Treatment of lissencephaly in Israel - complete relief of symptoms

Causes of the disease

The disease is diagnosed extremely rarely, however, in those isolated clinical pictures it is important to add that lissencephaly can be focal and total, having a slightly different course of the pathological process.
The etiology lies in the prenatal period, when the fetus should develop convolutions. Ideally, this formation begins in the third month of pregnancy and ends approximately in the fifth, however, when certain pathogenic factors arise, a serious disorder occurs, in which there is a complete absence of convolutions and grooves. In this clinical picture, the cerebral cortex has a smooth surface. Modern experts have identified the following reasons that have a negative impact on the processes of formation of the nervous system:

the influence of environmental pollution and ionizing radiation; infectious diseases (herpes, listeria, cytomegalovirus, toxoplasma, etc.) genetic predispositions (gene mutations); mother's illness.

Symptoms and course of the disease

This rare disease rapidly progresses in the prenatal period, and manifests itself in a small patient at 2–5 months of life. This diagnosis is characterized by the following symptoms: signs of hypertension, myoclonus, epileptic seizures, developmental delay and typical dementia.

Patients with such a terrible diagnosis in the first year of life are not much different from their peers, but later the alarming signs of lissencephaly are quite obvious. It all starts with a clear delay in physical and mental development, a lack of basic psycho-speech skills. Later, parents notice a lack of motor skills and control of the functions of the pelvic organs. Such a child stands out noticeably from the crowd, attracting everyone's attention, but he does not understand the world around him. This disease is often accompanied by other equally serious diagnoses, and any complication can cause unexpected death. According to statistics, such children rarely survive into adolescence.

In medicine, there are two main types of this disease and about twenty modifications. Thus, the first type is characterized by a 4-layer structure of the cortex, and it is combined with diseases such as heterotopia, schizencephaly, micro- and macrogyria. The second type is characterized by the absence of the cortical layer, so this disease is combined with damage to the eyes, cerebellum, and pontine hypoplasia. After the birth of a child, it is very difficult to diagnose lissencephaly, but there are still some differences with healthy children. Such patients are characterized by a smaller head shape, insignificant growth, the presence of paresis, convulsions and paralysis.

Lissencephaly, schizencephaly, porencephaly: causes, symptoms, prognosis

Smoothing of the convolutions of the cerebral cortex (agyria) is formed in utero.
The pathogenetic mechanism for the development of the nosology is a violation of embryogenesis caused by the pathology of the spread of neuroblasts from the primary neural tube. Smoothing of the surface is accompanied by a decrease in mental and intellectual activity. Concomitant neurological disorders gradually increase. The disease is fatal in infancy.

The absence of cerebral convolutions excludes the optimal functioning of the second signaling system, which exists only in humans. Folding increases the functional surface of the brain.

Even early detection using brain MRI cannot save the life of a child with type 1 or type 2 lissencephaly.

During pregnancy, congenital malformations of cerebral structures are determined by ultrasound examination (ultrasound). The reliability of the procedure is 60%, so sometimes congenital malformations of the brain are detected after MRI, although intrauterine monitoring of pathology does not determine pathological conditions.

An example of a magnetic resonance imaging report:

1. Bilateral ventriculomegaly;
2. Increased liquor spaces;
3. Smoothness of the cerebral convolutions;
4. Incomplete absence of folds in the parietal and frontotemporal regions;
5. Dilatation of the lateral ventricles.

The nosology is often combined with the stigmas of cerebral dysembryogenesis - macrocephaly, agyria, microcephaly.

Medical sources claim that pathology can be detected by ultrasound after the twenty-sixth week of pregnancy.

MRI: normal and lissencephaly

Lissencephaly type 2 is alternatively called Norman-Roberts syndrome. Canadian scientists who discovered the disease consider the mutation of the “RELN” gene to be the main cause of the disease.

The DNA region responsible for nosology encodes the formation of the “Reelin” protein. The syndrome is characterized by many clinical changes:

1. Lymphedema (lymphedema);
2. Epileptic seizures;
3. Sloping forehead;
4. Thickening of the cerebral cortex;
5. Agyria (smoothness of the cerebral sulci);
6. Macrocephaly;
7. Microcephaly.

Perinatal ultrasound detects most cases of the disease.

Life expectancy forecast

The main factor that determines the prognosis of the life expectancy of a child diagnosed with lissencephaly is the severity of the disease. So some of the patients have more or less normal intellectual development.

In general, children with a more severe form of pathology are not able to live longer than 10 years, but even having reached this age, their development still remains at the level of a 4-6 month old child.

The main cause of death in patients is mainly due to aspiration of nutrients or fluids, very severe attacks, or respiratory diseases.

Causes of lissencephaly

The formation of the intracerebral cortex in the fetus goes through several stages of development. First, neurons divide. Gradually, nerve cells migrate from the original matrix to their permanent locations. The remaining stages of embryogenesis are accompanied by the specialization of cell layers responsible for anatomical structures.

The complex process of brain formation must take place under the strict control of biochemical mechanisms. Any external intervention disrupts intrauterine development.

The main causes of lissencephaly:

1. Intrauterine hypoxia (oxygen starvation);
2. Viral infections;
3. Chromosomal abnormalities (defects in the formation of the Reelin protein on chromosome 7).

Intrafamily cases of transmission of the disease are quite rare. If the nosology occurs in several family members, genetic counseling is required.

The average prevalence of type 1 nosology is 11% per million newborns. Most situations are caused by genetic defects of the LIS1 gene. In second place is cerebellar hypoplasia due to a defect in the TUBA1A gene.

After hereditary anomalies, viral infection in the first trimester of pregnancy is in second place.

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Main types of lissencephaly

There are over twenty morphological forms of the disease:

• Classic form (type I) with LIS1 mutation, Miller-Dieker syndrome;
• Form with hereditary defect DCX;
• Isolated variety without mutations;
• Agenesis of the corpus callosum due to an abnormality of the X chromosome;
• Cerebellar hypoplasia with reelin coding disorder (Norman-Roberts syndrome);
• Microlissencephaly;
• Cobblestone appearance with Fukuyama syndrome, Walker-Warburg syndrome, musculocular-brain form.

Muscular dystrophy with Fukuyama mental retardation is transmitted in an autosomal recessive manner. Hereditary myotonia has a progressive course.

Features of schizencephaly, porencephaly, holoprosencephaly

Bilateral cleft of the cerebral hemispheres is formed at the stage of embryogenesis. The morphological structure of the formation can be open or closed.

Unilateral localization of pathology on MRI images may resemble a cyst. Along the cleft there are pathological areas of cerebral parenchyma - microgyria, zones of increased repeated activity, spastic paralysis.

Porencephaly is characterized by the formation of cystic cavities within the cerebral parenchyma. The causes of the pathology are hemorrhage inside the brain, heart attacks, strokes. The typical location of the cyst is the Sylvian fissure.

In rare cases, porencephaly is characterized by the formation of abnormal passages between the cystic cavity and the ventricular spaces. The nosology is often characterized by other stigmas of disembryogenesis:

1. Microcephaly;
2. Encephalocele;
3. Agiriya.

A child with a developmental defect experiences neurological disorders:

• Oligophrenia (mental retardation);
• Epilepsy attacks;
• Atrophic changes in the optic discs;
• Tetraparesis.

Concomitant changes complicate the clinical picture:

• Arterial and venous hemorrhages;
• Intracranial hypertension (in case of impaired circulation of cerebrospinal fluid);
• Cerebral infarctions;
• Hemiparesis;
• Focal epileptic foci.

Pseudoporencephalic cysts often have a unilateral (one-sided) location. They are often combined with defects of the central nervous system and defects in cell migration.

Schizencephaly on MRI

Holoprosencephaly - what is it?

The disease occurs due to the pathological division of the chemical substance prosencephalon.

Classification of nosology by severity:

1. Lobarnaya;
2. Semi-lobar;
3. Alobar.

The heaviest is the last form. With it, a number of congenital anomalies are observed:

• Underdevelopment of the premaxillary bone;
• Sinophthalmos;
• Cebocephaly.

Against the background of multiple anomalies, parts of the face are difficult to distinguish. Associated neuronal migration defects:

• Synostosis (fusion of nerve ganglia);
• Presence of one cerebral ventricle.

The etiological mechanisms of hereditary defects have not been established. Holoprosencephaly is fatal in most cases, but the incomplete form can lead to disability.

DiGeorge syndrome

With DiGeorge syndrome, patients have a congenital form of aplasia of the parathyroid glands and thymus. It is a type of idiopathic isolated hypoparathyroidism. It is quite rare.

In this disease, pathological changes concern the parathyroid (parathyroid) glands, which exhibit dysgenesis or agenesis. The thymus gland (thymus) is absent from birth. As a result of the combination of such pathologies, a sharp decrease in the number of T-lymphocytes occurs, and immunological deficiency is formed. In addition, this syndrome is accompanied by the formation of congenital anomalies of large vessels.

The disease is autosomal and is determined by the presence of a mutation on chromosome 22. In most cases, the cause is a sporadic deletion of 22q11 (less commonly, microdeletion of 22q11.2). Inheritance occurs according to the dominant principle and is not related to gender. Some authors do not agree with this characterization and argue in favor of an autosomal recessive type with varying expressiveness.

The disease is characterized by disruption of the process of embryogenesis of 3-4 gill pouches, which leads to disruption of the thymus and parathyroid glands.

In the clinic, the most constant symptoms are candidomycosis and hypoparathyroidism, quite often accompanied by disruption of the formation of the mouth, nose and ears.

The thymus remains undeveloped due to developmental disorders in the embryonic period. The thymic epithelium does not support the normal development of T cells. As a result, a specific form of immunodeficiency is formed, in which the humoral immune response and the response at the cellular level are weakened. If a child has such a pathological disorder of immunity, he will have increased sensitivity to infections of bacterial, viral and fungal origin.

The syndrome can occur in the form of a genetically determined absence of the parathyroid glands or isolated insufficiency of the parathyroid glands - accompanied by hypocalcemic seizures that begin from birth. Immunological deficiency leads to the appearance of various infectious diseases. Typically, a combination of symptoms causes heart failure. In addition, infectious diseases cause death.

Diagnosis of the syndrome involves identifying pathologies typical of the syndrome: distortions of the shape of the face and skull, the presence of immunological deficiency, thymic aplasia, dysgenesis or agenesis of the parathyroid glands. The most pronounced manifestations of the disease are candidomycosis and hypoparathyroidism.

Symptoms of lissencephaly

Clinical manifestations of the nosology are determined immediately after the birth of the child. Not only genetic defects are noted, but also swallowing disorders in the baby, increased muscle tone, and developmental delay from peers.

Symptoms of lissencephaly in a child 2-5 months old:

1. Oligophrenia;
2. Mental development disorder;
3. Myoclonus;
4. Increased blood pressure.

At first, mental retardation is not evident. After the first year of life, disorders of psycho-speech skills are observed. Children are irritable, anxious, and muscle activity is reduced.

When compared with peers, there is a significant lag in development, formation of the muscular system, innervation of internal organs, and the pelvis.

With a mild course of the disease, the child can live until adolescence. External anomalies limit social communication. Patients rarely live to be eighteen years old, but there are about twenty types of pathology. Manifestations of the first type:

1. Macrogyria;
2. Schizencephaly;
3. Microcephaly;
4. Four-layer structure of the cortex;
5. Pontine hypoplasia;
6. Underdevelopment of the cerebellum.

It is difficult to determine lissencephaly in the absence of positive results of intrauterine ultrasound. The clinical picture appears after birth. Muscle paralysis and cramps appear immediately or during the first year.

In most cases, ultrasound examination will help establish the diagnosis of lissencephaly. A doctor may order magnetic resonance imaging for a pregnant woman and baby. MRI is harmless, but is not performed in the first trimester due to the lack of practical information about the effect of the magnetic field on the fetus.

Treatment of the disease

There is no effective treatment for lissencephaly, and the prognosis for the health and life of the sick child is unfavorable.

Surgical treatment is used (transplantation of stem cells, growth factors with embryonic tissue). Positive results are extremely rare, a complete cure is impossible (probably only a slight improvement in the child’s condition). The percentage of side effects is very high (danger of brain surgery, infection, inflammatory reactions, tissue incompatibility). Very often, due to the child’s condition, surgical treatment is deliberately refused.

Drug therapy (glycine, vitamins, actovegin, cerebralysin, anticonvulsants) is rather supportive, and virtually no improvements are observed.

Massage courses and physical therapy are used as rehabilitation treatment.

In some cases, long-term treatment makes it possible to recreate or restore “images” of visual, auditory, motor, speech and some other behavioral reactions in the functional systems of the brain. The patient can learn to crawl and fix his gaze on the light. Sometimes it is possible to develop a tracking reaction, distinguishing the shapes and colors of objects. But the likelihood of such results is minimal. For most patients, this remains unattainable.

Most patients with this diagnosis are destined to live their lives in an unknown world. Of course, some people can crawl, distinguish colors and faces, but with this diagnosis this happens extremely rarely.

The first signs of lissencephaly in newborns

Early detection of nosology helps to prolong the baby’s life, but it cannot save him from death. The first signs in newborns:

1. Small head;
2. Apathy, lethargy;
3. Wide interocular distance;
4. Epileptic convulsive syndrome;
5. Hypertonicity of muscles;
6. Increased width between the lungs and kidneys;
7. Activation of pathological reflexes;
8. Sloping frontal part.

During the first year of life, other manifestations appear - speech disorders, urinary incontinence, increased breathing and heart rate.

Lethal pterygum (Norman-Roberts) syndrome occurs in type 1 lissencephaly. A number of manifestations are added to the above-described manifestations:

• Difficulty sitting;
• Inability for the baby to maintain a vertical position;
• The appearance of generalized muscle twitching;
• Anomalies of the craniofacial region (wide eyes, sloping forehead, bumps on the back of the head);
• Ocular nystagmus;
• Decreased muscle tone.

Cerebellar ataxia is characterized by a lack of coordination. The child cannot maintain balance or maintain an upright position. Parents first pay attention to the difficulties of planting and maintaining a horizontal position.

Consequences and prognosis for lissencephaly

The disease has an unfavorable course. Life expectancy with lissencephaly is short, most patients die in infancy. If the lesion has no pronounced manifestations, a mild degree, with symptomatic treatment, patients can live until puberty. Cases of patients with this diagnosis in adulthood have been recorded, but the quality of life suffers significantly. If a disease is detected in the fetus during gestation, the question of artificial termination of pregnancy arises.

The negative consequences of the pathology are caused by complications from the internal organs, namely:

• development of pneumonia;
• damage to the cardiovascular system;
• pathologies of the digestive tract;
• disturbances in the functioning of the urinary organs.

Diagnosis of lissencephaly

The diagnosis is made immediately after birth using ultrasound, CT and MRI. Manifestations can be detected in utero from 20 weeks. Detection of the slightest disturbances in the development of the fetal brain requires additional diagnostics. Depending on the degree of damage, a decision is made on the possibility of terminating the pregnancy. If hereditary forms are suspected, genetic counseling is carried out for all family members.

Late verification of pathology requires constant conservative treatment. Therapy for severe forms is carried out in a hospital under the supervision of qualified doctors.

The main types of diagnosis of lissencephaly:

• Magnetic resonance imaging (MRI of the head) shows soft tissue. The study reveals cerebral anomalies, cysts, fluid accumulations, inflammatory foci;
• Intrauterine ultrasound of the head is performed at 22-27 weeks, when the process of furrow formation is observed;
• Computed tomography (CT) helps to verify changes in gray and white matter, additional solid formations. The examination leads to radiation exposure of tissues, so for children it is performed according to strict indications;
• Electroencephalography (EEG) verifies foci of increased brain activity and areas of parenchymal hyperactivity.

The most reliable study is MRI for lissencephaly in newborns, which allows you to determine the smallest anomalies.

Advantages of Top Ichilov

1. An integrated approach to treatment - the therapy involves experienced specialists from different fields, each of whom has extensive clinical practice.
2. Quick diagnosis with determination of the exact type of lissencephaly, including the use of cutting-edge genetic techniques.
3. A wide range of means to relieve symptoms - the latest anticonvulsants, brain bypass surgery, physiotherapy and exercise therapy, etc.
4. The patient and his accompanying persons benefit from the free assistance of a personal curator-interpreter. In the hospital, comfortable conditions have been created for the stay of both the child and his parents.

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