Tic disorders: administrative prevalence and co-occurrence with attention-deficit/hyperactivity disorder in a German community sample.

Coexistence of tics and attention-deficit/hyperactivity disorder (ADHD) has important clinical and scientific implications. Existing data on the co-occurrence of tic disorders, Tourette Syndrome (TS), and ADHD are largely derived from small-scale studies in selected samples and therefore heterogeneous. The Nordbaden project captures the complete outpatient claims data of more than 2.2 million persons, representing 82% of the regional population in 2003. Based upon the number of diagnosed cases of tic disorders, TS, and ADHD, we determined 12-months administrative prevalence rates as well as rates of co-occurrence. Both tic disorders and ADHD were diagnosed most often in the age group 7-12 years (any tic disorder: 0.8%; ADHD: 5.0%). With increasing age, the administrative prevalence difference in favor of males disappeared, with tic disorders being somewhat more frequently reported in females than males in the age groups above 30 years. The highest rate of ADHD co-occurring with tic disorders was found in adolescents (age 13-18 years, 15.1%). Tic disorders were observed in 2.3% of patients with ADHD. Administrative prevalence rates of tic disorders and TS were substantially lower compared to rates found in community-based epidemiological studies, suggesting that a large number of cases remain undetected and untreated under present conditions of routine outpatient care.

[The health economics of attention deficit hyperactivity disorder in Germany. Part 1: Health care utilization and cost of illness]. / Gesundheitsökonomie der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung in Deutschland Teil 1: Versorgungsepidemiologie und Krankheitskosten.

In the German region of Nordbaden, 5% of children (aged 7-12 years) and 1.3% of adolescents (aged 13-19 years) were diagnosed with attention deficit hyperactivity disorder (ADHD) in 2003. About two thirds of these patients were not seen by a physician specialized in psychiatry. Now the National Association of Statutory Health Insurance Physicians in Germany (Kassenaerztliche Bundesvereinigung, KBV) has developed a proposal for the integrated provision of care for these patients, combining a guidelines-oriented multidisciplinary approach with a system of quality assurance. Against this background, currently available ADHD-related data are presented, covering epidemiology, comorbidity and differential diagnosis, health care utilization, and cost of illness. According to administrative data analyses from Nordbaden, direct medical costs for patients with ADHD, from the perspective of statutory health insurance (SHI), exceed those of matched controls by a factor of >2.5. On this basis, ADHD-related expenditures of the German SHI may be estimated at around EUR 260 million in 2003, and almost certainly will have continued to grow further since. In addition to this, a diagnosis of ADHD is associated with substantial indirect cost. Although the literature on the burden of ADHD is incomplete, it seems plausible that the cost of illness might be comparable to that reported for alcohol and addiction disorders. Thus we anticipate an increasing relevance of formal health economic evaluations of health care programs offered to patients with ADHD.

[The health economics of attention deficit hyperactivity disorder in Germany. Part 2: Therapeutic options and their cost-effectiveness]. / Gesundheitsökonomie der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung in Deutschland. Teil 2: Therapeutische Optionen und ihre Kosteneffektivität.

Attention deficit hyperactivity disorder (ADHD) has been associated with a continuous increase of health care utilization and thus expenditures. This raises the issue of cost-effectiveness of health care provided for patients with ADHD. Comparative health economic evaluations generate relevant insights and typically report incremental cost-effectiveness ratios (ICERs) of alternatives versus an established standard. Typically, results of cost-effectiveness analyses (CEAs) are reported in terms of incremental cost-effectiveness ratios (ICERs). International evaluations, as well specific adaptations to Germany, indicate an acceptable to attractive cost-effectiveness--according to currently used international benchmarks--of an intense medication management strategy based on stimulants, primarily methylphenidate, with ICERs ranging from 20,000 EUR to 37,000 EUR per quality-adjusted life year (QALY) gained. Economic modeling studies also suggest cost-effectiveness of long-acting modified-release preparations of methylphenidate, owing to improved treatment compliance associated with simplified once daily administration schemes. Atomoxetine, in contrast, appears economically inferior compared to long-acting stimulants, given its higher acquisition costs and at best equal clinical effectiveness. There are currently no data supporting the cost-effectiveness of psychotherapeutic or behavioral interventions. Economic evaluations, which have been published to date, are generally limited by time horizons of up to 1 year and by their prevailing focus on ADHD core symptom improvement only. Therefore, further research into the cost-effectiveness of ADHD treatment strategies seems warranted.

Expensive drugs for rare disorders: to treat or not to treat? The case of enzyme replacement therapy for mucopolysaccharidosis VI.

BACKGROUND: Mucopolysaccharidosis VI (MPS VI) is a very rare, chronically debilitating lysosomal storage disorder that develops in people with an enzyme deficiency. Clinical characteristics and progression rates vary widely between patients. The recent introduction of enzyme replacement therapy (ERT) has improved considerably the lives of patients with MPS VI, at an annual cost of treatment between euro 150,000 and euro 450,000 per patient. SCOPE: This Commentary article addresses the controversial topic of granting reimbursement for expensive treatment options for orphan diseases, such as MPS VI. The discussion reflects clinical, economic and ethical aspects and incorporates insights from the relevant literature (based on a Medline search to September 2008) on MPS VI, efficacy of ERT, orphan drugs, and the economics and ethics of health-care prioritisation. FINDINGS: Although ERT for MPS VI received marketing authorisation in the European Union in January 2006, patients' access to this therapy varies geographically due to differences between national reimbursement schemes for orphan drugs. Some inclusion and exclusion criteria for treatment of MPS VI patients with ERT appear arbitrary and may contribute to the exclusion from treatment of patients who could benefit in the long term. Reimbursement schemes which rely on proof of short-term treatment effectiveness may discriminate against slowly progressive patients, as health gain can often not be confirmed over a short period of time in these patients. Conventional cost-effectiveness analysis remains silent on crucial issues related to budgetary impact, i.e. opportunity cost from a system perspective, and fair access to treatment. CONCLUSIONS: To prevent patients from being deprived of effective treatment, it is suggested that inclusion and exclusion criteria for treatment should be primarily based on a careful individual assessment of expected long-term clinical benefits. Once treatment has been agreed to as the correct option on clinical grounds, it is further argued that the conventional cost-effectiveness criterion currently in widespread use does not offer a sufficient basis for rejecting reimbursement of expensive treatments for exceptionally rare disorders, providing that decisions on reimbursement are intended to reflect public preferences.

The use of cost-effectiveness by the National Institute for Health and Clinical Excellence (NICE): no(t yet an) exemplar of a deliberative process.

Democratic societies find it difficult to reach consensus concerning principles for healthcare distribution in the face of resource constraints. At the same time the need for legitimacy of allocation decisions has been recognised. Against this background, the National Institute for Health and Clinical Excellence (NICE) aspires to meet the principles of procedural justice, specifically the conditions of accountability for reasonableness as espoused by Daniels and Sabin, that is, publicity, relevance, revisions and appeal, and enforcement. Although NICE has adopted a highly standardised approach and continuously publishes key documents on its website, its technology appraisal programme does not fulfil the publicity condition of accountability for reasonableness. Economic models are not made sufficiently transparent to enable public scrutiny, and decision criteria other than cost-effectiveness remain enigmatic. NICE's reliance on cost-utility analysis and "plausible" cost-per-quality-adjusted life year (QALY) benchmarks further raises serious issues with regard to the relevance condition of accountability for reasonableness. This is illustrated by counterintuitive cost-per-QALY rankings that are difficult to justify using reflective equilibrium methods, and by the current debate surrounding expensive therapies for rare diseases ("orphan" treatments). In addition, an excessive focus on QALYs may stand in the way of exploiting the best available effectiveness evidence. The NICE mechanism for revision and appeals is also more restrictive than provided in accountability for reasonableness. As to the enforcement condition, no effective quality assurance processes are in place for technology assessments, and implementation of guidance remains imperfect. NICE, despite impressive efforts, appears to have a long way to go before meeting the conditions of accountability for reasonableness.

Calcium regulating hormones after oral and intravenous calcium administration.

The aim of this study was to determine the changes in serum calcium concentration and in the concentrations of calcium regulating hormones after a single oral or intravenous calcium administration. Standard dosages of calcium, as used in routine patient care, were employed. Intact parathyrin, calcitonin, calcitriol, calcidiol, total calcium, ionized calcium, total protein and phosphate were determined in 12 healthy young men before and up to 8 h after oral and intravenous administration of calcium. During a fortnight there were four study days with 1000 mg calcium orally (p.o.), 2000 mg orally, 180 mg calcium intravenous (i.v.) and a control day without calcium. During the study the men were on a low calcium diet. We observed a sharp increase in the calcium concentration after i.v. administration (15 min: total Ca: + 0.48 +/- 0.32 mmol/l; ionized Ca: + 0.25 +/- 0.15 mmol/l; p < 0.01). The concentration increase after the two oral loads was nearly identical. The maximal concentration of total calcium was reached after 120 min (1000 mg: + 0.1 +/- 0.04 mmol/l; p < 0.001; 2000 mg: + 0.12 +/- 0.04 mmol/l; p < 0.001). There was a significant increase in urinary calcium after all modes of calcium administration. Calcitonin increased significantly only after i.v. injection of calcium (+ 9.2 +/- 3.4 pmol/l; p < 0.001) while parathyrin decreased significantly after all modes of calcium administration (i.v.: 15 min: -1.9 +/- 0.88 pmol/l; p < 0.01; 1000 mg: 90 min: -0.78 +/- 0.75 pmol/l; p < 0.001; 2000 mg: 90 min: -1.02 +/- 0.57 pmol/l; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporin A in aplastic anemia--report of a workshop.

The management of aplastic anemia continues to challenge clinical investigators. With bone marrow transplantation or immunosuppression the prognosis of the patient with aplastic anemia has improved remarkably. For patients who are not eligible for bone marrow transplantation, antilymphocyte globulin has become the standard treatment. There is growing evidence that some patients also respond to immunosuppression with cyclosporin A. Further data suggest that combination of cyclosporin A with antilymphocyte globulin or androgens might be beneficial. An international workshop summarized the data on cyclosporin A treatment in aplastic anemia and attempted to create guidelines for the use of cyclosporin A in the management of aplastic anemia.

Glutamate decarboxylase-immunoreactive neurons in the aging rat hippocampus are more resistant to ischemia than CA1 pyramidal cells.

Glutamate decarboxylase (GAD)-immunoreactive, supposedly GABAergic inhibitory, neurons in various fields of the rat hippocampus and pyramidal cells in area CA1 were quantified 1 week after transient cerebral ischemia by 4-vessel occlusion. Whereas the number of CA1 pyramidal cells in Toluidine blue-stained semithin sections were found reduced by 50% when compared with controls there was no loss of GAD-immunoreactive cells in vibratome sections of hippocampus proper and fascia dentata. These data suggest that GABAergic hippocampal neurons are more resistant to ischemia than CA1 pyramidal cells.

Fine structure of GABAergic neurons and synapses in the human dentate gyrus.

Surgical tissue samples of the human dentate gyrus were immunostained for glutamate decarboxylase (GAD), the gamma-aminobutyric acid (GABA)-synthesizing enzyme, and studied by both light and electron microscopy. Immunoreactive neurons and terminals displayed similar morphological characteristics as known from studies in laboratory animals. Thus, GAD-positive neurons prevailed in the hilar region, whereas immunoreactive terminals were most frequently observed in the granular layer forming symmetric synaptic contacts with dendrites, cell bodies and axon initial segments of granule cells.

Cholinergic neurons in the hippocampus. A combined light- and electron-microscopic immunocytochemical study in the rat.

We report here on cholinergic neurons in the rat hippocampal formation that were identified by immunocytochemistry employing a monoclonal antibody against choline acetyltransferase (ChAT), the acetylcholine-synthesizing enzyme. In general, ChAT-immunoreactive cells were rare, but were observed in all layers of the hippocampus proper and fascia dentata with a preponderance in zones adjacent to the hippocampal fissure and in the part of CA1 bordering the subiculum. All immunoreactive cells found were non-pyramidal neurons. They were relatively small with round or ovoid perikarya, which gave rise to thin spine-free dendrites. These hippocampal neurons were very similar to ChAT-immunoreactive cells in the neocortex of the same animals but were quite different from cholinergic neurons in the basal forebrain, medial septal nucleus, and neostriatum, which were larger and more intensely immunostained. Electron-microscopic analysis of ChAT-immunoreactive cells in the hippocampus and fascia dentata revealed synaptic contacts, mainly of the asymmetric type, on cell bodies and smooth proximal dendrites. The nuclei of the immunoreactive cells exhibited deep indentations, which are characteristic for non-pyramidal neurons. Our results provide evidence for an intrinsic source of the hippocampal cholinergic innervation in addition to the well-established septo-hippocampal cholinergic projection.

Non-pyramidal neurons in the guinea pig hippocampus. A combined Golgi-electron microscope study.

Morphological characteristics of non-pyramidal neurons in the guinea pig hippocampus (regions CA1 and CA3) were analyzed by a correlated light and electron microscopic approach. Following Golgi impregnation, the cells were first studied under the light microscope and classified according to the location of their cell bodies and the distribution of their dendrites in the different hippocampal layers. Next, the Golgi impregnated non-pyramidal neurons were gold-toned and deimpregnated, allowing an electron microscopic analysis of the identified structures. With regard to cell body location and dendritic pattern, non-pyramidal cells are a rather heterogeneous group of neurons. Their perikarya were found in all hippocampal layers and their dendrites had a less regular orientation when compared to pyramidal neurons and granule cells. Two basic types, i.e., "vertical" and "horizontal" non-pyramidal neurons are described. Many cells were of an intermediate type with dendrites extending in all directions. Non-pyramidal cell dendrites were mostly devoid of spines but exhibited numerous varicosities. Non-pyramidal cell axons could sometimes be seen extending towards the pyramidal cell layer. A surprising uniformity was observed when the impregnated, identified non-pyramidal neurons were studied in the electron microscope. Their perikarya exhibited a well-developed endoplasmic reticulum and indented nuclei. Both the cell bodies and the varicose dendrites were densely covered with synaptic boutons which mainly formed asymmetric synaptic contacts. Only occasionally were symmetric synaptic contacts observed. Non-pyramidal cell dendrites extending into the stratum lucidum of CA3 were found to be contacted by the giant boutons of mossy fiber axons. In addition to synaptic contacts, the dendrites of gold-toned non-pyramidal neurons formed gap junctions with neighboring dendrites. The results are discussed in relation to recent immunocytochemical studies which have shown non-pyramidal neurons in the hippocampus to contain gamma-aminobutyric acid and/or various neuropeptides.