Possible Chronic Graft-versus-host Disease in the Central Nervous System Manifesting as Cerebellar Ataxia after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia

Abstract

A 44-year-old woman was admitted to our hospital with a fever, dizziness, and gait disturbance after undergoing allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia followed by graft-versus-host disease. She presented with cerebellar ataxia, nystagmus, and numbness of the lower extremities. Brain magnetic resonance imaging and perfusion scintigraphy showed progressive cerebellar involvement. Cerebrospinal fluid tests showed mildly elevated protein and IgG levels without pleocytosis. Anti-ganglioside antibodies were detected, but their levels did not follow the patient's clinical course. The patient did not respond sufficiently to steroids or other immunotherapies. We herein report the clinical characteristics of this case and a literature review.

Introduction

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for malignant hematological diseases, but it occasionally causes chronic graft-versus-host disease (GVHD), which can affect the skin, mucosa, gastrointestinal tract, liver, lungs, and skeletal muscles (1). It rarely affects the central nervous system (CNS) (2).

We herein report a case of GVHD of the CNS (CNS-GVHD) and discuss issues with its diagnosis and treatment.

Case Report

A 44-year-old Japanese woman was admitted to our hospital because of a fever, dizziness, and gait disturbance after undergoing allogeneic HSCT for acute myeloid leukemia followed by GVHD. She had been healthy until being diagnosed with acute myeloid leukemia (AML; M2 according to the French-American-British Classification; WHO classification: AML, not otherwise specified; AML with maturation) at 42 years old after developing thrombocytopenia.

Her first course of chemotherapy involved idarubicin and cytosine arabinoside (Ara-C), which achieved a hematological complete response. In addition, four courses of chemotherapy for consolidation (mitoxantrone and Ara-C; daunorubicin and Ara-C; aclarubicin and Ara-C; and vincristine, Ara-C, vindesine, and etoposide) were also administered successfully.

She underwent allogeneic HSCT from an umbilical cord blood donor nine months after being diagnosed with leukemia. The recipient patient had type A [Rh+] blood and exhibited the following human leukocyte antigen (HLA) serotypes: A31, A24/B56, B60/C4, C10/DR9, 12. The cord blood donor was a woman with type B [Rh+] blood and the following HLA serotypes: A11, A31/B56, B60/C1, C4/DR9, 12. As a result, the HLA disparity at the antigen level was classified as 6/8 matched (A and C were mismatched), and 2 mismatches were seen (1 each in both the host-versus-graft and graft-versus-host directions). Regarding the blood type differences between the donor and recipient, there was a major/minor mismatch. The Flu/iv Bu/Mel regimen (30 mg/m²/day fludarabine for 6 days, 3.2 mg/kg/day intravenous busulfan for 4 days, and 40 mg/m²/day melphalan for 2 days) was used as the conditioning regimen for the HSCT. The GVHD prophylaxis regimen involved tacrolimus (0.03 mg/kg/day) and mycophenolate mofetil (MMF, 30 mg/kg/day).

After the transplantation, the patient developed acute GVHD (intestinal, grade 1) on day 26, which was successfully treated with prednisolone (1 mg/kg). She was then treated with tacrolimus, MMF, and prednisolone to keep the acute GVHD in remission, although the dose of each medication was tapered based on blood concentration monitoring. Her symptoms of acute GVHD had almost disappeared by around day 90, when she was being treated with prednisolone (2.5 mg/day) and a minimal dose of tacrolimus (0.2 mg/day). However, she developed chronic GVHD, involving dry eyes and skin eruptions, on day 120. Her chronic GVHD was initially controlled with prednisolone (7.5 mg/day) and titrated tacrolimus (0.2 mg/day) with voriconazole.

Eleven months after transplantation, she gradually presented with gait disturbance, dizziness, and numbness of the lower extremities. Twelve months after the transplantation, she had a slight fever and visited our hospital. She had a history of intussusception at 4 years old, bronchial asthma at 43 years old, and sudden deafness of the right ear also at 43 years old. She consumed alcohol occasionally but had no history of smoking or illicit drug use. She had no relevant family history.

Her physical findings were unremarkable, except for malaise (body mass index: 17.9 kg/m²) and a fever (38.1℃), and a neurological examination revealed ataxic speech, diplopia (horizontal), nystagmus (gaze-evoked and downbeat), ataxia of the limbs and trunk, and hypesthesia of the distal parts of the bilateral lower extremities.

Blood cell counts and routine biochemical analyses, including vitamin (B1 and B12) and thyroid hormone levels, produced unremarkable results, and serological tests for treponema pallidum, human immunodeficiency virus, and human T-lymphotropic virus were negative. Blood cultures did not detect any bacterial growth. Furthermore, a hematological examination did not indicate the recurrence of leukemia. The concentration of tacrolimus in the patient's blood was not excessive (2.7 ng/mL), and her serum C-reactive protein level was within the normal range. She was positive for rheumatoid factor (64 IU/mL; normal: <15) but negative for anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies (for myeloperoxidase and proteinase 3), and anti-thyroid antibodies (anti-thyroglobulin and thyroid peroxidase).

Chest X-ray and whole-body computed tomography produced unremarkable results. Brain magnetic resonance imaging (MRI) with/without gadolinium enhancement and perfusion scintigraphy showed no abnormalities (Fig. 1A, B). Brain MR angiography (MRA) also produced unremarkable findings. A nerve conduction study revealed mildly decreased amplitudes for the compound muscle action potentials of the right tibial nerve, which was suggestive of axonal degeneration, but no slowing of conduction velocities or conduction blocks were seen.

Figure 1.

Brain magnetic resonance imaging [MRI; fluid attenuated inversion recovery (FLAIR), axial and sagittal images] and perfusion scintigraphy [3-dimensional-stereotactic surface projections (3D-SSP)] with N-isopropyl-(¹²³I)-p-iodoamphetamine (¹²³I-IMP). Brain MRI (A) and 3D-SSP (B) performed 11 months after transplantation showed no marked changes, but follow-up MRI (C) and scintigraphy (D) performed 18 months after transplantation showed cerebellar atrophy and decreased perfusion in the cerebellum.

A cerebrospinal fluid (CSF) examination showed mildly elevated protein levels (72 mg/dL) but no pleocytosis (4 /μL). The patient's immunoglobulin G (IgG) index was elevated (1.05). In addition, her CSF interleukin-6 level was 3.1 pg/mL (normal: <4.3 pg/mL), and her CSF myelin basic protein level was <40.0 ng/mL. No malignant cells were detected. A microbiological examination did not detect any growth of bacteria, fungi, or mycobacterium in the CSF. Polymerase chain reaction tests of the CSF for viruses [herpes simplex virus, herpes zoster virus, Epstein-Barr virus, cytomegalovirus, human herpesvirus-6 (HHV-6), HHV-7, and human polyomavirus 2] were negative. No oligoclonal bands were detected in the CSF.

The patient was found to be positive for serum anti-ganglioside IgG antibodies (+++ for GM1, + for GD1a, +++ for GD1b, and +++ for GD3; the antibody levels were graded as -, +, ++, +++, or ++++) but not the equivalent serum IgM antibodies. She was negative for paraneoplastic anti-neuronal antibodies [amphiphysin, CV2, PNMA2 (Ma2/Ta), Ri, Yo, Hu, recoverin, SOX1, titin, zic4, GAD65, and Tr (DNER)]. She was also negative for serum anti-N-terminal alpha enolase, gliadin (IgG and IgM), voltage-gated calcium channel, metabotropic glutamate receptor, leucine-rich glioma inactivated 1 (LGI-1), and contactin-associated protein 2 (CASPR2) antibodies.

Steroids (including 1 g/day methylprednisolone for 3 days), plasma exchange (PE), and intravenous immunoglobulins (IVIG; 400 mg/kg, 5 days) did not have sufficient efficacy. The patient's symptoms gradually worsened, and head tremors (in the vertical, horizontal, or lateral directions) and diffuse muscular atrophy emerged. Repeated rituximab (375 mg/m², 6 times) treatment was partially effective. Re-tests of the patient's CSF after the treatment did not show any marked improvement (protein: 56-83 mg/dL; IgG index: 0.72-0.99). Follow-up MRI and brain perfusion scintigraphy performed 18 months after the transplantation showed progressive cerebellar atrophy and a decreased uptake in the cerebellum (Fig. 1C, D). Re-tests for anti-ganglioside antibodies performed five months after the first tests produced the following results: + for GM1-IgG, + for GM2-IgM, - for GM2-IgG, - for GD1a, + for GD1b, and + for GD3.

Twenty-three months after transplantation, the patient presented with acute consciousness disturbance and right hemiparesis. MRI showed subarachnoid hemorrhaging (SAH) and a cerebral infarction in the left hemisphere, which were consistent with vasospasm. MRA revealed narrowing of the bilateral middle cerebral arteries but did not show any aneurysms, arterial dissections, or bleeding points (Fig. 2). She did not exhibit thrombocytopenia or coagulopathy at that time. She received mechanical ventilation and intravenous infusion of fasudil hydrochloride. She was removed from mechanical ventilation on the 11th day, but tracheostomy and percutaneous endoscopic gastrostomy were performed because of pulmonary aspiration and dysphagia. She was moved to a rehabilitation institution after treatment. At present (30 months after the transplantation), she is alive and oriented but bedridden.

Figure 2.

Magnetic resonance imaging findings obtained 25 months after transplantation. Diffusion-weighted imaging (A) showed a broad high-intensity area in the left cerebral hemisphere, and an apparent diffusion coefficient (ADC) map (B) showed that the lesion exhibited a low signal intensity, which suggested cytotoxic edema or a cerebral infarction. Fluid attenuated inversion recovery (FLAIR) images (C and D) showed hyperintense areas in the cerebral sulci and interpeduncular cistern, and T2*-weighted images (E and F) showed low-intensity areas in the cerebral sulci and lateral ventricles, which suggested subarachnoid hemorrhaging. Magnetic resonance angiography (G and H) showed narrowing in the bilateral middle cerebral arteries, which suggested vasospasm.

Discussion

The initial neurological symptoms of this case were progressive cerebellar dysfunction, but a thorough examination excluded recurrent leukemia, new malignancies, stroke, infection, demyelinating diseases, toxicity, metabolic disorders, and other diseases. The patient's elevated IgG index suggested intrathecal immune activation, so she was diagnosed with ‘possible’ CNS-GVHD according to the relevant criteria (2).

CNS-GVHD is a very rare complication associated with HSCT, and Grauer's criteria require [1] chronic GVHD affecting other organs, [2] neurological signs of CNS involvement without any other explanation, [3] corresponding brain MRI abnormalities, [4] abnormal CSF findings (pleocytosis, elevated protein or IgG levels, oligoclonal bands), [5] appropriate findings in a pathological brain biopsy or post-mortem examination, and/or [6] a response to immunosuppressive therapy (items [1] and [2] are mandatory).

We found 38 previous cases that met the above criteria (3-28) (Table). Twenty of them were pathologically examined, and the findings included cerebrovascular disturbance, demyelination, and immune-mediated encephalitis. Most of the reported cases showed white matter abnormalities or abnormal enhancement of the parenchyma or meninges on MRI. However, our case did not show relevant white matter abnormalities or abnormal enhancement on MRI; therefore, demyelination seemed unlikely to be the main pathology in this case. In addition, our case did not show pleocytosis in the CSF, so pan-encephalitis was also deemed unlikely. The histopathology of our case was not determined, but microvasculitis and parenchymal microscopic inflammation were both possibilities.

Table.

Review of CNS-GVHD Cases.

Reference	Age	Sex	Primary disease	HSCT type/donor source	HLA disparity (HLA-A, B, C, and DR antigens)	GVHD	Main neurological symptoms/signs	Neuroimaging	CSF	Treatment	Outcome	Tissue (inflammatory cell infiltrates)
3	32	M	CML	Allo-BMT/ sibling	Matched	a/cGVHD	Muscular atrophy, dysphagia, dysarthria	Not reported	Normal	Not reported	Death (on day 1,120 post-graft)	+
4	9	F	AA	Allo-BMT/ sibling	Matched	cGVHD	Seizure, coma	Generalized cortical atrophy	Pleocytosis, protein increase	Not reported	Death	+
4	13	M	ALL	Allo-BMT/ sibling	Matched	cGVHD	Mental activity change	WML	Not reported	Not reported	Death	+
5	43	M	CML	Allo-BMT/ unreported	Unreported	a/cGVHD	Vertigo, hemianopsia, aphasia, hemiparesis	WML, ischemic areas, hemorrhages	Protein increase	CS, CPM	Death	+
5	32	F	AML	Allo-BMT/ unreported	Unreported	a/cGVHD	Aphasia, hemiparesis, seizures	Ischemic areas, WML	Normal	CS, CPM	Death	Not done
5	19	M	ALL	Allo-BMT/ unreported	Unreported	cGVHD	Confusion, spastic hemiparesis	WML	Normal	CS	CR	Not done
5	32	M	CLL	Allo-BMT/ unreported	Unreported	a/cGVHD	Aphasia, apraxia, dementia, tetraparesis	WML, hemorrhages	Normal	CS, CPM	Stable disease	Not done
5	53	M	CLL	Allo-BMT/ unreported	Unreported	a/cGVHD	Cognitive deficit, aphasia	WML, frontoparietal ischemia	Pleocytosis	Not reported	Progressive disease	Not done
6	25	M	TCL	Allo-BMT/ mother	HLA-A mismatch	cGVHD	Oscillopsia, ataxia, dysarthria, wide-based gait, Romberg sign, Babinski sign	WML, pontine lesion	Mild pleocytosis, oligoclonal bands	CS, PP	Stability	Not done
7	18	F	AML	Allo-BMT/ unrelated	HLA-C mismatch	a/cGVHD	Confusion, seizures, progressive spasticity	Generalized atrophy, WML	Pleocytosis, red blood cells, protein increase	CS	PR	+
8	51	F	AML	Allo-BMT/ sibling	Matched	a/cGVHD	Diplopia, dysarthria, gait disturbance	WML	Normal	Spontaneous resolution	Clinical CR, MRI PR	Not done
9	55	F	NHL	Allo-BMT/ related	Matched	cGVHD	Headache, dizziness, progressive ataxia	Cerebellar hemorrhage, WML	Not reported	Tac	PR	Not done
10	44	F	TCL	Allo-HSCT/ sibling	Matched	a/cGVHD	Hemiparesis, seizure	WML	Normal	CS	Improvement	+
10	58	F	ALL	Allo-PBSCT/ unrelated	5/6 matched	a/cGVHD	Encephalopathy, seizure	Multiple lesions	Protein increase	CS	PR, death (184 days after allo-HSCT of multiorgan failure)	+
11	41	M	FL	Allo-HSCT/ sibling	Matched	cGVHD	Hemiparesis	Parietal lobe lesion	Normal	CS, CyA	PR	+
12	56	M	NHL	Allo-PBSCT/ unreported	Unreported	cGVHD	Weakness, nausea, vomiting, dizziness, tinnitus, falls	Corpus callosum lesion, WML	Not reported	CS, MMF	Death (2 m)	+
13	32	F	MDS	Allo-BMT/ sibling	Matched	cGVHD	Blurred vision, weakness, numbness, urinary retention	WML, spinal cord lesion	Normal	CS, CyA	PR	Not done
14	35	M	CML	Allo-BMT/ unrelated	Unreported	a/cGVHD	Speech arrests, intermittent acoustic phenomena (noise, music, voices), hearing loss, seizures	Cortical/subcortical lesions	Not reported	CS, CPM, MTX	CR	+
14	28	F	AML	Allo-BMT/ unrelated	Unreported	a/cGVHD	Asthenia, impairment of visual acuity, depression, cognitive deficits, seizure, deterioration of vigilance and memory	WML	Protein increase, oligoclonal bands	CS, CPM	CR	+
14	20	M	SCID	Allo-BMT/ father	Unreported	cGVHD	Reduction of visual acuity, hearing loss, hemiparesis	Multiple lesions, hemorrhage, gadolinium enhancement of the meninges and cranial nerves	Pleocytosis, protein increase	CS, CPM	PR, death (sepsis and multiorgan failure 1 yr after CNS symptoms)	+
14	33	M	CLL	Allo-BMT/ unrelated	Unreported	a/cGVHD	Impairment of visual acuity, speech, and gait	brain atrophy	Pleocytosis, protein increase	CS, CPM	Death (acute aspiration 6 yrs after BMT)	+
15	7	F	AA	Allo-BMT/ related	Matched	cGVHD	Behavioral changes, poor attention span, cognitive deficits, abnormal movements	Uncal lesion	Normal	CS, IVIG	CR	Not done
16	33	M	Fanconi anemia	Allo-HSCT/ unrelated	Matched	a/cGVHD	Myelitis, memory disorders	Pan-myelitis	Lymphocytosis, protein increase, oligoclonal bands	CS, IVIG, PP	Stable disease	+
16	29	F	Fanconi anemia	Allo-HSCT/ unrelated	HLA-A mismatch	cGVHD	Cerebellar syndromes, cranial nerve deficits, polyradiculoneuritis	Normal	Protein increase	CS, PP, IVIG	PR, death (30 m after CNS symptoms)	Not done
16	50	M	MPN	Allo-HSCT/ related	Matched	cGVHD	Hemiparesis, paresthesia	WML	Normal	CyA	CR	Not done
16	36	M	CML	Allo-HSCT/ related	Matched	a/cGVHD	Cerebellar and vestibular syndromes, hemiparesis, hypesthesia, cranial nerve deficits	Multifocal lesions	Protein increase	CS	Death (8 m after CNS symptoms)	Not done
17	46	F	AML	Allo-PBSCT/ related	One-allele mismatch	a/cGVHD	Headache, difficulty writing, shaking hands, memory loss	WML	Pleocytosis, protein increase	CS, Tac	CR	+
18	45	F	AML	Allo-HSCT/ daughter	5/10 matched	cGVHD	Hemichorea-hemiballismus	Focal lesions	Normal	Haloperidol, clonazepam, CS	Improved	+
19	66	M	AML	Allo-PBSCT/ unrelated	Matched	a/cGVHD	Drowsiness, apathy	WML	Normal	CS	CR, relapsed myelitis	Not done
20	58	M	ALL	Allo-PBSCT/ unrelated	Matched	cGVHD	Bradypsychia, cognitive impairment, dyspraxia, ataxia, pyramidal syndrome, autonomic dysfunction	WML	Protein increase, oligoclonal bands	CS, CyA, RTX	CR	Not done
21	59	F	CLL	Allo-BMT/ unreported	Unreported	a/cGVHD	Arm weakness and dysarthria	Infarction, MCA stenosis	Not reported	MCA-STA bypass	Stable disease	+
22	62	F	CMML	Allo-HSCT/ sibling	Matched	cGVHD	Diplopia, nystagmus, slurred speech, gait disturbance, bilateral dysdiadochokinesis, ataxia	Cerebellar atrophy	Anti-GAD65 antibody positivity	CS, IVIG, RTX	Death (4 m after CNS symptoms, aspiration pneumonia)	Not done
23	37	F	MDS	Allo-PBSCT/ unrelated	Matched	cGVHD	Seizure	WML, spinal cord	IgG increase	CS, PP	CR	+
24	54	M	CLL	Allo-HSCT/ unreported	Unreported	GVHD	Ischemic stroke, ataxic hemiparesis	Multifocal arterial stenoses or occlusion	Not reported	CS, CPM	Death (2 m after CNS symptoms, bacterial meningitis)	-
25	22	F	AML	Allo-HSCT/ father	Unreported	a/cGVHD	Drowsiness, dysphoria, dysphasia, gaze to the right, hemiplegia, Babinski sign, Kernig sign	WML	IgG increase	CS, IVIG	Improved	Not done
26	54	F	ATL	Allo-HSCT/ unrelated	HLA-A mismatch	a/cGVHD	Cognitive impairment	WML	Protein increase	CS, MMF	Improved	+
27	15	F	AA	Allo-PBSCT/ father	5/10 matched	cGVHD	Vertigo, nausea, vomiting, delusions, paroxysmal restlessness, insomnia	Normal	IgG increase, oligoclonal bands	CS, rapamycin, MMF, IVIG, ruxolitinib, RTX	Improved	Not done
28	17	F	AA	Allo-HSCT/ mother	Unreported	cGVHD	Headache, hemiplegia	WML, internal carotid artery occlusion	Oligoclonal bands	CS, IVIG, rivaroxaban	Improved	Not done
This case	44	F	AML	Allo-CBT/ unrelated	HLA-A and C mismatches	a/cGVHD	Ataxia, nystagmus	Cerebellar atrophy	Protein increase, IgG index increase	CS, PE, IVIG, RTX	Progression	Not done

a/c: acute and chronic, AA: aplastic anemia, ALL: acute lymphocytic leukemia, allo: allogeneic, AML: acute myeloid leukemia, ATL: adult T-cell leukemia, BMT: bone marrow transplantation, c: chronic, CBT: umbilical cord blood transplantation, CLL: chronic lymphocytic leukemia, CML: chronic myeloid leukemia, CMML: chronic myelomonocytic leukemia, CNS: central nervous system, CPM: cyclophosphamide, CR: complete response, CS: corticosteroids, CSF: cerebrospinal fluid, CyA: cyclosporin A, F: female, FL: follicular lymphoma, GVHD: graft-versus-host disease, HLA: human leukocyte antigen, HSCT: hematopoietic stem cell transplantation, IVIG: intravenous immunoglobulins, M: male, m: months, MCA: middle cerebral artery, MDS: myelodysplastic syndrome, MMF: mycophenolate mofetil, MPN: myeloproliferative neoplasms, MRI: magnetic resonance imaging, MTX: methotrexate, NHL: non-Hodgkin lymphoma, PBSCT: peripheral blood stem cell transplantation, PE: plasma exchange, PP: plasmapheresis, PR: partial response, RTX: rituximab, SCID: severe combined immunodeficiency disease, STA: superficial temporal artery, Tac: tacrolimus, TCL: T-cell lymphoma, WHL: white matter lesion, yr(s): year(s)

Our case was characterized by progressive cerebellar atrophy without intra-parenchymal lesions, which is a very rare manifestation of CNS-GVHD. A case of GVHD and anti-glutamic acid decarboxylase antibody-positive cerebellar atrophy has been reported, but it involved a patient with a 20-year history of diabetes mellitus and hypothyroidism secondary to Hashimoto's thyroiditis, which suggested a preceding predisposition to autoimmune disease (22). Our patient also developed SAH, and such hemorrhagic changes may be related to vasculitis or vasculopathy caused by CNS-GVHD (5,9,14).

The mechanisms underlying CNS-GVHD remain unclear, but previous studies have mentioned that the infiltrating cells mainly consisted of CD3⁺ and CD8⁺ T-lymphocytes and to a lesser degree CD68⁺ monocytes/microglia. The expression of cell adhesion molecules, such as C-C chemokine receptor type 5, also plays an important role in the disease (14). Donor-derived cell infiltrates have also been described in a previous case (7). It is possible that CNS-GVHD is related to cell-mediated immunity and, to some extent, humoral immunity. A recent report suggested that GVHD of the CNS is mediated by the upregulation of tumor necrosis factor expression in microglia (29). CNS-GVHD shows various clinical features, and a previous case had anti-voltage-gated sodium channel LGI-1 and thyroglobulin antibodies (15), while another case had anti-CASPR2 antibodies (20), which may imply overlapping mechanisms with autoimmune-mediated limbic encephalitis.

The present patient was positive for anti-ganglioside antibodies (GM1, GD1a, GD1b, and GD3), and the clinical manifestations were suggestive of some degree of peripheral neuropathy. However, the clinical significance of these antibodies for the CNS manifestations encountered in this case is uncertain, as the reductions in the levels of these antibodies seen after the immunotherapies did not match the changes in the clinical severity of the condition. Previous reports have mentioned HSCT-related acute or chronic neuropathies (2,30), but little is known about the relationship between such neuropathies and anti-ganglioside antibodies. The treatments for such neuropathies include steroids, immunosuppressants, PE, and IVIG. Our case was not responsive to PE or IVIG. Furthermore, the absence of anti-GQ1b antibodies from the patient's serum and the clinical manifestations of the condition were inconsistent with Miller-Fisher syndrome or Bickerstaff encephalitis. The patient's elevated IgG index suggested intrathecal IgG production, but an extensive survey did not detect any other auto-antibodies except for anti-ganglioside antibodies. However, we cannot exclude the possibility that our case involved unknown anti-neuronal antibodies; therefore, further studies are needed to examine this issue.

The treatment of CNS-GVHD is still challenging, as it is often resistant to immunotherapy and carries a high risk of mortality, as reported previously (31). Its prognosis and outcomes are unsatisfactory, and opportunistic infections are also possible during immunotherapy.

Our study had several limitations, especially in terms of the lack of histopathological data. We were unable to perform a brain biopsy because of its invasiveness and the lack of appropriate targets. No surrogate biomarkers of CNS-GVHD have been established yet, so the diagnosis of CNS-GVHD is made by excluding other diseases.

In conclusion, we reported a rare case of possible CNS-GVHD, which was characterized by progressive cerebellar ataxia and nystagmus after allogeneic HSCT for acute myeloid leukemia, and discussed the problems with the diagnosis and treatment of the disease. Further studies are necessary to elucidate the mechanisms underlying CNS-GVHD, as well as to determine appropriate diagnostics and treatments for the condition.

The authors state that they have no Conflict of Interest (COI).