Considerations for the Management of Optic Neuritis in the Inpatient Setting

Our understanding of the significance of optic neuritis has changed over the past decades. Originally considered to be merely (or mainly) a potential sign of impending multiple sclerosis (MS), optic neuritis now just as easily conjures up thoughts of neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) in the mind of the general neurologist, not to mention the long list of other known causes, which are discussed in the following. The approach to the acute management of optic neuritis in the inpatient setting also has changed. For example, full brain and spinal cord MRI with and without contrast, in addition to MRI orbits, is not unreasonable, and the panel of bloodwork checking for MS mimickers has expanded. In cases of atypical optic neuritis, the workup may be even more involved.

General neurologists and neurohospitalists are often the first-line practitioners managing these acute cases in the inpatient setting, and their management and workup decisions can have important effects on the immediate and long-term prognosis. Optic neuritis attacks in NMOSD, for example, can cause profound and irreversible vision loss, in contrast to the optic neuritis of MS, which typically is self-limiting and has good recovery, even without steroids.¹ In some cases, it may be reasonable to start preventative treatment with a disease-modifying therapy (DMT) in the inpatient setting prior to discharge.

This article summarizes the current understanding of optic neuritis, the differences in how it presents among the different diseases, considerations for acute treatment, suggestions for workup depending on the clinical presentation, and other management considerations for the general neurologist or neurohospitalist working in the inpatient setting and caring for people with acute presentation of optic neuritis.

Presentation of Acute Optic Neuritis

It is well known that acute optic neuritis classically presents with subacute loss of visual acuity and color vision and is associated with eye pain, particularly with eye movement. Depending on the affected area of the optic nerve, direct fundoscopic examination results may be normal, such as in retrobulbar optic neuritis. Thus, normal fundoscopic examination results should not deter the practitioner from offering treatment if the clinical signs and symptoms otherwise fit (eg, afferent pupillary defect present on examination). Painless vision loss originating from the optic nerve is more suggestive of optic neuropathy than neuritis, but pain can be absent in about 8% of cases.²

The presence of additional clinical or radiographic features that are considered atypical for optic neuritis can point toward a particular differential diagnosis, and recognizing these features is key to discerning the optic neuritis of MS from that of other causes. For example, the presence of flame hemorrhages on fundoscopic examination can point toward infectious (eg, West Nile virus, rickettsiosis) or inflammatory (eg, sarcoidosis, lupus, vasculitic) etiologies, whereas the presence of a macular star can point toward other infectious causes (eg, syphilis, Lyme disease, toxoplasmosis). Meanwhile, the presence of longitudinally extensive optic nerve lesions or perineuritis on MRI can point toward NMOSD or MOGAD, respectively.^3,4 If visual acuity seems paradoxically intact, one should consider autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy-associated optic neuritis, in which preservation of visual acuity and visual fields can occur.⁵ Atypical optic neuritis is a loosely defined term and can include cases of bilateral or sequential presentation, painlessness, patterns of vision loss different from expected, or the presence of additional clinical or radiographic features. Having atypical optic neuritis correlates with a lower risk of developing MS later in life, suggesting that an alternative etiology indeed may be at play.⁶

Front-line physicians evaluating the acute case of optic neuritis must have a broad understanding of the various causes of optic neuritis to treat and manage it appropriately. If an infectious cause is suspected, for example, it is important to treat with the appropriate antimicrobial agent to help speed recovery and improve outcomes, rather than treating with intravenous steroids alone. Indeed, treatment with intravenous methylprednisolone (IVMP) monotherapy without antibiotics has been shown to aggravate disease activity in cases of optic neuritis caused by syphilis, human immunodeficiency virus, Lyme disease, or tuberculosis.^7-11 Common presentations of various causes of optic neuritis are summarized in Table 1.

Treatment Considerations for Acute or Recurrent Optic Neuritis

Ever since the Optic Neuritis Treatment Trial results² were published in 1992, IVMP at a total dose of 1,000 mg daily for at least 3 days has been the standard treatment for acute optic neuritis. This is true regardless of cause, keeping in mind that antimicrobial therapy may need to be administered concomitantly if infectious sources are suspected or confirmed.^7-11

Subsequent studies have investigated the use of oral steroids, intravenous immunoglobulin (IVIg), and plasma exchange (PLEX) as well. All these options may be available to the neurohospitalist at the time of evaluation of an acute optic neuritis attack, and knowledge and discernment are needed for effective treatment.

Whereas monotherapy with oral prednisone at a dose of 1 mg/kg/day was shown to increase the risk of recurrence in the Optic Neuritis Treatment Trial,² it has since been demonstrated that monotherapy with 1,250 mg of oral prednisone daily has similar effects on long-term visual recovery as using IVMP 1,000 mg daily.¹² Furthermore, the two routes—oral and intravenous—may be fairly similar in their overall tolerability and safety.¹³ Whereas this argues for an additional option in the outpatient setting (the oral route is easier to arrange and administer on an outpatient basis), the intravenous route seems to have remained as the preferred route for the inpatient setting.

It has long been known that treatment with IVMP generally speeds the time to visual recovery after optic neuritis but does not change the degree of eventual recovery.¹ However, this is generally untrue for cases of NMOSD-related optic neuritis; in such cases, early treatment with IVMP within 5 days of symptom onset is crucial for improving the chances of complete or nearly complete visual acuity recovery in the long run.^14,15 Therefore, a person presenting with early profound vision loss (such as can occur in NMOSD attacks) should be considered for prompt treatment while diagnostic investigations are underway.

A lack of response to the first round of IVMP in NMOSD-related optic neuritis should not prompt treatment with more IVMP. Using multiple rounds of IVMP has not been shown to improve visual outcomes.^15,16 In these cases, consideration can be made to initiate PLEX subsequent to or concurrent/alternating with the first round of IVMP.¹⁷ Early initiation of IVMP is more important than the timing of PLEX initiation in NMOSD-related optic neuritis.¹⁵ It has been suggested that PLEX be added to the IVMP regimen not only if the person is seropositive for NMO immunoglobulin G (IgG), but also if the person is seropositive for MOG IgG or is otherwise presenting with a recurrent attack of optic neuritis.⁷ IVIg has not been shown to be beneficial in the acute treatment of optic neuritis,^18,19 despite its potential role in maintenance or preventative therapy in the outpatient setting.

Workup Considerations for Acute or Recurrent Optic Neuritis in the Inpatient Setting

Once treatment for acute optic neuritis is underway, the next step in management generally is a decision of what workup to pursue during hospitalization. An MRI of the orbits with and without contrast likely has already been obtained to help verify the clinical suspicion for acute optic neuritis, in addition to an ophthalmologic consultation checking for an afferent pupillary defect, visual acuity loss, visual field loss, red desaturation, optic disc edema, or other fundoscopic findings. Knowing what workup to pursue next, and how extensive the remaining workup needs to be, can be a challenging decision for the neurohospitalist, even when putting aside factors such as socioeconomic considerations. Some may choose not to pursue any additional workup, deferring to the outpatient setting. However, delayed or lost follow-up can lead to poorer long-term outcomes, whereas early recognition and treatment of diseases such as NMOSD, paraneoplastic syndromes, or infectious etiologies can improve prognosis. On the other hand, a provider who is uncomfortable or unfamiliar with the evaluation of acute optic neuritis may “shotgun-order” extensive and unnecessary workup looking into numerous different causes simultaneously. A more judicious approach would be to tailor the workup to the case at hand. Based on the data gathered from the neurologic and ophthalmologic history and examination, together with the findings from the MRI orbits, a sensible plan for any additional workup to pursue usually can be synthesized. For example, a person who reports a history of bilateral lower extremity numbness and is found to have a sensory level on neurologic examination might warrant spinal cord imaging; if a chronic transverse myelitis plaque is identified, the next step might include checking serum aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies, especially if that plaque is centrally located in the cord or is longitudinally extensive, spanning three or more vertebral levels. If the plaque is <1 vertebral level and is located dorsolaterally in the cord, then an MRI brain should be obtained to investigate further for MS. Any atypical spinal cord lesions that are not classic in size, shape, or location for MS, NMOSD, or MOGAD should be considered for primary intramedullary spinal cord tumors such as ependymomas, astrocytomas, or hemangioblastomas, as well as for secondary tumors such as metastases. In such cases, neurosurgical and oncologic evaluations and follow-up spinal cord imaging may be warranted.^20,21

As another example, the person with one enhancing “Dawson’s finger” and one enhancing cerebellar peduncle lesion on MRI brain simultaneous with acute optic neuritis (thereby meeting dissemination in space) but no other brain or spinal cord lesions may warrant a lumbar puncture (LP) to check for cerebrospinal fluid (CSF) oligoclonal bands to satisfy dissemination in time to expedite MS diagnosis according to the 2017 McDonald criteria.

In cases of recurrent optic neuritis without other localizing neurologic attacks by history and without any brain or spinal cord demyelinating lesions on MRI, the possibilities of NMOSD, MOGAD, or chronic relapsing inflammatory optic neuropathy become more likely than MS. For people presenting with fever, headache, papilledema, encephalopathy, rashes, oral ulcers, other cranial neuropathies, or other atypical signs and symptoms, this should prompt investigations checking into other inflammatory, infectious, or paraneoplastic causes. Additional serologic and CSF testing might be warranted in such cases, as well as additional imaging, such as chest computed tomography (as in the case of sarcoid) or radiographs of the hands (as in cases of rheumatoid arthritis or lupus), to name a few. Inpatient consultation to other specialties to assist with the workup should be considered if the suspicion for systemic inflammatory disease is high. Neurologic involvement can be the presenting symptom of systemic inflammatory diseases, such as in neurosarcoidosis or transverse myelitis occurring in antiphospholipid syndrome from lupus.

One might argue that such testing should be deferred to the outpatient setting. However, this may not always be feasible, or may delay diagnosis and appropriate care. The wait time to see a neuroinflammatory specialist may be months, or in some geographic areas may not be an option at all. As another example, failing to order the appropriate workup on the inpatient LP may lead to a repeat LP being contemplated as outpatient. The inpatient neurologist may also have difficulty in deciding what MRIs to order: Does an MRI of the brain need to be obtained in all individuals? When should spinal cord imaging be pursued? After optic neuritis as a first neurologic attack, the risk of later developing MS was higher for individuals who had white matter lesions on baseline MRI brain.⁶ Therefore, obtaining an MRI brain with and without contrast, at a bare minimum, is appropriate after an acute presentation of typical optic neuritis. Delaying this test to the outpatient setting may miss the opportunity to identify dissemination in time on a follow-up scan 3 to 6 months later. Spinal cord imaging, however, has not been shown to be as beneficial in assisting with the earlier diagnosis of MS.²² Obtaining MRIs of the cervical and thoracic spinal cord may be more prudent when the suspicion is for NMOSD, MOGAD, or other diseases; for example, as in the person with bilateral or sequential optic neuritis. Those with atypical brain lesions or a paucity of brain lesions should also be considered for spinal cord imaging if the suspicion is still for MS, as the presence of two or more spinal cord lesions can help identify primary progressive MS earlier, as per the 2017 McDonald criteria.

Ultimately, the judicious use of hospital-based testing lies in the hands of the discerning physician. Generally, neither a strictly conservative nor a shotgun approach to workup is suitable, and the inpatient neurologist should instead use the presenting signs and symptoms of the case at hand to guide the inpatient treatment and workup decisions accordingly.

Discharge Considerations and Posthospitalization Follow-Up

The classic optic neuritis that occurs with MS typically has a favorable visual prognosis. About 75% of individuals may recover their vision to an acuity of 20/20 or better.²³ Good visual recovery can also be expected with MOGAD-related optic neuritis.^24,25 Poor recovery of visual acuity at follow-up after an attack of optic neuritis is more typical for NMOSD, and a subsequent attack of optic neuritis in this disease may have even more devastating long-term effects.²⁶ It is known that the disability accumulated in NMOSD is from the acute attacks, and prevention of them is crucial to preserving long-term neurologic function. Therefore, the early identification and treatment of individuals with NMOSD is paramount. Testing for NMOSD in the inpatient setting is fairly simple and can include serum neuromyelitis optica/aquaporin-4 IgG, preferably by cell-based assay (rather than the less sensitive ELISA), and does not need to include CSF testing. Ideally, testing would be done before initiation of PLEX, to help prevent a false-negative result. A negative serum NMO IgG result does not rule out NMOSD, and repeat testing can be pursued in the outpatient setting, but testing while inpatient is worthwhile, because the currently available Food and Drug Administration–approved therapies are limited to people with seropositive NMOSD. A positive serum neuromyelitis optica IgG result can help facilitate earlier treatment and may help overcome insurance barriers encountered in outpatient follow-up.

One might be tempted to initiate DMT even prior to discharge. Careful consideration should be made as to whether the individual meets the diagnostic criteria for MS or for another disease. It is well known that some DMTs for MS, such as the interferons, natalizumab, and the S1P modulators including fingolimod, can worsen NMOSD. Therefore, use of a broad-spectrum DMT, such as rituximab, which acts against both MS and antibody-driven autoimmune disorders, could be considered. If given, close follow-up should be arranged to plan for the second induction dose 14 days after the first, either in the inpatient rehabilitation or outpatient setting. For MOGAD, the anti-CD20 monoclonal antibodies including rituximab have recently been shown to be less effective than originally thought in controlling or preventing attacks.^27,28 Even if an alternative DMT is anticipated for outpatient use (such as eculizumab or inebilizumab in the case of seropositive NMOSD), the initiation of DMT while inpatient can still be beneficial, because it may provide up to 6 months of additional coverage in the form of immunosuppression, allowing more time for a person to establish care and seek insurance authorization for an alternative DMT in the outpatient setting.

In cases of isolated recurrent optic neuritis without history of other localizing neurologic attacks, the likelihood of the underlying etiology being NMOSD or MOGAD remains fairly high. Chronic relapsing inflammatory optic neuropathy should also be considered. For these cases, discharging the patient on maintenance therapy with daily oral prednisone or a prolonged oral prednisone taper may be warranted.^29-32 Arranging for close follow-up with an outpatient ophthalmologist and neurologist after an acute attack of optic neuritis, regardless of the degree of visual recovery achieved in the inpatient setting, may help improve the long-term prognosis.

Summary

Optic neuritis, although commonly an attack of MS, can be a presenting sign of numerous diseases spanning various etiologies. Discerning the optic neuritis of MS from that of other demyelinating disease or differential diagnoses is imperative in the proper inpatient treatment and management of the individual with acute symptoms. By recognizing atypical signs and symptoms and pursuing the appropriate workup, the inpatient neurologist can affect the clinical outcome and potentially the long-term prognosis in acute optic neuritis.