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.
NEUROMYELITIS OPTICAOpinion statement: Neuromyelitis optica (NMO) or Devic’s disease typically involves the optic nerve and the spinal cord and most often relapsing The pathogenesis is one of an acute inflammatory process targeting astrocytes and resulting in demyelination, as well as axonal injury.Introduction: In its classically described form, Neuromyelitis optica (NMO) can be a devastating illness.
DIAGNOSIS AND PATHOGENESIS Myelopathy and a fully contiguous spinal cord lesion on MRI of more than three spinal segments, which is centrally located in the post acute phase. Visual involvement comprising simultaneous bilateral severe on, acute visual failure with a chiasmal MRI lesion, or an altitudinal hemianopia. An unequivocally positive anti-AQP4
Intractable hiccough (lasting more than 2 days) with evidence of a linear medullary periaqueductal lesion on MRI. Systemic lupus erythematosus (SLE) or Sjogren’s syndrome satisfying clinical diagnostic criteria. antibody/NMO-IgG. (personal communication; CarrollWM, Saida T, Fujihara K and Kira JI for theTokyo consensus group.
PATHOLOGY 4 Patient biopsied (3 Mayo: Belgium):3 cerebellum 1 Pons Marked lymphocytic infiltrate (Predominantly CD3 reactive T lymphocytes, Some CD20 positive B lymphocytes. CD68 positive histiocytes and activated microglia present) White matter with perivascular predominance and more diffuse parenchyma inflammatory infiltrate.
Myelin intact, special stains for fungi, Mychobecteria negative No characteristic finding of sarcoidosis, histiocytosis, lymphoma, lymph omatoid, granulomatosis Multiple sclerosis or other disease
Postvaccinial Viral (human T-cell Hematomyelia lymphotropic virus and (arteriovenousRabies HIV cause more chronic malformation, myelopathies) cavernoma,Diphtheria-tetanus-polio bleeding diathesis, Herpesvirus: herpes Osler-Weber-RenduSmalrpox simplex virus, syndrome) varicella-zoster virusMeasles cytomegalovirus, human herpes virus Fibrocartilaginous diskRubella types 6 and 7 embolism Epstein-Barr virusJapanese B encephalitis Neoplastic Flaviviruses: Dengue Primary intramedullaryEpstein-Barr virus feverJapanese B B tumors (lymphoma, encephalitis, st Louis ependymoma,Pertussis encephalitis tickborn actrocytoma, and encephalitis, West hemangionlastomaInfluenza Nile virus or metastatic intramedullary tumorsHepatitis B
Infection Orthomyxovirus: Paraneoplastic (mayBacterial Influenza A virus also cause chronic Spinal cord abscess myelopathy)(epidural or Paramyxovirus:intraparenchymal) Measles virus Lung and breastdue to spread from Mums virus carcinomas mostsystemic infection common Picornaviruses:Myco plasma Coxackievirus types A Amphiphysin andBorrelia burgdorferi AndB, echoviruses Collapsein Enteroviruses 70 and 71 Response- mediatorTreponema pallidum hepatitis A and C protein 5-lgG most common autoantibodyMyconacterium Poliovirus types I,2 associationsTuberculosis And 3 Other inflammatoryActinomyces Disorders Systemic lupusFungal Erythematosus Blastomyces Siogren syndrome Coccidiodes Mixed connective tissue Cryptococcus disorder Aspergillus
COMPARIS0NON OF MS, NEUROMYELITIS, OPTIC, ACUTE DISSEMINATED ENCEPHALOMYELITIS, ANDPARANEOPLASTIC MYELOPATHIES AND ACUTE IMMUNE/OARANEO PLASTIC MOTOR NEURON DISEASECharacteristic Multiple Neuromyelitis Acute Paraneoplastic Auto immune/ Sclerosis Optica disseminated Myelopathy Paraneoplastic Motor neuron DiseaseAntecedent Variable Variable Typical No Noinfection orImmunizationMedian age 29 29 Children to 62 Vriableof onset(years)sex( F:M) 2;1 3-9:1 Similar Similar Slight female PredominateFrequency Common Intermediate Intermediate Rare Extremely rareEpidemiology White Disproportio Any Unknown Unknown nately
Characteristic Multiple Neuromyelitis Acute Paraneoplastic Auto immune/ Sclerosis Optica disseminated Myelopathy Paraneoplastic Motor neuron DiseaseMyelitis Subacute Subacute Subacute Insidious Mixed upperpresentation presentation presentation presentation and lower motor encephalitis neuron; ALS or primary lateral sclerosis PresentationCourse 85% relapsing 85% relapsing Monophasic Chronic Chronic progressive progressive (may progressive mimic primary progressive multiple sclerosis)Impairment Mild to Mild to Mild to Severe (most Severe (but moderate after moderate after moderate wheelchair progression attack attack dependent may be more within 2 benign than years) ALS)
Characteristic Multiple Neuromyelitis Acute Paraneoplastic Auto immune/ Sclerosis Optica disseminated Myelopathy Paraneoplastic Motor neuron DiseaseCSF <50 x 106/L >50 x 1061L <50 x 106/1 <50 x 106/1 Unknown, WBCs; OCBs WBCs WBCs, WBCs, some reports 85% (lymphocytes elevated elevated of elevated ); OCBs protein often protein often protein usually marked; marked; absent OCBs 30% OCBs 30%Spine MRI Short lesions; Long lesion Variable Symmetric Normal usually (>3 vertebral tract- periphery of segments); specific/gray cord; variable central lesion matter— enhancement on axial; specific variable enhancement enhancement ; can be normalCancer None Rarely None Most Mostassociations commonly frequently breast and breast and lung lung carcinomas carcinomas and lymphoma
Characteristic Multiple Neuromyeli Acute Paraneoplasti Auto Sclerosis tis Optica disseminate c immune/ d Myelopathy Paraneoplas tic Motor neuron DiseaseNeural None Neuromyeliti None Collapsin Variableautoantibody s response-associations optica lgG mediator protein5 and amphiphysin lgGs most commonBrain MRI Periventricul Hypothalami Subcortical, Normal Normal ar white c,periventricu may involve matter lar, deep gray lesions particularly matter thirdffourth ventricle; cloudlike enhancement
Characteristic Multiple Neuromyeliti Acute Paraneoplasti Auto Sclerosis s Optica disseminated c immune/ Encephalomy Myelopathy Paraneoplasti eliti c Motor neuron DiseaseChronic Interferon Azathioprine None Cancer Cancertreatment Beta steroids, treatment. treatment. glatiramer mycophenola steroids, IVIg. steroids, IVIg, acetate, te mofetil, plasmaphere cyclophospha natalizumab rituximab sis,cyclophos mide, in severe phamide,azat azathioprine, cases hioprine,myc mycophenola ophenolate te mofetil mofetilPrognosis Majority Moderate to Good; Poor; most Poor ambulatory severe monophasic Wheelchair response to after 20 years disability dependent treatment; over time; within 2 to 5 may have most patients years slower disabled oroaression than ALS
INVESTIGATIONS Mayo clinic extensive work –up negative Serology, CT Body, Mammogram, testicular U/s Pet Congestival, Lung parenchymal biopsies. ACE,ANA ssB minimally elevated one patient each Paraneoplatic screen negative in all 5 of 6 mayo Pets tested (4serum: 2CSF) NMO-lgG Negative in 4 all checked
Autoimmune Disease Clues to Diagnosis Supportive Diagnostic TestsSystemic sclerosis! Skin thickening and Serology: anti-Scl-70scleroderma calcinosis, nail bed or anticentromere infarcts, antibodies telangiectasias, Raynaud phenomenon, gastroesophageal reflux diseaseBehçet disease Mediter.ranean/Mid Ophthalmic dle Eastern descent, examination, oral ulcers, genital gynecologic ulcers, erythema examination, nodosum, anterior pathergy test uveitis
PARANEOPLASTIC AUTO ANTIBODIES ASSOCIATED WITH MYELOPATHY Frequency of Myelopathy Most Frequent Cancer Association AssociationStrong association withcancer (>70%)Amphiphy.sin-lgG 24% Breast and small cell lungCRMP-5-lgG 16% S.mall cell lung, fhymomaANNA-i (anti-Hu) 11% Small cell lungANNA-2 (anti-Ri) 18% Breast or lungANNA-3 18% LungPCA-1 (anti-Yo) 5% Ovary, breast, fallopian tubePCA-2 10% 10% Lung
Paraneoplastic Auto antibodies Associated with Myelopathy Frequency of Most Frequent Cancer Myelopathy Association AssociationMal (anti-Ma) 4% Lung, gastrointestinal tract, Breast, germ cell, nonHodgkin LymphomaMa2 (anti-Ta) 3% Germ cell======================================================================= =====Weakness association with cancer (30%)AQp4 NMO-lgG 2%- 3% Breast, Lung, thymomaCalcium channel (N unknow Breast and LungAnd P/Q types)Voltage- gated 1% Breast, LungPotassium channel
TREATMENTCorticostrioids: High-dose methyiprednisolone (HDMP) has a number of actions believed to contribute to its effectiveness in MS relapse Standard dosage: Usually 0.5 to 1.0 g is given intravenously or orally each day for 3 to 5 days, The clinical efficacy of HDMP in NMO is widely regarded as less successful than in MS.
Contraindication: A history of any hypersensitivity reaction to corticosteroids. Caution must be exercised in the decision to use corticosteroids in poorly controlled diabetes mellitus or hypertension, pregnancy, lactation, affective disorders, systemic infection (including tuberculosis), and active peptic ulceration. Main side effects: Fluid retention, transient gastric irritation, insomnia, facial flushing, dysgeusia, hyperglycemia, and glucosuria, as well as (rarely) psychosis, pancreatitis, anaphylactoid reaction, or aseptic necrosis of hip and shoulder joints.
Plasma Exchange: PE removes circulating autoantibodies, macromolecular immune complexes, inflammatory cytokines, and other mediators Standard dosage: Exchanges of 1.5 plasma volumes for each of five treatments over 10 days. Patients with suboptimal peripheral venous access may require a central line. Contraindication: Bleeding diabetes, including thrombocytopenia, systemic infection recent myocardial ischemia.
Complication: Infection is the main risk of this treatment, but hemodynamic instability (eg, systemic hypotension) may occur, as well as thrombotic, traumatic, or pulmonary catheter complications.Lumphocytapheresis: LCA removes circulating lymphocytes and has been reported to be useful in otherwise refractory NMO attacks 129,301. It is usually performed twice weekly for 3 to 4 weeks, removing 4 to 3x 10 lymphocytes per ,treatment
PREVENTION OF RECURRENT RELAPSE: Given the devastating effects that NMO can wreak on the spinal cord and the anterior visual pathway, prevention of a second or any subsequent attack is of paramount importance. This approach is emphasized by the infrequent occurrence of an overt progressive phase in NMO, as is seen in MS, thereby indicating that most if not all disability derives from relapses. As mentioned above, some predictive factors may assist in the assessment of risk for another attack, but by and large, all patients should be considered at high risk for at least the 5 years following the last attack.
From the current understanding of the pathogenesis of NMO and the experience of those who have treated many such patients, measures directed at humoral immune mechanisms seem to offer the best option. Moreover, there have been reports that interferon-j3 (currently employed for MS) is ineffective 15,31,32., Class 1111, and relapses have even occurred in association with such treatments 133,341. Immunosuppressive drugs are the mainstay treatment for NMO. Corticosteroids have been used for the longest period and were combined with azathioprine in one of the first reports of a series of NMO patients 13, Class 1111. Azathioprine is the most widely used immunosuppressive medication, but mycophenolate mofetil (MMF), cyclophosphamide, and mitoxantrone have all been used with mixed results.
AZATHIOPRINE: Is in imidazolyl derivative of mercaptopurine and an immune suppressant. Standard dosage: Usually commenced at 1 mg/kg per day for 6 to 8 weeks, then increased by 0.5 mg/kg every 4 weeks up to 1.5 to 2.0 mg/kg per day Contraindication: Previous azathioprine hypersensitivity and pregnancy. Azathioprine probably should not be used for NMO with liver disease, renal impairment, or hematologic disorders. There is also a risk of increased sensitivity of myelo suppression in patients with
Main drug interactions: Interactions may occur with methotrexate, MMF, angiotensin-converting enzyme antihypertensive medications, and warfarin. Main side effects: Fever, chills, alopecia, erythematous or maculopapular rash, nausea, vomiting, anorexia, diarrhea, aphthous stomatitis, pancreatitis, hematologic suppression, Megaloblastic anemia, hepatotoxicity, hepatic veno-occiusive disease, arthralgia, retinopathy, and hypersensitivity reactions. There is a small risk of later malignancies.
Mycophenolate mofetil: MMF is a prodrug of mycophenolic acid, which has selective effects on the immune system, preventing T-cell and B-cell proliferation and B-cell antibody formation Standard dosage: 1 g to 3 g per day in two divided doses. Usually commenced at 500 mg per day and increased every 2 weeks to 2 to 3 g per day
Main drug interaction: Oral iron and other mineral supplements and rifampicin reduce its effectiveness. Anovulatory medications containing ethinyl estradiol are less effective. Main side effects: These include hematologic abnormalities (leukopenia and neutropenia),gastrointestinal symptoms (abdominal pain, diarrhea, nausea, vomiting,dyspepsia),.an increased risk of lymphoproliferative disease and othermalignancies, headache, and tremor. The potential risks during pregnancydemand that women of childbearing age should use effective contraception before commencing therapy, during therapy, and for 6 weeks after therapy has ceased
Ratuximab A cytoiyticanti-CD20+ chirneric monodonal antibody it targets immature B cells and B cells hut not antibody- producing plasma cells or hemopoietic stem cells. Standard dose: 1000 mg infused twice, 2 weeks apart, or 2) 375 mg/rn2 infused once per week for 4 weeks.
Contraindication: Allergy to rituximab, which will also include allergy to murine proteins. Main side effects: From its use in rheumatology and hematology, a number of serious adverse effects are known to occur. Although the number of reported NMO cases treated with rituximab is small, the same attendant risks are likely. These include infusion reactions, cutaneous allergic reactions, progressive multifocal leukoencephalopathy, hepatitis B reactivation, cardiac arrhythmia and ischemia, intestinal obstruction, and hernatologic cytopenias. The safety of rituximab during pregnancy is unknown
Mitoxantron DNA synthesis and repair is disrupted by mitoxantrone 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 body surface area each month for 3 or 4 m6nths,followed by further infusions every 3 months until the total cumulative dosereaches 140 mg/rn2.
Contraindication: Neutropenia, left ventricular ejection fraction less than 50% at any time (should be tested before each dose), liver dysfunction, pregnancy, or inadequate contraception. Use with caution in patients with previous myocardial or coronary artery disease, previous mediastinal irradiation, or exposure to cardiotoxic medications. Main side effects: Cardiotoxicity, acute myeloid leukemia, hepatotoxicity, myelosuppression, ovarian failure.
Corticosteroids and other treatment Regular low-dose oral corticosteroid has been reported to be effective in a small series of NMO patients Standard dosage: Usually given at 10 to 25 mg per day, titrated as required. There are no studies specifically looking at daily or alternate- day regimens in NMO. The recommended practice is to commence with a daily dose of 1 mg/kg (60 mg/d or 75 mg/d are useful ptactical commencement doses) and then reduce to either an alternate-day regimen of 20 to 25 mg per day or to a daily dose of 10 to 15 mg per day over the next 8 to 12 weeks.
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
Main side effects: The many adverse effects of long-term steroids are well known. Osteoporosis, fluid retention, adrenal suppressioii, hypertension, hyperglycemia, t runcal obesity, lens opacification, and cutaneous changes are the most common. Caution should also bexercised in patients with known peptic ulcer disease, pregnancy, or psychotic tendency. If long-term treatment is planned, measues to prevent osteoporosis should be instituted
Cyclophosphamide Is a well-known antineoplastic agent that is converted in the liver to active alkylating compounds Standard dosage: A typical oral dose for adult NMO would be 1 to 5 mg/kg per day for initial and maintenance doses. The typical intravenous dose is 40 to 50 mg/kg given over 2 to 5 days. The dose for patients undergoing bone marrow transplantation may be as‘ high as 60 mg/kg per day for 21ays.
Contraindication: Bone marrow suppression and previous hyper sensitivity. Pregnancy should be avoided. Main drug interaction ; Concomitant use of barbiturates can increase the degree of leucopenia. The effect of donepezil, rivastigmine, and galantamine may be augmented by increased cholinesterase inhibition Main side effects: Alopecia, hemorrhagic cystitis (prevented by the use of fluids and mesna),bone marrow suppression, oral ulceration, lethargy, nausea and vomiting. bowel disturbance, temporary or (rarely) permanent sterility, late risk of cancer.
Assistive devices, physical therapy, and other treatment: Blindness, spastidty, painful tonic spasms, pain, dysuria, constipation, depression, and ventilatory support may all require attention in patients with NMO. Aids, physical therapy, and pharmacologic treatment of these conditions can improve the quality of life. Anticonvulsants, antispasticity drugs, antidepressants, and laxatives are common pharmacologic treatments to address symptoms.
Regular physiotherapy, ankle splints, botulinus toxin, walking aids, and wheelchairs help patients manage the residua of myelopathy. Occupational therapy and low-vision aids can assist those left with visual impairment
Emerging therapies: An open-label study of the effects of eculizumab (anti-complement [C5] monodonal antibody) in NMO is currently under way at theMayo Clinic . Potential therapies in the future indude those that target other B-cell proteins, such as APRIL (A PRoliferation-Inducing Ligand) and BAFF (B-cell ) Activation Factor of the TNF Family), in order to suppress antibody production by reducing plasma cell numbers [481, as well as the use of hemopoietic stem cell transplantation .
Another novel approach may be the modulation of the AQP4 M23 isoform to prevent or limit its targeting by anti-AQP4 antibody .Pediatric consideration; The separation of acute disseminated encephalomyelitis, MS, and NMO in children remains problematic
TREATMENT AND OUT COME 7 Patient 1g Iv methylprednisolone all improved initially. PO prednisone in 1 without marked early improvement. Varied long-term outcome- ranged from excellent to incomplete with substantial deficits remaining Myelopathy in Belgium case.
CONCLUSION Definable, treatable, inflammatory, CNS brainstem- predominant syndrome Similar clinical, Radiological, Pathological Syndrome responsive to Immunosuppression especially steroids No other diseases found despite extensive and prolonged follow –up
Difficulty biopsy: rule out other competing, diseases, consider biopsy Therapy with high dose corticosteroids. Prolonged therapy commonly needed, immunosuppression with steroid- sparing Medications
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