International Journal of Hematology
https://doi.org/10.1007/s12185-019-02702-1

CASE REPORT

A case of central nervous system graft‑versus‑host disease
following allogeneic stem cell transplantation
Gi‑June Min1 · Silvia Park1 · Sung‑Soo Park1 · Jae‑Ho Yoon1 · Sung‑Eun Lee1 · Byung‑Sik Cho1,2 · Ki‑Seong Eom1,2 ·
Seok Lee1,2 · Hee‑Je Kim1,2 · Chang‑Ki Min1,2 · Seok‑Goo Cho1 · Dong‑Wook Kim1,2 · Jong‑Wook Lee1 · Yoo‑Jin Kim1,2
Received: 10 April 2019 / Revised: 1 July 2019 / Accepted: 4 July 2019
© Japanese Society of Hematology 2019

Abstract
Graft-versus-host disease (GVHD) is a serious complication of allogeneic stem cell transplantation (SCT). Here, we report
a rare case of GVHD involving the central nervous system (CNS). A 35-year-old woman was diagnosed with myelodysplastic syndrome unclassifiable and underwent allogeneic peripheral blood SCT for disease progression to myelodysplastic
syndrome with excess blasts-2. One year following SCT, she experienced chronic oral and hepatic GVHD symptoms, which
were managed with oral steroids and tacrolimus. Sixteen months after SCT, she developed sudden-onset, generalized,
tonic–clonic-type seizures. Magnetic resonance imaging and cerebrospinal fluid evaluation showed multiple discrete white
lesions and elevated IgG levels. Brain biopsy revealed periventricular plaques with the destruction of axons, representing a
demyelinating disease of the CNS. We diagnosed the case as CNS GVHD. Neurologic symptoms gradually improved with
methylprednisolone pulse therapy and total plasma exchange combined with a calcineurin inhibitor; the brain lesions nearly
disappeared after decreasing steroid maintenance dosage, and were completely resolved 1 year after the onset of CNS GVHD.
The patient is CNS GVHD-symptom-free, 3-year post-transplantation. Thus, CNS GVHD should be considered in cases of
newly developed neurologic symptoms in SCT recipients showing evidence of preceding chronic GVHD.
Keywords Central nervous system graft-versus-host disease · Allogeneic stem cell transplantation · Demyelination

Introduction
Allogeneic stem cell transplantation (SCT) is an important
therapeutic option to treat hematologic diseases, but its use
is limited by a wide spectrum of adverse events. Among
them, graft-versus-host disease (GVHD) is a major serious complication contributing to patient morbidity and
mortality. GVHD is a systemic syndrome mediated by
immunocompetent donor ­CD3+ T cells, and its frequent
targets are the mouth, eye, skin, gastrointestinal tract, and
liver. However, only a few reports have described GVHD
affecting the central nervous system (CNS). CNS GVHD
* Yoo‑Jin Kim
yoojink@catholic.ac.kr
1

2

Department of Internal Medicine, Seoul St. Mary’s
Hematology Hospital, College of Medicine, The Catholic
University of Korea, Banpo‑daero 222, Seocho‑Gu,
Seoul 06591, Republic of Korea
Leukemia Research Institute, College of Medicine, The
Catholic University of Korea, Seoul, Korea

remains controversial because involvement of the CNS is
less common and hard to distinguish from common neurological complications of SCT [1, 22]. The neurological
complications observed in allogeneic SCT recipients are
usually related to CNS infection, metabolic abnormalities,
cerebrovascular events, drug toxicity, Epstein–Barr virusassociated lymphoproliferative disease, posterior reversible
encephalopathy syndrome, and leptomeningeal relapse of
malignancy [2]. In the present study, we report a case of
alloimmune-mediated encephalomyelopathy considered to
be chronic CNS GVHD with demyelinating features after
receiving allogeneic SCT, which was successfully treated
with steroid pulse therapy and an immunosuppressant.

Case report
In October 2014, a 35-year-old woman visited the hospital
with a complaint of moderate dyspnea and was diagnosed
with myelodysplastic syndrome (MDS) unclassifiable. In
2015, she became transfusion-dependent, and bone marrow

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G.-J. Min et al.

aspiration revealed disease progression to MDS excess
blasts-2. The patient underwent allogeneic SCT using HLAidentical unrelated donor peripheral blood, with a conditioning regimen of fludarabine (30 mg/m2/day for 5 days),
anti-thymocyte globulin (ATG; 2.5 mg/kg/day for 4 days),
and busulfan (3.2 mg/kg/day for 2 days). Tacrolimus plus a
short course of methotrexate was administered for GVHD
prophylaxis. Approximately 1 year after allogeneic SCT, the
patient started to suffer from the dry mouth with lichen-type
features and partial limitation of oral intake associated with
mildly elevated bilirubin levels, but did not reach > 3 mg/dL.
These overall mild-grade chronic GVHD (oral score 1, liver
score 1, and overall score mild, because the patient had two
organs’ involvement with a maximum score of 1) symptoms
were managed with oral steroids and tacrolimus.
The patient presented to the emergency department
12 months after chronic GVHD diagnosis with sudden-onset
generalized tonic–clonic (GTC)-type seizures, with a duration of 30 s. A neurological examination revealed symmetrical lower leg weakness [Medical Research Council (MRC)
grade 2] associated with hypoesthesia below T2 level and

increased knee- and ankle-deep tendon reflex. The patient
also complained of a moderate headache and blurred vision
in both eyes. However, there was no pathologic reflex, and
following a mini-mental state examination, the cranial nerve
and cerebellar function test results were normal. Brain magnetic resonance imaging (MRI) revealed T1 low, T2 high
multifocal ring enhancement lesions in the left occipital,
right frontal, and left-inferior frontal–subcortical periventricular area with mild perilesional edema, which is consistent with demyelinating features (Fig. 1a, b). A spine MRI
showed multifocal nodular leptomeningeal enhancement and
nodular intramedullary enhancing lesions along the spinal
cord, predominantly at the mid-thoracic spine (Fig. 1c).
Because these multifocal lesions in brain and spine MRI
find highly suspicious of invasive fungal infection or disease
relapse as Chloroma, we decided to stopped oral steroids
(prednisolone) 5 mg and tacrolimus 0.5 mg after reviewed
imaging studies.
The cerebrospinal fluid (CSF) was clear, with normal
pressure and white blood cell counts (1 cell/μL); total protein was 27.8 mg/dL, glucose 119 mg/dL, and LDH below

Fig. 1  A brain MRI revealed T2 FLAIR high multifocal ring
enhancement lesions in the left occipital (a), right frontal (b), and
left-inferior frontal–subcortical periventricular area (a), with mild
perilesional edema, which is consistent with the demyelinating
feature. A spine MRI showed multifocal nodular leptomeningeal

enhancement and nodular intramedullary enhancing nodules (indicated by arrows) along the spinal cord, predominantly at the mid-thoracic spine (c). A follow-up brain MRI showed interval improvement
of multiple non-enhancing T2 and FLAIR hyperintensity lesions in
the bilateral frontal and temporal lobes (d, e)

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A case of central nervous system graft-versus-host disease following allogeneic stem cell…

50 U/L. There was no evidence of malignancy and bacterial or fungal growth according to the cytology and culture
results, respectively. The CSF tests for Acid-Fast Bacilli
stain, culture, with Mycobacterium tuberculosis reverse
transcription polymerase chain reaction (RT-PCR), cytomegalovirus RT-PCR, varicella zoster virus RT-PCR, herpes
simplex virus culture with type I/II RT-PCR, enterovirus
culture, toxoplasma IgM/IgG using enzyme-linked immunosorbent assay, cryptococcus antigen assay, treponema
pallidum antibody, and CSF latex agglutination test for
Streptococcus pneumoniae, Streptococcus Group B, Haemophilus influenzae, Neisseria meningitidis (A, B, C, W135,
X, and Y), and Escherichia coli K1 species were negative.
The oligoclonal band and anti-aquaporin4 IgG were not
detected, but the IgG level was elevated to 3.69 mg/dL (reference range; 0.63–3.35 mg/dL) in the CSF sample. Levels

of serum autoimmune markers such as anti-SS-A/Ro, antiSS-B/La, anti-nuclear antibody, anti-neutrophil cytoplasmic
antibody, rheumatoid factor, serum C3, C4, CH50, and IgG/
A/M were all within normal limits. For diagnosis, the patient
underwent a navigation-guided craniotomy, with brain mass
excision biopsy using an ultrasonogram-guided trans-sulcus
approach. The brain specimen revealed a loss of myelin fibers, perivascular T-cell infiltration (­ CD3+), and macrophage
infiltration associated with reactive gliosis. Immunohistochemistry revealed infiltration of CD3, CD20, and CD68expressing lymphocytes and monocytes associated with
loss of myelin fiber shown by neurofilament and glial fibrillary acidic protein (GFAP) (Fig. 2a–f). Alpha thalassemia/
mental retardation syndrome X-linked (ATRX) gene, isocitrate dehydrogenase 1 (IDH-1), and antigen Ki-67 staining
were performed to rule out any possibilities of malignancy,

Fig. 2  The pathology sample of the cerebrum excision biopsy
revealed the loss of myelin fibers, macrophage infiltration, and reactive gliosis, which is consistent with perivascular inflammation predominately located in brain parenchyma. Hematoxylin–eosin staining
revealed lympho-histiocytic vasculitis with perivascular infiltration
around small and medium vessels (magnification ×100) (a). The
inflammatory cells were T lymphocytes expressing CD3 (magnification ×100) (b) moderate expression of CD20 (magnification ×100)
(c) and CD68 (magnification ×100) (d) associated with loss of myelin

fiber shown by neurofilament (magnification ×100) (e) and GFAP
(magnification ×100) (f) according to immunohistochemistry, but not
ATRX (magnification ×100) (g) IDH-1 (magnification ×100) (h) and
Ki-67 2% (magnification ×100) (i). ATRX status is one of the critical markers that define the molecular classification of gliomas. IDH-1
immunohistochemistry reliably detects IDH-1 mutation in gliomas
and other solid malignancies combined with Ki-67, which is strictly
associated with cell proliferation and correlated with the clinical
course of malignancy

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G.-J. Min et al.

especially gliomas or other CNS-origin tumors, and results
showed negative findings (Fig. 2g–i).
Since there was no evidence of another disease, we diagnosed the condition as CNS GVHD with demyelinating features. The patient was treated with intravenous methylprednisolone pulse therapy (1 g/day for 7 days), subsequently
tapered by 50% of the preceding dose every 3 days, total
plasma exchange every other day for six times, in combination with tacrolimus, maintaining a therapeutic plasma
level of 10–15 ng/mL. About 3 weeks after initiation of
treatment, we changed intravenous methylprednisolone to
an equivalent dose of oral prednisolone and tapered its dose
by 10 mg every 3 days until reaching the maintenance dose
of 0.1 mg/kg/day. The motor symptoms improved gradually
after 4 weeks, and the patient could ambulate with minor
support. The patient was discharged with strength in the
lower extremities at MRC grade 4, steady improvement in
sensory numbness, and improved vision, dry mouth, and
bilirubin levels. A follow-up brain MRI, at 4 weeks from
the start of methylprednisolone treatment, showed interval
improvement of multiple non-enhancing T2 and FLAIR
hyperintensity lesions in the bilateral frontal and temporal
lobes (Fig. 1d, e).
The patient’s improved neurological symptoms remained
stable one and a half years after transplantation, despite the
tapering of the oral prednisolone dose to 0.1 mg/kg/day,
and a lower therapeutic range of oral tacrolimus. After the
patient’s motor and sensory functions were fully recovered
(to MRC grade 5), steroid maintenance therapy was stopped
1 year after the onset of CNS GVHD, and there has been no
evidence of relapse or newly developing neurologic symptoms since then.

Discussion
Following allogeneic SCT, patients are at risk of comorbidities due to acute or chronic GVHD and any organ systems
can be involved in the latter [3]. However, there are only a
few reports of patients with CNS manifestation as a feature
of GVHD [1, 4–17]. A rodent study suggested that the brain
and other CNS tissue can be a target for GVHD [18, 19], but
it is not yet considered a typical feature in the NIH consensus 2014 [20], and the incidence or disease course of CNS
GVHD remains controversial because of its rarity. There is a
debate about whether CNS manifestations of chronic GVHD
constitute an independent clinical entity, or they only result
from complications of the cumulative effects of heavy treatments and procedures during allogeneic SCT [21].
Recently, the Openshaw group suggested helpful diagnostic guidelines for patients presenting both chronic GVHD
and unexplained CNS signs and symptoms [22]. In following year, CNS manifestations of chronic GVHD were also

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described as a distinct entity in the Consensus Conference
on Clinical Practice in chronic GVHD [23]. There is a total
of six diagnostic criteria, which include two mandatory features: (i) occurrence with chronic GVHD affecting other
organs and (ii) neurological signs of CNS involvement without another explanation. The other four facultative features
are: (i) corresponding brain MRI abnormality, (ii) abnormal
CSF features (pleocytosis, elevated immunoglobulin G or
protein level, and oligoclonal bands), (iii) pathological brain
biopsy or post-mortem examination, and (iv) response to
immunosuppressive therapy. In the present case, the patient
met all six diagnostic criteria for CNS GVHD and responded
well to steroid pulse therapy with maintenance immunosuppressive therapy without any evidence of relapse.
Myelin-specific antibodies or T lymphocytes are a major
cause of demyelination, which coordinates an immunemediated attack against the myelin sheath. There are a few
case reports of demyelination during chronic GVHD affecting the optic nerve, cerebral white matter, spinal cord, or
the CNS and peripheral nervous system simultaneously, but
histology of patients with demyelinating CNS GVHD features is very rare [6, 10, 14, 16, 24]. We found increased
numbers of diffusely infiltrating C
­ D3+, ­CD20+, and CD68
cells with a loss of myelinated nerve fibers by Luxol fast blue
staining, which is consistent with that observed in demyelinating disorders such as multiple sclerosis (MS) [25]. MRI
imaging revealed multiple white matter lesions of the brain
and spinal cord, also consistent with the findings of MS [25].
Distinguishing CNS GVHD with demyelinating features
from other immune-mediated demyelinating disorders only
by clinical findings might not be possible. Hence, patients
should have at least one additional systemic sign of chronic
GVHD before CNS GVHD is suspected, and like in this
case, the patient should fulfill the proposed diagnostic criteria to make a definite (meeting all six criteria) or possible
(meeting two mandatory and at least two facultative criteria)
CNS GVHD diagnosis.
The treatment of CNS GVHD is not different from that of
conventional chronic GVHD treatment and should include
immunosuppression. This patient was treated with steroid
pulse therapy combined with a therapeutic dose of tacrolimus. The short-term supportive total plasma exchange every
other day was added, similar to MS treatment. Following
steroid pulse therapy combined with calcineurin for chronic
GVHD [2, 26], the patient’s neurologic symptoms gradually
improved. The patient’s clinical course became temporarily
worse during tapering of the dose of methylprednisolone
without modifying the therapeutic dose of tacrolimus. However, unlike the typical clinical course of MS (wherein gradual deterioration is observed during the relapsing–remitting
form of the disease), the patient’s neurological symptoms
finally improved after the steroid maintenance dose and did
not relapse after discontinuation.

A case of central nervous system graft-versus-host disease following allogeneic stem cell…

In conclusion, CNS GVHD should be considered in case
of newly developed neurologic symptoms in SCT recipients who had evidence of preceding chronic GVHD. CNS
GVHD is a rare and severe complication after allogeneic
SCT that can be difficult to diagnose. Continued gathering,
reporting, and work-up of similar cases remain important to
develop accurate treatment strategies and differential diagnosis criteria.

Compliance with ethical standards
Conflict of interest The authors declare that there is no conflict of interest regarding the publication of this article.
Human/animal rights This study conducted according to the Declaration of Helsinki and the Institutional Review Board and Ethics Committee guidelines of the Seoul St. Mary’s Hospital.

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