CNS manifestations in acute and chronic graft-versus-host disease

Abstract

Despite the growing evidence supporting the existence of CNS involvement in acute and chronic graft-versus-host disease (CNS-GvHD), the characteristics and course of the disease are still largely unknown. In this multicentre retrospective study, we analysed the clinical, biological, radiological and histopathological characteristics, as well as the clinical course of 66 patients diagnosed with possible CNS-GvHD (pCNS-GvHD), selected by predetermined diagnostic criteria. Results were then contrasted depending on whether pCNS-GvHD onset occurred before or after Day 100 following allogeneic haematopoietic stem cell transplantation (allo-HSCT). The median time between allo-HSCT and pCNS-GvHD onset was 149 days (interquartile range25-75 48-321), and pCNS-GvHD onset occurred before Day 100 following transplantation in 44% of patients. The most frequent findings at presentation were cognitive impairment (41%), paresis (21%), altered consciousness (20%), sensory impairment (18%) and headache (15%). Clinical presentation did not significantly differ between patients with pCNS-GvHD occurring before or after Day 100 following transplantation. Brain MRI found abnormalities compatible with the clinical picture in 57% of patients, while CT detected abnormalities in only 7%. Seven patients had documented spinal cord MRI abnormalities, all of them with pCNS-GvHD occurring after Day 100 following transplantation. In the CSF, the white blood cell count was increased in 56% of the population (median 18 cells/μl). Histopathological analyses were performed on 12 specimens and were suggestive of pCNS-GvHD in 10. All compatible specimens showed parenchymal and perivascular infiltration by CD3+ and CD163+ cells. Immunosuppressive therapy was prescribed in 97% of patients, achieving complete clinical response in 27%, partial improvement in 47% and stable disease in 6%. Response to immunosuppressive therapy did not differ significantly between patients with pCNS-GvHD occurring before or after Day 100 following transplantation. Clinical relapse was observed in 31% of patients who initially responded to treatment. One-year overall survival following pCNS-GvHD onset was 41%. Onset before Day 100 following haematopoietic stem cell transplantation [hazard ratio with 95% confidence interval: 2.1 (1.0-4.5); P = 0.041] and altered consciousness at initial presentation [3.0 (1.3-6.7); P = 0.0077] were associated with a reduced 1-year overall survival probability. Among surviving patients, 61% had neurological sequelae. This study supports that immune-mediated CNS manifestations may occur following allo-HSCT. These can be associated with both acute and chronic GvHD and carry a grim prognosis. The clinical presentation as well as the radiological and biological findings appear variable.

Keywords: GvHD; brain lesions; encephalitis; immune-mediated; neurological complications; spinal cord lesions.

Figure 1

Flow chart describing patients’ inclusion. Survey data were received for a total of 82 patients. After revision of each case report form by the principal investigator, 16 patients were excluded: three patients because they did not meet inclusion criteria (less than two supportive criteria); one patient because of multiple missing data; and 12 patients because an alternate diagnosis was deemed more probable (three patients with stroke without radiological or histopathological evidence of vasculitis, two patients with lumbosacral polyradiculopathy, two patients with cytokine release syndrome (CRS)-associated encephalopathy, one patient with Lambert-Eaton myasthenic syndrome, one patient with progressive multifocal leukoencephalopathy, one patient with Human Herpesvirus 6 encephalitis, one patient with invasive fungal disease with brain involvement and one patient with posterior reversible encephalopathy syndrome). Sixty-six patients were therefore included. GvHD = graft-versus-host disease.

Figure 2

Clinical course and MRI findings of three illustrative cases. (A) Patient 1 was admitted for behavioural changes and cognitive decline associated with headache and blurred vision progressing over weeks. Two years earlier, he had received an allogeneic haematopoietic stem cell transplantation (allo-HSCT) for primary myelofibrosis. Those symptoms were concomitant with the development of classic signs of mouth and skin chronic graft-versus-host disease (cGvHD). Brain MRI showed multifocal T2/fluid-attenuated inversion recovery (FLAIR)-hyperintense white matter lesions. CSF was unremarkable. After ruling out infectious differential diagnoses, including notably progressive multifocal leukoencephalopathy, the patient was treated with a combination of high-dose corticosteroids, rituximab and cyclophosphamide, which allowed complete resolution of the symptomatology. (B) Patient 2 was admitted to the intensive care unit for a decreased level of consciousness and movement disorders 2 weeks following allo-HSCT for myelodysplastic syndrome. Brain MRI showed T2/FLAIR hyperintense lesions involving the pons and the cerebellar peduncles, with areas of restricted diffusion. CSF analysis revealed increased white blood cell (WBC) count (65 cells/mm³) and high protein level (1.355 g/l). There was no sign of extra-neurological GvHD. The patient was treated with weekly intrathecal infusions of corticosteroids associated with systemic mycophenolate, which allowed improvement of the symptomatology and complete disappearance of the brain lesions. (C) Patient 3 presented with tetraparesis, proprioceptive ataxia and sphincter dysfunction progressing over days. Two years earlier, she had been treated with allo-HSCT for acute lymphoblastic leukaemia. She had no previous or active extra-neurological GvHD. Spinal cord MRI showed a longitudinally extensive T2-weighted hyperintense lesion extending from level C1 to the conus medullaris (top), with areas of enhancement after gadolinium injection (bottom). Brain MRI was normal. CSF analyses showed increased WBC count (17 cells/mm³) and protein level (2.564 g/l). She was treated with high-dose systemic corticosteroids and tacrolimus, which allowed complete resolution of the clinical symptoms and regression of the lesions visualized with MRI.

Figure 3

One-year probability of survival following possible CNS-graft-versus-host disease onset. (A) Whole cohort (light blue area indicates 95% confidence interval), (B) according to the interval between allogeneic haematopoietic stem cell transplantation (allo-HSCT) and possible CNS-graft-versus-host disease (pCNS-GvHD) onset and (C) according to the presence or not of altered consciousness at initial presentation.