General Child Neurology
May. 31, 2021
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This article includes discussion of tuberous sclerosis complex, Bourneville-Pringle disease, Bourneville disease, diffuse cortical histioatypia, epiloia (obsolete), Pringle disease, TSC, and tuberous sclerosis.
Tuberous sclerosis complex is a constellation of signs and symptoms that constitute the diagnosis. In this update, the authors give a succinct overview of the topic while outlining advances in the treatment of multiple manifestations of the disease. New trials for management of multiple clinical manifestations with precision medicine using mTOR inhibitors are discussed.
• Tuberous sclerosis is a neurocutaneous disorder with significant neurologic implications, especially with regards to epilepsy and cognition. There have been tremendous gains made in recognizing and managing the protean disease manifestations just in the last decade.
• Epilepsy is a common manifestation early in life.
• Autism is a very frequent manifestation of this disease, affecting about half of all patients.
• TAND, tuberous sclerosis complex associated neuropsychiatric disorders, are increasingly recognized and include a wide range of disorders such as behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties.
• Tumors are common and have a significantly improved prognosis with advances in treatment.
• Significant progress has occurred in the last decade in management of the clinical features of the disease based on advances in understanding of the pathogenesis and pathophysiology, specifically with the use of mTOR inhibitors.
Désiré-Magloire Bourneville reported “tuberous sclerosis of cerebral circumvolutions” with “confluent vesiculopapular eruption on her nose, cheeks and forehead” in the necropsy of a young girl who had recurrent status epilepticus (14). The term “tuberous sclerosis” here refers solely to the discrete pathologic entity in the brain – a distinctive cortical pathology of raised, opaque, and sclerotic cerebral gyri with a potato-like firmness. Interestingly, almost 20 years previously, and perhaps unbeknownst to him, Von Recklinghausen had reported of a newborn infant with several cardiac "myomata" and numerous scleroses in the brain (109). Bourneville also reported periventricular white nodules projecting into the lateral ventricles of the brain, and tumors in the kidneys (14).
Subsequently, dermatologists in France (05) and in England (83) described a facial hamartoma, namely adenoma sebaceum, which was subsequently linked to seizures and mental retardation. Later, many authors reported of the association of “tuberous sclerosis” with dermatologic (78; 80), renal, cardiac, and pulmonary (69) abnormalities. The term “tuberous sclerosis complex,” therefore, best reflects involvement of multiple organ systems with development of distinctive tumors, or hamartomas. These associations in general and the Vogt triad (epiloia, an acronym for epilepsy, low IQ, and "adenoma sebaceum") in particular helped diagnose tuberous sclerosis complex in the living (108).
Recognition of the hereditary nature (07) of tuberous sclerosis, its wide clinical spectrum and evolution of the concept of "phacomatoses" (Greek "phakos" meaning "mother spot") (104) were seminal advances in the history of tuberous sclerosis complex. The radiological identification of intracranial calcification in tuberous sclerosis in 1924 (70) and the publication of a classic paper on this disease (19) were landmarks. Molecular techniques leading to identification of 2 tuberous sclerosis genes, TSC1 in chromosome 9q34.3 (40) and TSC2 in 16p13.3 (52) have been of momentous significance.
In 2006, the first case series reporting success in treating human astrocytomas with tuberous sclerosis complex by targeting mammalian (now mechanistic) target of rapamycin (mTOR) with oral rapamycin was published (38). Subsequently, reports of success of rapamycin (sirolimus) and everolimus in renal angiomyolipoma and lymphangioleiomyomatosis were published (112; 12). Everolimus and sirolimus (rapamycin) are being evaluated for multiple indications in tuberous sclerosis complex including epilepsy, subependymal giant cell astrocytomas, angiolipomas, and other tumors in multiple trials.
Tuberous sclerosis complex is characterized by a wide phenotypic spectrum, occurring in approximately 1 in 6000 to 10,000 individuals (90; 77). The diagnosis of tuberous sclerosis complex is based on the lesions found on clinical examination, imaging, and pathologic studies.
Revised diagnostic criteria of tuberous sclerosis complex include major and minor features (74). Fundamental to the first revision was consensus that there are no truly pathognomonic clinical signs for tuberous sclerosis complex; the signs that were once regarded as specific sometimes occur as isolated findings in individuals with no other clinical or genetic evidence of tuberous sclerosis complex. Major features are signs with a high degree of specificity for tuberous sclerosis complex, whereas minor features are less specific. Although the skin is the most commonly involved organ, the brain, kidneys, retina, heart, lungs, and the large arteries are all frequently involved. The revision in June 2012 includes genetic criteria for diagnosis and eliminates probable disease as a diagnostic class (74). It is anticipated that use of the genetic criteria will allow presymptomatic diagnosis of tuberous sclerosis complex in some individuals, allowing earlier implementation of surveillance and treatment with potential for better clinical outcomes.
Genetic diagnostic criteria. The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a definite diagnosis of tuberous sclerosis complex (TSC). A pathogenic mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 proteins (eg, frameshift or nonsense mutation), prevents protein synthesis (eg, large genomic deletion), or is a missense mutation whose effect on protein function has been established by functional assessment.
Other TSC1 or TSC2 variants whose effect on function is less certain do not meet these criteria, and are not sufficient to make a definite diagnosis of tuberous sclerosis complex. Molecular testing of the TSC1 and TSC2 genes yields a positive mutation result for 75% to 90% of tuberous sclerosis complex–affected individuals categorized as “definite” by the 1998 Consensus Conference Clinical Diagnostic Criteria. Ten percent to 25% of tuberous sclerosis complex patients have no mutation identified by conventional genetic testing, and a normal result does not exclude tuberous sclerosis complex, or have any effect on the use of clinical diagnostic criteria to diagnose tuberous sclerosis complex. Whole exome sequencing in blood, saliva, or cells from skin tumor biopsy yields evidence of mosaicism and intronic mutations in almost all of these patients.
Clinical diagnostic criteria.
1. Hypomelanotic macules (> /=3, at least 5 mm diameter)
1. “Confetti” skin lesions
Definite tuberous sclerosis complex
1. 2 major features or,
Possible tuberous sclerosis complex
1. 1 major feature or,
If both renal angiomyolipoma and lymphangioleiomyomatosis are present, other features of tuberous sclerosis complex should be present for a definite diagnosis.
Clinical manifestations according to organ systems. The type, size, number, and sometimes the location of involved lesions and organ systems dictate the clinical presentation.
Skin lesions are found in 96% to 100% of patients with tuberous sclerosis complex, who usually seek medical attention because of seizures, making it a prototypical neurocutaneous disorder. There exist 2 types of skin lesions: hamartomas (including facial angiofibromas, fibrous cephalic plaques, shagreen patches, and ungual fibromas) and hamartias (such as white spots or hypomelanotic macules) (72; Gomez 1988a; 89).
Hamartomas present in infancy to adulthood, whereas hamartias predominantly present in infancy to childhood. Of all patients with tuberous sclerosis complex, 87% have hypomelanotic macules, 75% have facial angiofibromas, 21% have ungual fibromas, 50% have shagreen patches, and almost none have no skin lesions at all. The most common skin manifestation, the hypomelanotic macule, is best seen with a Wood’s lamp and is often noted over the buttocks and trunk. The facial angiofibromata are usually bilateral, in a butterfly distribution over the nasolabial folds and malar area. They have been recognized to manifest secondary to ultraviolent sunlight exposure as a form of a second hit (102). Shagreen patches occur over the lower trunk and flank. They may appear in the neck, upper trunk, buttocks, and thighs as well. Fibrous cephalic plaques may be the most specific dermatological finding in tuberous sclerosis complex. In addition, dental pits have been noted in 90% of the patients with tuberous sclerosis complex, approximately 10 times more often than in the general population (35).
The CNS manifestations of tuberous sclerosis complex, noted in about 90% of afflicted children, include seizures, cortical dysplasia, tumors, intellectual disability, autism, ADHD, and sleep disorders. Tuberous sclerosis complex associated neuropsychiatric disorders (TAND) is a term to describe the wide range of disorders including behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties associated with tuberous sclerosis complex.
• Seizures are by far the most common presenting complaint (in 84% of patients and in greater than 95% of all infants). All types of seizures can occur, but the predilection is to present with infantile spasms when they occur in early infancy. A third of all children with tuberous sclerosis complex develop infantile spasms. The absence of seizures during infancy foreshadows better cognitive development. Patients with infantile spasms may progress to develop Lennox-Gastaut syndrome. Earlier onset portends a worse prognosis for developmental delays and subsequent intractable partial epilepsy. Improved development has been proven to occur when infantile spasms and partial seizures are controlled. Although infantile spasms in tuberous sclerosis complex are clinically similar to those due to other causes, the spasms may present very early and be preceded by, or coexist with, focal seizures. Subtle focal seizures, characterized by unilateral tonic or clonic activity affecting the face or limbs, eyes, and neck, may go unrecognized until there are more obvious infantile spasms (92).
Epilepsy in older children and adults with tuberous sclerosis complex is characterized by multiple seizure types, most likely reflecting the presence of multiple tubers with variable epileptogenic potential in most patients. The majority of tuberous sclerosis complex adults have more than 1 seizure type, with focal-onset seizures in most (93%). Almost two thirds of epilepsy is refractory, despite using multiple antiepileptic medications and nonpharmacological approaches. The refractory group is characterized by a younger age at diagnosis, a previous history of infantile spasms and/or Lennox-Gastaut syndrome, lower educational achievement, a higher prevalence of psychiatric problems, and association with TSC2 mutations (92).
• Cortical dysplasia occurs in 90% of patients. This manifests as cortical tubers and lines of migration. Patients with tuberous sclerosis complex and early-onset seizures or mental retardation tend to have large numbers or sizes of cortical tubers on MRI (94). Tubers are glioneuronal hamartomas, occurring in more than 90% of patients. CNS tumors are found in 5% to 15% of individuals afflicted with tuberous sclerosis complex. These tumors differ in their location, radiological characteristics, and biological behavior (99). Subependymal nodules are present in almost 80% of patients and can be identified prenatally or at birth. They are commonly low-grade dysplasias, which share histology with subependymal giant cell astrocytomas, whose presentation may vary from totally asymptomatic to obstructive hydrocephalus and death.
• Subependymal giant cell astrocytomas are hamartomas that are located near the foramen of Monro, are greater than 0.5 cm in size, and grow and enhance with gadolinium on MRI, occurring in 10% to 15% of patients with tuberous sclerosis complex. They are now recognized to be glioneuronal in origin. Subependymal giant cell astrocytoma growth acceleration is related to young age, size greater than 2 cm, and TSC 2 genotype. They most commonly manifest between 8 and 14 years of age.
• Less commonly, there are aggressive tumors like pineal giant cell astrocytomas, glioblastoma multiforme, or spongioblastoma. Ependymoma, neurinoma, acoustic neuroma, hemangioma, and neuroblastoma have also been reported. Hemimegalencephaly has been observed in a higher frequency of tuberous sclerosis complex patients compared to normals.
• Sleep disorders such as night waking, early waking, seizure-related sleep problems, and excessive daytime sleepiness are among the most frequent behavioral features of tuberous sclerosis complex (45).
• Tuberous sclerosis complex–associated neuropsychiatric disorders (TAND) is terminology proposed to describe the interrelated functional and clinical manifestations of brain dysfunction seen in tuberous sclerosis complex, including behavioral problems, autism spectrum disorders, intellectual disabilities, psychiatric disorders, neuropsychological deficits, psychosocial issues, and school and occupational difficulties (29). Autism and ADHD occur in about 40% to 50% of patients with tuberous sclerosis complex. The specific phenotypic profile of autism spectrum disorder in tuberous sclerosis complex was reviewed and was found to converge significantly with nonsyndromic autism spectrum disorder (46). Given the high prevalence of TAND issues and that unaddressed TAND concerns contribute significantly to poor outcome, as well as the fact that individuals with tuberous sclerosis complex have very high health care resource consumption, the importance of recognizing and addressing TAND concerns cannot be overestimated (31).
Astrocytic retinal hamartomas are found in about 50% of patients with tuberous sclerosis complex on indirect ophthalmoscopy (88). They are histopathologically similar to subependymal nodules and subependymal giant cell astrocytomas. They may continue to grow past adolescence, but they are seldom symptomatic. Pigmentary changes and punched out lesions may also be found on retinoscopy. An increased incidence of association with subependymal giant cell astrocytomas, angiofibrolipoma, cognitive impairment, and epilepsy has been noted in the presence of retinal findings (03).
Renal lesions occur in more than half of children at the time of initial evaluation. Eighty percent of children are affected by 10 years of age (34).
Cardiac involvement is common in tuberous sclerosis complex and is found in up to 80% of patients (84). Rhabdomyomas are common in infants, occurring in approximately half who undergo echocardiography and can be diagnosed by fetal ultrasound. The majority of afflicted patients are asymptomatic and their tumors regress spontaneously, often completely disappearing (111; 101). Prenatal identification of rhabdomyomas by fetal ultrasound appears to be sensitive in identifying tuberous sclerosis complex postnatally (04), with a 75% to 80% risk for tuberous sclerosis complex. Arrhythmias and symptoms due to mechanical effects of the rhabdomyomas on the heart can occur at any time as an initial presentation, although most likely in the perinatal period. Wolff-Parkinson-White syndrome can occur in the absence of rhabdomyomas (103). Giant intracranial aneurysms involving the internal carotid artery have also been reported (51).
Pulmonary issues include lymphangioleiomyomatosis, clear cell tumors of the lung, and multifocal micronodular pneumonocyte hyperplasia (82). Pulmonary lymphangioleiomyomatosis is the third leading cause of mortality after CNS and renal phenotypes (93) in tuberous sclerosis patients. The prevalence of lymphangioleiomyomatosis in tuberous sclerosis complex has been reported to be as high as 80% (20). It usually presents in women in their third or fourth decade with recurrent spontaneous pneumothorax, hemoptysis, chylothorax, and respiratory failure. An overwhelming majority of women have cystic lung disease by the age of 40. Female patients with tuberous sclerosis complex and lymphangioleiomyomatosis are also highly likely to manifest renal angiomyolipomas. Sporadic lymphangioleiomyomatosis occurs later, has a more severe course, and is also associated with renal angiomyolipomas about a third of the time. This has led to the consensus that the presence of both constitutes a single major criterion.
The vascular lesions of tuberous sclerosis complex are secondary to a defect in the arterial walls of large and midsize arteries, resulting in aneurysms. Other findings include angiomyolipomas in various organs, thyroid and parathyroid adenomas, liver, colon and rectal polyps, gingival fibromas, chordomas, and bone cysts.
Clinical manifestations by age. The clinical findings vary according to age. The fetal period may be punctuated by seizures and arrhythmias, whereas the neonate may present with Wolff-Parkinson-White syndrome, hydrops fetalis, and ultrasound evidence of multiple renal cysts or rhabdomyomas. Infantile spasms, retinal hamartomas, and the pathognomonic hypomelanotic macules mark infancy. Developmental retardation may also present during this period. Early childhood features include autism, seizures, and hypomelanotic macules, whereas subependymal giant cell astrocytomas, angiofibromas, and ungual fibromas present in late childhood. Adolescents develop shagreen patches, and adults manifest with pulmonary lymphangioleiomyomatosis and renal angiomyolipomas (43).
The spectrum and severity of organ involvement determines morbidity and mortality for patients with tuberous sclerosis complex, with complications of renal disease being the most common cause of death. In general, it appears that TSC2 mutation presents with a more severe spectrum than TSC1 mutations.
Complicated CNS involvement is a common cause of death. Children and young adults are at particular risk from status epilepticus and sudden unexpected death in epilepsy (SUDEP). Patients with severe mental retardation are at increased risk of death from respiratory infections.
Respiratory failure occurs in about 40% of patients with biopsy-proven lymphangioleiomyomatosis (93). The risk of hemorrhage is 25% to 50% in patients with renal angiomyolipomas; these patients may present in hypovolemic shock. Cardiac dysrhythmias, including Wolff-Parkinson-White syndrome, may be problematic, although death from obstruction of ventricular outflow is rare (75). Severe congestive cardiac failure can occur in infancy. Thoracic and abdominal aneurysms can present anytime during childhood, including infancy, and have a high likelihood of rupture. The natural history of the disease is changing with the use of precision medicine, specifically with the use of the mTOR inhibitors, to prevent progression of angiolipomas to hemorrhage and perhaps early use of antiseizure medications to prevent cognitive decline.
The following is a fictitious case.
A 6-month-old girl presented with a history of spells manifesting for 1 week prior to presentation to the physician. These episodes were characterized by a brief flexion of her neck and abduction and extension of the arms. They occurred 5 to 10 times in a cluster, many times a day, predominantly while awakening. The clusters had been gradually lengthening in duration over time. She occasionally cried after a cluster. She had stopped smiling and tracking. She no longer cooed or played with her toys.
She was born vaginally at term following an uncomplicated pregnancy. Her birth was unremarkable except for an episode of tachycardia diagnosed as Wolf-Parkinson-White syndrome. Her development had been age appropriate and the family history was unremarkable. In retrospect, the family recalled brief episodes of facial grimacing associated with right-sided head turn for a few weeks prior to the onset of the spells described above.
On exam she was nondysmorphic and alert. She did not smile, coo, or track consistently. On Wood’s light exam, she had a few hypopigmented macules on her trunk. Cranial nerve, sensory, and motor exam were normal for her age.
Brain MRI revealed cortical tubers and subependymal nodules on both T1 and T2 images. Cardiac echo revealed a rhabdomyoma. EEG revealed hypsarrhythmia. The child was initiated on vigabatrin and did well without clinical seizures for the next 4 months.
This child met the criteria for definite tuberous sclerosis complex, having 4 major criteria for diagnosis.
mTOR dysregulation is associated with most manifestations of the disease complex.
Genetics. Tuberous sclerosis complex is an autosomal-dominant disorder caused by a genetic mutation in 1 of 2 different genes. Chromosomal bands 9q34.3 and 16p13.3 are the loci for the 2 genes; they are respectively called TSC1 (tuberous sclerosis complex 1) and TSC2 (tuberous sclerosis complex 2) (40; 52). The 16p13.3 TSC2 gene, identified first, and its 5.5 kilo base TSC2 transcript encode a 200 KDa protein called tuberin. The 9q34.3 TSC1 gene, identified from a 900-kilobase region containing over 30 genes, and its 8.6 kilo base TSC1 transcript encode a 140 KDa protein called hamartin.
As of January 19, 2019, 928 unique allelic DNA variants of TSC1 and 2689 unique DNA allelic variants of TSC2 have been reported. More information is available at LOVD tuberous sclerosis database.
Pathogenic variants in TSC2 and TSC1 occur in a 2:1 ratio among tuberous sclerosis complex patients. Only 5% to 10% of patients have no mutation identified or a variant of unknown significance after assessment with ultra-deep next-generation sequencing. Some patients previously assessed to have no mutation identified often have had low level mosaic pathogenic variants or pathogenic variants in introns that affect splicing.
There are differences in the phenotypic expressions of TSC1 and TSC2 gene mutations. For instance, TSC2 mutations express a more severe phenotype – more severe renal involvement, intellectual disability, more cerebral and facial lesions, less reproductive fitness (47), and more pulmonary involvement. Complex partial seizures, focal seizures, and infantile spasms are more likely in TSC2. There does not appear to be a strict correlation between mutation and clinical phenotype. Mutation occurrence is more common in TSC2, accounting for approximately 75% to 80% of sporadic cases. About 80% of cases are caused by de novo mutation (87), with an estimated 15% or more of the individuals with tuberous sclerosis complex exhibiting somatic mosaicism and another 1% or so having germline mosaicism. Tuberous sclerosis complex could appear as sporadic disease in the general population.
Response of tumors including subependymal giant cell astrocytomas and angiomyolipomas to mTOR inhibitors is independent of mutation type and also occurs in patients with no mutation identified (79).
Cell biology and pathophysiology. The pathology of tuberous sclerosis complex reflects abnormalities in cell size, number, morphology, and location, implying multiple roles of the genes. Wild TSC2 and TSC1 function as tumor suppressor genes. With the mutation of either one, their defective product is unable to inactivate the tumor growth caused by a second random somatic cell mutation (loss of heterozygosity). The multifocal nature of tuberous sclerosis complex is best explained by the Knudson 2-hit hypothesis, where the second hit is a somatic mutation that completely abrogates TSC1-TSC2 function by accelerating the effect of the first systemic hit/mutation. Both alleles of TSC1 or TSC2 have to be inactivated for development of tumors, ie, loss of heterozygosity.
The protein products tuberin and hamartin function together with the protein product of the TBC1D7 gene in cellular signaling pathways (105; 106), forming the TSC protein complex. The TSC protein complex is purported to participate in protein translation, cell growth, proliferation, adhesion, migration, and intracellular trafficking. The TSC complex is the principal cellular inhibitor of the mechanistic target of Rapamycin (mTOR, previously called mammalian target of rapamycin) (76), while also being the sensor of cellular growth conditions. Thus, mutation of hamartin or tuberin in tuberous sclerosis complex leads to hyperactivation of the downstream mTOR pathway and the associated kinase signaling cascades and translational factors, resulting in increased cell growth and proliferation. Tuberin and hamartin are coexpressed in several cells, including kidney, brain, lung, and pancreas, and mutations in either hamartin or tuberin lead to a single disorder.
By sharing homology with a GTPase activating protein for Rap 1 and GTPase Rheb (Ras homologue enhanced in brain), the TSC complex inactivates GTP-bound Rheb (117). Active Rheb is an upstream positive modulator of mTOR (96). Therefore, a loss of function mutation in TSC1-TSC2 will enhance Rheb, activate mTOR constitutively, and critically upregulate cell growth and proliferation through p70S6kinase (64), ribosomal S6 proteins, and eukaryotic initiation factor 4E binding protein 1 (4E-BP1).
Mechanistic target of rapamycin, mTOR, exists as 2 complexes with differing functions. mTOR complex 1 (mTORC 1) with its cofactor, Raptor (regulatory associated protein of mTOR), activates mTOR’s protein kinase domain and is sensitive to rapamycin. This activation results in increased mRNA transcription and protein synthesis. TSC mutation leads to loss of inhibition of mTORC1. This causes constitutive activation of mTOR and, in turn, abnormal cellular proliferation and differentiation, producing the hamartomatous lesions of tuberous sclerosis complex. mTOR complex 2 (mTORC 2), with its cofactor Rictor (rapamycin insensitive component of mTOR), regulates protein synthesis in a manner distinct from mTORC1 and is unaffected by Rheb or rapamycin.
Loss of TSC1 or TSC2 in mature postmitotic hippocampal neurons in vitro causes enlarged somas, abnormal dendritic spines, and enhancement of glutamatergic neurotransmission. Elevated extracellular glutamate levels are assumed to contribute to excitotoxic neuronal death, abnormal glutamatergic synaptic physiology, and impaired behavioral conditioning and learning (73). It has been shown that the seizure activity often originates from the mildly hypometabolic regions adjacent to the cortical tubers rather than directly from the tuber in humans. mTOR dysregulation is also involved in tuberous sclerosis–related epileptogenesis through a range of potential mechanisms, including alteration of neuroblast migration, cortical lamination, cell body size, and dendritic arborisation, synaptic plasticity, and by altering neuronal excitability through modulation of the expression of voltage-gated potassium channels.
Risk of epilepsy and encephalopathy are associated with TSC2 genotype, TSC2 mutation, abnormal neuronal morphology, disruption of GABAergic interneuron development, abnormal astrocyte glutamate uptake, synaptic abnormalities, inflammatory changes, impaired long-term potentiation, high tuber brain proportion, and white matter abnormalities (113; 21).
Tuberous sclerosis complex occurs in 1 of 6000 to 10,000 individuals, with two thirds of cases being sporadic (77). A study in Sweden showed a peak prevalence of 1 in 6800 for individuals between 11 and 15 years of age, and 1 in 12,900 for all individuals younger than 20 years of age. The TSC2 gene is associated with the vast majority of cases, both familial and sporadic. Boys are typically more severely affected.
Tuberous sclerosis complex is of autosomal-dominant inheritance with high penetration; the risk of an affected parent having an affected child is 50%. However, occurrence of tuberous sclerosis complex in a majority is sporadic and, in part, may be because there exists high intrafamilial heterogeneity. Thus, a mildly affected asymptomatic parent is at high risk of having a child with epilepsy and severe mental retardation. The mutation rate for tuberous sclerosis complex is high, and most of the severely affected children have a new mutation. Reduced expression of the gene, non-expression, and somatic and germline mosaicism, make determination of the true rate of mutation difficult. Prenatal detection of tuberous sclerosis complex in an at-risk fetus is possible by echocardiography or ultrasonography, demonstrating cardiac rhabdomyomas or multicystic kidneys. A prenatal head MRI may be helpful after the 20th week of gestation to identify large cortical tubers.
Preimplantation and prenatal genetic tests are available and should be offered in addition to genetic counseling. Linkage studies of the entire family with affected and unaffected individuals may be done. Mutational analysis and multiplex ligation-dependent probe amplification have been used to assess genotype and phenotypic correlation.
Tuberous sclerosis complex is a systemic disorder involving multiple organs, including brain, skin, heart, lungs, and kidneys; only skeletal muscle, peripheral nerves, and craniospinal nerve roots are not involved. Consequently, the differential diagnosis of each presenting symptom or constellation of symptoms is extensive. This necessitates that tuberous sclerosis complex be considered in the differential diagnosis of many presenting problems, including seizures, developmental delay or mental retardation, autism, ADHD, hemiplegia, uremia, intra-abdominal hemorrhage, and respiratory failure. Similarly, tuberous sclerosis complex should be considered as the underlying cause of a variety of tumors that may occur in different organ systems. However, tumors that occur in tuberous sclerosis complex are typically rare in the general population and infrequently progress to malignancy. Only renal cell carcinoma occurs earlier and with greater frequency in tuberous sclerosis complex (13; 18).
All patients should have a 3-generation family history obtained to determine if additional family members are at risk of diagnosis. Genetic testing is recommended for counseling purposes or when the diagnosis of tuberous sclerosis complex is suspected but cannot be clinically confirmed. A negative genetic test result does not exclude tuberous sclerosis complex diagnosis. Patients that meet clinical criteria for tuberous sclerosis complex have the diagnosis regardless of the results of the genetic testing.
Evaluation for initial diagnosis and clinical monitoring requires attention to the following organ systems: (1) the skin, with natural or ultraviolet light, looking for facial angiofibroma, shagreen patches, fibrous cephalic plaques, periungual fibromas, and hypomelanotic spots; (2) the retina, by indirect ophthalmoscopy after mydriasis; (3) the brain, with MRI and EEG; (4) the kidneys, with MRI, assessment of glomerular filtration rate, and blood pressure; (5) the lungs, with imaging by high-resolution CT in adults, particularly women, in addition to pulmonary function tests; (6) the heart, with fetal echocardiogram if prenatal ultrasound reveals rhabdomyomas, echocardiogram in pediatric patients under 3 years of age, and routine ECGs in all patients (42); and (7) a detailed dental examination.
Studies with MR of the brain have found that T1-weighted imaging is best for identification of subependymal nodules, whereas fluid-attenuated inversion recovery pulse images are more sensitive than spin-echo sequences to cortical and subcortical tubers (53). T2-weighted images may show subcortical white matter changes, and shadows from subependymal nodules may indent the walls of the ventricles.
MR imaging demonstrates cyst-like structures that are commonly seen immediately adjacent to cortical tubers or within dysplastic lesions (107).
Newer imaging modalities are becoming available for evaluating the disease burden and for noninvasive surgical planning. They have added significantly to our knowledge of the disease. Magnetization transfer imaging (MTI) can depict more tubers and white matter anomalies than conventional spin echo images in older children and adults. Dual inversion recovery MRI has been reported to depict cortical tubers as very bright signals in comparison to high-resolution T2 or FLAIR imaging. Computational morphometry MRI has been used to objectively quantify the brain lesions in tuberous sclerosis complex. This has revealed that the highest frequency of tubers is in the frontal lobes and the highest density is in the parietal lobe. Decreased bilateral gray matter volumes and white matter tracts have been reported to correlate with memory deficits in tuberous sclerosis complex. Proton magnetic resonance spectroscopy (MRS) studies have shown a pattern of decreased N-acetylaspartate/creatine and increased myoinositol/creatine ratios in tubers, reflecting decreased neurons and increased glial cells, respectively. Evidence of hypomyelination in tuberous sclerosis complex is also reflected by the low fractional anisotropy values of the perilesional white matter. Increased apparent diffusion coefficient (ADC) value has been noted in epileptogenic tubers and hamartomas and may be used to identify the epileptogenic cortical tuber. Diffusion tensor imaging (DTI) can potentially be used to detect and define the epileptic circuitry as it evolves with chronicity and increasing severity of epilepsy. Interictal 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) scanning in tuberous sclerosis complex has detected small cortical tubers similar to FLAIR images, but with a larger area of glucose hypometabolism. It has also been shown that the seizure activity often originates from the mildly hypometabolic regions adjacent to the cortical tubers rather than directly from the tuber. Alpha[11C]methyl-L-tryptophan positron emission tomography (AMT-PET) has been used in the identification of the epileptogenic zone (68). MRI with HASTE (Half Fourier Acquisition with Single shot Turbo spin Echo) and MPRAGE (Magnetization Prepared Rapid Gradient Echo) are newer modalities used to assess for subtle evidence of cortical tubers and subependymal nodules (60).
EEG is recommended at initial diagnosis of all patients, irrespective of a history of seizures. This should be followed by a 24 hour video EEG monitoring if there are any abnormalities on routine EEG or if there are any symptoms of neuropsychiatric disease.
Genetic testing. The gold standard genetic test recommended is a TSC1/TSC2 next-generation sequencing panel, reflexed to deletion/duplication analysis of the TSC1 and TSC2 genes if the sequencing is negative (79).
Genetic testing is indicated if: (1) clinical features do not permit a definite diagnosis; and (2) there is benefit from identification of the causative mutation for screening of family members or for prenatal or preimplantation diagnosis.
Conventional genetic testing with Sanger sequencing and deletion/duplication analysis only yields a diagnosis in 75% to 90% of patients. Next-generation sequencing yields a higher yield, including cases with mosaicism and intronic variants affecting splicing.
The LOVD database can be used for clarification of pathogenic variants. Occasionally variants may only be detected in saliva or skin cells rather than blood. When an extremely low-level variant is identified, presence of the same variant should be confirmed in multiple tissue samples.
Multispecialty involvement is indicated in the management, and regional tuberous sclerosis complex clinics in the United States specialize in this. The website for the Tuberous Sclerosis Alliance is a comprehensive resource for physicians and patients alike. Consensus clinical management and surveillance recommendations for individuals with tuberous sclerosis complex have been published (62). The TOSCA registry has been established internationally to clarify the natural history and eliminate lacunae in knowledge of the disease (55).
Surveillance for epilepsy. In view of both the frequent association and potentially devastating developmental outcome of infantile spasms in tuberous sclerosis complex, diagnosis and management of infantile spasms solely based on clinical grounds has been suggested, even in the absence of classical EEG findings (97). A published meta-analysis has identified a 95% response rate in this clinical setting (44). Also, prophylactic management of patients based on early EEG changes has been shown to improve cognition and seizure control with lesser need for polypharmacy in the long run (49). Asleep and awake EEG monitoring is recommended every month for the first 6 months and then every 6 to 8 weeks, until 2 years of age, unless there are other abnormalities (24). If routine EEG is abnormal, 24-hour VEEG monitoring is recommended, especially if TAND features are present. Epileptiform discharges appear to have a 100% positive predictive value for subsequent seizures, and preceded the clinical appearance of seizures by almost 2 months in three quarters of patients in a study (114).
EPISTOP, a long-term, prospective study evaluating clinical and molecular biomarkers of epileptogenesis in a genetic model of epilepsy - tuberous sclerosis complex, was the first prospective study of epileptogenesis in human infants with tuberous sclerosis complex (92). The trial ended in October 2018 and results are awaited. Among other things the trial monitored babies using serial EEGs, with a choice to use vigabatrin on the basis of a deteriorating EEG prior to clinical seizures. Only 55% of EEGs were normal at 1 month of age. Thirty percent of infants had multifocal interictal discharges at 1 month of age. Seventy percent of all children seized between 6 and 12 months of age, with two thirds having clinical and one third manifesting subclinical seizures. Early treatment with vigabatrin was associated with normalization of EEG in 80%, significant decrease in drug related epilepsy, and normalization of cognitive abilities (49).
Drug treatment in epilepsy. Seizures are frequently refractory to treatment. While recommending both low-dose ACTH and vigabatrin, the American Academy of Neurology recommended low dose ACTH preferentially over vigabatrin as the drug of choice for short-term treatment in tuberous sclerosis complex-related infantile spasms, based on Level C studies (41). The TSC Consensus Meeting for SEGA and Epilepsy Management in 2012 (24) and the UK guidelines (01), however, recommended vigabatrin as the first drug of choice for infantile spasms and focal seizures secondary to tuberous sclerosis. Vigabatrin was approved in the United States in 2009 for the adjunctive treatment of refractory complex partial seizures and as treatment of infantile spasms (98). Literature review suggests 25 to 50 mg/kg per day may be a good starting point. Typically, 100 to 150 mg/kg per day of vigabatrin is used. Generic vigabatrin was FDA-approved in January 2019.
Approximately 1 in 3 individuals on vigabatrin suffer visual field loss, revealing a progressive “dose-adverse response” relationship. In a study, the lowest cumulative dose causing defects was 720 g, and the shortest duration of vigabatrin causing defects was 24 months (86). Patients on vigabatrin need close monitoring for visual field defects with any of the several known ocular techniques. These could include electroretinography, multifocal electroretinography, electrooculography, field-specific visual evoked potentials, and optical coherence tomography. Some of these techniques require sedation or anesthesia and certain centers have adopted regular ophthalmology evaluations instead. Visual field testing is recommended at the onset of therapy, at 3-month intervals for the first 18 months, and every 6 months afterwards. Insomnia, agitation, and constipation occur in fewer patients.
In some centers, valproate or topiramate have been added to vigabatrin if the spasms were refractory to monotherapy with vigabatrin. ACTH, parenterally as a gel, and oral prednisone have been used in management of infantile spasms. There has been an inordinate increase in the cost of ACTH since 2008, preventing its use in many cases.
There is no head-to-head study for the preferred antiepileptic medication for localization-related epilepsy. Several medications are used, and polypharmacy is common. GABAergic medications are suggested including topiramate, carbamazepine, and oxcarbazepine (23). Studies suggest that carbohydrate restriction alone (ie, modified Atkin’s® or low glycemic index diet) may have similar benefits to that of the classical ketogenic diet.
Ketogenic diet is recommended in early childhood refractory epilepsy even in conjunction with vigabatrin (26). Growing evidence suggests that mTOR inhibitors may be helpful in the management of epilepsy for patients with tuberous sclerosis complex and may lead to improvement in cognition. These include rapamycin (sirolimus), everolimus, and temsirolimus, a prodrug for sirolimus. These agents work by dissociating mTORC1 from its cofactor Raptor, thereby inactivating it. The results of a randomized, multicenter, placebo-controlled phase 3 study of adjunctive everolimus in 366 individuals for refractory focal epilepsy in tuberous sclerosis complex (EXIST-3) revealed that both low dose and higher dose everolimus led to the primary endpoint of 50% reduction in seizure frequency (p < 0.008, and p < 0.001) in comparison to placebo (39). Percentage reduction of seizure frequency was also statistically significant. The greatest response was in the group with children younger than 6-years-old, in contrast to other older ages. The extension of the randomized control trial to 48 weeks duration involved 361 of the 366 patients receiving the everolimus from 18 weeks to over 2 years. A trough range of 3 to 15 ng/ml of the everolimus was the goal. Responses improved with time, with a response rate of at least a 50% reduction in seizure frequency reaching greater than 40% at 2 years (Franz et al 2018).
An open-label study of everolimus in patients with refractory epilepsy over 48 months revealed similar findings (63). The PREVENT trial commenced in December 2016 in the U.S. to assess cognitive and developmental effects of early treatment with vigabatrin in infants with tuberous sclerosis complex who have not yet developed seizures and to evaluate the preventive effect of vigabatrin. Results are expected in May 2020. With the proven benefit in Lennox-Gastaut syndrome of various etiologies, cannabidiols are being studied as antiepileptic management in tuberous sclerosis complex.
Everolimus was approved by the FDA for the adjunctive treatment of refractory partial onset seizures in tuberous sclerosis complex if 2 antiseizure drugs have been ineffective in children more than 2-years-old.
Surgery in epilepsy. Patients with focal seizures should be considered for epilepsy surgery (06), promptly if 2 medications have failed. The source of the seizures can be identified and resected even if other tubers or diffuse EEG abnormalities are present. In patients with unlocalized epilepsy patterns, seizure control may be obtained by corpus callosotomy (57). Surgical treatment of patients with tuberous sclerosis complex and intractable epilepsy is most effective when a single tuber or epileptogenic area can be identified. Early epilepsy surgery has been advocated as a means for better prognosis in intractable epilepsy (115). A study revealed that the long-term outcomes of seizure freedom and neuropsychiatric abilities were improved with earlier surgery, early achievement of seizure freedom, and better presurgical cognitive abilities (67).
Surveillance and management of subependymal giant cell astrocytomas (SEGAs). SEGAs need to be managed with serial MRI every 1 to 3 years in the first 2 decades of life, even if they are asymptomatic. Monitoring every 6 months is recommended for SEGAs greater than 1 cm in size. Neuroimaging should be continued beyond 25 years in patients with evidence of SEGAs prior to 25 years of age, but the frequency can be decreased beyond this period (62). Signs of increased intracranial pressure, positional headache, irritability, and loss of seizure control should be recognized as possible indicators of a symptomatic subependymal giant cell astrocytoma and urgent neuroimaging should be performed in such an instance.
Gross total resection is the procedure of choice for management and is usually curative (50). However, if the tumor cannot be completely resected or if regrowth occurs, or if SEGAs are multiple or infiltrative, rapamycin or everolimus are indicated in management. Surgery is indicated for asymptomatic SEGAs as well, if there is ventriculomegaly, or increase in size of the lesion on imaging. Everolimus can be considered as an alternative in this situation. Regrowth is known to occur on discontinuation of mTOR inhibitors (61). Everolimus was approved by the FDA in 2010 for SEGA management.
Everolimus has been used in children as young as 12 months of age with excellent benefit in SEGA size and seizure control (EXIST-1 trial) (59). An extension prospective study over 4 years confirmed the sustained efficacy of everolimus in reducing SEGA tumor burden. Almost 60% of patients who received treatment for 4 years exhibited a clinically relevant (30%) reduction in their primary SEGA (36). The EMINENTS study, performed in a small cohort of patients, revealed that a smaller and less frequent dosage of everolimus may be a reasonable maintenance protocol once the standard protocol of daily everolimus to maintain a serum level of 5 to 15 ng/ml is used with good efficacy in SEGA patients for at least a year (100).
Tuberous sclerosis–associated neuropsychiatric disorders (TAND). Early psycho-educational or neuropsychological assessment is important to identify problems in cognitive development and to develop appropriate teaching strategies. Problems with inattention, hyperactivity, aggression, or autistic features may necessitate psychological or psychiatric consultation. The transition from special education resources in the classroom to vocational rehabilitation opportunities in young adulthood should be carefully monitored (30). Periodic assessment is advised at each developmental age in childhood to tailor appropriate support services through the school, and psychosocially. The following timeline is recommended (31):
• Perform screening for TAND features at least annually.
• Perform comprehensive formal evaluation for TAND at key developmental points: infancy (0-3 years), preschool (3-6 years), pre-middle school (6-9 years), adolescence (12-16 years), early adulthood (18-25 years), and as needed thereafter.
Abrupt behavioral changes in patients should precipitate an evaluation for SEGA, metabolic and toxic etiologies, subclinical status epilepticus, and renal failure. A TAND checklist has been validated under a pilot study. It has been suggested as a starting point to address the significant burden of disease associated with tuberous sclerosis in a scheduled and organized manner (65). Several current clinical trials are looking to assess the benefit of mTORC1 inhibition on behavioral and cognitive outcomes: (1) Trial of RAD001 and neurocognition in tuberous sclerosis complex (NCT01289912); (2) TRON (NCT01954693), interventional everolimus vs. placebo in the treatment of neuropsychological deficits; (3) RAPT (NCT01929642), everolimus and sirolimus in children with tuberous sclerosis and self-injurious behavior; and (4) RAPIT (NCT01730209), efficacy of everolimus in the treatment of autism and neuropsychological deficits in children with intellectual disability (25). The first 3 of these studies are complete and the results are awaited. Direct cognitive benefits have not been proven at this juncture. An excellent review on TAND is available (32).
Surveillance and management of renal complications. Blood pressure and renal function (with glomerular filtration rate) have to be monitored annually. Measurement of serum cystatin C concentration can be used to evaluate glomerular filtration rate. It is critical to manage the severe hypertension associated with renal cysts appropriately, as surgical decompression alone to relieve parenchymal compression is inadequate. Caution must be exercised in use of ACTH/prednisone in the above setting, especially with coexistent polycystic kidney disease. A renin-aldosterone-angiotensin system inhibitor is advised as first line therapy. Angiotensin converting enzyme inhibitors should be avoided in patients on mTOR inhibitors. Zonisamide and topiramate used as antiepileptics increase risk of nephrolithiasis.
It is recommended that newly diagnosed cases of tuberous sclerosis have renal MRI scanning for early detection of polycystic kidney disease associated with contiguous gene deletions spanning the TSC2/PKD1 genes. Lifelong renal MRI is recommended every 1 to 3 years in all age groups because renal angiomyolipomas may enlarge rapidly, even in children, and recur (34). Immunologic staining for HMB-45 for angiomyolipomas and cytokeratin for renal cell carcinoma is recommended as fat-poor angiomyolipomas can be hard to discern from renal cell carcinomas on imaging.
A large, double-blind, placebo-controlled multicenter trial (EXIST-2) revealed clear benefit from everolimus in angiomyolipomas and sporadic lymphangioleiomyomatosis (10). The 4-year update of the open-label extension trial was positive as well, with consistent response and safety (11). An open-label long-term extension of the EXIST-1 trial revealed that 73.2% of 41 patients achieved a renal angiomyolipoma response (36). Pediatric patients being treated for SEGAs were analyzed for angiomyolipoma response in the EXIST-1 study. More than 75% of patients had a greater than 50% reduction in sum volume of the angiomyolipomata from baseline, with sustained reductions over nearly 4 years of treatment (08).
Tuberous sclerosis complex consensus guidelines are that asymptomatic, rapidly growing renal angiomyolipomas greater than 3 cm in diameter and those greater than 4 cm in diameter should be treated with an mTOR inhibitor.
Everolimus was approved for renal angiomyolipomas by the FDA in 2012. Large renal angiomyolipomas can be managed by embolization or nephron-sparing surgery. The success of transarterial therapeutic embolization, even in angiomyolipomas as large as 4cm or greater (33; 58), makes surgery a less preferred option, especially for central lesions.
Patients with renal or pulmonary failure require meticulous medical care and may be candidates for organ transplant.
Surveillance and management of pulmonary complications. An important recommendation is that women with tuberous sclerosis complex have a noncontrast, high-resolution chest CT once at 18 years of age, then every 5 to 10 years if asymptomatic, and at any time if inexplicable or persistent respiratory symptoms occur (62). A single CT image slice at the level of the carina has been suggested by some experts as a reasonable screening method with low radiation exposure (20).
A baseline pulmonary function test is indicated in women at age 18. Annual pulmonary function tests and high-resolution computed tomography every 2 to 3 years are also indicated in patients with lymphangioleiomyomatosis and lung cysts.
A serum vascular endothelial growth factor type D (VEGF-D) level may be helpful to establish a baseline for future lymphangioleiomyomatosis development or progression.
Counseling on smoking risks and estrogen use in oral contraceptive preparations, which can compound the impact of lymphangioleiomyomatosis, should also occur. Talc pleurodesis and pleurectomy are avoided in patients who are candidates for lung transplantation in the future. Patients should be vaccinated for influenza and pneumococcus (37).
Everolimus has been proven to be effective in a large trial for sporadic lymphangioleiomyomatosis (10).
Lymphangioleiomyomatosis-associated chylous pleural effusions have been shown to decrease or even resolve with sirolimus therapy. Also, pulmonary function seems to stabilize or improve with sirolimus treatment of lymphangioleiomyomatosis, and this response seems to be durable for at least 2 years (95). The U.S. Food and Drug Administration approved mTOR inhibitors for lung issues in tuberous sclerosis complex patients in 2015.
Management of cardiac complications. In patients with asymptomatic rhabdomyomas, a follow-up echocardiogram should be performed every 1 to 3 years until regression of the rhabdomyomas is documented. In addition to a baseline 12-lead ECG, an ECG is recommended at minimum every 3 to 5 years to monitor for conduction defects. Cardiac symptoms including congestive cardiac failure and arrhythmias may require symptomatic treatment, including medications, ablative procedures, pacemakers, resective surgery for obstructive tumors and, rarely, heart transplant (28). Screening abdominal sonography and chest radiography should be performed every 2 to 3 years before puberty and every year after puberty, for vascular aneurysms (48).
Management of ophthalmological complications. In patients with symptomatic retinal hamartomas with persistent and recurrent vitreous hemorrhage, pars plana vitrectomy is a therapeutic strategy (71). Surveillance of lesion growth by periodic imaging has been advised, although no conclusive guidelines exist yet. Annual eye examination is advised in asymptomatic patients.
Management of dermatological manifestations. The TREATMENT trial randomized patients to 1% rapamycin, 0.1% rapamycin, and vehicle alone in ages 3 through 61 years. There was clinical response to both doses of rapamycin on the angiofibroma grading scale. Highest benefit was within 6 months of initiation of treatment (56). Other studies have evaluated sirolimus as well, and in children were noted to respond better than adults, perhaps due to lesser size and fibrosis (66; 110). Various surgical methods of management are also available. Annual skin survey is recommended to assess for symptomatic or rapidly changing lesions.
Management of dental manifestations. Dental assessments are advised every 3 to 6 months, and panoramic x-rays should be performed by 7 years of age, if not performed previously.
Pancreatic tumors are treatable and can be easily recognized through annual abdominal MRIs. They were a preventable cause of death in a mortality study (02).
mTOR inhibitors. Everolimus is the only orally available mTOR inhibitor, which is typically titrated up from a dose of 4.5 mg/m2 body surface area to achieve a drug level in the range of 5 to 15 ng/ml. Rapamycin or sirolimus is available for parenteral and topical use. The most common side effects on mTOR inhibitors are stomatitis and upper respiratory tract infections. Other side effects include rash, gastrointestinal symptoms, increased total cholesterol, decreased fibrinogen levels, decreased white blood cell counts, anorexia, and urinary tract infections. Death and pneumonia were recorded as adverse effects of everolimus, attributed to decreased immune function. The overall mortality rate was rather high (0.7%) in the EXIST-3 extension trial, attributed to immune suppression. A publication has practical information for the management of side effects of mTOR inhibitors (27). A Cochrane review on rapalogs has been published (91).
Death is most likely due to renal causes. Epilepsy and SUDEP (sudden unexpected death in epilepsy) are important causes of death as well. Pulmonary lesions are causes as well. Renal cysts may be associated with renal failure, and renal angiomyolipoma may cause occasional massive intra-abdominal bleeding.
Seizures are harder to control, with more than two thirds of patients having intractable epilepsy in comparison to the general population. Seizures persist in about 40% of surgically treated patients (16). Unfavorable prognostic factors for epilepsy include onset in infancy, presence of several seizure types, multifocal electroencephalogram (EEG) discharges when awake that generalize in sleep and/or secondary bilateral synchrony, and occurrence of new EEG foci during evolution of the disease (22).
Prognostic markers of intellectual disability include cortical tubers in the frontal and temporal regions (85), cerebellar tubers, TSC2 mutations, and refractory seizures. Infantile spasms and early age of epilepsy onset also correlate with poor cognition. A longitudinal observational study conducted by the TACERN (TSC Autism Center of Excellence Network) study group supports some of these historical observations (17).
Obstructive hydrocephalus caused by a subependymal giant cell astrocytoma was an important cause of death before contemporary neuroimaging and neurosurgical techniques.
Bleeding within a subependymal giant cell astrocytoma is a rare complication that may be fatal.
Complications during pregnancy relate chiefly to renal disease and the risk of rupture of renal angiomyolipoma vessels (81; 54). There is a greater risk of pneumothorax and chylous effusion during pregnancy. Renal failure, preeclampsia, and severe intrauterine growth retardation may also occur. Renal ultrasonography or CT is recommended in pregnant patients to evaluate renal function.
Special precautions for general anesthesia are related to CNS involvement by tumors (subependymal giant cell astrocytomas) causing intracranial hypertension or status epilepticus, to the kidneys causing renal failure, to the lungs causing respiratory failure, to the great vessels with aneurysm that may rupture, or to the heart with cardiac arrhythmia.
Bernard L Maria MD
Dr. Maria of Thomas Jefferson University has no relevant financial relationships to disclose.See Profile
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