INDEX

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

INTRODUCTION

CLINICAL TYPES OF NEUROMYELITIS OPTICA

MANAGEMENT

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 "the optic neuritis and the myelitis were both the result of a common cause," 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: "neuromyélite optique aiguë." 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.

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 "acute disseminated myelitis" (neuromyelitis optica) and "diffuse sclerosis" (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 "neuroallergic reaction."

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]

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 neuropathy3. No clinical involvement beyond the spinal cord or optic nerves4. The disease can be monophasic or multiphasic

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 MRI3. CSF: Decreased serum/CSF albumin ratio with normal CNS daily IgG synthesis and usually absence of

oligoclonal bands4. 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

Mandler and colleagues (University of New Mexico)[27]

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 myelitis3. 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 segments3. 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 eye3. Severe, fixed, attack-related weakness (MRC </=2) in one or more limbs

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 neuritis3. No clinical neurological involvement beyond the spinal cord or optic nerves4. Monophasic or polyphasic course

de Seze and colleagues (CHRU de Lille, France)[31]

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]

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

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.

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.

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

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

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.

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

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

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

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)

Differential diagnosis

Collagen vascular diseases and autoantibody syndromes

Systemic lupus erythematosus

Sjögren syndrome

Mixed connective tissue disease

Linear scleroderma

p-ANCA autoantibodies

Anticardiolipin autoantibodies

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

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

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

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.

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

Disease entity T2 hyperintensity

Number of

segments involved

Contrast element Pathology

Idiopathic transverse myelitis

Central, multisegmental

4-8 In transverse myelitis enhancement is peripheral to the centrally located area of high T2 signal intensity rather than in the very same area.

Nonspecific necrosis that affects gray and white matter indiscriminately and destroys axons and cell bodies as well as myelin.

Spinal multiple sclerosis

 

Peripheral 1-2 In contrast to transverse myelitis, enhancement in MS occurs in the same location of high-signal-intensity lesions seen on T2-weighted images.

White matter demyelination only.

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

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.

from C7 to T2. (C) T2-weighted image showing a contingous area of increased signal intensity spanning from C6 to T3.

Figure 2. case with acute transverse myelitis in NMO. Notice spinal cord swelling and the MRI T2 central hyperintensity and the central dot sign. Also notice the involvement of the complete cross section of the spinal cord.

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

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 "opticospinal" 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

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

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

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

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-

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.

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