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Letm and ltd nmo need for immunosuppression
1. LETM And Limited NMO
Need For Immunosuppression
Dr. A.V. Srinivasan
MD.,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, Chennai
Former Head, Institute of
Neurology- Madras medical college.
2. NEUROMYELITIS OPTICA
Opinion 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.
3. 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
4. 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.
5. 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.
6. Myelin intact, special stains for
fungi, Mychobecteria negative
No characteristic finding of
sarcoidosis, histiocytosis, lymphoma, lymph
omatoid, granulomatosis
Multiple sclerosis or other disease
18. Postvaccinial Viral (human T-cell Hematomyelia
lymphotropic virus and (arteriovenous
Rabies HIV cause more chronic malformation,
myelopathies) cavernoma,
Diphtheria-tetanus-polio bleeding diathesis,
Herpesvirus: herpes Osler-Weber-Rendu
Smalrpox simplex virus, syndrome)
varicella-zoster virus
Measles cytomegalovirus,
human herpes virus Fibrocartilaginous disk
Rubella types 6 and 7 embolism
Epstein-Barr virus
Japanese B encephalitis Neoplastic
Flaviviruses: Dengue Primary intramedullary
Epstein-Barr virus feverJapanese B B tumors (lymphoma,
encephalitis, st Louis ependymoma,
Pertussis encephalitis tickborn actrocytoma, and
encephalitis, West hemangionlastoma
Influenza Nile virus or metastatic
intramedullary tumors
Hepatitis B
19. Infection Orthomyxovirus: Paraneoplastic (may
Bacterial Influenza A virus also cause chronic
Spinal cord abscess myelopathy)
(epidural or Paramyxovirus:
intraparenchymal) Measles virus Lung and breast
due to spread from Mums virus carcinomas most
systemic infection common
Picornaviruses:
Myco plasma Coxackievirus types A Amphiphysin and
Borrelia burgdorferi AndB, echoviruses Collapsein
Enteroviruses 70 and 71 Response- mediator
Treponema pallidum hepatitis A and C protein 5-lgG most
common autoantibody
Myconacterium Poliovirus types I,2 associations
Tuberculosis And 3
Other inflammatory
Actinomyces Disorders
Systemic lupus
Fungal Erythematosus
Blastomyces Siogren syndrome
Coccidiodes Mixed connective tissue
Cryptococcus disorder
Aspergillus
20. DIFFERENTIAL DIAGNOSIS OF CRONIC MYELOPATHIE
Idiopathic Inflammatory Spinocerebellar ataxias
Demyelinating Diseases
ALS
Primary progressive Vascular
multiple sclerosis Cerebral autosomal
Autoimmune dominant
Paraneoplastic myelopathy
arteriopathy Anteriopathy with
Other autoimmune subcortical infarcts and
Myelopathy Leukoencephalopathy
Autoimmune/paraneoplastic
motor neuron disorders Dural arteriovenous
malformatiorv’fistula
22. COMPARIS0NON OF MS, NEUROMYELITIS, OPTIC, ACUTE DISSEMINATED ENCEPHALOMYELITIS, AND
PARANEOPLASTIC MYELOPATHIES AND ACUTE IMMUNE/OARANEO PLASTIC MOTOR NEURON DISEASE
Characteristic Multiple Neuromyelitis Acute Paraneoplastic Auto immune/
Sclerosis Optica disseminated Myelopathy Paraneoplastic
Motor neuron
Disease
Antecedent Variable Variable Typical No No
infection or
Immunization
Median age 29 29 Children to 62 Vriable
of onset
(years)
sex( F:M) 2;1 3-9:1 Similar Similar Slight female
Predominate
Frequency Common Intermediate Intermediate Rare Extremely
rare
Epidemiology White Disproportio Any Unknown Unknown
nately
23. Characteristic Multiple Neuromyelitis Acute Paraneoplastic Auto immune/
Sclerosis Optica disseminated Myelopathy Paraneoplastic
Motor neuron
Disease
Myelitis Subacute Subacute Subacute Insidious Mixed upper
presentation presentation presentation presentation and
lower motor
encephalitis
neuron; ALS or
primary lateral
sclerosis
Presentation
Course 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)
24. Characteristic Multiple Neuromyelitis Acute Paraneoplastic Auto immune/
Sclerosis Optica disseminated Myelopathy Paraneoplastic
Motor neuron
Disease
CSF <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
normal
Cancer None Rarely None Most Most
associations commonly frequently
breast and breast and
lung lung
carcinomas carcinomas
and
lymphoma
25. Characteristic Multiple Neuromyeli Acute Paraneoplasti Auto
Sclerosis tis Optica disseminate c immune/
d Myelopathy Paraneoplas
tic
Motor
neuron
Disease
Neural None Neuromyeliti None Collapsin Variable
autoantibody s response-
associations optica lgG mediator
protein5 and
amphiphysin
lgGs most
common
Brain MRI Periventricul Hypothalami Subcortical, Normal Normal
ar white c,periventricu may involve
matter lar, deep gray
lesions particularly matter
thirdffourth
ventricle;
cloudlike
enhancement
26. Characteristic Multiple Neuromyeliti Acute Paraneoplasti Auto
Sclerosis s Optica disseminated c immune/
Encephalomy Myelopathy Paraneoplasti
eliti c
Motor
neuron
Disease
Chronic Interferon Azathioprine None Cancer Cancer
treatment 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
mofetil
Prognosis 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
27.
28. 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
30. Autoimmune Disease Clues to Diagnosis Supportive
Diagnostic Tests
Systemic sclerosis! Skin thickening and Serology: anti-Scl-70
scleroderma calcinosis, nail bed or anticentromere
infarcts, antibodies
telangiectasias,
Raynaud
phenomenon,
gastroesophageal
reflux disease
Behçet disease Mediter.ranean/Mid Ophthalmic
dle Eastern descent, examination,
oral ulcers, genital gynecologic
ulcers, erythema examination,
nodosum, anterior pathergy test
uveitis
31. PARANEOPLASTIC AUTO ANTIBODIES ASSOCIATED WITH MYELOPATHY
Frequency of
Myelopathy Most Frequent
Cancer
Association Association
Strong association with
cancer (>70%)
Amphiphy.sin-lgG 24% Breast
and small cell lung
CRMP-5-lgG 16% S.mall cell
lung, fhymoma
ANNA-i (anti-Hu) 11% Small cell
lung
ANNA-2 (anti-Ri) 18% Breast or
lung
ANNA-3 18% Lung
PCA-1 (anti-Yo) 5% Ovary,
breast, fallopian tube
PCA-2 10% 10% Lung
32. Paraneoplastic Auto antibodies Associated with Myelopathy
Frequency of Most Frequent
Cancer
Myelopathy Association Association
Mal (anti-Ma) 4% Lung,
gastrointestinal tract,
Breast, germ
cell, nonHodgkin
Lymphoma
Ma2 (anti-Ta) 3% Germ cell
=======================================================================
=====
Weakness association with cancer (30%)
AQp4 NMO-lgG 2%- 3% Breast,
Lung, thymoma
Calcium channel (N unknow Breast
and Lung
And P/Q types)
Voltage- gated 1% Breast,
Lung
Potassium channel
33.
34. TREATMENT
Corticostrioids:
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.
35. 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.
36. 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.
37. 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
38. 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.
39. 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.
40. 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
41. 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.
42. 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
43. 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
44. 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.
45. 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
46. 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.
47. 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.
48. 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.
49. 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.
Main drug interaction: Certain
anticonvulsarits, antidepressants,
anticoagulants, antihypertensives,
immur.osuppressants, atypical
50. 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
51. 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
.
52. 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.
53. 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.
54. 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
55. 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 [47].
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 [49].
56. Another novel approach may be the
modulation of the AQP4 M23 isoform to
prevent or limit its targeting by anti-AQP4
antibody [50].
Pediatric consideration;
The separation of acute disseminated
encephalomyelitis, MS, and NMO in
children remains problematic
57. 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.
58. 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
59. Difficulty biopsy: rule out other
competing, diseases, consider biopsy
Therapy with high dose corticosteroids.
Prolonged therapy commonly needed,
immunosuppression with steroid- sparing
Medications
