Pediatric neuro-ophthalmology

Su Ann Lim and R. Michael Siatkowski

Purpose of review Introduction

This review will update the ophthalmologist on recent Pediatric neuro-ophthalmology is unique in that it
developments in pediatric neuro-ophthalmology. straddles three medical fields. This article reviews litera-
Recent findings ture in this field published in 2003.
Research into the genetics of congenital strabismus
syndromes has brought new insights into the development of Higher cortical function: cortical visual
the ocular motor system. There is also new literature on impairment, PVL, blindsight
childhood ocular myasthenia gravis and childhood Perinatal hypoxia is the most common cause of cortical
neurosarcoidosis. The results of three different surgical visual impairment in developed countries. The pattern
treatments for congenital nystagmus are described. Reviews of injury differs depending on age, severity, and duration
on cortical visual impairment, dyslexia, Aicardi syndrome, and of insult. In term infants, damage mainly affects the wa-
neuronal ceroid lipofuscinosis are presented. tershed zones of the cerebral cortex (frontal and parieto-
Summary occipital regions). Premature infants primarily sustain
Pediatric neuro-ophthalmology is a diverse and challenging periventricular injury (Fig. 1). An age-related change in
field. As we strive to provide excellent care to these patients, the intervascular boundary zones may account for this.
we will use the results of basic science, genetic, and The deep venous system develops earlier than the sub-
neurobiological research. cortical and cortical systems. As a result, the watershed
zone is the subcortical area in preterm infants, as op-
Keywords posed to the parieto-occipital cortex in term infants. Ad-
cortical visual impairment, optic nerve hypoplasia, Wolfram ditionally, the anaerobic response of the periventricular
syndrome, dyslexia, sarcoidosis, myasthenia gravis, congenital area to hypoxia results in tissue-damaging acidosis [1••].
fibrosis syndrome, migraine
Patients with periventricular leukomalacia (PVL) have a
Curr Opin Ophthalmol 15:437–443. © 2004 Lippincott Williams & Wilkins. poorer prognosis compared with patients with cortical
lesions. Cats with visual cortex ablation develop in-
creased projection of retinal ganglion cells through the
thalamus to the posteromedial lateral suprasylvian cor-
tex. The optic radiation injury in PVL damages these
Department of Ophthalmology, Dean A. McGee Eye Institute, University of adaptive retinothalamic projections. In addition, there is
Oklahoma College of Medicine, Oklahoma City, Oklahoma, USA
a higher incidence of strabismus (53.8% vs 12.1%) and
Correspondence to R. Michael Siatkowski, MD, Department of Ophthalmology, nystagmus (50% vs 4.8%) in patients with PVL as op-
Dean A. McGee Eye Institute, University of Oklahoma College of Medicine, 608
Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA
posed to cortical lesions [1••].
Tel: 405 271 1094; fax: 405 271 3013; e-mail: RMichael-Siatkowski@dmei.org
Blindsight is the unconscious residual visual ability
Supported in part by an unrestricted grant for Research to Prevent Blindness, NY,
NY (RMS) within a visual field defect caused by a lesion in the
striate cortex [2]. It is still unclear whether blindsight in
Current Opinion in Ophthalmology 2004, 15:437–443
humans is due to small areas of residual visual cortex,
Abbreviations normal brain plasticity, or collicular visual potential [3,4].
ADOA autosomal dominant optic atrophy
DS Duane syndrome
IIN idiopathic infantile nystagmus
Optic nerve hypoplasia
LHON Leber hereditary optic neuropathy The constellation of bilateral optic nerve hypoplasia, ab-
MS multiple sclerosis sent septum pellucidum, thin or absent corpus callosum,
NAFX expanded nystagmus acuity function
NCL neuronal ceroid lipofuscinoses and possible pituitary dysfunction is termed septo-optic
OMA ocular motor apraxia dysplasia or de Morsier syndrome. Weiss and Kelly [5•]
ONH optic nerve hypoplasia
PVL periventricular leukomalacia developed an equation to estimate visual potential from
SN spasmus nutans presenting Teller acuity, optic disc size, and visual
© 2004 Lippincott Williams & Wilkins evoked potentials.
1040-8738
Untreated endocrine dysfunction may severely impair a
child’s development. Because of the difficulty and cost
437
438 Pediatrics and strabismus
Figure 1. Periventricular leukomalacia in a 3-year-old boy with
extreme prematurity and periventricular hemorrhages in the
neonatal period
The cortical sulci (arrows) impinge directly on the ventricle. Reprinted with
permission [43].
of performing hormonal assays in children, there is a
need to identify children at greatest risk of endocrinop-
athy.
Posterior pituitary ectopia and infundibular hypoplasia
correlate with endocrine dysfunction [6,7]; however, ap-
proximately 10% of patients without these abnormalities
have pituitary dysfunction [7]. The risk of endocrinopa-
thy is greatest if both septum pellucidum and hypotha-
lamic-pituitary axis are abnormal (61%) [8•].
Tear Fahnehjelm et al. [9] found that children with ONH
and neonatal hypoglycemia, neonatal jaundice, or retinal
venous tortuosity were also at increased risk of hormone
deficiencies.
Hereditary optic neuropathies: Wolfram
syndrome, Leber hereditary
optic neuropathy
Wolfram syndrome [10] consists of diabetes insipidus,
diabetes mellitus, optic atrophy, nerve deafness, and uri-
nary tract abnormalities. Its inheritance is autosomal re-
cessive. Patients may also have growth retardation and
hypogonadism; the former results from atrophic changes
in the hypothalamo-hypophyseal regions, and the latter
may be either primary or secondary to hypothalamic dys-
function.
Mitochondria are essential for the cell’s energy produc-
tion via oxidative phosphorylation and ATP synthesis.
The optic nerve head may constitute an energetic choke-
point that is particularly sensitive to disruption of mito-
chondrial function. During times of oxidative stress, for
example, smoking or illness, energy production is pref-
erentially impaired in this region and vision is compro-
mised. The antioxidant and neuroprotective effect of es-
trogens [11] may explain the decreased incidence of
Leber hereditary optic neuropathy (LHON) in females.
Howell [12•] postulates a link between LHON, autoso-
mal dominant optic atrophy (ADOA), juvenile-onset pri-
mary open angle glaucoma, and toxic and nutritional op-
tic neuropathies.
The OPA1 gene in ADOA codes for a protein involved in
GTP binding. The GLC1 (TIGR) gene in juvenile-
onset open angle glaucoma codes for the protein myo-
cilin. Both of these proteins affect the structural integ-
rity of mitochondria. The link to toxic neuropathies is
less clear, but both chloramphenicol and ethambutol dis-
rupt mitochondrial respiratory chain function. Mitochon-
drial dysfunction may be the final common pathway in
all of these neuropathies.
Multiple sclerosis (MS) and LHON may occur simulta-
neously. Up to 0.5% of MS patients have a primary
LHON mutation [13]. Conversely, MS occurs in 5.1% of
the LHON pedigrees. The LHON mutation may render
the optic nerve more susceptible in MS.
Compressive anterior visual
pathway disease
The most common suprasellar tumors in children are
craniopharyngiomas and optic gliomas. Cysts and calci-
fication on neuroimaging are more common in cranio-
pharyngiomas.
Bisson et al. [14] present two cases of hypothalamic-
opticochiasmatic gliomas that mimicked craniopharyn-
giomas on neuroimaging; CT showed cystic suprasellar
masses with calcification; with MRI, these cystic masses
enhanced and extended into the third ventricle. This
highlights the need for the patient, family, and neuro-
surgeon to recognize that final diagnosis, management,
and prognosis can be determined only after histopatho-
logic review.
Congenital ocular motor abnormalities:
congenital fibrosis of the extraocular
muscles, Duane syndrome,
Moebius syndrome
Rather than being a primary myopathy, congenital fibro-
sis of the extraocular muscles (CFEOM) likely results
from a neurodevelopmental abnormality. There are
three recognized CFEOM phenotypes [15]. Patients

with classic CFEOM (CFEOM1) have bilateral restric-
tive ophthalmoplegia and ptosis. The primary position of
the eyes is infraducted and they are unable to elevate
their globes above midline. It is inherited in an autoso-
mal dominant fashion. The CFEOM1 phenotype maps
to the FEOM1 locus on chromosome 12. Neuropatho-
logic studies have revealed absence of the superior divi-
sion of the oculomotor nerve in the midbrain, suggesting
a primary developmental abnormality of the oculomotor
nucleus.
Patients with CFEOM2 have bilateral ptosis and a large
angle exotropia with severely limited horizontal and ver-
tical movements. This has an autosomal recessive inher-
itance. CFEOM2 maps to the FEOM2 locus on chromo-
some 11. Affected individuals have homozygous
mutations in the transcription factor gene, ARIX. ARIX
is essential to the development of the oculomotor and
trochlear nuclei in mice and zebrafish.
Individuals with CFEOM3 have more variable motility
defects. The CFEOM3 phenotype maps to chromo-
some 16.
Duane syndrome (DS) is caused by faulty development
of the abducens nucleus in the brainstem and aberrant
innervation of the lateral rectus by axons destined for the
medial rectus. Recent research has identified the locus
for DS to chromosome 2 [16].
Moebius syndrome is a developmental anomaly of the
facial and abducens nuclei. Other cranial nerves may be
involved, including the V, IX, and XII, resulting in
speech and communication problems. Goldberg et al.
[17] performed gracilis muscle transplantation on af-
fected children and demonstrated universal improve-
ment in speech. This is an important option for these
children who may erroneously be regarded as unintelli-
gent because of their poor verbal and facial communica-
tion ability.
Nystagmus and related ocular oscillations:
transient idiopathic nystagmus in infants,
idiopathic infantile nystagmus,
opsoclonus–myoclonus syndrome
In infants, transient neonatal nystagmus is usually be-
nign and does not indicate visual or neurologic disease.
Good et al. [18••] describes this in 11 children with onset
before 10 months of age (mean 2.7 months). It persisted
only a few months and completely disappeared by 12
months. No cause was found despite extensive workup.
The nystagmus was horizontal in five patients, vertical in
three, upbeat in one, and monocular in one. Two pa-
tients had delayed visual maturation, one had regressed
retinopathy of prematurity, and one had coloboma, af-
fecting the macula in one eye. In the postnatal period,
any disruption of afferent visual input can potentially
Pediatric neuro-ophthalmology Lim and Siatkowski 439
affect an unstable ocular motor system, resulting in nys-
tagmus.
Kim et al. [19] report a patient diagnosed with spasmus
nutans (SN) as a neonate. When this resolved at age 2,
his parents noticed head thrusting during attempted gaze
shift, typical of ocular motor apraxia (OMA). MRI re-
vealed cerebellar vermian hypoplasia. This patient also
had delayed developmental milestones, suggesting that
SN and OMA may be caused by developmental delay.
This case also supports the recommendation for neuro-
imaging in SN.
Idiopathic infantile nystagmus (IIN) starts at birth or
early infancy when visual fixation develops. It results
from instability of ocular motor control and may develop
with or without an accompanying sensory deficit [20].
The predominantly pendular waveform in infants con-
verts to jerk as the visual system matures, allowing better
acuity through longer foveation periods. Waveforms with
brief foveation periods are associated with poor vision
and vice versa [21].
The most common association of IIN is bilateral anterior
visual pathway disease. Surgical treatments in these pa-
tients have been attempted to improve binocular visual
acuity by extending foveation times, reduce torticollis if
there is a null point, or less commonly, improve oscillop-
sia.
Alio et al. [22•] published their results in 42 patients
using extended hang-back recession of all four horizontal
recti, 14 mm from the insertion. If strabismus was pres-
ent, a recession of 13 mm or 15 mm was performed, with
larger recession on the medial recti for esotropia or the
lateral recti for exotropia. The muscular body was
pushed back with a cotton tip to ensure that it would
hang back the full amount. Results at least 1 year after
surgery demonstrated improvement of best-corrected
binocular vision in 45.2% of patients (0.1 to 0.3 logMar,
P = 0.06), mainly in those with unassociated sensory de-
privation. Torticollis decreased in all cases. Strabismus
was the main complication with this procedure, with 11
of 42 patients (26.1%) requiring a second surgery or botu-
linus toxin injection.
Tenon capsule may prevent posterior displacement of
the muscle in large hang-back recessions. Alio et al. sug-
gest modifying their original hang-back technique
whereby the suture is placed 7 mm posterior to the origi-
nal insertion.
Kose et al. [23] describe a similar technique using non-
absorbable 5.0 Dacron loop sutures passed 8 mm poste-
rior to the original insertion.
440 Pediatrics and strabismus
A novel surgical treatment for IIN has been suggested
based on the hypothesis that nerve endings at the ten-
dino-scleral interface of extraocular muscles innervate af-
ferent fibers of the ophthalmic division of the trigeminal
nerve, influencing eye-movement control. A simple te-
notomy may disrupt these impulses and decrease the
amplitude of nystagmus. Hertle et al. [24•] describe their
results in 10 patients with IIN. Care must be taken when
comparing the results of this study with other similar
studies, as the primary outcome measure was the
eXpanded Nystagmus Acuity Function (NAFX), a func-
tion that predicts the best-corrected potential acuity on
the basis of eye movement recordings during fixation on
a small, light-emitting diode of their fixing eye. One year
after tenotomy, 9 of 10 patients had increases in their
NAFX. However, binocular visual acuity measured with
the ETDRS Chart improved in only 5 of 10 patients. In
addition, IIN often varies throughout the day and from
day to day, further complicating interpretation.
Opsoclonus is involuntary, rapid, back-to-back saccades,
with no intersaccadic interval. In children, it is due to
paraneoplastic effects of neuroblastic tumors. Gambini
et al. [25] report that neuroblastoma patients with opso-
clonus had histologically more benign tumors as opposed
to tumors in patients without it.
Dyslexia
Dyslexia is characterized by an unexpected difficulty in
reading in persons who otherwise possess normal intel-
ligence, motivation, and education. It affects 5% to
17.5% of the population, and has a male predilection. A
strong hereditary component is recognized; a family his-
tory of dyslexia is the most important risk factor for de-
veloping dyslexia. Linkage analysis implicates chromo-
some 1, 2, 6, and 15 in the transmission of this disorder
[26•,27••].
There are two major theories behind this disorder: the
phonological and general sensorimotor theory. Ramus et
al. [28] support the phonological theory, correlating with
the consensus of most experts in the field. However,
many dyslexics also have concomitant generalized sen-
sory-motor dysfunction, suggesting more diffuse central
nervous system involvement.
Anatomic correlations have implicated widely different
brain areas in dyslexia, including the frontal lobes, tem-
poroparietal region, cerebellum, insular, caudate, left
temporal lobe, and thalamus [29,30].
Shaywitz and Shaywitz [27••] believe that two systems
necessary for skilled, automatic reading are faulty in dys-
lexia. One involves decoding or analyzing individual
units of words or phonemes (for example, bat has three
phonemes; bah, ahh and tah) and is located in the left
parietotemporal region. The other process is comprehen-
sion, located in the left occipitotemporal area. The mul-
tiple different abnormal sites of activation in dyslexics
may be evidence of attempts to compensate for one pri-
mary dysfunctional area by shifting to other ancillary re-
gions.
Management of dyslexia consists of early remediation
(phonemic awareness, phonics, reading comprehension
strategies) and providing accommodations in older chil-
dren (extra time for reading, spell check computer pro-
gram, tape recorders). There is no evidence to support
other treatment modalities.
Pediatric migraine and headaches
Although migraine with aura may occur in children, they
may also present with isolated gastrointestinal distress or
somnambulism. A history of motion sickness or inability
to read in a car supports the diagnosis.
The most common dietary triggers are cheese, chocolate,
nuts and processed meats. Because of the increase in
underage alcohol consumption and the trend for adoles-
cent girls to substitute diet colas for food, alcohol and
caffeine withdrawal headaches must also be considered
this population. In addition, caffeine withdrawal may ex-
acerbate migraine attacks. There is also an association
between fasting hypoglycemia, dehydration, ice cream,
and fatty foods with migraine [31•]. A trial of excluding
possible headache triggers should be attempted prior to
before prophylactic drug therapy.
Pediatric neurosarcoidosis
Unlike adult disease, pediatric neurosarcoidosis shows
no female preponderance and no increased prevalence in
African-Americans. In adults, neurosarcoid most com-
monly presents with facial nerve palsy or headache. Sei-
zures and pituitary dysfunction occur in only 10% of the
cases. In contrast, Baumann and Robertson [32•] report
that seizures are a common presenting symptom in chil-
dren (38%). Cranial nerve palsies appear only after pu-
berty. Twenty-one percent of children may have evi-
dence of hypothalamic dysfunction. A striking difference
is the presence of an intracranial mass lesion (24%) in
children.
Childhood ocular myasthenia gravis
Kim et al. [33••] reviewed 24 children with ocular my-
asthenia, and are the first to report the incidence of am-
blyopia in this condition (21%). Two findings differ from
previous reports. First is the frequency of vertical stra-
bismus seen in this series (13/21 patients). Second is the
increased frequency of abduction compared with adduc-
tion deficits (15.4% vs 2.6%), contrary to other reports
where the medial rectus muscle is most frequently in-
volved [34,35]. Nevertheless, myasthenia gravis remains
a great mimicker, and any pattern of extraocular muscle
paresis can develop. Response to treatment is better for
 Pediatric neuro-ophthalmology Lim and Siatkowski 441

ptosis than for ophthalmoplegia, and many patients re- Figure 2. Aicardi syndrome
quire prednisone in combination with pyridostigmine.

The role of thymectomy is still controversial but should

be considered in all cases with thymoma, or in patients
without thymoma, but who are refractory to medical
treatment. All data in the literature are based on data
from nonrandomized studies [36]. In addition, the type
of surgical procedure varies from radical thymectomy at
one end of the spectrum to thorascopic thymectomy at
the other. Roberts et al. [37] describe their series of 61
patients with ocular myasthenia gravis treated with
transsternal or transcervical thymectomy. One patient
died as a result of the surgery, and two patients had
pneumothorax.

Skelly et al. [38•] report their success with thorascopic

thymectomy in five children. Complete excision oc-
curred in all cases, and there were no complications.
Thorascopic thymectomy seems equally effective as
open surgery, with advantages of decreased postopera-
tive pain, shorter hospitalization, and improved cosmesis.
A cluster of peripapillary lacunae surround an enlarged, anomalous right optic
However, more studies are needed to determine the in-
disc. Reprinted with permission [44].
dications, timing, and surgical approach of thymectomy
for myasthenia gravis.

Aicardi syndrome maculopathy with temporal disc pallor (Fig. 3). Electro-
Aicardi syndrome is an X-linked dominant disorder with retinography shows diminished a and b waves in both
the clinical triad of infantile spasms, agenesis of the cor- scotopic and photopic conditions. Neuroimaging may be
pus callosum, and chorioretinal lacunae. Mental retarda- normal or reveal mild cortical atrophy.
tion, costovertebral anomalies, and intractable epilepsy
may also occur. Although the chorioretinal lacunae are
pathognomonic, other ocular malformations may be seen The infantile form of the disease also causes visual loss,
(for example, microphthalmos, cataract, retinal detach- but most patients have significant neurologic manifesta-
ment, ONH, coloboma) [39•]. Aicardi syndrome may be tions by the time vision is affected.
confused with congenital TORCH infections because
both can produce chorioretinal abnormalities, seizures,
and mental retardation. Differentiating features are the Figure 3. Batten disease
lack of pigment at the edges and the atrophic, yellowish-
white appearance of the lacunae in Aicardi syndrome
(Fig. 2).

Neuronal ceroid lipofuscinoses

The neuronal ceroid lipofuscinoses (NCL) are a group of
autosomal recessive neurodegenerative diseases, charac-
terized by brain and retinal atrophy. Gene products of six
of the eight forms of NCL have now been discovered.
These fall into two categories comprising either soluble
lysosomal enzymes (CLN1 and CLN2) or predicted
transmembrane proteins of unknown structure and func-
tion (CLN3, CLN5, CLN6, and CLN8) [40•].

Juvenile NCL (Batten disease) usually presents with vi-

sual loss before other neurologic signs occur. Presenting
visual acuity is hand motion or worse in 50% of cases
[41]. Funduscopic findings vary, from a subtle, diffuse
grainy appearance of the retina to the classic bull’s eye
Fundus photograph reveals corrugation in the internal limiting membrane, fine
granularity in the maculae, and a depressed foveal light reflex. There is an
indistinct hyperpigmented bull’s-eye zone of atrophy. Reprinted with permission
[41].
442 Pediatrics and strabismus
Although the majority of the gene products responsible
for this disorder have been identified, the precise mecha-
nism by which these result in clinical disease remains
elusive. At present, there is no known treatment for
NCL. Hematopoietic stem cell transplantation has been
attempted for infantile NCL, but without success [42].
Conclusion
This article reviews the advances made in the last year
on various entities frequently seen in pediatric neuro-
ophthalmology. It is by no means complete, and the cli-
nician will encounter many other conditions in clinical
practice (optic neuritis, cranial nerve palsies, and so on).
Presentation, diagnosis, and management may be very
different in children as compared with adults.
References and recommended reading
Papers of particular interest, published within the annual period of review,
have been highlighted as:
• Of special interest
•• Of outstanding interest
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Prospective case series that confirms the correlation of presenting acuity, optic
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11 Wang J, Green PS, Simpkins JW: Estradiol protects against ATP depletion,
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First paper published that describes this under-recognized condition. In addition,
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22 Alio JL, Chipont E, Mulet E, et al.: Visual performance after congenital nystag-
• mus surgery using extended hang back recession of the four horizontal rectus
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Largest series reporting results of hang-back recession of the four horizontal recti
for congenital nystagmus.
23 Kose S, Egrilmez DG, Uretmen O, et al.: Retroequatorial recession of hori-
zontal recti with loop suture in the treatment of congenital nystagmus. Stra-
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24 Hertle RW, Dell’Osso LF, FitzGibbon EJ, et al.: Horizontal rectus tenotomy in
• patients with congenital nystagmus: results in 10 adults. Ophthalmology
2003, 110:2097–2105.
First series reporting the results of horizontal rectus tenotomy in patients with con-
genital nystagmus.
25 Gambini C, Conte M, Bernini G, et al.: Neuroblastic tumors associated with
opsoclonus-myoclonus syndrome: histological, immunohistochemical and
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Epub 2003 Apr 23.
26 Ramus F: Developmental dyslexia: specific phonological deficit or general
• sensorimotor dysfunction? Curr Opin Neurobiol 2003, 13:212–218.
Reviews the evidence behind the different theories for the development of dyslexia,
and summarizes the current view on the subject.
27 Shaywitz SE, Shaywitz BA: The science of reading and dyslexia. J AAPOS
•• 2003, 7:158–166.
Summarizes the current views on the etiology, diagnosis, and clinical management
of dyslexia.
28 Ramus F, Rosen S, Dakin SC, et al.: Theories of developmental dyslexia:
insights from a multiple case study of dyslexic adults. Brain 2003, 126:841–
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29 Breier JI, Simos PG, Fletcher JM, et al.: Abnormal activation of temporopari-
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30 Eckert MA, Leonard CM, Richards TL, et al.: Anatomical correlates of dys-
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31 Millichap JG, Yee MM: The diet factor in pediatric and adolescent migraine.
• Pediatr Neurol 2003, 28:9–15.
Good review on the dietary triggers involved in childhood and adolescent migraine.
32 Baumann RJ, Robertson WC Jr: Neurosarcoid presents differently in children
• than in adults. Pediatrics 2003, 112:e480–e486.
First paper that addresses the issue that neurosarcoidosis may present differently
in children.
33 Kim JH, Hwang JM, Hwang YS, et al.: Childhood ocular myasthenia gravis.
Ophthalmology 2003, 110:1458–1462.
••
This is the first paper on purely ocular myasthenia gravis in childhood. It is interest-
ing that adduction deficits were encountered less commonly than abduction ones.
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