1. 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 michael.lunn@uclh.nhs.uk

3. 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?

4. What is a nerve?

7. A nerve conducts electrical impulses around the nervous system

9. skin

10. Brandner S - NHNN Normal nerveCIDP Nerve from real life – normal and damaged

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

12. 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?

13. What is a neuropathy?

14. 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

15. Neuropathy represents damage to the myelin sheath or the axon

16. How common is it? Prevalence (per 100,000) Martyn CN and Hughes RAC Peripheral Neuropathies in Epidemiology of Neurological Disorders BMJ 1997 All types 2400 Carpal tunnel 5800 f 600 m Diabetic300 HMSN8 - 41 CIDP and Waldenström's> 1

17. 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. 18 Symptoms of peripheral neuropathy Positive – Pins and needles – Pain – Muscle twitching – Cramps – Restlessness – Tremor Negative – Loss of sensation – numbness – Weakness – Wasting

20. Distal length dependent neuropathy symptoms

21. 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. 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. 2000Current Medicine, Inc

23. 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?

24. 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

25. An EMG Lab…

26. Median Sensory Study

27. A B Conduction velocity = A/B ms -1

29. What does Waldenström's neuropathy look like?

30. 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

32. Widely spaced myelin

33. 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?

34. Inflammatory Peripheral Neuropathy

35. 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

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

37. 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

40. Lunn et al Brain 2002

41. 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

42. Treatment for Waldenstrom’s Neuropathy

43. 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

44. 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/m 2 usual dose – recent high dose study added improvement Some published cases of worsening We give in close discussion with haematology services

45. Mechanisms of B-cell Functions Dalakas M Neurology 2008;70:2252

46. B cell development 2 Dalakas M 2008 Nature

47. Rituximab Chimeric (Mouse-human) anti- CD20 antibody 1 st monoclonal approved for use in cancer (1997) Depletes CD20 +ve cells in hours to days for 8-12months

48. 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

49. 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

50. Where might I find out more? GBS Support Group – http://www.gbs.org.uk http://www.gbs.org.uk GBS-CIDP Foundation International – http://www.gbs-cidp.org/ http://www.gbs-cidp.org/ The Neuropathy Trust – http://www.neurocentre.com/ http://www.neurocentre.com/

51. Johns Hopkins University Dept of Neurology Kazim A Sheikh John W. Griffin Tony W. Ho David R. Cornblath Guy M. McKhann NIH, Bethesda Richard Proia Second Teaching Hospital Shijiazhang, China Chun Y. Li Beijing Children Hospital H Wu Johns Hopkins University Dept of Pharmacology Ronald L. Schnaar James E.K. Hildreth Susan Fromholt Saki Itonori Guy’s Hospital Dept of Neuroimmunology Richard Hughes Norman Gregson National Hospital for Neurology and Neurosurgery Ken Smith Mary Reilly Patrick Berthoud Charitable Trust

52. MRC Centre for Neuromuscular Disease