Central Nervous System Disorders (CNSD) Following Hematopoietic Stem Cell Transplantation (HSCT): A Prospective Study from the Infectious Diseases Working Party (IDWP) and the Transplant Complications Working Party (TCWP), European Society of Blood and Marrow Transplantation (EBMT)
Authors: Schmidt-Hieber Martin , Ljungman Per T. , Gilbert Patrick , Knelange Nina , Drozd-Sokolowska Joanna , Basak Grzegorz , Einsele Hermann , Tridello Gloria , Ben Abdeljelil Nour , Kulagin Alexander , Balaguer Rosello Aitana , Metafuni Elisabetta , Faraci Maura , Gozdzik Jolanta , Martino Rodrigo , Raiola Anna Maria , Peffault De Latour Regis , Kuskonmaz Baris , Biffi Alessandra , Czyzewski Krzysztof , Gabriel Melissa Ann , Martínez-Lopez Joaquín , Mikulska Malgorzata , Peric Zinaida , Averbuch Dina , Styczynski Jan , De La Camara Rafael 
Published: December 2024

Introduction:
A few studies have been published on the central nervous system disorders (CNSD) after HSCT. Prospective studies including a control group are lacking.
Methods:
A prospective, observational study with infectious and non-infectious CNS disorders (iCNSD and niCNSD, respectively) after HSCT as primary objectives was conducted by the IDWP and the TCWP of EBMT. For each case patient (i.e. HSCT recipient with a CNSD), two control patients were allocated and analysed prospectively by applying the following selection criteria: not developing a CNSD until inclusion and surviving after HSCT the same time as the respective case patient until development of a CNSD (the inclusion date). Control patients were stratified by age (children vs adults), centre and HSCT type (allogeneic vs. autologous).
Results:
A total of 183 patients (61 patients with a CNSD, 122 controls) from 15 centres (8 countries) were included in this study between January 2021 and April 2024. Hereby, 57 patients with a CNSD (93%) underwent allogeneic and 4 patients (7%) autologous HSCT. Nineteen (31%) case patients were children (&lt;18 years), and 42 (69%) adults (≥ 18 years).
Twenty-two patients (36%) had a proven/probable iCNSD, 28 patients (46%) had a proven/probable niCNSD and 11 patients (18%) had a possible infectious or non-infectious or unclassified CNSD. Forty-eight patients (79%) had an acute onset of the CNSD while onset was non-acute in 13 patients (21%). Human herpes virus 6 iCNSD was the most frequent proven/probable CNS infection (n=7) while infections by Toxoplasma spp. (n=5), Aspergillus spp. (n=3), bacteria (n=2), adenovirus (n=1) or different pathogens/unspecified infections (n=4) occurred less frequently. In patients with proven/probable niCNSD drug-induced changes were dominant (n=12) but vascular pathologies (bleeding, strokes etc., n=6) occurred also besides other (n=6, e.g. metabolic encephalopathy, posterior reversible encephalopathy syndrome or CNS relapse of the underlying disease) or unspecified causes (n=4). The median interval from HSCT to the CNSD onset was 31 days (range -1-153 days) for patients with proven/probable iCNSD (n=22) and 27 days (range -5-363 days) for patients with proven/probable niCNSD (n=28, p&gt;0.05).
Magnetic resonance imaging (MRI) was done in 45/61 patients (74%). Abnormalities associated with the CNSD were described in 15/20 patients (75%) with proven/probable iCNSD and 12/19 (63%) of patients with proven/probable niCNSD (p&gt;0.05).
A grade 3/4 eastern cooperative oncology group status at inclusion was more frequently present in CNSD (34/60 evaluable patients, 57%) than control patients (12/122 patients, 10%, p&lt;0.001). Other variables such as median age, sex matching, HLA matching, disease status (71% complete remission in total), conditioning type, T cell depletion and stem cell source were comparable between cases and controls. Distribution of comorbidities was also largely comparable between both groups albeit a pre-existing CNS disease prior to HSCT was more frequent in the CNSD than in the control group (20% vs. 9%, p&gt;0.05). Patients with a CNSD at inclusion were more frequently on ward (53/60 patients, 88%) than controls (72/122 patients, 59%, p&lt;0.001). Among controls - none of them having a CNSD between HSCT and study inclusion - , 2/111 patients (1.8%, 95%-confidence interval (CI) 0.2-6.4%) developed a CNSD at day +100 after study inclusion and 9/117 patients (7.7%, 95%-CI 3.6-14.1%) at last follow-up.
Overall survival was lower (p&lt;0.001) in patients with a CNSD - 85% (95%-CI 76-94%) at one month and 49% (95%-CI 35-63%) at 24 months - compared to controls - 99% (95%-CI 98-100%) and 82% (95%-CI 74-89%), respectively. Causes of death among cases were the CNSD (n=14/29, 48%), HSCT-related causes other than the CNSD (n=5, 17%) relapse/progression (n=3, 10%) or other reasons (n=7, 24%). Relapse/progression was the most frequent death cause among controls (n=13/18, 72%, p&lt;0.001). At last follow-up, 14/22 patients (64%) with a proven/probable iCNSD had died, compared to 11/28 patients (39%) with a proven/probable niCNSD (p&gt;0.05).
Conclusions:
CNSD represent a significant complication after HSCT. Hereby, non-infectious causes prevail over CNS infections. A pre-existing CNS disease prior to HSCT might be a risk factor for a CNS complication after HSCT. Patients with a CNSD after HSCT have a reduced overall survival with the CNSD itself being the main cause of death.