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Arch Gen Psychiatry 1987;44: dyskinesia following neuroleptic withdrawal symptoms 4dpiui purchase detrol paypal. Effect of sodium valproate trolled medicine shoppe best 1 mg detrol, long-term study of the comparative incidence of treat- on tardive dyskinesia medicine woman cast 2 mg detrol overnight delivery. Identifying risk factors for tardive dyskinesia in a schizophrenic patient treated with the atypical Chapter 126: Tardive Dyskinesia 1841 antipsychotic substance quetiapine. Animal models of depression and schizo- patients with schizophrenia before and after acute neuroleptic phrenia. J Neurol Neurosurg Psychiatry 1986;49: psychopharmacology. Spontaneous orofacial movements induced in Psychiatry 1998;155:1521–1528. Tardive dyskinesia in nomenology, pathophysiology and putative relationship to tar- elderly psychiatric patients: a 5-year study. A controlled, cial dyskinesia and dopaminergic function in rats after 6 months dose-response study of sertindole and haloperidol in schizophre- of neuroleptic treatment. BERTRAM Epilepsy is a chronic condition characterized by sponta- ment of uncontrolled seizures. Removal of the hippocampus neously recurring seizures. Although often viewed and dis- (together with adjacent structures) often successfully con- cussed as a single clinical entity, epilepsy is a symptom of trols seizures in 'intractable' patients whose seizures do not several disorders that affect the brain. For these reasons, a general con- is quite extensive and includes tumors, congenital malfor- sensus has developed that the hippocampus is the key to mations, genetic alterations in receptors or channels, and understanding and treating limbic epilepsy, and much of acquired structural abnormalities such as those following the research directed at MTLE has focused on this area of trauma or infection. However, there is increasing evidence that other causes, such as rolandic epilepsy, are self-limited and benign, structures of the limbic system, such as the amygdala, parts whereas others are progressive (1). The seizures in some of the neocortex, and the entorhinal cortex, which is a phy- forms of epilepsy may arise from the entire brain at one logenetically older part of the cortex that controls the infor- time, whereas in other forms they start in a particular region mation flow into and from the hippocampus (3), also play or focus. Any region of the brain can serve as a seizure focus, important roles in the initiation and propagation of seizures but seizure onset is commonly observed in the temporal in MTLE. Although there are multiple causes for epilepsy origi- Support for the involvement of nonhippocampal limbic nating in the temporal lobe, the most common form is the sites in MTLE comes from a variety of sources. As reviewed mesial temporal lobe epilepsy syndrome (MTLE), sometimes in this chapter, extrahippocampal areas frequently show also termed limbic epilepsy because of the apparent involve- pathologic structural changes on histologic examination. The common clinical pattern during the seizure epi- of diffuse limbic onset without a regional predilection (4, sode includes staring and lack of responsiveness, frequently 5). Imaging studies have also indicated that there is atrophy accompanied by automatisms of hand activity and mastica- or metabolic change in medial temporal structures other tion. There is often (but not always) a history of prolonged than the hippocampus, as well as in subcortical structures febrile convulsions in early childhood and common patho- with limbic connections (6–8). Surgical results have sug- logic features of atrophy and neuronal loss in the hippocam- gested that it is necessary to remove more than the hippo- pus, a structure located on the medial border of the temporal campus to achieve successful outcome (9,10). Seizure onset is frequently detected in the hippocam- is ample evidence from a variety of animal models of limbic pus when EEG depth recordings are made directly from epilepsy that extrahippocampal sites participate in epilepto- this area in patients undergoing evaluation for surgical treat- genesis, demonstrate anatomic and neuropathologic changes, and show alterations in cellular physiology. In many instances, changes in these regions are greater than Robert Schwarcz: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland. Scharfman: Neurology Research Center, Helen Hayes Hospital, The advent of new imaging techniques, the development West Haverstraw, New York. Bertram: Department of Neurology, University of Virginia of several useful new animal models of limbic epilepsy that Medical Center, Charlottesville, Virginia. In this chapter, centrality of the hippocampus and associated 'limbic' brain we review current knowledge of the neuropathology, physi- regions in MTLE (psychomotor epilepsy). By the 1950s, sup- ology, anatomy, and neurochemistry of MTLE and com- port had developed among leading epilepsy researchers for pare the hippocampus with extrahippocampal limbic re- the concepts that MTLE (a) was a 'network' disorder, gions.

Introduction of rigorous infection-control strategies has led to a remarkable decline in the spread of H BV infection in dialysis units hair treatment purchase detrol cheap. Physicians also are increasingly recognizing the association between chronic hepatitis C virus (H CV) infection and glomerular disease medications on carry on luggage order detrol with visa, both in native kidneys and renal allografts medicine 4211 v purchase detrol without a prescription. Liver disease caused by H CV is a major factor in morbidity and mortality among patients with ESRD treated with dialysis and transplantation. The first part of this chapter focuses mainly on issues related to H CV infection. The second part of this chapter examines the renal complications in patients with human immunodeficiency virus (H IV) infection. O ur knowledge about H IV has increased greatly, and dram atic advances have occurred in the treatm ent of patients with acquired im m unodeficiency syndrom e (AIDS). For the first tim e since the dis- C H A P T ER covery of the disease, deaths are decreasing. N evertheless, in the United States, as of June 30, 1997, there were over 600,000 cum ula- tive cases of H IV infection, with over 400,000 deaths. W orldwide, the H IV epidem ic continues to spread; an estim ated 20 m illion per- sons are infected with H IV. Recent advances in the clinical m anage- m ent of these patients result from better understanding of the repli- cation kinetics of H IV, assays to m easure viral load, availability of 7 7. The incidence of renal aggressive protocols com bining antiviral drugs substantially com plications in this population is expected to increase further reduce H IV replication. Thus, prolonged survival of patients as patients live longer. Hepatitis B and C Virus FIGURE 7-1 RENAL DISEASE ASSOCIATED W ITH Renal disease associated with hepatitis B. Infection with HEPATITIS B VIRUS INFECTION hepatitis B virus (H BV) m ay be associated with a variety of renal diseases [1,2]. M any patients are asym ptom atic, with plas- m a serology positive for hepatitis B surface antigen (H BsAg), hepatitis B core antibody (H BcAb), and hepatitis B antigen Lesion Clinical presentations Pathogenesis (H BeAg). The pathogenetic role of H BV in these processes has Membranous nephropathy Nephrotic syndrome Deposition of HBeAg been docum ented prim arily by dem onstration of hepatitis B anti- with anti-HBeAb gen-antibody com plexes in the renal lesions [1,3,4]. Three m ajor Polyarteritis nodosa Vasculitis, nephritic Deposition of circulating form s of renal disease have been described in H BV infection. In antigen-antibody m em branous nephropathy, it is proposed that deposition of complexes H BeAg and anti-H Be antibody form s the classic subepithelial Membranoproliferative Nephrotic, nephritic Deposition of complexes im m une deposits [1,3–5]. Polyarteritis nodosa is a m edium -sized glomerulonephritis containing HBsAg and vessel vasculitis in which antibody-antigen com plexes m ay be HBeAg deposited in vessel walls [1,2]. Finally, m em branoproliferative glom erulonephritis is characterized by deposits of circulating HBeAg— hepatitis B antigen; HBsAg— hepatitis B surface antigen. Furtherm ore, evidence exists suggesting direct involve- m ent of H CV-containing im m une com plexes in the pathogenesis of Disease Renal manifestations Serologic testing this renal disease. Sansono and colleagues dem onstrated Mixed cryoglobulinemia Hematuria, proteinuria Positive cryoglobulins; H CV-related proteins in the kidneys of eight of 12 patients with [6–11] (often nephrotic), rheumatoid factor cryoglobulinem ia and m em branoproliferative glom erulonephritis variable renal insufficiency often present (M PGN ) by indirect im m unohistochem istry. Convincing clinical Membranoproliferative Hematuria, proteinuria Hypocomplementemia; data exist suggesting that H CV is responsible for som e cases of glomerulonephritis (often nephrotic) rheumatoid factor and cryoglobulins may be M PGN and possibly m em branous nephropathy [13–15]. In one present report of eight patients with M PGN , purpura and arthralgias were Membranous Proteinuria Complement levels normal; uncom m on and cryoglobulinem ia was absent in three patients. Establishing the diagnosis of H CV infection in these diseases is im portant because of the potential therapeutic benefit of -interferon treatm ent.

These investigators medications affected by grapefruit 1 mg detrol, therefore medications dictionary purchase detrol 1mg on line, in­ results as suggesting that major depression complicating de­ terpreted depressed mood as reflecting 'demoralization' mentia is responsive to somatic antidepressant treatments treatment esophageal cancer cheap detrol online mastercard, rather than major depressive disorder. Given these prob­ but both investigators acknowledged that standardized, lems, it is not surprising that estimates of the prevalence of double-blinded, placebo-controlled studies of antidepres­ depression in AD are widely disparate. Perhaps the true sants in dementia patients with major depression are prevalence of concurrent depression in AD lies somewhere needed. As early as 1955, Sir Mar- The SSRI antidepressants are theoretically attractive tin Roth (21) addressed the issue of differentiating the com­ drugs for the treatment of depression in AD. Decreased mon 'affective coloring' seen in dementia patients from numbers of serotoninergic neurons in the dorsal raphe nu­ the relatively uncommon 'sustained depressive symptom cleus and decreased concentrations of the serotonin metabo- complex. Enhancing serotoninergic neurotransmission by inhib­ iting serotonin reuptake theoretically might alleviate depres­ sion in AD. Furthermore, the adverse effect profile of SSRIs Psychopharmacologic Approaches is relatively benign compared with those of the tricyclics It continues to be disappointing that the extensive interest and MAOIs. SSRIs are not anticholinergic, nor do they in defining the prevalence of depression complicating AD produce orthostatic hypotension. These theoretic advan­ has generated few interpretable studies evaluating the out- tages likely account for the increasing use of SSRIs in elderly come of antidepressant treatment in such patients. These reports Placebo-Controlled Outcome Trials suggest that depression complicating AD may respond to tricyclic antidepressants (22,23), monoamine oxidase inhib­ Despite the widespread use of antidepressants in patients itor (MAOI) antidepressants (24), or selective serotonin with AD and other dementing disorders (32), it is clear that reuptake inhibitors (SSRI) (25). In an open trial of nortrip­ this use is not grounded in an adequate empiric database. Depression Scale (HAM-D) scores (27) from 17 before Reifler et al. Although the reduction in (n � 13) or placebo (n � 12) subjects who met DSM­ depressive signs and symptoms was substantial in AD pa­ III criteria for both primary degenerative dementia of the tients with concurrent depression, it was less robust than in Alzheimer type and major depressive episode. AD outpa­ a similarly treated group of elderly nondemented depressed tients (mean age, 72) had a mean Mini-Mental State Exami­ patients. Another open trial of 'naturalistic' somatic antide- nation (MMSE) score of 17 [very comparable with the mean pressant treatment of inpatients with dementia and concur- MMSE scores of the demented, depressed patients studied rent depression was reported by Greenwald et al. Imipramine (mean depression have several implications. First, the robust re­ dose, 83 mg/d; mean plasma level of imipramine plus des­ sponses of the placebo group make it essential to include a methylimipramine, 116 ng/mL) or placebo was prescribed placebo group in future antidepressant drug outcome trials for 8 weeks. Substantial, highly significant, and almost iden­ in dementia patients if the results are to be interpretable. Imipramine was controlled trial demonstrating efficacy of behaviorally based generally well tolerated in these subjects. However, its cen­ psychotherapy for depression in AD outpatients is consis­ tral anticholinergic effect likely accounted for subtle decre­ tent with this interpretation (38). Second, the absence of ments in cognitive function in the imipramine group. The SSRI adverse effects on cognitive function or blood pressure improvement in HAM-D scores was similar to that achieved regulation is an advantage for this class of antidepressant in the open inpatient studies reported by Greenwald et al. More placebo-controlled trials of (28) and Reynolds et al. This outpatient study demon­ SSRIs (and other newer antidepressants, such as venlafaxine strated that depressive signs and symptoms can be reduced and nefazodone) in AD patients with concomitant depres­ in outpatients with AD, but the mechanism of treatment sion would be informative.

A large 12-week symptoms kidney pain buy genuine detrol, multi- receiving placebo (defining response as much or very much center treatment 0 rapid linear progression buy detrol 1mg free shipping, placebo controlled symptoms 24 purchase detrol in united states online, double-blind trial of sertraline improved on the improvement item of the Clinical Global in three fixed doses (50, 100, or 200 mg per day), found Impression Scale). Of special interest, Goodman and associ- sertraline at 50 and 200 mg per day to be significantly more ates (83) demonstrated the selective efficacy of SSRIs in effective than placebo, but the 100-mg dose was not more OCD because fluvoxamine (up to 300 mg per day) was effective than placebo. Clinical outcome was not correlated significantly more effective than the norepinephrine reup- with sertraline plasma levels (86). Paroxetine A large multicenter placebo controlled study of paroxetine Sertraline in three fixed doses (20, 40, and 60 mg per day) found that Although one early study did not find sertraline to be supe- the 40- and 60-mg doses were significantly more effective rior to placebo in the treatment of OCD (84), several subse- than placebo, but the lower dose (20 mg) was not more quent studies have demonstrated its efficacy in OCD. There was a suggestion of a Chouinard and associates (85) found sertraline (up to 200 dose–response relationship, and paroxetine was well toler- mg per day) to be more effective than placebo on all out- ated in the acute dose study phase. Chapter 114: Current and Experimental Therapeutics of OCD 1651 Citalopram occur as a result of alpha1-adrenergic antagonism (44). Citalopram, the most selective of the SSRIs, has not been SSRIs are relatively safe compared to TCAs. In a 24-week open pilot deaths have been reported following overdose with SSRIs. In a 10-week single-blind study of 30 patients side effects can contribute to noncompliance, sexual dys- with OCD who underwent randomized treatment with flu- function is seen in as many as one-third of patients (92) but voxamine, paroxetine, or citalopram, there were no signifi- may not be readily reported unless the clinician specifically cant differences found between the three treatments, al- inquires about it. There are little systematic data on the though the study was underpowered to detect significant treatment of SSRI-induced sexual dysfunction, but case re- differences between active treatments (88). Recent con- ports and clinical practice have shown that effective inter- trolled treatment trials suggest efficacy in OCD (89). There also exists a clinically significant discontin- ising, it has been withdrawn from use owing to several re- uation syndrome that occurs on abrupt discontinuation of ports of Guillain-Barre syndrome occurring during treat- an SSRI with short half-life (71). Drug Interactions Venlafaxine Patients treated for OCD often take concurrent medica- Venlafaxine, a serotonin/norepinephrine reuptake inhibi- tions; therefore, potential drug interactions should be con- tor, has not been systematically studied in controlled trials sidered when selecting an antiobsessional agent. In addition in OCD, but open pilot data suggest potential efficacy and to well-established drug interactions known to occur with the need for controlled trials (90). The hypo- tensive effects of clomipramine can be exacerbated by - Side Effects methyldopa, -adrenergic blockers, clonidine, diuretics, Efficacy must be balanced against side effects in choosing and low-potency antipsychotics. Quinidine and other class treatment options, and side-effect profile is magnified in Ia antiarrhythmics as well as thioridazine, mesoridazine, and OCD because the treatment is likely to be chronic. All SRIs pimozide may add to cardiotoxic effects of TCAs. Common can cause side effects attributable to their serotonergic ac- medications that have anticholinergic effects can synergize tion. Clomipramine, a TCA, is most apt to cause anticholin- with TCAs to produce anticholinergic toxicity, including ergic and antiadrenergic side effects, whereas SSRIs tend to antihistamines, antiparkinsonians, low-potency antipsy- cause fewer side effects mediated via nonserotonergic recep- chotics, over-the-counter sleeping pills, and antispasmodics tor systems (43–45,91–95). Conversely, TCAs such as clomipramine TCAs such as clomipramine have a quinidine-like anti- can potentiate the effects of warfarin or block the effects of arrhythmic effect that slows intracardiac conduction (95). Although generally an issue only in patients with known SSRIs can participate in drug interactions as a conse- cardiac disease, occasional adverse effects may be seen in quence of effects on the hepatic cytochrome P-450 system patients with no documented pre-existing condition. As each SSRI is metabolized by one or more isoen- thermore, in overdose, the cardiac conduction effects of zymes of cytochrome P-450, they may either inhibit or in- TCAs lead to much greater toxicity than the SSRIs. This duce the corresponding enzymatic activity, thereby affecting is important, because there is an increased rate of suicide the metabolism of other drugs. Conversely, other medica- attempts in OCD, especially when associated with comor- tions can inhibit or induce the P-450 system, thereby modu- bid disorders. TCAs have anticholinergic effects that can lating the metabolism of SRIs.

In case E1 symptoms pregnancy buy detrol visa, provider clinicians appear not to have fully understood the new integrated care model medications after stroke purchase detrol 1mg without prescription. In case E2 symptoms leukemia buy cheap detrol, provider clinicians continued to query the concept of the single point of entry for urgent and emergency care. In case F, provider staff had little contact with, or even knowledge of, the ACO concept that was being developed within an innovative and highly collaborative strategic arena. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 77 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. CROSS-CASE FINDINGS AND COMPARISONS Factors shaping clinical leadership Tables 6–8 summarise what was has been achieved through the exercise of clinical leadership across the three arenas in our eight cases, dividing them into the same two groups as above. The tables summarise the factors that were found to help or hinder forms of clinical leadership capable of bringing about service innovations. We have already seen that the coherence of implementation of service redesign was greater in the four cases in Table 5, and this is reflected in the specificity of the achievements documented. The achievements shown emphasise service outcomes, whereas those in Table 6 mostly emphasise service arrangements that have yet to deliver improved outcomes. However, Tables 5 and 6 emphasise that both groups of four cases involved clinicians grappling with both favourable and unfavourable conditions as they engaged with the challenges of service redesign. TABLE 6 Cases demonstrating less consistent relationships between arenas of clinical leadership Case study: clinical leadership activities Case F: towards an Case D: system and Case E1: redesigning Case E2: redesigning accountable managed Arena multilevel redesign integrated care urgent care care organisation Strategic Six CCGs working GPs in formal lead roles CCG establishes review Devolved locality plans commissioning together across a shape aspirations for of urgent-care services, for city-wide integration and budget county to address integrated care service given inconsistent of health and social care holding existing poor redesign across a formal facilities and services under development, performance and collaboration between across its area and with the LA and CCG financial shortfalls. In four CCGs and LAs increasing demand discussing the form of a parallel, finance-led health and social care CCG-level initiatives, ACO with strong influence from NHSE Operational GP federation supports GPs in formal lead roles Clinical leads of a GP Specific collaborative commissioning, establishment of a local shape nature and out-of-hours centre, an projects between CCG monitoring and pilot integrating primary objectives of integrated urgent-care centre, a and LA (e. BCF and evaluation care across practices care programme, and walk-in centre, A&E and Warm Homes scheme), with community communicate these to GP extended hours where health funds services, with support GP community explore models for contribute to improving from NHSE rather than consistent access to homes and advising the CCGs urgent care residents Operational GP practice-led GPs in practice Working party of GPs GPs and acute providers delivery and initiatives for sharing networks call for more and acute A&E clinicians involved in specific and shaping of capacity across a locality focus on operational agree on telephone relatively narrow scope practice and integrating with detail and education of access as first point of improvements to existing community services and different staff groups. As yet, little community hospitals Community services working party designs engagement or run by primary care struggle to understand protocols. Some GPs involvement in the staff, supported by GP the new models of continue to advocate conception of the ACO federation and to an integrated care extended-hour GP extent by CCGs services as first port of call 78 NIHR Journals Library www. The first key enabler concerns the nature of the clinical leadership itself – in the sense of what it is that clinicians see themselves as providing leadership about. Throughout all of our cases, clinical leadership can be seen as closely bound to aspirations to improve health outcomes and the experience of patients. Variously the benefits being sought include: l improving the quality and consistency of primary care, thereby decreasing the burden on acute care l improving understanding of patient preferences and needs, and communication between service providers and patients l achieving simpler patient journeys and better integration of care both within the health service and with other partners l improving efficiency and reducing wasted resources l improving system resilience and delivery. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 79 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. CROSS-CASE FINDINGS AND COMPARISONS TABLE 8 Factors affecting the exercise of clinical leadership in less integrated cases Case study: clinical leadership activities Achievements, facilitating Case F: towards an factors and Case D: system and Case E1: redesigning Case E2: redesigning accountable managed challenges multilevel redesign integrated care urgent care care organisation Key Primary care networks, Large-scale programme Principle of first-line Productive relationship achievements integrating GP practices for integrated care, with access to urgent care by with LA, including 800 with some specialist services to support telephone agreed homes benefiting from clinics, have emerged in self-care, care Warm Homes scheme, a few localities co-ordination and attracting £1M external appropriate discharge investment; well from hospital. Clearly positioned in reputation argued and widely and relationship terms disseminated strategic for the emerging new rationale for this structures at regional level Factors Some GPs have history Shared history among Clinicians in various Established partnership facilitating of collaborating to GPs of collaborating to services have previous at senior level between clinical lead address issues arising improve health of a experience of defending GP chairperson and from poor performance disadvantaged locality; the future of their strategic manager; of local acute sector culture of independence services while responding established collaboration from national NHS to the need for between CCG, LA and direction; good relations rationalisation and other public agencies between GPs and acute integration sector clinicians Challenges CCG clinical leads Lack of understanding Some providers involved Clarifying the scope, facing clinical experience at practice level of how are reluctant to move a boundaries and leadership disempowerment in new models of care service model where governance mechanisms terms of influencing should function; some their service would no for an ACO covering emerging service confusion as a result of longer be first point of primary care and models, squeezed multiple initiatives call. Concerns for the community services; between initiatives coming from highly future viability of some bringing operational emerging from GP committed and services are not fully clinical leadership into practice grouping and ambitious strategic addressed implementation of the larger-scale STPs leaders ACO Such benefits provide the core of a set of values that clinicians in both commissioning and providing roles have used to spread awareness of and commitment to new models of service provision.

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