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Case record...Aicardi syndrome
1. CASE OF THE WEEK
PROFESSOR YASSER METWALLY
CLINICAL PICTURE
CLINICAL PICTURE:
11 years old female patient presented with congenital left sided hemiaplasia and Lennox Gastaut syndrome. The patient's family
gave a history of west syndrome during the first year of the patient's life. Fundus examination revealed chorioretinal lacunae.
EEG examination revealed 1.5 C/S slow spike/slow wave discharge of Lennox Gastaut syndrome. The patient's scholastic
achievement was very poor.
RADIOLOGICAL FINDINGS
RADIOLOGICAL FINDINGS:
Figure 1. Precontrast MR T1 images showing a huge right sided intraventricular /parenchymal cyst associated with agenesis of
the septum pellucidum. The corpus callosum is markedly hypoplastic and deficient. The cerebral cortex is lissencephalic. Notice
the right sided hemimegalencephaly and the subependymal nodular heterotopia. Subcortical band heterotopia can also be
appreciated.
Figure 2. Precontrast MR T1 images showing a huge right sided intraventricular /parenchymal cyst associated with agenesis of
the septum pellucidum. The corpus callosum is markedly hypoplastic and deficient. The cerebral cortex is lissencephalic. Notice
the right sided hemimegalencephaly and the subependymal nodular heterotopia.
2. Figure 3. MR T2 images showing a huge right sided intraventricular /parenchymal cyst associated with agenesis of the septum
pellucidum. The corpus callosum is markedly hypoplastic and deficient. The cerebral cortex is lissencephalic. Notice the right
sided hemimegalencephaly and the subependymal nodular heterotopia. Subcortical band heterotopia can also be appreciated.
Figure 4. Precontrast MR T1 images showing A huge right sided intraventricular /parenchymal cyst. The cerebral cortex is
lissencephalic. Notice the right sided hemimegalencephaly and the subependymal nodular heterotopia. Subcortical band
heterotopia can also be appreciated.
3. Figure 5. Precontrast MR T1 images showing a huge right sided intraventricular /parenchymal cyst. The corpus callosum is
markedly hypoplastic and deficient. The cerebral cortex is lissencephalic. Notice the subependymal nodular heterotopia and
hypoplasia of the optic nerve. The cerebellum and brain stem are also hypoplastic.
Figure 6. Precontrast MR T1 images
showing a huge right sided
intraventricular /parenchymal cyst. The
cerebral cortex is lissencephalic. Notice
the right sided hemimegalencephaly and
the subependymal nodular heterotopia.
Figure 7. Precontrast MR T1 images showing
marked hypoplasia of the cerebellum and
brain stem.
4. Figure 8. Chorioretinal lacunae
Criteria that are highly suggestive of Aicardi syndrome
Partial or complete callosal agenesis
Cortical dysplasia
Gross asymmetry of the hemispheres
Periventricular or subcortical heterotopias
Cysts of the choroid plexus or around the third ventricle is highly suggestive of AS
DIAGNOSIS:
DIAGNOSIS: AICARDI SYNDROME ASSOCIATED WITH MULTIPLE CORTICAL DYSPLASIAS THAT INCLUDE
HEMIMEGALENCEPHALY, LISSENCEPHALY, HETEROTOPIAS, AND SEPTO-OPTIC DYSPLASIA.
DISCUSSION
DISCUSSION:
The Aicardi syndrome (AS) is classically defined as a triad of abnormalities that includes agenesis of the corpus callosum,
infantile spasms, and chorioretinal lacunae (1,2). Other eye defects and costovertebral and other malformations occur frequently.
The syndrome has been observed exclusively in individuals with two X chromosomes, and only one familial case is known (3,4).
Progress in neuroimaging has revealed that the central nervous system malformation in AS is not limited to agenesis of the
corpus callosum but consists of a complex of abnormalities characterized by severe neuronal migration defects with
periventricular and subcortical heterotopias, cortical polymicrogyria, and a tendency toward the development of cystic
formations in the choroid plexuses and in other parts of the brain (3-5). The migration anomalies may even be more important
for the definition of AS than callosal agenesis, which is a non- specific finding. Similarly, the eye abnormalities are often complex,
and defects of closure of the primitive cupula are commonly present (6-8).
The incidence of AS is unknown. More than 300 cases are known to this writer, and at least 170 cases have been published. In
series of infantile spasms, AS may account for up to 4% of cases (9), but a selection bias is probable in series originating from
tertiary referral centers.
CLASSICAL FINDINGS IN AICARDI SYNDROME
The classical picture of AS has been outlined in several articles (3,6, 1 0, I 1). The seizures are typically infantile spasms. These
have been the only seizure type in 86 of 184 patients (47%) and have been associated with other seizures, especially partial motor
attacks, in 65 of 184 patients (35%) (6). The partial seizures often begin before the infantile spasms, at times as early as the first
few days of life (6,12). The age at first seizure was less than 3 months in 68% of 146 patients and less than I month in 23%. The
age at the first spasm in 137 patients was less than I month in 18% and less than 3 months in 56%. Typical tonic spasms have
been reported even during the neonatal period, and AS is one possible cause of the quot;early infantile epileptic encephalopathyquot;
described by Ohtahara et al. (13). Partial seizures and infantile spasms often occur in association, a focal or lateralized tonic or
clonic seizure being followed by a similarly lateralized cluster of spasms. The focal seizure is manifested on the EEG by a
localized discharge of repetitive spikes lasting 10-30 s. The spasms follow immediately after the spikes and are associated with a
series of slow complexes, often with a superimposed fast rhythm that is usually of higher amplitude on the side of the initial
5. partial discharge. The complexes occur 6- 20 s apart, and no paroxysmal activity appears between them. The initial partial
seizure and the spasms that follow appear to represent a single attack that usually occurs on awakening or on changing from slow
wave to REM sleep (12,14). Such periodic spasms are also associated with other brain malformations (14).
Typical hypsarrhythmia is rare in AS (18% of 137 cases). The most common interictal EEG abnormality is an asymmetrical
pseudo-periodic tracing with bursts of paroxysmal irregular slow and sharp waves of 3- to 6-s duration, separated by a relatively
flat EEG for 5-20 s. Such bursts may occur independently over each hemisphere or may remain unilateral, with various
abnormalities over the other hemisphere, the so-called quot;split-brainquot; EEG (6). The tracings more commonly evolve into multifocal
paroxysmal abnormalities than into typical hypsarrhythmia. At a late stage, spike-and- wave complexes are unusual (6,9).
The choroidal lacunae are multiple rounded whitish or pinkish areas ranging in size from one-tenth to several disc diameters.
They are in the same plane as the retina, so that vessels do not bend on crossing their border. Pigment deposits may be visible at
their periphery and may increase with age (6,15). The largest lacunae tend to cluster around the disc, whereas small pinkish
lesions tend to be more peripheral. They are usually bilateral, but unilateral lacunae can be seen even when the opposite eye is
not microphthalmic. Typical lacunae are probably pathognomonic of AS. Colobomata are a very common finding and are of
significance for the diagnosis, especially when lacunae are few or atypical. Unlike the lacunae, they are frequently unilateral.
Colobomatous discs are surrounded by pigmented rings in many cases. Other eye abnormalities, including persistence of the
primary vitreous, anterior synechiae, and microphthalmia, are not uncommon. In one patient, the appearance was that of retinal
detachment suggestive of the Walker- Warburg syndrome. Interestingly, despite the very abnormal ophthalmoscopic aspect,
useful vision is often preserved as far as can be assessed. The ERG has been found normal or only mildly altered in several
patients. The visual evoked potentials are usually present but abnormal, probably as a result of the cortical abnormalities. The
fundoscopic appearance results from thinning of the choroid and sclera in the areas corresponding to the lacunae where the
pigment epithelium is depigmented or hypopigmented (7), with degeneration of the rods and cones (8). There is no evidence of
inflammatory lesions, and the appearance is suggestive of an early developmental disorder.
Agenesis of the corpus callosum was complete in 137 of 152 patients for whom the information was available and was partial in
15 (10%). Partial agenesis is usually posterior (6), but cases of agenesis of both the genu and the splenium, with preservation of
the body of the callosum, are known (16). The ventricular contour is not smooth as it is in most cases of callosal agenesis and the
ventricles, including the third ventricle, have markedly irregular contours. In most cases there is also marked asymmetry
between the two hemispheres, the larger one commonly but not consistently contralateral to a hemiplegia when present or to the
side most involved by the spasms. Various abnormalities of the posterior fossa have also been reported (6).
The neurologic and mental impairment in AS is almost always very marked. The estimated survival rate in one study (17) was
75% at 6 years and 40% at 15 years. Epilepsy persists in most patients as infantile spasms, which is unusual with other causes.
Approximately one-third of patients are unable to feed themselves and only one-quarter are able to walk. Only rare patients can
use two-word sentences (3). One patient had relatively well-developed language at age 14 years (17). According to McGregor et
al. (17), a worse prognosis was correlated with larger lacunar size. Hemiplegia is commonly present but it is seldom isolated, and
some degree of contralateral involvement is the rule. Mild microcephaly is common but is never present at birth. Indeed, some
infants have large heads that may result from hydrocephalus or from the development of large intracranial cysts. Although an
occasional patient has been operated on for shunting of hydrocephalus due to aqueductal stenosis or for drainage of a cyst, this is
seldom justified because the cysts do not usually continue to increase in postnatal life and ventricular dilatation usually remains
static even when marked.
NEW FINDINGS IN AICARDI SYNDROME
Over the past few years the diagnosis of AS has been facilitated by modern imaging techniques. These have shown that agenesis
of the corpus callosum is virtually never an isolated finding but is part of a complex of developmental abnormalities. Migration
anomalies are probably present in all cases. They include periventricular and/or subcortical nodular heterotopias, which are
responsible for the irregular contours of the lateral ventricles, and cortical dysplasia with thickening of the cortical plate and
abnormal rectilinear or blurred interface between gray and white matter involving one or both hemispheres to a variable degree.
These dysplastic areas probably correspond pathologically to polymicrogyria (3, 5,15,18,19). Periventricular heterotopias are
easily detectable, but the diagnosis of subcortical heterotopias and cortical dysplasia requires high-quality MRI. Cysts are
frequently revealed on MRI. They can involve the glomus of the choroid plexus on one or both sides and/or the region of the third
ventricle and pineal gland, where they may be single or multiple and may be quite large (Fig. 1). The cysts give a slightly more
intense signal than CSF and their walls may enhance with gadolinium contrast. Cysts around the third ventricle were probably
responsible for the distorted appearance of this ventricle on MRI or CT scan, which could not result from heterotopias. Cysts of
the cerebral hemispheres are uncommon. Cysts of the posterior fossa have been reported (3,6). Most of them correspond to
partial agenesis of the cerebellar vermis, to a megacisterna magna, or to arachnoid cysts. True intraparenchymal cysts are
uncommon. The combination of cysts of the choroid plexus in association with agenesis of the corpus callosum permits the
antenatal diagnosis of AS (20). Solid tumors, especially papillomas of the choroid plexus, have been reported in several patients
(3,6) and may be multiple (21). Peripheral embryonic tumors have also been described (22,23).
6. Figure 1. Huge cyst in a case of Aicardi syndrome. The cyst probably arises
from the pineal area and develops into the left parietooccipital lobe, displacing
and compressing the lateral ventricle. Note also agenesis of the corpus
callosum and abnormal appearance of the posterior cortex on both sides,
suggestive of migration disorder.
The combination of partial or complete callosal agenesis, cortical dysplasia, gross asymmetry of the hemispheres, periventricular
or subcortical heterotopias, and cysts of the choroid plexus or around the third ventricle is highly suggestive of AS (3).
Incomplete forms in which one or several components are lacking are not uncommon. Such forms are confirmed as AS by the
presence of other typical manifestations, especially choroidal lacunae. There is probably no good reason to single out one
component of the malformation complex so that cases without callosal agenesis but with heterotopias and/or cortical dysplasia
can be diagnosed when other cardinal features are present. Two such cases (both with lacunae and one with vertebral
abnormalities) are known to this author.
Criteria that are highly suggestive of Aicardi syndrome
Partial or complete callosal agenesis
Cortical dysplasia
Gross asymmetry of the hemispheres
Periventricular or subcortical heterotopias
Cysts of the choroid plexus or around the third ventricle is highly suggestive of AS
Figure 2. Image shows a cross-section of an eye in a patient with Aicardi syndrome. The arrow
indicates chorioretinal lacunae.
PATHOLOGY
Pathologic data on AS are scanty, and detailed microscopic examination of the brain is available for only two cases (5,18). Total
or partial absence of the corpus callosum was found in all verified cases, usually with the presence of Probst bundles. Other
structures may be lacking, such as the first cranial nerve and the mammary bodies. Other commissures, e.g., the fornix or the
anterior commissure (6), may be absent, but this is inconstant.
Abnormalities of gyration were found in all studied cases (5-7,15,18). Their macroscopic aspect is variable, but microgyria is
found microscopically and is of the unlayered type (18), taking the form of a thin, undulating cellular ribbon without any laminar
organization. Fusion of the molecular layers of facing convolutions may result in the appearance of a pachygyric cortex (5).
Heterotopias include subcortical neurons scattered in the white matter. Cysts have been reported in several cases (3,18,24) and
were of ependymal origin.
Pathologic findings are consistent with an etiologic factor acting before the end of the migration period and the development of
the corpus callosum, which is complete by 14 weeks of gestational age (25).
NOSOLOGIC LIMITS OF AS: THE PROBLEM OF INCOMPLETE FORMS
7. Because there is no laboratory marker specific for AS, the classical triad remains the cornerstone of diagnosis. The existence of
incomplete forms, however, seems likely, and cases without callosal agenesis have been already discussed. In addition to the two
cases above, six cases of possible AS without callosal agenesis are known (6). All six had infantile spasms and choroidal lacunae,
and four had irregular ventricular contours on CT. None of these patients underwent an MRI. Cases without infantile spasms
have been reported (6) and may not be rare. Recognition of the spasms may be difficult because they are often quite
asymmetrical and atypical and are frequently associated with partial seizures, which may be the predominant seizure type.
Isolated partial seizures are not unusual at onset or late in the course, but they may be absent altogether.
The existence of AS cases without lacunae is particularly difficult to accept, because these are considered pathognomonic for the
syndrome. There are, however, female patients with a suggestive brain malformation,, infantile spasms, and other abnormalities
who might represent atypical forms. I know of three such patients who presented with infantile spasms and agenesis of the corpus
callosum. Two of these had periventricular heterotopias on CT scan and an asymmetrical burst-suppression pattern on EEG.
One girl had bilateral colobomata of the disk and another a small pigmented retinal area on one side. None of them had
undergone MRI.
GENETIC AND CYTOGENETIC DATA
The original hypothesis that AS is an X-linked dominant disorder that is lethal at an early stage of gestation for affected
hemizygous male conceptuses appears most compatible with the observed data (2,3,6). Only females are affected, with the
exception of two phenotypical males with two X chromosomes (26). The male child with an XY karyotype reported by Curatolo
et al. (27) is too atypical to be included (6,28, 29). This hypothesis is also consistent with the sporadic occurrence of the syndrome.
Only one instance of familial recurrence in two sisters is reported (4) and this remains difficult to explain because no
chromosomal abnormality was found in these patients. Another finding difficult to reconcile with the hypothesis is the occurrence
of AS in only one of a pair of monozygotic twins, the co-twin being completely normal as a young adult (30). If this report is
confirmed, it might be explained by extreme nonrandom inactivation of the abnormal X chromosome in the normal twin or, less
probably, by a postzygotic mutation during early embryonic development.
The strong suspicion of an abnormality of an X chromosome in patients with AS has been reinforced by the finding of skewed X
inactivation in the lymphocytes of some patients (31). Patients with nonrandom inactivation were found to be more severely
affected than those with a random pattern, suggesting that selection against abnormal cells in the developing neural tissue led to
aberrant brain development. However, a normal inactivation pattern has been found in other cases (30,32).
A possible locus for AS on the short arm of the X chromosome has been suggested by several case reports of eye abnormalities
with callosal agenesis or other brain abnormalities (33-36) associated with translocations or other chromosomal abnormalities at
Xp22.3. However, none of the reported patients had the typical triad of AS, even though microphthalmia (3), chorioretinal lesions
reminiscent of the lacunae (Aughton et al., personal communication, 1991), other eye abnormalities (33,34), agenesis of the corpus
callosum (36) or other brain defects (35), and costovertebral malformations (33) were present in variable associations. Four of
these children also had focal dermal hypoplasia or Golz disease, a sex linked disorder with lethality for hemizygous males
mapping at Xp22.3 (36). Such cases suggest that the Xp22.3 region is involved in the genesis of both Golz syndrome and AS. They
could represent contiguous gene syndromes involving both loci. Intensive search for an AS gene in the Xp22.3 region is being
pursued.
SUMMARY
SUMMARY
AS is an uncommon malformation complex that affects mostly the eyes and the central nervous system. Brain malformation
constitutes the core of the syndrome. Agenesis of the corpus callosum is the most easily detectable but probably not the most
characteristic feature. Migration anomalies, including periventricular and subcortical nodular heterotopias and cortical
dysplasia, and a tendency towards the formation of ependymal cysts in the glomus of the choroid plexuses and/or near of the
third ventricle, are major components of the complex and may occur even in the presence of a complete corpus callosum. The
resulting seizures, usually asymmetrical infantile spasms, and mental retardation constitute a severe disability with a much
reduced life expectancy. The syndrome is probably due to a chromosomal accident involving one X chromosome. The Xp22.3
region is a prime candidate for location of one or several responsible genes, and demonstration of a DNA abnormality in this
region will permit a better definition of the limits of the syndrome and perhaps help our understanding of some aspects of the
development of the central nervous system.
AS is an uncommon malformation complex that affects mostly the eyes and the central nervous system. Brain malformation
constitutes the core of the syndrome. Agenesis of the corpus callosum is the most easily detectable but probably not the most
characteristic feature. Migration anomalies, including periventricular and subcortical nodular heterotopias and cortical
dysplasia, and a tendency towards the formation of ependymal cysts in the glomus of the choroid plexuses and/or near of the
third ventricle, are major components of the complex and may occur even in the presence of a complete corpus callosum. The
8. resulting seizures, usually asymmetrical infantile spasms, and mental retardation constitute a severe disability with a much
reduced life expectancy. The syndrome is probably due to a chromosomal accident involving one X chromosome. The Xp22.3
region is a prime candidate for location of one or several responsible genes, and demonstration of a DNA abnormality in this
region will permit a better definition of the limits of the syndrome and perhaps help our understanding of some aspects of the
development of the central nervous system.
The diagnosis of AS is based upon the classic triad of corpus callosal agenesis, chorioretinal lacunae and infantile spasm. But
there is a range of costovertebral, ocular and cerebral abnormalities associated with this disorder.(2) The cerebral gray-matter
heterotopias and other cortical malformations act as epileptogenic foci.(2) Their seizures typically start in early childhood and
are usually intractable. Besides infantile spasm, other seizure types are also demonstrated. Dissociated burst-suppression or
burst-suppression pattern appearing asymmetrically in either cerebral hemisphere is a characteristic EEG finding in AS.(8) The
developmental delay in AS is generally profound, involving both motor and language skills. Chevrie and Aicardi in their analysis
of 184 patients of AS observed that none had acquired meaningful speech.(9) But of late a larger spectrum of the disease has been
recognized and it had been found that higher functioning AS individuals do exist.(2) Most of the AS cases die at an early age
primarily due to aspiration pneumonitis. But some do live into their adolescent years and even in their twenties.(2) Good visual
function in AS patients do occur if the fovea is uninvolved with chorioretinal lacunae.
Cerebral heterotopias, interhemispheric cysts, optic nerve coloboma, microphthalmia, thoracolumbar kyphoscoliosis are the
known associated features in AS. Severe psychomotor impairment and absence of meaningful speech had also been noted.
(3,4,5,6)
Addendum
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REFERENCES
References
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26. Hopkins IJ, Humphrey 1, Keith CG, Susman M, Webb GC, Turner EK. The Aicardi syndrome in a 47XXY male. Aust
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27. Curatolo P, Libutti G, Dalla Piccola B. Aicardi syndrome in a male infant. J Pediatr 1980;96: 286-7.
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29. Hunter AGW. Aicardi syndrome in a male infant [Reply]. J Pediatr 1980;97:1041.
30. Costa T, Greer W, Duckworth M, Rysiecki M, Musarella M, Ray P. Monozygotic twins discordant for Aicardi syndrome
[Abstract]. Am J Hum Genet 1990;47(suppl 5)202:14.
31. Neidich JA, Nussbaum RL, Packer RJ, Emanuel BS, Puck JM. Heterogeneity of clinical severity and molecular lesions in
Aicardi syndrome. J Pediatr 1990; 1 16:911-7.
32. Wieacker P, Zimmer J, Ropeers HH. X-inactivation pattern in two syndromes with probable X-linked dominant, male lethal
inheritance. Clin Genet 1985;28:238-42.
33. Ropers HH, Zuffardi 0, Biancai E, Tiepolo L. Agenesis of corpus callosum, ocular and skeletal anomalies (X-linked dominant
Aicardi's syndrome) in a girl with balanced X/3 translocation. Hum Genet 1982;61:364-8.
34. Donnenfeld AE, Graham JM, Packer RJ, Aquino R, Berg SZ, Emanuel BS. Microphthalmia and chorioretinal lesions in a girl
10. with an Xp22.2 pter deletion and partial 3p trisomy: clinical observations relevant to Aicardi syndrome gene localization. Am J
Med Genet 1990;37:182-6.
35. Al-Gazali LI, Muller RF, Caine A, et al. An XX male and two (X;Y) females with linear skin defects and congenital
microphthalmia: a new syndrome at Xp22.3. J Med Genet 1988;25:638-9.
36. Friedman PA, Rao KW, Jeplin SW, Aylsworth AS. Provisional deletion mapping of the focal dermal hypoplasia (FDH) gene
to Xp22.31 [Abstract]. Am J Hum Genet 1988;43:A50.
32- Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for
electronic publication, version 9.4a October 2008