Chronic relapsing inflammatory optic neuropathy

Chronic relapsing inflammatory optic neuropathy (CRION) is a form of recurrent optic neuritis that is steroid responsive and dependent.^[1] Patients typically present with pain associated with visual loss.^[1] CRION is a clinical diagnosis of exclusion, and other demyelinating, autoimmune, and systemic causes should be ruled out.^[3] 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,^[4] 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^[3] or B-cell depleting therapy.^[4] Relapse that occurs after reducing or stopping steroids is a characteristic feature.^[3]

Chronic relapsing inflammatory optic neuropathy[1]
Other names	Chronic relapsing inflammatory optic neuritis
Specialty	Ophthalmology, Neurology, Neuro-ophthalmology
Diagnostic method	Consensus Diagnostic Criteria[2]
Differential diagnosis	Optic neuritis subgroups[2]
Treatment	Corticosteroids[2]

Signs and symptoms

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]

Pathogenesis

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]

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.^[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

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]

Prognosis

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

Epidemiology

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]

See also

• Optic neuritis
• Optic neuropathy