Optic neuritis (ON) in children is a special type of ON, the onset of which is less common than adult ON, but the clinical features are different from adult ON, such as the onset of infection is relatively common before the onset of the disease, often showing a subacute course of bilateral optic papillitis. At the same time, in the treatment of childhood ON, there is still a lack of standards for the treatment of typical ON as in adults.
In addition, the necessity and dosage of systemic glucocorticoid therapy and its impact on the physical, mental and prognostic regression of the child are issues that have yet to be proven. This article will provide an overview of the epidemiology and etiology of childhood ON, clinical manifestations, diagnosis and differential diagnosis, regression, status and progress of relevant treatment studies in recent years.
1, epidemiology and etiology
In the optic neuritis treatment trial (ONTT) study, the average incidence of adult typical ON was 5.1/100,000 and the prevalence was 115/100,000, of which 69% were female patients. The prevalence of ON in children is less common, with an estimated prevalence of 3.2/100,000 in the foreign literature, with a mean age of onset of 9-10 years and no significant gender differences in the onset of prepubertal children.
The etiology of ON is complex and varied, with idiopathic demyelinating optic neuritis (IDON), or classic ON, being the most common in adults, and other relatively rare infectious or autoimmune-related inflammatory optic neuropathies.
The etiology of ON in children is poorly reported in the literature, and it is believed that the etiology can be divided into the following categories: idiopathic demyelinating, systemic diseases such as infections (measles, mumps, varicella, brucellosis, rubella, etc.), secondary autoimmune diseases (including polyarteritis nodosa, systemic lupus erythematosus, Sjogren’s syndrome, etc.) and other causes (post-vaccination, trauma, metabolic disorders and poisoning, unknown causes).
Among them, ON is particularly associated with CNS demyelinating diseases including multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO). The latter may be the cause of the former and may also be the cause of the latter.
2, clinical manifestations
Typical adult ON is characterized by acute or subacute onset of vision loss in one eye, accompanied by headache, ocular pain and ocular rotation pain. In children, ON involves both eyes (60%-70%) and is often preceded by viral infection, fever and other prodromal symptoms or a recent history of vaccination.
In the majority of patients with monocular onset or disparate visual impairment in both eyes, a positive relative transmission pupillary disorder can be detected; a decrease in contrast sensitivity can also be observed, with approximately 50% of pediatric patients showing color vision abnormalities and mostly showing multiple acquired red-green color vision impairment.
In children with visual field examinations, many different types of visual field defects are often seen, with central dark spots being the most common (about 40%), and peripheral visual field narrowing (15%) or paracentral dark spots (10%) are also seen. On fundus examination, optic papillar edema is seen in only 1/3 of adults with ON at the initial stage, while 64-69% of pediatric patients present with optic papillitis or optic papillar edema and parapapillary exudation. 1 year later, approximately 85% of children develop optic papillar pallor.
The exact timing of visual abnormalities in children with ON is often difficult to determine clinically because of unclear complaints, but several studies have shown that visual impairment is generally severe at the time of presentation: more than 60% of children have visual acuity below 0.1 (20/200), which is more severe than typical ON visual impairment in adults (about 64.1% of patients with ONTT have visual acuity >0.1), but most children’s visual acuity can be significantly restored within a short period of time. However, most children’s visual acuity can be significantly restored within a short period of time.
Wilejto et al. reported that 83% of children with ONT had visual acuity of 0.5 or more after a mean follow-up of 2.4 years; some studies have also found that children with young age (<6 years) or normal brain MRI had relatively good visual acuity recovery.
3. Diagnosis and differential diagnosis
Based on the typical clinical manifestations, fundus changes and visual field damage, it is not difficult to diagnose this disease. Visual evoked potential (VEP), as a more sensitive and reliable objective quantitative examination, has a greater diagnostic value for children with ON, especially for children with slurred speech. In the early stage of acute ON, 83% of cases present with VEP signal absence or decreased amplitude; when visual loss occurs, 45-65% of pediatric patients have abnormal VEP latency, and VEP abnormalities can last for 6-12 months.
Quantitative analysis of retinal nerve fiber layer (RNFL) changes using optical coherence tomography (OCT) revealed significant thinning of the RNFL in children with ON compared to normal children. The fat suppression sequence MRI of the orbit in neuroimaging can show thickening and signal enhancement of the involved optic nerve, which is an auxiliary diagnosis for some idiopathic demyelinating optic neuritis.
During clinical diagnosis, clinicians need to determine whether ON in children occurs as a clinically isolated syndrome (CIS), i.e., after one occurrence of ON, no further CNS disease occurs, or whether it occurs as a precursor to CNS demyelinating lesions, in addition to assessing the patient’s visual dysfunction, so relevant neurological examination is very important.
Among them, MRI of the head is informative for early diagnosis of multiple sclerosis, selection of treatment options and prognosis of patients by knowing whether there are demyelinating spots in the white matter of the brain; cerebrospinal fluid can also provide a basis for demyelinating lesions: protein-cell separation, increased IgG synthesis rate, positive oligoclonal bands and increased myelin basic protein can indicate optic nerve or CNS or nerve root demyelination.
However, because cerebrospinal fluid examination is invasive, clinical attention should be paid to selective application. For children with acute optic neuritis with atypical history and other clinical manifestations, clinical routine hematology and imaging tests as well as certain bacteriological, immunological and even genetic tests of blood and cerebrospinal fluid for the etiology of the infection should also be performed.
The main diseases that should be differentiated from childhood ON include Leber’s hereclitory optic neuropathy (LHON), optic nerve retinitis, and compression optic neuropathy.
LHON is a mitochondrial hereditary disease, often occurring in young males, manifesting as irreversible, painless visual loss in both eyes simultaneously or sequentially, with visual acuity below 0.1, and complete blindness is rare; early fundus examination reveals congestion of the optic papillae, peripapillary microvascular tortuous dilatation, rare exudation and hemorrhage, and no dye leakage from the FFA lesion area; poor efficacy to various drugs; 3 points of mitochondrial DNA mutations (11778, 3460, 14484) are the etiology of nearly 90% of LHON patients; therefore, genetic testing should be performed in children with ON in both eyes when the etiology is unknown to exclude LHON.
Optic nerve retinitis, also known as optic papillar retinitis, often manifests as a loss of vision in one eye, with unexplained infection before or at the same time, the most common of the potential causes is cat-scratch disease caused by Baltons, followed by syphilis, Lyme disease, toxoplasmosis, toxoplasmosis, etc.; in addition to the performance of optic papillitis, the fundus is visible as optic papillary edema and exudation spreading to the adjacent retinal tissue, especially macular edema, which can In addition to the manifestation of optic papillitis, the fundus may show optic papillar edema and exudation spreading to the adjacent retinal tissues, especially macular edema, which may appear as radial folds and punctate or fan-shaped asteroidal exudation.
Compressive optic neuropathy is due to compression or infiltration by intraorbital or intracranial tumors or metastatic carcinoma. Clinically, the possibility of compressive optic neuropathy should be considered in patients with unilateral or bilateral progressive visual acuity loss and visual field defects of unknown origin, or patients with a clinical diagnosis of optic neuritis but no improvement after treatment or temporary improvement followed by visual acuity loss again; cranial CT and MRI examinations are helpful for the diagnosis of intraorbital and intracranial occupying lesions. The diagnosis should be made.
4, disease regression
Some children with ON eventually develop related CNS demyelinating diseases, mainly including the following.
(1) MS: The ONTT study showed that approximately 50% of adults with classic ON develop clinically definite multiple sclerosis (CDMS) 15 years after the onset of the disease. The risk of developing CDMS is stratified according to the presence of associated lesions on T2-weighted images in baseline brain MRI: patients with normal MRI have a 25% chance of developing CDMS, whereas patients with ≥1 asymptomatic brain lesion have a 72% risk of developing CDMS.
The current correlation between childhood ON and MS is still based on retrospective studies in small samples, and overall, the conversion rate of CDMS in childhood ON is lower than in adult patients, with a distribution of 0%-33%. 13%, 19%, 22% and 26%, respectively.
In studies of risk factors for conversion to MS, most of the literature suggests a higher rate of MS conversion in children with monocular involvement; only 2 studies to date have argued the opposite, suggesting a greater risk of conversion to CDMS in both eyes with sequential ON or recurrent ON. Other studies have proposed that female patients and the presence of oligoclonal bands in the cerebrospinal fluid are more likely to convert to CDMS.
A recent meta-analysis of the results of 14 completed studies reported that age of onset may be the most direct correlate, with older children having a higher risk of converting ON to CDMS than younger ones.
Mikaeloff et al. suggested that patients older than 10 years of age at the time of first onset of ON and with MRI showing periventricular and/or subcortical demyelinating lesions and optic nerve demyelinating lesions had the highest risk of conversion to CDMS.
Wilejto et al. concluded from a study of 36 children with ON that brain MRI confirmed the presence of 1-2 white matter lesions significantly associated with the development of MS (p<0.0001). Several other studies have also suggested an increased risk of MS in ON patients with white matter lesions in MRI.
(2) ADEM: ADEM is a rare white-limited, extensively invasive inflammatory demyelinating disease of the CNS, and some investigators have suggested that childhood ON is more closely associated with ADEM than MS. The disease is most commonly seen in children 6-10 years of age with amnesia, and is rare in adults. It can take 3 clinical forms: monosheptic course, relapsing course, and polyphasic course. The etiology is unknown, but patients often have a history of viral infection or vaccination a few days to weeks before the onset of the disease.
Recently, an antibody against myelin and/or oligodendrocyte glycoproteins was found in a group of ADEM patients, suggesting that the autoimmune response to CNS may be part of the pathogenesis of ADEM.
Acute optic neuritis is one of its clinical manifestations, accompanied by behavioral changes (such as irritability, confusion) and altered consciousness (lethargy, coma) and other encephalopathic manifestations, and may also appear like meningitis, coma, hemiplegia or paraplegia, etc. Combining the typical clinical manifestations, relevant laboratory tests and imaging features, the diagnosis of ADEM is not difficult, but attention must be paid to differentiate it from MS. bilateral optic nerve involvement with more severe loss of consciousness and cognitive impairment.
In cerebrospinal fluid, oligoclonal bands appear sharply in the early stages, but disappear as the disease progresses; in brain MRI, multiple demyelinating lesions in the brain, cerebellum, cerebral decidua and spinal cord white matter can be seen, and these lesions tend to appear at the same time, with less axonal damage.
In terms of prognosis, although ADEM has more severe neurological dysfunction, its regression is generally ideal with effective symptomatic supportive treatment.
(3) NMO: NMO, also known as DPvie disease, is a severe inflammatory demyelinating autoimmune disease of the central nervous system that occurs between the ages of 5 and 60 years, with a marked tendency to develop in young adults and a marked tendency to develop in women. The disease mainly affects the optic nerve and spinal cord, manifesting as bilateral optic neuritis, severe loss of vision or even fire blindness, and visual field changes with diffuse loss of light sensitivity and dark spots in the heart of the scarf; myelitis occurs simultaneously or sequentially with optic neuritis, typically manifesting as acute transverse myelitis involving more than 3 segments of the cervical and thoracic segments.
In clinical diagnosis and treatment, we should pay attention to the differentiation between NMO and MS: MRI examination of NMO patients shows corresponding damage to the optic nerve, optic chiasm and cervicothoracic spinal cord, and there are no abnormal findings in the brain parenchyma in the early stage, and the changes in the internal tissues are manifested only after multiple relapses and remissions; whereas MS involves brain tissue earlier, and when the lesion involves the spinal cord, the scope of the lesion rarely exceeds 1 or 2 vertebral segments; there are fewer NMO in CSF examination, and even no lgG oligoclonal bands. There are few or no lgG oligoclonal bands in CSF, while 90% of MS have IgG oligoclonal bands.
In recent years, Lennnn et al. identified an autoantibody called NMO-IgG in the serum of adult patients with NMO, whose target antigen is aquaporin-4 (AQP4), and the AQP4 protein was significantly reduced or even lost in adult patients with NMO.
In 2008, BailwPll et al. earlier provided the seropositivity rate of NMO-IgG in children with inflammatory demyelinating diseases of the central nervous system (78% of them had positive NMO-IgG in childhood recurrent NMO sera), suggesting that the importance of NMO-IgG in the diagnostic process of childhood NMO should be emphasized.
Currently, for acute onset NMO, high-dose methylprednisolone shock followed by prednisone 1 mg.kg-1.d-1 orally is mostly used, and plasma exchange therapy is performed for those who are ineffective, and low-dose prednisone combined with immunosuppression can prevent NMO recurrence. In terms of prognosis, NMO is significantly worse than MS, and about 30% of NMO patients die of respiratory failure due to myelitis involving the high cervical segment of the spinal cord.
5.Treatment
The most authoritative treatment plan for adult typical ON is still the criteria proposed by the ONTT study, which are summarized as follows: (1) High-dose intravenous glucocorticosteroids can accelerate visual recovery when replaced by oral medication, but there is no long-term effect of improving visual acuity. (2) Oral glucocorticosteroids alone do not improve vision and can increase the recurrence rate. (3) Injection of glucocorticoids followed by oral medication reduces the incidence of CDMS in the first 2 years, but the therapeutic effect decreases after 3 years.
Due to the lack of evidence-based medical evidence on ON treatment in children, injectable methylprednisolone sodium succinate is still used as the main first-line drug.
The clinical use of injectable methylprednisolone sodium succinate is mostly by intravenous injection followed by oral administration, where a long course of oral hormone is recommended for its effectiveness in reducing the recurrence rate of ON, specifically intravenous methylprednisolone sodium succinate 4-30 mg.kg-1.d-1, followed by oral glucocorticoids for 4-6 weeks after 3-5 d. The initial dose is 1 mg/kg, which should be tapered, and should also be avoid long-term use to prevent growth retardation in the child.
Glucocorticoids should be contraindicated in children with a history of systemic or fungal infections, and live or live attenuated vaccines should be avoided during administration; attention should be paid to whether patients have adverse side effects such as insomnia, increased appetite (often leading to obesity), systemic hypertension, increased blood glucose, peptic ulcer formation, aseptic necrosis of the femoral head, and steroidal myopathy when high-dose intravenous methylprednisolone sodium vitrate is administered.
Although these side effects are less common in pediatric patients, they should still be treated with hormones along with gastric protection and calcium supplementation, while closely observing changes in the child’s condition.
In addition to glucocorticosteroids as the first-line clinical drugs, immunoglobulins and immunosuppressive drugs can be used when the disease is recurrent or when glucocorticosteroid treatment is ineffective. Intravenous immunoglobulin (0.4-2 g.kg-1.d-1) is usually administered for 2-5 d as a course of treatment, and can be used every month, every other month, or every 3 months for a year, and should be contraindicated in children with allergies, IgA deficiency, or the presence of anti-IgA antibodies.
If immunosuppression is necessary, clinicians tend to use azathioprine (2.5-3 mg.kg-1.d-1) and methotrexate (7.5 mg per week), which must be monitored closely to prevent toxic reactions such as hemocytopenia, hepatotoxicity, gastrointestinal disorders, hemorrhage, anemia, fever, infections and increased incidence of malignancy in children with leukopenia, hepatic disorders, immunodeficiency syndromes. It should be prohibited for those who suffer from leukopenia, liver disease, immunodeficiency syndrome.
Other drugs and therapies used for treatment, such as adrenocorticotropic hormone, interferon, antigen-specific immunotherapy, plasma exchange, hyperbaric oxygen, extracorporeal counterpulsation, and traditional Chinese medicine, have been tried, but there are no credible conclusions, and they need to be further practiced and discussed.
El-Dairi et al. proposed a more complete treatment plan for clinicians’ reference, namely, for children with suspected ON, relevant neuro-ophthalmological examinations, including visual field, OCT and serological examinations (to exclude cat-scratch disease, Lyme disease, NMO), corresponding localized enhanced MRI examinations (usually including brain, cervical medulla, orbit), and cerebrospinal fluid examinations (including protein, glucose, cell counts) will be routinely performed. (including protein, glucose, cell count, oligoclonal bands, IgG tests).
Treatment was intravenous methylprednisolone (30 mg.kg-1.d-1, no more than 1 g/d) if there were no contraindications and if the child’s parents agreed. 3 d later, prednisone (1 mg.kg-1.d-1, then tapered to no less than 4 d for 11 d) was switched to an intravenous dose. Follow-up neuro-ophthalmologic examinations will be performed at week 4, month 3 and month 6 after the improvement of the disease, and children with abnormal initial brain MRI examinations will be reexamined at month 3.
In clinical practice, clinicians should develop individualized treatment plans according to the patient’s specific situation, and should closely observe changes in the patient’s condition and possible glucocorticoid side effects when choosing glucocorticoids, and choose other types of drugs appropriately according to the patient’s treatment response. At the same time, in view of the diverse causes of childhood ON, ophthalmologists should also carry out specialist consultations and targeted treatment for different causes in the consultation and treatment process.
6.Summary
The clinical diagnosis, treatment and prognosis of childhood ON are not the same as those of typical adult ON. childhood ON is mostly bilateral, often preceded by prodromal infection, and the fundus is mostly characterized by optic papillitis or optic papilledema.
Treatment is still based on glucocorticoid shocks, visual recovery is relatively ideal; in terms of prognosis, childhood ON can occur as CIS, may also be associated with ADEM, some patients can also be transformed into MS or NMO, so the diagnosis and treatment of neurological assessment and follow-up is also particularly important.
The etiology, diagnosis, and treatment of childhood ON are still being explored, and most of the available data are retrospective analyses and observational trials. In order to achieve the purpose of guiding clinical practice, there is a need for more evidence-based research data, such as large sample multicenter controlled clinical trials, systematic evaluation and analysis.
At the annual meeting of the North American Neuro-Ophthalmology Society in Vancouver, Canada, Grant Liu and colleagues from the University of Pennsylvania suggested a prospective study of optic neuritis treatment in children.