Aicardi syndrome: More than meets the eye

SURVEY OF OPHTHALMOLOGY

VOLUME 37 - NUMBER 6. MAY-JUNE 1993

AFTERIMAGES

, JONATHAN

WIRTSCHAFTER, EDITOR

Aicardi Syndrome: More Than Meets the Eye SUSAN H. CARNEY, M.D.,’ MICHAEL C. BRODSKY, M.D.,’ WILLIAM V. GOOD, M.D.,5 CHARLES M. GLASIER, M.D.,’ MAY L. GREIBEL, M.D.3 AND CHRISTOPHER CUNNIFF, M.D.4

Abstract. An eight-month-old girl with infantile spasms and apparent blindness had electroencephalographic findings compatible with Aicardi syndrome. In addition to optic nerve hypoplasia, there were multiple congenital retinal malformations in the right eye, including choriol-etinal lacunae, anomalous retinal vessels, posterior scleral ectasia, and a peripheral fibrous ridge. Magnetic resonance imaging demonstrated agenesis of the corpus callosum, absence of the septum pellucidum, optic nerve and chiasmal hypoplasia, pachygyria, cortical heterotopias, colpoccphaly, and hypoplasia of the cerebellar vermis. This patient illustrates the broad spectrum of cerebroretinal malformations now known to characterize Aicardi syndrome. (Surv Ophthalmol 37:4 19-424, 1993)

Key words. hypoplasia

Aicardi syndrome septo-optic dysplasia l

l

magnetic

resonance

imaging

l

optic nerve

parent blindness and infantile spasms. She was the first child of nonconsanguinous parents and the product of a normal pregnancy, labor, and delivery. According to the parents, the infant had never responded to visual or auditory stimuli. At three months of age she began having seizures consisting of upward jerking of her extended arms, arching backward of her head and trunk, and upward deviation of her eyes. On physical examination, her height was at the 5th percentile, her weight fell within the 2540th percentile, and her head circumference was below the 5th percentile. Neurologic examination demonstrated diffusely increased muscle tone and severe global developmental delay. Results of brain stem auditory evoked testing were compatible with mild bilateral hearing loss. On ophthalmic examination, she did not follow large colored objects or respond to bright lights. The

The salient features of a syndrome described by Aicardi et al in 1965 include infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae.:’ Of more than 200 patients who have since been reported as having Aicardi syndrome, all have been female except for one male who had an XXY karyotype.” As new systemic associations have emerged, advances in neuroimaging have revised our concept ofAicardi syndrome to include multiple midline and cerebral hemispheric malformations including, but not limited to, agenesis of the corpus callosum. We describe the broad spectrum of retinal and central nervous system (CNS) malformations in an infLmt with Aicardi syndrome.

Case Report An eight-month-old girl was referred to Arkansas Children’s Hospital for evaluation of ap419

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in the right eye. 1 -optic disc; 2-peripapillary chorioFig. 1. Lefi: Schematic diagram of retinal malformations retina1 lacuna; 3 -retinal excavation; 4 - midperipheral chorioretinal lacuna; 5 -fibrous ridge. The retinal vasculature consists of a major artery and vein that descends inferiorly along the nasal border of the retinal excavation, then loops around superiorly to once again ascend to the temporal border of the excavation. Right: Retinal photograph of the right eye demonstrating multiple congenital anomalies. The optic disc is small and poorlydefined. An oblong lacunar area of depigmentation extends inferonasally from the optic disc (top arrow). A dense pigment crescent is interposed between the optic disc and adjacent lacuna. A large vascular trunk emerges superiorly from the optic disc then bifurcates to enter the choroid. Middle arrow denotes nasal border of inferior retinal excavation. (The temporal border is not shown). Within the excavation is a lacunar area of depigmentation hemmed with light pigment deposition (lower arrow). Note the anomalous course of the retinal vessels.

left pupil reacted briskly to light, but the right pupil was unreactive to light and there was a right afferent pupillary defect. Cycloplegic retinoscopy revealed a refractive error of -4.50 in the right eye and -9.50 in the left eye. The anterior segment and vitreous were normal bilaterally. Multiple retinal malformations were present in the right eye (Fig. 1). On initial retinal examination, no optic disc was visible. A large vascular trunk emerged superiorly from the normal position of the optic disc, then bifurcated to descend into the choroid. Subsequent examination of retinal photographs demonstrated a small area of neural tissue corresponding to the optic disc surrounding the vascular trunk. An oblong area of lacunar depigmentation abutted the optic disc inferonasally. A thick irregular pigment crescent was interposed between the optic disc and the adjacent lacuna. A dome-shaped area of inferior retinal excavation extended from the optic disc to the ora serrata. Within the excavation was a well-circumscribed lacunar area of depigmentation, hemmed with pigment. The retinal vasculature consisted of a major artery and vein that

descended inferiorly along the nasal border of the retinal excavation, then looped around superiorly and once again descended along the temporal border of the excavation. The entire retina was supplied by sparse tributaries of these anomalous vessels. A gray fibrous ridge covered the inferior retinal periphery and was contiguous with the ora serrata. The left retina showed mild optic nerve hypoplasia and a subtle pigment granularity throughout the posterior pole. An electroencephalogram showed modified hypsarrythmia with a chaotic high voltage background and multifocal epileptiform discharges throughout the left hemisphere. There was also striking asymmetry of the background frequency and amplitude between the two hemispheres, and isolated epileptiform spikes were present in the right hemisphere, predominantly occipitally. Infantile spasms occurring during the EEG were associated with an electrodecremental pattern. Endocrinologic evaluation revealed deficient growth hormone and cortisol levels, and replacement therapy was initiated. Chest x-ray and cervical/thoracic spine x-rays were normal. Labora-

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Fig.

2. MRI demonstrating multiple CNS malformations. ~J’/@JVI$: Sagittal Tl -weighted (TR = 60O;TE = 20) demonstrating agenesis of the corpus callosum (upper solid arrow denotes the normal position of the corpus callosum), an arachnoid cyst in the region of the quadrigeminal cistern (open arrow), and hypoplasia of the cerebellar vermis with cystic dilatation of the fourth ventricle (Dandy-Walkelvariant) (lower solid arrow). i~ppr? right: Coronal Tl-weighted image (TR = 600,TE = 20) demonstrating absent corpus callosum (black arrow denotes the normal position of the corpus callosum) and hypoplasia of the optic chiasm (white arrow). Note that the right side of the chiasm (left side of picture) is smaller than the left, consistent with the clinical finding of more severe optic nerve hypoplasia in the right eye. Lou~r left: Coronal inversion recovery image (TR = 20OO:TE = 20) demonstrating pachygyria (thickened dysmorphic cortex with decreased cortical gyri and sulci) in the right image demonstrating gray matter hetcrotopias in the right temporal lobe (arrow). Lower right: Axial Tl-weighted temporal lobe (upper arrow), small areas of probable polymicrogyriajust medial to the occipital poles (more severe in the left hemisphere), dilatation of the posterior horns of the lateral ventricles (also known as colpocephaly [open arrows]) and an arachnoid cyst in the region of the quadrigeminal cistern (lower arrow).

tory

evaluation

included

a normal

serum creatine phosphokinase, count and electrolytes. TORCH

urinalysis,

complete blood titers were nega-

tive. Results of a lumbar puncture were normal. Magnetic resonance (MR) imaging of the head demonstrated multiple CNS malformations in-

volving the hemispheres

midline structures and cerebral (Fig. 2). The corpus callosum and were absent. The optic pellucidurn

septum nerves and chiasm

were diminished

in size. Dif-

fuse cortical heterotopias (nodules of ectopic gray matter) and pachygyria (thickened dysmor-

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phic cortex with decreased cortical gyri and sulci) were seen in the right cerebral hemisphere. Areas of probable polymicrogyria were seen just medial to the occipital poles, better seen on the left. The posterior horns of the lateral ventricles were dilated (colpocephaly). The cerebellar vermis was hypoplastic and there was cystic dilatation of the fourth ventricle (Dandy-Walker variant). A cerebrospinal fluid (CSF)-intensity mass compatible with an arachnoid cyst was present in the region of the quadrigeminal plate cistern.

Discussion Aicardi syndrome is a cerebroretinal disorder of unknown etiology. There is no definitive diagnostic test for Aicardi syndrome; rather, the diagnosis is established when infantile spasms and chorioretinal lacunae occur in combination with a characteristic profile of neuroradiologic and electrophysiologic abnormalities. The pathognomanic ocular finding in Aicardi syndrome is the hypopigmented, usually rounded area referred to as a “chorioretinal lacuna.“’ Aicardi first described these lesions as areas of “atrophic choroiditis” (pseudotoxoplasmic)” which are typically clustered around the optic disc.“’ These chorioretinal lesions appear yellowish-white in color and have distinct borders, which are often lightly pigmented.“” The absence of pigment within chorioretinal lacunae helps distinguish them from similar lesions caused by infectious chorioretinitis.” The lacunae range in size from less than 0.1 to several disc diameters and are usually seen bilaterally.“’ However, cases of Aicardi syndrome have been reported in which chorioretinal lacunae were unilateral.“‘~” Chorioretinal lacunae have rarely been observed in other disorders, including amniotic band syndrome”’ and oral-facial-digital syndrome Type (VIII),” and in a family with a rare autosomal dominant form of microcephaly.‘” However, in a female infant with infantile spasms, the finding of multiple peripapillary chorioretinal lacunae is considered pathognomonic of Aicardi syndrome.“~“~“‘~“‘~‘~~ 'li.":1.!!!l.40

Histologically, chorioretinal lacunae consist of well-circumscribed full-thickness defects limited to the retinal pigment epithelium and choraid.“‘,“’ The overlying retina remains intact, but it is often histologically abnormal. Klein described retinal photoreceptor degeneration, and McMahon noted atrophy of the outer retinal segments overlying chorioretinal lacunae.‘7,“’ Del Pero et al described severe disruption of the

CARNEYETAL retinal architecture, consisting of anterior insertion of the retina onto the ciliary body, replacement of the neurosensory retina by a thin glial network, and formation of photoreceptor folds at the edges of lacunae in Aicardi syndrome.‘” Although chorioretinal lacunae are the most consistent ocular malformation in Aicardi syndrome, a number of variable ocular findings have been recognized. In a review of 184 cases of Aicardi syndrome, Chevrie and Aicardi documented optic disc colobomas in 80 cases and optic nerve hypoplasia in five cases.” Taylor has noted congenital optic disc pigmentation in some infants with Aicardi syndrome.“’ Other ocular abnormalities frequently associated with Aicardi syndrome include microphthalmos, retrobulbar cyst, pseudoglioma, retinal detachment, macular scars, cataract, pupillary membranous remnants, iris synechiae and iris coloborna.“,“,’ Infantile spasms are usually the earliest clinical manifestation of Aicardi syndrome.‘” Clinically, infantile spasms are brief muscular contractions with rapid head nodding or hyperextension, often with flexion or extension of the trunk and arms.“‘L Multiple episodes commonly occur daily. Infantile spasms usually become apparent between three and six months of age but may begin anytime within the first year of life. Infantile spasms usually cease before two years of age, but are frequently supplanted by other types of seizures. The neurodevelopmental prognosis is better in patients with idiopathic infantile spasms than in patients with a known etiology, regardless of treatment. ACTH, prednisone, valproic acid, and clonazepam have been used with variable success.‘~” Etiologies to consider when evaluating a child with infantile spasms include intrauterine and neonatal infection, inherited and acquired metabolic disorders, hypoxic-ischemic encephalopathy, tuberous sclerosis, Down syndrome, and cerebral malformations. ‘i~L”‘~“‘i The most common systemic findings associated with Aicardi syndrome are vertebral malformations (fused vertebrae, scoliosis, spina bifida) and costal malformations (absent ribs, additional ribs, fused or bifurcated ribs).” Other systemic associations include muscular hypotonia, microcephaly, dysmorphic facies and auricular anomalies. ‘i.i.“‘i.“’The intriguing association between choroid plexus papilloma and Aicardi syndrome has been documented in five patients.‘“~“‘~“” Survival into adolescence or early adulthood is rare in Aicardi syndrome.” Death is usually the result of pulmonary infection, which may be aggravated by kyphoscoliosis.” The neurodevelop-

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mental prognosis is poor due to profound mental retardation and intractable seizures.“’ Children with Aicardi syndrome may display a reasonable degree of visual function.!’ All reported cases of Aicardi syndrome have been in females except for one 47, XXY male.” A single case report of Aicardi syndrome in a 46, XY male was disputed by Aicardi and Hunter because there were no chorioretinal lacunae and the disc abnormalities were unlike those usually seen in the syndrome.‘,“,“’ Aicardi syndrome is thought to result from an X-linked mutational event that is lethal in males. Molecular evidence supporting an X-linked mode of inheritance was presented by Neidich et al, who demonstrated profoundly skewed X-inactivation patterns in three of seven girls with Aicardi syndl-ome.“” Chevrie and Aicardi have suggested that all affected cases represent fresh gene mutations, since no cases of affected siblings have been reported.” Although early infectious intrauterine insults can lead to severe CNS anomalies, tests for infective agents have been consistently negative.“” No teratogenic drug or other toxin has yet been associated with Aicardi syndrome.“’ Based upon the pattern of ocular and CNS malformations in Aicardi syndrome, it is speculated that a developmental injury to the CNS must occur between the fourth and eighth week ofgestation.!‘,‘.’ Until recently, agenesis of the corpus callosum was diagnosed by CT scanning or pneumoencephalography. The poor sensitivity of (:T scanning to mild degrees of callosal thinning ma) account for isolated case reports of Aicardi syndrome in patients without detectable callosal abnormalities.‘” In addition to callosal agenesis, CT scanning in Aicardi syndrome has demonstrated a number of structural CNS malformations including asymmetry of the cerebral hemispheres, arachnoid cysts, cerebellar hypoplasia with 01 without Dandy-Walker malformation, colpocephaly and cortical heterotopias.“‘~“~“‘.“’ Two neuropathologic studies of Aicardi syndrome showed extensive cerebral hemispheric disorganization (cortical heterotopias, pachygyria, poly‘u’ which led Chevrie and Aicardi to microgyria) suggest that these patients have a major disturbance of neuronal migration.!’ Relative to CT scanning, MR imaging provides superior contrast resolution and multiplanar MR imaging is exquisitely imaging capabilities.’ sensitive to gray-white matter differentiation and therefore depicts a number of subtle but clinically relevant CNS anomalies that are poorly visualized on CT scanning.4,“,‘7.‘“.9” In our patient, MR imaging showed cortical migration anomalies

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(pachygyr-ia, p 01y microgyria,

subcortical heterotopias) and multiple structural malformations (Dandy-Walker variant, colpocephaly, midline arachnoid cyst). In addition, our patient had agenesis of the corpus callosum, absence of the septum pellucidum and bilateral optic nerve hypoplasia and therefore falls within the spectrum of septo-optic dysplasia.x The occasional overlap between septo-optic dysplasia and Aicardi syndrome was documented by Aicardi in his original abstract.” In summary, Aicardi syndrome is now known to comprise a broad spectrum of cerebroretinal malformations. MR imaging enables us to precisely define CNS malformations and subtle neuronal migration anomalies intrinsic to Aicardi syndrome. Our patient exemplifies the diversity of cerebroretinal malformations in Aicardi syndrome and illustrates the crucial role of MR imaging in establishing the diagnosis.

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Patricia O’Neil provided the diagram in Figure I This study was supported in part by a grant from Research to Prevent Blindness, Inc. Reprint address: Michael C. Brodsky, M.D., Arkansas Children’s Hospital, X00 Marshall, Little Rock, Arkansas 72?02