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Neuromuscular
RESEARCH PAPER
Immune-mediated neuropathies following stem cell transplantation Chafic Karam,1,2 Michelle L Mauermann,1 Patrick B Johnston,3 Rajat Lahoria,1 JaNean K Engelstad,1 P James B Dyck1 1
Peripheral Nerve Division, Department of Neurology, Mayo Clinic Rochester, Rochester, Minnesota, USA 2 University of North Carolina, Chapel Hill, North Carolina, USA 3 Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota, USA Correspondence to Dr P James B Dyck, Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA; [email protected] Received 28 August 2013 Revised 25 October 2013 Accepted 27 October 2013 Published Online First 22 November 2013
ABSTRACT Objective To study the clinical, electrophysiological and pathological characteristics and outcome of immune-mediated neuropathy (IMN) following stem cell transplantation (SCT). Methods Retrospective chart review of the Mayo Clinic Rochester SCT database between January 1997 and August 2012. Results Of the 3305 patients who underwent SCT, 12 patients (0.36%) had IMN. The median time from SCT to IMN was 7 months. IMN typically presented as an asymmetric radiculoplexus neuropathy (7/12 patients) or acute polyradiculoneuropathy (Guillain–Barré syndrome) (4/12). Neurophysiology showed demyelinating neuropathy in four patients and axonal neuropathy in eight. Cerebrospinal fluid protein was increased in five of six patients (median 67 mg/dL). The Neuropathy Impairment Score (NIS) improved in all patients (mean NIS 43–10, p=0.016). Six patients died. One patient died from complications of IMN and one died from complications of the haematological disease. Five patients had recurrence of their malignancy within 4 months of the IMN and of these, four died. Conclusions IMN occurs rarely in patients after SCT. Two possible mechanisms include (1) an immune reconstitution syndrome, supported by stereotypical neuropathy types (radiculoplexus and polyradiculoneuropathies), monophasic course and temporal association with SCT and (2) a paraneoplastic phenomenon, supported by frequent early malignancy recurrence following IMN.
INTRODUCTION
To cite: Karam C, Mauermann ML, Johnston PB, et al. J Neurol Neurosurg Psychiatry 2014;85:638–642. 638
Stem cell transplantation (SCT) is the preferred therapy for many patients with high-risk haematologic disease because of its curative potential.1 Unfortunately, complications following SCT are common and are expected to increase parallel to the increasing number of SCTs performed.1 Among the many neurological complications of SCT, immune-mediated neuropathy (IMN) remains obscure and poorly understood.2–8 Prior small case series and case reports described some forms of IMN following SCT, and raised different hypotheses as why this association may occur3 5 7 These reports did not provide an estimate of the frequency of IMN following SCT or give a long-term prognosis of this condition. One study reviewed the rate of Guillain–Barré syndrome (GBS) following SCT and estimated its incidence at 0.27%.2 However, the authors only looked at the ICD9 code for GBS and did not include other
IMNs such as chronic inflammatory demyelinating polyneuropathy (CIDP), brachial or lumbosacral plexopathies, multiple mononeuropathies, polyradiculopathies or others.2 In order to establish an association of IMN following SCT and to study its clinical course and its implication and effect on survival, we searched the Mayo Clinic database and reviewed the clinical, electrophysiological and pathological characteristics and outcome of IMN in patients who underwent SCT.
MATERIALS AND METHODS Patients’ selection The Mayo Clinic institutional review board approved the research protocol. We searched for patients older than 18 years who were seen at the Mayo Clinic in Rochester, Minnesota, and who developed an IMN following SCT between January 1997 and August 2012. To identify these patients, we looked for specific Current Procedural Terminology (CPT) and International Classification of Diseases (ICD9) codes. The CPT code was used to obtain the list of patients who underwent SCT. For the IMNs, we used the ICD9 codes 353, 354, 355 and 357. These ICD9 codes cover nerve root and plexus disorders (353), mononeuritis of upper limb and mononeuritis multiplex (354), mononeuritis of lower limb and unspecified site (355 and 356) and inflammatory and toxic neuropathy (357). The search initially yielded 50 charts. We reviewed the charts for demographics, clinical presentation, type of underlying malignancy before the SCT, time of the SCT and onset of IMN, type of chemotherapy received, pattern of IMN, laboratory (including cerebrospinal fluid (CSF) obtained via lumbar puncture) and nerve conduction studies/ electromyography (NCS/EMG) findings, treatments received, Neuropathy Impairment Score (NIS) before and after treatment, when available, and outcome.
Definition of IMN New onset of acute or subacute weakness and sensory symptoms (loss or gain) were used to determine IMN. Asymmetrical and proximal EMG abnormalities supporting the clinical findings or adding to the suspicion of an acquired process as well as CSF examination showing elevated protein with normal cells were also considered clues for the diagnosis of IMN. Patients with chronic lengthdependent polyneuropathy not related to the timing of SCT, neuropathy related to treatment,
Karam C, et al. J Neurol Neurosurg Psychiatry 2014;85:638–642. doi:10.1136/jnnp-2013-306657
Downloaded from http://jnnp.bmj.com/ on March 16, 2015 - Published by group.bmj.com
Neuromuscular neoplastic infiltration or compression of peripheral nerves, IMN prior to SCT, polyneuropathy, organomegaly, endocrinopathy, M-protein and skin abnormalities (POEMS) syndrome or those with infectious neuropathies were excluded from the study.
RESULTS The results are summarised in table 1. Of the 3305 patients who underwent SCT at the Mayo Clinic in Rochester, Minnesota, between January 1997 and August 2012, 50 patients were identified as potentially having IMN following SCT. From these 50 patients, 38 were excluded from the analysis because they did not meet our criteria for IMN following SCT: 12 patients had POEMS syndrome, 7 had neuropathy related to chemotherapy, 6 had neurolymphomatosis, 4 had zoster polyradiculopathy, 4 had amyloid-related neuropathy, 2 had mechanical polyradiculopathy and 3 had IMNs prior to SCT. The 12 (0.36%) who met the criteria for IMN following SCT were studied.
Patient characteristics The patients’ median age was 59.5 years (range 24–71). Nine patients were men. The underlying haematological diagnoses were six non-Hodgkin lymphomas, three acute myeloid leukaemias, two multiple myelomas and one myelodysplastic syndrome. Six patients had allogeneic SCT and six had autologous SCT. One patient ( patient 8) had dermatitis felt to be secondary to graft versus host disease (GVHD) and was on steroids. All patients were considered in haematologic remission at the time of the IMN. Whole-body positron emission tomography (PET) scan and MRI of the plexus or roots affected were performed to rule out neurolymphomatosis. Two of the patients had nerve tissue examined to further rule out neurolymphomatosis. The median time between the SCT and the onset of the IMN was 7 months (range 5 days to 58 months). All but one patient ( patient 6) had the IMN less than 2 years after their SCT. Patient 6 developed IMN 58 months after the SCT. The IMN phenotypes were seven asymmetric radiculoplexus neuropathy (five lumbosacral and two brachial), four acute polyradiculoneuropathy (GBS) and one multiple mononeuropathies. NCS/ EMG showed predominantly demyelinating neuropathy in four patients and axonal neuropathy in eight. A fascicular sciatic nerve biopsy looking for recurrent lymphoma was performed in one ( patient 6) and showed increased segmental demyelination on teased nerve fibres (8%), mild multifocal fibre loss on semithin epoxy sections and frequent scattered inflammatory cells in the endoneurium (figure 1) but no evidence of lymphoma. These results were interpreted to be in keeping with inflammatory demyelination. On one autopsy case ( patient 4) cauda equina root examination showed axonal loss and frequent inflammatory cells in the endoneurium. The autopsy did not show recurrence of the malignancy. The CSF protein was increased in five of six patients in whom this test was obtained. Median CSF protein was 67 mg/dL (range 43–207 mg/dL). The CSF cytology in all of these patients was negative for malignant cells.
Acute polyradiculoneuropathies (GBS) In the four patients with acute polyradiculoneuropathies, the peak severity (weakness) ranged from 1 day to 2 weeks. One patient had back pain prior to the onset of symptoms and one had flu-like illness. In one patient, there was dysautonomia with significant orthostatic hypotension and urinary retention. No significant sensory symptoms were reported. Three out of the four patients required mechanical ventilation because of their
IMN and two patients died. NCS/EMG suggested axonal polyradiculoneuropathy in one, mixed axonal and demyelinating polyradiculoneuropathy in another and primarily demyelinating polyradiculoneuropathy in two. NCS were not repeated to differentiate demyelination from pseudo-demyelination in these patients. Three of these GBS patients had CSF examination. The CSF protein ranged from 43 to 96 mg/dL (median 56 mg/dL). The CSF cell count ranged from 0 to 12 cells/mcL. All patients were treated with intravenous immunoglobulin, plasmapheresis or both. There was significant neurological improvement in the two patients who survived. The NIS decreased from 120 to 10 points in one patient and the other patient was able to walk without assistance after being bedbound (the neurological examination was not complete enough on the second patient to determine a NIS).
Radiculoplexus neuropathies and multiple mononeuropathies Seven patients had radiculoplexus neuropathy (five lumbosacral and two brachial) and one had multiple mononeuropathies. The radiculoplexus neuropathies were bilateral in four patients. The progression of weakness in these patients was rapid but slower than in the GBS patients with the peak severity (weakness) ranging between 2 and 8 weeks. Pain was the major initial symptom with seven out of the eight patients having pain in the neck/shoulder or lower back/groin radiating to the arm or leg depending on the location of their radiculoplexus neuropathy. The patient with multiple mononeuropathies experienced pain in the limb with nerve involvement. Numbness and tingling were present in five out of the eight patients and allodynia was present in one. Four patients were treated with steroids. The NIS improved in all patients with a decrease from a mean NIS of 30 to 10 points whether or not they received treatment. CSF was obtained in three of these radiculoplexus neuropathy patients. CSF protein ranged from 53 to 207 mg/dL (median 78 mg/dL) and the CSF cells ranged from 1 to 42 cells/mcL.
Patients’ outcome Overall, six of the 12 patients died. One patient died from IMN’s complications. That patient had GBS, developed respiratory failure and died of sepsis in the setting of pneumonia while on a ventilator. One patient died from complication of her haematological disease due to immunosuppression; she had invasive fungal rhinosinusitis and pontine infarction 1 week after the onset of GBS. Five patients had recurrence of their malignancy within 4 months of the onset of IMN and four of them died from their malignancy. None of these patients had evidence for neurolymphomatosis (based on PET scan, plexus MRI or both) and they were considered to be in haematological remission at the time of the IMN. When these four patients died from their malignancies, none of their IMN was active or worsening. Of the patients who had allogeneic transplant, one had cutaneous GVHD and was on oral prednisone 60 mg daily when he developed the IMN. None of the other allogeneic transplant patients had GVHD. Of the total of six patients who died, two died while their neuropathy was active and the other four died after improvement of their neuropathy. Three of the deceased patients had GBS, whereas two had radiculoplexus neuropathy and one had multiple mononeuropathy. A follow-up NIS was available on eight patients, six of whom received immunotherapy. The NIS improved in all patients. The mean NIS improved from 43 to 10 ( p=0.016).
Karam C, et al. J Neurol Neurosurg Psychiatry 2014;85:638–642. doi:10.1136/jnnp-2013-306657
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Table 1
Summary of patients’ characteristics, neuropathy and outcome Gender
Type of cancer
Haematopoietic stem cell transplant type
Pattern of neuropathy
Time from SCT to neuropathy
CSF
1
59
Men
B cell lymphoma
Autologous
Multiple mononeuropathy
6 months
NA
2
60
Men
Multiple myeloma
Autologous
5 days
NA
3
65
Men
Multiple myeloma
Autologous
2 months
NA
None
4
59
Men
Non-Hodgkin lymphoma
Autologous
Bilateral brachial radiculoplexus neuropathy Bilateral lumbosacral radiculoplexus neuropathy Acute polyradiculoneuropathy
Dexamethasone taper over 2 months Intravenous steroids
13 months
protein 53, cell 0
IVIG
5
60
Women
Non-Hodgkin lymphoma
Autologous
Acute polyradiculoneuropathy
16 months
NA
IVIG
6
67
Men
B cell lymphoma
Autologous
58 months
24
Women
Acute myeloid leukaemia
Allogeneic
protein 53, cell 1 protein 56, cell 11
None
7
Right lumbosacral radiculoplexus neuropathy Acute polyradiculoneuropathy
8
66
Men
Allogeneic
9
33
Men
Myelodysplastic syndrome Non-Hodgkin lymphoma
10
37
Men
11
51
Women
12
71
Men
Non-Hodgkin lymphoma Acute myeloid leukaemia Acute myeloid leukaemia
Allogeneic
Allogeneic Allogeneic
Allogeneic
Right lumbosacral radiculoplexus neuropathy Right brachial radiculoplexus neuropathy Asymmetric lumbosacral radiculoplexus neuropathy Acute polyradiculoneuropathy
Asymmetric lumbosacral radiculoplexus neuropathy y
3 months
21 months
NA
8 month
Treatment for the neuropathy
Neuropathy outcome
Patients’ outcome
Improved NIS from 16 to 4 (at 3 months) Improved NIS from 41 to 16 (at 6 months) Improved NIS from 50 to 5 (at 1 month) NIS 80
Deceased at 12 months from lymphoma relapse Alive at 24 months. In remission Deceased at 48 months from relapse Deceased at 1 month from AIDP (respiratory failure) Alive at 12 months. In remission
Improved NIS from 120 to 10 (at 5 months) Improved NIS from 24 to 12 (at 3.5 months)
Plasmapheresis
protein 207, cell 42 NA
Already on prednisone for cutaneous GVHD Intravenous steroids
Improved NIS from 40 to 10 (at 4.5 months) Improved NIS from 20 to 10 (at 2.5 months)
None
Improved NIS NA
12 months
protein 94, cell 12
IVIG, plasmapheresis, then prednisone
2 months
protein 78, cell 2
None
Improved NIS NA from bedbound to ambulatory Improved NIS from 24 to 14 (at 4.75 months)
5 months
AIDP, acute inflammatory demyelinating polyradiculoneuropathy; CSF, cerebrospinal fluid; GVHD, graft versus host disease; IVIG, intravenous immunoglobulin; NIS, Neuropathy Impairment Score; SCT, stem cell transplantation.
Alive at 96 months. In remission Deceased at 1 month (died from fungal sepsis and meningitis) Alive at 36 months. In remission Alive at 96 months. In remission Deceased at 6 months from relapse Deceased at 4 months from relapse Alive at 15 months. In remission
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Karam C, et al. J Neurol Neurosurg Psychiatry 2014;85:638–642. doi:10.1136/jnnp-2013-306657
Patient
Age at presentation
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Neuromuscular
Figure 1 Fascicular nerve biopsy of the right sciatic nerve. (A) Teased nerve fibres showing increased demyelination (arrowheads) and rare axonal degeneration; (B) H&E section showing scattered individual inflammatory cells within the endoneurium; and (C and D) semithin epoxy sections showing regenerating clusters and onion bulbs (arrowheads).
DISCUSSION To date, IMN following SCT has been given little attention. The prior case reports and small series have highlighted acute inflammatory demyelinating polyradiculoneuropathy (AIDP), CIDP and one case of pure autonomic failure as the types of IMNs occurring after SCT.2 5 7 Our series adds to the current literature by being larger and including focal and asymmetric radiculoneuropathies and multiple mononeuropathies. To our knowledge, these phenotypes of IMNs following SCT have not been described in the literature. We did not find any cases of CIDP following SCT. This may be related to different classification of these neuropathies in different academic centres (eg, radiculoplexus neuropathies may have been classified as CIDP). The overall frequency of IMNs following SCT in our study was 0.36%. Taken separately, the frequency of GBS neuropathy in our series is 0.12%, which is similar to the only prior study (0.2%).2 There are no data concerning the incidence of IMNs in the general population to comment with confidence whether the rate of IMNs following SCT was increased compared with the background rate.9 10 These rates are low and we cannot state with certainty that the association between IMNs and SCT is meaningful. However, we have probably underestimated these frequency numbers as some patients may not have been identified because of our screening method (ICD9 codes), the retrospective study design and because some patients may have mild symptoms that were not recorded or were lost to follow-up. Although most of the IMNs occurred in close temporal association with the SCT, the neuropathy in patient 6 developed almost 5 years after SCT and might be considered as coincidental. Most of cancer patients at our institution (approximately 80%) receive autologous rather than allogeneic transplantation. In the series however, the number of patients developing IMN following SCT is equal. This suggests that an allogeneic transplant may be a relative risk factor for developing IMN, but the number of patients in this study is too small to make any definite conclusion. In allogeneic patients, GVHD is typically a concern and some of those IMNs may have a GVHD basis. On
the other hand, GVHD typically affects more than one organ and is usually more diffuse. In our study, only one patient had concomitant IMN with definite GVHD. Early relapse of the haematologic malignancy in patients with IMNs following SCT was commonly seen (5/12 patients studied). Those patients, who had relapse of the haematological malignancy, had a poor prognosis (four died). But this does not necessarily mean that IMN presages malignancy relapse. There was no specific pattern of neuropathy that would suggest cancer recurrence. In these patients, it is impossible to completely rule out neurolymphomatosis but this is unlikely since (1) they were felt to be in haematological remission by their haematologists, (2) neurolymphomatosis is a lymphoma involving the peripheral nerve and when it occurs, it is accompanied by neurological deterioration, and that was not the case in these patients in whom the neuropathy was improving (although immunosuppressant treatment may temporarily mask neurolymphomatosis) and (3) there was no evidence for neurolymphomatosis on PET scans or MRI. Furthermore, one patient with a high index of suspicion for neurolymphomatosis had a negative fascicular sciatic nerve biopsy (see figure 1), and another patient had an autopsy, which also did not show neurolymphomatosis or systemic lymphoma recurrence. Another hypothetical explanation for the IMN is paraneoplastic. The close relation between the time of cancer relapse and the occurrence of the IMN suggests a possible paraneoplastic aetiology. Furthermore, recovery from the IMN did not preclude cancer recurrence suggesting that continued follow-up for cancer recurrence is necessary. IMN following SCT may be a monophasic syndrome since the two non-treated cases with long-term follow-up had spontaneous improvement. However, one cannot make conclusions about the natural history of a syndrome based on the outcome of only two patients. Overall, the neurological deficits improved in 10 out of the 12 patients (virtually all who did not die in the acute setting). In total, eight patients were treated with immunotherapy and six of them had improvement in symptoms and deficits. Most of the IMNs (11 out of the 12 patients studied) occurred within 21 months following the SCT. During this time, the immune system is reconstituting and IMNs may be related to an immune reconstitution syndrome. This would support use of immunotherapy in managing these patients, despite the spontaneous improvement of the neuropathy in some. Naturally, recurrence of cancer should be excluded prior to starting immunotherapy. IMN following SCT is a diagnosis of exclusion and careful evaluation of these patients is necessary. It could be due to two mechanisms—an immune reconstitution syndrome causing an inflammatory response in the nerves and a paraneoplastic syndrome. The main concern for patients with IMN following SCT is cancer recurrence. Evaluation by an expert haematologist, NCS/EMG testing, CSF examination, imaging with whole-body PET scan and MRI of the nerve and targeted nerve biopsy are helpful in assessing for cancer recurrence. Even with a careful investigation, cancer recurrence is still possible and close follow-up is recommended. Contributors CK, MLM and PJBD: conceptualisation, design, analysis or interpretation of the data and drafting and revising the manuscript for intellectual content. LR, PBJ and JKE: analysis or interpretation of the data. Competing interests PJBD is member of the JNNP editorial board. Chafic Karam serves as WriteClick deputy editor for Neurology. Ethics approval The Mayo Clinic institutional review board. Provenance and peer review Not commissioned; externally peer reviewed.
Karam C, et al. J Neurol Neurosurg Psychiatry 2014;85:638–642. doi:10.1136/jnnp-2013-306657
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Pasquini MC. W.Z.C.u.a.o.o.h.s.c.t.C.S.S. 2011. http://www.cibmtr.org Delios AM, Rosenblum M, Jakubowski AA, et al. Central and peripheral nervous system immune mediated demyelinating disease after allogeneic hemopoietic stem cell transplantation for hematologic disease. J Neurooncol 2012;110:251–6. Openshaw H. Peripheral neuropathy after bone marrow transplantation. Biol Blood Marrow Transplant 1997;3:202–9. Openshaw H, Slatkin NE, Parker PM, et al. Immune-mediated myelopathy after allogeneic marrow transplantation. Bone Marrow Transplant 1995;15:633–6. Rodriguez V, Kuehnle I, Heslop HE, et al. Guillain-Barre syndrome after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2002;29:515–17.
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Roskrow MA, Kelsey SM, McCarthy M, et al. Selective automatic neuropathy as a novel complication of BMT. Bone Marrow Transplant 1992;10:469–70. Amato AA, Barohn RJ, Sahenk Z, et al. Polyneuropathy complicating bone marrow and solid organ transplantation. Neurology 1993;43:1513–18. Wen PY, Alyea EP, Simon D, et al. Guillain-Barre syndrome following allogeneic bone marrow transplantation. Neurology 1997;49:1711–14. Laughlin RS, Dyck PJ, Melton LJ III, et al. Incidence and prevalence of CIDP and the association of diabetes mellitus. Neurology 2009;73:39–45. Souayah N, Yacoub HA, Khan HM, et al. Guillain-Barre syndrome after influenza vaccination in the United States, a report from the CDC/FDA vaccine adverse event reporting system (1990–2009). J Clin Neuromuscul Dis 2012;14:66–71.
Karam C, et al. J Neurol Neurosurg Psychiatry 2014;85:638–642. doi:10.1136/jnnp-2013-306657
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Immune-mediated neuropathies following stem cell transplantation Chafic Karam, Michelle L Mauermann, Patrick B Johnston, Rajat Lahoria, JaNean K Engelstad and P James B Dyck J Neurol Neurosurg Psychiatry 2014 85: 638-642 originally published online November 22, 2013
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Neuromuscular
RESEARCH PAPER
Immune-mediated neuropathies following stem cell transplantation Chafic Karam,1,2 Michelle L Mauermann,1 Patrick B Johnston,3 Rajat Lahoria,1 JaNean K Engelstad,1 P James B Dyck1 1
Peripheral Nerve Division, Department of Neurology, Mayo Clinic Rochester, Rochester, Minnesota, USA 2 University of North Carolina, Chapel Hill, North Carolina, USA 3 Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota, USA Correspondence to Dr P James B Dyck, Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA; [email protected] Received 28 August 2013 Revised 25 October 2013 Accepted 27 October 2013 Published Online First 22 November 2013
ABSTRACT Objective To study the clinical, electrophysiological and pathological characteristics and outcome of immune-mediated neuropathy (IMN) following stem cell transplantation (SCT). Methods Retrospective chart review of the Mayo Clinic Rochester SCT database between January 1997 and August 2012. Results Of the 3305 patients who underwent SCT, 12 patients (0.36%) had IMN. The median time from SCT to IMN was 7 months. IMN typically presented as an asymmetric radiculoplexus neuropathy (7/12 patients) or acute polyradiculoneuropathy (Guillain–Barré syndrome) (4/12). Neurophysiology showed demyelinating neuropathy in four patients and axonal neuropathy in eight. Cerebrospinal fluid protein was increased in five of six patients (median 67 mg/dL). The Neuropathy Impairment Score (NIS) improved in all patients (mean NIS 43–10, p=0.016). Six patients died. One patient died from complications of IMN and one died from complications of the haematological disease. Five patients had recurrence of their malignancy within 4 months of the IMN and of these, four died. Conclusions IMN occurs rarely in patients after SCT. Two possible mechanisms include (1) an immune reconstitution syndrome, supported by stereotypical neuropathy types (radiculoplexus and polyradiculoneuropathies), monophasic course and temporal association with SCT and (2) a paraneoplastic phenomenon, supported by frequent early malignancy recurrence following IMN.
INTRODUCTION
To cite: Karam C, Mauermann ML, Johnston PB, et al. J Neurol Neurosurg Psychiatry 2014;85:638–642. 638
Stem cell transplantation (SCT) is the preferred therapy for many patients with high-risk haematologic disease because of its curative potential.1 Unfortunately, complications following SCT are common and are expected to increase parallel to the increasing number of SCTs performed.1 Among the many neurological complications of SCT, immune-mediated neuropathy (IMN) remains obscure and poorly understood.2–8 Prior small case series and case reports described some forms of IMN following SCT, and raised different hypotheses as why this association may occur3 5 7 These reports did not provide an estimate of the frequency of IMN following SCT or give a long-term prognosis of this condition. One study reviewed the rate of Guillain–Barré syndrome (GBS) following SCT and estimated its incidence at 0.27%.2 However, the authors only looked at the ICD9 code for GBS and did not include other
IMNs such as chronic inflammatory demyelinating polyneuropathy (CIDP), brachial or lumbosacral plexopathies, multiple mononeuropathies, polyradiculopathies or others.2 In order to establish an association of IMN following SCT and to study its clinical course and its implication and effect on survival, we searched the Mayo Clinic database and reviewed the clinical, electrophysiological and pathological characteristics and outcome of IMN in patients who underwent SCT.
MATERIALS AND METHODS Patients’ selection The Mayo Clinic institutional review board approved the research protocol. We searched for patients older than 18 years who were seen at the Mayo Clinic in Rochester, Minnesota, and who developed an IMN following SCT between January 1997 and August 2012. To identify these patients, we looked for specific Current Procedural Terminology (CPT) and International Classification of Diseases (ICD9) codes. The CPT code was used to obtain the list of patients who underwent SCT. For the IMNs, we used the ICD9 codes 353, 354, 355 and 357. These ICD9 codes cover nerve root and plexus disorders (353), mononeuritis of upper limb and mononeuritis multiplex (354), mononeuritis of lower limb and unspecified site (355 and 356) and inflammatory and toxic neuropathy (357). The search initially yielded 50 charts. We reviewed the charts for demographics, clinical presentation, type of underlying malignancy before the SCT, time of the SCT and onset of IMN, type of chemotherapy received, pattern of IMN, laboratory (including cerebrospinal fluid (CSF) obtained via lumbar puncture) and nerve conduction studies/ electromyography (NCS/EMG) findings, treatments received, Neuropathy Impairment Score (NIS) before and after treatment, when available, and outcome.
Definition of IMN New onset of acute or subacute weakness and sensory symptoms (loss or gain) were used to determine IMN. Asymmetrical and proximal EMG abnormalities supporting the clinical findings or adding to the suspicion of an acquired process as well as CSF examination showing elevated protein with normal cells were also considered clues for the diagnosis of IMN. Patients with chronic lengthdependent polyneuropathy not related to the timing of SCT, neuropathy related to treatment,
Karam C, et al. J Neurol Neurosurg Psychiatry 2014;85:638–642. doi:10.1136/jnnp-2013-306657
Downloaded from http://jnnp.bmj.com/ on March 16, 2015 - Published by group.bmj.com
Neuromuscular neoplastic infiltration or compression of peripheral nerves, IMN prior to SCT, polyneuropathy, organomegaly, endocrinopathy, M-protein and skin abnormalities (POEMS) syndrome or those with infectious neuropathies were excluded from the study.
RESULTS The results are summarised in table 1. Of the 3305 patients who underwent SCT at the Mayo Clinic in Rochester, Minnesota, between January 1997 and August 2012, 50 patients were identified as potentially having IMN following SCT. From these 50 patients, 38 were excluded from the analysis because they did not meet our criteria for IMN following SCT: 12 patients had POEMS syndrome, 7 had neuropathy related to chemotherapy, 6 had neurolymphomatosis, 4 had zoster polyradiculopathy, 4 had amyloid-related neuropathy, 2 had mechanical polyradiculopathy and 3 had IMNs prior to SCT. The 12 (0.36%) who met the criteria for IMN following SCT were studied.
Patient characteristics The patients’ median age was 59.5 years (range 24–71). Nine patients were men. The underlying haematological diagnoses were six non-Hodgkin lymphomas, three acute myeloid leukaemias, two multiple myelomas and one myelodysplastic syndrome. Six patients had allogeneic SCT and six had autologous SCT. One patient ( patient 8) had dermatitis felt to be secondary to graft versus host disease (GVHD) and was on steroids. All patients were considered in haematologic remission at the time of the IMN. Whole-body positron emission tomography (PET) scan and MRI of the plexus or roots affected were performed to rule out neurolymphomatosis. Two of the patients had nerve tissue examined to further rule out neurolymphomatosis. The median time between the SCT and the onset of the IMN was 7 months (range 5 days to 58 months). All but one patient ( patient 6) had the IMN less than 2 years after their SCT. Patient 6 developed IMN 58 months after the SCT. The IMN phenotypes were seven asymmetric radiculoplexus neuropathy (five lumbosacral and two brachial), four acute polyradiculoneuropathy (GBS) and one multiple mononeuropathies. NCS/ EMG showed predominantly demyelinating neuropathy in four patients and axonal neuropathy in eight. A fascicular sciatic nerve biopsy looking for recurrent lymphoma was performed in one ( patient 6) and showed increased segmental demyelination on teased nerve fibres (8%), mild multifocal fibre loss on semithin epoxy sections and frequent scattered inflammatory cells in the endoneurium (figure 1) but no evidence of lymphoma. These results were interpreted to be in keeping with inflammatory demyelination. On one autopsy case ( patient 4) cauda equina root examination showed axonal loss and frequent inflammatory cells in the endoneurium. The autopsy did not show recurrence of the malignancy. The CSF protein was increased in five of six patients in whom this test was obtained. Median CSF protein was 67 mg/dL (range 43–207 mg/dL). The CSF cytology in all of these patients was negative for malignant cells.
Acute polyradiculoneuropathies (GBS) In the four patients with acute polyradiculoneuropathies, the peak severity (weakness) ranged from 1 day to 2 weeks. One patient had back pain prior to the onset of symptoms and one had flu-like illness. In one patient, there was dysautonomia with significant orthostatic hypotension and urinary retention. No significant sensory symptoms were reported. Three out of the four patients required mechanical ventilation because of their
IMN and two patients died. NCS/EMG suggested axonal polyradiculoneuropathy in one, mixed axonal and demyelinating polyradiculoneuropathy in another and primarily demyelinating polyradiculoneuropathy in two. NCS were not repeated to differentiate demyelination from pseudo-demyelination in these patients. Three of these GBS patients had CSF examination. The CSF protein ranged from 43 to 96 mg/dL (median 56 mg/dL). The CSF cell count ranged from 0 to 12 cells/mcL. All patients were treated with intravenous immunoglobulin, plasmapheresis or both. There was significant neurological improvement in the two patients who survived. The NIS decreased from 120 to 10 points in one patient and the other patient was able to walk without assistance after being bedbound (the neurological examination was not complete enough on the second patient to determine a NIS).
Radiculoplexus neuropathies and multiple mononeuropathies Seven patients had radiculoplexus neuropathy (five lumbosacral and two brachial) and one had multiple mononeuropathies. The radiculoplexus neuropathies were bilateral in four patients. The progression of weakness in these patients was rapid but slower than in the GBS patients with the peak severity (weakness) ranging between 2 and 8 weeks. Pain was the major initial symptom with seven out of the eight patients having pain in the neck/shoulder or lower back/groin radiating to the arm or leg depending on the location of their radiculoplexus neuropathy. The patient with multiple mononeuropathies experienced pain in the limb with nerve involvement. Numbness and tingling were present in five out of the eight patients and allodynia was present in one. Four patients were treated with steroids. The NIS improved in all patients with a decrease from a mean NIS of 30 to 10 points whether or not they received treatment. CSF was obtained in three of these radiculoplexus neuropathy patients. CSF protein ranged from 53 to 207 mg/dL (median 78 mg/dL) and the CSF cells ranged from 1 to 42 cells/mcL.
Patients’ outcome Overall, six of the 12 patients died. One patient died from IMN’s complications. That patient had GBS, developed respiratory failure and died of sepsis in the setting of pneumonia while on a ventilator. One patient died from complication of her haematological disease due to immunosuppression; she had invasive fungal rhinosinusitis and pontine infarction 1 week after the onset of GBS. Five patients had recurrence of their malignancy within 4 months of the onset of IMN and four of them died from their malignancy. None of these patients had evidence for neurolymphomatosis (based on PET scan, plexus MRI or both) and they were considered to be in haematological remission at the time of the IMN. When these four patients died from their malignancies, none of their IMN was active or worsening. Of the patients who had allogeneic transplant, one had cutaneous GVHD and was on oral prednisone 60 mg daily when he developed the IMN. None of the other allogeneic transplant patients had GVHD. Of the total of six patients who died, two died while their neuropathy was active and the other four died after improvement of their neuropathy. Three of the deceased patients had GBS, whereas two had radiculoplexus neuropathy and one had multiple mononeuropathy. A follow-up NIS was available on eight patients, six of whom received immunotherapy. The NIS improved in all patients. The mean NIS improved from 43 to 10 ( p=0.016).
Karam C, et al. J Neurol Neurosurg Psychiatry 2014;85:638–642. doi:10.1136/jnnp-2013-306657
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Table 1
Summary of patients’ characteristics, neuropathy and outcome Gender
Type of cancer
Haematopoietic stem cell transplant type
Pattern of neuropathy
Time from SCT to neuropathy
CSF
1
59
Men
B cell lymphoma
Autologous
Multiple mononeuropathy
6 months
NA
2
60
Men
Multiple myeloma
Autologous
5 days
NA
3
65
Men
Multiple myeloma
Autologous
2 months
NA
None
4
59
Men
Non-Hodgkin lymphoma
Autologous
Bilateral brachial radiculoplexus neuropathy Bilateral lumbosacral radiculoplexus neuropathy Acute polyradiculoneuropathy
Dexamethasone taper over 2 months Intravenous steroids
13 months
protein 53, cell 0
IVIG
5
60
Women
Non-Hodgkin lymphoma
Autologous
Acute polyradiculoneuropathy
16 months
NA
IVIG
6
67
Men
B cell lymphoma
Autologous
58 months
24
Women
Acute myeloid leukaemia
Allogeneic
protein 53, cell 1 protein 56, cell 11
None
7
Right lumbosacral radiculoplexus neuropathy Acute polyradiculoneuropathy
8
66
Men
Allogeneic
9
33
Men
Myelodysplastic syndrome Non-Hodgkin lymphoma
10
37
Men
11
51
Women
12
71
Men
Non-Hodgkin lymphoma Acute myeloid leukaemia Acute myeloid leukaemia
Allogeneic
Allogeneic Allogeneic
Allogeneic
Right lumbosacral radiculoplexus neuropathy Right brachial radiculoplexus neuropathy Asymmetric lumbosacral radiculoplexus neuropathy Acute polyradiculoneuropathy
Asymmetric lumbosacral radiculoplexus neuropathy y
3 months
21 months
NA
8 month
Treatment for the neuropathy
Neuropathy outcome
Patients’ outcome
Improved NIS from 16 to 4 (at 3 months) Improved NIS from 41 to 16 (at 6 months) Improved NIS from 50 to 5 (at 1 month) NIS 80
Deceased at 12 months from lymphoma relapse Alive at 24 months. In remission Deceased at 48 months from relapse Deceased at 1 month from AIDP (respiratory failure) Alive at 12 months. In remission
Improved NIS from 120 to 10 (at 5 months) Improved NIS from 24 to 12 (at 3.5 months)
Plasmapheresis
protein 207, cell 42 NA
Already on prednisone for cutaneous GVHD Intravenous steroids
Improved NIS from 40 to 10 (at 4.5 months) Improved NIS from 20 to 10 (at 2.5 months)
None
Improved NIS NA
12 months
protein 94, cell 12
IVIG, plasmapheresis, then prednisone
2 months
protein 78, cell 2
None
Improved NIS NA from bedbound to ambulatory Improved NIS from 24 to 14 (at 4.75 months)
5 months
AIDP, acute inflammatory demyelinating polyradiculoneuropathy; CSF, cerebrospinal fluid; GVHD, graft versus host disease; IVIG, intravenous immunoglobulin; NIS, Neuropathy Impairment Score; SCT, stem cell transplantation.
Alive at 96 months. In remission Deceased at 1 month (died from fungal sepsis and meningitis) Alive at 36 months. In remission Alive at 96 months. In remission Deceased at 6 months from relapse Deceased at 4 months from relapse Alive at 15 months. In remission
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Karam C, et al. J Neurol Neurosurg Psychiatry 2014;85:638–642. doi:10.1136/jnnp-2013-306657
Patient
Age at presentation
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Neuromuscular
Figure 1 Fascicular nerve biopsy of the right sciatic nerve. (A) Teased nerve fibres showing increased demyelination (arrowheads) and rare axonal degeneration; (B) H&E section showing scattered individual inflammatory cells within the endoneurium; and (C and D) semithin epoxy sections showing regenerating clusters and onion bulbs (arrowheads).
DISCUSSION To date, IMN following SCT has been given little attention. The prior case reports and small series have highlighted acute inflammatory demyelinating polyradiculoneuropathy (AIDP), CIDP and one case of pure autonomic failure as the types of IMNs occurring after SCT.2 5 7 Our series adds to the current literature by being larger and including focal and asymmetric radiculoneuropathies and multiple mononeuropathies. To our knowledge, these phenotypes of IMNs following SCT have not been described in the literature. We did not find any cases of CIDP following SCT. This may be related to different classification of these neuropathies in different academic centres (eg, radiculoplexus neuropathies may have been classified as CIDP). The overall frequency of IMNs following SCT in our study was 0.36%. Taken separately, the frequency of GBS neuropathy in our series is 0.12%, which is similar to the only prior study (0.2%).2 There are no data concerning the incidence of IMNs in the general population to comment with confidence whether the rate of IMNs following SCT was increased compared with the background rate.9 10 These rates are low and we cannot state with certainty that the association between IMNs and SCT is meaningful. However, we have probably underestimated these frequency numbers as some patients may not have been identified because of our screening method (ICD9 codes), the retrospective study design and because some patients may have mild symptoms that were not recorded or were lost to follow-up. Although most of the IMNs occurred in close temporal association with the SCT, the neuropathy in patient 6 developed almost 5 years after SCT and might be considered as coincidental. Most of cancer patients at our institution (approximately 80%) receive autologous rather than allogeneic transplantation. In the series however, the number of patients developing IMN following SCT is equal. This suggests that an allogeneic transplant may be a relative risk factor for developing IMN, but the number of patients in this study is too small to make any definite conclusion. In allogeneic patients, GVHD is typically a concern and some of those IMNs may have a GVHD basis. On
the other hand, GVHD typically affects more than one organ and is usually more diffuse. In our study, only one patient had concomitant IMN with definite GVHD. Early relapse of the haematologic malignancy in patients with IMNs following SCT was commonly seen (5/12 patients studied). Those patients, who had relapse of the haematological malignancy, had a poor prognosis (four died). But this does not necessarily mean that IMN presages malignancy relapse. There was no specific pattern of neuropathy that would suggest cancer recurrence. In these patients, it is impossible to completely rule out neurolymphomatosis but this is unlikely since (1) they were felt to be in haematological remission by their haematologists, (2) neurolymphomatosis is a lymphoma involving the peripheral nerve and when it occurs, it is accompanied by neurological deterioration, and that was not the case in these patients in whom the neuropathy was improving (although immunosuppressant treatment may temporarily mask neurolymphomatosis) and (3) there was no evidence for neurolymphomatosis on PET scans or MRI. Furthermore, one patient with a high index of suspicion for neurolymphomatosis had a negative fascicular sciatic nerve biopsy (see figure 1), and another patient had an autopsy, which also did not show neurolymphomatosis or systemic lymphoma recurrence. Another hypothetical explanation for the IMN is paraneoplastic. The close relation between the time of cancer relapse and the occurrence of the IMN suggests a possible paraneoplastic aetiology. Furthermore, recovery from the IMN did not preclude cancer recurrence suggesting that continued follow-up for cancer recurrence is necessary. IMN following SCT may be a monophasic syndrome since the two non-treated cases with long-term follow-up had spontaneous improvement. However, one cannot make conclusions about the natural history of a syndrome based on the outcome of only two patients. Overall, the neurological deficits improved in 10 out of the 12 patients (virtually all who did not die in the acute setting). In total, eight patients were treated with immunotherapy and six of them had improvement in symptoms and deficits. Most of the IMNs (11 out of the 12 patients studied) occurred within 21 months following the SCT. During this time, the immune system is reconstituting and IMNs may be related to an immune reconstitution syndrome. This would support use of immunotherapy in managing these patients, despite the spontaneous improvement of the neuropathy in some. Naturally, recurrence of cancer should be excluded prior to starting immunotherapy. IMN following SCT is a diagnosis of exclusion and careful evaluation of these patients is necessary. It could be due to two mechanisms—an immune reconstitution syndrome causing an inflammatory response in the nerves and a paraneoplastic syndrome. The main concern for patients with IMN following SCT is cancer recurrence. Evaluation by an expert haematologist, NCS/EMG testing, CSF examination, imaging with whole-body PET scan and MRI of the nerve and targeted nerve biopsy are helpful in assessing for cancer recurrence. Even with a careful investigation, cancer recurrence is still possible and close follow-up is recommended. Contributors CK, MLM and PJBD: conceptualisation, design, analysis or interpretation of the data and drafting and revising the manuscript for intellectual content. LR, PBJ and JKE: analysis or interpretation of the data. Competing interests PJBD is member of the JNNP editorial board. Chafic Karam serves as WriteClick deputy editor for Neurology. Ethics approval The Mayo Clinic institutional review board. Provenance and peer review Not commissioned; externally peer reviewed.
Karam C, et al. J Neurol Neurosurg Psychiatry 2014;85:638–642. doi:10.1136/jnnp-2013-306657
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Karam C, et al. J Neurol Neurosurg Psychiatry 2014;85:638–642. doi:10.1136/jnnp-2013-306657
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Immune-mediated neuropathies following stem cell transplantation Chafic Karam, Michelle L Mauermann, Patrick B Johnston, Rajat Lahoria, JaNean K Engelstad and P James B Dyck J Neurol Neurosurg Psychiatry 2014 85: 638-642 originally published online November 22, 2013
doi: 10.1136/jnnp-2013-306657 Updated information and services can be found at: http://jnnp.bmj.com/content/85/6/638
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