Autoimmune glial fibrillary acidic protein astrocytopathy …

Neuroimmunology

Updated 08.15.2024
Released 12.26.2019
Expires For CME 08.15.2027

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy

Authors: Andrew McKeon MD, Michael Gilligan MD

See Contributor Disclosures

Editor: Francesc Graus MD PhD

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy

In This Article

Quick Link

Introduction

Overview

Autoimmune glial fibrillary acidic protein astrocytopathy is a form of monophasic or relapsing steroid-responsive meningoencephalomyelitis often accompanied by a hallmark radial periventricular brain MRI enhancement pattern and inflammatory cerebrospinal fluid with lymphocytic pleocytosis. GFAP-IgG was first described at the Mayo Clinic in the United States and subsequently confirmed by multiple international groups (39; 10).

Key points

	• Autoimmune GFAP astrocytopathy manifests as a meningoencephalomyelitis (or limited form thereof) with dramatic steroid-responsiveness. Early relapses may occur if steroids are deescalated and discontinued quickly.
	• Brain MRI may reveal a typical pattern of radial gadolinium enhancement; the spine MRI abnormalities are often hazy and longitudinally-extensive T2 hyperintensities with central cord enhancement.
	• CSF testing for GFAP-IgG is more specific. Both the characteristic astrocytic, filamentous immunofluorescence pattern of CNS tissue staining (meeting all criteria) and positivity for GFAP-alpha isoform-specific-IgG are required for diagnosis.
	• In most cases, the etiology is unknown, but post-herpes viral may account for many cases. In 25% of patients a neoplasm is detected after neurologic symptoms onset (most common being ovarian teratoma).

Historical note and terminology

In 1999, Uchida and colleagues identified glial fibrillary acidic protein antibodies in the serum and cerebrospinal fluid samples of two pug dogs with canine necrotizing encephalitis, a severe and rapidly progressive form of encephalitis characterized by mood alteration, ataxia and seizures, and features of necrosis and lymphocytic inflammation in pathological studies (36). Further studies confirmed the presence of GFAP-IgG in larger cohorts with similar clinical phenotype (30).

In humans, GFAP-IgG was described as a biomarker of meningoencephalomyelitis in 2016 by Fang and associates in a cohort of 16 patients who presented with subacute cognitive and behavioral impairment, inflammatory CSF, pathology consistent with lymphocytic inflammation, and robust steroid therapy-responsiveness (07). Some of those cases had been previously reported, though utilizing pathologic descriptors for nomenclature, such as “nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM)” (02) or “chronic microglial encephalomyelitis” (01).

Clinical manifestations

Presentation and course

	• Autoimmune GFAP astrocytopathy presentation is subacute (over days to a few weeks).
	• Flu-like symptoms are common prior to onset of neurologic symptoms.
	• Headache, neck stiffness, blurred vision, altered mental status, seizures, and psychiatric symptoms are the most common presenting manifestations.

The most common clinical phenotype is consistent with meningoencephalitis, which may or may not be associated with myelitis (12). On the contrary, isolated myelitis is rarely found (05; 29). Onset is acute or subacute in the majority of patients, and prodromal flu-like symptoms with fever, cough, rhinorrhea, and sore throat are commonly reported. Subsequently, patients develop meningeal symptoms (headache, neck-stiffness, vomiting), encephalopathy, seizures, psychiatric disorders, and tremor. Hyponatremia has been reported at presentation in 23% to 50% of patients (10; 17). Ataxia and other movement disorders (including parkinsonism) are less commonly part of the clinical phenotype but may be more frequent in older patients (18). Dysautonomia occurs in 25% of patients (08). Rhombencephalitis featured prominently (65%) in a French cohort of GFAP astrocytopathy with prominent eye movement disorders, dysphagia, and cerebellar signs (10). Peripheral neuropathy occurs in up to 24% (typically as part of a multifocal syndrome) and presents usually with a lower-limb-predominant axonal or demyelinating motor neuropathy (27; 10; 04). Given the prodromal symptoms and meningeal involvement, patients are frequently diagnosed speculatively with “test negative” meningitis of infectious etiology. When spinal cord involvement occurs, it manifests with predominant bowel and bladder dysfunction and sensory symptoms, whereas motor impairment is milder in comparison to other autoimmune myelopathies (such as classical neuromyelitis optica). Ocular findings include blurred vision with optic disc edema but intracranial pressure is generally normal or only slightly elevated (03). Isolated new onset daily headache with autoimmune GFAP-compatible MRI findings has been reported (31).

Median age at onset of autoimmune glial fibrillary acidic protein astrocytopathy is in the fifth decade, although patients of all ages may be affected (08; 05; 10); both sexes are affected equally. Children account for about 10% of patients. Clinical phenotypes in the pediatric and adult populations appear to be the same (05; 15; 10).

Neoplasia is detected in one third, the majority after neurologic symptom-onset (08; 10). The most common neoplasm reported is ovarian teratoma, occurring in women usually when n-methyl-D-aspartate receptor (NMDA-R)-IgG, aquaporin-4 (AQP4)-IgG, or both are in coexistence. The positive predictive value for teratoma when all three antibodies coexist is 71% (08), though approximately 50% of NMDA-R encephalitis patients in general have teratoma detected. Other diverse neoplasms have been described, including adenocarcinomas, lymphoma, renal cell carcinoma, and others. (08; 05; 10).

Although the coexistence of AQP4-IgG seems not to influence the clinical phenotype of glial fibrillary acidic protein astrocytopathy, patients with NMDAR-IgG and GFAP-IgG manifest with typical features of NMDA-R-encephalitis (08; 40). Coexisting autoantibodies less frequently reported include those specific for glutamic acid decarboxylase 65, striational, ganglionic acetylcholine receptors, Purkinje cell cytoplasmic antibody type 1 (PCA-1 or anti-Yo, seen with ovarian adenocarcinoma), antineuronal nuclear antibody type 1 (ANNA-1 or anti-Hu, seen with small-cell lung cancer), leucine-rich glioma inactivated 1, contactin-associated protein-like 2, gamma-aminobutyric acid A, myelin oligodendrocyte glycoprotein (MOG), and voltage gated calcium channels (08; 20; 24; 40).

Prognosis and complications

Autoimmune GFAP astrocytopathy may be monophasic with complete or incomplete recovery after steroid therapy. A relapsing-remitting course has been described in 20% to 50% of the patients who have required long-term immunosuppression, especially if the initial steroid treatment is tapered early on (08; 05; 19). Progressive neurologic decline has been described in patients that have not received any immunotherapy (05; 20). Although limited prognostic factors have been identified to date, a pooled analysis of published cases suggests that the presence of myelitic lesions in GFAP autoimmunity is associated with a better response to initial immunotherapy, but also higher risk of subsequent relapse compared to cases without myelitis (38). Overall, the outcome is generally favorable if patients are treated with corticosteroids early, at high doses and for long periods. The outcomes are worse in patients not treated with immunosuppression (deaths have been described), with underlying malignancies or coexisting autoimmunity, as seen in the cases of NMDAR encephalitis. In contrast to reports from other countries, Chinese patients had severe disease and less immunotherapy-responsiveness. It is not apparent whether this was due to delayed initiation of therapy in erstwhile idiopathic cases, more severe disease among an Asian population, or other factors yet to be unearthed (24; 44).

Clinical vignette

Prior to the discovery of GFAP-IgG as a biomarker of autoimmune CNS disease, a 51-year-old man presented with subacute (over 2 months) cognitive impairment, tremor, and gait imbalance. He also reported a prodrome of new onset chronic daily headache, abdominal constipation, and urinary retention. On examination, he had diffuse hyperreflexia, significant action and rest tremor, and intermittent myoclonus.

His brain MRI demonstrated T2 signal abnormalities and enhancing linear lesions in a periventricular distribution (see below image A-B) The spinal cord MRI revealed T2-hyperintense lesions involving the cervical and thoracic segments (see below image C-D). His CSF was remarkable for lymphocytic pleocytosis (212 cells/mcL [normal, ≤ 5], 97% lymphocytes), elevated protein (145 mg/dL [normal, ≤ 35]), and six CSF-exclusive oligoclonal bands (normal, < 4). A CT-scan of his entire trunk did not reveal systemic inflammation or malignancy. Histological examination of right frontal brain tissue after biopsy revealed microglial nodules and lymphocytic inflammation, without evidence of vasculitis or granulomatous disease. The patient received a course of IV methylprednisolone 1 g daily for 5 days, followed by oral prednisone taper (60 mg/kg for 1 month, taper over a total of 4 months). Five months later, during the taper (while on prednisone 10 mg per day) he had reaggravation of his symptoms. His steroids were increased again at 60 mg/day and long-term immunosuppression was initiated with mycophenolate mofetil (500 mg twice per day for 1 month followed by 1000 mg twice per day). The patient reported a complete recovery of cognitive and behavioral symptoms after 3 months whereas subtle gait sensory ataxia and diffuse hyperreflexia were still evident after two years of clinical and radiological surveillance. The steroids were eventually tapered off over 1 year starting 3 months after the initiation of mycophenolate mofetil. Extensive evaluations for malignancy were unrevealing. Follow-up brain imaging demonstrated complete resolution of enhancement and mild reduction of the T2-hyperintense lesion burden. The spinal cord follow-up MRI revealed moderate atrophy of the cervical and thoracic portions but without signal abnormalities (see image E).

Autoimmune GFAP astrocytopathy patient imaging

(A) Brain MRI with FLAIR sequences revealing hyperintense lesions in the periventricular white matter of both hemispheres, with postgadolinium radial enhancement in T1 sequences (B). (C) Thoracic spine MRI with sagittal T2 images ...

This patient was retrospectively diagnosed, after autoantibody discovery, with autoimmune GFAP astrocytopathy on the basis of GFAP-IgG detection in both CSF and serum samples.

This description is of a real GFAP-IgG positive patient; some of the disease course and treatment details were altered for better disease illustration.

Biological basis

• The etiology and pathobiology of autoimmune GFAP astrocytopathy are poorly understood. The GFAP-IgG antibody itself should not be pathogenic but may be a surrogate marker of anti-GFAP T cell effectors.

The glial fibrillary acidic protein is the main constituent of intermediate filament type 3 in astrocytes and a key component of the astrocyte’s cytoskeleton participating both in cell structure (eg, cellular integrity, resilience) and function (signal transduction) (25). GFAP is also important in astrocytic regeneration, motility, and migration (33; 22).

So far, 10 different GFAP isoforms have been identified (16). For diagnostic purposes of GFAP-IgG, the alpha and epsilon isoforms are currently used (see below in Diagnostic workup). At the Mayo Clinic, the alpha isoform alone is currently used for antigen-specific autoantibody-diagnosis (08), whereas Long and colleagues use both alpha and epsilon, as they have found some patients with GFAP-IgG specific solely for the epsilon isoform (24). The alpha isoform seems to be the most widely expressed and can be found in the astrocytes in the brain, spinal cord, and in the peripheral nervous system. The epsilon isoform is most abundant in neural progenitor niches in periventricular regions, the hippocampus, and the central spinal cord (16).

Etiology and pathogenesis

Etiology. Similar to other autoimmune diseases, in most cases of GFAP autoimmunity the disease trigger cannot be identified. Paraneoplastic cases are described and account for 25% to 30% of cases. Accompanying neoplasms, such as teratomas, are known to express GFAP, suggesting a tumor antigen-driven immune response that targets GFAP, initiated in the tumor bed and then targeting the central nervous system (05; 43). In the same context, a few cases have also been reported after immune checkpoint inhibitor therapies for cancer (08; 05).

EBV DNA has been detected in CSF in some reported cases, indicating possible evolution of autoimmune GFAP astrocytopathy alongside or in the wake of EBV encephalitis. Other post-herpes autoimmune GFAP encephalitides include post-herpes simplex virus type 1 or and post-varicella zoster virus (05; 23; 37), suggesting that antigen release secondary to a CNS viral infection might trigger antigen-specific autoimmunity as seen in cases of NMDA-R encephalitis (21). SARS-CoV-2 infection has also been reported as a trigger (34).

The intracellular location of GFAP suggests that GFAP-IgG is a biomarker of the disease without pathogenic potential, which would predict cytotoxic (CD8+) T cells as disease effectors of this disease. In an animal model of GFAP autoimmunity, Sasaki and colleagues demonstrated the role of GFAP-specific CD8 T cells in causing CNS inflammation targeting both the gray and white matter of the brain and spinal cord (28). The composition and location of the lesions and the disease course were dependent on the disease trigger (spontaneous vs. viral triggers). In humans, reported HLA associations include HLA-A*3303 and HLA-DBP1*0501, with carriers of HLA-A*3303 having a longer hospital stay than non-carriers (32). Some insights have also been provided by available histopathology. A study of eight patients reported marked perivascular lymphocytic infiltration of cerebral white matter (42). In seven of eight, CD8+ cytotoxic T cells were predominant, particularly adjacent to dystrophic neurons and astrocytes. Macrophage infiltrates were also prominent. A prior study from the same group reported four patients with evidence of extensive perivascular inflammation along with microglial activation (24). The infiltrates were characterized by perivascular B cells and intraparenchymal T cells as well as antibody-secreting cells.

A collaborative U.S.-European study reported 11 human cases (two autopsies and nine CNS biopsies) and one pug dog case (11). The authors reported lymphocytic infiltrates predominating, though one human autopsy case also had granulomatous inflammation (11). In humans, lymphocytic infiltrates were composed of B and T cells, including tissue-resident memory T cells. Astrocytic damage was absent in these later stage human cases, but CD8+/perforin+/granzyme staining adjacent to astrocytes indicated the influence of cytotoxic T cells. A prominent immunoreactivity of astrocytes with the complement factor C4d was also observed. In contrast, the earlier-stage GFAP-IgG positive pug dog encephalitis showed astrocyte damage early in the disease course. The authors hypothesized that early in the disease course cytotoxic T cell and possibly complement-mediated astrocytic damage occurs, but that astrocytic regeneration occurs later in the disease course. This may explain the clinical recovery generally encountered with this disease, which contrast with many other cytotoxic T cell mediated diseases (eg, anti-Yo, ataxia). The cytokine profile of patients with GFAP autoimmunity is enriched for factors associated with the tumor necrosis factor-signaling pathway, as is also the case in aquaporin-4-positive NMOSD. Some cytokines such as MIP-3α have demonstrated an association with clinical severity in GFAP IgG autoimmunity (09).

Differential diagnosis

In patients with prominent meningeal involvement and encephalitis, an infectious meningitis or meningoencephalitis is high in the differential diagnosis, especially in patients with prodromal symptoms (41). Given the subacute presentation, viral or mycobacterial meningitis are more probable in the differential diagnosis than bacterial. Other considerations include neurosarcoidosis and other inflammatory CNS conditions, which can also present with similar MRI findings. Screening for inflammatory changes elsewhere in the body with a CT or PET-CT might be useful in cases of sarcoidosis. CNS lymphoma and meningeal carcinomatosis are also part of the differential diagnosis as is CNS vasculitis and lymphomatoid granulomatosis. In the past it is likely that some GFAP astrocytopathy cases have been diagnosed as “microvascular vasculitis”, with a negative angiogram and steroid-responsiveness (08). When the clinical presentation is mainly characterized by subacute cognitive decline together with movement disorders such as tremor or myoclonus, also rapidly evolving neurodegenerative diseases and Creutzfeldt-Jakob disease could be considered even though the CSF changes point toward an infectious/inflammatory disease.

In patients presenting with myelitis and blurred vision, neuromyelitis optica or MOG-IgG related autoimmunity are often considered in the differential diagnosis, as is neurosarcoidosis. Patients with GFAP-IgG-associated myelitis have a milder myelopathic presentation than AQP4-IgG seropositive patients and a more subacute course (29). In autoimmune GFAP astrocytopathy, patients present with papillitis with preserved vision. This presentation contrasts with the vision loss (at least temporary) and eye pain accompanying AQP4 and MOG autoimmune CNS disorders (03).

Association between disorders of T-cell function and GFAP autoimmunity have been reported. These include HIV infection, chronic lymphopenia, and exposure to immune checkpoint inhibitors, and they were observed in 23% of the total cohort (08; 10).

Diagnostic workup

• CSF testing for white cell count and GFAP-IgG is critical. Serum antibody testing does not suffice.

GFAP-IgG in the CSF of patients detected by both tissue-based immunofluorescence assays showing the characteristic pattern of immune-fluorescence on CNS tissue with filamentous staining of the ependymal/sub-ependymal and pial/sub-pial regions and the myenteric plexus as well as a confirmation by a GFAP-specific transfected-cell-based assay are necessary to make the serological diagnosis. CNS-tissue staining by indirect immunofluorescence using patients’ samples may sometimes reveal a GFAP-like pattern with linear ependymal and subependymal staining with limited parenchymal involvement and/or without myeneteric plexus staining.

Indirect immuno-fluorescence assay on a composite of mouse tissues (brain, gastric mucosa, and kidney)

GFAP-IgG positive patient (A-C): (A) hippocampal filamentous staining of the pia and subpia; (B) prominent staining of the ependymal and subependymal regions in the periventricular tissue; (C) myenteric plexus IgG-binding. GFAP-Ig...

These patients do not have GFAP-IgG and are negative by GFAP-specific cell-binding assays, showcasing the necessity of both testing platforms for accurate diagnosis. In a patient with the right clinical phenotype of meningoencephalomyelitis and no CSF available, serum positivity for GFAP-IgG might be sufficient. In the Mayo Clinic cohorts, all patients had antibody specificities for the GFAP-alpha isoform with or without GFAP-epsilon isoform positivity, whereas in a clinical cohort by Long and colleagues there were patients that had antibodies reacting only with the GFAP-epsilon isoform. Serum positivity alone may yield false positive results as well as only antigen-specific assays without strict detection criteria, as mentioned above. The titer does not predict disease severity (08).

CSF analysis shows abnormalities in 54% to 90% of cases (05; 20). Lymphocytic pleocytosis is reported in 85% to 100% (05; 24) and elevated protein in about 80% (05); CSF-exclusive oligo-clonal bands are found in up to 77% of patients (08; 10). When performed, EEG generally shows nonspecific abnormalities and diffuse slow waves, whereas epileptic discharges are rarely found. In a single pediatric case, extreme delta brush has been reported (35).

Brain MRI is abnormal in 42% to 51% of patients (05; 20; 10) and shows T2-hyperintensities involving the subcortical white matter, periventricular areas, the basal ganglia, hypothalamus, brainstem, and the cerebellum. In about 50% of cases, the brain MRI shows a characteristic pattern with linear perivascular gadolinium enhancement, perpendicular to the ventricles (08; 05; 20). This radial enhancement is considered to be a radiological hallmark of this disease, although not a pathognomonic sign because it can also be found in other neurologic conditions such as neurosarcoidosis, CNS vasculitis, and others. Although classically periventricular, linear radial enhancement on MRI can also be observed infratentorially within in the brainstem (26). Reversible lesions in the splenium of the corpus callosum have emerged as an additional radiological feature associated with GFAP-IgG autoimmunity (14). Ten percent of patients from a French cohort demonstrated reversible splenial lesions with restricted diffusion on MRI imaging similar to that observed in mild encephalopathy/encephalopathy with reversible splenial lesion (MERS) syndrome (10).

Leptomeningeal, punctate, serpentine, and ependymal enhancement have also been reported. In the spinal cord MRIs, the most common abnormalities seen are T2-hyperintense longitudinally extensive lesions, sometimes ill-defined with linear or hazy enhancement along the course of the central canal (29).

Every patient that is diagnosed with GFAP-IgG autoimmunity needs to have a cancer screening according to age, sex, and risk factors. A whole-body CT or PET scan should be considered, as multiple neoplasms have been found in the adult population. In women, a pelvic ultrasound should be part of the work-up, as ovarian teratomas are the neoplasms most often encountered. A mammogram in women and a testicular ultrasound in men should complete the cancer screening, when appropriate.

Management

• Corticosteroids are the mainstay of treatment for autoimmune GFAP astrocytopathy.

To date, there are no prospective studies of treatments for autoimmune GFAP astrocytopathy. However, there are some limited retrospective studies and expert opinion recommendations (class 4 evidence). This disease is characterized by remarkable steroid responsiveness. The authors recommend initial intravenous high-dose steroids (IV methylprednisolone) with subsequent oral or directly high-dose oral steroids (prednisone 1 mg/kg or equivalent). Initial high-dose steroids should be continued for 3 to 6 months before tapering, as early relapses happen if steroids are tapered prematurely, with clinical and radiological improvement documented before. For prednisone, we suggest decreasing by 10 mg/month until 10 mg, followed by 1 mg/month taper until cessation. Long-term steroid use should be accompanied by PCP prophylaxis and osteoporosis prophylaxis. Intravenous immunoglobulin and plasma exchange have been used and could be considered options in patients with an absolute contraindication to steroids, though IVIg may not be as effective in some patients (13). More than 70% of patients respond well to first-line immunotherapy (05; 19; 10).

In the acute phase for severe cases (decreased level of consciousness, dysautonomia, refractory seizures) intensive care unit admission may be required for airway protection and hemodynamic stabilization.

In those patients with relapsing-remitting courses after steroid withdrawal (20% to 50%) a steroid-sparing agent can be introduced (08; 05; 24; 19). Long-term treatments include classic immunosuppressants such as azathioprine or mycophenolate mofetil. The authors have primarily treated patients with mycophenolate mofetil. Depending on severity, availability and tolerance methotrexate and cyclophosphamide might be other considerations. A small cohort of patients had good responses to tacrolimus (38). The correct duration of the treatment is unknown, but the authors suggest 2 to 5 years before considering cessation. In cases that relapse after discontinuation of immunosuppression, long-term immunosuppression should be considered. If a concomitant neoplasm is found, cancer treatment is necessary as soon as possible to also optimize neurologic therapeutic results and outcomes.

Outcomes

Patients with GFAP-IgG autoimmunity when appropriately treated have a good prognosis, with a median modified Rankin score of 2 at 20 months follow-up in a Mayo Clinic cohort (08). This was corroborated by a French series in which 89% of patients had good outcome (Rankin score < 2) with a median follow-up of 14 months (10). Progressive neurologic decline and death has been reported in patients, especially if not undergoing treatment (05). The outcomes vary among different studies, and in the study by Long and colleagues there were patients with worse outcome (24); it is not clear if this was dependent on diagnostic delay, treatment modalities, or a more severe disease in an Asian population. In general, however, GFAP astrocytopathy is characterized by a marked response to steroid therapy (05; 19). In cases of coexisting autoimmunity targeting the NMDAR, the prognosis is similar to patients with NMDAR encephalitis. In paraneoplastic cases, the underlying malignancy may dictate prognosis.

References

01: Aksamit AJ, Weinshenker B, Parisi J. Chronic microglial encephalomyelitis (CME). Ann Neurol 2012;72(Suppl 16):S110.
02: Caselli RJ, Boeve BF, Scheithauer BW, O’Duffy JD, Hunder GG. Nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM): a reversible form of encephalopathy. Neurology 1999;53(7):1579-81. PMID 10534272
03: Chen JJ, Aksamit AJ, McKeon A, et al. Optic disc edema in glial fibrillary acidic protein autoantibody-positive meningoencephalitis J Neuroophthalmol 2018;38(3):276-81. PMID 29210929
04: Deng B, Wang J, Qiu Y, et al. Clinical and electrophysiological characteristics of peripheral neuropathy in autoimmune glial fibrillary acidic protein astrocytopathy: an observational study and literature review. Ther Adv Neurol Disord 2023; 7(16). PMID 37057197
05: Dubey D, Hinson SR, Jolliffe EA, et al. Autoimmune GFAP astrocytopathy: prospective evaluation of 90 patients in 1 year. J Neuroimmunol 2018a;321:157-63. PMID 29793728
06: Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018b;83(1):166-77. PMID 29293273
07: Fang B, McKeon A, Hinson SR, et al. Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoencephalomyelitis. JAMA Neurol 2016;73(11):1297-307. PMID 27618707
08: Flanagan EP, Hinson SR, Lennon VA, et al. Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: analysis of 102 patients. Ann Neurol 2017;81(2):298-309. PMID 28120349
09: Fu CC, Huang L, Xu LF, et al. Serological biomarkers in autoimmune GFAP astrocytopathy. Front Immunol 2022;13:957361. PMID 35983033
10: Gravier-Dumonceau A, Ameli R, Rogemond V, et al. Glial fibrillary acidic protein autoimmunity: a French cohort study. Neurology 2022;98(6):e653-68.** PMID 34799461
11: Guo Y, Endmayr V, Zekeridou A, et al. New insights into neuropathology and pathogenesis of autoimmune glial fibrillary acidic protein meningoencephalomyelitis. Acta Neuropathol 2024;147(1):31. PMID 38310187
12: Hagbohm C, Ouellette R, Flanagan EP, et al. Clinical and neuroimaging phenotypes of autoimmune glial fibrillary acidic protein astrocytopathy: A systematic review and meta-analysis. Eur J Neurol 2024;31(7):e16284. PMID 38506182
13: Heide ES, Chaudhari A, Pirverdian A, Lai S, Courtney A. Failure of IVIG in steroid-responsive autoimmune glial fibrillary acidic protein astrocytopathy: a case report. Mult Scler Relat Disord 2021;51:102933. PMID 33866078
14: Héraud C, Capet N, Levraut M, et al. Glial fibrillary acidic protein (GFAP) astrocytopathy presenting as mild encephalopathy with reversible splenium lesion. Neurol Ther 2022;11(1):499-505. PMID 34843090
15: Huang H, Bai K, Fu Y, et al. Glial fibrillary acidic protein astrocytopathy in pediatric patients: a retrospective study. Front Pediatr 2021;8:626564. PMID 33569363
16: Kamphuis W, Mamber C, Moeton M, et al. GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS One 2012;7(8):e42823. PMID 22912745
17: Ke G, Jian S, Yang T, Zhao X. Clinical characteristics and MRI features of autoimmune glial fibrillary acidic protein astrocytopathy: a case series of 34 patients. Front Neurol 2024;15:1375971. PMID 38585352
18: Kimura A, Takekoshi A, Shimohata T. Characteristics of movement disorders in patients with autoimmune GFAP astrocytopathy. Brain Sci 2022;12(4):462. PMID 35447992
19: Kimura A, Takekoshi A, Yoshikura N, Hayashi Y, Shimohata T. Clinical characteristics of autoimmune GFAP astrocytopathy. J Neuroimmunol 2019;332:91-8. PMID 30991306
20: Iorio R, Damato V, Evoli A, et al. Clinical and immunological characteristics of the spectrum of GFAP autoimmunity: a case series of 22 patients. J Neurol Neurosurg and Psychiatry 2018;89(2):138-46. PMID 28951498
21: Leypoldt F, Titulaer MJ, Aguilar E, et al. Herpes simplex virus-1 encephalitis can trigger anti-NMDA receptor encephalitis: case report. Neurology 2013;81(18):1637-9. PMID 24089390
22: Li D, Liu X, Liu T, et al. Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes. Glia 2020;68(5):878-97. PMID 31626364
23: Li J, Xu Y, Ren H, Zhu Y, Peng B, Cui L. Autoimmune GFAP astrocytopathy after viral encephalitis: a case report. Mult Scler Relat Disord 2018;21:84-7. PMID 29499442
24: Long Y, Liang J, Xu H, et al. Autoimmune glial fibrillary acidic protein astrocytopathy in Chinese patients: a retrospective study. Eur J Neurol 2018;25(3):477-83. PMID 29193473
25: Middeldorp J, Hol EM. GFAP in health and disease. Prog Neurobiol 2011;93(3):421-43. PMID 21219963
26: Mirian A, Sharma M, Budhram A. Linear radial brainstem enhancement in autoimmune glial fibrillary acidic protein astrocytopathy. JAMA Neurol 2022;1;79(1):82-3. PMID 34747976
27: Paul P, McKeon A, Pittock SJ, et al. GFAP IgG associated inflammatory polyneuropathy. J Neuroimmunol 2020;15;343:577233. PMID 32272393
28: Sasaki K, Bean A, Shah S, et al. Relapsing-remitting central nervous system autoimmunity mediated by GFAP-specific CD8 T cells. J Immunol 2014;192(7):3029-42. PMID 24591371
29: Sechi E, Morris PP, McKeon A, et al. Glial fibrillary acidic protein IgG related myelitis: Characterisation and comparison with aquaporin-4-IgG myelitis. J Neurol Neurosurg Psychiatry 2019;90(4):488-90. PMID 30032117
30: Shibuya M, Matsuki N, Fujiwara K, et al. Autoantibodies against glial fibrillary acidic protein (GFAP) in cerebrospinal fluids from pug dogs with necrotizing meningoencephalitis. J Vet Med Sci 2007;69(3):241-5. PMID 17409638
31: Shosha E, Connolly C, Budhram A. Case report: Headache as the sole neurological symptom in autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. Front Neurol 2024;15:1366263. PMID 38699059
32: Shu Y, Huang R, Li Q, et al. Autoimmune glial fibrillary acidic protein astrocytopathy is associated with HLA-A*3303 and HLA-DPB1*0501. Ann Neurol 2024;95(5):901-6. PMID 38400794
33: Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathologica 2010;119(1):7-35. PMID 20012068
34: Tajiri M, Takasone K, Kodaira M, Kimura A, Shimohata T, Sekijima Y. Autoimmune glial fibrillary acidic protein astrocytopathy following SARS-CoV-2 infection. Intern Med 2024;63(2):337-9. PMID 37952950
35: Theroux LM, Goodkin HP, Heinan KC, Quigg M, Brenton JN. Extreme delta brush and distinctive imaging in a pediatric patient with autoimmune GFAP astrocytopathy. Mult Scler Relat Disord 2018;26:121-3. PMID 30245384
36: Uchida K, Hasegawa T, Ikeda M, Yamaguchi R, Tateyama S. Detection of an autoantibody from pug dogs with necrotizing encephalitis (pug dog encephalitis). Vet Pathol 1999;36(4):301-7. PMID 10421096
37: Wang C, Zhang H, Lu W, Zhan Y. The EBV connection: a severe case of GFAP-A with central hypoventilation unresponsive to IVIG and literature review. Eur J Med Res 2024;29(1):415. PMID 39135139
38: Xiao J, Chen X, Shang K, et al. 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. J Neuroimmunol 2021;15;360. PMID 34600199
39: Yang X, Liang J, Huang Q, et al. Treatment of autoimmune glial fibrillary acidic protein astrocytopathy: follow-up in 7 cases. Neuroimmunomodulation 2017;24(2):113-9. PMID 28922662
40: Yang X, Xu H, Ding M, et al. Overlapping autoimmune syndromes in patients with glial fibrillary acidic protein antibodies. Front Neurol 2018;9:251. PMID 29755396
41: Yang X, Zhang C, Zhang J, et al. Autoimmune glial fibrillary acidic protein astrocytopathy mimics infectious meningitis: two case reports. Mult Scler Relat Disord 2020;45:102350. PMID 32645637
42: Yuan Z, Li H, Huang L, et al. CD8(+) T-cell predominance in autoimmune glial fibrillary acidic protein astrocytopathy. Eur J Neurol 2021;28(6):2121-5. PMID 33590610
43: Zekeridou A, Lennon VA. Neurologic autoimmunity in the era of checkpoint inhibitor cancer immunotherapy. Mayo Clin Proc 2019;94(9):1865-78. PMID 31358366
44: Zekeridou A, McKeon A, Flanagan EP. A path to understanding autoimmune GFAP astrocytopathy. Eur J Neurol 2018;25(3):421-2. PMID 29193488

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Andrew McKeon MD

Dr. Andrew McKeon of Mayo Clinic received consulting fees from Roche/Genentech and Janssen.
See Profile
Michael Gilligan MD

Dr. Gilligan of Mayo Clinic has no relevant financial relationships to disclose.
See Profile

Editor

Francesc Graus MD PhD

Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.
See Profile

Former Authors

Cecilia Zivelonghi MD MBBS
Anastasia Zekeridou MD PhD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: Female = male
Heredity: None
Population groups selectively affected: None
Occupation groups selectively affected: None

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy

Associated Disorders

Neoplasms
Other organ or nonorgan specific autoimmune disorders
Overlapping nervous-system targeting autoimmunity
Conditions associated with T cell dysfunction (lymphopenia of unknown origin, HIV, exposure to immune checkpoint inhibitor treatment)

Differential Diagnosis

infectious meningitis/meningoencephalomyelitis
neurosarcoidosis
other autoimmune/paraneoplastic/postinfectious encephalitides
demyelinating disorders including MOG-IgG autoimmunity
neuromyelitis optica and AQP4-IgG autoimmunity
- meningeal carcinomatosis
- CNS lymphoma
- CNS vasculitis
- chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS)

Autoimmune glial fibrillary acidic protein astrocytopathy …

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pediatric population

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Autoantibodies: mechanism and testing

Multiple sclerosis: treatment of its symptoms

Anti-GQ1b antibody syndrome

Paraneoplastic syndromes

Anti-IgLON5 disease

Balo concentric sclerosis

Anti-LGI1 encephalitis

Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pediatric population

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Autoantibodies: mechanism and testing

Multiple sclerosis: treatment of its symptoms

Anti-GQ1b antibody syndrome

Paraneoplastic syndromes

Anti-IgLON5 disease

Balo concentric sclerosis

Anti-LGI1 encephalitis

Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies

This is an article preview.
Start a Free Account
to access the full version.