Our findings from a review of 23 neuroimaging studies of individuals with Aicardi syndrome indicate that polymicrogyria is present universally and that heterotopias are much more common than previously appreciated [Barkovich et al., 2001
; Palmer et al., 2006
; Smith et al., 1996
; Yamagata et al., 1990
]. We observed a consistent pattern of frontal predominance of polymicrogyria with a strong predilection for the perisylvian region. Interestingly, underdevelopment of the operculum was found in almost three-fourths of our patients and was associated frequently with perisylvian polymicrogyria. All subjects had heterotopias, which were most often found near the body of the lateral ventricles with small, single periventricular nodules present in nearly all. We further observed frontal-lobe subcortical heterotopias and cerebellar heterotopias which have been described before [Smith et al., 1996
]. We found that posterior fossa abnormalities are much more common in Aicardi syndrome (95%) than prior reports, and we describe tectal enlargement as a new finding. We confirmed that type 2b midline cysts [Barkovich et al., 2001
] are the most common cysts in Aicardi syndrome, while the second most common cysts occur in the lateral ventricles. The presence of cyst wall contrast enhancement in most of the ventricular, midline, and intraparenchymal cysts mimics the contrast enhancement seen in the choroid plexus which can also contain papillomas in Aicardi syndrome, perhaps suggesting a common origin of these findings.
Although posterior fossa abnormalities have been described previously in Aicardi syndrome [Barkovich et al., 2001
; Donnenfeld et al., 1989
; Smith et al., 1996
; Yamagata et al., 1990
] (), our data suggest that their prevalence and characteristics have been underappreciated thus far. This prompted a more detailed characterization of the posterior fossa and cerebellum. The cerebellar vermis abnormalities, including inferior vermian hypoplasia and superior foliar prominence, were subtle and the superior foliar prominence was also highly variable. Given that all subjects had epilepsy, these cerebellar vermis findings may be related to exposure to antiepileptic medication. However, since they were present in subjects who were less than 4 months of age (and as early as the first day of life), we speculate that superior foliar prominence and hypoplasia of the cerebellar vermis may be related to decreased cell proliferation as well as atrophy due to medication exposure. The cerebellar hemispheres were strikingly abnormal in 59% of subjects and showed unilateral hypoplasia or dysplasia with associated large cisterna magna, subcortical and/or periventricular cerebellar heterotopias, and cerebellar intraparenchymal cysts and extra-axial cysts. We did not observe that cerebellar abnomalities were associated with cyst development, but we cannot exclude that they result from enlargement of the cisterna magna and cerebellar abnormalities. This reflects the overall asymmetry in brain development which has been classically described supratentorially.
Enlargement of the tectum has not been reported before. What causes this in Aicardi syndrome is unclear. The tectum contains the inferior colliculi, which are involved in hearing, and the superior colliculi, which are involved in vision and visual motor control. Children with Aicardi syndrome have maldevelopment of their anterior visual system demonstrated by chorioretinal lacunae and optic nerve dysplasias. We speculate that secondary effects on the visual pathways may influence the size of the tectum. We have not examined an age-matched population of children with ocular or anterior segment dysgenesis to ascertain whether this finding is associated possibly with other purely ocular conditions presumably occurring at similar times in embryonic and fetal development.
We did not review callosal agenesis and dysgenesis in detail, as their presence is an inclusion criterion for the primary diagnosis, and therefore they were seen in all reviewed studies; however agenesis was found in two-thirds and dysgenesis one-third of our cohort. An individual with Aicardi syndrome and a normal corpus callosum was described recently [Iturralde et al., 2006
] and other mildly affected individuals who have partial callosal agenesis, more limited brain and ocular defects and prolonged survival have also been reported [Abe et al., 1990
; Matlary et al., 2004
; Menezes et al., 1994
; Palmer et al., 2006
]. This suggests that callosal dysgenesis and other classic manifestations may not always be present in this condition [Aicardi, 2005
] and it emphasizes the importance of other neuronal migration abnormalities, such as polymicrogyria and heterotopias, in the diagnosis of Aicardi syndrome. Whether microforms of Aicardi syndrome would not be diagnosed under current criteria must await the discovery of the causative gene(s). We believe that, until such time, these intracranial details will aid the differentiation of Aicardi syndrome from other neurodevelopmental disorders and should help clinicians to establish a clinical diagnosis of Aicardi syndrome in those individuals who have an atypical presentation without callosal dysgenesis or typical chorioretinal lacunae. We propose further that the unique constellation of frontal dominant polymicrogyria (especially perisylvian involvement), nodular periventricular heterotopias, intracranial cysts, underopercularization, and posterior fossa abnormalities with vermian hypoplasia, dysplasia of the cerebellar hemispheres, and tectal enlargement should prompt further evaluation for Aicardi syndrome. This should include an ophthalmological examination, evaluation for seizures and typical EEG abnormalities, and a skeletal survey to search for costovertebral segmentation defects.
That Aicardi syndrome has been reported only in females and 47,XXY males suggests that the causative gene is located on the X-chromosome [Hopkins et al., 1979
]. Despite active research for many years [Prakash et al., 1999
; Schaefer et al., 1996
; Schaefer et al., 1997
; Van den Veyver, 2002
; Van den Veyver et al., 1998
; Van den Veyver et al., 2004
], the gene has proven elusive. The isolated nature of the disorder precludes linkage analysis. Efforts to identify a locus that contains the Aicardi syndrome gene by array-based comparative genomic hybridization for a copy number loss or gain have not yet yielded any genomic region of interest [Yilmaz et al., 2007
] (and our unpublished data). An alternative approach for gene identification is the selection of functional candidate genes for mutation analysis. Considering the high gene content of the X-chromosome, a targeted, functional, or protein interaction-based approach might offer the best candidate genes first. The findings in two other X-linked conditions are relevant to our observations. The first is X-linked bilateral perisylvian polymicrogyria, which has been mapped to Xq28 [Villard et al., 2002
]. The second is oculocerebrocutaneous syndrome (OCCS), an X-linked disorder primarily affecting males that has been reported to have extensive phenotypic overlap with Aicardi syndrome [Moog et al., 2005
]. Our data suggest that this clinical overlap also includes abnormalities of the cerebellum and posterior fossa. The genes for neither of these syndromes possibly allelic to Aicardi syndrome have been identified. Finally, the comparison of the intracranial features of Aicardi syndrome to those of other conditions with neuronal migration abnormalities, autosomal or X-linked, or to those of mice with specific gene inactivations, may offer valid candidate genes from relevant developmental pathways. Such an approach has been successful for other neuronal migration defects [Barkovich et al., 2005
; Lian and Sheen, 2006