Le neuropatieimmunomediate: cosa fare nei pazienti non responsivi alle terapie convenzionali?

1. 12° CONVEGNO
PATOLOGIA IMMUNE E
MALATTIE ORFANE 2009
Torino, 22-24 gennaio 2009
Le neuropatie
immunomediate: cosa
fare nei pazienti non
responsivi alle terapie
convenzionali?
Eduardo Nobile-Orazio
Dip. Scienze Neurologiche,
Università di Milano,
Centro Congressi Torino
Neurologia 2, IRCCS Istituto
Incontra
Clinico Humanitas
Via Nino Costa, 4 – Torino

2. IMMUNE-MEDIATED NEUROPATHIES
I. Idiopathic neuropathies
1 Guillain Barré Syndrome (GBS):
• Acute inflammatory demyelinating polyneuropathy (AIDP)
• Acute motor (-sensory) axonal neuropathy (AMAN & AMSAN)
• (Miller) Fisher Syndrome and other regional or functional variants
2 Subacute inflammatory demyelinating polyneuropathy
3 Chronic inflammatory demyelinating polyneuropathy (CIDP)
• (?) chronic relapsing axonal form (CIAP)
4 Multifocal demyelinating (motorsensory) neuropathy (Lewis-Sumner)
5 Multifocal motor neuropathy (MMN)
II. Neuropathies associated with other disorders
6 Neuropathies associated with monoclonal gammopathies:
- IgG & IgA (?)
- IgM: anti-MAG; anti-sulfatides, -GM1, -GD1a, -GD1b, -ChSC,; antigen unknown
7 Paraneoplastic neuropathies:
- subacute sensory neuronopathy: anti-Hu (mostly in lung carcinoma);- not anti-Hu
- subacute motor neuronopathy in lymphoma (?)
8 Vasculitic neuropathies (?)

3. CHRONIC INFLAMMATORY
DEMYELINATING POLYRADICULO-
NEUROPATHY (CIDP)
Chronically progressive, stepwise, or recurrent
symmetric proximal and distal weakness and
sensory dysfunction of two or more extremities,
developing over at least 2 months; cranial nerves
may be affected
Absent or reduced tendon reflexes in all
extremities
Elevated cerebrospinal fluid protein with
leukocyte count < 10/mm3
Electrophysiological and/or morphological features
of a demyelinating neuropathy

4. List of presumed CIDP variants
Clinical
• DADS (Distal Acquired Demyelinating Symmetric)
• Pure sensory (ataxic) neuropathy
• Pure motor neuropathy
• Focal or multifocal neuropathy
• Lewis-Sumner syndrome (MDN; MADSAM)
• MMN (Multifocal Motor Neuropathy)
Pathological
• Axonal CIDP
Adapted from: Hahn et al (Dyck & Thomas, Peripheral Neuropathy
2005; Said (Neuromusc Dis 2006) & Koller et al (NEJM 2005)

5. CIDP AND CLINICAL VARIANTS
Rotta et al.
Cranial Neurop.
With CNS
J Neurol Sci 2000
5%
involv.
8%
RLS1%
Markedly
asymmetric CLASSIC
8% CIDP
46%
Pure Sensory
15%
Subclassification of chronic dysimmune
DADS 17%
neuropathies in 102 patients
87 pts. with AAN dem features in >
SENSORY
1 motor or > 2 sensory nerves MMN
MF S-M
ATAXIC
13%
(MDN)
(SENSORY
6%
CIDP)
5%
MOTOR
MOTOR
SENSORY
DEMYEL
(TYPICAL
(MOTOR
CIDP)
Bushby & Donaghy J CIDP)
70%
6%
Neurol 2003

6. Steroids
IVIG better
Steroid better
Steroid worse
IVIg

8. 1) Clinical Criteria: Inclusion
A Typical CIDP
Chronically progressive, stepwise, or recurrent symmetric proximal
and distal weakness and sensory dysfunction of all extremities,
developing over at least 2 months; cranial nerves may be affected
Absent or reduced tendon reflexes in all extremities
B Atypical CIDP
One of following but otherwise as in A (DTR may be normal in unaffected limbs)
Predominantly distal weakness (distal acquired demyelinating
symmetric, DADS)
Pure motor or sensory presentations including chronic sensory
immune polyradiculoneuropathy affecting the central process of the
primary sensory neuron.
Asymmetric presentations (multifocal acquired demyelinating
sensory and motor, MADSAM, Lewis-Sumner syndrome)
Focal presentations (e.g., involvement of the brachial plexus or of
one or more peripheral nerves in one upper limb)
CNS involvement (may occur in typical or atypical CIDP)

9. EVIDENCES FOR
IMMUNE PATHOGENESIS IN CIDP
• Pathological evidence of demyelination with macro-
phage and T cell infiltrates and Ig deposits in nerve;
• Association with HLA-B8 (HLA-CW7 & HLA-DR2);
• Increased circulating (Th1) cytokine levels;
• Similarity with chronic EAN in Lewis rat (P0, P2; T
cell mediated) & rabbit (myelin, GalC; ab. mediated);
• Passive transfer studies with serum (α-P0) of CIDP;
• Serum antineural reactivity in patients’ sera;
• Response to immune therapy (Steroids, PE, IVIg);

10. JNNP 1999;
66:677-680
• Prevalence of CIDP in SE England: 1.32/100.000 on 1/1/95
(3.5/100,000 in Piemonte on 31/12/2001; Chiò et al, JNNP 2007)
• On the prevalence date:
• Mean age: 54.4 years (range 10-95)
• Mean age of onset: 45.6 years (41.8 for RR, 50 for CP) (59.6)
• Mean duration of CIDP: 8.9 years (range 2-490 months) (7.3)
• 13% of patients required aid to walk (11.6%)
• 54% were still on treatment
• The average Rankin score at the worse relapse was 3.5
• 54% of patients had been severely disabled (Rankin
score 4 or 5) at some time during the illness (8.5%)

11. Treatment of CIDP
1. Indication for initiating treatment
2. Therapy for initial management
A. Steroids
B. Plasma exchange
C. IVIG
3. Therapy for long-term management
A. Steroids
B. Plasma exchange
C. IVIG
D. Immunosuppressive agents
E. Interferons
4. Dosage, regimen, and duration of treatment
5. General treatment
6. Patient’s support group

12. CORTICOSTEROIDS FOR CIDP
Mehndiratta MM & Hughes RAC
Cochrane Database of Systematic Reviews 2008 (4)
PLASMAEXCHANGE FOR CIDP
Mehndiratta MM, Hughes RAC, Agarwal P
Cochrane Database of Systematic Reviews 2008 (4)
IVIg FOR CIDP
van Schaik IN, Winer JB, de Haan R, Vermeulen M
Cochrane Database of Systematic Reviews 2008 (4)

13. OPEN ISSUES IN CIDP TREATMENT
What therapy should we first use
in CIDP (IVIg, steroids or PE)?
Which is the most effective therapy?
Which is the best tolerated therapy?
Which is the most convenient therapy?

14. Comparison of effective therapies in CIDP
20 patients; cross-over;
IVIg (0,4->0,2g/kg/wk x 6wks)
vs. PE (2->1/wk x 6 wks)
IVIg = PE
Ann Neurol 1994
24 patients; cross-over;
IVIg (2g/kg) vs Prednisolone
(60->10 mg x 6 wks)
IVIg =Prednisolone
Ann Neurol 2001
Steroids, PE & IVIg are similarly effective (~60%)
as initial therapy in CIDP

15. Italian Register for response to treatment
in CIDP patients
Cocito D, Paolasso I, Jann S, Benedetti L, Briani
C, Comi C, Fazio R, Mazzeo A, Sabatelli M,
Nobile-Orazio E.
Torino, Milano, Genova, Padova, Novara,
Messina, Roma.
Italian PNS meeting, Alba, April, 2008

16. Response to initial therapy in CIDP
Therapy Responder Non Respond. Side Effect
87 (64%) 49 (36%) 18 (13%)*
Steroids
136 (51%)
90 (78%) 25 (22%) 5 (4%)*
IVIg
115 (43%)
9 (56%) 7 (44%) 4 (25%)
PE
16 (6%)
186 (69%) 81 (31%)
TOTAL
267
* Steroids vs IVIg: p= 0.02

17. Advantage & Disadvantage
of Steroids and IVIg in CIDP
• Steroids • IVIg
– Pros: – Pros:
• Low cost • Well tolerated
• Easy oral assumption • Few side effects
• No need for hospital stay • Less contraindications
- Cons: – Cons
- Major side effects - High cost
especially on the long term - Repeated periodic hospital
- More contraindications access (1-2d/month)

18. EFNS/PNS Recommendations
1) Initial Treatment
1. Patients with very mild symptoms not or slightly interfering
with daily activities may be monitored without treatment.
2. IVIg or corticosteroids should be considered in sensory and
motor CIDP in presence of troublesome symptoms (Level B
recommend.). The presence of contraindications to either
treatment should influence the choice (Good Practice Point)
3. The advantages and disadvantages should be explained to
the patient who should be involved in the decision making
(Good Practice Point).
4. In pure motor CIDP IVIg should be considered as the initial
treatment (Good Practice Point)
5. If IVIg and corticosteroids are ineffective PE should be
considered (Level A recommendation)

19. What to do in CIDP patients not
responsive to conventional therapy?
Review the therapy
regimen prescribed

20. Dosage, Regimen & Duration of Treatment:
Steroids
1. Common initial doses of corticosteroids are prednisone
or predniso(lo)ne 1 mg/kg or 60 mg daily but there is a
wide variation in practice. There is no evidence and no
consensus about whether to use daily or alternate day
prednisone or prednisolone or intermittent high dose
monthly intravenous or oral regimens.
2. For patients starting on corticosteroids a course of up to
12 weeks on their starting dose should be considered
before deciding whether there is no treatment response.
If there is a response, tapering the dose to a low
maintenance level over one or two years and eventual
withdrawal should be considered.

21. Dosage, Regimen & Duration of Treatment:
IVIg
1. The usual first dose of IVIg is 2.0 g/kg (0.4 g/kg on 5
consecutive days). For patients starting on IVIg,
observation to discover the occurrence and duration of
any response to the first course should be considered
before embarking on further treatment. Between 15
and 30% of patients do not need further treatment.
2. If patients respond to IVIg and then worsen, repeated
doses should be considered. Repeated doses may be
given over one or two days. The amount per course
needs to be titrated according to individual response.
Repeated courses may be needed every 2 – 6 weeks.
3. If a patient becomes stable on a regime of intermittent
IVIg, the dose per course should be reduced before the
frequency of administration is lowered

22. Recommendations for Treatment
2) Maintenance Treatment
1. If the first line treatment is effective continuation should
considered until maximum benefit, then dose reduced to the
lowest effective maintenance dose (Good Practice Point).
2. If response is inadequate or maintenance doses are high,
combination treatments or adding immunosuppressant/
modulatory drug may be considered (Good Practice Point).
3. Advice about foot care, exercise, diet, driving and life style
management should be considered. Neuropathic pain should
be treated with drugs according to EFNS guideline (Attal et
al 2005, in preparation). Depending on patients’ needs,
orthoses, physiotherapy, occupational therapy,
psychological support and referral to a rehabilitation
specialist should be considered (Good Practice Points)
4. Information about patient support groups should be offered
to those who would like it (Good Practice Point)

23. Response to second therapy in CIDP
patients NR to initial treatment
1st Treat. 2nd Treat. No. Treated Responsive Intolerant
Steroids -> –> IVIg 38 0
21 (56%)
(N=43 )
–> PE 5 0
1 (20%)
IVIg -> –> STE 14 1 (7%)
6 (43%)
(N=14 )
PE - > –> STE 5 0
2 (40%)
(5 pt)

24. Risultati: pazienti NR
250
200
89 %
81 %
150
66%
NR
R
100
50
34%
19%
11%
0
I SCELTA SWITCH OL

25. What to do in unresponsive CIDP patients?
Reconsider the Diagnosis
1. POEMS
2. Osteosclerotic myeloma
3. Neural B-cell lymphoma
4. Amyloidosis
5. PN+ IgM anti-MAG
6. CMT1

26. Immunosuppressant and immunomodula-
tory drugs reported to be beneficial in CIDP
Class IV evidence (see Hughes et al. 2004)
1. Azathioprine
2. Cyclophosphamide
3. Ciclosporin
4. Etanercept
5. Interferon alpha
6. Interferon beta1a
7. Mycophenolate mofetil
8. Rituximab (anti-CD20)

27. Cytotoxic and Interferons for CIDP
Hughes RAC, Swan AV, van Doorn PA
Cochrane Database of Systematic Reviews 2004 (4)
• Reviewers’ conclusion:
• Only two RCT assessing the effect of azathioprine or
interferon beta have been performed in CIDP.
• The evidence is inadequate to decide whether
azathioprine, interferon beta or any other immuno-
suppressive drug or interferon is beneficial in CIDP.
• More research is needed to determine whether
immunosuppressive drugs or interferon are beneficial
for CIDP.

28. RCT OF AZATHIOPRINE IN CIDP
Dyck et al, Neurology 1985; 35: 1173-6
• 27 CIDP patients
• Randomized open controlled trial (not blind)
• Azatioprine (2mg/kg) + Prednisone (120mg/alt day
→ 0) versus Prednisone alone for 9 months
• No significant difference in any of the 16 parameters
examined between the two groups
BUT
1. Azathioprine Dose & duration insufficient
2. Only analyzed the adjunctive effect and not the
steroid-sparing effect of Azathioprine

29. AZATHIOPRINE IN CIDP
Open or retrospective studies
• Dalakas et al 1981: 3 mg/kg, improvement in 3/4
steroid resistant CIDP patients
• McCombe et al 1987: improvement observed in 4/7
CIDP patients
Total responder to Azathioprine 7/11 (64%)
Barohn et al 1989: 56/59 (95%) CIDP patients responded to
prednisone followed by azathioprine in case of relapse or poor
response: number treated with azathioprine not mentioned.
Simmons et al 1995: 8 of 50 treated patients with CIDP received
Azathioprine, results not mentioned
Monaco et al 2004: low dose azathioprine (1 mg/kg) and
Prednisolone (0.25-05 mg/kg) were mentioned to prevent relapse in
CIDP particularly in poor responders to IVIg but data not reported

30. CYCLOSPORINE IN CIDP
Open or retrospective studies
Hodgkinson et al 1990 & Barnett et al 1998:
• 14/14 CIDP patients treated with 10mg/kg (3-7)→5mg (2-3)
improved in disability or relapse rate; 11/19 (including 5 with
paraproteinemia) had side effects (4 nephrotoxicity & 4HBP)
Mahattanakul et al 1996:
• 3/8 (37%) CIDP patients poorly responsive or intolerant to
conventional therapy improved with Cys-A 3-5 mg/kg/d, and
could reduce or suspend PE or steroids.
Matsuda et al 2004:
• 7/7 CIDP patients poorly responsive to conventional therapy
improved in disability and grip strength within 3 months of
Cys-A 5mg/kg/d. None had side effects
Odaka et al 2005:
• 4/5 CIDP patients improved with Cys-A 3mg/kg/d.
Visudtibhan et al 2005:
• 2/2 steroid resistant CIDP children markedly improved in
strength and/or reduced relapses with Cys-A 5mg/kg/d.
Total responder to Cyclosporine 30/36 (83%)

31. CYCLOPHOSPHAMIDE (CTX) IN CIDP
Open or retrospective studies
• Oral:
• Prineas et al 1976: 4 patients had sustained improvement with
oral CTX 50-150 mg/d
• Dalakas et al 1981: 1 patient improved with oral CTX 2mg/kg
• McCombe et al 1987: 4/5 patients improved with CTX (dose
& route ?)
• Bouchard et al 1999: 0/2 patients unresponsive to Steroid,
IVIg & PE respond to oral CTX 2mg/kg x 6-12 months
• pulsed i.v.:
• Good et al, 1995: 1g/m2/mo x 6 mos effective in 11/15 (73%)
patients not responding to other therapies
• Branagan et al 2002 & Gladstone et al 2005: 200mg/kg in 4d
effective in 4/5 (80%) patients unresponsive to other therapies
Total responder to Cyclophosphamide 24/32 (75%)

32. MAJOR SIDE EFFECTS OF CYCLOPHOSPHAMIDE
High Dose Low Dose
Side effect (>6mg/kg/die,i.v.) (<3mgKg/die,oral)
____________________________________________________________
Nausea and vomit severe * mild
Hemorragic cystitis severe * microscopic hematuria
Leucopenia rapid onset * slow onset
Thromocytopenia severe but rare *
Hair loss alopecia * moderate
Mucosal ulceration severe *
Infection HZV & bacterial
Cardiotoxicity rare
Amenorrea rare, can be permanent same
Azoospermia rare, can be permanent same
Remote bladder cancer yes yes
Remote leukemia & lymphoma yes yes
SIADH rare
Liver toxicity, Pulmonar fibrosis rare
____________________________________________________________
With low CTX dose, most side effect are reversible

33. MYCOPHENOLATE MOFETIL IN CIDP
Open or retrospective studies
• Chaudhry et al 2001: 1/3 patients treated with MMF 2g/d
improved in strength and reduced steroids.
• Mowzon et al 2001: 2/2 patients improved in strength &
sensation, 1 relapsed at MMF suspension & improved at restart
• Benedetti et al 2004: 2/2 patients reduced IVIg by 50% without
deterioration and could suspend concomitant azathioprine
• Umapathi et al 2002: 0/4 patients improved in or could reduce
concomitant steroids, PE or IVIg
• Gorson et al 2004: 3/13 (23%) patients failing or relapsing after
conventional therapy improved with MMF (1gx2/d x 2-36 mos).
No significant improvement in Rankin, sensory & MRC scores; 5
patients (24%) had one or more side effects.
• Radziwill et al 2006: effective in 4/7 patients (in 1 only on pain)
• Total responder to Mycophenolate 12/31 (39%)

34. RCT OF INTERFERON β−1a IN CIDP
Hadden et al, Neurology1999; 53: 57-61
• 10 consecutive treatment-resistant CIDP patients.
• Randomized, double-blind, cross-over.
• Interferon β−1a (Rebif), s.c. (3 MIU 3 x wk x 2 wks ->
6MIU 3 x wk x 10 wks), vs. placebo, 4 wks washout.
• Clinically important improvement in 1 patient with INF-
β and 2 with placebo.
• No significant clinical or neurophysiologic effect.
INF-β is not effective in treatment-resistant CIDP

35. INTERFERON β−1a IN CIDP
Vallat et al (Neurology 2003; 60(suppl3) S23-8
• 20 IVIg resistant, deteriorating
CIDP patients.
• Prospective, open label,
baseline versus treatment study.
• Interferon β−1α (Avonex) im,
30 µg 1 x week x 6 mos.
• 7 (35%) improved, 10 (50%)
stable, 3 (15%) deteriorated
• Significant improvement in
NDS score (IT/PP, p: .0005),
clinical grading (PP, p: .05) but
not grip strength.
• Improvement of CMAP areas.

36. INTERFERON β−1a ADJUNCTIVE TO IVIg IN CIDP
Gorson et al (AAN 2008, in preparation)
• 67 IVIg dependent CIDP patients.
• Multicenter RCT, IFNβ-1a, 30 or 60 ug (45 pts) vs
placebo (22 pts) once or twice weekly
• After 16 wks IVIg discontinued and restarted upon
worsening by 2 or more MRC points (0-60).
• The mean IVIg dose in week 16-32 (1g/kg) in IFNβ-1a
treated did not differ from placebo (1.9g/kg)
• In both groups 47% of patients did not relapse by 32
weeks
• Patients more severe (MRC <51) or more intensely
treated with IVIg (>0.95g/kg/mo) treated with IFNβ-
1a required less IVIg than placebo treated patients.

37. OTHER IMMUNESUPPRESANT IN CIDP
Uncontrolled studies
Rituximab
• Beneficial in 5 patients (Briani et al 2004;Knecht et al 2004;
Bodley Scott et al 2005; Gono et al 2006; Munch et al. 2007)
Methotrexate
• 7/10 (70%) patients improved by at least 2 MRC point and 2
also in disability with MTX 10-15 mg/wk alone (1) or in
association with steroids or IVIg or both. 3 patients worsened
including 1 who died. None suspended concomitant therapy
(Fialho et al 2006)
Etanercept (soluble TNF-α receptor)
• 3/10 (30%) therapy refractory or intolerant patients signifi-
cantly improved and 3 possibly improved. (Chin et al 2003)
Tacrolimus (FK506)
• 1 patient improved (Ahlmen et al 1998)
Campath 1 H
• 1 patient improved (Hirst et al.2006)

38. RMC Trial
A Pilot Randomised controlled trial of Methotrexate for
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
EudraCT Number – 2005-003382-16
Co-Sponsors: King’s College London, Guy’s & St Thomas’ NHS
Principal investigator: Professor Richard A C Hughes
Centres: 26 in 5 European countries (6 centres in Italy)
Patients: 60 patients randomised.
Trial design: oral methotrexate or placebo (7.5 mg/wk increasing
to 10 mg weekly after 4 weeks and 15 mg weekly after 8 weeks)
and folic acid 5 mg twice weekly for 40 weeks. After 16 weeks
corticosteroids or IVIg were reduced, subject to satisfactory
progress, at a rate of 20% of the baseline dose every 4 weeks.
Primary outcome: At least 20% reduction in mean weekly dose of
steroids or IVIg from week 37-40 compared with week 1– 4.
Secondary outcome: change in disability and impairment from
baseline to week 16 and to week 40.

39. Methotrexate (n=27) Placebo (n=32)
10
14/27 (52%) responders 14/32 (44%) responders
8
Frequency
6
4
2
0
-100 -50 0 50 100 -100 -50 0 50 100
Percentage Change
Graphs by Treatment Group
Adjusted odds ratio 1.21 (95% CI 0.40 to 3.70).

40. Immunosuppressant and immunomodulatory
drugs in CIDP
A literature overview A bunch of experts’ view
1. Cyclosporin (83%) 1. Azathioprine 10
2. Azathioprine (64%) 2. Methotrexate 6
3. Cyclosporin 4
3. Cyclophosphamide (75%)
4. Mycophenolate mofetil 1
4. Methotrexate (70%)
5. Cyclophosphamide 1
5. Interferon α (64%)
6. Rituximab (anti-CD20)
6. Mycophenolate mofetil (39%)
Interferon α
7.
Interferon β 1a
7. (35%)
Interferon β 1a
8.
8. Rituximab (anti-CD20) (?%)
9. Etanercept
9. Etanercept (30%)
RMC Trial Meeting, London, April 2008
10. Autologous hematopoietic stem cell
transplantation

41. 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
• Frequent (80%) response to IVIg

43. 1) Clinical Criteria for MMN
A) Core criteria (both must be present)
1. Slowly progressive or stepwise progressive, asymmetric limb
weakness, or motor involvement having a motor nerve
distribution in at least two nerves, for more than one month#
2. No objective sensory abnormalities except for minor vibration
sense abnormalities in the lower limbs.
B) Supportive clinical criteria
3. Predominant upper limb involvement
4. Decreased or absent tendon reflexes in the affected limb
5. Absence of cranial nerve involvement
6. Cramps and fasciculations in the affected limb
C) Exclusion criteria
7. Upper motor neuron signs
8. Marked bulbar involvement
9. Sensory impairment beside for minor vibration loss in the legs
10. Diffuse symmetric weakness during the initial weeks
11. Laboratory: CSF protein > 1 g/l

44. EVIDENCES FOR
IMMUNE PATHOGENESIS IN MMN
• IgM antibodies to GM1 or other gangliosides are
present in 30-50% of MMN patients (but may be
also found in other PN and MND) and often though
not always decrease during clinical improvement;
• Deposits of IgM were found at the nodes of Ranvier
of sural nerves in a patient with CB (and MND);
• CB can be induced in vitro & vivo by serum from
MMN patients with and without anti-GM1 IgM;
• Most patients with MMN respond to immune
therapies (IVIg and CTX).

45. Disability progression in MMN
Years of neuropathy 5 10 15 20
• N° pts 21 17 12 7
• N° pts Rankin 2 3 4 3
score > 3
100
isab p tie ts
le a n
80
60
42%
40 33%
17.5%
%d
20
9.5%
0
5 10 15 20
Years from onset neuropathy

46. IMMUNE THERAPIES IN MMN
No. No. (%) No. (%)
Therapy treated improved worsened
________________________________________________
Steroids (alone) 64 (62) 7 (11%) 14(22%)
Plasmaexch.(alone) 21 (20) 4 (20%) 2 (10%)
IVIg: 383
↓↓ impairment: 303/373 (81%)
↓↓ disability: 91/123 (74%)

47. IVIg for Multifocal Motor Neuropathy
Van Schaik I, van den Berg L, de Haan R, Vermeulen M
Cochrane Database of Systematic Review, 2005, April 18
• Reviewers’ summary and conclusion:
• Four RCT assessing the effect of IVIg in MMN have been
performed including a total of 34 patients.
• Strength improved in 78% pts treated with IVIg vs 4% with
placebo; disability improved in 39% treated and 11%
untreated patients
• IVIg has beneficial effect on strength in MMN and provide a
non-significant trends toward improvement in disability
• More research is needed to discover whether IVIg improves
disability and is cost-effective.

48. LONG-TERM IVIg THERAPY IN MMN
• Azulay et al., J Neurol Neurosurg Psychiatry 1997
• 8/12 (66%) responding pts required repeated Ig x 9-48 mos,
uneffective in 3 after 3 mos; 2 (11%) in remission after 1 yr.
• Van den Berg et al., Brain 1998
• 6/7 (86%) responding pts required weekly Ig (0.4g/kg/wk) x
2-4 yrs (follow-up); 3 (43%) had some deterioration.
Periodic IVIg are necessary in most MMN patients

49. Neurology
2004
10 MMN patients responding to Summed dCMAP
IVIg treated with periodic IVIg
infusions for 5-12 yrs (mean 8.2)
Mean MRC
Summed pCMAP

50. Disability progression in MMN
Years of neuropathy 5 10 15 20
Treated patients 6 5 7 4
Rankin > 3 0 0 1 (14%) 1 (25%)
Untreated patients 15 12 5 3
Rankin > 3 2 (12%) 3 (25%) 3 (60%) 2 (66%)
100
ts
le atien
80
p< 0.01
)
(R k > 3
p< 0.01
isab p
60
an in
Treated
40 Not
treated
%d
20
0
5 10 15 20
Years from onset neuropathy

51. Neurology
2005; 63: 1264
10 MMN patients responding to IVIg
treated with periodic IVIg infusions for
3.5-12 yrs (mean 7.2) Mean monthly
dose 1.6g/kg+/-0.8 vs 0.5-1g/kg
radial
peroneal

52. OTHER IMMUNE THERAPIES IN MMN
• To treat patients not responsive to IVIg
• To treat patients progressively less
responsive or unresponsive to IVIg
• To reduce the cost of IVIg use
• To reduce patients’ dependency from
IVIg and Hospital admission

53. OTHER IMMUNE THERAPIES IN MMN
No. No. (%)
Therapy treated improved
_______________________________________________
Cyclophoshamide i.v. 40 30 (75%)
“ “ oral 6 3 (50%)
β
Interferon-β1a 12 6 (50%)
Azathioprine, (alone) 10 (4) 5 (2) (50%)
Mycophenolate 1 0
Cyclosporine 2 2
Rituximab 14 11 (?)
(81% of 21, incl. 7 MAG+)

54. INTERFERON-β1a IN
MULTIFOCAL MOTOR NEUROPATHY
• Martina et al 1999 (JNNP,1999)
• 3 MMN, 1 Motor CIDP, resistant to IVIg, steroid or CTX
• 6MIU sc , 3 x wk, x 6-12 mos;
• All improved in MRC sumscore, ambulation & dexterity,
but only 2 improved in Rankin score.
• Van den Berg-Vos et al 1999 (Neurology, 2000)
• 9 MMN pts IVIg responsive; 6MIU sc, 3 x wk, x 6 mos;
• No effect in 6 patients (67%), 4 of whom deteriorated and
returned to IVIg; 3 patients (33%) with shorter & less
severe disease improved on INF-β more than on IVIg.
β
INF-β1a may be effective in some MMN patients

55. Interferon β-1a in IVIg responsive MMN
Radziwill AJ et al, INC , Paris 2008
• 3 MMN patients receiving IVIg infusions every
2nd to 6th week prior to study entry.
• A prospective 9-month pilot trial of s.c. INF b-1a,
12 MIU, 3 times a week; IVIg therapy
maintained.
• Intervals of IVIg prolonged from 6 to 8 weeks in
1 patient and from 5 to 6 weeks in 1 patient.
They both observed a quicker recovery after
IVIg and a slower relapse before IVIg. The third
patient had no change.
• No major changes in the strength disability,
quality of life or a reduction of combined
treatment costs.

56. • 14 MN (11+CB) & α-
GM1 IgM; 7 with PN & α-
ΜAG IgM; 13 untreated
• Rituximab: 375mg/ m2/
wk x 4 -> (16) 1/wk x 2->
1/10 wks- > 2yrs
• Strength ↑ 23% after 2
years (81% pts ↑ 12%)
• IgM ↓ to 55%; Abs ↓ to
43%
• No major side effects

57. Adjunctive Rituximab to IVIg in MMN
2 pats
(1 MMN)
No effect
Neurology 2003
1 pat:
Ig every
12 instead
of 7 days
Neurology 2004
2 pats:
1Ig+24%
1Ig- 43%
Tot: 2/4
Muscle Nerve 2007

58. An open-label trial of Rituximab in MMN
Chaudhry & Cornblath, INC , Paris 2008
• 6 patients with MMN under chronic IVIg therapy
treated with 2 doses of Rituximab 1g iv, 2 weeks
apart.
• Primary outcome total amount of IVIg used during
12-month study compared to 12 months prior.
• Secondary outcomes: changes in MRC sumscores,
grip strength, disability & handicap scores, & safety.
• No significant change in IVIg use in the group over
the 12-month study. 2 able to reduce their IVIg use
by 11%.
• No significant change in any score (MRC, grip
strength, overall disability, Rotterdam handicap
scale), although some improved on these measures.
• Rituximab can be safely given to people with MMN
but in this pilot study was unable to reduce the

59. JNNP 1997
Pts. treated: 6
Follow-up: 47 mos (37-61)
Remission after 1-4 yrs of
IVIg+CTX: 3 (50%)
Requiring reduced doses of
IVIg: 3 (50%)
Pts. with severe side
effects: 2 (33%)

60. • 28 pts randomized
• 1 pt with MMF ↓↓ IVIg by 50%.
• No signif. ↓↓ of IVIg after 12 mo.
• Pts did not have drug toxicity.
•No signif. progression after 12 mo
• Muscle strength, FS unchanged
after 3 months & GMI-IgM after
12 months.
Adjunctive MMF was safe but did not alter MMN course
or allow IVIg reduction

61. Oral methotrexate in multifocal
motor neuropathy patients treated
with IVIg: preliminary results of
an open pilot study
Fabrizia Terenghi, Chiara Casellato, Francesca
Gallia, Eduardo Nobile-Orazio
Department of Neurological Science, Milan University
2nd Neurology, IRCCS Istituto Clinico Humanitas,
Rozzano, Milan
Dario Cocito, Serena Grimaldi
Department of Neuroscience, Turin University, Turin

62. Patients
We reviewed the effect of MTX in 8 patients with
MMN diagnosed according to EFNS/PNS criteria
(2006) who were clinically stable under chronic
maintenance IVIg therapy which had not been
modified during the previous 3 IVIg courses
• Gender: 7M/1F
• Mean age at onset: 42.6 yrs (22-63)
• Mean years of MMN: 7.6 yrs (2-15)
• Mean duration of IVIg: 5.5 yrs (1-13)
• Mean current IVIg dose: 81g (55-135)/3-4wks

63. Adjunctive MTX in MMN: Summary
Terenghi et al, INC , Paris 2008
• MTX was well or moderately well tolerated
by 5/8 patients with MMN.
• In 7/8 patients the association of MTX to
IVIg was followed by mild to moderate (1-15
MRC) improvement and in 1 by some
deterioration (4 MRC) in muscle strength
(mean improvement: 5.5; p: 0.0543).
• In 5/7 pts IVIg were reduced by up to 10%
to 30% without clinical worsening while
more consistent Ig reduction (50%) or
suspension could be achieved in only 2 pts
(mean Ig reduction 32%; p: 0,0253)

64. EFNS/PNS TREATMENT RECOMMENDATIONS
1. IVIg (2 g/kg over 2 to 5 days) should be considered as
first line treatment (Level A recommendation) when
disability is sufficiently severe to warrant treatment.
2. Steroids are not recommended (Good Practice Point).
3. If IVIg is initially effective, repeated IVIg should be
considered (Level C) and its frequency guided by the
response (Good Practice Point). Typical treatment
regimens are 1 g/kg every 2 to 4 weeks, or 2 g/kg every
1 to 2 months (Good Practice Point).
4. Only if IVIg is not sufficiently effective immunosup-
pression may be considered. Cyclophosphamide,
cyclosporin, azathioprine, interferon β1a, or rituximab
are possible agents (GPP).
5. Toxicity makes cyclophosphamide less desirable (GPP)

65. Fabrizia Terenghi
Department of
Gianluca Ardolino
Neurological Sciences,
Chiara Casellato
IRCCS Humanitas
Clinical Institute Barbara Bossi
Milan University, Francesca Gallia
Rozzano, Milan, Claudia Giannotta

66. Immunosuppressant & Immunomodulatory
treatments for MMN
Umapathi T, Hughes RAC, Nobile-Orazio E, Leger JM
Cochrane Database of Systematic Reviews 2008 update
Reviewers’ conclusion:
• In the only RCT, mycophenolate mofetil did not significantly
improve strength or function or reduce the need for IVIg
• The use of corticosteroids, and occasionally plasma exchange,
has been associated with deterioration.
• There are some reports of benefit but also of serious adverse
events from cyclophosphamide either as a primary agent or
for patients who do not respond or lose their response to IVIg
or require frequent infusions
• There is still little or no evidence about azathioprine, β
interferon, rituximab or ciclosporin,
• Trials of IS should be undertaken but non-randomised
studies do not suggest a particular favourite candidate.

67. Acta Neurol Scand. 2008 Jun;117(6):432-4. Epub 2007 Dec 12
No benefit of treatment with cyclophosphamide and autologous
blood stem cell transplantation in multifocal motor neuropathy.
Axelson HW, Oberg G, Askmark H.
We report on a patient who responded to IVIG, but temporarily deterio-
rated dramatically after treatment with high-dose cyclophosphamide and
autologous blood stem cell transplantation. Today the situation is the same
as before the treatment with cyclophosphamide and blood stem cell
transplantation, i.e. IVIG is given every 4 weeks.

68. Neurology 2007

69. IVIg
m
0
10
20
30
40
50
60
70
80
ar
-0
6
ap
r-0
m6
ag
7.5 mg
-0
6
gi
u-
06
lu
g-
06
ag
o-
06
15 mg
se
t- 0
6/ 6
10
/
-10%
25 06
/1
0/
16 0 6
/1
1/
-20%
12 0 6
-
/1
2/
06
4/
1/
0
-30%
25 7
/1
/0 *
15 7
/2
/0
7
8/
3/
0
28 7
/3
/0
19 7
/4
/0
17 7
Patient 1 (CP)
/5
/0
7
MTX x 18 months
gi
u-
07
gi
u-
0
'1
5/ 7
07
' 0 /07
2/
08
' 2 /07
7/
08
/0
7
se
t- 0
7
ot
IVIg
*
t-0
7
MRC
60
65
70
75
80
85
MRC

70. OTHER INTERFERONS IN CIDP
Uncontrolled studies
β
INF-β 1b:
• 1 patient with relapsing CIDP poorly or transiently responsive
to IVIg or PE had no further relapse after INF-β 1b (Betaferon)
8 M IU/alt. d, s.c. (Cocco et al, 2005)
α
INF-α 2a:
• 2 patients unresponsive to Steroids, AZT, Cys-A & short
benefit from IVIg made a complete & sustained recovery with
INF-α 2a (Roferon-A) 2-3m IU x2/wk (Sabatelli et al 1995)
• 9/14 (64%) patients unresponsive to other therapy improved
with 3 mil IU x 3/wk x 6 wks including 6 with a sustained
improvement (Gorson et al, 1998)
• 1 patient with CIDP unresponsive to steroids, IVIg, PE, AZT
and CTX made a complete & sustained recovery 6 mos after
INF-α 2a (Roferon-A) 3 M IU x2/wk (Pavesi et al, 2002)
α µ
PEG INF-α 2b (1µg/kg/wk) + Ribavirine (1200mg/d):
• 1 patient with HCV, improved after 7 wks (Corcia et al 2004)

71. POSTER SESSION VII: THURSDAY, APRIL 17 / 11:30 A.M.–2:30 P.M.
P07.101 Efficacy of Interferon Beta-1a in Patients
with Chronic Inflammatory Demyelinating
Polyradiculoneuropathy (CIDP)
Kenneth Gorson, Richard Hughes, Didier Cros,
John Pollard, Jean Vallat, Katherine Riester,
Gudarz Davar, Katherine Dawson,Alfred Sandrock

72. 1) Diagnostic Categories in MMN
A) Definite MMN
Core criteria and exclusion criteria AND definite CB
with normal sensory NCS in > 1 nerve
B) Probable MMN
Core criteria and exclusion criteria AND probable CB
with normal sensory NCS in > 2 nerve
Or
Core criteria and exclusion criteria AND probable CB
with normal sensory NCS in one nerve AND at least
one supportive criteria.
Supportive criteria
1. Elevated IgM anti-GM1 antibodies
2. MRI Gad enhancement/hypertrophy of the brachial plexuses
3. Clinical improvement following IVIg treatment

73. IMMUNE THERAPIES IN MMN
No. No. (%) No. (%)
Therapy treated improved worsened
________________________________________________
Steroids (alone) 64 (62) 7 (11%) 14 (22%)
Plasmaexchange, (alone) 21 (20) 4 (20%) 2 (10%)
Azathioprine, (alone) 4 (3) 3 (75%)
Cyclophoshamide (iv) 42 (34) 20 (48%)(iv 53%)
β
Interferone-β1a 12 5 (42%)
IVIg 383 303/373 (81%) impair.
91/123 (74%) disability

74. SIDE EFFECTS OF CTX IN MMN PATIENTS
_____________ORAL CTX_____________
Pat. mg/ period total Side
No. day months dose(g) effects
_______________________________________________________
→
1. 100→75 23 63.0 -
→
2. 150→50 41 129.0 Haemorrhagic cystitis
& Amenorrhea
→
3. 25→50 43 33.0 -
→
4. 200→100 13 58.3 Haemorrhagic cystitis
& Azoospermia
→
5. 150→50 37 67.5 -
→
6. 150→50 37 90.0 -
_______________________________________________________

75. JNNP 2008;
79: 93-96
• Retrospective analysis of response to IVIg in 40 MMN patients
including 22 treated de novo.
• 14/20 (70%) de novo patients improved by at least 1 MRC point in
2 affected muscles after 6 months
• At the end of follow up (2.2+-2 years):
• 8/40 (22%) had stable remission after 6 months of IVIg for >
6 months without additional therapy
• 25/45 (68%) were IVIg dependent including 8 receiving
additional IS
• Non significant predictive factor for IVIg response (including
GM1 abs and NCS)

76. MTX treatment
Oral methotrexate as 2.5 mg tablets starting
at 7.5 mg and increasing at 4 weekly
intervals to 10 then to 15 mg once weekly
Oral folic acid 10 mg weekly
After 4 months of combined therapy,
patients who were stable or improving were
planned to reduce their IVIg doses by ~10%
of their baseline dose every 2-3 IVIg courses
until suspension
Mean duration of MTX treatment: 12.6 mos (4-18)

77. Immunosuppressive treatment for MMN
Umapathi T, Hughes RAC, Nobile-Orazio E, Leger JM
Cochrane Database of Systematic Reviews 2005 (3)
Reviewers’ conclusion:
• There are no randomised controlled trials of immuno-
suppressive agents as primary or adjunctive or second-
line therapy in MMN on which to base practice.
• Non-randomised study suggest a possible therapeutic
role of CTX in primary treatment and moderate effect
as adjunctive or second-line therapy in MMN.
• Randomised controlled trials are needed to establish
the value of immunosuppressive agents in MMN.
IVIg is the gold standard of treatment for MMN.

78. EFNS/PNS TREATMENT RECOMMENDATIONS
1. IVIg (2 g/kg over 2 to 5 days) should be considered as
first line treatment (Level A recommendation) when
disability is sufficiently severe to warrant treatment.
2. Steroids are not recommended (Good Practice Point).
3. If IVIg is initially effective, repeated IVIg should be
considered (Level C) and its frequency guided by the
response (Good Practice Point). Typical treatment
regimens are 1 g/kg every 2 to 4 weeks, or 2 g/kg every
1 to 2 months (Good Practice Point).
4. ONLY (ENO) If IVIg is not sufficiently effective immu-
nosuppression may be considered. Cyclophosphamide,
cyclosporin, azathioprine, interferon β1a, or rituximab
are possible agents (Good Practice Point).
5. Toxicity makes cyclophosphamide less desirable (GPP)

79. 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)

80. Prevalence of clinical neuropathy in
different monoclonal gammopathies
Osteosclerotic myeloma (POEMS) 50-85%
WM 30-50%
MGUS 5-37%
Amyloidosis (AL) 10-20%
Cryoglobulinemia 7-15%
Multiple myeloma 3-14%
Lymphoma 2-8%

81. 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%)

82. 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)
6% S; S>M; SM Ax or Dem Pestronk et al 1991
Sulfatide
2% S>M Dem Ilyas et al 1986
GQ1b+Disyalo
(CANOMAD) (Willison et al 2000)
3% M; M>S Dem Bollensen et al 1989
GD1a
2% M; M>S Dem Ilyas 1988
GM2
<2% M; LMNS Focal Dem Latov et al 1988
GM1
(MMN) (Pestronk et al 1988)
<2% SM Axonal Sherman et al 1983
ChS-C

83. 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

84. PN ASSOCIATED WITH ANTI-MAG IgM
Homogeneous clinical and electrophysiological features
consistent with a chronic, slowly progressive,
predominantly sensory, demyelinating neuropathy
p
MAG + (42) MAG - (26)
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
81%/19% 27%/73% < 0.0005
MGUS/WM-NHL
Nobile-Orazio et al 1994

85. 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%)
73.3 (58-84)
Mean age at PN onset: 61.2 (42-78)
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)

86. 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

87. 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 α 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%)

88. RCT in PN & anti-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-blind, cross-over
11 PN+IgM (9 MAG); IVIg effective in 2 IgM (18%) (1 MAG, 11%)
• Comi et al 2002: IVIg vs placebo x 1 mos; double-blind, cross-over
22 PN+IgM (11/19 MAG); IVIg slightly better (p=0.05) than placebo
• Mariette et al 1997: IFN-a vs IVIg x 12 mos; open
20 PN+MAG; Sensory improvement in 8/10 IFN-a and 1/10 IVIg
• Mariette et al 2000: IFN-a vs placebo x 6 mos; double blind
24 PN+MAG; No difference between IFN-a and placebo.
• Niermejier et al 2007: Oral CTX+ Prednisone (16) vs Placebo (19) x 6 mos
double-blind; 35 PN+IgM (17 MAG); No difference in functional
scales (33% better vs 21%); MRC, sensory & DL better at 6 mos.

89. RITUXIMAB (α-CD20 MAB)
IN PN AND ANTI-MAG IgM
Renaud et al 2003 Muscle Nerve
• 9 pts with PN & anti−ΜAG
• 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

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

91. Worsening of neuropathy under Rituximab
• 1 patient with WM had acute worsening of pre-existing
neuropathy consistent with GBS during therapy with
Rituximab and fludarabine (Noronha et al 2006)
• 1 patient with NHL in complete remission developed GBS
during Rituximab maintenance therapy(Carmona et al 2006)
• 1 patient with NHL developed GBS soon after combined
CHOP and Rituximab therapy (Terenghi et al 2007)
• 3 patients 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.
• 1 patient 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)

92. Ongoing or unpublished trials of Rituximab in anti-MAG PN
A Double-Blind, Placebo-Controlled Study of Rituximab in
Patients with Anti-MAG Antibody-Demyelinating
Polyneuropathy (A-MAG-DP)
Dalakas MC, et al; Bethesda, MD
1. Placebo-controlled study on 26 patients randomized to 4 weekly
infusions of . 375 mg/m2 Rituximab or placebo.
2. The INCAT scores of patients with baseline disability >1, significantly
. improved (p < 0.05) 8 months after Rituximab compared to placebo.
3. We conclude that Rituximab is an effective treatment in 75% of
patients . with A-MAG-DP with disability > 1 INCAT scores.
Presented at 2006 ANA meeting, Ann Neurol 2006; 60, Suppl. 10: S91
French- Suisse Double-Blind, Placebo-Controlled Study
of Rituximab in Patients with Anti-MAG Polyneuropathy
Leger JM, Steck A

93. Immunetherapy for anti- MAG PN
Lunn MPT & Nobile-Orazio E
The Cochrane Library 2006, Issue 1
Reviewers’ conclusion:
• There is inadequate reliable evidence from trials of
immunotherapies in anti-MAG neuropathy to
recommend any particular immunotherapy.
• IVIg is relatively safe a may produce some short-
term benefit.
• Large randomised trials of at least 12 months
duration are required to assess the efficacy of
existing or novel therapies.

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

96. Fabrizia Terenghi
Department of
Gianluca Ardolino
Neurological Sciences,
Chiara Casellato
IRCCS Humanitas
Clinical Institute Barbara Bossi
Milan University, Francesca Gallia
Rozzano, Milan, Claudia Giannotta

98. 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 (IgM PCD)
– Unknown (MGUS, mostly IgG & IgA)

99. Mycophenolate Mofetil in Dysimmune Neuropathies:
a preliminary study
Benedetti et al. Muscle & Nerve 2004; 29:748-749
MMN Pts. treated: 4
Follow-up: 9 mos (6-12)
2 (50%)1*
Suspension of IVIg after 4 -> 12 mos:
1 (25%)1*
IVIg reduced by 50% after 4 -> 6 mos:
IVIg reduced by 25% only for 4 mos: 1 (25%)
*Pts. Suspending MM for side effects:2 (50%)

100. Results: MTX efficacy in MMN (1)
During combined MTX & IVIg therapy,
before or during IVIg reduction:
7/8 patients improved by > 1 MRC point
(mean 6.8, range1-15)(4 pts before, 3 during
Ig reduction)
1/8 patient had clinical worsening and
relevant side effects and suspended MTX
after 4 months
The improvement in muscle strength
(mean 5.5, range: -4+15) achieved at any
time during therapy was not significant
(p: 0.0543)

101. Results: MTX efficacy in MMN (2)
During IVIg reduction in 7 patients:
5 pats worsened or started to lose the
improvement after reducing Ig by more
than 10-30% of baseline dose
1 patient deteriorated after reducing Ig by
more than 50%
1 patient suspended Ig without worsening
The mean maximal Ig reduction
obtained without deterioration was 32%
(range 0 to 100%)

102. MTX in MMN: effect on MRC & Ig dose
Pt. Time 0 4m -10/15% -20/25% -30/40% -40/50% - 55+% Max eff Last visit
MRC(Ig (Igdose)(mos)
MTX (5-6 m) (6-7 m) (8-9 m) (10-12m (>12m Red.
CP 71 72 72 71 69 nd nd 20% 72 (60g,
+10%) (18)
(55g) (45g) (40g)
CT 66 69 68 63 nd nd nd 10% 66 (120g
-10%) (18)
(135) (120) (105)
NU 97 97 98 99 98 97 95 50% 97 (40g,
-50%) (12)
(80) (40g) (35g)
FA 73 69 nd nd nd nd nd 0 69 (80g
=) (4)
(80g) (80g)
SG 70 70 73 70 69 nd nd 25% 67 (80g
=) (11)
(80g) (60g) (50g)
GM 87 89 88 89 89 92 97 100% 97 (0g
-100%) (16)
(60g) (0g)
(35) (15gr)
CR 79 79 85 86 94 84 nd 30% 84 (60g,
-25%) (15)
(80g) (65g) (55g) (45gr)
SA 50 64 60 58 55 nd nd 20% 55 (80g
=) (7)
(80g) (65g) (65g)
MRC 74 76 76 76 76 75 75 76
32%
M Ig 81g 60

103. 5) CIDP: Diagnostic Categories
Definite CIDP
1) Clinical Criteria I A or B & II with Electrodiagn. criteria Def.
2) or Probable CIDP + at least 1 Supportive Criterion
3) or Possible CIDP + at least 2 Supportive Criteria
Probable CIDP
1) Clinical criteria I A or B & II with Electrodiagn. criteria Prob.
2) or Possible CIDP + at least 1 Supportive Criterion
Possible CIDP
1) Clinical criteria I A or B & II with Electrodiagn. criteria Poss.
CIDP (definite, probable, possible) with concomitant dis.
I: Inclusion A: Typical CIDP; B: Atypical CIDP; II: Exclusion

104. STEROIDS IN CIDP
• McCombe et al 1987: Steroids* effective in 65% of 49
patients (*undefined steroid and dosage);
• Barohn et al 1989: Prednisone* initially effective in
95% of 59 patients (*100/d x 2-4wks -> alternate day);
• Molenaar et al 1997: Pulsed dexamethasone* effective
in 70% of 10 patients (*40mg/d x 4d every 28d x 6 times);
• Dyck et al 1982: Oral Prednisone significantly effec-
tive in a open RCT on 35 previously untreated CIDP
patients (*120->100->...->2.5mg/d, each for 1wk, total 3 mos)
Steroids (oral or iv) effective in CIDP (~ 60% pts)

105. CORTICOSTEROIDS FOR CIDP
Mehndiratta MM & Hughes RAC
The Cochrane Library 2002, Issue 4
Reviewers’ conclusion:
• A single randomised, controlled trial with 35
partecipants provided weak evidence to support
the conclusions from non-randomised studies that
oral corticosteroids reduce impairment in CIDP.
• Corticosteroids are known to have serious long
term-side effects. The long-term risk and benefits
have not been adequately studied.

106. PLASMA EXCHANGE IN CIDP
I) Randomized Controlled Trials:
1. Dyck et al. N Eng J Med 1986
• 29 stable or worsening pts; double-blind, Plasma (15 pts) vs
sham exchange (14 pts) (6 each in 3 wks)
• 5/15 PE patients improved in NDS more than any control
Plasma exchange superior to sham exchange
2. Hahn et al. Brain 1996
• 18 untreated pts; double-blind, cross-over, Plasma vs sham
exchange (10 in 4 wks, 5 wks wash-out)
• 12/15 (80%) completing (66% treated) improved with PE;
8/12 (66%) PE responders relapsed 7-14d after stopping PE
PE significantly though transiently effective
II) Cochrane Review 2004, Issue 3 (Mehndiratta et al):
PE provide short term benefit in 2/3 of CIDP pts often followed
by rapid deterioration. Adverse effects are not uncommon

107. IVIg IN CIDP
Randomized, placebo-controlled trials
1) Hahn et al. Brain 1996
• 30 CIDP patients; randomized, double-blind, cross-over; IVIg
(0.4g/kg x 5d) vs placebo
• 19/30 (63%) pts improved at 28 d on IVIg vs 5/30 (17%) on PL
• 8/9 CP CIDP responders steadily recovered while 10/10 R
CIDP relapsed 3-22 wks after IVIg (all improved again)
IVIg significantly effective in CIDP
2) Mendell et al. Neurology 2001
• 33 untreated CIDP patients; randomized, double-blind, cross-
over; IVIg (1g/kg days 1, 2 & 21) vs placebo (PL)
• 11/33 (33%) improved on IVIg vs 2/23 (9%) on PL (p: .019);
• ↑↑ in muscle strength by day 10-> 42 (p:.006) after IVIg vs PL
IVIg is effective as initial treatment in CIDP

108. IVIg IN CIDP
Van Schaik et al, Cochrane library, 2002, Issue 2
IVIg is effective for at least 2-6 weeks in CIDP

109. PLASMA EXCHANGE VS IVIg IN CIDP
(Effect of long-term treatment)
Choudhary et al. QJM 1995
• Retrospective study of 105 CIDP patients
• 23/33 patients (70%) improved with PE: 30% of
responders required repeated courses for 8-60 mos
• 14/22 patients (64%) improved with IVIg: 50% of
responders required repeated courses for 6-51 mos
• More complications after PE (10) than IVIg (0)
Similar long-term efficacy of PE & IVIg in CIDP
but PE has more side effects

110. IMMUNESUPPRESSIVE THERAPIES IN CIDP
• Azathioprine+ Prednisone no better than Prednisone in a
RCT. Dose & duration unsuffcient (Dyck et al, 1985);
• Cyclosporin A effective in 37% pts not responding to other therapies.
(Hodgkinson et al 1990; Mahattanakul et al 1996);
• Cyclophosphamide pulsed i.v.:
• 1g/m2/mo x 6 mos effective in 11/15(73%) pats not responding to
other therapies (Good et al, 1995)
• 200mg/kg x4d effective in 4 pats not responding to other therapies
(Branagan et al 2002)
• Mycophenolate effective in 6/22 (27%)(Chaudhry et al 2001; Mowzon
et al 2001;Umapathi et al 2002;Gorson et al 2004) therapy res/dep
α
• INF-α 2a effective in 56% unresponsive pats (Gorson et al, 1998)
• Etanercept (soluble TNF-α receptor) effective in 3(+3?)/10 (30%)
therapy refractory or intolerant patients (Chin et al 2003)
• INF β−1a not effective in RCT on 10 therapy-resistant pats
(Hadden et al . 1999), effective in open trail on 20 IVIg resistant
patients (Vallat et al 2003).

111. Etanercept (soluble TNF-α receptor) in CIDP
Chin et al, J Neurol Sci 2003; 210: 19-21
• 10 CIDP patients refractory or intolerant to standard
immune therapy.
• Open study.
• Etanercept (Enbrel) 25 mg x 2/week 4-6 mos
• Muscle strength, sensory thresholds & functional
abilities
• 3 significantly improved and 3 possibly improved
Etanercept may be effective in CIDP but its efficacy
needs to be confirmed in RCT

112. Mycophenolate mofetil in CIDP
Gorson et al, Neurology 2004; 63: 715-717
• 13 CIDP patients, 8 with PN+IgM, failing or relapsing
after conventional immune therapy.
• Retrospective study.
• Mycophenolate mofetil 1gx2/d x 2-36 mos (Mean 15)
• No significant improvement in Rankin, sensory & MRC
scores
• 3 (23%) with CIDP and 1 PN+IgM (13%) improved
• 5 patients (24%) had one or more side effects (3 nausea,
2 malaise, 2 headache, 1 diarrhea); 1 suspended x nausea
MM had a modest effect on 20% of patients

113. IMMUNE THERAPY FOR CIDP
• IVIg, PE & steroids are similarly effective as initial
therapy in CIDP;
• PE is unsuitable for the long term treatment of CIDP;
• Steroids have more contraindications than IVIg especially
in aged people (diabetes, cardiac disease, hypertension,)
• IVIg is better tolerated but more expensive than steroids;
• Studies are needed to establish the most effective and safe
therapy for the long-term treatment of CIDP.
Steroids are probably the first option in CIDP while the
efficacy of IVIg should be balanced by its cost. IVIg is
the first option in children and in pts with
contraindications to steroids

114. Italian Register for response to treatment in
CIDP patients
Cumulative response to IS of NRs
DRUG N R
Azatioprina 11 6 (54%)
Rituximab 8 4 (50%)
Cyclophosphamide 6 4 (66%)
Methotrexate 4 3 (75%)
Mycophenolate 3 2 (66%)
1 1
α-IFN
Cyclosporine A 1 0
Cocito et al 2008

115. Italian Register for response to treatment in
CIDP patients
Risposta cumulativa a IS
DRUG N R SE
Azatioprina 65 41 (63%) 8 (12%)
13 3 (23%) 3 (23%)
α-IFN
Rituximab 11 6 (54%) 0
8 5 (62%) 2 (25%)
Cyclophosph.
Cyclosporine A 8 4 (50%) 4 (50%)
Methotrexate 6 3 (50%) 2 (33%)
Mycophenolate 6 4 (66%) 0
Cocito et al 2008

116. Distinguishing features between CIDP and MMN
Features CIDP MMN
Distribution Symmetric Asymmetric (MN)
Arms >legs no Yes (80%)
Sensory loss yes no
Gen. Areflexia yes no
Reduced CV no
yes
Reduced SNAP no
yes
↑ CSF proteins Rare (1/3)
yes
↑ GM1 IgM yes (30-40%)
no
S. Nerve biopsy Often normal
demyelination
Steroid effective No (1/10)
yes (2/3)
IVIg effective yes (4/5)
yes (2/3)
Modified from Van den Berg-Vos et al Neurology 2000;

117. Electrodiagnostic Criteria in MMN
1. Definite motor CB:
proximal vs distal neg. CMAP area reduction >
50% whatever the nerve segment length. Negative
distal CMAP amp. must be >20% of lower NL & > 1
mV & increase of proximal CMAP duration
(temporal dispersion: TD) ≤ 30%.
2. Probable motor CB:
negative CMAP area reduction of > 30% over a
long segment of an UL nerve with TD ≤ 30%;
OR
negative CMAP area reduction of > 50% with TD
> 30%.
3. Normal sensory nerve conduction in upper limb
segments with CB and normal SNAP amplitudes.

118. IVIg IN MMN
Randomized controlled trials
• Federico et al., Neurology 2000
• 16 MMN patients; double-blind, placebo-controlled,
crossover, trial; IVIg 0.4g/kg/day x 5 days
• 11/16 (69%) improved after IVIg, none after placebo; signifi-
cant improvement in disadbility, strength & CB after IVIg
• Leger et al., Brain 2001
• 19 MMN patients, 10 never treated with IVIg, 9 relapsing
after previous response to IVIg; double -blind, placebo-
controlled, crossover trial; IVIg 0.5g/kg/day x 5 days
• 12/18 (67%) improved after IVIg, 2/18 (11%) after placebo;
significant improvement in daily activities but not MRC score.
IVIg significantly better than placebo in MMN

120. Mean MRC score in 10 MMN patients
under chronic IVIg therapy
Terenghi et al, Neurology 2004

121. Brain 2002;
125: 1875-86

123. Patient 3 (NU)
100 100
MTX x 13 mos
96
7.5 mg 15 mg
92
88
84
80
76
*
72
68
-12%
64
60
56
-25%
52
90
48
-37.5%
44
40
36
-50% -50%
32
-55%
28
24
20
16
IVIg
12
MRC
8
4
0 80
gen-07 feb-07 mar-07 apr-07 mag-07 giu-07 lug-07 ago-07 '30/08/07 '27/09/07 '25/10/07 '23/11/07 '20/12/07 '22/01/08 '21/02/08

124. Summary
• MTX was well or moderately well tolerated by
all but one patient with MMN.
• In 6/7 patients the association of MTX to IVIg
was followed by a variable (1-18 MRC, mean
7) improvement in muscle strength.
• In four patients monthly IVIg dose could be
reduced by 10% to 35% without clinical
deterioration whereas a more consistent Ig
reduction (50%) or complete suspension
could be only achieved in 2 patients (33%)
• A mean Ig reduction of 34% could be reached
without deterioration (range 0-100%)

125. EFFECTS OF CYTOSTATIC-IMMUNE
THERAPIES IN PN & ANTI-MAG IgM
Pts. treated for >6 mos: 19 (15)
(for the PN)
Mean yrs of therapy: 4 (0.5-11)
Patients improved: 9 (47%)
Patients with therapy- 10 (53%)
related complications: 2 piastrinopenia (CTX)
4 H.Zoster (Chlor)
1 hepatitis (Chlor)
1 severe hypotension (PE)
2 ac. leukemia (dec.)(Chlor)
1 pulm. edema (dec)(Steroids)
Nobile-Orazio et al 2000

126. Terenghi et al, JPNS 2007