E. Steve Roach

Management of Stroke in Infants and Children: A Scientific Statement From a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young

PURPOSE The purpose of this statement is to review the literature on childhood stroke and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are responsible for diagnosing and treating infants, children, and adolescents with cerebrovascular disease. METHODS The Writing Group members were appointed by the American Heart Association Stroke Councils Scientific Statement Oversight Committee. The panel included members with several different areas of expertise. Each of the panels recommendations was weighted by applying the American Heart Association Stroke Councils Levels of Evidence grading algorithm. After being reviewed by panel members, the manuscript was reviewed by 4 expert peer reviewers and by members of the Stroke Council Leadership Committee and was approved by the American Heart Association Science Advisory and Coordinating Committee. We anticipate that this statement will need to be updated in 4 years. RESULTS Evidence-based recommendations are provided for the prevention of ischemic stroke caused by sickle cell disease, moyamoya disease, cervicocephalic arterial dissection, and cardiogenic embolism. Recommendations on the evaluation and management of hemorrhagic stroke also are provided. Protocols for dosing of heparin and warfarin in children are suggested. Also included are recommendations on the evaluation and management of perinatal stroke and cerebral sinovenous thrombosis in children.

RENAL LESION GROWTH IN CHILDREN WITH TUBEROUS SCLEROSIS COMPLEX

PURPOSE Renal lesions, including angiomyolipoma, renal cysts (simple and polycystic kidney disease) and renal cell carcinoma, develop in patients with tuberous sclerosis complex. While there is limited information that these lesions may grow in adults with tuberous sclerosis complex, the incidence, characterization and growth rate in children have not been reported. Also, the age at which these lesions first appear, thus providing insight into their natural history, is unknown. We present our data from a longitudinal renal surveillance study of children with tuberous sclerosis complex. MATERIALS AND METHODS Since 1985 children with tuberous sclerosis complex at our hospital have undergone periodic renal imaging by ultrasonography or computerized tomography to monitor renal lesions. A total of 35 girls and 25 boys 1 to 18 years old have undergone at least 2 or more annual renal ultrasounds. RESULTS On initial evaluation 33 of 60 children (55%) (mean age 6.9 years) had an identifiable renal lesion, which increased to 48 of 60 (80%) at followup (mean age 10.5 years). Angiomyolipoma was the most frequent lesion (75%) followed by simple renal cysts (17%). Angiomyolipomas increased in size and/or number in 10 of 18 boys (56%) and 18 of 27 girls (66%). The largest growth rate in 1 year was from 0 to 4 cm. and from 5 to 9 cm. in diameter. The youngest patient demonstrated lesions at age 2 years. The average age at which a normal ultrasound became abnormal was 7.2 years. While a total of 27 patients had a normal ultrasound on entering the study, lesions had developed in 15 at followup (11 with angiomyolipomas, 4 with cysts). Five patients had cysts that had disappeared at followup. A 7-year-old boy had a 9 cm. renal cell carcinoma removed. One patient has renal lesions characteristic of autosomal dominant polycystic kidney disease. CONCLUSIONS Renal involvement in patients with tuberous sclerosis complex begins in infancy, and angiomyolipoma is the most common lesion (75%). Angiomyolipomas are more likely to grow than remain stable, although the rate of growth varies. Simple renal cysts may appear or disappear with time but angiomyolipomas do not disappear. An initially normal renal ultrasound does not rule out future development of lesions. Periodic surveillance is indicated in children with tuberous sclerosis complex.

Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.

Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder marked by hamartoma growth in multiple organ systems. We performed mutational analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. We identified mutations in 72% (199/257) of de novo and 77% (53/68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in two previous large studies. We showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. We also observed results consistent with two similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. On performing meta-analyses of our data and the other two largest studies in the literature, we found significant correlations for several features that individual studies did not have sufficient power to conclude. Male patients showed more frequent neurologic and eye symptoms, renal cysts, and ungual fibromas. Correlating genotypes with phenotypes should facilitate the disease management of tuberous sclerosis complex.

Diagnosis of tuberous sclerosis complex.

Tuberous sclerosis complex is a dominantly inherited disorder affecting multiple organs; because of its phenotypic variability, the diagnosis of tuberous sclerosis complex can be difficult in the young or in individuals with subtle findings. Recently revised consensus diagnostic criteria for tuberous sclerosis complex reflect an improved understanding of its clinical manifestations and its genetic and molecular mechanisms. The diagnostic criteria are based on the premise that there are probably no truly pathognomonic clinical signs for tuberous sclerosis complex; signs that were once regarded as specific occur as isolated findings in individuals with no other clinical or genetic evidence of tuberous sclerosis complex. Consequently, the revised criteria require tuberous sclerosis complex—associated lesions of two or more organ systems or at least two dissimilar lesions of the same organ to confirm the diagnosis. The addition of DNA testing complements clinical diagnosis and allows more precise genetic counseling and, in some individuals, prenatal diagnosis. Nevertheless, the 15% false-negative rate for DNA testing and the occurrence of germline mosaicism in about 2% of individuals with tuberous sclerosis complex make it difficult to exclude the diagnosis of tuberous sclerosis complex in family members. (J Child Neurol 2004; 19:643-649).

Germ-Line Mutational Analysis of the TSC2 Gene in 90 Tuberous-Sclerosis Patients

Ninety patients with tuberous-sclerosis complex (TSC) were tested for subtle mutations in the TSC2 gene, by means of single-strand conformational analysis (SSCA) of genomic DNA. Patients included 56 sporadic cases and 34 familial probands. For all patients, SSCA was performed for each of the 41 exons of the TSC2 gene. We identified 32 SSCA changes, 22 disease-causing mutations, and 10 polymorphic variants. Interestingly, we detected mutations at a much higher frequency in the sporadic cases (32%) than in the multiplex families (9%). Among the eight families for which linkage to the TSC2 region had been determined, only one mutation was found. Mutations were distributed equally across the gene; they included 5 deletions, 3 insertions, 10 missense mutations, 2 nonsense mutations, and 2 tandem duplications. We did not detect an increase in mutations either in the GTPase-activating protein (GAP)-related domains of TSC2 or in the activating domains that have been identified in rat tuberin. We did not detect any mutations in the exons (25 and 31) that are spliced out in the isoforms. There was no evidence for correspondence between variability of phenotype and type of mutation (missense versus early termination). Diagnostic testing will be difficult because of the genetic heterogeneity of TSC (which has at least two causative genes: TSC1 and TSC2), the large size of the TSC2 gene, and the variety of mutations. More than half of the mutations that we identified (missense, small in-frame deletion, and tandem duplication) are not amenable to the mutation-detection methods, such as protein-truncation testing, that are commonly employed for genes that encode proteins with tumor-suppressor function.

Nontraumatic Brain Hemorrhage in Children: Etiology and Presentation

The clinical and radiographic findings of 68 children and adolescents with nontraumatic intraparenchymal brain hemorrhage were analyzed retrospectively. There were 43 boys and 25 girls, and the average age was 7.1 years (range, 3 months to 18 years). The most common presenting symptom was a combination of headache or vomiting (40 cases, or 58.8%). Hemiparesis was the major presenting sign in 11 (16.2%) of the children, seizures occurred in 25 (36.8%) patients, and 6 (8.8%) children were irritable. Only 2 (2.9%) children were comatose at presentation. One or more risk factors for hemorrhage were found in 61 (89.7%) of 68 children. A third (23 cases, or 33.8%) had an arteriovenous malformation or fistula; altogether 29 (42.6%) children had some type of congenital vascular anomaly. Hematologic or coagulation disorders were present in 22 (32.4%) patients, and 9 (13.2%) patients had brain tumors. Hemorrhage could not be attributed to systemic hypertension in any child. The likelihood of establishing the cause of bleeding was greater when evaluation included cerebral angiography (97.3% versus 80.4% without angiography). Half (34 cases, or 50.0%) of the patients regained normal neurologic function. Six (8.8%) patients died, either directly or partly as a consequence of the hemorrhage. The remaining patients had various neurologic sequelae, including 17 (25.0%) with hemiparesis, 5 (7.4%) with aphasia, 7 (10.3%) with epileptic seizures, and 3 (4.4%) with hydrocephalus. More detailed follow-up studies are needed to obtain more information about the frequency of cognitive sequelae. (J Child Neurol 2000;15:284-289).

Germ-Line Mosaicism in Tuberous Sclerosis: How Common?

Two-thirds of cases of tuberous sclerosis complex (TSC) are sporadic and usually are attributed to new mutations, but unaffected parents sometimes have more than one affected child. We sought to determine how many of these cases represent germ-line mosaicism, as has been reported for other genetic diseases. In our sample of 120 families with TSC, 7 families had two affected children and clinically unaffected parents. These families were tested for mutations in the TSC1 and TSC2 genes, by Southern blotting and by single-strand conformational analysis. Unique variants were detected in six families. Each variant was present and identical in both affected children of a family but was absent in both parents and the unaffected siblings. Sequencing of the variants yielded two frameshift mutations, one missense mutation, and two nonsense mutations in TSC2 and one nonsense mutation in TSC1. To determine which parent contributed the affected gametes, the families were analyzed for linkage to TSC1 and TSC2, by construction of haplotypes with markers flanking the two genes. Linkage analysis and loss-of-heterozygosity studies indicated maternal origin in three families, paternal origin in one family, and either being possible in two families. To evaluate the possibility of low-level somatic mosaicism for TSC, DNA from lymphocytes of members of the six families were tested by allele-specific PCR. In all the families, the mutant allele was detected only in the known affected individuals. We conclude that germ-line mosaicism was present in five families with mutations in the TSC2 gene and in one family with the causative mutation in the TSC1 gene. The results have implications for genetic counseling of families with seemingly sporadic TSC.

Towards a Consensus-Based Classification of Childhood Arterial Ischemic Stroke

Background and Purpose— The implementation of uniform nomenclature and classification in adult arterial ischemic stroke (AIS) has been critical for defining outcomes and recurrence risks according to etiology and in developing risk-stratified treatments. In contrast, current classification and nomenclature in childhood AIS are often overlapping or contradictory. Our purpose was to develop a comprehensive consensus-based classification system for childhood AIS. Methods— Using a modified-Delphi method, members of the International Pediatric Stroke Study (IPSS) developed the Childhood AIS Standardized Classification And Diagnostic Evaluation (CASCADE) criteria. Two groups of pediatric stroke specialists from the IPSS classified 7 test cases using 2 methods each: (1) classification typical of the individual clinicians current clinical practice; and (2) classification based on the CASCADE criteria. Group 1 underwent in-person training in the utilization of the CASCADE criteria. Group 2 classified the same cases via an online survey, including definitions but without training. Inter-rater reliability (IRR) was assessed via multi-rater unweighted &kgr;-statistic. Results— In Group 1 (with training), IRR was improved using CASCADE criteria (&kgr;=0.78, 95% CI=[0.49, 0.94]), compared with typical clinical practice (&kgr;=0.40, 95% CI=[0.11, 0.60]). In Group 2 (without training), IRR was lower than among trained raters (&kgr;=0.61, 95% CI=[0.29, 0.77]), but higher than current practice (&kgr;=0.23, 95% CI=[0.03, 0.36]). Conclusions— A new, consensus-based classification system for childhood AIS, the CASCADE criteria, can be used to classify cases with good IRR. These preliminary findings suggest that the CASCADE criteria may be particularity useful in the setting of prospective multicenter studies in childhood-onset AIS, where standardized training of investigators is feasible.

Complete Inactivation of the TSC2 Gene Leads to Formation of Hamartomas

The work was supported by National Institutes of Health grant R29NS32300-05 and by a National Tuberous Sclerosis Association Senior Investigator Award (97-4) to H.N.

The tuberous sclerosis complex: a comprehensive review

Tuberous sclerosis was first reported by von Recklinghausen in 1862 and named by Bourneville in 1880. Transmission is autosomal dominant, but roughly 65% to 85% of the patients arise via spontaneous mutation. The incidence of tuberous sclerosis is estimated between 1:6,000 and 1:10,000 individuals. The notion of the “classic triad” of epilepsy, mental retardation, and facial angiofibromata (adenoma sebaceum) has been frequently cited in literature. However, few affected individuals develop all of the aforementioned signs, and emphasis of these limited features is misleading. It seems more appropriate to recognize that tuberous sclerosis complex may present as a wide spectrum of disease. The diagnostic criteria for Tuberous Sclerosis Complex were revised by a subcommittee at the recent Tuberous Sclerosis Consensus Conference. These clinical diagnostic criteria are outlined in Table 1. Pathologically, tuberous sclerosis is a disorder of cellular migration, proliferation, and differentiation. Manifestations may be systemic and variable. A variety of associated lesions have been reported in the literature including subependymal brain nodules and calcifications, astrocytomas, retinal phacomas, sclerotic bone lesions, dental enamel pitting, and hamartomatous or cystic lesions of the brain, heart, lungs, kidneys, spleen, liver, uterus, and soft tissues. Although many of the clinical manifestations of tuberous sclerosis are secondary to hamartomatous growths, true neoplasms do occur, particularly in the kidneys and brain. Depending on the degree of clinical expression and organ involvement specifically, select patients may experience significant morbidity and mortality. Advances in genetics, imaging modalities, medical therapies, and surgical techniques have unmasked some of the mysteries surrounding this fascinating disorder and, undoubtedly, will continue to affect the associated complications.