Gammopatie monoclonali e neuropatia. Enrica Morra Ospedale Niguarda Ca Granda Milano

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1 Gammopatie monoclonali e neuropatia Enrica Morra Ospedale Niguarda Ca Granda Milano

2 Paraprotein and Neuropathy PDN

3 Paraprotein and Neuropathy Journal of the Peripheral Nervous System 15: , 2010

4 Inflammatory Peripheral Neuropathy Idiopathic Acute Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) Acute motor axonal neuropathy (AMAN) Acute motor - sensory axonal neurop athy (AMSAN) Fisher Syndrome and other regional variants Pharyngeal - cervical - brachial Paraparetic Facial palsies Pure oculomotor Functional variants of GBS Pure dysautonomia Pure sensory GBS Ataxic GBS Subacute Subacute inflammatory demyelinati ng polyradiculoneuropathy (SIDP) Chronic Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Multifocal motor neuropathy with conduction block (MMNCB) Chronic relapsing axonal neuropathy Chronic ataxic sensory neuronopathy Paraproteinemic neuropathy Monoclonal gammopathy of undetermined significance (MGUS) Multiple myeloma Solitary plasmacytoma Lymphoma or chronic lymphocytic leukaemia Waldenström s macroglobulinaemia Cryoglobulinaemia Cold agglutinin disease Primary amyloidosis POEMS syndrome Va sculitic Neuropathy Primary vasculitis Polyarteritis nodosa and Churg - Strauss disease Wegener s vasculitis Isolated nerve vasculitis Temporal arteritis Systemic autoimmune diseases with associated vasculitis Rheumatoid arthritis Systemic lupus erythematosus Sjörgren s syndrome Mixed connective tissue disease Other Serum sickness Infectious, malignant, related to chemotherapy Inflammatory neuropathy associated with infection Paraneoplastic Metabolic HIV neuropathies, including CMV neuropathy Leprosy Lyme disease Chaga s disease Sub - acute sensory neuropathy/neuronopathy - small cell lung carcinoma and anti - Hu Abs Other paraneoplastic tumour - antibody syndromes Diabetic lumbo - sacral plexopathy

5 Recommended investigations for patients with neuropathy and monoclonal gammopathy Neurological Full general examination Detailed objective clinical functional neuromuscolar assessment baseline and repeated at regular intervals Detailed electrophysiology with determination of: - Distal motor latency (DML) - Motor nerve conduction velocity (MNCV) - Terminal latency index (TLI) Assessment for conduction block (CB) and temporal dispertion (TD) Cerebrospinal fluid study: cellularity, cytospin protein level In selected cases: - serum VEGF level - MR imaging Nerve histology

6 Recommended investigations for patients with neuropathy and monoclonal gammopathy Hematology /Imaging /Histopathology Serum immunofixation electrophoresis. Total IgG, IgA, IgM concentration Physical examination: -lymphadenopathy, hepatosplenomegaly -macroglossia -signs of POEMS syndrome Full blood count, renal and liver function, calcium phosphate, ESR, C reactive protein, beta2m, LDH, rheumatoid factor Serum cryoglobulins Serum free light chains 24 hours urine collection for protein quantification, Bence Jones protein Skeletal survey (radiographic X ray, CT, MRI) Ultrasound or CT of chest, abdomen and pelvis PET may be considered in selected cases Bone marrow examination

7 Neuropathies and paraproteins Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Distal acquired demyelinating sensory neuropathy (DADS) Distal length dependent (axonal/painful) sensory neuropathies - Small fibre neuropathy Multiple mononeuropathies

8 CIDP phenotype Clinical features Other characteristics Typical CIDP (> 50%) Hematological SM symmetric, proximal and Association with distal, legs>arms different infectious or disorders Pure sensory CIDP (10-30%) Lewis-Sumner Syndrome (15%) Spectrum of Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) DADS (Distal Acquired Demyelin. Sensory PN) (10%) Pure Motor CIDP (<10%) Focal CIDP (2%) Pure sensory symmetric, proximal and distal, legs > arms, predominant ataxia possible SM asymmetric, arms > legs Sensory predominant, mild weakness possible, distal, legs>arms Pure motor, symmetric, proximal and distal Motor or SM, involv. of 1plexus or 1 or more nerves in one limb Cranial nerve involvement possible Cranial nerve involvement possible Often monoclonal IgM gammopathy, (DADS-M) with and without anti-mag

9 Paraproteinemic neuropathies and MGUS MGUS is the most common monoclonal gammopathy associated with Neuropathy with characteristic clinical, electrophysiologic and pathologic features - Up to 30-35% of pts with MGUS have neuropathy % patients with myeloma have neuropathy (pre-rx). 10% patients with neuropathy have MGUS IgM>IgG>IgA in association with neuropathy Paraprotein Proportion with paraprotein and neuropathy (%) Proportion with paraprotein without neuropathy (%) IgM IgG IgA κ light chain over-represented Ramchandren and Lewis 2012

10 IgM anti-mag paraproteinemic demyelinating peripheral neuropathy 50% of pts with IgM-MGUS and PN have anti-mag (myelinassociated glycoprotein) antibodies IgMκ paraprotein in serum Causal link between anti-mag and neuropathy (animal model: complement mediated demyelinization and neuropathy; reducing titers of anti-mag improves NP) In the 50% of pts with IgM-MGUS, PN and anti-mag, electron microscopy of biopsed nerves shows deposition of IgM on nerve myelin with associated separation of the outer layers of compacted myelin Characteristic neurophysiology and pathology

11 Myelin separation

12 Widely spaced myelin

13 IgM anti-mag paraproteinaemic demyelinating peripheral neuropathy Distal acquired demyelinating sensory neuropathy (DADS) Clinical features Predominantly distal Chronic (duration over 6 months) Slowly progressive Symmetric Predominantly sensory impairement with ataxia Relatively mild or no weakness and often tremor Elderly male - Few patients have proximal weakness more typical of IgG and IgA - Some CIDP patients have distal weakness without paraprotein Joint Task Force of the EFNS and the PNS, 2010

14 IgM anti-mag paraproteinaemic demyelinating peripheral neuropathy Distal acquired demyelinating sensory neuropathy (DADS) Electrophysiology Uniform symmetrical reduction of conduction velocity; more severe sensory than motor involvement Disproportionately prolonged distal motor latency Terminal Latency Index < 0.25 Absent sural potential Partial motor conduction block very rare Joint Task Force of the EFNS and the PNS, 2010

15 IgM anti-mag paraproteinemic demyelinating peripheral neuropathy Distal acquired demyelinating sensory neuropathy (DADS) Diagnosis IgM paraprotein, more commonly kappa light chain than lambda High titre ELISA against the peripheral MAG Severity of neuropathy does not correlate with level of circulating anti MAG. Possibly clinical presentation influenced by affinity (Flurti et al 2003) Weakly positive anti MAG are less specific, may occurr in the absence of neuropathy Testing for antibodies anti MAG should be considered in all patients with paraproteinemic demyelinating peripheral neuropathy If negative, then testing for IgM antibodies against other neural antigens

16 Most frequently antineural IgM reactivties Antigens Frequency Clinical impairement Nerve Pathology MAG 50-60% S>>M Demyelinating Sulfatide 6% S,S>>M, SM Axonal or demyelinating Chondroitin Sulfate C <2% SM Axonal Trisulfated Heparin disaccharide Gangliosides GM1+/-GD1b Disialosyl gangliosides GD1a GD1b GM2 8% Painful S>>M Axonal <3% MMN* S>>M M SM MMN or M Focal demyeliniation Demyelinating Demyelinating Axonal Cytoskeletal proteins? SM, CIDP Mostly axonal? *Multifocal Motor Neuropathy: purely motor, multifocal partial motor conduction blocks Invariable response to HD iv Ig Nobile Orazio, 2009

17 IgM anti-mag paraproteinemic demyelinating peripheral neuropathy Treatment Focus on any eventual need for specific hematological therapy caution neurotoxic drugs Treatment in IgM MGUS relies on the treating neurologist Treatment considered if functionally relevant pts without significant disability: no evidence that immunosuppressive or immunomodulatory treatment is beneficial Pts may be offered symptomatic treatment for paresthesiae pts with chronic or progressive disability treatment may be considered therapy directed at reducing circulating IgM or anti MAG ab by: - removal: plasma exchange - inhibition: IVIg - reduction of synthesis: corticosteroids, immunosuppressive IFN alpha, Cytotoxic agents No consensus on which treatment to use first

18 IgM anti-mag paraproteinaemic demyelinating peripheral neuropathy Treatment Plasma exchange: - review uncontrolled trials: effective temporarily in 50% of pts - not confirmed in 2 controlled studies - PE plus chlorambucil no more effective than clorambucil alone Corticosteroids: - half of patients respond when given in association with other therapies - seldom effective alone Intravenous Immunoglobulin: - only treatment with randomized studies -10/22 pts improved with Ig; 4/22 with placebo but short follow-up - IVIg confers short term benefit Interpheron alpha: - comparative trial versus IVIg: benefit of IFN in sensory symptoms - not confirmed in a randomized placebo controlled trial Nobile Orazio, 2000 Oksenhendler 1995 Comi et al 2002 Dalakas et al 1996 Mariette et al 1997, 2000

19 IgM anti-mag paraproteinaemic demyelinating peripheral neuropathy Immunosuppressive Treatment Chlorambucil effective in 1/3 of pts when used alone Cyclophosphamide -randomized trial CTX versus placebo: no benefit -effective when used high dose oral or IV with steroids -half of patients respond when given in association with other therapies -seldom effective alone Fludarabine, cladribine -studies limited Rituximab promising in some studies - 8 non randomised studies: 6 (79 pts) positive; 1 (3 pts) negative) - 1 RCT (Dalakas 2009) with serious flaws reported positive - DADs-M anti-mag : motor and sensory improvement, particularly in pts with aggressive disorders; sustained clinical benefit ( 84 m. in 80 %) - Disease recurrence correlated with high anti-mag titer, both baseline and during f-up (need of additional R courses?) - Ineffective in reducing sensory deficit versus placebo (Leger 2013) Lunn and Nobile Orazio2006; Benedetti 2008; Niermeijier et al 2007; Dalakas 2009 Lunn et al 2012 Cochrane Library

20 IgM paraproteinemic (anti-mag) neuropathy treatment Is treatment required at all? Indications: Haematological Progressive motor or sensory loss with instability Progressive and disabling tremor Younger age Shorter disease duration

21 IgG and IgA paraproteinemic demyelinating neuropathy Clinically and electrophysiologically indistinguishable from typical CIDP No clinical homogeneity -Proxymal and distal weakness -Motor or Sensory or Mixed impairement -Areflexia Electrophisiological feature: demyelinating neuropathy, axonal loss, both More rapid progression than IgM PDN A minority has the clinical and electrophysiological phenotype of IgM PDN No specific antibody associated (may be present)

22 IgG and IgA paraproteinemic demyelinating neuropathy Treatment Evidence from randomized trials inadequate Only one small randomized trail showing plasma exchange short benefit The long-term benefits and side effects of repeated PE not investigated May respond to treatment regimens used for CIDP pts without MGUS (considered sensory variants of CIDP) - Steroids - IVIg - Plasma exchange Lunn et al, 2009

23 Amyloid neuropathy High suspicion if: -pain -weight loss -macroglossia -cardiomiopathy 20% of patients with systemic light-chain AL present with neuropathy 80% demonstrate a monoclonal protein (most frequently IgG) Lambda light chains predominate Coexist with MM in 10% of cases

24 Amyloid neuropathy Length dependent axonal -Sensory loss with prominent small fibre involvement -Pain is often burning, especially nocturnally, or as lancinating stabs -Pain and temperature are selectively involved Mononeuropathies - esp: Carpal Tunnel v common Autonomic involvement - distal limb anhydrosis, orthostatic hypotension, difficulty voiding urine, and erectile and ejaculatory difficulty. - diarrhoea and gastroparesis may be prominent. -pupils involved (not in hereditary amyloid) Nerves may be thickened

25 POEMS Polyneuropathy-Orgamegaly-Endocrinopathy M protein-skin changes Usually has an underlyng osteosclerotic myeloma with IgG or IgA lambda protein 85%-100% of patients with Osteosclerotic variant of MM have neuropathy Major diagnostic criteria: -Polyneuropathy -Monoclonal plasma cell prolipherative disorder (lambda) -Sclerotic bone marrow lesions or Castleman disease -Raised Vascular Endothelial Growth Factor level (and TNF-α) Minor diagnostic criteria: - Organomegaly - Extravascular volume overload (edema, pleural effusion, ascites) - Endocrinopathy(hypertrichosis, hyperpigmentation, plethora, flushing, dermal glomeruloid hemangiomata, white nails) - Papilledema - thrombocytosis/polycythemia No specific diagnostic test for POEMS, VEGF are normal or slightly high in CIDP Electrophysiology: mixed demyelination and axonal loss

26 POEMS Poor prognosis: m Therapy: -High dose melphalan -Autologous Stem cell transplantation (in younger pts) -Lenalidomide/thalidomide -Anti VEGF monoclonal antibodies -Cyclophosphamide

27 Treatment of PN by plasma cell disorder Disease Most commonly Treatment associated paraprotein POEMS IgG or IgA lambda Sclerotic plasmocytoma= radiation therapy Thalidomide, bortezomib, stem cell therapy WM IgM kappa Specific WM treatment Primary: DRC Rituximab +Bendamustine? Rituximab + Carlfinzomib? Collaborative clinical trials needed MM IgG kappa Specific Myeloma treatment can cause or exacerbate existing PN (Newly diagnosed: SCT) Light chain AL IgG or IgA lambda Overall poor prognosis Melphalan- Dexamethasone, bortezomib, lenalidomide, cyclophosphamide stem cell transplant

28 Waldenström Macroglobulinemia Associated with neuropathy in 5-10% of cases Usualy IgM kappa with or without anti MAG antibodies Clinically indistinguishable from IgM MGUS-related neuropathy with anti MAG Ab Electrophysiologic studies: demyelination Pathologic studies: widening of lamellae

29 Multiple Myeloma Peripheral neuropathy due to: - perineurial or perivascular IgG kappa deposition or - treatment-related toxicity Rarely seen with IgM paraprotein Mild symmetric sensory greater than motor symptoms in distal extremities May be present concurrent amyloid deposition (symptoms more painful) Electrophysiology: axonal damage Histopathology: demyelin. mostly lacking

30 Neuropathy associated with other IgM reactivities or pathogenetic mechanisms No antineural reactivity can be identified: approximately 30% of patients -Cryoglobulinemia -Direct lymphoplasmacytic infiltration of nerves, -Microangiopathy of the vasa nervorum, -Endoneurial accumulation of M protein -Amyloidosis nerve biopsy vasculitis may play an important role supported by increased density of T cells on sural nerve biopsy compared with normal individuals and pts with chronic idiopathic axonal polyneuropathy Neuropathy has a progressive course, frequently responds to steroids Eurelings et al 2003; Turner et al 2003

31 Peripheral neuropathy associated with WM Niguarda series Peripheral neuropathy 18 patients 6 pts Distal Symmetrical Sensory Electrophysiological studies: NS No Hyperviscosity Syndrome No Lymphoma related symptoms 12 pts 10 Typical DADS 2 CIDP without anti MAG 5 pts anemia 6 bone marrow inv. > 50% 1 lymphadenopathy OBSERVATION WM TREATMENT

32 Peripheral neuropathy associated with WM Niguarda series 12 treated patients 2 Rituximab monotherapy 10 DRC Haematological response: Response on Neurological Symptoms: 11 PRs 1 SD 1 complete recovery 2 partial amelioration 9 no response