AUTHOR INFORMATION

Section 1 of 12

Authored by Marc P DiFazio, MD, Consulting Staff, Private Practice

Coauthored by Ronald G Davis, MD, MPH, FAAP, Assistant Professor, Department of Neurology, Division of Child and Adolescent Neurology, Children's Hospital of Boston and Harvard University Medical School

Marc P DiFazio, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, Child Neurology Society, and Movement Disorders Society

Edited by James Bowman, MD, Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Marc P DiFazio, MD
Editor's Email:	James Bowman, MD

eMedicine Journal, March 29 2006, VOLUME 7, Number 3

INTRODUCTION

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Background: In 1965, a French neurologist, Dr Jean Dennis Aicardi, described 8 children with infantile spasm-in-flexion, agenesis of the corpus callosum, and variable ocular abnormalities. 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.

Further patient study demonstrated other less consistent characteristics outside the classic triad of findings. These additional characteristics include abnormal facies, cleft lip and palate, and vertebral body abnormalities. Most children have a moderate-to-severe degree of mental retardation, although less severely affected children occasionally are described. To date, only 2 affected children have been male.

Pathophysiology: At present, no etiology explains all the manifestations of Aicardi syndrome. Findings are ascribed to neural tube overdistension during embryogenesis at 4-8 weeks' gestation, but experimental evidence is lacking, and the cause remains unknown.

Frequency:

• Internationally: Although cases occur throughout the world, exact incidence and prevalence is unknown. In a series of children with infantile spasm, 2% had Aicardi syndrome. 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, in fact, have normal neurodevelopment, which significantly increases the potential numbers of children with Aicardi syndrome.

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.

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.

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.

CLINICAL

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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. Some children are diagnosed in utero with brain-structure abnormalities.



• 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. 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.



• 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. Additional seizure types noted include hemiconvulsions, complex partial seizures, and focal motor seizures.



• Electroencephalogram (EEG) findings are not consistent. In the relevant clinical scenario, a burst suppression pattern arising independently from each hemisphere suggests Aicardi syndrome.



• 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 and are bedridden. Children with Aicardi syndrome typically lack even rudimentary abilities to interact with their environments.



• Ocular abnormalities limit visual ability, blinding most children. Certain malignancies develop more frequently, including embryonic soft tissue carcinoma, hepatoblastoma, and angiosarcoma.

Physical:

• Ocular


• • Pathognomonic lesions, called chorioretinal lacunae, commonly cluster around the optic disc of the eye and are described as punched-out, white- or yellow-colored 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 exist in Aicardi syndrome, this manifestation is required for diagnosis.
  
  
  
  • Other common ocular lesions include the following:
    • Microphthalmos

    • Retrobulbar cyst

    • Cataract

    • Coloboma

    • Retinal detachment

    • Iris synechiae
  
  
  
• Craniofacial


• • Microcephaly, hemifacial asymmetry, microphthalmia, or plagiocephaly may be present.
  
  
  
  • Cleft lip and palate also occur with increased frequency.
  
  
  
• Musculoskeletal


• • Skeletal malformations are common but are not uniform in all patients.
  
  
  
  • Costovertebral abnormalities, such as hemivertebrae, fused vertebrae, and rib abnormalities, may be present.
  
  
  
  • Scoliosis resulting from these deformities can be disfiguring and disabling.
  
  
  
• Neurodevelopmental


• • Patients typically have profound mental retardation; however, the disease course may have a milder expression in some than was thought historically.
  
  
  
  • Some children may walk and speak, although rarely. One of the few studies to examine natural history indicates that 21% of patients could ambulate, and 29% could communicate. These abilities appeared independent of seizure frequency, EEG findings, or other clinical features studied during the first year of life.
  
  
  
  • If present, hypotonia, spasticity, or hemiplegia may complicate gross motor development.
  
  
  

Causes:

• Causes of various clinical manifestations are unknown.



• Events early in gestation, probably in weeks 4-8, are suspected causes. The exact etiology of these events remains elusive, although considerations have included in utero exposure to toxins, mild hypoxia, and infections. Investigation of these potential etiologies has been unrevealing.



• A genetic basis for the syndrome is favored, specifically an X-linked dominant mutation with lethality in male hemizygotes. Spontaneous mutation is most likely because siblings appear to be spared, but parental gonadal mosaicism could be the basis for a reported pair of sisters with the condition.



• The only male patients have been described with an XXY genotype.



• Skewed X chromosome inactivation may account for some clinical heterogeneity. However, one center has reported no evidence of skewing in 10 patients studied, suggesting that an alternative reason for differences in the phenotype may exist.

DIFFERENTIALS

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Other Problems to be Considered:

Infantile spasm
Developmental delay
Mental retardation
Agenesis of the corpus callosum
Congenital infection

WORKUP

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Lab Studies:

• If the clinical scenario is convincing, extensive laboratory studies are not indicated.


• • Most children should have high-resolution karyotyping. If the diagnosis is doubtful, consider evaluating for inborn metabolic error and congenital infection.
  
  
  
  • If typical clinical findings manifest in a male, look for an XXY chromosomal pattern.
  
  
  
  • Children with partial manifestations may have translocations that can influence reproductive choices of parents.
  
  
  

Imaging Studies:

• Neuroimaging can delineate the degree of CNS dysgenesis and help evaluate other potential etiologies of intractable epilepsy and developmental delay.



• MRI is preferred because its anatomic resolution is superior to 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.



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



• Electroencephalographic


• • Abnormalities are common.
  
  
  
  • Most patients suffer from multiple types of seizures, but EEG findings are inconsistent.
  
  
  
  • A pattern highly suggestive of the diagnosis in the typical clinical context is the presence of a burst suppression pattern arising independently from each hemisphere. In one case, the EEG prompted a search for other characteristics to establish the diagnosis.
  
  
  
  • EEG findings, along with diminished seizure frequency, commonly evolve as a patient ages. Nevertheless, some findings have shown an evolution from epileptic encephalopathy with suppression-burst (Ohtahara syndrome) to West syndrome and, subsequently, to the Lennox-Gastaut syndrome.
  
  
  

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

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Medical Care:

• Seizures


• • Use conventional epilepsy therapies for the many possible seizure manifestations.
  
  
  
  • Infantile spasm requires specific interventions and typically is unresponsive to conventional anticonvulsants. This seizure type may be especially recalcitrant to therapy.
    • Adrenocorticotropic hormone (ACTH) is effective for some patients and should be considered.

    • Vigabatrin, a more recently introduced therapy for infantile spasm, blocks gamma-aminobutyric acid (GABA)–T, an enzyme that breaks down GABA, the major inhibitory neurotransmitter in the brain. Although concerns have been raised about possible ophthalmologic sequelae (eg, constriction of the visual fields) after using vigabatrin, it has been effective for infantile spasm without the serious life-threatening adverse effects of ACTH. If retinal disruption from the congenital insult is deemed sufficiently severe, the serious nature and sequelae of infantile spasm may outweigh the risks of using vigabatrin. However, this medication is not currently approved for use in the United States, which precludes its frequent usage there.
  
  
  
• Pulmonary


• • Profound mental retardation, immobilization, seizures, and scoliosis may contribute to cardiopulmonary dysfunction.
  
  
  
  • Patients have a shortened life span and commonly die from pulmonary infections.

  • Aggressive pulmonary toilet and alternate feeding routes (eg, feeding tubes) may help slow pulmonary deterioration.
  
  
  

Surgical Care: No information has been published on cortical resection or the use of vagus nerve stimulation for seizures in Aicardi syndrome.

Consultations:

• Consultation with a child neurologist is probably needed during the first year of life.



• A pediatric ophthalmologist is best able to confirm retinal lacunae.



• If the diagnosis is doubtful, or if subsequent children are planned, a geneticist with expertise in dysmorphology is often helpful.



• Consult a cardiac, pulmonary, or gastroenterologic specialist if complications arise from scoliosis, pulmonary function, or feeding or aspiration difficulties.

Diet:

• No specific dietary recommendations exist.



• Use of the ketogenic diet to control seizures associated with this condition is not documented.

MEDICATION

Section 7 of 12

Multiple medications are now available to treat infantile spasm, the most common initial epileptic manifestation of Aicardi syndrome. Consider vigabatrin, although not FDA-approved, because of this disorder's ocular involvement and the drug's successful use in other conditions that have infantile spasm as a major manifestation. Vigabatrin is currently unavailable in the United States and cannot be considered the drug of choice. Initiate a detailed discussion with the family before therapy about the multiple medications available and the potential complications of each. Individualize treatment to best suit the patient and the capabilities and wishes of the family.

Drug Category: Anticonvulsant agents -- Effective management requires a detailed and accurate classification of seizure types.

Drug Name	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.
Adult Dose	40-80 U IM/SC qd/qod
Pediatric Dose	20-40 U/d IM or 80 U IM qod for 3 mo or 1 mo after seizures cease
Contraindications	Documented hypersensitivity; osteoporosis; ocular herpes simplex; recent surgery; systemic fungal infections; scleroderma; CHF
Interactions	May decrease effects of aspirin, indomethacin, and insulin; diuretics increase effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use lowest possible dose and reduce gradually if a decrease in dose desired; adrenocortical insufficiency may persist for months after discontinuing therapy (reinitiate corticosteroid therapy in any situation of stress); do not administer live attenuated viral or bacterial vaccines to individuals receiving immunosuppressive doses of corticotropin

Drug Name	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.
Adult Dose	2-3 g/d PO qd or divided bid; initiate at low doses and gradually titrate upward
Pediatric Dose	50-150 mg/kg/d PO has been used for infantile spasm
Contraindications	Documented hypersensitivity
Interactions	Lowers phenytoin levels by 15-30%; may increase carbamazepine levels
Pregnancy	D - Unsafe in pregnancy
Precautions	Closely monitor visual fields in patients able to comply with testing; discontinue drug (withdraw must be gradual) if visual symptoms develop (ie, concentric and predominantly nasal visual field constriction with temporal sparing); drowsiness is the most common adverse effect; psychotic effects (eg, hallucination, paranoia) or increased seizure activity may develop with abrupt initiation or withdrawal

FOLLOW-UP

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Complications:

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



• Seizures or their treatments (eg, 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:

• 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.



• Children commonly die in the first decade of life, although some have lived into the second or third decades.

Patient Education:

• For excellent patient education resources, visit eMedicine’s Brain and Nervous System Center and
  Children’s Health Center. Also, see eMedicine’s patient education articles Epilepsy and Seizures in Children.



• Patients may also be referred to the Aicardi Syndrome Foundation.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• To date, no evidence exists of an exogenous prenatal event that would explain this condition’s various manifestations.



• Because of reports of affected siblings, a discussion of recurrence risk with the family is crucial.

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which of the following are cardinal characteristics of Aicardi syndrome?

A: Female sex
B: Corpus callosal agenesis
C: Chorioretinal lacunae
D: Infantile spasm
E: All of the above

The correct answer is E: Aicardi syndrome is associated with various congenital abnormalities; however, the most common findings are callosal agenesis, mental retardation, infantile spasm, and retinal colobomata. All patients have been female, although a single male patient with the phenotype has been described. Less consistent findings include vertebral body anomalies, facial abnormalities, and varying degrees of mental retardation.

CME Question 2: Which pathognomonic finding of Aicardi syndrome is shown in the following picture?

A: Retinal infarction
B: Cataracts
C: Lens dislocation
D: Coloboma
E: Chorioretinal lacunae

The correct answer is E: The pathognomonic lesion of Aicardi syndrome is the chorioretinal lacunae. Although other ocular lesions exist in Aicardi syndrome, this manifestation is required for diagnosis.

Pearl Question 1 (T/F): The cardinal clinical features of Aicardi syndrome include choroidoretinal lacunae and seizures.

The correct answer is True: Other important characteristics are agenesis of the corpus callosum, mental retardation, and occurrence in females. Less consistently found manifestations include costovertebral abnormalities and palatal malformations.

Pearl Question 2 (T/F): The most common seizure manifestation seen in Aicardi syndrome at presentation is generalized tonic-clonic convulsions.

The correct answer is False: Infantile spasm is the most common seizure manifestation seen at presentation in Aicardi syndrome, although other seizure types commonly develop as well.

Pearl Question 3 (T/F): The suspected mode of inheritance for Aicardi syndrome is autosomal recessive.

The correct answer is False: The suspected inheritance pattern of Aicardi syndrome is X-linked with lethality in males.

Pearl Question 4 (T/F): The CNS malformation most consistently seen in Aicardi syndrome is agenesis of the corpus callosum.

The correct answer is True: In Aicardi syndrome, agenesis of the corpus callosum is usually complete but may be partial.

PICTURES

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Caption: Picture 1. Cross-section of an eye in a patient with Aicardi syndrome. The arrow indicates chorioretinal lacunae.
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BIBLIOGRAPHY

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• Aicardi J, Lefebvre J, Lerique-Koechlin A: A new syndrome: spasm in flexion, callosal agenesis, ocular abnormalities. Electroencephalogr Clin Neurophysiol 1965; 19: 609-10.
• Aicardi J: Aicardi syndrome. Brain Dev 2005 Apr; 27(3): 164-71[Medline].
• Carney SH, Brodsky MC, Good WV, et al: Aicardi syndrome: more than meets the eye. Surv Ophthalmol 1993 May-Jun; 37(6): 419-24[Medline].
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• Molina J, Mateos F, Merino M, et al: Aicardi syndrome in two sisters. J Pediatr 1989 Aug; 115(2): 282-3[Medline].
• Neidich J, Nussbaum R, Packer R, et al: Heterogeneity of clinical severity and molecular lesions in Aicardi syndrome. J Pediatr 1990 Jun; 116(6): 911-7[Medline].
• Ohtsuka Y, Oka E, Terasaki T, Ohtahara S: Aicardi syndrome: a longitudinal clinical and electroencephalographic study. Epilepsia 1993 Jul-Aug; 34(4): 627-34[Medline].
• Pianetti Filho G, Fonseca LF, da Silva MC: Choroid plexus papilloma and Aicardi syndrome: case report. Arq Neuropsiquiatr 2002 Dec; 60(4): 1008-10[Medline].
• Prats Vinas JM, Martinez Gonzalez MJ, Garcia Ribes A, et al: Callosal agenesis, chorioretinal lacunae, absence of infantile spasms, and normal development: Aicardi syndrome without epilepsy?. Dev Med Child Neurol 2005 Jun; 47(6): 419-20; discussion 364[Medline].
• Rosser T, Acosta M, Packer R: Aicardi syndrome: spectrum of disease and long-term prognosis in 77 females. Pediatr Neurol 2002 Nov; 27(5): 343-6[Medline].
• Rosser T: Aicardi syndrome. Arch Neurol 2003 Oct; 60(10): 1471-3[Medline].
• Sabin A, Feldman H: Chorioretinopathy associated with other evidence of cerebral damage in childhood. J Pediatr 1949; 35: 296-309.
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