To describe a recently characterized autoimmune, inflammatory central nervous system (CNS) disorder known as autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy.
Affected patients ...present with symptoms of one or more of meningitis (headache and neck ache), encephalitis (delirium, tremor, seizures, or psychiatric symptoms), and myelitis (sensory symptoms and weakness). Optic disc papillitis (blurred vision) is common. CNS inflammation is evident in characteristic T1 postgadolinium enhancement of GFAP-enriched CNS regions, and lymphocytic cerebrospinal fluid (CSF) white cell count elevation. CSF is more reliable than serum for GFAP-immunoglobulin G (IgG) testing. Ovarian teratoma commonly coexists, particularly among patients with accompanying N-methyl-D-aspartate receptor or aquaporin-4 autoimmunity. Parainfectious autoimmunity is suspected in some other patients, though the culprit organism is rarely verified. Pathophysiologic relevance of T cells is underscored by neuropathology and cases of dysregulated T-cell function (HIV or checkpoint inhibitor cancer therapy). Corticosteroid-responsiveness is a hallmark of the disease. Relapses occur in approximately 20% of patients, necessitating transition to a steroid-sparing drug. Reported outcomes vary, though in the authors' experience, early and sustained intervention usually portends recovery.
Autoimmune GFAP astrocytopathy is a treatable autoimmune CNS disease diagnosable by GFAP-IgG testing in CSF. This disease presents opportunities to explore novel mechanisms of CNS autoimmunity and inflammation.
GAD65 neurological autoimmunity McKeon, Andrew; Tracy, Jennifer A.
Muscle & nerve,
July 2017, Letnik:
56, Številka:
1
Journal Article
Recenzirano
ABSTRACT
The glutamic acid decarboxylase 65‐kilodalton isoform (GAD65) antibody is a biomarker of autoimmune central nervous system (CNS) disorders and, more commonly, nonneurological autoimmune ...diseases. Type 1 diabetes, autoimmune thyroid disease, and pernicious anemia are the most frequent GAD65 autoimmune associations. One or more of these disorders coexists in approximately 70% of patients with GAD65 neurological autoimmunity. Neurological phenotypes have CNS localization and include limbic encephalitis, epilepsy, cerebellar ataxia, and stiff‐person syndrome (SPS), among others. Classic SPS is a disorder on the spectrum of CNS hyperexcitability which also includes phenotypes that are either more restricted (stiff‐limb syndrome) or more widespread (progressive encephalomyelitis with rigidity and myoclonus). GAD65 antibody is not highly predictive of a paraneoplastic cause for neurological disorders, but diverse cancer types have been occasionally reported. For all phenotypes, responses to immunotherapy are variable (approximately 50% improve). GAD65 autoimmunity is important to recognize for both coexisting nonneurological autoimmune associations and potential immunotherapy‐response. Muscle Nerve 56: 15–27, 2017
Seizures are a well‐recognized and often prominent manifestation of autoimmune encephalitic syndromes. Progress in detection of pathogenic neural autoantibodies has led to increased awareness of ...autoimmune causes of seizures. Clinical studies of patients with these autoantibodies have improved our understanding of the seizure characteristics, treatments, and seizure prognosis in these disorders. The International League Against Epilepsy (ILAE) Autoimmunity and Inflammation Taskforce proposes conceptual definitions for two main diagnostic entities: (a) acute symptomatic seizures secondary to autoimmune encephalitis, and (b) autoimmune‐associated epilepsy, the latter of which suggests an enduring predisposition to seizures. Such a distinction is relevant when discussing the pathophysiology, treatment, prognosis, and social consequences of these disorders. We discuss the role of biomarkers in the application of these conceptual definitions and illustrate their use in patients cared for by members of the task force.
Objective
A novel autoimmune central nervous system (CNS) disorder with glial fibrillary acidic protein (GFAP)‐IgG as biomarker was recently characterized. Here, 102 patients with GFAP‐IgG positivity ...are described.
Methods
The 102 included patients had: (1) serum, cerebrospinal fluid (CSF), or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining; (2) confirmation of IgG reactive with specific GFAP isoforms (α, ɛ, or κ) by cell‐based assays; and (3) clinical data available. Control specimens (n = 865) were evaluated by tissue (n = 542) and cell‐based (n = 323) assays.
Results
Median symptom onset age was 44 years (range = 8–103), and 54% were women. The predominant phenotype (83 patients; 81%) was inflammation of meninges, brain, spinal cord, or all 3 (meningoencephalomyelitis). Among patients, highest specificity for those phenotypes was observed for CSF testing (94%), and highest sensitivity was for the GFAPα isoform (100%). Rare GFAP‐IgG positivity was encountered in serum controls by tissue‐based assay (0.5%) or cell‐based assay (1.5%), and in CSF controls by cell‐based assay (0.9%). Among patients, striking perivascular radial enhancement was found on brain magnetic resonance imaging in 53%. Although cases frequently mimicked vasculitis, angiography was uniformly negative, and spinal imaging frequently demonstrated longitudinally extensive myelitic lesions. Diverse neoplasms encountered were found prospectively in 22%. Ovarian teratoma was most common and was predicted best when both N‐methyl‐D‐aspartate receptor–IgG and aquaporin‐4–IgG coexisted (71%). Six patients with prolonged follow‐up had brisk corticosteroid response, but required additional immunosuppression to overcome steroid dependency.
Interpretation
GFAPα‐IgG, when detected in CSF, is highly specific for an immunotherapy‐responsive autoimmune CNS disorder, sometimes with paraneoplastic cause. Ann Neurol 2017;81:298–309
Objective
To evaluate the incidence and prevalence of autoimmune encephalitis and compare it to that of infectious encephalitis.
Methods
We performed a population‐based comparative study of the ...incidence and prevalence of autoimmune and infectious encephalitis in Olmsted County, Minnesota. Autoimmune encephalitis diagnosis and subgroups were defined by 2016 diagnostic criteria, and infectious encephalitis diagnosis required a confirmed infectious pathogen. Age‐ and sex‐adjusted prevalence and incidence rates were calculated. Patients with encephalitis of uncertain etiology were excluded.
Results
The prevalence of autoimmune encephalitis on January 1, 2014 of 13.7/100,000 was not significantly different from that of all infectious encephalitides (11.6/100,000; p = 0.63) or the viral subcategory (8.3/100,000; p = 0.17). The incidence rates (1995–2015) of autoimmune and infectious encephalitis were 0.8/100,000 and 1.0/100,000 person‐years, respectively (p = 0.58). The number of relapses or recurrent hospitalizations was higher for autoimmune than infectious encephalitis (p = 0.03). The incidence of autoimmune encephalitis increased over time from 0.4/100,000 person‐years (1995–2005) to 1.2/100,000 person‐years (2006–2015; p = 0.02), attributable to increased detection of autoantibody‐positive cases. The incidence (2.8 vs 0.7/100,000 person‐years, p = 0.01) and prevalence (38.3 vs 13.7/100,000, p = 0.04) of autoimmune encephalitis was higher among African Americans than Caucasians. The prevalence of specific neural autoantibodies was as follows: myelin oligodendrocyte glycoprotein, 1.9/100,000; glutamic acid decarboxylase 65, 1.9/100,000; unclassified neural autoantibody, 1.4/100,000; leucine‐rich glioma‐inactivated protein 1, 0.7/100,000; collapsin response‐mediator protein 5, 0.7/100,000; N‐methyl‐D‐aspartate receptor, 0.6/100,000; antineuronal nuclear antibody type 2, 0.6/100,000; and glial fibrillary acidic protein α, 0.6/100,000.
Interpretation
This study shows that the prevalence and incidence of autoimmune encephalitis are comparable to infectious encephalitis, and its detection is increasing over time. Ann Neurol 2018;83:166–177
As a result of the burgeoning growth of disease-specific neural autoantibody markers available for diagnostic patient evaluation, there has been increasing awareness of autoimmune central nervous ...system (CNS) disorders in hospital practice. Hospital-based neurologists have also taken great interest in these disorders since many occur in the setting of an occult systemic cancer which can be detected and treated at an early stage, and many affected patients are responsive to immunotherapy. Associated neurological disorders are typically subacute in onset, some are common or classic (eg, limbic encephalitis, cerebellar degeneration), but others have atypical or multifocal presentations. For patients with a suspected paraneoplastic disorder, many and costly oncological evaluations may be required for diagnosis. Comprehensive serological and cerebrospinal fluid (CSF) evaluation for neural autoantibodies may permit a focused cancer evaluation (eg, antineuronal nuclear antibody type 1 ANNA-1 is associated with small cell lung carcinoma), and in some circumstances may indicate the likelihood of a good response to therapy (eg, voltage-gated potassium channel complex antibody) or poor neurological prognosis (eg, purkinje cell cytoplasmic antibody type 1 antiYo). Positron-emission tomography–computed tomography (PET-CT) imaging of trunk may increase the diagnostic yield for certain cancers where other modalities have been negative. For some patients, rapid treatment with immunotherapy may facilitate marked improvement, or full recovery; multiple sequential trials of one or more of steroids, intravenous immunoglobulin or plasma exchange, or combination therapy are often required. For patients with N-methyl-d-aspartate receptor antibody encephalitis, early treatment with immunosuppressants and weeks or months of supportive intensive care may additionally be required. One or more of clinical examination, electroencephalogram (including video telemetry), and imaging provide objective parameters to which posttreatment outcomes can be compared.
Autoimmune Encephalitis Misdiagnosis in Adults Flanagan, Eoin P; Geschwind, Michael D; Lopez-Chiriboga, A Sebastian ...
JAMA neurology,
01/2023, Letnik:
80, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Autoimmune encephalitis misdiagnosis can lead to harm.
To determine the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis.
This retrospective multicenter study ...took place from January 1, 2014, to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics including Mayo Clinic (n = 44), University of Oxford (n = 18), University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), University of Washington in St Louis (n = 6), and University of Utah (n = 4). Inclusion criteria were adults (age ≥18 years) with a prior autoimmune encephalitis diagnosis at a participating center or other medical facility and a subsequent alternative diagnosis at a participating center. A total of 393 patients were referred with an autoimmune encephalitis diagnosis, and of those, 286 patients with true autoimmune encephalitis were excluded.
Data were collected on clinical features, investigations, fulfillment of autoimmune encephalitis criteria, alternative diagnoses, potential contributors to misdiagnosis, and immunotherapy adverse reactions.
A total of 107 patients were misdiagnosed with autoimmune encephalitis, and 77 (72%) did not fulfill diagnostic criteria for autoimmune encephalitis. The median (IQR) age was 48 (35.5-60.5) years and 65 (61%) were female. Correct diagnoses included functional neurologic disorder (27 25%), neurodegenerative disease (22 20.5%), primary psychiatric disease (19 18%), cognitive deficits from comorbidities (11 10%), cerebral neoplasm (10 9.5%), and other (18 17%). Onset was acute/subacute in 56 (52%) or insidious (>3 months) in 51 (48%). Magnetic resonance imaging of the brain was suggestive of encephalitis in 19 of 104 patients (18%) and cerebrospinal fluid (CSF) pleocytosis occurred in 16 of 84 patients (19%). Thyroid peroxidase antibodies were elevated in 24 of 62 patients (39%). Positive neural autoantibodies were more frequent in serum than CSF (48 of 105 46% vs 7 of 91 8%) and included 1 or more of GAD65 (n = 14), voltage-gated potassium channel complex (LGI1 and CASPR2 negative) (n = 10), N-methyl-d-aspartate receptor by cell-based assay only (n = 10; 6 negative in CSF), and other (n = 18). Adverse reactions from immunotherapies occurred in 17 of 84 patients (20%). Potential contributors to misdiagnosis included overinterpretation of positive serum antibodies (53 50%), misinterpretation of functional/psychiatric, or nonspecific cognitive dysfunction as encephalopathy (41 38%).
When evaluating for autoimmune encephalitis, a broad differential diagnosis should be considered and misdiagnosis occurs in many settings including at specialized centers. In this study, red flags suggesting alternative diagnoses included an insidious onset, positive nonspecific serum antibody, and failure to fulfill autoimmune encephalitis diagnostic criteria. Autoimmune encephalitis misdiagnosis leads to morbidity from unnecessary immunotherapies and delayed treatment of the correct diagnosis.
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