Central Nervous System Complications After Allogeneic Hematopoietic Cell Transplantation – Treatment Related Morbidity, Toxicity, Graft Versus Host Disease Or New Autoimmunity

Graft versus host disease (GvHD) is still the leading complication of allogeneic hematopoietic cell transplantation (HCT). While the skin, liver and gut are the main sites of GvHD manifestation, evidence is emerging that the central nervous system (CNS) may also be involved. Vascular and infectious complications after allogeneic HCT are rare and represent a diagnostic and therapeutic challenge, as the differentiation between inflammatory, vascular, infectious and malignant causes of CNS symptoms can be difficult. Most data available so far are based on animal models or case reports. We recently reported the development of new-autoinflammatory T cell responses against autoantigens of the retina as part of the CNS (ASH Annual Meeting 2012, Abstract #3060). In this study, we evaluated CNS manifestations of GvHD and other CNS complications not directly associable with inflammatory CNS changes after allogeneic HCT. Data of 854 patients that underwent allogeneic HCT at our institution between 2003 and 2012 were analyzed. We identified 25 patients (3%) suffering from 39 different CNS manifestations. The cohort comprised 12 women and 13 men with a median age of 38 years at transplantation (range 20-69 years) and of 39 years at the onset of CNS symptoms (range 21-69 years). Patients had been treated for ALL (n=10, 40%), AML (n=13, 52%), PMF (n=1, 4%) and PNH (n=1, 4%). Median onset of CNS symptoms was 3 months after allogeneic HCT (range 0-24 months). By that time, 19 patients (76%) were in complete remission, 6 patients (24%) had experienced relapse. Patients had been transplanted 1-3 times (total 37 HCT) with myeloablative (n=14, 38%) or dose-reduced intensity conditioning regimen protocols (n=23, 62%). 13 HCT were performed with grafts from related (35%), 24 with grafts from unrelated donors (65%). HLA-identical, mismatched and haploidentical grafts were given in 18, 11 and 8 cases, respectively. Patients with ALL undergoing prophylactic CNS irradiation tended to be more at risk for inflammatory CNS complications. Ten of all investigated patients suffered from visual loss due to retinal affection. Six of them experienced inflammation of the optic nerve and the retina (5 without detection of viruses or other causes, 1 due to CMV), and 3 patients experienced severe optical nerve atrophy. Infections of the CNS were seen in 3 cases and were due to VZV, HHV-6 and toxoplasmosis. Cerebral vasculitis was present in 6 further patients, while 8 patients had severe leukencephalopathy. Unspecific CNS symptoms including sedation and seizures were observed in 4 patients. Here, the underlying cause could not be further discriminated. Five further patients suffered from bleeding (n=4) or ischemic (n=1) CNS complications. The symptoms of 2 patients could be attributed to isolated meningeal relapse of the disease. Of 4 patients with ocular symptoms (cone degeneration and CNS vascultitis, n=1; anemic retinopathy, n=1; optic neuritis, n=2) we obtained peripheral mononuclear cells (PBMC) which were evaluated in ELISPOT and intracellular cytokine staining assays. Before testing, PBMC were prestimulated for 12 days with T cell epitopes derived from retinal proteins (membrane-bound retinal guanylate cyclase 1 protein (retGC), guanylate cyclase activating proteins 1 and 2 (GCAP1 and GCAP2) and retinoid binding protein 3 (RBP3)) that had been identified by polymorphic protein sequence based prediction of epitopes using the internet based databases EpiToolKit and SYFPEITHI. In one patient with cone degeneration and optic nerve atrophy, antigen specific T cells against retGC derived epitopes could be detected. Our data indicate that CNS complications of allogeneic HCT may differ with regard to the affected organ (eye, CNS vascular system, brain) and the pathophysiology of the symptoms (inflammation, toxicity). Most of the complications were associated with inflammatory changes of the eye and the brain representing either GvHD or new autoimmunity. Without immunohistochemic examination, differentiation between GvHD and new autoimmunity is difficult, since inflammatory reactions of allogeneic T cells may be due to recognition of neo-autoantigens.