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Waldenstrom’s and the Nervous System

Waldenstrom’s and the Nervous System. From Peripheral Nerve to Brain Fred H. Hochberg, MD. Purpose. Define the effects of WM IgM on Nerve Describe the investigations and therapy Describe Bing-Neel syndrome (brain) If IgM causes nerve damage does it cause Bing-Neel?.

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Waldenstrom’s and the Nervous System

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  1. Waldenstrom’s and the Nervous System From Peripheral Nerve to Brain Fred H. Hochberg, MD

  2. Purpose • Define the effects of WM IgM on Nerve • Describe the investigations and therapy • Describe Bing-Neel syndrome (brain) • If IgM causes nerve damage does it cause Bing-Neel?

  3. WM Causes Neurologic Illness • Peripheral neuropathy – POEMS • Hyperviscosity > 3cP • Invasion of CSF with WM cells • Transformation into NHL • CN, myelopathy. • Bing - Neel

  4. “M spike” Neuropathies • MAG – Myelin Associated Glycoprotein = sensation, gait and tremor • GALOP – Gait, Auto-antibody, Late age, Onset, Polyneuropathy • POEMS – Polyneuropathy, Organomegaly, Edema, M spike, Skin change

  5. Nerve Damage • Antibody mediated, as with MGUS. • MGUS PN: symmetric progressive, distal, sensory:rare motor, cranial nerve palsies, mononeuropathy, and mononeuropathy multiplex. • POEMS: (WM) organomegaly, endocrinopathy, and skin changes, IgM

  6. WM Neuropathy • 20% of WM (28% +Ab) • IgM: anti-myelin Ab • IgM leaks through tight junctions into peri- and endoneurial space • . * Menke, 2006 #15

  7. WM: IgM Ab to Nerve Fats Motor Neuropathies 1(NICOLE BAUMANN) To trisulfated heparin disacc. [8%] SGPG [6%]), GM1 [<10%]) MAG [50%]). • MAG links Schwann cells to axons. • Thus IgM anti-MAG produces axonal atrophy. • IgM causes separation of myelin lamellae • IgM to sulfatide causes sensory axon loss . * Rudnicki, 1998 #16** Levine, 2006 #18

  8. WM: Anti glycolipid- Motor • WM 47 % had peripheral neuropathy vs. 9 % controls. • 8 % demyelination was found (4% with anti-MAG antibodies, 4 % without). • MGUS have anti-MAG more than WM? . • MGUS neuropathy presents earlier • MGUS then have less M-protein . • MGUS Rx defers WM. *

  9. WM: PN anti-MAG Anti-MAG antibodies induce widenings of the peripheral myelin lamellae of a myelin sheath bar = 0.5 µm

  10. WM PN Vital 1997

  11. WM: PN widened lamellae Vital 1997

  12. Demyelination and Remyelination Demyelin Remyelin.

  13. Sural Nerve Biopsy

  14. Punch Biopsy

  15. Punch Biopsy

  16. IgM Deposition in Epidermal Nerves C fiber C-fiber 67 year old with WM. IgM 2700 mg. Severely painful neuropathic symptoms. Normal NCVs.

  17. Tensor Imaging and Peripheral Nerve

  18. DTI and spinal cordZurich 2006 AJNR

  19. WM: IgM PN 3 • sulphatide Ab (5% WM): sensory axon loss; • MAG Ab (4% of WM): sensorimotor axon loss and demyelination. • NO MAG: Demyelination in 4% of WM • Rare PN infiltration by lymphoplasmacytic B cells. • More profound motor involvement is described. • 10% of multifocal motor neuropathy with conduction block have IgM monoclonal gammopathy. • Can be severe motor, mononeuropathy multiplex and autonomic (BP, constipation, and impotence). • Nerve compression syndromes (CTS) seen in amyloidosis.

  20. WM: PN 2 • PN (anti-MAG): • Sensory, sensory ataxia, slowly progressive . • 47% of 119 WM patients (versus 9% of 58 controls) had discomfort and sensory loss in the legs. • 35% lower vibration in WM, • 3.4 times more likely abnormal pin sensation • 5.5 times more likely gait disorders. (Levine, Journal of Neurology, Neurosurgery, and Psychiatry 2006;77:224-228 Pestronk)

  21. POEMS • Vision: pressure 29% to 55% blurring, bleeding retina, inflammation • Skin thickening/shiney, blood flow • Swelling-Belly, Fingers or whole body • Hormonal-Diabetes (25%), Thyroid low (25%), breast tissue (60%), menses (60%), impotence (70%); Erectile • Large Spleen, Lymph nodes • Kidney failure • Thrombotic events

  22. Bortezomib-Velcade Neuropathy • SUMMIT trial: 80% P.N. prior to therapy • 34% peripheral neuropathy with therapy, • 22% grade 1 or 2. • APEX study: • 36% neuropathy, • 7% grade 3 or 4 toxicity. • >50% better within 3 months of therapy • The dose is reduced if sensory neuropathy

  23. Sensory Testing at HomeHow to spend the evening • Sensation: 10-g fishing line touches first toe. Repeat four times (R and L): guess when it was not perceived. • Vibration testing (On/Off): 128-Hz tuning fork to first toe. Do twice with and without dampening. • Vibration: report the end of vibration • Superficial pain: Neurotip (Owen Mumford, Oxford, U.K.) to determine number of times the pain was not perceived. Perkins Toronto 2001 - DM

  24. Stand on One Foot – Repels Friends (2001 – Springer)

  25. WM Controls Peripheral Neurop 48% 19% <0.001 PN Diagnosed 22% 0% <0.001 Vibratory Score 4.9 7.1 <0.001 Pin loss 37% 11% <0.001 Gait Abnl 31% 5% <0.001 Demyel 8% 0% <0.001

  26. Therapy of IgM Neuropathy • Motor Weakness • Progressive or disabling weakness • Proximal weakness • Elevated levels of IgM • Specific Autoantibodies • MAG • GM-1 • Sulfatide • Sensory • Disabling Pain • Non-length dependent • Electrophysiology • Demyelinating • Proximal • Distal • Active denervation

  27. Treatment MAG Neuropathies Pestronk et al, JNNP 2004 • Rituximab improves distal strength and gait. • RTX- 375 mg/M2 2/w then 1/10 wks for 1 year • Response may take 2 years • Little change in sensory symptoms or sural responses

  28. Treatment of IgM Related Small Fiber Neuropathy Average Reduction in IgM 44%. Levine et al, ANS 2008

  29. Treatment: Demyelinating PN with MGUS • 10-20% CIDP have MGUS • symmetric proximal and distal weakness • elevated CSF protein • electrical proximal demyelination and conduction block • MGUS is IgG or IgA • Respond well to immunotherapy • Corticosteroids • IVIG • Plasmaphresis

  30. Demyelinating PN – IgM MGUS • Clinical phenotype unlike previous group • 90% are men usually >60 years old • gait unsteadiness • Demyelinating features seen at nerve terminus • Predominantly sensory symptoms with mild distal weakness. • “CIDP-MGUS or IgM MGUS” is now Distal Acquired Demyelinating Neuropathy (DADS) 1 30-50% have IgM against MAG No difference between MAG positive and MAG negative pts Katz et al, Neurology 2000

  31. Distal Aquired Demyelinating Polyneuropathy with IgM (DADS-M) 1: Dyck et al, N Eng J of Med 1991. 2: Dalakas et al Ann Neurol 1996. 3:Mariette et al Neurology 2000. 4: Levine et al Neurology 1999. 5: Pestronk et al JNNP 2003. 6: Renaud et al Muscle Nerve 2003. 7: Renaud et al Neurology 2006. 8: J Periph Nerv Systm 2006 • Respond poorly to immunotherapy • No benefit with plasmaphresis 1 • 20% improvement with IVIG2 Dalakas • Interferon a no benefit 3 • 4 case series: Rituximab benefit 4-7 • Mayo clinic controlled trial of Rituximab in MGUS related neuropathies • European Neurological Societies 2006 guidelines advocated withholding treatment unless there is significant disability 8

  32. Axonal PN with IgM Disorders • Sulfatide • 30% may have motor weakness and gait disorder. • 3% of CIDP pts • 4% of WM pts • No controlled studies of therapy. • Potential benefit from cyclophosphamide or Rituximab. • Ab negative • Unclear relationship between IgM and PN • often pain and sensory symptoms without motor . • Search for other causes of PN or mimics of PN • Treatment: symptomatic

  33. Potential Aides in Neuropathy • Biotin, choline, inositol, thiamine • B12 • Alpha-lipoic acid useful reduction in pain and numbness in diabetes • Approved in Germany. • antioxidant • Gamma linolenic acid in oils (borage, grape seed, black currant) • double-blind: gradual reversal of nerve damage

  34. Neurontin • Diabetic neuropathy • significant reduction in pain • 26 percent were pain-free vs.15 percent with placebo • Post-herpetic neuralgia (zoster) (double blind) • significant reduction in average daily pain • Neurontin (16%) pain-free vs. placebo (8.8%) • Neurontin improved sleep and life quality.Fatigue, dizziness and tremor

  35. Skin stem cells reform nerves- Midha, Calgary

  36. Rate of regeneration • Myelin repair begins within 24 hours • Axon repair starts at same time • Axon sprouts diminish further away from the cell body • Rate of growth is .5 to 9mm/day • Regeneration can occur even a year after damage

  37. ALADIN I, ALADIN III, SYDNEY, NATHAN II Ziegler 1258 ALA or placebo patients • alpha-lipoic acid intravenously 3 weeks • Total Symptom Score (TSS) in the feet. • TSS (baseline to the end of i.v.) ALA> Placebo by 24% • daily changes in TSS: ALA daily improved pain, burning, numb • responder rates (> or =50% improved TSS): 53%:37%, • Neuropathy Impairment Score (NIS) LExt, ALA>Placebo by 16% • pin-prick and touch-pressure sensation • adverse events did not differ between the groups.

  38. GLA - Glasgow • Twenty-two: distal diabetic PN • double-blind, placebo study – 360mg oral gamma-linolenic acid . • 6 months:. • improved neuropathy symptom score • median nerve motor conductions • compound muscle action potential amplitude • median and sural sensory nerve action potentials

  39. What is ‘Bing-Neel’ ? • Jens Bing and Axel Neel (1936*) • nerve root + cord dysfunction with WM-associated hyperglobulinemia • Two cases combined lymphoplasmacytic infiltrates (meninges, roots and cord) with antibody-mediated damage; one the latter • ‘universal toxic effect…and not to a local effect’ . Marrow not studied. • No myeloma…clinical, x-ray, autopsy” * Bing, J; Neel, A. Two Cases of Hyperglobulinaemia with Affection of the Central Nervous System on a Toxi-Infectious Basis (Myelitis, polyradiculitis, Spinal Fluid Chages) Acta Medica Scandinavica 88:fascicle V-V1, 492-506, 1936

  40. Case 2 con. • ‘Toxic Infective’ ‘Polyradiculitis and ‘myelo-encephalopathia’ with degenerative changes in the spinal cord, anterior/posterior roots • Anterior horn cells-ganglion cells: fatty changes One single medullary vessel had round cell infiltrate • No mention was made of lymphoplasmacytic infiltrate nor of bone marrow findings.

  41. Presentation • Presented with generalized fatigue and hiccoughs in February 2003. Symptoms likely began in September 2002 and became manifest following a vacation to Northern Germany. • “Every five or six seconds the hiccough came and much stronger and louder in the night perhaps from being in the horizontal position.” Spared were lips and tongue and speech during the spells. These hiccoughs could not be stopped.

  42. Presentation • Headaches • Psychiatric changes • Visual hallucinations • Seizures – hiccoughs and LOC • Gait changes • Right hand alterations

  43. Drappatz

  44. Classical Bing-Neel Syndrome Overview • Three cases: Bing and Neel (1936) and Bing, Fog et al. (1937) • Waldenstrom’s Macroglobulinemia (WM) with central nervous system (CNS) infiltration • Clinical: encephalopathy, strokes, seizures, hemorrhages, Bell’s Palsy, neuropathy, ocular involvement, numbness, weakness, headaches

  45. Literature and MGH series (n=66)Manifestation of Bing-Neel Syndrome

  46. Misapplied Bing-Neel Syndrome in Literature

  47. Hypothesis: Two types of Bing-Neel • Type A – WM Cells of brain and/or CSF • Histologically-proven WM • marrow biopsy, flow of blood or other fluid (e.g. CSF, pleural, etc.) • Brain or dura with WM invasion • From biopsy or autopsy • CSF flow cytometry demonstrating WM invasion • CSF with > 5 WBCs

  48. Hypothesis: Two types of Bing-Neel • Type B – Non-cellular infiltration • Patient with histologically-proven WM • From tissue biopsy, flow cytometry of blood or other fluid (e.g. CSF, pleural, etc.) • No histology showing cellular WM infiltration of the brain, dura or CSF • Antibody-mediated neurologic disease • E.g. ANA, ro, la • Brain involvement from imaging but without all features related to infiltration of cells • E.g. MRI with white matter abnormalities and clinical neurological symptoms but without histology • CSF < 5 WBCs

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