Monogenic forms of hypertension

Arterial hypertension in childhood is less frequent as compared to adulthood but is more likely to be secondary to an underlying disorder. After ruling out more obvious causes, some patients still present with strongly suspected secondary hypertension of yet unknown etiology. A number of these children have hypertension due to single gene mutations inherited in an autosomal dominant or recessive fashion. The finding of abnormal potassium levels (low or high) in the presence of suppressed renin secretion, and metabolic alkalosis or acidosis should prompt consideration of these familial diseases. However, mild hypertension and the absence of electrolyte abnormalities do not exclude hereditary conditions. In monogenic hypertensive disorders, three distinct mechanisms leading to the common final pathway of increased sodium reabsorption, volume expansion, and low plasma renin activity are documented. The first mechanism relates to gain-of-function mutations with a subsequent hyperactivity of renal sodium and chloride reabsorption leading to plasma volume expansion (e.g., Liddle's syndrome, Gordon's syndrome). The second mechanism involves deficiencies of enzymes that regulate adrenal steroid hormone synthesis and deactivation (e.g., subtypes of congenital adrenal hyperplasia, apparent mineralocorticoid excess (AME)). The third mechanism is characterized by excessive aldosterone synthesis that escapes normal regulatory mechanisms and leading to volume-dependent hypertension in the presence of suppressed renin release (glucocorticoid remediable aldosteronism). Hormonal studies coupled with genetic testing can help in the early diagnosis of these disorders.

Neurophysiological correlates of delinquent behaviour in adult subjects with ADHD

The attention deficit/hyperactivity disorder (ADHD) shows an increased prevalence in arrested offenders compared to the normal population. The aim of the present study was to investigate whether ADHD symptoms are a major risk factor for criminal behaviour, or whether further deficits, mainly abnormalities in emotion-processing, have to be considered as important additional factors that promote delinquency in the presence of ADHD symptomatology. Event related potentials (ERPs) of 13 non-delinquent and 13 delinquent subjects with ADHD and 13 controls were compared using a modified visual Go/Nogo continuous performance task (VCPT) and a newly developed version of the visual CPT that additionally requires emotional evaluation (ECPT). ERPs were analyzed regarding their topographies and Global Field Power (GFP). Offenders with ADHD differed from non-delinquent subjects with ADHD in the ERPs representing higher-order visual processing of objects and faces (N170) and facial affect (P200), and in late monitoring and evaluative functions (LPC) of behavioural response inhibition. Concerning neural activity thought to reflect the allocation of neural resources and cognitive processing capability (P300 Go), response inhibition (P300 Nogo), and attention/expectancy (CNV), deviances were observable in both ADHD groups and may thus be attributed to ADHD rather than to delinquency. In conclusion, ADHD symptomatology may be a risk factor for delinquency, since some neural information processing deficits found in ADHD seemed to be even more pronounced in offenders with ADHD. However, our results suggest additional risk factors consisting of deviant higher-order visual processing, especially of facial affect, as well as abnormalities in monitoring and evaluative functions of response inhibition.

Theta burst stimulation reduces disability during the activities of daily living in spatial neglect

Left-sided spatial neglect is a common neurological syndrome following right-hemispheric stroke. The presence of spatial neglect is a powerful predictor of poor rehabilitation outcome. In one influential account of spatial neglect, interhemispheric inhibition is impaired and leads to a pathological hyperactivity in the contralesional hemisphere, resulting in a biased attentional allocation towards the right hemifield. Inhibitory transcranial magnetic stimulation can reduce the hyperactivity of the contralesional, intact hemisphere and thereby improve spatial neglect symptoms. However, it is not known whether this improvement is also relevant to the activities of daily living during spontaneous behaviour. The primary aim of the present study was to investigate whether the repeated application of continuous theta burst stimulation trains could ameliorate spatial neglect on a quantitative measure of the activities of daily living during spontaneous behaviour. We applied the Catherine Bergego Scale, a standardized observation questionnaire that can validly and reliably detect the presence and severity of spatial neglect during the activities of daily living. Eight trains of continuous theta burst stimulation were applied over two consecutive days on the contralesional, left posterior parietal cortex in patients suffering from subacute left spatial neglect, in a randomized, double-blind, sham-controlled design, which also included a control group of neglect patients without stimulation. The results showed a 37% improvement in the spontaneous everyday behaviour of the neglect patients after the repeated application of continuous theta burst stimulation. Remarkably, the improvement persisted for at least 3 weeks after stimulation. The amelioration of spatial neglect symptoms in the activities of daily living was also generally accompanied by significantly better performance in the neuropsychological tests. No significant amelioration in symptoms was observed after sham stimulation or in the control group without stimulation. These results provide Class I evidence that continuous theta burst stimulation is a viable add-on therapy in neglect rehabilitation that facilitates recovery of normal everyday behaviour.

Orofacial dyskinesia induced by nasal Ritalin(R) (methylphenidate) sniffing: A rare case report from Switzerland

Ritalin® (methylphenidate) is an amphetamine-like prescription stimulant commonly used in the treatment of attention deficit hyperactivity disorder in children and adults. Recently, the recreational use of Ritalin has increased, particularly among young adults. Well-known symptoms of intoxication include signs of sympathetic nervous stimulation, such as agitation, anxiety, tachycardia, hypertension, headache, tremor, and dizziness. This case report describes oral dyskinesia as a rare presentation of Ritalin intoxication, with the review of pathophysiology and some epidemiological data.

Behavioral Assessment of Core ADHD Symptoms Using the QbTest

Objective: Hyperactivity, one of the core symptoms of ADHD, has been mostly neglected in neuropsychological assessment of childhood ADHD. The neuropsychological Quantified behavior Test (QbTest) separately assesses all three core symptoms of ADHD on a behavioral level. Factor structure of the QbTest and its concurrent and discriminant validity are presented. Method: An exploratory factor analysis (n = 828 children) was performed. In a second sample (n = 102 children) a Multi-Trait-Multi-Method (MTMM) approach was used for validity analyses. Results: A three factorial model explained 76 % of the total variance, with the resulting QbTest factors significantly influenced by age and gender. The MTMM approach yielded promising results for discriminant, yet inconsistent findings for concurrent validity between the QbTest and another attention test as well as for Conners' Parent and Teacher Rating Scales. Conclusion: Results indicate that the QbTest may be helpful for the behavioral assessment of childhood ADHD, yet further studies on its psychometric quality and clinical utility are needed. (J. of Att. Dis. 2012; XX(X) 1-XX).

German validation of the Conners Adult ADHD Rating Scales (CAARS) II: reliability, validity, diagnostic sensitivity and specificity

The German version of the Conners Adult ADHD Rating Scales (CAARS) has proven to show very high model fit in confirmative factor analyses with the established factors inattention/memory problems, hyperactivity/restlessness, impulsivity/emotional lability, and problems with self-concept in both large healthy control and ADHD patient samples. This study now presents data on the psychometric properties of the German CAARS-self-report (CAARS-S) and observer-report (CAARS-O) questionnaires.

Coping With a Family Member's Death: Parenting, Religiosity, and Parent-Child Communication

The present study had three major aims. First, this study was a basic descriptive exploration of the frequency and nature of parent-child communication about death. Second, this study conducted a quantitative analysis to identify predictors of communication and bereaved children¿s emotional and behavioral problems. Third, this study was also a qualitative analysis of parents¿ descriptions of how religious views shape conversations about death and how conversations are beneficial. Based on prior research, it was predicted that positive child outcomes would be associated with parental warmth, religiosity, adaptive coping, positive religious coping, and frequent parent-child communication about death. Conversely, it was predicted that negative child outcomes would be associated with parental psychological control, maladaptive coping, negative religious coping, and less frequent parent-child communication about death. Additionally, it was hypothesized that parents¿ religious and spiritual views would shape parent-child communication about death, and parents would describe numerous benefits of discussing death with children. Parents completed a series of survey measures assessing their religiosity, coping strategies, parent-child communication about death, and their children¿s emotional and behavioral symptoms. Almost 80% of parent-child dyads discussed death at least once a week, and children initiated approximately half of these conversations. Parent-child communication about death was predicted by parents¿ warmth toward and acceptance of their children and inversely predicted by children¿s hyperactivity and social problem solving. Higher levels of children¿s social problem solving could predict lower frequency of parent-child communication about death if children were holding frequent, meaningful, and comforting conversations with friends and other adults. Higher levels of parents¿ psychological control predicted more emotional and behavioral problems in the child. Parents¿ adaptive coping had significant relationships with all of the dimensions of parent-child communication about death. Qualitative analyses revealed that parents perceived their religious beliefs as shaping conversations about death and grief as an individualized journey. A majority of parents described the emotional, social, and intellectual benefits of holding parent-child conversations about death. This study contributes to the literature by further describing parent-child communication about death, identifying its predictors, and investigating parents¿ religiosity and coping strategies in relation to child well-being. Overall, this study revealed the importance of assessing global parenting characteristics (i.e., warmth/acceptance and psychological control) when examining parent-child relationships and communication about death. Furthermore, this unique study illustrates the value of qualitative data when examining parent-child communication about death and religiosity.

Bipolar disorder risk alleles in children with ADHD

Bipolar disorder (BD) and attention deficit/hyperactivity disorder (ADHD) may share common genetic risk factors as indicated by the high co-morbidity of BD and ADHD, their phenotypic overlap especially in pediatric populations, the high heritability of both disorders, and the co-occurrence in families. We therefore examined whether known polygenic BD risk alleles are associated with ADHD. We chose the eight best SNPs of the recent genome-wide association study (GWAS) of BD patients of German ancestry and the nine SNPs from international GWAS meeting a 'genome-wide significance' level of α = 5 × 10(-8). A GWAS was performed in 495 ADHD children and 1,300 population-based controls using HumanHap550v3 and Human660 W-Quadv1 BeadArrays. We found no significant association of childhood ADHD with single BD risk alleles surviving adjustment for multiple testing. Yet, risk alleles for BD and ADHD were directionally consistent at eight of nine loci with the strongest support for three SNPs in or near NCAN, BRE, and LMAN2L. The polygene analysis for the BP risk alleles at all 14 loci indicated a higher probability of being a BD risk allele carrier in the ADHD cases as compared to the controls. At a moderate power to detect association with ADHD, if true effects were close to estimates from GWAS for BD, our results suggest that the possible contribution of BD risk variants to childhood ADHD risk is considerably lower than for BD. Yet, our findings should encourage researchers to search for common genetic risk factors in BD and childhood ADHD in future studies.

Treatment of hyperactive children: increased efficiency through modifications of homeopathic diagnostic procedure

BACKGROUND: The rigorous test to which homeopathy was subject in our recent double-blind clinical trail of homeopathic treatment of attention deficit hyperactivity disorder (ADHD) necessitated optimized treatment meeting the highest standards. METHODS: Optimization was performed in three steps: (1) In successfully treated children, prescriptions leading to an insufficient response were analysed by a general questionnaire to identify unreliable symptoms. (2) Polarity analysis, a further development of Bönninghausen's concept of contraindications, was introduced in response to the frequently one-sided symptoms. This enabled us to use few but specific symptoms to identify the medicine whose genius symptoms exhibit the closest match to the patient's characteristic symptoms. (3) We investigated the influence of the primary perception symptoms on the result of the repertorization. Perception symptoms are not normally recorded during a patient interview even though they are among the most reliable facts related by the patients. At the same time we were able to improve the continuity of improvement of ADHD symptoms using liquid Q-potencies. RESULTS: Introducing the questionnaire, polarity analysis, and including perception symptoms, lead to an improvement in the success rate of the first prescription from 21% to 54%, of the fifth prescription from 68% to 84%.

Study design, baseline patient characteristics and intervention in a cross-cultural framework: results from the ADORE study

OBJECTIVE : To describe the methodology and to present the baseline findings of the Attention-deficit/hyperactivity Disorder Observational Research in Europe (ADORE) study, the primary objective of which is to describe the relationship between treatment regimen prescribed and quality of life of children with ADHD in actual practice. METHODS : In this 2-year prospective observational study, data on diagnosis, prescribed treatment and outcomes of ADHD were collected at seven time points by paediatricians and child psychiatrists on 1,573 children recruited in 10 European countries. The data presented here from the 1,478 patients included in the analyses describe the baseline condition, initial treatment regimen prescribed and quality of life of families with children with ADHD. RESULTS : Patients had a mean age of 9.0 years (SD 2.5) and 84% were male. Physicians diagnoses were made using DSM-IV (43 %), ICD-10 (32%) and both DSM-IV and ICD-10 (12 %). Mean age of awareness of a problem was 5.1 years, suggesting an average delay of approximately 4 years between awareness and diagnosis of ADHD. Baseline ADHD rating scale scores (physicianrated) indicated moderate to severe ADHD. Parent-rated SDQ scores were in agreement and suggested significant levels of co-existing problems. CGI-S, CGAS and CHIPCE scores also indicated significant impairment. Patients were offered the following treatments after the initial assessment: pharmacotherapy (25 %), psychotherapy (19 %), combination of pharmacotherapy and psychotherapy (25 %), other therapy (10 %) and no treatment (21 %). CONCLUSION : The ADORE study shows that ADHD is similarly recognised across 10 European countries and that the children are significantly impaired across a wide range of domains. In this respect, they resemble children described in previous ADHD samples.

Reorganization of CA3 area of the mouse hippocampus after pilocarpine induced temporal lobe epilepsy with special reference to the CA3-septum pathway

We showed that when CA3 pyramidal neurons in the caudal 80% of the dorsal hippocampus had almost disappeared completely, the efferent pathway of CA3 was rarely detectable. We used the mouse pilocarpine model of temporal lobe epilepsy (TLE), and injected iontophoretically the anterograde tracer phaseolus vulgaris leucoagglutinin (PHA-L) into gliotic CA3, medial septum and the nucleus of diagonal band of Broca, median raphe, and lateral supramammillary nuclei, or the retrograde tracer cholera toxin B subunit (CTB) into gliotic CA3 area of hippocampus. In the afferent pathway, the number of neurons projecting to CA3 from medial septum and the nucleus of diagonal band of Broca, median raphe, and lateral supramammillary nuclei increased significantly. In the hippocampus, where CA3 pyramidal neurons were partially lost, calbindin, calretinin, parvalbumin immunopositive back-projection neurons from CA1-CA3 area were observed. Sprouting of Schaffer collaterals with increased number of large boutons in both sides of CA1 area, particularly in the stratum pyramidale, was found. When CA3 pyramidal neurons in caudal 80% of the dorsal hippocampus have almost disappeared completely, surviving CA3 neurons in the rostral 20% of the dorsal hippocampus may play an important role in transmitting hyperactivity of granule cells to surviving CA1 neurons or to dorsal part of the lateral septum. We concluded that reorganization of CA3 area with its downstream or upstream nuclei may be involved in the occurrence of epilepsy.

Randomised controlled trials of homeopathy in hyperactive children: treatment procedure leads to an unconventional study design. Experience with open-label homeopathic treatment preceding the Swiss ADHD placebo controlled, randomised, double-blind, cross-over trial

BACKGROUND: Treatment of patients with attention deficit hyperactivity disorder (ADHD) with homeopathy is difficult. The Swiss randomised, placebo controlled, cross-over trial in ADHD patients (Swiss ADHD trial) was designed with an open-label screening phase prior to the randomised controlled phase. During the screening phase, the response of each child to successive homeopathic medications was observed until the optimal medication was identified. Only children who reached a predefined level of improvement participated in the randomised, cross-over phase. Although the randomised phase revealed a significant beneficial effect of homeopathy, the cross-over caused a strong carryover effect diminishing the apparent difference between placebo and verum treatment. METHODS: This retrospective analysis explores the screening phase data with respect to the risk of failure to demonstrate a specific effect of a randomised controlled trial (RCT) with randomisation at the start of the treatment. RESULTS: During the screening phase, 84% (70/83) of the children responded to treatment and reached eligibility for the randomised trial after a median time of 5 months (range 1-18), with a median of 3 different medications (range 1-9). Thirteen children (16%) did not reach eligibility. Five months after treatment start, the difference in Conners Global Index (CGI) rating between responders and non-responders became highly significant (p = 0.0006). Improvement in CGI was much greater following the identification of the optimal medication than in the preceding suboptimal treatment period (p < 0.0001). CONCLUSIONS: Because of the necessity of identifying an optimal medication before response to treatment can be expected, randomisation at the start of treatment in an RCT of homeopathy in ADHD children has a high risk of failure to demonstrate a specific treatment effect, if the observation time is shorter than 12 months.

Cognitive functioning, behavior, and quality of life after stroke in childhood

Rationale: To provide a better understanding of cognitive functioning, motor outcome, behavior and quality of life after childhood stroke and to study the relationship between variables expected to influence rehabilitation and outcome (age at stroke, time elapsed since stroke, lateralization, location and size of lesion). Methods: Children who suffered from stroke between birth and their eighteenth year of life underwent an assessment consisting of cognitive tests (WISC-III, WAIS-R, K-ABC, TAP, Rey-Figure, German Version of the CVLT) and questionnaires (Conner's Scales, KIDSCREEN). Results: Twenty-one patients after stroke in childhood (15 males, mean 11;11 years, SD 4;3, range 6;10-21;2) participated in the study. Mean Intelligence Quotients (IQ) were situated within the normal range (mean Full Scale IQ 96.5, range IQ 79-129). However, significantly more patients showed deficits in various cognitive domains than expected from a healthy population (Performance IQ p = .000; Digit Span p = .000, Arithmetic's p = .007, Divided Attention p = .028, Alertness p = .002). Verbal IQ was significantly better than Performance IQ in 13 of 17 patients, independent of the hemispheric side of lesion. Symptoms of ADHD occurred more often in the patients' sample than in a healthy population (learning difficulties/inattention p = .000; impulsivity/hyperactivity p = .006; psychosomatics p = .006). Certain aspects of quality of life were reduced (autonomy p = .003; parents' relation p = .003; social acceptance p = .037). Three patients had a right-sided hemiparesis, mean values of motor functions of the other patients were slightly impaired (sequential finger movements p = .000, hand alternation p = .001, foot tapping p = .043). In patients without hemiparesis, there was no relation between the lateralization of lesion and motor outcome. Lesion that occurred in the midst of childhood (5-10 years) led to better cognitive outcome than lesion in the very early (0-5 years) or late childhood (10-18 years). Other variables such as presence of seizure, elapsed time since stroke and size of lesion had a small to no impact on prognosis. Conclusion: Moderate cognitive and motor deficits, behavioral problems, and impairment in some aspects of quality of life frequently remain after stroke in childhood. Visuospatial functions are more often reduced than verbal functions, independent of the hemispheric side of lesion. This indicates a functional superiority of verbal skills compared to visuospatial skills in the process of recovery after brain injury. Compared to the cognitive outcome following stroke in adults, cognitive sequelae after childhood stroke do indicate neither the lateralization nor the location of the lesion focus. Age at stroke seems to be the only determining factor influencing cognitive outcome.

Persistent versus transient depressive symptoms in relation to platelet hyperactivation: a longitudinal analysis of dementia caregivers

BACKGROUND: Depressive symptoms and caregiving stress may contribute to cardiovascular disease (CVD) via chronic platelet activation; however, it remains unclear whether this elevated activation constitutes a trait or state marker. The primary objective was to investigate whether persistent depressive symptoms would relate to elevated platelet activation in response to acute psychological stress over a three-year period. METHODS: Depressive symptoms (Brief Symptom Inventory) were assessed among 99 spousal dementia caregivers (52-88 years). Platelet P-selectin expression was assessed in vivo using flow cytometry at three time-points over the course of an acute stress test: baseline, post-stress, and after 14 min of recovery. Two competing structural analytic models of depressive symptoms and platelet hyperactivity with three yearly assessments were compared. RESULTS: Although depressive symptoms were generally in the subclinical range, their persistent elevation was associated with heightened platelet reactivity and recovery at all three-years while the change in depressive symptoms from the previous year did not predict platelet activity. LIMITATIONS: These results focus on caregivers providing consistent home care, while future studies may extend these results by modeling major caregiving stressors. CONCLUSIONS: Enduring aspects of negative affect, even among those not suffering from clinical depression are related to hemostatic changes, in this case platelet reactivity, which might be one mechanism for previously reported increase in CVD risk among elderly Alzheimer caregivers.

Exploring the genetic link between RLS and ADHD

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder of childhood onset. Clinical and biological evidence points to shared common central nervous system (CNS) pathology of ADHD and restless legs syndrome (RLS). It was hypothesized that variants previously found to be associated with RLS in two large genome-wide association studies (GWA), will also be associated with ADHD. SNPs located in MEIS1 (rs2300478), BTBD9 (rs9296249, rs3923809, rs6923737), and MAP2K5 (rs12593813, rs4489954) as well as three SNPs tagging the identified haplotype in MEIS1 (rs6710341, rs12469063, rs4544423) were genotyped in a well characterized German sample of 224 families comprising one or more affected sibs (386 children) and both parents. We found no evidence for preferential transmission of the hypothesized variants to ADHD. Subsequent analyses elicited nominal significant association with haplotypes consisting of the three SNPs in BTBD9 (chi2 = 14.8, df = 7, nominal p = 0.039). According to exploratory post hoc analyses, the major contribution to this finding came from the A-A-A-haplotype with a haplotype-wise nominal p-value of 0.009. However, this result did not withstand correction for multiple testing. In view of our results, RLS risk alleles may have a lower effect on ADHD than on RLS or may not be involved in ADHD. The negative findings may additionally result from genetic heterogeneity of ADHD, i.e. risk alleles for RLS may only be relevant for certain subtypes of ADHD. Genes relevant to RLS remain interesting candidates for ADHD; particularly BTBD9 needs further study, as it has been related to iron storage, a potential pathophysiological link between RLS and certain subtypes of ADHD.