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