Proposal for Diagnostic Criteria for Manifestations of Chronic Graft-versus-Host Disease in Peripheral Nervous System and Muscles

Atypical neurological graft-versus-host disease (cGVHD) is a rare complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In addition to central nervous system (CNS) involvement, patients with cGVHD may also exhibit pathology of the peripheral nerves, muscles or neuromuscular junction. In this report, we propose more detailed diagnostic criteria for these manifestations and apply them in a case series of peripheral nervous system and muscles (PNSM) involvement of cGVHD. Based on an interdisciplinary evaluation applying the recent provisional criteria for atypical manifestations of cGVHD, we propose a scoring system to diagnose and classify the four distinct forms of atypical cGVHD affecting the PNSM: immune-mediated inflammatory polyneuropathy, small-fiber polyneuropathy, neuromuscular junction disorder, and myositis. The proposed scoring system was retrospectively applied to all patients who underwent allo-HSCT at the University Hospital of Regensburg between 2007 and 2022 and presented with suspected cGVHD involving the PNSM. The objective was to advance the understanding of neurological manifestations associated with cGVHD by systematically evaluating neurological symptoms, diagnostic findings, and the clinical trajectories of affected patients. Out of 770 patients who underwent allo-HSCT, 15 (1.9%) were identified with cGVHD affecting the PNSM. According to the proposed scoring system, six patients were classified as possible and nine patients as probable atypical cGVHD of the PNSM. 1st-line treatment comprised intravenous immunoglobulin for most cases (10/15). A clinical response to 1st-line therapy was observed in 11 patients. In total, 12 patients showed response to immunosuppressive treatment (IST) while two patients did not respond to IST and one patient did not receive IST, but was successfully treated with pyridostigmine. Nine patients suffered from long-term neurologic sequelae. The 6-months and 1-year overall survival following PNSM-cGVHD onset was 12/15 and 9/15 patients, respectively. Cause of death was at least partly attributed to PNSM-cGVHD in three patients; up to last follow-up, non-relapse related mortality was 6/15 patients and relapse-related mortality 2/15 patients. With an incidence of 1.9%, PNSM-cGVHD is a rare but serious complication after allo-HSCT associated with long-term neurologic sequelae; early diagnosis and IST are mandatory. We propose a modified scoring system to diagnose this entity as a basis for larger multicenter studies.