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International Journal of Molecular... May 2020Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main... (Review)
Review
Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population. Here, we reviewed the main clinical characteristics of neurological syndromes associated with GAD Ab, focusing on pathophysiologic mechanisms.
Topics: Autoimmune Diseases of the Nervous System; Autoimmunity; Cerebellar Ataxia; Glutamate Decarboxylase; Humans; Limbic Encephalitis; Neurons; Stiff-Person Syndrome
PubMed: 32456344
DOI: 10.3390/ijms21103701 -
Frontiers in Immunology 2021Autoimmune encephalitis (AE) is an immune-mediated disease involving the central nervous system, usually caused by antigen-antibody reactions. With the advent of... (Review)
Review
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.
Topics: Animals; Autoimmune Diseases; Clinical Trials as Topic; Disease Models, Animal; Drug Resistance; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunotherapy; Limbic Encephalitis; Plasma Exchange; Rituximab; Treatment Outcome
PubMed: 34975890
DOI: 10.3389/fimmu.2021.790962 -
Journal of Neurology, Neurosurgery, and... Mar 2022To compare acute treatment responses and long-term outcome in leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis.
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.
Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Autoantibodies; Autoimmune Diseases; Female; Humans; Immunoglobulins, Intravenous; Intracellular Signaling Peptides and Proteins; Limbic Encephalitis; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Young Adult
PubMed: 34824144
DOI: 10.1136/jnnp-2021-327302 -
Mimics of Autoimmune Encephalitis: Validation of the 2016 Clinical Autoimmune Encephalitis Criteria.Neurology(R) Neuroimmunology &... Nov 2023The clinical criteria for autoimmune encephalitis (AE) were proposed by Graus et al. in 2016. In this study, the AE criteria were validated in the real world, and common...
BACKGROUND AND OBJECTIVES
The clinical criteria for autoimmune encephalitis (AE) were proposed by Graus et al. in 2016. In this study, the AE criteria were validated in the real world, and common AE mimics were described. In addition, criteria for probable anti-LGI1 encephalitis were proposed and validated.
METHODS
In this retrospective cohort study, patients referred to our national referral center with suspicion of AE and specific neuroinflammatory disorders with similar clinical presentations were included from July 2016 to December 2019. Exclusion criteria were pure cerebellar or peripheral nerve system disorders. All patients were evaluated according to the AE criteria.
RESULTS
In total, 239 patients were included (56% female; median age 42 years, range 1-85). AE was diagnosed in 104 patients (44%) and AE mimics in 109 patients (46%). The most common AE mimics and misdiagnoses were neuroinflammatory CNS disorders (26%), psychiatric disorders (19%), epilepsy with a noninflammatory cause (13%), CNS infections (7%), neurodegenerative diseases (7%), and CNS neoplasms (6%). Common confounding factors were mesiotemporal lesions on brain MRI (17%) and false-positive antibodies in serum (12%). Additional mesiotemporal features (involvement extralimbic structures, enhancement, diffusion restriction) were observed more frequently in AE mimics compared with AE (61% vs 24%; = 0.005). AE criteria showed the following sensitivity and specificity: possible AE, 83% (95% CI 74-89) and 27% (95% CI 20-36); definite autoimmune limbic encephalitis (LE), 10% (95% CI 5-17) and 98% (95% CI 94-100); and probable anti-NMDAR encephalitis, 50% (95% CI 26-74) and 96% (95% CI 92-98), respectively. Specificity of the criteria for probable seronegative AE was 99% (95% CI 96-100). The newly proposed criteria for probable anti-LGI1 encephalitis showed a sensitivity of 66% (95% CI 47-81) and specificity of 96% (95% CI 93-98).
DISCUSSION
AE mimics occur frequently. Common pitfalls in AE misdiagnosis are mesiotemporal lesions (predominantly with atypical features) and false-positive serum antibodies. As expected, the specificity of the criteria for possible AE is low because these criteria represent the minimal requirements for entry in the diagnostic algorithm for AE. Criteria for probable AE (-LGI1, -NMDAR, seronegative) and definite autoimmune LE are applicable for decisions on immunotherapy in early disease stage, as specificity is high.
Topics: Humans; Female; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Male; Retrospective Studies; Limbic Encephalitis; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Antibodies
PubMed: 37582614
DOI: 10.1212/NXI.0000000000200148 -
BMJ Case Reports Jun 2014We present a case of paraneoplastic limbic encephalitis, describing the presenting features, diagnosis and management plan. Limbic encephalitis is one differential of...
We present a case of paraneoplastic limbic encephalitis, describing the presenting features, diagnosis and management plan. Limbic encephalitis is one differential of rapidly progressive dementia. We describe a rational approach to the diagnosis of the patient with rapid cognitive decline.
Topics: Aged; Brain; Confusion; Diagnosis, Differential; Female; Headache; Humans; Limbic Encephalitis; Magnetic Resonance Imaging; Neuroimaging; Seizures
PubMed: 24891487
DOI: 10.1136/bcr-2014-204591 -
CMAJ : Canadian Medical Association... May 2019
Review
Topics: Autoantibodies; Autoimmune Diseases; Cerebrospinal Fluid; Electroencephalography; Guidelines as Topic; Humans; Limbic Encephalitis; Magnetic Resonance Imaging; Neuroimaging
PubMed: 31085562
DOI: 10.1503/cmaj.181548 -
Neurology India 2022
Topics: Humans; Fluorodeoxyglucose F18; Limbic Encephalitis; Positron-Emission Tomography; Magnetic Resonance Imaging
PubMed: 36352635
DOI: 10.4103/0028-3886.359207 -
Cureus Aug 2021Limbic encephalitis is an autoimmune cause of encephalitis. In addition to the usual symptoms of encephalitis such as altered consciousness, fever, and focal... (Review)
Review
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.
PubMed: 34603897
DOI: 10.7759/cureus.17529 -
Frontiers in Immunology 2023An analysis of the clinical features of autoimmune encephalitis accompanied by anti-amphiphysin antibodies.
OBJECTIVE
An analysis of the clinical features of autoimmune encephalitis accompanied by anti-amphiphysin antibodies.
METHODS
The data of encephalitis patients with anti-amphiphysin antibodies were retrospectively evaluated, including demographics, neurological and laboratory findings, imaging, treatment, and prognostic predictions.
RESULTS
Ten patients aged between 29 and 78 years (median age 52 years) were included. The male: female ratio was 4:6. Limbic encephalitis was found in nine patients while epileptic seizures were present in seven patients. All patients showed anti-amphiphysin antibody positivity in sera while one ninth was positive for CSF antibody. The EEG findings were abnormal, including reductions in background activity, and the presence of diffuse slow waves, sharp waves, and spikes and waves. Five patients showed signs of increased T2 signals in the medial temporal lobe on MRI while PET showed either hyper- or hypo-metabolic changes in several brain regions, including the temporal lobe, hippocampus, basal ganglia, frontal and parietal cortices. Nine of ten patients were treated with immunotherapy, with improvements of varying degrees. There was a significant reduction in seizure frequency, and all patients were seizure-free at last follow-up.
CONCLUSION
Autoimmune encephalitis with anti-amphiphysin antibodies has a variety of clinical manifestations. The most common symptom is limbic encephalitis. Although relief from seizures can be achieved relatively easily, many patients suffer psychiatric, cognitive, and sleep sequelae. The disease was found to be associated with a lower incidence of cancer than has been previously reported for paraneoplastic neurologic syndromes.
Topics: Humans; Male; Female; Adult; Middle Aged; Aged; Limbic Encephalitis; Retrospective Studies; Encephalitis; Seizures; Autoimmune Diseases of the Nervous System
PubMed: 37090693
DOI: 10.3389/fimmu.2023.1084883 -
Journal of Neurovirology Feb 2017The roseoloviruses, human herpesvirus (HHV)-6A, HHV-6B, and HHV-7, can cause severe encephalitis or encephalopathy. In immunocompetent children, primary HHV-6B infection... (Review)
Review
The roseoloviruses, human herpesvirus (HHV)-6A, HHV-6B, and HHV-7, can cause severe encephalitis or encephalopathy. In immunocompetent children, primary HHV-6B infection is occasionally accompanied by diverse clinical forms of encephalitis. Roseolovirus coinfections with heterologous viruses and delayed primary HHV-7 infection in immunocompetent adults result in very severe neurological and generalized symptoms. Recovery from neurological sequelae is slow and sometimes incomplete. In immunocompromised patients with underlying hematological malignancies and transplantation, frequent single or simultaneous reactivation of roseoloviruses elicit severe, lethal organ dysfunctions, including damages in the limbic system, brain stem, and hippocampus. Most cases have been due to HHV-6B with HHV-6A accounting for 2-3%. The most severe manifestation of HHV-6B reactivation is post-transplantation limbic encephalitis. Seizures, cognitive problems, and abnormal EEG are common. Major risk factors for HHV-6B-associated encephalitis include unrelated cord blood cell transplantation and repeated hematopoietic stem cell transplantation. Rare genetic disorders, male gender, certain HLA constellation, and immune tolerance to replicating HHV-6 in persons carrying chromosomally integrated HHV-6 might also predispose an individual to roseolovirus-associated brain damage. At this time, little is known about the risk factors for HHV-7-associated encephalitis. Intrathecal glial cell destruction due to virus replication, overexpression of proinflammatory cytokines, and viral mimicry of chemokines all contribute to brain dysfunction. High virus load in the cerebrospinal fluid, hippocampal astrogliosis, and viral protein expression in HHV-6B-associated cases and multiple microscopic neuronal degeneration in HHV-7-associated cases are typical laboratory findings. Early empirical therapy with ganciclovir or foscarnet might save the life of a patient with roseolovirus-associated encephalitis.
Topics: Adult; Antiviral Agents; Child; Cord Blood Stem Cell Transplantation; Cytokines; Encephalitis, Viral; Foscarnet; Ganciclovir; Hematopoietic Stem Cell Transplantation; Herpesvirus 6, Human; Humans; Immunocompetence; Immunocompromised Host; Limbic Encephalitis; Neuroglia; Risk Factors; Roseolovirus Infections
PubMed: 27538995
DOI: 10.1007/s13365-016-0473-0