Aicardi's Syndrome

Aicardi syndrome is a rare X-linked dominant disorder marked by agenesis of the corpus callosum, chorioretinal lacunae and infantile spasms.

The disease is related to the following processes:  congenital and has an incidence of about  1 / 100.000.

Presentation

Clinical manifestations of Aicardi syndrome are heterogeneous and variable [6]. The classic features include corpus callosum agenesis, seizures and chorioretinal lacunae. Infantile spasms are present in the majority of patients. Most of the girls develop seizures before one year.

Chorioretinal lacunae are the pathognomonic of Aicardi syndrome and are white or yellow-white, well demarcated, punched out depigmented lesions in the retinal epithelium. Other ocular abnormalities include microphthalmos, cataract, coloboma, iris abnormalities, optic nerve dysplasia, optic nerve hypoplasia and retinal detachment.

Various CNS abnormalities seen in Aicardi syndrome are complete or partial agenesis of corpus callosum, ependymal cysts, choroid plexus papillomas, periventricular heterotopias, hydrocephalus, cerebellar agenesis and porencephalic cysts [7] [8].
Dysmorphic facial features comprise of cleft lip and palate, microcephaly and nasal bridge and nasal tip abnormalities.
All children with Aicardi syndrome have moderate to severe mental retardation, intellectual impairment and undeveloped communication abilities.

Musculoskeletal abnormalities manifesting in this syndrome are scoliosis, small hands, rib and vertebral anomalies, axial hypotonias and limb hypertonias. Children are unable to walk due to a combination of neurologic and musculoskeletal abnormalities. Dermatological manifestations include vascular malformations and pigmentation disorders.

Many tumors are also associated with Aicardi syndrome. Choroid plexus papillomas are the most common. Others include angiosarcomas, hepatoblastomas and embryonal carcinomas.

Workup

In patients presenting with typical clinical features, the diagnosis of Aicardi syndrome is clinical and extensive investigations are not required.

Diagnosis is definite if all three classic features are present. The presence of two classic and two major or supporting features is suggestive of Aicardi syndrome:

Classic Triad

  • Corpus callosum agenesis
  • Infantile spasms
  • Chorioretinal lacunae

Major features

  • Cortical malformations
  • Heterotopias
  • Cysts around third ventricle
  • Optic nerve coloboma

Supporting features

  • Microphthalmia
  • Vertebral and rib anomalies
  • Asymmetric cerebral hemispheres
  • Vascular malformations
  • “Split Brain” EEG

Karyotyping is done in most patients. The differential diagnoses of Aicardi syndrome include oculocerebrocutaneous syndrome and neuronal migration disorders.

MRI is preferred over CT scan for neuroimaging because of better details. Neuroimaging abnormalities seen in such patients are agenesis of the corpus callosum, enlarged ventricles, porencephalic cysts, choroid plexus papillomas and heterotopias. CT scan may show cerebral calcification. Neuroimaging helps to identify the potential causes of intractable seizures in such patients.

Musculoskeletal abnormalities can be identified by X-rays.
EEG in Aicardi syndrome patients is abnormal and shows burst suppression pattern coming from each cerebral hemisphere. EEG may also show multifocal spike and wave discharges.

Review by an experienced pediatric ophthalmologist is essential to identify chorioretinal lacunae and other ocular abnormalities [9].

Treatment

Treatment is required for seizures which includes anticonvulsants. Infantile spasms are usually unresponsive to conventional anticonvulsants and require treatment with ACTH (corticotropin) and Vigabatrin [10].

A ketogenic diet may also be tried. Follow up by a pediatric neurologist for seizures are often required. Neurosurgery may be necessary in cases of intractable epilepsy.

Prognosis

The prognosis of children with Aicardi syndrome is variable. Mental retardation and intractable epilepsy are common. Physical, occupational, speech therapy and musculoskeletal support for scoliosis may be tried.

Death is common in the first or second decade. Patients often succumb to pulmonary complications.

Etiology

Aicardi syndrome is an X-linked dominant disorder. It is caused by a sporadic X-linked genetic mutation in females. It is lethal in males in the early embryonic period.

The gene responsible for this disorder has not been identified yet. Only two male children with XXY genotype with this syndrome have been reported [4] [5].

Epidemiology

Cases of Aicardi syndrome have been reported throughout the world in all races. The exact prevalence is unknown. At least 800 cases have been described in the US alone. The disease presents in neonatal period and infancy.

It is reported that Aicardi syndrome is a more frequent cause of mental retardation and epilepsy in young girls as compared to earlier estimates [3].

Sex distribution
Age distribution

Pathophysiology

The exact mechanism for the myriad manifestations of this syndrome is unknown. The syndrome has been attributed to over distention of neural tube during embryogenesis at 4-8 weeks gestation.

Exposure to various toxins and infections in utero has also been implicated in the pathogenesis of this disease.

Prevention

There are no guidelines for prevention of Aicardi syndrome.

Summary

Aicardi syndrome is a rare neurodevelopmental syndrome which is characterized by the classic triad of agenesis of the corpus callosum, infantile spasms and chorioretinal lacunae. The syndrome was described by a French neurologist Dr. Jean Dennis Aicardi in 1965 [1].

It is an X-linked dominant condition which is seen almost exclusively in females. Female infants presenting with seizures, dysmorphic features and characteristic ocular abnormalities are diagnosed in the first year of life [2].

The clinical course and prognosis is variable. Treatment is mostly symptomatic.

Children with disease suffer from intractable epilepsy and die of pulmonary complications.

Patient Information

Aicardi syndrome is an uncommon disease of girls which occurs by birth. It is caused by an abnormality in genetic material and affects girls only. Hundreds of cases of this disease have been reported in the world.

Baby girls with this disease develop fits and absence of a part of brain called corpus callosum which connects the right part of brain with the left. Lesions or holes (called lacunae) are present in the retina (back of the eye where images from the eye are formed). There are also holes in the brain where normal brain tissue should be present. As a result, babies do not develop normally and have developmental delays. There are also abnormalities of bones and muscles, eyes and face.

The disease is usually picked up in the first year of life. Infants with this disease have difficult to control fits, problems with seeing and delays in development.

The disease is diagnosed by expert child specialists. Tests such as CT scan brain and MRI brain may be required. EEG is a test which is done to find out more about the fits. X-rays help to diagnose abnormalities of muscle and bone. An eye specialist can help in the diagnosis by identifying the scars and lesions at the back of the eye.

There is no definite treatment of this disease at the moment. Drugs used to control fits are used. Rehabilitation therapy helps to reduce the symptoms and disability of this disease.

Children with Aicardi syndrome have moderate to severe mental retardation and difficult to control fits. The known age range is variable and may be up to 30 years or more. But in some cases, respiratory problems may cause earlier death.

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References

  1. Aicardi J, Lefebvre J, Lerique-Koechlin A. A new syndrome: spasm in flexion, callosal agenesis, ocular abnormalities. Electroencephalogr Clin Neurophysiol. 1965; 19:609-10.
  2. Steffensen TS, Gilbert-Barness E, Lacson A, Margo CE. Cerebellar migration defects in aicardi syndrome: an extension of the neuropathological spectrum. Fetal Pediatr Pathol. 2009;28(1):24-38.
  3. Kroner BL, Preiss LR, Ardini MA, Gaillard WD. New incidence, prevalence, and survival of Aicardi syndrome from 408 cases. J Child Neurol. May 2008;23(5):531-5.
  4. Zubairi MS, Carter RF, Ronen GM. A male phenotype with Aicardi syndrome. J Child Neurol. Feb 2009;24(2):204-7.
  5. Prontera P, Bartocci A, Ottaviani V, Isidori I, Rogaia D, Ardisia C, et al. Aicardi syndrome associated with autosomal genomic imbalance: coincidence or evidence for autosomal inheritance with sex-limited expression?. Mol Syndromol. Apr 2013;4(4):197-202.
  6. Aicardi J. Aicardi syndrome. Brain Dev 2005. Apr;27(3):164-171.
  7. Chevrie JJ, Aicardi J. The Aicardi syndrome. In: Pedley TA and Meldrum BS, eds. Recent Advances in Epilepsy. Edinburgh: Churchill Livingstone, 1986. p.3.
  8. Barkovich AJ, Norman D. Anomalies of the corpus callosum: correlation with further anomalies of the brain. AJR Am J Roentgenol 1988. Jul;151(1):171-179.
  9. Shah PK, Narendran V, Kalpana N. Aicardi syndrome: the importance of an ophthalmologist in its diagnosis. Indian J Ophthalmol. May-Jun 2009;57(3):234-6.
  10. Chau V, Karvelas G, Jacob P, Carmant L. Early treatment of Aicardi syndrome with vigabatrin can improve outcome.Neurology. 2004;63:1756–7.

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