Elżbieta Jurkiewicz

Long-term effect of everolimus on epilepsy and growth in children under 3 years of age treated for subependymal giant cell astrocytoma associated with tuberous sclerosis complex.

BACKGROUND Tuberous sclerosis complex (TSC) is a genetic disorder characterized by increased mammalian target of rapamycin (mTOR) activation and growth of benign tumors in several organs throughout the body. In young children with TSC, drug-resistant epilepsy and subependymal giant cell astrocytomas (SEGAs) present the most common causes of mortality and morbidity. There are also some reports on the antiepileptic and antiepileptogenic potential of mTOR inhibitors in TSC. However, the data on everolimus efficacy and safety in young children are very limited. AIMS To show the long-term safety data and the effect of everolimus treatment on epilepsy in children under the age of 3 who received everolimus for SEGAs associated with TSC. METHODS We present the results of everolimus treatment in 8 children under the age of 3 who participated in EXIST-1 study. Five patients presented with active, drug-resistant epilepsy at baseline. The mean follow-up is 35 months (33-38 months) and all children are still on treatment. RESULTS In 6 out of 8 children, at least a 50% reduction in SEGA volume was observed. In 1 child with drug-resistant epilepsy, everolimus treatment resulted in cessation of seizures and in 2 other children, at least a 50% reduction in the number of seizures was noted. The incidence of adverse events (AE) was similar to that observed in older children and adults. CONCLUSIONS This study suggests that everolimus is effective and safe in infants and young children with epilepsy and SEGA associated with TSC and offers a valuable treatment option.

Effective everolimus treatment of inoperable, life-threatening subependymal giant cell astrocytoma and intractable epilepsy in a patient with tuberous sclerosis complex

We present successful everolimus treatment of a huge subependymal giant cell astrocytoma in a 10-year old boy with tuberous sclerosis complex. The patient underwent several partial tumor resections complicated by intraoperative cardiac arrest. The tumor has been regrowing and produced severe clinical symptoms. Everolimus treatment resulted in marked tumor regression, significant improvement in patients ambulation and cessation of seizures. Moreover, the therapy was well tolerated. These findings indicate that everolimus treatment should be considered as a therapeutic option alternative to surgery in patients with tuberous sclerosis complex.

Cerebral tuber count and its impact on mental outcome of patients with tuberous sclerosis complex

Purpose:  The aim of the study was to reveal the relationships between the tuber count of the brain found in patients with tuberous sclerosis complex (TSC) and their cognitive outcome.

Surgical Treatment of Subependymal Giant Cell Astrocytoma in Tuberous Sclerosis Complex Patients

BACKGROUND Subependymal giant cell astrocytoma is a brain tumor associated with tuberous sclerosis complex. There are two treatment options for subependymal giant cell astrocytomas: surgery or mammalian target of rapamycin inhibitor. The analysis of outcome of subependymal giant cell astrocytoma surgery may help characterize the patients who may benefit from pharmacotherapy. METHODS Sixty-four subependymal giant cell astrocytoma surgeries in 57 tuberous sclerosis complex patients with at least a 12-month follow-up were included in the study. The tumor size, age of the patients, mutation in the TSC1 or TSC2 gene, indication for the surgery, and postsurgical complications were analyzed. RESULTS The mean age of patients at surgery was 9.7 years. Mean follow-up after surgery was 63.7 months. Thirty-seven (57.8%) tumors were symptomatic and 27 (42.2%) were asymptomatic. Patients with TSC2 mutations developed subependymal giant cell astrocytoma at a significantly younger age than individuals with TSC1 mutations. Four patients (6.2% of all surgeries) died after surgery. Surgery-related complications were reported in 0%, 46%, 83%, 81%, and 67% of patients with tumors <2 cm, between 2 and 3 cm, between 3 and 4 cm, >4 cm, and bilateral subependymal giant cell astrocytomas, respectively, and were most common in children younger than 3 years of age. The most common complications included hemiparesis, hydrocephalus, hematoma, and cognitive decline. CONCLUSIONS Our study indicates that subependymal giant cell astrocytoma surgery is associated with significant risk in individuals with bilateral subependymal giant cell astrocytomas, tumors bigger than 2 cm, and in children younger than 3 years of age. Therefore, tuberous sclerosis complex patients should be thoroughly screened for subependymal giant cell astrocytoma growth, and early treatment should be considered in selected patients.

Epilepsy in newborns with tuberous sclerosis complex.

BACKGROUND Epilepsy affects up to 90% of TSC patients and majority of them have seizure at the age of 3-5 months, after a period of latent epileptogenesis, but some develop epilepsy earlier. AIMS The aim of this work was to identify incidence, clinical characteristics, and risk factors for neonatal onset of epilepsy in a large cohort of TSC patients. METHODS A retrospective review of medical data of 421 TSC patients was performed. Patients who developed epilepsy within first 4 weeks of life were included in the study. Clinical and treatment data, EEG, MRI, and genetic analyses were assessed. RESULTS Epilepsy was present in 366 (86.9%) patients. Twenty-one (5.7%) developed epilepsy as newborns. Mean follow-up was 44.86 (6-170) months. Six patients were seizure free and 15 had drug-resistant seizures at the end of follow-up. Mental retardation was found in 81% of patients. In 11 (52.4%) patients brain MRI revealed large malformations of cerebral cortex, meeting the criteria for focal cortical dysplasia (FCD). FCD was revealed in both TSC1 and TSC2 mutation cases. Other risk factors for neonatal epilepsy included: perinatal complications and congenital SEGAs. Presence of FCD was associated with more severe epilepsy and worse neuropsychological outcome. Epilepsy surgery resulted in improvement in seizure control. CONCLUSIONS Neonatal onset of epilepsy in TSC is frequently associated with large malformations of cerebral cortex. Patients with FCD are at high risk of severe drug-resistant epilepsy and poor neuropsychological outcome. Early epilepsy surgery may be beneficial and should be considered in such cases.

Pontine tegmental cap dysplasia A hindbrain malformation caused by defective neuronal migration

A 13-month-old girl presented with developmental delay, generalized hypotonia, vertical pendular nystagmus, and cranial nerves IV, V, and VII paresis. MRI (figure) revealed pontine hypoplasia with ectopic dorsal transverse pontine fibers (tegmental cap). Concomitant profound sensorineural deafness and a butterfly Th2 vertebra led to the syndromic diagnosis …

MRI findings in the young infant with brainstem disconnection and extracerebral features. Report of one case and review of the literature

We present the young infant with the extremely rare brain abnormality-brainstem disconnection. Additionally, several extracerebral abnormalities were diagnosed: bilateral anotia, micrognatia, hypertelorism, scoliosis, ribs and vertebral anomalies. MR brain examination precisely demonstrated absence of the pons, with disruption between midbrain and hypoplastic medulla oblongata. The thin strands connecting the medulla with the midbrain and medulla with both cerebellar hemispheres were revealed. The large hamartoma of the tuber cinereum was found. In this study we review case reports published previously.

Clinical and radiological pictures of two newborn babies with manifestations of chondrodysplasia punctata and review of available literature.

Summary Background: Chondrodysplasia punctata (CDP) is a rare, heterogeneous congenital skeletal dysplasia, characterized by punctate or dot-like calcium deposits in cartilage observed on neonatal radiograms. A number of inborn metabolic diseases are associated with CDP, including peroxisomal and cholesterol biosynthesis dysfunction and other inborn errors of metabolism such as: mucolipidosis type II, mucopolysacharidosis type III, GM1 gangliosidosis. CDP is also related to disruption of vitamin K-dependent metabolism, causing secondary effects on the embryo, as well as fetal alcohol syndrome (FAS), chromosomal abnormalities that include trisomies 18 and 21, Turner syndrome. Case Report: This article presents clinical data and diagnostic imaging findings of two newborn babies with chondrodysplasia punctata. Children presented with skeletal and cartilage anomalies, dysmorphic facial feature, muscles tone abnormalities, skin changes and breathing difficulties. One of the patients demonstrated critical stenosis of spinal canal with anterior subluxation of C1 vertebra relative to C2. The aim of this article is to present cases and briefly describe current knowledge on etiopathogenesis as well as radiological and clinical symptoms of diseases coexisting with CDP. Conclusions: Radiological diagnostic imaging allows for visualization of punctate focal mineralization in bone epiphyses during neonatal age and infancy. Determining the etiology of chondrodysplasia punctata requires performing various basic as well as additional examinations, including genetic studies.

Rhombencephalosynapsis - isolated anomaly or complex malformation?

Summary Background: Rhombencephalosynapsis (RES) is a rare malformation of the posterior cranial fossa, characterized by fusion of the cerebellar hemispheres, medial cerebellar peduncles and dentate nuclei. Over the period of 7 years 8 cases of this anomaly have been diagnosed in two pediatric centers in Warsaw including one on the prenatal magnetic resonance imaging (MRI). Material/Methods: Material consists of involves one fetus examined at the gestational age of 27 and 33 weeks and 7 children (5 girls and 2 boys) aged 8 months – 16 years. All of them underwent brain MRI with the use of 1.5T scanners. Results: In 1 case RES was an isolated anomaly, in 1 case it was accompanied by hydrocephalus only, in the remaining 6 cases RES was an element of a complex malformation. The additional anomalies were as follows: callosal hypoplasia in 3 children, abnormalities of gyration in 2, brainstem hypoplasia in 2, isolated fourth ventricle in 1, abnormal white matter signal intensity in 4 (in 2 cases in supratentorial compartment, in 1 in the cerebellum and in 1 in the pons), abnormally dilated extraaxial fluid collections in 2, syringohydromyelia in 2. In 5 cases RES was total, in 3 – partial. Conclusions: Rhombencephalosynapsis has a very characteristic appearance on magnetic resonance imaging which allows diagnosis of this malformation at any age, including prenatal period.

MR venography in children and adolescents with multiple sclerosis does not show increased prevalence of extracranial veins anomalies

BACKGROUND Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system that affects mainly young adults, but can occur also in children and adolescents. The pathogenesis of MS is still not fully understood and chronic cerebrospinal venous insufficiency (CCSVI) was suggested to be implicated in MS. Although there is no strong evidence to support this hypothesis, a considerable number of MS patients, including adolescents, have undergone endovascular treatment procedures. The aim of this study was the evaluate the prevalence of extracranial venous system anomalies in children and adolescents with multiple sclerosis in comparison to age-matched controls. MATERIAL AND METHODS Twenty-one children with clinically definite diagnosis of MS (mean age 13.8 years), and 19 age-matched controls (mean age 12.5 years) were investigated using 1.5 T scanner with coronal 3D contrast-enhanced coronal venography. The diameters of internal jugular veins (IJV) at both sides of the neck were estimated separately, from the level C1 to Th1. RESULTS Anomalies of the extracranial venous system were found in 10 MS patients (47.6%) and 13 controls (68.4%). Normal anatomy of extracranial veins was recognized in 11 MS patients (53%) and 6 controls (31%). Comparison of the measurement results for MS patients and the control group revealed that there are no significant statistical differences in cross-section areas for a given level. CONCLUSIONS We found no evidence to suggest that MS children and adolescents have more extracranial veins anomalies than healthy patients. Considering the risk of such treatment, endovascular interventions should be discourage.