Management and outcomes of pediatric optic neuritis in a tertiary hospital in Riyadh, Saudi Arabia: a retrospective study

Abstract

Background

Although pediatric optic neuritis (PON) is a rare condition, current advancements in its diagnosis, investigation, and treatment suggest that a more precise risk assessment is necessary given the history of irreversible damage and functional degeneration of the optic nerve. Additionally, after further investigations and/or new neurological events, the initial diagnosis is revised.

Aim

To report clinical profile, management and outcome of different demyelinating disease phenotypes of pediatric optic neuritis (PON) in individuals under the age of 18 years in a tertiary center in the Kingdom of Saudi Arabia (KSA).

Study method

We analyzed the electronic medical records of pediatric patients under the age of 18 years who first experienced different phenotypes of demyelinating PON between January 2000 and December 2020 as part of this retrospective case series. We studied the clinical characteristics, serology, imaging data, treatment regimens, and follow-up of the patients. Descriptive statistics were calculated.

Results

The majority of patients were less than 10 years old (63.6%), males (63.6%) and had bilateral involvement (72.7%). Among the 11 patients diagnosed with PON, 5(45.5%) had isolated pediatric optic neuritis, 1 (9.1%) had multiple sclerosis (MS), 1(9.1%) had neuromyelitis optica spectrum disorder (NMOSD), 1 (9.1%) had acute disseminated encephalomyelitis (ADEM) and 3 (27.2%) had myelin oligodendrocyte glycoprotein (MOG) antibody associated disease (MOGAD). Despite poor vision at presentation, most of the patients improved, 81.1% achieved a BCVA of ≥ 20/40, and 36.6% attained 20/20 visual acuity. Four patients experienced recurrence.

Conclusions

The overlapping features of disease phenotypes in PON make it difficult to identify the underlying cause. The findings of this retrospective case series suggest the need for a future prospective multicenter study for a better understanding of the different phenotypes.

Introduction

Inflammatory disease of the optic nerve, known as optic neuritis (ON), is characterized by visual impairment, periorbital discomfort, color vision deficiency, and visual defects. These symptoms can occur in isolation or frequently co-occur in an acute or subacute manner [1]. Pediatric optic neuritis (PON) can be sporadic and reversible, or it might be a manifestation of a neurologic, infective, or systemic disease. There are a wide variety of etiologies for PON; it can be idiopathic or due to an autoimmune, infectious, granulomatous, vasculitis, paraneoplastic, or demyelinating disorder, which is by far the most common cause [2, 3]. Accurately assessing and diagnosing pediatric optic neuritis (PON) is crucial because of its significant impact on quality of life, especially when it evolves into several demyelinating diseases, such as multiple sclerosis (MS), neuromyelitis optica spectrum disease (NMOSD), or myelin oligodendrocyte glycoprotein (MOG) antibody associated diseases (MOGAD) [4]. Recently, the disease phenotypes and causative mechanisms for PON have been studied, and these different phenotypes have unique features regarding treatment and prognosis [5].

In the Kingdom of Saudi Arabia (KSA), there is still insufficient rigorous research on PON. No study was done in this field for verifying the clinical profile of PON in KSA. By this case series study, we aimed to examine the PON records presented at King Abdulaziz Medical City (KAMC), Riyadh (KSA), and report the presentation, visual acuity (VA) outcomes, treatment modalities, recurrence, and prevalence of associated demyelinating diseases.

Method

Study design

This retrospective case series study of PON included individuals aged less than 18 years who presented from January 2000 to December 2020 at KAMC (KSA). After approval from the ethical committee, we collected information from the electronic medical records of patients who visited the neurology and ophthalmology clinics at NGHA.

The inclusion and exclusion criteria were as follows: patients younger than 18 years of age who presented with acute-onset visual symptoms and signs of PON with demyelinating disease were included and excluded patients with other causes of optic neuropathy like vascular, genetic, toxic, compressive or metabolic optic neuropathy. The demographic parameters and PON-related factors, including presenting symptoms, laterality, associated neurological symptoms, visual acuity (VA), color vision, pupil and optic disc findings, neuroimaging results, cerebrospinal fluid (CSF) analyses, aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibody levels, and any treatment provided and outcome, were obtained from these individuals’ records and documented. In our setting, all pediatric patients seen in the pediatric emergency room were triaged under the care of general pediatrics, and then neurological cases were transferred under the care of pediatric neurology. For those cases like optic neuritis a multidisciplinary team which includes pediatric ophthalmologist, infectious disease specialist, geneticist or immunologist are involved.

The diagnoses were confirmed on the basis of the following diagnostic categories: isolated ON and multiple sclerosis (MS), according to the 2013 International Pediatric Multiple Sclerosis Study Group consensus criteria; neuromyelitis optica (NMO) spectrum disorder (NMOSD), according to the 2015 International Panel for NMO diagnosis criteria; and acute disseminated encephalomyelitis (ADEM) and ADEM-ON, according to the 2013 Pediatric Multiple Sclerosis Study Group consensus criteria [6]. We collected the last follow-up data at least 6 months after the PON episode to determine the final VA.

Ethics statement

The study obeyed the tenets of the Declaration of Helsinki and received approval from the Institutional Review Board and Ethics Committee at the King Abdullah International Medical Research Center, Riyadh, KSA (RYD-22-7850-145315). Owing to the retrospective nature of the study, informed consent was waived by deidentifying patient information.

Statistical analysis

In this cross sectional study, the data are presented as frequencies and proportions. These variables included age, sex, eye involvement, presenting symptoms, ocular signs, visual acuity, fundoscopy, diagnosis, treatment, outcome, and recurrence. We calculated the Karl‒Pearson correlation coefficient to evaluate the relationships between continuous variables. The statistical package IBM SPSS (release 20) was used for data management and analysis.

Results

We enrolled a total of 11 patients with PON who satisfied the inclusion criteria: 36.4% were female, and 63.6% were male. The age distribution of PON patients is shown in Fig. 1. Other demographic and clinical profiles of patients who presented with PON are described in Table 1. Most of the cases were bilateral (72.7%). In total, 64% of the patients presented with a VA worse than 20/40. Optic disc swelling (63.6%) and pallid disc (45.4%) was the most common fundoscopic finding. Our data revealed that there were five cases of isolated optic neuritis (45.5%), one case of NMSOD (9%), one case of MS (9%), one case of ADEM (9%) and three cases of MOG (27.2%). All patients received the Optic Neuritis Treatment Trial (ONTT) protocol (3–5 days of intravenous methylprednisolone (IVMP) 20–30 mg/kg/day (maximum 1 g daily) followed by oral prednisolone tapering over 1–4 weeks starting with a dose of 1 mg/kg/day). All patients who were diagnosed with MS, NMSOD, ADEM and MOG ON had abnormal brain or spine MRI images. The MRI characteristics of each subcategory are summarized in Table 2. We investigated the correlation between visual acuity at presentation and visual acuity after 6 months of treatment, but the Karl Pearson correlation coefficient was 0.385 (p = 0.243).

Fig. 1

Age distribution of pediatric patients with optic neuritis at presentation

Table 1 Clinical parameters in different phenotypes of PON

Discussion

With increasing knowledge of the disease phenotypes of demyelinating PON, there is a need to study the clinical syndromes and their appropriate treatment and prognosis. Although the incidence of optic neuritis is greater in adults than in pediatric patients, PON accounts for one-fourth of all childhood-acquired demyelinating syndrome cases [2]. Compared with adult cases, which occur at an incidence rate of 5.1 per 100,000 person-years, pediatric optic neuritis is extremely rare, with a yearly incidence of 0.15–0.57 per 100,000 person-years [7,8,9]. In a population based cohort study it was found pediatric acquired demyelinating disease is common in black followed by Asian Pacific Islanders, White and at last Hispanics [7]. Incidence of pediatric acquired demyelinating syndromes per 100,000 children are studied in different parts of the world 0.9 (Canada), 1.6 (Southern California), 2.29 (Denmark), 0.66 (Netherlands) and 5.1 (Minnesota).But no similar data from KSA is available or studied before for comparison [10,11,12,13,14]. Compared with younger children, adolescents have a significantly greater incidence of PON [15]. However the present study showed 63.6% cases in the age group less than 10 years. In our study, there was a male preponderance (63.6%) and a greater proportion of bilateral cases (72.8%). In younger children, there was no gender predilection, but there was a greater predilection in females in the adolescent group [16]. Previous studies have reported that 32–50% of cases presented bilaterally, which is higher than that reported in adults with ON [17,18,19,20]. Past studies have reported that PON patients experience optic disc edema more frequently (50–74%) than adult optic neuritis AON patients do (35%) and that young people have eye pain less frequently (43–49%) than adults do (92%) [19, 21,22,23]. However, in this study, the most prevalent presenting complaints were headache and eye pain, whereas the most common optic disc finding was optic disc edema, followed by disc pallor, which is similar to the findings of previous studies. More than half of PON patients presented with visual acuity worse than 20/40 whereas at 6 months 81.1% cases improved better than 20/40. This case series discusses the clinical profile of 11 PON patients with 5 different demyelinating diseases.

Multiple sclerosis-related optic neuritis (MS-ON)

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. One-fourth of children who present with PON subsequently receive a diagnosis of pediatric-onset MS (POMS) [20]. This conversion to MS is greater in adults, with 50% over 15 years, whereas in children, it is 22–29% [24]. We had only one patient with MS-ON who presented with blurred vision and eye pain in the right eye. The visual acuity at presentation of the affected eye was 20/200. Although optic disc edema is rarely observed in MS-ON patients, in this case, it was present. MRI of the brain, optic nerve, and spine was done which showed periventricular and infratentorial T2 hyper intense discrete lesions in the brain with minimal focal prominence of right retro bulbar optic nerve. Intravenous methyl prednisone (30 mg/kg/day) was given for 5 days, followed by oral steroids given with incomplete recovery and one recurrence in the following year. According to reports, children with MS-ON have a poor visual prognosis; only 27% of them recover visually after a year, and 68% of them continue to experience visual field impairment [24]. In this case, there was also a persistent field defect and incomplete recovery. Earlier studies have concluded that POMS has a higher relapse rate, which is earlier than that of adult MS, an increasing accumulation of MRI lesions, faltering age-expected brain growth, and cognitive impairment [25,26,27,28]. Although the progression of MS is slower in younger children because the disease starts earlier than it does in adults, irreversible disability develops approximately 10 years earlier [29, 30]. During the acute phase, MS-ON patients often adhere to the widely recognized optic neuritis treatment trial (ONTT) regimen. In cases where the use of steroids is contraindicated or where there is a poor IVMP response, alternative treatment is given via two–four days of intravenous immunoglobulin (IVIG) at a dose of 2 g/kg or 5–7 plasma exchanges (PLEX) over 10–14 days. The use of disease-modifying medications (DMDs) in children, such as fingolimod, IFNb-1a, peginterferon b1a, dimethyl fumarate, teriflunomide, alemtuzumab, natalizumab, and rituximab, is intended to reduce lifelong disabilities. In our case, DMDs were offered, but the parents declined.

Neuromyelitis Optica (NMO) spectrum disorder (NMOSD)

Although NMOSD is rare in the pediatric age group, accounting for only 3–5% of demyelinating cases, it is more prevalent in Black and East Asian ethnicities [31, 32]. Autoimmune astrocytopathy and neuronal necrosis lead to glial dysfunction and demyelination, causing severe damage [31, 33, 34]. Bilateral involvement, poor visual recovery despite vigorous treatment, nerve enhancement in the posterior optic nerve segment, optic chiasma, and a tract with absent MRI brain lesions are red flags for NMOSD. In our case it was nine year old boy who presented with nausea, headache, headache and blurred vision with 20/400 visual acuity and disc swelling in both eyes. MRI of the optic nerve demonstrated enhancement of T2signal in the anterior segment of optic nerve and MRI spine showed multiple spinal cord lesions mainly centered at cervicothoracic region. The serology was double negative (AQP4 IgG and MOG-IgG).The ONTT protocol, followed by rituximab, was given. Although the patient recovered completely with 20/20 visual acuity in both eyes, two years later, he experienced transverse myelitis and documented developmental delay. Positive AQP4 antibody result carry risk of poor prognosis and predictive of relapsing course and it was repeated in this patient but was negative report.

Acute disseminated encephalomyelitis (ADEM)

Acute disseminated encephalomyelitis (ADEM) is a progressive autoimmune process that usually affects children. Clinically, it presents as an acute multifocal demyelinating disease affecting the brain (encephalopathy), spinal cord, and, less commonly, optic nerve (optic neuritis), with a prior history of infection or vaccination [34, 35]. Although ADEM is considered a relatively rare illness, the incidence of ADEM yearly is estimated to be 0.07 to 0.9 per 100,000 children [36]. Our patient was a 14-year-old female who presented with blurred vision and eye pain with a 1-month prior history of upper respiratory infection, earache, and unsteadiness. The ophthalmology examination revealed that the right eye visual acuity is counting fingers 1 m, with a relative afferent pupillary defect and optic disc edema. An MRI revealed tortuous optic nerves with a normal brain and spine. The patient recovered completely with 20/20 vision but experienced recurrence after 3 months with unsteadiness, bilateral decreased vision, and an MRI showing brachium pontis enhancement and spine involvement. AQP4 and MOG IgG was done which were negative for this case. Kumar et al. reported a similar case and responded to the ONTT protocol with a complete recovery, as in our case [37]. Diagnosis of ADEM is challenging, as most of the time, MRI at presentation may turn normal, as in our case also in the above case, but later, when MRI showed T2-hyperintense lesions mainly involving white matter of brain and spinal cord without periventricular lesions it favored diagnosis of ADEM [38, 39].

Isolated pediatric optic neuritis

The Pediatric Eye Disease Investigator Group (PEDIG) and the Neuro-Ophthalmology Research Disease Investigator Consortium (NORDIC) jointly conducted a prospective PON 1 study, which provided the longest follow-up of PON visual acuity outcomes and insights into the risk of disease recurrence and the development of associated demyelinating diseases [19]. According to a meta-analysis, 70% of children older than 10 years old presented with unilateral optic neuritis, whereas 72% of children under 10 years old presented with bilateral involvement [20]. In the present study, the majority (45.4%) of our patients had isolated optic neuritis, most of whom (80%) were males, were above the age of 10 years, and had bilateral eye involvement.20% of isolated ON patients presented with eye pain, while 40% presented with headache, and another 40% presented with visual field loss. More than half (60%) of the patients presented with optic disc swelling. Patients were treated with the ONTT regimen; most patients had excellent outcomes with improved visual acuity at subsequent visits and one had recurrence. In a retrospective multicenter study, of 115 children with isolated ON with normal brain MRI 8% met the criterion for MS during the 4 year follow-ups [40]. Despite the fact that an isolated optic neuritis cannot be diagnosed without a period of follow-up, defining its prevalence is more challenging.

Myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD)

MOGAD is a unique demyelinating disease that manifests as optic neuritis in children older than 11 years and as acute disseminated encephalomyelitis (ADEM) in children less than 11 [41, 42]. Important features that can assist differentiate MOG-ON from optic neuritis caused by other etiologies include bilateral involvement, disc swelling both clinically and radiologically, and longitudinally extensive optic nerve hyper intensity with accompanying optic perineuritis on MRI [43]. Our first case was a three year-old child who presented with hypo activity and meningismus upon admission and was empirically treated for meningitis. After 2 days, poor eye fixation, altered sensorium, and increased white blood cells in the cerebrospinal fluid raised suspicion of an alternative diagnosis. The ophthalmology examination revealed visual acuity 20/60 both eyes with bilateral optic disc edema, and the ONTT protocol was initiated. Once abnormal brain and optic nerve MRI results with positive MOG Ig results were obtained, the patient was started on intravenous immunoglobulin and rituximab. The symptoms completely resolved, with a normal disc and a visual acuity of 20/25 in both eyes. The second patient had a similar presentation, but the age was nine years. This child was also MOG-IgG positive with nonspecific T2 hyper intensities in MRI brain, short T2 hyper intensities in cervical region along edematous extended lesions in the anterior segment of optic nerve and recovered completely with 20/20 visual acuity using the ONTT protocol and intravenous immunoglobulin. Third case was nine year old child with right eye pain and blurred vision with disc swelling in the right eye .MRI of optic nerve showed T2 hyper intense signal of anterior short segment of optic nerve with frontal cortical and juxta cortical high T2 signal in MRI brain. All three patients were MOG Ig positive and AQP4 IgG negative. Once received positive MOG results these children were treated with a combination of intravenous immunoglobulin (IVIG) at a dose of 0.4 g/kg/day for five days, high-dose oral steroids (methylprednisolone 1 mg/kg/day for three days), followed by a tapering dose of oral prednisone, and rituximab (375 mg/m² on days 0 and 14). All three patients achieved good visual recovery, as previously documented. 58% of pediatric NMOSD cases were MOG antibody positive, according to a prospective study conducted in Europe.⁽⁴⁴⁾56–73% of patients who present with MOGAD-ON fully restore their visual acuity, which is better than that of adult patients [45]. According to a prospective 2-year study 50% of pediatric patients with MOGAD and multiphasic disseminated encephalomyelitis (MDEM) experienced cognitive problems, while no patients with recurrent ON alone (i.e., no episodes of ADEM or NMOSD) experienced cognitive problems [46]. However, patients with recurrent MOGAD-ON are at a high risk of losing their vision. In order to direct treatment for patients with relapsing disease, a MOGAD diagnosis at the onset of ON is crucial [47].

Our study revealed that during follow-up, the diagnosis of some individuals who received treatment with PON may have been revised. Moreover, the PON in the Saudi community has clinical and paraclinical features that support findings from earlier international studies. The overlapping features of disease phenotypes in PON in terms of neuroimaging, serology, and clinical presentation make it difficult to identify the underlying cause.

Limitations

The type of study is a retrospective case series with limited available data. There was a lack of a suitable denominator to calculate the incidence, and there were no comparison groups. Additionally, we could not retrieve data from the visual field, optical coherence tomography, or cerebrospinal fluid analysis. On the basis of the findings of this retrospective analysis, we recommend a multicenter prospective study of a large number of patients in Saudi Arabia.

Conclusion

The information provided by this case series study from KSA may aid in understanding high variability in demyelinating PON and the need to assess its natural history in order to identify its pathogenic mechanism and evolution. To identify the optimal treatment choices, possible sequelae, and predictors of different phenotypes of PON, more extensive prospective and multicenter research is required.

Table 2 MRI characteristics of Pediatrics optic neuritis