gammopatie monoclonali e neuropatia · 2020. 7. 9. · multifocal motor neuropathy with conduction...
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Enrica Morra Ospedale Niguarda Ca’ Granda
Milano
Gammopatie monoclonali e
neuropatia
Paraprotein and Neuropathy
PDN
Paraprotein and Neuropathy
Journal of the Peripheral Nervous System 15: 185-195, 2010
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
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 HIV neuropathies, including CMV neuropathy Leprosy Lyme disease Chaga’s disease Paraneoplastic
Sub - acute sensory neuropathy/neuronopathy - small cell lung carcinoma and anti - Hu Abs
Other paraneoplastic tumour - antibody syndromes Metabolic Diabetic lumbo - sacral plexopathy POEMS syndrome
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
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
Recommended investigations for patients with neuropathy and monoclonal gammopathy
Hematology /Imaging /Histopathology
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
CIDP phenotype Clinical features Other characteristics
Typical CIDP
(> 50%)
SM symmetric, proximal and distal, legs>arms
Association with different infectious or Hematological disorders
Pure sensory CIDP
(10-30%)
Pure sensory symmetric, proximal and distal, legs > arms, predominant ataxia possible
Cranial nerve involvement possible
Lewis-Sumner Syndrome
(15%)
SM asymmetric, arms > legs Cranial nerve involvement possible
DADS (Distal Acquired
Demyelin. Sensory PN) (10%)
Sensory predominant, mild weakness possible , distal, legs>arms
Often monoclonal IgM gammopathy, (DADS-M) with and without anti-MAG
Pure Motor CIDP (<10%) Pure motor, symmetric, proximal and distal
Focal CIDP (2%) Motor or SM, involv. of 1plexus or 1 or more nerves in one limb
Spectrum of Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
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. - 3.5% patients with myeloma have neuropathy (pre-Rx).
• 10% patients with neuropathy have MGUS
• IgM>IgG>IgA in association with neuropathy
• κ light chain over-represented
Paraprotein Proportion with paraprotein and neuropathy (%)
Proportion with paraprotein without
neuropathy (%) IgM 50 15
IgG 35 75
IgA 15 10
Ramchandren and Lewis 2012
IgM anti-MAG paraproteinemic
demyelinating peripheral neuropathy
50% of pts with IgM-MGUS and PN have anti-MAG (myelin-
associated 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
Myelin separation
Widely spaced myelin
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
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
IgM anti-MAG paraproteinaemic
demyelinating peripheral neuropathy Distal acquired demyelinating sensory neuropathy (DADS)
Joint Task Force of the EFNS and the PNS, 2010
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
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
IgM anti-MAG paraproteinemic
demyelinating peripheral neuropathy Distal acquired demyelinating sensory neuropathy (DADS)
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
8% Painful S>>M Axonal
Gangliosides GM1+/-GD1b Disialosyl gangliosides GD1a GD1b
GM2
<3% MMN* S>>M M SM
MMN or M
Focal demyeliniation Demyelinating Demyelinating Axonal
? Cytoskeletal proteins ? SM, CIDP Mostly axonal
Most frequently antineural IgM reactivties
*Multifocal Motor Neuropathy: purely motor, multifocal partial motor conduction blocks Invariable response to HD iv Ig
Nobile Orazio, 2009
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
IgM anti-MAG paraproteinemic 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
Nobile Orazio, 2000 Oksenhendler 1995 Comi et al 2002 Dalakas et al 1996 Mariette et al 1997, 2000
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
IgM anti-MAG paraproteinaemic demyelinating peripheral neuropathy
Treatment
Lunn and Nobile Orazio2006; Benedetti 2008; Niermeijier et al 2007; Dalakas 2009 Lunn et al 2012 – Cochrane Library
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)
IgM anti-MAG paraproteinaemic demyelinating peripheral neuropathy
Immunosuppressive Treatment
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
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)
May respond to treatment regimens used for CIDP pts without MGUS (considered sensory variants of CIDP)
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
Lunn et al, 2009
- Steroids - IVIg - Plasma exchange
IgG and IgA paraproteinemic demyelinating neuropathy Treatment
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
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
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
Poor prognosis: 12-33 m
Therapy:
-High dose melphalan -Autologous Stem cell transplantation (in younger pts) -Lenalidomide/thalidomide -Anti VEGF monoclonal antibodies -Cyclophosphamide
POEMS
Treatment of PN by plasma cell disorder
Disease Most commonly associated paraprotein
Treatment
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
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
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
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
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
nerve biopsy
Eurelings et al 2003; Turner et al 2003
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
OBSERVATION
12 pts 10 Typical DADS 2 CIDP without anti MAG
5 pts anemia 6 bone marrow inv. > 50% 1 lymphadenopathy
WM TREATMENT
Peripheral neuropathy associated with WM Niguarda series
12 treated patients 2 Rituximab monotherapy
10 DRC
Haematological response: 11 PRs 1 SD Response on Neurological Symptoms: 1 complete recovery
2 partial amelioration 9 no response
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