Outcome of childhood-onset epilepsy from adolescence to adulthood: Transition issues.

This is the second of three papers that summarize the second symposium on Transition in Epilepsies held in Paris in June 2016. This paper addresses the outcome for some particularly challenging childhood-onset epileptic disorders with the goal of recommending the best approach to transition. We have grouped these disorders in five categories with a few examples for each. The first group includes disorders presenting in childhood that may have late- or adult-onset epilepsy (metabolic and mitochondrial disorders). The second group includes disorders with changing problems in adulthood (tuberous sclerosis complex, Rett syndrome, Dravet syndrome, and autism). A third group includes epilepsies that change with age (Childhood Absence Epilepsy, Juvenile Myoclonic Epilepsy, West Syndrome, and Lennox-Gastaut syndrome). A fourth group consists of epilepsies that vary in symptoms and severity depending on the age of onset (autoimmune encephalitis, Rasmussen's syndrome). A fifth group has epilepsy from structural causes that are less likely to evolve in adulthood. Finally we have included a discussion about the risk of later adulthood cerebrovascular disease and dementia following childhood-onset epilepsy. A detailed knowledge of each of these disorders should assist the process of transition to be certain that attention is paid to the most important age-related symptoms and concerns.

Tuberous sclerosis complex without tubers and subependymal nodules: a phenotype-genotype study.

Tuberous sclerosis complex (TSC) is caused by a mutation in the TSC1 or TSC2 genes. However, 15% of patients have no mutation identified. Tubers and subependymal nodules (SENs) are the typical brain lesions in TSC and are present in 90-95% of patients. The objective of this study is to characterize the specific genotype-phenotype of patients without these lesions. We analyzed the features of 11 patients without typical TSC neuroanatomic features. Ten had TSC1/TSC2 mutational analysis, which was negative. Clinically they had lesions thought to be of neural crest (NC) origin, such as hypomelanotic macules, facial angiofibromas, cardiac rhabdomyomas, angiomyolipomas, and lymphangioleiomyomatosis. We hypothesize that patients without tubers and SENs reflect mosaicism caused by a mutation in TSC1 or TSC2 in a NC cell during embryonic development. This may explain the negative results in TSC1 and TSC2 testing in DNA from peripheral leukocytes.

Hepatic manifestations of tuberous sclerosis complex: a genotypic and phenotypic analysis.

Hepatic manifestations of tuberous sclerosis complex: a genotypic and phenotypic analysis. A retrospective review of the clinical records and radiological images of 205 patients with tuberous sclerosis complex (TSC) was performed to evaluate the prevalence and progression of hepatic lesions; examine the association of hepatic phenotype with genotype, age, and gender; and investigate the relationships between hepatic, renal, and pulmonary involvement. Hepatic angiomyolipomas (AML), cysts, and other benign lesions were identified in 30% of the cohort, and some lesions grew significantly over time. However, no patient had clinical symptoms or complications from hepatic lesions. TSC2 patients exhibited a higher frequency of AML compared to TSC1 patients (p = 0.037), and patients with no mutation identified exhibited a higher frequency of cysts compared to TSC2 patients (p = 0.023). Age was positively correlated with frequency of hepatic involvement (p < 0.001), whereas hepatic phenotype was independent of gender. Presence of hepatic AML was associated with presence of renal AML (p = 0.001). These findings confirm a high rate of asymptomatic hepatic lesions in TSC and further characterize the TSC phenotype.

Pancreatic neuroendocrine tumors in patients with tuberous sclerosis complex.

We explored pancreatic neuroendocrine tumors (PanNETs) associated with tuberous sclerosis complex (TSC) to determine their incidence in the TSC population; define their clinical, radiological, and pathological characteristics; and investigate their association with underlying genotypes. Retrospectively reviewed abdominal imaging of 219 patients with TSC, evaluating the incidence, size, and architecture of pancreatic lesions. Pathology records at Massachusetts General Hospital (MGH) were reviewed for all PanNET diagnoses in patients with TSC. Literature was reviewed for TSC-related PanNET cases. Nine patients with TSC were found to have a pancreatic lesion(s) on abdominal imaging and six patients have been diagnosed with a PanNET by pathology at MGH. Twelve cases of TSC-associated PanNETs have been reported in the literature. Of these 18 PanNET cases, one third were cystic, and the average age at resection was 26 years. Germline TSC2 mutations were found in all patients for whom genetic data were available (n = 3). We did not identify pancreatic angiomyolipomas in this series. Our results suggest that PanNETs are the most common pancreatic lesion in patients with TSC. Focal pancreatic mass lesions, solid or cystic, in patients with TSC should be considered possible PanNETs, and resection of the lesion may be clinically indicated.

Growth Curves of Subependymal Giant Cell Tumors in Tuberous Sclerosis Complex.

BACKGROUND AND PURPOSE: Growth of subependymal giant cell tumor and subependymal nodules has not been well-characterized. The purpose of this study was to determine whether growth curves can differentiate subependymal giant cell tumors from subependymal nodules. MATERIALS AND METHODS: Brain MR imaging of patients with tuberous sclerosis complex were retrospectively reviewed from 2002 to 2018. All lesions in the region of the foramen of Monro were measured. Lesions were categorized on the basis of maximal diameter at the most recent scan: small lesions (<1 cm), indeterminate lesions (>1 cm), and resected lesions (>1 cm and surgically resected). Growth velocity and acceleration on serial imaging were analyzed, and growth rates were calculated between 0 and 20 years of age and compared among the 3 categories. RESULTS: Forty-one patients were analyzed. The average age at the earliest scan was 5.9 (SD = 5.7) years. One hundred twenty-six small, 27 indeterminate, and 10 resected lesions were measured. Subependymal giant cell tumors grew faster than indeterminate lesions between 6 and 15 years of age. Indeterminate lesions grew faster than small lesions at 0-10 years of age. Resected lesions showed increased velocity and acceleration of growth compared with indeterminate lesions and small lesions on serial imaging. CONCLUSIONS: Growth differentiates subependymal nodules and subependymal giant cell tumors within the first 20 years of life, and the use of velocity and acceleration of growth may refine the diagnostic criteria of subependymal giant cell tumors. Additionally, 6-15 years of age may be an important period to monitor subependymal giant cell tumors at the foramen of Monro because increased growth may help to identify subependymal giant cell tumors that will continue to grow and result in obstructive hydrocephalus.

TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a prominent finding in the setting of tuberous sclerosis complex (TSC). OBJECTIVE: The present study was designed to compare cystic lung changes consistent with LAM in patients with a TSC1 disease-causing mutation, TSC2 disease-causing mutation, or no mutation identified (NMI). METHODS AND RESULTS: We conducted a retrospective review of the chest computed tomography (CT) of 45 female and 20 male patients with TSC and found cysts consistent with LAM in 22 (49%) women and two (10%) men. In the female population, changes consistent with LAM were observed in six of 15 (40%) patients with TSC1, 11 of 23 (48%) with TSC2, and five of seven (71%) with NMI. While the predominant size of cysts did not differ across these three groups, TSC2 women with LAM had a significantly greater number of cysts than did TSC1 patients (p = 0.010). CONCLUSIONS: These findings suggest a higher rate of LAM in TSC1 than previously recognised, as well as a fundamental difference in CT presentation between TSC1 and TSC2.

Juvenile cataract in association with tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by benign hamartomas occurring in multiple organ systems including the brain, kidneys, heart, lungs, liver, skin, and the eyes. Typical retinal findings associated with TSC include astrocytic hamartoma and achromic patch. While rare cases of cataract occurring in the setting of TSC have been reported, this is the first analysis of a large series of individuals with TSC that aims to quantify the frequency of this finding and to describe its clinical and genetic associations. MATERIALS AND METHODS: This is a retrospective chart review of 244 patients from the Herscot Center for Tuberous Sclerosis Complex at the Massachusetts General Hospital who underwent complete ophthalmic examination. We describe the clinical and genetic findings in five individuals with TSC and juvenile cataract. RESULTS: Four of five cases (80%) were unilateral. The cataract was described as having an anterior subcapsular component in 3 of 5 cases (60%). Three individuals (60%) underwent lensectomy with intraocular lens (IOL) implant and two individuals (40%) were observed. Genetic testing revealed a known disease-causing mutation in TSC2 in 100% of cases. CONCLUSIONS: Recent evidence suggests that mTOR signaling may play a role in cataract formation which could explain the relatively high incidence of juvenile cataract in this population. Juvenile cataract is a potentially under-recognized ocular manifestation of TSC.

Distinct clinical characteristics of tuberous sclerosis complex patients with no mutation identified.

Tuberous Sclerosis Complex (TSC) is a multi-system disorder that is highly variable in its clinical presentation. Current molecular diagnostic methods permit identification of mutations in either TSC1 or TSC2 in 75-85% of TSC patients. Here we examine the clinical characteristics of those TSC patients who have no mutation identified (NMI). A retrospective review of our patient population that had comprehensive testing for mutations in TSC1/TSC2 identified 23/157 (15%) that were NMI. NMI patients had a lower incidence of brain findings on imaging studies, neurological features, and renal findings than those with TSC2 mutations. In contrast, NMI patients had a lower incidence of seizures than TSC patients with TSC1 mutations, but had a higher incidence of both renal angiomyolipomas and pulmonary lymphangioleiomyomatosis. This distinct constellation of findings suggest that NMI patients may have a unique molecular pathogenesis, different from that seen in TSC patients with the usual mutations in TSC1 and TSC2. We suggest that the mechanisms of disease in these patients include both mosaicism for a TSC2 mutation, and unusual non-coding region mutations in TSC2.

Role of mutational analysis in diagnosis of tuberous sclerosis complex.

We describe three cases in whom identification of a disease-causing mutation in the TSC1 or TSC2 gene preceded the appearance or detection of symptoms sufficient for a clinical diagnosis of tuberous sclerosis complex (TSC). We suggest that genetic testing be given a more prominent role in the evaluation of individuals with a family history of TSC or symptoms suggestive of TSC and propose that diagnostic criteria be revised to include genetic testing.

Genetic diversity and population structuring of Schistosoma mansoni in a Brazilian village.

The digenean trematode Schistosoma mansoni is responsible for chronic schistosomiasis worldwide, and in Brazil alone an estimated 35 million people are at risk. To evaluate epidemiological patterns among human definitive hosts, we assessed genetic diversity and population subdivision of S. mansoni infrapopulations in human hosts from the highly endemic village of Virgem das Graças in the state of Minas Gerais, Brazil. We believe this is the largest such survey to date. Genetic diversity of parasites, measured over eight polymorphic microsatellite loci, was relatively high and standard measures of inbreeding indicated that the population was panmictic. Furthermore, there was no significant isolation-by-distance of parasite infrapopulations, and measures of population subdivision indicated significant but low to moderate levels of population differentiation. We conclude that patients within this village sample from a broad range of schistosome genetic diversity and effectively act as "genetic mixing bowls" for the parasites. These results contrast with those previously observed in the Brazilian village of Melqui ades and thus provide the opportunity for comparisons of environmental and epidemiological differences that are likely to influence host-parasite coevolution and parasite transmission.

Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation.

The mechanisms by which growth factor-induced signals are propagated to the nucleus, leading to the activation of the transcription factor CREB, have been characterized. Nerve growth factor (NGF) was found to activate multiple signaling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133 (Ser-133). NGF activates the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs), which in turn activate the pp90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases, all three members of which were found to catalyze CREB Ser-133 phosphorylation in vitro and in vivo. In addition to the ERK/RSK pathway, we found that NGF activated the p38 MAPK and its downstream effector, MAPK-activated protein kinase 2 (MAPKAP kinase 2), resulting in phosphorylation of CREB at Ser-133. Inhibition of either the ERK/RSK or the p38/MAPKAP kinase 2 pathway only partially blocked NGF-induced CREB Ser-133 phosphorylation, suggesting that either pathway alone is sufficient for coupling the NGF signal to CREB activation. However, inhibition of both the ERK/RSK and the p38/MAPKAP kinase 2 pathways completely abolished NGF-induced CREB Ser-133 phosphorylation. These findings indicate that NGF activates two distinct MAPK pathways, both of which contribute to the phosphorylation of the transcription factor CREB and the activation of immediate-early genes.

The value of multichannel MEG and EEG in the presurgical evaluation of 70 epilepsy patients.

OBJECTIVE: To evaluate the sensitivity of a simultaneous whole-head 306-channel magnetoencephalography (MEG)/70-electrode EEG recording to detect interictal epileptiform activity (IED) in a prospective, consecutive cohort of patients with medically refractory epilepsy that were considered candidates for epilepsy surgery. METHODS: Seventy patients were prospectively evaluated by simultaneously recorded MEG/EEG. All patients were surgical candidates or were considered for invasive EEG monitoring and had undergone an extensive presurgical evaluation at a tertiary epilepsy center. MEG and EEG raw traces were analysed individually by two independent reviewers. RESULTS: MEG data could not be evaluated due to excessive magnetic artefacts in three patients (4%). In the remaining 67 patients, the overall sensitivity to detect IED was 72% (48/67 patients) for MEG and 61% for EEG (41/67 patients) analysing the raw data. In 13% (9/67 patients), MEG-only IED were recorded, whereas in 3% (2/67 patients) EEG-only IED were recorded. The combined sensitivity was 75% (50/67 patients). CONCLUSION: Three hundred and six-channel MEG has a similarly high sensitivity to record IED as EEG and appears to be complementary. In one-third of the EEG-negative patients, MEG can be expected to record IED, especially in the case of lateral neocortical epilepsy and/or cortical dysplasia.

Prevalence of and factors associated with frailty and disability in older adults from China, Ghana, India, Mexico, Russia and South Africa.

BACKGROUND: The severe burden imposed by frailty and disability in old age is a major challenge for healthcare systems in low- and middle-income countries alike. The current study aimed to provide estimates of the prevalence of frailty and disability in older adult populations and to examine their relationship with socioeconomic factors in six countries. METHODS: Focusing on adults aged 50+ years, a frailty index was constructed as the proportion of deficits in 40 variables, and disability was assessed using the World Health Organization Disability Assessment Schedule (WHODAS 2.0), as part of the Study on global AGEing and adult health (SAGE) Wave 1 in China, Ghana, India, Mexico, Russia and South Africa. RESULTS: This study included a total of 34,123 respondents. China had the lowest percentages of older adults with frailty (13.1%) and with disability (69.6%), whereas India had the highest percentages (55.5% and 93.3%, respectively). Both frailty and disability increased with age for all countries, and were more frequent in women, although the sex gap varied across countries. Lower levels of both frailty and disability were observed at higher levels of education and wealth. Both education and income were protective factors for frailty and disability in China, India and Russia, whereas only income was protective in Mexico, and only education in South Africa. CONCLUSIONS: Age-related frailty and disability are increasing concerns for older adult populations in low- and middle-income countries. The results indicate that lower levels of frailty and disability can be achieved for older people, and the study highlights the need for targeted preventive approaches and support programs.

Structure of the precursor to an enzyme mediating COOH-terminal amidation in peptide biosynthesis.

Many bioactive peptides terminate with an amino acid alpha-amide at their COOH terminus. The enzyme responsible for this essential posttranslational modification is known as peptidyl-glycine alpha-amidating monooxygenase or PAM. We identified cDNAs encoding the enzyme by using antibodies to screen a bovine intermediate pituitary lambda gt11 expression library. Antibodies to a beta-galactosidase/PAM fusion protein removed PAM activity from bovine pituitary homogenates. The 108,207 dalton protein predicted by the complete cDNA is approximately twice the size of purified PAM. An NH2-terminal signal sequence and short propeptide precede the NH2 terminus of purified PAM. The sequences of several PAM cyanogen bromide peptides were localized in the NH2-terminal half of the predicted protein. The cDNA encodes an additional 430 amino acid intragranular domain followed by a putative membrane spanning domain and a hydrophilic cytoplasmic domain. The forms of PAM purified from bovine neurointermediate pituitary may be generated by endoproteolytic cleavage at a subset of the 10 pairs of basic amino acids in the precursor. High levels of PAM mRNA were found in bovine pituitary and cerebral cortex. In corticotropic tumor cells, levels of PAM mRNA and pro-ACTH/endorphin mRNA were regulated in parallel by glucocorticoids and CRF.

Effect of secretagogues on components of the secretory system in AtT-20 cells.

The mouse corticotrope tumor cell line AtT-20/D16v was used to investigate the effects of chronic treatment with various secretagogues on individual components of the secretory pathway. Secretagogues acting in part through receptors linked to guanine nucleotide-binding regulatory proteins [CRF and somatostatin (SS)] and agents by-passing membrane receptors (phorbol myristate acetate and dexamethasone) were examined. Effects on the secretory product were evaluated by measuring levels of pro-ACTH/endorphin mRNA and hormone secretion. Effects on posttranslational processing enzymes were evaluated by measuring levels of the mRNAs encoding carboxypeptidase-E and peptidyl-glycine-alpha-amidating monooxygenase (PAM); cellular levels of PAM activity were also measured. The mRNAs encoding the G-proteins in AtT-20 cells were identified, and secretagogue effects on the G-protein signal transduction system were evaluated by measuring levels of the mRNAs encoding (alpha s, alpha)i2, and beta 2. No single parameter adequately characterizes the regulatory state of the complex secretory apparatus. Although levels of pro-ACTH/endorphin (PAE) mRNA accurately reflected hormone secretion after chronic CRF or dexamethasone treatment, chronic SS treatment elevated PAE mRNA levels in the face of reduced hormone secretion. Levels of PAM mRNA generally changed in parallel with levels of PAE mRNA; in contrast, levels of carboxypeptidase-E mRNA were unaffected by any of the secretagogues tested. Secretagogues acting through distinct G-proteins (CRF and SS) as well as dexamethasone brought about a coordinate increase in the level of the mRNAs encoding the three G-protein subunits examined. Treatment with phorbol myristate acetate caused a slight decrease in the levels of the G-protein subunit mRNAs.

Tissue-specific regulation of peptidyl-glycine alpha-amidating monooxygenase expression.

Peptidyl-glycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) is present in a variety of tissues, where it plays a vital role in the processing of numerous peptide substrates, often conferring bioactivity. PAM is present in high amounts in heart atrial myocytes and the pituitary gland, where activity is present in both soluble and membrane forms. We used AtT-20 cells, a mouse corticotrope tumor cell line, and primary heart atrial cultures to establish the occurrence of tissue-specific regulation of PAM expression. In the AtT-20 cells, PAM expression is regulated in parallel with the source of its peptide substrate, pro-ACTH/endorphin. PAM mRNA levels are increased to 132 +/- 5% of control values by treatment with (Bu)2-cAMP and decreased to 55 +/- 7% of control values by treatment with dexamethasone. Treatment with (Bu)2cAMP decreases PAM specific activity in the AtT-20 cells to 68 +/- 4% of the control value, presumably due to secretion of enzyme from the cells; dexamethasone treatment decreases PAM specific activity to 57 +/- 1% of the control value. In contrast, in heart atrial cultures, dexamethasone stimulates PAM expression. In atrial cultures exposed to dexamethasone for 48 h, PAM mRNA and PAM specific activity are elevated to 230 +/- 50% and 220 +/- 20% of control values, respectively; secretion of PAM activity is increased to 230% of the control value. As for AtT-20 cells, treatment of atrial cultures with (Bu)2cAMP increases PAM mRNA levels. Thus, PAM expression is regulated in a tissue-specific manner by dexamethasone in the two tissues examined. In AtT-20 cells, time-course studies and studies with cycloheximide indicate that dexamethasone exerts its effects on PAM mRNA levels by an indirect mechanism involving protein synthesis.

Angiotensin-converting enzyme in the testis and epididymis: differential development and pituitary regulation of isozymes.

Angiotensin-converting enzyme (ACE, EC 3.14.5.1) is found in particulate fractions of the epididymis but not in soluble epididymal fractions or in the testis of 4-week-old rats. [3H]Captopril autoradiography of testis and epididymis from 4-week-old rats confirms the association of ACE with epididymal ducts but not the testis. ACE appears in the testis between 4 and 6 weeks of age. Soluble ACE is not detectable in the epididymis until 6-7 weeks of age. Within the epididymis, regions closest to the testis develop soluble ACE activity about 1 week before those nearest to the vas deferens. Hypophysectomy of 10 week-old-rats depletes greater than 95% of ACE activity from the testis and soluble fractions of the epididymis, with little change in ACE levels from particulate fractions of the epididymis. [3H]Captopril autoradiography after hypophysectomy reveals luminal and epithelial ACE in the epididymis. The presence of particulate ACE in the epididymis under conditions where there is no testicular ACE indicates that the two forms are synthesized separately. However, soluble ACE from the epididymis might be derived from the membrane-associated ACE of the testis. Such a relationship is supported by the lag of 1 week between the development of ACE in the initial segment of the epididymis and the tail of the epididymis, and by the occurrence of soluble epididymis ACE only in those animals with testicular ACE activity.

Myelin basic protein reactive Th2 T cells are found in acute disseminated encephalomyelitis.

Acute disseminated encephalomyelitis (ADEM), a postinfectious illness of the central nervous system (CNS), is thought to be an autoimmune disease. Here, we characterized the cytokines secreted by myelin-reactive T cells generated from patients with ADEM. The frequency of MBP-reactive T cell lines was ten-fold higher in patients with ADEM compared to patients with encephalitis and normal subjects. Whereas there was no significant IFN-gamma secretion, the predominant cytokine secreted by MBP-reactive T cell lines was IL-4 in patients with ADEM. In contrast, IL-4 secretion was only rarely detected in the controls. The presence of high frequencies of MBP-reactive IL-4 secreting T cells in subjects with ADEM during their recovery phase may be similar to myelin reactive IL-4 secreting T cells observed during the spontaneous recovery of animals with EAE.

Electroencephalogram and clinical focalities in juvenile myoclonic epilepsy.

Partial seizures and asymmetric abnormalities seen on electroencephalogram (EEG) are infrequent in juvenile myoclonic epilepsy, but when present, can lead to a misdiagnosis of partial seizures. We report four patients with juvenile myoclonic epilepsy who had generalized spike or polyspike and wave discharges on EEG in addition to clinical and EEG evidence of focality. The clinical course and response to therapy was similar to that in typical juvenile myoclonic epilepsy.