From the Department of Ophthalmology and O.R.L. (SG, CF, GS, LC), University of Bari; the Department of Neuroimaging (RD), University of Bari; and the Department of Pediatric Neurology (VS, DG), Children’s Hospital “Giovanni XXIII”, Bari, Italy.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Silvana Guerriero, MD, Università degli Studi di Bari, Piazza G. Cesare, 11, 70124 Bari, Italy.
Aicardi syndrome, first described in 1965,1 is a neurodevelopmental disorder that primarily affects females.2–4 The incidence of Aicardi syndrome is unknown, although it is presumed to be rare; however, at least 188 individuals have been described in North America and Europe and the true prevalence is likely underestimated. There is no ethnic preference.
It appears to be an X-linked dominant disorder that is lethal in males, but no genes or candidate regions on the X-chromosome have been definitively identified.5 Because genetic data are lacking, the diagnosis of Aicardi syndrome is generally based on clinical and radiologic findings.
Initially, the differential diagnosis was characterized by a clinical triad of agenesis of the corpus callosum, typical chorioretinal lacunae, and infantile spasms.1,6,7 However, as more cases were reported, it became clear that other neurological and systemic defects are common. Indeed, not all affected girls have all three features of the classic triad.
In 1998, Aicardi reported that corpus callosum agenesis is not the hallmark of the disease; in fact, it is not essential for diagnosis if other features, such as cerebral pathologies (eg, cysts, heterotopias, or cortical dysplasia), are present.8 In 2005, in an extensive review, the same author proposed that the typical lesion in this disease is chorioretinal lacunae, whereas those cases without agenesis of the corpus callosum but with chorioretinal lesions may be considered atypical variants of Aicardi syndrome.9,10 Modern imaging techniques have improved diagnosis and have shown that Aicardi syndrome is a complex neurodevelopmental disorder with additional neuronal and extraneuronal manifestations.
The patient was a 14-year-old girl who had been born the first child of non-consanguineous parents after an uncomplicated pregnancy. Her perinatal course and psychomotor development were uneventful before the onset of seizure. At 3 months of age, typical infantile spasms were observed. The initial electroencephalogram (EEG) showed a hypsarrhythmia variant primarily involving the left hemisphere. During sleep, the EEG tracings were usually characterized by bursts of high-amplitude, slow, sharp waves separated by intervals of low-amplitude activity.
On physical examination at the age of 3 months, the head was normocephalic and neurological examination revealed normal muscle tone. A computed tomography scan demonstrated an arachnoid cyst of the posterior fossa that was probably responsible for the dislocated appearance of the fourth ventricle. Complete clinical and EEG responses were achieved with early treatment with a cycle of adrenocortico-tropic hormone.
At 3 years of age, the patient was admitted to our department after developing seizures of myoclonic type that occurred more frequently on awakening. During subsequent examinations, the seizures occurred with daily frequency despite vigorous antiepileptic treatment, including valproate, carbamazepine, oxcarbazepine, and felbamate given at different times and associations. Interestingly, she presented with audiogenic reflex seizures triggered by sudden sounds.
At the last clinical follow-up visit (11 years of follow-up) at age 14 years, extensive investigations demonstrated the following clinical features.
Visual acuity was 20/20 bilaterally. The anterior segment was normal. On funduscopy, bilateral multiple, rounded pinkish areas, albeit with a variable extension, were present, ranging in size from 1/10 to 2 disk diameters. They were on the same plane as the retina, so the vessels did not bend when crossing their borders. The largest lacunae were around the disk, whereas there were smaller lesions more peripherally. There was also a bilateral coloboma of the optic disk in the right eye resembling a “morning glory” anomaly (Figs. 1 and 2).
Figure 1. Retinal Lacunae and Colobomatous Papilla in the Right Eye.
Figure 2. Retinal Lacunae and Colobomatous Papilla in the Left Eye.
Brain magnetic resonance imaging showed anomalies in the posterior fossa, consisting of a large porencephalic cavity involving the inferior right cerebellar hemisphere, peripherally crossed by some fibrous trabeculae, and a cortical dysplasia of the superior surface of the same cerebellar hemisphere and the superior vermis (Fig. 3). Such anomalies can have a vascular pathogenesis occurring during fetal life (mostly in the first trimester) and can sometimes be an expression of Aicardi syndrome, generally linked to a typical agenesis of the corpus callosum.11 To our knowledge, the isolated presence of the described lesions has never previously been observed in Aicardi syndrome.
Figure 3. Axial FSE T2 Image. The Right Cerebellar Hemisphere Is Partially Occupied by an Encephaloclastic Pseudocystis, Peripherally Crossed by Narrow Trabeculae. The Lateral Aspect of the Fourth Ventricle Is Slightly Compressed. The Inferior Vermis Morphology Is Normal.
Anteroposterior and lateral radiographs showed thoracolumbar kyphoscoliosis.
Aicardi syndrome is an uncommon congenital disorder defined by the diagnostic clinical triad of hypogenesis or agenesis of the corpus callosum, early onset of seizures, and characteristic chorioretinal lacunae. Eye findings are important in the diagnosis of Aicardi syndrome. Choroidal lacunae are considered pathognomonic, but other abnormalities are frequently associated, such as severe optic nerve dysplasia, optic nerve hypoplasia, and persistent fetal vasculature (persistent hyperplastic primary vitreous humor). All eye findings can be unilateral or bilateral and asymmetric.
Although chorioretinal lacunae are virtually pathognomonic for Aicardi syndrome, they have also been reported in orofaciodigital syndrome type IX (OFD 9) (MIM 258865).12 Microphthalmia and other developmental eye defects may also be seen in other X-linked dominant disorders, such as Goltz syndrome and microphthalmia with linear skin defects. However, these two disorders have characteristic skin defects and other features that are not present in Aicardi syndrome.
In our experience, the observed mildly delayed cognitive development suggests that patients with lesser degrees of cerebral and ocular pathology have less neurological impairment.
Our case confirms that classic chorioretinal lacunae constitute a pathognomonic sign even in the absence of agenesis of the corpus callosum.
- Aicardi J, Lefebvre J, Lerique-Koechlin A. A new syndrome: spasms in flexion, callosal agenesis, ocular abnormalities. Electroencephalogr Clin Neurophysiol. 1965;19:609–610.
- Hopkins IJ, Humphrey F, Keith CG, Susman M, Webb GC, Turner EK. The Aicardi Syndrome in a 47, XXY, male. Aust Paediatr J. 1979;15:278–280.
- Aicardi J. Evolution of epilepsy surgery in childhood: the neurologist’s point of view. Epileptic Disord. 1999;1:243–247.
- Van den Veyver IB. Microphthalmia with linear skin defects (MLS), Aicardi, and Goltz syndromes: are they related X linked dominant male–lethal disorders?Cytogenetic Genome Res. 2002;99:289–296. doi:10.1159/000071606 [CrossRef]
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- Aicardi J, Bherie JJ, Rousselie F. Spasma-in-flexion syndrome, callosal agenesis, chorioretinal abnormalities. Arch Fr Pediatr. 1969;26:1103–1120.
- Donnenfeld AE, Packer RJ, Zackai EH, Chee CM, Sellinger B, Emanuel BS. Clinical, cytogenetic, and pedigree findings in 18 cases of Aicardi syndrome. Am J Med Genet. 1989;32:461–467. doi:10.1002/ajmg.1320320405 [CrossRef]
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- Aicardi J. Aicardi syndrome. Brain Dev. 2005;27:164–171. doi:10.1016/j.braindev.2003.11.011 [CrossRef]
- Iturralde D, Meyerle C, Yannuzzi L. Aicardi syndrome: chorioretinal lacunae without corpus callosum agenesis. Retina. 2006;26: 977–978. doi:10.1097/01.iae.0000224937.78389.15 [CrossRef]
- Barkovich AJ, Simon EM, Walsh CA. Callosal agenesis with cyst: a better understanding and new classification. Neurology. 2001;23:220–227.
- Guerieri F, Sammito V, Ricci B, Iossa M, Bellussi A, Neri G. Possible new type of oral-facial-digital syndrome with retinal abnormalities: OFDS type (VII). Am J Med Genet. 1992;42:789–792. doi:10.1002/ajmg.1320420608 [CrossRef]