OVERVIEW: What every practitioner needs to know

Are you sure your patient has optic neuritis? What are the typical findings for this disease?

Optic neuritis is an acute inflammation of the optic nerve often due to demyelination or direct infection of a nerve with an accompanying inflammatory immune response. The primary symptoms a patient will report will be a painful reduction or total loss of vision in an affected eye. Optic neuritis can be present in one or both optic nerves at initial presentation, and it can recur in a previously affected optic nerve. Optic neuritis is less common in children than it is in adults, but when it does occur in children it is usually secondary to a potentially identifiable primary overall process such as post-infectious/post-vaccination sequelae (most common), acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), Lyme disease, or multiple sclerosis.

Typical findings:

Reduced visual acuity or blindness in the affected eye(s)
Loss of color vision in the affected eye(s)
Pain that worsens with movement of the affect eye(s)
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Specific Manifestations in Children

Pediatric patients with optic neuritis, when compared to adult patients, are more likely to present with more severe visual loss (i.e., more profound loss of color discrimination, light perception, and motion detection) in affected eyes, and children are more likely (over 50%) to present with both eyes affected. Anterior optic neuritis and prominent optic nerve swelling are also more common in children. There is no sex difference in optic neuritis in pre-pubertal individuals (after puberty the female:male ratio is similar to the adult 2:1 ratio) and there is no ethnic predilection in the pediatric population.

What other disease/condition shares some of these symptoms?

Optic neuritis (inflammation of the optic nerve) is one of many possible optic neuropathies which can affect vision. A more thorough list includes:

Papillitis (inflammation of the head of the optic nerve)
Retrobulbar neuritis (inflammation of the optic nerve sparing the head)
Compression of the optic nerve
Papilledema (optic nerve disturbances due to increased intracranial pressure)
Ischemia of the optic nerve
Infiltration of the optic nerve by foreign cells (i.e. neoplastic, infectious, or inflammatory cells)
Metabolic/toxic optic neuropathies

What caused this disease to develop at this time?

Optic neuritis results from selective targeting of the white matter of the optic nerve by immune cells. Its precise causes are unknown but this phenomenon is usually a manifestation of a more global autoimmune process such as multiple sclerosis. Optic neuritis can occur alone or with other symptoms of autoimmune disease. The presence of optic neuritis with evidence of other central nervous system disease is definitive for the diagnosis of a demyelinating disease such as multiple sclerosis.

There is evidence to suggest that in children there is frequently a vaccination or a febrile illness (especially during springtime) preceding the onset of optic neuritis implying a potential relationship between some childhood illnesses and optic neuritis.

Unlike adults with optic neuritis, in children there is more often an identified primary cause, particularly Acute Disseminated Encephalomyelitis (ADEM). Other causes include post-infectious/parainfectious and initial manifestation of a larger disease process.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

While laboratory testing is often done to identify possible causes of optic neuritis, the most important initial examination in a patient presenting with vision loss is the ophthalmologic examination. This examination will define the extent of any visual loss or change and sometimes visualization of the optic disc itself may reveal pallor or bulging either of which is characteristic of inflammation.

Generally, if the history and physical examination are consistent with an idiopathic optic neuritis, then ancillary testing is not needed aside from an urgent (not emergent) Magnetic Resonance Imaging (MRI) scan (see below).

Tests to consider if a diagnosis of optic neuritis is suspected to be secondary to another diagnosis may include:

Aquaporin-4 Antibody. This is a specific assay for neuromyelitis optica/Devic’s disease which typically presents with optic neuritis and transverse myelitis.

Complete Blood Count with differential to assess for leukocytosis and presence of infection or active autoimmune process.

C-Reactive Protein (CRP). If elevated, this study is further evidence of infection.

Erythrocyte Sedimentation Rate (ESR) which, if elevated, may indicate a systemic inflammatory process.

Anti-Nuclear Antibody (ANA) Screen. An elevated, significant ANA titer is suggestive of autoimmune processes such as systemic lupus erythematosus.

Rapid Plasma Reagin. If syphilis is suspected this is a necessary diagnostic test.

Viral Screen. If available, and if there is suspicion of an infectious etiology, identifying the prescence of an active viral infection associated with elevated risk of optic neuritis could be helpful in establishing a parainfectious etiology.

Serum lactate, serum amino acids, urine organic acids. If a mitochondrial disease or amino acidopathy is suspected, these optional assays would be useful diagnostically.

Cerebrospinal Fluid (CSF) Studies including white blood cell count, protein, glucose, and Gram stain, and culture. Anti-treponemal antibody titer would be required for a diagnosis of neurosyphilis. These studies are usually normal in optic neuritis although a CSF pleocytosis and mildly elevated protein can be present in cases of fulminant disease.

Would imaging studies be helpful? If so, which ones?

While not necessary for the diagnosis of optic neuritis per se, patients presenting with optic neuritis would benefit from a MRI study of the brain using a sequence protocol specific for multiple sclerosis if available. Otherwise, a standard MRI with T1, T2, FLAIR sequences and contrast enhancement are sufficient. While newer MRI scanning techniques can reveal optic nerve swelling consistent with optic neuritis, the rationale for the brain MRI is more to assess for associated findings that may identify a primary etiology such as multiple sclerosis.

Optical Coherence Tomography (OCT) is a new investigative technique which allows direct non-invasive measurement of a cross-sectional thickness of the retinal nerve fiber layer. This measurement can be used serially to assess thinning of that layer which would be a finding consistent with an acute optic neuritis and, if progressive, confirm a demyelinating disease such as multiple sclerosis. If it is available, it would be helpful to obtain for longitudinal follow-up.

Visual Evoked Responses (VER) examinations, in which the latency between a visual stimulus and a sensory response in the occipital lobe is measured, can be used to confirm mild optic neuritis in cases where the clinical and neurological examinations are inconclusive and other modalities such as OCT (see above) are unavailable.

If there is any historical or physical examination evidence to suggest that sarcoidosis is in the differential diagnosis, a chest CT scan with contrast is needed to assess for evidence of sarcoidosis.

If you are able to confirm that the patient has optic neuritis, what treatment should be initiated?

There is historical controversy regarding whether the optimal treatment of optic neuritis is intravenous followed by oral corticoseroids. A multi-center trial in adults, the Optic Neuritis Treatment Trial, generated the finding that the treatment of optic neuritis associated with the best outcomes (i.e., 2-week assessment of visual acuity, likelihood of recurrence and likelihood of developing multiple sclerosis) was intravenous methylprednisolone.

The dose this group recommends is 250 mg every 6 hours (1000 mg daily) for a duration of treatment of 3-5 days. The optimal duration of intravenous steroid treatment is not known in children, but if little to no clinical improvement is seen at 3 days, a 5-day course is an option to consider since the majority of studies report that maximum recovery of vision is noted within 5 days of starting steroid treatment . There are published studies demonstrating some evidence of intravenous dexamethasone yielding similar outcomes to methylprednisolone in optic neuritis in the context of relapsed multiple sclerosis, but methylprednisolone remains the more established medication for acute optic neuritis.

After high dose methylprednisolone is completed, oral corticosteroids should be given for at least 28 days (4-6 weeks) of treatment following completion of IV therapy. Shorter durations of oral corticosteroid tapers have been associated with higher relapse risk. Initial starting dose of oral steroids is recommended at 1 mg/kg/day or a maximum starting dose of 60 mg daily. There is no established taper protocol, but a reduction of 5 mg every 3 days from the initial 60 mg dose would achieve the desired goal duration of treatment in a safe manner.

This same regimen (3-5 days IV methylprednisolone followed by 28 or more days of oral steroids) is advised for recrudescence of optic neuritis even in the presence of other treatments for primary causes.

As a primary treatment, there are few studies that suggest plasma exchange can ameliorate some disability in severe demyelinating disease manifestations, including optic neuritis. Unfortunately, these studies are small and given the practical limitations inherent in the use of plasma exchange in an acute setting, there is no evidence that it is superior to high dose steroid treatment. However, many more retrospective studies have established plasma exchange as a secondary treatment in cases of optic neuritis refractory to initial treatment with steroids.

In cases with minimal-to-no visual improvement during steroid treatment, plasma exchange is a “rescue” option that improves outcomes acutely and long-term in several studies of adult patients. This treatment should be initiated as soon as possible and could be considered as early as 3 days into steroid treatment. There is no established exchange volume (1:1), frequency (daily versus every 2 days), or total number of exchanges though there is some recent evidence that five total exchanges of at least 1:1 volume on an alternating day basis are sufficient.

Multiple studies have confirmed that unlike steroid treatment, a single course of plasma exchange does not prevent future relapses. Steroid treatment can and likely should continue concurrently while plasma exchange occurs.

Double-blinded, placebo controlled studies of intravenous immunoglobulin (IVIG) have failed to demonstrate any benefit of IVIG in the treatment of optic neuritis in children.

What are the adverse effects associated with each treatment option?

The side effects of corticosteroids are well-documented and include hyperglycemia, hypertension, psychosis/mood changes, gastrointestinal ulceration/bleeding, hypokalemia, insomnia, and opportunistic infections. These side effects are thankfully uncommon and are not usually associated with a need for early termination of treatment. There is evidence for prevention of gastrointestinal ulceration while taking corticosteroids through the use H2-antagonists and proton pump inhibitors.

Plasma exchange is generally a safe and well-tolerated procedure in children. It requires surgical implantation of a catheter suitable for exchange which has the usual surgical risks of bleeding and infection. Long-term the catheter is a potential infectious and embolic source. There are patients in whom plasma exchange is contraindicated. Hemodynamically unstable patients, or patients with cardiovascular compromise as a result of myocardial infarction, arrhythmias, or coronary artery disease are contraindicated from exchange. Severe, uncorrectable coagulopathies are also a contraindication. Patients with severe hepatic failure and renal failure are also not appropriate for plasma exchange therapy.

During therapy, there are multiple complications reported, but most are easily corrected through readily available means. Hypotension and bradycardia are frequently encountered and may require fluid support. Hypocalcemia and other electrolyte abnormalities can also require intervention and electrolytes should be monitored. Coagulopathy, anemia, and deep vein thrombosis/pulmonary embolism are also serious, potentially mortal, complications in rare instances.

What are the possible outcomes of optic neuritis?

In children, optic neuritis has a good prognosis with most case review series reporting over 75% of patients having their baseline or 20/20 vision at follow-up following steroid treatment.

Practitioners should be aware of a rare, recently diagnosed entity termed “Chronic Relapsing Isolated Optic Neuritis” (“CRION”) reported in approximately 50 patients in the literature. This relapsing form of optic neuritis is invariably steroid responsive often bilateral optic neuritis found without evidence of other CNS involvement.

Though the data used to justify steroid treatment are predominantly derived from adult studies, retrospective studies in children yield equivalent, even better, visual outcomes than those seen in adults. When intravenous steroids are followed by oral steroid tapers, the risk is very low of a significant adverse outcome. When high dose oral steroids are utilized instead of intravenous preparations, the number of reported complications and need to discontinue render this option unacceptable in terms of safety and in terms of outcomes, which are worse.

What causes this disease and how frequent is it?

Optic neuritis is less frequent in children than adults for whom an incidence rate of 5/100,000 and a prevalence of 115/100,000 is cited. Comparable data in children is not readily available due to low frequency, but it is believed to be less frequent.

There is an observed increase in cases of optic neuritis during the Spring months (March-May) in the Northern hemisphere implying a parainfectious relationship. No specific disease is solely associated with increased risk but infections endemic at the times of increased optic neuritis risk include viral (Epstein-Barr, parainfluenza, influenza, measles, mumps, Rubella, and varicella) and bacterial (
Mycoplasma pneumoniae) species. Vaccination against smallpox, measles, and rabies are also reported to confer an elevated risk in published reports.

Unlike adult demyelinating diseases, it appears that environmental, not genetic, factors predominantly influence the manifestation of demyelinating diseases in early life. Specifically, while in adults longer distance from the equator and a European ethnic background appear to be positively correlated with disease, these same factors do not correlate with disease in children. There are case reports of familial NMO with multiple family members with aquaporin-4 autoimmunity. There may also be mitochondrial DNA polymorphisms that increase likelihood of manifesting optic neuritis. Unlike other manifestations of demyelinating disease, there is no consistent report of Human Leukocyte Antigen (HLA) regions conferring increased risk of isolated optic neuritis.

How do these pathogens/genes/exposures cause the disease?

The specific autoimmunity and inflammatory changes leading to optic neuritis remain a mystery. However, pediatric patients with progressive disease appear to have lymphocytes within the intrathecal compartment sensitized to a variety of self-antigens which may represent inappropriate recognition of self moieties by the intrinsic immune system. However, given the rapid response and better outcomes in children long-term, it appears that this process if arrested is self-limited and, in time, routine surveillance of the immune system removes these self-reactive species from the active immunity pool.

Other clinical manifestations that might help with diagnosis and management

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What complications might you expect from the disease or treatment of the disease?

The side effects of treatment are discussed above, but generally long-term there are no significant sequelae of glucocorticoids nor plasma exchange to merit discussion.

The predominant complication of optic neuritis is visual impairment, and in the worst case, blindess. In children, estimates of residual visual impairment range from 25-33% of patients undergoing all treatments. Regardless of which treatment is being employed (intravenous steroids and/or plasma exchange), prompt initiation of treatment is the most important determinant of improvement in vision at discharge and at follow-up.

Additionally, optic neuritis is a possible initial manifestation of demyelinating diseases such as multiple sclerosis or NMO. Estimates vary, but over 20% of patients with optic neuritis will at initial or follow-up examination meet established criteria for multiple sclerosis. Retrospective studies suggest this percentage rises in patients who present with optic neuritis and other identifiable central nervous system demyelinating lesions, a positive CSF study (IgG index or oligclonal bands), or history of prior demyelinating events.

Are additional laboratory studies available; even some that are not widely available?

OCT and VER are not universally available and are discussed above.

How can optic neuritis be prevented?

There are no prophylactic or preventative treatments for optic neuritis.

While vaccination is suggested to confer a small risk of optic neuritis, the overwhelming evidence is that the majority of risk is associated with infectious entities for which no vaccine exists.

Low serum levels of Vitamin D and parental cigarette usage confer increased risk of developing multiple sclerosis but are not independently established risk factors for optic neuritis.

What is the evidence?

The most cited placebo-controlled study of the treatment of optic neuritis is the Optic Neuritis Treatment Trial (ONTT) which established that IV methylprednisolone is the treatment of choice for optic neuritis. The findings of this study also include longitudinal outcome data, all summarized above. There are no comparable studies in children, unfortunately.

Beck, RW, Gal, RL. “Treatment of acute optic neuritis: a summary of findings from the optic neuritis treatment trial”. Arch Ophthalmol. vol. 126. 2008 Jul. pp. 994-5.

Beck, RW, Trobe, JD, Moke, PS, Gal, RL, Xing, D, Bhatti, MT. “Optic Neuritis Study Group. High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial”. Arch Ophthalmol. vol. 121. 2003 Jul. pp. 944-9.

Keltner, JL, Johnson, CA, Cello, KE, Dontchev, M, Gal, RL, Beck, RW. “Visual field profile of optic neuritis: a final follow-up report from the optic neuritis treatment trial from baseline through 15 years”. Arch Ophthalmol. vol. 128. 2010 Mar. pp. 330-7.

“Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up”. Arch Neurol. vol. 65. 2008 Jun. pp. 727-32.

“Visual function 15 years after optic neuritis: a final follow-up report from the Optic Neuritis Treatment Trial”. Ophthalmology. vol. 115. 2008 Jun. pp. 1079-1082.

The justification of plasma exchange as a valid rescue therapy can be found in these studies:

Llufriu, S, Castillo, J, Blanco, Y, Ramió-Torrentà, L, Río, J, Vallès, M. “Plasma exchange for acute attacks of CNS demyelination: Predictors of improvement at 6 months”. Neurology. vol. 73. 2009 Sep 22. pp. 949-53.

Trebst, C, Reising, A, Kielstein, JT, Hafer, C, Stangel, M. “Plasma exchange therapy in steroid-unresponsive relapses in patients with multiple sclerosis”. Blood Purif.. vol. 28. 2009. pp. 108-15.

Tumani, H. “Corticosteroids and plasma exchange in multiple sclerosis”. J Neurol. vol. 255. 2008 Dec. pp. 36-42.

Wang, KC, Wang, SJ, Lee, CL, Chen, SY, Tsai, CP. “The rescue effect of plasma exchange for neuromyelitis optica”. J Clin Neurosci. vol. 18. 2011 Jan. pp. 43-6.

The clinical manifestations, associated MRI findings, and outcome in pediatric patients summarized above can be found in these studies:

Bonhomme, GR, Waldman, AT, Balcer, LJ, Daniels, AB, Tennekoon, GI, Forman, S. “Pediatric optic neuritis: brain MRI abnormalities and risk of multiple sclerosis”. Neurology. vol. 72. 2009 Mar 10. pp. 881-5.

Brady, KM, Brar, AS, Lee, AG, Coats, DK, Paysse, EA, Steinkuller, PG. “Optic neuritis in children: clinical features and visual outcome”. J AAPOS. vol. 3. 1999 Apr. pp. 98-103.

Morales, DS, Siatkowski, RM, Howard, CW, Warman, R. “Optic neuritis in children”. J Pediatr Ophthalmol Strabismus. vol. 37. 2000 Sep-Oct. pp. 254-9.

Yeh, EA, Weinstock-Guttman, B, Lincoff, N, Reynolds, J, Weinstock, A, Madurai, N. “Retinal nerve fiber thickness in inflammatory demyelinating diseases of childhood onset”. Mult Scler. vol. 15. 2009 Jul. pp. 802-10.

Wilejto, M, Shroff, M, Buncic, JR, Kennedy, J, Goia, C, Banwell, B. “The clinical features, MRI findings, and outcome of optic neuritis in children”. Neurology. vol. 67. 2006 Jul 25. pp. 258-62.

Ongoing controversies regarding etiology, diagnosis, treatment

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