Working up a child with demyelinating optic neuritis: Striking a balance!

Pediatric optic neuritis (PON) is one of the commonest causes of acute vision loss in children. Although it might often be postinfectious or postvaccination, recent understanding and available evidence suggest that it can be the first manifestation of a neuro-inflammatory syndrome such as multiple sclerosis, neuromyelitis optica spectrum disorder, acute disseminated encephalomyelitis or myelin oligodendrocyte glycoprotein associated optic neuritis. Therefore, neuroimaging, serological testing, cerebrospinal fluid analysis, testing for various systemic autoimmune conditions become a part of the workup. However, this can be exhaustive and expensive, especially in countries with limited access to health insurance. Many recent studies suggest that neuroimaging and few clinical features can provide clues to the underlying etiology. However, serological tests can provide a confirmatory evidence. Therefore, in this mini-review, we propose a balanced approach to the evaluation of PON, based on the available literature emanating in the last decade. Copyright:

Optic neuritis is one of the most common conditions that we see in the Neuro-Ophthalmology practice. The estimated incidence of pediatric optic neuritis (PON) is reported to vary from 0.15 to 4.4/100,000 person-years in various ethnicities.[12] Although PON resembles adult optic neuritis (AON), there are a few important differences in the clinical presentation between the two.

While optic neuritis especially in younger children tends to be bilateral and manifests as papillitis, unilateral retrobulbar neuritis is more common in the adults.[345] Children with optic neuritis often present with profound vision loss, i.e. best-corrected visual acuity <20/200 at presentation.[56] However, pain on eye movements is relatively infrequent in PON as compared to adults,[56] although it matches the reported prevalence from the southeast Asia.[4] These differences are particularly marked in younger children, however, optic neuritis in adolescents tends to resemble AON. It is important as these features raise concern for atypical presentation and possible chances of poor recovery in adults, these features are usual in PON whether isolated or associated with a neuroinflammatory condition.

Common neuro-inflammatory syndromes that cause demyelinating optic neuritis in children include multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectrum disorder (NMOSD), or Myelin-oligodendrocyte glycoprotein (MOG) associated optic neuritis.[45789] Following the widespread availability of MOG antibody testing, studies have shown a high frequency of positivity for MOG antibodies in children presenting with optic neuritis.[57]

Given these considerations, it has become challenging and imperative to have a greater understanding and perform more elaborate testing in children with optic neuritis. Recently published prospective multicentric PON study conducted by the Pediatric Eye Disease Investigator Group highlighted the above aspects in 44 children.[5] They reported that at 6-month follow-up, based on the clinical presentation, magnetic resonance imaging (MRI) findings, and serological testing, the final diagnosis in this study was: Isolated optic neuritis in 48%, MOG associated optic neuritis in 18%, MS in 11%, ADEM in 16%, and NMOSD in 7%.[5] Further, in this study, they could reclassify four patients with idiopathic ON (9%), 1 (2%) patient with ADEM, and 2 (5%) with seronegative NMO as MOG-positive ON,[5] highlighting that MOG optic neuritis is one of the predominant etiologies in this age group, and serological testing for MOG should be part of the routine workup in these patients. However, this study could not provide clues to specific neuro-inflammatory etiologies.

This data suggests that even though idiopathic, postinfectious, and postvaccination optic neuritis are frequent in children, nearly one out of two (50%) of patients might have an underlying neuro-inflammatory disorder, and appropriate work-up (neuroimaging, serological testing, and cerebrospinal fluid [CSF] analysis) should be performed in these patients.

While this is an ideal scenario, it can be expensive and exhaustive for both the children and the parents. This assumes greater significance in countries where health insurance coverage is limited.

The knowledge derived from prior studies, especially in the last decade (2010-till date) suggests that a few clinical and important radiological features help in knowing the etiological diagnosis for optic neuritis. In general, concomitant neurological symptoms such as limb weakness, numbness, or ataxia, may suggest any of these associated central nervous system demyelinating diseases, but it is not specific to any etiology. ADEM[8] and MOG-associated optic neuritis[9] are likely to have associated constitutional symptoms, prolonged vomiting, hiccups, and new-onset seizures. Further, both might have onset following a prior viral illness or vaccination. Although both might be similar in onset, patients with ADEM usually have a monophasic illness,[8] while MOG-associated optic neuritis might have recurrences in about one-third of patients.[79]

Another study by Hacohen et al.[10] evaluated clinical characteristics, MOG-Ab, and aquaporin-4 Ab, intrathecal oligoclonal bands, and Epstein-Barr virus (EBV) serology results of 110 children with recurrent demyelinating optic neuritis. They reported the following observations:

Clinical Clues to Multiple Sclerosis versus Nonmultiple Distinguish Sclerosis Demyelinating Syndromes

In their series, Hacohen et al. observed that patients with MS were older (median age: 13 years vs. 7 years, P < 0.0001), did not show any ethnicity predilection, and presented more frequently in girls than boys (2.1:1), with brain MRI lesions (white matter, cerebellum, brainstem at presentation) as compared to children with Non-MS etiologies.[10] Interestingly, presentation like ADEM was never observed in MS. MS patients showed CSF oligoclonal bands and EBV sero-positivity but did not show positivity for NMO and MOG antibodies.

Clinical Clues to Distinguish Myelin-Oligodendrocyte Glycoprotein - Optic Neuritis versus Neuromyelitis Optica Spectrum Disorder

Hacohen et al.[10] also reported that patients with MOG optic neuritis were younger (median age: 6 years vs. 10.6 years, P = 0.048), but did not show any gender or racial predilection as compared to children with NMO. Further, they reported that children with MOG more frequently had ADEM-like presentation and patients with NMO were more likely to have a clinically isolated syndrome other than optic neuritis or transverse myelitis. They reported that patients with NMO were more likely to have area postrema syndrome (P = 0.007) while children with MOG optic neuritis were more likely to have cerebellar symptoms, seizures, and constitutional symptoms although it did not reach statistical significance.

Significance of Neuroimaging Findings

Radiological findings such as characteristics and distribution of white matter lesions on MRI brain and spine provide clues to the likely etiology of the underlying demyelinating syndrome (MS, NMOSD, and MOG associated optic neuritis) in patients with optic neuritis.[51112]

Dutra et al.[11] have nicely summarized radiological features in common demyelinating disorders causing optic neuritis. In short, these characteristic features include: [11]

Multiple sclerosis

Optic nerve lesions are often unilateral and involve short segments of the optic nerve. Involvement of the optic chiasm is unusual. Brain lesions tend to involve one of the following white matter tracts: periventricular, subcortical, juxtacortical, or infratentorial. Spinal cord lesions are usually in the white matter tracts and involve short segments.

Neuromyelitis optica spectrum disorder

In NMO optic nerve lesions can be bilateral, involve long-segments of or entire optic nerve, prechiasmatic optic nerve and even optic nerve chiasm. Brain lesions are observed in the peri-ependymal or deep white matter areas. Spinal cord lesions again tend to be large, and often involve ≥3 contiguous segments of the spinal cord (also called longitudinally extensive transverse myelitis lesions). Further spinal cord lesions can involve both white matter and central gray matter.

Myelin-oligodendrocyte glycoprotein

In MOG optic nerve lesions can be bilateral, involve long segments of the optic nerve, but often spare optic chiasm. Brain lesions tend to be in peri-ependymal or deep white matter areas. However, larger, and widespread lesions in the entire white matter might be seen similar to ADEM. Spinal cord lesions again tend to be similar to the NMO, but often involve the caudal part of the spinal cord (vs. cervical/thoracic spine in NMOSD).

Acute disseminated encephalomyelitis

Imaging characteristics of the optic nerve and brain tend to closely mimic MOG optic neuritis. Brain lesions in both MOG and ADEM can be large and have perilesional edema. However, spinal cord lesions are unusual in these patients.

Thus, the above evidence suggests the following:

Neuro-inflammatory syndromes account for nearly 50% of cases of PON

MOG optic neuritis is frequent in younger children while MOG-optic neuritis and MS tend to predominate in relatively older children

Although few clinical clues suggest specific associated neuroinflammatory disorders, radiological characteristics and distribution of lesions give clues to the underlying etiology.

Therefore, the following recommendations could be followed in workup of children with pediatric optic neuritis

Neuroimaging in these patients is mandatory and should focus on obtaining adequate imaging of the optic nerves and the brain. MRI of the brain (with fluid-attenuated inversion recovery, FLAIR sequences) and orbits with fat suppression techniques with and without gadolinium (contrast) should be obtained.

Ideally, MRI whole spine screening should be obtained in all patients, but definitely at least in patients with recurrent disease or those with other neurological symptoms.

Serological testing

Ideally in all children, serological testing for NMO and MOG antibodies should be obtained. This will help identify and reclassify the disease appropriately. However, this might be considered optional in children with radiological evidence supportive of MS, and socioeconomic constraints.

Cerebrospinal fluid analysis

Many authorities recommend obtaining CSF analysis in all patients at initial presentation. However, if not possible, this can be reserved for patients with high suspicion of MS, recurrent optic neuritis, or atypical diseases mimicking optic neuritis.

Further work-up

Although it might be ideal to obtain further serological testing for infectious causes (syphilis, Lyme disease, borreliosis, etc.,), autoimmune diseases (Serum angiotensin-converting enzyme, antinuclear antibody testing, extractable nuclear antigen testing), Leber hereditary optic neuritis and other atypical causes these can be reserved for patients with presentation such as neuroretinitis, recurrence, and poor recovery even, after few weeks of initial therapy.

While a discussion about the management of each individual neuro-inflammatory syndrome is beyond the scope of this article, it is always imperative to also involve the pediatric neurologist in decision-making and care for starting immuno-modulator therapy according to the final etiology.

Financial support and sponsorship

Hyderabad Eye Research Foundation, Hyderabad.