Autoimmune encephalitis in glial fibrillary acidic protein astrocytopathy.

Autoimmune encephalitis due to glial fibrillar acidic protein (GFAP) astrocytopathy is a rare cause of subacute neuropsychiatric changes. In this case, a young patient presented with a viral prodrome and meningismus, followed by progressive encephalopathy and movement disorders over the span of 2 weeks. Due to his clinical trajectory, inflammatory cerebrospinal fluid (CSF) analysis, initial normal brain imaging and negative serum autoimmune encephalopathy panel, his initial diagnosis was presumed viral meningoencephalitis. The recurrence and progression of neuropsychiatric symptoms and myoclonus despite antiviral treatment prompted further investigation, inclusive of testing for CSF autoimmune encephalopathy autoantibodies, yielding a clinically meaningful, positive GFAP autoantibody. This case highlights the importance of appropriately testing both serum and CSF autoantibodies when an autoimmune encephalitic process is considered. Through this case, we review the clinical and radiographic manifestations of GFAP astrocytopathy, alongside notable pearls pertaining to this autoantibody syndrome and its management.

Case report: Atypical case of autoimmune glial fibrillary acidic protein astrocytopathy following COVID-19 vaccination refractory to immunosuppressive treatments.

A 54-year-old Japanese man presented with headache and fever the day after SARS-CoV-2 vaccination. He became deeply unconscious within a week. Brain MRI showed periventricular linear enhancements and a few spotty lesions in the cerebral white matter. Cerebrospinal fluid (CSF) testing showed mild pleocytosis. He was treated with intravenous methylprednisolone and plasma exchange. However, the white matter lesions enlarged to involve the brainstem and cerebellum, and long cord spinal lesions appeared. Anti-glial fibrillary acidic protein (GFAP) antibody was positive in the CSF and serum, and he was therefore diagnosed as autoimmune GFAP-astrocytopathy (GFAP-A). In addition, high-dose immunoglobulin therapy was administered twice, but his symptoms did not improve; the white matter lesions enlarged further, and modified Rankin Scale score increased to 5. A brain biopsy specimen showed infiltration of macrophages and CD4 + lymphocytes together with neuron and oligodendrocytic injuries and glial scar. Although GFAP-A generally responds well to steroids, the present case developed GFAP-A following SARS-CoV-2 vaccination, with refractory to intensive immunosuppressive therapy and atypical pathologic findings of infiltration of CD4 + lymphocytes and demyelination.

The discrimination between autoimmune glial fibrillary acidic protein astrocytopathy and tuberculous meningitis.

OBJECTIVE: The differential diagnosis between autoimmune glial fibrillary acidic protein astrocytopathy (AGFAPA) mimicking tuberculous meningitis and tuberculous meningitis (TBM) remains challenging in clinical practice. This study aims to identify the clinical, laboratory parameters, and clinical score systems that may be helpful in differentiating AGFAPA from TBM. METHOD: Overall 22 AGFAPA patients who were initially misdiagnosed as TBM (AGFAPA-TBM) and 30 confirmed TBM patients were included. The clinical, laboratory, imaging parameters, Thwaites systems, and Lancet consensus scoring systems (LCSS) of all patients were reviewed. Logistic regression was employed to establish a diagnostic formula to differentiate AGFAPA-TBM from TBM. The receiver operating characteristic (ROC) curve was applied to determine the best diagnostic critical point of the formula. RESULTS: Urinary retention was more frequent in AGFAPA-TBM patients (72.7% vs 33.3%, p = 0.012). A significantly lower ratio of T-SPOT. TB was noted in AGFAPA-TBM patients (9.1% vs 82.1%, p < 0.001). We found the LCSS was able to differentiate AGFAPA-TBM from TBM (AUC value 0.918, 95% CI=0.897-0.924). Furthermore, we set up a new scoring system with three variables: urinary retention, T-SPOT. TB, and cerebral imaging criteria in LCSS. The proposed diagnostic score ranges from -8 to 2, and a score of ≥ 0 was suggestive of AGFAPA-TBM (AUC value 0.938, 95% CI=0.878-0.951). CONCLUSIONS: This study is the first to evaluate the Thwaites system and LCSS in AGFAPA-TBM and TBM. We provide an alternative diagnostic formula to differentiate AGFAPA-TBM from TBM and suggest testing for GFAP antibodies to avoid misdiagnosis when this scoring system meets AGFAPA-TBM.

Overlapping Epstein-Barr virus encephalitis and autoimmune glial fibrillary acidic protein astrocytopathy.

We describe three cases of overlapping Epstein-Barr virus (EBV) Encephalitis and Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy (GFAP-A). The three cases all presented with initial symptoms of fever, headache, coma, and posture tremor of the upper limbs, then followed by limb weakness and dysuria. All of the three cases were on ventilators. Case 1 and 2 improved dramatically after intravenous methylprednisoloneand immunoglobulin treatment. However, case 3 presented dyspneic, and died from gastrointestinal hemorrhage. The GFAP-A triggered by EBV intracranial infection could initially masquerade as EBV encephalitis only, and the detection of GFAP antibody is essential for differentiation.

Metabolic profiling in the hypothalamus of aged mice.

Metabolic abnormalities are tightly connected to the perturbation of normal brain functions, thereby causing multiple neurodegenerative diseases. The hypothalamus is the master unit that controls the whole-body energy homeostasis. Thus, altered metabolic activity in the hypothalamus could be a crucial clue to better understand the development of metabolic disorders during aging. The current study aimed to investigate the changes in hypothalamic metabolites according to the aging process using gas chromatography-mass spectrometry. We identified that multiple metabolites and neurotransmitters were effectively reduced in the hypothalamus of aged mice. In addition, we observed increased levels of genes linked to the production and utilization of monocarboxylates in the aged hypothalamus, indicating the initiation of metabolic activity to produce alternative nutrient sources. Lastly, we found a reduced number of astrocytes in the hypothalamus of aged mice, suggesting that reduced nutrient availability in the hypothalamus might be associated with the decreased activity of astrocytes during aging. Collectively, the present study suggests that the deterioration of metabolic activities in the hypothalamus might be a primary cause and/or outcome of metabolic diseases associated with the aging process.

Autoimmune glial fibrillary acidic protein astrocytopathy in children: a retrospective study.

OBJECTIVE: To describe the clinical features of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy in children. METHOD: Data from 11 pediatric patients with autoimmune GFAP astrocytopathy were retrospectively analyzed. RESULTS: All of the patients showed encephalitis and meningoencephalitis or meningoencephalomyelitis with or without myelitis. 45.4% of the patients had fever, 27.3% headaches, 18.2% dizziness, 18.2% drowsiness, and 18.2% mental disorders. Cerebrospinal fluid (CSF) was detected in all patients. The white blood cell counts (WBC) (90.9%), lactic dehydrogenase levels (72.7%), protein level (36.4%), and adenosine deaminase activity (ADA) level (27.3%) were elevated, and the CSF glucose levels (72.7%) were slightly reduced. Nine patients (90%) were found to have brain abnormalities, of which five (50.0%) patients had abnormal symmetrical laminar patterns or line patterns hyperintensity lesions on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images in the basal ganglia, hypothalamus, subcortical white matter and periventricular white matter. The linear radial enhancement pattern of the cerebral white matter was only seen in two patients, with the most common being abnormal enhancement of leptomeninges (50%). Five patients had longitudinally extensive spinal cord lesions. CONCLUSION: The findings of pediatric patients with autoimmune GFAP astrocytopathy are different from previous reports.

Glial Fibrillary Acidic Protein Autoimmunity: A French Cohort Study.

BACKGROUND AND OBJECTIVES: To report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies. METHODS: We retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers. RESULTS: We identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies. DISCUSSION: GFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.

Evaluation of Traumatic Spinal Cord Injury in a Rat Model Using 99mTc-GA-5 as a Potential In Vivo Tracer.

Spinal cord injury (SCI) refers to the damage suffered in the spinal cord by any trauma or pathology. The purpose of this work was to determine whether 99mTc-GA-5, a radiotracer targeting Glial Fibrillary Acidic Protein (GFAP), can reveal in vivo the reactivation of astrocytes in a murine model with SCI. A method for the 99mTc radiolabeling of the mouse anti-GFAP monoclonal antibody GA-5 was implemented. Radiochemical characterization was performed, and radioimmunohistochemistry assays were used to evaluate the integrity of 99mTc-GA-5. MicroSPECT/CT was used for in vivo imaging to trace SCI in the rats. No alterations in the GA-5's recognition/specificity ability were observed after the radiolabeling. The GA-5's radiolabeling procedure implemented in this work offers a practical method to allow the in vivo following of this monoclonal antibody to evaluate its biodistribution and specificity for GFAP receptors using SPECT/CT molecular imaging.

Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy in Children: A Retrospective Analysis of 35 Cases.

Objective: To analyze the clinical manifestations, imaging, electroencephalography, treatment, and prognosis of 35 cases of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) in children. Methods: Children hospitalized in the Department of Neurology, Hunan Children's Hospital, China, between January 2015 and June 2021, owing to autoimmune diseases of the central nervous system were subjected to a cell-based assay (CBA). The assay identified 40 children positive for GFAP-immunoglobulin (Ig)G antibodies in the serum and/or the cerebrospinal fluid. Based on clinical manifestations and imaging characteristics, five children who were only positive for GFAP-IgG antibodies in serum were excluded, and the remaining 35 children were diagnosed with autoimmune GFAP-A. The clinical data derived from the 35 children were retrospectively analyzed. Results: A total of 35 children, including 23 males and 12 females with a mean age of 6.3 ± 0.6 years, manifested clinical symptoms of fever (62.9%), headache (42.9%), convulsions (42.9%), abnormal mental behavior (51.4%), disorders of consciousness (54.3%), visual disturbance (22.9%), ataxia (11.4%), paralysis (40%), and autonomic dysfunction (25.7%). One child exhibited only the clinical symptom of peripheral facial nerve palsy. Eleven out of 35 children were also positive for other antibodies. In addition to the common overlapping autoimmune syndromes, one case of autoimmune GFAP-A also manifested as Bickerstaff's brainstem encephalitis. Linear periventricular enhancement upon MRI was significantly less frequent in children (8.5%) than in adults. In pediatric patients, MRI contrast enhancement was principally seen in the meninges and brain lobes. Although repeated relapse (17.1%) and sequelae symptoms (20%) occurred in some cases, most children showed a favorable prognosis. Spearman's rank correlation showed that the antibody titer was not significantly associated with the severity of the initial disease conditions. Conclusions: The disease diagnosis in children seropositive for GFAP antibodies only should receive a comprehensive diagnosis based on their clinical symptoms, imaging, electroencephalographic characteristics, and treatment responses. Some patients with relapses should receive repeated gamma globulin and corticosteroid therapy or the addition of immunosuppressants to their therapeutic regimen, and slow-dose tapering of corticosteroids and extended treatment are recommended for patients with overlapping autoimmune syndromes.

Clinical, neuroradiological, diagnostic and prognostic profile of autoimmune glial fibrillary acidic protein astrocytopathy: A pooled analysis of 324 cases from published data and a single-center retrospective study.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a recently defined autoimmune meningoencephalomyelitis, associated with GFAP-IgG antibody. A pooled analysis of 324 cases from published literature and a retrospective single-center study were performed, firstly reveals the possibility that patients with myelitic lesions respond better to initial immunotherapy, but are prone to relapse, suggesting a more aggressive and long-term immunosuppressive medication for them. Moreover, our results showed using tacrolimus at maintenance stage exhibited a less tendency to relapse, providing a possibly new choice to future clinical treatments.

Autoimmune glial fibrillary acidic protein astrocytopathy resembling isolated central nervous system lymphomatoid granulomatosis.

We report two patients with meningoencephalomyelitis without evidence of extra central nervous system (CNS) involvement. Brain MRI showed linear perivascular radial gadolinium enhancement patterns and spinal cord MRI showed longitudinal extensive T2-hyperintensity lesions. Pathological findings from brain biopsies were angiocentric T-cell predominant lymphoid infiltrates that lacked Epstein-Barr virus-positive atypical B cells. The patients were initially suspected to have isolated CNS-lymphomatoid granulomatosis (LYG). Thereafter, glial fibrillary acidic protein (GFAP)-immunoglobulin G were detected in their cerebrospinal fluid. This finding suggested autoimmune GFAP astrocytopathy. We speculate there is a link between isolated CNS-LYG and autoimmune GFAP astrocytopathy.

Autopsy Case of Meningoencephalomyelitis Associated With Glial Fibrillary Acidic Protein Antibody.

BACKGROUND AND OBJECTIVES: To describe the autopsy findings and neuropathologic evaluation of autoimmune meningoencephalomyelitis associated with glial fibrillary acidic protein (GFAP) antibody. METHODS: We reviewed the clinical course, imaging, laboratory, and autopsy findings of a patient with autoimmune meningoencephalomyelitis associated with GFAP antibody who had a refractory course to multiple immunosuppressive therapies. RESULTS: The patient was a 70-year-old man who was diagnosed as GFAP antibody-associated autoimmune meningoencephalomyelitis. MRI of the head showed linear perivascular enhancement in the midbrain and the basal ganglia. Despite treatment with high-dose corticosteroids, plasma exchange, IV immunoglobulins, and cyclophosphamide, he died with devastating neurologic complications. Autopsy revealed a coexistent neuroendocrine tumor in the small intestine and diffuse inflammation in the brain parenchyma, perivascular spaces, and leptomeninges, with predominant T-cells, macrophages, and activated microglia. B-cells and plasma cells were absent. There was no astrocyte involvement with change in GFAP immunostaining. DISCUSSION: This case illustrates autoimmune meningoencephalomyelitis associated with GFAP antibody in the CSF and coexistent neuroendocrine tumor. The autopsy findings were nonspecific and did not demonstrate astrocyte involvement. Further accumulation of cases is warranted to delineate the utility and pathogenic significance of the GFAP autoantibody.

Autoimmune GFAP astrocytopathy presenting with remarkable CNS hyperexcitability and oculogyric crises.

The autoimmune GFAP astrocytopathy has been associated with meningoencephalomyelitis that usually responds to glucocorticoids. We report a 20-year-old man that developed an acute and severe meningoencephalomyelitis with remarkable CNS hyperexcitability and oculogyric crises. CSF analysis showed hypoglycorrhachia, pleocytosis, elevated ADA, and CSF-immunofluorescence characteristic of autoimmune GFAP astrocytopathy. MRI showed lesions at thalamus, corpus-callosum, dorsal pons and dentate nucleus with associated myelitis. Immunotherapy led to a full recovery, although MRI activity was observed at follow-up. CNS hyperexcitability, typically seen in other immune-mediated syndromes, represents a novel presenting form to be included as part of the clinical spectrum of this entity.

Autoimmune glial fibrillary acidic protein astrocytopathy mimicking acute disseminated encephalomyelitis: A case report.

INTRODUCTION: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an increasingly recognized type of steroid-responsive autoimmune disease of the nervous system. Defined in 2016, it is associated with the presence of anti-GFAP immunoglobulinG in the serum or cerebrospinal fluid (CSF) of affected patients. PATIENT CHARACTERISTICS: Herein, we report a case of acute neurological symptoms, including headache, fever, confusion, and paralysis of the lower extremities. CSF analysis revealed lymphocytic pleocytosis and elevated protein levels, indicating acute disseminated encephalomyelitis, and the patient was given immunotherapy. Cranial magnetic resonance imaging showed multifocal T2/fluid-attenuated inversion recovery hyperintense signal changes in the periventricular white matter, and electromyography testing showed changes consistent with severe sensorimotor neuropathy, indicating the involvement of the brain and peripheral nerves. DIAGNOSES: Finally, a diagnosis of autoimmune GFAP astrocytopathy was confirmed due to the presence of GFAP-immunoglobulinG in the patient's CSF. INTERVENTIONS: The patient was treated with one course of intravenous immunoglobulin therapy, then followed with intravenous methylprednisolone (1.0 g/d for 3 days) and oral prednisolone. OUTCOMES: At 1 week after intravenous immunoglobulin therapy, his level of consciousness improved. However, flaccid paralysis persisted without substantial improvement. CONCLUSION: In conclusion, the provision of an accurate early diagnosis and appropriate treatment are crucial for improving the prognosis of patients with autoimmune GFAP astrocytopathy. Further, this case highlights the importance of recognizing the role of peripheral nerve involvement in GFAP autoimmunity.

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles attenuate experimental autoimmune encephalomyelitis via regulating pro and anti-inflammatory cytokines.

The therapeutic effects of mesenchymal stem cells-extracellular vesicles have been proved in many inflammatory animal models. In the current study, we aimed to investigate the effect of extracellular vesicles (EVs) derived from human umbilical cord-MSC (hUCSC-EV) on the clinical score and inflammatory/anti-inflammatory cytokines on the EAE mouse model. After induction of EAE in C57Bl/6 mice, they were treated intravenously with hUCSC-EV or vehicle. The clinical score and body weight of all mice was registered every day. On day 30, mice were sacrificed and splenocytes were isolated for cytokine assay by ELISA. Cytokine expression of pro-/anti-inflammatory cytokine by real-time PCR, leukocyte infiltration by hematoxylin and eosin (H&E) staining, and the percent of glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) positive cells by immunohistochemistry were assessed in the spinal cord. Our results showed that hUCSC-EV-treated mice have lower maximum mean clinical score (MMCS), pro-inflammatory cytokines, and inflammatory score in comparison to the control mice. We also showed that hUCSC-EV administration significantly improved body weight and increased the anti-inflammatory cytokines and the frequency of Treg cells in the spleen. There was no significant difference in the percent of GFAP and MBP positive cells in the spinal cord of experimental groups. Finally, we suggest that intravenous administration of hUCSC-EV alleviate induce-EAE by reducing the pro-inflammatory cytokines, such as IL-17a, TNF-α, and IFN-γ, and increasing the anti-inflammatory cytokines, IL-4 and IL-10, and also decrease the leukocyte infiltration in a model of MS. It seems that EVs from hUC-MSCs have the same therapeutic effects similar to EVs from other sources of MSCs, such as adipose or bone marrow MSCs.

Uncommon manifestations of a rare disease: a case of autoimmune GFAP astrocytopathy.

BACKGROUND: Manifestations of intractable hyponatremia and hypokalemia in autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy have been rarely reported. CASE PRESENTATION: A 75-year-old male patient presented as the case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) and intractable hypokalemia, showed fever, fatigue, and mental disorders. Signs and symptoms of meningoencephalitis, ataxia, and cognitive abnormalities. Magnetic resonance imaging (MRI) revealed multiple white matter lesions of the central nervous system. He had GFAP-IgG in the cerebrospinal fluid (CSF). After treatment with corticosteroids, his symptoms were alleviated gradually, and the level of electrolytes was normal. However, head contrast-enhanced MRI + susceptibility-weighted imaging (SWI) showed a wide afflicted region, and the serum GFAP-IgG turned positive. Considering the relapse of the disease, ha was treated with immunoglobulin and mycophenolate mofetil (MMF) to stabilize his condition. CONCLUSION: This case showed a rare disease with uncommon manifestations, suggesting that careful examination and timely diagnosis are essential for disease management and satisfactory prognosis.