Neuromyelitis optica spectrum disorder
Neuromyelitis optica spectrum disorders | |
---|---|
Other names | Neuromyelitis optica (NMO), Devic's disease, Devic's syndrome |
intravenous immunoglobulin, cyclophosphamide | |
Frequency | Up to 1 in 10,000[1] |
Neuromyelitis optica spectrum disorders (NMOSD) are a spectrum of autoimmune diseases characterized by acute inflammation of the optic nerve (optic neuritis, ON) and the spinal cord (myelitis).[1][2][3] Episodes of ON and myelitis can be simultaneous or successive. A relapsing disease course is common, especially in untreated patients.[1][4]
- Neuromyelitis optica (NMO) is a particular disease within the NMOSD spectrum. It is characterised by optic neuritis and longitudinally extensive myelitis. In more than 80% of NMO cases, the cause is
Signs and symptoms
The signs and
Spinal cord effects
The most common initial manifestation of the disease is inflammation of the spinal cord (myelitis)., affecting an entire cross-section of the spinal cord, and showing bilateral symptoms.
Optic effects
The second most common initial manifestation of the disease is inflammation of the optic nerve and/or optic chiasm (optic neuritis, ON).[4] ON may lead to varying degrees of visual impairment with decreased visual acuity, although visual field defects, or loss of color vision, may occur in isolation or prior to formal loss of visual acuity. Compared to idiopathic ON and ON due to multiple sclerosis (MS), ON due to NMOSD more often results in severe visual loss at onset, with bilateral involvement, and permanent visual deficits.[4]
Brain effects
Less commonly than the spinal cord and optic nerve, NMOSD can affect the
Disease course
Signs and symptoms usually follow a relapsing and remitting course, but occasionally can be progressive (monophasic). Deficits can be temporary or permanent, the latter especially in the absence of treatment.[citation needed]
Fatigue
Fatigue is a common symptom, with studies showing that as many as 77% of people with NMOSD have fatigue.[10][11] Fatigue has been found to correlate with quality of life in people with NMOSD.[12][13]
Comparison with MS
NMO and multiple sclerosis (MS) can be similar in clinical and radiological presentation, and MS may very rarely present with an NMO-like phenotype (e.g. in patients with long-standing MS resulting in confluent spinal cord lesions mimicking the longitudinally extensive spinal cord lesions typically seen in NMO). In consequence, NMO was in the past wrongly considered a clinical variant of MS. However, NMO is not related to MS in the vast majority of cases and differs from MS substantially in terms of pathogenesis, clinical presentation, magnetic resonance imaging, cerebrospinal fluid findings, disease course, and prognosis.[1]
Causes
NMOSD is caused by an
Why autoimmunity develops is largely unknown. Multiple genetic and environmental factors are known to increase the risk of developing NMOSD. The strongest risk factor is being female, especially in AQP4-IgG-positive NMOSD.[1] Multiple human leukocyte antigen (HLA) alleles are associated with NMOSD.[1]
NMO was associated in the past with many systemic diseases. Some researchers have pointed out that some other cases could be
The discovery of NMO-IgG (anti-AQP4) has opened a new avenue of research into the causes.[citation needed]
Pathophysiology
Anti-AQP4+ variants
NMOSD is usually caused by
The astrocytes surround the
Within astrocytes, AQP4 is primarily found in astrocytic
NMOSD selectively affects the optic nerve, spinal cord, and brain stem. This selectivity can be explained by the increased amount of AQP4 in these structures, and, furthermore, by the increased amount of AQP4 aggregates in the optic nerve and spinal cord.[1] The increased BBB permeability at the area postrema helps explain involvement there.[1] AQP4 is present in tissues outside the central nervous system (e.g. the kidneys), but these tissues aren't affected in NMOSD, at least in part because of the presence of autoimmune downregulators outside of the central nervous system.[1]
In NMOSD, areas of brain tissue that appear normal in conventional
Most research into the
AQP4-IgG levels are coarsely correlated with NMOSD disease activity, those levels generally increasing before relapse and declining during remission, with higher levels being correlated to more severe disease manifestation.[1]
NMO-IgG-negative cases are less understood. It seems that astrocytes are spared in these cases.[27]
Anti-MOG+ variants
The second most frequent autoantibody in NMO is MOG-IgG, which targets myelin oligodendrocyte glycoprotein (MOG). MOG is an integral membrane glycoprotein found on the surface of oligodendrocytes and the outermost surface of myelin sheaths.[1] Its function is not entirely known.[1] MOG-IgG is produced outside the central nervous system (CNS) despite MOG existing only in the CNS (with the BBB separating the two), leading to the hypothesis that MOG drained via cerebral spinal fluid into lymph nodes causes autoimmune reaction formation.[1]
MOG-IgG-positive NMOSD brain lesions, as seen under a microscopic, show demyelination with preservation of oligodendrocytes and axons, presence of inflammatory cells, and IgG and complement deposits.[1] MOG-IgG levels coarsely correlate with disease severity, with levels being higher during active disease, and higher levels being associated with more severe disease manifestation.[1]
Antibodies against MOG are considered mostly absent in similar diseases, such as MS.
Together with
The clinical course and the response to therapy is different for various diseases classed within these groups, showing a better prognosis for those in the NMO-Ab(−)/MOG-Ab(−) group, and a worse prognosis for those in the NMO-Ab(+)/MOG-Ab(+) group.[30] The MOG-related NMO can be radiologically identified by the conus involvement. Myelin-oligodendrocyte glycoprotein antibody–positive patients were more likely to have conus involvement on spinal magnetic resonance imaging.[31]
Diagnosis
NMOSD is diagnosed using consensus clinical criteria, which have undergone multiple revisions, most recently in 2015.[32][33]
Diagnostic criteria are more relaxed for
If AQP4-IgG is undetected, or its status is unknown, two core clinical criteria, each with supportive MRI findings, along with the ruling out of alternative diagnoses, are needed for an NMOSD diagnosis.[35]
Core criteria | Additional MRI findings for absent/unknown AQP4-IgG |
---|---|
Optic neuritis | Either 1) brain MRI showing normal findings or only nonspecific white matter lesions, or 2) optic nerve MRI showing T2-hyperintensity, or T1 enhancing lesion, greater than 1/2 optic nerve length or involving optic chiasm |
Acute myelitis | intramedullary lesion > 3 contiguous segments, or spinal atrophy ≥ 3 contiguous segments |
Area Postrema Syndrome (prolonged episodes of hiccuping or vomiting/nausea) | dorsal medulla/area postrema lesions |
Acute brainstem syndrome | periependymal brainstem lesions |
Symptomatic MRI showing diencephalon lesion (s) |
None additional |
Symptomatic cerebral syndrome with NMOSD-typical brain lesion(s) | None additional |
Rarely, it has been reported that some courses of
NMOSD with MOG-IgG is considered a manifestation of
Spectrum constituents
After the development of the NMO-IgG test, the spectrum of disorders comprising NMO was expanded. The spectrum is now believed to consist of:
- Standard NMO, according to the diagnostic criteria described above
- Limited forms of NMO, such as single or recurrent events of longitudinally extensive myelitis, and bilateral simultaneous or recurrent optic neuritis
- Asian optic-spinal multiple sclerosis (OSMS), or AQP4-negative form of inflammatory demyelinating diseases of the central nervous systemspectrum, sometimes called optic-spinal MS
- Longitudinally extensive autoimmunedisease
- Optic neuritis or myelitis associated with lesions in specific brain areas such as the hypothalamus, periventricular nucleus, and brainstem[41]
- NMOautoantibodies.[29]
Differential diagnosis
Another problem for diagnosis is that AQP4-ab in MOG-ab levels can be too low to be detected. Some additional biomarkers have been proposed.[46][47]
NMO differs from MS in that it usually has more severe
Recently, the presence of AQP4 has been found to distinguish standard MS from NMO; but as MS is a heterogeneous condition,[49] and some MS cases are reported to be Kir4.1 channelopathies[50] (autoimmunity against the potassium channels), it is still possible to consider NMO as part of the MS spectrum. Besides, some NMO-AQP4(−) variants are not astrocytopathic, but demyelinating.[51]
Also, an overlap with Sjögren syndrome has been reported.[53]
Evolution of diagnostic criteria
Since the discovery of the
The term neuromyelitis optica spectrum disorders (NMOSD) has been designed to allow incorporation of cases associated with non-AQP4
These variants are expected to respond to the same treatments as standard NMO.[55] Some authors propose to use the name "autoimmune aquaporin-4 channelopathy" for these diseases,[15] while others prefer a more generic term "AQP4-astrocytopathy", which also includes deficiencies of AQP4 with a non-autoimmune origin.[56]
Treatment
There is no cure for NMO, but it is treatable. Some patients recover, but many are left with impairment of vision and limbs, which can be severe in some cases.[57]
Attacks
Long term neurologic deficits are the cumulative effects of acute attacks, emphasizing the importance of acute treatment.
Plasmapheresis can be an effective treatment when attacks progress after the administration of corticosteroids.[41] This treatment involves the patient's own blood being pumped out, blood cells being removed from the plasma and mixed with a solution, then the new blood mixture being pumped back in.[57]
Secondary prevention
Prophylactic treatment, to prevent relapses of NMO, is generally employed; but the exact duration of such treatment is debatable.[60]
FDA-approved pharmaceuticals
FDA-approved pharmaceuticals against AQP4-IgG-positive NMOSD, shown to be effective in phase III clinical trials, first became available in 2019.[1] As of 2020, they are among the most expensive drugs worldwide.[1] They are not available in pill form, which, along with their high price, limits their accessibility.[1] These new drugs' effectiveness against AQP4-IgG-negative NMOSD is unknown.[1]
Drug (brand) | Brand | Date of FDA approval | Mechanism of action | Note |
---|---|---|---|---|
Eculizumab | Soliris | 2019 | Monoclonal antibody against complement protein C5 | Approved for AQP4-IgG-positive NMOSD[61] |
Inebilizumab | Uplizna | 2020 June | Monoclonal antibody against CD19+ B cells | [62] |
Satralizumab | Enspryng | 2020 August | Monoclonal antibody against IL-6 | Approved forAQP4-IgG-positive NMOSD[63][64] |
Off-label treatments
Many treatments are used despite the lack of phase III clinical trials testing their efficacy.[1] Neither inferiority nor superiority to the newer, FDA approved drugs has been clearly demonstrated; and, considering their being relatively inexpensive and being availability in pill format, these drugs are the current standard treatment.[1] Most of these medications affect the immune system in various ways.[58][41][65]
Drug (brand) | Mechanism of action | Note |
---|---|---|
azathioprine (Imuran, Azasan) | Inhibits purine metabolism | First reported effective in 1998 and was mainstay of treatment 10+ years thereafter. Sometimes combined with steroids due to months-long onset of action.[1] |
mycophenolate mofetil (CellCept) |
Inhibits purine metabolism | Has partially replaced azathioprine due to proposed better efficacy and tolerability. Sometimes combined with steroids due to months-long onset of action.[1] |
corticosteroid | [66] | |
mitoxantrone | DNA synthesis/repair inhibitor | |
methotrexate | Inhibits folate metabolism | |
cyclophosphamide | DNA crosslinker | |
rituximab (Rituxan) | antibody against CD20 – B cell depletion[67] | The most commonly used treatment for NMOSD today.[68] |
intravenous immunoglobulin (IVIG) |
||
hematopoietic stem cell transplantation (HSCT) | can be used in severe cases of NMO. Available data suggests that this procedure can reduce inflammatory activity in the short term, but a clear majority of the patients will relapse within 5 years.[69] |
It is important to note that certain immunosuppressants used to treat MS—such as interferon-β, fingolimod, natalizumab, and alemtuzumab—worsen NMO disease progression and should not be used to treat NMO.[70]
Prognosis
Normally, some improvement appears in a few weeks, but severe residual symptoms and even disability may persist.[citation needed]
The disease can be monophasic, i.e. a single episode with permanent remission afterwards. However, at least 85% of patients have a relapsing form of the disease with repeated attacks of transverse myelitis and/or optic neuritis. In patients with the monophasic form, the transverse myelitis and optic neuritis occur simultaneously or within days of each other. On the other hand, patients with the relapsing form are more likely to have weeks or months between the initial attacks, and to have better motor recovery after the initial transverse myelitis event. Relapses usually occur early, with about 55% of patients having a relapse in the first year and 90% in the first five years.[18]
It is possible that the relapsing form is related to the anti-AQP4+ seropositive status and the monophasic form related to its absence.[71] Unlike MS, NMO rarely has a secondary progressive phase in which patients have increasing neurologic decline between attacks without remission. Instead, disabilities arise from the acute attacks.[18]
Approximately 20% of patients with monophasic NMO have permanent visual loss, and 30% have permanent paralysis in one or both legs. Among patients with relapsing NMO, 50% have blindness or paralysis within five years. In some patients (33% in one study), transverse myelitis in the cervical spinal cord resulted in respiratory failure and subsequent death. However, the spectrum of NMO has widened, due to improved diagnostic criteria; and the options for treatment have improved. As a result, researchers believe these estimates will be lowered.[18]
Epidemiology
Prevalence varies by region, ranging from 0.5 to 10 cases per 100,000 people.[1] Unlike MS, prevalence has not been found to be related to latitude.[1] NMO is more common in women than men, with women comprising over two-thirds of patients and more than 80% of those with the relapsing form of the disease.[18]
A retrospective study found that prevalence of neuromyelitis optica spectrum disorders was 1.5% among a random sample of neurological patients, with a MS:NMOSD ratio of 42:7. Among 13 NMOSD patients, 77% had long spinal cord lesions, 38% had severe optic neuritis, and 23% had brain or brainstem lesions. Only 56% had clinically definite NMO at follow-up.[72]
NMO is more common in Asians than Caucasians. In fact, Asian optic-spinal multiple sclerosis (OSMS) (which constitutes 30% of the cases of MS in Japan) has been suggested to be identical to NMO (differences between OSMS and classic MS in Japanese patients). In the indigenous populations of tropical and subtropical regions, MS is rare; but when it appears, it often takes the form of OSMS.[73]
The majority of NMO patients have no affected relatives, and it is generally regarded as a nonfamilial condition.[18]
Rarely, NMO may occur in the context of other autoimmune diseases (e.g. connective tissue disorders, paraneoplastic syndromes) or infectious diseases. In some cases, the etiology remains unknown (idiopathic NMO).[citation needed]
History
First reports on an association of
In 2002,
Research directions
Since the discovery of
There is little research into the primary causes of the anti-AQP4 auto-antibodies. It has been noticed that some cases could be
In addition, several NMO variants have been discovered with antibodies other than those against AQP4, turning NMO into a
Research into new autoantibodies
An autoantibody—glial fibrillary acidic protein (GFAP)—was found in 2016, in transverse myelitis (LETM) and atypical NMO, leading to the concept of autoimmune GFAP astrocytopathy.[37]
Other autoantibody being researched is
Finally, other proteins under study are
The group
- NMO derived from an AQP4-Ab+) – around 80% of total NMO cases
- NMO derived from an anti-MOG associated encephalomyelitis[39] – around 10% of total cases
- Connexin-43 NMO
- Idiopathic NMO, defined by the absence of all previous antibodies
Antibody negative neuromyelitis optica
Some cases of NMO are not due to autoantibodies. They constitute an overlap between NMO and MS.
As of 2019 some statistical studies showed that antibody-negative NMO can be classified into three groups, and that this classification has a pathogenic meaning.[87]
Later studies have increased the number of groups up to four.[88]
Notable patients
See also
- Anti-AQP4 disease
- Demyelinating disease
- Idiopathic inflammatory demyelinating diseases
- Multiple sclerosis
- Tocilizumab
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