Patogenesi e terapia della Neuropatia Motoria Multifocale

Transcription

1 26 Settembre 2014 Patogenesi e terapia della Neuropatia Motoria Multifocale Francesca Gallia Neurologia 2, Ist. Clin. Humanitas Rozzano, Milano

2 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

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4 Prevalence of MMN Prevalence was estimated to be 1-2 per 100,000 inhabitants (Nobile-Orazio et al, 2005) and was 0.6 per 100,000 inhabitants in the Dutch study (Cats et al. 2010) MMN is more frequent in men than women (Nobile- Orazio et al, 2.6:1; Cats et al, 2010: 2.7:1) Age at onset is 41 y.o. with 80% of reported patients between 20 and 50 y.o. (Nobile-Orazio et al, 2005). MMN affects men earlier than women (38 vs 45 y.o.) (Cats et al, 2010).

5 CLINICAL FEATURES OF MMM Total reported patients until Men/women (ratio) 200/76 (2.6:1) Mean age of onset (range) 41.0 (15-72) Progression: chronic progressive 82% step-wise/rel.-rem. 14%/4% Limb weakness: 100% Asymmetric 94% Distal > proximal 87% Upper > lower limbs 79% Muscle atrophy (often mild) 86% Fasciculations 58% Cramps 55% Deep tendon reflexes: Reduced or absent 72% Normal or Brisk 28% Sensory impairment (minor) 20%

6 Distinguishing features in CIDP, LSS, MMN, MND Features CIDP LSS MMN LMND Distribution Symmetric Multineuropathic Multineuropathic Asymm or Symm Arms >legs no yes (40-70%) yes (80%) sometimes Distal>prox. no yes yes often Sensory loss yes yes no no Gen.Areflexia yes no no no Cranial/bulbar yes no no yes Motor CB yes yes yes no Reduced CV yes no no no ReducedSNAP yes yes no no CSF proteins yes rare (1/3) rare (1/3) no GM1 IgM no no yes (30-40%) rare (5-10%) Sural biopsy demyelin. demyelin. normal normal Steroid response yes (2/3) yes (2/3) no (1/10) no IVIg effective yes (2/3) yes (1/2) yes (4/5) no

7 2010 EFNS/PNS Criteria for MMN A) Core criteria (both must be present) 1. Asymmetric limb weakness, or motor involvement having a nerve distribution in > 2 nerves, slowly progressive or stepwise progressive, for > 1 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 7. Response to immune therapy C) Exclusion criteria 8. Upper motor neuron signs 9. Marked bulbar involvement 10. Sensory impairment beside minor vibration loss in the legs 11. Diffuse symmetric weakness during the initial weeks JPNS 2010

8 2010 EFNS/PNS NCS Criteria for MMN 1. Definite motor CB: prox. 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.

9 Neurology 2002;58: /6 patients improved with IVIg

10 Neurology 2006: 67: 592-6) 14/20 (70%) with CB vs.7/13 (54%) without CB (including 7 without any demyelinating features) improved with IVIg

11 Case Report: 26 y.o. woman History: 1 yr progressive left hand weakness in the muscles of ulnar nerve, extending 6 mos later to muscles of median nerve; N.E: Severe weakness (1-2) & atrophy in left ulnar nerve; mild weakness (4) & atrophy in left median nerve. Normal sensation. DTR slightly reduced distally in left arm.

12 2010 EFNS/PNS Supportive Criteria for MMN Elevated IgM anti-gm1 antibodies Increased CSF proteins but < 100 mg/dl MRI Gadolinium enhancement/ hypertrophy of the brachial plexuses (or high resolution sonography) Clinical improvement after IVIg therapy

13 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 1 nerve AND > 1 supportive criteria: C) Possible MMN - Core criteria and exclusion criteria AND normal sensory NCS and response to IVIg or - Core criteria 1 in 1 nerve and clinical involvement of 1 nerve, no sensory loss, exclusion criteria AND definite or probable CB with normal NCS in 1 nerve

14 LOCALIZATION OF GM1 & Gal(β1-3)GalNAc PNS Motor nerve terminals at NMJ Compact myelin Outer myelin Paranodal myelin Nodes of Ranvier Schwann cells Illa et al, Ann Neurol, 1995 CNS Gray > white matter Isolated spinal motor neuron Axon network & gray matter

15 ANTI-GM1 IgM ANTIBODIES BY ELISA IN MOTOR NEURON SYNDROMES

16 JNNP 2013 IgM antibody Frequency versus controls Sensitivity Specificity Positive Predictive value GM1 p< % 93% 65.5% GM1 >1/2560 p< % 99.3% 91.2% GM2 n.s. 7.5% 98.1% 50% NS6S n.s. 22.5% 91.4% 39.1% Galactocerebroside p< % 70.4% 37.5% GM1-Gal p< % 85.2% 58.8% GM1-Gal >1/2560 p< % 92.2% 66.6% GM1-Gal >1/5120 p< % 98.6% 88.9%

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18 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 decrease during clinical improvement; Deposits of IgM were found at the nodes of Ranvier of sural nerve 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). Illa et al

19 Disability progression in MMN Years of neuropathy N pts N pts Rankin 2 score > % disable patients % 33% 17.5% 9.5% Years from onset neuropathy

20 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%)

21 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.

22 PATIENTS : 44 subjects; 41 completed the study. DESIGNS: double-blind, cross-over IGIV 10% versus placebo. RESULTS: Greater decline from baseline (61% vs 34%) in grip strength after placebo (p=0.005). A greater proportion of subjects deteriorated under placebo (36% vs 12%; p=0.021) CONCLUSIONS: IGIV,10% safe, tolerated & effective in MMN

23 LONG-TERM IVIg THERAPY IN MMN Azulay et al., J Neurol Neurosurg Psychiatry /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 /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

24 Neurology MMN patients responding to IVIg treated with periodic IVIg infusions for 5-12 yrs (mean 8.2) Summed dcmap Mean MRC Summed pcmap

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26 JNNP 2011; 82: 87-91)

27 Are IVIg similarly effective in the maintenance treatment of MMN? MRC sum score MMN patients treated for 5 years Flebogamma IgVena Gammagard Kiovig Flebogamma IgV Gammagard Kioving Average initial MRC Average final MRC

28 Disability progression in MMN Years of neuropathy Treated patients Rankin > (14%) 1 (25%) Untreated patients Rankin > 3 2 (12%) 3 (25%) 3 (60%) 2 (66%) 100 % disable patients (Rankin > 3) p< 0.01 p< 0.01 Treated Not treated Years from onset neuropathy

29 SHOULD WE CONSIDER 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

30 Eur J Neurol 2009; 16: a) 9 patients in a single blinded cross-over study of IVIg vs SCIg b) IVIg (+4.3%) & SCIg (+3.6%) were equally effective for 3 courses J Periph Nerv Syst 2009; 14: a) 5/5 deteriorated or did not tolerate 50% reduced SCIg b) 4/5 maintained for 6 mos improvement with equal dose of SCIg

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32 OTHER IMMUNE THERAPIES IN MMN No. No. (%) Therapy treated improved Cyclophoshamide i.v (75%) oral 6 3 (50%) Interferon-β1a 15 8 (53%) Azathioprine, (alone) 10 (4) 5 (2) (50%) Rituximab (61%) Eculizumab 13 7 (54%) Mycophenolate 1 0 Cyclosporine 2 2

33 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

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35 Immunosuppressant & Immunomodulatory treatments for MMN Umapathi T, Hughes RAC, Nobile-Orazio E, Leger JM Cochrane Database of Systematic Reviews 2012 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.

36 TREATMENT OF MMN 2010 EFNS/PNS 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 immunosuppression may be considered. Cyclophosphamide, interferon β1a, cyclosporin, azathioprine are possible agents (GPP). 5. Toxicity makes cyclophosphamide less desirable (GPP)