Aicardi syndrome is an X—linked genetic disease characterized by a combination of agenesis of the corpus callosum with the formation of chorioretinal lacunae and variable embryonic skeletal abnormalities. A typical clinical picture is a triad of signs: infantile spasms, mental retardation, visual impairment. Diagnosis is carried out using electroencephalography, cerebral MRI, ophthalmoscopy, study of visual potentials, radiography. Genetic diagnostic methods have not yet been found. Palliative treatment with the appointment of combinations of anticonvulsants for constant intake, periodic courses of corticosteroids.
Q04.0 Congenital anomaly of the corpus callosum
Aicardi syndrome refers to rare disorders of the embryonic development of the nervous system. It was first described in 1965 by the French pediatric neurologist Jean Aicardi as a disease characterized by the following triad of signs: agenesis of the corpus callosum, ophthalmological disorders, muscle spasms. The name of the syndrome in honor of J. Aikardi was given in 1972. Its further study expanded the list of characteristic clinical signs, including facial dysmorphic disorder, mental retardation, spinal column anomalies. The development of neuroimaging and genetic research methods has made the diagnosis more accurate. According to world statistics, there are about 500 cases in total. The syndrome is associated with the pathology of the X chromosome, it occurs exclusively in girls. Male fetuses have anomalies that are incompatible with life.
The disease is a genetic pathology associated with a violation of the site on the X chromosome. It is believed that it has a dominant X-linked inheritance. Theoretically, the probability of the birth of a sick girl from a mother suffering from the syndrome is 50%. The presence of a pathological X chromosome in boys leads to intrauterine death.
In practice, genetic transmission has not been recorded, since sick girls cannot have offspring due to pronounced psychomotor disorders. All investigated cases of Aicardi syndrome occurred de novo. There are mainly sporadic variants of the disease. The exception is the only known case of two sisters. Due to the small number of cases, it is difficult to conduct a reliable study of mutagenic triggers.
The pathogenetic mechanisms of the disease are under study. It is assumed that gene mutations cause a disorder of neuronal migration occurring between the 12th and 24th weeks of embryonic development. In embryogenesis, the migration of neocortical neurons to the periphery leads to the formation of the cortex and subcortical zones. Its disorders cause dysgenesis of the corpus callosum, abnormal formation of convolutions and architectonics of the brain.
Normally, interhemispheric pathways pass through the corpus callosum, so its dysembriogenesis entails a violation of the connections between the hemispheres. Macroscopically, microgyria, cerebral cortex subatrophy, periventricular cysts, heterotopia, agenesis of the corpus callosum are detected in the brain. Microscopically, thinning of the layers, a decrease in the number of vessels, and hyperplasia of the pigment epithelium are noted in the retina.
Children with Aicardi syndrome are born without visible pathologies, usually on time. In most cases, pregnancy and childbirth proceed without complications. The disease manifests itself with infantile spasms in the first months of life. Spasms are focal epiprimes, with Aicardi pathology they are characterized by great variability.
Myoclonia, tonic convulsions, retropulsions, propulsions are possible. Symmetrical and asymmetric, single and serial seizures are observed, the tendency to seriality is typical. Flexor spasms are observed in 97% of patients. In 42% of cases of the disease, infantile spasms are combined with other types of epiprimes, both focal and generalized. Focal seizures occur with the involvement of mainly facial muscles.
Delayed psychomotor development is characteristic of all patients with the syndrome. There is a depletion of emotional reactions, lost contact with others, stops the development of skills and pre-speech development. Later, motor disorders are joined: hemi- and tetraparesis with an increase or decrease in muscle tone, spasticity is possible. In some cases, a moderate developmental delay, a mild degree of oligophrenia is described.
Ophthalmological anomalies are variable, including: optic nerve atrophy, microophthalmia, coloboma. Possible cataract, retinitis pigmentosa. Clinically, there is a significant decrease in visual function. The gastrointestinal tract is characterized by instability of the stool, problems with feeding, gastroesophageal reflux.
Facial asymmetry, hypertelorism, anomalies of the auricle, protruding incisors are described among maxillofacial dysmorphia. 33% of patients have dysembriogenetic changes of the spine and ribs in the form of semi-vertebrae, spina bifida, agenesis of the rib, abnormal rib-vertebral articulation. At the age of 7 years, growth is typically slowed down, at puberty — a delay in sexual development.
Hemangiomas, nevi and other dermatological manifestations are described in 20% of patients. In 7% of cases, Aicardi syndrome occurs with limb abnormalities: finger hypoplasia, syndactyly, captodactyly.
Pronounced oligophrenia, motor disorders from the first months of life cause a deep disability of the child. Girls need constant care, half of them are incapable of basic self-care. Violation of muscle innervation in the absence of permanent rehabilitation measures is accompanied by hypotrophy, in cases of spasticity — the development of contractures.
Convulsive syndrome with generalized seizures and cluster seizures exacerbates neurological deficits, oligophrenia. Vertebral anomalies lead to the development of severe scoliosis. Patients with Aicardi syndrome are prone to recurrent pneumonia, have a greater risk of neoplasms.
The appearance of a child with facial anomalies, a reduced tip of the nose, laterally positioned eyebrows allows the doctor to assume a genetic disease. In the neurological status, muscle hypotension or unilateral spasticity, a decrease in muscle strength in the extremities, a revival of reflexes, and a decrease in mental development are indicative. Diagnosis of the syndrome is carried out jointly with geneticists, but a specific genetic analysis has not yet been developed. The following studies are assigned:
- Electroencephalography. The most typical EEG sign of Aicardi syndrome is hypsarrhythmia, which appears after the manifestation of infantile spasms. The difference in the EEG pattern of the two hemispheres is typical, the phenomenon of a “split brain”. In a number of patients, the encephalographic picture has an erased character. The presence of variable convulsive seizures causes polymorphism of EEG changes.
- Ophthalmoscopy. Reveals the presence of chorioretinal lacunae visualized as whitish depegmented areas of the retina. Bilateral lacunae are located asymmetrically, in 10-20% of cases foci are diagnosed only in one eye. Ophthalmoscopy of older patients is diagnosed with cataract, coloboma and/or optic disc atrophy.
- Visual evoked potentials (SVP). They are being investigated to determine visual acuity in infancy and to conduct differential diagnostics with other ophthalmological diseases. In young patients with no changes in the fundus, visual acuity may correspond to the age norm.
- MRI of the brain. Visualizes complete or partial underdevelopment of the corpus callosum, signs of cortical atrophy, pachygyria, expansion of furrows. The third ventricle is dilated, together with the lateral ventricles it is displaced upwards, cerebral cysts are revealed around it. There is a change in the shape of the lateral ventricles, multiple areas of heterotopia with no differentiation of the layers of the cortex, hydrocephalus.
- Radiography of the skeleton. It is necessary for the diagnosis of bone abnormalities accompanying Aicardi syndrome.
Perinatal DNA diagnostics has not been developed. Detection of pathology is possible during ultrasound examination of a pregnant woman. According to ultrasound of the 1st trimester, diagnosis of agenesis of the corpus callosum is possible. Later, microcephaly, intracranial brushes, vertebral anomalies, and other malformations are detected.
It is necessary to differentiate the pathology of Aicardi from other early multisystem lesions, including a combination of dysgenesis of cerebral structures and retinal disorders. The first symptom of septooptic dysplasia is horizontal nystagmus, which is absent in patients with Aicardi syndrome. A distinctive feature of tuberous sclerosis is the presence of dermatological symptoms: hyperpigmentation, angiofibromas, areas of “shagreen” skin. Papillo-renal syndrome occurs with kidney damage. Differential diagnosis with congenital TORH infections is carried out on the basis of laboratory examination data.
Aicardi syndrome should be distinguished from Aicardi-Gutierrez disease with an autosomal recessive type of inheritance. The latter refers to progressive leukodystrophy of childhood, characterized by loss of acquired skills, lymphocytosis of cerebrospinal fluid, increased levels of alpha-interferon, calcifications in subcortical structures.
Palliative medical care and rehabilitation measures are at the heart of the disease therapy. The basic scheme is a combination of anticonvulsant and hormonal pharmaceuticals, which makes it possible to reduce the frequency of epiprimes. The main components of treatment are:
- Anticonvulsants. At the first stage, monotherapy is carried out in the maximum tolerated dosage. Since infantile spasms with Aicardi syndrome are resistant to anticonvulsants, it is necessary to switch to a combined therapy regimen, including 2-3 drugs.
- Glucocorticoids. They have shown their effectiveness with intramuscular administration for 1-3 months. In some cases, longer-term glucocorticoid treatment is possible according to a doctor’s prescription.
- Rehabilitation therapy. It is aimed at maintaining motor activity, preventing muscle atrophy, the formation of contractures with spasticity. Therapeutic measures include massage and special gymnastics, developed individually taking into account the existing anomalies. Children with an average degree of cognitive deficit are shown classes with a psychologist, a speech therapist for the maximum possible development of skills.
Prognosis and prevention
According to various data, the average life expectancy for Aicardi syndrome is 8-18 years. 25% of cases of the disease end in death at an early age, the cause of death is repeated complicated pneumonia. Of the remaining girls, only half have self-service skills, 75% are unable to move independently. Severe oligophrenia is associated with the early onset of convulsive syndrome.
Since Aicardi syndrome is a genetic disease with unspecified etiofactors of gene mutations, its specific prevention is difficult. It is possible to carry out general preventive measures aimed at protecting women from harmful effects during pregnancy.