Chronic Relapsing Inflammatory Optic Neuritis (CRION)

From EyeWiki


Disease Entity

Disease

Chronic relapsing inflammatory optic neuropathy (CRION) is a rare form of autoimmune optic neuropathy[1][2] Kidd et al. described CRION in 2003[2]. CRION is characterized by vision loss +/- pain, the occurrence of symptoms for more than one episode, symptom resolution with immunosuppressive therapy, and relapse with treatment withdrawal[1][2].

Etiology

The etiology of CRION is likely immune-mediated since the disease responds well to immunosuppressive therapy. However, the exact cause is unknown[1][2].

Risk Factors

A higher incidence of CRION has been reported in females than in males (1.7x-2.3x higher)[1][3]. Patients with African or African-Caribbean descent may also have a higher risk of developing CRION[4].

Pathophysiology

Inflammation of the optic nerve causes pain and loss of visual function[2]. Several studies have found a close association between myelin oligodendrocyte glycoprotein Immunoglobulin (MOG-IgG) antibodies and CRION, suggesting that these antibodies may be the cause of inflammation[5][6][7]. Demyelination of the nerve and axon damage can cause long term loss of visual function[2].

Diagnosis

Other causes of optic neuritis should be ruled out before the diagnosis of CRION.

Signs and symptoms

Most patients experience rapid onset of pain followed by subacute onset of vision loss[8]. Pain elicited with eye movements is most common, but pain can also manifest as headache or periorbital pain[1][9]. The vision loss typically peaks around 1-2 weeks, after which patients often improve after steroid therapy[8]. Loss of visual acuity may occur in either one or both eyes, and cases of bilateral vision loss might occur either simultaneously or consecutively[1][2][10][11][12][13]. The vision loss is variable but can be mild, moderate or severe and can even progress to no light perception[2].

CRION is defined by relapses and may recur up to 30 times[14]. Intervals between episodes can be between days to years[1][2][15]. Pain and vision loss resolve with immunosuppressive therapy but return upon withdrawal[1][15].Visual loss symptoms can also manifest without pain[2]. Other potential visual abnormalities include changes in color vision and findings of relative afferent pupillary defect (RAPD)[2][15]. Uveitis has been associated with CRION in a limited number of instances[12].

Diagnostic criteria

There are 5 diagnostic criteria recommended for identifying CRION[1] :

1) History of optic neuritis symptoms with more than one episode of recurrence[1]

2) Clinical evidence of visual function loss[1]

3) NMO-IgG negative labs[1] (and probably MOG should be excluded as well)

4) Brain and orbital MR contrast imaging shows enhancement of inflamed optic nerves[1]

5) Symptoms respond to immunosuppressive treatment and relapse when treatment is withdrawn[1]

Some studies do not recommend the criteria of steroid dependence in diagnosing CRION[15][16], since there may be difficulty in accurately identifying steroid dependence[16]. Instead, they recommend that the criteria of symptoms of optic neuritis combined with progressive vision loss are better suited for identifying patients with CRION[16].

Diagnostic procedures

Ophthalmic and neurological examination should be performed to assess visual acuity and function[17][18]. Relative afferent pupillary defect (RAPD) is seen in patients who present with unilateral symptoms[17]. Mild papilledema may be present upon optic disc examination[8].

Automated perimetry and ophthalmic electrophysiology testing can assist in evaluation of visual function[1]. Visual field constriction, scotomas, and altitudinal visual field defects are other potential visual abnormalities in patients with CRION[2].

Imaging

There are no defining radiographic features of CRION[1]. One study demonstrated that diffusion tensor imaging (DWI) on MRI may identify white matter abnormalities that differentiate CRION from multiple sclerosis or NMO[19]. MRI of orbits may show enlarged optic nerves or enhancement with contrast[2]. Interestingly, the MRI lesions of CRION may be more frequently seen in the infraorbital region of the optic nerve[2]. Another study using spectral domain optical coherence tomography (SD-OCT) found that the retinal nerve fiber layer in patients with CRION is significantly thinner than that of patients with relapsing remitting multiple sclerosis[20].

Laboratory test

Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are commonly found in patients with CRION (57%-92% sensitivity)[5][6][7]. The presence of MOG-IgG may be associated with a higher risk of bilateral visual loss and higher frequency of episodes[5]. However, MOG-IgG is not specific for CRION and is found in other inflammatory disorders of the central nervous system[21]. Patients with symptoms of optic neuritis should receive workup for anti-aquaporin 4 (AQP4) and neuromyelitis optica IgG (NMO-IgG) antibodies[22]. If either of these antibodies test positive, suspicion for NMO increases due to the high specificity of the antibodies for detecting NMO. ANA testing and additional CSF and serological workup should be negative to exclude other possible causes of optic neuritis.

Differential diagnosis

Multiple sclerosis associated optic neuritis (MSON)

Other immune-mediated optic neuropathies: Neuromyelitis optica (NMO), single isolated optic neuritis (SION), relapsed isolated optic neuritis (RION) unclassified optic neuritis (UCON)

Systemic diseases (e.g. sarcoidosis, systemic lupus erythematous)

Infectious diseases (e.g. herpes simplex virus types 1 and 2, HIV, syphilis)

Vascular causes (giant cell arteritis)

Management

The goals of management are to restore visual function in the acute phase and preserve vision in the long term.

General treatment

Symptoms are managed with immunosuppressive therapy such as steroids, azathioprine, methotrexate, cyclophosphamide, and intravenous immunoglobulin (IVIG)[2]. Pain resolves quickly with immunosuppressive therapy, and vision loss is arrested and can even be completely reversed[1].

Phases of therapy

These are the recommended guidelines for different phases of treatment published by a 2013 review of 122 cases[1].

1) Acute

Treatment with intravenous (IV) methylprednisolone at 1 mg/kg is recommended for 3-5 days to improve pain and visual loss symptoms[1]. Plasmapheresis can be substituted for IV methylprednisolone.

2) Intermediate

After 3-5 days of treatment during the acute phase, oral steroids (prednisone) should be given at 1 mg/kg with gradual tapering to identify minimal effective dose[1]. During the taper, visual function should be monitored regularly.

3) Long term

Upon determining the minimal effective dose of oral steroids, a non-steroid medication should be added to create the long-term treatment regimen. Candidates include azathioprine[23], methotrexate[24], cyclophosphamide[24], and mycophenolate[25].

Other studies demonstrate that prednisolone use is still effective for chronic cases of CRION[15][26]. Osteoporosis prophylaxis is recommended in all patients who use steroids for prolonged periods of time[27].

Complications

CRION may cause permanent damage to the retinal nerve fiber[6]. Lack of treatment or sudden withdrawal of immunosuppressive therapy can also result in permanent loss of vision[2][15].

Prognosis

Early detection and treatment improve visual acuity outcomes[1]. Patients might require long term immunosuppressive therapy to prevent recurrence of symptoms[15]. There may be a risk for permanent visual loss and blindness if steroid therapy is not maintained after symptom remission[28]. An increased frequency of episodes is also correlated with a worse prognosis for visual outcomes[6].

Summary

CRION is an idiopathic autoimmune disease of the optic nerves characterized by vision loss +/- pain and at least one recurrence. Other key characteristics include symptom improvement with immunosuppressive therapy and the worsening of symptoms when therapy is stopped. Although not a diagnostic criterion, MOG-IgG antibodies have been associated with CRION. Workup should be performed to exclude other causes of optic neuritis and vision loss before the diagnosis of CRION is made. Management involves the use of immunosuppressives: steroids, azathioprine, methotrexate, cyclophosphamide, and IVIG. Patients should remain on appropriate immunosuppressive therapy to keep symptoms in remission, otherwise there is risk for recurrent episodes and permanent vision loss.

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 Petzold A, Plant GT. Chronic relapsing inflammatory optic neuropathy: a systematic review of 122 cases reported. J Neurol. 2014;261(1):17-26. doi:10.1007/s00415-013-6957-4
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 Kidd D, Burton B, Plant GT, Graham EM. Chronic relapsing inflammatory optic neuropathy (Crion). Brain. 2003;126(2):276-284. doi:10.1093/brain/awg045
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