1
Eurelings
MS#200202183
Increase of sural nerve T cells in progressive axonal polyneuropathy and monoclonal gammopathy
M. Eurelings, MD, L.H. van den Berg, MD, PhD, J.H.J. Wokke, MD, PhD, H. Franssen, MD, PhD, A.F.J.E. Vrancken, MD, N.C. Notermans, MD, PhD.
From: the Department of Neurology, the Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands.
Address correspondence to:
M. Eurelings, MD, Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, G03.228
P.O. Box 85500, 3508 GA Utrecht, The Netherlands
Telephone: 0031302509111, Telefax: 0031302542100, E-mail:
Keywords: nerve biopsy, immunohistochemistry, T cell infiltration, polyneuropathy, monoclonal gammopathy.
Acknowledgments: We wish to thank G.H. Jansen, MD, H. Veldman and C.W.A.M. Engels for their expertise and S. Kalmijn, PhD for her statistical advise.
The research of L.H. van den Berg was supported by a fellowship from the Royal Netherlands Academy of Arts and Sciences.
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Abstract
The authors investigated whether T cells have a role in the pathogenesis of axonal polyneuropathy and monoclonal gammopathy by comparing the presence of T cells in sural nerves of 23 patients with axonal polyneuropathy and monoclonal gammopathy (12 IgM, 11 IgG), of 15 patients with chronic idiopathic axonal polyneuropathy and of 10 autopsy cases. Seven patients with an increased T cell density had a progressive disease course, and four of these patients were treated with prednisone with a good response, suggesting that vasculitis plays a role in the pathogenesis.
Introduction
A causal relationship between IgM monoclonal gammopathy and demyelinating polyneuropathy is supported by the detection of IgM antibody activity against myelin-associated glycoprotein (MAG).1 The association of monoclonal gammopathy and axonal polyneuropathy is less clear and the pathogenic role of antibodies against sulfatide, chondroitin sulfate and gangliosides is unknown.2, 3 A substantial number of patients with axonal polyneuropathy and monoclonal gammopathy had similar characteristics as patients with chronic idiopathic axonal polyneuropathy (CIAP), suggesting that monoclonal gammopathy may be a coincidental finding.4However, a subset of patients with axonal polyneuropathy and monoclonal gammopathy has a more progressive disease course and worse disability than patients with CIAP.4
An immunologic mechanism and a role for T cells in the pathogenesis of axonal polyneuropathy has been suggested by the finding of T cell clones in peripheral blood in idiopathic sensory axonal polyneuropathy;5 and the detection of perivascular T cells in sural nerve biopsies in cryoglobulinemia, which most frequently appears as a monoclonal protein.6 Furthermore, increased sural nerve T cells were most pronounced in chronic inflammatory demyelinating polyneuropathy or demyelinating polyneuropathy associated with monoclonal gammopathy with a more severe disease course.7, 8
In the present study we investigated the presence of T cells in sural nerves of patients with axonal polyneuropathy associated with monoclonal gammopathy.
Patients and methods
We studied 48 sural nerve biopsies of 23 patients with axonal polyneuropathy and monoclonal gammopathy (12 IgM, 11 IgG) (taken before start of treatment), 15 patients with chronic idiopathic axonal polyneuropathy (CIAP), and 10 normal autopsy controls. Laboratory analysis was performed to exclude all known causes of neuropathy, including cryoglobulinemia, hepatitis C infection and primary amyloidosis; anti-MAG and anti-sulfatide antibodies were measured. All patients underwent hematological evaluation.9 The polyneuropathy was classified as axonal or demyelinating as previously described.9 The course of the polyneuropathy was determined as either progressive (deterioration of the neuropathy leading to decline of motor and sensory sumscores of more than one point and/or disability on the Rankin disability score over months), or slowly progressive (deterioration over years). Treatment consisted of intermittent cyclophosphamide and prednisone, or monotherapy with prednisone. A positive treatment response was defined as improvement of motor and sensory sumscores and/or disability on the Rankin disability score during the year following treatment.9
Immunohistochemical staining was performed to examine the density of T cells, B cells and macrophages using anti-CD3, -CD4, -CD8, -CD20 and -CD68 antibodies.7We considered the T cells to be increased if the T cell density exceeded those of CIAP patients and normal controls.7Of the sural nerve biopsies with increased T cell densities, hematoxylin and eosin sections were examined to identify signs diagnostic of necrotizing vasculitis (inflammation of the vessel wall and necrosis of the vessel wall) and suggestive of vasculitis (mural or perivascular inflammation without tissue necrosis, or (previous) necrosis of the arteriole wall without inflammation).10
Statistical analysis was performed using the Mann-Whitney test to compare T cell densities between subgroups. The Fisher exact test was used for comparison of clinical symptoms between patients with increased and normal T cell densities. We performed the analysis with all patients included and with exclusion of patients with definite vasculitis or hematologic malignancies.
Results
T cells were found in all sural nerves of patients and controls (figure 1A and 2). Occasionally, a CD20+ B cell was present in large perivascular T cell infiltrates. Macrophages were found in all biopsies in the endoneurium and epineurium. T cell densities ranged between 7 and 27/mm2 (median 11) in patients with CIAP. All patients with CIAP had slowly progressive sensory axonal polyneuropathy. T cell densities ranged between 3 and 27/mm2 (median 18) in normal controls. The sural nerves of seven patients with polyneuropathy and monoclonal gammopathy had increased T cells. Of the sural nerve biopsies with increased T cells, one biopsy had evidence of previous necrosis of the vessel wall with intimal proliferation and perivascular infiltration (Patient 1). One biopsy fulfilled the diagnostic criteria of necrotizing vasculitis (Patient 2). Patients 3, 13 and 14 had perivascular infiltration suggestive of vasculitis (figure 1B), of whom patient 3 had Sjögren’s disease. Patients 4 and 15 had no signs of vasculitis. T cells were localized mostly perivascularly in the endoneurium and epineurium in all biopsies. The percentage of epineurial and perivascular T cells was higher in biopsies with increased T cells (p<0.05, p>0.05 when patients with definite vasculitis or hematologic disease were excluded, figure 3a, b). In all sural nerve biopsies, CD8+ T cells were present in the endoneurium and epineurium (figure 3c).
T cell densities ranged between 4 and 183/mm2 (median 11, (E)T-1) in patients with axonal polyneuropathy and IgM monoclonal gammopathy. Four patients with a progressive disease course had increased T cell densities (two with symmetric and two with asymmetric features, three with pain). Two patients had IgM deposition in the sural nerve biopsy, one of these had anti-sulfatide antibodies. T cell densities ranged between 1 and 75/mm2 (median 17, (E)T-1) in patients with axonal polyneuropathy and IgG monoclonal gammopathy. Three patients with a progressive disease course had increased T cell densities (two with asymmetric and one with symmetric features with pain (E)T-1). All four patients with axonal polyneuropathy and increased T-cells who were treated with prednisone responded (p<0.05, p>0.05 with vasculitic or hematologic patients excluded (E)T2a, b, c). Of the five patients with axonal polyneuropathy and normal T cell densities who were treated with cyclophosphamide and prednison, only one patient with non-Hodgkin’s lymphoma responded. Four other patients had hematological malignancies (two non-Hodgkin’s lymphoma, one Waldenström’s macroglobulinemia and one multiple myeloma).
Discussion
In this study we identified two groups of axonal polyneuropathy and monoclonal gammopathy: (1) axonal polyneuropathy with increased T cell densities in the sural nerve biopsies, all of whom were progressive and (2) axonal polyneuropathy without increased T cell densities in the sural nerve biopsies, most of whom were slowly progressive.
In patients with a progressive painful axonal polyneuropathy (deterioration of the neuropathy leading to decline of motor and sensory sumscores of more than one point and/or disability on the Rankin disability score over months) vasculitic polyneuropathy is the most likely explanation for the elevated T cell density although necrosis of the vessel wall was missing as diagnostic criterion in five of these seven patients.10 The vasculitic signs in these sural nerve biopsies resembled the findings in cryoglobulinemic vasculitic neuropathy,6 i.e. perivascular inflammation, intimal proliferation and focal or multifocal fiber degeneration, but cryoglobulinemia was excluded in all patients.
In axonal polyneuropathy and monoclonal gammopathy without increased T cell densities an antibody-mediated pathogenesis is possible since two patients had IgM deposition in the sural nerve biopsy and one of these patients had anti-sulfatide antibodies.2, 3In these patients with axonal polyneuropathy and a slowly progressive course, a sural nerve biopsy is non-contributive and should not be performed.
Although only nine patiens in our study were treated with various treatment strategies, patients with increased T cell densities seem to respond to treatment with prednisone. In patients with progressive axonal polyneuropathy and monoclonal gammopathy a sural nerve biopsy is useful to identify a possible vasculitic neuropathy or increased T cell density since treatment response and prognosis may differ.
References
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Legend to figure 1:
Hematoxylin eosin staining (A) of transverse section of the sural nerve from a patient with axonal polyneuropathy associated with IgG monoclonal gammopathy showing perivascular infiltration around small epineurial arterioles and CD3 staining (B) showing perivascular T cells (76/mm2), bar=100m.
Legend to figure 2:
T cell numbers/mm2 in the sural nerve. normal = autopsy controls; CIAP = chronic idiopathic axonal polyneuropathy; IgG = axonal polyneuropathy and IgG monoclonal gammopathy; IgM = axonal polyneuropathy and IgM monoclonal gammopathy. The short horizontal line represents median. Long horizontal line represents the upper limit for CIAP patients and normal controls.
Legend to figure 3:
Percentage of T cells in the endoneurium (a), perivascular (b) and percentage of CD8+ T cells (c) in the total sural nerve. normal = autopsy controls; CIAP = chronic idiopathic axonal polyneuropathy; IgG = axonal polyneuropathy and IgG monoclonal gammopathy; IgM = axonal polyneuropathy and IgM monoclonal gammopathy. The short horizontal line represents median.