Severe Optic Neuritis Research Articles

Pediatric acquired CNS demyelinating syndromes: Features associated with multiple sclerosis.

Approximately one-third of children with an acquired demyelinating syndrome (ADS) will be diagnosed with multiple sclerosis (MS), either at onset according to the 2010 McDonald criteria, or on the basis of clinical or MRI evidence of relapsing disease, in the majority of patients within 2-4 years. ADS in adolescents, female patients, and patients with polyfocal deficits is associated with the highest likelihood of MS, while children with acute disseminated encephalomyelitis, those with documented preceding infection, and ADS presentation in young children more commonly portends a monophasic outcome. While pediatric MS associates with similar genetic risk alleles as have been documented in adult-onset MS, such associations are not diagnostically valuable at the individual level. The presence of antibodies directed against aquaporin-4 strongly supports a diagnosis of neuromyelitis optica, and should be assayed in children manifesting with severe optic neuritis, longitudinally extensive myelitis, or brainstem/hypothalamic syndromes. Further research will determine whether other antibody signatures are indicative of relapsing demyelination distinct from MS.

Plasma exchange response in 34 patients with severe optic neuritis

Optic neuritis could lead to severe visual impairment despite corticosteroids. Our aim was to evaluate the rate of visual improvement in patients treated with plasma exchange (PLEX) for severe steroid unresponsive optic neuritis and to identify predictive factors of outcome. Thirty-four patients (41 optic nerves damaged) with remaining visual acuity of 0.1 or less despite steroid pulse therapy were treated with PLEX from September 2010 to May 2015. Demographic and clinical neuro-ophthalmic findings, and spectral domain-optical coherence tomography data before PLEX treatment were analyzed. The mean symptom duration before PLEX was 34.6 days (median 28days; range 6-92 days). After PLEX, the median final visual acuity was 0.8 and in 56% of cases, final acuity was 0.5 or better. Past history of ipsilateral optic neuritis was associated significantly with poor outcome defined as final acuity less than 0.5. No significant difference in the visual outcome after PLEX was found between multiple sclerosis and neuromyelitis optica. In conclusion, this observational study showed that PLEX as second-line therapy led to a functionally important visual recovery in more than half patients with severe optic neuritis.

Isolated new onset 'atypical' optic neuritis in the NMO clinic: serum antibodies, prognoses and diagnoses at follow-up.

Severe, recurrent or bilateral optic neuritis (ON) often falls within the neuromyelitis optica spectrum disorders (NMOSD), but the diagnosis can be particularly challenging and has important treatment implications. We report the features, course and outcomes of patients presenting with atypical ON when isolated at onset. We retrospectively analyzed 69 sequential patients referred to a single UK NMO center with isolated ON at onset. Aquaporin-4 antibody (AQP4-Ab) assessment was performed in all patients and IgG1 myelin-oligodenrocyte glycoprotein (MOG-Ab) in AQP4-Ab(neg) patients. 37 AQP4-Ab positive (AQP4-Ab(pos)) and 32 AQP4-Ab negative (AQP4-Ab(neg)) patients (8 with MOG-Ab) were identified. The AQP4-Ab(neg) group included heterogeneous diagnoses: multiple sclerosis (MS), NMO, relapsing isolated ON (RION), monophasic isolated ON and relapsing acute disseminated encephalomyelitis (ADEM)-like syndromes. Compared to AQP4-Ab(neg) patients, AQP4-Ab(pos) patients had a worse residual visual outcome from first attack (median VFSS 4 vs. 0, p = 0.010) and at last assessment (median VFSS 5 versus 2, p = 0.005). However, AQP4-Ab(neg) patients with RION also had poor visual outcome. Up to 35% of AQP4-Ab(neg) patients developed a LETM and two developed low positivity for AQP4-Ab over time. Eight AQP4-Ab(neg) patients (25%) were MOG-Ab positive, covering a range of phenotypes excluding MS; the first ON attack was often bilateral and most had relapsing disease with a poor final visual outcome [VFSS 4, range (0-6)]. In conlcusion, AQP4-Ab positivity is confirmed as a predictor of poor visual outcome but AQP4-Ab(neg) RION also had a poor visual outcome. Of those without AQP4-Ab, 25% had MOG-Ab and another 25% developed MS; thus, MOG-Ab is associated with AQP4-Ab(neg) non-MS ON.

PND57 - Quality of Life in neuromyelitis optica: a Systematic review

Neuromyelitis optica (NMO) is an inflammatory CNS disease, that presents with severe optic neuritis and transverse myelitis. It is often accompanied by severe motor and sensory disability. In the past few years, NMO has gained lot of interest and shares a controversial relationship with multiple sclerosis (MS). It is not yet known whether NMO differs in its effect on quality of life (QoL) when compared with MS. We aimed to evaluate the QoL in patients with NMO by conducting a systematic review of published peer-reviewed studies. A literature search was performed in “MEDLINE” and “EMBASE” using search terms “quality of life”, “neuromyelitis optica”, and “Devic’s”. The search was limited to English language. All studies that got published before November 2014 were retrieved. Studies that included patients with NMO and reported use of validated QoL instrument were considered eligible for qualitative analysis. Two independent researchers were involved in study selection and data extraction. A total of seven studies met the inclusion criteria. All the studies were conducted in different countries: The United states of America, United Kingdom, France, Japan, and Argentina. The number of patients included in the studies ranged from 18-50. The common QoL instruments used included: Short form-36 and different pain severity scores. Three studies used MS patients as the comparator while two compared the data with normal subjects. Most studies reported that QoL is lower in NMO patients as compared to the ones suffering from MS and is much worse than normal subjects. The lower QoL score corresponded with higher pain scores in NMO patients as compred to MS patients. Our review showed that NMO patients are associated with higher levels of pain and lower QoL scores than MS patients. However, available evidence seems to be insufficient and more research is warrented in this context.

Pediatric anti-myelin oligodendrocyte glycoprotein syndrome: case series of a newly recognized central nervous system inflammatory disease

Pediatric acquired demyelinating syndromes have overlapping clinical and imaging features, but management and prognosis vary. We describe four children between the ages of 3 and 10 presenting with inflammatory brain disease - one with polyfocal neurological symptoms, one with severe bilateral optic neuritis and two with transverse myelitis, all without encephalopathy. All brain MRIs had extensive involvement of both deep grey and subcortical white matter. Three patients had longitudinally extensive spinal cord lesions. Clinical and radiological findings did not meet criteria for multiple sclerosis, acute disseminated encephalomyelitis, or neuromyelitis optica (NMO). NMO IgG testing was negative. All patients had resolution of clinical and imaging findings after treatment with steroids and IVIg. We found, elevated levels of anti-myelin oligodendrocyte glycoprotein antibodies in all four patients. Three of the children receive monthly IVIg infusions. Two of the patients relapsed once within 18 months of their initial attack and have since remained relapse free for 32 months and 43 months, respectively. The third patient (transverse myelitis) has not had any relapses since her initial attack 15 months ago. It appears that children with this syndrome may have more favourable outcomes when compared to other CNS relapsing inflammatory conditions.

Aquaporin 4 antibody [NMO Ab] status in patients with severe optic neuritis in India.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system that causes attacks of optic neuritis and transverse myelitis. The discovery of a specific serum marker for NMO-IgG antibody [aquaporin 4 antibody/AQP4 Ab] has revolutionised the treatment of demyelinating diseases. Severe vision loss can be seen in optic neuritis (ON) associated with both multiple sclerosis (MS) and NMO. Identifying this antibody in optic neuritis patients can help us to establish the likelihood of these patients developing NMO (Jarius et al. Neurol Sci 298:158-162, 2010). It is important to differentiate these two entities as the treatment strategies of MS and NMO are different. To the best of our knowledge, there is no published literature regarding the importance of identifying this antibody in severe optic neuritis in Indian patients. Hence we decided to screen our severe optic neuritis patients for this AQP4 Ab. To investigate the presence of aquaporin 4 antibody and determine its prognostic value for visual and neurological outcome, in patients with bilateral and recurrent [severe] ON without any previous neurological manifestations presenting to a neuro-ophthalmology clinic in India. Single centre, prospective study. 40 patients (27 female patients and 13 male) with severe optic neuritis [patients with no visual improvement by 4 weeks from onset of vision loss] who presented either as recurrent attacks or as bilateral and severe optic neuritis between January 2010 and June 2011 were enrolled. Clinical features, visual outcome and sequential neurological events were compared between the seropositive and the seronegative groups. Aquaporin 4 antibodies were detected from serum using ELISA technique and IIF technique. Presence of this antibody in the serum was considered to be seropositive status and patients who did not have this antibody were considered seronegatives. AQP4 antibodies were detected in 8 of the 40 patients with severe ON (20 %).The female to male ratio in the seropositive group was 8:0. The NMO antibody titer ranged from 0.3 to 760 U/ml. ANA positivity in seropositive patients was statistically significant (p = 0.043). All seropositive patients had significantly poorer visual outcome as compared with the seronegative patients (p = 0.04).

Therapy of NMO spectrum disorders.

Neuromyelitis optica (NMO) is an autoimmune demyelinating condition of the central nervous system often associated with aquaporin-4 (AQP4) autoantibodies manifesting as severe optic neuritis and long segment myelitis with tendency to relapse. Seronegative patients and who do not meet the NMO criteria are classified as having NMO Spectrum Disorder (NMOSD), but are treated identically to clinically definite NMO. Acute relapse is treated with intravenous methylprednisolone for 5 days with or without subsequent treatment with plasma exchange (PE). This must be followed by oral steroid to prevent rebound worsening and further relapse. For relapse prevention, immunosuppressive agents that have been found to be effective are azathioprine, rituximab, mycophenolate mofetil, methotrexate, and mitoxantrone; although none of which have been validated in randomized, controlled trial. Some patients do relapse with monotherapy, and switching to more effective agent or use of combination therapy is beneficial in such situation. There is no consensus about the duration of preventive therapy, but generally 2-3 years of relapse-free period is considered the minimum, taking into account the risks of long-term toxicity of these agents.

P057 - Remarkable response of seropositive neuromyelitis optica to rituximab therapy – First report from kingdom of Bahrain

Background Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system that causes severe optic neuritis and myelitis attacks. Humoral immunity seems to have a prominent role in the pathogenesis of the disease. Recently the nature and understanding of NMO have been revolutionized by two factors (1) the identification of both a NMO IgG as a sensitive and specific diagnostic marker and (2) the identification of both specific radiological and pathologic features of the disease. Also with the limited treatment options, recently positive results reported with the use of the anti-CD20 monoclonal antibody rituximab are promising. Objectives We present 2 cases, first to be reported in Kingdom of Bahrain, of NMO with positive NMO IgG and favorable response to Rituximab. Methods and results Case # 1: 56 year old female patient. She had on 2008 left optic neuritis with residual visual loss. On September 2011 she had right optic neuritis. For both she received Methylprednisolone plus therapy for 4 days with partial response and residual visual loss. On October 2011, she developed severe myelitis with severe spastic paraplegia (grade 0–1) and urinary retention. The patient became bed bound. Her initial MRI of brain showed few scattered lesions for which the patient was diagnosed as multiple sclerosis and maintained on Betaferon injection as a disease modifying therapy. The repeated MRI showed long segment lesion of the spinal cord and her blood test was positive to NMO IgG. The patient did not respond to steroid or IVIg therapy. However, she responded remarkably well to Rituximab injection. In 3 months she is fully independent in her movements with almost normal power and continent. Case # 2: 43 year old female patient. On 2009, she developed a right optic neuritis that responded well to steroid therapy. 2 years later she developed spastic Paraparesis due to myelitis, she responded partially to steroid therapy and was put on Avonex injection as her MRI brain showed changes was diagnosed as MS in private hospital. However, one year later, she developed another sever myelitis that made her wheelchair bound with bladder involvement. Her MRI showed fairly long segment involvement of spinal cord. Her serum test showed positive NMO IgG. I gave her Rituximab injection therapy on which she showed remarkable improvement. In 3 months she is able to walk by herself and she independent in her ADL and bladder continent. Conclusion The remarkable recovery of these 2 patients from their severe disability in this case report support other reports of the effectiveness of Rituximab in the treatment of NMO and the humoral immunity nature of the illness. These are the first cases of NMO with positive IgG to be reported from Bahrain. NMO is not often seen in Bahrain despite high prevalence of MS.

IVIG IN NMO REFRACTORY/INTOLERANT TO RITUXIMAB

Background Neuromyelitis optica (NMO) is typically a severe relapsing inflammatory disease of optic nerves and spinal cord. Prednisolone, Azathioprine, Mycophenolate and Methotrexate are commonly used first-line immunosuppressants, stepping up to Rituximab if relapses occur. Results We report 3 NMO/ NMO spectrum disorder patients who stabilised on maintenance IVIG. Case 1: A 26 year-old woman who had 11 relapses over 10 years despite multiple immunosuppressants (including Rituximab) has remained in remission for 23 months with IVIG. Case 2: A 47 year old woman with 6 relapses over 8 years despite immunosuppressants was started on Rituximab with good effect. But Rituximab had to be discontinued due to respiratory problems. After starting 6 weekly IVIG infusions she has had no further relapses after 2.8 years. Case 3: A 59 year old woman with Aquaporin-4 antibody positive NMO spectrum disorder (3 episodes of severe optic neuritis over 5 years) was intolerant to Azathioprine (leukopenia). As baseline CD 19 counts were near 0, Rituximab was not given and she was initiated on 6 weekly IVIG and remains relapse free after 11 months. Conclusions IVIG seems to be effective in preventing NMO relapses.

Axonal transport rate decreased at the onset of optic neuritis in EAE mice

Optic neuritis is frequently the first symptom of multiple sclerosis (MS), an inflammatory demyelinating neurodegenerative disease. Impaired axonal transport has been considered as an early event of neurodegenerative diseases. However, few studies have assessed the integrity of axonal transport in MS or its animal models. We hypothesize that axonal transport impairment occurs at the onset of optic neuritis in experimental autoimmune encephalomyelitis (EAE) mice. In this study, we employed manganese-enhanced MRI (MEMRI) to assess axonal transport in optic nerves in EAE mice at the onset of optic neuritis. Axonal transport was assessed as (a) optic nerve Mn2+ accumulation rate (in % signal change/h) by measuring the rate of increased total optic nerve signal enhancement, and (b) Mn2+ transport rate (in mm/h) by measuring the rate of change in optic nerve length enhanced by Mn2+. Compared to sham-treated healthy mice, Mn2+ accumulation rate was significantly decreased by 19% and 38% for EAE mice with moderate and severe optic neuritis, respectively. The axonal transport rate of Mn2+ was significantly decreased by 43% and 65% for EAE mice with moderate and severe optic neuritis, respectively. The degree of axonal transport deficit correlated with the extent of impaired visual function and diminished microtubule-associated tubulins, as well as the severity of inflammation, demyelination, and axonal injury at the onset of optic neuritis.

Seronegative Neuromyelitis Optica Spectrum - The challenges on disease definition and pathogenesis

Neuromyelitis optica spectrum disorders (NMOSD) are characterized by severe optic neuritis and/or longitudinally extensive transverse myelitis, and some brain lesions are also unique to NMOSD. Serum autoantibodies against aquaporin-4 (AQP4) are detected in most cases of NMOSD. However, some patients with NMOSD remain seronegative despite repetitive testing during attacks with highly sensitive cell-based assays. The differential diagnosis of NMOSD is not restricted to multiple sclerosis and it includes many diseases that can produce longitudinally extensive myelitis and/or optic neuritis. We review the clinical features, imaging, and laboratory findings that can be helpful on the diagnostic work-up, discuss the differences between AQP4 antibody positive and negative patients with NMOSD, including features of NMOSD with antibodies against myelin oligodendrocyte glycoprotein.

Treatment with atacicept enhances neuronal cell death in a rat model of optic neuritis

We investigated the effect of atacicept, a recombinant fusion protein blocking BLyS and APRIL and acting on B cells, on degeneration of retinal ganglion cells (RGCs) during experimental autoimmune encephalomyelitis (EAE). We used myelin oligodendrocyte glycoprotein in Brown Norway rats to induce a variant of EAE which involves B cells and leads to severe optic neuritis. Intraperitoneal treatment with atacicept at some of the studied dose levels (100 or 200μg) resulted in increased apoptosis of retinal ganglion cells whereas at a tenfold lower dose or in vehicle-treated animals no such effect became apparent. Also the extent of inflammation, demyelination, and axonal loss of the optic nerve was more pronounced in rats treated with the higher atacicept dose level. The present study describes observational evidence for adverse effects of atacicept on neuronal survival during EAE.

Cytokines and Chemokines in Neuromyelitis Optica: Pathogenetic and Therapeutic Implications

Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extensive transverse myelitis. The discovery of an NMO-specific autoantibody to the aquaporin-4 (AQP4) water channel has improved knowledge of NMO pathogenesis. Many studies have focused on inflammatory and pathological biomarkers of NMO, including cytokines and chemokines. Increased concentrations of T helper (Th)17- and Th2-related cytokines and chemokines may be essential factors for developing NMO inflammatory lesions. For example, interleukin-6 could play important roles in NMO pathogenesis, as it is involved in the survival of plasmablasts that produce anti-AQP4 antibody in peripheral circulation and in the enhancement of inflammation in the central nervous system. Therefore, assessment of these useful biomarkers may become a supportive criterion for diagnosing NMO. Significant advances in the understanding of NMO pathogenesis will lead to the development of novel treatment strategies. This review focuses on the current advances in NMO immunological research, particularly that of cytokines and chemokines.

Recent insights into the pathology of multiple sclerosis and neuromyelitis optica

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system. Traditionally, demyelinating lesions in the white matter have been regarded as the most important pathological feature in MS, but recent pathological and imaging studies confirmed substantial changes in grey matter and normal-appearing white matter. MS lesions are characterized by inflammation, demyelination, axonal damage and astrogliosis. During early MS lesion formation acute axonal injury is extensive and correlates with inflammation. In addition to focal lesions, diffuse wide-spread changes including neuroaxonal degeneration and compartmentalized inflammation are likely to contribute to increasing disability in progressive MS. Neuromyelitis optica (NMO) is classically characterized by severe transverse myelitis and optic neuritis, but brain lesions are also present in the majority of NMO patients. The discovery of the NMO-specific antibody demonstrated that NMO is a disease entity distinct from MS. This antibody binds to aquaporin-4 expressed in astrocytes and ependymal cells. NMO lesions are characterized by inflammation, demyelination, axonal damage and a marked loss of aquaporin-4. Early NMO lesions demonstrate a pronounced humoral inflammatory response and astrocytic cell death with loss of aquaporin-4, followed by inflammatory demyelination and axonal damage. These recent findings contribute to a better understanding of different mechanisms leading to inflammatory demyelination.

Clinical Spectrum and Treatment of Neuromyelitis Optica Spectrum Disorders: Evolution and Current Status

Neuromyelitis optica (NMO) is an inflammatory neurologic disease clinically characterized by severe optic neuritis (ON) and transverse myelitis (TM). The relationship between NMO and multiple sclerosis (MS) has long been a matter of debate. However, the discovery of an NMO-specific autoantibody, NMO-immunoglobulin G/aquaporin 4 (AQP4) antibody, has dramatically advanced our understanding of the disease, and the clinical, magnetic resonance imaging (MRI), optical coherence tomography, and laboratory examinations have clarified unique features of NMO that are distinct from MS. The term NMO spectrum disorders (NMOSD) incorporating spatially limited forms was introduced, as patients with recurrent or simultaneous bilateral ON or recurrent longitudinally extensive TM (LETM) alone are also often AQP4 antibody-seropositive. Moreover, studies of seropositive cases have shown that more than half of them have brain lesions, some of which are unique to NMO, and can be the onset manifestation. Some clinical features of AQP4 antibody-seronegative NMO differ from seropositive, but it remains unknown whether they are pathologically distinct. Immunosuppressive treatments are effective for acute attacks and prevention of relapses of NMOSD, and new molecularly targeted drugs are under investigation. Importantly, some disease modifying drugs for MS may exacerbate NMOSD, making early differential diagnosis of the two diseases crucial. We review the evolving clinical spectrum, the updated clinical, MRI, neuro-ophthalmological and laboratory findings, and the current status of treatment in NMOSD.

Should we sequence everyone’s genome? Yes

<b>Background:</b> Neuromyelitis optica (NMO) is a disease of the CNS characterized by severe optic neuritis and longitudinally extended transverse myelitis. Recent studies suggest that anti-aquaporin-4 (AQP4) antibodies, NMO-specific biomarkers, are...

Aquaporin-4 antibody–positive cases beyond current diagnostic criteria for NMO spectrum disorders

To analyze aquaporin-4 (AQP4) antibody-positive patients who do not fulfill the current diagnostic criteria of neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD). We used a cell-based assay (CBA) with AQP4-transfected cells to detect AQP4 antibody in 298 consecutive patients with inflammatory CNS disorders seen at Tohoku University Hospital from 2007 to 2012. The patients were diagnosed as NMO, NMOSD, multiple sclerosis, or others using the respective current diagnostic criteria. The seropositive samples by CBA were also tested using a commercial ELISA. Seventy-two patients were AQP4 antibody positive. Among them, 18.1% (13/72) did not meet the NMO or NMOSD criteria (7 with monophasic optic neuritis, 2 with attacks restricted to the brainstem, and 4 with myelitis with less than 3 vertebral segments) and 84.6% (11/13) of these had only a single attack. The ELISA results were negative in 38.4% (5/13) of those patients, and they had lower antibody titers by CBA than patients with NMO/NMOSD. Although these patients had a shorter follow-up and few attacks, they shared some clinical features with NMO/NMOSD patients such as onset age, female predominance, presence of other autoantibodies, severe optic neuritis attacks, centrally located spinal cord lesions, persisting hiccups, and nausea or vomiting episodes. AQP4 antibody-positive patients with single or recurrent attacks of optic neuritis, myelitis, or brain/brainstem disease not fulfilling the current criteria of NMO or NMOSD may not be uncommon, and they should also be included in the NMO spectrum.

Anti-Aquaporin-4 Antibody-Seronegative NMO Spectrum Disorder with Baló's Concentric Lesions

A 34-year-old woman developed simultaneous bilateral severe optic neuritis and subsequent myelitis. Two months after the first attack, she developed a headache and dysesthesia in the left arm. Brain magnetic resonance imaging revealed multiple hyperintense lesions in the white matter of the right hemisphere, some of which were Baló-like concentric lesions. Our diagnosis was neuromyelitis optica spectrum disorder with Baló's concentric sclerosis (BCS), although the patient was negative for anti-aquaporin-4 (anti-APQ4) antibodies. Our case suggests that Baló's concentric sclerosis overlaps with neuromyelitis optica spectrum disorder and that this overlapping is caused by a mechanism that does not involve anti-AQP4 antibodies.

Severe optic neuritis in a patient with combined neuromyelitis optica spectrum disease and primary Sjögren’s syndrome: a case report

IntroductionOptic neuritis, although uncommon, can be the initial presentation of Sjögren’s syndrome. Coexisting Sjögren’s syndrome has also been reported with neuromyelitis optica spectrum disorder. This case report highlights the association between the two diseases and the importance of rheumatological and neurological evaluations in patients with such diagnoses. Distinction of neuromyelitis optica with coexisting connective tissue disease has both prognostic and therapeutic significance for the patient.Case presentationWe report a case of a 56-year-old Chinese woman who presented with bilateral asymmetric visual loss secondary to optic neuritis. She was subsequently found to be seropositive for neuromyelitis optica immunoglobulin G (NMO-IgG) (anti-aquaporin-4 antibody) and was diagnosed with neuromyelitis optica spectrum disorder. She also fulfilled the international criteria for Sjögren’s syndrome. Despite initial high dose immunosuppressive therapy, she failed to regain vision in one eye.ConclusionPatients presenting with optic neuritis and severe visual loss should be screened for neuromyelitis optica and treated appropriately. Neuromyelitis optica has been associated with systemic autoimmune diseases, in particular Sjögren’s syndrome, and current evidence indicates that they are two distinct entities. We recommend that both diagnoses be considered in cases of optic neuritis with severe visual loss.

Two cases of lumbosacral myeloradiculitis with anti-aquaporin-4 antibody

Neuromyelitis optica (NMO) is an inflammatory disease of the CNS which is typically characterized by severe optic neuritis and transverse myelitis. Since the discovery of anti-aquaporin-4 (AQP4) antibody,[1][1],[2][2] an NMO-specific autoantibody, other unique features of NMO have been clarified.