Neuromyelitis optica spectrum disorders (NMOSD) is an autoimmune disorder of young adults' results from astrocytic aquaporin–4 (AQP–4) channelopathy. The AQP–4 IgG antibodies may be present in the context of some paraneoplastic disorders which should be suspected when NMOSD occurs in elderly patients.

3. ◘ NMOSD new diagnostic criteria.
◘ Anti-AQP-4 and anti-MOG IgG.
◘ NMOSD differential diagnosis.
◘ NMOSD prognosis and treatment.

4. ◘ NMO is a severe autoimmune inflammatory disorder of the CNS
characterized by recurrent ONs and LETM lesion.

6. ◘ SET is a 63 year old male presented 2 years ago by acute
quadriparesis due to LETM did not responded IVMP
and the patient got bed ridden
◘ 6-months ago, the patient developed visual impairment
due to sequential ONs did not responded again to
IVMP but partially responded to IVIG.
◘ The patient was AQP–4 positive and diagnosed
NMOSD.
◘ 2-months later he developed progressive weight loss,
dyspnea and hemoptysis with CT chest showed
bronchogenic carcinoma.
◘ The patient died within few weeks

7. ◘ MSM is a 40 year old lady presented by acute
onset of progressive ataxia, diplopia and facial
diplegia with partial response to IVIG on the
basis of GBS diagnosis.
◘ MRI showed T2 hyperintense lesion (left > right)
involving the paramedian pontine tegmentum,
dorso-lateral medulla and inferior cerebellar
peduncle.
◘ The patient was AQP-4 IgG seropositive.

8. ◘ In 1894, Eugene Devic and Fernand Gault
described the postmortem picture of a 45 year
women with severe demyelination and
necrosis in ON and spinal cord with no brain
lesions and called it “De la neuromyélite
optique aiguë ” or “Devic’s Disease”.
◘ In 2004, Vanda A. Lennon, and colleagues
discovered AQP-4 antibodies.
Eugene Devic (1858 – 1930)
Vanda A. Lennon (Mayo Clinic)

9. ◘ NMOSD is a rare disorder with a reported prevalence of 0.5 – 10 /
100,000.
◘ Female: male ratio is 9: 1.
◘ NMOSD commonly occur between 32 – 45 years.

10. ◘ AQP-4 is the most abundant water channels in
the CNS, highly expressed in the astrocytic foot
processes to regulate water homeostasis.
◘ Outside the CNS, AQP-4 channels could be
found in the kidneys, gastric parietal cells,
airways, skeletal muscles, and endocrine glands,
but pathologic changes in NMOSD are limited
to the CNS.

11. ◘ Central gray matter around the central canal
of the spinal cord.
◘ Posterior part of the ON and optic chiasma.
◘ Peri-aqueductal areas.
◘ Area postrema.
◘ Peri-ependymal surface of the corpus
callosum and lateral, third as well as the
fourth ventricles.
◘ Subpial regions.

12. ◘ When the AQP–4 antibodies cross the BBB,
they attack the water channels on the
surface of the astrocytes leading to extensive
astrocytic loss through complement
mediated cytotoxicity.
◘ Loss of astrocytic trophic support results in
oligodendrocyte apoptosis with subsequent
neuronal demyelination and finally axonal
degeneration.

14. ◘ The initial presentation in > 50% of cases with simultaneous or rapid
sequential bilateral longitudinally extensive ONs.
◘ Results in altitudinal visual field defect with selective affection of upper
and/or lower fields as well as RAPD in asymmetrical ONs.

15. ◘ In acute stages, the ON becomes swollen with long
segment ONs appears as hyperintense in T2-WI
affecting more than half of the ON length (usually
the posterior part extending to the optic chiasm
and even the optic tracts).
◘ No specific pattern of enhancement but the
distribution could differentiate NMOSD from MS.
◘ In chronic stages, the ON get atrophied with
decreased diameter at the lesion sites.

16. ◘ NMOSD is characterized by LETM involving ≥ 3
contiguous vertebral segments
◘ The spinal cord get swollen in acute stages and
atrophied (thinned) in chronic stages.
◘ Cervical segments are usually involved with rostral
extension to the medulla (area postrema).
◘ Usually associated with early painful tonic spasms
defined as a paroxysmal episode of intense pain
that accompanies tonic posturing of the limbs.

17. ◘ Typically, spinal cord lesions are bright, spotty
and hyperintense in T2-WI corresponding to
dark lesions on T1-WI.
◘ NMOSD have no specific enhancing patterns
which may be patchy or ring-like and
disappears in long standing lesions (> 3-months)
or after steroid therapy.
◘ In cross sections:
(1) Involves > 50% of cross spinal cord section.
(2) Central cord predominance with > 70% of the
lesion resides in the central grey matter.

18. ◘ Short segment TM may be the first presentation
in 20% of NMOSD cases and its poor
recognition may delay the diagnosis and expose
the patient to hazardous MS immunotherapies.
◘ Short segment TM could be categorized from its
NMOSD cross sectional features.
◘ For suspicious cases with short segment TM,
order serum AQP-4 IgG antibody status.

19. ◘ AP is located in the dorsomedial part of the
medulla and projecting to the caudal part of the
4th ventricle
◘ AP modulates the hemostatic responses and is
heavily expressed with AQP-4 receptors
◘ AP is involved in 20% of cases of NMOSD
resulting in intractable vomiting and hiccups.

20. ◘ Acute brainstem syndromes (8–
30%):
- Trigeminal autonomic cephalalgia
- Diplopia, facial palsy and vestibular ataxia.
- Eight and half Syndrome.
- Dysarthria.
◘ Acute diencephalic syndrome:
- Narcolepsy and hypersomnia.
- Anorexia, inappropriate ADH secretion
(diabetes insipidus).
- Hypothermia and respiratory affection.
- Hyperprolactinemia.

21. (1) Circumventricular areas.
(2) Thalamus and hypothalamus.
(3) Extensive subcortical ADEM like lesion.
(4) Extensive corpus callosum lesions typically
involves its ependymal surface, with
marbled or “arch bridge” appearance.
(5) Longitudinal involvement of the
corticospinal tract extending to the cerebral
peduncle and pons.
(6) Periependymal cerebral lesions.

22. ◘ Non-enhancing lesions are more common than enhancing ones which could be
detected in 9 – 36% of NMOSD cases.
◘ Enhancement disappear after few weeks of activity or steroid therapy.
◘ Enhanced brain lesions in NMOSD are associated with higher relapse rates.
◘ Patterns of brain NMOSD enhancement include:
(1) Patchy (cloud-like) heterogenous enhancement with poorly defined margins.
(2) Peri-ependymal linear (pencil-thin) enhancement.
(3) Flame-like appearance which is the sum of both.
(4) Thick or linear leptomeningeal enhancement (in few cases of NMOSD).
◘ Nodular or ring enhancements in brain lesions are in favor of MS.

23. Leptomeningeal
Pencil-thin
Enhancement
Cloud Enhancement

25. ◘ At least one attack of either:
1- Optic neuritis.
2- Acute transverse myelitis.
◘ Plus at least 2 of the following:
1- Normal MRI brain or not meeting the diagnostic
criteria for MS
2- LETM with MRI lesions ≥ 3 vertebral segment.
3- AQP-4 IgG positive status.

26. ◘ This term had introduced in 2007 to cover
AQP-4 IgG seropositive patients with
either:
(1) Limited NMO criteria as cerebral, diencephalic, and
brainstem lesions characteristic of NMO.
(2) Overlap syndrome with coexisting autoimmune
disorders e.g., SLE or Sjögren syndrome.
(3) Optico-spinal MS (prominent in Asia and represents
an interphase between NMO and MS).
◘ The term had extended to include also some
AQP-4 IgG negative cases like anti-MOG
IgG patients.

27. ◘ At least one core clinical characteristic.
◘ AQP4-IgG–positive status.
◘ Exclusion of alternative diagnoses.

28. (1) Acute optic neuritis with severe
bilateral simultaneous or sequential visual
loss.
(2) Long extensive transverse myelitis.
(3) Area postrema syndrome.
(4) Acute brainstem syndromes.
(5) Acute diencephalic syndrome.
(6) Symptomatic cerebral syndrome
with NMOSD-typical brain lesions.

29. ◘ At least 2 core clinical characteristics meeting all of the following:
(1) At least one core clinical characteristic must be ONs, LETM, or area postrema
syndrome.
(2) Dissemination in space (the 2 clinical characters may occur in single or multiple
attacks).
(3) Fulfillment of additional MRI requirements including acute ONs, acute LETM,
area postrema syndrome or acute brainstem syndrome associated periependymal
lesions.
◘ Negative test for AQP4-IgG, or testing unavailable.
◘ Exclusion of alternative diagnoses.

30. MOG is a component of myelin sheaths that is expressed in the outer
surface of oligodendrocytes and only present in the CNS

31. ◘ MOG-IgG antibodies could be detected in a subset of monophasic or
multiphasic CNS demyelinating disorders including ADEM, ONs, TM,
AQP-4 negative NMOSD and MS.

32. ◘ MOG-IgG positive NMOSD has younger age
of onset, equal sex incidence and a
favorable outcome than AQP–4 positive
cases.
◘ Younger age usually start by cerebral
affection while older start with ON.
◘ MOG-IgG–positive status usually affects the
conus and thoracolumbar spinal segment
with bilateral anterior ON involvement.
◘ Characterized by simultaneous or rapid
sequential ONs and TM.

33. (A) ADEM-like pattern with multifocal, poorly demarcated, large (> 1–2 cm)
lesions.
(B) Leukodystrophy-like pattern with extensive, confluent, symmetric lesions.
(C) Nonspecific pattern with small, patchy, slight lesions.

34. ◘ Constitute 3–5% of all NMOSD cases, and usually
have a better outcome.
◘ ON in pediatric-onset NMOSD may affect a short
segment indistinguishable from MS.
◘ At the same time, spinal cord lesions are difficult
to be differentiated from that of ADEM, MS, or
monophasic TM.
◘ Brain lesions occur in 30% of cases but the
distribution and cloud enhancement should
raise suspicion of NMOSD.

35. ◘ Late-onset NMOSD is characterized by clinical
onset after 50 years of age.
◘ A higher rate of LETM with severe motor
impairment.
◘ Lower frequency of ON and brain
involvement.
◘ Reported cases included paraneoplastic disorders
(esophageal and bronchogenic carcinoma),
sarcoidosis and post infective (herpes zoster and
chronic HCV infection).

37. ◘ Demyelinating:
- MS, NMOSD, ADEM and idiopathic TM.
◘ Infectious:
- Bacterial: Syphilis, Mycobacterium tuberculosis, Lyme
disease
- Viral: Herpes simplex virus type-2, varicella-zoster virus,
cytomegalovirus, Epstein-Barr virus, coxsackie virus,
enterovirus, hepatitis A and C
- Parasitic: Neurocysticercosis, Schistosoma, Gnathostoma
angiostrongylosis
- Fungal: Actinomyces, Coccidioides immitis, Aspergillus,
Blastomyces dermatitidis
◘ Paraneoplastic:
- Antiamphiphysin (breast carcinoma)
- Anti-CRMP-5 (small cell lung cancer)
◘ Autoimmune/Inflammatory:
- Systemic lupus erythematosus
- Sjogren syndrome
- Antiphospholipid syndrome
- Neurosarcoidosis
- Behcet disease
- Mixed connective tissue disease

39. ◘ Demyelinating:
- Multiple sclerosis
- Neuromyelitis optica
- Shilder’s disease
- Encephalitis periaxialis concentrica
◘ Infectious & Para-infectious:
- Herpes zoster, lyme disease, syphilis, tuberculosis, dengue,
mumps, varicella zoster, toxoplasmosis, measles,
leptospirosis, chickungunya, west Nile, adenovirus,
brucellosis, coxsackievirus, cat scratch disease, hemolytic
streptococcal infection, meningococcal infection, typhoid
fever, Whipple’s disease
◘ Post-vaccination:
- Vaccinations against tuberculosis, hepatitis B, rabies, tetanus,
meningitis, anthrax, measles, rubella & influenza
◘ Autoimmune/Inflammatory:
- Systemic lupus erythematosus
- Sjogren syndrome
- Neurosarcoidosis
- Behcet disease

40. (1) Continuous worsening for more than 4-weeks
(sarcoidosis or neoplasm).
(2) Hyperacute onset in less than 4-hours (cord
ischemia or infarction).
(3) Partial TM (MS)
(4) Oligoclonal bands are in favor of MS despite
their presence in 20% of NMOSD.
(5) Persistent Gadolinium enhancement > 3
months.
(6) Diffuse, spinal cord involvement (Progressive
MS).

41. ◘ Differentiation between NMOSD and MS is a
crucial first step as MS – DMT like
interferon-β, fingolimod, natalizumab or
dimethyl fumarate cause NMOSD
worsening.
(1) Optic nerve:
- Unilateral, short-segment and usually anterior
involvement with less chiasmal involvement.
(2) Spinal cord:
- Short longitudinal extension (≤ 2 vertebral segments).
- In cross sections, the lesion is eccentric, affects < 50%
of spinal cord segment and predominantly dorso-
lateral.

42. (3) Infratentorial Lesions:
- Pons (e.g. intra-pontine trigeminal nerve), middle
cerebellar peduncles, cerebellar white matter.
(4) Supratentorial Lesions:
- Small ovoid lesions in the callosal-septal interface.
- Periventricular Dawson fingers: ovoid and
perpendicular to the lateral ventricle.
- Lesions adjacent to the temporal horns of the lateral
ventricles (not involved in NMOSD).
- Juxta-cortical lesions involving subcortical U-fibers.
- Cortical lesions

44. ◘ Recent studies done by high field strength MRI (3–7 T) have shown that the
presence of the central vein sign within white matter lesions is a hallmark
of MS which reliably differentiates it from NMOSD. It could also
differentiate RRMS from PPMS.

45. Idiopathic Acute TMMS related TM LETM due to NMOSD
◘ Acute bilateral symptoms and signs due to spinal cord, a clear sensory
level, no extra-axial compression of the spinal cord, evidence of
inflammation within the spinal cord, and progression to nadir in 4 h to 21
days.

46. ◘ Usually monophasic with polyfocal CNS affection
including ONs, LETM and bilateral cerebral white
matter lesions.
◘ No AQP4-Ab, equal sex incidence and relatively
more common in pediatric population.
◘ The most important differentiating points are the
history of preceding infection and the existence of
ENCEPHALOPATHY manifested by either
alteration in consciousness or behavioral change.
◘ MRI, putamenal lesions are in favor of ADEM and
hypothalamic lesions are going with NMOSD.
◘ Re-diagnosis of MS or NMOSD for a case of ADEM
in subsequent phases is possible.

47. ◘ Described by Desmond Kidd et al. in 2003 and
since that time, only few cases are studied.
◘ Most studies consider CRION disease as a distinct
entity not related to NMOSD.
◘ The absence of TM which occur very early MOG
positive cases weaken this possibility of being
AQP-4 negative NMOSD.
◘ Characterized by subacute severe relapsing,
bilateral, simultaneous or sequential visual loss,
ocular pain persists after the onset of visual loss
and dramatic response to systemic steroids.

48. ◘ Acute phase: IV steroids pulse therapy for 3–5
days or plasmapheresis.
◘ Intermediate phase: Oral steroids at a starting dose of 1
mg/kg which gradually tapered to the least
effective dose.
◘ Long term: Azathioprine, methotrexate,
cyclophosphamide, mycophenolate,
cyclosporine or IVIG (CRION patients treated
with IVIG remained stable for an average of 4
years following cessation of steroids).

49. Posteriorpart is suppliedby branchesfromthe
ACA,A.comandICA
Anterior part is suppliedby ophthalmicartery
(ICA)anditscentralretinalandposterior ciliary
branches
The anterior and posterior segments of the ON are different in their
blood supply as well as antigen expression (AQP-4 and MOG)

50. ◘ May be arteritic or non-arteritic (NAION).
◘ The most common cause of acute optic
neuropathy in old age patients.
◘ AION is caused by vasoconstriction of the
short posterior ciliary arteries with resultant
ischemia of the posterior circulation of the
globe including the ON.
◘ More common in patients with congenitally
smaller discs due to arterial compression at
ON head.
◘ AION and post-AION optic atrophy.
◘ Causes altitudinal visual field defect,
associated with retinal hemorrhage and
exudate.

52. ◘ In the past century, NMOSD had known as a
disreputable disease carrying a high degree of
disabilities through induction of necrotizing
inflammatory ONs and LSTM.
◘ Roughly half of patients have severe visual
and/or motor impairments within 5 years of
disease onset.
◘ These outcomes are expected to improve as
advances in understanding NMOSD
pathogenesis and introduction of more
targeted therapies.

53. ◘ Absence of myelitis e.g. isolated ON.
◘ Younger age at disease onset.
◘ Complete remission following the first attack.
◘ Lower attack frequency during the first year.
◘ Lower serum and CSF AQP–4–IgG titer.

54. ◘ AQP–4–IgG antibody titer in serum and CSF increases with relapse and
proportional with disease severity.
◘ Glial fibrillary acidic protein is a highly sensitive biomarker for astrocytic
damage and is elevated in over 98 % of NMO patients.
◘ T-helper 17-mediated biomarkers (serum and CSF) including IL-8, IL-17, IL-21,
and IL-23 and granulocyte colony stimulating factor (G-CSF) are increased during
relapses.
◘ T-helper 2-mediated IL-4 in serum is elevated in NMOSD.
◘ T-helper 1-mediated interferon-γ and TNF-α are elevated in NMOSD.

56. ◘ Both initial and recurrent acute
episodes should be treated with
IVMP (pulse therapy) for 3–5
days followed by oral steroid
taper.

57. ◘ A monoclonal antibody against CD20 (a human B-
lymphocyte and plasma cells antigen).
◘ It is now considered as the first-line
immunosuppressive therapy for NMOSD both AQP-4
and MOG positive cases.
◘ 5-years follow-up studies showed that rituximab
treated NMOSD patients had 87% marked reduction
in relapse rate with improvement or stability of the
neurological deficit.
◘ Other studies showed relapsing of disease activities
following rituximab discontinuation.

58. ◘ Initial dosing is either 2 infusions of 1 g spaced 2
weeks apart or 4 weekly 375-mg/m2 body surface
area administrations.
◘ Maintenance therapy includes:
- Redosing every 6 to 9 months.
- Redosing when the CD19 population exceeds 0.1%.
- Therapeutic target of < 0.05% circulating
peripheral memory B cells (CD27+ cells in
peripheral blood mononuclear cells).

59. ◘ Traditional:
- Mycophenolate mofetil.
- Azathioprine.
- Cyclophosphamide.
- Methotrexate.
◘ Emerging Drugs:
- Eculizumab.
- Inebilizumab (anti-CD19 receptors
monoclonal IgG antibodies).
- Tocilizumab or satralizumab (anti- IL-6
receptors monoclonal IgG antibodies).

60. (1) Rare cases with double seronegative
AQP–4 and MOG – IgG NMOSD are
possible.
(2) High field strength MRI is needed to
differentiate NMO and MS.
(3) For ONs orbital films including fat
suppression techniques may be needed.
(4) Do not exclude the possibility of NMOSD
in first episode short segment TM.

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