Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Graft-versus-host disease is common in allogeneic bone marrow recipients, but neuromuscular complications are unusual (8%). The most common neuromuscular complication is an immune-mediated myositis that responds to treatment with immunosuppressive therapies.
SOURCE: Saw JL, Sidiqi MH, Mauermann ML, et al. Immune-mediated neuromuscular complications of graft-versus-host disease. Muscle Nerve 2021;63:852-860.
Graft-versus-host disease (GVHD), seen in 30% to 70% of adult patients following allogeneic stem cell (bone marrow) transplantation, occurs when immune cells, transplanted from a non-identical donor, recognize the recipient as foreign. GVHD is divided into acute GVHD, occurring within the first 100 days and manifested by rash, nausea, vomiting, diarrhea, and rising bilirubin, and chronic GVHD, occurring later and affecting the skin (67%), mouth (60%), liver (52%), joints and fascia (48% each), gastrointestinal tract (30%), and genitalia (12%). Central and peripheral nervous system manifestations are uncommon in GVHD. Neuromuscular complications, reportedly seen in 8% of patients, were the subject of this study.
A retrospective chart review identified patients 18 years or older with a diagnosis of GVHD, seen between April 2013 and July 2018 at Mayo Clinic, Rochester, MN. Separately, patients with a new neuromuscular complication, including any variety of myopathy, myositis, myasthenia, neuropathy, radiculopathy, or plexopathy, were identified electronically. Lastly, chart review was undertaken to identify patients with a high suspicion of an immune-mediated neuromuscular complication. Patients were excluded if they failed to fulfill 2014 National Institutes of Health consensus criteria for GVHD, if they did not manifest at least one non-neurological complication of GVHD, or if they did not appear to have an immune-mediated process. An immune process was defined as histological evidence of myositis or elevated creatine kinase with fibrillation potentials on needle electromyography for myositis and clinical or electrophysiologic findings characteristic of immune or inflammatory neuropathy for neuropathy patients. Any patient with a neuromuscular junctionopathy was included.
Among 688 patients with GVHD, 20 (2.9%) developed immune-mediated neuromuscular complications, including myositis (n = 17; 2.5%), manifested most often as proximal weakness with or without axial weakness (n = 12), axial weakness with head drop (n = 2), generalized weakness (n = 1), or predominant respiratory failure or skin induration with no weakness (n = 1 each). Neuropathy (n = 2; 0.3%) manifested as neuralgic amyotrophy or acute inflammatory demyelinating polyneuropathy (AIDP) in one patient each, and myasthenic syndrome (n = 1; 0.15%), manifested as fluctuating foot drop. Mean age at transplant was 54 years, and mean age at neurological presentation was 55 years, a mean delay of 14 months, with male predominance (n = 13; 66%). Acute leukemia was the primary malignancy in 60% of subjects, with a lymphoproliferative disorder present in 20%, myelodysplastic syndrome in 15%, and a myeloproliferative disorder in one patient. Most patients (40%) had both acute and chronic GVHD at the onset of the neuromuscular condition, with 35% (n = 7) having acute GVHD and 25% (n = 5) having chronic GVHD.
Muscle biopsy in 11 patients demonstrated a predominantly macrophage, perimysial infiltration in 10 and an endomysial and perimysial lymphocytic infiltration in one. Treatment with immunosuppressive agents, including steroids alone or in combination with rituximab, intravenous immunoglobulin (IVIG), or tacrolimus, was given to 19 patients, all of whom responded. Eleven patients experienced subsequent GVHD flares requiring additional treatment, including sirolimus, cyclosporine, and mycophenolate mofetil. Over a median follow-up of 83 months, 35% (n = 7) died, five from GVHD, and two from infection. Myositis is the most common neuromuscular GVHD complication and usually is macrophage predominant.
Central nervous system complications of GVHD occur more commonly than those affecting the peripheral nervous system and include seizures, posterior reversible encephalopathy syndrome (PRES), and stroke. Electronic retrieval and review of articles between 1983 and 2017 using several databases, including Medline, revealed that although seizures were significantly associated with both acute and chronic GVHD, PRES was significantly associated with acute GVHD, whereas stroke was associated with chronic GVHD.1
- Sheikh MA, Im A, Ballen K, Hashmi SK. Association of graft-versus-host-disease with neurologic complications: Clinical paradigm and future directions. Bone Marrow Transplant 2021;56:1471-1473.