e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 3 ( 2 0 0 9 ) 4 5 2 – 4 5 7

Official Journal of the European Paediatric Neurology Society

Original article

Childhood optic neuritis: The pediatric neurologist’sperspective

Gul Cakmaklıa, Aslı Kurnea, Alev Guvenb, Aysxe Serdarogluc,Haluk Topaloglue, Serap Teberd, Banu Anlare,*aHacettepe University Faculty of Medicine, Department of Neurology, Ankara, TurkeybMinistry of Health, Ankara Training and Research Hospital for Children, Ankara, TurkeycGazi University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Ankara, TurkeydAnkara University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Ankara, TurkeyeHacettepe University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Ankara, Turkey

a r t i c l e i n f o

Article history:

Received 25 June 2008

Received in revised form

9 September 2008

Accepted 10 September 2008

Keywords:

Optic neuritis

Etiology

Children

Autoimmune

Multiple sclerosis

* Corresponding author. Hacettepe UniversitTurkey.

E-mail address: banlar@hacettepe.edu.tr1090-3798/$ – see front matter ª 2008 Europdoi:10.1016/j.ejpn.2008.09.003

a b s t r a c t

Background: Optic neuritis in children may be an isolated, usually postinfectious event, or

the symptom of a more widespread disorder.

Aim: To investigate the etiological spectrum of optic neuritis in children in association with

diagnostic findings and follow-up results.

Methods: We retrospectively examined the records of 31 children aged 4–15 (mean 9.7� 2.9)

years in whom isolated optic neuritis was the presenting neurological symptom.

Results: Monophasic bilateral optic neuritis was the most common presentation (45%),

followed by the unilateral (32%) and recurrent (22%) forms. Initial cranial MRI was

abnormal in 12/31 patients. During a mean follow-up of 2.2 years (6 months–15 years), 6/14

bilateral cases, 9/10 unilateral and 5/7 recurrent cases were diagnosed with various

disorders including total eight with MS. The MS group tended to start with unilateral optic

neuritis, was older (mean 11.6� 1.5 vs. 8.8� 2.9 years), and included more girls than the

other groups.

Conclusions: Optic neuritis in children is frequently part of a systemic or neurological

disorder even in the presence of normal cranial imaging. These patients should be eval-

uated and followed-up in pediatric neurology clinics.

ª 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights

reserved.

1. Introduction of differential diagnoses and appropriate laboratory investi-

Acute optic neuropathy (ON) is an inflammatory disorder of

the optic nerve. Its etiology, incidence and outcome in

children differ from adults, and the clinician faces a list

y Faculty of Medicine, D

(B. Anlar).ean Paediatric Neurology

gations to detect treatable causes and estimate outcome.1

However the various causes of childhood ON are not rep-

resented in most series reported so far. Our aim in this

study was to review etiological factors, clinical presentation,

epartment of Pediatrics, Division of Pediatric Neurology, Ankara,

Society. Published by Elsevier Ltd. All rights reserved.

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 3 ( 2 0 0 9 ) 4 5 2 – 4 5 7 453

magnetic resonance imaging (MRI) and final diagnoses in our

series of childhood ON.

2. Materials and methods

We retrospectively analyzed the medical records of 0–16-year-

old patients who presented to the departments of pediatric

neurology of participating hospitals with acute ON as first and

only neurological symptom between 2000 and 2008. The

diagnosis was based on at least two of the following criteria:

visual loss, relative afferent pupillary defect, or visual field

defect, all in the absence of retinal and cortical lesions.1,2 ON

was classified as bilateral (BON) if both eyes were involved

simultaneously or within three weeks. Recurrent ON (RON)

was defined as a new attack, either unilateral or bilateral,

encountered after an interval of four weeks or longer.

Detailed history was recorded for recent infections and

immunizations, other neurological and systemic symptoms,

and family history of autoimmune disorders. Visual evoked

potentials and magnetic resonance imaging (MRI) were per-

formed in all patients. Laboratory examinations including

serology for infections or vasculitic syndromes and cerebro-

spinal fluid analysis were done as indicated by clinical

features, and repeated in recurrent cases. Treatments given

for each attack, short-term and long-term clinical responses

were recorded.

3. Results

There were 31 patients (18 girls, 13 boys, F/M:1.3) who expe-

rienced their first optic neuritis episode between ages 4–15

(mean 9.7� 2.9) years. Two of them (cases 5 and 10, Table 1)

have been reported before.3,4 Mean follow-up period was 2.2

years (range: 6 months–15 years). Family history was positive

for autoimmune disorder in first- or second-degree relatives in

8 patients (25%) (Table 1). Initial cranial MRI was abnormal in

12/31 patients, spinal MRI in 5/8, and orbital MRI in 3/8

patients. Serologic tests for infectious and autoinflammatory

disorders (antibody titers against nuclear, DNA, smooth

muscle, extractable nuclear, neutrophil cytoplasmic antigens,

serum complement levels) and lumbar puncture were per-

formed in 5, 27, and 16 patients, respectively.

Acute BON was the most common clinical presentation

(n¼ 14, 45%), followed by UON (n¼ 10, 32%), recurrent unilat-

eral (n¼ 5, 16%), or bilateral ON (n¼ 2, 6.4%) (Table 1).

Acute BON: Six/14 patients in this group (median age: 8)

had a history of febrile illness including mumps and varicella

in the preceding 7–14 days, or serological proof of recent viral

infection (rubella and mumps IgM). Five who had normal

cranial MRI were considered as postinfectious ON, and one

with bilateral lesions in the periventricular white matter and

brain stem on cranial MRI received the diagnosis of ADEM

(case 6). All in this group fully recovered with intravenous (iv)

pulse methylprednisolone (MP) treatment for five days fol-

lowed by oral MP tapered in 2–3 weeks, and none had any

recurrence.

One patient presented as neuromyelitis optica with bilat-

eral optic neuritis and long segment myelitis shortly after

(case 11). Serological markers for inflammatory disorders

were negative, and no other attacks occurred. One other

patient developed new neurological symptoms during follow-

up and was diagnosed with MS (case 7). One patient (case 8)

was being followed-up with the diagnosis of familial Medi-

terranean fever (FMF) and his ON was attributed to the disease

after exclusion of other causes. Other patients had further

symptoms and were diagnosed with CNS vasculitis and

primary antiphospholipid syndrome4 (cases 9 and 10). The

remaining 3/14 BON patients received no definite diagnosis

and despite the absence of a history of antecedent infection,

were considered as possible postinfectious BON. One of them

had bilateral optic nerve contrast enhancement on orbital

MRI, and two had normal cranial MRI. All recovered well with

MP treatment.

Acute UON (n¼ 10): Five patients (ages 8–13) in this group

were diagnosed with MS: four had typical lesions on cranial

MRI at the time of UON, but one whose UON had started after

immunization against hepatitis B had normal MRI and

developed symptoms and lesions consistent with MS three

years later. Case 21 has lesions on cranial MRI but his short

follow-up does not allow a specific diagnosis yet. One other

patient (case 22) was found to have asymptomatic cervical

spinal lesions on MRI. His family history revealed a progres-

sive neurological disorder in maternal cousins, and further

investigations showed a mitochondrial deletion in peripheral

blood DNA. Case 24 had selective IgA deficiency and multiple

cerebral lesions: her ON was interpreted as autoimmune.

Recurrent ON: Seven patients (6–13 years, median 11.6

years) whose ON started as UON (n¼ 5) or BON (n¼ 2) had

recurrences 2–6 months later. Two were diagnosed as clini-

cally definite MS in the first year of follow-up. Their cranial

MRI revealed typical multiple demyelinating periventricular

plaques, some showing contrast enhancement. They were

treated with pulse MP at each attack, one with good recovery

and the other with unilateral reduced vision. Case 27 devel-

oped transverse myelitis after the ON attacks. The cranial MRI

was normal whereas thoracal spinal MRI showed a hyperin-

tense lesion over 4 spinal segments. Serum markers for

vasculitis and infections (anti-nuclear, anti-DNA, anti-smooth

muscle, anti-extractable nuclear, anti-neutrophil cytoplasmic

antibodies, serum complement levels, sedimentation rate,

C-reactive protein) were negative: on the other hand, CSF

protein was elevated (66 mg/dl) and oligoclonal bands were

observed. This patient was classified as neuromyelitis optica

or optico-spinal form of MS. One other patient in this group

(case 28) developed relapsing and progressive motor symp-

toms and corresponding spinal cord lesions in the presence of

normal cranial MRI. She was diagnosed with Sjogren’s

syndrome 9 years later when she developed anti-nuclear and

anti-SS-A autoantibodies and her Schirmer test, parotid

scintigraphy, and minor salivary gland biopsy showing

moderate lenfomononuclear cell infiltration were found

diagnostic, although she did not complain of dry mouth and

dry eye. The visual acuity was severely impaired and response

to MP was limited. Case 29 in this group had the highest

number of recurrences with 6 UON attacks, all treated with iv

and oral MP, and controlled only after continuous oral pred-

nisone was given as maintenance treatment. A history of

autoimmune hemolytic anemia was present in his mother. He

Table 1 – Patients’ clinical and relevant laboratory findings.

Case Sex Age Antecedent/familial/predisposing factor

Lab/MRI Treatment Visual recoveryþoutcome

Diagnosis Follow-up(years)

Bilateral ON cases

1 F 9 Mumps IgM Pulse MP Complete Postinf ON 0.5

2 M 8 Chickenpox Pulse MP Complete Postinf ON 1

3 M 7 Mumps Pulse MP Complete Postinf ON 1

4 M 4 Fever Pulse MP Complete Postinf ON 1

5 F 6 Rubella Rubella IgM Pulse MP Complete Postinf ON 2

6 F 10 Fever Cranial MRI (þ) Pulse MP Complete ADEM 2

7 F 12 Cranial MRI Normal Pulse MP Completeþ other

neurological symptoms

MS 3

8 M 5 Familial Mediterranean Fever Cranial MRI Normal Pulse MP Complete FMF 0.5

9 F 6 Cranial MRIþ Pulse MP Completeþ other

neurological symptoms

CNS vasculitis 5

10 F 7 2 brothers

died from glomerulonephritis

Antiphospholipid Ab (þ) Pulse MP, azathioprine Poor Primary antiphospholipid

syndrome

3

11 F 10 Behcet’s disease

in paternal aunt

and uncle, history

of 3 abortions

in mother

Spinal MRIþNMO Ab (�) Oral pred. Complete Neuromyelitis optica? 1

12 M 8 Pulse MP Complete 0.5

13 M 6 Pulse MP Complete 6

14 M 9 Pulse MP Complete 1

Unilateral ON cases

15 F 13 Chronic plaques

on cranial MRI

Pulse MP Complete MS 3

16 F 8 Multiple lesions

on cranial MRI

Pulse MP Complete MS 2

17 M 12 Multiple lesions

on cranial MRI

Pulse MP Complete MS 2

18 F 12 Hepatitis B vaccine Cranial MRI later (þ) Pulse MP Completeþ other neurological

symptoms

MS 5

19 F 12 Behcet’s disease in grandmother Cranial MRI later (þ) Pulse MP Completeþ other neurologcal

symptoms

MS 1

20 F 8 Familial Mediterranean

fever in father

Multiple lesions on

cranial MRI

Pulse MP Complete ADEM 1

21 M 13 Scleroderma in mother Multiple lesions on

cranial MRI

– Complete MS? 0.2

22 M 15 Cervical MRI (þ) Pulse MP Incomplete Mitochondrial 2

23 M 13 Cerebral angiography (þ)

congenital narrowing

– Poor Ischemic ON 1

24 F 13 Selective IgA deficiency,

autoimmune

lymphoproliferative

disorder

Cranial MRI (þ),

immunological tests (þ)

Systemic treatment Died of multiorgan failure Systemic autoimmune

disorder

0.5

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was classified as relapsing inflammatory ON of autoimmune

nature, but no definite diagnosis. One patient in this group

(case 30) had positive serology for anti-NMO.

The sex distribution or the incidence of a family history of

autoimmune disease (5/31, 16%) did not differ among the RON,

BON and UON subgroups. Perinatal history was remarkable

for low birth weight (<2500 g) in 7/26 (26%) patients whose

records were available. A specific diagnosis for the etiology of

ON could be made in 11/14 of BON, 9/10 of UON, and 6/7 of RON

cases (p:ns). The final diagnosis was MS in 7 girls and 1 boy, of

whom 1/14 had BON, 5/10 UON ( p< 0.05), and 2/7 RON (p:ns).

Mean age of onset in MS was 11.6� 1.5 years: the difference

was significant ( p< 0.01) compared to 8.8� 2.9 in the non-MS

group. Recovery of vision did not differ among BON, RON and

UON subgroups: complete, partial, or poor vision were

observed in 22, 5, and 3 patients in this series (73, 16 and 10%,

respectively, one patient died without re-assessment of

vision).

4. Discussion

This series illustrates the etiological spectrum and manage-

ment of ON in pediatric neurology clinics. It contains most, if

not all, ON cases diagnosed in these institutions: occasional

cases such as traumatic ON diagnosed in neurosurgery clinics,

or toxic ON due to long-term use of certain drugs might have

been followed-up in other departments and underrepresented

in this series.

The etiology of childhood ON is most commonly post-

infectious in many reports: a preceding viral infection has

been reported in 28–46% in other series2,5 and 16% of ours, of

whom all had BON. These figures may vary according to the

reliability of the history and the extent of laboratory investi-

gations: the latter were not done in a standard protocol in our

study. Not included here but previously published from our

institutions are ON cases associated with Lyme and brucella

infections.6,7 Because infections are common, lumbar punc-

ture has been recommended in young children and the rate of

abnormal findings reported as 10–40%.5,8,9 Immunizations,

especially hepatitis B vaccine, have also been associated with

ON in the literature. We had only one post-immunization case

who interestingly developed other neurological symptoms

and was diagnosed later with MS.

Etiology is also related to age, sex and type of involvement.

Although Luchinetti et al. found no effect of gender, age,

ophthalmological findings, or family history on the develop-

ment of MS, younger children appear more likely to have

ADEM or postinfectious ON while older (mean 12.2 years) and

female patients (F:M 1.6) are somewhat more represented in

series from demyelinating disease clinics.2,5,9–11 Bilateral

involvement may imply postinfectious etiology. BON is

frequent in most childhood ON series 1,5,10–12 but certain

studies report UON at higher or equal frequency.9,13 Some

discrepancies may arise from the definition of simultaneous

vs. sequential ON, due to the different cutoff periods, 2 or 4

weeks, accepted as interval.

MS is the most frequently discussed disorder in association

with ON. In general, a lower risk of recurrence and progression

to MS is reported compared to adults.10 A variable proportion

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 3 ( 2 0 0 9 ) 4 5 2 – 4 5 7456

of children with ON develop MS, depending to a certain extent

on age, sex and ethnicity. Rates as 6/40, 4/20 or 5/10 have been

reported in 1–8 years follow-up.14–16 Regional or ethnic

differences may play a role, the risk being lower in Asians: for

instance, 2/22 Thai children followed-up for 6–20 years,17 and

1/23 Korean, compared to 9 (8 female) out of 21 Finnish chil-

dren with the same follow-up of one year, developed MS.11,12

Our cases who received the diagnosis of MS were older than

the others, and girls outnumbered boys. All developed

symptoms and findings of MS within 3 years after ON. The rate

may change with longer follow-up, but probably not to a great

extent because the second MS-defining demyelinating event

in children usually presents within 1–2 years (mean 7.9

months) after ON.2 The association of UON with MS is sup-

ported or contradicted in various studies.8,11 The presence of

neurologic findings outside the visual system, associated with

the subsequent diagnosis of MS, was not a criterion for our

study because only isolated ON cases were included. The

value of MRI in predicting MS has been extensively discussed

in adult patients. In a series of 13 children with ON, all those

diagnosed with MS had at least one white matter lesion on

MRI at the time of ON.2 On the other hand, three of our MS

cases had normal MRI at initial presentation with ON. We

therefore recommend consideration of this diagnosis even in

the presence of normal MRI. Of our 12 abnormal cranial MRI

results, only 7 belonged to MS patients, emphasizing the

importance of radiological differential diagnosis.

Normal cranial MRI and extensive myelitis on spinal MRI

were observed in 2 patients. In recent years aquaporin-4

autoimmunity has been found in association with ON and

myelopathy: 20% of adults with RON are seropositive for

NMO–IgG.18 However in children with ON, none of the

monophasic, and only one of the five recurrent cases were

positive for this antibody.19 Our 2 patients with myelitis have

been found negative for anti-NMO, and only one out of three

RON cases (and no myelitis) who have been tested was posi-

tive (case 30).

Other autoimmune diseases associated with ON in our

series were systemic autoinflammatory disorders such as FMF,

immune deficiency, Sjogren’s syndrome. Although the central

nervous system manifestations of FMF are rare, a possible

association with ON has been reported before.20 ON may rarely

be the presenting feature of primary Sjogren syndrome and

may occur before or simultaneously with this diagnosis.21

Interestingly serological markers of this patient were negative

at the beginning; seropositivity developed later during the

course of the disease. The addition of immunosuppressive

therapy slowed down the progression of the disease although

serious sequelae had developed before diagnosis.

Our series comprised one case of ischemic neuropathy due

to vascular occlusion. Ischemic ON has been reported in few

cases in children: predisposing factors in children are post-

dialysis hypotension, hypovolemia, chronic anemia, hyper-

coagulability or vasculitis, unlike adults where hypertension,

diabetes, atherosclerosis, hypercholesterolemia and smoking

play a role.22 One child had mitochondrial disease which was

suspected on the ground of a family history and exclusion of

other diseases. Mitochondrial mutations are not rare in ON of

unknown etiology and may underlie many unexplained ON

cases.23

Recurrences occur in 5/20 children and do not necessarily

indicate MS.15 For instance 4 patients (10%) in the series of

Kriss et al., two with UON and two with BON, had one or more

recurrent attacks and only one of them developed other

evidence of MS.5 Similarly, 1/27 Brazilian and 2/22 Thai chil-

dren had recurrent ON.9,17 Persistent recurrence in one eye

could suggest an anatomical abnormality, such as ‘‘reduced

reserve’’ of the nerve. For instance the optic nerve fiber

density and the anatomic reserve capacity are lower if the

optic nerve head is small. Children in our series had a higher

incidence of low birth weight, 26%, than the 10% expected

from our center.24 This suggests that children with reduced

reserve are more likely to experience ON symptoms, and that

optic neuropathies, or optic nerve insults, are more frequent

than noticed clinically: they may remain subclinical in indi-

viduals with adequate reserve.

Visual prognosis is perceived as satisfactory in children,

especially young patients with bilateral disease, although

UON has also been reported to have better or similar visual

prognosis.1,8,9,25 In our series ischemic and systemic etiologies

were associated with incomplete recovery while all patients

with a history of antecedent infection had BON and self-

limitation with good prognosis. Outcome may also vary with

the length of follow-up: although improvement is observed in

early weeks, recovery of vision can take up to six years.16 The

role of treatment in prognosis is controversial: an uncon-

trolled study reported better visual prognosis in children

receiving intravenous steroids than in those without any

treatment.11 Controlled studies are lacking in children.

Because we observed the effect of etiology on outcome, we

suggest trials to ascertain etiologically homogenous groups.

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