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Paraproteinemia related neuropathies
neuropathies
Eduardo
Eduar
Nobile-Orazio
Dept. Neurological
Neur
Sciences, Milan University
2° Neurology
Neur
,
ology IRCCS Humanitas Clinical
Clinical Institute,
Rozzano, Milan, Italy

Monoclonal Gammopathy and
and Neuropathy
Kelly et al 1981
Causes of PN in 692
28 patients (8%) with
patients at May
pyo Clinic:
idiopathic PN (
p(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 di
diseases
5%

Prevalence of clinical neuropathy in
different monoclonal gammopathies
Ot
Osteo l
sc eroti
tic
l
mye oma (POEMS)
(POEMS)
50-85%
WM
30-50%
MGUS
5-37%
Amyloido
Am
sis
yloido
(AL)
(AL)
10-20%
Cryoglobulinemia
7-15%
Multiple myeloma
3-14%
Lymphoma
Lym
2-8%

Type and mechanism 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
y(
) (+
( MM)
Activation of VEGF (POEMS)
Drug related toxicity (often painful)
M-protein reactivity with nerve (IgM PCD)
Unknown (MGUS, mostly IgG & IgA)

Prevalence of neuropathy in MGUS
Authors
No. of
Clinical
Subclinical
Total
patients
PN
PN
PN
Osby et al 1982
21
24%
48%
71%
Krol et al 1985
19
5%
5%
11%
Nobile-Orazio
74
8%
8%
16%
et al 1991
Vrethem et al
19
37%
16%
53%
1993

Prevalence of PN in MGUS in relation to isotype
No. of
Clinical
Subclinical
Total
patients
PN
PN
PN
Total MGUS
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 t
a our I tit
ns
t
u e (1984
(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
MAG/SGPG/P0 50%
S>>M
(DADS-M)
(Katz et al 2000)
Sulfatide
6%
S; S>M; SM
Ax or Dem
Pestronk et al 1991
Sulfatide
GQ1b+Disyalo
2%
S>M
Dem
Ilyas et al 1986
(CANOMAD)
(Willison et al 2000)
ll
l
GD1a
3%
M; M>S
Dem
Bollensen et a 1989
GM2
2%
M; M>S
Dem
Ilyas 1988
GM2
;
y
GM1
<2%
M; LMNS
Focal Dem
Latov et al 1988
(MMN)
(Pestronk et al 1988)
ChS-C
<2%
SM
Axonal
Sherman et al 1983

PN ASSOCIATED
ASSOCIA
WITH ANTI
ANTI--MAG
MAG IgM
N Eng J Med, 1980

PREVALENCE OF NEUROPATHY
ASSOCIATED
ASSOCIA
WITH ANTI-
ANTI MAG IgM
IgM
· Monoclonal gammopathies (MG) occur
in 1% of pop
ppulation > 50 years (3% > 70
years);
· 1
10
0--20
20%
% of MG are IgM (100
(100--20
200/
0/
100,000 > 50 years
years);
);
· 15
15--3
30%
0% of IgM MG patients have PN
(15-60/100,
60/100 000);
· 40
40--50%
50% of PN +IgM MG patients have
anti
anti-
a
-MAG
MA
Ig
GgM:
M
The prevalence
pr
of PN+anti
PN+anti--MAG
MAG
Ig
I M in the p
gpopulation >50 years
may be at least 10/100,000

PN ASSOCIATED
ASSOCIA
WITH ANTI
ANTI--MAG
MAG IgM
Hl
Homogeneous c i
lini l
ca and l
e
t
ec
h
rop
i
ys l
o ogi l
ca features:
slowly progressive, distal, symmetric, predominantly
sensory, demyelinating
demyelinating neuropathy (DADS
(DADS phenotype)
MAG + (42)
MAG - (26)
p
Type
Type of PN
S or S>M
62%
31%
< 0.025
SM
31%
38%
ns
n.s.
M>S
7%
31%
< 0.01
NCS Peroneal
Per
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

LONG-TERM PROGNOSIS OF PN & ANTI-MAG IgM
(Nobile
(
-
Nobile Orazio et al, Brain
Brain 2000)
At entry
At last follow
follow--up
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
(0--3)
3)
2 (1
(1--5)
5)
Walk+support
alk+support/or
/or unable/tremor
2
2/0/0
/0/0
6
6/1/5
/1/5
To
T tal
o
disabled (Rankin>2):
(Rankin>2):
2 (8%)
11
11 (44%
(44%))
(24%at 10 yrs;
50%at 15 yrs)
yrs
Patients deceased:
8(32%)
6% at 10,33% at 15 yr)

Pathogenetic role of anti
anti--MAG
MAG IgM
1. Anti-MAG IgM almost always
associated with PN or predict
its onset
2. Clinical & electrophysiological
homogeneous features of the
neuropathy;
3. Pathological evidence of
demyelination with IgM &
complement deposits in nerve;
4. Complement mediated nerve
demyelination induced in
animals by anti MAG IgM;
5. Improvemt correlates with
reduction of anti-MAG IgM

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
29
18 (62%)
double dose
8
4 (50%)
Cladribine
1
1
Other therapies
7
1 (14%
14 )
%
________________________________
Total patients
391
158 (40%)

EFFECTS OF CYTOSTATIC
CYTOSTATIC--IMMUNE
IMMUNE
THERAPIES IN PN &A
& NTI-
ANTI MAG IgM
IIgM
Pts. treated for >6 mos:
19 (15)
(for the PN)
()
Mean yrs of therapy:
4 (0.5
(0.5--11)
11)
P
Patients
atients improved:
9 (%
(47
(
)
(%
%)
Patients with
with therapy
therapy--
10 (53%)
related complication
complications:
s:
2 piastrinopenia (CTX)
4 H.Zoster (Chlor)
1 hepatitis (Chlor)
1 severe hypotension (PE)
2 ac. l
k
eu
i
em a (dec.
(d
)(Chlor)
1 pulm. edema (dec)(Steroids)
Nobile
Nobile--Orazio
Orazio et al 2000

RCT in PN &
&anti
anti--MAG
MAG IgM
·
Dyck et al. 1991: PE (2/wk x 3 wks) vs sham exchange; double-blind
39 PN+MGUS (21 IgM); PE effective in IgG/IgA, not IgM MGUS
·
Oksenhendler et al.1995: Chloranbucil (Ch) +/- PE (15 in 4 mos); open
44 PN+IgM (33 MAG); No difference between Ch and Ch+PE
·
Dalakas et al 1996: IVIg vs placebo x 3 mos; double
double--blind,
blind, cross
cross--over
over
11
1 PN+IgM (9 MAG); IVIg
IVIg effective in 2 IgM ((18%)
18%) (1 MAG, 11%)
·
Comi et al 2002:
2002 IVIg vs placebo x1m
x 1
o
x1m s
o ;
mos double-blind,
blind cross
ccross-over
22 PN
PN+
+IgM
IgM ((11/19
11/19 MAG)
MAG);; IVIg slightly better (p=0.05) than placebo
·
Mari tt
e e t
e
l
a 1997: IFN- vs IVIg x 12 mos; open
20 PN+MAG; Sensory improvement in 8/10 IFN- and 1/10 IVIg
·
Mariette et al 2000: IFN- vs placebo x 6 mos; double blind
24 PN+MAG; No difference between IFN- and placebo.

THERAPY OF NEUROPATHY AND ANTI-MAG IgM
No.
No (%)
Therapy
treated improved
________________________________
Plasmaexchange
80
36 (45
(4 %)
5
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
29 18 (62%
(
)
double dose
8
4 (50%)
Cladribine
1
1
Other therapies
7
1 (14%
14 )
%
________________________________
Total patients
391
158 (40%)

RITUXIMAB (-CD20 MAB)
IN PN AND ANTI-MAG IgM
Renaud et al 2003 Muscle Nerve
· 9 pts with PN & anti-AG
· Rituximab 375mg/m2/wk x 4
· B cells decreased in all
· IM
IgM in l
a l
ll by 35% to 82
82 %
· Anti-MAG by > 50% in 8/9
· NDS in 6 (<5 in 4, >10 in 2)
. 1 (16) , 2 =
· Ulnar MCV
MCV by >10%
>
in 7

JPNS
2007,
12:102-7
· 13 patients with PN & anti
anti MAG
-
IgM
IgM M
-
protein
-
.
· Anti-MAG IgM significantly reduced after 1 year.
· 8 patients
patients (62%)
(62%) impro
impr ved in INCAT
INCA sensor
sensory & MRC
score and 7 (54%) in disability too.
· Improvement
Impr
in INCAT
INCA sensory
sensory sumscore correlated
corr
with lower anti-MAG titres at entry and at follow-up.
Antibody reduction below
below a critical
critical level may be
be
necessary to achieve clinical improvement

Terenghi et al, JPNS 2007; 12;142-3

Worsening of neuropathy under Rituximab
· 1 patient with WM had acute worsening of pre-existing
neuropathy consistent with GBS during therapy with
Rituximab and
and fludarabine (Noronha
(Nor
et al., 2006)
· 1 patient with NHL in complete remission developed GBS
during Rituximab maintenance therapy
therapy(Carmona et al 2006
· 3 patients with neuropathy & IgM M-protein with anti-MAG
(Broglio et al, 2005; Renaud et al., 2003) or anti-ganglioside
(Roj
G
as- ar í
c a et l
a ., 2003) IM
IgM h d
a severe
di
and progressive
worsening of neuropathy within one month after
treatment with Rituximab.
· 1 patient with WM & mild sensory neuropathy evolved to
severe vasculitic mononeuritis multiplex with conversion of
tI
type I to type II
II cryoglobuli
linemia during Rituximab therapy
(Mauermann et al., 2007)

Immuntherapy for PN & anti
anti-- MAG
MAG IgM
Lunn MPT & Nobile
Nobile--Orazio
Orazio E
The Cochrane Library 2006, Issue 1
Reviewers' conclusion:
· There is
is inadequate
inadequate reliable evidence from trials
trials of
immunotherapies in anti
anti--MAG
MAG neuropathy to
recommend any
an particular
p
yp
immunotherapy
immunotherap .
py
y
· IVIg is relatively safe a may produce some short
short--
term benefit.
· Large randomised trials of at least 12 months
duration are required to assess the efficacy of
it
exi
ex s i
ting
ti
or novel th
therap
th
ies.

Good practice points for treatment of
IgM PDN
PDN
1.
In patients without significant disability, consideration
should be
be given
given to withholding immunosuppressive or
immunomodulatory treatment, providing symptomatic
treatment for tremor and paraesthesiae, and giving
reassurance that symptoms are unlikely to
to worsen
worsen
significantly for several years.
2.
In patients with sig
pgnificant disability or rapid worsening,
g,
IVIg or PE should be considered as initial treatment,
although their efficacy is unproven.
3.
In
ii
patients wi h
t moderate or severe di
di b
sa ili
bility,
immunosuppressive treatment should be considered,
although its long term efficacy remains unproven.
Preliminary reports suggest that Rituximab may be a
promising therapy.

Neuropathy associated with anti-
disyalosil IgM M-proteins
· Chronic
· Ataxic
· Neuropathy (S>>M)
· Ophtalmop
pplegia
· M-protein
· Agglutinins (cold)
(cold)
· Dysialosil antibodies
Willison et al 2001

Neuropathy and IgG MGUS
Pats. No.
Clinical PN
Subclinical PN
Total PN
IM
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 I
+ gG MGUS
Reported
Type
T
of progre
prog ss
s i
s on
i
ENG
EN
cla
cl ssi
ass f
i ic
i atio
cati n
o
patients relaps/remitt progressive Dem
Ax Mixed
205
54
127
94
65
13
Pats No.
CIDP-like
Sensorimotor or
(Authors)
(M>S/S>M/SM) sensory axonal PN
17
10
7
(Di Troia 1999)
(7/2/1)
()
(5/2)
14
5
9
()
(Hermosilla 1966)
(0/0/5)
(4/5)

Time relationship between IgG
MGUS and PN
PN
CIDP like
Sensory
Sensor
(10)
axonal (7)
MGUS bef. PN
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
PN

Response to immune therapies in PN+IgG MGUS
No. of
No. responding
At
Au h
thors
Pt
Pats.
Dl
Demyel.
Al
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
(1 + IS
IS, 1+
1+ IS
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
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;

NEUROPA
NEUROP T
A HY
T
A
ASSOCIATED
SSOCIA
WITH IgG
IgG--MGUS
MGUS
PN is unfrequent in patients with IgG MGUS, but is less
etherogeneous than expected from a casual association
consisting in two main clinical forms:
1. A chronic progressive or relapsing demyelinating PN
(moderate to severe) clinically indistinguishable from
CIDP and frequently
fr
re
r sponding to immune therapy;
therapy
2. A slowly progressive sensorimotor or sensory axonal
PN (usually mild), seldom responding to immune therapy;
In both cases there is little evidence that the M-protein
play a primary
primary pathogenetic role
role in
in neural
neural damage.

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%) (1 POEMS)

Clinical and electrophysiological
electrophysiological
features of PN+IgA MGUS
Tf
Type of imp i
a rment ENG
EN
l
c assififi t
ca ition
Patien
tie ts No. S, S>M SM
S
M, M>S
,S DemA
e
x Mixed
Reported 21
4124
10
6
4
Our
61
3
2
2
2
2

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

NEUROPA
NEUROP T
A HY
T
A
ASSOCIATED
SSOCIA
WITH IgA
IgA--MGUS
MGUS
SUMMARY
SUMMAR
The very small number of reported patients with PN
and IgA MGUS and their etherogeneous clinical
presentation do not permit
permit to establish a clinical
phenotype for this PN.
Even if anti-
anti neural reactivity or
or endoneurial
endoneurial deposits
deposits
of IgA M-proteins and response to immune therapy
have been occasionally reported suggesting, at least in
some
ti
pa ents a possibl
ible immune
t
pa h
th
i
ogenes s for th
the
PN, in our opinion the mere finding of IgA MGUS
in a patient with PN is not sufficient to supp
ppport the
immune pathogenesis and therapy for the PN.

Department of
Fabrizia Terenghi
Nl
Neurolo i
gical Sciences,
Gianluca A d
r oli
lino
IRCCS Humanitas
Chiara Casellato
Clinical I tit
ns ute
Barbara Bossi
Milan University,
RMil
Claudia Giannotta
Rozzano, Milan,
Claudia Giannotta

Type and mechanism 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
y(
) (+
( MM)
Activation of VEGF (POEMS)
"Paraneoplastic" (anti-amphyphisin abs) (HL)
M-protein reactivity with nerve (IgM PCD)
Unknown (MGUS, mostly IgG & IgA)

18 patients
14 M, 4 F
Age at onset:
28-72 (M: 53)
Chronic Ataxic Neuropathy (S>>M):
Motor impairment: none (4), mild (10), substantial (4)
Ataxia: none (2), mild (6), substantial (10)
Ophtalmop
pplegia: none (2)
() or mild (12
(
),
), substantial(4)
()
Course: relapsing in 13, progressive in 5
IgM M-protein (MGUS): 17
Cold Agglutinins:
A
9 patients
patients
Anti-Dysialosil abs: by definit.(GD1b:16; GD3:14; GT1b:14; GQ1b:17)
ENG: definite/probable Demyelinating PN 11; axonal 6
Nerve (3) or DRG biopsy (1): no IgM deposits, Inflamm. in 1
CSF: proteins increased in 11/16

TREATMENT
TREA
OF NEUROPA
NEUROP T
A HY
T
ASSOCIATED
ASSOCIA
WITH ANTI-MAG IgM
IgM
SUMMARY
SUMMAR
Until therapies with a better efficacy/safety profile become
available the following approach can be proposed:
Symptomatic therapy for tremor and paresthesias and
reassurance on the usually good prognosis for several years
may be sufficient in patients not impaired in their daily
py life
f
Due to its safe profile and efficacy plasma exchange may be
probably preferred as first line treatment during worsening or
in slightly impaired patients
Immune/cytostatic therapies should be reserved for at least
moderately impaired patients in whom Rituximab is now
probably the preferred option.

Neuropathy and
and Monoclonal Gammopathy
Gammopathy
·Malignant monoclonal gammopathies
Multiple myeloma (overt, smoldering, etc)
Plasmocito
Plasmocit ma (solitary,
t
ex
d
rame ull
)
ary
Malignant lymphoproliferative diseases:
· Waldenström's macroglobulinemia
· Malignant lymphoma
· Chronic lymphocytic leukemia
Heavy chain diseases
Amyloidosis (AL) (Primary, +myeloma)
·
Monoclonal gammopathy of undetermined
significance (MGUS)

Immunological findings in PN + IgG MGUS
N o.
IgG anti-neural reactivity/
Authors
pats.
IgG deposits in nerve
D alakas et al 1981
7
Light chain deposits on blood vessels in 3
Sl
S ew e l
ll et al 1981
1981
1
IG
IgG deposit
its/reacti
tivit
ity w it
ith nerve m yeli
lin
B osch et al 1982
1
IgG deposits on m yelin sheaths
Fazio et al 1992
3
IgG reactivity w ith 68kD neurofilam ents
M oorhouse et al 1992
1
IgG deposits on endoneurium /vasanervorum
B rom berg et al 1992
17
Ig reactivity w ith M AG in 2
B leasel et al 1993
5
IgG reactivity w ith
with m yelin/S chw ann/vasa in 3
V rethem et al 1993
3
IgA reactivity w ith M AG in 1
D i Troia et al 1999
17
Ig reactivity w ith various neural antigens in 7*
P onsford et al 2000
11
Nt
N o an i
tin-neural reacti
tivit
ity in any
E urelings et al 2001
25
Anti-G Q 1b Ig in 1
Total
91
23
(IgG reactivity in 5/ IgG deposits in 3)
* A sim ilar reactivity found in 13/35 patients w ith IgG M G U S w ithout neuropathy

Immunological findings in PN+IgA MGUS
Authors
No. Ig neural reactivity/d
/ eposits in nerve
Dhib-Jalbut
1
IgA anti-endoneurium by IIF and to several
1986
myeloma
m
prot
pr e
ot in
i ba
bands
nds by immunobl
m
ot
Bailey 1986
1
Myelin and endo-perineurial deposits of IgA
Nem
Ne n
m i 1991
1991
3
Ig
IgG to
to 68kD
68kD NF/a
NF xona
/a
l
xona de
deposi
posits
ts of
of IgG
IgG
Farrer 1996
1
Polyclonal IgA anti-LM1 & IgM anti-MAG
Vallat
Vallat 2000
1
WML with
with my
myelin
elin de
deposits
posits of
of IgA and
and C3d
Ponsford 2000
1
No anti-neural reactivity
Eurelings 2001
2001
2
No anti
an -
ti neural
r
reactivity
Our series
14
No IgA reactivity in 14/no IgA deposits in 1
Total
23
Ig deposits in 5 (2
(2 IgA)/
IgA)/
anti-neural Ig in 6 (1 IgA-M)

Response to immune therapies in
patients with PN + IgA MGUS
Re
R s
e p
s ondi
p
ng/
ondi
Authors
treated
Therapy
Bos
Bo c
s h
c et
et al
al. 1982
1982
0/1
0/
Ste
St r
e o
r i
o d
i s
d , PE, Aza
Az t
a h
t i
h o
i p
o r
p i
r n
i e
n
Yeung et al. 1991
3/3
Steroids (1+IS)
Sim
Si m
m o
m n
o s
n et
et al
al. 1993
1993
3/3
3/
Ste
St r
e oi
ro ds
ids (1
(1 +IV
+I I
V g)
Ig)
Farrer et al. 1996
1/1
Steroids (PE uneffective)
Pons
Pon f
s o
f r
o d
r et
et al
al. 2000
0/1
0/
nk
Our series
0/4
Steroids
Tot
To a
t l
a
7/13
7/

PLASMA EXCHANGE IN PN AND MGUS
Dy
Dyck
ck et al N Eng J Med 1991
· 39 patients with
w
with PN+MGUS (18 IgG/IgA
IgG/IgA,
IgG/IgA 21 IgM)
· Randomised, double
double--blind,
blind, placebo
placebo--controlled
controlled -->
> open
· Plas
a ma
m
Plasma (2PE/
E wkx3w
w
(2PE/wk x 3
k
kx3w s)(19p
wks)(19 ts)v
pts) ss
vs ham
a
sham ex
e ch
c an
a ge
exchange
(20 pts)(sham followed by PE in open)
· PE improved NDS, weakness & sCMAP
sCMAP more than
sham both in the double
double--blind
blind and open trial
· Patients with
w
with IgG/IgA better
better than
than those
those with
w
with IgM in
in
both the double
double--blind
blind and open trial
PE i
sig
s
i
n fi
iificant
ifi
lly eff
fffect
ff
ive
i
in
i PN+I G/I A
PN+IgG/IgA MGUS
MGUS

NEUROPA
NEUROP T
A HY
T
A
ASSOCIATED
SSOCIA
WITH IgG
IgG--MGUS
MGUS
SUMMARY
SUMMAR (2)
In patients with a CIDP-like neuropathy the detection
of IgG MGUS may represent a
kf
marker of a
dysimmune origin of the neuropathy, but does not
justify a diff
dif erent
f
clinical
clinical classification or
or a diff
dif erent
therapeutical approach from CIDP-I.
The old age and the freq
gquent 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
use of immune therapies in these patients
patients.

THERAPY OF NEUROPATHY AND ANTI-MAG IgM
No.
No (%)
Therapy
treated improved
________________________________
Rituximab
12
7 (64%)
double dose
7
4 (57%)
Cyclophosphamide
24
13 (54%)
Fludarabine
27
14 (52%)
5/16 (31%) in one trial
Plasmaexchange5
g
2
26 (50%)
Steroids
38
18 (47%)
Chlorambucil
76
31 (41%)
Interferon
24
8 (33%)
IVIg
26
5 (19%)
Cladribine
1
1
Other therapies
5
1 (20%
20 )
%
________________________________
Total patients
268
128 (48%)

Predictors of response to Rituximab in patients
with neuropathy and
and anti-MAG IgM
IgM
L Benedetti, C Briani, M Grandis, T Vigo, M Gobbi, E Ghiglione, M Carpo,
D Cocito, C Caporale, M Sormani, G Mancardi, E Nobile-Orazio, A Schenone
·13 patients with neuropathy and anti-MAG IgM-M-protein.
·Anti-MAG IgM titres significantly reduced after 1 year.
·8 patients (62%) improved in both the INCAT sensory and
MRC sumscore and 7 (54%) also in INCAT disability score.
·Impr
·
ovement
Impr
in INCAT
INCA sensory
sensory sumscore correlated
corr
with
lower anti-MAG antibody at entry and at follow-up.
·Rituximab is efficacious in the majority
jy of patients
p
particularl
p
y
on sensory impairment and in those with moderately elevated
antibody titers.
·Antibody
·
re
r duction below a critical level
level may be
be necessary
necessary
to achieve clinical improvement.
JPNS 2007, 12: 102-7

GUILLAIN-BARRE' SYNDROME AFTER CHOP &
RITUXIMAB THERAPY IN NON-HODGKIN LYMPHOMA
Terenghi et al, JPNS 2007

Worsening of neuropath
gp
y under Rituximab
· One patient with Waldenström's macroglobulinemia
had acute worsening of
of pre
pre-existing neuropathy
consistent with GBS during therapy with Rituximab
and fludarabine (Noronha et al., 2006)
()
· Three patients with neuropathy & IgM M-protein with
anti-MAG (Brog
(glio et al, 2005; Renaud et al., 2003) or
anti-ganglioside (Rojas-García et al., 2003) IgM had
severe and progressive worsening of neuropathy
within one month
month after tre
tr atment
eatment with Rituximab.
· One patient with NHL in complete remission
developed GBS
GBS during Rituximab
Rituximab maintainance
maintainance therapy
therapy
(Carmona et al., 2006).