Neuropathy in monoclonal gammopathy
Eduardo Nobile-Orazio
Dept. Translational Medicine, Milan University.
2nd Neurology, IRCCS Humanitas Clinical Institute,
Rozzano, Milan, ITALY
The author reports no Conflict of Interest
Neuropathy in Monoclonal Gammopathy
Osteosclerotic Myeloma (POEMS) 50-85%
WM
30-50%
MGUS
5-37%
Amyloidosis
10-20%
Cryoglobulinemia
7-15%
Multiple Myeloma
3-14%
Lymphoma
2-8%
Monoclonal Gammopathy and Neuropathy
Kelly et al 1981
Causes of PN in 692
28 patients (8%) with
patients at Mayo Clinic:
idiopathic PN (4% of to-
· Idiopathic
48%
tal PN) had monoclonal
· Secondary
52%
gammopathy including:
Diabetes
31%
MGUS
16
Inherited
7%
Amyloidosis
7
Alcohol
4%
Multiple myeloma
3
Vitamin def.
3%
WM
1
Malignancy
2%
Heavy Chain Disease 1
Other diseases
5%
Type and mechanisms of neuropathy in
plasma cell dyscrasias
· Mono-, multi-, cranial neuropathy &
radiculopathy (MM, WM, LL, lymphoma)
direct infiltration
nerve/root compression
hyperviscosity
bleeding diathesis
cryoglobulinemia (also )
· Symmetric polyneuropathy
Amyloidosis (AL) (+MM)
Activation of VEGF (POEMS)
Drug related toxicity (often painful)
M-protein reactivity with nerve (MGUS, IgM)
Unknown (MGUS, mostly IgG & IgA)
Prevalence of PN in MGUS in relation to isotype
No. of
Clinical
Subclinical
Total PN
patients
PN
PN
Total MGUS
74
8%
8%
16%
IgG
34
3%
3%
6%
IgA
14
7%
7%
14%
IgM
26
15%
15%
31%
IgM vs IgG+IgA: p < 0.025
Nobile-Orazio et al. 1991
PN+MG at our Institute (1984-2000)
PN+IgM
95 (83%)
PN+IgG
15 (13%)
PN+IgA
5 (5%)
Anti-neural reactivities of IgM M-proteins in PN
Antigens
%
PN type
Pathology
Authors
MAG/SGPG/P0 50%
S>>M
Dem
Latov et al 1980
(DADS-M)
(Katz et al 2000)
Sulfatide
6%
S; S>M; SM
Ax or Dem
Pestronk et al 1991
GQ1b+Disyalo
2%
S>M
Dem
Ilyas et al 1986
(CANOMAD)
(Willison et al 2000)
GD1a
3%
M; M>S
Dem
Bollensen et al 1989
GM2
2%
M; M>S
Dem
Ilyas 1988
GM1
<2%
M; LMNS
Focal Dem
Latov et al 1988
(MMN)
(Pestronk et al 1988)
ChS-C
<2%
SM
Axonal
Sherman et al 1983
Open issues in anti-nerve antibody
testing in IgM related neuropathies
1. How useful are anti-nerve antibodies in
identifying different forms of IgM
related neuropathies?
2. Are different antibodies associated with
different response to treatment?
3. What is the role of these antibodies in
the pathogenesis of these neuropathies?
NEUROPATHY ASSOCIATED WITH ANTI-
MAG IgM MONOCLONAL GAMMOPATHY
· Slowly progressive Distal, Acquired,
Demyelinating Symmetric (DADS)
predominantly sensory, ataxic, PN
often associated with arm tremor;
· Estimated prevalence of 20/100,000,
mostly affecting men aged 50-70 yo;
· Electrophysiologically characterized by
signs of a demyelinating PN with
disproportionately increased DL
compared to CV (reduced TLI); CB rare
· Pathologically characterized by
demyelination, abnormally spaced
myelin lamellae by EM and IgM &
complement deposits in nerve by IF
PN ASSOCIATED WITH ANTI-MAG IgM
Homogeneous clinical and electrophysiological features
consistent with a chronic, slowly progressive,
predominantly sensory, demyelinating neuropathy
MAG + (42)
MAG - (26)
p
Type of PN
S or S>M
62%
31%
< 0.025
SM
31%
38%
n.s.
M>S
7%
31%
< 0.01
NCS Peroneal
Mean MCV
22.9 m/s
39.6 m/s
< 0.000001
< 35 m/s
90%
23%
< 0.0001
MGUS/WM-NHL
81%/19%
27%/73%
< 0.0005
Nobile-Orazio et al 1994
- 140 pts. (72% Dem, 28% Ax, 44% MAG+) followed for 23 yrs:
-Demyelination & higher onset age risk of disabiliy, MAG+
Anti-MAG IgM (>1/3,200) in PN+IgM
Abs
MAG
GM1
GM2
GD1a
GD1b
Sulfatide
Disease (No.)
75
47
9
7
10
6
MMN (41)
12 (29%) 4 (10%)
1
1
CIDP (57)
6 (10%)
1
1
2 (3%)
Lewis Sumner (5)
1
PN+IgA (2)
PN+IgG (23)
2 (10%)
PN+IgM(166)
75 (45%) 10 (6%)
1
3 (2%)
4 (2%)
6 (4%)
POEMS (8)
2 (25%)
1
1
1
Other PN (89)
2 (3%)
Unknown PN(64)
3 (3%)
Monon. mul. (9)
1
Radic-plexop.(21)
3 (14%)
MND (63)
6 (9%)
2 (3%)
2 (3%)
Nobile-Orazio et al. 2008
Total 539
. High titers of anti-MAG IgM predict the
development of PN in asymptomatic IgM patients
CLINICAL NEUROPATHY AFTER 3-12 YEARS (Mean 6)
IN 24 ASYMPTOMATIC PATIENTS WITH IgM M-
PROTEIN IN RELATION TO ANTI-MAG TITERS
Anti-MAG
No.
CLINICAL NEUROPATHY
titers
Pats.
First visit
Last visit
High titers
4
0
3 (75.0%)
Low titers
7
0
1 (14.3%)
Negative
13
0
2 (15.4%)
Total
24
0
6 (25.0%)
Fisher exact test: High vs. Low titers + Negative: p = 0.03529
Meucci et al 1999
Pathogenetic role of anti-MAG IgM
1. Anti-MAG IgM are almost
invariably associated with PN
or predict its onset
2. Clinical & electrophysiological
homogeneous features of the
neuropathy;
3. Pathological evidence of
demyelination and IgM &
complement deposits in nerve;
4. Complement mediated nerve
demyelination induced in
animals by anti MAG IgM;
5. Improvement correlates with
reduction of anti-MAG IgM
RCT in PN & anti-MAG IgM
Plasma exchange (PE)
·
Dyck et al 1991: effective in IgG/IgA, not IgM MGUS
·
Oksenhendler 1995: No difference if associated with Chlorambucil
High dose Intravenous Immunoglobulina (IVIg)
·
Dalakas et al 1996:: effective in 2/11 IgM (18%) (1/9 MAG, 11%)
·
Comi et al 2002: IVIg slightly better (p=0.05) than placebo
Interferon Alfa (IFN-)
·
Mariette et al 1997: Sensory improvement in 8/10 IFN-a
·
Mariette et al 2000: No difference between IFN-a and placebo.
Oral CTX+ Prednisone
·
Niermejier et al 2007: No difference in functional scales with
placebo; sensory & DL better at 6 mos.
Rituximab
·
Dalakas et al 2009: 4/13 (31%) patients on Rituximab improved by
1 point in INCAT score compared to 0/13 controls (p = 0.096);
Placebo
Rituximab
Ann Neurol 2009; 65: 286-293
· RCT on 26 patients with 4 weekly infusions
of Rituximab, 375 mg/m2, versus placebo.
· After 8 months, 4/13 (31%) patients on
Rituximab improved by 1 point in INCAT
score compared to 0/13 controls (p = 0.096; p
= 0.036 without 1 pat. with 0 score at entry)
· Time to 10 m walk reduced in the Rituximab
group (p = 0.042);
· IgM reduced at 8 month by 34% and anti-
MAG by 50% in the Rituximab group
· Rituximab was the first drug shown to be
effective in some anti-MAG patients..
A RANDOMIZED CONTROLLED TRIAL OF RITUXIMAB
IN DEMYELINATING NEUROPATHY ASSOCIATED
WITH ANTI-MAG IGM GAMMOPATHY (RIMAG STUDY)
Léger J-M1, Viala K1, Bombelli F1, Nicolas G2, Créange A3, Vallat J-M4, Pouget
J5, Preux P-M6; for the RIMAG Trial Group (France and Switzerland).
·
Randomized double-blind controlled study with Rituximab (4 weekly
infusions of 375 mg/m2) (26 patients) vs Placebo (28 patients);
·
54 pts with PN & anti-MAG IgM in 9 centres in France & 1 in Switz-
erland. INCAT sens. score (ISS) 4, VAS score >4, ataxia score 2.
·
Primary outcome: Change of ISS between baseline & 12 mos.
·
Secondary outcome: disability Hughes score, MRC, self-evaluation sc.
·
7 patients did not complete the trial (6 with Rituximab and 1 placebo).
47 patients (20 rituximab, 27 placebo) eligible for final analysis.
·
After 12 months, no difference in mean ISS variation between
Rituximab (1.3+ 3.0) & placebo (1.0 + 2.8). More pts under Rituximab
improved in Hughes scale (20 vs 0%) and self ev. scale (26.3 vs 4%)
Rituximab was not effective on primary outcome
· Prospective open label trial
· 17 pts with PN & IgM MGUS (6 anti-MAG +)
· Rituximab 375 mg/sq/week x 4 weeks
· Follow-up 12 months (12-30 mos)
· Outcome:
ODSS: 2/17 (12%) improved, 1 (6%) deteriorated
MRS: 5/17 (30%) improved
MRC: 4/17 (25%) improved >5%
SSS:
9/17 (53%) improved >5%, 4 (25%) worse
ODSS or MRC: 6 (35%) improved
Rituximab appeared to be as effective and better
tolerated that CTX +Prednisone or Fludarabine
Long-term effect of Rituximab in anti-MAG
polyneuropathy
Benedetti et al Neurology 2008, 71:1742-37
· 10 patients with PN & anti-MAG IgM improved at
month 12 after Rituximab (375 mg/sq/week x 4 weeks),
by > 1 point in 2 of MRC, INCAT or ISS.
· 36 month follow-up
· 8/10 maintained or further improved at month 24
· 6/10 maintained the improvement at month 36
· Anti-MAG IgM reduced by 93% at month 12, 80% at
month 24, 60% at month 36.
· All patients deteriorating during follow-up but none of
those stable had baseline titers >1/100,000
· CD19+ B cell undetectable at 1 month & in 8 at 1 year
The benefit of rituximab lasted 24 months in 80% & 36
months in 60% of responding patients
Anti-neural reactivities of IgM M-proteins in PN
Antigens
%
PN type
Pathology
Authors
MAG/SGPG/P0 50%
S>>M
Dem
Latov et al 1980
(DADS-M)
(Katz et al 2000)
Sulfatide
6%
S; S>M; SM
Ax or Dem
Pestronk et al 1991
GQ1b+Disyalo
2%
S>M
Dem
Ilyas et al 1986
(CANOMAD)
(Willison et al 2000)
GD1a
3%
M; M>S
Dem
Bollensen et al 1989
GM2
2%
M; M>S
Dem
Ilyas 1988
GM1
<2%
M; LMNS
Focal Dem
Latov et al 1988
(MMN)
(Pestronk et al 1988)
ChS-C
<2%
SM
Axonal
Sherman et al 1983
RESULTS: Sulfatide >1/16,000 (ELISA)
Abs
MAG
GM1
GM2
GD1a
GD1b Sulfatide
Diseases
75
47
9
7
10
6
MMN (41)
12 (29%) 4 (10%)
1
1
CIDP (57)
6 (10%)
1
1
2 (3%)
Lewis Sumner (5)
1
PN+IgA (2)
PN+IgG (23)
2 (10%)
PN+IgM(166) 75(100%) 10 (6%)
1
3 (2%)
4 (2%) 6 (100%)
POEMS (8)
2 (25%)
1
1
1
Other PN (89)
2 (3%)
Unknown PN(64)
3 (3%)
Monon. mul. (9)
1
Radic-plexop.(21)
3 (14%)
MND (63)
6 (9%)
2 (3%)
2 (3%)
Total: 539
Nobile-Orazio et al 2008
RESULTS: SULFATIDE *
PN+IgM (4%+) vs other PN (0%+): p <0.0005
PN+IgM vs 103 pts with IgM no PN (0%+): p <0.025
Sensitivity
Specificity
PPV
IG
Diagnostic values for PN+IgM among total PN pts
>1/16,000
4%
100%
100%
+69%
> 1/8,000
4%
98%
43%
+12%
Diagnostic values for PN among total IgM M-protein pts
4%
100%
100%
+38%
* 6 patients with titer >1/16,000 (including 4 also MAG+)
Clinical and electrophysiological features of
patients with high anti-sulfatide IgM
P. Hem.
Ab
Clinical Median
Dis
Titer
CV
1. IgMl,
512000 SM,
NR
MGUS
ataxia
2. IgMl,
512000 M
10
NHL
3. IgMk,
512000 SM,
35
MGUS
ataxia
4. IgMl,
32000
SM,
20
MGUS
ataxia
5. IgMk,
32000
SM,
34
MGUS
ataxia
IgM
TCC
Carpo et al , J Neurol Sci 2000
Anti-Disyalo Gangliosides (GD1b, GQ1b) IgM
Abs
MAG
GM1
GM2
GD1a
GD1b
GQ1b*
Diseases
75
47
9
7
10
4
MMN
12 (29%) 4 (10%)
1
1
CIDP
6 (10%)
1
1
2 (3%)
2 (8%)
Lewis Sumner
1
PN+IgA
PN+IgG
2 (10%)
PN+IgM
75(100%) 10 (6%)
1
3 (2%)
4 (2%)
1
POEMS
2 (25%)
1
1
1
1
Other PN
2 (3%)
Unknown PN
3 (3%)
Mononeur. mul.
1
Radicoloplexop.
3 (14%)
MND
6 (9%)
2 (3%)
2 (3%)
18 patients
14 M, 4 F
Age at onset:
28-72 (M: 53)
Chronic
Ataxic
10 substantial
Neuropathy (S>>M):
Motor impairment:
14 none or mild
Ophtalmoplegia:
6
Demyel. EMG
11
M-protein (IgM MGUS) 17
Agglutinins (cold)::
9
Dysialosil antibodies:
all (by def.)
Therapy:
9/13 responded to IVIg
(Attarian et al JNNP 2010)
Anti-nerve antibody in IgM related
neuropathies
1.
Testing for anti-nerve antibodies in IgM related
neuropathies help identifying specific clinical forms
of the neuropathy, characterizing their prognosis and
defining their most effective therapy.
2.
Even if the specific pathogenetic role of these
antibodies in the neuropathy is not always defined,
their finding support the hypothesis that the
neuropathy is immune mediated and help explaining
the higher prevalence of neuropathy in IgM than
IgG or IgA monoclonal gammopathies.
Neuropathy and IgG MGUS
Pats. No. Clinical PN Subclinical PN Total PN
IgM
26
15%
15%
31%
IgG
34
3%
3%
6%
IgA
14
7%
7%
14%
Patients with PN+MG observed
at our Institute in 1984-2000
PN+IgM
95 (83%)
PN+IgG
15 (13%)
PN+IgA
5 (5%)
Clinical and electrophysiological
features of PN+IgG MGUS
Reported
Type of progression
ENG classification
patients relaps/remitt progressive Dem Ax Mixed
205
54
127
94
65
13
Pats No.
CIDP-like
Axonal PN
(Authors)
(M>S/S>M/SM)
(SM or S)
17
10
7
(Di Troia 1999)
(7/2/1)
(5/2)
14
5
9
(Hermosilla 1996)
(0/0/5)
(4/5)
Response to immune therapies in
PN+IgG MGUS
Responders
Therapy
CIDP-like
54/67
Steroids, IVIg, PE
(81%)
(Immunosuppr.)
Axonal PN
7/34
Steroids, IVIg, PE
(21%)
(Immunosuppr.)
Immunological findings in 91
patients with PN+IgG MGUS
No. of
Site/Reactivity
patients
IgG deposits in
6
Myelin (2), endoneurium/
nerve
vasa (1), light chains in
small vessels(3)
Anti-neural IgG
9
Nerve myelin (2), vessels
reactivity
(1), Schwann cells (1),
MAG (3), 68kD NF (1),
GQ1b (1)
Time relationship between IgG
MGUS and PN
CIDP like
Sensory
(10)
axonal (7)
MGUS bef. PN
0
2
(time interval)
(6 mos, 9 yrs)
PN bef. MGUS
8
2
(time interval)
(6.8 yrs,1-18 yrs)
(1 & 8 yrs)
PN = MGUS
2
3
Other causes
0
3
for PN
Neuropathy and IgA MGUS
Pats. No. Clinical PN Subclinical PN Total PN
IgM
26
15%
15%
31
IgG
34
3%
3%
6%
IgA
14
7%
7%
14%
Patients with PN+MG observed
at our Institute in 1984-2000
PN+IgM
95 (83%)
PN+IgG
15 (13%)
PN+IgA
5 (5%)
Clinical and electrophysiological
features of PN+IgA MGUS
Clinical impairment
ENG classification
S or
M or
Patients
No S>M
SM
M>S
Dem
Ax
Mixed
Reported 28
5
18
34
7
17
Our
6
1
3
22
2
2
POEMS syndrome
· Polyneuropathy
(100%)
SM, D>A, CIDP-like, severe
· Organomegaly
(80%)
· Endocrinopathy
(70%)
· M-protein
(75%)
(50% IgG-50%IgA;mostly )
· Skin changes
(90%)
S e rum V E G F le ve ls
8 000
· osteosclerotic myel.
(80%)
7 000
6 000
· lymphadenopathy
(40%)
5 000
l
/mgpF 4000
· peripheral edema
(30%)
VEG
3 000
· ascites
(10%)
2 000
1 000
· high CSF proteins
(100%)
0
POEMS
CIDP
GBS
PN+IgM
MMN
MGUS/MM
ALS
Other PN
NS
P at ients' G r oups
Ann Neurol 2000; 47:808-11
· 72 y.o man;
· 1 year progressive paresthesias,
sensation & ataxia;
· IgA MGUS (1,240 mg/dl);
· SCV (m/sec): LL 10-21, UL 21-42
· Deposits of IgA & C3d in nerve
NEUROPATHY AND MGUS
SUMMARY
In patients with IgM MGUS there is consistent
evidence for a pathogenetic role of the M-protein in the
neuropathy, particularly when directed against MAG,
sulfatide or gangliosides. Despite these evidences, the
efficacy of immune/cytostatic therapies in these patients
still remains to be adequately confirmed.
In patients with IgG MGUS there is little evidence
to support a primary pathogenetic role of the M-protein in
PN. Immune therapies are however often effective in
patients with a CIDP-like presentation
The few reports on PN and IgA MGUS and the
heterogeneous findings do not allow conclusions on the
pathogenicity of this association and on the efficacy of
immune therapies. These should be considered only in
patients with some evidence of anti-nerve reactivity
Department of
Fabrizia Terenghi
Translational Medicine,
Francesca Gallia
IRCCS Humanitas
Elda Judica
Clinical Institute
Davide Di Pietro
Milan University,
Claudia Giannotta
Rozzano, Milan,
Antonella Scarale
Treatment for IgG/IgA paraproteinaemic PN
Allen D, Lunn MPT, Niermeijer J, Nobile-Orazio E
The Cochrane Library 2007, Issue 1
Reviewers' conclusion:
· One RCT with 18 participants revealed a modest short-term
benefit of plasma exchange in IgG or IgA paraproteinaemic PN,
over a short follow-up, when compared to sham exchange. Four
other trials were identied but these were not RCT. The evidence
from randomised controlled trials for the treatment of IgG or
IgA paraproteinaemic PN is currently inadequate.
· Observational or open trial data provide limited support for the
use of treatments such as plasma exchange, cyclophosphamide
combined with prednisolone, IVIg and corticosteroids. These
show potential therapeutic promise but the potential benefits
must be weighed against adverse effects.
RESULTS: MAG *
PN+IgM (45%+) vs other PN (0%+): p <0.000001
PN+IgM vs 103 pts with IgM no PN (7%+): p <0.00001
Sensitivity
Specificity
PPV
IG
Diagnostic values for PN+IgM among total PN pts
45%
100%
100%
+69%
Diagnostic values for PN among total IgM M-protein pts
45%
93%
91%
+29%
* 75 patients with titer >1/3,200
RITUXIMAB (-CD20 MAB)
IN PN AND ANTI-MAG IgM
Renaud et al 2003 Muscle Nerve
· 9 pts with PN & antiAG
· Rituximab 375mg/m2/wk x 4
· B cells decreased in all
· IgM in all by 35% to 82 %
· Anti-MAG by > 50% in 8/9
· NDS in 6 (<5 in 4, >10 in 2)
. 1 (16) , 2 =
· Ulnar MCV by >10% in 7
THERAPY OF NEUROPATHY AND ANTI-MAG IgM
No.
No (%)
Therapy
treated improved
________________________________
Plasmaexchange
80
36 (45%)
Chlorambucil
78
31 (40%)
Steroids
46
18 (39%)
Cyclophosphamide
38
18 (47%)
IVIg
45
8 (18%)
Interferon
32
9 (27%)
Fludarabine
27
14 (52%)
5/16 (31%) in one trial
Rituximab
16
10 (62%)
double dose
8
4 (50%)
Cladribine
1
1
Other therapies
7
1 (14%)
________________________________
Total patients
378
150 (40%)
Anti-neural IgM antibodies in PN+IgM
Abs
MAG
GM1
GM2
GD1a
GD1b
Sulfatide
Disease (No.)
75
47
9
7
10
6
MMN (41)
12 (29%) 4 (10%)
1
1
CIDP (57)
6 (10%)
1
1
2 (3%)
Lewis Sumner (5)
1
PN+IgA (2)
PN+IgG (23)
2 (10%)
PN+IgM(166)
75 (45%) 10 (6%)
1
3 (2%)
4 (2%)
6 (4%)
POEMS (8)
2 (25%)
1
1
1
Other PN (89)
2 (3%)
Unknown PN(64)
3 (3%)
Monon. mul. (9)
1
Radic-plexop.(21)
3 (14%)
MND (63)
6 (9%)
2 (3%)
2 (3%)
Nobile-Orazio et al. 2008
Total 539
Response to immune therapies in
patients with PN + IgA MGUS
Responding/
Authors
treated
Therapy
Bosch et al. 1982
0/1
Steroids, PE, Azathioprine
Hemachudha et al 1989
1/1
PE
Yeung et al. 1991
3/3
Steroids (1+IS)
Simmons et al. 1993
3/3
Steroids (1 +IVIg)
Farrer et al. 1996
1/1
Steroids (PE uneffective)
Ponsford et al. 2000
0/1
nk
Mehndiratta et al 2004
1/1
Steroids
Our series
0/4
Steroids
Total
9/15
Response to immune therapies in PN+IgG MGUS
No. of
No. responding
Authors
Pats.
Demyel.
Axonal
Therapy
Contamin 1976
1
1/1
Steroids
Read 1978
3
2/3
Steroids (1+IS)
Noring 1980
2
1/1
Steroids
Dalakas 1981
7
4/4
IS (3 +steroids)
Bosch 1982
1
1/1
Steroids+IS+PE
Fineman 1990
1
1/1
PE
Yeung 1991
11
4/5
Steroids (1 + IS, 1+ IS & PE)
Waterston 1992
1
1/1
IS
Moorhouse 1992
1
0/1
Steroids
Bleasel 1993
5
5/5
Steroids+IS, PE
Notermans 1996a
11
0/3
Steroids +IS
Notermans 1996b
5
4/5
Steroids +IS
Hermosilla 1996
14
4/4
0/3
IVIg(1+1PE,2+IS)/Steroids(1+IS)
Gorson 1997
16
15/20§
3/12§
Steroids, PE, IVIg,
Di Troia 1999
17
6/8
1/3
Steroids,PE,IS,IVIg/Steroids
Ponsford 2000
8
6
Steroids (5)
Gorson 2002
20
5/7
3/13
IVIg
Total
124
54/67
7/34
(81%)
(21%)
§ including patients with IgM MGUS; IS: immunosuppressants; PE: plasma exchange;
Immunological findings in PN + IgG MGUS
No.
IgG deposits in nerve/
Authors
pats.
IgG anti-neural reactivity
Dalakas et al 1981
7
Light chain deposits on blood vessels in 3
Sewell et al 1981
1
IgG deposits/reactivity with nerve myelin
Bosch et al 1982
1
IgG deposits on myelin sheaths
Fazio et al 1992
3
IgG reactivity with 68kD neurofilaments
Moorhouse et al 1992
1
IgG deposits on endoneurium/vasanervorum
Bromberg et al 1992
17
Ig reactivity with MAG in 2
Bleasel et al 1993
5
IgG reactivity with myelin/Schwann/vasa in 3
Vrethem et al 1993
3
IgA reactivity with MAG in 1
Di Troia et al 1999
17
Ig reactivity with various neural antigens in 7*
Ponsford et al 2000
11
No anti-neural reactivity in any
Eurelings et al 2001
25
Anti-GQ1b Ig in 1
Total
91
IgG deposits in 3
IgG reactivity in 5
* A similar reactivity found in 13/35 patients with IgG MGUS without neuropathy
POEMS syndrome: diagnostic criteria
· Major criteria:
Polyneuropathy
Monoclonal plasma cell cell proliferative dis.
Sclerotic bone lesions
Castelman disease
VEGF elevation
· Minor criteria:
Organomegaly (hepatosplenomegaly or lymphadenopathy)
Edema (edema, ascites, pleural effusion)
Endocrinopathy (adrenal, thyroid, pituitary,
gonadal, paratiroid pancreatic)
Skin changes (Hyperpigmentation, hypertri-
chosis, plethora, hemangiomata, white nails)
Papilledema
Thrombocytosis/polycythemia,
Dispenzieri et al. Blood 2006
Neuropathy and Monoclonal Gammopathy
·Malignant monoclonal gammopathies
Multiple myeloma (overt, smoldering, etc)
Plasmocitoma (solitary, extramedullary)
Malignant lymphoproliferative diseases:
· Waldenström's macroglobulinemia
· Malignant lymphoma
· Chronic lymphocytic leukemia
Heavy chain diseases
Amyloidosis (AL) (Primary, +myeloma)
· Monoclonal gammopathy of undetermined
significance (MGUS)
Prevalence of neuropathy in patients
with IgM monoclonal gammopathy
Diagnosis
No.
No. with PN
% with PN
studied
IgM MGUS
31
14
45%
IWM
24
8
33%
WM
10
4
40%
Total IgM
65
26
43%
19 clinical PN
29% clinical PN
Baldini et al 1994
J Neuroimmunol 2008, 193:87-93
1. Four cats immunized with SGPG
developed high titers of anti-
MAG/SGPG IgM antibodies.
2. All four cats developed clinical
signs of sensory and motor
neuropathy within 11 months
from immunization.
3. Pathology revealed sensory
ganglionitis with inflammatory
infiltrates in DRG. No nerve or
root pathology.
JPNS
2007,
12:102-7
· 13 pts with PN+anti-MAG
· 8 pts (62%) improved in
INCAT sens.& MRC score
& 7 (54%) in disability.
· Improvement correlated
with lower anti-MAG at
entry and follow-up.
Antibody reduction below
a critical level may be
necessary to achieve
improvement
Worsening of neuropathy under Rituximab
· 1patient with WM had acute worsening of pre-existing
neuropathy consistent with GBS during therapy with
Rituximab and fludarabine (Noronha et al 2006)
· 1patient with NHL in complete remission developed GBS
during Rituximab maintenance therapy(Carmona et al 2006)
· 1patient with NHL developed GBS soon after combined
CHOP and Rituximab therapy (Terenghi et al 2007)
· 3patients with neuropathy with anti-MAG (Broglio et al
2005; Renaud et al 2003) or -ganglioside (Rojas-García et al
2003) IgM M-protein had severe worsening of neuropathy
within one month after treatment with Rituximab.
· 1patient with WM & mild sensory PN evolved into severe
vasculitic mononeuritis multiplex with conversion of type I
to II cryoglobulin during Rituximab (Mauermann et al 2007)
2010 EFNS/PNS PDN GUIDELINES
Good practice points for treatment of IgM PDN
1. In patients without significant disability there is no
evidence that immunosuppressive/modulatory treatment is
beneficial. Patients may be offered treatment for tremor
and paresthesia, and reassurance that symptoms are unlikely
to worsen significantly for years.
2. In patients with significant chronic or progressive disability,
immunosuppressive/modulatory treatment may be
considered, although none are of proven efficacy. IVIg or PE
may be considered, but benefit may be short term and
repeated treatments may be required. To achieve longer-term
benefit, clinicians have used rituximab, cyclophospha-mide
with prednisolone, fludarabine, and chlorambucil. All
remain unproven and all have risks which must be balanced
against any possible benefits.
JNNP 2010; 15: 185-195
PN associated with anti-Sulfatide IgM
Authors, years
Clinical presentation of PN
Pathology
Pestronk et al, 1991
S (Pan or SF), S>M, SM
+/- IgM-M
Axonal
Demyelinating
Lopate et al, 1997
Normal
Ilyas et al, 1992
NK (PN)
+ anti-MAG IgM
Demyelinating
Quattrini et al, 1992
S, SM
Axonal
Demyelinating
Nemni et al, 1993
S
Axonal
van den Berg et al, 1993
S, SM
+/- anti-MAG/SGPG IgM
Axonal
Demyelinating
Eurelings et al, 2001
Nobile-Orazio et al, 1994
SM
+/- IgM-M
Demyelinating
Carpo et al, 2000
Petratos et al, 2000
SM
Demyelinating
Erb et al, 2000
S, SM
Axonal
Dabby et al, 2000
S (Pan or SF), SM
+/- IgM-M
Axonal
Demyelinating
Normal
8 patients (2 with IgM-
MGUS) with chronic S or
S>M, mostly axonal PN
Neurology 1991
AGE
HPTLC
Multifocal Motor Neuropathy
Rare disorder characterized by:
· progressive, predominantly
distal, multineuropathic limb
weakness, usually more
pronounced in the arms;
· minimal or no sensory loss;
· multifocal persistent partial
motor conduction block.
· Frequent (30-50%) association
with anti-GM1 IgM antibodies
· 80% of patients respond to Ig
NEUROPATHY ASSOCIATED WITH IgG-MGUS
SUMMARY
In patients with a CIDP-like neuropathy the
detection of IgG MGUS does not justify a
different clinical classification or a different
therapeutical approach from CIDP-I.
The old age and frequent presence of other
possible causes for the neuropathy in patients with
sensory or sensorimotor axonal neuropathy and
IgG MGUS may be consistent with a coincidental
association, and is probably not sufficient per se to
warrant the use of immune therapies.
Immunological findings in PN+IgA MGUS
Authors
No. Ig neural reactivity/deposits in nerve
Dhib-Jalbut 1986
1
IgA anti-endoneurium by IIF and to several
myeloma
protein bands by immunoblot
Bailey 1986
1
Myelin and endo-perineurial deposits of IgA
Nemni 1991
3
IgG to 68kD NF/axonal deposits of IgG
Farrer 1996
1
Polyclonal IgA anti-LM1 & IgM anti-MAG
Vallat 2000
1
WML with myelin deposits of IgA and C3d
Mehndiratta 2004
1
Myelin deposits of IgA
Ponsford 2000
1
No anti-neural reactivity
Eurelings 2001
2
No anti-neural reactivity
Our series
14
No IgA reactivity in 14/no IgA deposits in 1
Total
25
IgA deposits in 3
anti-neural Ig in 6 (1 IgA-M)
NEUROPATHY ASSOCIATED WITH IgA-MGUS
SUMMARY
The very small number of reported patients with PN
and IgA MGUS and their etherogeneous clinical
presentation do not permit to establish a clinical
phenotype for this PN.
Even if anti-neural reactivity or endoneurial deposits
of IgA M-proteins and response to immune therapy
have been occasionally reported suggesting, at least in
some patients a possible immune pathogenesis for the
PN, in our opinion the mere finding of IgA MGUS
in a patient with PN is not sufficient to support the
immune pathogenesis and therapy for the PN.
LONG-TERM PROGNOSIS OF PN & ANTI-MAG IgM
(Nobile-Orazio et al, Brain 2000)
At entry
At last follow-up
No. of patients (M/F):
26 (22/4)
25 (96%)
Mean age at PN onset:
61.2 (42-78)
73.3 (58-84)
Years of follow-up:
8.5 (2-13)
Mean years from PN onset :
3.4 (0-10)
11.8 (3-18)
Median Rankin score
1 (0-3)
2 (1-5)
Walk+support/or unable/tremor
2/0/0
6/1/5
Total disabled (Rankin>2):
2 (8%)
11 (44%)
(24%at 10 yrs;
50%at 15 yrs)
Patients deceased:
8(32%)
6% at 10,33% at 15 yr)