Topic of the month...Neuromyelitis optica

1. INDEX
 INTRODUCTION
 CLINICAL TYPES OF NEUROMYELITIS
OPTICA
 MANAGEMENT
INTRODUCTION
Whether neuromyelitis optica (NMO), the co-occurrence of myelitis and optic neuritis, is a variant of multiple
sclerosis (MS) or a unique disease is controversial. Distinct neuropathological features and a fulminant clinical
course argue in favor of NMO as a distinct disease. However, the combination of neurological impairments of
myelitis and optic neuritis occurs in patients with several inflammatory disorders, including multiple sclerosis
and collagen vascular diseases. NMO is also associated with certain infectious diseases. The fact that the NMO
phenotype occurs in a variety of disease states suggests that NMO does not represent a specific clinical entity.
To better understand NMO and its associations with recognized diseases, a systematic review of the literature
using MEDLINE was conducted. The history of NMO, its nosology, associations with other diseases, and
current concepts of its pathogenesis and treatment is reviewed in this article.
The syndrome of neuromyelitis optica (NMO) is defined as the co-occurrence of optic neuritis with myelitis.
This combination of neurological impairments occurs in patients with multiple sclerosis (MS), acute
disseminated encephalomyelitis (ADEM), systemic lupus erythematosus (SLE), and Sjögren syndrome. It also

2. occurs in association with viral and bacterial infections. However, most often, no underlying cause can be
found. The clinical course of NMO is variable. It may occur as a monophasic illness that is either fulminant
and fatal or associated with varying degrees of recovery. Polyphasic courses characterized by relapses and
remissions also occur. Over the last century much debate has revolved around whether NMO is a distinct
disease, at least in a subset of patients, and what its relationship is to MS and other inflammatory disorders.
This review focuses on the history of NMO, its nosology, reported associations with other disorders, and
current concepts of pathogenesis. Whether or not the NMO phenotype corresponds to a unique biologic
process will await the identification of a disease-specific marker and, ultimately, the elucidation of the
syndrome's pathogenesis.
HISTORICAL OVERVIEW
In 1870, the first account of an association between myelitis and an optic nerve disorder was reported by T.C.
Allbutt.[1] He described a case of myelitis followed by optic nerve changes approximately 3 months later;
however, details of the case report are scant and pathology was not presented. Erb[2] (1879) published a case
report of a 52-year-old man who developed recurrent optic neuritis followed by transverse myelitis. The
patient made a partial recovery from his myelopathy but had sustained impairments in visual acuity. In the
same year Steffan[3] described a similar case. Seguin[4] (1880) reviewed Erb's case, a case of Noyes,[5] and a
third case of optic neuritis and subacute transverse myelitis that he observed personally. He considered the
association to be accidental and not a clinical syndrome. Dreschfeld[6] (1882) described the first case of optic
neuritis and myelitis that was autopsied and demonstrated inflammatory changes in the spinal cord and optic
nerves. In contrast, examination of the brain was normal. Dreschfeld credited Gowers for recognizing that
quot;the optic neuritis and the myelitis were both the result of a common cause,quot; and this report first suggested
that this combination of symptoms is a clinical syndrome.
Several additional cases were also described in the early medical literature.[7-9] Devic's student Gault (1894)
reviewed 16 previously reported similar cases and studied another case for his doctoral thesis.[10-12] Gault
and Devic proposed that these cases of optic neuritis and myelitis represented a distinct clinical entity:
quot;neuromyélite optique aiguë.quot; Using the clinical criteria proposed by Gault and Devic, additional case reports
of NMO gradually accumulated in the literature and were successively reviewed by Goulden (1914, 52 cases),
[13] Beck (1927, 71 cases),[14] Stansbury (1949, 200 cases),[15] and Peters (1958, 300 cases).[16] Many cases
included in these reviews had pathological changes in the brainstem and cerebrum that in retrospect are
consistent with other diagnoses such as ADEM, acute MS (Marburg variant), and relapsing MS. Other cases
are probably secondary to infectious (syphilis or measles) or toxic (lead and cadmium poisoning) etiologies.
Thus, in all likelihood, the broad clinical definition of NMO used in these studies allowed inclusion of cases
with diverse etiologies. As a result, several authors began to question the concept of NMO as a unique disease.
[17,18]
 Neuromyelitis Optica as a Distinct Disease
In support of the view that NMO can be a unique disease are the striking neuropathological features that were
reported in typical cases of NMO. Demyelination of the optic nerves and infiltration of the spinal cord with
inflammatory cells were recognized in many early cases.[6,9-12,19] For example, Beck (1927)[14] described
rarefaction of the spinal cord and optic nerves, polymorphonuclear infiltrates, extensive demyelination, and
destruction of the spinal cord extending continuously through multiple segments. These features were felt to be
distinct from the pathology observed in MS. Similarly, Hassin (1937)[20] and Lowenberg et al (1947)[21]
described involvement of both gray and white matter of the spinal cord, marked inflammatory infiltrates, and
the absence of gliosis, changes that were thought to be distinct from findings in both MS and necrotic myelitis.
Stansbury (1949)[15] reviewed the neuropathology of 20 cases of NMO and proposed that the lesions
progressed through a series of stages. The earliest stage is characterized by acute inflammation: lesions show
prominent perivascular exudates of polymorphonucleocytes, leukocytes, and plasma cells. The next stage is
characterized by evidence of tissue destruction and demyelination in the perivascular foci. In this stage,
smaller lesions seem to coalesce into larger lesions, and axis-cylinder destruction is noted. Gray matter
structures of the cord may be involved either alone or by extensions from adjacent white matter lesions.

3. Necrotic lesions are frequently observed in the cord, and smaller necrotic foci are sometimes found within the
optic nerves. The next stage is characterized by reactive microgliosis. Numerous microglial cells, frequently
with lipid-laden phagosomes containing myelin, are typically seen in this stage. The final stage is characterized
by astrocytosis and the formation of glial scars. Stansbury noted that glial scarring is less frequent and usually
only partial, in contrast to typical MS plaques.
 Neuromyelitis Optica as a Subtype of Other Demyelinating Disorders
The fact that many of the pathological findings in NMO are also present in typical cases of MS led many
authors to consider NMO as a form of MS. Dreschfeld[19] recognized that quot;acute disseminated
myelitisquot; (neuromyelitis optica) and quot;diffuse sclerosisquot; (multiple sclerosis) were similar. Although some of the
reported cases of NMO had a chronic course,[5] the cases that came to autopsy were typically fulminant. As a
result, it is possible that the pathological differences observed between NMO and MS reflect the severity of the
demyelinating attack and not a distinct pathological process. In the discussion of Lowenberg et al's (1947)[21]
observations on NMO and its relationship to MS and necrotic myelitis, Putnam (1947)[21] noted that necrosis
of the spinal cord was unlikely to occur in patients with NMO who recovered from an acute attack; thus,
lesions in the remitting cases were probably different from lesions in autopsied cases. Furthermore, Putnam
and Forster (1942)[18] described 6 of 12 patients with NMO who eventually developed other neurological signs
consistent with MS; thus, these authors suggested that NMO was a presentation of MS. This view was shared
by Ferraro (1937),[17] who considered all forms of demyelinating disease to be varying presentations with the
same primary etiology, a quot;neuroallergic reaction.quot;
Several cases of NMO in the early literature had diffuse brain involvement.[22] In retrospect, such cases are
most likely examples of ADEM. Indeed, Miller and Evans,[23] citing similarities in pathology, suggested that
NMO was a form of ADEM. Both NMO and ADEM can produce both gray and white matter involvement,
perivascular infiltration, and areas of focal necrosis. However, such an explanation fails to account for cases of
NMO that have a relapsing-remitting course.
 Diagnostic Criteria
Several sets of diagnostic criteria for NMO have been proposed (Table 1). However, none has received
widespread acceptance. For example, the criteria of Gault and Devic seem too broad and do not exclude
coexistent myelitis and papillitis from infection, injury, or tumor. Undoubtedly, this resulted in some confusion
in the early literature. By contrast, the definition used by Shibasaki et al is probably too restrictive, excluding
polyphasic cases or those that evolve over more than 1 month. The criteria of O'Riordan et al allow for
polyphasic and unilateral optic neuritis cases but are also probably too restrictive in requiring the myelitis to
be both rapid and transverse. The newer criteria of both Mandler et al and Wingerchuk et al utilized magnetic
resonance imaging (MRI) to exclude alternative diagnoses. However, specific MRI features that distinguish
NMO from other demyelinating disorders are not well described. Nevertheless, refinements used to define
NMO incorporating MRI imaging in the diagnostic algorithm have led to the identification of a subset of
patients who seem different from typical MS patients in terms of their disease severity, prognosis, and
response to treatment.
Table 1. Comparison of the Definitions of Neuromyelitis Optica
Gault and Devic (Lyon, France)[10-12]
Retrobulbar neuritis or papillitis accompanied by acute myelitis and occasionally other neurological
symptoms or signs not restricted to the spinal cord or optic nerves
Shibasaki et al (Kyushu University, Japan)[24]
Acute bilateral visual impairment (optic neuritis) and transverse myelitis occurring successively within an
interval of 4 weeks that follows a monophasic course
O'Riordan and colleagues (Queen Square, England)[26]

4. 1. Complete transverse myelitis: an acutely developing and severe paraparesis or tetraparesis affecting
motor and sensory pathways with or without sphincteric involvement, evolving over 1 to 14 days, with a
sensory level and in the absence of cord compression
2. Acute unilateral or bilateral optic neuropathy
3. No clinical involvement beyond the spinal cord or optic nerves
4. The disease can be monophasic or multiphasic
Mandler and colleagues (University of New Mexico)[27]
1. Clinical: Acute involvement of spinal cord and optic nerves, either coincidental or separated by months
or years, independent of its subsequent progression but without the development of brainstem,
cerebellar, or cortical features at any time in the disease course
2. Imaging: Normal-appearing brain MRI; enlargement and cavitation on spinal cord MRI
3. CSF: Decreased serum/CSF albumin ratio with normal CNS daily IgG synthesis and usually absence of
oligoclonal bands
4. Pathology: Spinal cord necrosis and cavitation with thickened vessel walls and absence of inflammatory
infiltrates; demyelination of optic nerves with or without cavitation; no demyelinating lesions in the
brain, brainstem, or cerebellum
Wingerchuk and colleagues (Mayo Clinic)[29]
Diagnosis requires all absolute criterion and one major supportive criteria or two minor supportive criteria
Absolute criteria:
1. Optic neuritis
2. Acute myelitis
3. No evidence of clinical disease outside of the optic nerve or spinal cord
Major supportive criteria:
1. Negative brain MRI at onset (does not meet criteria for multiple sclerosis[141])
2. Spinal cord MRI with signal abnormality extending over >/=3 vertebral segments
3. CSF pleocytosis of >50 WBC/mm3 or >5 PMNs/mm3
Minor supportive criteria:
1. Bilateral optic neuritis
2. Severe optic neuritis with fixed visual acuity worse than 20/200 in at least one eye
3. Severe, fixed, attack-related weakness (MRC </=2) in one or more limbs
de Seze and colleagues (CHRU de Lille, France)[31]
1. An acutely developing myelopathy affecting motor and sensory pathways with or without sphincter
dysfunction, evolving in less than one month
2. An acute unilateral or bilateral optic neuritis
3. No clinical neurological involvement beyond the spinal cord or optic nerves
4. Monophasic or polyphasic course

5. CNS, central nervous system; CSF, cerebrospinal fluid; IgG, immunoglobulin G; MRC, Medical Research Council;
MRI, magnetic resonance imaging; PMN, polymorphonuclear neutrophil; WBC, white blood cell.
 Clinical Features
NMO is a rare syndrome in Western countries, constituting less than 1% of demyelinating disease.[24,25]
Clinical, MRI, and spinal fluid features from several case series are summarized in Table 2. Men and women
were initially thought to be equally affected, although in more recent case series women are overrepresented.
[15,26-31] The age of onset ranges from childhood[32] to late adulthood[27,33-36] with the incidence
apparently tapering off after the fifth decade.[37] Cases can present with either visual loss or myelopathy.
Occasionally, optic nerve and spinal cord symptoms begin simultaneously. Either one or both eyes may be
involved, and the extent of myelitis is variable. In most cases, involvements of the spinal cord and optic nerves
occur within 3 months of each other, although some authors have included patients with 2 or more years
between these occurrences.[29] Approximately one third of cases are preceded by a prodrome of fever,
myalgia, headache, or sore throat.[29,37] Generally, NMO is sporadic, although there are a few case reports of
familial occurrences.[38-40]
Table 2. Clinical Features of Neuromyelitis Optica Combined from Recent Case Series[26-29,31]
Feature Number (Proportion)
Women/men 87/36 (2.3:1)
Average age at onset 37
Monophasic/polyphasic 72/40 (1.8:1)
Optic neuritis presentation 50 (45%)
Transverse myelitis presentation 43 (38%)
Combined ON/TM presentation 19 (17%)
Autoimmune disease/antibodies 28/104 (27%)
Antecedent infection 22/91 (24%)
Normal brain (MRI) 48/63 (76%)
Abnormal spinal cord (MRI) 55/58 (95%)
CSF pleocytosis 63/85 (74%)
>50 cells/mm3 27/84 (32%)
CSF polymorphonucleocytes 34/67 (51%)
CSF oligoclonal bands 23/77 (30%)
CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; ON/TM, optic neuritis/transverse myelitis.
NMO is often fulminant and acute, as described in the early literature. Some patients have a monophasic
illness, especially in the pediatric population.[32] Others have polyphasic illness characterized by relapses and
remissions with variable degrees of recovery between episodes (Table 2). The proportion of patients in each of
these two groups varies depending on the criteria used to define NMO (Table 1). One series found that
approximately one third of patients with relapsing NMO die from respiratory failure as a consequence of
diaphragmatic paralysis from cervical cord lesions.[29] In this series, the most important prognostic factor was
whether the disease had a monophasic or polyphasic course. The 5-year survival rate for patients with a

6. monophasic course, typified by closely clustered occurrence of bilateral optic neuritis with myelitis (occurring
within 1 month), was 90%. In contrast, the 5-year survival rate for patients with recurrent disease was 68%.
In the pediatric population, NMO is frequently preceded by infection (72%).[32] Pediatric cases typically have
a monophasic course and many have complete neurological recovery.[32,41] Because of pediatric NMO's
frequent association with preceding infection, monophasic course, and generally good outcome, some authors
consider pediatric NMO to be a variant of ADEM.[32,42]
 Initial Presentation
The differential diagnosis for cases of NMO is concise. Cases have been associated with collagen vascular
disease and infectious, toxic, and idiopathic etiologies. The association of NMO with systemic and infectious
disease is discussed later. A list of possible associated etiologies and potential diagnostic studies is presented in
Table 3.
Table 3. Approach to the Neuromyelitis Optica Syndrome
Differential diagnosis
Collagen vascular diseases and autoantibody syndromes
 Systemic lupus erythematosus
 Sjögren syndrome
 p-ANCA autoantibodies
 Anticardiolipin autoantibodies
 Mixed connective tissue disease
Viral and mycobacterial infections
 Varicella-zoster virus
 Epstein-Barr virus
 HIV
 Tuberculosis
Toxic exposures
 Clioquinol
 Antitubercular medication
Idiopathic central nervous system demyelinating diseases
 Asian-type multiple sclerosis
 Western-type multiple sclerosis
 Acute disseminated encephalomyelitis
 Neuromyelitis optica
Diagnostic evaluation
 Complete history, physical, and neurological examination
 Basic laboratory studies
 Complete blood count, serum chemistries, urinalysis with microscopic examination, chest X-ray with
posteroanterior and lateral views, HIV testing, and PPD placement with controls for anergy
 MRI
 Spine, brain, and optic nerves with and without gadolinium contrast administration
 CSF analysis

7.  Cell counts, total protein, glucose, IgG index, IgG synthetic rate, oligoclonal bands, VDRL, polymerase
chain reaction for herpes zoster virus and Epstein-Barr virus, bacterial and mycobacterial stains and
cultures
 Collagen vascular disease studies
 ESR, ANA, ds-DNA, ENA, p-ANCA, anticardiolipin antibodies, rheumatoid factor, anti-SSA and anti-
SSB antibodies
 For a patient with serological markers for Sjögren syndrome or a history of xerostomia and
xerophthalmia, consider a Schirmer test (lacrimation), salivary gland scintigraphy, and salivary
gland/lacrimal gland biopsies
ANA, antinuclear antibody; ds-DNA, double-stranded DNA; ENA, extractable nuclear antigen; ESR, erythrocyte
sedimentation rate; HIV, human immunodeficiency virus; IgG, immunoglobulin G; p-ANCA, perinuclear
antineutrophil cytoplasmic antibody; PPD, purified protein derivative; SSA, Sjögren syndrome antigen A; SSB,
Sjögren syndrome antigen B; VDRL, Venereal Disease Research Laboratory.
It is not currently possible to predict whether a patient presenting with optic neuritis or myelitis will develop
NMO. The co-occurrence of bilateral optic neuritis should raise concern about the development of subsequent
myelitis. However, because of the rarity of NMO in Western countries, bilateral optic neuritis is still more
commonly associated with the subsequent development of MS than NMO in these environments.[43] Although
a schema for the comprehensive evaluation of optic neuritis is beyond the scope of this review, its differential
diagnosis is presented in Table 4.
Table 4. Approach to Optic Neuritis
Differential diagnosis
Collagen vascular diseases
 Systemic lupus erythematosus
 Sjögren syndrome
 Wegener granulomatosis
Autoimmune
 Postvaccination
 Sarcoidosis
 Bee sting
 Autoimmune optic neuropathy
Viral infections
 Varicella-zoster virus
 Herpes zoster virus
 Epstein-Barr virus
 Cytomegalovirus
 Human immunodeficiency virus (HIV)
 Measles
 Mumps

8.  Rubella
 Adenovirus
 Enterovirus
 Hepatitis A virus
Bacterial infections
 Mycobacterium tuberculosis (tuberculosis)
 Borrelia burgdorferi (Lyme disease)
 Treponema pallidum (syphilis)
 Bartonella henselae (cat-scratch disease)
 Toxoplasma gondii (toxoplasmosis)
 Mycobacterium pneumoniae
 Sinus infections
Paraneoplastic optic neuritis
Idiopathic demyelinating diseases
 Idiopathic optic neuritis
 Multiple sclerosis
 Acute disseminated encephalomyelitis
 Neuromyelitis optica
Optic neuritis mimics
 Infiltrative processes
 Infiltrating neoplasms (e.g., lymphoma, leukemia, myeloma, carcinomatous meningitis)
 Optic nerve glioma
 Optic nerve glioblastoma
 Optic sheath meningioma
 Langerhans cell disorders
 Paraneoplastic
 Cancer-associated retinopathy (CAR)
 Cancer-associated cone dysfunction (CACD)
 Melanoma-associated retinopathy (MAR)
 Diffuse uveal melanocytic proliferation (DUMP)
 Paraneoplastic ganglion cell neuronopathy (PCGN)
Vascular disease
 Nonarteritic anterior ischemic optic neuropathy
 Giant cell arteritis
 Diabetic retinopathies
 Microangiopathy of the brain, retina, and inner ear (Susac's syndrome)
 Acute posterior multifocal placoid pigment epitheliopathy
 Eale's disease (noninflammatory occlusive disease of the retinal vasculature)
 Cogan's syndrome (interstitial keratitis, vestibular dysfunction, and deafness)
 Amaurosis fugax

9.  Central retinal vein occlusion
 Aneurysms and arteriovenous malformations
 Systemic hypercoaguable states, including anticardiolipin syndrome
Nutritional and toxic
 Vitamin B12 deficiency
Toxins (e.g., ethyl alcohol, ethambutol, methanol, amiodarone, clioquinol, chemotherapeutic agents)
Radiation-induced optic neuropathy
Genetic mitochondrial disease
 Leber's hereditary optic neuropathy
 Kearns-Sayre syndrome
 MELAS (mitochondrial encephalopathy with lactic acidosis and strokes)
 NARP (neuropathy, ataxia, and retinitis pigmentosa syndrome)
Exudative
 Central serous chorioretinopathy
 Optic disc drusen
Others
 Ophthalmic migraine
Big blind spot syndromes (acute zonal occult outer retinopathy, acute macular neuroretinopathy, multiple evanescent
white dot syndrome, acute idiopathic blind spot enlargement syndrome)
The development of progressive myelopathy in the absence of antecedent neurologic symptoms and without
signs indicating dissemination beyond the spinal cord is a diagnostic challenge. In such patients, once
compressive etiologies have been excluded, MS is the most common cause of this syndrome in the Western
world. Clinically useful features that suggest an MS origin for a progressive myelopathy include painless
presentation; no systemic symptoms; asymmetric involvement of the cord; no family history of myelopathy;
MRI evidence of multifocal cord or brain white matter involvement; abnormal brainstem or visual evoked
responses; and a cerebrospinal fluid (CSF) profile with variable mononuclear cell pleocytosis, no
polymorphonuclear leukocytes or eosinophils, normal glucose and total protein, increased immunoglobulin G
(IgG) synthesis, and oligoclonal bands. Features of myelitis that may suggest impending optic nerve
involvement are the presence of polymorphonucleocytes or eosinophils and the absence of oligoclonal bands in
the CSF, a normal brain MRI scan, and abnormal visual evoked potentials. An approach to the differential
diagnosis and diagnostic work-up for acute myelitis presentations is outlined in Table 5.
Table 5. Approach to Myelitis
Differential diagnosis
Collagen vascular diseases and autoantibody syndromes
 Systemic lupus erythematosus
 Sjögren syndrome
 Mixed connective tissue disease
 Linear scleroderma
 p-ANCA autoantibodies
 Anticardiolipin autoantibodies

10.  Primary angiitis of the central nervous system
 Postvaccination
 Hashimoto's encephalopathy (myelopathy)
Viral infections
 Varicella-zoster virus
 Epstein-Barr virus
 Cytomegalovirus
 Herpes simplex 1 and 2
 HIV
 HTLV-I, HTLV-II with HIV coinfection
 Enteroviruses
 Mumps
 Measles
 Rubella
 Hepatitis A, B, C
 Group B arboviruses (West Nile and dengue)
 Lymphocytic choriomeningitis virus
Bacterial and mycobacterial infections
 Borrelia burgdorferi (Lyme disease)
 Brucella melitensis (brucellosis)
 Treponema pallidum (syphilis)
 Bartonella henselae (cat-scratch disease)
 Clostridium tetani (tetanus)
 Mycobacterium tuberculosis (tuberculosis)
 Mycoplasma pneumoniae
 Chlamydia pneumoniae
 Bacterial meningitis, intraparenchymal abscess, and epidural abscess
Parasitic
 Schistosoma haematobium, Schistosoma mansonii, Schistosoma japonicum Toxocara spp.
Toxic exposure and nutritional deficiency
 Clioquinol exposure
 Antitubercular medication exposure
 Subacute combined degeneration (vitamin B12 deficiency)
Demyelinating and dysmyelinating diseases
 Multiple sclerosis
 Acute disseminated encephalomyelitis
 Neuromyelitis optica
 Adrenomyeloneuropathy
Neoplastic
 Lymphoma, leukemia, and other infiltrating tumors

11. Paraneoplastic: Hodgkin's lymphoma
Sarcoidosis
Vascular
 Spinal dural arteriovenous malformation
Diagnostic evaluation
Complete history (including travel and animal contacts), physical, and neurological examination
Basic laboratory studies
 Complete blood count, serum chemistries, vitamin B12, urinalysis with microscopic examination, chest X-ray
with posteroanterior and lateral views, HIV testing, and PPD placement with controls for anergy
MRI
 Spinal cord with and without gadolinium contrast administration; brain with and without gadolinium contrast
administration and with sagittal T2- or proton density-weighted images
Electrophysiology studies
 Visual evoked potentials and nerve conduction studies
Collagen vascular disease and autoantibody studies
 ESR, ANA, ds-DNA, ENA, RF, anti-SSA, anti-SSB, anticardiolipin antibodies, and p-ANCA; thyroid
function tests, antimicrosomal antibodies, and antithyroglubulin antibodies for Hashimoto's encephalopathy
(myelopathy)
 For a patient with serological markers for Sjögren syndrome or a history of xerostomia and xerophthalmia,
consider a Schirmer
 test (lacrimation), salivary gland scintigraphy, and salivary/lacrimal gland biopsies
CSF Studies
 Cell counts, protein, glucose, IgG index, IgG synthetic rate, oligoclonal bands, angiotensin-converting enzyme
CSF infectious etiology studies
 PCR for varicella-zoster, Epstein-Barr, herpes simplex type I and II, and cytomegalovirus viruses; antibody
studies for human T-cell lymphotrophic virus type I, Borrelia burgdorferi, Mycoplasma pneumoniae, and
Chlamydia pneumoniae; viral cultures for enteroviruses; cultures and stains for aerobic and anaerobic
bacteria, fungi, Mycobacterium tuberculosis and Brucella melitensis; and VDRL
Serum infectious etiology studies
 IgG and IgM enterovirus antibody titers, IgM mumps, measles, and rubella antibodies, group B arbovirus
antibodies (West Nile and dengue), Brucella melitensis antibodies, Chlamydia psittaci antibodies, Bartonella
henselae antibodies, schistosomal antibodies; cultures for Brucella melitensis, hepatitis A, B, and C studies,
and RPR
Additional studies for infection
 Nasal-pharyngeal and anal swabs/cultures for enteroviruses; stool O&P for Schistosoma ova; wound cultures
for Clostridium tetani (if applicable)
Sarcoidosis evaluation
 Serum angiotensin-converting enzyme (ACE), serum calcium, and 24-hour urine calcium; for patients with
hilar adenopathy or elevated ACE, consider CT of chest, total body gallium scan, and lymph node biopsy to
search for systemic Sarcoidosis
 Serum and 24-hour urine for very long chain fatty acids for adrenomyeloneuropathy
 CT myelogram and spinal angiogram for spinal dural arteriovenous malformation

12. ANA, antinuclear antibody; CT, computed tomography; ds-DNA, double-stranded DNA; ENA, extractable nuclear
antigen; ESR, erythrocyte sedimentation rate; HIV, human immunodeficiency virus; HTLV, human T-cell
lymphotropic virus; IgG, immunoglobulin G; O&P, ova and parasites; p-ANCA, perinuclear antineutrophil
cytoplasmic antibody; PPD, purified protein derivative; RF, rheumatoid factor; SSA, Sjögren's syndrome antigen A;
SSB, Sjögren syndrome antigen B; VDRL, Venereal Disease Research Laboratory.
 Physical Examination Findings
Ophthalmoscopic examination may be normal or find signs of optic neuritis with blurring of the discs. Some
patients have mild papilledema, although hemorrhages and exudates are rare. Optic atrophy with disc pallor
may be seen in chronic cases. Visual field testing typically reveals a central scotoma, although other visual field
changes such as color blindness,[2] bitemporal hemianopsia,[14] paracentral scotoma,[44] and altitudinal
deficits[45] are reported. The pupils are dilated in response to the visual loss but are otherwise normal.
Extraocular movement abnormalities,[15] Horner's syndrome,[22] and nystagmus[46] were reported by some
authors, although in retrospect these cases were probably misclassified.
The spinal cord symptoms in NMO are not different from those of other causes of myelitis.[37] Some authors
[26] maintain that the myelitis should be transverse and complete, although not all cases adhere to this
requirement. Lhermitte's symptom is frequent and patients may suffer from painful tonic spasms.[47,48]
Cerebral and brainstem findings should not be present; if they are present, a search for alternative etiologies is
warranted.
 Laboratory Findings
 CSF
The CSF is often abnormal with mildly elevated protein and the presence of pleocytosis including
polymorphonucleocytes.[29] Cell counts vary broadly and are reported to be as high as 3000 cells/mm3.[49] In
recent case series cell counts over 50 have been reported in as many as one third of patients, although such
elevated cell counts should raise suspicion of alternative diagnoses. The opening pressure is usually normal but
can be elevated.[50] Oligoclonal bands can be present but are reported to be seen less often than in typical
cases of MS.[26,27,29]
 Imaging
The spinal cord MRI is typically abnormal with areas of increased signal intensity spanning several sections of
the spinal cord on T2-weighted images and with gadolinium enhancement (Fig. 1).[28,29,51,52] Swelling of the
cord may occur and can sometimes be mistaken for a tumor.[26,53] The optic nerves can also be enhanced
with gadolinium on TI-weighted images.[54] By contrast, the brain MRI is often normal or may show
nonspecific changes.[27] One study directly compared brain MRI scans from typical MS patients with those in
NMO and found lesions in T2-weighted images in one of seven NMO patients in contrast to multiple lesions
observed in all patients with MS.[28] Another study noted that with serial scans intraparenchymal white
matter lesions can evolve over time in patients with NMO.[29] A brain MRI study without evidence of
demyelination at the time of presentation is considered by some to be important in establishing a diagnosis of
NMO.[29]
 The MRI picture characteristic of transverse myelitis
1. A centrally located multisegmental (3 to 8 spinal segments) MRI T2 hyperintensity that occupies
more than two thirds of the cross-sectional area of the cord is characteristic of transverse myelitis.
The MRI T2 hyperintensity commonly shows a slow regression with clinical improvement. The
central spinal cord MRI T2 hyperintensity represents evenly distributed central cord edema. MRI

13. T1 Hypointensity might be present in the same spinal segments that show T2 hyperintensity
although to a lesser extent. The MRI T2 hyperintensity is central, bilateral, more or less
symmetrical and multisegmental. (Fig. 2)
2. MRI T2 central isointensity, or dot (within and in the core of the MRI T2 hyperintensity) might be
present and is believed to represent central gray matter squeezed by the uniform, evenly
distributed edematous changes of the cord. (central dot sign). It might not be of any clinical
significance.
3. Contrast enhancement is commonly focal or peripheral and maximal at or near the segmental MRI
T2 hyperintensity. In idiopathic transverse myelitis enhancement is peripheral to the centrally
located area of high T2 signal intensity rather than in the very same area. The prevalence of cord
enhancement is significantly higher in patients with cord expansion.
4. Spinal cord expansion might of might not be present and when present is usually multisegmental
and better appreciated on the sagittal MRI T1 images. Spinal cord expansion tapers smoothly to
the normal cord, and is of lesser extent than the high T2 signal abnormality.
5. Multiple sclerosis plaques (and subsequent T2 hyperintensity) are located peripherally, are less
than 2 vertebral segments in length, and occupies less than half the cross-sectional area of the cord.
In contrast to transverse myelitis, enhancement in MS occurs in the same location of high-signal-
intensity lesions seen on T2-weighted images.
Table 6. Differences between idiopathic transverse myelitis and spinal multiple sclerosis
Number
T2 of
Disease entity Contrast element Pathology
hyperintensity segments
involved
Idiopathic transverse Central, 4-8 In transverse myelitis Nonspecific necrosis that
myelitis multisegmental enhancement is peripheral to affects gray and white
the centrally located area of matter indiscriminately and
high T2 signal intensity rather destroys axons and cell
than in the very same area. bodies as well as myelin.
Spinal multiple Peripheral 1-2 In contrast to transverse White matter demyelination
sclerosis myelitis, enhancement in MS only.
occurs in the same location of
high-signal-intensity lesions
seen on T2-weighted images.
Figure 1. Cervical spinal
cord MRI in the sagittal
plane of a 28-year-old
woman with polyphasic
neuromyelitis optica. (A) T1-
weighted image showing
thickening of the cord from
C7 to T2 with patchy areas
of subtle intraparenchymal
hyperintensity. (B) T1-
weighted image, post
gadolinium contrast
administration, showing
several enhancing lesions

14. from C7 to T2. (C) T2-
weighted image showing a
contingous area of increased
signal intensity spanning
from C6 to T3.
Figure 2.
case w
acute
transverse
myelitis
NMO. No
spinal c
swelling
the MRI
central
hyperinten
and
central
sign. A
notice
involvemen
of
complete
cross sect
of the sp
cord.
 Imaging of optic neuritis
MR imaging is more sensitive for imaging multifocal plaques in the optic nerve, chiasm or white matter. MR
imaging abnormalities, reflected by increased signal intensities on the T2-weighted images and enhancement
postgadolinium introduction have been demonstrated in 56% to 72% of adult patients with isolated optic
neuritis and in 90% to 98% of patients with clinically definitive MS. The diagnostic yield is increased when
inversion recovery sequences are used and possibly with the addition of a surface coil. The demonstration of
increased signal intensity of the optic nerve and chiasm, however, are nonspecific and do not allow a diagnosis
of MS. The site of the lesion and the length of the longitudinal extent vary. They may be located anterior near
the optic nerve head, throughout the entire orbital optic nerve, intracanalicular, and intracranial portions of
the optic nerve. A single lesion or several discontinuous lesions may be present within the respective optic
nerves. The retrobulbar segment is most commonly involved. The optic nerve is generally enlarged and active
lesions produce intense enhancement after gadolinium introduction.

15. In cases of an acute inflammation or demyelination of one or both optic nerves, which is often a manifestation
of multiple sclerosis, diffuse enlargement of the optic nerve in a cylindrical fashion will be appreciated , owing
to a generalized edema of the nerve. This is easily appreciated in cases of unilateral neuritis. In cases of
bilateral optic neuritis, the nerves must be measured and compared with the normal standard in order to
make the determination of optic nerve widening . Enhancement of the optic nerve in optic neuritis is unusual
but has been reported, presumably as a result of increased vascular permeability. CT scans in the coronal
plane simply demonstrate a widened nerve with a homogeneous density throughout its width. In cases of optic
neuritis owing to inflammatory conditions such as syphilis, toxoplasmosis, tuberculosis, or to viral infections,
the CT findings are similar to those seen in the acute demyelinating process. The findings are usually totally
reversible following appropriate medical treatment. In patients presenting with acute papilitis only, a normal
CT scan may be obtained.
Figure 3. Precontrast CT scan studies showing two cases with optic neuritis( MS). Notice the diffuse
enlargement of both optic nerves.
CLINICAL TYPES OF NEUROMYELITIS OPTICA
 Asian-Type (Opticospinal) Multiple Sclerosis and Neuromyelitis Optica
 Neuromyelitis Optica and Multiple Sclerosis In Japan
The prevalence of MS in Japan is estimated to be 1.6 to 1.8 per 100,000, substantially lower than in Western
countries.[55] However, the proportion of patients with NMO in this population is reported to be higher than
in Western populations. Okinaka et al[56] collected 270 cases of demyelinating disease diagnosed in Japan
between the years 1890 and 1955. Clinical involvement was restricted to the spinal cord and optic nerves in 145
of these cases. The very high numbers with presumed NMO in this series suggested that NMO is more
prevalent than typical MS in Japan; however, sampling bias makes this interpretation uncertain. Kuroiwa and
colleagues[57-59] reviewed cases of demyelinating disease at Kyushu Hospital from 1958 to 1973. They found
63 cases of MS; 59 met Schumacher criteria for MS,[60] and 4 were autopsy proved. Spinal cord and optic
nerve presentations were observed in 51% of these cases. In addition, six cases of acute monophasic NMO were
identified, corresponding to 6% of all cases of demyelinating disease. Although this estimate is considerably
lower than the prior estimates, it is still much higher than in Western case series. Kuroiwa and colleagues[61]
collected 1084 patients with MS from across Japan in 1972 to 1973. Eighty-two (7.6%) met their criteria for
NMO (Table 1), again demonstrating a high proportion of NMO in Japan. When the cases from this survey of
probable MS (Schumacher criteria) and classic NMO are combined, 82% had optic nerve involvement and
82% had spinal cord involvement. These data indicate that demyelinating disease in the Japanese has a
predilection for involvement of the optic nerves and spinal cord.
 Pathology of Japanese Multiple Sclerosis
In an attempt to correlate pathologic changes with the clinical presentations of cases of demyelinating disease
in Japan, Shibasaki and Kuroiwa[62] analyzed 54 autopsied cases. Of 13 cases of NMO, 4 had lesions
restricted to the optic nerves and spinal cord; additional lesions were present in the brainstem in 8 patients

16. and in the cerebrum in 4 patients. The majority of cases (9 of 13) had lesions that were not confined to the
spinal cord and optic nerves, underscoring the heterogeneity of clinically defined NMO. Moreover, the
pathological changes in some cases were consistent with both MS and NMO, demonstrating that overlap
occurs between these conditions. These observations led Kuroiwa and colleagues to conclude that NMO was a
type of MS and that the majority of patients in Japan suffered from quot;opticospinalquot; MS. Opticospinal MS was
considered to be a transitional form of MS combining features of the more aggressive acute NMO and typical
Western-type MS. In Caucasians, a clinical predilection for optic neuritis and/ or spinal cord involvement was
found to aggregate in some multicase MS families, further supporting a biological basis for an opticospinal
phenotype.[63]
 Comparison of Multiple Sclerosis in Asian Populations
In a survey of MS in Asian countries, Kuroiwa and colleagues[64] found several patterns that distinguish MS
in Asia from MS in Western countries. Visual impairment occurred in 70% of patients in this series in
comparison with 34% from a U.S. Army series. In addition to the frequent occurrence of visual impairment,
which was often bilateral and severe, presentations of NMO were not rare. The authors proposed that
demyelinating disease in Western and Asian countries shared a common pathogenesis, with typical Western
MS and classic NMO being at opposite ends of a continuum. In a comparison of patients from Japan and
England, Shibasaki and colleagues[24] found that visual loss at the onset of illness and severe visual deficits
were more frequent in Japanese patients. Frequent and severe involvement of the spinal cord and brainstem
was also more common in the Japanese than in the English. A low incidence of MS and relatively higher
proportion of NMO were also reported in Malaysia[65] and India.[66-71]
Observed clinical differences between Eastern and Western MS led to the hypothesis that the clinical
phenotype of demyelinating disease in Asian-type MS may be due to immunogenetic variation. Kira and
colleagues[72] studied the HLA locus in a series of Japanese patients with MS. They found that, unlike the
findings in Western MS,[73] the DR2-associated DRB1*1501 and DRB5*0101 alleles were not associated with
NMO (0%). Additional support for an immunogenetic contribution to the phenotype of Asian MS came from
further studies of the human leukocyte antigen (HLA) locus.[74-76] DPA1*0202 and DPB1*0501 alleles were
associated with the NMO phenotype in Japanese patients but not with healthy control subjects or Japanese
patients with typical MS. The HLA alleles with the strongest association with Western-type MS in Japanese
patients were found to be DRB1*1501 and DRP1*0301. These findings are consistent with an association of the
extended DRB1*1501, DQB1*0602 haplotype with the disseminated form of MS. This finding has been
consistent in many, but not all, studies.[77] Linkage disequilibrium between the DR and DP loci is
considerably less tight than between the DR and DQ loci. Whether the DPA1*0202 and DPB1*0501 alleles will
be found to correlate with NMO in other Asian or Western patients remains to be seen.
The clinical course of MS in Japan may be changing. Fewer patients present with Asian-type (opticospinal) MS
and relatively greater numbers present with Western-type MS. Nakashima and colleagues[78] found that 60%
of cases collected from the 1970s had opticospinal MS. In comparison, only 5% of cases collected form the
1990s had the Asian MS phenotype. It is possible that increased awareness of MS in Japan has led to the
identification of cases of Western-type MS that would not have been recognized previously because of the
assumption of the rarity of the disease in Japan. Nevertheless, this striking observation also argues for an
environmental influence on the clinical phenotype of MS because the genetic background in Japan has not
changed significantly during the 30 years spanned by this study. The increased travel of Japanese to Western
countries and vice versa hypothetically may have led to the introduction into Japan of infectious or toxic
agents or of lifestyle, including dietary, adaptations that may influence the phenotype of central nervous
system (CNS) demyelinating disease.
 Neuromyelitis Optica in Tropical Countries
Although genetic factors such as the HLA locus are likely to influence the clinical manifestations of
demyelinating disease, environmental factors may also play a role. NMO occurs in individuals with diverse
genetic backgrounds who reside in tropical environments, raising the possibility that this phenotype may be
promoted by an environmental trigger or triggers prevalent in these areas of the world. Further studies are

17. needed to elucidate the interaction between genetic and environmental factors that predispose persons of
certain racial groups to NMO.
Osuntokun[79] reviewed hospital records in Nigeria from 1957 to 1969 to survey all cases of neurological
disease. Interestingly, he found 2 cases of MS but identified 95 cases of NMO, estimating a prevalence of 43 per
100,000 of hospital cases. Autopsy confirmation was not available for this case series. Nevertheless, these
findings are consistent with the observation that MS is rare in the tropics. However, if one considers NMO to
be a form of MS, then the prevalence of 43 per 100,000 hospital cases is comparable to that in similar series in
Western hospitals. That NMO was present in 98% of cases of identified demyelinating disease in Nigeria is
striking and warrants further investigation.
The polyphasic NMO phenotype was also observed in seven of eight black South African patients with CNS
demyelinating disease.[80] Oligoclonal bands were not found in any of these patients. MRI imaging of the
spinal cord revealed lesions that spanned several segments of the spinal cord, and MRI imaging of the brain
showed disseminated lesions in the cerebral white matter consistent with MS. This pattern is reminiscent of the
opticospinal form of MS observed in Japanese patients. The almost exclusive occurrence of the NMO
phenotype in native African blacks with MS-like syndromes is strikingly different from the low prevalence of
this phenotype in Caucasian patients. This suggests that, at least in this population, NMO may represent a
distinct disease.
Cabre and colleagues[30] surveyed French African-Caribbeans in Martinique from 1997 to 1999 and identified
62 cases with definite or probable MS by Poser criteria and 17 cases of NMO by the Wingerchuk et al criteria
[29] (17.3% of CNS demyelinating disease). In this series, NMO was found to affect women exclusively and a
trend for a lower frequency of oligoclonal bands was observed in the NMO group.
One study of 67 consecutive patients diagnosed with MS in São Paulo, Brazil reported that a high percentage
of patients had NMO.[81] Thirty percent of patients had predominantly optic nerve and spinal cord
involvement, and 12% had simultaneous bilateral optic neuritis and transverse myelitis (Shibasaki et al's
definition of NMO, Table 1). Neither MRI nor autopsy data are available for these patients. The authors
compared the high percentage of NMO observed in their series with the Japanese MS literature and concluded
that factors other than race give rise to the phenotypic expression of demyelinating disease. This study is best
interpreted with caution because the spectrum of demyelinating disease in Brazil is unknown and many levels
of bias can occur in case series from a single hospital.
 Neuromyelitis Optica in Indigenous Americans
One study of MS in Manitoba, Canada in Algonkian and Athapaskan indigenous people identified seven cases
of MS.[82] The disease course in these patients was more aggressive than in typical MS; five of seven patients
had the NMO phenotype, although MRI showed scattered lesions throughout the brain. None of these patients
had the HLA DRB1*1501 allele that is associated with Western-type MS. The pattern of CNS demyelinating
disease in these patients is reminiscent of that in Japanese MS patients with the NMO phenotype. In the one
case in which autopsy data were available, necrosis and inflammatory infiltrates were present in the spinal
cord. One optic nerve showed mild demyelination and the other severe axonal loss. Demyelinating plaques in
the cerebral hemispheres were also present. These findings are similar to the autopsy results for several
Japanese patients who presented with the NMO phenotype but were found to have pathological findings of
both NMO and MS.[56]
 Neuromyelitis Optica and Systemic Diseases
NMO has been associated with several systemic diseases including collagen vascular diseases, autoantibody
syndromes, infections, and toxic exposures (Table 3). In addition to a complete history and physical
examination to look for evidence of systemic disease, specific laboratory testing for many of these conditions
should be considered in the evaluation of patients presenting with NMO.
 Neuromyelitis Optica with Endocrinopathies

18. Vernant and colleagues[83] described a series of eight women from Martinique and Guadeloupe who suffered
from NMO and endocrinopathies. Seven of the eight patients had secondary amenorrhea that coincided with
exacerbations of NMO. One postmenopausal patient and two others had galactorrhea with
hyperprolactinemia. Four patients had hypothyroidism, and one patient had diabetes insipidus. The authors
suggested that three patients who were hyperphagic and obese suffered from hypothalamic dysfunction. In one
patient, a thyrotropin-releasing hormone stimulation test indicated hypothalamic dysfunction as a cause of
hyperprolactinemia. In three patients, gadolinium enhancement of the hypothalamic-hypophyseal region was
present on brain MRI. All patients suffered from recurrent optic neuritis and myelitis that was resistant to
various immunosuppressive therapies and ultimately led to blindness and paraplegia. Oligoclonal bands were
found in only one patient. The authors suggested that this series constituted a distinct clinical entity because
endocrinopathies were not previously associated with NMO.
Hyperprolactinemia was found in a subset of Japanese patients with MS.[84] Nine of 48 Japanese women with
MS had elevated prolactin levels, and 7 of these women had Asian-type MS. Amenorrhea and galactorrhea
were present in two women with Asian-type MS. Elevated prolactin levels were not found in Japanese men
from the same series. Several patients developed symptoms referable to areas of the CNS other than the optic
nerves and spinal cord. The authors suggested that optic nerve inflammation can spread to damage the
tuberoinfundibular dopaminergic neurons and subsequently disinhibit prolactin secretion. In theory,
prolactinemia may enhance humoral and proinflammatory TH1 cellular responses and thereby augment
disease activity. However, prolactin is an acute phase reactant, and circulating levels of this hormone increase
in a nonspecific manner in many inflammatory conditions.[85]
 Neuromyelitis Optica in Collagen Vascular Disease
 Systemic Lupus Erythematosus
Several case reports associate NMO with SLE. The first published report was that of a 21-year-old woman
with a 4-year history of paraparesis and incontinence who developed right-sided retrobulbar optic neuritis.[86]
A diagnosis of SLE was made during a prolonged hospital admission. The patient eventually succumbed to
bronchopneumonia. Autopsy showed demyelination, inflammatory infiltration, and necrosis of the spinal cord
and right optic nerve. No brain lesions were identified, and a diagnosis of NMO was established. The authors
estimated that the chances of a patient having both SLE and NMO were 1 in 5,000,000 and considered that
chance association in their patient was unlikely. They reviewed the literature on myelopathy and SLE and
questioned whether a common pathogenetic mechanism was present in their case. A nonfatal case of NMO
complicated the pregnancy of a 27-year-old woman with SLE.[87] In the fourth month of pregnancy she
developed transverse myelitis and optic neuritis. MRI studies of the brain and spinal cord were normal. CSF
showed an elevated IgG index. The patient was treated with glucocorticoids and plasma exchange, made a
complete recovery, and was able to give birth to her child. Transverse myelitis recurred postpartum and again
3 years later. This case is noteworthy because the use of glucocorticoids and cyclophosphamide was associated
with complete remission. Currently, a total of 25 similar cases are reported in the literature. A
pathophysiological link between SLE and NMO has not yet been established, although some authors have
suggested a role for anticardiolipin antibodies and the lupus anticoagulant.[26,31,88-94]
 Sjögren Syndrome
NMO was associated with a case of Sjögren syndrome in a 51-year-old woman who presented with subacute
transverse myelopathy.[95] The diagnosis was established on the basis of diminished lacrimation and
salivation, abnormal antibody studies, and sialography. She was treated with oral glucocorticoids and
recovered. However, 7 years later she presented with a sensory level at T6 and acute left optic neuritis that
progressed to total blindness. CSF was normal and brain MRI showed swelling of the left intraorbital optic
nerve but an otherwise normal brain. She was again treated with glucocorticoids and gradually recovered her
vision. This case demonstrates that the combination of transverse myelitis and optic neuritis can be associated
with other autoimmune diseases. The authors observed that the anti-Ro (SSA [Sjögren syndrome antigen A])
antibody was present in 7 of 11 patients with optic neuropathy associated with Sjögren syndrome and
speculated on a role for this antibody in the pathogenesis of CNS manifestations of Sjögren syndrome, citing

19. cross-reactivity between Ro and HuD, the antigen associated with paraneoplastic encephalomyelitis and
sensory neuronopathy.[96,97] Sjögren syndrome was associated with four cases of NMO in the Mayo Clinic
series, although details were not provided.[29]
Interestingly, 4 of 13 patients (31%) in the CHRU de Lille series had Sjögren syndrome; although, in three of
these cases the diagnosis of Sjögren syndrome was not made until several years after the onset of neurological
symptoms.[31] All patients in this series underwent complete screening for Sjögren syndrome including history
of xerostomia and xerophthalmia, a Schirmer test, minor salivary gland biopsy, and salivary gland
scintigraphy as per the revised European criteria for Sjögren syndrome.[98] The association of NMO with
Sjögren syndrome in this series suggests that underlying systemic collagen vascular disease may be
underdiagnosed in earlier series that did not include a comprehensive evaluation for Sjögren syndrome.
 P-ANCA (perinuclear antineutrophil cytoplasmic antibodies)
NMO was also described in a patient with perinuclear antineutrophil cytoplasmic antibodies (p-ANCA),
antinuclear antibody (ANA), SSA, and SSB (Sjögren syndrome antigen B) antibodies.[99] A 52-year-old man
presented with transverse myelitis and then, over a 6-month period, developed optic neuritis affecting first the
right and then the left eye. Brain MRI was normal but spinal cord MRI showed a contrast-enhancing lesion.
He was treated with glucocorticoids but eventually developed permanent bilateral blindness and myelopathy.
Sjögren syndrome was excluded despite the presence of anti-SSA and SSB antibodies. The role of p-ANCA
antibodies in the pathogenesis of what was considered to be a vasculitic process is uncertain. p-ANCA
antibodies were also found in a proportion of Japanese patients with opticospinal type MS.[100]
 Anticardiolipin Antibodies
Karussis and colleagues[101] followed a group of 20 MS patients who also had high anticardiolipin (ACL)
antibody titers. Patients in this series did not suffer from the ACL syndrome (thrombosis and recurrent
abortion), but many experienced a progressive myelopathy and one patient had NMO.[101] Interestingly, ACL
titers were also observed in a group of Japanese patients with opticospinal MS; these patients also had high
lesion loads on brain MRI.[102] Whether ACL has a role in the pathogenesis of myelitis, NMO, or MS remains
to be established.
 Mixed Connective Tissue Disease
Neurological manifestations of mixed connective tissue disease (MCTD) are rare, although several case reports
associate transverse myelitis with MCTD.[103-105] One report described a 19-year-old woman with MCTD
who experienced recurrent bouts of either unilateral optic neuropathy or transverse myelopathy over several
years.[106] The patient was treated successfully with plasmapheresis and immunosuppressive medications.
 Neuromyelitis Optica in Infectious Disease
Viral. In several series NMO frequently followed an infectious prodrome characterized by headache, myalgia,
and upper respiratory symptoms. In a few cases, a known infectious agent was identified. NMO was observed
in a 29-year-old man approximately 3 weeks after acute infectious mononucleosis.[107] His CSF was
inflammatory; he was treated with glucocorticoid and made a complete recovery. Varicella-zoster infections
are associated with acute myelitis, and several case reports associated acute varicella infection with NMO.[108-
111] Recovery in these cases was variable despite treatment with acyclovir and corticosteroids. Another report
described a 41-year-old woman who presented with left optic neuritis and transverse myelitis in the setting of
untreated human immunodeficiency virus (HIV) infection.[112] She underwent a comprehensive work-up for
opportunistic infections and granulomatous disease that was not diagnostic. A brain MRI was normal and the
CSF was inflammatory but without oligoclonal bands. Her symptoms resolved with antiretroviral medications
and glucocorticoid treatment. Given the extraordinary range of neurological complications associated with
primary HIV infection, it is plausible that NMO was a consequence of HIV infection. In all of these cases of
NMO associated with viral infections the symptoms of optic neuritis and myelitis were separated by a few days
to weeks. Thus, when the symptoms of optic neuritis and myelitis co-occur within days to a few weeks, a

20. comprehensive search for possible infectious etiologies is probably warranted.
Tuberculosis. NMO was observed in patients with tuberculosis.[113,114] In these cases, visual loss and myelitis
were not thought to be due to direct CNS infection with tuberculosis or antitubercular drugs. In one series, 6 of
10 cases of NMO identified at a South African hospital suffered from pulmonary tuberculosis.[115] The
authors interpreted this relationship to be causal, suggesting that an antimycobacterial immune response was
involved in the pathogenesis of NMO. However, given that tuberculosis is endemic in this hospital's
community, the association may be due to chance.
Subacute Myelo-Optico-Neuropathy. That NMO could have a toxic etiology was suggested by observations of a
syndrome that occurred in Japan during the 1960s and consisted of abdominal symptoms followed by
transverse myelopathy, optic neuropathy, and peripheral neuropathy. Pathologically, demyelination and
axonal injury of the spinal cord, optic nerves, and peripheral nerves was observed.[116] A case-control
analysis found a strong association between exposure to clioquinol, an intestinal antiseptic, and the
development of subacute myelo-optico-neuropathy (SMON).[117] Subsequent experiments demonstrated that
clioquinol can cause myelo-optic neuropathy in dogs.[118,119] Antitubercular treatment was also associated
with SMON.[120] From a clinical perspective, SMON may superficially resemble NMO, and in all cases a
history of possible toxic exposure should be sought. The presence of peripheral neuropathy clearly
distinguishes cases of SMON from those of typical NMO. However, some overlap may occur, as evidenced by
one report of typical NMO with evidence of segmental demyelinating peripheral neuropathy demonstrated by
teased fiber preparation of the sural nerve.[121]
 Pathogenesis
In experimental autoimmune encephalomyelitis (EAE), various myelin antigens are used to induce
autoimmune reactions that serve as models for CNS demyelinating disease. A quantitatively minor myelin
protein termed myelin oligodendrocyte glycoprotein (MOG) is highly encephalitogenic in many species and
can induce a relapsing or progressive disease with prominent CNS demyelination closely resembling human
MS.[122,123] Storch and colleagues[124,125] found that 40% of rats with MOG-induced EAE accumulated
selective demyelination of the optic nerves and spinal cord. This may serve as an animal model for NMO. An
important distinction of this type of MOG-induced EAE from other antigen-induced forms of acute EAE is the
requirement for anti-MOG antibodies for induction of the full demyelinating phenotype to be present. Thus,
both T- and B-cell responses play important roles in induction of this MS-like lesion.
A small study found that anti-MOG antibodies were present in four patients with NMO but not in patients
with isolated myelitis or optic neuritis,[126] suggesting that autoimmunity against MOG may be a biological
marker for NMO in some patients. However, anti-MOG antibodies were also found in some patients with MS
and in some control individuals and thus are unlikely to be specific for NMO.[127,128] Further evidence is
needed to determine whether anti-MOG antibodies have a role in the pathogenesis of either MS or NMO and,
if so, whether some subsets of MOG autoantibodies are pathogenic.
Several autopsied cases of NMO revealed the presence of abnormal vasculature in the spinal cord.[129,130]
These changes were compared with the observations of Marie, Foix, and Alajouanine[131] in their description
of subacute necrotic myelitis. Many cases of the Marie-Foix-Alajouanine syndrome are thought to be due to
necrosis of a dural arteriovenous malformation. The presence of similar vascular abnormalities in some cases
of NMO raises the question of an underlying vascular anomaly in some cases. However, it is difficult to
rationalize how a spinal dural arteriovenous malformation could produce optic neuritis. Alternatively, the
vascular changes observed in some cases of NMO and Marie-Foix-Alajouanine syndrome may be secondary to
a primary inflammatory process.
That the spinal cord vasculature may be a target for autoimmune inflammation in NMO is supported by a
recent autopsy series, in which NMO lesions were compared to MS, ADEM, and spinal cord infarction lesions.
[132] In this study, 100% of actively demyelinating NMO lesions were associated with vessel hyalinization, a
finding not present in the MS, ADEM, or infarcted lesions. Furthermore, immunoglobulin, activated
complement (C9 neo antigen) and macrophages immunoreactive for myelin proteins, including MOG, co-

21. localized to the perivascular region. These findings suggest that spinal cord blood vessels are targeted for
autoimmune attack and that a humoral response with complement activation has a role in tissue destruction.
These results are consistent with the observations made by Stansbury who proposed that perivascular
inflammation was the initial stage in the pathogenesis of NMO lesions.[133]
MANAGEMENT
Unfortunately, there are no proven effective therapies for NMO. Glucocorticoids are typically used to treat
cases acutely and may be beneficial.[29,31,134] Some patients appear to become glucocorticoid dependent and
experience relapses when the dosage of prednisone is lowered.[29] Plasma exchange may be tried in patients
who do not respond to glucocorticoids.[135] In an uncontrolled case series, 6 of 10 patients with NMO treated
with plasma exchange showed moderate or marked improvement.[136] Interferons and sometimes
immunosuppressant drugs are used with the hope that further relapses will be prevented, but prospective data
in support of their efficacy are lacking.[27,29] In one uncontrolled series seven patients with NMO were
treated with long-term prednisone and azathioprine and were observed to improve after 6 months of therapy.
[137] Because patients with NMO can improve spontaneously, it is not possible to determine from this
uncontrolled series whether this regimen was of any benefit. One case report described a possible benefit of
lymphocytaplasmapheresis in a 26-year-old pregnant patient with NMO.[138] Based on recent experimental
[126] and pathological[132] evidence, it seems likely that immunoglobulins and complement deposition play a
role in the pathogenesis of NMO. Consequently, therapies directed toward inhibiting complement (such as
soluble Cr-1),[139] depletion of B-cells (anti-CD20),[140] or plasma exchange[136] should be investigated in
randomized, controlled trials.
CONCLUSION
Since the time when the association of myelitis and optic neuritis was first noted, much debate has focused on
whether this observed pattern of illness occurs by chance or represents a distinct clinical entity. In fact, it is
now clear that NMO represents a syndrome that can have diverse underlying pathoetiologies. Distinct diseases
including collagen vascular, infectious, and toxic etiologies may present with symptoms of myelitis and optic
neuritis. There is also a clear association of myelitis and optic neuritis with otherwise typical forms of MS. In
these cases, a reasonable argument can be advanced that genetic or environmental factors, or both, influence
whether a demyelinating syndrome will manifest as a relatively selective disorder of the spinal cord and optic
nerves.
In comparison with Western MS patients, a disproportionately high proportion of Asian patients with CNS
demyelination have lesions restricted to the spinal cord and optic nerves. In Caucasian (United States)
multicase MS families, early manifestations of restricted optic nerve-spinal cord involvement were found to
aggregate significantly in certain families, arguing that an underlying genetic basis influences these clinical
manifestations.[63] There is also genetic evidence from studies of Japanese MS suggesting that some HLA
genes may distinguish NMO from Western-type MS. Although HLA haplotypes may have a role in the
pathogenesis of this syndrome, they do not yet explain any of the outstanding questions that are unique in this
syndrome.
Many key questions remain unanswered. Why is there a predisposition for the spinal cord and optic nerves?
Why is the brain spared? Why does necrosis occur in both gray and white matter structures of the cord? The
observation that MOG, other autoantibodies, and complement deposition are found in some NMO cases
suggests that humoral-mediated autoimmunity may contribute to the pathogenesis of this syndrome. If this is
true, B-cell selective immunosuppressant drugs, soluble complement inhibitors, and plasma exchange may
have a role in the treatment of NMO. Given the rarity of the syndrome in Western countries, randomized
treatment trials will require collaboration between many centers in order to enroll sufficient numbers of
patients to complete a study.
References

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