The relationship between clinical presentation and the nature of care in adults with intellectual disability and epilepsy - national comparative cohort study.

BACKGROUND: A quarter of People with Intellectual Disabilities (PwID) have epilepsy compared with 1% of the general population. Epilepsy in PwID is a bellwether for premature mortality, multimorbidity and polypharmacy. This group depends on their care provider to give relevant information for management, especially epilepsy. There is no research on care status relationship and clinical characteristics of PwID and epilepsy. AIM: Explore and compare the clinical characteristics of PwID with epilepsy across different care settings. METHOD: A retrospective multicentre cohort study across England and Wales collected information on seizure characteristics, intellectual disability severity, neurodevelopmental/biological/psychiatric comorbidities, medication including psychotropics/anti-seizure medication, and care status. Clinical characteristics were compared across different care settings, and those aged over and younger than 40 years. RESULTS: Of 618 adult PwID across six centres (male:female = 61%:39%), 338 (55%) received professional care whereas 258 (42%) lived with family. Significant differences between the care groups existed in intellectual disability severity (P = 0.01), autism presence (P < 0.001), challenging behaviour (P < 0.001) and comorbid physical conditions (P = 0.008). The two groups did not vary in intellectual disability severity/genetic conditions/seizure type and frequency/psychiatric disorders. The professional care cohort experienced increased polypharmacy (P < 0.001) and antipsychotic/psychotropic use (P < 0.001/P = 0.008).The over-40s cohort had lower autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) comorbidity (P < 0.001/P = 0.007), increased psychiatric comorbidity and challenging behaviour (P < 0.05), physical multimorbidity (P < 0.001), polypharmacy (P < 0.001) and antipsychotic use (P < 0.001) but reduced numbers of seizures (P = 0.007). CONCLUSION: PwID and epilepsy over 40 years in professional care have more complex clinical characteristics, increased polypharmacy and antipsychotic prescribing but fewer seizures.

Pharmacological management of fragile X syndrome: a systematic review and narrative summary of the current evidence.

INTRODUCTION: Fragile X syndrome (FXS) is the most common inherited cause of Intellectual Disability. There is a broad phenotype that includes deficits in cognition and behavioral changes, alongside physical characteristics. Phenotype depends upon the level of mutation in the FMR1 (fragile X messenger ribonucleoprotein 1) gene. The molecular understanding of the impact of the FMR1 gene mutation provides an opportunity to target treatment not only at symptoms but also on a molecular level. METHODS: We conducted a systematic review to provide an up-to-date narrative summary of the current evidence for pharmacological treatment in FXS. The review was restricted to randomized, blinded, placebo-controlled trials. RESULTS: The outcomes from these studies are discussed and the level of evidence assessed against validated criteria. The initial search identified 2377 articles, of which 16 were included in the final analysis. CONCLUSION: Based on this review to date there is limited data to support any specific pharmacological treatments, although the data for cannabinoids are encouraging in those with FXS and in future developments in gene therapy may provide the answer to the search for precision medicine. Treatment must be person-centered and consider the combination of medical, genetic, cognitive, and emotional challenges.

A review of the pharmacotherapeutic considerations for managing epilepsy in people with autism.

INTRODUCTION: Autism, like other neurodevelopmental disorders (NDDs), has a strong association with epilepsy. There are known common genetic pathways in both autism and epilepsy. There are also specific genetic syndromes associated with both complex epilepsy and the autism phenotype. AREAS COVERED: This review explores the evidence for common genetic etiologies and pathophysiological pathways in relation to both epilepsy and autism. Autism with comorbid epilepsy are associated with a high prevalence of medical and psychiatric comorbidities. This paper discusses how this influences assessment, treatment, and outcomes. The evidence for the treatment of specific seizure types in the context of NDDs is also examined alongside clinical commentary. EXPERT OPINION: Despite the strong association, there is a limited evidence base to support the efficacy and tolerability of anti-seizure medications specifically in autism, with no Level 1 evidence or National Guidance available. Autism and epilepsy should be approached under a NDD model with cautious introduction and titration of anti-seizure medication. Alongside this, there is evidence to support a move toward precision medicine in specific genetic syndromes such as Tuberous Sclerosis Complex and other genetic seizure disorders. The first-line treatments that should be considered for focal seizures include carbamazepine, lamotrigine, and levetiracetam.

Epilepsy in adults with neurodevelopmental disability - what every neurologist should know.

This seminar in epileptology addresses Learning Objective 6.1.4 of the International League against Epilepsy Curriculum: Demonstrate the ability to recognize and manage the special needs of persons with epilepsy (and Neurodevelopmental Disorders [NDDs]). The review identifies the essential competencies for neurologists working with people with epilepsy and NDDs, and these competencies are discussed alongside clinical examples. Furthermore, the seminar explores the opportunities offered by integrated service provision between neurology and services for NDD. The epileptic encephalopathies are not a subject of this seminar paper as they are circumscribed by other ILAE learning objectives. This seminar frames the complexity of seizures in association with NDD with a focus on major NDDs; intellectual disability, autism spectrum disorder, and attention deficit hyperactivity disorder. The evidence presented considers epidemiology, co-morbidities, risk factors, mortality, and the diagnostic and treatment challenges. People with NDDs and epilepsy have higher rates of physical and psychiatric co-morbidity, polypharmacy, neuropsychiatric side effects of drugs, and premature mortality including sudden unexpected death in epilepsy. There is a limited Level 1 evidence base to guide assessment and treatment for seizures in adults with NDDs. Therefore, throughout this seminar, the evidence presented for associations and treatment should be observed in context along with its limitations. The evidence for pharmacological treatment of seizures in association with NDDs is presented alongside expert commentary and guidance. There is Level 2 evidence to support treatment with some of the newer anti-seizure medications including brivaracetam, lacosamide, eslicarbazepine acetate, and perampanel as second-line choices. Seizures with a co-morbid NDD should be considered as a collective complex clinical presentation and not discrete conditions. This seminar was co-designed, co-produced and co-authored by an expert by experience and includes case studies and a video to highlight what can go wrong and how it can be avoided.

Heavy metal contamination in Phrynops geoffroanus (Schweigger, 1812) (Testudines: Chelidae) in a River Basin, São Paulo, Brazil.

The Piracicaba River basin is considered the most disturbed river basin in the state of São Paulo. Considerable amounts of agricultural residues are seasonally drained into the river, and the region is also highly urbanized and industrialized with an incipient sewage treatment system. The presence of heavy metals has been previously reported for the water and riverbed in Piracicaba river basin. In this study we evaluated 13 heavy metals in the blood of 37 Geoffroy's side-necked turtles, Phrynops geoffroanus, from Piracicaba River and Piracicamirim Creek, one of its tributaries. Blood levels of As, Co, Cr, Se and Pb varied among sites, whereas Sn varied between males and females. However, no obvious pathology was detected. Serum level of Cu (2,194 ng g(-1)) and Pb (1,150 ng g(-1)) found in this study are the highest ever described for any reptile; however, no clinical symptoms have been detected in the present study. There is no information about the time scale of such contamination, which could be currently subclinical and yet lead to a breakdown in the population reproductive success in a few years. Based on the present study, legal enforcement is urged in order to locate and extirpate heavy metal sources in the Piracicaba River basin. In addition, monitoring should include humans and commercial fish consumed in local markets.

Glucocorticoids of bison bulls in relation to social status.

A primary response to stress is an increase in circulating adrenal glucocorticoids (GC) such as cortisol. Two hypotheses propose differential stress responses to agonistic and aggressive interactions in social groups. If subordinate animals are subjected to social and psychological stressors leading to chronic GC elevation, the 'stress of subordination' hypothesis predicts that GCs will be higher in subordinates than dominants. Alternatively, if dominant animals are subject to physiological stressors (e.g., fight at higher rates than subordinates) or hierarchies are unstable, the 'stress of domination' hypothesis predicts higher GCs in dominant individuals. Both models predict that GC levels will peak during the breeding season. We tested these predictions in bison bulls (Bison bison) using fecal steroid analysis to characterize GC concentration and behavioral observations to determine dominance rank, copulatory success, and tending status of bulls. Fecal samples were collected during 2003 from adult bison bulls during pre-rut (June), rut (July-August), and post-rut (September). Matched sample data indicated that mean GC levels (ng/g feces) of bulls strongly peaked during the 4-week rut, doubling from pre-rut to rut and then declining again during post-rut. High ranked dominant bulls maintained higher GC levels than lower ranked subordinate bulls. Dominance rank was positively correlated with copulatory success and age, and dominant bulls were more likely to tend (guard) cows as they approached estrus. There was a positive correlation between GC level and copulatory success, with prime-aged bulls (> or =7 years) obtaining the most copulations. GC levels were positively correlated with bull androgen levels determined in a previous study. These results support the 'stress of domination' hypothesis, indicating that dominant bison bulls pay a significant physiological price for high social status and the opportunity to mate.

Fecal androgens of bison bulls during the rut.

The influence of sex hormones is a key proximate factor underlying male reproductive behavior in mammals. Effective conservation policies for the remaining purebred plains bison (Bison bison bison) herds require knowledge of the physiology underlying bison reproductive biology. We used fecal steroid analysis to characterize androgen levels in adult bison bulls before, during, and after the rut, and to examine androgen levels of bulls differing in reproductive status, age, and mating success. Fieldwork was carried out at the Fort Niobrara National Wildlife Refuge in north-central Nebraska. All adult bison in the herd were individually known by unique brands. Fecal samples were collected during 2003 from bulls during pre-rut (June), rut (July-August), and post-rut (September), and behavioral observations focused on reproductive status and mating success during the rut. Matched sample data indicated that androgen levels (ng/g feces) of bulls peaked during the rut, doubling from pre-rut to rut and then declining by 75% during post-rut. Dominant bulls that tended (guarded) cows maintained higher androgen levels than bulls that were not tending. There was a positive correlation between bull age (associated with mating success) and androgens, with higher androgen levels in prime-aged bulls compared with younger bulls. Nonetheless, there was no correlation between mating success (measured by number of copulations observed) and androgen level. This suggests that while androgens may provide the proximate motivation to compete for matings, other factors determine the mating success of bison bulls.

Maternal infant bonding enhanced after atrial septostomy in cyanotic neonates in a general hospital.

UNLABELLED: Seventeen newborns in a general hospital had a successful atrial septostomy when indicated. Mostly done at the bedside under echocardiographical guidance, the successful introduction of this procedure enabled the infants to remain with mother to facilitate feeding and bonding prior to elective transfer to a children's hospital for corrective surgery. BACKGROUND: Atrial septostomy is a well-recognised intervention in the newborn to facilitate atrial mixing in transposition of the great arteries (TGA) or to decompress an atrium where the connecting AV valve is absent or stenosed, e.g. tricuspid atresia (TA). AIMS: To review the outcome of this procedure in a general hospital with appropriate neonatal and cardiological facilities. METHODS: Retrospective review over an 11-year period. RESULTS: Seventeen inborn infants had successful atrial septostomies, 11 with TGA and 6 with TA. All done under general anaesthesia, 15 were performed in the newborn nurseries, under echocardiographic guidance, and 2 in the catheter laboratory. No complications occurred. Eleven had a prenatal diagnosis made. All infants were able to be subsequently nursed by their mothers, affording prime time facilitating feeding and bonding. They were electively transferred to a children's hospital for corrective surgery. CONCLUSIONS: Atrial septostomy can be safely performed in a general hospital with appropriate neonatal and cardiological expertise. Such intervention allows for elective transfer of the infant for corrective surgery, allowing the infant and mother to be initially cared for at the one hospital, thereby facilitating maternal contact, feeding and bonding, doing away with the added stress of emergency transfer.

Identification of a series of C(21)O(2) pregnanes from fecal extracts of a pregnant black rhinoceros (Diceros bicornis minor).

Fecal extracts from a pregnant black rhinoceros, Diceros bicornis, were analyzed by radioimmunoassay, HPLC, and by GC-mass spectrometry. From 40 g of dried feces a total of 33 pregnanes in the C(21)O(2) series, including a number of novel 17 alpha epimers were identified. No progesterone was recovered. The principal progesterone metabolite by mass was 5 alpha-pregnan-3 beta,20 alpha-diol (44.5%), which did not cross react with the antibody used in our RIA. The antibody recognized progesterone and pregnanes with 20-one configuration, which when combined made up less than 15% of the total C(21)O(2) steroid mass. Of the 33 pregnanes in the C(21)O(2) series identified, 81%, by mass, were in the 5 alpha-configuration. These results are compared with studies in other rhinoceros species (Asian and Sumatran) in which pregnanes in the 5 beta-configuration are the major fecal metabolites, and the white rhinoceros in which pregnanes in the 5 alpha-configuration are the dominant form.

Effects of trapping and subsequent short-term confinement stress on plasma corticosterone in the brown treesnake (Boiga irregularis) on Guam.

The effects of capture in a live trap and subsequent handling stress on plasma concentrations of corticosterone and other sex steroids were examined in wild male and female brown treesnakes (Boiga irregularis), an introduced species on Guam that has been implicated in the extirpation or decline of many of that island's vertebrate species. Males and females that spent 1 night in a trap had plasma levels of corticosterone about four and two times higher, respectively, than those of the respective free-ranging controls. Mean plasma levels of corticosterone of snakes that had spent 3 nights in a trap were intermediate between, but not significantly different from, those of snakes that had spent 1 night in a trap and free-ranging snakes, suggesting that some acclimation to capture occurred during this period. Snakes that were taken from traps and held in collecting bags for 10 min and 2 h prior to blood sampling had levels of corticosterone about two and three times higher, respectively, than those of control snakes that were taken from traps and bled immediately. Concentrations of plasma corticosterone in free-ranging females were about two times higher than those of males but were well within the range of basal levels observed in other reptiles. Few snakes of potential reproductive size were reproductive (males: 1 of 35; females: 2 of 33), and plasma concentrations of testosterone and progesterone in nonreproductive males and females, respectively, were accordingly low. The possible relationship between corticosterone and these sex steroids, therefore, could not be adequately assessed, although there was a positive relationship between plasma progesterone and corticosterone in the nonreproductive females. Nonetheless, as a prerequisite for studies on the seasonal hormonal cycles of this species on Guam, our observations raise the possibility that the stress caused by trapping could affect the levels of other sex steroids and that, therefore, such studies should use free-ranging individuals.

Alligator aromatase cDNA sequence and its expression in embryos at male and female incubation temperatures.

In all species of crocodilians, sex is determined not by genetic mechanisms, but by the temperature at which the egg is incubated. In the American alligator (Alligator mississippiensis) the thermosensitive period (TSP) for sex determination is a 7- to 10-day window within stages 21-24 of development, around the middle third of the incubation period. Treating embryos with estrogen during the TSP produces female offspring, even at male incubation temperatures. Conversely, blocking embryonic estrogen synthesis at female-inducing temperature prevents development of the female phenotype. Therefore, it has been suggested that estrogen plays a role in determination of sex in the alligator. Estrogen is produced from an androgen substrate by cytochrome P450 aromatase (CYP19). If estrogen plays a critical role in sex determination, there should be differences in aromatase expression between embryos at male- and female-producing temperatures during the TSP. Therefore, to address this question, we cloned and characterized the alligator CYP19 cDNA. Based on the sequence information, a quantitative kinetic reverse transcriptase-polymerase chain reaction (TaqMan) assay was designed to measure expression of the alligator aromatase gene in RNA extracted from the gonadal and brain regions of alligator embryos incubated at male- or female-producing temperatures from prior to the TSP through hatching. Aromatase expression was detected in the brain region from the earliest stage tested (stage 20) through hatching. The hypothalamus had significantly higher expression than the forebrain or hindbrain in both male and female embryos. Expression was not significantly different in the gonadal region between embryos at male and female temperatures until after the TSP, when there was a dramatic increase in expression at female temperature. These data indicate that aromatase expression and, thus, estrogen production, are not the initial trigger for sex determination but play an essential role in ovarian differentiation in the alligator. J. Exp. Zool. 290:439-448, 2001.

Changes in gonadal and adrenal steroid levels in the leatherback sea turtle (Dermochelys coriacea) during the nesting cycle.

The reproductive endocrinology of nesting leatherback turtles (Dermochelys coriacea) was studied during the 1996-1997 and 1997-1998 nesting seasons at Los Baulas National Park, Playa Grande, Costa Rica. Blood samples were collected from nesting females throughout the season. Females were observed to nest up to 10 times during the nesting season. Plasma steroids were measured by radioimmunoassay and total plasma calcium was measured by flame atomic absorption spectrophotometry. Plasma testosterone and plasma estradiol levels declined throughout the nesting cycle of the female. Testosterone declined from a mean of 10.18 +/- 0.77 ng/ml at the beginning of the nesting cycle to 1.73 +/- 0.34 ng/ml at the end of the nesting cycle. Estradiol declined in a similar manner, ranging from a mean of 190.95 +/- 16.80 pg/ml at the beginning of the nesting cycle to 76.52 +/- 12.66 pg/ml at the end of the nesting cycle. Plasma progesterone and total calcium levels were relatively constant throughout the nesting cycle. Lack of fluctuation of total calcium levels, ranging from a mean high of 97.46 +/- 11.37 microg/ml to a mean low of 64.85 +/- 11.20 microg/ml, further suggests that vitellogenesis is complete prior to the arrival of the female at the nesting beach. Clutch size (both yolked and yolkless eggs) did not vary over the course of the nesting cycle.

Sex differences in plasma corticosterone in desert tortoises, Gopherus agassizii, during the reproductive cycle.

Blood samples from 30 female and 20 male adult desert tortoises, Gopherus agassizii, were collected at monthly intervals during the annual reproductive cycle (April to October). Plasma corticosterone and the sex steroids in each of the samples were analyzed by radioimmunoassay. Mean corticosterone levels in males were significantly higher than in females (P < 0.001) in every month. Male tortoises showed a marked seasonal pattern in plasma corticosterone with a highly significant peak in July, August, September, and October that corresponded with a similar peak in plasma testosterone. Testosterone and corticosterone in the male showed a highly significant correlation (P < 0.0001). The pattern of corticosterone in the female was less marked, with a significant peak in May during the mating and nesting season, but no association with the peak in estradiol in late summer was apparent. The highest levels of corticosterone in the males were associated with the peak in spermatogenesis and intense male-male combat. These results support similar data from other reptiles that suggest increased glucocorticoid secretion during periods of increased activity and metabolism.

Seasonality in plasma thyroxine in the desert tortoise, Gopherus agassizii.

To characterize seasonal changes in thyroid function in a terrestrial reptile, thyroid hormones were measured over a period of 2 years in desert tortoises, Gopherus agassizii, maintained at the Desert Tortoise Conservation Center in Las Vegas, Nevada. In all samples, triiodothyronine was nondetectable (less than 0.1 ng/ml). Thyroxine (T(4)) exhibited distinct cycles in both sexes, being lowest during hibernation and rising toward the time of emergence. Females exhibited only one peak in T(4), during the early spring. In males, T(4) levels peaked in early spring and again in late summer. The desert tortoise has distinct activity patterns that include increased feeding, mating, and locomotor activity in the early spring and increased mating and combat in the late summer. In an experiment to determine whether food intake influences T(4), food was withheld for 2 weeks. Compared to continuously fed controls, T(4) declined significantly in unfed tortoises, but increased significantly within 36 h of refeeding, indicating that thyroid activity is responsive to nutrient intake. The second seasonal peak of T(4) only in males suggests that male reproductive activity in late summer is associated with thyroid activation. To evaluate this possibility, adult, subadult, and juvenile males were sampled during the months of the second seasonal peak in T(4). Although all three age groups showed similar foraging and thermoregulatory behaviors, T(4) peaked in July only in the reproductively active adults, which also exhibited significantly higher testosterone levels. Elevated T(4) in desert tortoises is thus associated with periods of increased feeding and reproductive activity, supporting a role for thyroid hormones in these energy-demanding activities.

Hyperlipidemia and reproductive failure in captive-reared alligators: vitamin E, vitamin A, plasma lipids, fatty acids, and steroid hormones.

Blood samples were collected from 26 captive-reared alligators (25 females; one male) and 12 (seven females and five males) wild "nuisance" alligators collected by wildlife personnel in south Louisiana in May 1995. The captive alligators, hatched from artificially incubated eggs in 1972-1973, had received vitamin E supplements during the 3 weeks before the blood sample was collected. Each sample was analyzed for vitamin E (alpha-tocopherol), vitamin A (retinol), total lipid, triacylglycerol, phospholipid, cholesterol, cholesteryl ester, free fatty acids, steroid hormones and a standard clinical blood panel. The fatty acid composition of the plasma lipid fraction was also analyzed. Results indicated that 18 of the captive females and three of the seven wild females were undergoing vitellogenesis, i.e. had elevated plasma estradiol and elevated plasma calcium. Vitellogenic females had higher vitamin E than non-vitellogenic females (77.4 microg/ml vs. 28.6 microg/ml in captive females; 24.0 microg/ml vs. 21 microg/ml in wild females). Plasma retinol was similar in all groups, ranging from 0.5 to 1.4 microg/ml and close to values reported in birds. All lipid fractions, with the exception of cholesteryl ester, were higher in captive alligators than in wild alligators. There were also significant differences in the fatty acid composition of wild and captive alligators. Plasma eicosapentaenoic and docasahexaenoic acid were higher in wild than in captive alligators, whereas linoleic was higher in captive than in wild.

Successful contraception in a herd of Chinese goral (Nemorhaedus goral arnouxianus) with melengestrol acetate.

Thirteen Chinese goral (Nemorhaedus goral arnouxianus) (five males and eight females) were each given 0.8 mg of melengestrol acetate orally in pelleted food for 224 days. The previous breeding season, six of the eight females calved (two were immature). No calf was born during the treatment season. The season after treatment, six females calved (one was immature prior to treatment). Two females were moved to other institutions, and the status of these is unknown. On the basis of this information, melengestrol acetate in feed was successful in preventing conception and was reversible. This treatment did not prevent the siring of offspring the following year and did not prevent a female that was subadult prior to the treatment from calving.

Neuroendocrine peptides (insulin, pancreatic polypeptide, neuropeptide Y, galanin, somatostatin, substance P, and neuropeptide gamma) from the desert tortoise, Gopherus agassizii.

The traditional view that Testudines (tortoises and turtles) should be regarded as the surviving clade of the anapsid reptiles rather than classified with the diapsid reptiles (snakes, lizards, and crocodiles) has recently been challenged. Neuropeptide Y, neuropeptide gamma, and somatostatin-14 were isolated from an extract of the brain, substance P and galanin from an extract of the intestine, and insulin and pancreatic polypeptide from an extract of the pancreas of the desert tortoise, Gopherus agassizii. Despite that crocodilians did not appear until the late Triassic, the amino acid sequences of the tortoise peptides resemble those of the American alligator quite closely. The primary structures of neuropeptide Y, somatostatin-14, and neuropeptide gamma are the same in tortoise and alligator. The primary structures of substance P, insulin, galanin, and pancreatic polypeptide in the two species differ by 1, 3, 5, and 8 amino acid residues, respectively. Although fewer neurohormonal peptides from squamates (lizards and snakes) have been characterized, the primary structures of neuropeptide gamma, insulin, and pancreatic polypeptide from the Burmese python and the desert tortoise differ by 3, 8, and 18 residues, respectively. The data suggest, therefore, a closer phylogenetic relationship between Testudines and Crocodilians than that derived from 'classical' analyses based on morphological criteria and the fossil record.