1.LETM And Limited NMONeed For ImmunosuppressionDr. A.V. SrinivasanMD.,DM.,Ph.D .,D.Sc (HON).F.I.A.N.,F.A.AN.Emeritus professor of Tamilnadu Dr.M.G.R Medical University.Adjunct Professor IIT, ChennaiFormer Head, Institute ofNeurology- Madras medical college.

2. NEUROMYELITIS OPTICAOpinion statement: Neuromyelitis optica (NMO) or Devics disease typicallyinvolves the optic nerve and the spinal cord and mostoften relapsing The pathogenesis is one of an acute inflammatoryprocess targeting astrocytes and resulting indemyelination, as well as axonal injury.Introduction: In its classically described form, Neuromyelitis optica(NMO) can be a devastating illness. 3. DIAGNOSIS AND PATHOGENESIS Myelopathy and a fully contiguous spinal cordlesion on MRI of more than three spinalsegments, which is centrally located in the postacute phase. Visual involvement comprising simultaneousbilateral severe on, acute visual failure with achiasmal MRI lesion, or an altitudinalhemianopia. An unequivocally positive anti-AQP4 4. Intractable hiccough (lasting more than 2days) with evidence of a linear medullaryperiaqueductal lesion on MRI. Systemic lupus erythematosus (SLE) orSjogrens syndrome satisfying clinicaldiagnostic criteria. antibody/NMO-IgG. (personalcommunication; CarrollWM, SaidaT, Fujihara K and Kira JI for theTokyoconsensus group. 5. PATHOLOGY 4 Patient biopsied (3 Mayo: Belgium):3cerebellum 1 Pons Marked lymphocytic infiltrate (PredominantlyCD3 reactive T lymphocytes, Some CD20positive B lymphocytes. CD68 positivehistiocytes and activated microglia present) White matter with perivascular predominanceand more diffuse parenchyma inflammatoryinfiltrate. 6. Myelin intact, special stains forfungi, Mychobecteria negative No characteristic finding ofsarcoidosis, histiocytosis, lymphoma, lymphomatoid, granulomatosis Multiple sclerosis or other disease 7. Autoimmune myelopathies 8. DIFFERENTIAL DIAGNOSIS OF ACUTE TRANSVERSE MYELATISDemyelinatingParasiticSystemic sclerosisDisorders Neurocysticercosis NeurocysticercosisMultiple sclerosis SchistosomaBehet syndromeNeuromyelitis opticaAcute disseminated GnathostomaVascular DisorderEncephalomyelitis AngiostrongylusAnterior and posteriorspinal arteryinfarctionIdiopathic Toxocara Arteriovenous fistula 9. PostvaccinialViral (human T-cellHematomyelia lymphotropic virus and (arteriovenousRabies HIV cause more chronic malformation, myelopathies)cavernoma,Diphtheria-tetanus-poliobleeding diathesis, Herpesvirus: herpesOsler-Weber-RenduSmalrpox simplex virus, syndrome) varicella-zoster virusMeaslescytomegalovirus, human herpes virus Fibrocartilaginous diskRubellatypes 6 and 7embolism Epstein-Barr virusJapanese B encephalitis Neoplastic Flaviviruses: Dengue Primary intramedullaryEpstein-Barr virus feverJapanese BB tumors (lymphoma, encephalitis, st Louis ependymoma,Pertussisencephalitis tickbornactrocytoma, and encephalitis, West hemangionlastomaInfluenzaNile virus or metastaticintramedullary tumorsHepatitis B 10. InfectionOrthomyxovirus:Paraneoplastic (mayBacterialInfluenza A virusalso cause chronic Spinal cord abscessmyelopathy)(epidural or Paramyxovirus:intraparenchymal)Measles virusLung and breastdue to spread from Mums virus carcinomas mostsystemic infectioncommon Picornaviruses:Myco plasmaCoxackievirus types A Amphiphysin andBorrelia burgdorferi AndB, echoviruses Collapsein Enteroviruses 70 and 71 Response- mediatorTreponema pallidum hepatitis A and C protein 5-lgG most common autoantibodyMyconacteriumPoliovirus types I,2associationsTuberculosis And 3 Other inflammatoryActinomycesDisorders Systemic lupusFungal ErythematosusBlastomycesSiogren syndromeCoccidiodesMixed connective tissueCryptococcus disorderAspergillus 11. DIFFERENTIAL DIAGNOSIS OF CRONIC MYELOPATHIEIdiopathic Inflammatory Spinocerebellar ataxiasDemyelinating DiseasesALSPrimary progressive Vascularmultiple sclerosisCerebral autosomalAutoimmunedominantParaneoplastic myelopathyarteriopathyAnteriopathy withOther autoimmunesubcortical infarcts andMyelopathyLeukoencephalopathyAutoimmune/paraneoplasticmotor neuron disordersDural arteriovenousmalformatiorvfistula 12. InfectiousCompression/StructuralHIV myelopathy TumorSpondylosisHuman T-cell lymphotropic TumorSyrinxSyrix virusassociatedmyelopathy/ Inflammatory tropical spastic paraparesis SarcoidosisBorrellosis VasculitisSchistosomiasis Bebcet syndromeBorrelia burgdorferiSjogren syndromeHereditary/Degenerative Deficiency statusVitamin- B12Hereditary spasticCopperparaparesisFriedreich ataxiaAdrenomyeloneuropathy 13. COMPARIS0NON OF MS, NEUROMYELITIS, OPTIC, ACUTE DISSEMINATED ENCEPHALOMYELITIS, ANDPARANEOPLASTIC MYELOPATHIES AND ACUTE IMMUNE/OARANEO PLASTIC MOTOR NEURON DISEASECharacteristic Multiple Neuromyelitis AcuteParaneoplastic Auto immune/ SclerosisOpticadisseminated Myelopathy ParaneoplasticMotor neuronDiseaseAntecedent VariableVariable TypicalNo Noinfection orImmunizationMedian age 2929 Children to62 Vriableof onset(years)sex( F:M)2;1 3-9:1SimilarSimilarSlight femalePredominateFrequencyCommonIntermediate Intermediate Rare ExtremelyrareEpidemiology White Disproportio AnyUnknownUnknown nately 14. Characteristic MultipleNeuromyelitis AcuteParaneoplastic Auto immune/ Sclerosis Opticadisseminated Myelopathy Paraneoplastic Motor neuron DiseaseMyelitis SubacuteSubacuteSubacute InsidiousMixed upperpresentation presentationpresentationpresentationand lower motor encephalitis neuron; ALS or primary lateral sclerosis PresentationCourse 85% relapsing 85% relapsing Monophasic ChronicChronicprogressiveprogressive(mayprogressivemimic primaryprogressivemultiplesclerosis)Impairment Mild toMild toMild toSevere (most Severe (but moderate after moderate after moderate wheelchair progression attack attackdependentmay be morewithin 2 benign thanyears) ALS) 15. Characteristic Multiple NeuromyelitisAcute Paraneoplastic Auto immune/SclerosisOptica disseminatedMyelopathy Paraneoplastic Motor neuron DiseaseCSF 50 x 1061L70%)Amphiphy.sin-lgG24% Breastand small cell lungCRMP-5-lgG 16% S.mall celllung, fhymomaANNA-i (anti-Hu) 11% Small celllungANNA-2 (anti-Ri)18%Breast orlungANNA-318%LungPCA-1 (anti-Yo) 5% Ovary,breast, fallopian tubePCA-2 10% 10%Lung 22. Paraneoplastic Auto antibodies Associated with Myelopathy Frequency of Most Frequent CancerMyelopathy AssociationAssociationMal (anti-Ma) 4%Lung, gastrointestinal tract,Breast, germ cell, nonHodgkinLymphomaMa2 (anti-Ta) 3%Germ cell======================================================================= =====Weakness association with cancer (30%)AQp4 NMO-lgG 2%- 3%Breast,Lung, thymomaCalcium channel (Nunknow Breast and LungAnd P/Q types)Voltage- gated1% Breast,LungPotassium channel 23. TREATMENTCorticostrioids: High-dose methyiprednisolone (HDMP)has a number of actions believed tocontribute to its effectiveness in MSrelapse Standard dosage: Usually 0.5 to 1.0 g isgiven intravenously or orally each day for3 to 5 days, The clinical efficacy of HDMPin NMO is widely regarded as lesssuccessful than in MS. 24. Contraindication: A history of anyhypersensitivity reaction to corticosteroids.Caution must be exercised in the decision touse corticosteroids in poorly controlleddiabetes mellitus or hypertension,pregnancy, lactation, affective disorders,systemic infection (including tuberculosis),and active peptic ulceration. Main side effects: Fluid retention, transientgastric irritation, insomnia, facial flushing,dysgeusia, hyperglycemia, and glucosuria,as well as (rarely) psychosis, pancreatitis,anaphylactoid reaction, or aseptic necrosisof hip and shoulder joints. 25. Plasma Exchange: PE removes circulating autoantibodies,macromolecular immune complexes,inflammatory cytokines, and other mediators Standard dosage: Exchanges of 1.5 plasmavolumes for each of five treatments over 10days. Patients with suboptimal peripheralvenous access may require a central line. Contraindication: Bleeding diabetes,including thrombocytopenia, systemicinfection recent myocardial ischemia. 26. Complication: Infection is the main risk ofthis treatment, but hemodynamic instability(eg, systemic hypotension) may occur, aswell as thrombotic, traumatic, or pulmonarycatheter complications.Lumphocytapheresis: LCA removes circulating lymphocytes andhas been reported to be useful in otherwiserefractory NMO attacks 129,301. It is usuallyperformed twice weekly for 3 to 4 weeks,removing 4 to 3x 10 lymphocytes per,treatment 27. PREVENTION OF RECURRENT RELAPSE: Given the devastating effects that NMO can wreakon the spinal cord and the anterior visualpathway, prevention of a second or anysubsequent attack is of paramount importance. This approach is emphasized by the infrequentoccurrence of an overt progressive phase inNMO, as is seen in MS, thereby indicating thatmost if not all disability derives from relapses.As mentioned above, some predictive factorsmay assist in the assessment of risk for anotherattack, but by and large, all patients should beconsidered at high risk for at least the 5 yearsfollowing the last attack. 28. From the current understanding of the pathogenesisof NMO and the experience of those who have treatedmany such patients, measures directed at humoralimmune mechanisms seem to offer the best option.Moreover, there have been reports that interferon-j3(currently employed for MS) is ineffective15,31,32., Class 1111, and relapses have evenoccurred in association with such treatments 133,341. Immunosuppressive drugs are the mainstaytreatment for NMO. Corticosteroids have been usedfor the longest period and were combined withazathioprine in one of the first reports of a series ofNMO patients 13, Class 1111.Azathioprine is the most widely usedimmunosuppressive medication, but mycophenolatemofetil (MMF), cyclophosphamide, and mitoxantronehave all been used with mixed results. 29. AZATHIOPRINE:Is in imidazolyl derivative of mercaptopurine andan immune suppressant. Standard dosage: Usually commenced at 1 mg/kgper day for 6 to 8 weeks, then increased by 0.5mg/kg every 4 weeks up to 1.5 to 2.0 mg/kg perday Contraindication: Previous azathioprinehypersensitivity and pregnancy. Azathioprineprobably should not be used for NMO with liverdisease, renal impairment, or hematologicdisorders. There is also a risk of increasedsensitivity of myelo suppression in patients with 30. Main drug interactions: Interactions may occurwith methotrexate, MMF, angiotensin-convertingenzyme antihypertensive medications, andwarfarin. Main side effects: Fever, chills, alopecia,erythematous or maculopapular rash, nausea,vomiting, anorexia, diarrhea, aphthous stomatitis,pancreatitis, hematologic suppression, Megaloblastic anemia, hepatotoxicity, hepaticveno-occiusive disease, arthralgia, retinopathy,and hypersensitivity reactions. There is a smallrisk of later malignancies. 31. Mycophenolate mofetil: MMF is a prodrug of mycophenolic acid,which has selective effects on the immunesystem, preventing T-cell and B-cellproliferation and B-cell antibody formation Standard dosage: 1 g to 3 g per day in twodivided doses. Usually commenced at 500mg per day and increased every 2 weeks to 2to 3 g per day 32. Main drug interaction: Oral iron and other mineral supplements andrifampicin reduce its effectiveness. Anovulatorymedications containing ethinyl estradiol are lesseffective. Main side effects: These include hematologicabnormalities (leukopenia andneutropenia),gastrointestinal symptoms (abdominalpain, diarrhea, nausea, vomiting,dyspepsia),.anincreased risk of lymphoproliferative disease andothermalignancies, headache, and tremor. The potential risks during pregnancydemand thatwomen of childbearing age should use effectivecontraception before commencing therapy, duringtherapy, and for 6 weeks after therapy has ceased 33. Ratuximab A cytoiyticanti-CD20+ chirnericmonodonal antibody it targets immatureB cells and B cells hut not antibody-producing plasma cells or hemopoieticstem cells. Standard dose: 1000 mg infused twice, 2weeks apart, or 2) 375 mg/rn2 infusedonce per week for 4 weeks. 34. Contraindication: Allergy to rituximab, which willalso include allergy to murine proteins. Main side effects: From its use in rheumatologyand hematology, a number of serious adverseeffects are known to occur. Although the numberof reported NMO cases treated with rituximab issmall, the same attendant risks are likely. These include infusion reactions, cutaneousallergic reactions, progressive multifocalleukoencephalopathy, hepatitis B reactivation,cardiac arrhythmia and ischemia, intestinalobstruction, and hernatologic cytopenias. Thesafety of rituximab during pregnancy is unknown 35. MitoxantronDNA synthesis and repair is disrupted bymitoxantrone in healthy and malignant cells,though the mechanism is not certain. Standard dosage: 1-month or 3-month intervals,or a sequential combination of these intervals.A typical regimen would be 12 mg/rn2 of bodysurface area each month for 3 or 4m6nths,followed by further infusions every 3months until the total cumulative dosereaches140 mg/rn2. 36. Contraindication: Neutropenia, left ventricularejection fraction less than 50% at any time(should be tested before each dose), liverdysfunction, pregnancy, or inadequatecontraception. Use with caution in patients with previousmyocardial or coronary artery disease, previousmediastinal irradiation, or exposure to cardiotoxicmedications. Main side effects: Cardiotoxicity, acute myeloidleukemia, hepatotoxicity, myelosuppression,ovarian failure. 37. Corticosteroids and other treatment Regular low-dose oral corticosteroid hasbeen reported to be effective in a smallseries of NMO patients Standard dosage: Usually given at 10 to 25mg per day, titrated as required. There areno studies specifically looking at daily oralternate- day regimens in NMO. The recommended practice is to commencewith a daily dose of 1 mg/kg (60 mg/d or 75mg/d are useful ptactical commencementdoses) and then reduce to either analternate-day regimen of 20 to 25 mg per dayor to a daily dose of 10 to 15 mg per dayover the next 8 to 12 weeks. 38. The recommended practice is tocommence with a daily dose of 1 mg/kg(60 mg/d or 75 mg/d are useful ptacticalcommencement doses) and then reduceto either an alternate-day regimen of 20 to25 mg per day or to a daily dose of 10 to15 mg per day over the next 8 to 12weeks.Main drug interaction: Certainanticonvulsarits, antidepressants,anticoagulants, antihypertensives,immur.osuppressants, atypical 39. Main side effects: The many adverse effectsof long-term steroids are well known.Osteoporosis, fluid retention, adrenalsuppressioii, hypertension, hyperglycemia, truncal obesity, lens opacification, andcutaneous changes are the most common. Caution should also bexercised in patientswith known peptic ulcerdisease, pregnancy, or psychotic tendency.If long-term treatment is planned, measuesto prevent osteoporosis should be instituted 40. Cyclophosphamide Is a well-known antineoplastic agent that isconverted in the liver to active alkylatingcompounds Standard dosage: A typical oral dose foradult NMO would be 1 to 5 mg/kg per day forinitial and maintenance doses. The typicalintravenous dose is 40 to 50 mg/kg givenover 2 to 5 days. The dose for patients undergoing bonemarrow transplantation may be as high as60 mg/kg per day for 21ays. 41. Contraindication: Bone marrow suppression and previous hypersensitivity. Pregnancy should be avoided. Main drug interaction ; Concomitant use ofbarbiturates can increase the degree ofleucopenia. The effect ofdonepezil, rivastigmine, and galantamine may beaugmented by increased cholinesterase inhibition Main side effects: Alopecia, hemorrhagic cystitis(prevented by the use of fluids and mesna),bonemarrow suppression, oralulceration, lethargy, nausea and vomiting. boweldisturbance, temporary or (rarely) permanentsterility, late risk of cancer. 42. Assistive devices, physical therapy, and othertreatment: Blindness, spastidty, painful tonic spasms,pain, dysuria, constipation, depression, andventilatory support may all require attentionin patients with NMO. Aids, physical therapy, and pharmacologictreatment of these conditions can improvethe quality of life. Anticonvulsants, antispasticity drugs,antidepressants, and laxatives are commonpharmacologic treatments to addresssymptoms. 43. Regular physiotherapy, ankle splints,botulinus toxin, walking aids, andwheelchairs help patients manage theresidua of myelopathy. Occupational therapy and low-vision aidscan assist those left with visualimpairment 44. Emerging therapies: An open-label study of the effects of eculizumab(anti-complement [C5] monodonal antibody) in NMOis currently under way at theMayo Clinic [47]. Potential therapies in the future indude those thattarget other B-cell proteins, such as APRIL (APRoliferation-Inducing Ligand) and BAFF (B-cell ) Activation Factor of the TNF Family), in order tosuppress antibody production by reducing plasmacell numbers [481, as well as the use of hemopoieticstem cell transplantation [49]. 45. Another novel approach may be themodulation of the AQP4 M23 isoform toprevent or limit its targeting by anti-AQP4antibody [50].Pediatric consideration; The separation of acute disseminatedencephalomyelitis, MS, and NMO inchildren remains problematic 46. TREATMENT AND OUT COME 7 Patient 1g Iv methylprednisolone allimproved initially. PO prednisone in 1 without marked earlyimprovement. Varied long-term outcome- ranged fromexcellent to incomplete with substantialdeficits remaining Myelopathy in Belgiumcase. 47. CONCLUSION Definable, treatable, inflammatory, CNSbrainstem- predominant syndrome Similar clinical, Radiological, PathologicalSyndrome responsive toImmunosuppression especially steroids No other diseases found despite extensiveand prolonged follow up 48. Difficulty biopsy: rule out othercompeting, diseases, consider biopsy Therapy with high dose corticosteroids. Prolonged therapy commonly needed,immunosuppression with steroid- sparingMedications 49. DEDICATED TO MY FAMILY FORMAKING EVERYTHING WORTHWHILE 50. READ NOT TO CONTRADICT OR CONFUTENOR TO BELIEVE AND TAKE FOR GRANTEDBUT TO WEIGH AND CONSIDER THANK YOUMy sincere thanks top.sampath (CRC)