Resident & Fellow Section

May 2, 2025

Pearls & Oy-sters: Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Presenting as Encephalomyelitis With Leptomeningeal Enhancement

Alex P. Vu https://orcid.org/0009-0006-3601-3761, Ronak K. Kapadia https://orcid.org/0000-0002-9820-0486, and Jodie I. Roberts https://orcid.org/0000-0002-8544-3171Authors Info & Affiliations

May 27, 2025 issue

104 (10)

https://doi.org/10.1212/WNL.0000000000213662

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Abstract

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an uncommon diagnosis in the differential for leptomeningeal enhancement. This case highlights the presentation, imaging features, and investigations important for diagnosis of GFAP astrocytopathy to ensure timely treatment of this corticosteroid-responsive disease. A 50-year-old man from Hong Kong presented with 10 days of progressive urinary retention, dysarthria, diplopia, and gait ataxia after a viral illness. Initial nonenhanced MRI brain was negative. After he developed encephalopathy, repeat MRI with gadolinium on admission day 6 revealed diffuse basal and spinal cord leptomeningeal enhancement. This imaging pattern, in combination with CSF eosinophilia and epidemiologic risk factors, precipitated empiric treatment for tuberculosis meningitis (including dexamethasone). Extensive investigations for an alternate infectious, autoimmune, or malignant diagnosis were negative. Dexamethasone cessation after a gastrointestinal bleed led to clinical and radiologic deterioration. This prompted further CSF and serum testing, which showed positive CSF GFAP-IgG immunofluorescence assay (IFA) (1:128) solidifying the diagnosis of autoimmune GFAP astrocytopathy. Induction with high-dose corticosteroids, intravenous immunoglobulins, and rituximab produced clinical and radiologic remission. Autoimmune GFAP astrocytopathy is an autoimmune disorder with a characteristic perivascular radial enhancement imaging pattern. However, a variety of other clinical and radiologic presentations may be seen, including leptomeningeal enhancement and T2/FLAIR hyperintensities. Diagnosis is confirmed with CSF GFAP-IgG testing. We provide a differential diagnosis for leptomeningeal enhancement and highlight clinical pearls for the diagnosis and management of autoimmune GFAP astrocytopathy.

Pearls

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Perivascular-radial gadolinium enhancement is the radiologic hallmark of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. However, other commonly described MRI patterns include leptomeningeal enhancement, multifocal T2/FLAIR brain hyperintensities, and longitudinally extensive spinal cord lesions.

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Most patients with GFAP astrocytopathy respond to corticosteroids and have a good functional outcome.

Oy-sters

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CSF testing by immunofluorescence assay and cell-based assay should be sent for suspected cases because sensitivity and specificity of GFAP-IgG are higher in CSF than in serum.

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An associated malignancy is found in one-third of cases, and coexisting antibodies are common (e.g., NMDA-R-IgG, MOG-IgG, and AQP4-IgG), either may be associated with resistance to first-line immunotherapies.

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Autoimmune GFAP astrocytopathy may mimic infectious causes of meningoencephalomyelitis with fever, lymphocyte-predominant CSF pleocytosis, leptomeningeal enhancement, or CSF eosinophils.

Case

A 50-year-old man from Hong Kong presented to the hospital with a 10-day history of subacute-onset progressive neurologic symptoms preceded by a viral upper respiratory tract infection with subjective fevers. He had no relevant medical history. His first symptom was urinary retention, followed by dysarthria, diplopia, and gait ataxia that resulted in multiple falls. He then developed a fluctuating level of consciousness with agitation that prompted presentation to hospital.

On initial neurologic examination, he was disoriented to location and time with dysarthria, symmetric bilateral upper extremity hyperreflexia, and right-sided dysmetria. There was no optic disc edema nor cranial nerve deficits. He required a Foley catheter for urinary retention. Nonenhanced MRI brain showed chronic bilateral cerebellar infarcts, and nonspecific T2/FLAIR white matter hyperintensities initially felt to be consistent with microvascular disease. Serum sodium was low (112 mmol/L, ref 135–145 mmol/L) on admission, but mentation did not improve with correction of his sodium levels. CT chest showed a left-sided pneumonia. On admission day 3, his respiratory status decompensated requiring intubation and transfer to the intensive care unit.

On admission day 5, he underwent a lumbar puncture that revealed elevated CSF protein (1.96 g/L, ref 0.15–0.45 g/L) and 68.0 10⁶/L nucleated cells (ref ≤5 10⁶/L) with lymphocytic predominance and 4.8 10⁶/L eosinophils. CSF glucose was normal, and there were no CSF-restricted oligoclonal bands. CSF was sent for acid-fast bacilli (AFB) staining and culture. Given his epidemiologic risk factors, presence of CSF eosinophils, and an indeterminate QuantiFERON-TB Gold test, he was empirically started on tuberculosis meningitis treatment that included dexamethasone. Repeat MRI brain and cervical spine with gadolinium enhancement on day 6 showed basal leptomeningeal enhancement with cranial nerve involvement of V, VI, and VII (Figure 1, A and B) and concerns for a developing communicating hydrocephalus. Repeat CSF sampling completed for additional diagnostic testing and repeat AFB CSF cultures showed an increased lymphocytic-predominant leukocytosis of 168.0 10⁶/L, CSF eosinophils (5.0 10⁶/L), and persistently elevated protein (1.32 g/L). On day 11, he was extubated and transferred to the neurology ward. Repeat full neuroaxis imaging showed persistent leptomeningeal enhancement with cranial nerve involvement and smooth leptomeningeal enhancement throughout the spine including the conus (Figure 1, C and D).

Figure 1 MRI Brain and Spinal Cord on Presentation

He was continued on tuberculosis treatment because QuantiFERON-TB Gold Plus was indeterminate. Owing to ongoing diagnostic uncertainty from inconclusive infectious testing, intravenous immunoglobulin 2 g/kg divided over 5 days was administered for empiric coverage of an autoimmune process. Tuberculosis medications were decreased to isoniazid monotherapy, and dexamethasone was tapered because of an upper gastrointestinal bleed. On day 22, repeat neuroaxis MRI showed new intramedullary signal abnormality in the spinal cord and brain with development of radial perivascular enhancement (Figure 2, A and B). Other autoimmune, paraneoplastic, infectious, and malignancy investigations were negative including NMDA-R-IgG, LGI1-IgG, Caspr2-IgG, GABA-B-IgG, AMPA-R-IgG, GQ1b-IgG, AQP4-IgG, MOG-IgG, ANCA, syphilis, HIV, cytology, and bacterial and fungal cultures. Enhanced CT imaging of his chest, abdomen, and pelvis; testicular ultrasound; and nuclear imaging (FGD-PET body and bone scan) did not show evidence of malignancy or granulomatous disease. AFB CSF and sputum cultures reported no growth. and repeat QuantiFERON-TB testing was negative.

Figure 2 MRI Brain 3 Weeks After Admission

Given radiologic progression with development of radial perivascular enhancement, autoimmune GFAP encephalomyelitis was suspected. Because GFAPα IgG testing is not available through our local laboratory, CSF and serum samples were sent to Mayo Clinic Laboratories. This yielded a positive GFAPα IgG (IFA titer of 1:128) in CSF, which was confirmed on a subsequent GFAP cell-binding assay. There was no GFAPα IgG reactivity in serum. The patient was diagnosed with autoimmune GFAP astrocytopathy and started on intravenous methylprednisolone 1,000 mg for 5 days concurrently with repeat IVIG 2 g/kg divided over 5 days. On day 47 of admission, he received an induction dose of rituximab 1,000 mg intravenously with repeat dose after 14 days. He was maintained on oral prednisone, which was tapered over 8 weeks after his initial dose of rituximab. These treatments resulted in clinical and radiologic improvement allowing for discharge on day 85 of admission after a course of physical rehabilitation. Three months after discharge, he was able to walk without a gait aid and was independent in his activities of daily living.

Discussion

Autoimmune GFAP astrocytopathy is an inflammatory disorder of the CNS first described in 2016¹ with an estimated prevalence of 0.6 per 100,000.² Affected individuals are generally middle-aged with no clear sex predilection.^3,4 Individuals present subacutely with varied manifestations including optic disc edema, headache, encephalopathy, autonomic dysfunction, ataxia, and myelopathy.^3-5 The classic radiologic description is radial perivascular enhancement, which is seen in 32%–53% of patients.^5,6 However, a multitude of other imaging patterns are seen including leptomeningeal enhancement (∼33%) and T2/FLAIR hyperintensities within the subcortical gray matter, brainstem, and periventricular regions (∼34%–45%).⁶ Approximately half of the patients have spinal cord involvement; spinal cord lesions are often longitudinally extensive (29%) and contrast enhancing (26%) and typically involve the central cord.⁶ CSF analysis is characterized by elevated protein and a lymphocytic-predominant pleocytosis.^3-5 Hyponatremia has been reported in 23%–50% of cases.⁵

GFAP astrocytopathy can be mistaken for infectious meningoencephalomyelitis in patients presenting with fever, headache, and altered level of consciousness.⁷ Clinicians can be further misled if CSF eosinophilia and basal leptomeningeal enhancement are present. In these cases, GFAP astrocytopathy is not considered until investigations for infectious causes are negative and empiric antimicrobial treatment has failed.^7,8 In this case, the suspicion of CNS tuberculosis became less likely with negative cultures, normal CSF glucose, and normal chest imaging leading to further testing.

This case demonstrates that GFAP astrocytopathy can initially present with leptomeningeal enhancement, which may coincide with or precede the classically described radial enhancement pattern. A broad differential for leptomeningeal enhancement tailored to this case can be considered including infectious (particularly tuberculosis, Lyme disease, cryptococcus neoformans); neoplastic (lymphoma, leptomeningeal carcinomatosis); and inflammatory causes, especially vasculitis, neurosarcoidosis, and MOGAD.^9-11 The diagnosis of GFAP astrocytopathy is confirmed with positive GFAP-IgG testing in CSF (which is preferred over serum testing because of increased sensitivity and specificity).⁴ Cell-based assays seem more accurate when compared with immunofluorescence assays.⁵ GFAP-IgG testing is not always included in routine antibody panels depending on the laboratory and may need to be requested.

Although the diagnosis of GFAP astrocytopathy hinges on the presence of GFAP-IgG antibodies in CSF, neuropathologic evidence suggests that GFAP-IgG is likely noncausative.^12-14 GFAP is an intracellular antigen, and GFAP autoimmunity is associated with a cytotoxic T-cell–mediated immune response.^1,12 Functionally, GFAP is the major intermediate filament protein in astrocytes. and complement C4d deposition on astrocytes has been seen in biopsy studies.¹² Histopathology is predominantly lymphocytic, although rare granulomatous pathology has been reported.^12,15

Although not present in this patient, GFAP astrocytopathy is associated with coexisting antibodies, particularly anti-NMDAR, anti-AQP4, and anti-MOG.^3-5 Up to one-third of patients may have associated malignancy, most commonly ovarian teratoma, adenocarcinoma, and glioma.^3,4 Lack of clinical improvement may warrant a combination of first-line therapies; however, this scenario may also signify the presence of indolent malignancy or coexisting autoimmune disease.³

Autoimmune GFAP astrocytopathy is recognized to be highly steroid-responsive, with best initial therapeutic approaches involving high-dose IV corticosteroids. Other first-line immunotherapies include IV immunoglobulin (IVIG) and plasma exchange, with >70% of patients responding to these treatments.^6-8 Long-term treatment recommendations have not been established; however, most patients receive one or more maintenance therapies including oral prednisone, rituximab, mycophenolate mofetil, cyclophosphamide, and azathioprine.^3-5 Although autoimmune GFAP astrocytopathy is reported to have a monophasic course in over 80% (median 1-year follow-up),⁵ long-term outcome studies are not available and, therefore, the natural history remains uncertain. Relapses most commonly occur during or after corticosteroid taper.^4,5,13 Negative conversion of GFAP-IgG CSF antibodies can be seen in 50% of patients 2 months after initiating treatment.⁵ Modified Rankin Scale (mRS) scores in follow-up show that prognosis is favorable, with most patients reaching an mRS score of 0–2.^5,13

This case of autoimmune GFAP astrocytopathy illustrates the variable presentation, neuroimaging, and CSF profile associated with this condition. Autoimmune GFAP encephalomyelitis may mimic infectious entities and should be considered in the differential diagnosis of leptomeningeal enhancement. We emphasize that GFAPα IgG testing should be performed in CSF and suggest malignancy screening and testing for coexisting antibodies in confirmed cases. Patients may be counseled optimistically because most are markedly corticosteroid responsive with minimal long-term disability.

References

Fang B, McKeon A, Hinson SR, et al. Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoencephalomyelitis. JAMA Neurol. 2016;73(11):1297.

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