INVITED REVIEW
NEUROMUSCULAR COMPLICATIONS OF HEMATOPOIETIC STEM CELL TRANSPLANTATION KATHERINE M. RUZHANSKY, MD, MS,1 and THOMAS H BRANNAGAN III, MD2 1
Medical University of South Carolina, Department of Neurology and Neurosurgery, Neuromuscular Division, 96 Jonathan Lucas Street, CSB 301, Charleston, South Carolina 29425 USA 2 Columbia University Medical Center, Peripheral Neuropathy Center, Neurological Institute, New York, New York, USA Accepted 29 May 2015 ABSTRACT: Neuromuscular diseases such as polymyositis, dermatomyositis, peripheral neuropathy, and disorders of neuromuscular transmission are reported to be complications of hematopoietic stem cell transplantation (HSCT). Although cases have been reported with allogeneic HSCT in the setting of chronic graft versus host disease, they are also known to occur without evidence thereof and even occur in the setting of autologous HSCT. The 2005 National Institutes of Health Consensus Criteria classify polymyositis and dermatomyositis as “distinctive” features, and neuropathy and MG as “other” features. These neuromuscular complications present very similarly to the idiopathic autoimmune disorders and respond to similar treatment modalities. Muscle Nerve 52: 480–487, 2015
Hematopoietic stem cell transplantation (HSCT) has been used increasingly to treat oncologic, metabolic, and autoimmune disorders, including autoimmune neuromuscular diseases since it was first used successfully in the late 1960s.1 Neurological problems, such as central nervous system disorders and infections occur in these patients and are often a major cause of morbidity and mortality.2 With regard to neuromuscular complications, patients may have persistence or progression of a preexisting neuromuscular disorder, or critical illness neuropathy or myopathy may develop due to prolonged hospitalization and medical complications. Additionally, medications used for Abbreviations: AchR, acetylcholine receptor; AchR Ab, acetylcholine receptor antibody; aGVHD, acute graft versus host disease; AIDP, acute inflammatory demyelinating polyradiculoneuropathy; AMAN, acute motor axonal neuropathy; ANA, antinuclear antibody; BMT, bone marrow transplant; cGVHD, chronic graft versus host disease; CIDP, chronic inflammatory demyelinating; CMV, cytomegalovirus; CSF, cerebrospinal fluid; DM, dermatomyositis; EBV, Epstein-Barr virus; EMG, electromyography; FISH, syndrome; GVHD, fluorescence in situ hybridization; GBS, Guillain-Barre graft versus host disease; GVL, graft versus leukemia; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplant; IFN, interferon; IL, interleukin; IMN, immune mediated neuropathy; IVIg, intravenous immunoglobulin; MG, myasthenia gravis; MuSK, muscle specific kinase; NCS, nerve conduction studies; NIH, National Institutes of Health; PDGF, platelet derived growth factor; PM, polymyositis; PN, peripheral neuropathy; TGF, tumor growth factor; Th, T helper; TLR, toll-like receptor; Treg, T regulatory cells. Key words: allogeneic; autologous stem cell transplant; bone marrow transplant; dermatomyositis; graft versus host disease; myasthenia gravis; neuromuscular complications; peripheral neuropathy; polymyositis Correspondence to: K. M. Ruzhansky; e-mail: [email protected] C 2015 Wiley Periodicals, Inc. V
Published online 4 June 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24724
480
NM Complications of HSCT
immunosuppression may cause toxic neuromuscular complications.3 Neuromuscular disorders can also occur as a result of the bone marrow transplantation itself. Neuromuscular disorders have been described rarely after an autologous stem cell transplant. However, after solid organ and allogeneic HSCT transplants, the reported incidence of neurologic complications is 30–80%.2 The extent of complications depends on multiple factors, such as type of hematologic malignancy, age, and histocompatibility of the recipient.4 The neuromuscular problems resulting from the bone marrow transplantation, including from graft versus host disease (GVHD), will be the focus of this review. HEMATOPOIETIC STEM CELL TRANSPLANT: AUTOLOGOUS AND ALLOGENEIC
Stem cell transplantation is being used more commonly to treat various hematological malignancies, bone marrow failure, immunodeficiency syndromes, and certain congenital metabolic disorders, as well as autoimmune disorders, including autoimmune neuromuscular disorders. Preparative regimens for HSCT have evolved over the years. Patients typically undergo varying degrees of myeloablation with total body irradiation and chemotherapy, depending on the amount of myelosuppression necessary.1 The rationale of the procedure is to reestablish the marrow function destroyed by the chemotherapy given to eradicate neoplastic cells. In autologous stem cell transplantation, a patient’s own hematopoietic progenitor cells are harvested from bone marrow or peripheral blood after administration of hematopoietic growth factors, whereas in an allogeneic hematopoietic stem cell transplants, cells are obtained from a human leukocyte antigen (HLA)-matched donor. Allogeneic HSCT is a curative modality in a substantial number of patients afflicted with these conditions, such as bone marrow failure. In allogeneic HSCT, however, chronic immunosuppression is necessary and can be complicated by GVHD, whereas this condition is not seen in autologous transplantation.3 Clinical manifestations and histopathology differentiates GVHD into acute and chronic types.5 MUSCLE & NERVE
October 2015
Table 1. Signs and symptoms of cGVHD from 2005 NIH Consensus Development Project on criteria for Clinical Trials in Chronic Graft-Versus-Host Disease* Organ or site Muscles, fascia, joints
Diagnostic
Distinctive
Other
Fasciitis, joint stiffness, or contractures due to sclerosis
Myositis or polymyositis
Edema, muscle cramps, arthritis or arthralgia
Other
Peripheral neuropathy Myasthenia gravis
*The diagnosis of cGVHD requires distinction from aGVHD, presence of at least 1 diagnostic clinical sign of cGVHD, and 1 distinctive manifestation confirmed by biopsy or other relevant tests.7
Acute GVHD (aGVHD) occurs within 100 days of transplantation and chronic GVHD (cGVHD), occurs thereafter.6 Although neurological complications of HSCT are almost exclusively seen in chronic GVHD (cGVHD) and thus pose a major obstacle to allogeneic HSCT, they may arise due to critical illness, progression of pre-existing neuromuscular illness, or the use of neurotoxic medications, such as chemotherapy conditioning regimens used pretransplant or infections. Because the immunopathogenesis of stem cell transplantation is incompletely understood, it is unclear if neurological complications are due to GVHD, the changes to the immune system following the transplant itself, or the above confounding factors. This review will focus exclusively on neuromuscular complications of stem cell transplant and GVHD. These include disorders of muscle, peripheral nerve, and the neuromuscular junction.6 GRAFT VERSUS HOST DISEASE: CLINICAL PRESENTATION AND PROPOSED PATHOPHYSIOLOGY
cGVHD is characterized by pleomorphic clinical manifestations and affects multiple tissues and organs. The syndrome resembles autoimmune immunologic disorders such as scleroderma, Sj€ ogren syndrome, primary biliary cirrhosis, and bronchiolitis obliterans. It occurs in 40–75% of patients with allogeneic HSCT.3 Symptoms usually present within 3 years after allogeneic HSCT and are often preceded by a history of aGVHD. The 2005 National Institutes of Health consensus criteria for cGVHD defines diagnostic, distinctive, other, and common manifestations of cGVHD.7 Table 1 lists neuromuscular conditions associated with cGVHD. Myositis and polymyositis (PM) are the only distinctive neuromuscular manifestations of cGVHD, whereas peripheral neuropathies (PN) and myasthenia gravis (MG) are less established and are therefore considered as other or associated features of GVHD. PN and MG alone, therefore, do not meet the diagnostic criteria for cGVHD, and other organ involvement is necessary to make this diagnosis.8 The pathophysiology of GVHD is complex and poorly understood. It resembles other autoimmune diseases, because it involves donor-derived NM Complications of HSCT
auto-reactive T-cell responses to host alloantigens. Although early studies proposed that cGVHD is a T-helper (Th)2 mediated disease based on the results from the nonirradiated parent!F1 mouse model, several other hypotheses are presently being considered. These include Th1 cells secreting cytokines5,8; thymic damage caused by the conditioning regimen, acute GVHD, or age-related involution atrophy5,8; by increased levels of tumor growth factor (TGF)-b15; or by T-regulatory cells, or Tregs, which are T-cell subsets that play an important role in peripheral tolerance. A strong correlation has been identified between B-cells or autoantibodies and cGVHD. GVHD has been linked to antibodies to Y chromosome-encoded histocompatibility antigens, elevated levels and increased genetic variation of B-cell activating factor, and increased number of B-cells expressing high levels of Toll-like receptor (TLR).9 Additionally, improvement after treatment of cGVHD with rituximab, which is a monoclonal antibody that binds to CD20 antigen on B-lymphocytes, further supports the contribution of B-cells to development of cGVHD.5,10 Early theories proposed that Th2 cells are responsible for cGVHD, but more recent studies suggest that Th1, Th2, and Th17 are upregulated early after HSCT. Th1 cells secrete interferongamma (IFN-c), and Th2 secrete interleukin (IL) 24, IL-5, and IL-13 cytokines. Th17 cells secrete IL-17. Nishimori et al. found significantly greater numbers of Th17 cells infiltrated into the lung and liver from allogeneic recipients than from syngeneic recipients. Donor-derived IFN-c and IL-17 were found following allogeneic but not syngeneic transplantation. Additionally, infusion of IFN-cand IL-17-negative donor cells attenuated cGVHD.11 This suggests that Th1, Th2, and Th17 cells contribute to development of GVHD. GRAFT VERSUS LEUKEMIA
An interesting phenomenon is the graft-versusleukemia (GVL) effect that occurs in allogeneic hematopoietic stem cell transplantation. Complete remission of malignant disease has been reported in allogeneic HSCT patients after withdrawal of MUSCLE & NERVE
October 2015
481
immunosuppression in patients whose cancer persisted after transplantation. Complete remission has also been observed in patients who were infused with donor-derived lymphocytes for persistent or recurrent malignancy. Most compellingly, proof of GVL exists in that partial or complete regression of malignancy is observed in patients who undergo low intensity conditioning regimens that enable stable engraftment of donor hematopoietic cells, but have little or no direct tumoricidal activity. The focus of many laboratories is an effort to enhance the GVL effect without aggravating GHVD.12 POLYMYOSITIS AND DERMATOMYOSITIS Clinical Features. Of those patients with inflammatory myopathies, polymyositis (PM) occurs in 35– 60%, and dermatomyositis (DM) is found in 15– 34%. Both are associated with malignancy.13 PM and DM are defined as manifestations of cGVHD based on the 2005 National Institute of Health Consensus.7 Myositis as a complication of cGVHD has been reported to occur in 7.6% of patients. The clinical and pathologic findings are often described as similar to those observed in idiopathic polymyositis.14 Bohan and Peter criteria define the diagnosis and use the presence or absence of rash to differentiate between polymyositis and dermatomyositis in the 2005 National Institutes of Health (NIH) Criteria for cGVHD.7,13 Histopathology and Immunopathogenesis. In PM, with cGVHD, there is fiber size variability, and there are scattered necrotic and regenerating fibers. Endomysial inflammatory infiltrates are mostly CD81 Tcells and macrophages.14 Reports of cGVHDassociated PM and DM are limited and controversial. In DM, a characteristic pathologic feature is perifascicular atrophy with small myofibers that are basophilic on hematoxylin-eosin staining within the perimysial perifascicular area. Inflammatory cell infiltrates may accumulate in the perivascular and perimysial regions. Necrotic fibers and wedge-shaped microinfarcts may also be present. The immunopathogenesis of dermatomyositis differs from that of polymyositis. Although it is incompletely understood, dermatomyositis has traditionally been considered a humoral-mediated disease, whereby antibody binding to endothelial autoantigens produces complement activation, vascular injury, and subsequent perifascicular atrophy. Polymyositis and Dermatomyositis in HSCT. Stevens et al.,15 in a 30-year retrospective chart review done at Fred Hutchinson Cancer Research Center, report that, among 1,859 individuals with cGVHD, 12 had PM. The diagnosis of PM was made on the basis of proximal muscle weakness, electromyography demonstrating myopathic motor unit potentials, muscle 482
NM Complications of HSCT
biopsy demonstrating endomysial lymphocytic infiltrate surrounding or invading individual nonnecrotic muscle fibers, and elevated serum muscle enzymes (i.e., creatinine kinase, aldolase, transaminases, or lactate dehydrogenase). The presence of 2 criteria designates possible PM, 3 criteria indicate probable, and 4 is definite. Histological assessments of cGVHD were based on biopsies of skin, oral mucosa, salivary glands, liver, and esophagus. Necrosis of individual epithelial cells or lymphoplasmocytic inflammation with destruction of architectural features was considered evidence of active cGVHD.15 At the time of onset of myositis, patients had evidence of systemic GVHD, and in 5 patients, myositis was part of the original presentation of cGVHD. The time from transplantation to development of cGVHD ranged from 3.3–16 months. Additionally, serum samples were tested for anti-nuclear antibody (PM). Of the 12 patients diagnosed with cGVHD, 8 had autoantibodies. Five had ANA, 4 had anti-smooth muscle antibodies, and 1 had anti-mitochondrial antibodies. No myositis-specific autoantibodies were found with the exception of 1 serum sample, where antibodies to U4/6 small nuclear RNA synthetase complex were seen.15 The clinical significance of autoantibodies in cGVHD is not clear. ANAs were found in sera of cGVHD patients, but the frequency does not seem to correlate with the occurrence of acute or cGVHD.16 At the time of myositis diagnosis in the 12 patients with cGVHD, 6 were on either prednisone or intravenous immunoglobulin (IVIg). The immunosuppression regimen was not known in the remainder of the cGVHD patients. Eleven of 12 patients responded to steroids and either azathioprine or cyclosporine, with a 3- to 7month response time; 1 outlier took over 48 months to respond to treatment. Because patients share characteristics with idiopathic polymyositis, including acute or subacute onset of weakness, elevated muscle enzymes, typical pathology on muscle biopsy and EMG, and response to treatment, the distinction between polymyositis as a manifestation of cGVHD and the idiopathic disease is unclear. No other patient risk factors in patient histories were identified, such as thyroid disease, active viral infections, or medications. No patients developed myositis with autologous stem cell transplant or without cGVHD. This suggests that it is unlikely that PM developed in these individuals by chance alone, as its incidence is much higher than in the general population. Additionally, many cases may go undiagnosed because many patients die before developing PM. Presumably, the lymphocytic infiltration found in cGVHD-associated myositis is also composed of donor cells, as the host’s cells have been eliminated by the conditioning regimen.15 MUSCLE & NERVE
October 2015
Dermatomyositis has also been reported in case series to have an association with cGVHD following allogeneic HSCT. Muscle biopsy demonstrated perifascicular atrophy in all cases. Treatment of cGVHD with tacrolimus and prednisone caused improvement in strength.14 Other cases of cGVHD and dermatomyositis have also been reported. There was electrophysiologic evidence of myopathy without biopsy in 1 patient, and in another, EMG was normal, but muscle biopsy demonstrated the pathognomonic perifascicular atrophy. Both patients were treated with prednisone.17,18 Although dermatomyositis has been linked to cGVHD, Sakamoto et al.19 report a case in which a male patient developed idiopathic dermatomyositis 14 years after undergoing a gender-mismatched allogeneic bone marrow transplant (BMT). The patient complained of proximal muscle weakness and dermatitis. Laboratory examinations revealed elevated creatinine kinase and liver function tests as well as presence of ANA at a titer of 1:640 and negative anti-Jo antibodies. EMG demonstrated electrophysiologic evidence of myopathy. This was confirmed by muscle biopsy, which demonstrated perifascicular atrophy. Inflammatory mononuclear cells were also noted in the endomysium, perimysium, and perivascular regions. The cells were predominantly CD41. Genotyping with XYfluorescence in situ hybridization (FISH) revealed that infiltrating cells in the muscle clearly had a Ypositive phenotype. On the basis of these findings, the patient was diagnosed to have autoimmune dermatomyositis and not cGVHD, as his donor was a woman. He was subsequently treated with oral prednisolone, with improvement of symptoms.19 This case report superseded the Stevens study and suggests the importance of chimerism analysis in any allogeneic BMT-related dermatomyositis to best define the nature of the disease in a gendermismatched allogeneic HSCT. This would be helpful if the transplant is gender-mismatched. Such analyses were not done in prior studies, although microchimerism has been reported in the Dermatology literature to cause autoimmune conditions in children. Fraternal and maternal microchimerism has been reported to cause a cGVHD like dermopathy.20,21 SYNDROME AND PERIPHERAL GUILLAIN-BARRE NEUROPATHY
Immune-mediated demyelinating disease after allogeneic HSCT is rare compared with inflammatory myopathies and occurs with a frequency of 1– 2%.22 In some cases, it is not entirely clear whether it is a true manifestation of cGVHD, due to a coincidentally coexistent autoimmune disease in the setting of immune system constitution, related to the NM Complications of HSCT
pretransplant chemotherapy conditioning regimen, or an underlying infection. Because of the uncertainty as to the cause of acute demyelinating neuropathy it is considered an “associated” symptom and does not meet criteria to define cGVHD.7,8 Several case reports and case series support the contention that Guillain-Barre syndrome (GBS) is related to cGVHD, with typical electrodiagnostic findings of demyelination, elevated CSF protein and demyelination and inflammation on nerve biopsy.23 The onset is usually within 21 months after HSCT, with a median of 7 months.24 The patients often have rash as a manifestation of cGVHD preceding the neuropathy.7,23 In 1 case, a woman received an allogeneic bone marrow transplant from her HLA identical brother, and FISH of the sural nerve biopsy demonstrated that 15% of infiltrating T-cells carried both X and Y chromosomes. These data conclusively demonstrate that the infiltrating T-cells were of donor origin from her brother.23 GBS may occur as an initial manifestation cGVHD followed by skin biopsy signs of cGVHD after cessation of immunosuppression, such as cyclosporine.25 IVIg and plasma exchange, may not be effective, and 1 patient improved 18 days after cyclosporine was re-initiated. A large retrospective chart review of 1,484 patients treated at Memorial Sloan Kettering Hospital between 1992 and 2010 looked at immunemediated demyelinating disease in patients who underwent allogeneic hematopoietic stem cell transplantation. Seven patients had immunemediated demyelinating disease, including 3 with acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 1 with autonomic neuropathy, and 3 with evidence of central demyelinating disease. One patient with AIDP and 1 patient with autonomic neuropathy had evidence of systemic GVHD.26 All patients were treated with immunomodulatory therapies and had improvement in symptoms. Demyelination without significant inflammatory infiltration on nerve or muscle biopsy supports an immune-mediated demyelinating disease, whereas GVHD would show CD81 Tcell lymphocytic infiltration.26 Immune-mediated neuropathy (IMN) following allogeneic hematopoietic stem cell transplant in the absence of cGVHD has also been reported.27 Cases of concurrent infections and demyelinating neuropathy make the immunopathogenesis challenging to discern. Patients have developed GBS following infections but also had reactivation of cGVHD. Improvement occurred after treatment with tacrolimus and IVIg. Preceding viral infection and an immunologic reaction to the virus may have been a trigger for both reactivation of GVHD and an immune-mediated neuropathy. Management MUSCLE & NERVE
October 2015
483
with immunosuppressive agents and IVIg suggest both cellular and humoral immunity play a role in immune-mediated neuropathy associated with allogeneic HSCT.28 Another patient developed axonal GBS in the setting of cytomegalovirus (CMV) colitis 58 days after developing GVHD and being treated successfully for the colitis. Sural nerve biopsy revealed axonal degeneration with infiltration of CD81 T-cells and macrophages. GBS was not thought to be due to either the aGVHD or CMV, because symptoms of acute GVHD had already resolved at the onset of GBS, while CMV antigenemia resolved without any therapy. One thought is that the CMV infection triggered the neuropathy by means of a humorally-mediated “cross-reactive” mechanism, which is what has been postulated in nontransplant patients. Because this patient’s sural nerve biopsy showed infiltration of donor-derived mature T-cells and few deposits of immunoglobulins, the authors assumed that CMV triggered peripheral expansion of mature donor-derived Tcells and thus played a role in the development of GBS versus the humorally mediated mechanism seen in nontransplant patients.29 In the pediatric literature from Poland, a retrospective analysis of 171 cases of HSCT (84 autologous and 87 allogeneic) identified 2 children with allogeneic HSCT who developed radiculitis post transplantation in the setting of to CMV and Epstein-Barr Virus (EBV) infection. Neither child was reported to have aGVHD or cGVHD.30 GBS in the immediate post transplantation period has also been reported in children age 16–18 by Rodriguez et al.31 None of the patients had evidence of aGVHD at the time of diagnosis, and only 1 had an infection. The clinical course of the patients was severe; 2 of the 3 patients developed dysautonomia, and 1 had multi-organ failure. It was thought that administration of cytosinearabinoside (Ara-C) was responsible for development of demyelinating neuropathy rather than a dysimmune reaction posttransplant due to the close temporal relationship between onset of symptoms and drug administration.31 A recent study from the Mayo Clinic reported on 3,305 patients who underwent HSCT between 1997 and 2010. Only 12 patients with immunemediated neuropathies, (including asymmetric radiculoplexopathies, GBS, and multiple mononeuropathies) were included in the analysis, as those who had chronic neuropathic conditions unrelated to the stem cell transplant were excluded. Six patients had allogeneic hematopoietic stem cell transplants, and 6 had autologous transplants. One of the patients who underwent allogeneic transplantation had manifestations of cutaneous GVHD, but no others did. All patients at the time of onset of the neuropathy were determined to be in hema484
NM Complications of HSCT
tologic remission, however, early relapse of hematologic malignancy in patients with IMN following SCT was seen in 5 of 12 patients.24 Two possible hypotheses for development of IMN exist. Because most of the IMN occurred within 21 months following HSCT, immune system reconstitution could be the cause. Improvement with the use of immunotherapy further supports this hypothesis. The close relationship between the time of cancer relapse and the occurrence of IMN suggests a possible paraneoplastic etiology.24 Although most of these neuromuscular complications are in the setting of allogeneic HSCT, rare neurological complications of autologous stem cell transplantation have also been reported. In addition to the 6 patients reported from the Mayo study, 3 patients with brachial plexopathy following autologous HSCT have been reported, as well as a patient with a brachial plexopathy 5 days after allogeneic HSCT, with no evidence of aGVHD. The association with recent autologous stem cell transplantation argues in favor of an autoimmune mechanism in the setting of immune reconstitution as discussed above.32 MYASTHENIA GRAVIS IN GVHD
MG may develop in patients after bone marrow transplantation and may be a manifestation of GVHD. A recent study by Heidarzadeh et al. reported all cases of MG after bone marrow transplantation in adults. Twenty-two adults and 1 child with MG after bone marrow transplant have been reported.33,34 Nineteen of the cases were associated with cGVHD after allogeneic HSCT, which supports the hypothesis that MG develops a result of targeting the new host’s neuromuscular junction by transplanted immune cells. In the case of the child, acetylcholine receptor-antibody (AchR-Ab) positive MG developed 22 months after allogeneic HSCT transplantation when the child was 34 months old. There are, however, 3 reported cases of MG in the absence of cGVHD, including 2 following autologous transplant. A case of MG with elevated AchR-Ab and elevated titin Ab following HSCT has been reported.4 Zaja et al. propose that 2 distinct autoimmune conditions may be responsible for the development of MG: cGVHD and adoptive autoimmunity. In cGVHD the appearance of autoantibodies and autoreactive lymphocytes, as well as the series of events involved in the pathogenesis of target cell damage, is well documented. The immune system itself is a major target, and immunological dysfunction may become an additional factor in the multifactorial generation of autoimmunity.35 Serum AChR-Abs have been reported in patients who do not have symptoms of MG. Not every patient who was seropositive had GVHD, and MG was also seen MUSCLE & NERVE
October 2015
Table 2. Summary of neuromuscular complications of HSCT associated with cGVHD and reported treatment modalities. NM disorder
Clinical manifestations
Associated with cGVHD
Treatment
Polymyositis Symmetrical proximal weakness 1/- dysphagia and respiratory muscle weakness
Distinctive feature based on NIH 2005 Consensus Criteria.7
Prednisone, azathioprine, cyclosporine
Symmetrical proximal weakness 1/- dysphagia and respiratory muscle weakness with classic rash
Distinctive feature based on NIH 2005 Consensus Criteria.7
Prednisone, tacrolimus, rituximab, IVIg
Weakness, absent reflexes, elevated CSF protein
“Other” feature based on NIH 2005 Consensus Criteria.7
Resumption of previously withdrawn/ de-escalated immunosuppression, IVIg, plasmapheresis
Ptosis, diplopia, bulbar and limb weakness
“Other” feature based on NIH 2005 Consensus Criteria.7
Resumption of previously withdrawn/de-escalated immunosuppression, prednisone, azathioprine, cyclosporine
Dermatomyositis
AIDP, CIDP
Myasthenia gravis
in a patient with autologous transplantation. Production of AChR-Abs after transplantation may be a manifestation of autoreactivity. This provides evidence against GVHD playing a role in autoimmunity.36 The frequent antibody positivity and infrequent manifestations of MG suggests that other factors are necessary to fully develop the clinical picture of MG.35 It has also been reported that certain HLA antigens are associated frequently with MG that develops after hematopoietic stem cell transplantation. Recurrent expression or co-expression of HLA-A2, HLA-B7, HLA-A35, HLA-DR2, and HLA-Cw4 has been reported. In patients younger than 40 years, HLA-A1, HLA-B8, and HLA-DR3 are expressed more commonly.35 Nearly all of the reported patients had serum AchR-Abs and only 3 reported patients had MuSK antibodies.33,37,38 Of the MuSK1 patients only 1 was reported to have evidence of cGVHD.33 MG in these patients is typically responsive to pyridostigmine and prednisone. De-escalation of immunosuppression has been reported to cause worsening of symptoms. Rituximab has been used with benefit in a patient with otherwise refractory symptoms and severe prednisone side effects. Rituximab induced marked Blymphocyte depletion with substantial reduction in the production of autoantibodies.35 In the GITMO (Italian group bone marrow transplant) study, the use of rituximab in treatment of refractory cGVHD was reviewed. Of the 38 patients who were included, 1 had a very severe form of MG. This patient went into complete remission with dose reduction of maintenance immunosuppressive therapy after rituximab. Overall, rituximab was effective in over 50% of patients with refractory NM Complications of HSCT
cGVHD and may confer a survival benefit. These data indicate that rituximab may reduce multiorgan involvement of some cGVHD manifestations. The beneficial effect of B-cell depletion highlights the potential primary pathological role of lymphocytes in the development of cGVHD.39 TREATMENT
In the PM study, patients were treated with prednisone and either azathioprine or cyclosporine, and in 1 patient methotrexate, with improvement of symptoms in most.15 Similarly, patients with DM were treated with steroids, tacrolimus, rituximab, and gammaglobulin with good response.14 DM due to cGVHD (presumably) and idiopathic DM both respond to treatment with prednisone. In patients with demyelinating neuropathies, IVIg was given with variable improvement. The patients who developed GBS tended to have more systemic illness, and it is less clear if the GBS is related to cGVHD, immune reconstitution, infection, or even conditioning chemotherapy.25,28,31 In 1 patient, it was thought to be a result of discontinuation of immunosuppression, and GBS was the presenting manifestation of cGVHD. In that patient, treatment with steroids, IVIg, plasmapheresis, and cyclosporine was necessary. Clinical improvement only occurred after cyclosporine was given. Although improvement may have lagged behind treatment institution, the clinical response to cyclosporine may reflect differences in pathological mechanisms between cGVHD-associated GBS and classical GBS.25 There is some evidence to suggest that development of MG is related to de-escalation of immunosuppression. Favorable response to resumption of immunosuppression further supports this hypothesis.40 Treatment with prednisone and either MUSCLE & NERVE
October 2015
485
cyclosporine or azathioprine has been reported to produce a good response.33 Symptomatic treatment with pyridostigmine has a favorable effect in patients with cGVHD-associated MG as well. SUMMARY
In summary, most complications of HSCT do not occur immediately post transplantation. The vast majority happen in those with allogeneic HSCT and in the setting of cGVHD. PM and DM are defined as distinctive criteria of cGVHD according to the 2005 NIH Consensus Criteria for cGVHD. Peripheral neuropathies and MG are defined as “other” features, because cases have been reported in the absence of cGVHD in the setting of immunosuppression withdrawal, infection, or chemotherapy. Treatment of PM and DM related to HSCT and cGVHD is essentially the same as that of the idiopathic conditions. In the cases where immunosuppression was de-escalated, re-initiation of immunosuppression in patients with GBS and MG is thought to help recovery when IVIg and plasmapheresis fail. Table 2 summarizes the neuromuscular complications of HSCT and treatments. A more comprehensive understanding of the immune system and physiology of allogeneic transplantation will ultimately shine light on the possible mechanisms of neuromuscular pathology and help target treatments. It is important to differentiate between idiopathic neuromuscular diseases, those caused by prolonged illness and immobility, and those related to the transplant itself. GVHD and GVL are immunological conditions that must be kept in mind and taken into consideration when treatments are considered. Based on a lecture given at the 60th annual meeting of the AANEM by Dr. Thomas Brannagan. Neither author has any conflicts of interest or any funding sources for our work. REFERENCES 1. Rodriguez TE. Neurologic complications of bone marrow transplantation. Handb Clin Neurol 2014;121:1295–1304. 2. Pless M, Zivkovic SA. Neurologic complications of transplantation. Neurologist 2002;8:107–120. 3. Saiz A, Graus F. Neurological complications of hematopoietic cell transplantation. Sem Neurol 2004;24:427–434. 4. Koeppen S, Thirugnanasambanthan A, Koldehoff M. Neuromuscular complications after hematopoietic stem cell transplantation. Support Care Cancer 2014;22:2337–2341. 5. Nishimori H, Maeda Y, Tanimoto M. Chronic graft-versus-host disease: disease biology and novel therapeutic strategies. Acta Med Okayama 2013;67:1–8. 6. Pustavoitau A, Bhardwaj A, Stevens R. Neurological complications of transplantation. J Intensive Care Med 2011;26:209–222. 7. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005;11:945–956. 8. Grauer O, Wolff D, Bertz H, Hildegard G, Kuhl JS, Lawitschka A, et al. Neurological manifestations of chronic graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: report from the Consensus Conference on Clinical Practice in chronic graftversus-host disease. Brain 2010;133:2852–2865.
486
NM Complications of HSCT
9. Matsuoka K, Kim HT, McDonough S, Bascug G, Warshauer B, Koreth J,et al. Altered regulatory T cell homeostasis in patients with CD41 lymphopenia following allogeneic hematopoietic stem cell transplantation. J Clin Invest 2010;120:1479–1493. 10. Zaja F, Bacigalupo A, Patriarca F, Stanzani M, Van Lint MT, Filı C, et al. Treatment of refractory chronic GVHD with rituximab: a GITMO study. Bone Marrow Transplant 2007;40:273–277. 11. Nishimori H, Maeda Y, Teshima T, Sugiyama H, Kobayashi K, Yamasuji Y, et al. Synthetic retinoid Am80 ameliorates chronic graftversus-host disease by down-regulating Th1 and Th17. Blood 2012; 119:285–295. 12. Warren EH, Deeg HJ. Dissecting graft-versus-leukemia from graftversus-host-disease using novel strategies. Tissue Antigens 2013;81: 183–193. 13. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344–347. 14. Allen JA, Greenberg SA, Amato AA. Dermatomyositis-like muscle pathology in patients with chronic graft-versus-host disease. Muscle Nerve 2009;40:643–647. 15. Stevens AM, Sullivan KM, Nelson JL. Polymyositis as a manifestation of chronic graft-versus-host disease. Rheumatology 2003;42:34–39. 16. Arin MJ, Scheid C, Hubel K, Krieg T, Groth W, Haerrmann G. Chronic graft-versus-host disease with skin signs suggestive of dermatomyositis. Clin Exp Dermatol 2006;31:141–143. 17. Ollivier I, Wolkenstein P, Gherardi R, Weschsler J, Kuentz M, Cosnes A, et al. Dermatomyositis-like graft-versus-host disease. Br J Dermatol 1998;138:558–559. 18. Leber B, Walker IR, Rodriguez A, McBride JA, Carter R, Brain MC. Reinduction of remission of chronic myeloid leukemia by donor leukocyte transfusion following relapse after bone marrow transplantation: recovery complicated by initial pancytopenia and late dermatomyositis. Bone Marrow Transplant 1993;12:405–407. 19. Sakamoto K, Imamura T, Niwa F, Komori S, Ishihara Y, Shiga K, et al. Dermatomyositis developed in a recipient of allogeneic BMT; the differentiation of chronic GVHD and autoimmune disease. Bone Marrow Transplant 2012;47:603–604. 20. Vabres P, Bonneau D. Childhood dermatosis due to microchimerism. Dermatology 2005;211:388–389; author reply 389. 21. Kowalzick L, Artlett CM, Thoss K, Baum HP, Ziegler H, Mischke D, et al. Chronic graft-versus-host-disease-like dermopathy in a child with CD41 cell microchimerism. Dermatology 2005;210:68–71. 22. Bulsara KR, Baron PW, Tuttle-Newhall JE, Clavien PA, Morgenlander J. Guillain-Barre syndrome in organ and bone marrow transplant patients. Transplantation 2001;71:1169–1172. 23. Haruki H, Koga M, Ogasawara J, Omoto M, Kawai M, Kanda T. Neuropathy in chronic graft-versus-host disease caused by donor T cells. Muscle Nerve 2012;46:610–611. 24. Karam C, Mauermann ML, Johnston PB, Lahoria R, Engelstad JK, Dyck PJ. Immune-mediated neuropathies following stem cell transplantation. J Neurol Neurosurg Psychiatry 2014;85:638–642. 25. Thone J, Lamprecht S, Hohaus A, Erbguth F, Bickel A. GuillainBarre syndrome as leading manifestation of graft-versus-host disease in an allogeneic bone marrow transplanted patient. J Neurol Sci 2010;292:114–116. 26. Delios AM, Rosenblum M, Jakubowski AA, DeAngelis LM. Central and peripheral nervous system immune mediated demyelinating disease after allogeneic hemopoietic stem cell transplantation for hematologic disease. J Neurooncol 2012;110:251–256. 27. Su L, Ji B, Hu R, Lan X, Xia C. Immune-mediated neuromuscular complications after haploidendtical hematopoietic stem cell transplantation. Chin Med J (Engl) 2014;127:2865–2867. 28. Doi Y, Sugahara H, Yamamoto K, Uji-ie H, Kakimoto T, Sakoda H. Immune-mediated peripheral neuropathy occurring simultaneously with recurrent graft-versus-host disease after allogenic hematopoietic stem cell transplantation. Leuk Res 2012;36:e63–e65. 29. Fujisaki G, Kami M, Murashige N, Kishi Y, Hori, A, Chizuka A, et al. Guillain-Barre syndrome associated with rapid immune reconstitution following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2006;37:617–619. 30. Zaucha-Prazmo A, Jasinski M, Drabko K, Choma M, Wojcik B, Kowalczyk JR. Neurologic complications in children after hemaopoietic stem cell transplantation: a single-center experience. Transplant Proc 2007;39:2905–2907. 31. Rodriguez V, Kuehnle I, Heslop HE, Khan S, Krance RA. GuillainBarre syndrome after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2002;29:515–517. 32. Rabinstein AA, Dispenzieri A, Micallef IN, Inwards DJ, Litzow MR, Wijdicks EF. Acute neuropathies after peripheral blood stem cell and bone marrow transplantation. Muscle Nerve 2003;28:733–736. 33. Heidarzadeh Z, Mousavi SA, Ostovan VR, Nafissi S. Muscle-specific kinase antibody associated myasthenia gravis after bone marrow transplantation. Neuromuscul Disord 2014;24:148–150. 34. Unal S, Sag E, Kuskonmaz B, Kesici S, Bayrakci B, Ayvaz DC, et al. Successful treatment of severe myasthenia gravis developed after
MUSCLE & NERVE
October 2015
allogeneic hematopoietic stem cell transplantation with plasma exchange and rituximab. Pediatr Blood Cancer 2014;61:928–930. 35. Zaja F, Barillari G, Russo D, Silvestri F, Fanin R, Baccarani M. Myasthenia gravis after allogeneic bone marrow transplantation. A case report and a review of the literature. Acta Neurol Scand 1997;96:256–259. 36. Smith CI, Hammarstrom L, Lefvert AK. Bone-marrow grafting induces acetylcholine receptor antibody formation. Lancet 1985;1:978. 37. Atassi N, Amato AA. Muscle-specific kinase (MuSK) antibodyassociated myasthenia gravis after bone marrow transplantation. Muscle Nerve 2008;38:1074–1075.
NM Complications of HSCT
38. Grover KM, Sripathi N, Elias SB. Muscle-specific kinase-antibodypositive myasthenia gravis after autologous bone marrow transplantation. J Clin Neuromuscul Dis 2012;13:146–148. 39. Zaja F, Russo D, Fuga G, Perella G, Baccarani M. Rituximab for myasthenia gravis developing after bone marrow transplant. Neurology 2000;55:1062–1063. 40. Mackey JR, Desai S, Larratt L, Cwik V, Nabholtz JM. Myasthenia gravis in association with allogeneic bone marrow transplantation: clinical observations, therapeutic implications and review of literature. Bone Marrow Transplant 1997;19:939–942.
MUSCLE & NERVE
October 2015
487
NEUROMUSCULAR COMPLICATIONS OF HEMATOPOIETIC STEM CELL TRANSPLANTATION KATHERINE M. RUZHANSKY, MD, MS,1 and THOMAS H BRANNAGAN III, MD2 1
Medical University of South Carolina, Department of Neurology and Neurosurgery, Neuromuscular Division, 96 Jonathan Lucas Street, CSB 301, Charleston, South Carolina 29425 USA 2 Columbia University Medical Center, Peripheral Neuropathy Center, Neurological Institute, New York, New York, USA Accepted 29 May 2015 ABSTRACT: Neuromuscular diseases such as polymyositis, dermatomyositis, peripheral neuropathy, and disorders of neuromuscular transmission are reported to be complications of hematopoietic stem cell transplantation (HSCT). Although cases have been reported with allogeneic HSCT in the setting of chronic graft versus host disease, they are also known to occur without evidence thereof and even occur in the setting of autologous HSCT. The 2005 National Institutes of Health Consensus Criteria classify polymyositis and dermatomyositis as “distinctive” features, and neuropathy and MG as “other” features. These neuromuscular complications present very similarly to the idiopathic autoimmune disorders and respond to similar treatment modalities. Muscle Nerve 52: 480–487, 2015
Hematopoietic stem cell transplantation (HSCT) has been used increasingly to treat oncologic, metabolic, and autoimmune disorders, including autoimmune neuromuscular diseases since it was first used successfully in the late 1960s.1 Neurological problems, such as central nervous system disorders and infections occur in these patients and are often a major cause of morbidity and mortality.2 With regard to neuromuscular complications, patients may have persistence or progression of a preexisting neuromuscular disorder, or critical illness neuropathy or myopathy may develop due to prolonged hospitalization and medical complications. Additionally, medications used for Abbreviations: AchR, acetylcholine receptor; AchR Ab, acetylcholine receptor antibody; aGVHD, acute graft versus host disease; AIDP, acute inflammatory demyelinating polyradiculoneuropathy; AMAN, acute motor axonal neuropathy; ANA, antinuclear antibody; BMT, bone marrow transplant; cGVHD, chronic graft versus host disease; CIDP, chronic inflammatory demyelinating; CMV, cytomegalovirus; CSF, cerebrospinal fluid; DM, dermatomyositis; EBV, Epstein-Barr virus; EMG, electromyography; FISH, syndrome; GVHD, fluorescence in situ hybridization; GBS, Guillain-Barre graft versus host disease; GVL, graft versus leukemia; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplant; IFN, interferon; IL, interleukin; IMN, immune mediated neuropathy; IVIg, intravenous immunoglobulin; MG, myasthenia gravis; MuSK, muscle specific kinase; NCS, nerve conduction studies; NIH, National Institutes of Health; PDGF, platelet derived growth factor; PM, polymyositis; PN, peripheral neuropathy; TGF, tumor growth factor; Th, T helper; TLR, toll-like receptor; Treg, T regulatory cells. Key words: allogeneic; autologous stem cell transplant; bone marrow transplant; dermatomyositis; graft versus host disease; myasthenia gravis; neuromuscular complications; peripheral neuropathy; polymyositis Correspondence to: K. M. Ruzhansky; e-mail: [email protected] C 2015 Wiley Periodicals, Inc. V
Published online 4 June 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24724
480
NM Complications of HSCT
immunosuppression may cause toxic neuromuscular complications.3 Neuromuscular disorders can also occur as a result of the bone marrow transplantation itself. Neuromuscular disorders have been described rarely after an autologous stem cell transplant. However, after solid organ and allogeneic HSCT transplants, the reported incidence of neurologic complications is 30–80%.2 The extent of complications depends on multiple factors, such as type of hematologic malignancy, age, and histocompatibility of the recipient.4 The neuromuscular problems resulting from the bone marrow transplantation, including from graft versus host disease (GVHD), will be the focus of this review. HEMATOPOIETIC STEM CELL TRANSPLANT: AUTOLOGOUS AND ALLOGENEIC
Stem cell transplantation is being used more commonly to treat various hematological malignancies, bone marrow failure, immunodeficiency syndromes, and certain congenital metabolic disorders, as well as autoimmune disorders, including autoimmune neuromuscular disorders. Preparative regimens for HSCT have evolved over the years. Patients typically undergo varying degrees of myeloablation with total body irradiation and chemotherapy, depending on the amount of myelosuppression necessary.1 The rationale of the procedure is to reestablish the marrow function destroyed by the chemotherapy given to eradicate neoplastic cells. In autologous stem cell transplantation, a patient’s own hematopoietic progenitor cells are harvested from bone marrow or peripheral blood after administration of hematopoietic growth factors, whereas in an allogeneic hematopoietic stem cell transplants, cells are obtained from a human leukocyte antigen (HLA)-matched donor. Allogeneic HSCT is a curative modality in a substantial number of patients afflicted with these conditions, such as bone marrow failure. In allogeneic HSCT, however, chronic immunosuppression is necessary and can be complicated by GVHD, whereas this condition is not seen in autologous transplantation.3 Clinical manifestations and histopathology differentiates GVHD into acute and chronic types.5 MUSCLE & NERVE
October 2015
Table 1. Signs and symptoms of cGVHD from 2005 NIH Consensus Development Project on criteria for Clinical Trials in Chronic Graft-Versus-Host Disease* Organ or site Muscles, fascia, joints
Diagnostic
Distinctive
Other
Fasciitis, joint stiffness, or contractures due to sclerosis
Myositis or polymyositis
Edema, muscle cramps, arthritis or arthralgia
Other
Peripheral neuropathy Myasthenia gravis
*The diagnosis of cGVHD requires distinction from aGVHD, presence of at least 1 diagnostic clinical sign of cGVHD, and 1 distinctive manifestation confirmed by biopsy or other relevant tests.7
Acute GVHD (aGVHD) occurs within 100 days of transplantation and chronic GVHD (cGVHD), occurs thereafter.6 Although neurological complications of HSCT are almost exclusively seen in chronic GVHD (cGVHD) and thus pose a major obstacle to allogeneic HSCT, they may arise due to critical illness, progression of pre-existing neuromuscular illness, or the use of neurotoxic medications, such as chemotherapy conditioning regimens used pretransplant or infections. Because the immunopathogenesis of stem cell transplantation is incompletely understood, it is unclear if neurological complications are due to GVHD, the changes to the immune system following the transplant itself, or the above confounding factors. This review will focus exclusively on neuromuscular complications of stem cell transplant and GVHD. These include disorders of muscle, peripheral nerve, and the neuromuscular junction.6 GRAFT VERSUS HOST DISEASE: CLINICAL PRESENTATION AND PROPOSED PATHOPHYSIOLOGY
cGVHD is characterized by pleomorphic clinical manifestations and affects multiple tissues and organs. The syndrome resembles autoimmune immunologic disorders such as scleroderma, Sj€ ogren syndrome, primary biliary cirrhosis, and bronchiolitis obliterans. It occurs in 40–75% of patients with allogeneic HSCT.3 Symptoms usually present within 3 years after allogeneic HSCT and are often preceded by a history of aGVHD. The 2005 National Institutes of Health consensus criteria for cGVHD defines diagnostic, distinctive, other, and common manifestations of cGVHD.7 Table 1 lists neuromuscular conditions associated with cGVHD. Myositis and polymyositis (PM) are the only distinctive neuromuscular manifestations of cGVHD, whereas peripheral neuropathies (PN) and myasthenia gravis (MG) are less established and are therefore considered as other or associated features of GVHD. PN and MG alone, therefore, do not meet the diagnostic criteria for cGVHD, and other organ involvement is necessary to make this diagnosis.8 The pathophysiology of GVHD is complex and poorly understood. It resembles other autoimmune diseases, because it involves donor-derived NM Complications of HSCT
auto-reactive T-cell responses to host alloantigens. Although early studies proposed that cGVHD is a T-helper (Th)2 mediated disease based on the results from the nonirradiated parent!F1 mouse model, several other hypotheses are presently being considered. These include Th1 cells secreting cytokines5,8; thymic damage caused by the conditioning regimen, acute GVHD, or age-related involution atrophy5,8; by increased levels of tumor growth factor (TGF)-b15; or by T-regulatory cells, or Tregs, which are T-cell subsets that play an important role in peripheral tolerance. A strong correlation has been identified between B-cells or autoantibodies and cGVHD. GVHD has been linked to antibodies to Y chromosome-encoded histocompatibility antigens, elevated levels and increased genetic variation of B-cell activating factor, and increased number of B-cells expressing high levels of Toll-like receptor (TLR).9 Additionally, improvement after treatment of cGVHD with rituximab, which is a monoclonal antibody that binds to CD20 antigen on B-lymphocytes, further supports the contribution of B-cells to development of cGVHD.5,10 Early theories proposed that Th2 cells are responsible for cGVHD, but more recent studies suggest that Th1, Th2, and Th17 are upregulated early after HSCT. Th1 cells secrete interferongamma (IFN-c), and Th2 secrete interleukin (IL) 24, IL-5, and IL-13 cytokines. Th17 cells secrete IL-17. Nishimori et al. found significantly greater numbers of Th17 cells infiltrated into the lung and liver from allogeneic recipients than from syngeneic recipients. Donor-derived IFN-c and IL-17 were found following allogeneic but not syngeneic transplantation. Additionally, infusion of IFN-cand IL-17-negative donor cells attenuated cGVHD.11 This suggests that Th1, Th2, and Th17 cells contribute to development of GVHD. GRAFT VERSUS LEUKEMIA
An interesting phenomenon is the graft-versusleukemia (GVL) effect that occurs in allogeneic hematopoietic stem cell transplantation. Complete remission of malignant disease has been reported in allogeneic HSCT patients after withdrawal of MUSCLE & NERVE
October 2015
481
immunosuppression in patients whose cancer persisted after transplantation. Complete remission has also been observed in patients who were infused with donor-derived lymphocytes for persistent or recurrent malignancy. Most compellingly, proof of GVL exists in that partial or complete regression of malignancy is observed in patients who undergo low intensity conditioning regimens that enable stable engraftment of donor hematopoietic cells, but have little or no direct tumoricidal activity. The focus of many laboratories is an effort to enhance the GVL effect without aggravating GHVD.12 POLYMYOSITIS AND DERMATOMYOSITIS Clinical Features. Of those patients with inflammatory myopathies, polymyositis (PM) occurs in 35– 60%, and dermatomyositis (DM) is found in 15– 34%. Both are associated with malignancy.13 PM and DM are defined as manifestations of cGVHD based on the 2005 National Institute of Health Consensus.7 Myositis as a complication of cGVHD has been reported to occur in 7.6% of patients. The clinical and pathologic findings are often described as similar to those observed in idiopathic polymyositis.14 Bohan and Peter criteria define the diagnosis and use the presence or absence of rash to differentiate between polymyositis and dermatomyositis in the 2005 National Institutes of Health (NIH) Criteria for cGVHD.7,13 Histopathology and Immunopathogenesis. In PM, with cGVHD, there is fiber size variability, and there are scattered necrotic and regenerating fibers. Endomysial inflammatory infiltrates are mostly CD81 Tcells and macrophages.14 Reports of cGVHDassociated PM and DM are limited and controversial. In DM, a characteristic pathologic feature is perifascicular atrophy with small myofibers that are basophilic on hematoxylin-eosin staining within the perimysial perifascicular area. Inflammatory cell infiltrates may accumulate in the perivascular and perimysial regions. Necrotic fibers and wedge-shaped microinfarcts may also be present. The immunopathogenesis of dermatomyositis differs from that of polymyositis. Although it is incompletely understood, dermatomyositis has traditionally been considered a humoral-mediated disease, whereby antibody binding to endothelial autoantigens produces complement activation, vascular injury, and subsequent perifascicular atrophy. Polymyositis and Dermatomyositis in HSCT. Stevens et al.,15 in a 30-year retrospective chart review done at Fred Hutchinson Cancer Research Center, report that, among 1,859 individuals with cGVHD, 12 had PM. The diagnosis of PM was made on the basis of proximal muscle weakness, electromyography demonstrating myopathic motor unit potentials, muscle 482
NM Complications of HSCT
biopsy demonstrating endomysial lymphocytic infiltrate surrounding or invading individual nonnecrotic muscle fibers, and elevated serum muscle enzymes (i.e., creatinine kinase, aldolase, transaminases, or lactate dehydrogenase). The presence of 2 criteria designates possible PM, 3 criteria indicate probable, and 4 is definite. Histological assessments of cGVHD were based on biopsies of skin, oral mucosa, salivary glands, liver, and esophagus. Necrosis of individual epithelial cells or lymphoplasmocytic inflammation with destruction of architectural features was considered evidence of active cGVHD.15 At the time of onset of myositis, patients had evidence of systemic GVHD, and in 5 patients, myositis was part of the original presentation of cGVHD. The time from transplantation to development of cGVHD ranged from 3.3–16 months. Additionally, serum samples were tested for anti-nuclear antibody (PM). Of the 12 patients diagnosed with cGVHD, 8 had autoantibodies. Five had ANA, 4 had anti-smooth muscle antibodies, and 1 had anti-mitochondrial antibodies. No myositis-specific autoantibodies were found with the exception of 1 serum sample, where antibodies to U4/6 small nuclear RNA synthetase complex were seen.15 The clinical significance of autoantibodies in cGVHD is not clear. ANAs were found in sera of cGVHD patients, but the frequency does not seem to correlate with the occurrence of acute or cGVHD.16 At the time of myositis diagnosis in the 12 patients with cGVHD, 6 were on either prednisone or intravenous immunoglobulin (IVIg). The immunosuppression regimen was not known in the remainder of the cGVHD patients. Eleven of 12 patients responded to steroids and either azathioprine or cyclosporine, with a 3- to 7month response time; 1 outlier took over 48 months to respond to treatment. Because patients share characteristics with idiopathic polymyositis, including acute or subacute onset of weakness, elevated muscle enzymes, typical pathology on muscle biopsy and EMG, and response to treatment, the distinction between polymyositis as a manifestation of cGVHD and the idiopathic disease is unclear. No other patient risk factors in patient histories were identified, such as thyroid disease, active viral infections, or medications. No patients developed myositis with autologous stem cell transplant or without cGVHD. This suggests that it is unlikely that PM developed in these individuals by chance alone, as its incidence is much higher than in the general population. Additionally, many cases may go undiagnosed because many patients die before developing PM. Presumably, the lymphocytic infiltration found in cGVHD-associated myositis is also composed of donor cells, as the host’s cells have been eliminated by the conditioning regimen.15 MUSCLE & NERVE
October 2015
Dermatomyositis has also been reported in case series to have an association with cGVHD following allogeneic HSCT. Muscle biopsy demonstrated perifascicular atrophy in all cases. Treatment of cGVHD with tacrolimus and prednisone caused improvement in strength.14 Other cases of cGVHD and dermatomyositis have also been reported. There was electrophysiologic evidence of myopathy without biopsy in 1 patient, and in another, EMG was normal, but muscle biopsy demonstrated the pathognomonic perifascicular atrophy. Both patients were treated with prednisone.17,18 Although dermatomyositis has been linked to cGVHD, Sakamoto et al.19 report a case in which a male patient developed idiopathic dermatomyositis 14 years after undergoing a gender-mismatched allogeneic bone marrow transplant (BMT). The patient complained of proximal muscle weakness and dermatitis. Laboratory examinations revealed elevated creatinine kinase and liver function tests as well as presence of ANA at a titer of 1:640 and negative anti-Jo antibodies. EMG demonstrated electrophysiologic evidence of myopathy. This was confirmed by muscle biopsy, which demonstrated perifascicular atrophy. Inflammatory mononuclear cells were also noted in the endomysium, perimysium, and perivascular regions. The cells were predominantly CD41. Genotyping with XYfluorescence in situ hybridization (FISH) revealed that infiltrating cells in the muscle clearly had a Ypositive phenotype. On the basis of these findings, the patient was diagnosed to have autoimmune dermatomyositis and not cGVHD, as his donor was a woman. He was subsequently treated with oral prednisolone, with improvement of symptoms.19 This case report superseded the Stevens study and suggests the importance of chimerism analysis in any allogeneic BMT-related dermatomyositis to best define the nature of the disease in a gendermismatched allogeneic HSCT. This would be helpful if the transplant is gender-mismatched. Such analyses were not done in prior studies, although microchimerism has been reported in the Dermatology literature to cause autoimmune conditions in children. Fraternal and maternal microchimerism has been reported to cause a cGVHD like dermopathy.20,21 SYNDROME AND PERIPHERAL GUILLAIN-BARRE NEUROPATHY
Immune-mediated demyelinating disease after allogeneic HSCT is rare compared with inflammatory myopathies and occurs with a frequency of 1– 2%.22 In some cases, it is not entirely clear whether it is a true manifestation of cGVHD, due to a coincidentally coexistent autoimmune disease in the setting of immune system constitution, related to the NM Complications of HSCT
pretransplant chemotherapy conditioning regimen, or an underlying infection. Because of the uncertainty as to the cause of acute demyelinating neuropathy it is considered an “associated” symptom and does not meet criteria to define cGVHD.7,8 Several case reports and case series support the contention that Guillain-Barre syndrome (GBS) is related to cGVHD, with typical electrodiagnostic findings of demyelination, elevated CSF protein and demyelination and inflammation on nerve biopsy.23 The onset is usually within 21 months after HSCT, with a median of 7 months.24 The patients often have rash as a manifestation of cGVHD preceding the neuropathy.7,23 In 1 case, a woman received an allogeneic bone marrow transplant from her HLA identical brother, and FISH of the sural nerve biopsy demonstrated that 15% of infiltrating T-cells carried both X and Y chromosomes. These data conclusively demonstrate that the infiltrating T-cells were of donor origin from her brother.23 GBS may occur as an initial manifestation cGVHD followed by skin biopsy signs of cGVHD after cessation of immunosuppression, such as cyclosporine.25 IVIg and plasma exchange, may not be effective, and 1 patient improved 18 days after cyclosporine was re-initiated. A large retrospective chart review of 1,484 patients treated at Memorial Sloan Kettering Hospital between 1992 and 2010 looked at immunemediated demyelinating disease in patients who underwent allogeneic hematopoietic stem cell transplantation. Seven patients had immunemediated demyelinating disease, including 3 with acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 1 with autonomic neuropathy, and 3 with evidence of central demyelinating disease. One patient with AIDP and 1 patient with autonomic neuropathy had evidence of systemic GVHD.26 All patients were treated with immunomodulatory therapies and had improvement in symptoms. Demyelination without significant inflammatory infiltration on nerve or muscle biopsy supports an immune-mediated demyelinating disease, whereas GVHD would show CD81 Tcell lymphocytic infiltration.26 Immune-mediated neuropathy (IMN) following allogeneic hematopoietic stem cell transplant in the absence of cGVHD has also been reported.27 Cases of concurrent infections and demyelinating neuropathy make the immunopathogenesis challenging to discern. Patients have developed GBS following infections but also had reactivation of cGVHD. Improvement occurred after treatment with tacrolimus and IVIg. Preceding viral infection and an immunologic reaction to the virus may have been a trigger for both reactivation of GVHD and an immune-mediated neuropathy. Management MUSCLE & NERVE
October 2015
483
with immunosuppressive agents and IVIg suggest both cellular and humoral immunity play a role in immune-mediated neuropathy associated with allogeneic HSCT.28 Another patient developed axonal GBS in the setting of cytomegalovirus (CMV) colitis 58 days after developing GVHD and being treated successfully for the colitis. Sural nerve biopsy revealed axonal degeneration with infiltration of CD81 T-cells and macrophages. GBS was not thought to be due to either the aGVHD or CMV, because symptoms of acute GVHD had already resolved at the onset of GBS, while CMV antigenemia resolved without any therapy. One thought is that the CMV infection triggered the neuropathy by means of a humorally-mediated “cross-reactive” mechanism, which is what has been postulated in nontransplant patients. Because this patient’s sural nerve biopsy showed infiltration of donor-derived mature T-cells and few deposits of immunoglobulins, the authors assumed that CMV triggered peripheral expansion of mature donor-derived Tcells and thus played a role in the development of GBS versus the humorally mediated mechanism seen in nontransplant patients.29 In the pediatric literature from Poland, a retrospective analysis of 171 cases of HSCT (84 autologous and 87 allogeneic) identified 2 children with allogeneic HSCT who developed radiculitis post transplantation in the setting of to CMV and Epstein-Barr Virus (EBV) infection. Neither child was reported to have aGVHD or cGVHD.30 GBS in the immediate post transplantation period has also been reported in children age 16–18 by Rodriguez et al.31 None of the patients had evidence of aGVHD at the time of diagnosis, and only 1 had an infection. The clinical course of the patients was severe; 2 of the 3 patients developed dysautonomia, and 1 had multi-organ failure. It was thought that administration of cytosinearabinoside (Ara-C) was responsible for development of demyelinating neuropathy rather than a dysimmune reaction posttransplant due to the close temporal relationship between onset of symptoms and drug administration.31 A recent study from the Mayo Clinic reported on 3,305 patients who underwent HSCT between 1997 and 2010. Only 12 patients with immunemediated neuropathies, (including asymmetric radiculoplexopathies, GBS, and multiple mononeuropathies) were included in the analysis, as those who had chronic neuropathic conditions unrelated to the stem cell transplant were excluded. Six patients had allogeneic hematopoietic stem cell transplants, and 6 had autologous transplants. One of the patients who underwent allogeneic transplantation had manifestations of cutaneous GVHD, but no others did. All patients at the time of onset of the neuropathy were determined to be in hema484
NM Complications of HSCT
tologic remission, however, early relapse of hematologic malignancy in patients with IMN following SCT was seen in 5 of 12 patients.24 Two possible hypotheses for development of IMN exist. Because most of the IMN occurred within 21 months following HSCT, immune system reconstitution could be the cause. Improvement with the use of immunotherapy further supports this hypothesis. The close relationship between the time of cancer relapse and the occurrence of IMN suggests a possible paraneoplastic etiology.24 Although most of these neuromuscular complications are in the setting of allogeneic HSCT, rare neurological complications of autologous stem cell transplantation have also been reported. In addition to the 6 patients reported from the Mayo study, 3 patients with brachial plexopathy following autologous HSCT have been reported, as well as a patient with a brachial plexopathy 5 days after allogeneic HSCT, with no evidence of aGVHD. The association with recent autologous stem cell transplantation argues in favor of an autoimmune mechanism in the setting of immune reconstitution as discussed above.32 MYASTHENIA GRAVIS IN GVHD
MG may develop in patients after bone marrow transplantation and may be a manifestation of GVHD. A recent study by Heidarzadeh et al. reported all cases of MG after bone marrow transplantation in adults. Twenty-two adults and 1 child with MG after bone marrow transplant have been reported.33,34 Nineteen of the cases were associated with cGVHD after allogeneic HSCT, which supports the hypothesis that MG develops a result of targeting the new host’s neuromuscular junction by transplanted immune cells. In the case of the child, acetylcholine receptor-antibody (AchR-Ab) positive MG developed 22 months after allogeneic HSCT transplantation when the child was 34 months old. There are, however, 3 reported cases of MG in the absence of cGVHD, including 2 following autologous transplant. A case of MG with elevated AchR-Ab and elevated titin Ab following HSCT has been reported.4 Zaja et al. propose that 2 distinct autoimmune conditions may be responsible for the development of MG: cGVHD and adoptive autoimmunity. In cGVHD the appearance of autoantibodies and autoreactive lymphocytes, as well as the series of events involved in the pathogenesis of target cell damage, is well documented. The immune system itself is a major target, and immunological dysfunction may become an additional factor in the multifactorial generation of autoimmunity.35 Serum AChR-Abs have been reported in patients who do not have symptoms of MG. Not every patient who was seropositive had GVHD, and MG was also seen MUSCLE & NERVE
October 2015
Table 2. Summary of neuromuscular complications of HSCT associated with cGVHD and reported treatment modalities. NM disorder
Clinical manifestations
Associated with cGVHD
Treatment
Polymyositis Symmetrical proximal weakness 1/- dysphagia and respiratory muscle weakness
Distinctive feature based on NIH 2005 Consensus Criteria.7
Prednisone, azathioprine, cyclosporine
Symmetrical proximal weakness 1/- dysphagia and respiratory muscle weakness with classic rash
Distinctive feature based on NIH 2005 Consensus Criteria.7
Prednisone, tacrolimus, rituximab, IVIg
Weakness, absent reflexes, elevated CSF protein
“Other” feature based on NIH 2005 Consensus Criteria.7
Resumption of previously withdrawn/ de-escalated immunosuppression, IVIg, plasmapheresis
Ptosis, diplopia, bulbar and limb weakness
“Other” feature based on NIH 2005 Consensus Criteria.7
Resumption of previously withdrawn/de-escalated immunosuppression, prednisone, azathioprine, cyclosporine
Dermatomyositis
AIDP, CIDP
Myasthenia gravis
in a patient with autologous transplantation. Production of AChR-Abs after transplantation may be a manifestation of autoreactivity. This provides evidence against GVHD playing a role in autoimmunity.36 The frequent antibody positivity and infrequent manifestations of MG suggests that other factors are necessary to fully develop the clinical picture of MG.35 It has also been reported that certain HLA antigens are associated frequently with MG that develops after hematopoietic stem cell transplantation. Recurrent expression or co-expression of HLA-A2, HLA-B7, HLA-A35, HLA-DR2, and HLA-Cw4 has been reported. In patients younger than 40 years, HLA-A1, HLA-B8, and HLA-DR3 are expressed more commonly.35 Nearly all of the reported patients had serum AchR-Abs and only 3 reported patients had MuSK antibodies.33,37,38 Of the MuSK1 patients only 1 was reported to have evidence of cGVHD.33 MG in these patients is typically responsive to pyridostigmine and prednisone. De-escalation of immunosuppression has been reported to cause worsening of symptoms. Rituximab has been used with benefit in a patient with otherwise refractory symptoms and severe prednisone side effects. Rituximab induced marked Blymphocyte depletion with substantial reduction in the production of autoantibodies.35 In the GITMO (Italian group bone marrow transplant) study, the use of rituximab in treatment of refractory cGVHD was reviewed. Of the 38 patients who were included, 1 had a very severe form of MG. This patient went into complete remission with dose reduction of maintenance immunosuppressive therapy after rituximab. Overall, rituximab was effective in over 50% of patients with refractory NM Complications of HSCT
cGVHD and may confer a survival benefit. These data indicate that rituximab may reduce multiorgan involvement of some cGVHD manifestations. The beneficial effect of B-cell depletion highlights the potential primary pathological role of lymphocytes in the development of cGVHD.39 TREATMENT
In the PM study, patients were treated with prednisone and either azathioprine or cyclosporine, and in 1 patient methotrexate, with improvement of symptoms in most.15 Similarly, patients with DM were treated with steroids, tacrolimus, rituximab, and gammaglobulin with good response.14 DM due to cGVHD (presumably) and idiopathic DM both respond to treatment with prednisone. In patients with demyelinating neuropathies, IVIg was given with variable improvement. The patients who developed GBS tended to have more systemic illness, and it is less clear if the GBS is related to cGVHD, immune reconstitution, infection, or even conditioning chemotherapy.25,28,31 In 1 patient, it was thought to be a result of discontinuation of immunosuppression, and GBS was the presenting manifestation of cGVHD. In that patient, treatment with steroids, IVIg, plasmapheresis, and cyclosporine was necessary. Clinical improvement only occurred after cyclosporine was given. Although improvement may have lagged behind treatment institution, the clinical response to cyclosporine may reflect differences in pathological mechanisms between cGVHD-associated GBS and classical GBS.25 There is some evidence to suggest that development of MG is related to de-escalation of immunosuppression. Favorable response to resumption of immunosuppression further supports this hypothesis.40 Treatment with prednisone and either MUSCLE & NERVE
October 2015
485
cyclosporine or azathioprine has been reported to produce a good response.33 Symptomatic treatment with pyridostigmine has a favorable effect in patients with cGVHD-associated MG as well. SUMMARY
In summary, most complications of HSCT do not occur immediately post transplantation. The vast majority happen in those with allogeneic HSCT and in the setting of cGVHD. PM and DM are defined as distinctive criteria of cGVHD according to the 2005 NIH Consensus Criteria for cGVHD. Peripheral neuropathies and MG are defined as “other” features, because cases have been reported in the absence of cGVHD in the setting of immunosuppression withdrawal, infection, or chemotherapy. Treatment of PM and DM related to HSCT and cGVHD is essentially the same as that of the idiopathic conditions. In the cases where immunosuppression was de-escalated, re-initiation of immunosuppression in patients with GBS and MG is thought to help recovery when IVIg and plasmapheresis fail. Table 2 summarizes the neuromuscular complications of HSCT and treatments. A more comprehensive understanding of the immune system and physiology of allogeneic transplantation will ultimately shine light on the possible mechanisms of neuromuscular pathology and help target treatments. It is important to differentiate between idiopathic neuromuscular diseases, those caused by prolonged illness and immobility, and those related to the transplant itself. GVHD and GVL are immunological conditions that must be kept in mind and taken into consideration when treatments are considered. Based on a lecture given at the 60th annual meeting of the AANEM by Dr. Thomas Brannagan. Neither author has any conflicts of interest or any funding sources for our work. REFERENCES 1. Rodriguez TE. Neurologic complications of bone marrow transplantation. Handb Clin Neurol 2014;121:1295–1304. 2. Pless M, Zivkovic SA. Neurologic complications of transplantation. Neurologist 2002;8:107–120. 3. Saiz A, Graus F. Neurological complications of hematopoietic cell transplantation. Sem Neurol 2004;24:427–434. 4. Koeppen S, Thirugnanasambanthan A, Koldehoff M. Neuromuscular complications after hematopoietic stem cell transplantation. Support Care Cancer 2014;22:2337–2341. 5. Nishimori H, Maeda Y, Tanimoto M. Chronic graft-versus-host disease: disease biology and novel therapeutic strategies. Acta Med Okayama 2013;67:1–8. 6. Pustavoitau A, Bhardwaj A, Stevens R. Neurological complications of transplantation. J Intensive Care Med 2011;26:209–222. 7. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005;11:945–956. 8. Grauer O, Wolff D, Bertz H, Hildegard G, Kuhl JS, Lawitschka A, et al. Neurological manifestations of chronic graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: report from the Consensus Conference on Clinical Practice in chronic graftversus-host disease. Brain 2010;133:2852–2865.
486
NM Complications of HSCT
9. Matsuoka K, Kim HT, McDonough S, Bascug G, Warshauer B, Koreth J,et al. Altered regulatory T cell homeostasis in patients with CD41 lymphopenia following allogeneic hematopoietic stem cell transplantation. J Clin Invest 2010;120:1479–1493. 10. Zaja F, Bacigalupo A, Patriarca F, Stanzani M, Van Lint MT, Filı C, et al. Treatment of refractory chronic GVHD with rituximab: a GITMO study. Bone Marrow Transplant 2007;40:273–277. 11. Nishimori H, Maeda Y, Teshima T, Sugiyama H, Kobayashi K, Yamasuji Y, et al. Synthetic retinoid Am80 ameliorates chronic graftversus-host disease by down-regulating Th1 and Th17. Blood 2012; 119:285–295. 12. Warren EH, Deeg HJ. Dissecting graft-versus-leukemia from graftversus-host-disease using novel strategies. Tissue Antigens 2013;81: 183–193. 13. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344–347. 14. Allen JA, Greenberg SA, Amato AA. Dermatomyositis-like muscle pathology in patients with chronic graft-versus-host disease. Muscle Nerve 2009;40:643–647. 15. Stevens AM, Sullivan KM, Nelson JL. Polymyositis as a manifestation of chronic graft-versus-host disease. Rheumatology 2003;42:34–39. 16. Arin MJ, Scheid C, Hubel K, Krieg T, Groth W, Haerrmann G. Chronic graft-versus-host disease with skin signs suggestive of dermatomyositis. Clin Exp Dermatol 2006;31:141–143. 17. Ollivier I, Wolkenstein P, Gherardi R, Weschsler J, Kuentz M, Cosnes A, et al. Dermatomyositis-like graft-versus-host disease. Br J Dermatol 1998;138:558–559. 18. Leber B, Walker IR, Rodriguez A, McBride JA, Carter R, Brain MC. Reinduction of remission of chronic myeloid leukemia by donor leukocyte transfusion following relapse after bone marrow transplantation: recovery complicated by initial pancytopenia and late dermatomyositis. Bone Marrow Transplant 1993;12:405–407. 19. Sakamoto K, Imamura T, Niwa F, Komori S, Ishihara Y, Shiga K, et al. Dermatomyositis developed in a recipient of allogeneic BMT; the differentiation of chronic GVHD and autoimmune disease. Bone Marrow Transplant 2012;47:603–604. 20. Vabres P, Bonneau D. Childhood dermatosis due to microchimerism. Dermatology 2005;211:388–389; author reply 389. 21. Kowalzick L, Artlett CM, Thoss K, Baum HP, Ziegler H, Mischke D, et al. Chronic graft-versus-host-disease-like dermopathy in a child with CD41 cell microchimerism. Dermatology 2005;210:68–71. 22. Bulsara KR, Baron PW, Tuttle-Newhall JE, Clavien PA, Morgenlander J. Guillain-Barre syndrome in organ and bone marrow transplant patients. Transplantation 2001;71:1169–1172. 23. Haruki H, Koga M, Ogasawara J, Omoto M, Kawai M, Kanda T. Neuropathy in chronic graft-versus-host disease caused by donor T cells. Muscle Nerve 2012;46:610–611. 24. Karam C, Mauermann ML, Johnston PB, Lahoria R, Engelstad JK, Dyck PJ. Immune-mediated neuropathies following stem cell transplantation. J Neurol Neurosurg Psychiatry 2014;85:638–642. 25. Thone J, Lamprecht S, Hohaus A, Erbguth F, Bickel A. GuillainBarre syndrome as leading manifestation of graft-versus-host disease in an allogeneic bone marrow transplanted patient. J Neurol Sci 2010;292:114–116. 26. Delios AM, Rosenblum M, Jakubowski AA, DeAngelis LM. Central and peripheral nervous system immune mediated demyelinating disease after allogeneic hemopoietic stem cell transplantation for hematologic disease. J Neurooncol 2012;110:251–256. 27. Su L, Ji B, Hu R, Lan X, Xia C. Immune-mediated neuromuscular complications after haploidendtical hematopoietic stem cell transplantation. Chin Med J (Engl) 2014;127:2865–2867. 28. Doi Y, Sugahara H, Yamamoto K, Uji-ie H, Kakimoto T, Sakoda H. Immune-mediated peripheral neuropathy occurring simultaneously with recurrent graft-versus-host disease after allogenic hematopoietic stem cell transplantation. Leuk Res 2012;36:e63–e65. 29. Fujisaki G, Kami M, Murashige N, Kishi Y, Hori, A, Chizuka A, et al. Guillain-Barre syndrome associated with rapid immune reconstitution following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2006;37:617–619. 30. Zaucha-Prazmo A, Jasinski M, Drabko K, Choma M, Wojcik B, Kowalczyk JR. Neurologic complications in children after hemaopoietic stem cell transplantation: a single-center experience. Transplant Proc 2007;39:2905–2907. 31. Rodriguez V, Kuehnle I, Heslop HE, Khan S, Krance RA. GuillainBarre syndrome after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2002;29:515–517. 32. Rabinstein AA, Dispenzieri A, Micallef IN, Inwards DJ, Litzow MR, Wijdicks EF. Acute neuropathies after peripheral blood stem cell and bone marrow transplantation. Muscle Nerve 2003;28:733–736. 33. Heidarzadeh Z, Mousavi SA, Ostovan VR, Nafissi S. Muscle-specific kinase antibody associated myasthenia gravis after bone marrow transplantation. Neuromuscul Disord 2014;24:148–150. 34. Unal S, Sag E, Kuskonmaz B, Kesici S, Bayrakci B, Ayvaz DC, et al. Successful treatment of severe myasthenia gravis developed after
MUSCLE & NERVE
October 2015
allogeneic hematopoietic stem cell transplantation with plasma exchange and rituximab. Pediatr Blood Cancer 2014;61:928–930. 35. Zaja F, Barillari G, Russo D, Silvestri F, Fanin R, Baccarani M. Myasthenia gravis after allogeneic bone marrow transplantation. A case report and a review of the literature. Acta Neurol Scand 1997;96:256–259. 36. Smith CI, Hammarstrom L, Lefvert AK. Bone-marrow grafting induces acetylcholine receptor antibody formation. Lancet 1985;1:978. 37. Atassi N, Amato AA. Muscle-specific kinase (MuSK) antibodyassociated myasthenia gravis after bone marrow transplantation. Muscle Nerve 2008;38:1074–1075.
NM Complications of HSCT
38. Grover KM, Sripathi N, Elias SB. Muscle-specific kinase-antibodypositive myasthenia gravis after autologous bone marrow transplantation. J Clin Neuromuscul Dis 2012;13:146–148. 39. Zaja F, Russo D, Fuga G, Perella G, Baccarani M. Rituximab for myasthenia gravis developing after bone marrow transplant. Neurology 2000;55:1062–1063. 40. Mackey JR, Desai S, Larratt L, Cwik V, Nabholtz JM. Myasthenia gravis in association with allogeneic bone marrow transplantation: clinical observations, therapeutic implications and review of literature. Bone Marrow Transplant 1997;19:939–942.
MUSCLE & NERVE
October 2015
487
