Childhood optic neuritis: The pediatric neurologist's perspective

european journal of paediatric neurology 13 (2009) 452–457

Official Journal of the European Paediatric Neurology Society

Original article

Childhood optic neuritis: The pediatric neurologist’s perspective Gu¨l C¸akmaklıa, Aslı Kurnea, Alev Gu¨venb, Aysx e Serdarog˘luc, Haluk Topalog˘lue, Serap Teberd, Banu Anlare,* a

Hacettepe University Faculty of Medicine, Department of Neurology, Ankara, Turkey Ministry of Health, Ankara Training and Research Hospital for Children, Ankara, Turkey c Gazi University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Ankara, Turkey d Ankara University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Ankara, Turkey e Hacettepe University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Ankara, Turkey b

article info

abstract

Article history:

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

Received 25 June 2008

the symptom of a more widespread disorder.

Received in revised form

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

9 September 2008

diagnostic findings and follow-up results.

Accepted 10 September 2008

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.

Keywords:

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

Optic neuritis

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

Etiology

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

Children

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

Autoimmune

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

Multiple sclerosis

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 evaluated and followed-up in pediatric neurology clinics. ª 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

1.

Introduction

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

of differential diagnoses and appropriate laboratory investigations to detect treatable causes and estimate outcome.1 However the various causes of childhood ON are not represented in most series reported so far. Our aim in this study was to review etiological factors, clinical presentation,

* Corresponding author. Hacettepe University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Ankara, Turkey. E-mail address: [email protected] (B. Anlar). 1090-3798/$ – see front matter ª 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2008.09.003

european journal of paediatric neurology 13 (2009) 452–457

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-yearold 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 performed in all patients. Laboratory examinations including serology for infections or vasculitic syndromes and cerebrospinal 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 experienced 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 performed in 5, 27, and 16 patients, respectively. Acute BON was the most common clinical presentation (n ¼ 14, 45%), followed by UON (n ¼ 10, 32%), recurrent unilateral (n ¼ 5, 16%), or bilateral ON (n ¼ 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 followed by oral MP tapered in 2–3 weeks, and none had any recurrence. One patient presented as neuromyelitis optica with bilateral optic neuritis and long segment myelitis shortly after

453

(case 11). Serological markers for inflammatory disorders were negative, and no other attacks occurred. One other patient developed new neurological symptoms during followup and was diagnosed with MS (case 7). One patient (case 8) was being followed-up with the diagnosis of familial Mediterranean 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 (n ¼ 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 progressive 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 (n ¼ 5) or BON (n ¼ 2) had recurrences 2–6 months later. Two were diagnosed as clinically 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 developed transverse myelitis after the ON attacks. The cranial MRI was normal whereas thoracal spinal MRI showed a hyperintense 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 symptoms and corresponding spinal cord lesions in the presence of normal cranial MRI. She was diagnosed with Sjo¨gren’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 prednisone 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

1 2 3 4 5 6 7

Bilateral ON cases F 9 M 8 M 7 M 4 F 6 F 10 F 12

Antecedent/familial/ predisposing factor

Lab/MRI

Treatment

Visual recovery þ outcome

Diagnosis

Follow-up (years)

Mumps IgM

Rubella IgM Cranial MRI (þ) Cranial MRI Normal

Pulse MP Pulse MP Pulse MP Pulse MP Pulse MP Pulse MP Pulse MP

Postinf ON Postinf ON Postinf ON Postinf ON Postinf ON ADEM MS

0.5 1 1 1 2 2 3

FMF CNS vasculitis

0.5 5

Primary antiphospholipid syndrome Neuromyelitis optica?

3

8 9

M F

5 6

Familial Mediterranean Fever

Cranial MRI Normal Cranial MRIþ

Pulse MP Pulse MP

10

F

7

Antiphospholipid Ab (þ)

Pulse MP, azathioprine

11

F

10

2 brothers died from glomerulonephritis Behcet’s disease in paternal aunt and uncle, history of 3 abortions in mother

Complete Complete Complete Complete Complete Complete Complete þ other neurological symptoms Complete Complete þ other neurological symptoms Poor

Spinal MRI þ NMO Ab ()

Oral pred.

Complete

Pulse MP Pulse MP Pulse MP

Complete Complete Complete

Pulse MP

Complete

MS

3

Pulse MP

Complete

MS

2

Pulse MP

Complete

MS

2

Pulse MP

MS MS

1

ADEM

1

12 13 14 15

Chickenpox Mumps Fever Rubella Fever

M 8 M 6 M 9 Unilateral ON cases F 13

1

0.5 6 1

16

F

8

17

M

12

18

F

12

Hepatitis B vaccine

Chronic plaques on cranial MRI Multiple lesions on cranial MRI Multiple lesions on cranial MRI Cranial MRI later (þ)

19

F

12

Behcet’s disease in grandmother

Cranial MRI later (þ)

Pulse MP

20

F

8

M

13

–

Complete

MS?

0.2

22 23

M M

15 13

Pulse MP –

Incomplete Poor

Mitochondrial Ischemic ON

2 1

24

F

13

Multiple lesions on cranial MRI Multiple lesions on cranial MRI Cervical MRI (þ) Cerebral angiography (þ) congenital narrowing Cranial MRI (þ), immunological tests (þ)

Pulse MP

21

Familial Mediterranean fever in father Scleroderma in mother

Complete þ other neurological symptoms Complete þ other neurologcal symptoms Complete

Systemic treatment

Died of multiorgan failure

Systemic autoimmune disorder

0.5

Selective IgA deficiency, autoimmune lymphoproliferative disorder

5

(continued on next page)

3

1 Anti-NMO (+)

3

Complete þ total 6 ON episodes Complete þ total 3 ON episodes Partial þ total 2 ON episodes

15 Primary Sjogren syndrome Poor

2 Neuromyelitis optica? Complete

2 MS Partial

2 MS Complete

Follow-up (years) Diagnosis Visual recovery þ outcome

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).

Pulse MP

Pulse MP

F 31

12

M 30

6

Maternal autoimmune hemolytic anemia M 29

9

Hyperthyroidism in sister F 28

13

F 27

11

History of 4 abortions in mother F 26

13

Cranial MRI, autoimmune serology normal Milimetric lesions on cranial MRI Cranial MRI normal

Pulse MP þ oral pred þ azathioprine Pulse MP

Pulse MP þ oral þ azathioprine

Pulse MP

Pulse MP

Multiple lesions on cranial MRI Multiple lesions on cranial MRI Spinal MRI (þ) NMO Ab () Oligoclonal bands (þ) Cranial MRI later (þ) Recurrent ON cases F 11 25

Age Sex Case

Table 1 (continued).

Antecedent/familial/ predisposing factor

Lab/MRI

Treatment

4.

Discussion

This series illustrates the etiological spectrum and management 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 postinfectious 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 investigations: 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 puncture 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 development 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

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european journal of paediatric neurology 13 (2009) 452–457

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 children 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 supported 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 positive (case 30). Other autoimmune diseases associated with ON in our series were systemic autoinflammatory disorders such as FMF, immune deficiency, Sjo¨gren’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 Sjo¨gren 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 postdialysis hypotension, hypovolemia, chronic anemia, hypercoagulability 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 children 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 individuals 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 selflimitation 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 uncontrolled 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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