Diagnosis Of Tuberous Sclerosis Complex Research Articles

Topical Rapamycin Therapy to Alleviate the Cutaneous Manifestations of Tuberous Sclerosis Complex

Background and ObjectivesFacial angiofibromas are disfiguring facial lesions, present in up to 80% of patients with tuberous sclerosis complex. Recent elucidation of the complex cell signaling pathways that are disrupted in tuberous sclerosis indicates that rapamycin may be successful in alleviating the appearance of these lesions. The objectives of the current study were to evaluate the safety of topically applied rapamycin in patients with tuberous sclerosis complex and to determine its potential effectiveness in treatment of facial angiofibromas.Patients and MethodsThe study was a prospective, randomized, double-blind, placebo-controlled study performed at the University of Texas Health Science Center at Houston. Study subjects were recruited from the patient populations at the University of Texas Tuberous Sclerosis Center of Excellence. All subjects were over the age of 13 years and had a diagnosis of tuberous sclerosis complex. Subjects were excluded if they were using any form of rapamycin or if they were pregnant. Study subjects applied the study product to their facial angiofibromas nightly for a duration of 6 months. The investigational product contained one of three doses of rapamycin compounded with Skincerity®: (i) no rapamycin; (ii) 1 mg of rapamycin per 30 cc (0.003%); or (iii) 5 mg of rapamycin per 30 cc (0.015%). Plasma rapamycin concentrations were measured monthly to test for systemic absorption. Complete blood counts were performed monthly to test for anemia, neutropenia, or thrombocytopenia. Upon completion of the trial, subjects were asked if the formulation had improved the appearance of their facial angiofibromas.ResultsTwenty-three subjects completed the study. There was no detectable systemic absorption of rapamycin (all blood concentrations were <1.0 ng/mL). There were no significant changes in white blood cell, red blood cell, or platelet counts. Seventy-three percent of subjects in the treatment arms versus 38% of subjects in the placebo arm reported a subjective improvement in the appearance of their facial angiofibromas.ConclusionThe application of low-dose topical rapamycin (0.003–0.015%) to the face can safely decrease the appearance of facial angiofibromas in patients with tuberous sclerosis complex.Trial RegistrationClinicalTrials.gov Identifier: NCT01031901

Resource Utilization in Children With Tuberous Sclerosis Complex and Associated Seizures

Seizures are a hallmark manifestation of tuberous sclerosis complex, yet data characterizing resource utilization are lacking. This retrospective chart review was performed to assess the economic burden of tuberous sclerosis complex with neurologic manifestations. Demographic and resource utilization data were collected for 95 patients for up to 5 years after tuberous sclerosis complex diagnosis. Mean age at diagnosis was 3.1 years, with complex partial and infantile spasms as the most common seizure types. In the first 5 years post-diagnosis, 83.2% required hospitalization, 30.5% underwent surgery, and the majority of patients (90.5%) underwent ≥3 testing procedures. In 79 patients with a full 5 years of data, hospitalizations, intensive care unit stays, diagnostic testing, and rehabilitation services decreased over the 5-year period. Resource utilization is cost-intensive in children with tuberous sclerosis complex and associated seizures during the first few years following diagnosis. Improving seizure control and reducing health care costs in this population remain unmet needs.

Tuberous Sclerosis Complex: Genotype/Phenotype Correlation of Retinal Findings

To evaluate genotype/phenotype correlations in individuals with astrocytic hamartoma (AH) and retinal achromic patch (AP) in the setting of tuberous sclerosis complex (TSC). Retrospective consecutive case series. A total of 132 patients enrolled in the Cleveland Clinic Foundation Tuberous Sclerosis Program (CCF-TSCP) and 907 patients from the Tuberous Sclerosis Alliance (TSC-A). Patient gender, age at TSC diagnosis, presence of TSC1 or TSC2 mutations, detailed ophthalmic examination findings, systemic manifestations, and whether or not the patient had a diagnosis of epilepsy or cognitive impairment were analyzed. Genotype/phenotype correlation of retinal findings and systemic disease manifestations. No significant difference was found in the prevalence of AH or AP in the CCF-TSCP (36.1%) and TSC-A (34.1%) groups (P = 0.743). Astrocytic hamartomas were bilateral in 43.3% and 18.1% (P=0.009) and multiple in 40.0% and 15.3% (P = 0.008) in the CCF-TSCP and TSC-A groups, respectively. In the CCF-TSCP group, the average number of AH was 4 (range, 2-7). Average tumor size was 1.0 disc diameter (range, 0.5-2.5 disc diameters). The most common location was along the arcades (41.5%), adjacent to the optic nerve (29.2%), and in the retinal periphery (27.7%). In the CCF-TSCP group, AP was observed in 12.0% of patients (40.0% bilateral, 50.0% multiple). The presence of retinal features was associated with giant cell astrocytoma (37.1% vs. 14.6%; P = 0.018), renal angiomyolipoma (60.0% vs. 27.1%; P = 0.003), cognitive impairment (77.1% vs. 43.8%; P = 0.002), and epilepsy (91.4% vs. 70.8% (P = 0.022) in those with and without retinal findings, respectively. In patients with retinal findings in both the CCF-TSCP and TSC-A groups, mutations in TSC2 were more frequent than in TSC1, 3.3 times and 5.8 times, respectively; in those without retinal findings, the relative rates were 0.67 times and 2.3 times, respectively. Individuals with retinal findings are more likely to have concomitant subependymal giant cell astrocytomas, renal angiomyolipomas, cognitive impairment, and epilepsy. TSC2 mutations are more frequent in patients with retinal findings than in those without retinal findings.

Multimodal Imaging in the Prenatal Diagnosis of Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in which benign hamartomas develop in multiple organ systems. Increasingly, stigmata of the disease, such as cardiac rhabdomyomas, are detected on routine prenatal ultrasound. Such a finding should prompt additional imaging studies in order to confirm diagnosis and to identify potential complications, which vary greatly from patient to patient. Early diagnosis allows for accurate parental counseling, coordination of high-level perinatal care, and subspecialty followup. We present a case of TSC in utero wherein access to and use of multiple imaging modalities confirmed diagnosis and allowed the patient to receive optimal care prior to birth.

Renal Angiomyolipoma With Cardiac Extension in Patient With Tuberous Sclerosis Complex

A 26-year-old woman with a clinical diagnosis of tuberous sclerosis complex, presenting the classical triad of seizures, mental retardation, and facial angiofibromas and reporting tachycardia, dyspnea during moderate physical activity, and 3 episodes of syncope in the past 30 days, was admitted to our hospital. Echocardiography revealed right cardiac chambers with increased dimensions related to a large echogenic tumor with an inferior component within the inferior vena cava (Figure 1). Computed tomography of the chest and abdomen without iodinated venous contrast media depicted a large tumor arising from the right kidney with adipose tissue, extending superiorly via inferior vena cava with right cardiac chambers involvement (Figure 2). MRI of the abdomen and heart showed the same large right kidney tumor with high signal intensity in T1- and T2-weighted images, signal intensity loss in T2-weighted images with fat saturation, and enhancement after the use …

OP35.03: Fetal cardiac rhabdomyoma: short‐term and long‐term outcome

Objectives: Rhabdomyoma is the most common type of cardiac tumor in fetuses and is often associated with tuberous sclerosis complex (TSC) with neurologic sequelae. The purpose of this study is to investigate short-term and long-term outcome of fetal cardiac rhabdomyoma. Methods: We analyzed the clinical characteristics of 23 cases prenatally diagnosed with cardiac rhabomyomas on fetal echocardiography at Asan Medical Center between January 1998 and December 2009. We performed postnatal workup including brain magnetic resonance imaging (MRI), echocardiography, abdominal ultrasonography and molecular genetic analysis to confirm the presence of cardiac rhabdomyomas associated with or without TSC. Results: Among 23 cases, 17 cases (74%) had available outcome and 6 cases (26%) were lost to follow-up. 1) The survival rate was 100% (17/17). 2) Among 17 cases, while spontaneous tumor regression occurred in 11 cases (65%), no change in tumor size and number was observed in the remaining 6 cases (35%). 3) There was no evidence of long-term cardiac dysfunction due to remnant rhabdomyomas, regardless of tumor size. 4) TSC was revealed in 9 patients (53%), of whom four (44%) showed neurodevelopmental morbidities. 5) Among 4 patients with neurologic impairment, three (75%) had TSC gene (TSC1/TSC2) mutation. 6) Seven (78%) of 9 TSC cases were non-familial. Conclusions: The overall outcome of isolated cardiac rhabdomyomas was favorable. We suggest that systematic evaluation of TSC be performed even in cases of cardiac rhabdomyomas without family history of TSC. Molecular diagnosis of TSC1 and TSC 2 might be helpful in predicting short-term and long-term neurodevelopmental outcome.

Mutation screening and prenatal diagnosis of tuberous sclerosis complex

To screen mutations of tuberous sclerosis complex (TSC) patients to confirm a clinical diagnosis of TSC, and to perform prenatal diagnosis for families with mutations. In this study, PCR-denaturing high-performance liquid chromatography(DHPLC), supplemented with sequencing when necessary, was used to screen TSC1 and TSC2 mutations in 21 patients from 19 pedigrees visited author's hospital in the last five years. For novel mutations, one hundred unrelated healthy individuals were screened to exclude the possibility of polymorphism. Seventeen different mutations were found in 21 patients of 19 pedigrees with 13 being novel mutations, including c. 2672delA, c. 2672insA of TSC1 gene and c.4918insCGCC, c.1143delG, Intron27+1 G>A, c.1957-1958delAG, Intron5+1 G>A, c.910insCT, c.2753 C>G, c.4078dupAGCAAGTCCAGCTCCTC, Intron 11 -1 G>A, Intron 14+1 G>A, c.684 C>A of TSC2 gene, indicating a high frequency of de novo mutations in TSC. Three of these mutations were in the TSC1 gene (N762S, c.2672insA and c. 2672delA), while all remaining 14 were in the TSC2 gene. Prenatal diagnosis for TSC was performed for 7 fetuses from these pedigrees. The six fetuses that tested negative for TSC mutations were carried to term and, to date, none of these children has shown symptoms of TSC. Author's data showed that a mutation detection rate of tuberous sclerosis was 89.5%(17/19) among patients in author's hospital. The ratio of TSC2 and TSC1 mutations was about 1:1 in the familial cases, but TSC2 mutation was more common than TSC1 mutation in sporadic cases. Author's data demonstrated that birth of TSC children for those with familial history of TSC could be prevented through prenatal diagnosis.

Clinically Relevant Imaging in Tuberous Sclerosis

Tuberous sclerosis (TS), also known as Bourneville disease or Bourneville–Pringle disease, is an autosomal dominant genetic disorder classically characterized by the presence of hamartomatous growths in multiple organs. TS and tuberous sclerosis complex (TSC) are different terms for the same genetic condition. Both terms describe clinical changes due to mutations involving either of the two genes named TSC1 and TSC2, which regulate cell growth. The diagnosis of TSC is established using diagnostic criteria based on clinical and imaging findings. Routine screening and surveillance of patients with TSC is needed to determine the presence and extent of organ involvement, especially the brain, kidneys, and lungs, and identify the development of associated complications. As the treatment is organ specific, imaging plays a crucial role in the management of patients with TSC.

Recognition of Tuberous Sclerosis in Adult Women: Delayed Presentation With Life-Threatening Consequences

Tuberous sclerosis complex (TSC) is associated with tumor development in the brain, retina, kidney, skin, heart, and lung. Seizures, intellectual disability, and characteristic skin lesions commonly manifest in early childhood, but some findings, notably renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM), emerge later, placing adults with undiagnosed TSC at increased risk for morbidity and mortality. To describe the clinical presentation and severity of TSC in adult women. Retrospective cohort study. National Institutes of Health Clinical Center, Bethesda, Maryland, 1995 to 2010. 79 women aged 18 years or older who were enrolled in an observational cohort study of TSC to evaluate disease manifestations. History, physical examination, pulmonary function testing, chest radiography, abdominal computed tomography, high-resolution chest computed tomography, and brain magnetic resonance imaging were used to evaluate patients. Among the 45 patients who received a diagnosis of TSC in adulthood, 21 presented with symptoms due to LAM, 19 with renal angiomyolipomas, and 10 with seizures. Of the 45 patients, 30 met clinical criteria for TSC in childhood that remained undiagnosed for a median of 21.5 years and 15 were older than 18 years before meeting the clinical criteria for TSC. Patients diagnosed in adulthood and those diagnosed in childhood had similar occurrences of pneumothorax, shortness of breath, hemoptysis, nephrectomy, and death. No men were included in the study, and selection was biased toward patients having pulmonary LAM. Women who received a TSC diagnosis in adulthood had minimal morbidity during childhood but were still at risk for life-threatening pulmonary and renal manifestations. Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute.

Prenatal sonographic diagnosis of tuberous sclerosis complex

We report the case of a male fetus with tuberous sclerosis complex (TSC), in whom multiple cardiac rhabdomyomas and renal angiomyolipomas were detected at 33 weeks by ultrasound with additional brain lesions detected on MRI, all confirmed after birth. DNA analysis of the TSC2 gene detected a de novo mutation in the TSC2 gene. Postnatal follow-up and neurological examination were normal, as were the results of Holter monitoring.

Coagulation abnormalities in children undergoing epilepsy surgery

Surgery is increasingly used to treat children with refractory epilepsy. Before surgery, the authors routinely evaluated the coagulation profile to identify coagulation abnormalities not established by personal and family history, physical examination, and routine screening tests. Thirty-nine consecutive children undergoing testing prior to epilepsy surgery were prospectively evaluated. The authors evaluated a detailed hematological history and an elaborative hematological panel including complete blood count, hepatic panel, anticoagulant levels, coagulation profile (prothrombin time, partial thromboplastin time, international normalized ratio, fibrinogen, thrombin time, von Willebrand antigen, ristocetin cofactor, factor VIII, and individual factor assays when indicated) and platelet aggregation studies (in the presence of adenosine diphosphate, epinephrine, collagen, and ristocetin). Patient variables included tuberous sclerosis complex (TSC), age at epilepsy onset, age at surgery, seizure frequency, number and type of antiepileptic drugs, recent or present ketogenic diet, and use of selective serotonin reuptake inhibitors. Ten children (25.6%) had either coagulation or platelet function abnormalities. Abnormal coagulation was identified in 5 children, and abnormal platelet function was discovered in 6. A diagnosis of TSC was associated with a platelet function abnormality (p = 0.012), whereas children without TSC had a higher rate of coagulopathy (p = 0.041). None of the other characteristics reached statistical significance. In 2 patients (5.1%) with TSC and platelet aggregation abnormalities, the authors noted normal standard screening laboratory studies and an uneventful detailed personal and family history. One of these 2 patients developed a significant intraoperative bleeding complication. A preoperative screening with standard laboratory studies and detailed history may not be adequate to fully examine underlying coagulation abnormalities in children with refractory epilepsy. Platelet aggregation studies should be considered in patients with TSC.

Metaplastic bone in a cortical tuber of a young patient with tuberous sclerosis complex

Cortical tubers are the most common brain lesions of the tuberous sclerosis complex (TSC).1 They vary widely in size, location, and appearance, may have a cystic or a calcified component, and are often epileptogenic.2,3 Histologically, tubers are hypomyelinated hamartomas, which are characterized by abnormal cortical lamination and are typically composed of giant or balloon cells, dysplastic neurons, and reactive astrocytes.4 We report the radiologic and pathologic findings of a resected calcified tuber identified as an epileptogenic focus. ### Case report. The patient is a 19-year-old right-handed woman with a known spontaneous TSC1 mutation. She was the product of a normal pregnancy. Seizure onset occurred at the age of 9 months and led to a diagnosis of TSC. Neuropathologic features include numerous cortical tubers and subependymal giant cell tumors (SGCT). The patient has experienced daily seizures since their onset. Multiple antiepileptic medications and other anticonvulsant treatments were tried without significant seizure control. The patient has a history of global developmental impairment. As part of the presurgical evaluation for neurosurgical intervention, an MRI showed SGCT, multiple tubers located in bilateral frontal, parietal, and occipital lobes, and a large (22 mm) T2 hypointense calcified lesion deep to the left superior frontal sulcus (figure). Review of prior scans revealed that the calcified component of this …

Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex

Background Epilepsy appears in 70–80% of patients with tuberous sclerosis complex, most commonly in the first year of age. Early manifestation of epilepsy is associated with drug-resistant epilepsy and mental retardation in more than 80% of patients. Clinical epileptic seizures are preceded by deterioration of EEG recording thus infants with high risk of epilepsy can be identified. Aims We hypothesized that preventative antiepileptic treatment of infants with multifocal activity on EEG might lower the incidence of drug-resistant epilepsy and mental retardation. Methods Forty-five infants with early diagnosis of tuberous sclerosis complex were included in the open-label study. They were divided in two groups: standard ( n = 31) and preventative one ( n = 14). In standard group the antiepileptic treatment was launched early, but after the onset of seizures. In preventative group medication was commenced when active epileptic discharges were seen on EEG, but before the onset of clinical seizures. Children were followed till the end of 2 years of age. Results At 24 months of age mental retardation was significantly more frequent and severe in “standard” vs “preventative” group (48% vs 14%; p = 0.031; mean IQ score 68.7 vs 92.3; p < 0.05). The “preventative” group was characterized by higher ratio of seizure-free patients (93% vs 35%; p = 0.004), lower incidence of drug-resistant epilepsy (7% vs 42%; p = 0.021) and lower number of patients requiring polytherapy (21% vs 55%; 0.039) than the “standard group. Conclusions Preventative antiepileptic treatment of infants with tuberous sclerosis complex and high risk of epilepsy markedly improves their neurodevelopmental outcome and reduces the incidence of drug-resistant seizures.

An Australian tuberous sclerosis cohort: Are surveillance guidelines being met?

This study aims to describe the phenotypic and genotypic characteristics of 45 Australian patients with tuberous sclerosis complex (TSC), to assess risk factors for intellectual disability, to compare patients with TSC1 and TSC2 mutations and to assess adherence to surveillance recommendations. Phenotypic features were recorded in 45 patients who fulfilled established criteria for a diagnosis of definite TSC. All patients underwent TSC1 and TSC2 sequencing and multiplex ligand probe amplification. Features were compared in patients with TSC1 mutations versus TSC2 mutations. Recent surveillance was recorded at the point of first contact. Surveillance adherence was compared in the adult and paediatric cohorts. This cohort consisted of 31 children and 14 adults with definite TSC. The rates of TSC manifestations and TSC1 and TSC2 mutation detection rates were consistent with previous studies. There was a trend towards greater severity for patients with TSC2 mutations compared with their TSC1 counterparts, particularly for autistic spectrum disorder, but this did not reach statistical significance. The presence of seizures was shown to be a risk factor for intellectual disability (P < 0.001). Overall, 12/45 patients (27%) were not undergoing recommended surveillance at the point of first contact. Surveillance guidelines were being followed in 3/31 (11%) children compared with 9/14 (64%) adult patients (P < 0.05). The genotypic and phenotypic characteristics of this TSC cohort were consistent with previous studies. Surveillance rates in adult patients were significantly lower than in paediatric patients. This highlights the need for patients with TSC to undergo a focussed transition into adult services.

Selected Case From The Arkadi M. Rywlin International Pathology Slide Seminar

Lymphangioleiomyomatosis (LAM) is a systemic, progressive, and fatal condition affecting almost exclusively women in their reproductive years. LAM most often occurs as a sporadic disease, but also occurs in women with tuberous sclerosis complex (TSC) (syndromic LAM). There are no pathologic differences between sporadic and syndromic LAM. Sporadic LAM is a rare disease with prevalence of approximately 1 to 2 cases per million women in the United States and among populations of white descent, and is even rarer among Asian and African individuals. Syndromic LAM affects 4% to 5% of women with TSC. Sporadic LAM is often found also in association with renal angiomyolipoma, the most common sign of TSC, but LAM associated with angiomyolipoma does not define TSC. Although LAM is not diagnostic for TSC either in isolation or in association with angiomyolipoma, still it is considered by some researchers as an incomplete expression (forme fruste) of TSC. LAM may involve the lungs and the axial lymphatics and lymph nodes of the thorax and retroperitoneum. In sporadic LAM, thoracic, intraabdominal, and cervical lymph nodes can be involved with or without lung involvement. The diagnosis of LAM is often delayed. A case of LAM in a young lady, which was complicated with pleural and peritoneal chylous effusions, is presented. The diagnosis was first made on a retroperitoneal lymph node biopsy. The patient had a prolonged prior history of respiratory problems owing to lung involvement, and eventually died 2 years after diagnosis. Focus on the clinicopathologic diagnosis of TSC is also made.

Tuberous Sclerosis Complex With a Single Brain Lesion on MRI Mimicking Focal Cortical Dysplasia

Of 105 children with epilepsy who had presurgical evaluation because of solitary extratemporal focal cortical dysplasia, the 5 cases reported here had a final diagnosis of tuberous sclerosis complex without classic findings on magnetic resonance imaging (MRI). Four were infants with spasms (n = 2) or partial seizures (n = 2); the fifth was a 12-year-old boy with right motor seizures. Cranial MRI indicated solitary left frontal dysplasia in two cases (one with calcification) and right frontal, left parietal, and right parietal dysplasia in one case each. Tuberous sclerosis complex was considered based on hypopigmented macules in three cases, on cardiac rhabdomyomas on echocardiography for hypotension in one case, and on calcification in the dysplastic region and a family history of seizures in one case. Four of the patients had mutations in the TSC1 (n = 2) and TSC2 (n = 2) genes. No mutation was found in the fifth patient, who had only TSC1 sequencing. Four had epilepsy surgery, and were seizure-free on one (three cases) or two antiepileptic drugs (one case) at 1-2 year follow-up. Pathologic examination revealed cortical dysplasia without any characteristic features of tuberous sclerosis complex. These findings suggest that, in tuberous sclerosis complex, solitary focal cortical dysplasia may be the only cranial MRI finding. Tuberous sclerosis complex should be considered when focal cortical dysplasia is associated with seizure onset in infancy, family history of seizures, and peridysplastic calcification.

CT of Sclerotic Bone Lesions: Imaging Features Differentiating Tuberous Sclerosis Complex with Lymphangioleiomyomatosis from Sporadic Lymphangioleiomymatosis

To determine if sclerotic bone lesions evident at body computed tomography (CT) are of value as a diagnostic criterion of tuberous sclerosis complex (TSC) and in the differentiation of TSC with lymphangioleiomyomatosis (LAM) from sporadic LAM. Informed consent was signed by all patients in this HIPAA-compliant study approved by the institutional review board. Retrospective analysis was performed of the body CT studies of 472 patients: 365 with sporadic LAM, 82 with TSC/LAM, and 25 with TSC. The images were reviewed by using a picture archiving and communication system workstation with bone settings (window width, 1500 HU; window level, 300 HU) and fit-to-screen option. CT image characteristics assessed included shape, size, and distribution of sclerotic bone lesions with subsequent calculation of differences in the frequency of these lesions. Most commonly the sclerotic bone lesions were round, measured 0.3 cm (range, 0.2-3.2), and were distributed throughout the spine. The frequencies differed among the three patient groups Four or more sclerotic bone lesions were detected in all 25 (100%) of those with TSC, with a sensitivity of .89 (72 of 82) and specificity of .97 (355 of 367) in the differentiation of sporadic LAM from TSC/LAM (P < .01). The number of sclerotic bone lesions at body CT is of potential value in the diagnosis of TSC and in the differentiation of patients with sporadic LAM from those with TSC/LAM. (c) RSNA, 2010.

Identification of the epileptogenic zone in patients with tuberous sclerosis: Concordance of interictal and ictal epileptiform activity

In the majority of patients with tuberous sclerosis complex (TSC) multifocal epileptiform activity is present interictally. Therefore, its value in identifying epilepsy surgery candidates has been doubted. We hypothesize that dominant interictal epileptiform foci are concordant with the ictal onset zone in TSC patients. Consistency and dominance of focal interictal epileptiform activity was assessed in 19 patients with a clinical definite diagnosis of TSC. The ictal onset zone was identified. Concordance between interictal en ictal findings was analyzed. If concordance was found epilepsy surgery was proposed. We found dominant, consistently present, focal interictal epileptiform activity in 14 of the 19 patients. Concordance between the dominant interictal focus and the ictal onset zone was found in 11 of the 14 patients (79%). In one patient the ictal onset zone could not be identified and discordance was present in two patients. Epilepsy surgery was performed in six patients rendering three of them seizure free, and one had a seizure reduction >90%. In these patients local concordance was found whereas regional concordance was found in the two patients who did not benefit from epilepsy surgery. A dominant as well as a consistent interictal focus is concordant with the ictal onset zone in the majority of TSC patients. Future studies of TSC patients addressing the value of interictal foci in the consideration of epilepsy surgery, in absence of clear ictal onset zone, are necessary.

Bipolar Disorder and Tuberous Sclerosis Complex: Is It A Mere Coincidence?

Tuberous sclerosis complex (TSC) is associated with significant psychiatric comorbidity mainly in the form of autistic disorders, hyperkinetic disorders, depression, and anxiety disorders. There are very few reports of bipolar disorder in TSC. The authors present the case of a patient with TSC having bipolar disorder manifesting as manic as well as depressive episodes. The diagnosis of TSC was based on the presence of facial angiofibromas, enamel pits, and shagreen patches on clinical examination, and the presence of cortical tubers and calcified subependymal nodules on neuroimaging. The patient presented during the manic phase of the illness and responded well to treatment with carbamazepine and haloperidol and became symptom free within 1 month. The patient's neuropsychological assessment revealed a borderline level of intellectual functioning and deficits in attention and concentration, recent memory, delayed and immediate recall, and visual retention. To our knowledge, this is the first report of TSC with bipolar disorder having both manic as well as depressive episodes. The nature of association between TSC and bipolar disorder, and its clinical implications are discussed.

Rapamycin as a Therapy of Choice After Renal Transplantation in a Patient With Tuberous Sclerosis Complex

Herein we have reported the use of rapamycin in immunosuppressive treatment after renal transplantation as a therapy of choice in a patient with diagnosis of tuberous sclerosis complex (TSC). TSC is a genetic disorder, caused by mutations of TSC1 or TSC2 genes. Products of these genes, hamartin and tuberin, create a complex that inhibits mammalian target of rapamycin (mTOR), a key protein engaged in regulation of the cell cycle. Mutations of TSC genes lead to constitutive activation of mTOR resulting in uncontrolled proliferation, differentiation, and migration of cells. As a consequence malformations of many organs arise. We have presented a case of a 47-year-old female TSC patient with multisystem involvement (skin, brain, lungs, and kidneys), who developed end-stage renal disease ESRD due to angiomyolipomas with subsequent bilateral nephrectomy. At the age of 44 years, she started hemodialysis treatments and 10 months later underwent kidney transplantation. Immunosuppressive treatment included the mTOR inhibitor rapamycin. Since the patient was discharged from hospital, she has remained in good clinical condition with stable graft function. Clinical evaluation after 2 years treatment with rapamycin revealed significant regression of skin lesions. Brain, chest, and abdominal cavity computed tomography images remained stable. No complications of immunosuppressive treatment or TSC were observed. Experimental and clinical studies have confirmed that rapamycin exerts beneficial effects in TSC, providing a new therapeutic option. Therefore an immunosuppressive regimen with rapamycin should be considered as the treatment of choice after kidney transplantation among patients with TSC seeking to avoid development or progression of disease complications.