|Year : 2007 | Volume
| Issue : 4 | Page : 231-239
Anu Jacob, Mike Boggild
Division of Neurology, The Walton Centre for Neurology and Neurosurgery, Liverpool, L9 7LJ, United Kingdom
Division of Neurology, The Walton Centre for Neurology and Neurosurgery, Liverpool, L9 7LJ
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Neuromyelitis optica (NMO) or Devic's disease was until recently regarded as an unusual or severe variant of multiple sclerosis. However the last decade has seen major advances in our understanding of the etiopathogenesis of NMO. Though unsettled, there seems to be increasing evidence that NMO is a distinct immune mediated, largely relapsing, inflammatory, demyelinating disease of the central nervous system that most commonly targets the optic nerves and spinal cord. Longitudinally extensive spinal cord lesions on MRI, a serum antibody (NMO-IgG) which reacts specifically with water channel aquaporin 4 (AQP-4), response to immunosuppressive therapies (rather than immunomodulation like in MS) seem to be distinguish it from MS. We review the evolving epidemiological, clinical, imaging and immunological features of NMO and discuss the therapeutic options available. We also review the longstanding debate on whether NMO and Asian optico-spinal multiple sclerosis are two distinct entities or one. We have reviewed the all the published literature on NMO from India and there seems to be a higher proportion of NMO in India than reported in the West. An early accurate diagnosis and treatment with widely available drugs could alter the prognosis of NMO. A fuller understanding NMO may be the doorway to insights into MS and other demyelinating disorders. The information presented in this review has been obtained from peer reviewed publications, conference abstracts and personal experience. The data on Indian patients has been obtained by a literature search using the national library of medicine search engine with the search terms: "neuromyelitis optica or multiple sclerosis or transverse myelitis or optic neuritis or demyelination and India".
Keywords: Aquaporin, demyelination, Devic, myelitis, neuromyelitis optica, optic neuritis
|How to cite this article:|
Jacob A, Boggild M. Neuromyelitis optica. Ann Indian Acad Neurol 2007;10:231-9
| Introduction|| |
Neuromyelitis optica (NMO) or Devic's disease was first described by Allbutt, who in 1870 reported a patient with a "sympathetic disorder of the eye" after an acute episode of myelitis.  A quarter of a century later Eugene Devic and his student Gault summarized 16 cases from the literature in addition to one of their own and the syndrome came to be known as Devic's disease. Our understanding of NMO did not change greatly over the course of next century. It remained largely regarded as an unusual or severe variant of multiple sclerosis. The last decade has seen major advances in our insights into the etiopathogenesis of NMO. , However the debate whether NMO is a separate entity or a form of multiple sclerosis is ongoing. ,,,
| Epidemiology and Genetics|| |
The exact incidence and prevalence data are hard to obtain in western populations as a result of the rarity of disease in Caucasian populations. In Japan, 15-40% of cases of demyelinating disease are "optico-spinal".  But whether these are truly NMO or a mix of western type MS, with predominant optic and spinal involvement and true NMO is uncertain. In NMO cohorts from Northern Europe and North America, non-Caucasians (African, Hispanic and Asian) are over-represented, though Caucasians still comprise the majority of patients in these series. , NMO probably accounts for less than 1% of patients with demyelinating disease in Western populations. Several series from India suggest a much higher figure of 9-24% of demyelinating disease even when rigid criteria for NMO are used. ,, Regardless of geographic variability NMO may still be an under diagnosed condition.
A small number of cases of familial NMO have been reported. These include identical twin sisters, one who developed the illness at age 24 and the other at age 26;  two sisters with bilateral ON followed by myelitis at 2 and 3 years;  two Japanese sisters aged 62 and 67  and two sisters of Spanish-American ancestry, who developed NMO at ages 26 and 28  and uniquely in a mother (aged 62) and daughter (aged 29). 
HLA studies in NMO are mostly from Japan. HLA DRB1*1501 , the allele that is most strongly associated with MS in the western population, is not associated with optico spinal multiple sclerosis (OSMS) although it is associated with Japanese "classical" MS.  HLA DP*0501 has been reported to be over-represented in Japanese patients with OSMS.  However this allele has a high frequency in the general Japanese population and whether this is a true association is not certain.
| Clinical Features|| |
The clinical course of NMO in a large cohort of 71 patients was relapsing in 68% and monophasic in 32% patients.  Relapsing NMO in the west has a female to male ratio of 5:1. Monophasic NMO affects both sexes equally. The median age of onset in Caucasians is in the fourth decade.  Pediatric cases have been reported. ,,
NMO is characterised by optic neuritis (ON) and transverse myelitis (TM). The ON can be unilateral or bilateral, simultaneous or separated by years. It is typically more severe than an ON attack caused by MS. The myelitis too is usually severe and may cause substantial disability at its nadir. Brain stem involvement can occur and may cause hiccoughs, nausea or respiratory failure.  Paroxysmal tonic spasms, which are sequelae of the myelitis, are more common in NMO compared with MS. Typically these last 10-30 seconds and are characterized by painful contractions of a limb musculature (they can be mistaken for partial seizures or may be labeled "functional"). It is important to recognize these as they readily respond to small doses of carbamazepine.
There is increasing evidence that NMO co-exists with a number of systemic connective tissue disorders, particularly SLE and Sjφgren's syndrome (SS). Myelitis and optic neuritis hitherto attributed to vasculitic complications of these disorders are likely due to co-existing NMO. , In fact approximately half of such patients are seropositive for NMO-IgG, whereas patients with SLE or SS who do not have optic neuritis or myelitis seem seronegative. 
| Diagnostic Criteria|| |
Several diagnostic criteria have been proposed; the most widely accepted are those put forward by the Mayo Clinic investigators in 1999,  which have recently been revised to reflect the importance of spinal cord MRI findings in this disorder.  These are summarized in [Table - 1].
Spinal cord MRI undertaken shortly after onset of a sub-acute myelitis (within days to weeks), typically show a centrally placed cord lesion - longitudinally extensive transverse myelitis (LETM) - typically extending over three or more vertebral segments [Figure - 1]. Cord edema and gadolinium enhancement is typical. Follow-up MRI studies may show cord atrophy, syrinx or complete resolution.
Though at disease onset MRI of the brain is usually normal, over time up to 60% will develop findings. They are unlike the lesions in typical MS; but in 10% patients they fulfil Barkhof criteria for MS.  These lesions are largely asymptomatic. Lesions in the brain stem, periventricular and hypothalamic regions have been noted. These are regions of high AQP-4 expression, the target antigen for NMO-IgG. , Transient encephalopathy or endocrinopathies have been associated with such findings. Diffusion tensor imaging of normal-appearing brain tissue using has shown abnormal diffusion in patients with NMO, probably related to secondary degeneration caused by lesions in the spinal cord and optic nerve.  Optic nerve imaging typically shows edema and contrast enhancement acutely and atrophy at later stages.
During an acute relapse, CSF usually shows a raised total protein with pleocytosis, often neutrophilic which at times leading to diagnostic confusion. Eosinophils may also be found in the CSF in NMO.  Several inflammatory chemo-attractant cytokines (interleukin [IL]-17 and IL-8, CSF Eotaxin-2, Eotaxin-3 and eosinophil cationic protein) have been found elevated in the CSF of NMO/OSMS patients. CSF oligoclonal bands (OCB) are uncommon and are present in only 10-20% patients, representing another differentiating feature from MS.
| Pathology|| |
NMO pathology is characterized by presence of inflammation, demyelination and necrosis that involves both grey and white matter, often resulting in cavitation. There is presence of vascular hyalinization and eosinophils may be abundant. Perivascular immune complex deposition in a 'rim and rosette' pattern is seen in the spinal cord, brain and optic nerves  [Figure - 2]. More recently, widespread absence of stainable AQP-4 in NMO lesions has been demonstrated by several groups.  In some of the lesions described only AQP-4 loss (associated with vasculocentric IgG and IgM deposits and complement activation) without evidence of demyelination or necrosis is seen. 
This suggests that aquaporin loss could be the earliest pathogenic event in NMO and supports the contention that NMO-IgG plays a central role in the etiopathogenesis of the disorder.
| Immunology|| |
NMO IgG/Anti AQP-4 antibody
In 2004 Lennon et al. , reported the discovery of NMO-IgG, the first 'disease specific' antibody in CNS demyelinating disease.  The antibody, identified by immuno-fluorescence has a sensitivity of 73% and specificity 91% for NMO. The antibody is also positive in a significant proportion of patients deemed to be at high risk of NMO (that is, patients with single or recurrent optic neuritis or myelitis).  The specificity of NMO-IgG has now been independently validated by several groups.  Whether NMO-IgG titre correlates with disease severity, attack severity or response to therapy is as yet unknown.
The target antigen of NMO-IgG has been recently identified as the water channel protein, aquaporin-4 (AQP-4).  AQP-4 is the dominant water channel within the central nervous system. It is located within the CNS on astrocytic foot processes abutting the abluminal aspect of blood vessels. AQP-4 is in close association with the cytoskeleton complex, which includes α-syntrophin, β-dystroglycan and dystrophin.  Central nervous system aquaporins also play a role in osmoreception, K+ siphoning and CSF formation and are strongly implicated in the pathogenesis of cerebral edema following water intoxication or focal cerebral ischemia.  Lennon et al. , have shown that NMO-IgG selectively binds to AQP-4. Though far from resolved, the proposed pathogenesis of NMO may follow his sequence of events: in individuals who may have an as yet unidentified predisposition (possibly genetic) an unknown antigenic stimulus leads to the production of circulating immunoglobulin (NMO-IgG/ anti AQP-4 antibody). Through a deficiency or disruption in the blood brain barrier, the antibodies access the extracellular domain of AQP-4. Complement activation and further inflammatory responses recruit neutrophils and eosinophils. Aquaporin loss occurs initially impairing water transport across the cell membrane. , These events culminate in demyelination, necrosis and axonal loss. Regions high in aquaporin-4, like the spinal cord, optic nerves and periventricular regions may bear the brunt of the injury.
The gene for AQP-4 is located on 18q11.2-q12.1. Though no pathogenic mutations have been identified so far, it is conceivable that at least in families with NMO that such a mutation may be involved in its pathogenesis. NMO is the first and the only CNS inflammatory demyelinating disorder to date in which a specific immunologic marker and its target have been identified.
Animal models of neuromyelitis optica
Developing mouse models that mirror human disease would be a major step forward in understanding pathogenesis of NMO. Two such mouse models (double-transgenic mouse strains [opticospinal EAE mouse]), which spontaneously develop an EAE-like neurological syndrome resembling NMO , have been developed by crossing TCRMOG and IgHMOG single-transgenic mice, both on a C57BL/6 background. At around 8 weeks of age these mice spontaneously developed demyelinating lesions located in the optic nerve and spinal cord. However these lesion were small (not longitudinally extensive) and there were no detectable AQP-4 specific antibodies in the serum or IgG or complement deposition in the lesions. A more definitive model that reflects human pathology more accurately is awaited.
The widening spectrum of neuromyelitis optica
With the availability of NMO-IgG several 'idiopathic/orphan' demyelinating entities can be brought under the NMO 'umbrella'. These include recurrent myelitis without evidence of ON and recurrent ON without evidence of myelitis. In a series of 29 consecutive patients with a single event of LETM, 40% were seropositive for NMO-IgG.  Of the nine seropositive cases followed up for 1 year or longer, 55% (5 patients) had a relapse of myelitis (4 patients) or developed ON (1 patient) within the first year of follow-up; an additional seropositive patient developed ON in the second year of follow-up. In contrast, no seronegative patient had a further neurological event. This finding raises the question of prophylactic or preventative treatment, with immunosuppressive drugs in those patients with a single attack of ON or TM and positive NMO-IgG.
Neuromyelitis optica in India
MS is relatively uncommon, compared to other neurological disorders in India accounting for 0.05%-1.85%  of hospital admissions. It is interesting that despite the trend to include NMO as a variant of MS in the western literature,  several Indian researchers had maintained the distinctive nature of the condition.  A literature search on the national library of medicine search engine with the search terms: neuromyelitis optica/MS/ transverse myelitis/optic neuritis/demyelination and India identified 19 articles relevant to NMO. Review of original articles from these and others referenced in these where available identified 59 cases of NMO reported from several hospital based series and case reports [Table - 2].
NMO forms 9-24% of the demyelinating diseases in India. However the true frequency of NMO is likely to be higher. There are several reasons for this: Firstly the criteria used for the diagnosis of NMO in most of these series (acute bilateral visual impairment and TM occurring successively within an interval of 4 weeks that follows a monophasic course , ) were restrictive. With the current criteria  several more 'MS or opticospinal MS' cases would probably be considered as NMO.
Secondly it has long been noted that there is a rather disproportionate involvement of optic nerve and spinal cord involvement (71%) , and relative paucity of OCBS amongst presumed 'MS' patients from India and Japan the so called "Asian MS or Optico-spinal MS". A high proportion of such cases from Japan have now been confirmed to have NMO after NMO IgG testing. The sensitivity (58%) and specificity (100%) of NMO IgG in Japanese OSMS were comparable to the results in North American patients with NMO.  This study and several others suggest, ,, that typical Asian optic-spinal patients and NMO are probably the same. It is likely that the same results apply to Indian patients as well.
A recent report of 6 patients with a " atypical central demyelinating disorder" characterized by " spinal cord involvement in a large vertical segment with cord swelling, optic neuritis, no lesions in the cerebral cortex, paraplegia with urinary retention during the acute phase, no oligoclonal band in cerebrospinal fluid, absence of any evidence of vasculitis, wide time-gap between spinal cord and optic nerve involvement" bears striking similarity to NMO.  But interestingly these patients had a good recovery from acute phase of disease and a relatively benign course which are atypical for NMO. NMO IgG testing was not available when this series was published. Dastur et al. , described the autopsy findings of 2 'atypical cases of MS'. The first of these was a woman with optic neuritis and recurrent myelitis. She also developed vertigo hiccoughs indicating brainstem involvement. She died of tracheostomy related complications. Her autopsy showed pathology limited to the cord, optic nerves and brain stem reminiscent of NMO. 
Careful case ascertainment with newer clinical criteria and testing of NMO IgG where indicated may reveal the true frequency of NMO. From the available literature from India, it does seem that NMO even by strict definitions is more common than in the West. With the current less restrictive current criteria it's likely that this is an underestimate. Whether any unique immunogenetic predisposition exists for such a predilection amongst Asians is not known. Population based studies to ascertain the true prevalence of the disease along with immunogenetic profiling of patients of Indian ethnicity are the necessary basic steps to answer these questions. Speculations on possible links between Asian and western MS has been made, , but proof of such a link is as yet awaited. Careful assessment for the diagnosis of NMO has to be made in 'optico-spinal presentations of MS'. It is especially important as NMO (in contrast from typical MS) has a disabling course with rapid attack accrual of disability. Immunosuppressive therapy with widely available drugs may have an impact on the outcomes of this disease.
Treatment of neuromyelitis optica
Managing a patient with NMO involves treating acute relapses, preventing further relapses, treating symptoms and importantly - rehabilitation.
| Treatment of Relapses|| |
Treatment recommendations in NMO are largely based on case series or expert opinion; there is little evidence to guide long-term management. An acute relapse of NMO (ON or LETM) should be treated as early as possible with intravenous corticosteroids, typically 1 gram of methylprednisolone for five consecutive days, after exclusion or treatment of concurrent infection. Therapeutic plasma exchange (TPE) should be considered when clinical symptoms and signs progress (or fail to improve) despite corticosteroid treatment. ,,, TPE has been shown to be beneficial in acute CNS demyelinating events unresponsive to steroids. In a randomized controlled, cross-over, double-blind trial 6 of 10 (60%) patients with acute attacks of NMO recovered moderately or markedly after TPE, a response rate greater than that seen in prototypic MS in the same study.  Typically seven exchanges each of 1 plasma volume done on alternate days are undertaken. We would consider exchange up to 3 months from relapse if significant deficits persist.
| Prevention of Relapses|| |
Since the majority of patients with NMO follow a relapsing course, often acquiring substantial disability within two or three relapses and because immunosuppression appears to reduce relapse rate, , treatments aiming at relapse prevention should be initiated as soon as the diagnosis of a relapsing NMO is made. [Table - 3] shows currently used immunosuppressive drugs in NMO.
It is important to note that no controlled trials dedicated to prevention of relapses have been conducted.
Therapy for NMO spectrum disorders (with relapsing longitudinally extensive myelitis or relapsing optic neuritis) is along the lines as NMO. Whether patients with a single attack of LETM or ON with a positive NMO IgG should be treated remains uncertain. Several authors argue that treatment should be initiated.  How long the treatment should be continued in those patients who have no further relapses with immunosuppressants is uncertain. We would suggest at least 5 years of relapse freedom before a gradual taper is attempted. The long term side effects of medications have to be weighed against the potential risk of relapses. Disease modifying drugs (interferons) that are used in MS have not been shown to be helpful. , Whether NMO-IgG titers could guide therapy is uncertain.
Symptom management and rehabilitation
Pain, spasticity, bladder and bowel symptoms and sexual dysfunction need to be tackled.
Tonic spasms usually respond to low doses (typically 100-200 mg bd.) of carbamazepine. Rehabilitation, physiotherapy, mobility and visual aids may be needed. Some patients with severe high cervical cord lesions will need long term home ventilatory support.
Prognosis of neuromyelitis optica
Most attacks in NMO are moderately or severely disabling; remissions are often incomplete and neurologic disability accumulates in a step-wise fashion.  A 'secondary progressive' course is unusual though it has been reported.  In the largest reported series more than half of patients developed severe visual loss in at least one eye or had inability to ambulate without assistance within 5 years of disease onset. The 5 year-mortality rate in relapsing patients was 32%. All patients died because of respiratory failure associated with attacks of myelitis.  However this group of patients was seen at a tertiary referral center (where more severe patients might be referred to) at a time when immunosuppressive treatments in NMO were not aggressively pursued. Therefore these outcomes may not reflect the current ones. However it is beyond question that attacks of NMO are generally more severe than those seen in MS and disabillity is acquired earlier than in relapsing remitting MS.
| Conclusion|| |
Neuromyelitis optica (NMO) is a distinct, relapsing demyelinating disorder. There are several features that seem to distinguish it from MS [Table - 4].
However the debate on whether it is an altogether different disease from MS is heated and ongoing. With advances in the knowledge of its pathogenesis there has been a resurgence of interest in this frequently disabling, often life-threatening, but treatable disease. It is important that these advances are reflected in clinical practice. A high index of suspicion and judicious use of the NMO-IgG/AQP-4 assay should facilitate early diagnosis. Hesitation to start therapy even after a secure diagnosis is a common mistake often exposing patients to potentially preventable attacks resulting in major morbidity. In due course a fuller understanding NMO may be the doorway to insights into MS and other demyelinating disorders.
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[Figure - 1], [Figure - 2]
[Table - 1], [Table - 2], [Table - 3], [Table - 4]
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