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
Benjamin V. Ineichen, Centre for
Reproducible Science, University of
Zürich, Zürich, Switzerland.
Email: benjamin.ineichen@uzh.ch
Funding information
University of Zurich, UZH Alumni;
Schweizerischer Nationalfonds zur
Förderung der Wissenschaftlichen
Forschung, Grant/Award Number:
P400PM_183884; ALF Medicine, Grant/
Award Number: ALF 20200224; CIMED,
Grant/Award Number: FoUI-­976444
Abstract
Objective: This study was undertaken to provide a comprehensive review of neuroimag-
ing characteristics and corresponding clinical phenotypes of autoimmune glial fibrillary
acidic protein astrocytopathy (GFAP-­A), a rare but severe neuroinflammatory disorder, to
facilitate early diagnosis and appropriate treatment.
Methods: A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-­
Analysis)-­conforming systematic review and meta-­analysis was performed on all avail-
able data from January 2016 to June 2023. Clinical and neuroimaging phenotypes were
extracted for both adult and paediatric forms.
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
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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-

In 2016, the discovery of a unique astrocyte-­specific IgG autoan-
tibody present in both cerebrospinal fluid (CSF) and serum was re-
ported in patients suffering from severe, corticosteroid-­responsive
meningoencephalomyelitis [1, 2]. The antigen, glial fibrillary acidic
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).
To date, a detailed understanding of causative mechanisms and
background factors for GFAP-­A is lacking.
Typically, the onset of GFAP-­A is acute or subacute, with prodro-
mal symptoms of headache, fever, or other viral states. Over days
and weeks, symptomatology may evolve to encompass movement
disturbances, visual impairment, psychiatric manifestations, and
autonomic dysfunction, among other symptoms of meningoen-
cephalomyelitis. The clinical picture may be further complicated by
coexisting neuronal autoantibodies and concurrent malignancies.
However, GFAP-­A generally exhibits a positive response to immuno-
therapies, particularly high-­dose corticosteroids administered intra-
venously, even though a propensity for relapses and, in some cases,
fatal outcomes have been reported [2–5].
Magnetic resonance imaging (MRI) plays a pivotal role in the di-
agnosis of GFAP-­A . Pathological findings in the brain and/or spinal
cord are present in a significant proportion of patients. A key diag-
nostic feature is perivascular contrast enhancement, recognized as
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-
igence, because many of its imaging findings overlap with other
autoantibody-­associated diseases, and also various types of infec-
tious meningitis/meningoencephalitis.
With the increasing number of reported cases in the literature,
there is a need for high-­level evidence addressing imaging phenotypes
ing characteristics and corresponding clinical phenotypes of GFAP-­A
was, therefore, performed. The aim is to guide in distinguishing com-
mon differential diagnoses to facilitate early diagnosis and appropriate
treatment. To further support this goal, recommendations for neuro-
imaging practices in the context of GFAP-­A are also provided.
M E TH O D S
Protocol registration
The study protocol was registered in PROSPERO (International
Prospective Register of Systematic Reviews; CRD42023392595,
https://​w ww.​crd.​york.​ac.​uk/​PROSP​ERO/​) and adhered to the
PRISMA (Preferred Reporting Items for Systematic Reviews and
Meta-­Analysis) guidelines [10].
Search strategy
A search for original studies published in full from January 2016 (the
year of the first publications of GFAP-­A) up to June 2023 was per-
formed in PubMed, Embase, and Web of Science. To maximize the
sensitivity, a broad search string only encompassing the term “astro-
cytopathy” was employed.
Inclusion and exclusion criteria
Included were original studies reporting on one or more patients with
GFAP-­A with documented GFAP-­IgG positivity, for which neuroim-
aging features were reported. This included case reports/series, co-
hort studies, randomized controlled trials, and case–control studies.

GFAP ASTROCYTOPATHY SYSTEMATIC REVIEW
Excluded were studies with only animal data, conference abstracts,
non-­English articles, and studies that reiterated previously reported
quantitative data. Reviews were excluded but retained as potential
sources of additional records.
Study selection and data extraction
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
screening. From eligible articles, the following data were extracted:
title, authors, publication year, study design, number of subjects per
group, mean/median age and sex of participants, age group (adults
vs. children, i.e., <18 years old), study country, antibody status and
detection method, clinical signs, MRI findings (brain, spinal cord, and
optic nerves), advanced neuroimaging findings (e.g., positron emis-
sion tomography [PET]), and response to corticosteroid therapy.
Data synthesis and analysis
Findings were summarized narratively. In addition, for demographic
parameters, neuroimaging findings, clinical phenotypes, and response
to corticosteroid therapy, data were pooled to obtain summary meas-
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-
ings for ≥10 adult subjects each and reported by at least three in-
dividual studies were included, and only summary-­level data were
used. Furthermore, a sensitivity analysis was performed on a sub-
group level, consisting of only the CSF GFAP-­IgG-­positive patients,
excluding patients presenting with seropositivity only. As the pri-
mary outcome, log-­transformed proportions were used. A random-­
effects model was fitted to the data. The amount of heterogeneity,
that is, τ 2, was estimated using the DerSimonian–Laird estimator.
The Q-­test for heterogeneity and the I2 statistic were calculated. A
two-­t ailed p-­value of <0.05 was considered statistically significant.
Publication bias
Publication bias was not assessed, as defined per protocol. However,
the risk of bias assessment was qualitatively assessed for the included
studies using an adjusted version of the Newcastle–Ottawa scale.
R E S U LT S
Eligible studies
In total, 641 studies were retrieved from our comprehensive data-
base search. After deduplication, 499 references remained for title
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3 of 16
and abstract screening, of which 143 studies were eligible for full-­
text search. After screening the full text of these studies, a total of
93 studies were included for the qualitative synthesis and 13 stud-
ies were eligible for a meta-­analysis (each comprising ≥10 patients).
The flow chart for study selection is presented in Figure S1.
Study characteristics and demographics
The 93 included studies comprised a total of 681 patients (375 males,
55%; 306 females, 45%). The 13 studies eligible for the meta-­analysis
comprised 535 patients (290 males, 54%; 245 females, 46%). Ages in
all 93 included studies ranged from 1 to 103 years, with a median age
of 46 years. Fifteen studies reported on a total of 88 paediatric cases
(onset age between 1 and 17 years). Further details on the demogra-
phy of the reported cases can be found in Table 1.
Risk of bias assessment
Most included studies showed a low risk of bias for the selection
domain. The selection domain was defined as whether patients pre-
sented with a clinical status of meningoencephalomyelitis (or some
variant thereof), with GFAP-­IgG detected.
Clinical features of GFAP-­A
Clinical phenotype
GFAP-­A was associated with an acute or subacute onset of men-
ingitis, encephalitis, and/or myelitis. Clinical phenotypes were
reported for 492 of 681 patients. Among these 492 patients,
meningoencephalomyelitis was most commonly observed (32%),
followed by meningoencephalitis (24%), encephalitis (12%), en-
cephalomyelitis (12%), myelitis (5%), and meningitis (4%). A com-
prehensive summary of the reported symptoms can be found in
Table 1.
The predominantly reported clinical symptoms were fever (61%
of patients), movement disturbances (59%), and headache (52%).
Movement disturbances included gait disturbance, ataxia, tremor,
limb weakness, and myoclonus. Autonomic dysfunction was less
commonly reported (38%), including urinary or bowel dysfunction,
erectile dysfunction, and blood pressure alterations.
Altered consciousness or confusion was observed in 38% of
patients. Other cognitive disturbances, such as attention deficits,
were noted in 34% of patients. In 23% of patients, there were overt
signs of psychosis such as hallucinations or severe behavioural al-
terations. Impaired visual acuity or eye movement disturbances
were documented in 28% of patients, and in approximately 50%
of these there were findings of optic disc oedema or papillitis on
clinical ophthalmological examination. Notably, 12% of patients
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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].

GFAP ASTROCYTOPATHY SYSTEMATIC REVIEW
Laboratory findings and autoimmunity
GFAP-­IgG was by definition detected in all 681 patients included
in this review. GFAP-­IgG was detected in CSF in a majority of cases
(593 patients, 87%), most commonly by cell-­based assay. GFAP-­IgG
was only detected in serum in 87 patients (13%) and found only by
stereotactic biopsy of the brain in one case [8].
Coexisting autoantibodies were reported in 179 patients
(Table 1). The meta-­analysis showed that up to 45% (95% CI = 32%–
59%) of patients can present with coexisting autoantibodies
(Figure 1c; nine studies, 212 patients). Among reported coexist-
ing autoantibodies, the most frequent was NMDAR-­IgG (28%),
followed by aquaporin-­4 (AQP4)-­IgG (16%) and myelin oligoden-
drocyte glycoprotein (MOG)-­IgG (8%). Less frequent coexisting
autoantibodies were antinuclear antibodies, anti-­Yo-­antibodies/
Purkinje cell cytoplasmic autoantibody type 1, thyroxine perox-
idase antibodies, ganglioside antibodies, anti-­Sjögren syndrome-­
related antigen A/B antibodies, and antineutrophil cytoplasmic
antibodies.
Response to immunotherapy
Treatment with immunotherapy, high-­d ose intravenous corticos-
teroids in particular (less commonly plasma exchange and intra-
venous immunoglobulin), was reported for 342 patients, of whom
302 patients (88%) responded well with a complete or partial
remission. The imaging response to intravenous corticosteroids
was often noted to be prompt, with rapid resolution of contrast
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-­
analysis on treatment response was in line with this finding, with
83% of patients (95% CI = 69%–91%) showing complete or partial
remission upon immunotherapy (Figure 1d; seven studies, 171
patients).
Neuroimaging phenotypes of GFAP-­A
Brain MRI findings
Brain MRI findings were reported in 543 patients. A detailed sum-
mary of imaging findings can be found in Table 1. In the meta-­
analysis, normal brain MRI findings were reported in 21% of patients
(95% CI = 15%–28%; Figure S2a; eight studies, 172 patients).
The most common neuroimaging manifestation was T2/FLAIR
hyperintensities, reported in 74% of patients (95% CI = 56%–87%)
in the meta-­analysis (Figure 2a; seven studies, 203 patients). These
hyperintensities were predominantly periventricular, extensive,
confluent, and hazy. Conversely, smaller and demarcated T2/
FLAIR hyperintensities in the deep white matter were less frequent.
Representative examples of neuroimaging findings in an adult case
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5 of 16
with GFAP-­A from our institution are presented in Figure 3, with a
graphical illustration in Figure 4.
Subcortical grey matter involvement was also prevalent, with
37% of patients presenting with T2/FLAIR hyperintensities and/or
contrast enhancement in the basal ganglia or thalami, frequently bi-
laterally. Cortical/juxtacortical involvement was detected in 16% of
patients. Mirroring the white matter manifestations, the grey matter
lesions were typically diffuse and/or hazy.
Contrast enhancement was observed in 58% of patients (95%
CI: 47%–68%) in the meta-­analysis (Figure 2b; 10 studies, 305
patients), most frequently located in areas with T2/FLAIR hy-
perintensities. Perivascular linear contrast enhancement was re-
ported in 45% of patients (95% CI = 31%–59%) in the meta-­analysis
(Figure 2c; nine studies, 234 patients). This enhancement typically
extended radially from the lateral ventricles but was also reported
in the cerebellum, brainstem, and basal ganglia [2, 9, 15–17].
Leptomeningeal contrast enhancement was present in 30% of pa-
tients (95% CI = 18%–46%) in the meta-­analysis (Figure 2d; eight
studies, 166 patients).
Brainstem pathology was reported in 34% of patients and cere-
bellar pathology in 19% of patients, mostly described as T2/FLAIR
hyperintensities. Area postrema lesions were highlighted in a few
studies [18–20].
Corpus callosum involvement was rather rare, reported in only
5% of the patients, and often associated with reversible splen-
ial lesion syndrome [21–24]. Findings of restricted diffusion were
found in only 3% of the patients, commonly in the corpus callosum.
Cerebral haemorrhage was reported in one single patient, located in
the thalamus [25].
Spinal cord MRI findings
Spinal cord MRI findings were commonly observed, with 49% of
patients (95% CI = 40%–62%) having an abnormal spinal cord MRI
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
thoracic involvement, and 23% had conus and/or cauda equina
involvement.
Longitudinally extensive myelitis, defined as lesions extend-
ing over three vertebral levels, was evident in 29% of patients.
Conversely, smaller spinal lesions with an extension of less than
three vertebral levels were noted in 10% of patients, frequently
manifesting in a multifocal or patchy pattern. The lesions were
predominantly located centrally within the cord, affecting the
grey matter, and characterized as hazy, subtle, or diffuse on T2-­
weighted imaging [1, 2, 7, 26, 27]. Notably, three case reports
described the lesions as bilateral longitudinal with an eccentric
location [28–30].
Spinal contrast enhancement was detected in 26% of patients,
specified as leptomeningeal in 16% and intraparenchymal (character-
ized as patchy, punctate, speckled, or scattered) in 15% of patients.
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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).
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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.
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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.
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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.
 |
10 of 16
Optic nerve MRI findings
Despite visual symptoms and optic disc oedema being described in
several case reports [33], MRI findings of optic neuritis were only
specifically reported in 19 patients. Bilateral optic neuritis was re-
ported in 10 cases [8, 14, 34–37]. Unilateral optic neuritis was re-
ported in six cases, whereas the rest of the cases were unspecified
[4, 15, 38]. Two of the cases were reported as having extensive le-
sions involving the optic chiasm [15, 36].
Advanced and nuclear neuroimaging findings
Advanced and nuclear neuroimaging modalities were reported in 21
patients.
Fluorodeoxyglucose PET findings were reported in 16 patients.
Whereas some authors reported normal findings [25], even in
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
[29, 37, 41].
Single-­photon emission computed tomography was applied in
two patients, demonstrating a decreased blood flow in the frontal
lobes in one case and an increased blood flow in the basal ganglia,
thalamus, and corona radiata in the other patient [42, 43].
MRI spectroscopy was evaluated in two patients, showing low
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
peak (a neuronal marker) were reported.
Paediatric clinical and neuroimaging phenotypes of
GFAP-­A
There were 88 paediatric cases with reports on neuroimaging phe-
notypes (54 males, 61%; 34 females, 39%), the largest study com-
prising 35 patients [35]. In the paediatric population, GFAP-­IgG was
detected in CSF in 66 patients (75%), and in serum only in the re-
maining 22 patients (25%).
In the paediatric cases, simultaneous autoantibodies were
detected in the CSF or serum in 19 patients (24%), and in five
(7%) patients there were reports of coexisting malignancy (two
cases of yolk sac tumour, paraganglioma, retroperitoneal tumour,
and ependymoma). The most common clinical phenotype was
meningoencephalitis (32%), followed by meningoencephalomy-
elitis (26%), encephalomyelitis (10%), encephalitis (8%), meningitis
(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,
and in 90% of the patients a good or partial response to immu-
nosuppressive treatment (most commonly corticosteroids) was
reported.
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HAGBOHM et al.
All 88 paediatric patients underwent brain MRI. Normal findings
were reported to a low extent (20%), and signal abnormalities were
located in the basal ganglia (38%), deep white matter (33%), brain-
stem (23%), cerebellum (16%), cortical/juxtacortical regions (10%),
and corpus callosum (15%). Restricted diffusion in the corpus callo-
sum was infrequently reported (5%).
Nearly all reported brain MRI scans (94%) included gadolinium-­
based contrast agents. Intracranial contrast enhancement was
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
contrast enhancement was also reported (9%).
Spinal cord MRI was performed in 71 paediatric patients, often
with normal findings (52%). Lesions occurred all along the spinal
cord, including longitudinally extensive myelitis (25%), whereas only
one case presented with short and patchy lesions. Leptomeningeal
enhancement was the most frequent enhancement pattern (11%).
Sensitivity analysis
A complementary meta-­analysis was performed for cases that had
confirmed GFAP antibodies in CSF (Figures S3–S5), that is, excluding
studies of cases with only seropositivity. This revealed consistent
results regarding overall effect sizes, for both clinical and imaging
characteristics, emphasizing the reliability of the findings.
DISCUSSION
The clinical spectrum of autoantibody-­m ediated neuroimmuno-
logical conditions has recently been expanded to include a new
entity, GFAP-­A . GFAP-­A is a rare but severe neuroinflammatory
disorder characterized by the presence of GFAP-­IgG autoantibod-
ies, predominantly detected in the CSF. Based on a systematic re-
view and meta-­analysis, covering data from the definition of the
disease in 2016 up until June 2023, we have generated a struc-
tured synthesis of the clinical and neuroimaging spectrum encoun-
tered with GFAP-­A .
The most notable imaging findings include the hallmark sign of
perivascular linear perivascular contrast enhancement, deep grey
matter signal abnormalities, hazy white matter hyperintensities, and
longitudinally extensive myelitis. This consolidation of the evidence
base may assist in raising the suspicion of GFAP-­A in patients with
acute onset neuroinflammation, and testing for GFAP-­IgG will dis-
tinguish these patients from those with other conditions, thereby
facilitating an early diagnosis and initiation of appropriate treatment.
Clinical phenotypes and response to treatment
Considering GFAP is an intracellular protein lacking a surface anti-
gen, the pathophysiological pathway leading to disease is obscure.

GFAP ASTROCYTOPATHY SYSTEMATIC REVIEW
It is hypothesized that GFAP-­IgG might be a surrogate marker for
an underlying cytotoxic T-­cell-­mediated autoimmune response [6].
Despite uncertain pathological mechanisms, the clinical pheno-
type, with prodromal infectious states, fever, and headache in con-
junction with a rather acute onset of psychiatric symptoms as well
as movement disorders, was unifying for a majority of the patients.
Interestingly, GFAP-­A cases have been reported in a wide age span,
including paediatric cases, and there is no clear sex predominance.
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-
though often asymptomatic, with reports of normal or only slightly
elevated intracranial pressure at lumbar puncture. The pathophysi-
ological mechanism of this phenomenon remains unclear, but inter-
estingly, GFAP is expressed in the retina, and it has been suggested
that the finding may be a result of inflammatory vasculopathy with
papillitis [33].
High-­dose intravenous corticosteroids are the most frequent
treatment in the acute stage, often with prompt and efficacious re-
sponse, although as many as every 10th patient requires intensive
care during the disease course. In terms of the long-­term prognosis,
previous studies have shown that relapses occur in up to 28% of pa-
tients within a 19-­month follow-­up [4], often during steroid tapering,
underlining the need for monitoring and consideration of mainte-
nance therapy.
The high frequency of other neuronal autoantibodies and malig-
nancies further emphasizes the need for careful diagnostic workup
[35, 44, 45]. Future studies are needed to show to what degree such
findings can explain clinical heterogeneity and possibly identify sub-
forms of GFAP-­A .
Neuroimaging phenotypes
The GFAP-­A hallmark of perivascular linear contrast enhancement
is reported in 45% of all patients in our meta-­analysis, in agree-
ment with previous larger publications [2, 14, 46, 47]. It is note-
worthy that this pattern has been observed not only in the brain
but also in the brainstem, cerebellum, and spinal cord. This finding
is dynamic and may potentially be underreported, because linear
perivascular enhancement was sometimes reported to be discov-
ered in retrospect after the detection of GFAP-­IgG. This indicates
that the perivascular enhancement pattern may be subtle and that
awareness of it and optimized imaging protocols are essential.
Temporal aspects are also crucial in the evaluation of neuroim-
aging findings in GFAP-­A [15]; however, details on the timing of
neuroimaging are lacking in many of the larger case series, imped-
ing a quantitative assessment of the temporal significance in this
systematic review.
Other consistent neuroimaging findings include diffuse sig-
nal abnormalities in both subcortical grey and white matter of
the brain [2, 47, 48], as well as longitudinally extensive myeli-
tis. Contrast enhancement of the spinal cord is to a large extent
|
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11 of 16
heterogeneous. Nevertheless, several studies reported a specific
finding of central canal contrast enhancement, corresponding to
GFAP-­e nriched regions in the rodent cord [2]. Potentially, this en-
hancement pattern could further add to the hallmark findings of
GFAP-­A .
Currently, there are few studies on advanced neuroimaging and
nuclear medicine modalities in GFAP-­A , and the diagnostic and prog-
nostic value of such modalities remains to be determined.
Paediatric perspective
Paediatric GFAP-­A tends to present with more subtle or even absent
imaging findings in the brain and spinal cord, although definite sub-
group analyses were not feasible due to the pooling of data. Larger
prospective studies are therefore needed.
Differential diagnostic cues
GFAP-­A , with its diverse manifestations, can resemble many other
diseases, including other neuroinflammatory disorders, infectious
diseases (e.g., M. tuberculosis, of which there are noteworthy ex-
amples), neurosarcoidosis, small vessel vasculitis, and lymphoma.
Clinical and laboratory features, as well as the usually prompt re-
sponsiveness to corticosteroids, may implicate differential diagnosis
in the field of autoimmune neuroinflammatory disorders. There are,
however, key clinical and imaging findings that may facilitate the di-
agnostic workup of GFAP-­A; these are summarized in Table 2, and 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-­
associated disease (MOGAD) and acute disseminated enceph-
alomyelitis (ADEM), with its prodromal state and psychiatric
symptoms in conjunction with altered consciousness. Although
GFAP-­A causes longitudinally extensive myelitis, permanent para-­
or tetraplegia was seldom reported in GFAP-­A , as opposed to
AQP4-­p ositive neuromyelitis optica spectrum disorder (NMOSD)
[49, 50]. Similarly, visual involvement in GFAP-­A is typically pain-
less and of a mild character compared to AQP4-­p ositive NMOSD,
with only rare cases of long-­term visual impairment or blindness
[8, 33, 36].
Neuroradiologically, the hallmark imaging finding of perivascu-
lar linear contrast enhancement in GFAP-­A is distinctive from other
neuroinflammatory disorders, although it is not pathognomonic,
because it may also be present in, for example, neurosarcoidosis,
small vessel vasculitis, and intravascular lymphoma [1]. The frequent
diffuse involvement of both subcortical grey and white matter is an-
other similarity with ADEM and MOGAD. Although subcortical grey
matter involvement occurs in MS, it is typically focal in the thalami,
and in AQP4-­positive NMOSD it is typically located in periventricu-
lar structures and the hypothalamus. In GFAP-­A , spinal cord lesions
are often longitudinally extensive, but usually more subtle, with less
 |

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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.
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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
Sagittal 3D T1-­weighted GRE IR/TSE
Axial 3D SWI
Coronal T2-­weighted TSE or STIR
GBCA administration
Axial T2-­weighted TSE
Axial DWI
Sagittal 3D T1-­weighted GRE IR/TSE
with GBCA
Sagittal 3D T2-­weighted FLAIR with
GBCA
White and grey matter hyperintensities, Sagittal T2-­weighted Spinal cord lesions; Dixon could
encephalitis TSE and/or STIR also be used
White and grey matter hypointensities, Sagittal T1-­weighted Precontrast image for
precontrast image for comparison (FLAIR) TSE comparison
Microbleeds, subarachnoid haemorrhage,
cortical superficial siderosis (ruling out
differential diagnosis)
Optical neuritis
Unless contraindicated GBCA administration Unless contraindicated
White and grey matter changes, encephalitis Axial T2-­weighted Spinal cord lesion topography
TSE
Infarcts, encephalitis (ruling out differential Sagittal T1-­weighted Blood–brain barrier
diagnosis) (FLAIR) TSE disruption, leptomeningeal
enhancement
Blood–brain barrier disruption, Axial T1-­weighted Coverage over suspected
leptomeningeal enhancement (FLAIR) TSE contrast enhancement
Leptomeningeal enhancement, perivascular
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-­
positive NMOSD. Furthermore, leptomeningeal and central canal
enhancement, as seen in GFAP-­A , is less characteristic of AQP4-­
positive NMOSD.
Recommendations on neuroimaging
Based on the findings in this review, we provide suggestions for
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
detecting contrast enhancement, 3D T2-­weighted FLAIR after gado-
linium may facilitate the detection of leptomeningeal enhancement.
The high frequency of spinal cord involvement in GFAP-­A underlines
the importance of spinal cord MRI.
Limitations
In our comprehensive study, we included patients presenting with
GFAP-­IgG in CSF and/or serum, but there are studies indicating
that the latter might be an unspecific finding [2, 48]. Notably, a
sensitivity analysis of only CSF-­p ositive patients revealed similar
results. Additionally, the presence of coexisting autoantibodies
and overlapping clinical and neuroimaging features, in for example
MOGAD and NMOSD, limits the ability to tease out GFAP-­A-­
specific findings in the current literature and discriminate it from
overlapping disorders. Furthermore, we report only patients who
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.
Finally, inevitable heterogeneity existed in the available data for
the meta-­analysis, emphasizing the diversity of included cohorts
and employed clinical care.
CO N C LU S I O N S
GFAP-­A can present with a range of neuroimaging and clinical find-
ings. A high clinical awareness of GFAP-­A is therefore necessary in
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
enhancement, deep grey matter involvement, and longitudinally
extensive myelitis may be indicative of GFAP-­A . Detection of coex-
isting autoantibodies and/or concomitant malignancy are important
factors to consider in the diagnostic workup of suspected cases.
Future studies should elaborate on the described clinical, laboratory,
and imaging features, explore the paediatric panorama of GFAP-­A ,
and evaluate the role of advanced MRI in the diagnostics and man-
agement of GFAP-­A .
 |
14 of 16
AU T H O R C O N T R I B U T I O N S
Benjamin V. Ineichen: Funding acquisition; supervision; conceptual-
ization; methodology; writing – original draft; project administration;
formal analysis; visualization; data curation; investigation. Caroline
Hagbohm: Conceptualization; investigation; writing – original
draft; data curation; formal analysis; validation. Russell Ouellette:
Conceptualization; visualization; writing – review and editing; in-
vestigation; validation. Eoin P. Flanagan: Investigation; validation;
writing – review and editing; conceptualization. Dagur I. Jonsson:
Investigation; validation; writing – review and editing. Fredrik Piehl:
Validation; writing – review and editing; investigation. Brenda
Banwell: Writing – review and editing; validation; investigation.
Ronny Wickström: Validation; writing – review and editing; inves-
tigation. Ellen Iacobaeus: Validation; writing – review and editing;
investigation. Tobias Granberg: Funding acquisition; supervision;
conceptualization; writing – original draft; project administration;
investigation.
AC K N OW L E D G M E N T S
We thank Nik Bärtsch for assistance with data analysis.
F U N D I N G I N FO R M AT I O N
This work was supported by Region Stockholm and Karolinska
Institutet through ALF Medicine (No. ALF 20200224 to T.G.) and
CIMED (CIMED FoUI-­976444 to TG) as well as grants of the Swiss
National Science Foundation (No. P400PM_183884, to BVI), and
the UZH Alumni (to B.V.I.). The sponsors had no role in the design
and conduct of the study; collection, management, analysis, and in-
terpretation of the data; preparation, review, and approval of the
manuscript; and decision to submit the manuscript for publication.
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
C.H. reports no disclosures. R.O. is funded by the Swedish Society
for Medical Research's Postdoctoral Grant (No. PG-­22-­0 440) and
has received speaker honoraria from Novartis. D.J. reports no disclo-
sures. F.P. has received research grants from Janssen, Merck KGaA,
and UCB; and fees for serving on data monitoring committees in
clinical trials with Chugai, Lundbeck, and Roche, and preparation of
an expert witness statement for Novartis. B.B. has served as a con-
sultant for Novartis, Roche, UCB, Sanofi-­Genzyme, and Biogen Idec.
E.P.F. has served on advisory boards for Alexion, Genentech, Horizon
Therapeutics, and UCB. He has received research support from
UCB. He has received speaker honoraria from Pharmacy Times. He
has received royalties from UpToDate. E.P.F. is a site principal inves-
tigator in a randomized clinical trial of rozanolixizumab for relapsing
myelin oligodendrocyte glycoprotein antibody-­associated disease
run by UCB. E.P.F. is a site principal investigator and a member of the
steering committee for a clinical trial of satralizumab for relapsing
myelin oligodendrocyte glycoprotein antibody-­associated disease
run by Roche/Genentech. E.P.F. has received funding from the NIH
(R01NS113828). E.P.F. is a member of the medical advisory board of
the MOG project. E.P.F. is an editorial board member of the Journal
of the Neurological Sciences and Neuroimmunology Reports. A patent
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HAGBOHM et al.
has been submitted on DACH1-­IgG as a biomarker of paraneoplastic
autoimmunity. R.W. has received honoraria for serving on advisory
boards for UCB, GW Pharma, and Octapharma and speaker's fees
from Eisai, Jazz Pharma, and Sanofi-­Genzyme. He has received fund-
ing from Region Stockholm Clinical Research Appointment. E.I. has
received honoraria for serving on advisory boards for Biogen, Sanofi-­
Genzyme, and Merck and speaker's fees from Biogen and Sanofi-­
Genzyme. She has received funding from Region Stockholm Clinical
Research Appointment (No. 108291). T.G. is funded by Region
Stockholm and Karolinska Institutet (Nos. ALF 20200224, ALF
Medicine FoUI-­987826, MedTechLabs FoUI-­991015, and CIMED
FoUI-­976444), the Swedish Research Council (No. 2023–03146), the
Swedish Society for Medical Research's Big grant (No. S19-­0227),
Alzheimersfonden (Nos. AF-­939915, AF-­968591, AF-­994629), and
Merck's Grant for Multiple Sclerosis Innovation. B.V.I. is funded by
the Swiss National Science Foundation (No. P400PM_183884 and
407940_206504), the UZH FAN Alumni Fellowship, and the Digital
Entrepreneur Fellowship from the University of Zürich.
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
in Github at https://​github.​com/​Ineic​hen-­​Group/​​GFAP_​astro​cytop​
athy_​SR.
ORCID
Eoin P. Flanagan https://orcid.org/0000-0002-6661-2910
Benjamin V. Ineichen https://orcid.org/0000-0003-1362-4819
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S U P P O R T I N G I N FO R M AT I O N
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