Anti-AQP4 diseases, are a group of diseases characterized by auto-antibodies 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 ...

. After the discovery of anti-AQP4 autoantibody in

neuromyelitis optica Neuromyelitis optica spectrum disorders (NMOSD), including neuromyelitis optica (NMO), are autoimmune diseases characterized by acute inflammation of the optic nerve (optic neuritis, ON) and the spinal cord (myelitis). Episodes of ON and myelitis ...

, it was found that it was also present in some patients with other clinically defined diseases, including

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

variants like optic-spinal MS. The collection of these condition has been named "anti-AQP4 disease" and "neuromyelitis optica spectrum disorders" (NMSD) and they are expected to respond to the same treatments as standard NMO. Some authors propose to use the name "autoimmune aquaporin-4

channelopathy 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, ...

" for these diseases, while others prefer a more generic term "AQP4-astrocytopathy" that includes also problems in AQP4 with a non-autoimmune origin.

Clinical Spectrum

After finding the anti-AQP4 autoantibody in cases outside the standard Devic's disease course, the spectrum was expanded. The spectrum is now believed to consist of: * Standard Devic's disease, according to the diagnostic criteria described above * Limited forms of Devic's disease, 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 re ...

, 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 ...

* optic-spinal MS (OSMS), previously considered a subtype of MS. This variant can present brain lesions like MS, 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

* Optic neuritis 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 and with higher AQP4 autoantibody levels * Optic neuritis or myelitis 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 classifi ...

s in specific brain 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 hypothalamu ...

periventricular nucleus The periventricular nucleus is a thin sheet of small neurons located in the wall of the third ventricle, a composite structure of the hypothalamus. It functions in analgesia. It is located in the rostral, intermediate, and caudal regions of t ...

, 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 cont ...

* Tumefactive demyelination: Tumefactive 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 responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...

. Devic's disease is currently considered a syndrome more than a disease, presenting an overlapping with the wide spectrum of multiple sclerosis in the form of Optic-Spinal MS.

Causes

The reason for the presence of anti-AQP4 autoantibodies is currently unknown. Some researchers have pointed out that it 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 ...

. It seems also clear 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. Comm ...

can produce NMO-IgG autoantibodies sometimes, leading to some cases of lupus-derived NMO.

Diagnosis

Differential diagnosis

AQP4-Ab-negative NMO presents problems for 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. ...

respect MS can help to establish a more accurate diagnosis. Oligoclonal bands in NMO are rare and they tend to disappear after the 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 lesions in MS. Other problem for diagnosis is that AQP4ab in MOGab levels can be too low to be detected. Some additional biomarkers have been proposed.

Treatment

Currently, there is no cure for Devic's disease, but symptoms can be treated. Some patients recover, but many are left with impairment of vision and limbs, which can be severe.

Attacks

Attacks are treated with short courses 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 nutrie ...

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 involv ...

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 hig ...

IV.

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 or do not respond to corticosteroid treatment. Clinical trials for these treatments contain very small numbers, and most are uncontrolled, though some report high success percentage.

Secondary prevention

Until recently, no placebo-controlled trials had established the effectiveness of treatments for the prevention of attacks. Most clinicians agree that long term

immunosuppression Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...

is required to reduce the frequency and severity of attacks. Commonly used immunosuppressant treatments include

azathioprine Azathioprine (AZA), sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used in rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus, ...

(Imuran) plus

prednisone Prednisone is a glucocorticoid medication mostly used to suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium due to cancer and ad ...

mycophenolate mofetil Mycophenolic acid (MPA) is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohn's disease and lupus. Specifically it is used following kidney, heart, and liv ...

plus prednisone, mitoxantrone, intravenous immunoglobulin (IVIG),

Rituximab Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in non-geriatric pa ...

, Soliris and cyclophosphamide. The disease is known to be auto-antibodies mediated, and (antibody-producing) B-cell depletion has been tried with monoclonal antibodies showing good results. Several other disease modifying therapies are being tried. In 2007, Devic's disease was reported to be responsive to

glatiramer acetate Glatiramer acetate (also known as Copolymer 1, Cop-1), sold under the brand name Copaxone among others, is an immunomodulator medication used to treat multiple sclerosis. Glatiramer acetate is approved in the United States to reduce the frequenc ...

and to low-dose corticosteroids. Use of

Mycophenolate mofetil Mycophenolic acid (MPA) is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohn's disease and lupus. Specifically it is used following kidney, heart, and liv ...

is also currently under research.

Hematopoietic stem cell transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...

(HSCT) is sometimes used in severe cases of NMO. Early data suggested that then-practiced forms of HSCT were very effective only in the short term. However, later study data had most patients thriving, with no relapses within 5 years.

References

{{Reflist Autoimmune diseases