Chronic Relapsing Inflammatory Optic Neuropathy
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Chronic relapsing inflammatory optic neuropathy (CRION) is a form of 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 ...
that is
steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...
responsive and dependent. Patients typically present with pain associated with
visual loss 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 ...
. CRION is a clinical
diagnosis of exclusion A diagnosis of exclusion or by exclusion (''per exclusionem'') is a diagnosis of a medical condition reached by a process of elimination, which may be necessary if presence cannot be established with complete confidence from history, examination o ...
, and other demyelinating, autoimmune, and systemic causes should be ruled out. An accurate antibody test which became available commercially in 2017 has allowed most patients previously diagnosed with CRION to be re-identified as having
MOG antibody disease MOG (myelin oligodendrocyte glycoprotein) antibody disease (MOGAD) or MOG antibody-associated encephalomyelitis (MOG-EM) is an Inflammatory demyelinating diseases of the central nervous system, inflammatory demyelinating disease of the central nerv ...
, which is not a diagnosis of exclusion. Early recognition is crucial given risks for severe visual loss and because it is treatable with immunosuppressive treatment such as steroids or B-cell depleting therapy. Relapse that occurs after reducing or stopping steroids is a characteristic feature.


Signs and symptoms

Pain, visual loss, relapse, and steroid response are typical of CRION. Ocular pain is typical, although there are some cases with no reported pain. Bilateral severe visual loss (simultaneous or sequential) usually occurs, but there are reports of unilateral visual loss. Patients can have an associated
relative afferent pupillary defect A relative afferent pupillary defect (RAPD), also known as a Marcus Gunn pupil (after Robert Marcus Gunn), is a medical sign observed during the swinging-flashlight test whereupon the patient's pupils excessively dilate when a bright light is ...
. CRION is associated with at least one relapse, and up to 18 relapses have been reported in an individual. Intervals between episodes can range from days to over a decade. Symptoms will improve with
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, and recurrence characteristically occurs after reducing or stopping steroids.


Pathogenesis

In 2013, 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 ...
was unknown. Given that CRION is responsive to immunosuppressive treatment, it was presumed to be immune-mediated, but this was uncertain as at the time there were no known associated autoimmune antibodies. In 2015, some research pointed to CRION belonging to the MOG antibody-associated encephalomyelitis spectrum. As of 2019, the correlation between CRION and MOG antibody-associated encephalomyelitis is so high that now CRION is considered the most common
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 ...
related to
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 ...
antibodies (MOG-IgG). As of 2021, some reports point out a second kind of CRION due to
anti-phospholipid antibodies Antiphospholipid syndrome, or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS can lead to blood clots (thrombosis) in both arteries and veins, pregnancy-relate ...
.


Diagnosis

In 2018, of 12 patients in a study who fulfilled the then-current diagnostic criteria for CRION, eleven (92%) were positive for MOG-IgG, and the last patient was borderline. Diagnosis requires exclusion of other neurological, ophthalmological, and systemic conditions. Any cause of
optic neuropathy Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. Damage and death of these nerve cells, or neurons, leads to characteristic featu ...
should be ruled out, including demyelinating (
MOG antibody disease MOG (myelin oligodendrocyte glycoprotein) antibody disease (MOGAD) or MOG antibody-associated encephalomyelitis (MOG-EM) is an Inflammatory demyelinating diseases of the central nervous system, inflammatory demyelinating disease of the central nerv ...
,
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 ...
, and
neuromyelitis optica Neuromyelitis optica spectrum disorders (NMOSD) are a spectrum of autoimmune diseases characterized by acute inflammation of the optic nerve (optic neuritis, ON) and the spinal cord ( myelitis).Banerjee S, Butcher R. Rituximab for the Treatment o ...
) and systemic disease (diabetic, toxic, nutritional, and infectious causes). Corticosteroid responsive optic neuritis not associated with
demyelinating disease A demyelinating disease refers to any disease affecting the nervous system where the myelin sheath surrounding neurons is damaged. This damage disrupts the transmission of signals through the affected nerves, resulting in a decrease in their con ...
should also be ruled out, including
sarcoidosis Sarcoidosis (; also known as Besnier–Boeck–Schaumann disease) is a disease involving abnormal collections of White blood cell, inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph n ...
,
systemic lupus erythematosus Lupus, formally called 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. Common ...
, or other systemic autoimmune disease. Hereditary causes such as
Leber's hereditary optic neuropathy Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; it predomin ...
are also part of the differential diagnosis. In 2014, there were no diagnostic biomarkers or imaging features typical of CRION.
Antinuclear antibodies Antinuclear antibodies (ANAs, also known as antinuclear factor or ANF) are autoantibodies that bind to contents of the cell nucleus. In normal individuals, the immune system produces antibodies to foreign proteins (antigens) but not to human pro ...
(ANA), B12,
folate Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
,
thyroid function tests Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid. TFTs may be requested if a patient is thought to suffer from hyperthyroidism (overactive thyroid) or hypothyroidism (underactive thyroid) ...
, anti-
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 ...
antibodies (NMO-IgG), and
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) can facilitate ruling out of other diseases. Most patients are seronegative for NMO-IgG and GFAP, biomarkers for neuromyelitis optica. ANA, indicative of autoimmune optic neuropathy, is also generally negative. CSF can also be evaluated for
oligoclonal band 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. Oligoclonal bands are present in ...
s typical of multiple sclerosis, which will not be present in CRION. A
chest X-ray A chest radiograph, chest X-ray (CXR), or chest film is a Projectional radiography, projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures. Chest radiographs are the most common fi ...
or
CT scan A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...
should be ordered if granulomatous optic neuropathy caused by sarcoidosis is suspected.
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 ...
can capture
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 ...
inflammation, but this finding is not present in all patients,
Diffusion tensor imaging Diffusion-weighted magnetic resonance imaging (DWI or DW-MRI) is the use of specific MRI sequences as well as software that generates images from the resulting data that uses the diffusion of water molecules to generate contrast in MR images. It ...
has been shown to detect widespread
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 ...
abnormalities in CRION patients with normal MRI findings. Five diagnostic criteria had been proposed in 2014: * History of optic neuritis with one relapse * Objectively measured visual loss * NMO-IgG seronegative * Contrast enhancement on imaging of acutely inflamed optic nerves * Response to immunosuppressive treatment and relapse on withdrawal or dose reduction. CRION has been included as a subtype in a 2022 international consensus classification of optic neuritis.


Treatment

Treatment consists of three phases of
immunotherapy Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
: *1. Acute phase: IV steroids (
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 at high doses durin ...
1 mg/kg) for 3–5 days or
plasmapheresis Plasmapheresis (from the Greek language, 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 ...
are given to restore visual function. *2. Intermediate phase: Oral steroids (typically
prednisone Prednisone is a glucocorticoid medication mostly used to immunosuppressive drug, 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 ...
1 mg/kg) with taper are given to stabilize vision. *3. Long-term phase: To avoid adverse effects of long-term steroids and to avoid relapse of disease, physicians can transition to a steroid-sparing agent. B-cell depleting therapy,
azathioprine Azathioprine, sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus er ...
,
methotrexate Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immunosuppressive drug, immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancy, ectopic pregnancies. Types of cancers it is u ...
,
cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
,
mycophenolate Mycophenolic acid 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 liver t ...
,
IVIG Immunoglobulin therapy is the use of a mixture of antibodies (normal human immunoglobulin) to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory demyelin ...
,
plasma exchange 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 ...
,
cyclosporine Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, ecz ...
, and
infliximab Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing ...
have been used. Visual acuity is dramatically worse with CRION than other forms of optic neuritis. Treatment with corticosteroids induces prompt relief of pain and improved vision. At times, patients obtain complete restoration of vision, although exact success rates are unknown.


Prognosis

Recurrence is essentially inevitable in patients without treatment, and patients ultimately will require lifelong immunosuppression to prevent relapse.


Epidemiology

CRION was first described in 2003. The disease is rare, with only 122 cases published from 2003 to 2013. There is female predominance with 59 females (48%), 25 males (20%), and no gender designation for the rest of the 122 reported cases (32%). Age ranges from 14 to 69 years of age, and the mean age is 35.6. The disease is noted to occur worldwide and across many ethnicities, with reported cases in all continents except Africa and Australia.


See also

*
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 ...
*
Optic neuropathy Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. Damage and death of these nerve cells, or neurons, leads to characteristic featu ...


References


External links

{{Eye pathology Eye diseases Steroid-responsive inflammatory conditions