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\begin{document}

\title{A case of Glial fibrillary acidotic protein (GFAP) meningoencephalitis
with Rheumatoid Arthritis}



\author[1]{Mehri  Salari}%
\author[2]{Masoud Etemadifar}%
\author[3]{Reyhaneh Soleymani}%
\author[4]{Aditya  Murgai}%
\author[5]{Ronak Rashedi}%
\affil[1]{Shahid Beheshti University of Medical Sciences}%
\affil[2]{Isfahan University of Medical Sciences}%
\affil[3]{Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical Center of Excellence}%
\affil[4]{Zydus hospital, Ahmedabad, India}%
\affil[5]{Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical Center of Excellence, Shahid Beheshti University of medical Sciences}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\begin{abstract}
The reported case is a 53-year-old woman with the history of
long-standing rheumatoid arthritis who first presented with acute-onset
dizziness and gait disturbance, periventricular linear and radial
enhancement pattern on MRI and normal CSF analysis, successfully treated
with an increase in the dose of oral steroids.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an
inflammatory disease of the central nervous system (CNS). It can affect
optic nerve, cerebral and cerebellar white matter, cortex, spinal cord
and meninges producing a wide spectrum of clinical manifestations.
Meningoencephalitis is the most common clinical presentation. Diagnosis
is confirmed by the presence of CSF immunoglobulin-G (IgG) against GFAP,
an intracellular astrocytic intermediate filament protein.(1)

Common clinical presentation includes encephalopathy, psychiatric
disorders, tremor, ataxia, seizures, myelopathy, and meningitis. (2,3)

This disorder is equally common in both men and women.(4) Association
with other autoimmune disorders like autoimmune thyroid disease, Type-1
diabetes mellitus, and rheumatoid arthritis is seen in about 20\% of the
cases. (3) Neoplasm is found in about 25\% of cases, most common being
ovarian teratoma. (3)

Brain imaging studies reveal a characteristic pattern of linear and
radial perivascular enhancement in the cerebral white matter,
originating from GFAP-enriched periventricular areas. Occasionally a
similar pattern of radial enhancement is seen in the cerebellum. (3,5)
CSF analysis invariably shows distinct inflammatory changes. (3) An
extensive inflammation is seen around microvessels in pathological
studies, which is in correlation with the radial inflammatory changes
seen in brain MRI. (6) Here we report a case of GFAP associated
meningo-encephalitis in a case of rheumatoid arthritis.

\textbf{Case report:}

A 53-year-old Iranian woman was visited in neurology clinic with a
history of acute onset dizziness and gait disturbance for 1 week. There
was no history of ear discharge, fullness, tinnitus or hearing loss. She
gave a history of long-standing rheumatoid arthritis and was on low dose
maintenance corticosteroid therapy. Physical examination revealed normal
higher mental functions, speech and cranial nerves. There was no
nystagmus, and saccades and pursuit were normal. Head impulse test was
normal. Gait examination showed wide base, ataxic gait with difficulty
in doing tandem walk. No dysmetria was seen in upper limbs. Rest of the
neurological exam was normal. Brain MRI showed periventricular linear
and radial enhancement pattern. CSF analysis including protein, glucose,
WBC, ADA, ACE, VDRL, and cytology were normal. She was treated with an
increase in the dose of oral steroids and all her symptoms improved in
few days.

After a year she once again presented with a subacute onset, moderate to
severe holocephalic headache. There was no papilledema and her
neurological examination was normal. This time again she responded to an
increase in the dose of oral steroids. A year later, for the third time
she presented with rapid cognitive decline and gait unsteadiness. This
time she had gaze evoked nystagmus and ataxic wide base gait on physical
exam. Brain MRI with contrast was repeated which showed bilateral
diffuse, pachymeningeal and leptomeningeal enhancement (Figure 1). CSF
examination was once again normal. Her work up for infective causes
including tuberculosis was negative. According to her Brain MRI imaging
with relapsing remitting course steroid responsive ataxia and aseptic
meningitis, a clinical decision was made to send her serum for GFAP IgG
antibodies, which came back as positive.

\textbf{Discussion:}

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy, is a
recently described clinical entity presenting with aseptic meningitis
and a variety of neurological manifestations. It is a relatively new
addition to an ever-increasing list of autoimmune cerebellar ataxia
syndromes. it is defined by the presence of GFAP IgG in serum and CSF
which shows a similar pattern of immuno-florescence like AQP4 antibody
binding to pial and subpial astrocytes. (1)

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy can
appear with other autoimmune diseases, systemic infections or as a
para-neoplastic disorder. (3,4,6) Many other antibodies including
NMDAR-IgG, AQP4-IgG, antinuclear, anti -endothelial cell, anti
-cardiolipin, anti -neutrophil cytoplasmic and anti -double -stranded
DNA can be found in serum of patients with GFAP astrocytopathy.(7)
30--40\% of patients may have symptoms of systemic infection before the
onset of CNS manifestations. (3) Some patients develop the disorders
after Herpes Simplex type 1 or Varicella zoster viral infections.(8,9)
Our case also had a history of long-standing rheumatoid arthritis. In a
previously published case series of 22 patients with GFAP associated
syndrome, three subjects had coexisting rheumatoid arthritis. GFAP has
also been identified as an auto-antigen in the synovial fluid of
patients with RA. (10) Pachymeningitis in GFAP astrocytopathy has never
been reported before but can rarely be seen in long standing rheumatoid
arthritis.

Clinical symptoms in our case responded very well to oral steroids. Most
of the cases show rapid clinical and radiological improvements upon
starting corticosteroids with 20--50\% of patients having relapsing
course requiring more prolonged therapy. (3,7,8,11,12) Prognosis varies
but is good with appropriate treatment in most of the cases. (2,13)

\textbf{Conclusion:}

This case highlights the co-occurrence of rheumatoid arthritis with GFAP
associated astrocytopathy, and expands on the previously reported cases
with similar association. This might also suggest a common immune
pathogenesis.

Abbreviations:

GFAP: Autoimmune glial fibrillary acidic protein

CNS: central nervous system

CSF: cerebrospinal fluid

IgG: immunoglobulin-G

AQP4: aquaporin-4

NMDAR: N-methyl-D-aspartate receptor

\textbf{References :}

1. Fang B, McKeon A, Hinson SR, Kryzer TJ, Pittock SJ, Aksamit AJ, et
al. Autoimmune glial fibrillary acidic protein astrocytopathy: A novel
meningoencephalomyelitis. JAMA Neurol {[}Internet{]}. 2016 Nov 1
{[}cited 2020 Oct 9{]};73(11):1297--307. Available from:
https://pubmed.ncbi.nlm.nih.gov/27618707/

2. Kunchok A, Zekeridou A, McKeon A. Autoimmune glial fibrillary acidic
protein astrocytopathy {[}Internet{]}. Vol. 32, Current Opinion in
Neurology. Lippincott Williams and Wilkins; 2019 {[}cited 2020 Oct 9{]}.
p. 452--8. Available from: https://pubmed.ncbi.nlm.nih.gov/30724768/

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
{[}Internet{]}. 2017 Feb 1 {[}cited 2020 Oct 9{]};81(2):298--309.
Available from: https://pubmed.ncbi.nlm.nih.gov/28120349/

4. Dubey D, Pittock SJ, Kelly CR, McKeon A, Lopez-Chiriboga AS, Lennon
VA, et al. Autoimmune encephalitis epidemiology and a comparison to
infectious encephalitis. Ann Neurol {[}Internet{]}. 2018 Jan 1 {[}cited
2020 Oct 9{]};83(1):166--77. Available from:
https://pubmed.ncbi.nlm.nih.gov/29293273/

5. Salvarani C, Brown RD, Calamia KT, Christianson TJH, Huston J,
Meschia JF, et al. Angiography-negative primary central nervous system
vasculitis: A syndrome involving small cerebral vessels. Medicine
(Baltimore) {[}Internet{]}. 2008 Sep {[}cited 2020 Oct
9{]};87(5):264--71. Available from:
https://pubmed.ncbi.nlm.nih.gov/18794709/

6. Yang X, Xu H, Ding M, Huang Q, Chen B, Yang H, et al. Overlapping
autoimmune syndromes in patients with glial fibrillary acidic protein
antibodies. Front Neurol {[}Internet{]}. 2018 Apr 25 {[}cited 2020 Oct
9{]};9(APR). Available from: https://pubmed.ncbi.nlm.nih.gov/29755396/

7. 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 {[}Internet{]}. 2018 Mar 1 {[}cited
2020 Oct 9{]};25(3):477--83. Available from:
https://pubmed.ncbi.nlm.nih.gov/29193473/

8. Dubey D, Hinson SR, Jolliffe EA, Zekeridou A, Flanagan EP, Pittock
SJ, et al. Autoimmune GFAP astrocytopathy: Prospective evaluation of 90
patients in 1 year. J Neuroimmunol {[}Internet{]}. 2018 Aug 15 {[}cited
2020 Oct 9{]};321:157--63. Available from:
https://pubmed.ncbi.nlm.nih.gov/29793728/

9. Li J, Xu Y, Ren H, Zhu Y, Peng B, Cui L. Autoimmune GFAP
astrocytopathy after viral encephalitis: A case report. Mult Scler Relat
Disord {[}Internet{]}. 2018 Apr 1 {[}cited 2020 Oct 9{]};21:84--7.
Available from: https://pubmed.ncbi.nlm.nih.gov/29499442/

10. Biswas S, Sharma S, Saroha A, Bhakuni DS, Malhotra R, Zahur M, et
al. Identification of Novel Autoantigen in the Synovial Fluid of
Rheumatoid Arthritis Patients Using an Immunoproteomics Approach. PLoS
One. 2013;8(2).

11. Iorio R, Damato V, Evoli A, Gessi M, Gaudino S, Di Lazzaro V, et al.
Clinical and immunological characteristics of the spectrum of GFAP
autoimmunity: A case series of 22 patients. J Neurol Neurosurg
Psychiatry. 2018;89(2):138--46.

12. 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 {[}Internet{]}. 2017 Oct 1 {[}cited 2020
Oct 9{]};24(2):113--9. Available from:
https://pubmed.ncbi.nlm.nih.gov/28922662/

13. McKeon A, Tracy JA, Pittock SJ, Parisi JE, Klein CJ, Lennon VA.
Purkinje cell cytoplasmic autoantibody type 1 accompaniments: The
cerebellum and beyond. Arch Neurol {[}Internet{]}. 2011 Oct {[}cited
2020 Oct 9{]};68(10):1280--7. Available from:
https://pubmed.ncbi.nlm.nih.gov/21670387/

Figure Legends:

Figure 1: Sagittal and axial T1-weighted post gadolinium brain MRI
showed bilateral diffuse, pachymeningeal and leptomeningeal enhancement.

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