UNIVERSITE DE GENEVE FACULTE DE MEDECINE Section de Médecine Clinique Departement de Pédiatrie Service de Pédiatrie Neuropédiatrie
Thèse préparée sous la direction du Dr. Charles-Antoine Haenggeli, PD
« ETUDE RETROSPECTIVE DE 29 ENFANTS AYANT PRESENTE UNE NEVRITE OPTIQUE EN SUISSE ENTRE 1990 ET 2000 »
Thèse
présentée à la Faculté de Médecine de l’Université de Genève
pour obtenir le grade de Docteur en Médecine
par
Christian KORFF
de
Collonge-Bellerive
Thèse n° 10462
Genève
2006
A ma mère, pour son amour
A mon père, qui aujourd’hui encore me guide, malgré son départ précoce
Remerciements
Je souhaiterais exprimer mes remerciements les plus sincères aux personnes suivantes:
Dr. Charles-Antoine Haenggeli, Neuropédiatre, Hôpital des Enfants, Genève, dont l’approche clinique des patients et de leurs parents a représenté un exemple et une source de motivation tout au long de mes années de formation;
Mes collègues neuropédiatres en Suisse, qui m’ont aidé de façon efficace à récolter les données des enfants traités pour une névrite optique : Prof. Jürg Lütschg, Hôpital des Enfants, Bâle; Dr. Maja Steinlin, Hôpital des Enfants, Berne; Prof. Eliane Roulet Perez, CHUV, Lausanne; Dr. Katarina Fuhrer, Hôpital des Enfants, St Gall; Dr. Andrea Capone Mori, Hôpital des Enfants, Zürich. Sans leur précieuse collaboration, ce travail n’aurait pas été possible;
Prof. Avinoam Safran, Médecin-Chef, Clinique d’Ophtalmologie, HUG, Genève, et Dr. Virginie Chaves- Vischer, Neuropédiatre, Genève, pour le partage de leur expérience et pour leurs conseils;
Mme Sarah Ahlm-Mass, Chicago, pour sa révision scrupuleuse de la version anglaise du texte;
Ma femme, Simona, pour son amour et son soutien; pour sa rigueur scientifique, que j’espère tous les jours égaler; et “last but not least”, pour le partage généreux de ses connaissances informatiques étendues, qui m’ont été de la plus grande aide dans la rédaction du texte et dans la réalisation des tableaux de résultats ;
Ma soeur, Stéphanie, et tous les membres de ma famille, pour leur confiance et leur soutien inconditionnels, particulièrement durant la période difficile qui a suivi la mort de mon père, qui coïncidait avec le début de ce travail.
Résumé
La névrite optique (NO) représente une des causes les plus fréquentes de perte rapide d’acuité visuelle chez l’adulte et chez l’enfant. Elle peut avoir de multiples étiologies, dont les maladies démyélinisantes, les infections et les maladies inflammatoires systémiques. Son pronostic est généralement bon chez l’enfant, mais son association potentielle avec une sclérose en plaques (SEP) est redoutée. L’étude du liquide céphalorachidien (LCR) et de l’imagerie par résonance magnétique (IRM) cérébrale peuvent révéler des critères diagnostiques pour une SEP lors d’un premier épisode isolé de NO. Les facteurs de risque pour une SEP chez l’adulte incluent la présence de lésions démyélinisantes à l’IRM et la présence de bandes oligoclonales dans le LCR au moment de la NO, mais de tels facteurs de risque n’ont à ce jour pas été identifiés chez l’enfant. Chez l’adulte, le traitement de la NO est la méthylprednisolone intraveineuse à doses élevées suivie par la prednisone orale. Ce schéma retarde l’apparition de signes de SEP à 2 ans, mais pas à 3 ans [Optic Neuritis Study Group, 2001]. Le traitement le plus efficace chez l’enfant n’a pas encore été défini.
Le but de cette étude rétrospective était d’essayer de répondre aux questions suivantes : 1. Quelle est la fréquence de la NO chez l’enfant en Suisse ?
2. Quels sont les bilans effectués et les traitements utilisés dans les différents centres ?
3. Quel est le pronostic de la NO chez l’enfant en ce qui concerne la récupération, le risque de rechute et le développement d’une SEP ?
4. Des facteurs de risque peuvent-ils être identifiés ?
Dans cette perspective, nous avons réuni les dossiers médicaux des enfants atteints d’une NO et hospitalisés dans l’un des hôpitaux pédiatriques universitaires suisses (Bâle, Berne, Genève, Lausanne, St Gall, Zürich) de 1990 à 2000, et avons revu leurs données.
Nos résultats montrent que :
1. l’incidence de la NO chez l’enfant est de 0.04/100000 habitants/année.
2. Les bilans et les traitements varient d’un hôpital à l’autre.
3. La proportion d’enfants qui développent une SEP est de 17%, résultat équivalent aux pourcentages rapportés précédemment [Cuendet-Graf et Taylor, 1991 ; Lucchinetti et al., 1997].
4. Bien que le rapport fille:garçon soit de 4:1, aucun facteur de risque pour le développement d’une SEP n’a pu être identifié.
Ce rapport montre que seule une étude multicentrique contrôlée en double-aveugle permettra de clarifier certains points tels que le traitement optimal et ses éventuels effets préventifs sur une rechute et sur le développement d’une SEP, ou encore l’identification de facteurs de risque.
En conséquence, et en guise de première étape, nous proposons un algorithme pour la prise en charge et le traitement des enfants présentant une NO, basé sur une revue de la littérature, et qui pourrait être suivi par l’étude susmentionnée.
Introduction
Cette étude a débuté avec l’histoire de Wanda, fillette de 6 ans hospitalisée a l’Hôpital des Enfants de Genève pour un deuxième épisode de perte rapide d’acuité visuelle 2 semaines après un vaccin Diphtérie- Tétanos-Coqueluche. Le bilan d’entrée a montré une NO rétrobulbaire bilatérale, une acuité visuelle inférieure à 0.1 des deux cotés, ainsi que des anticorps contre la diphtérie et le tétanos anormalement élevés. L’examen neurologique, l’IRM cérébrale et le LCR se sont avérés normaux. Elle a bénéficié d’un traitement de méthylprednisolone intraveineuse suivie de prednisone orale et a montré une récupération rapide et complète.
La NO, maladie inflammatoire du nerf optique, un tractus du système nerveux central, est rare. Son incidence (nombre de nouveaux cas/100000 habitants/an) chez l’adulte est estimée à 5/100000, selon une étude de population dans le Minnesota [Rodriguez et al., 1995]. Son incidence rapportée est plus basse chez l’enfant : seuls 94 enfants ont été identifiés à la Clinique Mayo au cours d’une période de 38 ans [Lucchinetti et al., 1997]. Les filles semblent plus affectées que les garçons après l’apparition de la puberté [Boomer et Siatkowski, 2003]. Malgré sa rareté, la NO est l’une des causes les plus fréquentes de perte rapide d’acuité visuelle chez l’adulte et chez l’enfant. Une perte rapide et sévère est plus fréquemment observée chez l’enfant.
La NO peut être unilatérale ou bilatérale, symétrique ou asymétrique. Elle peut impliquer la partie intraoculaire (papillite) ou la partie extraoculaire (névrite rétrobulbaire) du nerf optique. Chez l’enfant, elle est plus souvent bilatérale et intraoculaire [Boomer et Siatkowski, 2003]. Les symptômes majeurs de la NO sont la perte de vision et la douleur orbitaire, spécialement au cours de mouvements oculaires.
L’examen clinique révèle un fond d’œil normal en cas de névrite rétrobulbaire (« Le patient et le médecin ne voient rien »), et une tuméfaction du disque optique en cas de papillite. Un déficit pupillaire afférent (phénomène de Marcus Gunn) est présent en cas d’implication unilatérale ou asymétrique. L’examen ophtalmologique révèle également des anomalies de la vision des couleurs et des déficits de champ visuel [Pelfrey et al., 2002]. La plupart des patients montrent une perception diminuée des couleurs rouge-verte ou bleue-jaune, l’une prédominant sur l’autre [Tekavcic-Pompe et al., 2003]. Les déficits bleu-jaune ont tendance a être plus fréquents dans la phase aigue de la maladie, alors que les déficits rouge-vert sont plus
fréquents à 6 mois de suivi [Tekavcic-Pompe et al., 2003]. Les déficits de champ visuel peuvent être ponctuels ou diffus. Ils peuvent être centraux ou périphériques [Schneck et Haegerstrom-Portnoy, 1997 ; Fang et al., 1999 ; Keltner et al., 1999].
Les étiologies de la NO sont multiples. Le plus souvent, la NO représente une inflammation autoimmune localisée faisant suite a une infection ou a une vaccination [Abd Elrazak, 1991; Beiran et al., 2000; Boiko et al., 2000; Brady et al., 1999; Cassidy et Taylor, 1999; Cuendet-Graf et Taylor, 1991; Inokuchi et al., 1997; Jacobson et al. 1991; Kumar et al., 1999; Linssen et al., 1997; Optic Neuritis Study Group, 2001;
Rodriguez et al., 1995; Weber et Mikulis, 1987; Yen et Liu, 1991]. Moins souvent, la NO fait partie d’une inflammation plus généralisée, telle qu’une encéphalomyélite démyélinisante aigue (ADEM), une SEP ou son sous-type, la neuromyélite optique (maladie de Devic) [Boiko et al., 2000; Brady et al., 1999; Cassidy et Taylor, 1999; Cuendet-Graf et Taylor, 1991; Frederiksen, 1998; Lucchinetti et al., 1997; Riikonen et al., 1988; Wingerchuk et al., 1999]. D’autres causes ont également été rapportées, telles que les vasculites, comme le lupus érythémateux disséminé [Ahmadieh et al., 1994] ou la polyarthrite rhumatoïde [Agildere et al., 1999], et certains agents toxiques comme l’ethambutol [Kahana, 1987], le tamoxifene [Noureddin et al., 1999] et les venins d’insectes [Maltzmann et al., 2000].
Le bilan d’entrée des patients présentant une NO comporte habituellement une formule sanguine complète, le dosage de la protéine C-réactive, la vitesse de sédimentation des érythrocytes, les sérologies pour les virus neurotropes et pour Borrelia Burgdorferi (maladie de Lyme) ; une ponction lombaire avec numération et différentiation de cellules, un électrophorèse des protéines, et une immunoélectrophorèse ; une IRM cérébrale ; et des potentiels évoqués visuels.
L’association potentielle entre la NO et la SEP est l’aspect le plus redouté. Plusieurs études prospectives montrent que la NO est souvent la première manifestation d’une SEP. Les résultats du Optic Neuritis Study Group ont montre que 38% de leurs 388 patients adultes avaient développé une SEP selon les critères de Poser [Poser et al., 1983] 10 ans après leur NO isolée [Beck et al., 2003]. Chez l’enfant, le risque de SEP est heureusement moins important. Apres un suivi de 10 ans, 13% du collectif de la plus grande série rapportée avaient développé une SEP, selon les mêmes critères [Lucchinetti et al., 1997].
Des recommandations de traitement ont été publiées par le Optic Neuritis Study Group [Optic Neuritis Study Group, 2001]. Le but était la récupération optimale de l’acuité visuelle et la réduction de
l’incidence ou le recul de l’apparition des signes de SEP. Alors que la prednisone orale semble augmenter le risque de rechute de NO sans avoir d’influence sur le développement d’une SEP, de hautes dose de méthylprednisolone intraveineuse (500-1000 mg/jour pendant 5 jours consécutifs) suivies de prednisone orale entraînent une récupération plus rapide des fonctions visuelles et une réduction du risque de SEP à 2 ans, mais pas à 3 ans de suivi, chez l’adulte. Le traitement optimal n’a pas encore été défini chez l’enfant.
Le LCR et l’IRM peuvent révéler des critères diagnostiques de SEP au moment d’un épisode isole de NO.
Chez l’adulte, 3 facteurs de risque pour le développement d’une SEP ont été identifiés : la présence de lésions de la substance blanche à l’IRM cérébrale, la présence d’anticorps oligoclonaux dans le LCR, et des antécédents neurologiques ou de NO controlatérale [Soderstrom et al., 1998 ; Beck et al., 2003]. Chez l’enfant, seul un facteur de risque a été identifié : la présence d’une NO bilatérale séquentielle (implication des 2 yeux a plus de 2 semaines mais moins de 3 mois de l’épisode initial) ou récurrente [Luccinetti et al., 1997].
Avec cette étude rétrospective, nous avons essayé de répondre aux questions suivantes concernant les enfants traites pour une NO en Suisse :
1. Quelle est la fréquence de la NO chez l’enfant en Suisse ? 2. Quels sont les bilans effectués chez les enfants atteints ? 3. Quels sont les traitements utilisés chez les enfants atteints ? 4. Quelle est la proportion des enfants qui développent une SEP ?
5. Des facteurs de risque pour une SEP après une NO peuvent-ils être identifiés ?
Summary
Optic neuritis (ON) is the most frequent cause of acute, complete or partial loss of visual acuity in adults and children. Etiology of ON is multiple and includes post-infectious demyelinating diseases, infections and systemic inflammatory diseases. Although prognosis is most often good in children, recurrences do exist, and the potential association of ON and multiple sclerosis (MS) is a major concern.
Both cerebrospinal fluid (CSF) studies and cerebral magnetic resonance imaging (MRI) may reveal the diagnostic criteria for MS during a first and clinically isolated episode of ON. ON might recur accompanied by other neurological abnormalities. Risk factors for MS in adults include the presence of demyelinating lesions on MRI and of oligoclonal bands in the CSF at the time of ON, but risk factors for MS in children with ON have not been recognized. In adults, the recommended treatment for ON is high dose intravenous methylprednisolone followed by oral prednisone. This regimen has been shown to postpone the appearance of signs of MS for 2 years, but not for 3 [Optic Neuritis Study Group, 2001].
The most efficient treatment in children has not yet been defined.
The aim of this retrospective study was to try to answer the following questions:
1. How frequent is childhood ON in Switzerland?
2. What work-up and treatment are used in the different centers?
3. What is the prognosis of childhood ON regarding recovery, relapse and development of MS?
4. Can any risk factors be identified?
For this purpose, we collected all medical records of children with a diagnosis of ON admitted to one of the teaching hospitals with a child neurology unit in Switzerland during the 10 year period from 1990 to 2000, and reviewed their data.
Our results show that:
1. The incidence of pediatric ON in Switzerland, according to our data, is 0.04 new cases/100000 inhabitants/year.
2. Work-up and treatment schedules for children with ON are variable in the different hospitals.
3. The percentage of children who developed MS is 17%, comparable to reported data [Cuendet-Graf and Taylor, 1991; Lucchinetti et al., 1997].
4. Although the girl:boy ratio was 4:1, no risk factor for the development of MS could be identified.
This study shows that only a controlled, double blind multicenter study will help to clarify issues such as optimal treatment and its possible preventive effect on recurrence and development of MS, as well as identification of risk factors.
We therefore propose, as a first step, an algorithm for work-up and treatment of children presenting with ON, based on the currently available data from the literature, which could be followed by the controlled study.
CONTENTS
1. Introduction……….2
2. Material and methods………..5
3. Results……….6
3.1. Patients……….6
3.2. Symptoms………...7
3.3. Signs………...8
3.3.1. Neurological examination……….8
3.3.2. Ophthalmological examination……….8
3.4. Work-up………...8
3.4.1. Blood exams………..8
3.4.1.1. Serologies………...8
3.4.2. Lumbar puncture………9
3.4.3. Brain imaging………...9
3.5. Treatment………..9
3.6. Follow-up………10
4. Discussion………..13
5. Conclusion……….21
6. Proposals………22
7. References………..24
INTRODUCTION
This study began with the history of Wanda. She was a 6 year-old girl admitted to Children’s Hospital, Geneva, for a second episode of acute visual loss 2 weeks after Diphtheria-Tetanus-Pertussis vaccinations. Work-up showed a bilateral retrobulbar optic neuritis (ON), a visual acuity of < 0.1 bilaterally, and abnormally elevated antibody titers against Diphtheria and Tetanus. Neurological examination, cerebral magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) were normal.
She was treated with intravenous methylprednisolone followed by oral prednisone and showed a fast and complete recovery.
ON, an inflammatory disease of the optic nerve, a central nervous system (CNS) tract, is a rare disorder. Its incidence (number of new cases/100000 inhabitants/year) in adults is estimated at 5/100000, according to a population-based study in Minnesota [Rodriguez et al., 1995]. The reported incidence is lower in children: only 94 children were identified at the Mayo Clinic over a 38 year-period [Lucchinetti et al., 1997]. Post-pubertal girls appear to be more frequently affected than boys [Boomer and Siatkowski, 2003]. Although ON is a rare disease, it is the major cause of acute or subacute decrease in visual acuity, both in adults and in children. Rapid and severe loss of visual acuity is more frequently observed in children [Brady et al., 1999].
ON can be unilateral or bilateral, symmetrical or asymmetrical. It can involve the intraocular part (papillitis) or the extraocular part (retrobulbar neuritis) of the optic nerve. In children, ON appears to be more frequently bilateral and intraocular [Boomer and Siatkowski, 2003]. The cardinal symptoms of ON are visual loss and orbital pain, especially with eye movements.
Clinical examination reveals normal optic fundi in retrobulbar neuritis (“The patient and the physician do not see anything”), and swelling of the optic disk in papillitis. An afferent pupillary defect (Marcus Gunn phenomenon) is present in the case of unilateral or asymmetrical involvement. The ophthalmological examination also reveals abnormal color vision and visual field defects [Pelfrey et al., 2002]. Most patients have decrceased perception of mixed red-green and blue-yellow colour, one type predominating over the other [Tekavcic-Pompe et al., 2003]. Blue-yellow defects have a tendency to be slightly more common in the acute phase of the disease, while red-green defects are more common at 6 months follow-up [Tekavcic-Pompe et al., 2003]. Visual field defects can be patchy or diffuse. They can
be central as well as peripheral [Schneck and Haegerstrom-Portnoy, 1997; Fang et al., 1999; Keltner et al., 1999]. Fourty-eight percent of the adults in the Optic Neuritis Treatment Trial had diffuse defects [Keltner et al., 1999]. Precise data are missing for children, but central scotomas, constrictive and altitudinal defects have been reported [Cuendet-Graf and Taylor, 1991; Boomer and Siatkowski, 2003].
Measure techniques vary between adults and children, and might explain this apparent difference. No differences were noted between these two categories in other series, however [V. Biousse, personal communication]. The etiologies of ON are multiple. Most often, ON represents a localized autoimmune inflammation following infections and immunizations [Abd Elrazak, 1991; Beiran et al., 2000; Boiko et al., 2000; Brady et al., 1999; Cassidy and Taylor, 1999; Cuendet-Graf and Taylor, 1991; Inokuchi et al., 1997; Jacobson et al. 1991; Kumar et al., 1999; Linssen et al., 1997; Optic Neuritis Study Group, 2001;
Rodriguez et al., 1995; Weber and Mikulis, 1987; Yen and Liu, 1991]; less often, ON is part of a more generalized inflammation, such as acute demyelinating encephalomyelitis (ADEM), multiple sclerosis (MS), and its subtype called neuromyelitis optica (Devic’s disease) [Boiko et al., 2000; Brady et al., 1999;
Cassidy and Taylor, 1999; Cuendet-Graf and Taylor, 1991; Frederiksen, 1998; Lucchinetti et al., 1997;
Riikonen et al., 1988; Wingerchuk et al., 1999]. Other causes include vasculitides, such as systemic lupus erythematosus [Ahmadieh et al., 1994] or rheumatoid arthritis [Agildere et al., 1999]; and toxics, such as ethambutol [Kahana, 1987], tamoxifen [Noureddin et al., 1999] and insect venoms [Maltzmann et al., 2000].
Work-up of patients with ON usually includes complete blood count (CBC), C-reactive protein (CRP), sedimentation rate, serologic tests for neurotropic viruses and Borrelia Burgdorferi (Lyme disease); CSF cell count and differential, protein electrophoresis, and immunoelectrophoresis; cerebral MRI; and visual evoked responses (VER).
The association of ON and MS is the major concern. Several prospective studies have shown that ON is frequently the first manifestation of MS. The results of the Optic Neuritis Study Group showed that 38 % of 388 adult patients have clinically definite MS (CDMS), utilizing the criteria of Poser et al. [Poser et al., 1983], 10 years after the isolated episode of ON [Beck et al., 2003]. In children, the risk of developing MS is fortunately lower. After a follow-up of 10 years, 13% had CDMS, according to the same diagnostic criteria [Lucchinetti et al., 1997].
Treatment recommendations have been published by the Optic Neuritis Study Group [Optic Neuritis Study Group, 2001]. The aim was optimal recovery and reduction of the incidence or delay in the onset of MS. Whereas oral prednisone appeared to increase the risk of relapse of ON and had no effect on subsequent development of MS, high dose intravenous methylprednisolone (500-1000 mg/day for up to 5 consecutive days) followed by oral prednisone has been shown to hasten recovery of visual function and to reduce the risk of MS at 2 years of follow-up, but unfortunately not at 3 years of follow-up, in adults.
The optimal treatment choice for children with ON has not yet been defined.
Both CSF and MRI can reveal diagnostic criteria for MS at the time of a clinically isolated episode of ON. In adults, 3 risk factors for the subsequent development of MS have been identified:
presence of white matter lesions on cerebral MRI, presence of oligoclonal antibodies in the cerebrospinal fluid, and a previous history of contralateral ON or other CNS dysfunction [Soderstrom et al, 1998; Beck et al., 2003]. In children with ON, only 1 significant risk factor has been identified: the presence of bilateral sequential (involvement of both eyes more than 2 weeks but less than 3 months after the initial event) or recurrent ON [Lucchineti et al., 1997].
With our retrospective study, we tried to answer the following questions regarding children with ON treated in Switzerland:
1. What is the incidence of childhood ON in Switzerland?
2. What is the work-up of affected children?
3. What is the treatment of affected children?
4. What is the proportion of children who develop MS?
5. Are there any identifiable risk factors for MS after childhood ON?
MATERIAL AND METHODS
We asked for the medical records of all patients younger than 16 years admitted to one of the 8 teaching hospitals with a child neurology unit in Switzerland during the 10-year period between 1991 and 2000. A total of 29 children with ON were identified in 6 of the 8 hospitals: Basel (1 patient), Berne (3), Geneva (9), Lausanne (5), St. Gallen (1), and Zurich (10). We reviewed all medical records in order to collect all available data on the following items:
1. Patient age and sex.
2. Localization of ON.
3. Preceding infection or vaccination.
4. Symptoms.
5. Ophthalmological signs.
6. Associated neurological abnormalities.
7. Blood serologies.
8. CSF studies.
9. Cerebral MRI studies.
10. Treatment.
11. Follow-up: diagnostic criteria and risk factors for MS.
RESULTS
The results are presented in tables 1-13.
Table 1: Patients, sex, age
Patient Boy Girl Age (years)
DL X 12 CH X 10 AS X 10 AP X 6 MT X 15.5 GI X 11 SA X 11 JM X 5 GF X 13 VD X 11 WW X 6 KO X 11 MT X 8 CC X 16 DC X 6.5 DJ X 13.5 LD X 10.5 CG X 9.5 SH X 4.5 JB X 6 SF X 12.5 MC X 14.5 AS X 9.5 SA X 16 MW X 7 SF X 7 AF X 7.5 BB X 10 ER X 11 TOTAL 29 15 (52%) 14 (48%)
MEAN AGE 10 (range 5-16)
Table 2: localization of ON
Retrobulbar Papillitis Total
Unilateral 12 (41%) 6 (21%) 18 (62%)
Bilateral 6 (21%) 5 (17%) 11 (38%)
Total 18 (62%) 11 (38%) 29
Table 3: Preceding infection or vaccination (during 4 weeks preceding the ON) Viral infections (69%)
Upper respiratory tract 14
Flu-like 5 Chickenpox 1 Vaccinations (7%)
Diphteria-Tetanus-Pertussis 1
Poliomyelitis 1
Total 22/29 (76%)
Table 4: Symptoms
Decrease of visual acuity 28 (97%)
Papillitis observed on examination 1 (3%) Progression of decrease of visual acuity to
minimum:
Hours/few days Weeks
24 (86%) 4 (14%)
Orbital pain 16 (57%)
Headache 8 (29%)
Photophobia 4 (14%)
Abnormal perception of colors 4 (14%)
Diplopia 1 (4%)
Metamorphopsia 1 (4%)
Table 5: Ophthalmological signs (reported in 22 patients)
Visual acuity > 0.5 17/22 (77%)
Visual field defects 13/22 (59%)
Afferent pupillary defect (Marcus Gunn sign) 4/22 (18%)
Abnormal color vision 2/22 (9%)
Abnormal visual evoked responses 13/18 (72%)
Table 6: Associated neurological abnormalities
Total 8/29 (28%)
Spastic hemiparesis, unilateral Babinski sign, ankle clonus or increased deep tendon reflexes
3
Paresis of one upper limb and paresthesia 2
Ataxia, dysarthria 3
Spastic paresis of lower limbs and spastic bladder 1 Decreased abdominal cutaneous reflexes 2
Table 7: Blood serologies (reported in 17 patients)
Normal 14 (82%)
Abnormal 3 (18%)
Diphtheria and tetanus 1 (6%) (following vaccination)
Borrelia Burgdorferi 1 (6%)
Epstein-Barr virus 1 (6%)
Herpes simplex virus 0
Varicella zoster virus 0
Cytomegalovirus 0
Measles 0
Mumps 0
Rubella 0
Table 8: Cerebrospinal fluid studies (reported in 20 patients)
Normal 15 (75%)
Abnormal 5 (25%)
Oligoclonal bands 3 (15%)
Increased white cell count and proteins 1 (5%)
Increased proteins 1 (5%)
Table 9: Cerebral MRI studies (reported in 23 patients)
Normal 8 (35%)
Abnormal 15 (65%)
Isolated optic nerve inflammation 5 (22%) Demyelinating lesions (hemispheres, brain stem
or spinal cord)
10 (43%)
Table 10: Treatment (reported in 28 patients)
Oral prednisone (1-2 mg/kg/day) 9 (32%) Intravenous methylprednisolone (500 mg/day for 3-
5 days)
5 (18%)
Intravenous methylprednisolone followed by oral prednisone
7 (25%)
Intravenous methylprednisolone followed by oral prednisone and antibiotics
1 (4%)
Antibiotics 1 (4%) (suspected Lyme disease)
None 5 (18%)
Follow-up
Follow-up data were available for all children, with observation periods varying from 1 to 53 months. During this period, 5 children (17%) developed clinically definite MS.
The mean delay between ON and the diagnosis of MS was 11.5 months for the 3 children whose episode of ON was a first demyelinating event. In 2 children, the episodes of ON occurred several months after a first episode of neurological dysfunction. In these patients, the diagnosis of MS was made at the time of their episode of ON.
The clinical characteristics of the 5 patients with MS are summarized in table 11.
The small number of patients with ON and MS does not allow to identify risk factors. 4/5 patients with MS were girls and 4/5 had unilateral ON.
Table 11: Clinical data of the 5 patients with MS
Patients Age Sex Clinical findings ON localization Preceding event Cerebrospinal fluid at the time of ON
MRI at the time of ON
Delay between ON and MS diagnosis
Diagnostic criteria (Poser)
DL 12 years female Decreased visual
acuity; orbital pain
Retrobulbar, unilateral None N/A Multiple demyelinating lesions
Neurological dysfunction (adiadochokinesis, unilaterally increased reflexes, unilateral abnormal sensitivity)
several months before ON
Neurological dysfunction, ON, abnormal MRI
SA 11.5 years Female Decreased visual acuity; orbital pain;
diplopia
Retrobulbar, unilateral Upper respiratory tract infection
Normal Normal 14 months. Multiple ON,
neurological dysfunction, later abnormal CSF
(oligoclonal bands) 4 episodes of ON, then flaccid tetraparesis, brainstem demyelinating lesions and oligoclonal bands in the CSF
MT 7.5 years Male Decreased visual acuity; orbital pain;
photophobia
Papillitis, unilateral Upper respiratory tract infection
Normal Multiple
demyelinating lesions
Acute disseminated encephalomyelitis (ADEM) at 5.5 years
ADEM, ON, abnormal MRI
SA 14 years Female Decreased visual acuity
Retrobulbar, unilateral N/A N/A Multiple
demyelinating lesions
28 months Second episode of ON, abnormal MRI
AF 7 years Female Decreased visual
acuity
Retrobulbar, bilateral Upper respiratory tract infection
N/A Normal 3 months Recurrence of
ON, then hemiparesis, abnormal MRI and CSF
DISCUSSION Epidemiology
Twenty-nine children with ON were identified in Switzerland over a 10 year-period, 14 girls and 15 boys (mean age: 10.5 years, range: 4.5-16 years). The number of patients in our study may not reflect the total number of patients with ON because occasional children might have been treated in ophthalmology clinics without being referred to us. The incidence in Switzerland was 0.04/100000, which confirms the rarity of this disorder in childhood previously reported, particularly in very young children [Lucchinetti et al., 1997; Cuendet-Graf and Taylor, 1991]. Ninety-four children with ON were identified over a period of 38 years in the largest study performed to date [Lucchinetti et al., 1997]. Their median age at presentation was 11 years (range, 2-16 years). The absence of significant gender predominance that we found was previously reported in pre-pubertal children [Brady et al., 1999; Boomer and Siatkowski, 2003], in contrast with an overall slight female preponderance (1.6:1) noted in the Mayo Clinic report [Lucchinetti et al., 1997], and the strong female preponderance observed in post-pubertal children [Brady et al., 1999], as well as in adults [Boomer and Siatkowski, 2003; Jin et al., 1998].
Symptoms and signs
97% of our patients presented with a decrease in visual acuity. One patient presented with an asymptomatic ON at 4 years and 10 months. Her young age probably explains the absence of reported complaints. 86% of the patients had a rapid progression of their symptomatology, over hours or days.
57% complained of pain on eye movements. The most frequent associated complaints were headaches in 29% of the children. This clinical presentation is similar to what patients reported in other studies [Lucchinetti et al., 1997; Cuendet-Graf and Taylor, 1991]. In the study reported by the Mayo Clinic, 98%
of the patients presented with a decrease in visual acuity, 37% had ocular pain and 37% had associated headache [Lucchinetti et al., 1997]. In our series, the clinical symptoms were not different in the patients with papillitis and with retrobulbar neuritis. For example, pain on eye movements, usually associated with retrobulbar ON, was also noted in 6 patients with papillitis.
Ophthalmological examination
An ophthalmological examination is required to narrow down the diagnosis of ON, or rare conditions included in the differential diagnosis, such as the stellate neuroretinitis of Leber, and to rule out disk swelling due to increased intracranial pressure. It also can identify features that have been described by the Optic Neuritis Study Group that carry a good prognosis (with a low likelihood of developing MS), such as absent light perception, severe optic disk swelling with peripapillary hemorrhages and retinal exudates [Beck et al., 2003]. VERs can identify clinically silent lesions [Frederiksen and Petrera, 1999]. In our series, 22 (75%) patients underwent an ophthalmological examination.
Sixty-two percent of our patients had unilateral ON. This is in contrast with the results of the studies by Boomer and Lucchinetti [Boomer and Siatkowski, 2003; Lucchinetti et al., 1997]. In the Mayo Clinic study, 39% of the children had unilateral involvement. The children with multiple unilateral episodes on alternating sides were considered as having unilateral ON in our study, whereas they were considered to have bilateral sequential ON in the Mayo Clinic group.
Sixty-two percent of our patients had retrobulbar ON with normal fundi. This is in contrast with the results of the Mayo Clinic study: only 40% of their patients had a normal fundoscopic examination. In other series on childhood ON, this proportion is even smaller. In the study of Boomer, only 13% of the children had normal optic fundi [Boomer and Siatkowski, 2003]. Koraszewska-Matuszewska et al. found that children younger than 14 years more frequently have papillitis and older children retrobulbar neuritis [Koraszewska-Matuszewska et al., 1995]. Similar findings have been reported by Morales et al. [Morales et al., 2000]. In their series, 72% of the children younger than 12 years had papillitis [Morales et al., 2000]. In our study, however, this age-related difference did not exist: 4 of the 7 patients (57%) older than 12 years had retrobulbar neuritis, whereas only 8 of the 22 patients (36%) younger than 12 years had papillitis. The 25% of the patients who did not have a formal and complete ophthalmological evaluation, were all examined by a pediatric neurologist. Therefore, the risk of misdiagnosis was, to our opinion, very low. The small size of our sample might by itself explain this unexpected finding.
Visual acuity was above 0.5 in 17 of 22 patients (77%) at the time of the initial ophthalmological examination. The relatively preserved visual acuity in our children contrasts with the more profound visual loss reported by others: visual acuity was at 20/100 or below in 84% of the patients in the series by
Morales [Morales et al., 2000], and in nearly 100% of the patients in the series of Kennedy [Kennedy and Carter, 1961].
Visual field defects were detected in 13 of 22 patients (59%). An afferent pupillary defect was detected in 4 of 22 patients (18%), who all had unilateral ON. Abnormal perception of colors was reported by 2 of 22 patients (9%). VER were recorded in 18 patients: 13 of them (72%) had abnormal responses. Similar results are reported in the Mayo Clinic study: visual field defects were found in 72%, an afferent pupillary defect in 27% and abnormal color vision in 24% of the patients [Lucchinetti et al., 1997].
Neurological examination
All of our patients were examined by a pediatric neurologist at the time of their admission for ON.
Eight patients (28%) showed coexisting neurological abnormalities: 1 had a subsequent diagnosis of clinically definite MS, 1 had sequelae of a previous neurological dysfunction and was also diagnosed with clinically definite MS, 2 had clinically probable MS, 1 had transverse myelitis, 1 had a previous episode of viral cerebellitis, and 2 had a single episode of ON (1 with bilateral Babinski sign, and 1 with unilaterally decreased strength and sensitivity of unknown origin). In the Mayo Clinic study, neurological abnormalities were observed in 46% of the 94 patients, at the time of ON and up to 1 month later [Lucchinetti et al., 1997]. Seizures were reported in 8 patients (9%) [Lucchinetti et al., 1997], whereas none of our patients had seizures. Interestingly, the neurological examination was normal at the time of ON in 3 of our 5 patients who subsequently developed MS. The 2 patients with abnormal neurological examination in addition to ON who were diagnosed with MS had sequelae of a previous neurological dysfunction. Thus, a normal neurological examination at the time of ON is not necessarily associated with a good prognosis. On the other hand, those abnormal neurological findings do not represent a significant risk factor for MS, according to previous reports [Lucchinetti et al., 1997; Beck et al., 2003]. Associated neurological abnormalities appear to be more common in ADEM and acute transverse myelitis [Lucchinetti et al., 1997; Beck et al., 2003].
Blood serologies
The occurrence of an infectious disease or a vaccination preceding the onset of ON was reported in 22 (76%) of our patients. This is similar to the results reported in other series. Sixty-six percent of the patients reported by Morales [Morales et al., 2000], and 55% of the pediatric patients reported by Riikonen [Riikonen, 1989] had infectious diseases during the weeks preceding the onset of ON. The Mayo Clinic study reported infectious diseases in 36% of their patients during the two weeks preceding the onset of ON [Lucchinetti et al., 1997]. In the literature, several infectious agents have been associated to ON: measles [Inokuchi et al., 1997; Lucchinetti et al., 1997], rubella [Yoshida et al., 1993; Lucchinetti et al., 1997], mumps [Khubchandani et al., 2002], varicella [Pina et al., 1997; Lucchinetti et al., 1997], infectious erythema [Wilhelm et al., 1998], Epstein-Barr virus [Beiran et al., 2000], cat scratch disease [Biousse, 2005], Lyme disease [Jacobson et al.,1991; Scott et al., 1997], brucella [Abd Elrazak, 1991], and toxoplasmosis [Fish et al., 1993]. Specific antibodies against Borrelia Burgdorferi were found in one of our patients without signs of Lyme disease. One patient had antibodies against Epstein-Barr virus.
One child in our study developed several episodes of ON together with clinical symptoms and radiologic signs of acute ethmoidal sinusitis. This etiology, considered to be due to the bacterial infection in adjacent structures, has been previously reported [Moorman et al., 1999; Kumar et al., 1999; Sanborn et al., 1984; Weber and Mikulis, 1987].
One of our patients had been vaccinated against diphtheria, tetanus, and pertussis during the weeks preceding 2 recurrent episodes of ON. IgM antibodies against diphtheria and tetanus were exceptionally elevated, 10 times higher than average responses to vaccination. Another patient had been vaccinated against poliomyelitis prior to the onset of ON. In the series of Riikonen [Riikonen, 1989], 6 patients had been vaccinated with live or attenuated viruses during the weeks preceding the ON. ON associated with vaccines against antituberculous vaccines (BCG) [Yen and Liu, 1991], hepatitis A and B and yellow fever [Voigt et al., 2001, tetanus-diphtheria-poliomyelitis [Burkhard et al., 2001], influenza [Hull and Bates, 1997], and rubella [Kline et al., 1982] have been reported. The unusually high levels of IgM in our first patient supports the hypothesis of an autoimmune mechanism for ON.
ON has also been described in patients with collagen-vascular diseases, such as systemic lupus erythematosus [Ahmadieh et al., 1994; Galindo-Rodriguez et al., 1999] or rheumatoid arthritis [Agildere et al., 1999]. The causal mechanism is supposed to be an autoimmune inflammation of blood vessels with
secondary involvement of the optic nerve. These diseases are rare in childhood, and none of the patients in our series was diagnosed with any of them.
A rare cause of ON reported in the literature is toxicity of medications, such as ethambutol [Kahana, 1987], tamoxifene [Noureddin et al., 1999], deferoxamine [Miller, 1996], and α-interferon [Miller, 1996]. No patient in our study had been treated with possibly toxic medications.
CSF
A lumbar puncture was performed in 20 patients (69%) at the time of ON. The results were abnormal in 5. Immunoelectrophoresis revealed increased proteins in 1, increased proteins and lymphocytes in 1, and oligoclonal bands, a diagnostic criterion for MS, in 1. In the Mayo Clinic study, 47% of the patients were reported to have abnormal CSF findings. Pleocytosis was the most frequent abnormality, found in 90% of their samples. Elevated proteins were found in 24% of the patients. No child was reported to have oligoclonal bands [Lucchinetti et al., 1997]. Oligoclonal bands were found to be a significant risk factor for MS in adults when associated with a periventricular demyelinating lesion on MRI [Soderstrom et al., 1998] or not [Cole et al., 1998].
MRI
Cerebral MRI was performed in 23 patients of our study. In 15 of them (65%) the studies showed cerebral abnomalies: in 5 patients (22%) inflammation of the optic nerve was seen with contrast enhancement. In 10 patients (43%), demyelinating lesions were seen on T2-weighted images. Details regarding the number, location and characteristics of the lesions were not reported, and the studies were not available.
Demyelinating lesions were reported in 33% of the children in the series of Riikonen [Riikonen, 1988] and in 57% of the children in the study of Morales [Morales et al., 2000]. A normal brain MRI at the time of ON seems to be associated to an excellent visual prognosis [Brady et al., 1999].
Treatment
Various treatment schedules were used in the different centers: oral prednisone, intravenous methylprednisolone, the association of both, or none. No schedule appeared to be associated to a better recovery of visual function or later development of MS. Few children had a fast and complete recovery of visual acuity without treatment, whereas other patients treated with steroids recovered more slowly.
As most cases of ON are considered to be due to a post-infectious inflammation, steroids are usually recommended. The results of the Optic Neuritis Treatment Trial indicated that high-dose intravenous methylprednisolone followed by oral prednisone accelerated visual recovery, but did not affect long-term visual recovery. This treatment schedule decreased the incidence of CDMS at 2 years, but unfortunately not at 3 years [Beck et al., 2003]. This study also showed that oral prednisone alone increased the risk of recurrence of ON. Thus, high-dose intravenous methylprednisolone for 3 to 5 days, followed by oral prednisone tapered off over 10 to 14 days is the recommended schedule for treatment of adults with ON [Beck et al., 2003; Boomer and Siatkowski, 2003], as well as children [Boomer and Siatkowski, 2003].
Despite the complete recovery observed in children without treatment, and the potentially severe side effects of corticosteroids, the recommended treatment of childhood ON is intravenous methylprednisolone (10-30 mg/kg/day), followed by oral prednisone (1 mg/kg/day). Since high rates of relapse have been observed when steroids were tapered too quickly, it is recommended that steroids be tapered off over at least 4 weeks [Boomer and Siatkowski, 2003].
One placebo-controlled prospective study in adults recently published showed a short-term neurological benefit and reduction of the number of demyelinating lesions on MRI with interferon β-1a in addition to steroids in patients with ON and a high risk of developing MS, defined by the presence of multiple clinically silent lesions on MRI [CHAMPS Study Group, 2001]. A benefit of interferon β-1a in children has not yet been demonstrated.
Follow-up
Five patients (17%) subsequently developed MS and their episode of ON was considered to represent the first demyelinating event. Four of them were girls. Cerebral MRI had been performed in all children who subsequently developed MS. It was normal in 2 but showed demyelinating lesions in 3.
Only 2 of the 5 children had a lumbar puncture during the episode of ON. CSF results were normal in both, whereas in the 3 children with oligoclonal bands, no CDMS was diagnosed during the observation period.
The association of ON and MS has been long recognized, and is a major concern. Acute monosymptomatic ON in adults has even been considered to be an early manifestation of MS. The risk for development of MS in adults with ON in the literature is quite variable: 13% [Perkin, 1979], 38%
[Beck et al., 2003], and 88% [Perkin, 1979] have been reported. Fortunately the risk appears to be lower in children with ON: it was evaluated at 13% in 79 pediatric patients after a follow-up of 10 years [Lucchinetti et al., 1997]. Although the number of patients with MS increases with each year of follow- up [Beck et al., 2003; Lucchinetti et al., 1997], it appears that most adults develop MS within the first 5 years after the episode of ON [Beck et al., 2003], whereas children develop MS within the first year after the episode of ON [Lucchinetti et al., 1997].
Risk factors
Risk factors for developing MS have been reported in adults. The most important of them is the presence of white matter lesions on cerebral MRI at the time of the ON. The presence of 1 or more white matter lesions of at least 3 mm in diameter is associated with a 56% risk of developing MS within 10 years. The risk is much lower (22%) in patients without MRI lesions [Beck et al., 2003]. According to the study of Soderstrom in adults [Soderstrom et al., 1998], the risk for MS is higher when one of the lesions is periventricular and when oligoclonal bands are present in the spinal fluid [Soderstrom et al., 1998], whereas normal cerebral MRI and absence of oligoclonal bands decrease the risk of MS [Soderstrom et al., 1998]. The presence of oligoclonal bands in the CSF is also associated to a higher risk for the development of MS [Cole et al., 1998]. In children, Lucchinetti et al. found a non-significant link between elevated CSF proteins and the subsequent development of MS [Lucchinetti et al., 1997].
Several symptoms and signs, observed in adult patients without MRI lesions, were found to be associated with a low risk of MS [Beck et al., 2003]: orbital swelling, absence of orbital pain, no light perception vision, and retinal hemorrhages, as well as male gender. In children, an increased risk of MS was determined by Lucchinetti et al. [Lucchinetti et al., 1997] in patients with bilateral sequential or
recurrent ON, and a decreased risk in patients whose ON was preceded by an infectious disease within 2 weeks. In our study, 3 of the 5 patients who developed MS had an infection during the 4 weeks preceding the ON.
Female gender has repeatedly been found to represent a risk factor for all autoimmune diseases, including MS. This has been explained by a higher secretion of pro-inflammatory interleukin-5 and interferon-γ by cells exposed to myelin proteins in women affected by MS compared to healthy female controls or affected males [Pelfrey et al., 2002]. This ratio is known to reverse during pregnancy, an explanation for the known protective effect of pregnancy for autoimmune diseases. Female gender predominated in our study, since 4 of 5 patients who developed MS were girls.
Two of our patients with ON had clinical signs or characteristic MRI findings of acute demyelinating encephalomyelitis (ADEM). ADEM is usually monophasic, and frequently associated with a depressed level of consciousness and confusion. ON accompanying ADEM is most often bilateral, and cerebral MRI exhibits bilateral large subcortical enhancing lesions.
One of our patients presented with signs of spinal cord involvement (spasticity of both legs, spastic bladder) together with ON. He had a second contralateral ON 2 months later. This clinical presentation is consistent with neuromyelitis optica (Devic’s disease) considered to be a particular form of MS.
5. CONCLUSION
The results of this retrospective multicenter study, which includes a small number of patients, do not differ from results of larger studies. It reveals that both work-up and treatment of children with ON are quite variable in the different pediatric centers in Switzerland, although in adults, recommendations for the management of ON do exist. Variable treatment schedules, small sample size and short mean follow-up, did not allow to identify any risk factors for the development of MS, nor a possible preventive effect of a particular treatment schedule.
We therefore plan a long-term, multicenter, randomized study in children, involving both Child Neurologists and Neuro-Ophthalmologists and will propose a standardized flowchart both for the work- up (figure 1) and treatment (figure 2) of children presenting with ON.
Figure 1 :Work-up
Rapid drop of visual acuity, pain on eye movements
Ophthalmologic examination
Neuropediatric examination:
associated neurological anomalies, neurological history, preceding
infections, vaccinations
Cerebral MRI
Lumbar puncture
Blood exams
T1, T2, FLAIR, contrast enhancement - Optic nerve
inflammation - Number, size and localization of other lesions
Cells, proteins, immunoglobulin, oligoclonal bands,
serologies
Serologies (neurotropic viruses+Borrelia), antibodies following
vaccinations, non- specific inflammatory
tests
Figure 2 : treatment Optic Neuritis
Inflammatory, demyelinating or autoimmune disease
Infectious diseases (Lyme)
Methylprednisolone 500 mg/d during 3 or 5 days, followed by oral prednisone 1 mg/kg/d tapered over 14 or 28 days.
If CDMS, β-interferon to be considered.
Antibiotics
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