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MRC Centre for Neuromuscular Disease Neuropathy and Waldenström's Macroglobulinaemia London January 2011 Dr Michael Lunn Consultant Neurologist and Clinical Lead in Neuroimmunology National Hospital for Neurology and Neurosurgery Queen Square London WC1N 3BG [email protected] 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 Nerve from real life – normal and damaged Normal nerve CIDP Brandner S - NHNN 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 Carpal tunnel Diabetic HMSN CIDP and Waldenström's 2400 5800 f 600 m 300 8 - 41 >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? Symptoms of peripheral neuropathy • Positive • Negative – Pins and needles – Pain – Loss of sensation – numbness – Muscle twitching – Cramps – Restlessness – Tremor – Weakness – Wasting 18 Distal length dependent neuropathy symptoms 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 21 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 22 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 B Conduction velocity = A/B ms-1 A 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 Vasculitic Neuropathy 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 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 lupuserythematosus Sjörgren’s syndrome Mixed connective tissue disease Other Serum sickness Infectious, malignant, related to chemotherapy 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 Inflammatory neuropathy associated with infection HIV neuropathies, including CMV neuropathy Leprosy Lyme disease Chaga’s disease 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 POEMS syndrome Paraneoplastic Sub-acute sensory neuropathy/neuronopathy - small cell lung carcinoma and anti-Hu Abs Other paraneoplastic tumour -antibody syndromes Metabolic Diabetic lumbo-sacral plexopathy 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) antiCD20 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/ National Hospital for Neurology and Neurosurgery Guy’s Hospital Dept of Neuroimmunology Ken Smith Mary Reilly Richard Hughes Norman Gregson Johns Hopkins University Dept of Neurology Kazim A Sheikh John W. Griffin Tony W. Ho David R. Cornblath Guy M. McKhann Johns Hopkins University Dept of Pharmacology Ronald L. Schnaar James E.K. Hildreth Susan Fromholt Saki Itonori NIH, Bethesda Richard Proia Second Teaching Hospital Shijiazhang, China Chun Y. Li Beijing Children Hospital H Wu Patrick Berthoud Charitable Trust MRC Centre for Neuromuscular Disease