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New generation antipsychotics versus low-potency conventionalantipsychotics: a systematic review and meta-analysis Stefan Leucht, Kristian Wahlbeck, Johannes Hamann, Werner Kissling IntroductionAlthough new generation antipsychotics are increasingly Background The clearest advantage of new generation, replacing conventional agents such as chlorpromazine and atypical antipsychotics is a reduced risk of extrapyramidal haloperidol in some countries, many issues about these side-effects (EPS), compared with conventional compounds.
compounds need to be clarified. Of all the new generation These findings might have been biased by the use of the high- drugs, only clozapine has proven better than low-potency potency antipsychotic haloperidol as a comparator in most of conventional drugs in patients with schizophrenia that is the trials. We aimed to establish whether the new drugs resistant to treatment.1 Whether the new antipsychotics induce fewer EPS than low-potency conventional have an effect on primary negative symptoms or only on secondary negative symptoms is debatable.2 Althoughresults of a meta-analysis showed that use of the new Methods We did a meta-analysis of all randomised controlled drugs led to a modest, but significant, reduction of trials in which new generation antipsychotics had been schizophrenic relapses, the role of improved compliance compared with low-potency (equivalent or less potent than in the analysis was unclear.3 According to the reviews of chlorpromazine) conventional drugs. We included studies that the Cochrane schizophrenia group,4,5 the main advantage met quality criteria A or B in the Cochrane Collaboration of the new drugs is a low risk of extrapyramidal side- Handbook, and assessed quality with the Jadad scale. The effects (EPS). Reduction of EPS is important because primary outcome of interest was the number of patients who they have been associated with non-compliance, and can had at least one EPS. We used risk differences and 95% CIs be disabling and stigmatising for patients. However, this finding was biased by the widespread use of high doses ofcomparator drugs, mainly haloperidol, which have a high Findings We identified 31 studies with a total of 2320 risk of EPS. Low-potency conventional antipsychotics participants. Of the new generation drugs, only clozapine was such as chlorpromazine are frequently used worldwide,6 associated with significantly fewer EPS (RD=–0·15, especially in poorer countries, and are also known to 95% CI –0·26 to –0·4, p=0·008) and higher efficacy than low- induce fewer EPS than haloperidol. Therefore, we did a potency conventional drugs. Reduced frequency of EPS seen systematic review and meta-analysis of all prospective, with olanzapine was of borderline significance (–0·15, –0·31 randomised controlled trials, in which new antipsychotics to –0·01, p=0·07). Only one inconclusive trial of amisulpride, had been compared with low-potency conventional quetiapine, and risperidone and no investigations of compounds. The main aim of our investigation was to ziprasidone and sertindole were identified, but some evidence establish whether new generation antipsychotics induce indicates that zotepine and remoxipride do not lead to fewer fewer EPS than low-potency conventional drugs. Our EPS than low-potency antipsychotics. Mean doses less than secondary aims were to compare efficacy and drop-out 600 mg/day of chlorpromazine or its equivalent had no higher rates of both generations of drugs, and to assess dose risk of EPS than new generation drugs. As a group, new generation drugs were moderately more efficacious than low-potency antipsychotics, largely irrespective of the comparator Identification of trialsRandomised controlled trials were identified that Interpretation Optimum doses of low-potency conventional compared new generation antipsychotics (amisulpride, antipsychotics might not induce more EPS than new clozapine, olanzapine, quetiapine, remoxipride, generation drugs. Potential advantages in efficacy of the new risperidone, sertindole, ziprasidone, and zotepine) with generation drugs should be a factor in clinical treatment low-potency conventional drugs (chlorpromazine, decisions to use these rather than conventional drugs. chlorprothixene, levomepromazine, melperone, meso-ridazine, methotrimeprazine, perazine, pipamperone, promethazine, prothipendyl, thioridazine). Chlorpromazine is a standard low-potency conventional Klinik und Poliklinik für Psychiatrie und Psychotherapie der antipsychotic. These drugs are labelled low-potency Technischen Universität München, Klinikum rechts der Isar, because high doses are needed to block dopamine München, Germany (S Leucht MD, J Hamann MD, W Kissling MD); and substantially.7 In sufficiently high doses, low-potency The Zucker Hillside Hospital, Glen Oaks, New York, 11004, USA drugs are not, in principle, less effective than high-potency (S Leucht MD); STAKES (National Research and Development Centre antipsychotics such as haloperidol. All antipsychotics less for Welfare and Health), Helsinki, Finland (Prof K Wahlbeck MD) potent than, or of equivalent potency to, chlorpromazine Correspondence to: Dr Stefan Leucht, Klinik und Poliklinik für Psychiatrie und Psychotherapie der Technischen Universität We included remoxipride even though it was withdrawn München, Klinikum rechts der Isar, Ismaningerstr 22, from the market several years ago, because we did not expect to find many studies of these drugs, and therefore wanted to include all scientifically interesting data.
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schizophreniform, orschizoaffective disorder (ICD-9) schizophreniform reductiondisorder (DSM-III-R) Schizophrenia with acute 20% PANSS exacerbation (DSM-III-R) GIR=Global improvement rating. n=sample size. NI=not indicated. NDCS=no diagnostic criteria specified. CGI=clinical global impression. BPRS=brief psychiatric ratingscale. NOSIE=nurses, observational scale of inpatient evaluation. PANSS=positive and negative symptoms scale. DSM-II to IV=various editions of the diagnostic andstatistical manual of diseases. ICD-9=international classification of diseases 9th edition. *Mean and/or range or upper limit of range are given dependent on dataavailable. Table 1: Characteristics of included studies THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
N=number of trials included in the analysis. n=total number of patients included in the analysis. RD=risk difference for comparison with low-potency conventionalantipsychotics. NI=not indicated. ··=no data.
Table 2: New generation antipsychotics versus conventional low-potency antipsychotics Exclusion of remoxipride in a sensitivity analysis did not change the overall results. Investigations were included We combined data from all eligible studies in a meta- only if they met quality criterion A (adequate analysis using risk differences, and used 95% CIs as a randomisation) or B (usually studies stated to be measure of effect size. The risk difference—ie, the risk of randomised without a precise explanation of the an unfavourable outcome in experimental treatment- randomisation method) as described in the Cochrane allocated participants, minus the corresponding risk in Collaboration Handbook.9 We used the Jadad scale10 (range controls—was used because we expected low frequencies 0–5) to assess the quality of randomisation, double- of EPS in both groups. The risk difference gives more meaningful results than relative risks and odds ratios in We searched the Cochrane schizophrenia group’s such situations. To combine the results of the individual register of randomised schizophrenia trials (up to March, studies, we used a random effects model.14 2002), using combinations of old and new generation Heterogeneity—ie, significant differences between the drug names. The register is compiled by methodical results of trials—was assessed by ␹2 test of heterogeneity.
searches of biological abstracts (1985–2002), CINAHL The Mantel-Haenszel ␹2 test was used for calculation of (1982–2002), Cochrane library (issue 1, 2002), two-tailed significances of outcomes. The number- dissertation abstracts (1861–2002), EMBASE needed-to-treat (NNT) was calculated for significant (1980–2002), LILACS (1982–2002), MEDLINE results. NNT indicates the number of patients who must (1966–2002), PSYNDEX (1977–1995), PsycINFO be treated to prevent one bad outcome, and is the inverse (1876–2002), RUSSMED (1988–2002), and Sociofile (1973–2002). Relevant journals and conference Studies with negative or non-significant results are less proceedings were searched by hand.4 Furthermore, we likely to be published than studies with significant results.
searched the reference lists of Cochrane reviews of new The possibility of such a publication bias, which can affect generation antipsychotics,5 other important reviews,2,11,12 the results of a meta-analysis, was examined using the funnel-plot method.15 In this method, the effect sizes of manufacturers of new generation antipsychotics and the individual studies are plotted against their sample sizes first authors of primary research articles to identify and if all studies that have been done are published, a recently published reports, and to request further symmetrical figure resembling a funnel should result. information on the trials we had identified.
To identify potential dose effects, studies were plotted All data were extracted independently by two reviewers according to dose of low-potency conventional drug.
(SL, KW). Only dichotomous variables were analysed, Results are presented as (weighted) risk differences along because continuous data from rating scales on EPS in with their 95% CIs. Values less than 0 indicate effects trials of new generation antipsychotics were often skewed.
favouring the new antipsychotics; 95% CIs that do not Furthermore, most trial samples were small, so judgment cross the y-axis are significant (p<0·05, two-tailed).
of normal distribution was difficult. The primary Calculations were done with review manager 4.1, the outcome of interest was the number of patients who had meta-analytic software used by the Cochrane at least one EPS. As a measure of efficacy, we used the number of patients with no clinically significant We did post-hoc meta-regression analyses using a improvement as defined by the research workers of the random effects model (MetaWin version 2.0) to rule out original studies. Additionally, we analysed the number of study quality measured in Jadad scores, or association of patients who received antiparkinsonian medication at duration of wash-out phase or publication year with the least once, and the ones who dropped out of studies because of side-effects. We could not analyse the numberof patients with specific EPS since only a few trials resulted in usable data for specific EPS, and it was often There was no funding source for this meta-analysis.
unclear whether investigators had failed to report on aspecific EPS or whether the side-effect was absent.
Furthermore, different names were used for specific EPS, A search of the Cochrane schizophrenia group yielded so classification was sometimes difficult. Thus, these 109 citations of which 60 were excluded. Four were not results are not shown, but only one of 38 tests gave a relevant, 29 did not use a low-potency antipsychotic comparator, 14 were not randomised (case series or THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
Heterogeneity ␹2 =15·08 125/646 109/606 Figure 1: Risk difference between groups for EPSNGA=new generation antipsychotic. LPA=low-potency conventional antipsychotic. n=number of patients with at least one EPS. N=number of patients ingroup.
controlled clinical trials), nine were reviews with no usable communication) and one from the meta-analysis by data, three investigated healthy volunteers, and one study was still in the planning phase. Thus, 49 references for Table 1 lists the main characteristics of the 31 trials 27 studies were identified (only the principal reference of (2320 patients in total) that were included. Clozapine was each study is indicated). We identified 3 studies from most widely assessed (15 investigations), followed by Cochrane reviews16,17 (HGDV Study Group, personal zotepine (five), olanzapine and remoxipride (four each), THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
Figure 2: Efficacy analysis: number of patients with no clinically significant response*Pooled RD after studies with comparator doses lower than 300 mg/day of chlorpromazine equivalent were excluded. NGA=new generation antipsychotic.
LPA=low-potency conventional antipsychotic. n=number of patients with at least one EPS. N=number of patients in group.
and quetiapine, risperidone, and amisulpride (one each).
The mean daily dose of chlorpromazine equivalents No randomised controlled trials comparing sertindole or ranged from 100 mg41 to 1330 mg;20 the median of the ziprasidone with a low-potency antipsychotic were mean daily dose was 440 mg. Six investigations used an identified. Chlorpromazine was the comparator drug adequate randomisation method (Cochrane quality score in most trials (n=22), but several others used A); all others were said to be randomised, but the exact thioridazine,12,25,38–40 methotrimeprazine,41 and perazine.16,42,44 method was not explained (Cochrane quality score B).
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treatment response to clozapine, not because ofcomparative drug dosing, but because of resistance to the comparator. Of the eight studies17,21,23–25,27,29,31 for which dichotomous response data were not available, only two29,31 showed significant effects of clozapine with respect to overall efficacy at endpoint. In three small trials, fewer participants treated with clozapine used antiparkinsonian medication (p=0·06) than conventional drugs. The riskdifference for drop-outs because of adverse events did not significantly differ between groups (table 2). In four trials of olanzapine (n=194), more patients on chlorpromazine than on olanzapine had at least one EPS, but this result was of borderline significance (p=0·07). It should be noted that in the study by Conley and others,34all patients in the chlorpromazine group were also given benzatropine prophylactically. Despite this prophylaxis, more patients in the chlorpromazine group had EPS, sowe can assume that the benefit of olanzapine would have been greater if benztropine had not been given.
Furthermore, in a fixed-effects rather than random-effects model (which might also have been appropriate since Only three were single-blind (patients masked) (HGDV there was no significant heterogeneity) the difference was Study Group, personal communication),32,33 all others significant (p=0·02). More patients in the olanzapine were double-blind. All but five trials12,17,22,31,44 gave specific group improved compared with chlorpromazine (NNT 5, 95% CI 2–50, p=0·03). No study provided data on the The mean Jadad score was 3·4 (median 4). The median use at least once of antiparkinsonian medication and no of the mean wash-out phase was 4 days (range 0–14).
significant difference in terms of drop-outs due to adverse With the exception of a 1-year study,32 all were short-term with a duration between 4 and 12 weeks (median In only one trial (n=201) was quetiapine compared with 6 weeks). Most investigations were small with a median of chlorpromazine.35 Quetiapine did not seem to be tolerated 41 participants (range 15–268). Most patients had better than chlorpromazine. However, the low mean dose schizophrenia, but 18 had schizoaffective disorders, 19 of chlorpromazine, 384 mg/day, should be taken into had schizophreniform disorders, 13 had delusional account. Furthermore, a greater number of participants disorders, and 69 had an unclear diagnosis. However, the taking quetiapine were rated as improved compared with reports were published from 1974 to 2000, during which time diagnostic criteria varied, and several studies used Remoxipride was compared with chlorpromazine36 and only clinical judgment for diagnosis (table 1). thioridazine37-39 in four trials (n=264); there was no Table 2 shows the pooled results of the new generation pronounced difference between drugs with respect to the antipsychotics (figures showing effect sizes of single outcome indices. In one study,36 dichotomous data were studies can be obtained from the authors upon request).
not shown for EPS, but there was no difference in The overall results of trials that did not report antiparkinsonian medication used between groups.
In only one small trial (n=42) was risperidone In only one small study with 30 participants16 was amisulpride compared with perazine (a phenothiazine that difference in any tolerability outcome was seen. Patients is biochemically similar to chlorpromazine), and no given risperidone improved significantly compared with substantial difference was found in any outcome analysed.
those given methotrimeprazine (NNT 3, 95% CI 2–100, 11 of 15 studies of clozapine provided data for the p=0·04). However, methotrimeprazine was used at very number of patients who had at least one EPS.
low doses (mean 100 mg/day maximum 150 mg/day).
Importantly, fewer patients treated with clozapine had Zotepine was compared with chlorpromazine12,42,44 and EPS, than those treated with chlorpromazine (NNT 7, perazine41,43 in five trials (n=322). Zotepine did not prove 95% CI 4–25, p=0·008). However, results of individual better than chlorpromazine in any outcome parameter studies were heterogeneous, which might be explained by analysed. For one trial,12 no information could be a dose effect. Ranking of studies according to mean daily obtained, with the exception of global efficacy, which was dose of chlorpromazine equivalents suggested that the similar to thioridazine. Two groups41,43 did not report benefit of the drug was lost when low chlorpromazine dichotomous response data, but recorded no significant doses were used. Of the four studies that did not include differences in mean brief psychiatric rating scale scores at dichotomous data, two groups28,31 noted significantly fewer patients with EPS with clozapine EPS, using rating scales, In figures 1 and 2, the results of all trials are plotted whereas other researchers17,24 did not. More patients treated with clozapine achieved a clinically significant chlorpromazine equivalents. The data suggest that with improvement (NNT 7, 95% CI 4–33, p=0·02) than did mean chlorpromazine doses of less than 600 mg/day—a those on chlorpromazine. A dose effect was seen when general cut-off for moderate doses8,11 derived from reports were sorted according to dose ratio of clozapine to graphical presentation of the results—there were no chlorpromazine. In studies with low ratios (ie, higher differences in risk of EPS. Indeed, the pooled risk doses of chlorpromazine than clozapine) patients difference for the 16 studies (n=1252) in which doses benefited more from clozapine than chlorpromazine.
lower than 600 mg of chlorpromazine per day were given There were several trials of patients resistant to treatment, was 0·01 (95% CI –0·03 to 0·04, p=0·7). However, in in which high doses of conventional drugs might have eight studies (n=465) with mean doses 600 mg or higher, been used. In these groups, there might have been a better the risk difference was –0·26 (95% CI –0·37 to –0·16; THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
NNT 4, 95% CI 3–6, p<0·0001). Additionally, a funnel- chlorpromazine equivalent) than conventional drugs is plot (figure 3) suggests that trials that showed no benefit clinically relevant only if low-potency antipsychotics are of the new drugs compared with conventional drugs, with sufficiently effective in this dose range. In an important respect of EPS, might not have been identified (p=0·05).15 review, Baldessarini and others46 concluded that no Funnel plots for other outcomes did not suggest additional benefit of efficacy is obtained by using doses higher than 500–600 mg/day chlorpromazine or its However, no clear overall dose-effect was found in an equivalent. Bollini and colleagues47 noted that doses analysis of the group of patients without significant higher than 375 mg/day of chlorpromazine equivalents did improvement. In a heterogeneous dataset in which some not result in increased efficacy. Other investigators patients were given less than (RD –0·11, 95% CI –0·12 to suggested that the optimum dose of chlorpromazine –0·02; NNT 9, 95% CI 5–50), and some 600 mg or more equivalents is between 540 mg/day and 940 mg/day.45 The (RD –0·18, 95% CI –0·30 to –0·06; NNT 6, 95% CI differing conclusions of these reviews of conventional 3–17) of chlorpromazine equivalent per day, significantly drugs45,47 might be caused by methodological difficulties.
more patients given new generation antipsychotics The search strategies used were not clearly indicated, so improved compared with those given conventional drugs that different trials might have been included, meta- (figure 2). Figure 2 also shows that the reduced efficacy of analytic procedures were not applied, and both reviews conventional drugs at a dose of less than 600 mg/day included low-potency as well as high-potency could partly result from three investigations with mean doses of less than 300 mg/day.18,39,40 Chlorpromazine doses Some specific EPS (eg, dystonia) might be considered less than 300 mg/day are often no more efficacious than worse than others (eg, tremor), but for the reasons placebo for patients with schizophrenia.46 Indeed, after indicated, it was not possible to adequately analyse exclusion of these three trials, the new drugs proved no specific EPS. Also, scale-derived continuous data could more efficacious than conventional ones (n=1023, be more sensitive than global EPS rates (eg, quetiapine RR –0·06, 95% CI –0·14 to 0·02, p=0·15).
induced less akathisia according to a scale).35 With metaregression, no significant associations were Interpretation of the NNT was restricted to the trial noted between Jadad scores, washout phase, publication populations, and might not be indicative of NNTs outside year, and the two main outcomes (all p>0·1). With the same method, dose of conventional drug was associated Many patients in the trials were chronically ill, and such with EPS (coefficient=–0·0003, p=0·0007), but not with patients are known to be less sensitive with respect to non-response (coefficient=0·0000, p=0·9). A similar EPS. In a long-term investigation, patients who had not result was obtained with an ANOVA model in which the received antipsychotics previously, and had only one studies with doses less than 600 mg/day or more were clinical episode, had fewer EPS with clozapine (mean compared with those 600 mg/day (at least one EPS, dose 292 mg/day), compared with chlorpromazine (mean 319 mg/day).31 This trial lasted for 1 year, by contrast with Finally, we confirmed the results by a sensitivity the reports included in our review. Unfortunately, we analysis, in which comparators other than chlorpromazine were not able to extract the mean doses of the acute phase were excluded. No significant differences between groups or any other usable data for meta-analysis.
in terms of at least one EPS were recorded in ten studies Compared with high-potency drugs, low-potency (n=906, RD 0·01, 95% CI –0·04 to 0·06, p=0·8), but in conventional antipsychotics are associated with more eight studies in which 600 mg/day or more of the drug was autonomic side-effects. Such side-effects are less used (n=465, RD –0·26, 95% CI –0·37 to –0·16, consistently monitored in drug trials than EPS, and they p<0·0001; NNT 4, 95% CI 3–6). A significant benefit of would therefore have been difficult to summarise in a the new drugs in terms of response to treatment was seen meta-analysis. Several new generation drugs—especially in nine studies that used less than 600 mg/day of the drug clozapine—are sedatives, and need slow titration to avoid (n=457, RD –0·13, 95% CI –0·24 to –0·01, p=0·03; hypotension. Furthermore, autonomic side-effects are NNT 8, 95% CI 4–100) and in six studies that used more dose related, and thus not problematic up to a threshold than this amount (n=482, RD –0·18, 95% CI –0·30 to dose of chlorpromazine. Finally, there were no significant –0·06, p=0·004; NNT 6, 95% CI 3–17). differences between groups with respect to dropoutsarising from adverse events. However, this is a broad The results of our review indicate that there is a Although we reviewed a large number of patients, reasonable amount of evidence to suggest that clozapine individual studies were usually old and small.
produces fewer EPS than conventional drugs. Less robust Investigations with few patients have results that are prone evidence points to a similar result for olanzapine. For to fluctuation. We think that small study size often led to amisulpride, quetiapine, and risperidone only one, heterogeneity that could not be accounted for solely by inconclusive, trial was identified. Further evidence shows design differences between individual trials, and especially that zotepine and remoxipride do not lead to fewer EPS not by the mean doses used. With respect to efficacy, than chlorpromazine or similar drugs. The data indicate a some of this heterogeneity might result from different dose effect because, for doses less than 600 mg/day response criteria used by the investigators. We avoided chlorpromazine or its equivalent, patients on new using mean values derived from scales, which might have generation antipsychotics were not at significantly lower been more uniform, because in small samples such results risk of EPS than those on low-potency conventional are frequently skewed and cannot be used for meta- drugs. Thus, at mean doses less than this threshold analysis. Furthermore, although our mean Jadad quality amount, conventional drugs might not be associated with score (3·4) was higher than that noted by Thornley and more EPS than new generation antipsychotics. This result Adams49 in a large sample of schizophrenia trials (2·5), we is important because a low risk of EPS is thought to be the share their concern about diagnostic criteria that change main advantage of an atypical antipsychotic.
with time, short duration of wash-out phases, and absent Our finding that the new generation drugs had no lower descriptions of allocation and masking methods.48 risk of EPS (at mean doses less than 600 mg/day The data do not indicate a clear dose effect in terms of THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
effectiveness, and show that the new drugs are better than data, John Kane for his comments on the manuscript, and Mark Fenton conventional ones for all doses, whether less or more than for his assistance in the literature search. S Leucht is a contributing editor 600 mg/day chlorpromazine. Thus, we were not able to for the Cochrane Schizophrenia Group. This meta-analysis received nofunding.
replicate the correlation between comparator dose andadvantage of the new generation drugs suggested byGeddes and colleagues,9 who focused on the high-potency antipsychotic, haloperidol. Similar benefits of new Wahlbeck K, Cheine M, Essali A. Clozapine for schizophrenia generation antipsychotics compared with high-potency (Cochrane review). Cochrane Database Syst Rev 2003; 3: CDD51334.
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be 110 more responders than with chlorpromazine.
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When the 1997 dengue epidemic occurred in Belém, was worried because several patients had also developed Brazil, I saw several patients with fever and other common jaundice and hemorrhages, and had died. The colleague symptoms of dengue including skin rash. I recall one was puzzled because he didn’t know that fatal cases of patient, who was the daughter of a colleague with the same rubella occurred or were accompanied by jaundice and clinical symptoms as the others. After the physical haemorrhages. When the samples were examined in our examination, I concluded that she also had dengue fever. I laboratory, it was observed that the cases diagnosed as only requested blood tests to confirm the case as dengue, rubella were in fact caused by Mayaro virus, an Alphavirus at the request of the relatives. To my surprise, the serology, related to chikungunya and Semliki Forest viruses, and including a convalescent sample, and the attempts at viral that the cases presenting with jaundice and haemorrhage isolation were negative. Due to my diagnosis, and pressure were in fact yellow fever. This was one of the first from her family, she had been discharged without further simultaneous epidemics of these two viruses in the tests. Subsequently, I was obliged to request them and Brazilian Amazon region, both transmitted by mosquitoes they showed an exuberant serological conversion for in the forest. Since then, I adopted a more conservative cytomegalovirus. During a rubella epidemic that happened position for the clinical diagnosis of diseases presenting in a small city near Belém several years ago, a doctor with fever and skin rash. The most prudent course is to telephoned to our laboratory to tell us the occurrence of request examinations for the viruses most prevalent in the several cases in the city. The picture was typical with fever, area and wait for the laboratory results. Some results can skin rash, arthralgia, and lymphadenopathy. The colleague Department of Arbovirus, Instituto Evandro Chagas, FUNASA, Ministry of Health, 66090-000, Belém, PA, Brazil (P F C Vasconcelos PhD) THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.

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Practice Test 4 While evaluating a patient 43 y/o male with back pain, your inquiry reveals possible immediate concern is the possibility of: A 46-year-old male presents with complaints of numbing and tingling to the fingers of the right hand, relating that he occasionally wakes in the middle of the night and the hand is 'asleep'. Additionally, he states that he has trouble lift

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