Received: 9 November 2023 | Accepted: 5 March 2024

DOI: 10.1111/ene.16284

REVIEW ARTICLE

Clinical and neuroimaging phenotypes of autoimmune glial

fibrillary acidic protein astrocytopathy: A systematic review
and meta-­analysis

Caroline Hagbohm1,2 | Russell Ouellette1,2 | Eoin P. Flanagan3,4 | Dagur I. Jonsson1,5 |

Fredrik Piehl1,6 | Brenda Banwell7 | Ronny Wickström8,9 | Ellen Iacobaeus1,10 |
Tobias Granberg1,2 | Benjamin V. Ineichen1,11
1
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
2
Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
3
Department of Neurology, Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota, USA
4
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
5
Department of Neurophysiology, Karolinska University Hospital, Stockholm, Sweden
6
Centre for Neurology, Academic Specialist Centre, Karolinska University Hospital, Stockholm, Sweden
7
Division of Child Neurology, Children's Hospital of Philadelphia, Department of Neurology and Department of Pediatrics, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania, USA
8
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
9
Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
10
Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
11
Center for Reproducible Science, University of Zürich, Zürich, Switzerland

Correspondence Abstract
Benjamin V. Ineichen, Centre for
Reproducible Science, University of Objective: This study was undertaken to provide a comprehensive review of neuroimag-
Zürich, Zürich, Switzerland. ing characteristics and corresponding clinical phenotypes of autoimmune glial fibrillary
Email: [email protected]
acidic protein astrocytopathy (GFAP-­A), a rare but severe neuroinflammatory disorder, to
Funding information facilitate early diagnosis and appropriate treatment.
University of Zurich, UZH Alumni;
Schweizerischer Nationalfonds zur Methods: A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-­
Förderung der Wissenschaftlichen Analysis)-­conforming systematic review and meta-­analysis was performed on all avail-
Forschung, Grant/Award Number:
P400PM_183884; ALF Medicine, Grant/ able data from January 2016 to June 2023. Clinical and neuroimaging phenotypes were
Award Number: ALF 20200224; CIMED, extracted for both adult and paediatric forms.
Grant/Award Number: FoUI-­976444
Results: A total of 93 studies with 681 cases (55% males; median age = 46,
range = 1–103 years) were included. Of these, 13 studies with a total of 535 cases were
eligible for the meta-­analysis. Clinically, GFAP-­A was often preceded by a viral prodromal
state (45% of cases) and manifested as meningitis, encephalitis, and/or myelitis. The most
common symptoms were headache, fever, and movement disturbances. Coexisting autoan-
tibodies (45%) and neoplasms (18%) were relatively frequent. Corticosteroid treatment

Tobias Granberg and Benjamin V. Ineichen contributed equally and share last authorship.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction
in any medium, provided the original work is properly cited and is not used for commercial purposes.
© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.

Eur J Neurol. 2024;00:e16284.  wileyonlinelibrary.com/journal/ene | 1 of 16

https://doi.org/10.1111/ene.16284
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2 of 16 HAGBOHM et al.

resulted in partial/complete remission in a majority of cases (83%). Neuroimaging often

revealed T2/fluid-­attenuated inversion recovery (FLAIR) hyperintensities (74%) as well as
perivascular (45%) and/or leptomeningeal (30%) enhancement. Spinal cord abnormalities
were also frequent (49%), most commonly manifesting as longitudinally extensive myeli-
tis. There were 88 paediatric cases; they had less prominent neuroimaging findings with
lower frequencies of both T2/FLAIR hyperintensities (38%) and contrast enhancement
(19%).
Conclusions: This systematic review and meta-­analysis provide high-­level evidence for
clinical and imaging phenotypes of GFAP-­A , which will benefit the identification and clini-
cal workup of suspected cases. Differential diagnostic cues to distinguish GFAP-­A from
common clinical and imaging mimics are provided as well as suitable magnetic resonance
imaging protocol recommendations.

KEYWORDS
central nervous system diseases, encephalopathy, GFAP protein, human, magnetic resonance
imaging, systematic review

I NTRO D U C TI O N of GFAP-­A . A systematic review and meta-­analysis of the neuroimag-

ing characteristics and corresponding clinical phenotypes of GFAP-­A
In 2016, the discovery of a unique astrocyte-­specific IgG autoan- was, therefore, performed. The aim is to guide in distinguishing com-
tibody present in both cerebrospinal fluid (CSF) and serum was re- mon differential diagnoses to facilitate early diagnosis and appropriate
ported in patients suffering from severe, corticosteroid-­responsive treatment. To further support this goal, recommendations for neuro-
meningoencephalomyelitis [1, 2]. The antigen, glial fibrillary acidic imaging practices in the context of GFAP-­A are also provided.
protein (GFAP), an intermediate filament protein abundantly ex-
pressed in the cytoskeleton of mature astrocytes, led to the defini-
tion of this disorder as autoimmune GFAP astrocytopathy (GFAP-­A). M E TH O D S
To date, a detailed understanding of causative mechanisms and
background factors for GFAP-­A is lacking. Protocol registration
Typically, the onset of GFAP-­A is acute or subacute, with prodro-
mal symptoms of headache, fever, or other viral states. Over days The study protocol was registered in PROSPERO (International
and weeks, symptomatology may evolve to encompass movement Prospective Register of Systematic Reviews; CRD42023392595,
disturbances, visual impairment, psychiatric manifestations, and https://​w ww.​crd.​york.​ac.​uk/​PROSP​ERO/​) and adhered to the
autonomic dysfunction, among other symptoms of meningoen- PRISMA (Preferred Reporting Items for Systematic Reviews and
cephalomyelitis. The clinical picture may be further complicated by Meta-­Analysis) guidelines [10].
coexisting neuronal autoantibodies and concurrent malignancies.
However, GFAP-­A generally exhibits a positive response to immuno-
therapies, particularly high-­dose corticosteroids administered intra- Search strategy
venously, even though a propensity for relapses and, in some cases,
fatal outcomes have been reported [2–5]. A search for original studies published in full from January 2016 (the
Magnetic resonance imaging (MRI) plays a pivotal role in the di- year of the first publications of GFAP-­A) up to June 2023 was per-
agnosis of GFAP-­A . Pathological findings in the brain and/or spinal formed in PubMed, Embase, and Web of Science. To maximize the
cord are present in a significant proportion of patients. A key diag- sensitivity, a broad search string only encompassing the term “astro-
nostic feature is perivascular contrast enhancement, recognized as cytopathy” was employed.
an imaging hallmark of autoimmune GFAP-­A [1, 4, 6]. Additionally,
manifestations such as longitudinally extensive myelitis and optic
neuritis have been documented [7–9]. The diagnosis requires dil- Inclusion and exclusion criteria
igence, because many of its imaging findings overlap with other
autoantibody-­associated diseases, and also various types of infec- Included were original studies reporting on one or more patients with
tious meningitis/meningoencephalitis. GFAP-­A with documented GFAP-­IgG positivity, for which neuroim-
With the increasing number of reported cases in the literature, aging features were reported. This included case reports/series, co-
there is a need for high-­level evidence addressing imaging phenotypes hort studies, randomized controlled trials, and case–control studies.
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GFAP ASTROCYTOPATHY SYSTEMATIC REVIEW 3 of 16

Excluded were studies with only animal data, conference abstracts, and abstract screening, of which 143 studies were eligible for full-­
non-­English articles, and studies that reiterated previously reported text search. After screening the full text of these studies, a total of
quantitative data. Reviews were excluded but retained as potential 93 studies were included for the qualitative synthesis and 13 stud-
sources of additional records. ies were eligible for a meta-­analysis (each comprising ≥10 patients).
The flow chart for study selection is presented in Figure S1.

Study selection and data extraction

Study characteristics and demographics
Titles and abstracts were screened for their relevance in Rayyan [11]
by two independent reviewers (C.H. and B.V.I.), followed by full-­text The 93 included studies comprised a total of 681 patients (375 males,
screening. From eligible articles, the following data were extracted: 55%; 306 females, 45%). The 13 studies eligible for the meta-­analysis
title, authors, publication year, study design, number of subjects per comprised 535 patients (290 males, 54%; 245 females, 46%). Ages in
group, mean/median age and sex of participants, age group (adults all 93 included studies ranged from 1 to 103 years, with a median age
vs. children, i.e., <18 years old), study country, antibody status and of 46 years. Fifteen studies reported on a total of 88 paediatric cases
detection method, clinical signs, MRI findings (brain, spinal cord, and (onset age between 1 and 17 years). Further details on the demogra-
optic nerves), advanced neuroimaging findings (e.g., positron emis- phy of the reported cases can be found in Table 1.
sion tomography [PET]), and response to corticosteroid therapy.

Risk of bias assessment

Data synthesis and analysis
Most included studies showed a low risk of bias for the selection
Findings were summarized narratively. In addition, for demographic domain. The selection domain was defined as whether patients pre-
parameters, neuroimaging findings, clinical phenotypes, and response sented with a clinical status of meningoencephalomyelitis (or some
to corticosteroid therapy, data were pooled to obtain summary meas- variant thereof), with GFAP-­IgG detected.
ures. Category classes were predefined. Subgroup analyses were per-
formed for neuroimaging phenotypes of paediatric patients.
For the meta-­analysis, studies describing clinical or imaging find- Clinical features of GFAP-­A
ings for ≥10 adult subjects each and reported by at least three in-
dividual studies were included, and only summary-­level data were Clinical phenotype
used. Furthermore, a sensitivity analysis was performed on a sub-
group level, consisting of only the CSF GFAP-­IgG-­positive patients, GFAP-­A was associated with an acute or subacute onset of men-
excluding patients presenting with seropositivity only. As the pri- ingitis, encephalitis, and/or myelitis. Clinical phenotypes were
mary outcome, log-­transformed proportions were used. A random-­ reported for 492 of 681 patients. Among these 492 patients,
effects model was fitted to the data. The amount of heterogeneity, meningoencephalomyelitis was most commonly observed (32%),
that is, τ 2, was estimated using the DerSimonian–Laird estimator. followed by meningoencephalitis (24%), encephalitis (12%), en-
The Q-­test for heterogeneity and the I2 statistic were calculated. A cephalomyelitis (12%), myelitis (5%), and meningitis (4%). A com-
two-­t ailed p-­value of <0.05 was considered statistically significant. prehensive summary of the reported symptoms can be found in
Table 1.
The predominantly reported clinical symptoms were fever (61%
Publication bias of patients), movement disturbances (59%), and headache (52%).
Movement disturbances included gait disturbance, ataxia, tremor,
Publication bias was not assessed, as defined per protocol. However, limb weakness, and myoclonus. Autonomic dysfunction was less
the risk of bias assessment was qualitatively assessed for the included commonly reported (38%), including urinary or bowel dysfunction,
studies using an adjusted version of the Newcastle–Ottawa scale. erectile dysfunction, and blood pressure alterations.
Altered consciousness or confusion was observed in 38% of
patients. Other cognitive disturbances, such as attention deficits,
R E S U LT S were noted in 34% of patients. In 23% of patients, there were overt
signs of psychosis such as hallucinations or severe behavioural al-
Eligible studies terations. Impaired visual acuity or eye movement disturbances
were documented in 28% of patients, and in approximately 50%
In total, 641 studies were retrieved from our comprehensive data- of these there were findings of optic disc oedema or papillitis on
base search. After deduplication, 499 references remained for title clinical ophthalmological examination. Notably, 12% of patients
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
4 of 16 HAGBOHM et al.

TA B L E 1 Demographics and clinical, laboratory, and TA B L E 1 (Continued)

neuroimaging findings of reported autoimmune GFAP
Involvement of brainstem 34% (119/353)
astrocytopathy.
Involvement of cerebellum 19% (74/400)
Demography and clinical features
Involvement of corpus callosum 5% (29/543)
Age, years median = 46 (mean = 43),
Restricted diffusion 3% (15/543)
range = 1–103
Imaging without specific findings 12% (63/543)
Sex Males 55% (375),
females 45% (306) Spinal cord MRI findings

GFAP-­IgG found in CSF 87% (593) Longitudinally extensive myelitis 29% (118/403)

Simultaneous neuroautoantibodies Overall found in 179/681 Short myelitis 10% (39/403)

patients, 28% Contrast enhancement 26% (89/336)
NMDAR-­IgG 28% (50/179) Leptomeningeal or central canal 16% (54/336)
AQP4-­IgG 16% (29/179) Other, punctate/patchy 15% (50/336)
MOG-­IgG 8% (15/179) Cervical location 71% (70/98)
Concomitant malignancy 14% (98/681) Thoracic location 65% (64/98)
Response to immunotherapy 88% (302/342) Lumbar/conus/caudal location 23% (23/98)
Clinical phenotype Imaging without specific findings 21% (83/403)
Meningoencephalomyelitis 31% (156/492)
Note: Percentages represent the proportion of patients with a specific
Meningoencephalitis 23% (119/492) feature with the parentheses conveying the number of patients with
Encephalitis 13% (60/492) the feature and the number of patients where the data were available.
Abbreviations: AQP4, aquaporin-­4; CSF, cerebrospinal fluid; FLAIR,
Encephalomyelitis 11% (58/492)
fluid-­attenuated inversion recovery; GFAP, autoimmune glial fibrillary
Myelitis 5% (26/492) acidic protein; Ig, immunoglobulin G; MOG, myelin oligodendrocyte
Meningitis 4% (20/492) glycoprotein; MRI, magnetic resonance imaging; NDMAR, N-­methyl-­d-­
aspartate receptor.
Specific symptoms
Fever 61% (243/398)
Movement disturbances 59% (294/496)
deteriorated severely in their neurological status, resulting in coma
Headache 52% (254/492)
and respiratory failure. Although a monophasic disease course was
Decreased consciousness 38% (186/496)
the most common clinical outcome, relapsing disease was also re-
Dysautonomia 38% (189/496)
ported [4].
Cognitive impairment 34% (168/496)
Visual symptoms 28% (142/611)
Psychiatric symptoms/psychosis 23% (115/496) Prior infection and malignancy status
Nuchal rigidity and/or Kernig sign 23% (116/496)
Seizures 16% (80/496) The meta-­analysis revealed that 45% (95% confidence interval [CI]
Respiratory failure/coma 12% (61/495) = 31%–61%) of patients had a viral prodromal state (Figure 1a; six
Area postrema-­related symptoms (i.e., 11% (55/496) studies, 187 patients), mostly comprising upper respiratory tract or
nausea, vomiting, hiccups) gastrointestinal infections but also rarer cases with human immuno-
Hyponatremia 7% (37/496, highlighted deficiency virus and bacterial infections, for example, Mycobacterium
mainly in case tuberculosis or Brucella [12, 13].
reports) Coexisting tumours were reported in 98 of the patients (five
High CSF opening pressure 3% (15/496) of whom were paediatric patients), the most frequent of which
Brain MRI findings was ovarian teratoma (32 patients). In the meta-­a nalysis, 18%
T2/FLAIR hyperintensities (95% CI = 12%–28%) of patients had a concomitant neoplasm
Deep white matter/periventricular 45% (232/510) (Figure 1b; 10 studies, 428 patients). Accompanying neoplasms
Subcortical grey matter 37% (146/398) included ovarian teratoma, B-­cell lymphoma, meningioma, glioma,
Cortical/juxtacortical 21% (51/312) adenocarcinoma of the prostate and colon, carcinoma of the lung

Unspecified 11% (61/543) and urinary bladder, ductal breast cancer, and melanoma. In 25
reported cases of malignancy, there were simultaneous autoanti-
Contrast enhancement
bodies, most commonly N-­m ethyl-­d-­aspartate receptor (NMDAR)-­
Perivascular linear 37% (146/399)
IgG in ovarian teratoma patients [2]. Notably, GFAP-­A onset was
Leptomeningeal 33% (90/273)
also reported to be associated with immune-­c heckpoint inhibitor
Other, punctate/patchy 19% (74//399)
treatment [2, 14].
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GFAP ASTROCYTOPATHY SYSTEMATIC REVIEW 5 of 16

Laboratory findings and autoimmunity with GFAP-­A from our institution are presented in Figure 3, with a
graphical illustration in Figure 4.
GFAP-­IgG was by definition detected in all 681 patients included Subcortical grey matter involvement was also prevalent, with
in this review. GFAP-­IgG was detected in CSF in a majority of cases 37% of patients presenting with T2/FLAIR hyperintensities and/or
(593 patients, 87%), most commonly by cell-­based assay. GFAP-­IgG contrast enhancement in the basal ganglia or thalami, frequently bi-
was only detected in serum in 87 patients (13%) and found only by laterally. Cortical/juxtacortical involvement was detected in 16% of
stereotactic biopsy of the brain in one case [8]. patients. Mirroring the white matter manifestations, the grey matter
Coexisting autoantibodies were reported in 179 patients lesions were typically diffuse and/or hazy.
(Table 1). The meta-­analysis showed that up to 45% (95% CI = 32%– Contrast enhancement was observed in 58% of patients (95%
59%) of patients can present with coexisting autoantibodies CI: 47%–68%) in the meta-­analysis (Figure 2b; 10 studies, 305
(Figure 1c; nine studies, 212 patients). Among reported coexist- patients), most frequently located in areas with T2/FLAIR hy-
ing autoantibodies, the most frequent was NMDAR-­IgG (28%), perintensities. Perivascular linear contrast enhancement was re-
followed by aquaporin-­4 (AQP4)-­IgG (16%) and myelin oligoden- ported in 45% of patients (95% CI = 31%–59%) in the meta-­analysis
drocyte glycoprotein (MOG)-­IgG (8%). Less frequent coexisting (Figure 2c; nine studies, 234 patients). This enhancement typically
autoantibodies were antinuclear antibodies, anti-­Yo-­antibodies/ extended radially from the lateral ventricles but was also reported
Purkinje cell cytoplasmic autoantibody type 1, thyroxine perox- in the cerebellum, brainstem, and basal ganglia [2, 9, 15–17].
idase antibodies, ganglioside antibodies, anti-­Sjögren syndrome-­ Leptomeningeal contrast enhancement was present in 30% of pa-
related antigen A/B antibodies, and antineutrophil cytoplasmic tients (95% CI = 18%–46%) in the meta-­analysis (Figure 2d; eight
antibodies. studies, 166 patients).
Brainstem pathology was reported in 34% of patients and cere-
bellar pathology in 19% of patients, mostly described as T2/FLAIR
Response to immunotherapy hyperintensities. Area postrema lesions were highlighted in a few
studies [18–20].
Treatment with immunotherapy, high-­d ose intravenous corticos- Corpus callosum involvement was rather rare, reported in only
teroids in particular (less commonly plasma exchange and intra- 5% of the patients, and often associated with reversible splen-
venous immunoglobulin), was reported for 342 patients, of whom ial lesion syndrome [21–24]. Findings of restricted diffusion were
302 patients (88%) responded well with a complete or partial found in only 3% of the patients, commonly in the corpus callosum.
remission. The imaging response to intravenous corticosteroids Cerebral haemorrhage was reported in one single patient, located in
was often noted to be prompt, with rapid resolution of contrast the thalamus [25].
enhancement as a sign of improved blood–brain barrier function,
followed by the resolution of T2/fluid-­attenuated inversion re-
covery (FLAIR) hyperintensities at a slower pace [15]. The meta-­ Spinal cord MRI findings
analysis on treatment response was in line with this finding, with
83% of patients (95% CI = 69%–91%) showing complete or partial Spinal cord MRI findings were commonly observed, with 49% of
remission upon immunotherapy (Figure 1d; seven studies, 171 patients (95% CI = 40%–62%) having an abnormal spinal cord MRI
patients). in the meta-­analysis (Figure S2b; five studies, 143 patients; see
also Table 1). Details on spinal lesion topography were specified
for 98 patients, of whom 71% had cervical involvement, 65% had
Neuroimaging phenotypes of GFAP-­A thoracic involvement, and 23% had conus and/or cauda equina
involvement.
Brain MRI findings Longitudinally extensive myelitis, defined as lesions extend-
ing over three vertebral levels, was evident in 29% of patients.
Brain MRI findings were reported in 543 patients. A detailed sum- Conversely, smaller spinal lesions with an extension of less than
mary of imaging findings can be found in Table 1. In the meta-­ three vertebral levels were noted in 10% of patients, frequently
analysis, normal brain MRI findings were reported in 21% of patients manifesting in a multifocal or patchy pattern. The lesions were
(95% CI = 15%–28%; Figure S2a; eight studies, 172 patients). predominantly located centrally within the cord, affecting the
The most common neuroimaging manifestation was T2/FLAIR grey matter, and characterized as hazy, subtle, or diffuse on T2-­
hyperintensities, reported in 74% of patients (95% CI = 56%–87%) weighted imaging [1, 2, 7, 26, 27]. Notably, three case reports
in the meta-­analysis (Figure 2a; seven studies, 203 patients). These described the lesions as bilateral longitudinal with an eccentric
hyperintensities were predominantly periventricular, extensive, location [28–30].
confluent, and hazy. Conversely, smaller and demarcated T2/ Spinal contrast enhancement was detected in 26% of patients,
FLAIR hyperintensities in the deep white matter were less frequent. specified as leptomeningeal in 16% and intraparenchymal (character-
Representative examples of neuroimaging findings in an adult case ized as patchy, punctate, speckled, or scattered) in 15% of patients.
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 of 16 HAGBOHM et al.

F I G U R E 1 Forest plot of proportions

of clinical and laboratory findings in
autoimmune glial fibrillary acidic protein
astrocytopathy (GFAP-­A). Pooled analyses
of studies reporting the proportion of viral
prodromal disease prior to GFAP-­A onset
(a), concomitant neoplasm (b), coexisting
autoantibodies (c), and response to
immunotherapy (such as intravenous
corticosteroids; d) are shown. Proportions
were extracted and pooled using the
random effects DerSimonian–Laird
method. CI, confidence interval.

Interestingly, a couple of studies reported the hallmark pattern of The meta-­analysis suggested that spinal cord MRI scans with
perivascular contrast enhancement within the spinal cord [17, 31], as no particular features were also relatively common, with 41% of
well as notable instances of contrast enhancement adjacent to the patients (95% CI = 26%–58%) having a normal spinal cord MRI
central canal [2, 7, 32]. (Figure S2c; eight studies, 172 patients).
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GFAP ASTROCYTOPATHY SYSTEMATIC REVIEW 7 of 16

F I G U R E 2 Forest plot of proportions

of brain and spinal cord imaging
findings in glial fibrillary acidic protein
astrocytopathy (GFAP-­A). Pooled analyses
of studies reporting the proportion
of the presence of cerebral (fluid-­
attenuated inversion recovery [FLAIR]-­)/
T2-­weighted (T2w) hyperintensities (a),
the presence of gadolinium-­enhancing
lesions (b), perivascular radial gadolinium
enhancement (c), and the presence of
(lepto)meningeal enhancement (d) are
shown. Proportions were extracted
and pooled using the random effects
DerSimonian–Laird method. CI,
confidence interval.
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
8 of 16 HAGBOHM et al.

F I G U R E 3 Neuroimaging findings in an adult case of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-­A). A male in his
mid-­60s with a history of hypertension presented to the emergency room with headache and fever. He subsequently developed nystagmus,
diplopia, ataxia, tremor, and myoclonic seizures. He further progressed with a loss of consciousness and apnoeas, and was intubated and
treated in the intensive care unit. Brain and spinal cord magnetic resonance imaging revealed lesions and characteristic leptomeningeal
enhancement in a perivascular radial distribution in the centrum semiovale (a–c), basal ganglia (d, e), pons, and cerebellum (g). There was also
leptomeningeal enhancement around the conus (f). Notably, bilateral lesions in the pons in proximity to the middle cerebellar peduncles had
restricted diffusion (h, i). Suspicion of autoimmune GFAP astrocytopathy was raised, and cerebrospinal fluid testing confirmed the presence
of GFAP-­IgG autoantibodies. No coexisting malignancy was found, and no other neuronal autoantibodies were detected. There was a
prompt response to corticosteroid treatment and continuous remission after initiation of anti-­CD20 therapy with rituximab.
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GFAP ASTROCYTOPATHY SYSTEMATIC REVIEW 9 of 16

F I G U R E 4 Lesion distribution of neuroinflammatory disorders. Schematic lesion distribution maps in the central nervous system
of neuroinflammatory disorders that may overlap clinically and neuroradiologically with autoimmune glial fibrillary acidic protein
astrocytopathy (GFAP-­A) are shown. MOGAD, myelin oligodendrocyte glycoprotein antibody disease; MS, multiple sclerosis; NMOSD,
astrocyte aquaporin-­4-­positive neuromyelitis optica spectrum disorder.
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
10 of 16 HAGBOHM et al.

Optic nerve MRI findings All 88 paediatric patients underwent brain MRI. Normal findings
were reported to a low extent (20%), and signal abnormalities were
Despite visual symptoms and optic disc oedema being described in located in the basal ganglia (38%), deep white matter (33%), brain-
several case reports [33], MRI findings of optic neuritis were only stem (23%), cerebellum (16%), cortical/juxtacortical regions (10%),
specifically reported in 19 patients. Bilateral optic neuritis was re- and corpus callosum (15%). Restricted diffusion in the corpus callo-
ported in 10 cases [8, 14, 34–37]. Unilateral optic neuritis was re- sum was infrequently reported (5%).
ported in six cases, whereas the rest of the cases were unspecified Nearly all reported brain MRI scans (94%) included gadolinium-­
[4, 15, 38]. Two of the cases were reported as having extensive le- based contrast agents. Intracranial contrast enhancement was
sions involving the optic chiasm [15, 36]. less common than in the pooled, predominantly adult, population.
Leptomeningeal enhancement was reported as slightly more fre-
quent (19%) than perivascular linear enhancement (13%). Unspecified
Advanced and nuclear neuroimaging findings contrast enhancement was also reported (9%).
Spinal cord MRI was performed in 71 paediatric patients, often
Advanced and nuclear neuroimaging modalities were reported in 21 with normal findings (52%). Lesions occurred all along the spinal
patients. cord, including longitudinally extensive myelitis (25%), whereas only
Fluorodeoxyglucose PET findings were reported in 16 patients. one case presented with short and patchy lesions. Leptomeningeal
Whereas some authors reported normal findings [25], even in enhancement was the most frequent enhancement pattern (11%).
areas with pathology on MRI [39, 40], others reported increased or
decreased uptake in different regions [27]. A few studies reported
high intramedullary metabolism associated with extensive myelitis Sensitivity analysis
[29, 37, 41].
Single-­photon emission computed tomography was applied in A complementary meta-­analysis was performed for cases that had
two patients, demonstrating a decreased blood flow in the frontal confirmed GFAP antibodies in CSF (Figures S3–S5), that is, excluding
lobes in one case and an increased blood flow in the basal ganglia, studies of cases with only seropositivity. This revealed consistent
thalamus, and corona radiata in the other patient [42, 43]. results regarding overall effect sizes, for both clinical and imaging
MRI spectroscopy was evaluated in two patients, showing low characteristics, emphasizing the reliability of the findings.
levels of myo-­inositol (an astrocyte marker) in one of the patients
[23]. In the other patient, an abnormally high choline peak (a marker
of increased cellular membrane turnover) and low N-­acetylaspartate DISCUSSION
peak (a neuronal marker) were reported.
The clinical spectrum of autoantibody-­m ediated neuroimmuno-
logical conditions has recently been expanded to include a new
Paediatric clinical and neuroimaging phenotypes of entity, GFAP-­A . GFAP-­A is a rare but severe neuroinflammatory
GFAP-­A disorder characterized by the presence of GFAP-­IgG autoantibod-
ies, predominantly detected in the CSF. Based on a systematic re-
There were 88 paediatric cases with reports on neuroimaging phe- view and meta-­analysis, covering data from the definition of the
notypes (54 males, 61%; 34 females, 39%), the largest study com- disease in 2016 up until June 2023, we have generated a struc-
prising 35 patients [35]. In the paediatric population, GFAP-­IgG was tured synthesis of the clinical and neuroimaging spectrum encoun-
detected in CSF in 66 patients (75%), and in serum only in the re- tered with GFAP-­A .
maining 22 patients (25%). The most notable imaging findings include the hallmark sign of
In the paediatric cases, simultaneous autoantibodies were perivascular linear perivascular contrast enhancement, deep grey
detected in the CSF or serum in 19 patients (24%), and in five matter signal abnormalities, hazy white matter hyperintensities, and
(7%) patients there were reports of coexisting malignancy (two longitudinally extensive myelitis. This consolidation of the evidence
cases of yolk sac tumour, paraganglioma, retroperitoneal tumour, base may assist in raising the suspicion of GFAP-­A in patients with
and ependymoma). The most common clinical phenotype was acute onset neuroinflammation, and testing for GFAP-­IgG will dis-
meningoencephalitis (32%), followed by meningoencephalomy- tinguish these patients from those with other conditions, thereby
elitis (26%), encephalomyelitis (10%), encephalitis (8%), meningitis facilitating an early diagnosis and initiation of appropriate treatment.
(2%), and myelitis (2%). In 20% of patients, there was no specified
clinical phenotype defined as the above. Visual symptoms were
present in 14%. Most publications evaluated treatment response, Clinical phenotypes and response to treatment
and in 90% of the patients a good or partial response to immu-
nosuppressive treatment (most commonly corticosteroids) was Considering GFAP is an intracellular protein lacking a surface anti-
reported. gen, the pathophysiological pathway leading to disease is obscure.
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GFAP ASTROCYTOPATHY SYSTEMATIC REVIEW 11 of 16

It is hypothesized that GFAP-­IgG might be a surrogate marker for heterogeneous. Nevertheless, several studies reported a specific
an underlying cytotoxic T-­cell-­mediated autoimmune response [6]. finding of central canal contrast enhancement, corresponding to
Despite uncertain pathological mechanisms, the clinical pheno- GFAP-­e nriched regions in the rodent cord [2]. Potentially, this en-
type, with prodromal infectious states, fever, and headache in con- hancement pattern could further add to the hallmark findings of
junction with a rather acute onset of psychiatric symptoms as well GFAP-­A .
as movement disorders, was unifying for a majority of the patients. Currently, there are few studies on advanced neuroimaging and
Interestingly, GFAP-­A cases have been reported in a wide age span, nuclear medicine modalities in GFAP-­A , and the diagnostic and prog-
including paediatric cases, and there is no clear sex predominance. nostic value of such modalities remains to be determined.
Visual impairment and eye movement disturbance are rather
common, despite few reports of MRI-­confirmed optic neuritis.
Notably, optic disc oedema and papillitis are relatively frequent, al- Paediatric perspective
though often asymptomatic, with reports of normal or only slightly
elevated intracranial pressure at lumbar puncture. The pathophysi- Paediatric GFAP-­A tends to present with more subtle or even absent
ological mechanism of this phenomenon remains unclear, but inter- imaging findings in the brain and spinal cord, although definite sub-
estingly, GFAP is expressed in the retina, and it has been suggested group analyses were not feasible due to the pooling of data. Larger
that the finding may be a result of inflammatory vasculopathy with prospective studies are therefore needed.
papillitis [33].
High-­dose intravenous corticosteroids are the most frequent
treatment in the acute stage, often with prompt and efficacious re- Differential diagnostic cues
sponse, although as many as every 10th patient requires intensive
care during the disease course. In terms of the long-­term prognosis, GFAP-­A , with its diverse manifestations, can resemble many other
previous studies have shown that relapses occur in up to 28% of pa- diseases, including other neuroinflammatory disorders, infectious
tients within a 19-­month follow-­up [4], often during steroid tapering, diseases (e.g., M. tuberculosis, of which there are noteworthy ex-
underlining the need for monitoring and consideration of mainte- amples), neurosarcoidosis, small vessel vasculitis, and lymphoma.
nance therapy. Clinical and laboratory features, as well as the usually prompt re-
The high frequency of other neuronal autoantibodies and malig- sponsiveness to corticosteroids, may implicate differential diagnosis
nancies further emphasizes the need for careful diagnostic workup in the field of autoimmune neuroinflammatory disorders. There are,
[35, 44, 45]. Future studies are needed to show to what degree such however, key clinical and imaging findings that may facilitate the di-
findings can explain clinical heterogeneity and possibly identify sub- agnostic workup of GFAP-­A; these are summarized in Table 2, and a
forms of GFAP-­A . schematic of lesion distribution compared to other neuroinflamma-
tory disorders can be found in Figure 4.
Clinically, GFAP-­A shows a resemblance with MOG antibody-­
Neuroimaging phenotypes associated disease (MOGAD) and acute disseminated enceph-
alomyelitis (ADEM), with its prodromal state and psychiatric
The GFAP-­A hallmark of perivascular linear contrast enhancement symptoms in conjunction with altered consciousness. Although
is reported in 45% of all patients in our meta-­analysis, in agree- GFAP-­A causes longitudinally extensive myelitis, permanent para-­
ment with previous larger publications [2, 14, 46, 47]. It is note- or tetraplegia was seldom reported in GFAP-­A , as opposed to
worthy that this pattern has been observed not only in the brain AQP4-­p ositive neuromyelitis optica spectrum disorder (NMOSD)
but also in the brainstem, cerebellum, and spinal cord. This finding [49, 50]. Similarly, visual involvement in GFAP-­A is typically pain-
is dynamic and may potentially be underreported, because linear less and of a mild character compared to AQP4-­p ositive NMOSD,
perivascular enhancement was sometimes reported to be discov- with only rare cases of long-­term visual impairment or blindness
ered in retrospect after the detection of GFAP-­IgG. This indicates [8, 33, 36].
that the perivascular enhancement pattern may be subtle and that Neuroradiologically, the hallmark imaging finding of perivascu-
awareness of it and optimized imaging protocols are essential. lar linear contrast enhancement in GFAP-­A is distinctive from other
Temporal aspects are also crucial in the evaluation of neuroim- neuroinflammatory disorders, although it is not pathognomonic,
aging findings in GFAP-­A [15]; however, details on the timing of because it may also be present in, for example, neurosarcoidosis,
neuroimaging are lacking in many of the larger case series, imped- small vessel vasculitis, and intravascular lymphoma [1]. The frequent
ing a quantitative assessment of the temporal significance in this diffuse involvement of both subcortical grey and white matter is an-
systematic review. other similarity with ADEM and MOGAD. Although subcortical grey
Other consistent neuroimaging findings include diffuse sig- matter involvement occurs in MS, it is typically focal in the thalami,
nal abnormalities in both subcortical grey and white matter of and in AQP4-­positive NMOSD it is typically located in periventricu-
the brain [2, 47, 48], as well as longitudinally extensive myeli- lar structures and the hypothalamus. In GFAP-­A , spinal cord lesions
tis. Contrast enhancement of the spinal cord is to a large extent are often longitudinally extensive, but usually more subtle, with less
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
12 of 16 HAGBOHM et al.

TA B L E 2 Comparison of clinical and neuroimaging phenotypes in GFAP-­A , MOGAD, AQP4+ NMOSD, and MS.

GFAP-­A MOGAD NMOSD MS

Clinical features and demographics

Median age at onset, years 46 23 38 32
Males 55% 72% 17% 33%
Myelitis +++ ++ +++ ++
Para-­/tetraplegia + + ++ −
Autonomic dysfunction ++ + + +
Headache +++ + + +
Fever +++ + + −
Cognitive impairment at onset ++ ++ + +
Altered consciousness ++ ++ + −
Psychosis ++ − − −
Visual symptoms + ++ +++ ++
Nuchal rigidity ++ − − −
Respiratory failure + + + −
Area postrema symptoms + + +++ −
Hyponatremia + N/A N/A N/A
Brain imaging findings
Periventricular white matter lesions ++ + +++ +++
White matter lesions: confluent, hazy +++ ++ − +
White matter lesions: focal, distinct ++ ++ + +++
Presence of Dawson fingers − − + +++
Cortical/juxtacortical lesions ++ + − +++
Subcortical grey matter lesions +++ ++ − +
Corpus callosum lesions + ++ + +++
Brainstem lesions ++ +++ +++ ++
Area postrema lesions + + +++ −
Contrast enhancement, perivascular +++ − − −
Contrast enhancement, leptomeningeal ++ ++ + +
Optic nerve imaging findings
Optic neuritis + +++ +++ ++
Optic disc oedema ++ ++ N/A −
Spinal cord imaging findings
Longitudinal extensive myelitis ++ ++ +++ −
Short lesions (<3 vertebral levels) + ++ + +++
Spinal lesions: hazy, speckled +++ ++ + +
Spinal cord oedema + + +++ +
Cervical spinal cord involvement +++ ++ +++ +++
Thoracic spinal cord involvement +++ +++ +++ ++
Conus involvement + +++ + −
Centrally located spinal lesions ++ ++ +++ +
Laterally located spinal lesions + + ++ +++
Contrast enhancement ++ + +++ +
Central canal contrast enhancement ++ − − −
Leptomeningeal contrast enhancement ++ + + −

Note: Summary based on the current literature review as well as previous reports in Carandini et al. [S51], Xiao et al. [4], and Carnero Contentti et al.
[S52]. The number of + symbols represents how frequent/typical the clinical feature or neuroimaging finding is per diagnosis.
Abbreviations: AQP4, aquaporin-­4; GFAP-­A , autoimmune glial fibrillary acidic protein astrocytopathy; MOGAD, myelin oligodendrocyte glycoprotein
antibody disease; MS, multiple sclerosis; N/A, data not available; NMOSD, AQP4-­positive neuromyelitis optica spectrum disorder.
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GFAP ASTROCYTOPATHY SYSTEMATIC REVIEW 13 of 16

TA B L E 3 Recommended neuroimaging protocol for diagnostics and monitoring of autoimmune glial fibrillary acidic protein
astrocytopathy.

Brain MRI Comment Spinal cord MRI Comment

Sagittal 3D T2-­weighted FLAIR White and grey matter hyperintensities, Sagittal T2-­weighted Spinal cord lesions; Dixon could
encephalitis TSE and/or STIR also be used
Sagittal 3D T1-­weighted GRE IR/TSE White and grey matter hypointensities, Sagittal T1-­weighted Precontrast image for
precontrast image for comparison (FLAIR) TSE comparison
Axial 3D SWI Microbleeds, subarachnoid haemorrhage,
cortical superficial siderosis (ruling out
differential diagnosis)
Coronal T2-­weighted TSE or STIR Optical neuritis
GBCA administration Unless contraindicated GBCA administration Unless contraindicated
Axial T2-­weighted TSE White and grey matter changes, encephalitis Axial T2-­weighted Spinal cord lesion topography
TSE
Axial DWI Infarcts, encephalitis (ruling out differential Sagittal T1-­weighted Blood–brain barrier
diagnosis) (FLAIR) TSE disruption, leptomeningeal
enhancement
Sagittal 3D T1-­weighted GRE IR/TSE Blood–brain barrier disruption, Axial T1-­weighted Coverage over suspected
with GBCA leptomeningeal enhancement (FLAIR) TSE contrast enhancement
Sagittal 3D T2-­weighted FLAIR with Leptomeningeal enhancement, perivascular
GBCA linear contrast enhancement

Note: Brain 3D imaging should ideally have an isotropic voxel size, preferably ≤1 mm. The spinal cord sagittal imaging should cover the entire spinal
cord and conus. Ideally, the axial T2-­weighted images should have the same coverage. Sagittal images should have a slice thickness of ≤3 mm and axial
images ≤4 mm. T1-­weighted TSE can preferably be performed as FLAIR, if possible. Some sequences have been placed after GBCA administration to
allow for appropriate contrast distribution before T1-­weighted imaging after contrast.
Abbreviations: 3D, three-­dimensional; DWI, diffusion-­weighted imaging; FLAIR, fluid-­attenuated inversion recovery; GBCA, gadolinium-­based
contrast agent; GRE IR, gradient-­recall echo with an inversion pulse; MRI, magnetic resonance imaging; STIR, short tau inversion recovery; SWI,
susceptibility-­weighted imaging; TSE, turbo spin echo.

generalized spinal cord oedema and swelling compared to AQP4-­ MOGAD and NMOSD, limits the ability to tease out GFAP-­A-­
positive NMOSD. Furthermore, leptomeningeal and central canal specific findings in the current literature and discriminate it from
enhancement, as seen in GFAP-­A , is less characteristic of AQP4-­ overlapping disorders. Furthermore, we report only patients who
positive NMOSD. were tested for GFAP-­IgG, and therefore the suspicion of GFAP-­A
astrocytopathy would have an inherent bias toward clinical and
MRI features already known to associate with this diagnosis.
Recommendations on neuroimaging Finally, inevitable heterogeneity existed in the available data for
the meta-­analysis, emphasizing the diversity of included cohorts
Based on the findings in this review, we provide suggestions for and employed clinical care.
MRI protocols in Table 3. We recommend imaging of the entire neu-
roaxis with the administration of gadolinium-­based contrast agents.
Although three-­dimensional (3D) T1-­weighted imaging is used for CO N C LU S I O N S
detecting contrast enhancement, 3D T2-­weighted FLAIR after gado-
linium may facilitate the detection of leptomeningeal enhancement. GFAP-­A can present with a range of neuroimaging and clinical find-
The high frequency of spinal cord involvement in GFAP-­A underlines ings. A high clinical awareness of GFAP-­A is therefore necessary in
the importance of spinal cord MRI. the diagnostic workup of patients with noninfectious encephalitis
and meningeal features, and prompt testing of GFAP-­IgG is rec-
ommended. Neuroradiological findings of perivascular contrast
Limitations enhancement, deep grey matter involvement, and longitudinally
extensive myelitis may be indicative of GFAP-­A . Detection of coex-
In our comprehensive study, we included patients presenting with isting autoantibodies and/or concomitant malignancy are important
GFAP-­IgG in CSF and/or serum, but there are studies indicating factors to consider in the diagnostic workup of suspected cases.
that the latter might be an unspecific finding [2, 48]. Notably, a Future studies should elaborate on the described clinical, laboratory,
sensitivity analysis of only CSF-­p ositive patients revealed similar and imaging features, explore the paediatric panorama of GFAP-­A ,
results. Additionally, the presence of coexisting autoantibodies and evaluate the role of advanced MRI in the diagnostics and man-
and overlapping clinical and neuroimaging features, in for example agement of GFAP-­A .
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
14 of 16 HAGBOHM et al.

AU T H O R C O N T R I B U T I O N S has been submitted on DACH1-­IgG as a biomarker of paraneoplastic

Benjamin V. Ineichen: Funding acquisition; supervision; conceptual- autoimmunity. R.W. has received honoraria for serving on advisory
ization; methodology; writing – original draft; project administration; boards for UCB, GW Pharma, and Octapharma and speaker's fees
formal analysis; visualization; data curation; investigation. Caroline from Eisai, Jazz Pharma, and Sanofi-­Genzyme. He has received fund-
Hagbohm: Conceptualization; investigation; writing – original ing from Region Stockholm Clinical Research Appointment. E.I. has
draft; data curation; formal analysis; validation. Russell Ouellette: received honoraria for serving on advisory boards for Biogen, Sanofi-­
Conceptualization; visualization; writing – review and editing; in- Genzyme, and Merck and speaker's fees from Biogen and Sanofi-­
vestigation; validation. Eoin P. Flanagan: Investigation; validation; Genzyme. She has received funding from Region Stockholm Clinical
writing – review and editing; conceptualization. Dagur I. Jonsson: Research Appointment (No. 108291). T.G. is funded by Region
Investigation; validation; writing – review and editing. Fredrik Piehl: Stockholm and Karolinska Institutet (Nos. ALF 20200224, ALF
Validation; writing – review and editing; investigation. Brenda Medicine FoUI-­987826, MedTechLabs FoUI-­991015, and CIMED
Banwell: Writing – review and editing; validation; investigation. FoUI-­976444), the Swedish Research Council (No. 2023–03146), the
Ronny Wickström: Validation; writing – review and editing; inves- Swedish Society for Medical Research's Big grant (No. S19-­0227),
tigation. Ellen Iacobaeus: Validation; writing – review and editing; Alzheimersfonden (Nos. AF-­939915, AF-­968591, AF-­994629), and
investigation. Tobias Granberg: Funding acquisition; supervision; Merck's Grant for Multiple Sclerosis Innovation. B.V.I. is funded by
conceptualization; writing – original draft; project administration; the Swiss National Science Foundation (No. P400PM_183884 and
investigation. 407940_206504), the UZH FAN Alumni Fellowship, and the Digital
Entrepreneur Fellowship from the University of Zürich.
AC K N OW L E D G M E N T S
We thank Nik Bärtsch for assistance with data analysis. DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are openly available
F U N D I N G I N FO R M AT I O N in Github at https://​github.​com/​Ineic​hen-­​Group/​​GFAP_​astro​cytop​
This work was supported by Region Stockholm and Karolinska athy_​SR.
Institutet through ALF Medicine (No. ALF 20200224 to T.G.) and
CIMED (CIMED FoUI-­976444 to TG) as well as grants of the Swiss ORCID
National Science Foundation (No. P400PM_183884, to BVI), and Eoin P. Flanagan https://orcid.org/0000-0002-6661-2910
the UZH Alumni (to B.V.I.). The sponsors had no role in the design Benjamin V. Ineichen https://orcid.org/0000-0003-1362-4819
and conduct of the study; collection, management, analysis, and in-
terpretation of the data; preparation, review, and approval of the REFERENCES
manuscript; and decision to submit the manuscript for publication. 1. Fang B, McKeon A, Hinson SR, et al. Autoimmune glial fibrillary
acidic protein astrocytopathy: a novel meningoencephalomyelitis.
JAMA Neurol. 2016;73:1297-­1307.
C O N F L I C T O F I N T E R E S T S TAT E M E N T
2. Flanagan EP, Hinson SR, Lennon VA, et al. Glial fibrillary acidic pro-
C.H. reports no disclosures. R.O. is funded by the Swedish Society tein immunoglobulin G as biomarker of autoimmune astrocytopa-
for Medical Research's Postdoctoral Grant (No. PG-­22-­0 440) and thy: analysis of 102 patients. Ann Neurol. 2017;81:298-­3 09.
has received speaker honoraria from Novartis. D.J. reports no disclo- 3. Shan F, Long Y, Qiu W. Autoimmune glial fibrillary acidic pro-
tein astrocytopathy: a review of the literature. Front Immunol.
sures. F.P. has received research grants from Janssen, Merck KGaA,
2018;9:2802. doi:10.3389/fimmu.2018.02802
and UCB; and fees for serving on data monitoring committees in 4. Xiao J, Chen X, Shang K, et al. Clinical, neuroradiological, diag-
clinical trials with Chugai, Lundbeck, and Roche, and preparation of nostic and prognostic profile of autoimmune glial fibrillary acidic
an expert witness statement for Novartis. B.B. has served as a con- protein astrocytopathy: a pooled analysis of 324 cases from pub-
lished data and a single-­center retrospective study. J Neuroimmunol.
sultant for Novartis, Roche, UCB, Sanofi-­Genzyme, and Biogen Idec.
2021;360:577718.
E.P.F. has served on advisory boards for Alexion, Genentech, Horizon 5. Qin N, Wu X, Ma Y, Wang J. Case report: autoimmune glial fibril-
Therapeutics, and UCB. He has received research support from lary acidic protein astrocytopathy misdiagnosed as tubercu-
UCB. He has received speaker honoraria from Pharmacy Times. He lous meningitis. Front Neurol. 2023;14:1123603. doi:10.3389/
has received royalties from UpToDate. E.P.F. is a site principal inves- fneur.2023.1123603
6. Kunchok A, Zekeridou A, McKeon A. Autoimmune glial fibrillary
tigator in a randomized clinical trial of rozanolixizumab for relapsing
acidic protein astrocytopathy. Curr Opin Neurol. 2019;32:452-­458.
myelin oligodendrocyte glycoprotein antibody-­associated disease 7. Sechi E, Morris PP, McKeon A, et al. Glial fibrillary acidic protein IgG
run by UCB. E.P.F. is a site principal investigator and a member of the related myelitis: characterisation and comparison with aquaporin-­
steering committee for a clinical trial of satralizumab for relapsing 4-­IgG myelitis. J Neurol Neurosurg Psychiatry. 2019;90:488-­490.
8. Mabrouki FZ, Aziouaz F, Sekhsoukh R, Yassine M. Subacute blind-
myelin oligodendrocyte glycoprotein antibody-­associated disease
ness revealing an autoimmune glial fibrillary acidic protein astrocy-
run by Roche/Genentech. E.P.F. has received funding from the NIH topathy. Cureus. 2021;13:e17588.
(R01NS113828). E.P.F. is a member of the medical advisory board of 9. Ma W, Huang C, Yang L, Luo J. MRI findings of autoimmune glial
the MOG project. E.P.F. is an editorial board member of the Journal fibrillary acidic protein astrocytopathy involving infratentorial: case
report. Radiol Case Rep. 2022;17:2515-­2518.
of the Neurological Sciences and Neuroimmunology Reports. A patent
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GFAP ASTROCYTOPATHY SYSTEMATIC REVIEW 15 of 16

10. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 state- with slowly progressive myelitis and longitudinally extensive spinal
ment: an updated guideline for reporting systematic reviews. BMJ. cord lesions. Intern Med. 2020;59:2777-­2781.
2021;372:n71. 30. Qin B, Wu R, Shu Y, et al. Protein a Immunoadsorption relieves au-
11. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan—a toimmune glial fibrillary acidic protein astrocytopathy after unsuc-
web and mobile app for systematic reviews. Syst Rev. 2016;5:210. cessful methylprednisolone treatment. Neuroimmunomodulation.
12. Li K, Wu J, Chen J, You Y. Glial fibrillary acidic protein astrocytop- 2021;28:187-­192.
athy and tuberculous meningoencephalitis occurring in a patient 31. Lin J, Lu L, Li J. Typical linear radial periventricular enhancement in
with Legionella pneumonia: a case report. BMC Neurol. 2023;23:69. a patient with glial fibrillary acidic protein (GFAP) astrocytopathy.
13. He Q, Liu J, Zhu Z, Tang Y, Long L, Hu K. Case report: revealing Neurol Sci. 2022;43:2895-­2897.
a special and rare autoimmune GFAP astrocytopathy in the spi- 32. Li X-­L , Han J, Zhao H-­T, Long Y-­M, Zhang B-­W, Wang H-­Y.
nal cord succeeding neurobrucellosis infection. Front Immunol. Autoimmune glial fibrillary acidic protein astrocytopathy with le-
2022;13:950522. sions distributed predominantly in the entire spinal cord. Ther Adv
14. Gravier-­Dumonceau A, Ameli R, Rogemond V, et al. Glial fibrillary Neurol Disord. 2020;13:1756286420909973.
acidic protein autoimmunity: a French cohort study. Neurology. 33. Chen JJ, Aksamit AJ, McKeon A, et al. Optic disc edema in glial
2022;98:e653-­e668. fibrillary acidic protein autoantibody-­positive meningoencephalitis.
15. Liao H, Chen Q, Zhang M, Chen W. MRI features and evolution of J Neuroophthalmol. 2018;38:276-­281.
autoimmune glial fibrillary acidic protein astrocytopathy: a retro- 34. Canissario R, Samkoff L, Jean MJ, Williams Z, Diep J. GFAP astro-
spective cross-­sectional and longitudinal study. Mult Scler Relat cytopathy presenting with profound intracranial hypertension and
Disord. 2022;58:103512. vision loss. J Neuroimmunol. 2022;373:577976.
16. Lin H, Huang Y, Zeng H, et al. Overlapping clinical syndromes in pa- 35. Fang H, Hu W, Jiang Z, et al. Autoimmune glial fibrillary acidic pro-
tients with glial fibrillary acidic protein IgG. Neuroimmunomodulation. tein astrocytopathy in children: a retrospective analysis of 35 cases.
2020;27:69-­74. Front Immunol. 2021;12:761354.
17. Mirian A, Sharma M, Budhram A. Linear radial brainstem enhance- 36. Han MM, Sheils CR, Crow RW. Vision loss associated with
ment in autoimmune glial fibrillary acidic protein astrocytopathy. autoimmune glial fibrillary acidic protein astrocytopathy. J
JAMA Neurol. 2022;79:82-­83. Neuroophthalmol. 2022;42:e485-­e 487.
18. Dang J, Lei S, Chen J. Autoimmune glial fibrillary acidic protein 37. Zhang W, Xie Y, Wang Y, et al. Clinical characteristics and prog-
astrocytopathy presented as isolated area postrema symdrome: a nostic factors for short-­term outcomes of autoimmune glial fibril-
case report. BMC Neurol. 2022;22:271. lary acidic protein astrocytopathy: a retrospective analysis of 33
19. Deng B, Wang J, Yu H, et al. Area postrema syndrome in auto- patients. Front Immunol. 2023;14:1136955.
immune glial fibrillary acidic protein astrocytopathy: a case se- 38. Liu L, Fang B, Qiao Z, et al. Clinical manifestation, auxiliary exam-
ries and literature review. Neurol Neuroimmunol Neuroinflamm. ination features, and prognosis of GFAP autoimmunity: a Chinese
2022;9:e200029. cohort study. Brain Sci. 2022;12:1662.
20. Gao X, Tang Y, Yang G-­D, Wei W. Autoimmune glial fibrillary acidic 39. Tokimura R, Matsuda N, Kobayashi S, Kimura A, Kanai K. Abnormal
protein astrocytopathy associated with area postrema syndrome: a evoked potentials in autoimmune glial fibrillary acidic protein astro-
case report. Front Neurol. 2021;12:803116. cytopathy. eNeurologicalSci. 2020;18:100229.
21. Equiza J, Rodríguez-­Antigüedad J, Campo-­C aballero D, et al. 40. Héraud C, Capet N, Levraut M, et al. Glial fibrillary acidic protein
Autoimmune GFAP astrocytopathy presenting with remarkable (GFAP) astrocytopathy presenting as mild encephalopathy with re-
CNS hyperexcitability and oculogyric crises. J Neuroimmunol. versible splenium lesion. Neurol Ther. 2022;11:499-­505.
2021;359:577695. 41. Osakada Y, Omote Y, Ikegami K, et al. A case of autoimmune GFAP
22. Lin J, Dong L, Yu L, Huang J. Autoimmune glial fibrillary acidic astrocytopathy with profound weight loss and increased uptake in
protein astrocytopathy coexistent with reversible splenial le- the spinal cord on 18F-­FDG PET. Neurol Clin Neurosci. 2021;9:95-­97.
sion syndrome: a case report and literature review. Front Neurol. 42. Wada T, Higashiyama Y, Kunii M, et al. Ocular flutter as the pre-
2023;14:1192118. senting manifestation of autoimmune glial fibrillary acidic protein
23. So H, Ohashi T, Yamagishi S, Mori H, Takanashi J. Case of auto- astrocytopathy. Clin Neurol Neurosurg. 2022;219:107307.
immune glial fibrillary acidic protein astrocytopathy associated 43. Yamamoto N, Inoue T, Kuki I, et al. A pediatric case of autoimmune
with Epstein–Barr virus reactivation. Clin Exp Neuroimmunol. 2022​ glial fibrillary acidic protein astrocytopathy with unique brain im-
;13:106-­110. aging patterns and increased cytokines/chemokines. Brain and
24. Wang S, Yuan J, Liu J. Autoimmune glial fibrillary acidic protein Development. 2022;44:753-­758.
(Gfap) astrocytopa-­thy accompanied with reversible splenial lesion 44. Ding J, Ren K, Wu J, et al. Overlapping syndrome of MOG-­IgG-­
syndrome (RESLES): a case report and literature review. Brain Sci. associated disease and autoimmune GFAP astrocytopathy. J Neurol.
2023;13:659. 2020;267:2589-­2593.
25. Di H, Yin Y, Chen R, Zhang Y, Ni J, Zeng X. Uncommon manifesta- 45. Huang Q, Yang H, Liu T, et al. Patients with suspected benign tu-
tions of a rare disease: a case of autoimmune GFAP astrocytopathy. mors and glial fibrillary acidic protein autoantibody: an analysis of
BMC Neurol. 2021;21:37. five cases. Int J Neurosci. 2019;129:1183-­1188.
26. Osakada Y, Omote Y, Taira Y, et al. Three cases of GFAP astrocy- 46. Long Y, Liang J, Xu H, et al. Autoimmune glial fibrillary acidic pro-
topathy, one with bilateral ovarian teratoma. Neurol Clin Neurosci. tein astrocytopathy in Chinese patients: a retrospective study. Eur J
2022;10:30-­3 4. Neurol. 2018;25:477-­483.
27. Toledano-­Illán C, Esparragosa Vázquez I, Zelaya Huerta MV, et al. 47. Kimura A, Takekoshi A, Shimohata T. Characteristics of movement
Autoimmune glial fibrillary acidic protein astrocytopathy: case re- disorders in patients with autoimmune GFAP Astrocytopathy. Brain
port of a treatable cause of rapidly progressive dementia. J Neurol. Sci. 2022;12:462.
2021;268:2256-­2258. 48. Dubey D, Hinson SR, Jolliffe EA, et al. Autoimmune GFAP as-
28. Allen A, Gulhar S, Haidari R, et al. Autoimmune glial fibrillary acidic trocytopathy: prospective evaluation of 90 patients in 1 year. J
protein astrocytopathy resulting in treatment-­refractory flaccid pa- Neuroimmunol. 2018;321:157-­163.
ralysis. Mult Scler Relat Disord. 2020;39:101924. 49. Yang X, Xu H, Ding M, et al. Overlapping autoimmune syndromes in
29. Kudo T, Kimura A, Higashida K, Yamada M, Hayashi Y, Shimohata T. patients with glial fibrillary acidic protein antibodies. Front Neurol.
Autoimmune glial fibrillary acidic protein astrocytopathy presenting 2018;9:251. doi:10.3389/fneur.2018.00251
 |

14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16284 by Cochrane Peru, Wiley Online Library on [06/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
16 of 16 HAGBOHM et al.

50. Rattanathamsakul N, Siritho S. Clinical and radiological features of

MS, NMOSD, and MOGAD, and evolution of the diagnostic pro- How to cite this article: Hagbohm C, Ouellette R, Flanagan
cesses in Thailand. Neurol Clin Neurosci. 2021;9:282-­291.
EP, et al. Clinical and neuroimaging phenotypes of
autoimmune glial fibrillary acidic protein astrocytopathy: A
systematic review and meta-­analysis. Eur J Neurol.
S U P P O R T I N G I N FO R M AT I O N
2024;00:e16284. doi:10.1111/ene.16284
Additional supporting information can be found online in the
Supporting Information section at the end of this article.