Neuromyelitis optica spectrum disorders (NMOSD) are a spectrum of autoimmune diseases characterized by acute
inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
of the
optic nerve
In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual system, visual information from the retina to the brain. In humans, the optic nerve i ...
(
optic neuritis
Optic neuritis (ON) is a debilitating condition that is defined as inflammation of cranial nerve II which results in disruption of the neurologic pathways that allow visual sensory information received by the retina to be able to be transmitted to ...
, ON) and the
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
(
myelitis).
[Banerjee S, Butcher R. Rituximab for the Treatment of Neuromyelitis Optica Spectrum Disorder nternet Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2021 Feb. Available from: https://www.ncbi.nlm.nih.gov/books/NBK571350/] Episodes of ON and myelitis can be simultaneous or successive. A relapsing disease course is common, especially in untreated patients.
* 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
immunoglobulin G autoantibodies
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
to
aquaporin 4 (
anti-AQP4), the most abundant
water channel protein in the central nervous system.
* Less common diseases with other manifestations are also part of the NMOSD spectrum.
Signs and symptoms
The signs and
symptom
Signs and symptoms are diagnostic indications of an illness, injury, or condition.
Signs are objective and externally observable; symptoms are a person's reported subjective experiences.
A sign for example may be a higher or lower temperature ...
s of NMOSD depend on the neurologic structures the disease affects, and, to some extent, the antibodies involved.
Spinal cord effects
The most common initial manifestation of the disease is inflammation of the spinal cord (myelitis).
Myelitis causes spinal cord dysfunction, which can result in
muscle weakness, paralysis in the limbs, lost or reduced sensation, spasms, loss of
bladder
The bladder () is a hollow organ in humans and other vertebrates that stores urine from the kidneys. In placental mammals, urine enters the bladder via the ureters and exits via the urethra during urination. In humans, the bladder is a distens ...
and bowel control, or erectile dysfunction.
The myelitis can be
transverse, 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
Optic neuritis (ON) is a debilitating condition that is defined as inflammation of cranial nerve II which results in disruption of the neurologic pathways that allow visual sensory information received by the retina to be able to be transmitted to ...
, ON).
ON may lead to varying degrees of visual impairment with decreased
visual acuity
Visual acuity (VA) commonly refers to the clarity of visual perception, vision, but technically rates an animal's ability to recognize small details with precision. Visual acuity depends on optical and neural factors. Optical factors of the eye ...
, although
visual field
The visual field is "that portion of space in which objects are visible at the same moment during steady fixation of the gaze in one direction"; in ophthalmology and neurology the emphasis is mostly on the structure inside the visual field and it i ...
defects, or loss of
color vision
Color vision, a feature of visual perception, is an ability to perceive differences between light composed of different frequencies independently of light intensity.
Color perception is a part of the larger visual system and is mediated by a co ...
, 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.
Brain effects
Less commonly than the spinal cord and optic nerve, NMOSD can affect the
brain stem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is co ...
.
Lesions in the brain stem or upper cervical spinal cord can cause respiratory insufficiency. Lesions in the
area postrema
The area postrema, a paired structure in the medulla oblongata of the brainstem, is a circumventricular organ having permeable capillaries and sensory neurons that enable its role to detect circulating chemical messengers in the blood and tra ...
of the
medulla oblongata
The medulla oblongata or simply medulla is a long stem-like structure which makes up the lower part of the brainstem. It is anterior and partially inferior to the cerebellum. It is a cone-shaped neuronal mass responsible for autonomic (involun ...
can cause
vomiting
Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
or
hiccups, as well as pain and tonic
spasm
A spasm is a sudden involuntary contraction of a muscle, a group of muscles, or a hollow organ, such as the bladder.
A spasmodic muscle contraction may be caused by many medical conditions, including dystonia. Most commonly, it is a musc ...
s.
Additional brain lesions are common but often asymptomatic (though
cognitive deficits, as well as
depression, may be underdiagnosed
sequalae). Lesions may also affect the
diencephalon
In the human brain, the diencephalon (or interbrain) is a division of the forebrain (embryonic ''prosencephalon''). It is situated between the telencephalon and the midbrain (embryonic ''mesencephalon''). The diencephalon has also been known as t ...
, mostly in
Aquaporin-4–
Immunoglobulin-G (AQP4-IgG) NMOSD.
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.
Fatigue
Fatigue
Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself.
Fatigue (in the medical sense) is sometimes associated wit ...
is a common symptom, with studies showing that as many as 77% of people with NMOSD have fatigue. Fatigue has been found to correlate with quality of life in people with NMOSD.
Comparison with MS
NMO and
multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
(MS) can be similar in clinical and radiological presentation, and MS may very rarely present with an NMO-like
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
(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
In pathology, pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes .
Descript ...
, clinical presentation,
magnetic resonance imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and ...
, cerebrospinal fluid findings, disease course, and prognosis.
Causes
NMOSD is caused by an
autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
attack on the nervous system. In more than 80% of cases,
IgG autoantibodies
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
against
aquaporin-4 (
anti-AQP4+) are the cause, and in 10–40% of the remaining cases, IgG antibodies against
MOG are the cause.
The cause of the remaining cases is still unknown, and it is likely heterogeneous.
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.
Multiple
human leukocyte antigen
The human leukocyte antigen (HLA) system is a complex of genes on chromosome 6 in humans that encode cell-surface proteins responsible for regulation of the immune system. The HLA system is also known as the human version of the major histo ...
(HLA) alleles are associated with NMOSD.
NMO was associated in the past with many systemic diseases. Some researchers have pointed out that some other cases could be
paraneoplastic.
It appears that
lupus can produce NMO-IgG autoantibodies, leading to cases of
lupus-derived NMO.
The discovery of NMO-IgG (
anti-AQP4) has opened a new avenue of
research
Research is creative and systematic work undertaken to increase the stock of knowledge. It involves the collection, organization, and analysis of evidence to increase understanding of a topic, characterized by a particular attentiveness to ...
into the causes.
Pathophysiology
Anti-AQP4+ variants
NMOSD is usually caused by
autoantibodies
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
targeting
aquaporin 4 (AQP4), a
channel protein in the
cell membrane
The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
that allows water to pass through the membrane.
AQP4
monomers
A monomer ( ; ''wikt:mono-, mono-'', "one" + ''wikt:-mer, -mer'', "part") is a molecule that can chemical reaction, react together with other monomer molecules to form a larger polymer chain or two- or three-dimensional network in a process called ...
form
tetramers
A tetramer () (''tetra-'', "four" + '' -mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula ...
, and the tetramers aggregate.
AQP4 is found in
astrocyte
Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of en ...
s, which are the basis for the
glymphatic system.
Thus, NMOSD involving AQP4-IgG can be considered an
astrocytopathy or
autoimmune astrocytic channelopathy, since the astrocytes are semi-selectively destroyed.
The astrocytes surround the
blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...
(BBB), a system responsible for preventing substances in the blood from entering the brain. For antibodies from the blood to reach astrocytes in the central nervous system (CNS), they must cross the BBB, the mechanism of which is not completely known. Some reports point to the
metalloproteinase-2 and
interleukin
Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
-6 as culprits responsible for the BBB failure. There is broad consensus that
AQP4/NMO-
IgG initially enters the brain via BBB-deficient sites such as the
area postrema
The area postrema, a paired structure in the medulla oblongata of the brainstem, is a circumventricular organ having permeable capillaries and sensory neurons that enable its role to detect circulating chemical messengers in the blood and tra ...
, where there is access to
cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
(CSF). In any case,
anti-AQP4 is produced mainly
intrathecally.
Within astrocytes, AQP4 is primarily found in astrocytic
foot processes that abut blood vessels and the linings of the brain (
meninges
In anatomy, the meninges (; meninx ; ) are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in the subarachnoid spac ...
).
NMOSD brain lesions, as seen
under a microscope, show IgG,
Immunoglobulin M
Immunoglobulin M (IgM) is the largest of several isotypes of antibodies (also known as immunoglobulin) that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen;
causing it to also ...
(IgM), inflammatory cells, and complement deposits around blood vessels.
AQP4-IgG is a member of the
IgG1 immunoglobulin family, which is an activator of the
complement system
The complement system, also known as complement cascade, is a part of the humoral, innate immune system and enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inf ...
, which seems to play an integral part in the autoimmune response.
There is a loss of astrocytes, and sometimes also a loss of neurons and
oligodendrocyte
Oligodendrocytes (), also known as oligodendroglia, are a type of neuroglia whose main function is to provide the myelin sheath to neuronal axons in the central nervous system (CNS). Myelination gives metabolic support to, and insulates the axons ...
s. Loss of cells other than astrocytes is a consequence of collateral inflammatory damage or astrocyte dysfunction.
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.
The increased BBB permeability at the area postrema helps explain involvement there.
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.
In NMOSD, areas of brain tissue that appear normal in conventional
magnetic resonance imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and ...
(MRI) can show damage in
diffusion tensor imaging (DTI), although less so compared to
multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
(MS).
Most research into the
pathology
Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...
of NMO has focused on the
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
. The damage can range from inflammatory
demyelination to
necrotic damage of the
white
White is the lightest color and is achromatic (having no chroma). It is the color of objects such as snow, chalk, and milk, and is the opposite of black. White objects fully (or almost fully) reflect and scatter all the visible wa ...
and
grey
Grey (more frequent in British English) or gray (more frequent in American English) is an intermediate color between black and white. It is a neutral or achromatic color, meaning that it has no chroma. It is the color of a cloud-covered s ...
matters. The inflammatory
lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals.
Types
There is no de ...
s in NMO have been
classified as type II lesions (
complement-mediated
demyelination), but they differ from MS pattern II
lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals.
Types
There is no de ...
s in their prominent
perivascular distribution. Therefore, the pattern of
inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
is often quite distinct from that seen in MS.
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.
NMO- IgG-negative cases are less understood. It seems that astrocyte
Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of en ...
s are spared in these cases.
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
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
found on the surface of oligodendrocytes and the outermost surface of myelin sheaths. Its function is not entirely known. 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.
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. 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.
Antibodies against MOG are considered mostly absent in similar diseases, such as MS. Therefore, it can be said that anti-MOG diseases are grouped within AQP4-IgG-negative NMOSD.[
Together with anti-AQP4 disease, anti-MOG diseases form the wider part of the NMO spectrum. The NMO cases are classified in four classes, according to the presence or absence of any of these two main auto-antibodies.]
The clinical course and the response to therapy is different for various diseases classed within these groups, showing a better prognosis
Prognosis ( Greek: πρόγνωσις "fore-knowing, foreseeing"; : prognoses) is a medical term for predicting the likelihood or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) ...
for those in the NMO-Ab(−)/MOG-Ab(−) group, and a worse prognosis
Prognosis ( Greek: πρόγνωσις "fore-knowing, foreseeing"; : prognoses) is a medical term for predicting the likelihood or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) ...
for those in the NMO-Ab(+)/MOG-Ab(+) group. The MOG-related NMO can be radiologically identified by the conus
''Conus'' is a genus of venomous and predatory cone snails.Bouchet, P.; Gofas, S. (2015). Conus Linnaeus, 1758. In: MolluscaBase (2015). Accessed through: World Register of Marine Species at http://www.marinespecies.org/aphia.php?p=taxdetails&i ...
involvement. Myelin-oligodendrocyte glycoprotein antibody
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
–positive patient
A patient is any recipient of health care services that are performed by Health professional, healthcare professionals. The patient is most often Disease, ill or Major trauma, injured and in need of therapy, treatment by a physician, nurse, op ...
s were more likely to have conus
''Conus'' is a genus of venomous and predatory cone snails.Bouchet, P.; Gofas, S. (2015). Conus Linnaeus, 1758. In: MolluscaBase (2015). Accessed through: World Register of Marine Species at http://www.marinespecies.org/aphia.php?p=taxdetails&i ...
involvement on spinal magnetic resonance imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and ...
.
Diagnosis
NMOSD is diagnosed using consensus clinical criteria, which have undergone multiple revisions, most recently in 2015.
Diagnostic criteria are more relaxed for seropositive AQP4– IgG cases than they are for seronegative AQP4-IgG ones. If AQP4-IgG is detected, then one core clinical criterion, along with the ruling out of alternative diagnoses, is sufficient for NMOSD diagnosis.
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.
Rarely, it has been reported that some courses of anti-NMDAR are consistent with NMO. Preliminary reports suggest that other autoantibodies
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
may play a role in rare cases of NMO.
NMOSD with MOG-IgG is considered a manifestation of anti-MOG associated encephalomyelitis.
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
Optic neuritis (ON) is a debilitating condition that is defined as inflammation of cranial nerve II which results in disruption of the neurologic pathways that allow visual sensory information received by the retina to be able to be transmitted to ...
* Asian optic-spinal multiple sclerosis (OSMS), or AQP4+ OSMS. This variant can present brain
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals.
Types
There is no de ...
s like MS does, but it should not be confused with an AQP4-negative form of inflammatory demyelinating diseases of the central nervous system spectrum, sometimes called ''optic-spinal MS''
* Longitudinally extensive myelitis or optic neuritis
Optic neuritis (ON) is a debilitating condition that is defined as inflammation of cranial nerve II which results in disruption of the neurologic pathways that allow visual sensory information received by the retina to be able to be transmitted to ...
associated with systemic autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
disease
* Optic neuritis
Optic neuritis (ON) is a debilitating condition that is defined as inflammation of cranial nerve II which results in disruption of the neurologic pathways that allow visual sensory information received by the retina to be able to be transmitted to ...
or myelitis associated with lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals.
Types
There is no de ...
s in specific brain
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
areas such as the hypothalamus
The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
, periventricular nucleus, and brainstem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...
* NMO -IgG negative NMO: AQP4 antibody
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
- seronegative NMO poses a diagnostic challenge. Some cases could be related to anti- myelin oligodendrocyte glycoprotein (MOG) autoantibodies
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
.
Differential diagnosis
AQP4-Ab-negative NMO presents problems for differential diagnosis
In healthcare, a differential diagnosis (DDx) is a method of analysis that distinguishes a particular disease or condition from others that present with similar clinical features. Differential diagnostic procedures are used by clinicians to di ...
. The behavior of the oligoclonal bands can help to establish a more accurate diagnosis. Oligoclonal bands in NMO are rare and they tend to disappear after attacks, while in MS they are nearly always present and persistent. It is important to notice for differential diagnosis that, though uncommon, it is possible to have longitudinal lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals.
Types
There is no de ...
s in MS.
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.
NMO differs from MS in that it usually has more severe sequelae after an acute episode than standard MS, which infrequently presents as transverse myelitis. In addition oligoclonal bands in the CSF as well as white matter
White matter refers to areas of the central nervous system that are mainly made up of myelinated axons, also called Nerve tract, tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distr ...
lesions on brain MRI
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
s are uncommon in NMO, but occur in over 90% of MS patients.
Recently, the presence of AQP4 has been found to distinguish standard MS from NMO; but as MS is a heterogeneous condition, and some MS cases are reported to be Kir4.1 channelopathies (autoimmunity
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease ...
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.
Tumefactive demyelinating lesions in NMO are not usual, but they have been reported to appear in several cases mistakenly treated with interferon beta
The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T cell, T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p2 ...
.
Also, an overlap with Sjögren syndrome has been reported.
Evolution of diagnostic criteria
Since the discovery of the AQP4 autoantibody
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
, it has been found that it appears also in patients with NMO-like symptoms that do not fulfill the clinical requirements to be diagnosed with NMO (recurrent and simultaneous optic nerve
In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual system, visual information from the retina to the brain. In humans, the optic nerve i ...
and spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
).
The term neuromyelitis optica spectrum disorders (NMOSD) has been designed to allow incorporation of cases associated with non-AQP4 biomarkers.[ Therefore, it includes all the clinical variants due to anti-AQP4, plus other non-related but clinically similar syndromes such as anti-MOG associated encephalomyelitis. Some cases with MOG+ and AQP4+ ]antibodies
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
have been found.[
These variants are expected to respond to the same treatments as standard NMO. Some authors propose to use the name "]autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
aquaporin-4 channelopathy" for these diseases,[ while others prefer a more generic term "AQP4- astrocytopathy", which also includes deficiencies of AQP4 with a non-]autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
origin.
Treatment
There is no cure
A cure is a substance or procedure that resolves a medical condition. This may include a medication, a surgery, surgical operation, a lifestyle change, or even a philosophical shift that alleviates a person's suffering or achieves a state of heali ...
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.
Attacks
Long term neurologic deficits are the cumulative effects of acute attacks, emphasizing the importance of acute treatment. Traditionally, attacks have been treated with short courses (3–5 days) of high dosage intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...
s, such as methylprednisolone IV ( Solu-Medrol). Early initiation of treatment with steroids has been shown to improve vision-related outcomes after acute attacks. However, there is no high-level evidence for steroids affecting long-term outcomes; this treatment strategy was borrowed from that for similar diseases (idiopathic optic neuritis and multiple sclerosis).
Plasmapheresis can be an effective treatment when attacks progress after the administration of corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...
s.[ This treatment involves the patient's own ]blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells.
Blood is com ...
being pumped out, blood cell
A blood cell (also called a hematopoietic cell, hemocyte, or hematocyte) is a cell produced through hematopoiesis and found mainly in the blood. Major types of blood cells include red blood cells (erythrocytes), white blood cells (leukocytes), ...
s being removed from the plasma and mixed with a solution, then the new blood mixture being pumped back in.
Secondary prevention
Prophylactic treatment, to prevent relapses of NMO, is generally employed; but the exact duration of such treatment is debatable.
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. As of 2020, they are among the most expensive drugs worldwide. They are not available in pill form, which, along with their high price, limits their accessibility. These new drugs' effectiveness against AQP4-IgG-negative NMOSD is unknown.
Off-label treatments
Many treatments are used despite the lack of phase III clinical trials testing their efficacy. 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. Most of these medications affect the immune system in various ways.
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.
Prognosis
Normally, some improvement appears in a few weeks, but severe residual symptoms and even disability
Disability is the experience of any condition that makes it more difficult for a person to do certain activities or have equitable access within a given society. Disabilities may be Cognitive disability, cognitive, Developmental disability, d ...
may persist.
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
Optic neuritis (ON) is a debilitating condition that is defined as inflammation of cranial nerve II which results in disruption of the neurologic pathways that allow visual sensory information received by the retina to be able to be transmitted to ...
. 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 patient
A patient is any recipient of health care services that are performed by Health professional, healthcare professionals. The patient is most often Disease, ill or Major trauma, injured and in need of therapy, treatment by a physician, nurse, op ...
s having a relapse in the first year and 90% in the first five years.[
It is possible that the relapsing form is related to the anti-AQP4+ seropositive status and the monophasic form related to its absence.] 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.[
Approximately 20% of patients with monophasic NMO have permanent visual loss, and 30% have permanent ]paralysis
Paralysis (: paralyses; also known as plegia) is a loss of Motor skill, motor function in one or more Skeletal muscle, muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory d ...
in one or both legs. Among patients with relapsing NMO, 50% have blindness
Visual or vision impairment (VI or VIP) is the partial or total inability of visual perception. In the absence of treatment such as corrective eyewear, assistive devices, and medical treatment, visual impairment may cause the individual difficul ...
or paralysis
Paralysis (: paralyses; also known as plegia) is a loss of Motor skill, motor function in one or more Skeletal muscle, muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory d ...
within five years. In some patients (33% in one study), transverse myelitis in the cervical spinal cord resulted in respiratory failure
Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a r ...
and subsequent death
Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose sh ...
. 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.[
]
Epidemiology
Prevalence varies by region, ranging from 0.5 to 10 cases per 100,000 people. Unlike MS, prevalence has not been found to be related to latitude
In geography, latitude is a geographic coordinate system, geographic coordinate that specifies the north-south position of a point on the surface of the Earth or another celestial body. Latitude is given as an angle that ranges from −90° at t ...
. 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.[
A retrospective study found that prevalence of neuromyelitis optica spectrum disorders was 1.5% among a random sample of neurological ]patient
A patient is any recipient of health care services that are performed by Health professional, healthcare professionals. The patient is most often Disease, ill or Major trauma, injured and in need of therapy, treatment by a physician, nurse, op ...
s, with a MS:NMOSD ratio of 42:7. Among 13 NMOSD patients, 77% had long spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals.
Types
There is no de ...
s, 38% had severe optic neuritis
Optic neuritis (ON) is a debilitating condition that is defined as inflammation of cranial nerve II which results in disruption of the neurologic pathways that allow visual sensory information received by the retina to be able to be transmitted to ...
, and 23% had brain
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
or brainstem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...
lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals.
Types
There is no de ...
s. Only 56% had clinically definite NMO at follow-up.
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
Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...
) has been suggested to be identical to NMO (differences between OSMS and classic MS in Japanese patients). In the indigenous populations of tropical
The tropics are the regions of Earth surrounding the equator, where the sun may shine directly overhead. This contrasts with the temperate or polar regions of Earth, where the Sun can never be directly overhead. This is because of Earth's ax ...
and subtropical regions, MS is rare; but when it appears, it often takes the form of OSMS.
The majority of NMO patients have no affected relatives, and it is generally regarded as a nonfamilial condition.[
Rarely, NMO may occur in the context of other ]autoimmune disease
An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
s (e.g. connective tissue disorders, paraneoplastic syndromes) or infectious diseases. In some cases, the etiology
Etiology (; alternatively spelled aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek word ''()'', meaning "giving a reason for" (). More completely, etiology is the study of the causes, origins ...
remains unknown (idiopathic
An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin.
For some medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause ...
NMO).
History
First reports on an association of spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
with optic nerve
In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual system, visual information from the retina to the brain. In humans, the optic nerve i ...
disorders date back to the late 18th and early 19th century. However, only an 1870 report by Sir Thomas Clifford Allbutt created sustained interest on the part of neurologists and ophthalmologists in this rare syndrome. In 1894, Eugène Devic and his PhD
A Doctor of Philosophy (PhD, DPhil; or ) is a terminal degree that usually denotes the highest level of academic achievement in a given discipline and is awarded following a course of graduate study and original research. The name of the deg ...
student Fernand Gault described 16 patients who had lost vision
Vision, Visions, or The Vision may refer to:
Perception Optical perception
* Visual perception, the sense of sight
* Visual system, the physical mechanism of eyesight
* Computer vision, a field dealing with how computers can be made to gain und ...
in one or both eyes and within weeks developed severe spastic weakness of the limbs, loss of sensation, and often of bladder
The bladder () is a hollow organ in humans and other vertebrates that stores urine from the kidneys. In placental mammals, urine enters the bladder via the ureters and exits via the urethra during urination. In humans, the bladder is a distens ...
control. They recognized these symptoms were the result of inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
of the optic nerve and spinal cord, respectively.
In 2002, Mayo Clinic
Mayo Clinic () is a Nonprofit organization, private American Academic health science centre, academic Medical centers in the United States, medical center focused on integrated health care, healthcare, Mayo Clinic College of Medicine and Science ...
researchers identified a humoral mechanism, targeting a perivascular protein, as the culprit of NMO, and in 2004 an unknown specific autoantibody was found. In 2005 they identified the aquaporin 4 protein as the target of the disease, and developed the first in-house test to aid in the diagnosis
Diagnosis (: diagnoses) is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in a lot of different academic discipline, disciplines, with variations in the use of logic, analytics, and experience, to determine " ...
of NMO by detection of an antibody
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
, AQP4- IgG, in the blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells.
Blood is com ...
.[ The first quantitative ]ELISA
The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay is a solid-phase type of enzyme immunoassay (EIA) to detect the presence of ...
(enzyme-linked immunosorbent assay) kits were soon developed, However, serum AQP4-IgG titer only moderately reflects disease activity, severity, or neurological prognosis. Later, some other autoantibodies
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
were found in NMO AQP4-negative cases, such as anti-MOG IgG, but some NMO anti-AQP4-negative cases still remain idiopathic.
Research directions
Since the discovery of AQP4 involvement, some research studies have focused on targeted treatment aimed at anti-aquaporin 4 antibodies
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
. The most established method for antibody removal is plasmapheresis. A number of drugs are being studied: aquaporumab (non-pathogenic antibody
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
blocker of AQP4-IgG binding), sivelestat ( neutrophil elastase inhibitor), and eculizumab ( complement inhibitor).
There is little research into the primary causes of the anti-AQP4 auto-antibodies. It has been noticed that some cases could be paraneoplastic.
In addition, several NMO variants have been discovered with antibodies other than those against AQP4, turning NMO into a heterogeneous disease. Six different patterns of damage have been reported in NMO, raising the possibility of six different types of auto-antibodies. As of 2019, only three of them are known.
Research into new autoantibodies
An autoantibody
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
—glial fibrillary acidic protein
Glial fibrillary acidic protein (GFAP) is a protein that is encoded by the ''GFAP'' gene in humans. It is a type III intermediate filament (IF) protein that is expressed by numerous cell types of the central nervous system (CNS), including astro ...
(GFAP)—was found in 2016, in transverse myelitis ( LETM) and atypical NMO, leading to the concept of autoimmune GFAP astrocytopathy.
Other autoantibody being researched is flotillin. It has been found in seronegative NMO and some MS patients.
Finally, other proteins under study are connexin 43 and anti- AQP1, although, as of 2015, there are only initial reports about the involvement of these protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s.
The group AQP4+/ MOG+ is very small and it can be considered a coincidence of two completely separate diseases in the same person. Assuming these cases can be verified, five different kinds of NMO are being considered:
* NMO derived from an autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
channelopathy ( AQP4-Ab+) – around 80% of total NMO cases
* NMO derived from an anti- MOG associated encephalomyelitis – around 10% of total cases
* Connexin-43 NMO
* Aquaporin-1 associated NMO which could be related to pattern III MS
* Idiopathic
An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin.
For some medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause ...
NMO, defined by the absence of all previous antibodies
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
Antibody negative neuromyelitis optica
Some cases of NMO are not due to autoantibodies
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
. They constitute an overlap between NMO and MS.
As of 2019 some statistical studies showed that antibody
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
-negative NMO can be classified into three groups, and that this classification has a pathogen
In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory of d ...
ic meaning.
Later studies have increased the number of groups up to four.
Notable patients
* Christine Hà (chef
A chef is a professional Cook (profession), cook and tradesperson who is proficient in all aspects of outline of food preparation, food preparation, often focusing on a particular cuisine. The word "chef" is derived from the term (), the di ...
and author
In legal discourse, an author is the creator of an original work that has been published, whether that work exists in written, graphic, visual, or recorded form. The act of creating such a work is referred to as authorship. Therefore, a sculpt ...
)
* Cassie Mitchell ( paralympian and biomedical engineering
Biomedical engineering (BME) or medical engineering is the application of engineering principles and design concepts to medicine and biology for healthcare applications (e.g., diagnostic or therapeutic purposes). BME also integrates the logica ...
professor
Professor (commonly abbreviated as Prof.) is an Academy, academic rank at university, universities and other tertiary education, post-secondary education and research institutions in most countries. Literally, ''professor'' derives from Latin ...
)
See also
* Anti-AQP4 disease
* Demyelinating disease
* Idiopathic inflammatory demyelinating diseases
* Multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
* Tocilizumab
Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arter ...
References
{{DEFAULTSORT:Neuromyelitis Optica
Autoimmune diseases
Demyelinating diseases of CNS
Myelin disorders
Rare diseases