Differential diagnosis and treatment strategy of neuromuscular disorders - PowerPoint Presentation

1. Differential diagnosis and treatment strategy of neuromuscular disorders2017住院醫師教育課程中醫大附醫 郭育呈20170820

2. OutlineClassification and clinical manifestations of dysimmune neuropathiesDiagnosis of dysimmune neuropathiesTreatment of dysimmune neuropathiesAutoimmune myasthenia gravisAChR Ab, MuSK Ab, LRP4 AbLambert-Eaton myasthenic syndrome (LEMS)2

3. Classification-IGuillain-Barre syndrome (GBS)AIDPAMANAMSANAcute sensory neuronopathyAcute pan-dysautonomiaRegional variants: MFS, oropharyngealOverlap: Miller Fisher-Guillain Barre overlap syndrome3Acta Neurol Scand 2005;112:115-125. Nat Clin Pract Neurol 2007;3:198-211.

4. Classification-IIChronic inflammatory demyelinating polyneuropathy (CIDP)Classical CIDP, axonal CIDP, sensory CIDP CIDP with DMCIDP with MGUS (IgM, IgG, IgA)MMN with and without conduction blockMADSAM (Lewis-Sumner syndrome)MASAMDistal acquired demyelinating sensory (DADS) neuropathy 4Acta Neurol Scand 2005;112:115-125.

5. Classification-IIIParaprotein-associated neuropathy, monoclonal gammopathiesWaldenstrom’s macroglobulinemiaAnti-myelin-associated glycoprotein (MAG) neuropathiesPolyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndromeMixed cryoglobulinemiaGait ataxia, late-onset polyneuropathy (GALOP) syndromeMonoclonal gammopathy with undetermined significance (MGUS)5Acta Neurol Scand 2005;112:115-125.

6. Diagnostic methodsClinical phenotypesElectrophysiological findingsCSF study- protein, IgG index (inherited, vasculitis)Serum protein electrophoresis (S-PEP)- serum immunoelectrophoresis (S-IEP) & serum immunofixation electrophoresis (S-IFE)Antibodies in the serumPathology6

7. Autoantibodies in the serumMonoclonal antibodies without identifiable antigenic targets (M proteins)Monoclonal and polyclonal autoantibodies that bind to specific neural componentsDiagnostic utilityProvide clues to the pathogenesis of neuropathic syndromeSuggest specific avenues of therapy7

8. Guillain Barre syndrome8GBS always follows an infection as URI or GI infectionCampylobacter jejuni, CMV, EBV, mycoplasma pneumonia Vaccination and stress events  debated25% artificial ventilation (vital capacity < 15-20 ml/kg)2/3 ANS dysfunctionUrinary retention and constipation are unusual at the onset of the disease but commonly develop at the nadir of the disease. Autoimmunity Reviews 2014;13:525-530.

9. Asbury et al, Ann Neurol 1990- 2/3- 80%- GBS at nadir> 1 week

10. Lancet Neurol 2008

11. Lancet Neurol 2008Antibodies to gangliosides

12. Guillain Barre syndrome12Autoimmunity Reviews 2014;13:525-530.20% disability after 1 yearAdverse prognostic factors: advanced age, the severity of disease at nadir, bed-bound, artificial ventilation. Plasma exchange or IVIg (0.4 gm/kg/day in 5 days)Oral steroid or pulse therapy with methylprednisolone alone  not beneficial

13. Multifocal motor neuropathy13Brain 2002;125:2591-2625.1-2/100,000, male > female, mean onset 40 y/oPure motor, asymmetric weakness80% initially affected forearm/hands, 10% LLs50% fasciculation and cramp, prominent than MNDHypo-reflexia (patchy or diffuse), 20-30% normo-/hyper-reflexiaMinor vibration impairment of lower limbs

14. Multifocal motor neuropathy14Cochrane reviewAutoimmun Rev 2014;13:525-530.Multifocal conduction blocks30-80% anti-GM1 IgM antibody (not specific)MMN without conduction block-> IVIg good responseIVIg is the first-line therapyUncontrolled studies: cyclophosphamide, interferon β-1a, cyclosporine, methotrexate, azathioprine and Rituximab

15. Autoimmun Rev 2014;13:525-53015EFNS criteria-JPNS 2010;15:295-301.

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17. MADSAM (Lewis-Sumner syndrome)17Multifocal acquired demyelinating sensory and motor (MADSAM) neuropathyPredominant distal, asymmetric weakness most affecting upper limbs with sensory impairmentInitial onset: distal part of an upper limb (70%)Numbness confined to dermatome (not stocking-glove)Mononeuropathy multiplex, demyelinating S-M polyHypo-reflexia with multifocal & asymmetric pattern, minority of patients with generalized hypo-reflexiaMN 1999;22:560-566. MN 2005;31:88-94.Brain 2004;127:2010-2017.

18. MADSAM (Lewis-Sumner syndrome)18Oculomotor nerve palsies for 2 patients (26%)Multifocal conduction block and demyelination (forearm)87% abnormal distal sensory potentials (sural n SNAPs)82% elevated CSF protein (MMN 9%)No anti-GM1 antibody (MMN 56%)Sural nerve biopsy: prominent demyelination (MMN no)MN 1999;22:560-566.Brain 2004;127:2010-2017.

19. MADSAM (Lewis Sumner syndrome)19A very focal motor fiber demyelination sparing the nerve endings, whereas sensory fiber involvement was widespread.Course: chronic progressive in 71% , relapsing-remitting in the others.IVIg 55%, 33% oral steroids  73% positive response to immune-mediated therapyBrain 2004;127:2010-2017.

20. 20MN 1999;22:560-566.

21. CIDPDADS neuropathyMADSAM neuropathyMMNWeaknessSymmetric, P+DSymmetric, D,Mild or no weaknessAsymmetric, D > P,Upper > LowerAsymmetric, D > P,Upper > LowerSensorySymmetricSymmetricMultifocal (nerve)NoDTRReduced, symmetricReduced, symmetricReduced(multifocal or diffuse)Reduced(multifocal or diffuse)NCV: demyelinatingSymmetricSymmetric, Prolonged DLAsymmetric (multifocal)Asymmetric (multifocal)CBFrequent(-)FrequentFrequentAbnormal SNAPsSymmetricUncommonAsymmetric (multifocal)SNAPs normalCSF proteinsHighHighHighNormalMonoclonal proteinIgG or IgAIgM-κ,50-70% MAG (+)RareRareAnti-GM1 AbRare(-)Rare50% (+), IgMPrednisoloneYesPoorYesNoPLEXYesPoorPossibleNoIVIgYesPoorYesYesCyclo-phosphamideYesPoorPossibleYes21Neurol Clin 2013;31:533-555.

22. Paraproteinemic demyelinating polyneuropathy22EFNS 2006 guideline. Euro J Neurol 2006;13:809-818.Clinical phenotypesImmunoglobulin classMonoclonal gammopathy of undertermined significance or malignant plasma cell dyscrasiaPresence of antibodies to MAGElectrophysiologyLikelihood that paraprotein is causing the neuropathy

23. Paraproteinemic demyelinating polyneuropathy23EFNS 2006 guideline. Euro J Neurol 2006;13:809-818.Paraprotein: an underlying disease of plasma cells in bone marrow (malignant or MGUS)IgM paraproteinemia vs IgG/IgAHeavy chain (IgM, IgG, or IgA) and light chain (kappa or lambda)

24. Classification of hematological conditions with a paraprotein24EFNS 2006 guideline. Euro J Neurol 2006;13:809-818.Malignant monoclonal gammopathiesMultiple myeloma (overt, asymptomatic (smouldering), non-secretory, or osteo-slcerotic)Plasmacytoma (solitary, extramedullary, multiple solitary)Malignant lympho-proliferative disease: - Waldenstrom’s macroglobulinemia - Malignant lymphoma - Chronic lymphocytic leukemiaHeavy chain diseasePrimary amyloidosis (AL) (with or without myeloma) Monoclonal gammopathy of undertermined significance (MGUS)

25. Investigation of paraprotein25EFNS 2006 guideline. Euro J Neurol 2006;13:809-818.Serum IFECBC-DC, BUN/Cr, AST/ALT, Ca, P, UA, ESR, CRP, LDH, RF, β2-microglobulin, RF and cryoglobulinsImmunoglobulin IgG, IgA and IgMUrine for Bence-Jones protein (free light chains), and, if positive  24 hour urine for protein quantificationSkeletal X ray: skull, pelvis, spine, ribs & long bones (shoulder to wrist & hip to ankle), 99mTc MIBI scan.Sonography or CT scan of abdomen & chestBone marrow aspiration

26. Investigation of paraprotein- PE26EFNS 2006 guideline. Eur J Neurol 2006;13:809-818.LymphadenopathyHepato-splenomegalyMacroglossiaSigns of POEMS syndrome

27. POEMS syndrome27Clinical lymphoma myeloma leukemia 2015;15:e15-21.Lytic lesionsosteosclerotic lesions

28. POEMS syndrome28JNNP 2012;83:476-479.Demyelinating polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changesPlasma cell dyscrasia and multiple organ disorderOverproduction of VEGF by plasmacytomas50% initial presentation with polyneuropathy, many are misdiagnosed as CIDP.CSF: albuminocytological dissociation

29. 29Am J Hemat 2014;89:214-223.2/21/31/6

30. POEMS syndrome (51) vs CIDP (46) 30JNNP 2012;83:476-479. JNNP 2012;83;480-486.MN 2002;26:189-193.POEMSCIDPPolyneuropathySymmetricSymmetricDemyelination70% definite CIDP criteria Albuminocytological dissociation; paraprotein70%; λ M-proteinNeuropathy onset49%, 60% initial CIDP DxSevere leg pain76%7%Muscle atrophy52%24%Distal weakness52%24%Median nerve- prolonged DLlessMedian nerve- TLIhigherTibial and sural nervesNo responseConduction block/temporal dispersionRare (6%)

31. POEMS syndrome vs CIDP31JNNP 2012;83:476-479.POEMSCIDPPolyneuropathySymmetricSymmetricDemyelination70% definite CIDP criteria Albuminocytological dissociation70%Neuropathy onset49%, 60% initial CIDP DxSevere leg pain76%7%Muscle atrophy52%24%Distal weakness52%24%Median nerve- prolonged DLlessMedian nerve- TLIHigher ? recheckTibial and sural nervesNo responseDemyelination predominant in the nerve trunk rather than in the distal nerve terminals.Axonal loss in the lower limb nerves.

32. Monoclonal gammopathy of undetermined significance (MGUS)32IgM MGUS (60%):Bone marrow biopsy normalNo S/S of tumor infiltration (constitutional symptoms, hyper-viscosity, organomegaly)Observation 12 monthsIgG or IgA MGUS (IgG 30%, IgA 10%):Monoclonal component ≤ 30 g/L (3 g/dL)Bence-Jones proteinuria ≤ 1 g/24 hNo lytic lesions in bone; bone marrow plasma cell <10%No anemia, hyper-Ca or chronic renal insufficiencyObservation 12 monthsEFNS 2006 guideline. Eur J Neurol 2006;13:809-818.

33. Nat Neurol Rev 2014

34. Treatment34GBS: IVIg, plasmapheresisCIDP: IVIg, steroid, plasmapheresisMMN: IVIgMADSAM: IVIg, steroidPOEMS: steroid, add-on IS, plasmapheresisMGUS: steroid, plasmapheresis, 2nd imuran

35. Hereditary or acquired ?HereditaryAcquiredPatterndiffuse, homogenousdisproportionate, asymmetricTemporal dispersionlimitedexcessiveDemyelinationuniformsegmentalFamily historyAD, AR, sporadicsporadic

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37. Charcot-Marie-Tooth diseasesMutations in the same gene can manifest as distinct phenotypes, the same phenotype can be caused by mutation in different genesIncidence 1/2500 in western countriesInsidious onset and progressionAD, X-linked, AR90% of CMT: PMP22, GJB1, MFN2, MPZDemyelinating CMT1: 50% casesNorway study: CMT1 (37%), CMT2 (35.9%)

38. Median nerve conduction velocitiesCMT1: AD demyelinating CMT CMT2: AD axonal CMT CMTX: X-linked CMT CMT4: AR CMTCMT3: early-onset, Dejerine-Sottas disease< 38 m/s  CMT1 demyelinating> 38 m/s  CMT2 axonal35-45 m/s  intermediate conduction velocities (GJB1, DNM2, YARS, MPZ, IFN2, GNB4)

39. CMT1ACMT1A: Absent sensory responses, reduced motor conduction velocities (~25 m/s), reduced amplitudes (secondary axonal loss) PMP22 duplicationRare require a wheel-chair during the lifetime

40. CMT-X1CMTX CMTX1, GJB1, gap junction protein (connexin 32)  15-20% of CMT.CMTX1: male more severe, female mild patternCMTX1: split hand syndrome (APB wasting >> FDI)Asymmetric pattern: HNPP, Acquired inflammatory neuropathies, GJB1CMTX1: intermediate nerve conduction velocitiesAcute CNS dysfunction as stroke-like event with MRI changes

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42. CMT225-30% of CMTCMT2A, MFN2 gene, 20% of axonal CMT, most common typeCMT2A: 23/27 cases non-ambulatory before 20 year old

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44. CMT: CMT1A (PMP22 duplication), CMTX (GJB1), HNPP (PMP22 deletion), MFN2CMT1: CMT1A (PMP22 duplication), HNPP (PMP22 deletion), CMT1B (MPZ)HNPP: marked slowing of ulnar & sural sensory NCV with or without reduced SNAP amplitudes, relatively preserved motor NCV, prolonged DLs in median and peroneal nerves crossing knees, CBs and focal slowing at entrapment sites CMT1X: asymmetric pattern, no episodic attacks

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49. # H-reflex: no responses, bilateral.

50. MicrosatteliteResult: PMP 22 duplication.

51. # 16 y/o boy,Right upper limb weakness after 拔河.

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55. HNPP

56. Familial amyloid neuropathy

57. JNNP 2015# Hot spot mutation in Taiwan: Ala97Ser

58. JPNS 2016

59. Misdiagnosis of FAP for CIDPTreatment-unresponsiveness Severe autonomic dysfunctionWeight lossHx of carpal tunnel syndrome  Red flags

60. Red flags for TTR-FAP

61. Myasthenia gravis61Lancet Neurology 2015;14:1023-1036.Autoantibodies to post-synaptic muscle endplates; B-cell mediatedAcetylcholine receptor (AChR), muscle-specific kinase (MuSK), lipoprotein-related protein 4 (LRP4) antibodiesChanges in antibody concentration might predict disease severity.10-15% of patients- full control is not possible

62. Lancet Neurol 2015

63. 60% ptosis or diplopia, or both.20% restricted to ocular MG90% of ocular MG remain in ocular type for > 2 yearsEOM-asymmetric, limbs weakness-symmetricLancet Neurol 2015

64. 肌無力症診斷工具Ocular MGGeneralized MG藥物注射試驗80%90%乙醯膽鹼抗體40-55%80-90%重覆電刺激50%75%單一纖維肌電圖85-95%92-99%冰敷試驗80%

65. MG classification AChRMuSKLRP4Percentage80%4%2%Population (50 y/o)Early onset: F>M (3/1)Late onset: M>FYoung femalesYoung femalesWeaknessOcular or generalizedBulbar and facial (40%)Ocular and limbs: less commonRespiratory crisisOcular (20%) or generalizedMild-to-moderateThymus pathologyEarly onset: hyperplasiaLate onset: normalNoNoThymectomy responseEarly onset: goodLate onset: poorCorrelation of Ab titer to severityNoYes?# Thymoma-associated MG: 10-15% of all MG, AChR Ab(+), generalized type. 30% of patients with thymoma will develop MG.NEJM 2017

66. Lancet Neurol 2015

67. Lancet Neurol 2015

68. Lambert-Eaton myasthenic syndrome (LEMS) J Neurol 2017-10% negative3 A’s:Areflexia,Autonomic dysfunction,Apraxia (functional difficulties of gait, with mild proximal leg weakness)- Late manifestation vs at onset (MG)LEMS- Subacute onset, - Fluctuation less prominent- Favored LEMS instead of MG-Later than 4th/5th stimulation (MG)-less than >50% of lower limits- NCV/EMG Triad- Pre-synatic disorder

69. MVC: maximal voluntary contraction, 10 s.Ulnar MNCV, ADMContinuum 2016

70. Thank you for your attention !70