Tuberous sclerosis is a genetic disease characterized by damage to the nervous system in the form of epilepsy and oligophrenia, polymorphic skin symptoms, tumor and non—tumor processes in somatic organs. The diagnostic algorithm consists of a nervous system examination (MRI, CT of the brain, EEG), ophthalmological examination, examination of internal organs (ultrasound, MRI of the heart, CT of the kidneys, lung radiography, rectoromanoscopy). The main directions of treatment are: antiepileptic therapy, neuropsychological correction, observation and timely surgical treatment of neoplasms.
ICD 10
Q85.1 Tuberous sclerosis
General information
Tuberous sclerosis (TS) is a hereditary neuroectodermal pathology manifested by skin changes, epileptic seizures, oligophrenia (mental retardation) and the appearance of neoplasms of various localization. Along with neurofibromatosis, Hippel-Lindau disease, Louis-Bar syndrome, Sturge-Weber disease, etc., TS refers to phacomatoses. The incidence is 1 case per 30 thousand population, among newborns — 1 case per 6-10 thousand. Not only family, but also sporadic cases are known. Moreover, the latter account for up to 70%.
Tuberous sclerosis was first described by Recklinghausen in 1862. Frenchman Bourneville in 1880 studied in detail the morphological changes occurring in the brain with this disease, and for the first time used the term “tuberous sclerosis”. In 1890, dermatologist Pringle made a description of facial angiofibromas in patients with TS. Therefore, in the literature on neurology, you can find a synonymous name for TS — Burneville-Pringle disease.
Causes
The disease has a genetic nature. Most cases are caused by the occurrence of new mutations and only 30% by autosomal dominant inheritance of gene aberrations present in the parents. Tuberous sclerosis type 1 is isolated, the development of which is caused by mutations in the gene 34 locus of the 9th chromosome responsible for encoding hamartin, and tuberous sclerosis type 2 associated with disorders in the 13th section of the 16th chromosome responsible for encoding tuberin.
The biochemical aspects of pathogenesis have not been fully studied. It is only known that normally hamartin and tuberin are factors of suppressing tumor growth. The morphological substrate is overgrown glial elements of cerebral tissue, histologically represented by giant cells with atypically enlarged nuclei and a large number of processes. Glial growths form sub-perpendicular nodes, cortical tubers and specific islets in the white matter. All these formations tend to calcify. Sub-perpendicular nodes often give rise to the formation of giant cell astrocytoma. In 10% of cases, damage to the cerebellar tissues is noted. Glial growths are also observed on the disc of the optic nerve and in the peripheral parts of the retina.
Symptoms
The clinic that tuberous sclerosis has is very variable. It includes damage to the central nervous system (CNS), dermatological and ophthalmological manifestations, neoplasms of internal organs. The debut occurs at various age periods, but tuberous sclerosis manifests more often during the first 5 years of life. There are different types of flow in severity. In mild cases, patients have a number of facultative nonspecific symptoms and often do not undergo diagnosis for the presence of TS. Tuberous sclerosis in the erased form proceeds without epiprimes, oligophrenia and behavior disorders.
Defeat of the central nervous system
Changes in the central nervous system are the dominant manifestations of TS. Among them, the most common (in 80-90% of cases) is convulsive syndrome, which usually manifests the disease. The episyndrome, which debuts in the first year of life, is characterized by infantile spasms (West’s syndrome), then transforming into Lennox-Gastaut syndrome. Atypical absences, somato- and sensorimotor paroxysms, secondary generalized seizures are possible. The occurrence at the age of one year, the high frequency and heterogeneity of seizures are accompanied by their resistance to anticonvulsant (antiepileptic) therapy. Epileptic paroxysms are the cause of mental retardation and behavioral disorders (aggressiveness, autism) in children.
In half of the cases, tuberous sclerosis is accompanied by oligophrenia expressed to varying degrees. Along with epilepsy, the cause of its development is considered to be the presence of cortical tubers. Already at a younger age, abnormal behavior is noted in children: general anxiety, capriciousness and discontent along with slowness, difficulty switching attention. The degree of these disorders is higher the earlier tuberous sclerosis occurred. Most patients also have sleep disorders. They are characterized by nocturnal awakenings, insomnia, somnambulism, early morning transition from sleep to wakefulness.
Dermatological symptoms
Skin changes accompany tuberous sclerosis in almost 100% of cases. They are characterized by a large polymorphism of elements and their combinations. Most often (in 90% of cases), hypopigmentation spots are observed, which usually occur in the first 3 years of life and subsequently increase their number. They are asymmetrically scattered on the buttocks, trunk and on the antero-lateral surfaces of the limbs. Depigmentation of eyelashes, eyebrows and hair is possible. In 14% of cases, areas of hyperpigmentation are detected in the form of spots more characteristic of neurofibromatosis. As a rule, there are no more than 5 of them.
According to various data, angiofibromas of the face are noted in 50-90% of patients and are formed mainly after the age of 4 years. These are multiple or single dense nodules in the form of millet grains, reddish or yellowish in color. “Shagreen skin” occurs in 21-68% of cases. Usually occurs in the period from 10 to 20 years. It represents asymmetric areas of tough roughened skin, localized on the back and lower back, having a size from 2-3 mm to 10 cm. Dermatoscopy shows that the shagreen areas consist of many fibrous hamartomas.
In 25% of cases tuberous sclerosis is accompanied by the formation of fibrous plaques, in 30% of cases — soft dermatofibromas. Up to 50% of patients after puberty have periarticular fibroids prone to progressive growth. The latter are more often located on the feet. They have the appearance of dull red nodules or papules surrounding the nail plate.
Ophthalmological symptoms
They are rarely noted, although almost half of patients with TS have the presence of optic nerve hamart and/or retinal hamart. Hamartomas may have a flat, smooth, slightly elevated surface or represent a knotty formation, sometimes there are mixed—type hamartomas – knotty in the center. The main manifestation of hamart is a progressive drop in vision, but their subclinical course is often observed. Other ophthalmological disorders are also possible: iris depigmentation, optic disc edema, coloboma, strabismus, eyelid angiofibromas, cataract.
Defeat of internal organs
Neoplasms of somatic organs accompanying tuberous sclerosis are characterized by multiplicity and frequent bilateral lesions of paired organs, they occur subclinically for a long time. The period of their manifestation ranges from 5 to 40 years. The most pathognomonic neoplasms for TS include: rhabdomyoma of the heart, lung cysts, polycystic kidney disease, liver hamartomas, rectal polyps. In 4.5% of cases with TS, malignant tumors are observed, more often renal cell carcinoma.
From the cardiovascular system, tumors of the heart are detected. In 30-60% of cases, these are rhabdomyomas. During their intrauterine development, antenatal fetal death may be observed. In half of newborns with TS, rhabdomyomas are detected accidentally during EchoCG. In young children, they are manifested by arrhythmia, WPW syndrome, tachycardia, ventricular fibrillation. The intramural position of the rhabdomyoma entails a disorder of contractility; obturation of the tumor mass of the cardiac chambers leads to heart failure. In older children, rhabdomyomas are mostly asymptomatic; possible blockage of the legs of the Gis beam, pseudo-ischemic deviations on the ECG. Often there is a regression and even complete disappearance of rhabdomyoma by the age of 6.
Lung damage is noted in patients with tuberous sclerosis after 30 years. On the X-ray, the “cellular lung” pattern characteristic of multiple pulmonary cysts is determined. Gastrointestinal tract lesions include oral tumors, dental enamel defects, multiple or single hamartomas in the liver, rectal polyps that are not prone to malignancy. Kidney damage is accompanied by tuberous sclerosis in 50-85%. There may be angiomyolipomas, cysts, glomerulosclerosis, nephrocalcinosis, interstitial nephritis, glomerulonephritis. Kidney pathology is the second cause of death in TS after the defeat of the central nervous system.
Diagnostics
It is possible to diagnose tuberous sclerosis only through the joint efforts of several specialists (neurologist, ophthalmologist, dermatologist, cardiologist, nephrologist) with a wide hardware examination of the patient. Cerebral epileptic activity is recorded using EEG and EEG samples. Neurosonography is possible in children under one year of age. CT and MRI are of the greatest importance in the diagnosis of CNS lesions. CT of the brain is more informative in relation to calcified tubers and sub—perpendicular nodes, and MRI of the brain is more informative in detecting non-calcified tubers. For the purpose of timely diagnosis of astrocytoma, children with tuberous sclerosis are recommended to undergo an MRI or CT examination at least once every 2 years.
A comprehensive examination of somatic organs is carried out: ECG, ultrasound and MRI of the heart, abdominal ultrasound, ultrasound and CT of the kidneys, urography, chest X-ray, rectoromanoscopy, colonoscopy. Diagnosis of ophthalmic lesions is carried out by direct and indirect ophthalmoscopy, scanning tomography of the retina.
Due to the large polymorphism of the manifestations accompanying tuberous sclerosis, diagnostic criteria developed in 1998 in Sweden are used to establish the diagnosis. They include primary, secondary and tertiary features. Tuberous sclerosis is reliable when there is 1 primary sign in combination with 2 secondary or tertiary. Tuberous sclerosis is likely in the presence of 1 secondary and 1 tertiary or 3 tertiary signs. Genetic analysis helps to put the final point in the diagnosis of tuberous sclerosis.
Treatment
Anticonvulsant therapy is a fundamental direction in the treatment of TS, since the degree of oligophrenia and ZPR directly correlates with the frequency of epiprimes, and the epileptic status can cause death. The choice of the drug depends on the type of paroxysms, with insufficient effectiveness of monotherapy, combined treatment is prescribed. In West’s syndrome, vigabatrin and tetracosactide are used. The drugs of the second stage are valproates. If tuberous sclerosis occurs with partial epiprimes, then the combination of valproates with carbamazepine is considered the basic therapy. In the absence of an effect, lamotrigine is included in this treatment regimen. With generalized epiprimes and partial paroxysms, modern anticonvulsants topiramate and levetiracetam can be used as a monopreparation and in combination with other antiepileptic drugs.
Therapy of oligophrenia is carried out mainly by neuropsychological correction and complex psychological support of the child. The appointment of nootropics and other stimulating neuropreparations is contraindicated due to the presence of episindrome. When an astrocytoma is detected, dynamic observation is carried out. Surgical removal of an intracerebral tumor is indicated only with a sharp increase in its size with an increase in intracranial pressure. The operation is performed by neurosurgeons.
In relation to neoplasms of somatic organs, mainly wait-and-see tactics are used. Surgical treatment is carried out according to indications, mainly in cases when the tumor causes significant organ dysfunction or there is a threat of its malignant course.