations, management, and disease course in pediatric autoimmune limbic encephalitis (LE). METHODS: In this retrospective observational study, from the UK Childhood Neuroinflammatory Disease network, we identified children from six tertiary centers with LE <18 years old between 2008 and 2021. Clinical and paraclinical data were retrieved from medical records. RESULTS: Twenty-five children fulfilling LE criteria were identified, with median age of 11 years (IQR 8, 14) and median follow-up of 24 months (IQR 18, 48). All children presented with seizures; 15/25 (60%) were admitted to intensive care. Neuroimaging demonstrated asymmetric mesial temporal changes in 8/25 (32%), and extra-limbic changes with claustrum involvement in 9/25 (38%). None were positive for LGI1/CASPR2 antibodies (Abs), 2/25 were positive for serum anti-NMDAR Abs, and 2/15 positive for anti-Hu Abs; one died from relapsing neuroblastoma. Two children had serum and CSF anti-GAD antibodies. Initial immune therapy included steroids in 23/25 (92%), intravenous immunoglobulin (IVIg) in 14/25 (56%), and plasma exchange in 7/25 (28%). The commonest second-line treatment was rituximab in 15/25 (60%). Median duration of hospital admission was 21 days (IQR 11, 30). At last follow-up, 13/25 (52%) had refractory seizures and 16/25 (64%) had memory impairment. Six children (24%) had modified Rankin Scale (mRS) scores ≥3. There was no significant difference in mRS, or long-term cognitive and epilepsy outcomes in those who received rituximab versus those who did not. INTERPRETATION: A diagnosis of autoimmune LE was associated with significant morbidity and adverse outcomes in this pediatric cohort.

A case of bilateral limbic and recurrent unilateral cortical encephalitis with anti-myelin oligodendrocyte glycoprotein antibody positivity.

BACKGROUND: Anti-myelin oligodendrocyte glycoprotein (MOG) antibody can be detected not only in acute disseminated encephalomyelitis or optic neuritis but also in limbic or cortical encephalitis. However, no previous reports have demonstrated a relapsing case of these two types of encephalitis. CASE REPORT: An 11-year-old girl presented with fever, headache, abnormal behavior, focal impaired awareness seizures (FIAS) on the left side, and MRI hyperintensities in the bilateral amygdala, hippocampus, and right posterior temporal cortex. The symptoms were alleviated with two courses of intravenous methylprednisolone (IVMP) and one course of immunoglobulin. At 16 years of age, the patient returned with left-sided headache and MRI hyperintensities in the left temporal, parietal, and insular cortices, which improved after 3 courses of IVMP. Oral prednisolone (PSL) was tapered over 6 months, when FIAS reappeared on the right side of the body. MRI showed recurrence in the same regions as in the second episode. She received 3 courses of IVMP, followed by gradually tapered PSL without relapse for 1.5 year. Anti-MOG antibodies were positive in both serum and the cerebrospinal fluid prior to treatment in all three episodes. CONCLUSION: Our results revealed that anti-MOG antibody-related bilateral limbic and unilateral cortical encephalitis can manifest with a variety of phenotypes over time in the same patient.

LGI1 antibody encephalitis: acute treatment comparisons and outcome.

OBJECTIVE: To compare acute treatment responses and long-term outcome in leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis. METHODS: Retrospective case series of 118 patients with LGI1 antibody encephalitis evaluated at Mayo Clinic across all US sites from 1 May 2008 to 31 March 2019. Patient clinical data were identified and analysed through the neuroimmunology laboratory and electronic medical record. LGI1 antibody detection was by cell-based indirect immunofluorescence assay of serum, cerebrospinal fluid or both. Clinical outcomes were faciobrachial dystonic seizure (FBDS) resolution, modified Rankin Scale (mRS) score, Kokmen Short Test of Mental Status (STMS) score (0-38 point scale) and neuropsychometric testing results. RESULTS: Compared with intravenous immunoglobulin (IVIg) (n=21), patients treated with single-agent acute corticosteroids (intravenous, oral or both) (n=49) were more likely to experience resolution of FBDS (61% vs 7%, p=0.002) and improvements in mRS score (ΔmRS score 2 vs 0, p=0.008) and median Kokmen STMS scores (ΔKokmen STMS score 5 points vs 0 points, p=0.01). In 54 patients with long-term follow-up (≥2 years), the median mRS score was 1 (range 0-6) and the median Kokmen STMS score was 36 (range 24-38) after all combinations of immunotherapy. Neuropsychometric testing in 32 patients with long-term follow-up (≥2 years) demonstrated short-term memory impairments in 37%. CONCLUSIONS: Corticosteroids appeared more effective acutely than IVIg in improving LGI1 antibody encephalitis in this retrospective comparison of immunotherapies. While improvement with immunotherapy is typical and long-term outcome is favourable, short-term memory deficits are noted in approximately a third of the patients.

Impact of T cells on neurodegeneration in anti-GAD65 limbic encephalitis.

OBJECTIVE: Direct pathogenic effects of autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GAD65) in autoimmune limbic encephalitis (LE) have been questioned due to its intracellular localization. We therefore hypothesized a pathogenic role for T cells. METHODS: We assessed magnet resonance imaging, neuropsychological and peripheral blood, and CSF flow cytometry data of 10 patients with long-standing GAD65-LE compared to controls in a cross-sectional manner. These data were related to each other within the GAD65-LE group and linked to neuropathological findings in selective hippocampectomy specimen from another two patients. In addition, full-resolution human leukocyte antigen (HLA) genotyping of all patients was performed. RESULTS: Compared to controls, no alteration in hippocampal volume but impaired memory function and elevated fractions of activated HLADR+ CD4+ and CD8+ T cells in peripheral blood and cerebrospinal fluid were found. Intrathecal fractions of CD8+ T cells negatively correlated with hippocampal volume and memory function, whereas the opposite was true for CD4+ T cells. Consistently, antigen-experienced CD8+ T cells expressed increased levels of the cytotoxic effector molecule perforin in peripheral blood, and perforin-expressing CD8+ T cells were found attached mainly to small interneurons but also to large principal neurons together with wide-spread hippocampal neurodegeneration. 6/10 LE patients harbored the HLA-A*02:01 allele known to present the immunodominant GAD65114-123 peptide in humans. INTERPRETATION: Our data suggest a pathogenic effect of CD8+ T cells and a regulatory effect of CD4+ T cells in patients with long-standing GAD65-LE.

Limbic encephalitis in a child with ovarian teratoma and influenza B. Case report and critical review of the history of autoimmune anti-N-methyl-d-aspartate receptor encephalitis.

We report the appearance of clinical symptoms and signs of N-methyl-d-Aspartate (NMDA) receptor encephalitis in a patient presenting just days after contraction of influenza B. The offending mature ovarian teratoma was identified and removed on the 10th day after the appearance of symptoms, with subsequent nearly complete resolution of symptoms over the subsequent 6 months. We provide a focused literature review of the clinical and pathophysiologic literature of anti-NMDA receptor encephalitis pertaining to influenza B virus and the pediatric population. Taken together, this study contributes to the pathophysiological understanding of anti-NMDA receptor encephalitis and aids clinicians in its early recognition and management.

Anti-GABAB receptor encephalitis associated with combined small cell lung carcinoma.

Autoimmune encephalitis with antibodies against the gamma-aminobutyric acid-B receptor is a relatively rare disease. We report a case with characteristic symptoms of limbic encephalitis associated with combined small cell lung carcinoma. The brain magnetic resonance imaging showed bilateral temporal lesions and the photoemission tomography revealed regional heterogenous metabolism across the brain. The double labeling of anti-gamma-aminobutyric acid-B receptor autoantibodies both in the tissues of neuroendocrine and small cell neoplasia was a unique feature of this patient.

Case Report/Case Series: Rare case of anti-LGI1 limbic encephalitis with rapidly progressive dementia, psychiatric symptoms, and frequently seizures: A case report.

RATIONALE: Anti leucine-rich glioma inactivated 1 (LGI1) limbic encephalitis (LE) is rare autoimmune encephalitis, characterized by acute or subacute cognitive impairment, faciobrachial dystonic seizures, mental disorders, and refractory hyponatremia. As a type of treatable rapidly progressive dementia with a good prognosis, early, and accurate diagnosis is essential. We present a case of anti-LGI1 LE who was initially misdiagnosed with Alzheimer disease because his clinical manifestations were similar to Alzheimer disease. PATIENT CONCERNS: A male patient presenting with rapidly progressive dementia, faciobrachial dystonic seizures, psychiatric disturbance, and refractory hyponatremia was admitted. The scores of Mini-Mental State Examination, Montreal Cognitive Assessment, and Neuropsychiatric Inventory were 19/30, 16/30, and 91/144, respectively. Brain magnetic resonance images indicated moderate atrophy of the hippocampus and abnormally hyperintensities in the left medial temporal and hippocampus. DIAGNOSIS: The patient was diagnosed with anti-LGI1 LE based on the presence of LGI-1 antibodies in the cerebrospinal fluid and serum and clinical manifestations. INTERVENTIONS: Patient was treated with glucocorticoid against LGI1, antiepileptic drug, cholinesterase inhibitors, and other adjuvant therapy. OUTCOMES: The patient showed marked improvement on immunotherapy. Clinical symptoms were disappeared and the LGI-1 antibodies in cerebrospinal fluid and serum were both negative at the time of discharge. CONCLUSIONS: Recognition of the specific symptoms and LGI-1 antibody test will be helpful for the early diagnosis, prompt immunotherapy, and good prognosis. This case raises the awareness that rapidly progressive dementia with frequent seizures could be caused by immunoreactions.

Epidemiology of neuronal surface antibody-mediated autoimmune encephalitis and antibody-based diagnostics.

Epidemiologic data on neuronal surface antibody (NSAb)-associated autoimmune encephalitides (NSAE) are scarce and heterogeneous. We review our 13-year-long biobank-data collection and provide the incidence of NSAE in two Italian provinces (approx. Population of 1,400,000) over a 5-year period (July 2013-June 2018). NSAbs were diagnosed in 75 out of 1179 tested patients (6.4%). The most common NSAbs were anti-LGI1 (30 cases), followed by NMDAR (24). Eleven cases of NSAE were diagnosed in Treviso and Trento provinces with an estimated incidence of 1.54 per 1,000,000 population (LGI1-encephalitis 0.84; C.I. 0.38-1.88). LGI1-E is the most frequent NSAE among adults.

Clinical and Prognostic Value of Immunogenetic Characteristics in Anti-LGI1 Encephalitis.

OBJECTIVE: Antibodies against leucine-rich glioma-inactivated 1 (LGI1-Abs) characterize a limbic encephalitis (LE) strongly associated with HLA-DRB1*07:01, although some patients lack LGI1-Abs in CSF or do not carry this allele. Whether they represent a different subtype of disease or have different prognoses is unclear. METHODS: Retrospective analysis of clinical features, IgG isotypes, and outcome according to LGI1-Ab CSF positivity and DRB1*07:01 in a cohort of anti-LGI1 LE patients. RESULTS: Patients with LGI1-Abs detected in both CSF and serum (105/134, 78%) were compared with those who were CSF negative (29/134, 22%). Both groups had similar clinical features and serum levels, but CSF-positive patients had shorter diagnostic delay, more frequently hyponatremia, inflammatory CSF, and abnormal MRI (p < 0.05). Human leukocyte antigen (HLA) genotyping was performed in 72/134 (54%) patients and 63/72 (88%) carried DRB1*07:01. Noncarriers (9/72, 12%) were younger, more commonly women, and had less frequently psychiatric and frontal symptoms (p < 0.05). No difference in IgG isotypes according to CSF positivity or HLA was found (p > 0.05). HLA and IgG isotypes were not associated with poor outcome (mRS >2 at last follow-up) in univariate analyses; CSF positivity was only identified as a poor outcome predictor in the multivariate analysis including the complete follow-up, whereas age and female sex also remained when just the first year was considered. CONCLUSIONS: LE without CSF LGI1-Abs is clinically indistinguishable and likely reflects just a lesser LGI1-Ab production. HLA association is sex and age biased and presents clinical particularities, suggesting subtle differences in the immune response. Long-term outcome depends mostly on demographic characteristics and the intensity of the intrathecal synthesis.

Encephalitis Induced by Durvalumab During Treatment of Metastatic Small-Cell Lung Cancer: Illustrative Case and Review of the Literature.

The immune checkpoint inhibitors have improved the standards of care in cancer treatment and have dramatically improved patient prognoses. These new antibodies turned to be an integral part of the standard of care for metastatic small-cell lung cancer. Platinum-based chemotherapy combined with checkpoint inhibitors, resulted in statistically significant improvement of progression free survival and overall survival. Immune checkpoint inhibitors immune-related adverse events have been observed and reported as a consequence of administering these innovative treatment drugs. Neurological immune-related adverse events are rare complications; however, they can be potentially fatal, particularly encephalitis. This report describes a 66-year-old female who received Durvalumab for metastatic small-cell lung cancer. Following 3 cycles of treatment, she developed encephalitis.

Neuronal Surface Antibody-Medicated Autoimmune Encephalitis (Limbic Encephalitis) in China: A Multiple-Center, Retrospective Study.

Objective: The epidemiological characteristics of patients with antibody-medicated autoimmune encephalitis in China remain unclear, and a large-scale epidemiological survey is necessary. Methods: A multiple-center retrospective study was performed. We collected 1,047 patients with suspected autoimmune encephalitis and ultimately enrolled 778 defined patients across centers in China. All patients were positive for serum [or cerebrospinal fluid (CSF)] antibodies. Demographic information and clinical data from January 2014 to January 2019 from 22 centers in China were reviewed. Results: A total of 778 patients with autoimmune encephalitis were enrolled in the study. In general, the ratio of males to females was ~1.2:1. The main subtypes of autoimmune encephalitis were NMDAR-AE (61.35%), LGI-1-AE (20.61%), and GABAbR-AE (12.40%). According to the characteristics of age of onset, the incidence of autoimmune encephalitis showed a "double peak" distribution entailing a 20-year-old age group and a 60-year-old age group. We next analyzed the proportion of patients with tumors in this cohort. More specifically, there were 34 patients with tumors and 85 with tumor marker positivity. Relapse occurred in 81 patients within at least 1 year's follow up study: 52 with NMDAR-AE (18.2%); 19 with LGI-1-AE (16.8%); 5 with GABAbR-AE (9%); and 3 with CASPR2-AE. Interpretation: Due to the vast differences in demographic features, the incidence of cancer and the genetic characteristics between the populations in China and Western countries, the demographics, sex distribution, concomitant tumor rate, clinical features, and relapse characteristics associated with autoimmune encephalitis in China shows a similar profile with Western countries with some minor differences.

Leucine Zipper 4 Autoantibody: A Novel Germ Cell Tumor and Paraneoplastic Biomarker.

OBJECTIVE: This study was undertaken to describe a novel biomarker of germ cell tumor and associated paraneoplastic neurological syndrome (PNS). METHODS: Archival sera from patients with germ cell tumor-associated PNS were evaluated. We identified a common autoantigen in a human testicular cancer cell line (TCam-2) by Western blot and mass spectrometry. Its identity was confirmed by recombinant-protein Western blot, enzyme-linked immunosorbent assay (ELISA), and cell-based assay. Autoantibody specificity was confirmed by analyzing assorted control sera/cerebrospinal fluid. RESULTS: Leucine zipper 4 (LUZP4)-immunoglobulin G (IgG) was detected in 28 patients' sera, 26 of whom (93%) were men. The median age at neurological symptom onset was 45 years (range = 28-84). Median titer (ELISA) was 1:300 (1:50 to >1:6,400, normal value < 1:50). Coexistent kelchlike protein 11-IgG was identified in 18 cases (64%). The most common presenting phenotype was rhombencephalitis (17/28, 61%). Other presentations included limbic encephalitis (n = 5, 18%), seizures and/or encephalitis (n = 2, 7%), and motor neuronopathy/polyradiculopathy (n = 4, 14%). The most common malignancy among cancer-evaluated PNS patients was seminoma (21/27, 78%). Nine of the 21 seminomas detected by whole-body fluorodeoxyglucose positron emission tomography scan (43%) were extratesticular. Both female patients had ovarian teratoma. Regressed testicular germ cell tumors were found in 4 patients. Exposure of T-cell-dendritic-cell cocultures from chronic immunosuppression-naïve LUZP4-IgG-seropositive patients to recombinant LUZP4 protein evoked a marked increase in CD69 expression on both CD4+ and CD8+ T cells when compared to vehicle-exposed and healthy control cultures. INTERPRETATION: LUZP4-IgG represents a novel serological biomarker of PNS and has high predictive value for germ cell tumors. The demonstrated antigen-specific T-cell responses support a CD8+ T-cell-mediated cytotoxic paraneoplastic and antitumor potential. ANN NEUROL 2021;89:1001-1010.

Clinical diagnosis of LGI1 antibody encephalitis in an 83-year-old woman.

An 83-year-old woman was referred to hospital with a 2-week history of short-lived episodic unpleasant sensations in her head and running down her body. This was accompanied by new short-term memory impairment and arm spasms. Initial investigations including blood tests and brain imaging did not reveal the diagnosis. The patient developed an increasing frequency of abnormal movements of her face and arm. These were clinically recognised as faciobrachial dystonic seizures (FBDS). FBDS are pathognomonic of an autoimmune encephalitis caused by an antibody directed against leucine-rich glioma-inactivated 1 (LGI1). The clinical diagnosis resulted in treatment with immunotherapy, leading to cessation of seizures and rapid cognitive recovery. Later, the predicted serology was confirmed. This reversible and under-recognised cause of cognitive impairment, typically affecting elderly patients, can be diagnosed clinically to enable early and effective treatment.

Immunotherapy for Refractory Autoimmune Encephalitis.

Autoimmune encephalitis (AE) is an immune-mediated disease involving the central nervous system, usually caused by antigen-antibody reactions. With the advent of autoantibody-associated diseases, AE has become a hot research frontier in neuroimmunology. The first-line conventional treatments of autoimmune encephalitis consist of steroids, intravenous immunoglobulin (IVIG), plasma exchange (PLEX), and second-line therapy includes rituximab. Despite considerable research and expanding clinical experience, current treatments are still ineffective for a significant number of patients. Although there is no clear consensus, clinical trial evidence limited, and the level of evidence for some of the drugs based on single reports, third-line therapy is a viable alternative for refractory encephalitis patients. With the current rapid research progress, a breakthrough in the treatment of AE is critical. This article aims to review the third-line therapy for refractory AE.

Metabolic Imaging Patterns on 18F-FDG PET in Acute and Subacute LGI1 Autoimmune Limbic Encephalitis.

Autoimmune encephalitis is a diverse group of neuropsychiatric disorders, which are difficult to diagnose clinically. The disorder presents acutely or subacutely with alteration of consciousness, cognitive decline, seizures, and abnormal movements. Autoantibodies are directed against intracellular antigens or extracellular domains of cell surface proteins, critical for neuronal excitability. F-FDG PET/CT has been used to diagnose the metabolic derangement in the brain due to various antibodies. Here we describe a case where acute and subacute phase of disease was visualized on serial F-FDG PET/CT.

18F-FDG PET/CT in Anti-Leucine-Rich Glioma-Inactivated 1 Antibody Encephalitis: Typical Pattern and Follow-up.

ABSTRACT: We report the case of a 55-year-old man presenting pseudopsychiatric behavior disorders of subacute-onset. MRI showed a FLAIR (fluid-attenuated inversion recovery) hyperintensity in the left hippocampus. The diagnosis of limbic encephalitis was raised, and the patient was referred for an 18F-FDG PET/CT. PET/CT depicted an increased uptake of the left mesiotemporal structures and also an increased uptake of both cerebellum and striatal areas. This pattern was compatible with an anti-leucine-rich glioma-inactivated 1 antibody encephalitis that was later confirmed.

[GABAB receptor autoimmune encephalitis presenting as transient epileptic amnesia].

This case was a 50-year-old healthy woman. After repeated transient amnesia, she developed tonic-clonic seizures and was admitted to our hospital. The brain MRI showed FLAIR hyperintensities in the left temporal lobe and EEG showed an epileptic discharge starting from the left temporal region. Based on these findings, we diagnosed temporal lobe epilepsy associated with acute limbic encephalitis. While she experienced recurrent transient amnesia, her cognitive functions were preserved except for her memory. These symptoms and EEG findings were consistent with transient epileptic amnesia (TEA). Acute limbic encephalitis that occurred in a healthy middle-aged woman may be antibody-mediated encephalitis, requiring immediate immunotherapies. In this case, GABAB receptor antibodies in cerebrospinal fluid were found positive. This is the first report showing that TEA was caused by GABAB receptor autoimmune encephalitis.

Efficacy of rituximab on seizure control and cognitive symptoms in leucine-rich, glioma-inactivated 1 (LGI1) limbic encephalitis: a high-density electroencephalography case study.

LGI1 encephalitis is an autoimmune disorder characterized by cognitive symptoms and seizures, which rarely respond to common antiepileptic drugs (AEDs). Rituximab (RTX) is a CD-20-depleting monoclonal antibody which has been used for the treatment of LGI1 encephalitis, however, its efficacy remains controversial. A 54-year-old woman came to our attention due to memory loss and gambling. Brain MRI revealed areas of bilateral hippocampal hyperintensity and LGI1 antibodies were found in both serum and cerebrospinal fluid. Immunotherapy with steroids was started, followed by intravenous immunoglobulins with partial improvement. The patient developed multiple generalized tonic-clonic seizures. She was then administered intravenous rituximab with significant improvement for both cognitive symptoms and seizure control. High-density EEG was recorded before treatment, seven days after the first dose and seven days after the second dose. Topoplot and power spectrum analysis were performed for each recording. Interictal epileptiform discharges, as well as theta power bands, were significantly reduced after each dose, while topoplot analysis showed reduced spreading over posterior and frontal electrodes for interictal epileptiform discharges of temporal origin. Our experience indicates that rituximab is a valid treatment for LGI1 encephalitis, demonstrating efficacy for both cognitive symptoms and seizure control. High-density EEG could represent a novel, safe and reproducible method to study epileptogenesis in autoimmune limbic encephalitis.

[Paraneoplastic anti-gamma aminobutyric acid (GABA)B receptor antibody limbic encephalitis associated with small cell lung cancer presenting as new-onset status epilepticus: a case report].

An 84-year-old man was admitted to our hospital with new-onset refractory status epilepticus of unclear etiology. On the third day, diffusion-weighted brain MRI demonstrated lesions in the right medial temporal and parietal lobes. As a CSF sample showed pleocytosis, paraneoplastic limbic encephalitis (PLE) associated with small cell lung cancer (SCLC) was suspected. The patient was also positive for anti-gamma aminobutyric acid (GABA)B receptor antibody in the CSF, which has recently been reported in elderly patients with SCLC-related PLE. Methylprednisolone pulse therapy ameliorated the symptoms. It is noteworthy that immune therapy often improves the symptoms of PLE with anti-GABAB receptor antibody, even though radical therapy for the lung cancer may be difficult.