CASE REPORT Neuromyelitis optica and other causes of demyelinating optic neuritis in children

Neuromyelitis optica and other causes of demyelinating optic neuritis in children

DD Shastry MBChB, FC Ophth(SA); Registrar ORCID: https://orcid.org/0000-0002-2727-172X

J Olivier MRCOphth, MMed(Ophth); Head of Department of OphthalmologyC Cullen MBBCh, FC Ophth(SA), Fellowship (Paediatric Ophthalmology and Adult Strabismus); Sessional ConsultantDr George Mukhari Academic Hospital, Department of Ophthalmology, Sefako Makgatho Health Sciences University, South Africa

Corresponding author: Dr DD Shastry, Department of Ophthalmology, PO Box 66, Medunsa, GaRankuwa 0204; email: dimple_deepa@hotmail.com; cell: 0724322398

Abstract

Optic neuritis in childhood is one of the most frequent presentations of an acquired demyelinating syndrome. Paediatric optic neuritis is, however, an infrequent clinical presentation.

We present an interesting case of an 8-year-old female with optic atrophy in the left eye accompanied by a right optic neuritis who subsequently developed a lower limb paralysis and right-sided blindness within a few weeks of discharge. Radiological imaging revealed demyelinating lesions of the transverse spinal cord. A diagnosis of neuromyelitis optica (NMO) was made and the patient was treated with immunosuppressive therapy.

This article describes the presentation of paediatric optic neuritis as well as the differences between three common aetiologies thereof, namely neuromyelitis optica (NMO), acute disseminated encephalomyelitis (ADEM) and paediatric multiple sclerosis (MS).

Management of paediatric optic neuritis is largely based on adult trials. It is necessary for the clinician to bear the diagnosis in mind if young patients present with similar clinical features. Ruling out such conditions is important to prevent permanent vision loss or other neurologic impairment.

Keywords: neuromyelitis optica, acute disseminated encephalomyelitis, multiple sclerosis, paediatric, optic neuritis

Funding: No funding was received for this study.

Conflict of interest: The authors declare they have no conflicts of interest with regard to this study.

Introduction

Paediatric optic neuritis (PON) is an uncommon clinical presentation and may be challenging to manage. There are few published case series in the literature, mainly from Europe and North America, with limited data from Asia and sub- Saharan Africa. The incidence in Canada is approximately 0.2 per 100 000.1 From the majority of these case series, <10% of children with ON are documented to develop a demyelinating condition. 2 ON in children presents differently from adults; children are more likely to have more severe visual deficit, a preceding viral illness or vaccination and bilateral optic nerve swelling. The Optic Neuritis Treatment Trial (ONTT) conducted on an adult population provided invaluable long-term data on visual outcomes in patients with ON as well as their risk of developing multiple sclerosis (MS). The treatment guidelines provided by the study are currently the standard of care for adult ON. It was demonstrated that at 15 years, the visual outcomes were good with 72% of patients enrolled to the study having a visual acuity better than or equal to 20/20 in the eye which had ON, and 66% of patients having better than or equal to 20/20 visual acuity in both eyes. 3 MS developed in only a small subgroup of patients.3 In contrast, far less is known about the spectrum and outcomes of ON in children.

Parainfectious causes are the most common aetiology of ON in children, while the most common aetiology in adults is MS. When PON occurs as a self-limiting isolated event it carries no prognostic implication with regard to the rest of the nervous system. Most children recover visual acuity spontaneously; however, in the cases that fail to recover, the impact on vision is lasting and may take the form of prominent low-contrast vision, colour perception and visual field deficits. Current management of PON is mainly based on adult trials and the results of the ONTT where IV methylprednisolone, if given within the first 15 days after onset, may accelerate visual recovery compared to placebo or oral steroids. 3 For most children with ON the recommended first-line treatment is IV methylprednisolone (20–30 mg/kg/d; maximum dose of 1 g/d) for 3–5 days; thereafter tapering prednisone over two weeks (1 mg/kg/d orally). Additional therapies (IV immunoglobulin G and plasma exchange) may be considered in children with diffuse central nervous system involvement who do not show response to IV methylprednisolone.

Acquired demyelinating syndromes in childhood commonly present with unilateral ON, followed by rapid bilateral involvement. Frequent relapses have a cumulative effect on visual loss. Herein lies the importance of PON to the ophthalmologist. While the initial disturbances may be limited to visual deficits, further investigations will reveal a specific aetiology. The aim of this article is to describe the differences between three common aetiologies of PON, namely neuromyelitis optica (NMO), acute disseminated encephalomyelitis (ADEM) and paediatric multiple sclerosis (MS) in presentation, diagnosis, treatment and prognosis (see summary in Table I). ADEM and MS are immune-mediated conditions while NMO is antibody-mediated. Ruling out these conditions is paramount to preventing permanent vision loss and other neurologic impairment.

Case presentation

A previously healthy 8-year-old girl was brought to the Ophthalmology Department with the concern of a sudden deterioration of vision in both her eyes. She reported difficulty in seeing for the past five days. The mother was concerned as the child had no prodromal symptoms, previous illness or trauma in the preceding weeks. Her systemic physical, including neurological, examination was normal.

Her visual acuity in both eyes revealed light perception with a relative afferent pupillary defect in the left eye. The left optic disc was pale and suggestive of optic atrophy. The right fundus examination showed a swollen optic disc with a blurred disc margin. The optic disc was pink and well perfused with no peripheral lesions or haemorrhages of the retina. The mother was not aware of any loss of vision in the left eye prior to consultation. A working diagnosis of optic neuritis (ON) was made.

The patient was admitted for treatment with high dose intravenous (IV) steroids (1 g/day IV for three days) followed by oral steroids for 11 days (1 mg/kg per day). The initial diagnostic work-up, which included tests for viral serology TORCH-S (toxoplasmosis, rubella, cytomegalovirus, herpes simplex, syphilis), as well as a brain magnetic resonance imaging (MRI) scan, was normal (Figure 1). After completing the steroid treatment, the patient’s vision in the right eye had returned to 20/20 (6/6) and all the disc changes had resolved at followup two weeks later. The left eye vision remained at light perception.

Figure 1. MRI brain and C-spine (T1-weighted) demonstrating normal initial study

Two months later, she was brought to the emergency department and re-admitted to the hospital with an acute inability to walk. She had started limping three days prior and was unable to see with her right eye. At this time, she also had urinary retention, associated headaches and loss of weight.

The cranial nerves and sensation were otherwise intact, with normal strength and deep tendon reflexes of the upper limbs. There was significantly reduced power of both lower limbs with absent reflexes and decreased tone and accompanying neck stiffness. Treatment was initiated for a meningitis while awaiting brain contrast tomography (CT) and lumbar puncture results. The CT and lumbar puncture results were unremarkable. A subsequent MRI orbit and spine was performed which showed longitudinal extensive spinal lesions over more than three segments (Figures 2–4). In the absence of encephalopathy, a presumptive diagnosis of neuromyelitis optica (NMO) was made. High dose IV methylprednisolone therapy was prescribed.

Figure 2 and 3. MRI spine demonstrating diffuse longitudinal high signal changes in the cervical and thoracic area on T2-weighted imaging extending more than four vertebrae levels (indicated with yellow arrow)

Figure 2 and 3. MRI spine demonstrating diffuse longitudinal high signal changes in the cervical and thoracic area on T2-weighted imaging extending more than four vertebrae levels (indicated with yellow arrow)

Figure 4. MRI spine demonstrating diffuse longitudinal high signal changes in the cervical and thoracic area on T1-weighted imaging (indicated with yellow arrow)

Despite treatment and physiotherapy rehabilitation, the patient’s symptoms and lower limb paralysis remained unchanged throughout the time of admission of four weeks. A follow-up examination of her right fundus revealed a pale optic disc, in keeping with light perception vision from optic atrophy. The high dose IV steroid treatment was changed to oral course and then gradually tapered. The patient was subsequently discharged home to continue physiotherapy rehabilitation. Over the next three months, she had some improvement in her lower limb power.

The patient presented again six months later, with an acute onset of difficulty in breathing with bilateral coarse crepitations on auscultation as well as decreased upper limb strength. Blood tests for aquaporin-4 (AqP4) antibodies were negative. She was treated with IV antibiotics and IV immunoglobulin (Polygam) and recovered from the respiratory tract infection. Gradually, she also regained some upper and lower limb power. There have been no further events in the past 18 months. However, the vision in both eyes remains unchanged at <20/200 (light perception).

Discussion

Neuromyelitis optica

Neuromyelitis optica (NMO) is a chronic inflammatory disease associated with a disease-specific autoantibody which affects the central nervous system (CNS). Recurrent episodes of ON and myelitis are presenting features, often with limited or no recovery, resulting in permanent blindness and/or limb paralysis. Other features associated with spinal cord lesions include urinary dysfunction. Global incidence and prevalence rates of NMO are lacking. In the developed world, the estimated prevalence ranges from less than 1 to 4.4/100 000.4 Paediatric cases are rare and account for only 3.4% of all NMO cases. 4 In non-Caucasian patients, there is a female dominance and average age of onset of 12 years. A first event of ON occurs in 50–70% of childhood NMO cases and transverse myelitis may occur in 30–50%. These two features may occur either alone or in combination.4,5 Within five years of onset half of the patients lose functional vision, suggesting that paediatric onset may be associated with more frequent and disabling ON. 5 NMO was previously regarded as a variant of MS but has recently been grouped under the class of neuromyelitis optica spectrum of disorders (NMOSD).4

The differential diagnoses of NMOSD includes various autoimmune, vascular, infectious or neoplastic aetiologies. In the early stages of disease, patients with NMOSD may have limited presenting features. Conditions such as MS, ADEM, idiopathic acute transverse myelitis, idiopathic ON, sarcoidosis, CNS lymphoma and systemic lupus erythematosus may have overlapping clinical signs and must be excluded before a diagnosis of NMOSD can be made, as the treatment differs vastly. The following tests are recommended to exclude these conditions: full blood count with differential, serum chemistry, blood sedimentation, coagulation studies, Treponema pallidum hemagglutination assay, antibodies associated with connective disorders (ANA/ENA, anti-ds-DNA antibodies, lupus anticoagulant, antiphospholipid antibodies, ANCA, etc.), vitamin B12, folic acid and analysis for copper deficiency. 4 Based on clinical presentation, urine chemistry and sedimentation as well as cerebrospinal fluid (CSF) analysis should also be performed.

Research efforts into the cellular mechanisms of NMO are being directed at autoantibodies (AqP4-IgG) that target aquaporin-4 (AqP4) channels. Cell-meditated cytotoxicity may occur when AqP4-IgG binds to AqP4 on the cell membrane of astrocytes, initiating complement- and antibodydependent inflammation cascades. AqP4‐IgG seropositivity ranges from 17–80% and is associated with a relapsing course.6,7 The Aqp4-IgG laboratory assay may not be readily available; however, it is a highly specific diagnostic test used to predict long-term prognosis and therapeutic response. Demographic and disease-related characteristics differ between seropositive and seronegative NMO patients. The diagnosis of NMOSD with AqP4-IgG requires the presence of at least one core clinical feature of NMOSD in either cerebrum, brainstem, dorsal medullar, optic nerve or spinal cord and positive AqP4-IgG, where alternative diagnosis have been excluded.8 The diagnosis of NMOSD without AqP4-IgG requires one clinical event involving at least one of the typical anatomic regions together with additional MRI criteria beyond longitudinally extensive transverse myelitis.6

The typical features of NMO on T2-weighted MRI are high signal, central longitudinal spinal cord lesions spanning over three or more vertebral segments. Contrast agents and follow-up examinations are recommended as one-third of patients with brain lesions show gadolinium enhancement in a cloud-like pattern.4 Optic nerve involvement is demonstrated as high signal longitudinal lesions which extend over more than half of the length of the optic nerve in T2-weighted or short T1-inversion recovery images.6 Most children present with acute transverse myelitis more often at relapses than at presentation. The role of optical coherence tomography in ophthalmology as an adjunct to diagnosis and disease progression monitoring has not yet been established.9

At present there is no curative treatment for NMO. Acute attacks in all patients with suspected NMOSD should be treated as soon as possible while diagnostic tests are underway to prevent irreversible optic nerve injury. A high dose of IV methylprednisone (1 g daily) is given for three to five days.10 Plasma exchange or IV immunoglobulin therapy is used in cases unresponsive to steroid treatment. Following stabilisation after the acute attack, it is advised that every patient with NMOSD be started on immunosuppressive therapy. Azathioprine, methotrexate, mycophenolate or rituximab may be considered and continued for up to five years after the attack.10 Seronegative NMO follows a monophasic course and immunosuppressive therapy may be tapered after some years of disease stability. The future of therapies may lie in anti-IL6 receptor, anti-complement and anti-AqP4-ab biologicals which are currently being investigated.11

The nature of NMO is either monophasic or relapsing. More than 90% of patients suffer further relapses, making the prognosis challenging. 5 Within the first year 60% of patients suffer a relapse and 90% relapse within three years. The prognosis of patients with relapses is not favourable as neurological injuries are cumulative and remissions are not constant.

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating disorder of the CNS that also presents with ON and an acute onset encephalopathy. The pathogenesis of ADEM is thought to occur when antigenic determinants of an infecting pathogen may be shared with those of myelin autoantigens (myelin oligodendrocyte protein and myelin basic protein).12 In 72–77% of patients a preceding non-specific viral or bacterial infection can be identified, with onset of symptoms classically occurring two to four weeks following an infection.13,14 Acute disseminated encephalomyelitis has an estimated incidence of around 0.3–0.6 per 100 000 per year.12 It is usually a monophasic disease with a median age of 5–8 years at presentation and a male predominance.

Acute disseminated encephalomyelitis produces multiple inflammatory lesions in the brain and spinal cord white matter causing various neurologic symptoms, which may occur concurrently at presentation. ON, weakness, gait abnormalities and paraesthesias are dependent on the location of these lesions. A preceding prodromal period may accompany symptoms such as malaise, headache, irritability, fever, nausea and vomiting. Acute disseminated encephalomyelitis progresses rapidly and deficits are most pronounced within two to five days.13 The major diagnostic criteria of ADEM are an acute or subacute onset of clinical CNS demyelinating disease with encephalopathy and polysymptomatic neurologic features.12 Encephalopathy is a differentiating feature of ADEM from other syndromes and is an essential symptom for a diagnosis of ADEM. Encephalopathy may present with subtle behavioural changes, such as lethargy or irritability, or with alterations in level of consciousness and coma in more severe cases. In two-thirds of patients the CSF analysis will reveal a lymphocyte predominance, mild pleocytosis and/or increased protein concentration.13

The characteristic patterns of CNS lesions on MRI imaging are most notable on T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging in the deep and subcortical white matter. Lesions vary in number and size, with diameters from <5 mm to 5 cm, and are ill-defined. Bilateral cerebral involvement and lesions in the thalamus and basal ganglia are common and highly suggestive of ADEM. Large confluent intramedullary lesions in the spinal cord may span multiple segments and demonstrate variable contrast enhancement on imaging.14 At least two additional MRI scans are recommended at follow-up over a period of five years after the first negative scan.12

First-line therapy for ADEM is systemic corticosteroids consisting of IV methylprednisolone 20–30 mg/kg per day for three to five days. Thereafter oral prednisone is continued at 1–2 mg/kg per day for one to two weeks with tapering over two to six weeks.14 IV immunoglobulin and plasmapheresis are alternate therapies for steroid unresponsive cases.

The majority of children with ADEM are reported to have a favourable outcome. Neurologic improvement is seen within days of treatment and full recovery occurs within weeks.14

Multiple sclerosis

Multiple sclerosis (MS) is most commonly diagnosed in young adults. Paediatric MS (early-onset MS or juvenile MS) is diagnosed in children before the age of 16 years. Although it occurs infrequently in children, there is a global increase in incidence and prevalence in this subgroup of patients. The incidence of MS is between 3% and 10% under 16 years of age and less than 1% under 10 years of age.15 Paediatric MS differs from adult MS in its disease course and clinical features. Children experience a slower disease course with more frequent relapses, which causes significant disability to accumulate by early adulthood. It is suggested that the condition is caused by dysregulation of the immune system followed by recurrent episodes of demyelination in the CNS. Research efforts are being directed towards identifying a genetic susceptibility and specific environmental triggers of MS.16

Children can have a polyfocal presentation at disease onset corresponding to areas within the brain, optic nerves or spinal cord of acute inflammation and demyelination. A wide range of manifestations may result from ON, sensory, brainstem-cerebellar and motor involvement, resulting in impaired vision, walking, balance, bladder and bowel control, numbness, tingling sensation and fatigue.15 Other features more common in children include symptomatic encephalopathy like headache, vomiting and altered level of consciousness. In 15–20% of MS children, the symptoms may be similar to ADEM.16

The CSF analysis of paediatric MS patients demonstrates the presence of oligoclonal bands in 40–50% of cases, which is distinctly less than in adults.16 Features of MS on MRI are best recognised using T2-weighted sequences and T2 FLAIR image sequences, which demonstrate multiple well-demarcated hypointense lesions in the periventricular and spinal cord as well as juxtacortical and infratentorial white matter. Absence of typical ‘black holes’, diffuse bilateral lesions and fewer than two periventricular lesions differentiates ADEM from MS patients. The revised McDonald criteria (2010) are used for diagnosis of paediatric MS which evaluates the presence of disseminated lesions on clinical and MRI findings.16 The risk of PON evolving into MS increases with age, the presence of lesions on brain MRI at initial presentation and new lesions in different sites on follow-up MRI.15 However, the true risk of development of MS is still uncertain in this subset of patients.17

Data on the optimal therapy of MS in the paediatric population is not well established. A multidisciplinary approach towards management is recommended, which includes physical therapy, occupational therapy and counselling. Symptom severity depends on the duration of the disease and severity of MS.16 Treatment is aimed at relieving some of the symptoms of the disease, such as fatigue, and improving quality of life. Corticosteroids are used in the acute setting to reduce inflammation. IV immunoglobulin and plasma exchange may be used for children who cannot tolerate corticosteroids. Paediatric MS is treated with the same disease-modifying therapies as for adult patients with MS. Interferon beta or glatiramer acetate is currently the first-line treatment in children with MS, demonstrating a favourable safety profile.15

Paediatric MS is an underdiagnosed and undertreated condition with slow progression. Overall development of disability is variable and may be moderate to severe but this is often reached at a younger age with significant impact on quality of life.

Conclusion

PON, though rare, is of significance to the ophthalmologist due to its association with neuroinflammatory diseases as the first presentation (NMO, ADEM, MS). The clinical signs differ from adult ON making a thorough systemic examination, neuroimaging and cerebrospinal fluid findings imperative for determining an aetiology. While the risk of developing MS in children with monosymptomatic ON and an abnormal brain MRI is unclear, it is likely less than in adults. However, it is recommended that these children be followed up closely. Steroids may alter the visual outcome in cases of NMO but typically only accelerate visual recovery. Timely initiation of diseasemodifying therapies in these patients can limit axonal damage earlier in the disease process thereby delaying disability accumulation, improve long-term prognosis and possibly visual recovery. Research efforts to further our knowledge into the mechanisms of these conditions and to identify the genetic and environmental risk factors are ongoing and may lead to more reliable preventative, diagnostic and treatment strategies in the future.

Acknowledgements

1. Professor J Olivier and Dr C Cullen for editing the final manuscript.

2. The Department of Radiology for providing the electronic images.

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