|Year : 2021 | Volume
| Issue : 4 | Page : 269-274
Relapsing neuromyelitis optica spectrum disorder
M Lakshmi Lavanya, G Butchi Raju, S Gopi, T Sateesh Kumar, U Aruna Kumari
Department of Neurology, Andhra Medical College, Visakhapatnam, Andhra Pradesh, India
|Date of Submission||28-Apr-2020|
|Date of Decision||06-Feb-2021|
|Date of Acceptance||10-Feb-2021|
|Date of Web Publication||22-Mar-2022|
Dr. G Butchi Raju
Department of Neurology, Superspeciality Block, King George Hospital/Andhra Medical College, Maharanipeta, Visakhapatnam - 530 002, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Background: Neuromyelitis optica spectrum disorder (NMOSD) is a devastating inflammatory disorder of the central nervous system. Relapsing NMOSD (RNMOSD) is being reported frequently, leading to severe and permanent relapse related disability.
Aims and Objectives: To study the clinical profile and imaging features of the NMOSD cases at the index time and addressing the long-term clinical spectrum of relapsing type of NMOSD who presented to the tertiary care hospital.
Materials and Methods: All patients who attended the King George Hospital, Visakhapatnam and fulfilled the diagnostic criteria of NMOSD were studied for the epidemiological details, type of clinical spectrum on relapses, imaging features and treatment prescribed, and were studied between April, 2011 and March, 2018.
Results: Total diagnosed cases were 28, out of which relapsing type were seen in 11 patients and all tested positive for antibodies. Female to male ratio is 3:1, and in RNMOSD group all were females. Most common clinical presentation was myelitis followed by optic neuritis. Noted clinical spectrum in the RNMOSD was unusual presentations like one each patient of Area-Postrema syndrome, diencephalic syndrome, cerebral syndrome, acute brainstem syndrome, and frequent relapses within a month in two. Five cases had also associated systemic autoimmune disorders.
Conclusion: RNMOSD is very rapidly evolving disease, affecting primarily young women with wide spectrum of neurological presentations and also other non-neurological systemic features. Early diagnosis and aggressive immune therapy in the early phase might be warranted in NMOSD for relapse prevention and improving the quality of life.
Keywords: Acquaporin, myelitis, Neuromyelitis;rder (NMOSD), optic neuritis, relapsing NMOSD
|How to cite this article:|
Lavanya M L, Raju G B, Gopi S, Kumar T S, Kumari U A. Relapsing neuromyelitis optica spectrum disorder. J NTR Univ Health Sci 2021;10:269-74
| Introduction|| |
Neuromyelitis optica (NMO), initially considered a severe variant of multiple sclerosis (MS), has been recognized as a recurrent autoimmune central nervous system (CNS) disorder with distinct clinical, neuroimaging, and laboratory findings in recent decades. The cases of NMO have been reported in all continents and races, more frequent in non-Caucasian, especially Asian countries. However, data regarding long-term follow-up of these patients especially from developing countries where it is still under-diagnosed and misdiagnosed is scarce.
In recent decades, NMO has evolved from NMO classical description to a broader disease spectrum, from monophasic illness to a polyphasic illness with multiple recurrences. Disease confined to optic nerve and spinal cord to now cerebrum, diencephalon and brain stem involvement with wide spectrum of clinical presentation are reported recently. NMOSD can coexist with several non-organ-specific or organ-specific autoimmune diseases. At least 5 years or longer of relapse-free clinical observation after the index event be required to label as a monophasic course, whereas an interval longer than 4 weeks between index attacks indicates relapsing disease.
In India, there are few epidemiological, clinical, and radiological data on NMOSD. It accounts for upto 13.9% of inflammatory demyelinating disorders of the CNS, and the usual median age of onset is around 35–45 years with prevalence of 1–4.4/100.000. In comparison to MS, NMO is associated with a greater imbalance between women and men; nearly 90% of patients with NMO are female.
Relapsing neuromyelitis optica (RNMOSD) is a devastating inflammatory disorder of the CNS which is being frequently reported these days. Extensive data on the course of RNMOSD are not available; this is largely because of the uncommon presentation of the disease. The mainstay of treatment for NMO/RNMO is immunosuppressive therapy, if untreated; it is associated with high morbidity and mortality. Although there is significant improvement in outcome with early and rapid treatment as compared to previous studies. So, an early differential diagnosis of RNMOSD from MS is particularly important because of the necessity of rapid introduction of immunosuppressive therapy, since MS disease-modifying drugs may exacerbate these disorders. The main goal in this study is to describe the long-term history of the varied clinical presentation and progression of disability in RNMOSD.
| Material And Methods|| |
The study population consisted of patients with NMOSD, from our prospectively maintained database during the period of April 2011 to March 2018 who satisfied the International Panel for NMO Diagnosis (IPND) criteria 2015. Based on this criteria, patients with recurrent ON or recurrent transverse myelitis with longitudinally extensive spinal cord lesions or brain stem or area postrema syndrome or diencephalon syndrome and seropositive for AQP4 autoantibodies were classified as NMO spectrum diseases. The patient who had relapses and remission with variable degree of recovery between episodes was labeled as RNMOSD as compared to patients with simultaneous or closely related ON and LETM without recurrence, that is, monophasic or classical NMOSD.
Assessment of patients
We performed observationally, retrospective analysis of this cohort, to study the epidemiological characteristics, clinical presentations, recurrence rate, treatment, and response to therapy. Time between onset of RNMO and the occurrence of unilateral and bilateral symptoms was noted. We assessed the following variables: sex, age, and symptoms at onset associated other non-neurological illness and whether the patient had recovered from the first attack and first interval attack.
| Results|| |
There were total 28 NMOSD patients included in the study, of which 11 cases were RNMOSD. The mean age of onset of symptom was 19.5 years in NMOSD group (range 9–46 years), whereas 15.5 years in RNMOSD group (range 9–28 years). Out of 28 cases, 21 were females and seven were males in NMOSD group, whereas in RNMOSD group, all were females. The age and sex distribution of the study population is shown in [Table 1]. All patients (100%) have fulfilled IPNMOSD criteria, of which only typical NMO presentation was noted in the 56%, whereas atypical NMOSD presentation was noted in the 44%.
Monophasic illness was noted in the 61% of the cases and 39% had relapsing course. The median recurrence rate was three/patient in the relapsing group. One patient has two relapses, five patients had three relapses, four patients had four relapses, and one patient had five relapses. The relapse rate was most common in between 10 and 20 year age group. Overall, the most common clinical presentations in both the groups were optic neuritis and myelitis. Most common initial presentations noted in the NMOSD group was optic neuritis and myelitis, whereas the RNMOSD group showed optic neuritis and myelitis like presentations in 46% (optic neuritis ˗18.4% and LETM ˗27.6%) and atypical presentations in 54% [Table 2]. Area-postrema syndrome-1 [Figure 1], diencephalon syndrome-1, cerebral syndrome-1 [Figure 2], acute brainstem syndrome-1 [Figure 3], and frequent relapses within a month in two. Out of the 11 patients in RNMOSD group, during their course of the illness myelitis in 11 patients, optic neuritis in 10 patients, area postrema in three patients, cerebral syndrome in two patients, brainstem syndrome in one patient, and diencephalon syndrome in two patients were noted [Table 3]. The mean age of initial symptom to second relapse was 2.5 years. Among the initial presentation, the rate of misdiagnosis was 10.5% with typical NMOSD spectrum, whereas 44% in the RNMOSD group. Similar illness of family history was not noted and also there was no statically significance of consanguinity documented. The clinical spectrum of RNMOSD group was showed in the [Table 3].
One interesting association of systemic autoimmune disorders was noted in our cohort. Most of these are connective tissue disorders, of which ichthyosis vulgaris in two cases, psoriasis in one case, systemic sclerosis in one case [Figure 4], SLE with ulcerative colitis and cortical sinus venous thrombosis [Figure 5] in one case were noted. Death was noted in two cases. Aquaporin-4 antibodies in NMOSD group was positive in 82%, whereas 100% positive in the RNMOSD group. CSF-analysis study showed CSF pleocytosis (predominantly lymphocytes) in seven patients, and maximum cell count in CSF was 55/mm 3 (range 2–55). CSF protein ranged from 16 to 60 mg%. The overall clinical presentation in the both typical NMOSD group and RNMOSD group was shown in [Table 1].
|Figure 4: Associated Dermatologic features- (a) Mechanistic feet in a girl with Scleroderma (b) Icthyosis Vulgaris (c) SLE with Arthritis (d) Psoriasis|
Click here to view
All the RNMOSD were treated with Azothioprine except for one patient who was treated with Rituximab in standard doses who had severe illness and expired on follow-up after completing the initiation phase.
| Discussion|| |
Previous studies have shown that NMOSD is a monophasic disorder; RNMOSD is a recent and an uncommon entity with devastating inflammatory disorder of the CNS. In monophasic form, men and women are affected equally but in the more recurrent disease course women (ratio 5–10:1) are over represented. In our study, monophasic NMO and RNMOSD, both forms showed female preponderance with female to male ratio of 3:1 in monophasic form, whereas all were female in the RNMOSD group; it could be because of bias toward patients for admission and treatment. One study from India showed higher prevalence in the male population. The age distribution in NMO ranges from pediatric population to late adulthood with the decrease in the incidence after the fifth decade; the median age of onset is in the second and third decade., The mean age of onset in one Indian study was 27 years, comparable to western cohorts. In our study the mean age of presentation was 20.5 years in typical NMOSD group whereas 15.5 years in the RNMOSD group. One study assessed the risk factors for the RNMOSD, in which female sex, older age at onset, and less motor disability at the initial insult were documented. Our study also showed female and less motor disability forms were risk factors for RNMOSD, but mean age of distribution in our cohort was 15.5 years. Another study showed RNMOSD affects almost exclusively in women, and age at onset is before 40 years of age. Recently, US Network of Pediatric MS Centers reported 38 cases of NMO in children and their clinical presentation.
Traditionally, NMO was considered a monophasic disorder consisting of simultaneous bilateral optic neuritis and transverse myelitis but relapsing cases were described in the 20th century. In most of the recent literature of NMO, monophasic course is (20–30%) while recurrent course (80–90%) is common and even primary or secondary progressive courses are also rare. In our study, RNMOSD was noted in 40% of the cases. NMO-IgG is 91–100% specific and 70–93% sensitive in NMO, has become a reliable tool to distinguish NMO spectrum of disorders from other demyelinating illnesses. Authors from India concluded that the NMO antibody positivity is less in comparison to western world. NMO-IgG sero-positivity was thought to be correlated with a high relapse rate and severe disease course. The present study also showed similar results, positive aquaporin antibodies were 82% in NMOSD group, and 100% in RNMOSD group.
RNMOSD group showed optic neuritis and myelitis like presentations in 46% (optic neuritis ˗ 18.4% and LETM ˗ 27.6%) and atypical presentations in 54% (Area-Postrema syndrome-1, Diencephalon syndrome-1, cerebral syndrome-1, acute brainstem syndrome-1) and frequent relapses within a month in two cases. Out of the 11 patients in RNMOSD group, during their course of the illness, myelitis in 11 patients, optic neuritis in 10 patients, area-postrema in three patients, cerebral syndrome in two, brainstem syndrome in one and diencephalon syndrome in two patients was noted . Among the initial presentation, the rate of misdiagnosis was 10.5% with typical NMOSD spectrum, whereas 44% in the RNMOSD group. One study showed that usually the second attack inter attack interval was within 2 years. Our study showed mean duration of interval was 2.5 years. In the study by Wingerchuk and Weinshenker, recurrent NMO showed more fatal course compared to monophasic illness. Mortality in a cohort of recurrent NMO from Brazil was 50%; our cohort showed a mortality rate of 18%. A second attack interval shorter than 1 year is useful in predicting early death and therefore may influence the choice of treatment. In our cohort also one patient with shorter inter attack interval showed early death.
A strong association of NMOSD with non-organ-specific autoimmune diseases [e.g., systemic lupus erythematosus (SLE), Sjögren syndrome (SS), rheumatoid arthritis (RA), undifferentiated connective tissue disease (UCTD)], and organ-specific autoimmune diseases (e.g., thyroid diseases, myasthenia gravis) were documented. Jinming Han, et al. in a review article highlighted the complexity and wide range of NMOSDs which have more than typical manifestations. These autoimmune disorders are more prevalent in the RNMOSD group and also one of the prognostic factor for disease progression. Our cohort also showed similar results in the form of association of RNMOSD group with non-organic autoimmune diseases. Ichthyosis vulgaris in two cases, Psoriasis in one, systemic sclerosis in one, and SLE with ulcerative colitis and cortical sinus venous thrombosis in one case were noted. The patient of RNMOSD associated with SLE, ulcerative colitis, and CSVT showed severe morbidity with early mortality with in the 3 years of symptom onset.
Previous studies showed that CSF abnormalities are detected in NMOSD (cell count, protein level, and oligoclonal bands). CSF pleocytosis, usually consisting of monocytes and lymphocytes; occasionally can be dominated by neutrophils. Various studies had CSF cell count of >50 cells/cu mm in 13–35%. In our study, CSF-analysis study showed pleocytosis (predominantly lymphocytes) in seven patients. The maximum cell count in CSF was 55/mm3 (range 2–55) and CSF protein ranged from 16 to 60 mg. Most of these abnormalities were noted in the group associated with autoimmune disease.
Treatment of RNMOSD is imunosuppresive therapy. Most of the patients in this study were started on Azathioprine in standard doses because of socioeconomic status. Recently, Mycophenylate Mofetil was studied in Chinese patients., Rituximab became standard care of therapy in RNMOSD to reduce the disability and prevent relapses. One of the study patients who had frequent relapses was started on Rituximab but succumbed to illness after the initial phase. In a study from India, mean annualized relapse rate reduced from 2.61 to 0.09 after therapy (P = 0.000685). Of 13 patients, 8 (61.54%) were completely relapse free after starting treatment with rituximab. Treatment was well tolerated and no serious adverse events were noted.
| Conclusion|| |
RNMOSD is very rapidly evolving disease, affecting primarily young women with wide spectrum of neurological presentations and also other non-neurological systemic features. Early diagnosis and aggressive immune therapy in the early phase might be warranted in NMOSD for relapse prevention and improving the quality of life.
The department acknowledges all the patients and their family members for collecting the data and photographs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Matiello M, Lennon VA, Jacob A, Pittock SJ, Lucchinetti CF, Wingerchuk DM, et al
. NMO-IgG predicts the outcome of recurrent optic neuritis. Neurology 2008;70:2197-200.
Jagtap SA, Mandliya A, Sarada C, Nair MD. Neuromyelitis optica and neuromyelitis optica spectrum disorder: Natural history and long-term outcome, an Indian experience. J Neurosci Rural Pract 2015;6:331-5.
] [Full text]
Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al
. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015;85:177-89.
Drori T, Chapman J. Diagnosis and classification of neuromyelitis optica (Devic's syndrome). Autoimmun Rev 2014;13:531-3.
Sellner J, Boggild M, Clanet M, Hintzen RQ, Illes Z, Montalban X, et al
. EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J Neurol 2010;17:1019-32.
Rivera JF, Kurtzke JF, Booth VJ, Corona VT. Characteristics of Devic's disease (Neuromyelitis optica) in Mexico. J Neurol 2008;255:710-5.
Pandit L. Neuromyelitis optica antibody (NMO-IgG) status in Indian patients with multiple sclerosis and allied demyelinating disorders. Neurol Asia 2008;13:175-8.
Lotze TE, Northrop JL, Hutton GJ, Ross B, Schiffman JS, Hunter JV. Spectrum of pediatric neuromyelitis optica. Pediatrics 2008;122:e1039-47.
Banwell B, Tenembaum S, Lennon VA, Ursell E, Kennedy J, Bar-Or A, et al
. Neuromyelitis optica - IgG in childhood inflammatory demyelinating CNS disorders. Neurology 2008;70:344-52.
Wingerchuk DM, Weinshenker BG. Neuromyelitis optica: Clinical predictors of a relapsing course and survival. Neurology 2003;60:848-53.
Cabre P, González-Quevedo A, Bonnan M, Saiz A. Relapsing neuromyelitis optica: Long term history and clinical predictors of death. J Neurol Neurosurg Psychiatry 2009;80:1162-4.
Chitnis T, Ness J, Krupp L, Waubant E, Hunt T, Olsen CS, et al
. Clinical features of neuromyelitis optica in children: US network of pediatric MS centers report. Neurology 2016;86:245-52.
Jarius S, Wildemann B. The history of neuromyelitis optica. J Neuroinflammation 2013;10:8.
Wingerchuk DM, Pittock SJ, Lucchinetti CF, Lennon VA, Weinshenker BG. A secondary progressive clinical course is uncommon in neuromyelitis optica. Neurology 2007;68:603-5.
Papadopoulos MC, Verkman AS. Aquaporin 4 and neuromyelitis optica. Lancet Neurol 2012;11:535-44.
Matsuoka T, Matsushita T, Kawano Y, Osoegawa M, Ochi H, Ishizu T, et al
. Heterogeneity of aquaporin-4 autoimmunity and spinal cord lesions in multiple sclerosis in Japanese. Brain 2007;130:1206-23.
Papais-Alvarenga RM, Miranda-Santos CM, Puccioni-Sohler M, de Almeida AM, Oliveira S, Basilio De Oliveira CA, et al
. Optic neuromyelitis syndrome in Brazilian patients. J Neurol Neurosurg Psychiatry 2002;73:429-35.
Nagaishi A, Takagi M, Umemura A, Tanaka M, Kitagawa Y, Matsui M, et al
. Clinical features of neuromyelitis optica in a large Japanese cohort: Comparison between phenotypes. J Neurol Neurosurg Psychiatry 2011;82:1360-4.
Han J, Yang M-G, Zhu J, Jin T. Complexity and wide range of neuromyelitis optica spectrum disorders: More than typical manifestations. Neuropsychiatr Dis Treat 2017;13:2653-60.
De Seze J, Stojkovic T, Ferriby D, Gauvrit JY, Montagne C, Mounier-Vehier F, et al
. Devic's neuromyelitis optica: Clinical, laboratory, MRI and outcome profile. J Neurol Sci 2002;197:57-61.
Huang Q, Wang J, Zhou Y, Yang H, Wang Z, Yan Z, et al
. Low-dose mycophenolate mofetil for treatment of NMOSD: A prospective multicenter study in South China. Front Immunol 2018;9:2066.
Jiao Y, Cui L, Zhang W, Zhang C, Zhang Y, Zhang X, et al
. Dose effects of mycophenolate mofetil in Chinese patients with neuromyelitis optica spectrum disorders: A case series study. BMC Neurol 2018;18:47.
Jade JD, Bansi S, Singhal B. Rituximab in neuromyelitis optica spectrum disorders: Our experience. Ann Indian Acad Neurol 2017;20:229-32.
] [Full text]
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]