Clinical and laboratory features of anti-MAG neuropathy without monoclonal gammopathy

Abstract

Antibodies against myelin-associated glycoprotein (MAG) almost invariably appear in the context of an IgM monoclonal gammopathy associated neuropathy. Very few cases of anti-MAG neuropathy lacking IgM-monoclonal gammopathy have been reported. We investigated the presence of anti-MAG antibodies in 69 patients fulfilling diagnostic criteria for CIDP. Anti-MAG antibodies were tested by ELISA and confirmed by immunohistochemistry. We identified four (5.8%) anti-MAG positive patients without detectable IgM-monoclonal gammopathy. In two of them, IgM-monoclonal gammopathy was detected at 3 and 4-year follow-up coinciding with an increase in anti-MAG antibodies titers. In conclusion, anti-MAG antibody testing should be considered in chronic demyelinating neuropathies, even if IgM-monoclonal gammopathy is not detectable.

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Clinical and laboratory features
of anti-MAG neuropathy without
monoclonal gammopathy
Elba Pascual-Goñi
1, Lorena Martín-Aguilar1, Cinta Lleixà1, Laura Martínez-Martínez4,
Manuel J. Simón-Talero3, Jordi Díaz-Manera1,2, Elena Cortés-Vicente1,2, Ricard Rojas-García1,2,
Esther Moga4, Cándido Juárez4, Isabel Illa1,2 & Luis Querol
1,2
Antibodies against myelin-associated glycoprotein (MAG) almost invariably appear in the context
of an IgM monoclonal gammopathy associated neuropathy. Very few cases of anti-MAG neuropathy
lacking IgM-monoclonal gammopathy have been reported. We investigated the presence of anti-MAG
antibodies in 69 patients fullling diagnostic criteria for CIDP. Anti-MAG antibodies were tested by
ELISA and conrmed by immunohistochemistry. We identied four (5.8%) anti-MAG positive patients
without detectable IgM-monoclonal gammopathy. In two of them, IgM-monoclonal gammopathy
was detected at 3 and 4-year follow-up coinciding with an increase in anti-MAG antibodies titers. In
conclusion, anti-MAG antibody testing should be considered in chronic demyelinating neuropathies,
even if IgM-monoclonal gammopathy is not detectable.
Polyneuropathy associated with IgM monoclonal gammopathy of uncertain signicance (MGUSP) is a rare
form of chronic immune-mediated neuropathy. More than 50% of these patients harbor antibodies against
myelin-associated glycoprotein (MAG)1,2. Patients with anti-MAG+ MGUSP present with a predominantly sen-
sory neuropathy with ataxia and tremor with poor response to immunotherapy3.
Anti-MAG antibodies were described to be invariably associated with IgM monoclonal gammopathy4, and
clinical practice guidelines recommend to test them in patients with detectable IgM monoclonal gammopathy5.
Anecdotal cases of neuropathy with anti-MAG antibodies lacking monoclonal gammopathy were reported6–8.
A recent Japanese study8 reported a prevalence of 5.6% of anti-MAG positive patients in a cohort of 36 patients
with chronic demyelinating polyneuropathy with no monoclonal gammopathy. Antibodies in these patients were
tested by enzyme-linked immunosorbent assay (ELISA) and conrmed by Western blot analysis.
Here we investigate the presence of anti-MAG antibodies in patients fullling diagnostic criteria for chronic
inammatory demyelinating polyradiculoneuropathy (CIDP) without IgM monoclonal gammopathy. Also, we
describe the clinical, electrophysiological and laboratory ndings of four patients with anti-MAG associated neu-
ropathy without any detectable monoclonal gammopathy at the time of diagnosis.
Results
Patients. We detected 69 patients (61% males, mean age 58 years) fulfilling CIDP diagnostic criteria.
Flowchart of the study population is represented in Fig.1A. Briey, nine patients with antibodies toward NF155
(n = 4; 5.8%), NF140/186 (n = 2; 2.9%), CNTN1 (n = 2, 2.9%) or CNTN1/CASPR1 (n = 1; 1.4%), all of them neg-
ative for anti-MAG antibodies, were excluded from the seronegative cohort. irteen patients had monoclonal
gammopathy (IgA n = 1; IgG n = 9; IgM n = 2; IgA + IgG n = 1) at diagnosis. e two CIDP patients with IgM
monoclonal gammopathy were anti-MAG negative. Finally, we tested anti-MAG antibodies by ELISA in 58 CIDP
seronegative patients. Anti-MAG antibodies were detected in four patients (6.9% of the seronegative patients;
5.8% of the whole CIDP cohort) without IgM monoclonal gammopathy.
1Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat
Autònoma de Barcelona, Barcelona, Spain. 2Centro para la Investigación Biomédica en Red en Enfermedades Raras
(CIBERER), Madrid, Spain. 3Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma
de Barcelona, Barcelona, Spain. 4Department of Immunology, Hospital de la Santa Creu i Sant Pau, Universitat
Autònoma de Barcelona, Barcelona, Spain. Correspondence and requests for materials should be addressed to L.Q.
(email: lquerol@santpau.cat)
Received: 31 January 2019
Accepted: 2 April 2019
Published: xx xx xxxx
OPEN
There are amendments to this paper
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Clinical and neurophysiological features. Clinical and epidemiological features of all four patients are
summarized in Table1. All of them were males, with ages ranging from 58 to 70 years. Patients 1 and 2 presented
with progressive distal sensory disturbances, while patient 4 presented with gait imbalance due to sensory ataxia.
Patient 3 was diagnosed of essential tremor and had an incipient neuropathy with impaired vibration sensation in
the lower limbs. Physical examination revealed mild to moderate sensory ataxia and mild to severe action tremor
in all patients. During follow-up, patients 1, 2 and 4 developed distal motor involvement. Nerve conduction stud-
ies (Table1) demonstrated prolonged distal motor latencies in patients 1 and 4 and mild to moderate reduction
of motor or sensory nerve conduction velocities in all four patients. Also, F-waves showed prolonged latencies in
patients 1, 2 and 3; and were absent in patient 4. Temporal dispersion was observed in patient 1, and compound
muscle action potentials or sensory nerve action potentials were reduced in all four patients. An additional le
shows nerve conduction studies in more detail (Supplementary Table1).
All patients were treated with intravenous immunoglobulin (IVIg) (2 g/Kg), and good response was observed
in patient 1 and 4, while partial response was observed in patients 2 and 3. Patient 2 was treated with azathio-
prine without response. Upon IgM MGUS detection, rituximab (375 mg/m2, once weekly for 4 weeks followed
by 1 additional dose 1 month later) was started and we observed disease stabilization. IVIg were suspended in
patient 4, due to toxicodermia and neither prednisone (1 mg/Kg/d), nor cyclosporine (125 mg/12 h) showed any
signicant benet.
Antibody assays. Anti-MAG antibodies tested positive at diagnosis in four patients by ELISA.
Immunoxation did not detect monoclonal gammopathy at diagnosis in any of these patients, and total IgM
levels were only mildly elevated in patient 3 (301 mg/dL, upper limit 230 mg/dL). Anti-MAG antibody titers and
presence of IgM monoclonal gammopathy by immunoxation was tested periodically in these patients depending
on their visit schedules. Follow-up anti-MAG antibody titers are shown in Fig.1B. Antibodies to sulfatides and
gangliosides were negative in all four patients.
In patients 1 and 2 we detected an IgM monoclonal gammopathy aer 3 and 4 years of follow-up respectively
(Fig.1B), while in patients 3 and 4 no monoclonal gammopathy has been detected yet (follow-up of 5 and 2
years respectively). In patient 1, the detection of monoclonal gammopathy coincided with a signicant increase in
anti-MAG antibody titers. At that time, hematological malignancy screening tests performed in patients 1 and 2
were negative. Both had a serum IgM-kappa monoclonal protein of less than 1 g/L, a negative Bence-Jones protein
Figure 1. Flowchart of the study population (A). Serial anti-MAG antibody titers during follow-up (B). e
asterisks highlight the detection of IgM MGUS in patients 1 and patient 2. e arrow indicates rituximab
administration. Immunohistochemistry studies with serum from patients 1–4 showing IgM binding on the
myelin sheaths. Immunouorescence intensity increased in patients 1 and 2 aer MGUS detection (C). Staining
pattern of patients anti-MAG- sulfatides+ MGUSP used as control are shown. Titers of anti-MAG and anti-
sulfatides antibodies are represented. (Anti-IgM, 20x and 40x original magnication). BTU Bühlmann test
units; IgM immunoglobulin M; MAG myelin-associated glycoprotein; MGUS monoclonal gammopathy of
uncertain signicance.
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urine test, and a radiographic X-ray skeletal survey without bone lesions. Accordingly, both patients were diag-
nosed of IgM MGUS and underwent hematological follow-up. Neither of them developed malignancy to date.
Immunohistochemistry. At diagnosis, serum from all four patients showed a typical anti-MAG reactivity
pattern in the immunohistochemistry assays. Immunostaining reactivity was indistinguishable from patients
with monoclonal gammopathy associated anti-MAG neuropathy and dierent from patients with anti-sulfatide
antibody- associated neuropathy (Fig.1C). e intensity of the myelin staining increased signicantly aer IgM
monoclonal gammopathy detection in patients 1 and 2.
Discussion
In this study, we identied anti-MAG antibodies in four patients fullling CIDP diagnostic criteria and no evi-
dence of monoclonal gammopathy. Only one patient had slightly increased total IgM levels at diagnosis, and
in two patients we detected an IgM MGUS aer 3 and 4 years of follow-up. All patients presented with clin-
ical, electrophysiological and serological features indistinguishable from those described in patients with
anti-MAG + MGUSP3.
Since their description, anti-MAG antibodies have always been associated to IgM monoclonal gammopathy4.
Anti-MAG have been shown to be specic for the diagnosis of MGUSP, while they are negative in healthy con-
trols2. Indeed, clinical guidelines5,9 only recommend to test anti-MAG antibodies in patients with IgM monoclo-
nal gammopathy. Although the association of IgM monoclonal gammopathy and anti-MAG antibodies is very
strong, these recommendations likely generate a selection bias. Our observations suggest that there is a subset
of patients with anti-MAG + polyneuropathy without any detectable monoclonal gammopathy that may remain
undiagnosed. A few other cases of anti-MAG neuropathy in the absence of monoclonal gammopathy have been
described6–8, supporting our observations.
In two of our patients an IgM monoclonal gammopathy was detected by serum immunoxation years aer
diagnosis, and in patient 1 it clearly coincided with an increase in anti-MAG titers. Longer follow-ups may lead
to detectable gammopathy in the other two patients but this remains to be conrmed. is phenomenon may
Patient 1 Patient 2 Patient 3 Patient 4
Age at onset, yr; Sex 58; M 70; M 70; M 68; M
Past medical history No Hypertension, diabetes Osteoarthritis,
Essential tremor Arthritis (methotrexate)
Clinical manifestations
Initial symptoms Distal sensory
disturbance
upper > lower limbs
Distal sensory disturbance
upper > lower limbs Postural tremor Gait ataxia
Limb weakness Distal > proximal mild Distal mild No Distal > proximal moderate
distal atrophy
Gait ataxia Mild Moderate Mild Moderate
Intention tremor Mild Moderate, upper limbs Severe, head and
upper limbs Moderate, upper limbs
Electrophysiological ndings
Prolonged motor distal
latencies + − − +
Reduction of NCV + + + +
Prolonged F-wave latencies + + + +
Conduction block − − − NA
Temporal dispersion + − − +
Reduced CMAPs + + +
Reduced SNAPs + + + +
Laboratory ndings
Cerebrospinal uid ndings
(protein; cell count) 1,1 g/L; 2cells/mm31,4 g/L; 2cells/mm3NA 0,44 g/L; 0cells/mm3
IgM levels * (presentation) 163 mg/dL 174 mg/dL 301 mg/dL 63 mg/dL
Anti-sulfatides and
gangliosides Negative Negative Negative Negative
Anti-MAG Abs titers
(presentation) 2500 9000 2050 1300
Monoclonal protein, levels
(follow-up) IgM-κ, < 1 g/L IgM-κ, < 1 g/L No No
Malignancy screening Negative Negative NA NA
Treat ment and response IVIg: good IVIg: partial azathioprine:
no rituximab: good IVIg: partial IVIg: good steroids: no
cyclosporine: no
Table 1. Summary of clinical and laboratory ndings of patients with anti-MAG neuropathy without
monoclonal gammopathy. *IgM normal values: 40–230 mg/dL. CMAPs: compound muscle action potential;
IVIg: intravenous immunoglobulin; κ: kappa light chain; M: male; NA: not available; NCV: nerve conduction
velocities; SNAPs: sensory nerve action potential; yr: years.
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imply that, either early IgM gammopathy is not detectable with current immunoxation techniques or that an
early antigen-driven autoimmune process is subsequently followed by a clonal expansion and appearance of the
monoclonal gammopathy. Whatever the case, these two patients suggest that anti-MAG antibody polyneuropathy
displays a spectrum of disease that includes patients that test negative for the presence of gammopathy. Either
early testing of anti-MAG or repeated testing of monoclonal gammopathy by immunoxation have to be con-
sidered then, especially in patients with clinical and electrophysiological features resembling typical anti-MAG+
MGUSP.
e prevalence of anti-MAG+ patients in our CIDP cohort (5.8%) was similar to that recently reported by
a Japanese group (5.7%)8. It is also comparable to the amount of anti-NF155+ patients in our study population
(4/69) and the prevalence of anti-NF155+ patients reported in other CIDP cohorts10. ese ndings support the
concept that CIDP is a heterogeneous disease in terms of immunopathology, clinical presentation and treatment
response. erefore, autoantibody proling, including detection of anti-MAG antibodies, is useful to guide diag-
nosis, prognosis and treatment selection in patients with chronic demyelinating neuropathy.
e treatment strategy in anti-MAG associated neuropathies is limited due to the low response rate to cur-
rent therapies. Treatment with IVIg, plasma exchange, prednisone or rituximab have shown benets in some
patients3,11. Two of our patients were initially diagnosed of seronegative CIDP and unsuccessfully treated with
immunosuppressant drugs such as azathioprine and cyclosporine that are not considered eective in anti-MAG+
MGUSP. us, within the standard therapies used in CIDP, anti-MAG antibodies helped us choose those thera-
pies that could yield better results (e.g IVIg). It would be interesting to assess in larger cohorts if early treatment
of these patients with B-cell depleting therapies, such as rituximab, would be more ecacious than if patients are
treated aer the development of the monoclonal gammopathy11,12. Moreover, due to the association of anti-MAG
antibodies to the presence of MGUS, all four patients underwent hematological follow-up to study the appearance
of monoclonal gammopathy.
In conclusion, we report four patients with anti-MAG neuropathy in the absence of IgM-monoclonal gam-
mopathy. Given these observations, we suggest to test anti-MAG antibodies in patients with chronic demyeli-
nating neuropathy, regardless of the detection of IgM monoclonal gammopathy, especially in those with distal,
sensory-ataxic involvement.
Methods
Patients, informed consent and protocol approvals. Patients prospectively observed during routine
neuromuscular practice between 2007–2017 fullling EFNS/PNS diagnostic criteria for CIDP were included.
We tested the presence of anti-MAG antibodies in serum. Patients with antibodies towards neurofascin-155
(NF155), nodal neurofascin-140 and 186 (NF140/186), contactin-1 (CNTN1), contactin-1/caspr-1 complex
(CNTN1/CASPR1) were excluded from the seronegative cohort. is study was conducted according to a pro-
tocol approved by the Institutional Ethics’ Committee of the Hospital de la Santa Creu i Sant Pau. All experi-
ments were performed in accordance with the relevant guidelines and regulations. Written informed consent
were obtained from all subjects.
Clinical and neurophysiological features. In anti-MAG+ patients we collected the age at onset, sex,
past medical history and clinical manifestations including initial symptoms and the presence of limb weakness
(proximal/distal), gait ataxia or intention tremor. We analyzed neurophysiological ndings including motor distal
latencies, nerve conduction velocities, F-wave latencies, and the presence of conduction blocks, temporal disper-
sion, reduced CMAPs or reduced SNAPs. We also collected therapies and response to them.
Antibody assays. e presence of monoclonal gammopathy (IgA, IgG or IgM) was evaluated by serum
protein electrophoresis and serum immunoxation electrophoresis studies (Sebia, France) at diagnosis and
follow-up. Antibodies against NF155, NF140/186, CNTN1 and CNTN1/CASPR1 were investigated by immu-
nocytochemistry as previously described13. Anti-MAG antibodies were tested by ELISA (Bühlmann laboratories
AG, Schönenbuch, Switzerland). We used a cut-o value of 1000 Bühlmann Titer Units (BTU), according to the
manufacturer’s instructions. In anti-MAG+ patients, antibodies to sulfatides and gangliosides were also inves-
tigated by ELISA as previously described14. Further, total levels of IgM in serum were investigated (Immage 800
Nephelometer Beckman Coulter).
Immunohistochemistry. Monkey peripheral nerve tissue slides (Inova Diagnostics, Inc., San Diego, CA)
were blocked with 5% normal goat serum in PBS, incubated with patients’ sera at 1:10 for 1 hour at room temper-
ature, washed and incubated with Alexa Fluor 594 goat antihuman IgM secondary antibody at 1:1000 for 1 hour.
Slides were mounted with Fluoromount medium (Sigma-Aldrich, St. Louis, MO). Immunostaining patterns were
analyzed and compared with controls. Sera from patients with anti-MAG+ MGUSP and anti-MAG- sulfati-
des + MGUSP were used as disease controls.
Data Availability
All data generated or analyzed during this study are included in this published article (and its Supplementary
Information Files).
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Acknowledgements
is project was supported by Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain and
FEDER under grant FIS16/00627, and personal grant SLT006/17/00131 of the Pla estratègic de recerca i innovació
en salut (PERIS), Departament de Salut, Generalitat de Catalunya, IP Luis Querol.
Author Contributions
E.P.G. and L.Q. were involved in study conceptualization, data collection, draing, analysis, and revising the
manuscript for intellectual content. L.M.A., C.L., L.M.M., M.S.T., J.D.M., E.C.V., R.R.G., E.M., C.J., I.I. were
involved in data collection and revising the manuscript for intellectual content.
Additional Information
Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-42545-8.
Competing Interests: EP-G, LM-A, CL, LM-M, MJS-T, JD-M, EC-V, RR-G, EM and CJ declare no competing
interests.LQ has provided expert testimony for Grifols, Genzyme and CSL Behring and received research funds
from Novartis Spain and Grifols (Spin Award). II provided expert testimony and received speaking fees and
travel grants from Pzer.
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