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Asist. Univ. Dr. Cojocaru Adriana – Președinte SNPCAR

Informații şi înregistrări: vezi primul anunț 


Autor: Gabriela Adriana Vișa Viorela Cotârlă Maria Cristina Dospinescu Gabriela Ariadna Gavrilă
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Tuberous sclerosis complex is a rare multisystemic disorder with autosomal dominant transmission which is characterized by the occurrence of some tumors most frequently found in the brain, skin but which can also emerge in the kidneys, hearts and eyes. Early diagnosis can be diffi cult because brain and skin lesions may be visible in a child at an older age. This is a presentation of the evolution of a patient with suspected tuberous sclerosis complex from the intrauterine period (week 36) when some cardiac formations were identifi ed.

The diagnosis was confirmed in the fi rst 4 months of life with the help of a multidisciplinary team that monitored the child from birth.

Tuberous sclerosis complex (TSC) neurological manifestations

The tuberous sclerosis complex is a rare multisystemic disorder with dominant autosomal transmission, variable and full expression. The tuberous sclerosis complex is characterized by the occurrence of tumours most frequently found in the brain and skin, which can also emerge in kidneys, heart and eyes [1] areas. TSC occurs in all races and ethnicities, and both sexes. The estimated prevalence in fetuses is 10-16 cases per 100,000. The estimated incidence at birth is 1 to 6,000-10,000 [1,2]. It is estimated that about 1 million people worldwide suffer from TSC. Every day, at least two children with TSC are born worldwide [3].

TSC was associated with two mutating genes: TSC1 located on chromosome 9 q34, encoding hamartin and TSC2 located on chromosome 16 p13.3, encoding tuberin [1,4]. In 20% of patients,the mutation cannot be located. Two thirds of cases result from sporadic mutations (de novo). TSC has an extremely variable phenotypic expression.

TSC1, identified in only 10% -30% of the TSC patients, is twice more likely to occur in hereditary than random cases [5].

TSC2, with an estimated occurrence percentage between 55% and 80% -90%, appears to be more common in sporadic cases. It is found in the more severe forms of TSC associated with PKD1, the gene involved in a form of the polycystic kidney disease [5].

The hamartin-tuberin complex inhibits the mechanistic target of rapamycin (mTOR), regulates cell growth and cellular proliferation by inactivating mutations, mTOR deregulation, resulting in hamartomatous tissue (malformed tissue, such as cortical tubers), hamartomas (benign growths such as facial angiofibromas and subependymal nodules), malignant hamartoblastomas (very rare). Overactive mTOR determines uncontrolled cell growth, proliferation, affects survival, metabolism and angiogenesis, all of which lead to tumor growth [3].

The diagnosis is based on an algorithm consisting of clinical criteria (Table I, II) [6].

The revised diagnostic criteria also include genetic criteria: the identification of a pathogenic mutation of either the TSC1 gene or the TSC2 gene in normal DNA tissue is sufficient to establish the certainty diagnosis of TSC [6].

The expression of clinical manifestations is age tapered and is highlighted in Fig. 1, the first manifestations being the presence of rhabdomyomas, followed by the occurrence of hypomelanicpatches [7].


In TSC the central nervous system (CNS) is almost invariably affected (in 85%–90% of children and teenagers) [3].

Three types of cerebral tumors are associated with TSC [3]:

1.Subependymal giant cell astrocytoma(SEGA: 5%–20%);

2.Cortical tubers;

3.Subependymal nodules(SEN: 90%–100%).

TSC may have debilitating neurological manifestations, including epilepsy (up to 90%), mental retardation (44% -64%, 30% deeply affected) and autism (15% -85%) [3].

TSC may also have potentially fatal complications, including hydrocephalus [3].


Treatment objectives in people with TSC are the same as those for others with chronic multisystemic conditions: providing the best quality of life possible, as few complications as possible, minimizing the treatment-related adverse effects, prescribing lesser medication [6].

Patients under TSC suspicion or with diagnosis confirmed on the basis of clinical or genetic criteria require systematic monitoring to detect the occurrence of anomalies in the brain, teguments, kidneys, heart, lungs, eyes, teeth.

The revised recommendations of the 2012 International Consensus in treating SEGA, neuropsychiatric disorders associated with TSC and seizures[6]

mTOR inhibitors are included in the treatment of several manifestations of TSC:

• At cerebral level – Surgical resection or mTOR treatment may be used for progressive, asymptomatic SEGA;

• At renal level – mTOR inhibitors are the recommended first-choice treatment for asymptomatic angiomyolipoma, progressive, measuring ˃ 3 cms in diameter;

• At pulmonary level – mTOR inhibitors may be used to treat patients with LAM, with moderate to severe or rapid progressionpulmonary disease.[6].

Inhibition of mTOR is a new therapeutic approach that simultaneously addresses the multiple aspects of TSC.

mTOR inhibitors may have the potential to provide targeted treatment for the full range of TSC associated manifestations, reducing the risk of potentially fatal complications with fatal.

However, the medical treatment cannot replace surgical interventions or other treatment options for certain situations. Each clinical choice should be carefully adjusted based on the patient, taking into account the risks and benefits of current treatment options.

The manifestation pattern of epilepsy associated with TSC

The onset of seizures often occurs in the first year of life and, in most cases, even in the first few months [7, 8]. 63% of patients experienced the onset of seizures in their first year of life. 38% of patients had infantile spasms.

Treatment options for epilepsy associated with TSC

The response to vigabatrin therapy initiated shortly after the onset of seizures or focal spasms is often rapid, with increased efficacy. However, only one-third of patients experience the disappearance of seizures with anti-epileptic drugs (AED). Pharmacoresistant epilepsy occurs in 62% of TSC patients [9].

Another option is the surgical treatment of epilepsy. Success is increased by early intervention and accurate localization of the epileptogenic region. However, epileptic seizures persist in one third of TSC surgically treated patients.

Stimulation of the vagal nerve may be an effective option in surgery incompatible patients.

Ketogenic diet can be an effective way of associated treatment.

Inhibition of mTOR has the potential to become a new therapeutic option.

Clinical challenges in the treatment of epilepsy associated with TSC

Epilepsy current treatments do not generally perturb the disease, they only suppress convulsions without treating the inherent causes [10].

mTOR signaling in TSC may influence downstream mechanisms of epileptogenesis [10].

Seizure control was improved by the pharmacological inhibition of mTOR [11,12], according to preclinical evidence that the mTOR inhibitors are effective in preventing, reducing or reversing epileptogenesis and seizures [12].

Hyperactivation of the mTOR pathway in the epilepsy associated with TSC leads to a dynamic process of epileptogenesisthat is not addressed by the current antiepileptic treatment (AED) [13].

In addition to the regular neurological monitoring in children with TSC, a regular general assessment is required according to The International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Consensus Conference [6] (Table no. III).


We present the case of a 4-year and 9-month-old boy, from a pregnancy with adequate progression up to 36 weeks, when the presence of tumoral formation in the cardiac area was highlighted in the regular ultrasound examinations. Birth occurred at 38 gestational weeks via caesarean section, birth weight 2750 g, Apgar Score = 10.

Due to the identification of prenatal cardiac tumors, the child was cardiologically and neurologically monitored and the suspicion of TSC was raised. After birth, the formations (rhabdomyomas) were isolated in the interventricular septum, on the bilateral ventricular wall. Progressively, they diminished in size, by the age of 4 there are only several 1-2 mm formations, at the mitral chordae level, with adequate cardiac function (Fig. 2). As the rhabdomyomas diminished in size, cardiac function improved from NYHA II to normal cardiac function, at present.

From the age of 8 months, the first depigmented skin patches occurred, being distributed of the thighs, chest and face.

The first epileptic seizures occurred at the age of 4 months, with the deviation of the eyes and of the head to the right, accompanied by vegetative phenomena, palpebral myoclonus, sight occlusion, myoclonus in the upper right limb, in salves, with daily frequency. The EEG route was hipsarrhythmic. Treatment with sodium valproate was initiated under which seizures persisted. Progressively, topiramate was introduced, followed by vigabatrin. From the age of 3 years, epileptic seizures have been partially controlled with medication, currently having 2-3 seizures per week (staring blankly, unresponsiveness). The EEG route is currently of the epileptiform type with a slow background theta on which rare peak discharges occur in the right fronto-temporal derivatives.

Psycho-motor development was delayed with age. The motor development was very slow, he started rolling at 1 year 6 months, he sits at 2 years old, he now stands by the edge of the bed and takes lateral steps, he does not walk by himself. Mental development is at the level of severe mental retardation (QI<34) , with autistic spectrum elements (motor stereotypes, no visual contact, low interest in toys), 10-month language –speaks in multi-syllables, does not understand the orders.

Regular eye examination does not reveal the development of ocular tumor formations, hypermetropia and astigmatism are diagnosed.

Cerebral MRI (3 months, 1 year, 6 months, 4 years old) reveals the presence of more voluminous cortical tubers in the right hemisphere, subependymal nodules, calcifications in the tubers, stationary evolution on the last investigation (Fig. 3, 4).

Repeated abdominal ultrasounds have not identified kidney or liver abnormalities.

TSC suspicion occurred in the intrauterine period through the diagnosis of intracardiac tumor formations. The TSC certainty diagnosis was performed at the age of 3 months after performing the MRI, with three major criteria being met: the presence of cardiac hamartomas, the presence of cortical tubers and subependymal nodules.

Genetic counseling is of great importance in the TSC patient`s family. Parents understood the risk of having other children with this condition. Genetic testing was not necessary because the diagnosis could be based on clinical criteria.

Case Particularity: Diagnosis suspicion arose prenatally, allowing patient monitoring and rapid onset of antiepileptic treatment.


Prenatal cardiac tumors are rare (0.08% to 0.2%) [14]. The most common histological forms are rhabdomyomas (60%), followed by teratomas (25%) and fibromas (12%) [14,15,16]

Out of these, only rhabdomyomas regress after birth. They can be observed after the 20th gestational week. Usually, the ultrasound identifies multiple ventricular tumor formations on ventricular level and suggests a high probability of association with TSC [17].

Rhabdomyomas may increase in volume in the second part of pregnancy under the influence of maternal hormonal changes and may cause complications such as fetal hydrops, cardiac arrhythmia, pericardial effusions. These complications may lead to pregnancy loss. After birth, these tumors generally regress up to the age of 2 years. In isolated cases, it is mentioned the possibility of rhabdomyomas increased incidence up to the age of adolescence.

There are authors who report the association in 100% of multiple rhabdomyomas cases in the intrauterine period and TSC. [18,19]

Hence, any detected intrauterine cardiac tumor formation requires subsequent monitoring, and those that regress indicate the probability of TSC [20].

Resorption of rhabdomyomas in the currently presented case correlates with normalization of cardiac function. From the imaging point of view, there is no recent increase in the number or volume of cortical tubers and there is no evidence of SEGA presence. The persistence of seizures under treatment is also associated with severe psychiatric retardation and according to the new recommendations, the epilepsy qualifies for treatment with mTor inhibitors, as an additional treatment to antiepileptic medication.


1. Any detected intrauterine cardiac tumor should raise suspicion of TSC.

2. Clinical manifestations of TSC occur throughout the patient’s life and can affect multiple organs. As a result, a multidisciplinary approach combining the efforts of various specialists is an integral part of coordinated health care: neurologist (pediatric / adult), nephrologist, urologist, pneumologist, hepatologist, cardiologist, dermatologist, ophthalmologist, pediatrician, family doctor, geriatric specialists.

3. Innovative concepts bring hope in controlling seizures and improving the quality of life for these patients.hepatologist, cardiologist, dermatologist, ophthalmologist, pediatrician, family doctor, geriatric specialists. 3. Innovative concepts bring hope in controlling seizures and improving the quality of life for these patients