MRC Centre for Neuromuscular Disease

Neuropathy and Waldenström's Macroglobulinaemia

London January 2011

Dr Michael Lunn

Consultant Neurologist and Clinical Lead in NeuroimmunologyNational Hospital for Neurology and Neurosurgery

Queen SquareLondon WC1N 3BG

michael.lunn@uclh.nhs.uk

Neuropathy and Waldenström's Macroglobulinaemia

• What is a nerve?• What is a neuropathy?• What are the symptoms and signs?• How is it diagnosed?• Why and how does Waldenstrom’s cause

neuropathy?• What can be done about it? Treatment.• Where might I find out more?

What is a nerve?

A nerve conducts electrical impulses around the nervous system

A nerve conducts electrical impulses around the nervous system

skin

Brandner S - NHNN

Normal nerve CIDP

Nerve from real life – normal and damaged

The nerve cell surface is covered in ‘targets’ for antibodies

Neuropathy and Waldenstrom’s Macroglobulinaemia

• What is a nerve?• What is a neuropathy?• What are the symptoms and signs?• How is it diagnosed?• Why and how does Waldenstrom’s cause

neuropathy?• Are there any similar conditions?• What can be done about it?• Where might I find out more?

What is a neuropathy?

What is a neuropathy?

• A neuropathy is present when a peripheral nerve is damaged

• There are many causes of peripheral neuropathy– Compression (carpal tunnel syndrome)– Diabetes– Toxins (e.g. alcohol) and vitamin deficiencies– Infections (e.g. leprosy)– Inflammatory causes

Neuropathy represents damage to the myelin sheath or the axon

How common is it?Prevalence (per 100,000)

Martyn CN and Hughes RAC Peripheral Neuropathies in Epidemiology of Neurological Disorders BMJ 1997

All types 2400Carpal tunnel 5800 f 600 mDiabetic 300HMSN 8 - 41CIDP and Waldenström's > 1

Neuropathy and Waldenstrom’s Macroglobulinaemia

• What is a nerve?• What is a neuropathy?• What are the symptoms and signs?• How is it diagnosed?• Why and how does Waldenstrom’s cause

neuropathy?• Are there any similar conditions?• What can be done about it?• Where might I find out more?

18

Symptoms of peripheral neuropathy

• Positive– Pins and needles– Pain

– Muscle twitching– Cramps– Restlessness– Tremor

• Negative– Loss of sensation –

numbness

– Weakness– Wasting

Distal length dependent neuropathy symptoms

21

Signs of peripheral nerve disease

• Weakness • Wasting• Loss of reflexes• Sensory loss• Ataxia (unsteadiness)• Thickening of nerves• Skin changes• Consequences of sensory loss – ulcers, arthropathy• Others

22

Distal wasting

Courtesy of imagesMD Taken from: Thomas D. Bird, S. Mark Sumi In Atlas of Clinical Neurology: Clinical Neurology. Edited by Roger N. Rosenberg.

Current Medicine, Inc. 2000

Neuropathy and Waldenstrom’s Macroglobulinaemia

• What is a nerve?• What is a neuropathy?• What are the symptoms and signs?• How is a neuropathy diagnosed?• Why and how does Waldenstrom’s cause

neuropathy?• Are there any similar conditions?• What can be done about it?• Where might I find out more?

How do we diagnose a neuropathy?

• Clinical symptoms and patient characteristics

• Clinical signs on examination

• Neurophysiological testing – nerve conduction studies and electromyography

• Special blood tests

An EMG Lab…

Median Sensory Study

A

B

Conduction velocity= A/B ms-1

What does Waldenström's neuropathy look like?

Anti-MAG paraproteinaemic demyelinating peripheral neuropathy (PDPN)

• Chronic progressive sensorimotor demyelinating neuropathy

– Older person (average 65-75 years), male– Numb in feet and unsteady– Tremor of hands (sometimes mild, sometimes worse)– Ataxic (unsteady) walking

• IgM paraprotein in serum• Paraprotein has ‘anti-MAG’ activity

• The antibody ‘sees’ a nerve sugar on MAG called HNK-1• also on some other nerve molecules but MAG most likely

• Characteristic pathology

Widely spaced myelin

Neuropathy and Waldenstrom’s Macroglobulinaemia

• What is a nerve?• What is a neuropathy?• What are the symptoms and signs?• How is it diagnosed?• Why and how does Waldenström's cause

neuropathy?• Are there any similar conditions?• What can be done about it?• Where might I find out more?

Inflammatory Peripheral Neuropathy Idiopathic

Acute Acute inflammatory demyelinating polyradiculoneuropathy (AIDP)

Acute motor axonal neuropathy (AMAN) Acute motor-sensory axonal neuropathy (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 demyelinating polyradiculoneuropathy (SIDP) Chronic Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Multifocal motor neuropathy with conduction block (MMNCB) Chronic relapsing axonal neuropathy Chronic ataxic sensory neuronopathy Paraproteinaemic 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

Vasculitic 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

Waldenström's causes an ‘inflammatory’ neuropathy

• Paraprotein associated neuropathies part of group of inflammatory neuropathies

• Inflammatory neuropathies have presumed ‘immune mediated’ pathogenesis

• Inflammatory cells infiltrate nerves and damage myelin and/or axons

The IgM in Waldenström's sometimes targets Myelin Associated Glycoprotein (MAG)

MAG

Myelin Associated Glycoprotein (MAG)

• A myelin sugar-protein • 1% brain protein 0.1% nerve proteins

• MAG is localised in specific sites on the myelin surface

• MAG associates with other signalling molecules that control the axon and the myelin

• MAG normal functions• Cell-cell recognition• signal transduction through the membrane, • myelin-axon inter-communication

Lunn et al Brain 2002

Conclusions

• Neurofilaments are significantly closer in diseased axons from patients with anti-MAG paraproteins.

• We think that thinned nerves are not able to transport substances so easily

• This leads to damage to the ends of the nerves

• Treating earlier may be of benfit but we don’t know for definite

Treatment for Waldenstrom’s Neuropathy

IgM paraproteinaemic (anti-MAG) neuropathy treatment

• Is treatment required at all?

• Do you need to treat the Waldenström's?

• IVIG confers short term benefit – RCT– Multiple other immunosuppressants used

• Melphalan, chlorambucil, cyclo +/- steroid, fludarabine

• Rituximab (anti-CD20) – promising in some studies• 8 studies – 6 (79 pts) positive (1 (3 pts) negative)• 3 fully published, 2 not adequately controlled• 1 Randomised trial published (Dalakas 2009) with serious flaws –

reported ‘positive’ • Another trial completed – mixed results• 375mg/m2 usual dose – recent high dose study added

improvement• Some published cases of worsening• We give in close discussion with haematology services

Mechanisms of B-cell Functions

Dalakas M Neurology 2008;70:2252

B cell development 2

Dalakas M 2008 Nature

Rituximab

• Chimeric (Mouse-human) anti-CD20 antibody

• 1st monoclonal approved for use in cancer (1997)

• Depletes CD20 +ve cells in hours to days for 8-12months

Rituximab - Safety• 84% infusion reactions – 97% mild• 30% post infusion infection – 1-2% severe

• Maintained Ig levels and T-cell function• Concomitant anti-T-cell therapy hazardous

• Serious infections more common with concomitant illness/immunosuppression– PML

• 2 cases in SLE treated with Rituximab (+ additional immunsuppressants)

• 23 cases in neoplasia Rx with Rituximab

• HACA antibodies uncommon• Some high titre, more common in AI disease• Effects unclear – may cause depletion failure

Other treatments

• Not usually painful – pain medications• Physiotherapy for walking and balance• Foot care• Walking and balance aids

– Ankle foot orthoses– Sticks– Walkers

• Driving advice

Where might I find out more?

• GBS Support Group– http://www.gbs.org.uk

• GBS-CIDP Foundation International– http://www.gbs-cidp.org/

• The Neuropathy Trust– http://www.neurocentre.com/

Johns Hopkins UniversityDept of Neurology

Kazim A SheikhJohn W. Griffin

Tony W. HoDavid R. CornblathGuy M. McKhann

NIH, Bethesda

Richard ProiaSecond Teaching HospitalShijiazhang, ChinaChun Y. Li

Beijing Children HospitalH Wu

Johns Hopkins UniversityDept of Pharmacology

Ronald L. Schnaar

James E.K. HildrethSusan FromholtSaki Itonori

Guy’s HospitalDept of Neuroimmunology

Richard HughesNorman Gregson

National Hospital for Neurology and Neurosurgery

Ken SmithMary Reilly

Patrick Berthoud Charitable Trust

MRC Centre for Neuromuscular Disease