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The nosology of demyelinating diseases with special predilection for the optic nerves and spinal cord is complex and confusing. Opticospinal multiple sclerosis (OSMS), Asian type multiple sclerosis (MS) and neuromyelitis optica (NMO) are terms frequently used, sometimes interchangeably. Whether there are differences between them and between these entities and conventional (Western type) MS (CMS) with isolated optic nerve and spinal cord involvement has been the subject of substantial recent debate. Some argue that absolute distinction between CMS and OSMS is not possible and that they represent a continuum with "pure NMO" at one extreme and CMS at the other. The utility and application of detection of longitudinally extensive spinal cord lesions, brain magnetic resonance imaging (MRI) abnormalities and anti-aquaporin-4 IgG in differentiating MS and NMO remains controversial. The issue is not purely semantic as prognosis and treatment response differ between NMO and MS. We review the historical background and basis of the arguments to shed some light on these unresolved issues.
The nosology of opticospinal forms of demyelinating diseases is confusing. A variety of terms have been proposed, some of which are strictly defined and others loosely defined. Some of the terms are eponyms (Devic's disease) [1-3], others based on where the condition is relatively most prevalent or first recognized (Asian versus western MS) . Since an IgG biomarker targeting aquaporin-4 was discovered to be a specific marker for neuromyelitis optica , based on the presumed pathogenesis (autoimmune aquaporinopathy , aquaporin-4 autoimmune syndrome or aquaporin-4 astrocytopathy) [6-9]. The nosology is not simply a semantic issue as the prognosis and the appropriate treatment strategy differ greatly between subtypes of opticospinal MS [10-12]. Two schools of thought exist. One contends that neuromyelitis optica and prototypic MS are two definable entities, and that with adequate data and followup, the vast majority of patients can be correctly classified as having one or other entity [13,14]. The other contends that there is a continuum between patients with "pure" opticospinal MS (which resembles neuromyelitis optica) and classic MS, and that none of the cardinal distinguishing features, including aquaporin-4 autoantibodies or detection of longitudinally extensive spinal cord lesions, distinguish between NMO and MS are specific [15-18].
In this review, we will consider the historical evolution of the concept of a distinct form of multiple sclerosis-like illness that selectively targets the optic nerve and spinal cord and explore the arguments that NMO and MS are distinct disorders.
1. What is opticospinal MS?
Neuromyelitis optica (NMO) also termed Devic's disease, is an idiopathic autoimmune demyelinating and necrotizing disease which most commonly targets the optic nerves and the spinal cord . Recently, the target of the specific autoantibody marker that occurs in NMO was discovered to be aquaporin-4, a water channel protein which is most strongly expressed on astrocytes . NMO was initially thought to be a monophasic disease in most patients; however, with liberalized criteria, it is now accepted that NMO is usually a relapsing disorder [5, 20]. Anti aquaporin-4 IgG (AQP4 IgG), and longitudinally extensive spinal cord lesions extending >3 vertebrae (LESCLs) are commonly observed in NMO [5, 20]. It is now increasingly accepted that brain lesions, either symptomatic or asymptomatic, occur in a high proportion of patients and in patients with brainstem, diencephalic and corpus callosum lesions, these lesions correlate well to regions with high AQP4 expression [7,21,22].
Multiple sclerosis is also an immune-mediated demyelinating disease of the CNS, in which the targets of the immune system are myelin proteins . The term Conventional or Western type MS (CMS) refers to the type of the disease which is mostly observed among Caucasians, that targets the brain as well as the optic nerves and spinal cord . Brain lesions at presentation is the rule rather than the exception and the characteristic shape and distribution of MS lesions is different from that seen in NMO [7, 21,22,24].
The prevalence of MS is low among populations of Asian descents, however, most cases reported from these populations have selective and severe involvement of the optic nerves and spinal cord which are diagnosed as having opticospinal MS (OSMS) or Asian type MS [4,16]. Clinically OSMS is also reported to have frequent relapses, severe disability, few brain lesions on MRI and LESCLs [4,16].
a. Is there an "official definition"? Or is it a term reflecting uncertainty of distinction between NMO and MS?
Asian investigators have used OSMS to classify patients with selective demyelinative involvement of optic nerve and spinal cord who due to the old strict criteria of NMO which required "acute bilateral visual impairment and transverse myelitis occur successively within an interval of about one month", could not be categorized under NMO. The clinical diagnostic criteria of OSMS or Asian- MS was first put forward by Kira and colleagues in 1996 earlier than any official criteria for NMO was published. According to this clinical criteria OSMS is diagnosed when the estimated main lesions are limited to the optic nerve and spinal cord and there are no cerebellar neither cerebral symptoms and the patient at least experiences one relapse (â‰¥two attacks). This criteria also considers minor brainstem signs acceptable. As the term itself suggest OSMS is believed to be a variety of MS, however, the clinical definition of OSMS is very similar to that of relapsing NMO according to new revised criteria for NMO which requires both optic neuritis and transverse myelitis as major criteria and the presence of tow of the following minor criteria: LESCL, NMO-IgG and brain MRI not suggestive of MS.
OSMS was reported to be accompanied by LESCLs extending over many vertebral segments on spinal cord MRI and could also be seropositive for NMO-IgG [Kira,1996, 2003, Lennon 2004]. In this case, if a patient diagnosed as having OSMS develops LESCL or becomes anti AQP4-IgG positive then according to above the patient fulfills the criteria for relapsing NMO [Wingerchuk et al, 2006]. If not OSMS fulfills the revised McDonald's criteria for MS in which the presentation starts with optic nerve and spinal cord involvements (two clinical attacks + 2 objective signs of involvement in the CNS) and does not necessarily need brain lesions on MRI [Polman et al, 2005].
In accordance with the above OSMS or Asian type MS falls under the category of relapsing NMO or MS, and does not seem to be a distinct entity. This view is strengthen by a study by Japanese investigators, that in their series of OSMS patients 2/3 of the patients had LESCLs, and they report that clinical features were similar to those of relapsing NMO, which in fact this subgroup of patients fulfilled the diagnostic criteria of NMO, and should be regarded as NMO. In addition, the remaining 1/3 of patients without LESCL are reported to present feature commonly seen in the CMS, which in fact could be regarded as MS based on the revised McDonald's criteria .Â Another study on Japanese patients diagnosed with MS, including 19 with OSMS and 13 with CMS reported positive NMO-IgG in 12 OSMS and 2 CMS patients. In the seropositive patients, LESCLs and permanent, complete blindness in at least one eye were considerably more observed compared to NMO-IgG-negative patients. In addition the two patients having CMS with NMO-IgG had unusual and atypical brain lesions for CMS, but in other respects had features suggesting NMO. The result of this study could be interpreted as that NMO IgG positive OSMS are similar to NMO and even CMS patient with NMO IgG should be regarded as NMO which exhibit brain abnormality and that the primary diagnosis should be reconsidered. [Clinical and MRI features of Japanese patients with multiple sclerosis positive for NMO-IgG]
Another source of debate in the diagnosis of demyelinating diseases of CNS is that Japanese investigators do not diagnose OSMS in patients with brain lesions, and also before the revised criteria for NMO, neither NMO could be diagnosed in a patient with brain lesion, thus some patients with opticospinal presentations and minor brain lesions would be classified into CMS. That could be one of the reasons that why about 10% of CMS patients were reported to be seropositive for NMO-IgG.
b. Historical considerations
Sir Thomas Clifford Allbutt an English physician was the first to describe an association between acute myelitis and visual loss ("sympathetic disorder of the eye") in 1870. More than two decades later, Eugene Devic, a French physician at L'Hopital de la Croix-Rousse in Lyon, described another case and encouraged his student Fernand Gault to work on a thesis in this regard. Although the disease is named after Devic's, however, it was Gault who suggested that the disease is a distinct clinical entity and termed it "neuro-myelite optique" or "neuropticomyelite" (neuromyelitis optica). The syndrome was initially characterized by a monophasic severe acute transverse myelitis and an acute or subacute optic neuropathy with or without recovery.[Jnnp 1996]. The studies on NMO were limited to occasional case reports from different parts of the world until last decades of the 20th century, when further studies were undertaken and more has been brought to light about the disease, signing a new era for NMO research.
i. Asians contributions to recognizing that OSMS is an entity distinct from MS
Although there have been some case reports of NMO from Asia, but MS was rarely reported from this region before the late 60', and it was believed that these were almost non-existent among Asian population [Miura, 1911; Shimazono, 1931, 1932]. The first studies from Asia were mostly undertaken by Japanese investigator, who started performing extensive studies to answer questions on epidemiological, clinical and pathological features on MS and NMO in Asia. Amongst the Asian investigators studies by Yoshigoro Kuroiwa and his colleagues, shed light on many aspects of MS and NMO in Asia and specially Japan.
Early Japanese studies showed that more than half of the demyelinating diseases diagnosed from 1890-1955 in Japan have the severe involvement of optic nerves and spinal cord and thus are NMO or opticospinal MS. Also about half of the patients diagnosed with NMO had a relapsing disease course, and considering that the definition of NMO at the time was restricted to monophasic disease, this lead to the invention of the termed "opticospinal MS". OSMS was believed to be a subtype of MS with relapses affecting the optic nerves and spinal cord.
Further studies from other Asian countries like Republic of China ( Taiwan), Korea,Â India,Â Indonesia , Thailand, Singapore , Malaysia and also from studies on Orientals in Hawaii found the same clinical picture to be more prevalent. These studies led to the conclusion that AsianÂ MS patient had a relatively higher frequency of optic nerve involvement, usually bilateral and severe, at the onset, as well as during the course of illness, and frequent occurrence of NMO. Early neuropathological studies in Asia confirmed the lower incidence of classical MS and a higher incidence of NMO or Devic's disease, preferential occurrence of lesions in the optic nerves and spinal cord, necrotizing lesions with occasional cavity formation not only in the spinal cord and optic nerves but also in the cerebrum, poor gliosis, and poor perivascular cuffing in the necrotic form. These studies also report mixed forms meaning that there were severe demyelination with tissue necrosis in the optic nerves and spinal cord with some lesions present in the brain-stem and cerebrum.
Studies were also extended to comparative studies between Caucasian MS patients and Eastern patients. [Shibasaki et al. in 1981, ]. These studies failed to show significant differences between the two groups when comparing the sex ratio, mode of onset, age at onset, duration of illness, and clinical course,Â and concluded that "MS is essentially the same disease in both groups". However, Severe bilateral optic nerve involvement; acute and recurrent transverse myelitis, and optic-spinal-brainstem and optic-spinal involvement were more prevalent and familial recurrence was rare among Asian compared to Caucasians. A study comparing American and Japanese autopsy cases showed that 47% of Japanese patients showed selective involvement of the optic nerves and spinal cord, whereas 13% of American cases also showed this limited involvement of the optic nerves and spinal cord. [Ikuta et al.]
The term NMO among Asian investigators was characterized by monophasic cases showing bilateral optic neuritis and transverse myelitis within an interval of less than several weeks. Kuroiwa and colleagues defined NMO in their diagnostic criteria of MS Research Committee of Japan, Ministry of Health and Welfare in 1975 as "acute bilateral visual impairment and transverse myelitis occur successively within an interval of about one month". The relapsing ones and those with unilateral optic neuritis were usually called OSMMS, but similar cases in the Western world were reported as relapsing neuromyelitis optica (NMO) or relapsing Devic's syndrome. The classification of MS subtypes according to the clinical picture was also extended and terms such as, Optic-brainstem-spinal-cerebellar, Optic-spinal , Optic-spinal-brainstem ,Optic-spinal-cerebellar ,Optic-brainstem , Optic-brainstem-cerebellar ,Brainstem-spinal, Brainstem-spinal-cerebellar ,Spinal-cerebellar ,Spinal-cerebral ,Optic-cerebral were used to define subtypes of MS most commonly seen in Asia. However the use of these termed was subsequently mostly abandoned, with the OSMS surviving to date. Finally in 1996, Kira and colleagues through a comaparative study of OSMS (Asian-type MS) and CMS ( Western-type MS) , proposed clinical classification criteria for OSMS.
Further Japanese studies showed that 15%-40% of MS cases in Japan are of the OSMS phenotype and compared to CMS, have higher female preponderance, older age at onset, frequent relapses, lesser familial occurrence, greater disability, lesser brain lesions on MRI, LESCLs, marked pleocytosis and neutrophilia in cerebrospinal fluid (CSF), and absence of oligoclonal bands in CSF.
In 1999, Wingerchuck and colleagues proposed the first official diagnostic criteria for NMO which needed three absolute criteria: (i) Optic Neuritis, (ii) acute myelitis, and (iii) no symptoms implicating other CNS regions in addition to presence of at least one of three major supportive criteria was required: (i) normal brain MRI at onset or not compatible with MS imaging criteria;(ii) LESCL and (iii) CSF reveals â‰¥50 WBC/mm3Â or â‰¥5 neutrophils/mm3, or presence of two of three minor supportive criteria: (i) bilateral ON, (ii) severe residual visual loss, or (iii) severe fixed post-attack weakness.
ii. Modern recognition and definition of NMO