Chronic relapsing inflammatory optic neuropathy

Pain, visual loss, relapse, and steroid response are typical of CRION.[1][3] Ocular pain is typical, although there are some cases with no reported pain.[3] Bilateral severe visual loss (simultaneous or sequential) usually occurs, but there are reports of unilateral visual loss.[3] Patients can have an associated relative afferent pupillary defect.[5] CRION is associated with at least one relapse, and up to 18 relapses have been reported in an individual.[6] Intervals between episodes can range from days to over a decade.[1] Symptoms will improve with corticosteroids, and recurrence characteristically occurs after reducing or stopping steroids.[3]

In 2013, the etiology was unknown.[1] Given that CRION is responsive to immunosuppressive treatment, it was presumed to be immune-mediated,[3] but this was uncertain as at the time there were no known associated autoimmune antibodies.[3][7]

In 2015, some research pointed to CRION belonging to the MOG antibody-associated encephalomyelitis spectrum.[8]

As of 2019, the correlation between CRION and MOG antibody-associated encephalomyelitis is so high that now CRION is considered the most common phenotype related to myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).[9]

As of 2021, some reports point out a second kind of CRION due to anti-phospholipid antibodies.[10]

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.[4] Diagnosis requires exclusion of other neurological, ophthalmological, and systemic conditions.[3] Any cause of optic neuropathy should be ruled out, including demyelinating (MOG antibody disease, multiple sclerosis, and neuromyelitis optica) and systemic disease (diabetic, toxic, nutritional, and infectious causes).[3] Corticosteroid responsive optic neuritis not associated with demyelinating disease should also be ruled out, including sarcoidosis, systemic lupus erythematosus, or other systemic autoimmune disease.[11] Hereditary causes such as Leber's hereditary optic neuropathy are also part of the differential diagnosis.[12]

In 2014, there were no diagnostic biomarkers or imaging features typical of CRION.[3] Antinuclear antibodies (ANA), B₁₂, folate, thyroid function tests, anti-aquaporin-4 antibodies (NMO-IgG), and glial fibrillary acidic protein (GFAP) can facilitate ruling out of other diseases.[3] Most patients are seronegative for NMO-IgG and GFAP, biomarkers for neuromyelitis optica.[3] ANA, indicative of autoimmune optic neuropathy, is also generally negative.[3] CSF can also be evaluated for oligoclonal bands typical of multiple sclerosis, which will not be present in CRION.[1] A chest X-ray or CT scan should be ordered if granulomatous optic neuropathy caused by sarcoidosis is suspected.[3]

Magnetic resonance imaging can capture optic nerve inflammation, but this finding is not present in all patients,[1][3][13] Diffusion tensor imaging has been shown to detect widespread white matter abnormalities in CRION patients with normal MRI findings.[14]

Five diagnostic criteria had been proposed in 2014:[3]

• 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.[2]

Treatment consists of three phases of immunotherapy:

• 1. Acute phase: IV steroids (methylprednisolone 1 mg/kg) for 3–5 days or plasmapheresis are given to restore visual function.[3]
• 2. Intermediate phase: Oral steroids (typically prednisone 1 mg/kg) with taper are given to stabilize vision.[3]
• 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,[4] azathioprine, methotrexate, cyclophosphamide, mycophenolate, IVIG, plasma exchange, cyclosporine, and infliximab have been used.[3]

Visual acuity is dramatically worse with CRION than other forms of optic neuritis.[3] Treatment with corticosteroids induces prompt relief of pain and improved vision.[1] At times, patients obtain complete restoration of vision, although exact success rates are unknown.[1]

Recurrence is essentially inevitable in patients without treatment, and patients ultimately will require lifelong immunosuppression to prevent relapse.[3][15]

CRION was first described in 2003.[1] The disease is rare, with only 122 cases published from 2003 to 2013.[3] There is female predominance with 59 females (48%), 25 males (20%), and no gender designation for the rest of the 122 reported cases (32%).[3] Age ranges from 14 to 69 years of age, and the mean age is 35.6.[3] The disease is noted to occur worldwide and across many ethnicities, with reported cases in all continents except Africa and Australia.[3]

• Optic neuritis
• Optic neuropathy