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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:
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.
Untreated endocrine dysfunction may severely impair a
child’s development. Because of the difficulty and cost
438 Pediatrics and strabismus

Figure 1. Periventricular leukomalacia in a 3-year-old boy with Mitochondria are essential for the cell’s energy produc-
extreme prematurity and periventricular hemorrhages in the
neonatal period
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.
The cortical sulci (arrows) impinge directly on the ventricle. Reprinted with
permission [43].
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
of performing hormonal assays in children, there is a the optic nerve more susceptible in MS.
need to identify children at greatest risk of endocrinop-
athy. Compressive anterior visual
pathway disease
Posterior pituitary ectopia and infundibular hypoplasia The most common suprasellar tumors in children are
correlate with endocrine dysfunction [6,7]; however, ap- craniopharyngiomas and optic gliomas. Cysts and calci-
proximately 10% of patients without these abnormalities fication on neuroimaging are more common in cranio-
have pituitary dysfunction [7]. The risk of endocrinopa- pharyngiomas.
thy is greatest if both septum pellucidum and hypotha-
lamic-pituitary axis are abnormal (61%) [8•]. Bisson et al. [14] present two cases of hypothalamic-
opticochiasmatic gliomas that mimicked craniopharyn-
Tear Fahnehjelm et al. [9] found that children with ONH giomas on neuroimaging; CT showed cystic suprasellar
and neonatal hypoglycemia, neonatal jaundice, or retinal masses with calcification; with MRI, these cystic masses
venous tortuosity were also at increased risk of hormone enhanced and extended into the third ventricle. This
deficiencies. highlights the need for the patient, family, and neuro-
surgeon to recognize that final diagnosis, management,
Hereditary optic neuropathies: Wolfram and prognosis can be determined only after histopatho-
syndrome, Leber hereditary logic review.
optic neuropathy
Wolfram syndrome [10] consists of diabetes insipidus, Congenital ocular motor abnormalities:
diabetes mellitus, optic atrophy, nerve deafness, and uri- congenital fibrosis of the extraocular
nary tract abnormalities. Its inheritance is autosomal re- muscles, Duane syndrome,
cessive. Patients may also have growth retardation and Moebius syndrome
hypogonadism; the former results from atrophic changes Rather than being a primary myopathy, congenital fibro-
in the hypothalamo-hypophyseal regions, and the latter sis of the extraocular muscles (CFEOM) likely results
may be either primary or secondary to hypothalamic dys- from a neurodevelopmental abnormality. There are
function. three recognized CFEOM phenotypes [15]. Patients
Pediatric neuro-ophthalmology Lim and Siatkowski 439

with classic CFEOM (CFEOM1) have bilateral restric- affect an unstable ocular motor system, resulting in nys-
tive ophthalmoplegia and ptosis. The primary position of tagmus.
the eyes is infraducted and they are unable to elevate
their globes above midline. It is inherited in an autoso- Kim et al. [19] report a patient diagnosed with spasmus
mal dominant fashion. The CFEOM1 phenotype maps nutans (SN) as a neonate. When this resolved at age 2,
to the FEOM1 locus on chromosome 12. Neuropatho- his parents noticed head thrusting during attempted gaze
logic studies have revealed absence of the superior divi- shift, typical of ocular motor apraxia (OMA). MRI re-
sion of the oculomotor nerve in the midbrain, suggesting vealed cerebellar vermian hypoplasia. This patient also
a primary developmental abnormality of the oculomotor had delayed developmental milestones, suggesting that
nucleus. SN and OMA may be caused by developmental delay.
This case also supports the recommendation for neuro-
Patients with CFEOM2 have bilateral ptosis and a large imaging in SN.
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- Idiopathic infantile nystagmus (IIN) starts at birth or
some 11. Affected individuals have homozygous early infancy when visual fixation develops. It results
mutations in the transcription factor gene, ARIX. ARIX from instability of ocular motor control and may develop
is essential to the development of the oculomotor and with or without an accompanying sensory deficit [20].
trochlear nuclei in mice and zebrafish. The predominantly pendular waveform in infants con-
verts to jerk as the visual system matures, allowing better
Individuals with CFEOM3 have more variable motility acuity through longer foveation periods. Waveforms with
defects. The CFEOM3 phenotype maps to chromo- brief foveation periods are associated with poor vision
some 16. and vice versa [21].

Duane syndrome (DS) is caused by faulty development The most common association of IIN is bilateral anterior
of the abducens nucleus in the brainstem and aberrant visual pathway disease. Surgical treatments in these pa-
innervation of the lateral rectus by axons destined for the tients have been attempted to improve binocular visual
medial rectus. Recent research has identified the locus acuity by extending foveation times, reduce torticollis if
for DS to chromosome 2 [16]. there is a null point, or less commonly, improve oscillop-
Moebius syndrome is a developmental anomaly of the
facial and abducens nuclei. Other cranial nerves may be Alio et al. [22•] published their results in 42 patients
involved, including the V, IX, and XII, resulting in using extended hang-back recession of all four horizontal
speech and communication problems. Goldberg et al. recti, 14 mm from the insertion. If strabismus was pres-
[17] performed gracilis muscle transplantation on af- ent, a recession of 13 mm or 15 mm was performed, with
fected children and demonstrated universal improve- larger recession on the medial recti for esotropia or the
ment in speech. This is an important option for these lateral recti for exotropia. The muscular body was
children who may erroneously be regarded as unintelli- pushed back with a cotton tip to ensure that it would
gent because of their poor verbal and facial communica- hang back the full amount. Results at least 1 year after
tion ability. surgery demonstrated improvement of best-corrected
binocular vision in 45.2% of patients (0.1 to 0.3 logMar,
Nystagmus and related ocular oscillations: P = 0.06), mainly in those with unassociated sensory de-
transient idiopathic nystagmus in infants, privation. Torticollis decreased in all cases. Strabismus
idiopathic infantile nystagmus, was the main complication with this procedure, with 11
opsoclonus–myoclonus syndrome of 42 patients (26.1%) requiring a second surgery or botu-
In infants, transient neonatal nystagmus is usually be- linus toxin injection.
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 Tenon capsule may prevent posterior displacement of
only a few months and completely disappeared by 12 the muscle in large hang-back recessions. Alio et al. sug-
months. No cause was found despite extensive workup. gest modifying their original hang-back technique
The nystagmus was horizontal in five patients, vertical in whereby the suture is placed 7 mm posterior to the origi-
three, upbeat in one, and monocular in one. Two pa- nal insertion.
tients had delayed visual maturation, one had regressed
retinopathy of prematurity, and one had coloboma, af- Kose et al. [23] describe a similar technique using non-
fecting the macula in one eye. In the postnatal period, absorbable 5.0 Dacron loop sutures passed 8 mm poste-
any disruption of afferent visual input can potentially rior to the original insertion.
440 Pediatrics and strabismus

A novel surgical treatment for IIN has been suggested sion, located in the left occipitotemporal area. The mul-
based on the hypothesis that nerve endings at the ten- tiple different abnormal sites of activation in dyslexics
dino-scleral interface of extraocular muscles innervate af- may be evidence of attempts to compensate for one pri-
ferent fibers of the ophthalmic division of the trigeminal mary dysfunctional area by shifting to other ancillary re-
nerve, influencing eye-movement control. A simple te- gions.
notomy may disrupt these impulses and decrease the
amplitude of nystagmus. Hertle et al. [24•] describe their Management of dyslexia consists of early remediation
results in 10 patients with IIN. Care must be taken when (phonemic awareness, phonics, reading comprehension
comparing the results of this study with other similar strategies) and providing accommodations in older chil-
studies, as the primary outcome measure was the dren (extra time for reading, spell check computer pro-
eXpanded Nystagmus Acuity Function (NAFX), a func- gram, tape recorders). There is no evidence to support
tion that predicts the best-corrected potential acuity on other treatment modalities.
the basis of eye movement recordings during fixation on
a small, light-emitting diode of their fixing eye. One year Pediatric migraine and headaches
after tenotomy, 9 of 10 patients had increases in their Although migraine with aura may occur in children, they
NAFX. However, binocular visual acuity measured with may also present with isolated gastrointestinal distress or
the ETDRS Chart improved in only 5 of 10 patients. In somnambulism. A history of motion sickness or inability
addition, IIN often varies throughout the day and from to read in a car supports the diagnosis.
day to day, further complicating interpretation.
The most common dietary triggers are cheese, chocolate,
Opsoclonus is involuntary, rapid, back-to-back saccades, nuts and processed meats. Because of the increase in
with no intersaccadic interval. In children, it is due to underage alcohol consumption and the trend for adoles-
paraneoplastic effects of neuroblastic tumors. Gambini cent girls to substitute diet colas for food, alcohol and
et al. [25] report that neuroblastoma patients with opso- caffeine withdrawal headaches must also be considered
clonus had histologically more benign tumors as opposed this population. In addition, caffeine withdrawal may ex-
to tumors in patients without it. acerbate migraine attacks. There is also an association
between fasting hypoglycemia, dehydration, ice cream,
Dyslexia and fatty foods with migraine [31•]. A trial of excluding
Dyslexia is characterized by an unexpected difficulty in possible headache triggers should be attempted prior to
reading in persons who otherwise possess normal intel- before prophylactic drug therapy.
ligence, motivation, and education. It affects 5% to
17.5% of the population, and has a male predilection. A Pediatric neurosarcoidosis
strong hereditary component is recognized; a family his- Unlike adult disease, pediatric neurosarcoidosis shows
tory of dyslexia is the most important risk factor for de- no female preponderance and no increased prevalence in
veloping dyslexia. Linkage analysis implicates chromo- African-Americans. In adults, neurosarcoid most com-
some 1, 2, 6, and 15 in the transmission of this disorder monly presents with facial nerve palsy or headache. Sei-
[26•,27••]. zures and pituitary dysfunction occur in only 10% of the
cases. In contrast, Baumann and Robertson [32•] report
There are two major theories behind this disorder: the that seizures are a common presenting symptom in chil-
phonological and general sensorimotor theory. Ramus et dren (38%). Cranial nerve palsies appear only after pu-
al. [28] support the phonological theory, correlating with berty. Twenty-one percent of children may have evi-
the consensus of most experts in the field. However, dence of hypothalamic dysfunction. A striking difference
many dyslexics also have concomitant generalized sen- is the presence of an intracranial mass lesion (24%) in
sory-motor dysfunction, suggesting more diffuse central children.
nervous system involvement.
Childhood ocular myasthenia gravis
Anatomic correlations have implicated widely different Kim et al. [33••] reviewed 24 children with ocular my-
brain areas in dyslexia, including the frontal lobes, tem- asthenia, and are the first to report the incidence of am-
poroparietal region, cerebellum, insular, caudate, left blyopia in this condition (21%). Two findings differ from
temporal lobe, and thalamus [29,30]. previous reports. First is the frequency of vertical stra-
bismus seen in this series (13/21 patients). Second is the
Shaywitz and Shaywitz [27••] believe that two systems increased frequency of abduction compared with adduc-
necessary for skilled, automatic reading are faulty in dys- tion deficits (15.4% vs 2.6%), contrary to other reports
lexia. One involves decoding or analyzing individual where the medial rectus muscle is most frequently in-
units of words or phonemes (for example, bat has three volved [34,35]. Nevertheless, myasthenia gravis remains
phonemes; bah, ahh and tah) and is located in the left a great mimicker, and any pattern of extraocular muscle
parietotemporal region. The other process is comprehen- 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

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 Fundus photograph reveals corrugation in the internal limiting membrane, fine
visual acuity is hand motion or worse in 50% of cases 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]. Funduscopic findings vary, from a subtle, diffuse [41].
grainy appearance of the retina to the classic bull’s eye
442 Pediatrics and strabismus

Although the majority of the gene products responsible 14 Bisson E, Khoshyomn S, Braff S, et al.: Hypothalamic-opticochiasmatic glio-
mas mimicking craniopharyngiomas. Pediatr Neurosurg 2003, 39:159–165.
for this disorder have been identified, the precise mecha-
15 Engle EC: The molecular basis of the congenital fibrosis syndromes. Strabis-
nism by which these result in clinical disease remains mus 2002, 10:125–128.
elusive. At present, there is no known treatment for 16 Evans JC, Frayling TM, Ellard S, et al.: Confirmation of linkage of Duane’s
NCL. Hematopoietic stem cell transplantation has been syndrome and refinement of the disease locus to an 8.8-cM interval on chro-
mosome 2q31. Hum Genet 2000, 106:636–638.
attempted for infantile NCL, but without success [42].
17 Goldberg C, DeLorie R, Zuker RM, et al.: The effects of gracilis muscle trans-
plantation on speech in children with Moebius syndrome. J Craniofac Surg
Conclusion 2003, 14:687–690.
This article reviews the advances made in the last year 18 Good WV, Hou C, Carden SM: Transient, idiopathic nystagmus in infants.
•• Dev Med Child Neurol 2003, 45:304–307.
on various entities frequently seen in pediatric neuro- First paper published that describes this under-recognized condition. In addition,
ophthalmology. It is by no means complete, and the cli- comprehensively reviews etiology and causes of nystagmus in children.
nician will encounter many other conditions in clinical 19 Kim JS, Park SH, Lee KW: Spasmus nutans and congenital ocular motor
practice (optic neuritis, cranial nerve palsies, and so on). apraxia with cerebellar vermian hypoplasia. Arch Neurol 2003, 60:1621–
Presentation, diagnosis, and management may be very
20 Dell’osso LF, Daroff RB: Nystagmus and saccadic intrusions and oscillations.
different in children as compared with adults. In Duane’s Clinical Ophthalmology Vol. 2. Revised edition 2004. Edited by
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36 Richman DP, Agius MA: Treatment of autoimmune myasthenia gravis. Neu- Describes the advances in cell biology and summarizes the characteristics of new
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