Aicardi Syndrome 

Updated: Nov 30, 2018
Author: Ravi Sunderkrishnan, MD; Chief Editor: Maria Descartes, MD 

Overview

Background

In 1965, a French neurologist, Dr Jean Dennis Aicardi, described 8 children with infantile spasm-in-flexion, total or partial agenesis of the corpus callosum, and variable ocular abnormalities.[1] This clinical scenario, already reported in 1949, was recognized as an entity distinct from congenital infections. An additional 7 patients were described in 1969, and in 1972, Dennis and Bower established the Aicardi syndrome designation.[2]

Further patient study demonstrated other less consistent characteristics outside the classic triad of findings. These additional characteristics include abnormal facies, cleft lip and palate, vertebral body abnormalities, and abnormalities of neuronal migration.[3] Most children have a moderate to severe degree of mental retardation, although less severely affected children occasionally are described.

Pathophysiology

At present, no exact etiology explains all the manifestations of Aicardi syndrome. It has been hypothesized that spontaneous mutation occurs at the Xp22 chromosome. Attempts to pinpoint the exact chromosomal abnormality are ongoing in clinical trials.[4]  

The identification of recurrent hypomethylation in the KCNAB3 gene's promoter and 5' areas in patients with Aicardi syndrome, as discussed in a study by Piras et al, may aid in the understanding of neuronal hyperactivity, as well as the neurodevelopmental and/or neuroinflammation pathways, in these individuals.[5]

Epidemiology

Frequency

United States

The estimated incidence in the United States in 1 in 105,000 live births.[6]

International

Although cases occur throughout the world, exact incidence and prevalence is unknown. In a series of children with infantile spasm, 2% had Aicardi syndrome. A study by Lund et al found the age-adjusted prevalence of Aicardi syndrome in Norway to be 0.63 cases per 100,000 females, as calculated for January 1, 2011.[7]

Given the phenotypic heterogeneity and diagnostic difficulties associated with young children, Aicardi syndrome may be a more frequent cause of mental retardation and seizure in girls than previously thought. Some children may, however, have normal neurodevelopment, which significantly increases the potential numbers of children with Aicardi syndrome.[6]

Mortality/Morbidity

Aicardi syndrome is often complicated by severe mental retardation, intractable epilepsy, and a resultant propensity to pulmonary complications. The condition often leads to death in the first decade. Sudden, unexplained death is common.

The estimated average age of death is 8.8 years (range, 1 mo to 33 y). On the basis of the severity of the disease, the chances of surviving until age 27 years is estimated to be 62%.[6] The oldest individual reported in a paper was 32 years old.[8]

Race

The syndrome occurs in people of diverse racial backgrounds throughout the world with no noted racial predominance.

Sex

Aicardi syndrome is thought to be an X-linked dominant disorder lethal to males. Except for 2 male children, all reported instances have been in females. Both males had XXY genotypes, which further supports an X-linked male lethal genetic substrate. This mutation appears to be de novo.[9, 10]

Age

Because Aicardi is a congenital syndrome, it is often first recognized during the neonatal period and infancy. Less severely affected individuals may live into childhood and adolescence, and diagnosis may be delayed. In one group of patients, diagnosis was delayed from 11-234 weeks after the onset of seizures.

 

Presentation

History

Aicardi syndrome is often diagnosed in female infants only after the onset of seizures or when the presence of dysmorphic facies prompts further evaluation.

If only visual abnormalities or developmental delays are present, the condition may not be recognized until the onset of seizures, or if ophthalmologic evaluations demonstrate characteristic chorioretinal lacunae, which are considered pathognomonic for Aicardi syndrome and are shown in the images below.

Cross-section of an eye in a patient with Aicardi Cross-section of an eye in a patient with Aicardi syndrome. The arrow indicates chorioretinal lacunae.
Chorioretinal lacunae. Chorioretinal lacunae.

Ocular abnormalities limit visual ability and are blinding in some children. A less common presentation is that of retro-orbital cysts and optic nerve hypoplasia.[11]

Presumably, asymptomatic children who have not undergone neuroimaging in utero are not recognized unless they are incidentally screened by an ophthalmologist or brain imaging specialist.

Some children are diagnosed in utero with brain-structure abnormalities. Most often, the absence of the corpus callosum on the fetal ultrasonogram prompts further imaging studies.

Anomalies of the sulci and gyri, periventricular heterotopia, associated cerebellar and brain stem anomalies with absent corpus callosum, can also be evaluated with magnetic resonance imaging (MRI) to aid in the diagnosis and to better determine the prognosis in Aicardi syndrome.[11]

Seizures are a common initial manifestation, most frequently infantile spasm. Chevrie et al reported 97% of patients had infantile spasm, and most of these had seizures when younger than 3 months.[12] Additional seizure types noted include hemiconvulsions, complex partial seizures, and focal motor seizures. A study by Govil-Dalela et al indicated that compared with children who have nonsyndromic agenesis of the corpus callosum, those in whom the agenesis is related to Aicardi syndrome suffer earlier onset of seizures and worse developmental outcomes, with neuroimaging revealing larger areas of brain abnormalities in these patients.[13]

Global developmental delay is uniform, and most patients have moderate to severe mental retardation. This characteristic is probably due to the combination of brain dysgenesis and intractable epilepsy, although some children may walk and, in rare cases, develop expressive language.

Most of these children are unable to walk, due to spastic hemiplegia, and are bedridden. Children with Aicardi syndrome typically lack even rudimentary abilities to interact with their environments.

Certain malignancies develop more frequently, including embryonic soft-tissue carcinoma, hepatoblastoma, and angiosarcoma.

Physical

Neurodevelopmental

The neurologic examination can reveal microcephaly, axial hypotonia, appendicular hypertonia with spasticity that often affects one side, and brisk deep tendon reflexes, as well as hemiparesis.[14]

Moderate to severe global developmental delay and intellectual disability are expected, but individuals with only mild or no learning disabilities or developmental delay have been reported.

Infantile spasms, seizures, or epilepsy develop before age 3 months. Electroencephalography (EEG) can reveal asynchronous multifocal epileptiform abnormalities with burst suppression and dissociation between the two hemispheres; hypsarrhythmia is sometimes identified.

Ocular

Pathognomonic lesions, called chorioretinal lacunae, commonly cluster around the optic disc of the eye and are described as punched-out, white or yellow defects. These lesions characteristically lack pigment, a characteristic that helps to distinguish them from lesions seen in infectious chorioretinitis. Classic chorioretinal lacunae do not enlarge or progress. Although other ocular lesions are present in Aicardi syndrome, this manifestation is pathognomonic for diagnosis.[15]

Other common ocular lesions include the following:

  • Microphthalmos
  • Retrobulbar cyst
  • Cataract
  • Coloboma
  • Retinal detachment
  • Iris synechiae
  • Remnants of fetal pupillary membrane

Craniofacial

Microcephaly, hemifacial asymmetry, microphthalmia, or plagiocephaly may be present. Short philtrum and cleft lip and palate are also seen.

Gastrointestinal

Constipation, gastroesophageal reflux, diarrhea, and feeding difficulties are perceived by parents to be the second most difficult problem to manage after seizures.[8]

Extremities

Small hands, along with an increased incidence of hand malformations, have been reported.

Musculoskeletal

Costovertebral abnormalities, such as hemivertebrae, fused or butterfly vertebrae, and rib abnormalities, may be present.

Scoliosis resulting from these deformities can be disfiguring and disabling. A study by Grigoriou et al indicated that Aicardi syndrome–related scoliosis progresses rapidly and does not respond to bracing. Scoliosis was first noticed in the study’s patients at a mean age of 3.9 years, at which time the mean Cobb angle was 22.5%, while the patients’ first orthopedic visit took place at a mean age of 5.8 years, when the progressed mean Cobb angle was 39.5%.[16]

Causes

The exact mutation and its cause in Aicardi syndrome are still unknown and disputed, although an X-linked dominant mutation in a gene on Xp22 is considered a likely source. It is suspected that events early in gestation, probably in weeks 4-8, give rise to the mutation. Because a patient with Aicardi syndrome can have an unaffected twin, the potential etiologies of prenatal hypoxia and prenatal toxin are no longer in favor.[14]

Spontaneous mutation is most likely, because siblings appear to be spared and have not been reported in parents of an affected female.

The only affected male patients have been described as having an XXY genotype. The presence of Aicardi syndrome in males with a 46,XY karyotype has been disputed, but new cases have been reported. It is possible that these cases are caused by mosaic mutations of the gene.[14]

Skewed X-chromosome inactivation may account for some clinical heterogeneity.[17]

According to one report, another etiologic possibility remains in which Aicardi syndrome is caused by a new mutation on an autosome (eg, 1p36), with sex-limited expression in females.[14]

The aforementioned study by Piras et al indicated that in patients with Aicardi syndrome, differential DNA methylation patterns exist in several neurodevelopmental and/or neuroimmunologic networks, with the investigators suggesting that these networks contribute to the syndrome’s pathogenesis.[5]  

 

DDx

Diagnostic Considerations

These include the following:

  • Infantile spasm

  • Developmental delay

  • Mental retardation

  • Agenesis of the corpus callosum

  • Congenital infection

  • Isolated agenesis of the corpus callosum (ACC)

  • Microophthalmia with linear skin defect (MLS) syndrome

  • Neuronal migration disorders

Differential Diagnoses

 

Workup

Laboratory Studies

No single laboratory finding exists to make a diagnosis. Rather, the diagnosis is made on the basis of clinical features, with neuroimaging studies to support the diagnosis.

Most children should have high-resolution karyotyping. If the diagnosis is doubtful, consider evaluating them for inborn metabolic error and congenital infection.

If typical clinical findings manifest in a male, look for an XXY chromosomal pattern.

Imaging Studies

Neuroimaging can delineate the degree of central nervous system (CNS) dysgenesis and help to evaluate other potential etiologies of intractable epilepsy and developmental delay.[18]

MRI is preferred because its anatomic resolution is superior to computed tomography (CT) scanning. Although CT scanning demonstrates the typical pattern of complete agenesis of the corpus callosum, partial agenesis and cortical migration abnormalities may not be evident.[19]

CT scanning can demonstrate calcifications (possible in congenital infections) better than MRI. If the diagnosis is questionable, CT scanning may be a helpful additional study.

Plain radiographs can help confirm the diagnosis by showing skeletal malformations. The most notable findings include costovertebral abnormalities, commonly affecting the thoracic vertebrae.

Other Tests

Ophthalmologic assessment

Evaluation by an experienced ophthalmologist is crucial, especially if optic malformation (eg, anterior chamber abnormalities) makes the examination more difficult.

Electroencephalography (EEG)

A pattern highly suggestive of the diagnosis in the typical clinical context is the presence of a burst suppression pattern, with complete asynchrony between the two hemispheres.

Often, 6 months after the onset of symptoms, the classic EEG may be replaced by multiple epileptic foci with a disorganized background.

Histologic Findings

Multiple brain malformations are common and may include complete or partial agenesis of the corpus callosum, cortical heterotopias, gyral malformation, and intraventricular cysts. These abnormalities do not affect all patients uniformly, and the brain's appearance may be grossly normal, with a preserved corpus callosum. Microscopic evaluation of the parenchyma commonly reveals disordered cellular organization and disruption of the normal layered appearance of the cortex.

Chorioretinal lacunae are described as well-circumscribed, punched-out lesions in the retinal pigment epithelium and choroid. The region of these abnormalities contains severely disrupted retinal architecture; all layers are thinned, choroidal vessel number and caliber are decreased, and pigmentary ectopia and pigmentary epithelial hyperplasia are present.

 

Treatment

Medical Care

There is no cure for Aicardi syndrome. Management of the different symptoms and manifestations is indicated in affected patients.

Seizures are treated with multiple antiepileptic medications; their effectiveness varies with each patient. According to one survey, the most effective treatment for seizures were ketogenic diet, vigabatran, lamotrigine, and topiramate.

Spasticity can result in contractures or limited range of motion that affects not only mobility but also hygiene care. Patients may benefit from specialized care with physical medicine and rehabilitation specialists as well as physical, occupational, and speech therapists.

Ongoing gastrointestinal issues and constipation can be managed under the care of a pediatrician or pediatric gastroenterologist.

Surgical Care

Palliative epilepsy surgery in the form of corpus callosectomy of a partial corpus callosum and the use of vagal nerve stimulation have been reported to be of variable benefit.[20]

Consultations

Consultation with a pediatric ophthalmologist and neurologist is generally required. As noted earlier, patients also benefit from physical and occupational rehabilitation and speech therapy.

Consultation with an orthopedic, pulmonary, or gastroenterologic specialist may be required if complications arise from scoliosis, pulmonary function, or feeding or aspiration difficulties.

Diet

Use of the ketogenic diet has been tried, to some effect, to control seizures associated with this condition, specifically infantile spasms.

 

Medication

Medication Summary

Multiple medications are available to treat infantile spasm, the most common initial epileptic manifestation of Aicardi syndrome. Initiate a detailed discussion with the family about the available medications. Individualize treatment to best suit the patient and the capabilities and wishes of the family.

Anticonvulsant agents

Class Summary

Effective management requires a detailed and accurate classification of seizure types.

Corticotropin (ACTH, Acthar)

Precise mechanism for infantile spasms unknown. Theorized that ACTH suppresses corticotropin-releasing hormone (CRH), which is an excitatory neuropeptide. Infants with infantile spasms may have increased CRH.

Vigabatrin (Sabril)

Currently not approved by FDA, and benefits of successful treatment of infantile spasm must be weighed against potentially serious ophthalmologic complications. May be obtained as an orphan drug from Aventis Pharmaceuticals for infantile spasm. Synthetic derivative of GABA.

 

Follow-up

Complications

See the list below:

  • Early sudden death is typical in severely affected individuals and is usually caused by pulmonary complications such as pneumonia.

  • Seizures or their treatments (eg, adrenocorticotropic hormone [ACTH]) may also be associated with increased morbidity (eg, hypertension, diabetes, infections) and death.

  • The aforementioned malignancies may develop, and choroid plexus papillomas may cause obstructive hydrocephalus.

Prognosis

See the list below:

  • Prognosis is uniformly poor, with most children unable to walk or communicate; those who can are not high-functioning and require continuous care for their needs.

  • Survival rates have been improving, with an estimated survival of 62% at age 27 years.

Patient Education

For patient education resources, see the Brain and Nervous System Center and Children's Health Center, as well as Epilepsy and Seizures in Children.

Patients may also be referred to the Aicardi Syndrome Foundation.