Neuromyelitis optica spectrum disorders (NMOSD), including neuromyelitis optica (NMO), are autoimmune diseases characterized by acute
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
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 information from the retina to the brain. In humans, the optic nerve is derived fro ...
(
optic neuritis
Optic neuritis describes any condition that causes inflammation of the optic nerve; it may be associated with demyelinating diseases, or infectious or inflammatory processes.
It is also known as optic papillitis (when the head of the optic nerv ...
, ON) and the
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spin ...
(
myelitis
Myelitis is inflammation of the spinal cord which can disrupt the normal responses from the brain to the rest of the body, and from the rest of the body to the brain. Inflammation in the spinal cord, can cause the myelin and axon to be damaged r ...
).
Episodes of ON and myelitis can be simultaneous or successive. A relapsing disease course is common, especially in untreated patients.
In more than 80% of cases, NMO is caused by
immunoglobulin G
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each 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.
P ...
to
aquaporin 4
Aquaporin-4, also known as AQP-4, is a water channel protein encoded by the ''AQP4'' gene in humans. AQP-4 belongs to the aquaporin family of integral membrane proteins that conduct water through the cell membrane. A limited number of aquaporins a ...
(
anti-AQP4), the most abundant
water channel protein in the central nervous system. A subset of anti-AQP4-negative cases is associated with antibodies against
myelin oligodendrocyte glycoprotein
Myelin oligodendrocyte glycoprotein (MOG) is a glycoprotein believed to be important in the myelination of nerves in the central nervous system (CNS). In humans this protein is encoded by the ''MOG'' gene. It is speculated to serve as a necessary ...
(
anti-MOG).
Rarely, NMO may occur in the context of other
autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly ...
s (e.g.
connective tissue disorders,
paraneoplastic syndrome
A paraneoplastic syndrome is a syndrome (a set of signs and symptoms) that is the consequence of a tumor in the body (usually a cancerous one), specifically due to the production of chemical signaling molecules (such as hormones or cytokines) by ...
s) or infectious diseases. In some cases, the
etiology
Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiología'') "giving a reason for" (, ''aitía'', "cause"); and ('' -logía''). More completely, e ...
remains unknown (
idiopathic
An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. From Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approximately "a disease of its own kind ...
NMO).
Multiple sclerosis (MS) and NMO 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 or physical form and structure, its developmental processes, its biochemical and physiological prop ...
(e.g. in patients with long-standing MS resulting in confluent spinal cord lesions mimicking the long spinal cord lesions typically seen in MS). In consequence, NMO was in the past wrongly considered a clinical variant of MS. However, NMO is not caused by MS in the vast majority of cases and differs from MS substantially in terms of
pathogenesis
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 from Greek πάθος ''pat ...
, clinical presentation,
magnetic resonance imaging, cerebrospinal fluid findings, disease course, and prognosis.
Signs and symptoms
The signs and
symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...
s of NMOSD depend on the neurologic structures the disease affects, and, to some extent, the antibodies involved. 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.
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
Muscle weakness is a lack of muscle strength. Its causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, includi ...
, paralysis in the limbs, lost or reduced sensation, spasms, loss of
bladder
The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters ...
and bowel control, or erectile dysfunction.
The myelitis can be
transverse
Transverse may refer to:
*Transverse engine, an engine in which the crankshaft is oriented side-to-side relative to the wheels of the vehicle
*Transverse flute, a flute that is held horizontally
* Transverse force (or ''Euler force''), the tangen ...
, affecting an entire cross-section of the spinal cord, and showing bilateral symptoms.
The second most common initial manifestation of the disease is inflammation of the optic nerve and/or
optic chiasm
In neuroanatomy, the optic chiasm, or optic chiasma (; , ), is the part of the brain where the optic nerves cross. It is located at the bottom of the brain immediately inferior to the hypothalamus. The optic chiasm is found in all vertebrate ...
(
optic neuritis
Optic neuritis describes any condition that causes inflammation of the optic nerve; it may be associated with demyelinating diseases, or infectious or inflammatory processes.
It is also known as optic papillitis (when the head of the optic nerv ...
, ON).
ON may lead to varying degrees of visual impairment with decreased
visual acuity
Visual acuity (VA) commonly refers to the clarity of vision, but technically rates an examinee's ability to recognize small details with precision. Visual acuity is dependent on optical and neural factors, i.e. (1) the sharpness of the retinal ...
, although
visual field
The visual field is the "spatial array of visual sensations available to observation in introspectionist psychological experiments". Or simply, visual field can be defined as the entire area that can be seen when an eye is fixed straight at a point ...
defects, or loss of
color vision
Color vision, a feature of visual perception, is an ability to perceive differences between light composed of different wavelengths (i.e., different spectral power distributions) independently of light intensity. Color perception is a part of ...
, 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.
Classically, NMO included only symptoms of myelitis and ON.
However, with the discovery of disease-causing antibodies, a broader spectrum of disease manifestations has been grouped with NMO into the diagnosis of NMOSD.
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 cont ...
.
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 dual role to detect circulating chemical messengers in the blood and ...
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 and throwing up) is the involuntary, 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, gastroenteri ...
or
hiccups
A hiccup (scientific name ''singultus'', from a Latin word meaning "to catch one's breath while sobbing"; also spelled hiccough) is an involuntary contraction ( myoclonic jerk) of the diaphragm that may repeat several times per minute. The hi ...
, 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 muscle ...
s.
Additional brain lesions are common but often asymptomatic (though
cognitive deficit
Cognitive deficit is an inclusive term to describe any characteristic that acts as a barrier to the cognition process.
The term may describe
* deficits in overall intelligence
Intelligence has been defined in many ways: the capacity for ab ...
s, as well as
depression, may be underdiagnosed
sequalae). Lesions may also affect the
diencephalon
The diencephalon (or interbrain) is a division of the forebrain (embryonic ''prosencephalon''). It is situated between the telencephalon and the midbrain
The midbrain or mesencephalon is the forward-most portion of the brainstem and is asso ...
, mostly in
Aquaporin-4
Aquaporin-4, also known as AQP-4, is a water channel protein encoded by the ''AQP4'' gene in humans. AQP-4 belongs to the aquaporin family of integral membrane proteins that conduct water through the cell membrane. A limited number of aquaporins a ...
–
Immunoglobulin-G (AQP4-IgG) NMOSD.
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.
P ...
against
aquaporin-4
Aquaporin-4, also known as AQP-4, is a water channel protein encoded by the ''AQP4'' gene in humans. AQP-4 belongs to the aquaporin family of integral membrane proteins that conduct water through the cell membrane. A limited number of aquaporins a ...
(
anti-AQP4+) are the cause, and in 10–40% of the remaining cases, IgG antibodies against
MOG
Mog may refer to:
Entertainment Characters
* Mog (''Final Fantasy VI''), in the game
* Mog (Judith Kerr), a cat in Kerr's children's books
* Mog, a half-man/half-dog in the film ''Spaceballs''
* A cat in the Meg and Mog children's books by Helen ...
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 or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for the regulation of the immune system. The HLA system is also known as the human version of t ...
(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
A paraneoplastic syndrome is a syndrome (a set of signs and symptoms) that is the consequence of a tumor in the body (usually a cancerous one), specifically due to the production of chemical signaling molecules (such as hormones or cytokines) by t ...
.
It appears that
lupus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Commo ...
can produce NMO-IgG autoantibodies, leading to cases of
lupus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Commo ...
-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 t ...
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.
P ...
targeting
aquaporin 4
Aquaporin-4, also known as AQP-4, is a water channel protein encoded by the ''AQP4'' gene in humans. AQP-4 belongs to the aquaporin family of integral membrane proteins that conduct water through the cell membrane. A limited number of aquaporins a ...
(AQP4), a
channel protein in the
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (the ...
that allows water to pass through the membrane.
AQP4
monomers
In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization.
Classification
...
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" + , , "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 e ...
s, which are the basis for the
glymphatic system.
Thus, NMOSD involving AQP4-IgG can be considered an
astrocytopathy
Astrogliosis (also known as astrocytosis or referred to as reactive astrogliosis) is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, ...
or
autoimmune astrocytic channelopathy, since the astrocytes are semi-selectively destroyed.
The astrocytes surround the
blood–brain barrier (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
A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myoge ...
-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 rela ...
-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 dual role to detect circulating chemical messengers in the blood and ...
, where there is access to
cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.
CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
(CSP). In any case,
anti-AQP4 is produced mainly
intrathecal
Intrathecal administration is a route of administration for drugs via an injection into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid (CSF) and is useful in spinal anesthesia, chemotherapy, or pa ...
ly.
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 (, ''singular:'' meninx ( or ), ) 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 ...
).
NMOSD brain lesions, as seen
under a microscope, show IgG,
Immunoglobulin M
Immunoglobulin M (IgM) is one of several isotypes of antibody (also known as immunoglobulin) that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antige ...
(IgM), inflammatory cells, and complement deposits around blood vessels.
AQP4-IgG is a member of the
IgG1
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG a ...
immunoglobulin family, which is an activator of the
complement system
The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and ...
, 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 (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in th ...
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 (MRI) can show damage in
diffusion tensor imaging (DTI), although less so compared to
multiple sclerosis (MS).
Most research into the
pathology
Pathology is the study of the causes and effects of disease or injury. 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 ...
of NMO has focused on the
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spin ...
. The damage can range from inflammatory
demyelination
A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...
to
necrotic
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dig ...
damage of the
white
White is the lightness, lightest color and is achromatic (having no hue). It is the color of objects such as snow, chalk, and milk, and is the opposite of black. White objects fully diffuse reflection, reflect and scattering, scatter all the ...
and
grey
Grey (more common in British English) or gray (more common in American English) is an intermediate color between black and white. It is a neutral or achromatic color, meaning literally that it is "without color", because it can be compos ...
matters. The inflammatory
lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals.
Types
There is no designated classif ...
s in NMO have been
classified as type II lesions (
complement
A complement is something that completes something else.
Complement may refer specifically to:
The arts
* Complement (music), an interval that, when added to another, spans an octave
** Aggregate complementation, the separation of pitch-clas ...
-mediated
demyelination
A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...
), 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 disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals.
Types
There is no designated classif ...
s in their prominent
perivascular distribution. Therefore, the pattern of
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
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" + , , "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 e ...
s are spared in these cases.
Anti-MOG+ variants
The second most frequent autoantibody in NMO is MOG-IgG, which targets myelin oligodendrocyte glycoprotein
Myelin oligodendrocyte glycoprotein (MOG) is a glycoprotein believed to be important in the myelination of nerves in the central nervous system (CNS). In humans this protein is encoded by the ''MOG'' gene. It is speculated to serve as a necessary ...
(MOG). MOG is an integral membrane glycoprotein
Glycoproteins are proteins which contain oligosaccharide 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 as g ...
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") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain stabl ...
for those in the NMO-Ab(−)/MOG-Ab(−) group, and a worse prognosis
Prognosis (Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain stabl ...
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 predatory sea snails, or cone snails, marine gastropod mollusks in the family Conidae.Bouchet, P.; Gofas, S. (2015). Conus Linnaeus, 1758. In: MolluscaBase (2015). Accessed through: World Register of Marine Species ...
involvement. Myelin-oligodendrocyte glycoprotein antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique m ...
–positive patient
A patient is any recipient of health care services that are performed by healthcare professionals. The patient is most often ill or injured and in need of treatment by a physician, nurse, optometrist, dentist, veterinarian, or other health ...
s were more likely to have conus
''Conus'' is a genus of predatory sea snails, or cone snails, marine gastropod mollusks in the family Conidae.Bouchet, P.; Gofas, S. (2015). Conus Linnaeus, 1758. In: MolluscaBase (2015). Accessed through: World Register of Marine Species ...
involvement on spinal magnetic resonance imaging.
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.
P ...
may play a role in rare cases of NMO.[Kun Jia et al., Anti-neurofascin-155 antibody-positive neuromyelitis optica spectrum disorders, ''Journal of Neurological Sciences'', January 16, 2019, DOI: https://doi.org/10.1016/j.jns.2019.01.024]
NMOSD with MOG-IgG is considered a manifestation of anti-MOG associated encephalomyelitis
MOG antibody disease (MOGAD) or MOG antibody-associated encephalomyelitis (MOG-EM) is an inflammatory demyelinating disease of the central nervous system. Serum anti-myelin oligodendrocyte glycoprotein antibodies are present in up to half of patie ...
.
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
Myelitis is inflammation of the spinal cord which can disrupt the normal responses from the brain to the rest of the body, and from the rest of the body to the brain. Inflammation in the spinal cord, can cause the myelin and axon to be damaged r ...
, and bilateral simultaneous or recurrent optic neuritis
Optic neuritis describes any condition that causes inflammation of the optic nerve; it may be associated with demyelinating diseases, or infectious or inflammatory processes.
It is also known as optic papillitis (when the head of the optic nerv ...
* Asian optic-spinal multiple sclerosis (OSMS), or AQP4+ OSMS. This variant can present brain
The brain is an 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 special ...
lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals.
Types
There is no designated classif ...
s like MS does, but it should not be confused with an AQP4-negative form of spectrum, sometimes called ''optic-spinal MS''
* Longitudinally extensive myelitis
Myelitis is inflammation of the spinal cord which can disrupt the normal responses from the brain to the rest of the body, and from the rest of the body to the brain. Inflammation in the spinal cord, can cause the myelin and axon to be damaged r ...
or optic neuritis
Optic neuritis describes any condition that causes inflammation of the optic nerve; it may be associated with demyelinating diseases, or infectious or inflammatory processes.
It is also known as optic papillitis (when the head of the optic nerv ...
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 describes any condition that causes inflammation of the optic nerve; it may be associated with demyelinating diseases, or infectious or inflammatory processes.
It is also known as optic papillitis (when the head of the optic nerv ...
or myelitis
Myelitis is inflammation of the spinal cord which can disrupt the normal responses from the brain to the rest of the body, and from the rest of the body to the brain. Inflammation in the spinal cord, can cause the myelin and axon to be damaged r ...
associated with lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals.
Types
There is no designated classif ...
s in specific brain
The brain is an 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 special ...
areas such as the hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...
, 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 ...
* NMO -IgG negative NMO: AQP4 antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique m ...
- seronegative NMO poses a diagnostic challenge. Some cases could be related to anti-myelin oligodendrocyte glycoprotein
Myelin oligodendrocyte glycoprotein (MOG) is a glycoprotein believed to be important in the myelination of nerves in the central nervous system (CNS). In humans this protein is encoded by the ''MOG'' gene. It is speculated to serve as a necessary ...
(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.
P ...
.
Differential diagnosis
AQP4-Ab-negative NMO presents problems for differential diagnosis. The behavior of the oligoclonal bands
Oligoclonal bands (OCBs) are bands of immunoglobulins that are seen when a patient's blood serum, or cerebrospinal fluid (CSF) is analyzed. They are used in the diagnosis of various neurological and blood diseases, especially in multiple sclerosis. ...
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 disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals.
Types
There is no designated classif ...
s in MS.
Another problem for diagnosis is that AQP4-ab in MOG
Mog may refer to:
Entertainment Characters
* Mog (''Final Fantasy VI''), in the game
* Mog (Judith Kerr), a cat in Kerr's children's books
* Mog, a half-man/half-dog in the film ''Spaceballs''
* A cat in the Meg and Mog children's books by Helen ...
-ab levels can be too low to be detected. Some additional biomarkers
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
have been proposed.
NMO differs from MS in that it usually has more severe sequelae
A sequela (, ; usually used in the plural, sequelae ) is a pathological condition resulting from a disease, injury, therapy, or other trauma. Derived from the Latin word, meaning “sequel”, it is used in the medical field to mean a complicati ...
after an acute episode than standard MS, which infrequently presents as transverse myelitis, and oligoclonal bands in the CSF
CSF may refer to:
Biology and medicine
* Cerebrospinal fluid, clear colorless bodily fluid found in the brain and spine
* Colony-stimulating factor, secreted glycoproteins
* Cancer slope factor, estimate the risk of cancer
* Classical swine fever ...
, as well as white matter
White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distributi ...
lesions on brain MRIs being uncommon in NMO, but occurring 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
Channelopathies are a group of diseases caused by the dysfunction of ion channel subunits or their interacting proteins. These diseases can be inherited or acquired by other disorders, drugs, or toxins. Mutations in genes encoding ion channels, wh ...
(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 channel
Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of c ...
s), 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.
Also, an overlap with Sjögren syndrome
Sjögren syndrome or Sjögren's syndrome (SjS, SS) is a long-term autoimmune disease that affects the body's moisture-producing (lacrimal and salivary) glands, and often seriously affects other organ systems, such as the lungs, kidneys, and nerv ...
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 information from the retina to the brain. In humans, the optic nerve is derived fro ...
and spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spin ...
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
).
The term neuromyelitis optica spectrum disorders (NMOSD) has been designed to allow incorporation of cases associated with non-AQP4 biomarkers
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
.[ 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
MOG antibody disease (MOGAD) or MOG antibody-associated encephalomyelitis (MOG-EM) is an inflammatory demyelinating disease of the central nervous system. Serum anti-myelin oligodendrocyte glycoprotein antibodies are present in up to half of patie ...
. Some cases with MOG
Mog may refer to:
Entertainment Characters
* Mog (''Final Fantasy VI''), in the game
* Mog (Judith Kerr), a cat in Kerr's children's books
* Mog, a half-man/half-dog in the film ''Spaceballs''
* A cat in the Meg and Mog children's books by Helen ...
+ and AQP4+ antibodies 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
Astrogliosis (also known as astrocytosis or referred to as reactive astrogliosis) is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, ...
", 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 ends a medical condition, such as a medication, a surgical operation, a change in lifestyle or even a philosophical mindset that helps end a person's sufferings; or the state of being healed, or cured. The m ...
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 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 in ...
s, such as methylprednisolone
Methylprednisolone (Depo-Medrol, Medrol, Solu-Medrol) is a synthetic glucocorticoid, primarily prescribed for its anti-inflammatory and immunosuppressive effects. It is either used at low doses for chronic illnesses or used concomitantly at high ...
IV ( Solu-Medrol). Early initiation of treatment with steroids have 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
Plasmapheresis (from the Greek πλάσμα, ''plasma'', something molded, and ἀφαίρεσις ''aphairesis'', taking away) is the removal, treatment, and return or exchange of blood plasma or components thereof from and to the blood circulati ...
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 in ...
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 in th ...
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
Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
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
Fingolimod, sold under the brand name Gilenya, is an immunomodulating medication, mostly used for treating multiple sclerosis (MS). Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preve ...
, natalizumab, and alemtuzumab
Alemtuzumab, sold under the brand names Campath and Lemtrada among others, is a medication used to treat chronic lymphocytic leukemia (CLL) and multiple sclerosis. In CLL, it has been used as both a first line and second line treatment. In MS i ...
—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, developmental, intellectual, mental, physical, s ...
may persist.
The disease can be monophasic, i.e. a single episode with permanent remission
Remission often refers to:
*Forgiveness
Remission may also refer to:
Healthcare and science
*Remission (medicine), the state of absence of disease activity in patients with a chronic illness, with the possibility of return of disease activity
*R ...
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 describes any condition that causes inflammation of the optic nerve; it may be associated with demyelinating diseases, or infectious or inflammatory processes.
It is also known as optic papillitis (when the head of the optic nerv ...
. 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 healthcare professionals. The patient is most often ill or injured and in need of treatment by a physician, nurse, optometrist, dentist, veterinarian, or other health ...
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
Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment� ...
, and 30% have permanent paralysis
Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 5 ...
in one or both legs. Among patients with relapsing NMO, 50% have blindness
Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment� ...
or paralysis
Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 5 ...
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 rise ...
and subsequent death
Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...
. 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 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 the south pole to 90° at the north po ...
. 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 (NMOSD) was 1.5% among a random sample of neurological ]patient
A patient is any recipient of health care services that are performed by healthcare professionals. The patient is most often ill or injured and in need of treatment by a physician, nurse, optometrist, dentist, veterinarian, or other health ...
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, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spin ...
lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals.
Types
There is no designated classif ...
s, 38% had severe optic neuritis
Optic neuritis describes any condition that causes inflammation of the optic nerve; it may be associated with demyelinating diseases, or infectious or inflammatory processes.
It is also known as optic papillitis (when the head of the optic nerv ...
, and 23% had brain
The brain is an 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 special ...
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 ...
lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals.
Types
There is no designated classif ...
s. Only 56% had clinically definite NMO at follow-up.
NMO is more common in Asians
Asian people (or Asians, sometimes referred to as Asiatic people)United States National Library of Medicine. Medical Subject Headings. 2004. November 17, 200Nlm.nih.gov: ''Asian Continental Ancestry Group'' is also used for categorical purpos ...
than Caucasian
Caucasian may refer to:
Anthropology
*Anything from the Caucasus region
**
**
** ''Caucasian Exarchate'' (1917–1920), an ecclesiastical exarchate of the Russian Orthodox Church in the Caucasus region
*
*
*
Languages
* Northwest Caucasian l ...
s. 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
The tropics are the regions of Earth surrounding the Equator. They are defined in latitude by the Tropic of Cancer in the Northern Hemisphere at N and the Tropic of Capricorn in
the Southern Hemisphere at S. The tropics are also referred to ...
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.[
]
History
First reports on an association of spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spin ...
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 information from the retina to the brain. In humans, the optic nerve is derived fro ...
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
Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
and ophthalmologists
Ophthalmology ( ) is a surgical subspecialty within medicine that deals with the diagnosis and treatment of eye disorders.
An ophthalmologist is a physician who undergoes subspecialty training in medical and surgical eye care. Following a medic ...
in this rare syndrome. In 1894, Eugène Devic and his PhD 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
Weakness is a symptom of a number of different conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, i ...
of the limbs, loss of sensation, and often of bladder
The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters ...
control. They recognized these symptoms were the result of inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
of the optic nerve and spinal cord, respectively.
In 2002, Mayo Clinic researchers identified a humoral
Humoral immunity is the aspect of immunity that is mediated by macromolecules - including secreted antibodies, complement proteins, and certain antimicrobial peptides - located in extracellular fluids. Humoral immunity is named so because it invo ...
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
Aquaporin-4, also known as AQP-4, is a water channel protein encoded by the ''AQP4'' gene in humans. AQP-4 belongs to the aquaporin family of integral membrane proteins that conduct water through the cell membrane. A limited number of aquaporins a ...
protein as the target of the disease, and developed the first in-house test to aid in the diagnosis
Diagnosis is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in many different disciplines, with variations in the use of logic, analytics, and experience, to determine " cause and effect". In systems engin ...
of NMO by detection of an antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique m ...
, 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 in th ...
.[ 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 uses a solid-phase type of enzyme immunoassay (EIA) to detect the presence ...
(enzyme-linked immunosorbent assay) kits were soon developed, However, serum AQP4-IgG titer
Titer (American English) or titre (British English) is a way of expressing concentration. Titer testing employs serial dilution to obtain approximate quantitative information from an analytical procedure that inherently only evaluates as posit ...
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.
P ...
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. The most established method for antibody removal is plasmapheresis
Plasmapheresis (from the Greek πλάσμα, ''plasma'', something molded, and ἀφαίρεσις ''aphairesis'', taking away) is the removal, treatment, and return or exchange of blood plasma or components thereof from and to the blood circulati ...
. A number of drugs are being studied: aquaporumab (non-pathogenic antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique m ...
blocker of AQP4-IgG binding), sivelestat
Sivelestat (INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they al ...
(neutrophil elastase
Neutrophil elastase (, ''leukocyte elastase'', ''ELANE'', ''ELA2'', ''elastase 2'', ''neutrophil'', ''elaszym'', ''serine elastase'', subtype ''human leukocyte elastase (HLE)'') is a serine proteinase in the same family as chymotrypsin and has bro ...
inhibitor), and eculizumab (complement
A complement is something that completes something else.
Complement may refer specifically to:
The arts
* Complement (music), an interval that, when added to another, spans an octave
** Aggregate complementation, the separation of pitch-clas ...
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
A paraneoplastic syndrome is a syndrome (a set of signs and symptoms) that is the consequence of a tumor in the body (usually a cancerous one), specifically due to the production of chemical signaling molecules (such as hormones or cytokines) by t ...
.
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 astroc ...
(GFAP)—was found in 2016, in transverse myelitis ( LETM) and atypical NMO, leading to the concept of autoimmune GFAP astrocytopathy.[Glial Fibrillary Acid Protein Immunoglobulin G (GFAP-IgG) Related Myelitis: Characterization and Comparison with Aquaporin-4-IgG Myelitis, Elia Sechi, P. Pearse Morris, Andrew McKeon, Sean Pittock, Shannon Hinson, Brian Weinshenker, Allen J. Aksamit, Evan A. Jolliffe, Anastasia Zekeridou, Dean Wingerchuk, Eoin P. Flanagan, Neurology Apr 2018, 90 (15 Supplement) S13.006]
Other autoantibody being researched is flotillin
Flotillin-1 is a protein that in humans is encoded by the ''FLOT1'' gene.
Caveolae are small domains on the inner cell membrane involved in vesicular trafficking and signal transduction. FLOT1 encodes a caveolae-associated, integral membrane pr ...
. 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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
s.
The group AQP4+/MOG
Mog may refer to:
Entertainment Characters
* Mog (''Final Fantasy VI''), in the game
* Mog (Judith Kerr), a cat in Kerr's children's books
* Mog, a half-man/half-dog in the film ''Spaceballs''
* A cat in the Meg and Mog children's books by Helen ...
+ 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
Mog may refer to:
Entertainment Characters
* Mog (''Final Fantasy VI''), in the game
* Mog (Judith Kerr), a cat in Kerr's children's books
* Mog, a half-man/half-dog in the film ''Spaceballs''
* A cat in the Meg and Mog children's books by Helen ...
associated encephalomyelitis
Encephalomyelitis is inflammation of the brain and spinal cord. Various types of encephalomyelitis include:
* '' Acute disseminated encephalomyelitis'' or ''postinfectious encephalomyelitis'', a demyelinating disease of the brain and spinal cord, ...
– around 10% of total cases
* Connexin-43
Gap junction alpha-1 protein (GJA1), also known as connexin 43 (Cx43), is a protein that in humans is encoded by the ''GJA1'' gene on chromosome 6. As a connexin, GJA1 is a component of gap junctions, which allow for gap junction intercellular ...
NMO
* Aquaporin-1
Aquaporin 1 (AQP-1) is a protein that in humans is encoded by the ''AQP1'' gene.
AQP-1 is a widely expressed water channel, whose physiological function has been most thoroughly characterized in the kidney. It is found in the basolateral and a ...
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. From Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approximately "a disease of its own kind ...
NMO, defined by the absence of all previous antibodies
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.
P ...
. They constitute an overlap between NMO and MS.
As of 2019 some statistical studies showed that antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique m ...
-negative NMO can be classified into three groups, and that this classification has a pathogen
In biology, a pathogen ( el, πάθος, "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 ger ...
ic meaning.
Later studies have increased the number of groups up to four.
Notable patients
* Christine Hà
Christine Huyen Tran Ha ( vi, Hà Huyền Trân; born May 9, 1979) is an American chef, writer and TV host. She is the first blind contestant of '' MasterChef'' and the winner of its third season in 2012.
Early and personal life
Hà was born a ...
(chef
A chef is a trained professional cook and tradesman who is proficient in all aspects of food preparation, often focusing on a particular cuisine. The word "chef" is derived from the term ''chef de cuisine'' (), the director or head of a k ...
and author
An author is the writer of a book, article, play, mostly written work. A broader definition of the word "author" states:
"''An author is "the person who originated or gave existence to anything" and whose authorship determines responsibility f ...
)
* Cassie Mitchell (paralympian
The Paralympic Games or Paralympics, also known as the ''Games of the Paralympiad'', is a periodic series of international multisport events involving athletes with a range of physical disabilities, including impaired muscle power and impaired ...
and biomedical engineering
Biomedical engineering (BME) or medical engineering is the application of engineering principles and design concepts to medicine and biology for healthcare purposes (e.g., diagnostic or therapeutic). BME is also traditionally logical sciences ...
professor
Professor (commonly abbreviated as Prof.) is an academic rank at universities and other post-secondary education and research institutions in most countries. Literally, ''professor'' derives from Latin as a "person who professes". Professor ...
)
See also
* Anti-AQP4 disease
* Demyelinating disease
A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...
* Idiopathic inflammatory demyelinating diseases
* Multiple sclerosis
* 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, a severe form of arthritis in children, and COVID19. It is a huma ...
References
{{DEFAULTSORT:Neuromyelitis Optica
Autoimmune diseases
Demyelinating diseases of CNS
Myelin disorders
Rare diseases