4.1 Patients’ characteristics
In our cohort and in literature, sex ratio was 1.3 and median age at HSCT was 35 years old (0.67–68). Allogeneic stem cell transplantations were performed for acute myelogenous leukemia (n = 9),[7,10,12,13,18,19] myelodysplastic syndrome (n = 1), acute lymphoblastic leukemia (n = 4),[5,8,12,24] myeloproliferative neoplasm (n = 3), chronic myelogenous leukemia (n = 6),[11–13] chronic myelomonocytic leukemia (n = 1), lymphoma (n = 9),[5,9,14–16,20–22,25] chronic lymphoid leukemia (n = 1), constitutional bone marrow failure (n = 3), and aplastic anemia (n = 2).[8,23] Fourteen patients received MAC,[5,9,10,13,17,18,21] 7 reduced intensity conditioning,[5,14,16,19,22] 1 patient did not have any conditioning, and 1 had sequential conditioning. Donors were matched-related donor (n = 14),[5,7,9,15,17–19,21,23] matched-unrelated donor (n = 8),[8,13,16,19,22] mismatch-unrelated donor (n = 3), cord blood (n = 2), and haplo-identical T depleted cells (n = 1). Acute GvHD history was reported for 26 cases, among them, 21 patients had at least 1 episode of acute GvHD.[5,10,12,16,18,20–22,26] Moreover, chronic GvHD episodes were reported before or during neurological symptoms in 25 patients[5,8,9,11–15,17,18,23,25] whereas 11 patients had no other cGvHD symptoms than those attributed to CNS GvHD[10,16,19–22,24] (Table 3).
4.2 Clinical features and histological results
Among the 39 patients with CNS GvHD, median symptoms onset was 385 days after HCST (7–7320). In our cohort and in literature, only immunosuppression modulations were found as triggering factor. Fourteen patients developed their neurological symptoms after decreased (cases 2, 5, and 6, and 3 patients from the literature)[9,11,18] or discontinuation (8 patients from the literature)[5,12–14,17,22] of immunosuppressive therapy after a median delay of 124.5 days (14–549). Interestingly, 1 patient received donor lymphocyte infusion for malignancy relapse and developed neurological symptoms 3 days later. Thirteen patients (cases 1, 3, 4, and 7, and 9 patients from the literature)[10,12,15,16,19–21,23] were already treated with immunosuppressive drugs at neurological symptoms onset.
Clinical features were heterogeneous: 7 patients developed stroke-like episodes (case 7 and 6 patients from the literature),[12,15,24,26] 3 patients developed lacunar syndrome,[12,13] 7 patients had multiple sclerosis-like presentation (cases 1, 4, and 5, and 4 patients from the literature),[17,19,25] 4 patients had acute demyelinating encephalomyelitis-like presentation,[7,16] 14 patients had an encephalitis (cases 2, 3, and 6, and 11 literature patients),[5,8,10,11,13,20–23] 1 patient had a mass syndrome, and 3 had nonspecific clinical presentations.[13,14,18]
Histological data were available for 17 patients. According to the Conference Consensus definition of CNS GvHD histological classification, neurological vasculitis was founded in 7 biopsies (case 1 and 6 patients from the literature),[10,12,13] demyelinating lesions in 5 biopsies[7,12,13] (3 patients presented both vasculitis and demyelinating lesions),[12,13] immune-mediated encephalitis in 5 biopsies (case 2 and 6 patients from the literature),[5,8,11,14] and 1 patient had noncaseating granuloma.
4.3 CNS GvHD diagnosis
In the Consensus Conference, occurrence of chronic GvHD affecting other organs is one of mandatory criteria to diagnose chronic CNS GvHD. No diagnosis criteria for acute GvHD were defined in literature. In our cohort and in previously published cases, 11 patients (28%), of whom 2 had a brain biopsy, did not have extra-CNS chronic GvHD. Interestingly, these patients had a different clinical presentation compared to patients with extra-CNS chronic GvHD history. First, CNS GvHD appeared earlier in this population: median neurological symptoms onset delay was 81.5 days (range 7–1095) versus 549 days (range 119–7300) for patients with extra-CNS chronic GvHD, P = .001. In the group of patients without chronic GvHD history, 8 patients out of 11 (73%) had an acute GvHD history and 3 patients had active acute GvHD at neurological symptoms onset (case 3 and 2 patients from the literature).[20,21] Moreover, clinical presentations seem to be different. Encephalitis was more frequent in the group of patients without chronic GvHD: 7/11 patients (64%, cases 2, 3, and 6, and 4 patients from the literature)[10,20–22] versus 7/25 patients (28%), P = .07. Conversely, stroke-like episodes and lacunar syndromes were less frequent: 1/11 (9%) versus 9/25 patients (36%), P = .13. This suggests that early encephalitis after allo-HSCT may be a clinical presentation of CNS involvement during acute GvHD (Table 4). However, due to the rarity of this complication, we were not able to identify in our series or in literature, patients at risk to develop CNS GvHD.
Consensus conference distinguishes 3 presentations of GvHD: cerebrovascular disease, demyelinating disease, and immune-mediated encephalitis. This study highlights the link between clinical presentation and histological lesions. Large and medium vessels vasculitis can be revealed by stroke-like episode or lacunar syndrome. Demyelinating disease can arise as acute demyelinating encephalomyelitis or as multiple sclerosis-like episodes. Both of these histological forms can be diagnosed by the association of specific clinical, biological, and imaging evidences (Table 2). However, histological sampling and analysis remains the only way to formally distinguish small vessel vasculitis and immune-mediated encephalitis, as both lesions might induce encephalitis symptoms (Table 2). Moreover, the biopsy may also help to exclude differential diagnoses such as EBV-related lymphoproliferative disorders. Interestingly, we were able to confirm in 2 cases that immune infiltration was of donor origin. In case of sex-mismatch, centromeric XY FISH assay is an easy way to determine the origin of infiltrating immune cells. Molecular chimerism can also be used when FISH cannot be performed and can also be applied to lymphocytes detected in CSF.
4.4 Treatment and outcome
Of 35 patients with available data, 34[5,7,9,10,12–17,19–23,25] received immunosuppressive therapy: 31 patients had been treated with corticosteroids[5,7,9,10,12–14,16,17,19–25] in combination with at least another immunosuppressive drug in 19 patients.[7,9,12–14,17,19,20,23,25] Other immunosuppressive treatments included intravenous immunoglobulin (IV Ig) (n = 6), plasmapheresis (n = 3), cyclophosphamide (n = 9),[12,13,19,25] anticalcineurin inhibitors (n = 4),[9,15,17] mycophenolate mofetil (n = 3), and methotrexate (n = 1), and 1 patient was also treated with etoposide because of secondary hemophagocytic lymphohistiocytosis (Table 5).
With immunosuppressive therapy, 10 patients reached complete response,[5,12,13,16,18,19,22,24] 15 had a partial response,[7,9,10,13,15,17,19,21,23] and 2 had a transient response[5,25] (TR). Disease remains stable for 2 patients and 7 patients had progressive disease.[12,14,20] Data were not available for 3 patients (Table 5).
At last follow-up, 7 patients (18%) were alive[5,7,16–18] and 18 patients (46%) were deceased.[5,7,8,11–14,20,21] Data were not available for 14 patients (Table 5).
4.5 Pathophysiology of CNS GvHD
CNS involvement of GvHD is controversial, especially since clinical manifestations of CNS GvHD are heterogeneous: cerebrovascular manifestations,[12,15,24,26] encephalitis,[5,8,9,11,14,20–22] or myelitis.[7,16–19] Interestingly, some human cases were histologically proven and revealed frequent T cell infiltration, supporting the hypothesis of an immune-mediated CNS disease after allo-HSCT. Furthermore, several animal models, including primate models, bring some evidence of CNS targeting by donor T cells during GvHD. In rat disease models, it has been demonstrated that GvHD was associated with diminished cerebellar RNA synthesis and transcription, and with ectopic protein and change in protein expression profile compared to syngeneic controls. In addition, immunosuppressive treatment of GvHD was able to restore cerebellar RNA synthesis and protein expression. In rat models of allo-HSCT, expression of c-Fos, a neural activation marker, increased in piriform, occipital, visual, and prefrontal neurons 3 days after GvHD onset. In murine models, allogeneic HSCT was also associated with a donor T cells-mediated alloimmune response in brain. Compared to syngeneic control, brain necropsies of transplanted mice revealed T cell infiltration, microglia activation, and angiitis-like abnormalities. In rats, T cell infiltration of CNS was associated with increased expression of class I and class II major histocompatibility antigens. In mouse models, cerebral endothelial adhesion molecule expression was modified: ICAM-1 and VCAM-1 expression were upregulated and could contribute to T cell infiltration in neural tissues. Recently, it has been demonstrated in murine and primate models with acute GvHD, that neurological symptoms and behavior modifications were caused by alloreactive activated donor CD8+ T cells.[32,33] T cell infiltration was prevented by immune prophylaxis. Few data are available about human CNS GvHD pathophysiology. Infiltration of T cells was described in 8 biopsies (case 1 and 2, and 6 patients from literature).[5,8,9,14] Consistently with data obtained in animal models, this infiltration was mainly composed of CD3+CD8+ cytotoxic T cells in 3 brain biopsies (case 1 and 2 biopsies from literature)[5,14] whereas only 1 showed CD3+/CD4+ cells infiltration. A recent paper demonstrated that this infiltration let to inflammatory cytokine production. IL-6 production together with indoleamine 2,3 deoxygenase upregulation played a central role in CNS GvHD by its action on host microglial cells. In this model, IL-6 blockade could partially reversed neuroinflammation.
To conclude, despite the paucity of human CNS GvHD described in the literature, analysis of CNS clinical biopsies and necropsies suggests that the CNS may be a target of GvHD. CNS GvHD is a rare and severe complication after allo-HSCT that can be difficult to diagnose. MRI and CSF analysis should be performed to eliminate all other etiology of CNS disorders, especially infections, drug toxicity, or relapses of underlying malignancies. Although brain biopsy may be difficult to achieve, histological analysis is useful to eliminate other diagnoses. CNS GvHD treatment is not consensual and mainly based on immunosuppressive drugs, especially high-dose corticosteroids. However, despite a frequent response to treatment, CNS GvHD remains associated with a dismal prognosis.
The authors thank Dr Pervinder Sagoo for her careful reading of the manuscript.
. Syed FI, Couriel DR, Frame D, et al. Central nervous system complications of hematopoietic stem cell transplant. Hematol Oncol Clin North Am 2016;30:887–98.
. Armstrong D, Hawkins E, Rouah E, et al. Graft-vs-host disease in the central nervous system. Am J Clin Pathol 1997;107:379.
. Rouah E, Gruber R, Shearer W, et al. Graft-versus-host disease in the central nervous system: a real entity? Am J Clin Pathol 1988;89:543–6.
. Santa Chiara U. Central nervous system graft-versus-host disease: consider progressive multifocal leukoencephalopathy among the differential diagnoses. Bone Marrow Transplant 2007;40:1095–6.
. Kamble RT, Chang CC, Sanchez S, et al. Central nervous system graft-versus-host disease: report of two cases and literature review. Bone Marrow Transplant 2007;39:49–52.
. Grauer O, Wolff D, Bertz H, et al. Neurological manifestations of chronic graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: report from the Consensus Conference on Clinical Practice in chronic graftversus-host disease. Brain 2010;133:2852–65.
. Delios AM, Rosenblum M, Jakubowski AA, et al. Central and peripheral nervous system immune mediated demyelinating disease after allogeneic hemopoietic stem cell transplantation for hematologic disease. J Neurooncol 2012;110:251–6.
. Iwasaki Y, Sako K, Ohara Y, et al. Subacute panencephalitis associated with chronic graft-versus-host disease. Acta Neuropathol (Berl) 1993;85:566–72.
. Kew AK, Macaulay R, Burrell S, et al. Central nervous system graft-versus-host disease presenting with granulomatous encephalitis. Bone Marrow Transplant 2007;40:183–4.
. Ma M, Barnes G, Pulliam J, et al. CNS angiitis in graft vs host disease. Neurology 2002;59:1994–7.
. Marosi C, Budka H, Grimm G, et al. Fatal encephalitis in a patient with chronic graft-versus-host disease. Bone Marrow Transplant 1990;6:53–7.
. Padovan CS, Bise K, Hahn J, et al. Angiitis of the central nervous system after allogeneic bone marrow transplantation? Stroke J Cereb Circ 1999;30:1651–6.
. Sostak P, Padovan CS, Eigenbrod S, et al. Cerebral angiitis in four patients with chronic GVHD. Bone Marrow Transplant 2010;45:1181–8.
. Saad AG, Alyea EP, Wen PY, et al. Graft-versus-host disease of the CNS after allogeneic bone marrow transplantation. J Clin Oncol 2009;27:e147–9.
. Campbell JN, Morris PP. Cerebral vasculitis in graft-versus-host disease: a case report. Am J Neuroradiol 2005;26:654–6.
. Harvey CM, Gottipati R, Schwarz S, et al. Acute disseminated encephalomyelitis following allo-SCT: central nervous system manifestation of GVHD. Bone Marrow Transplant 2014;49:854–6.
. Matsuo Y, Kamezaki K, Takeishi S, et al. Encephalomyelitis mimicking multiple sclerosis associated with chronic graft-versus-host disease after allogeneic bone marrow transplantation. Intern Med 2009;48:1453–6.
. Tomonari A, Tojo A, Adachi D, et al. Acute disseminated encephalomyelitis (ADEM) after allogeneic bone marrow transplantation for acute myeloid leukemia. Ann Hematol 2003;82:37–40.
. Voss M, Bischof F. Recurrent myelitis after allogeneic stem cell transplantation. Report of two cases. BMC Neurol 2010;10:1.
. Yamamoto H, Uchida N, Ishiwata K, et al. Possible graft-versus-host disease involving the central nervous system soon after cord blood transplantation. Am J Hematol 2009;84:764–6.
. Provenzale JM, Graham ML. Reversible leukoencephalopathy associated with graft-versus-host disease: MR findings. Am J Neuroradiol 1996;17:1290–4.
. Shortt J, Hutton E, Faragher M, et al. Central nervous system graft-versus-host disease post allogeneic stem cell transplant. Br J Haematol 2006;132:245–7.
. Rathore GS, Leung KS, Muscal E. Autoimmune encephalitis following bone marrow transplantation. Pediatr Neurol 2015;53:253–6.
. Takatsuka H, Okamoto T, Yamada S, et al. New imaging findings in a patient with central nervous system dysfunction after bone marrow transplantation. Acta Haematol 2000;103:203–5.
. Solaro C, Murialdo A, Giunti D, et al. Central and peripheral nervous system complications following allogeneic bone marrow transplantation. Eur J Neurol 2001;8:77–80.
. Sostak P. Cerebral endothelial expression of adhesion molecules in mice with chronic graft-versus-host disease. Stroke 2004;35:1158–63.
. Griffin WST, Head JR, Pardue S, et al. Changes in RNA synthesis and messenger RNA content in the cerebellum of rats with graft versus host disease
. J Neurochem 1980;35:880–8.
. Griffin WST, Snider BJ, Morrison MR. Normalization of cerebellar RNA synthesis and mRNA levels after treatment of graft versus host disease
. J Neurochem 1982;39:1412–7.
. Furukawa H, Yamashita A, del Rey A, et al. c-Fos expression in the rat cerebral cortex during systemic GvH reaction. Neuroimmunomodulation 2004;11:425–33.
. Padovan CS, Gerbitz A, Sostak P, et al. Cerebral involvement in graft-versus-host disease after murine bone marrow transplantation. Neurology 2001;56:1106–8.
. Hickey WF, Kimura H. Graft-vs.-host disease elicits expression of class I and class II histocompatibility antigens and the presence of scattered T lymphocytes in rat central nervous system. Proc Natl Acad Sci 1987;84:2082–6.
. Hartrampf S, Dudakov JA, Johnson LK, et al. The central nervous system is a target of acute graft versus host disease
in mice. Blood 2013;121:1906–10.
. Kaliyaperumal S, Watkins B, Sharma P, et al. CD8-predominant T-cell CNS infiltration accompanies GVHD in primates and is improved with immunoprophylaxis. Blood 2014;123:1967–9.
. Belle L, Zhou V, Stuhr KL, et al. Host interleukin 6 production regulates inflammation but not tryptophan metabolism in the brain during murine GVHD. JCI Insight 2017;2:
Keywords:Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
allogeneic hematopoietic stem cell transplantation; graft versus host disease; neurological disorders