Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease. It causes a multifocal inflammation of the central nervous system (CNS) that primarily affects the optic nerves and spinal cord, and typically results in attacks of visual loss and paralysis.
Associations between optic nerve and spinal cord disease were noted in the 19th century, especially after Devic’s description of “neuro-myélite opticique aiguë” (acute optic neuromyelitis).1
In the 20th century, “Devic disease” was considered a severe monophasic and spinal optical variant of multiple sclerosis that did not involve the brain.2 However, the discovery of IgG class antibodies that bind to the aquaporin water channel -4 (AQP4-IgG) in serum from patients with Devic disease, but not from those with typical multiple sclerosis, established neuromyelitis optica as a distinct entity with a chronic, relapsing course.3-5
Studies of patients who are AQP4-IgG-seropositive have led to the recognition that many additional clinical and neuroimaging findings occur, including brain involvement, which are included with the term neuromyelitis optica spectrum disorder.6,7 AQP4-IgG autoantibody is detectable in more than 80% of patients with NMOSD and is pathogenic, initiating inflammatory lesions of the CNS and clinical manifestations of the disease.8,9
| Epidemiology |
NMOSD accounts for 1 to 2% of all cases of CNS inflammatory demyelinating disease in the United States and Europe, with multiple sclerosis being much more common, but NMOSD accounts for one-third or more of CNS inflammation cases in Asian and Asian populations. other non-white populations.
Incidence and prevalence estimates ranged from 0.037 to 0.73 cases per 100,000 person-years and from 0.7 to 10.0 cases per 100,000 person-years, respectively, but these estimates varied widely among studies, with the highest rates among Africans and in the Afro-Caribbean region and lower rates among whites and people in Australasia, probably reflecting genetic and environmental influences and differences in verification methods.10
A population-based study in the United States showed a higher prevalence for blacks (13.0 cases per 100,000 people) than for whites (4.0 per 100,000).11
The median age at the onset of the disorder is 40 years , but the disorder can affect people of any age, and up to 20% of cases are in children or adults over 65 years of age.
Seropositive disease has a female preponderance that approaches 90%, while seronegative cases have an equal distribution by sex.10,12 Up to 3% of cases are familial.13 Whole genome sequencing has shown that AQP4- IgG is associated with variants in the major histocompatibility complex region, and there is a causal relationship between known risk variants and systemic lupus erythematosus, which can coexist with antibody-positive NMOSD.14
It has been suggested that environmental factors may play a role in the genesis of the disorder, but none have been identified. In pediatric NMOSD, unlike multiple sclerosis, common exposures to the herpes virus, including Epstein-Barr virus, are not involved.15
Acute attacks of NMOSD, including the initial episode, usually occur in the absence of an identified precipitating event, but approximately one-third of cases are preceded by an infection, which is often viral, and in rare cases, an acute attack follows vaccination.2 However, no specific infection or vaccine has been strongly implicated as triggering disease activity. The initial attack of NMOSD with AQP4-IgG has been associated with the use of immune checkpoint inhibitor therapies.16,17
| Clinical features |
Six core clinical syndromes have been identified in NMOSD.
They are classified by their location: optic nerve, spinal cord, area postrema of the dorsal cord, other regions of the brainstem, diencephalon or cerebrum. These syndromes manifest as acute attacks and relapses of neurological dysfunction, with symptoms typically evolving over a period of days.7
The most common syndromes are optic neuritis and transverse myelitis, as well as area postrema syndrome, which causes intractable or repetitive vomiting and hiccups. Multifocal lesions may give rise to a simultaneous or rapidly sequential combination of syndromes (eg, optic neuritis and myelitis).
Attacks are identified on the basis of new clinical symptoms and objective neurological signs (except in the case of isolated symptoms of the area postrema) and by ruling out other causes, such as infection, which may mimic an attack. Detection of new lesions on magnetic resonance imaging (MRI) in a relevant neuroanatomical region provides supportive evidence that a neurological event is due to NMOSD.
Sentinel stroke involves the optic nerve or spinal cord in more than 85% of affected adults. Patients with optic neuritis present with unilateral or bilateral visual loss or scotoma, dyschromatopsia, and ocular pain exacerbated by eye movement that is indistinguishable from optic neuritis in multiple sclerosis or an idiopathic form.
Acute transverse myelitis causes limb weakness, numbness, sensory loss or pain below the level of injury, and bladder and bowel dysfunction. Other symptoms of myelitis include Lhermitte’s sign (paresthesias of the trunk or extremities), caused by flexion of the neck, and episodes of paroxysmal tonic spasms lasting 15 to 60 seconds, with painful agonist and antagonist muscle contraction, often confused. with seizures. Severe upper cervical myelitis can cause neurogenic respiratory failure.2
Area postrema syndrome is the characteristic presentation of NMOSD in 10% of patients and occurs at some time during the illness in 15 to 40% of patients.18,19 Vomiting lasts a median of 2 weeks and , in up to two-thirds of cases, herald an attack of neuritis or optic myelitis.19
The syndrome may accompany myelitis when a destructive cervical lesion ascends to the brainstem, or it may be isolated and caused by non-destructive dorsal spinal cord lesions. When the syndrome is isolated, especially as the inaugural presentation of NMOSD, patients are typically evaluated by internists or gastroenterologists for intractable vomiting, and diagnosis may be delayed until there are subsequent neurological symptoms.
The other NMOSD syndromes occur less frequently, except that cerebral syndromes are common in children and cause generalized or focal signs, including encephalopathy, hemiparesis, hemianopsia, or seizures.7,20
Brainstem lesions may cause oculomotor dysfunction, hearing loss, vertigo, dysarthria, or other cranial nerve symptoms; As with optic neuritis, these features alone are not initially distinguishable from similar syndromes in multiple sclerosis. Lesions in diencephalic structures such as the thalamus and hypothalamus have been reported to cause narcolepsy-like symptoms, endocrinopathies, temperature dysregulation, eating disorders, and a syndrome of inappropriate antidiuretic hormone secretion.
| Neuroimaging |
Confirmation that an attack is due to NMOSD is greatly aided by the detection on MRI of characteristic lesions in the brain, optic nerve, optic chiasm, or spinal cord.21 In the acute phase, MRI sequences T2-weighted sequences may show new inflammatory lesions or enlarged lesions, and T1-weighted sequences obtained with gadolinium may show enhancement of actively inflamed lesions.
Abnormalities on orbital MRI have a predilection for the optic chiasm or adjacent posterior optic nerve, but may occupy the entire length of the nerve.
MRI of the spinal cord typically shows longitudinally extensive transverse myelitis, defined as a lesion that is at least three contiguous vertebral segments in length.2,22 Although this pattern is characteristic of NMOSD, about 15% of sentinel myelitis attacks are associated with a shorter lesion that mimics multiple sclerosis.23
Detection of a dorsal spinal cord lesion with the use of MRI confirms area postrema syndrome, but the lesion is small and visible for a few days.7 Seen on MRI, focal lesions in the brainstem, diencephalon, or cerebrum, even those that are asymptomatic, they may also be indicative of NMOSD.7
| Diagnosis |
International consensus-based criteria for the diagnosis of NMOSD7 require the manifestation of one or more of the six typical syndromes and emphasize that clinico-radiological correlations and a positive serological test for AQP4-IgG distinguishes NMOSD from multiple sclerosis and other disorders.
About 80% of cases are seropositive, but current criteria allow the diagnosis of NMOSD if the AQP4-IgG test is negative or unavailable, which may be the case in some low-income regions of the world. However, according to international consensus criteria, the diagnosis of NMOSD is almost assured if there is a characteristic first attack and AQP4-IgG antibodies are present.7
The standard AQP4-IgG serum reference test is a live cell-based flow cytometry assay with greater than 80% sensitivity and greater than 99% specificity.24,25 False-positive low titer results may occur using linked immunosorbent assays. to enzymes and, in an atypical case, should prompt reconsideration of the diagnosis and confirmation with a cell-based assay.
False-negative AQP4-IgG results may occur if serum is sampled during treatment with immunosuppressive drugs or after plasma exchange. Retesting is recommended in these cases, with an interval after discontinuation of treatment or during a relapse.7 The AQP4-IgG cerebrospinal fluid test is relatively insensitive.
Categorization of NMOSD with AQP4-IgG negative or unknown requires clinical and MRI criteria and a search for other causes of CNS symptoms.7 The most common alternative diagnosis is a CNS demyelinating disorder associated with serum antibodies against oligodendrocyte glycoprotein. of myelin (MOG-IgG). This disorder overlaps with both AQP4-IgG seropositive NMOSD and multiple sclerosis, both of which can also cause optic neuritis or myelitis.26
Patients with clinical NMOSD syndromes typically undergo testing for both antibodies; however, AQP4-IgG and MOG-IgG antibodies rarely coexist. Patients who test negative for both antibodies can be described as "double seronegative" NMOSD, a category that could be narrowed with the discovery of new autoantibodies.
| Course of the disease |
Attacks of NMOSD typically reach maximum severity within several days, stabilize, and then resolve spontaneously, frequently leaving moderate to severe and permanent functional deficits.27 In more than 90% of cases, the disease has a relapsing, similar course. to that of multiple sclerosis, with a period of months or years between attacks.
Neurological deterioration is stable or may decrease during remission, but relapses lead to gradual accumulation of disability. The type, frequency and severity of relapses are influenced by age, sex and ethnicity. 28,29 Data on these factors have been obtained from retrospective series. Among women with seropositive NMOSD, relapse rates have been higher during the first 3 months after delivery than in the period before or during pregnancy, and the risk of miscarriage has been increased.30
Five years after disease onset, almost a quarter of untreated AQP4-IgG seropositive patients require walking assistance, more than 40% are blind in at least one eye, and mortality approaches 10%.28 31 Hospitalization rates and health resource use are substantial.32 In contrast to relapsing multiple sclerosis, in which late neurodegeneration and progressive functional decline can dominate the clinical picture, NMOSD rarely has a secondary progressive course. .33
| Associations with other disorders |
Up to half of patients with NMOSD and AQP4-IgG have other detectable serum autoantibodies (e.g., thyroperoxidase, antinuclear, and Ro/SS-A), and one-third have an autoimmune disease, most commonly thyroiditis, systemic lupus erythematosus, or Sjögren’s syndrome.2
It is advisable to perform AQP4-IgG testing before making a diagnosis of “lupus myelitis” or other CNS complications of rheumatologic diseases, because AQP4-IgG seropositivity generally indicates the coexistence of one of these diseases and NMOSD, with NMOSD generally representing CNS syndrome.34
Up to 5% of antibody-positive NMOSD cases are paraneoplastic, and the search for an occult malignancy may be considered in patients with risk factors for cancer, particularly in patients in whom NMOSD develops at an older age.
| Pathological features and pathogenesis |
AQP4 is an integral water channel membrane protein expressed by many cell types, including gastrointestinal, lung, retinal, kidney, and muscle cells. In the CNS, AQP4 is expressed in astrocytes abutting endothelial cells, which form the glia limiting component of the blood-brain barrier.
When the barrier is breached, or in regions such as the area postrema where it is lacking, circulating AQP4-IgG gains access and binds to its target antigen, initiating inflammatory responses that generate NMOSD lesions.
The pathological hallmarks of NMOSD with AQP4-IgG are a focal inflammatory lesion of the CNS with marked or complete loss of AQP4.35,36 Human immunopathological findings support the concept that NMOSD is an autoimmune astrocytopathy9 and that AQP4-specific autoantibodies initiate a lytic and sublytic astrocyte disease with variable potential for reversibility.35,37,38
Animal and tissue-based models using patient-derived monoclonal antibodies may reproduce some features of NMOSD, further supporting the pathogenic role of AQP4-IgG.39
Putative steps in pathogenesis begin with defects in immune tolerance checkpoints that allow the development of a pool of autoreactive B cells from which AQP4-IgG can originate.41
Cross-reactivity with bacterial antigens resembling AQP4 or, in paraneoplastic cases, initiation of an antibody-mediated response to tumor cell expression of AQP4 may be the mechanism of origin. Complementary activation is an immediate consequence of the selective binding of AQP4-IgG to its antigen.
Activated complement, together with interleukin-6, increases the permeability of the blood-brain barrier and is a chemoattractant, signaling eosinophils and neutrophils to enter the evolving lesion and degranulate. Astrocyte injury occurs through the effects of C5 and components of the complement membrane attack complex. Demyelination occurs as a secondary consequence of myelinolysis and oligodendrocyte injury.42
Despite widespread tissue expression of AQP4, extra-CNS clinical disease such as myositis is rare.43 One potential explanation for the selective vulnerability of the CNS is that the CNS lacks protective complement-regulating proteins that are coexpressed with AQP4 in tissues. peripherals such as the kidney.44
| Treatment |
> Acute relapses and symptoms
Acute relapses are initially treated with intravenous glucocorticoids, but one study has shown short-term remission of symptoms in only 19% of patients treated with these drugs.27 Moderate to severe relapses, including those with incomplete response to glucocorticoids, may improve with early administration of plasmapheresis.27
Managing the residual effects of relapses, such as gait impairment, weakness and spasticity, neuropathic pain, decreased vision, neurogenic bladder and bowel, and cognitive and mood disorders, can improve quality of life.
> Preventive immunotherapy
The primary goal of NMOSD management is the prevention of relapse, both for patients who are AQP4-IgG seropositive at initial presentation, who have a greater than 70% risk of relapse in the following year, and for all patients, whether AQP4-IgG seropositive or seronegative, who have an established course of relapses.
Relapse prevention is expected to preserve long-term neurological function because the accumulation of lesions with each attack would be avoided; A secondary progressive course of NMOSD, independent of relapses, is rare.
As of 2019, there were no approved medications for NMOSD, but observational data suggested that immunosuppression reduces the frequency of relapse among AQP4-IgG-seropositive patients and AQP4-IgG-seronegative patients,45,46 and a small, randomized, controlled study with placebo showed a benefit of rituximab in seropositive patients.47
The most commonly used drugs have been rituximab, mycophenolate mofetil and azathioprine. Many patients who do not have access to newly approved medications (discussed below) continue to receive these therapies if they are in long-term remission on one of these treatments or if they have recurrent, seronegative NMOSD; These medications are also used in children. Low-dose prednisone (or another glucocorticoid), methotrexate, mitoxantrone, or cyclophosphamide is used for relapse prevention in several regions of the world.
Three monoclonal antibody therapies approved for adults with NMOSD and AQP4-IgG48 autoantibodies are eculizumab, inebilizumab, and satralizumab; each targets steps in the immunopathogenesis of NMOSD and have been tested in trials. In randomized, double-blind, placebo-controlled trials, time to first adjudicated relapse was used as the primary outcome.
Differences in trial design have included enrollment criteria (i.e., whether enrollment has been restricted to AQP4-IgG positive patients), definition of attack, and the use of placebo alone or placebo added to existing therapy as comparator.
In one trial, eculizumab, which inhibits C5 and presumably C5b-mediated membrane attack complex formation, reduced the risk of relapse by 94% compared with placebo in AQP4-IgG-seropositive adults, some of whom were receiving concomitant immunosuppressants.49
No formal inferences could be made regarding disability or quality of life outcomes, because the follow-up period after a relapse was limited (6 weeks) and the difference between groups on a measure of disability progression was not significant. . Patients receiving eculizumab as monotherapy represented 24% of trial participants, and the reduction in risk of relapse in this group was similar to the reduction in the group of patients receiving eculizumab in addition to established immunosuppressive therapy.
Upper respiratory tract infections and headache were more common in the eculizumab group. There were no infections due to encapsulated organisms such as Neisseria meningitidis; Infections are a known risk of complement inhibition. One death occurred due to pulmonary empyema.
Inebilizumab targets CD19; depletes a broader spectrum of the B cell lineage, including antibody-producing plasmablasts and plasma cells, than anti-CD20 rituximab. In a phase 2-3 trial that included AQP4-IgG-seropositive and AQP4-IgG-seronegative patients and did not allow concomitant treatment with immunosuppressive medications, the risk of relapse was reduced by 73% overall and by 77% among seropositive patients.50
Inebilizumab reduced rates of cumulative disability, cumulative lesions on brain MRI, and hospitalization. Two patients died, one from a relapse of NMOSD and the other from an undetermined CNS cause.
Satralizumab targets the interleukin-6 receptor and therefore inhibits the downstream effects of interleukin-6; another drug targeting this receptor, tocilizumab, reduced the risk of relapse compared with azathioprine in a randomized, open-label trial.51
Two trials of satralizumab have been completed for the treatment of patients who have NMOSD with or without AQP4-IgG, one of which allowed for concurrent immunosuppressive therapy.52,53 Efficacy was achieved only in the seropositive groups in the two studies, with a 74%, and a 79% reduction in the risk of relapse, and no deaths or cancers occurred.
Considerations in selecting one of the newly approved preventive therapies include efficacy, problems with current treatment (side effects or lack of response), safety, frequency and route of administration, potential for adherence, effect on vaccine response, planning for the conception, access and cost of medicines.
Several drugs appear to be relatively safe when taken during pregnancy, but data are limited.30 Other than confirmation of eligibility on the basis of AQP4-IgG seropositive status, there are no biomarkers to facilitate drug selection.
Extension studies for approved medications did not identify important additional safety concerns and showed low relapse rates, but inferences about sustained efficacy and long-term risks are limited because these studies were not blinded to participants and investigators, observations were not controlled, and the longest study extension followed treated patients for an average of 4 to 5 years.54,55
Monitoring AQP4-IgG titers or lesions seen on MRI is not currently recommended for therapeutic decision-making, but serum biomarkers such as glial fibrillary acidic protein are being studied to confirm or predict clinical relapse.56 Relapses will likely lead to a change in therapy, possibly to a drug with a different mechanism of action, but a consensus definition of treatment failure and more data are needed.
Combination therapy, other immunosuppressive drugs, and autologous stem cell transplantation57 have been considered for treatment-refractory disease. Indefinite treatment is recommended for NMOSD with AQP4-IgG, as retrospective data suggest that discontinuing preventive therapies leads to high relapse rates.58
Research into new treatments, guided by an understanding of the pathobiological characteristics of NMOSD, focuses on approaches for the restoration of immunological tolerance; inhibition of AQP4-IgG binding or pathogenicity; targeting the effects of complement, granulocytes and microglia; and neuroprotection.59,60
| Summary |
The canonical clinical features of neuromyelitis optica have been complemented by other characteristic syndromes and the finding of pathogenic AQP4-IgG autoantibodies. The expanded spectrum of disease, NMOSD, is treated with medications that target steps in pathogenesis.
Promising approaches to predict and prevent relapses, improve recovery from relapses, and achieve immune tolerance are under investigation.
| Comment |
The present work highlights the need to think about optic pneumomyelitis spectrum disorders in both children and adults. The discovery and use of AQP4-IgG antibodies allows for diagnostic confirmation, although it is not totally essential for this.
Making the appropriate diagnosis, early, evaluating the possibility of differential diagnoses, would allow therapeutic management that tends to control the disease and its relapses, improving the quality of life of the affected people.
