Di et al. BMC Neurology
(2021) 21:37
https://doi.org/10.1186/s12883-021-02070-6

CASE REPORT

Open Access

Uncommon manifestations of a rare
disease: a case of autoimmune GFAP
astrocytopathy
Hong Di1, Yue Yin1, Ruxuan Chen2, Yun Zhang1* , Jun Ni3 and Xuejun Zeng1

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

Background
Autoimmune GFAP astrocytopathy is a new autoimmune disease of the central nervous system (CNS).
The common clinical features, including fever, headache,
encephalopathy, involuntary movement, myelitis, and
visual abnormalities, have been reported. Antibodies in
CSF against GFAP-α is a biomarker and expressed in
most cases with autoimmune GFAP astrocytopathy. Furthermore, the clinical manifestations were mostly typical,
and obvious electrolyte disorder was rarely reported in
this disease. Although only 9 cases of hyponatremia in
autoimmune GFAP astrocytopathy have been reported,
* Correspondence: zhangyun10806@pumch.cn
1
Department of General Internal Medicine, Peking Union Medical College
Hospital, Chinese Academy of Medical Science and Peking Union Medical
College, Beijing 100730, China
Full list of author information is available at the end of the article

all the cases showed hyponatremia during hospitalization
that was not presented as the initial symptom. Herein,
we firstly reported a case of autoimmune GFAP astrocytopathy presented as SIADH and intractable hypokalemia at the onset of the disease.

Case presentation
A 75-year-old male, with a history of hypertension, coronary heart disease and atrial fibrillation, presented at
our hospital (Peking Union Medical College Hospital,
Beijing, China) on May 23, 2019, with fever, anorexia,
and fatigue for > 1 month. Since April 22, the patient
had developed a recurrent fever for unknown causes, accompanied by anorexia and fatigue. His temperature
peaked twice daily at a maximum of 38.5 °C. The symptoms worsened gradually after 10 days, and at a community hospital, high white blood cells and low blood

© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
changes were made. The images or other third party material in this article are included in the article's Creative Commons
licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons
licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.

Di et al. BMC Neurology

(2021) 21:37

sodium were detected. He was administered electrolyte
supplements and cephalosporins for 3 days. The fever
was controlled, hyponatremia was not corrected, and anorexia and fatigue were aggravated. Slowly, he was unable to walk without assistance. On May 16, the patient
developed unresponsiveness, lethargy, and dysuria, and
was sent to several hospitals afterward. Physical examination revealed that the tendon reflexes of the lower
limbs were weakened, and Romberg’s sign was positive;
cranial nerve function,sensory function, muscle force
and tension were all normal,bilateral Babinski signs and
Kernig’s sign were negative. Laboratory tests showed
that the white blood cell count fluctuated between 8.49
and 14.85 × 109/L (predominantly neutrophils), and
serum electrolyte levels were 128 mmol/L for sodium
(Na+), 86 mmol/L for chloride (Cl−), and 3.2 mmol/L for
potassium (K+). Other liver and kidney indexes, ESR,
CRP, immunoglobulin, complement, myocardial enzymes, and BNP were unremarkable. The 24-h Holter
test revealed sustained atrial fibrillation. Lung computed
tomography (CT) showed bronchiectasis with slight inflammatory exudation and emphysema. Brain MRI revealed multiple abnormal signals in the brain stem, the
bilateral basal ganglia, the thalamus, the corpus callosum, the left frontal lobe, and the left semi-oval center,
leading to a preliminary diagnosis of pulmonary infection with cerebral lacunar infarction. The patient was
then catheterized and given sodium supplements and
ceftazidime for 7 days, followed by levofloxacin for 3
days and low molecular weight heparin 5000 U once
daily. Consequently, there was no visible improvement,
and the patient was transferred to our hospital for further investigation and treatment on May 27. The patient
had been in a feeble condition during the disease course.
He had poor sleep and reduced appetite and had lost 15
kg in weight. During hospitalization at other hospitals,
he had a history of nausea and vomiting. He also had experienced diarrhea but defecated only once or twice a
day. Nonetheless, his urine volume and color were normal. On admission, the patient was afebrile but still unconscious. He had a blood pressure of 114/86 mmHg
and a heart rate of 103 beats/minute. His body mass
index (BMI) was 19.4 kg/m2. The superficial lymph
nodes were not palpable. No rales or rhonchi were
heard. Arrhythmia, short pulse, and cardiac auscultation
were generally normal. The liver and spleen were not
palpable below the ribs. Also, no limb edema was detected. Ataxia and suspicious neck resistance were noted.
He had normal muscle tension, knee reflexes were elicited, and negative Babinski signs were observed. The patient was unable to cooperate for further examination.
The patient’s blood electrolytes test documented that
the Na+ was 129 mmol/L, and K+ was 3.1 mmol/L; therefore, sodium and potassium were supplemented. Blood

Page 2 of 5

and urine osmotic pressure was normal. Thyroid and adrenal functions were also normal. Therefore, the SIADH
was suspected and potential causes were investigated.
The following tests were either normal or negative: antiHCV, anti-HIV, and anti-syphilis antibodies; Legionella
pneumophila antibodies; blood Cryptococcus antigen
(qualitative) test, and Brucella agglutination test; T-spot.
TB test; inflammatory markers; anti-nuclear antibodies;
Lupus anticoagulant; antiphospholipid antibodies, antineutrophil cytoplasmic antibodies; blood tumor biomarkers and serum immunofixation electrophoresis;
positron emission tomography/computed tomography
(PET/CT).
Lumbar puncture revealed normal opening pressure.
The total white blood cell count of the CSF was 34 ×
106/L, consisting of all mononuclear cells (LY% 90,
MONO% 10). Total protein was 1.58 g/L, and glucose
was not decreased. IL-6 and TNF-α were elevated, while
IL-8 and IL-10 were normal. Epstein–Barr virus (EBV)DNA was 500 copies/mL, and Cytomegalovirus (CMV)DNA and next-generation sequencing (NGS) were unremarkable. Anti-LGI1, anti-CASPR2, anti-NMDA and
Hu.Yo.Ri antibodies in the blood and the CSF were
negative. Brain contrast-enhanced MRI + diffusionweighted MRI (DWI) + fluid-attenuated inversion recovery (FLAIR) + SWI displayed multiple abnormal signals
in both thalami, the basal ganglia, the left cerebellum,
the pons, and the white matter of the bilateral cerebrum
(Fig. 1a1-a4, b1-b4).
After excluding the potential infections or malignancies, multiple autoimmune leukodystrophy of the nervous system was considered, and since June 18, after
explaining the current condition to the patient, he
agreed to be on intravenous infusion of immunoglobulin
(IVIG) 20 g daily for 5 days and intravenous methylprednisolone 40 mg daily. The patient began to gain strength
in the legs on day 3 and could stand with assistance. On
June 25, using the tissue based indirect immunefluorescence test, we detected that anti-GFAP antibody
was positive for CSF, while anti-GFAP and anti-MOG
antibodies for serum were negative, thereby leading to
the diagnosis of autoimmune GFAP astrocytopathy. The
patient was given intravenous methylprednisolone 1 g
daily for 3 days, followed by an oral taper with prednisolone 50 mg daily. After the first 3 days, his blood sodium was maintained with oral supplements. The
patient was conscious and had good orientation, and
thus, was therefore discharged on June 28.
The patient’s symptoms improved gradually, and
hence, the use of prednisolone was reduced. The patient
was on 40 mg daily prednisolone during the subsequent
follow-up and no sodium supplements; his blood electrolytes were within the normal range (K+ 4.2 mmol/L
and Na+ 141 mmol/L). CSF analysis revealed that white

Di et al. BMC Neurology

(2021) 21:37

Page 3 of 5

Fig. 1 MRI findings of the patient. MRI on May 31, 2019 (a1–a4) showed patchy abnormal lesions in the bilateral thalamus, basal ganglia, pons,
and bilateral white matter on T2 and FLAIR image. MRI with contrast on June 5 (b1–b4) revealed no enhanced lesions on the T1 image and the
abnormal lesions on the T2 image were similar to the previous MRI scan. On July 26 (c1–c4), the FLAIR images revealed that abnormal signals
were more severe and diffused than the previous MRI findings. DWI image showed new cerebral infarction in the right basal ganglia, and SWI
found a small hemorrhage in the left thalamus (indicated by arrows). MRI with contrast on July 30 (d1–d4), new cerebral infarction was found in
the right optic radiation, and the infarction of the right basal ganglia was similar to the previous scan (indicated by arrows). Also, no lesions were
enhanced. DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; SWI,
susceptibility-weighted imaging

cell count dropped to 22 × 106/L, and the protein level
was lowered to 0.67 g/L. Nonetheless, on August 9, antiGFAP antibody in CSF and serum were both positive on
a repeat testing, and head contrast-enhanced MRI + SWI

showed a wide afflicted region (Fig. 1c1-c4, d1-d4).
Given that the disease was not well-controlled, 20 g daily
intravenous immunoglobulin was administered for 5
days along with 0.5 g MMF twice daily. Consequently,

Di et al. BMC Neurology

(2021) 21:37

the patient reported improved strength of the upper and
lower limbs and could walk for 2 km on plain ground. In
the subsequent follow-ups, he was on a continual gradual reduction in prednisone that was finally maintained
at a 5 mg daily dosage plus 0.5 g MMF twice/day.

Discussion and conclusions
This is a case of autoimmune GFAP astrocytes disease
presented as SIADH and intractable hypokalemia. Fever,
fatigue, and mental disorders were prominent in this patient. Severe electrolyte disorders could lead to similar
clinical manifestations but not explain the signs of meningoencephalitis, ataxia, and cognitive abnormalities.
Further examinations showed an increased CSF lymphocyte count and protein level and multiple white matter
lesions of the central nervous system, accompanied by
positive CSF anti-GFAP antibodies. These manifestations
pointed to a diagnosis of GFAP astrocytopathy.
GFAP astrocytopathy is a newly defined autoimmune
disease of the central nervous system. It usually occurs
in patients > 40 (median age of onset: 44–50)-years-old
[1] and affects men and women equally. A study of 19
Chinese GFAP patients showed that females accounted
for 68%(13/19) of the total cases, and the overall median
age of onset was 54 (23–73) years. Among the 102
GFAP patients reported by the Mayo clinic, 54%(55/102)
were female, and the overall median age of onset was 44
(8–102)-years-old [2]. The disease is acute or subacute,
assuming a gradually aggravating or relapsing-remitting
pattern. The clinical manifestations include fever, headache, encephalopathy, involuntary movement, myelitis,
and visual abnormalities. The study by Lennon et al.,
comprising of 102 patients [3] found that the three most
common clinical manifestations were encephalitis and
meningitis (54.5%, 56/102), myelitis (10.5%, 11/102), and
encephalomyelitis (8%, 8/102). However, a Chinese study
on 19 patients with GFAP astrocytopathy disease
showed [4] that myelitis (68.4%), headache (63.2%), and
optic neuritis (63.2%) were common manifestations.
Currently, there is no diagnostic consensus for GFAP
astrocytopathy. Accumulating evidence including positive anti-GFAP-IgG antibodies in the CSF, signs of the
central nervous system inflammation, or specific manifestations on the cranial MRI support the clinical suspicion of GFAP astrocytopathy. Among these, the antiGFAP antibodies in the CSF, especially at a higher titer
than that in the serum, confirmed the diagnosis. However, for patients with typical presentations of meningoencephalomyelitis, whose anti-GFAP antibodies are
negative, clinical judgment should be made based on a
careful appraisal of other evidence [2]. Remarkable linear
enhancement oriented radially to the ventricles in cranial MRI, which is also a specific manifestation of this
disease. Reportedly [1], that normal cranial and spinal

Page 4 of 5

MRI is rare in patients with GFAP astrocytopathy, and
the T2-weighted sequences would reveal some abnormalities in about half of the patients. In this case, the patient’s clinical manifestations are consistent with the
common clinical manifestations of the disease. However,
the patient’s condition was complicated by prominent
electrolyte disorders. Hyponatremia was considered to
be caused by SIADH. Thus, it could be speculated that
hyponatremia might be caused by excessive production
of antidiuretic hormone (ADH) as a result of the lesions
in the hypothalamus. The electrolyte disturbances were
controlled after treatment with steroids, which confirmed that SIADH was secondary to GFAP astrocytopathy. The study by Kimura et al. encompassed 14 patients
with GFAP astrocytopathy disease [5]; 8/14 (57%)
showed hyponatremia during hospitalization. A retrospective study of 19 patients with GFAP astrocytopathy
in China [4] showed that only 1 patient presented SIAD
H.
Currently, the pathophysiological mechanism of GFAP
astrocytopathy is not clarified. In a previous pathological
study on GFAP astrocytopathy, MRI located lesions near
the small blood vessels, with fewer astrocytes and showing dysregulation of T cells. Previous case reports [1]
showed that GFAP astrocytopathy might be secondary
to other diseases. About 25% of the patients were found
to have tumors, among which, 75% were teratomas, and
20% of the patients had autoimmune diseases, including
type 1 diabetes and rheumatoid arthritis. Another study
[4] showed that 13/19 Chinese patients had other autoantibodies, including anti-nuclear antibody, antiendothelial cell antibody, anti-neutrophil cytoplasm antibody, anti-double-stranded DNA antibody, anti-RA33
antibody, and anti-SSA/Ro antibodies. About 30–34% of
the cases were preceded by an infection. Our case is an
elderly male. Although there is no evidence of malignancies, the disease could still be a sign of the paraneoplastic syndrome before the tumor became visible.
Therefore, regular tumor screening should be considered. Moreover, no evidence of autoimmune diseases
was found. The infection screening found that EBVDNA was low titer but positive in cerebrospinal fluid;
however, the patient had no manifestations of the infection. Also, the high sensitivity second-generation sequencing to evaluate the CSF pathogenesis did not find
any evidence of viral infection; therefore, EBV infection
was not considered.
The hallmark of autoimmune GFAP astrocytopathy is
immunosuppressive therapy. Typically, the disease has
good response to the initial treatment with glucocorticoids in a monophasic course. However, about 20% of
the patients experience disease relapse or become
steroid-dependent and require combined immunosuppressive therapy [1]. At present, the reported prognosis

Di et al. BMC Neurology

(2021) 21:37

of the disease is diversified. Some patients reported a
good prognosis, while the long-term follow-up of 7 patients in China [6] showed that severe disability and
poor prognosis are common, which might be related to
delayed diagnosis (the average time for diagnosis is 12
months) and severe symptoms. Our patient was diagnosed 1 month after the disease onset, which was significantly shorter than the average. Interestingly, symptoms
abated after treatment with steroids, yet the continuously positive antibodies and the progression in imaging
warranted combined immunosuppressant therapy.
Moreover, clinicians should be cautious while monitoring potential malignancies or other underlying processes
during follow-ups.
Electrolyte disorders are not uncommon in the elderly
but occasionally could reveal severe diseases. Thus, careful examination and increased awareness of rare etiologies are required in clinical decision-making for optimal
disease management and improved prognosis.
Abbreviations
GFAP: Glial fibrillary acidic protein; SIADH: Syndrome of inappropriate
antidiuretic hormone secretion; MRI: Magnetic resonance imaging;
CSF: Cerebrospinal fluid; SWI: Susceptibility-weighted imaging;
MMF: Mycophenolate mofetil; CNS: Central nervous system; CT: Computed
tomography; BMI: Body mass index; PET/CT: Positron emission tomography/
computed tomography; EBV: Epstein–Barr virus; CMV: Cytomegalovirus;
NGS: Next-generation sequencing; DWI: Diffusion-weighted MRI; FLAIR: Fluidattenuated inversion recovery; ADH: Antidiuretic hormone
Acknowledgements
We thank all the physicians from PUMCH participated in the caring of the
patient.
Authors’ contributions
DH designed and wrote the manuscript. YY, CRX and ZXJ examined the
patient. NJ analysed the neuroimages. ZY examined the patient, designed
the case report and helped draft the manuscript. All authors read and
approved the final manuscript.
Funding
This work was supported by grants from National Natural Science
Foundation of China (Grand No.81901667), and Clinical and Translational
medical research fund of Chinese Academy of Medical Sciences
(No.2019XK320013).
The funders had no role in the design of the study and collection, analysis,
and interpretation of data and in writing the manuscript.
Availability of data and materials
All data generated and analysed during this study are included in this article.
Ethics approval and consent to participate
This study was approved by The Institutional Review Board (IRB) of Peking
Union Medical College Hospital (PUMCH).
Consent for publication
A signed informed consent was obtained from the patient for publication of
this case report and accompanying neuroimages.
Competing interests
The authors declare no competing interests.
Author details
1
Department of General Internal Medicine, Peking Union Medical College
Hospital, Chinese Academy of Medical Science and Peking Union Medical

Page 5 of 5

College, Beijing 100730, China. 2Department of Internal Medicine, Peking
Union Medical College Hospital, Chinese Academy of Medical Science and
Peking Union Medical College, Beijing 100730, China. 3Department of
Neurology, Peking Union Medical College Hospital, Chinese Academy of
Medical Science and Peking Union Medical College, Beijing 100730, China.
Received: 5 November 2020 Accepted: 21 January 2021

References
1. Kunchok A, Zekeridou A, McKeon A. Autoimmune glial fibrillary acidic
protein astrocytopathy. Curr Opin Neurol. 2019;32(3):452–8.
2. Shan F, Long Y, Qiu W. Autoimmune glial Fibrillary acidic protein
Astrocytopathy: a review of the literature. Front Immunol. 2018;9:2802.
3. Flanagan EP, Hinson SR, Lennon VA, Fang B, Aksamit AJ, Morris PP, et al.
Glial fibrillary acidic protein immunoglobulin G as biomarker of
autoimmune astrocytopathy: analysis of 102 patients. Ann Neurol. 2017;
81(2):298–309.
4. Long Y, Liang J, Xu H, Huang Q, Yang J, Gao C, et al. Autoimmune glial
fibrillary acidic protein astrocytopathy in Chinese patients: a retrospective
study. Eur J Neurol. 2018;25(3):477–83.
5. Kimura A, Takekoshi A, Yoshikura N, Hayashi Y, Shimohata T. Clinical
characteristics of autoimmune GFAP astrocytopathy. J Neuroimmunol. 2019;
332:91–8.
6. Yang X, Liang J, Huang Q, Xu H, Gao C, Long Y, et al. Treatment of
autoimmune glial Fibrillary acidic protein Astrocytopathy: follow-up in 7
cases. Neuroimmunomodulation. 2017;24(2):113–9.

Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.