ABSTRACT
OBJECTIVE: Antibodies against glutamic acid decarboxylase (GAD), originally associated with stiff person syndrome (SPS), define the GAD antibody-spectrum disorders that also include cerebellar ataxia, autoimmune epilepsy, limbic encephalitis, progressive encephalomyelitis with rigidity and myoclonus (PERM), and eye movement disorders, all of which are characterized by autoimmune neuronal excitability. This article elaborates on the diagnostic criteria for SPS and SPS spectrum disorders, highlights disease mimics and misdiagnoses, describes the electrophysiologic mechanisms and underlying autoimmunity of stiffness and spasms, and provides a step-by-step therapeutic scheme. LATEST DEVELOPMENTS: Very-high serum GAD antibody titers are diagnostic for GAD antibody-spectrum disorders and also predict the presence of GAD antibodies in the CSF, increased intrathecal synthesis, and reduced CSF γ-aminobutyric acid (GABA) levels. Low serum GAD antibody titers or the absence of antibodies generates diagnostic challenges that require careful distinction in patients with a variety of painful spasms and stiffness, including functional neurologic disorders. Antibodies against glycine receptors, first found in patients with PERM, are seen in 13% to 15% of patients with SPS, whereas amphiphysin and gephyrin antibodies, seen in 5% of patients with SPS spectrum disorders, predict a paraneoplastic association. GAD-IgG from different SPS spectrum disorders recognizes the same dominant GAD intracellular epitope and, although the pathogenicity is unclear, is an excellent diagnostic marker. The biological basis of muscle stiffness and spasms is related to autoimmune neuronal hyperexcitability caused by impaired reciprocal γ-aminobutyric acid-mediated (GABA-ergic) inhibition, which explains the therapeutic response to GABA-enhancing agents and immunotherapies. ESSENTIAL POINTS: It is essential to distinguish SPS spectrum disorders from disease mimics to avoid both overdiagnoses and misdiagnoses, considering that SPS is treatable if managed correctly from the outset to prevent disease progression. A step-by-step, combination therapy of GABA-enhancing medications along with immunotherapies ensures prolonged clinical benefits.
Subject(s)
Autoantibodies , Glutamate Decarboxylase , Stiff-Person Syndrome , Humans , Stiff-Person Syndrome/diagnosis , Stiff-Person Syndrome/immunology , Stiff-Person Syndrome/physiopathology , Stiff-Person Syndrome/blood , Glutamate Decarboxylase/immunology , Autoantibodies/blood , Male , Female , Muscle Rigidity/diagnosis , Muscle Rigidity/immunology , Muscle Rigidity/drug therapy , Encephalomyelitis/diagnosis , Encephalomyelitis/immunology , Encephalomyelitis/blood , Middle Aged , Adult , Cerebellar Ataxia/diagnosis , Cerebellar Ataxia/immunology , Cerebellar Ataxia/blood , Cerebellar Ataxia/physiopathology , Limbic Encephalitis/diagnosis , Limbic Encephalitis/immunology , Limbic Encephalitis/therapy , Limbic Encephalitis/blood , Limbic Encephalitis/physiopathologyABSTRACT
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.
Subject(s)
Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Glutamate Decarboxylase/immunology , Limbic Encephalitis/immunology , Limbic Encephalitis/pathology , Adult , Autoimmune Diseases/blood , Autoimmune Diseases/cerebrospinal fluid , Cross-Sectional Studies , Female , Humans , Limbic Encephalitis/blood , Limbic Encephalitis/cerebrospinal fluid , Magnetic Resonance Imaging , Male , Middle Aged , Young AdultABSTRACT
Limbic encephalitis with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leucocyte antigen and CSF proteomic profiles. Patients with anti-AK5 limbic encephalitis were mostly male (20/26, 76.9%) with a median age of 66 years (range 48-94). The predominant symptom was severe episodic amnesia in all patients, and this was frequently associated with depression (17/25, 68.0%). Weight loss, asthenia and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%) and increased Tau (11/14, 78.6%). Temporal lobe hyperintensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably towards severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with the highest titres in nine CSF-serum paired samples. A temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T cells, intense granzyme B expression and abundant macrophages/microglia. Human leucocyte antigen (HLA) analysis in 11 patients showed a striking association with HLA-B*08:01 [7/11, 63.6%; odds ratio (OR) = 13.4, 95% confidence interval (CI): 3.8-47.4], C*07:01 (8/11, 72.7%; OR = 11.0, 95% CI: 2.9-42.5), DRB1*03:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7-55.7), DQB1*02:01 (8/11, 72.7%; OR = 13.5, 95% CI: 3.5-52.0) and DQA1*05:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7-55.7) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR = 16.5, 95% CI: 4.8-57.1). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 control subjects and 10 cases with other more common non-paraneoplastic limbic encephalitis (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed 31 and seven significantly upregulated proteins in anti-AK5 limbic encephalitis, respectively mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 limbic encephalitis result from a distinct T cell-mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy.
Subject(s)
Adenylate Kinase/cerebrospinal fluid , Autoantibodies/cerebrospinal fluid , Limbic Encephalitis/cerebrospinal fluid , Limbic Encephalitis/diagnostic imaging , Adenylate Kinase/blood , Aged , Aged, 80 and over , Autoantibodies/blood , Female , Humans , Limbic Encephalitis/blood , Male , Middle Aged , Proteomics/methodsABSTRACT
Limbic encephalitis (LE) forms a spectrum of autoimmune diseases involving temporal lobe epilepsy and memory impairment. Imaging features of LE are known to depend on the associated antibody and to occur on the brain network level. However, first studies investigating brain networks in LE have either focused on one distinct antibody subgroup or on distinct anatomical regions. In this study, brain graphs of 17 LE patients with autoantibodies against glutamic acid decarboxylase 65 (GAD-LE), four LE patients with autoantibodies against leucine-rich glioma-inactivated 1, five LE patients with autoantibodies against contactin-associated protein-like 2, 26 age- and gender-matched healthy control subjects, and 20 epilepsy control patients with hippocampal sclerosis were constructed based on T1-weighted structural magnetic resonance imaging scans and diffusion tensor imaging. GAD-LE showed significantly altered global network topology in terms of integration and segregation as compared to healthy controls and patients with hippocampal sclerosis (P < .01, analysis of variance with Tukey-Kramer post hoc tests). Linear regression linked global network measures with amygdala volume and verbal memory performance (P < .05). Alterations of local network topology show serotype dependence in hippocampus, amygdala, insula, and various cortical regions. Our findings reveal serotype-dependent patterns of structural connectivity and prove the relevance of in silico network measures on clinical grounds.
Subject(s)
Amygdala/diagnostic imaging , Autoantibodies , Epilepsy/diagnostic imaging , Limbic Encephalitis/diagnostic imaging , Memory Disorders/diagnostic imaging , Nerve Net/diagnostic imaging , Adult , Aged , Autoantibodies/blood , Biomarkers/blood , Cohort Studies , Epilepsy/blood , Female , Glutamate Decarboxylase/blood , Humans , Hypertrophy , Intracellular Signaling Peptides and Proteins/blood , Limbic Encephalitis/blood , Male , Memory Disorders/blood , Middle AgedABSTRACT
Inflammation plays a role in the pathogenesis of immune-mediated epilepsy, but also in epilepsy of other etiology such as hippocampal sclerosis. This study aimed to characterize immune cell signatures in the peripheral blood (PB) and cerebrospinal fluid (CSF) in temporal lobe epilepsy (TLE) of different etiologies. We retrospectively evaluated CSF routine parameters and immune cell profiles using flow cytometry in a cohort of 51 patients and 45 age-matched controls with functional disorders. Groups were comprised of patients with nonlesional TLE (n = 26), TLE due to hippocampal sclerosis (n = 14), or limbic encephalitis with antibodies against the 65-kDa isoform of glutamic acid decarboxylase (GAD65-LE; n = 11). TLE patients showed increased proportions of human leukocyte antigen-DR isotype (HLA-DR)-expressing CD4+ T lymphocytes in the CSF. Furthermore, they were characterized by a shift in monocyte subsets toward immature CD14low CD16+ cells in the PB and blood/CSF-barrier dysfunction. Whereas TLE patients in general showed similar immune cell profiles, patients with GAD65-LE differed from other TLE patients by increased proportions of HLA-DR-expressing CD8+ T lymphocytes and type 2/3 oligoclonal bands. These findings point to a role of innate and adaptive immunity in TLE. CSF parameters may help to discriminate epilepsy patients from controls and different forms of TLE from each other.
Subject(s)
Adaptive Immunity/physiology , Epilepsy, Temporal Lobe/blood , Epilepsy, Temporal Lobe/cerebrospinal fluid , Immunity, Innate/physiology , Limbic Encephalitis/blood , Limbic Encephalitis/cerebrospinal fluid , Adult , Aged , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Epilepsy, Temporal Lobe/diagnosis , Female , Hippocampus/metabolism , Hippocampus/pathology , Humans , Limbic Encephalitis/diagnosis , Lymphocytes/metabolism , Male , Middle Aged , Monocytes/metabolism , Retrospective Studies , Sclerosis/blood , Sclerosis/cerebrospinal fluid , Sclerosis/diagnosisABSTRACT
Anti-Leucine-rich glioma-inactivated-1 encephalitis is a subtype of autoimmune encephalitis characterized by cognitive impairment, faciobrachial dystonic seizures, and behavioural changes. There is no reported case from Nepal. We report a case of a 54-year old male who presented with abnormal body movement, behavioural changes, rapid eye movement sleep behavioural changes, and cognitive decline. Investigations revealed magnetic resonance imaging findings of fluidattenuated inversion recovery intensity signal in bilateral temporal lobes with anti-leucine-rich glioma-inactivated-1 antibody in serum leading to diagnosis of anti-leucine-rich glioma-inactivated-1 encephalitis. He was treated with steroids and intravenous immunoglobulin. Timely diagnosis is vital to prevent complications and improve outcomes.
Subject(s)
Intracellular Signaling Peptides and Proteins , Limbic Encephalitis , Mental Disorders , Anticonvulsants/therapeutic use , Autoantibodies/blood , Autoantibodies/immunology , Autoimmune Diseases of the Nervous System/blood , Autoimmune Diseases of the Nervous System/diagnosis , Autoimmune Diseases of the Nervous System/immunology , Autoimmune Diseases of the Nervous System/therapy , Cognitive Dysfunction/etiology , Dystonic Disorders/etiology , Glucocorticoids/therapeutic use , Humans , Immunoglobulins, Intravenous/therapeutic use , Intracellular Signaling Peptides and Proteins/blood , Intracellular Signaling Peptides and Proteins/immunology , Limbic Encephalitis/blood , Limbic Encephalitis/diagnosis , Limbic Encephalitis/immunology , Limbic Encephalitis/therapy , Magnetic Resonance Imaging , Male , Mental Disorders/etiology , Methylprednisolone/therapeutic use , Middle Aged , Nepal , Problem Behavior , Seizures/etiologyABSTRACT
Autoantibodies against leucine-rich glioma inactivated 1 (LGI1) are found in patients with limbic encephalitis and focal seizures. Here, we generate patient-derived monoclonal antibodies (mAbs) against LGI1. We explore their sequences and binding characteristics, plus their pathogenic potential using transfected HEK293T cells, rodent neuronal preparations, and behavioural and electrophysiological assessments in vivo after mAb injections into the rodent hippocampus. In live cell-based assays, LGI1 epitope recognition was examined with patient sera (n = 31), CSFs (n = 11), longitudinal serum samples (n = 15), and using mAbs (n = 14) generated from peripheral B cells of two patients. All sera and 9/11 CSFs bound both the leucine-rich repeat (LRR) and the epitempin repeat (EPTP) domains of LGI1, with stable ratios of LRR:EPTP antibody levels over time. By contrast, the mAbs derived from both patients recognized either the LRR or EPTP domain. mAbs against both domain specificities showed varied binding strengths, and marked genetic heterogeneity, with high mutation frequencies. LRR-specific mAbs recognized LGI1 docked to its interaction partners, ADAM22 and ADAM23, bound to rodent brain sections, and induced internalization of the LGI1-ADAM22/23 complex in both HEK293T cells and live hippocampal neurons. By contrast, few EPTP-specific mAbs bound to rodent brain sections or ADAM22/23-docked LGI1, but all inhibited the docking of LGI1 to ADAM22/23. After intrahippocampal injection, and by contrast to the LRR-directed mAbs, the EPTP-directed mAbs showed far less avid binding to brain tissue and were consistently detected in the serum. Post-injection, both domain-specific mAbs abrogated long-term potentiation induction, and LRR-directed antibodies with higher binding strengths induced memory impairment. Taken together, two largely dichotomous populations of LGI1 mAbs with distinct domain binding characteristics exist in the affinity matured peripheral autoantigen-specific memory pools of individuals, both of which have pathogenic potential. In human autoantibody-mediated diseases, the detailed characterization of patient mAbs provides a valuable method to dissect the molecular mechanisms within polyclonal populations.
Subject(s)
Antibodies, Monoclonal/metabolism , Autoantibodies/immunology , Intracellular Signaling Peptides and Proteins/immunology , ADAM Proteins/metabolism , Animals , Antibodies, Monoclonal/immunology , Autoantibodies/blood , Autoantibodies/metabolism , Autoantigens/metabolism , Brain/metabolism , Epitopes/immunology , HEK293 Cells , Hippocampus/metabolism , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Limbic Encephalitis/blood , Male , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Protein Binding/immunology , Protein Domains/immunologyABSTRACT
OBJECTIVE: Antibodies against glutamic acid decarboxylase 65 (anti-GAD65) are associated with a number of neurologic syndromes. However, their pathogenic role is controversial. Our objective was to describe clinical and paraclinical characteristics of anti-GAD65 patients and analyze their response to immunotherapy. METHODS: Retrospectively, we studied patients (n = 56) with positive anti-GAD65 and any neurologic symptom. We tested serum and CSF with ELISA, immunohistochemistry, and cell-based assay. Accordingly, we set a cutoff value of 10,000 IU/mL in serum by ELISA to group patients into high-concentration (n = 36) and low-concentration (n = 20) groups. We compared clinical and immunologic features and analyzed response to immunotherapy. RESULTS: Classical anti-GAD65-associated syndromes were seen in 34/36 patients with high concentration (94%): stiff-person syndrome (7), cerebellar ataxia (3), chronic epilepsy (9), limbic encephalitis (9), or an overlap of 2 or more of the former (6). Patients with low concentrations had a broad, heterogeneous symptom spectrum. Immunotherapy was effective in 19/27 treated patients (70%), although none of them completely recovered. Antibody concentration reduction occurred in 15/17 patients with available pre- and post-treatment samples (median reduction 69%; range 27%-99%), of which 14 improved clinically. The 2 patients with unchanged concentrations showed no clinical improvement. No differences in treatment responses were observed between specific syndromes. CONCLUSION: Most patients with high anti-GAD65 concentrations (>10,000 IU/mL) showed some improvement after immunotherapy, unfortunately without complete recovery. Serum antibody concentrations' course might be useful to monitor response. In patients with low anti-GAD65 concentrations, especially in those without typical clinical phenotypes, diagnostic alternatives are more likely.
Subject(s)
Autoantibodies/blood , Autoimmune Diseases of the Nervous System , Cerebellar Ataxia , Epilepsy , Glutamate Decarboxylase/immunology , Limbic Encephalitis , Outcome Assessment, Health Care , Stiff-Person Syndrome , Adolescent , Adult , Aged , Aged, 80 and over , Autoantibodies/cerebrospinal fluid , Autoimmune Diseases of the Nervous System/blood , Autoimmune Diseases of the Nervous System/drug therapy , Autoimmune Diseases of the Nervous System/physiopathology , Cerebellar Ataxia/blood , Cerebellar Ataxia/drug therapy , Cerebellar Ataxia/physiopathology , Child , Child, Preschool , Epilepsy/blood , Epilepsy/drug therapy , Epilepsy/physiopathology , Female , Humans , Immunotherapy , Limbic Encephalitis/blood , Limbic Encephalitis/drug therapy , Limbic Encephalitis/physiopathology , Male , Middle Aged , Retrospective Studies , Stiff-Person Syndrome/blood , Stiff-Person Syndrome/drug therapy , Stiff-Person Syndrome/physiopathology , Young AdultABSTRACT
Background: Limbic encephalitis can be associated with antibodies directed against intracellular antigens or cell surface antigens, or can be sero-negative. It is still unclear if rituximab can benefit sero-negative limbic encephalitis.Case presentation: Here, we report that a sero-negative limbic encephalitis patient with refractory seizures was treated successfully with rituximab combined with anti-epileptic drugs. Pulsed intravenous methylprednisolone (IVMP) combined with intravenous immunoglobulin (IVIg) in this patient resulted in limited effect.Conclusion: We conclude that rituximab may be tried in sero-negative limbic encephalitis if IVMP combined with IVIg failed, and delayed use of rituximab could also be effective.
Subject(s)
Anticonvulsants/pharmacology , Immunologic Factors/pharmacology , Limbic Encephalitis/blood , Limbic Encephalitis/drug therapy , Rituximab/pharmacology , Seizures/drug therapy , Anticonvulsants/administration & dosage , Drug Synergism , Drug Therapy, Combination , Humans , Immunoglobulins, Intravenous/administration & dosage , Immunologic Factors/administration & dosage , Limbic Encephalitis/complications , Methylprednisolone/administration & dosage , Rituximab/administration & dosage , Seizures/etiologyABSTRACT
A encefalite límbica vem sendo descrita como um distúrbio neurológico raro, que afeta seletivamente as estruturas do sistema límbico. Clinicamente, é caracterizada como uma desordem neurológica debilitante, que se desenvolve como encefalopatia rapidamente progressiva, causada por inflamação encefálica. Objetivamos aqui relatar um caso de encefalite do sistema límbico de provável etiologia autoimune para melhor conhecimento da comunidade médica, bem como averiguar métodos diagnósticos deste quadro. Paciente do sexo masculino, 59 anos, admitido em nosso serviço com queixa de confusão mental. O exame clínico evidenciou desorientação, disartria, paresia e parestesia no hemicorpo esquerdo, dificuldade de marcha, desvio de rima e histórico de epilepsia há 2 anos. No estudo por ressonância magnética do crânio, foram observadas extensas lesões que acometiam a região mesial do lobo temporal direito, todo o hipocampo e giro para-hipocampal direito, estendendo-se pelo fórnix até a porção posterior do hipocampo esquerdo, substância branca do lobo frontal bilateral. Mediante os resultados da investigação complementar, o paciente foi tratado com pulsoterapia de metilpredinisolona por 5 dias, resultando na regressão parcial dos sintomas. Atualmente, o paciente se encontra em seguimento ambulatorial para acompanhamento. A encefalite límbica é uma doença rara, porém muito importante de ser investigada e diagnosticada precocemente, uma vez que a progressão da doença pode causar incapacidade e sequelas irreversíveis.
Limbic encephalitis has been described as a rare neurological disorder affecting the limbic system structures selectively. Clinically, it is characterized as a debilitating neurological syndrome that develops as a quickly progressive encephalopathy caused by brain inflammation. This paper reports a case of limbic encephalitis, probably of autoimmune etiology, aiming to improve the knowledge of the medical community, and to promote a debate on diagnosis methods for this pathology. The patient is male, 59 years old, and was admitted at our service complaining of mental confusion. The clinical examination showed disorientation, dysarthria, left hemiparesis and paresthesia, gait difficulties, light asymmetrical smile, and history of epilepsy 2 years ago. The magnetic resonance imaging of skull showed extensive lesions affecting the mesial region of the right temporal lobe, the entire hippocampus, and right parahippocampal gyrus, extending through the fornix to the posterior portion of the left hippocampus, white matter of bilateral frontal lobe. Based on the complementary investigation results, the patient was treated with intravenous methylprednisolone for five days. Currently, he is being followed in the outpatient's department. Although being rare, limbic encephalitis shall be investigated and diagnosed early because its progression can lead to disability and irreversible sequelae
Subject(s)
Humans , Male , Middle Aged , Autoimmunity , Limbic Encephalitis/diagnostic imaging , Paresis/etiology , Paresthesia , Carbamazepine/therapeutic use , Prednisone/therapeutic use , Magnetic Resonance Spectroscopy , Tomography, X-Ray Computed , Confusion/etiology , Limbic Encephalitis/complications , Limbic Encephalitis/immunology , Limbic Encephalitis/cerebrospinal fluid , Limbic Encephalitis/drug therapy , Limbic Encephalitis/blood , Limbic Encephalitis/virology , Dysarthria/etiology , Electroencephalography , Epilepsy/drug therapy , Hyponatremia , Anti-Inflammatory Agents/therapeutic use , Anticonvulsants/therapeutic use , Neurologic ExaminationABSTRACT
Brain tumors and paraneoplastic syndromes can cause various neuropsychiatric symptoms. Rarely, psychiatric symptoms may be the initial presentation of the underlying neurologic lesion. Brain imaging studies are crucial in the diagnosis of brain tumors. Paraneoplastic syndromes are mostly immune-mediated, and antineuronal antibodies may be detected in the blood or cerebrospinal fluid. Clinical suspicion is very important in assisting the diagnostic workup. Treatment of the psychiatric symptoms depends on the nature of the symptoms. Selection of the psychotropic agent has to be done carefully to minimize complications such as seizures and delirium secondary to anticholinergic toxicity. With advances in targeted therapies, immunology, and genetics, the future appears more promising.
Subject(s)
Autoantibodies/blood , Brain Neoplasms/blood , Brain Neoplasms/drug therapy , Paraneoplastic Syndromes, Nervous System/blood , Paraneoplastic Syndromes, Nervous System/drug therapy , Humans , Immunologic Factors/therapeutic use , Limbic Encephalitis/blood , Limbic Encephalitis/drug therapy , Limbic Encephalitis/psychology , Paraneoplastic Syndromes, Nervous System/psychology , Psychopharmacology , Psychotropic Drugs/therapeutic useABSTRACT
BACKGROUND AND PURPOSE: Limbic encephalitis is an autoimmune disease. A variety of autoantibodies have been associated with different subtypes of limbic encephalitis, whereas its MR imaging signature is uniformly characterized by mesiotemporal abnormalities across subtypes. Here, we hypothesized that patients with limbic encephalitis would show subtype-specific mesiotemporal structural correlates, which could be classified by supervised machine learning on an individual level. MATERIALS AND METHODS: T1WI MPRAGE scans from 46 patients with antibodies against glutamic acid decarboxylase and 34 patients with antibodies against the voltage-gated potassium channel complex (including 10 patients with leucine-rich glioma-inactivated 1 autoantibodies) and 48 healthy controls were retrospectively ascertained. Parcellation of the amygdala, hippocampus, and hippocampal subfields was performed using FreeSurfer. Volumes were extracted and compared between groups using unpaired, 2-tailed t tests. The volumes of hippocampal subfields were analyzed using a multivariate linear model and a binary decision tree classifier. RESULTS: Temporomesial volume alterations were most pronounced in an early stage and in the affected hemispheric side of patients. Statistical analysis revealed antibody-specific hippocampal fingerprints with a higher volume of CA1 in patients with glutamic acid decarboxylase-associated limbic encephalitis (P = .02), compared with controls, whereas CA1 did not differ from that in controls in patients with voltage-gated potassium channel complex autoantibodies. The classifier could successfully distinguish between patients with autoantibodies against leucine-rich glioma-inactivated 1 and glutamic acid decarboxylase with a specificity of 87% and a sensitivity of 80%. CONCLUSIONS: Our results suggest stage-, side- and antibody-specific structural correlates of limbic encephalitis; thus, they create a perspective toward an MR imaging-based diagnosis.
Subject(s)
Autoantibodies/immunology , Limbic Encephalitis/diagnostic imaging , Limbic Encephalitis/immunology , Machine Learning , Neuroimaging/methods , Adult , Autoantibodies/blood , Autoantigens/immunology , Brain/diagnostic imaging , Brain/immunology , Female , Glutamate Decarboxylase/immunology , Humans , Intracellular Signaling Peptides and Proteins/immunology , Limbic Encephalitis/blood , Magnetic Resonance Imaging/methods , Male , Middle Aged , Retrospective StudiesABSTRACT
We report the case of a 42-year-old woman who presented with vertigo and migraine and rapidly developed cognitive decline and seizures. Both serum and cerebro-spinal fluid samples showed high titer of anti-glutamic acid decarboxylase (anti-GAD65) antibodies (998,881â¯IU/ml and 54,687â¯IU/ml respectively). Limbic encephalitis was diagnosed and high dose steroids treatment started. During one-year follow-up, without further immunomodulatory therapy, the patient became seizure free, and cognitive functions returned to normal. Serum anti-GAD65 antibodies titer decreased significantly but remained elevated (192,680â¯IU/ml). We discuss the prognostic and pathogenic value of high titer anti-GAD65 antibodies and its variations in a case of autoimmune limbic encephalitis.
Subject(s)
Autoantibodies/blood , Autoimmune Diseases/blood , Autoimmune Diseases/diagnostic imaging , Glutamate Decarboxylase/blood , Limbic Encephalitis/blood , Limbic Encephalitis/diagnostic imaging , Adult , Female , Humans , Predictive Value of TestsABSTRACT
GDF-15, a member of the transforming growth factor beta superfamily, regulates inflammatory and apoptotic pathways in various diseases, such as heart failure, kidney dysfunction, and cancer. We aimed to clarify potentially confounding variables affecting GDF-15 and demonstrate its utility as a mitochondrial biomarker using serum samples from 15 patients with mitochondrial diseases (MD), 15 patients with limbic encephalitis (LE), 10 patients with multiple sclerosis/neuromyelitis optica spectrum disorders (MS/NMOSD), and 19 patients with amyotrophic lateral sclerosis (ALS). GDF-15 and FGF-21 were significantly elevated in MD. GDF-15 and FGF-21 showed a good correlation in MD but not in LE, MS, and ALS. GDF-15 was potentially influenced by age in LE, MS/NMOSD, and ALS but not in MD. FGF-21 was not correlated with age in MS/NMOSD, ALS, LE, and MD. GDF-15 was not correlated with clinical features in LE or BMI or body weight in ALS. GDF-15 positively correlated with the Expanded Disability Status Scale (EDSS) in MS/NMOSD, while EDSS showed no correlation with age. In conclusion, the results revealed that GDF-15 may be influenced by EDSS in MS/NMOPSD and by age in LE, MS/NMOSD, and ALS but not in MD. Mitochondrial damage in MS/NMOSD is a potentially confounding variable affecting GDF-15.
Subject(s)
Fibroblast Growth Factors/blood , Growth Differentiation Factor 15/blood , Mitochondrial Diseases/blood , Multiple Sclerosis/blood , Adult , Age Factors , Aged , Aged, 80 and over , Amyotrophic Lateral Sclerosis/blood , Biomarkers/blood , Disability Evaluation , Female , Humans , Limbic Encephalitis/blood , Male , Middle Aged , Neuromyelitis Optica/blood , Young AdultSubject(s)
Autoantibodies/blood , Limbic Encephalitis/blood , Lung Neoplasms/blood , Motor Neuron Disease/blood , Paraneoplastic Syndromes/blood , Small Cell Lung Carcinoma/blood , Antibodies, Antinuclear/blood , Antibodies, Neoplasm/blood , Humans , Limbic Encephalitis/complications , Limbic Encephalitis/diagnosis , Lung Neoplasms/complications , Lung Neoplasms/diagnosis , Male , Middle Aged , Motor Neuron Disease/complications , Motor Neuron Disease/diagnosis , Paraneoplastic Syndromes/complications , Paraneoplastic Syndromes/diagnosis , Small Cell Lung Carcinoma/complications , Small Cell Lung Carcinoma/diagnosis , Treatment OutcomeABSTRACT
BACKGROUND: Human herpesvirus 6 (HHV6) is a cause of post-transplant acute limbic encephalitis (PALE). Seizures are associated with this disorder yet no predictive biomarkers have been identified. The objective of this study was to evaluate lab and neurodiagnostic biomarkers in patients with HHV6 associated PALE. METHODS: A retrospective chart review was performed at our institutions between 2000 and 2017. Patients were identified through a clinical database. Inclusion criteria included: age less than 18 years, HHV6 (quantitative real-time PCR or meningoencephalitis panel) tested in CSF and serum. Biomarkers of serum and CSF viral load, EEG, and MRI were reviewed along with clinical data. RESULTS: In total, 11 patients met inclusion criteria. All patients had undergone hematopoietic stem cell transplantation. Five of 11 patients had seizures as part of their clinical course, all being controlled with antiepileptic monotherapy. Seizure semiology was focal-onset in three cases and generalized in two. Neuroimaging was normal in all patients within seven days but six patients developed T2 signal intensities in the temporal lobes on repeat imaging between 14-28 days. The median CSF HHV6 viral load for all patients was 47 300 copies/mL although the median viral load was 2586 copies/mL in patients who had seizure compared to 473 969 copies/mL in those who had not (P = 0.02). Those with seizures tended to be younger (median 6.5 years compared to 11 years, P = 0.27). All patients with seizures had an EEG with 80% demonstrating abnormalities. CONCLUSION: In patients with post-hematopoietic stem cell transplant HHV6 associated PALE, lower CSF viral load may be associated with a higher likelihood to have seizures. This may indicate a primary infection as opposed to secondary reactivation phenomenon.
Subject(s)
Encephalitis, Viral/diagnosis , Hematopoietic Stem Cell Transplantation/adverse effects , Herpesvirus 6, Human/isolation & purification , Limbic Encephalitis/diagnosis , Postoperative Complications/diagnosis , Roseolovirus Infections/diagnosis , Seizures/diagnosis , Acute Disease , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Child , Electroencephalography , Encephalitis, Viral/complications , Encephalitis, Viral/virology , Female , Humans , Limbic Encephalitis/blood , Limbic Encephalitis/cerebrospinal fluid , Limbic Encephalitis/virology , Magnetic Resonance Imaging , Male , Postoperative Complications/blood , Postoperative Complications/cerebrospinal fluid , Postoperative Complications/virology , Retrospective Studies , Roseolovirus Infections/complications , Roseolovirus Infections/virology , Seizures/blood , Seizures/cerebrospinal fluid , Seizures/virology , Viral LoadABSTRACT
Limbic encephalitis (LE) with antibodies against leucine-rich glioma inactivated protein 1 (LGI1) is an auto-antibody mediated disorder with characteristic symptoms as dysfunction of memory, faciobrachial dystonic seizures and neuropsychiatric symptoms as emotional lability. Limbic encephalitis with LGI1 antibodies has been known so far as a disease of adults. We describe the case of a 14-year-old boy presenting with typical dysfunction of memory and LGI1 antibodies. To the best of our knowledge, this is the youngest patient with LGI1 antibody mediated limbic encephalitis described so far. Improved knowledge of this autoimmune syndrome in children and adolescents permit rapid immunomodulatory treatment, which could help to prevent irreversible lesions, such as hippocampal atrophy.