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Do steroids benefit patients with bacterial meningitis? Vincent Quagliarello and W. Michael Scheld

Bacterial meningitis causes substantial neurological morbidity and mortality worldwide. The use of corticosteroids as adjunctive therapy to antibiotics has been studied in clinical trials and debated for decades. A new meta-analysis attempts to reconcile some of the disparate findings from trials in this field.

Bacterial meningitis remains a persistent global public health problem, despite the efficacy and availability of conjugated vac-cines, which have reduced the burden of this disease in the us and many other high-income countries.1 the wHo estimates an annual global incidence of bacterial meningi-tis of ≈698,000 episodes, resulting in 156,000 deaths (almost half of which are in children under the age of 5 years). in middle-income and low-income countries, meningitis is the fourth leading cause of disability.2

the value of corticosteroids as comple-mentary therapy to antibacterials for patients with bacterial meningitis has been debated for over 30 years. more than 20 clini cal trials have been conducted in chil-dren and adults, and have demonstrated inconsistent benefits in terms of survival and neurological morbidity. a recent meta-analysis by van de Beek and colleagues attempts to reconcile the disparate findings from individual trials, and asks whether adjunctive steroids improve outcomes only in certain subsets of patients.3

evidence-based guidelines for acute manage ment of meningitis have been pub-lished and updated on the basis of various efforts to define optimal antibiotic and adjunctive treatment measures—in particu-lar the use of adjunctive cortico steroids—for improving clinical outcomes.4,5 over the past three decades, experimental and clinical studies have tested the efficacy of adjunctive

dexamethasone for bacterial meningitis, in view of the biological plausi bility of reducing the effects of the acute innate inflammatory response within the Cns.6

a 2007 Cochrane meta-analysis of 20 clinical trials concluded that the benefits of steroids in meningitis seemed to vary depending on age and nation of origin.7 For children (aged >1 month), adjunctive steroids reduced the rate of severe hearing loss from 11.0% to 6.6% overall, but the benefit was evident only for those in high-income countries. For children in low-income countries, adjunctive steroids were neither beneficial nor deleterious. in adults, adjunctive steroids reduced overall mortal-ity from 21.7% to 11.7%. although potential sources of bias were recognized in this sys-tematic review (for example, selection bias, participant withdrawal, competing risks of outcomes, and heterogeneity of study proto-cols), the authors recommended adjunctive steroids for all adults with bac terial meningi-tis, and for children with bacterial meningitis in high-income countries with appropriate access to acute medical care. the authors cautioned at the time, however, that two ongoing trials in adults with bacterial men-ingitis in low-income countries were yet to be published, and that questions remained about whether specific subgroups of children from low-income countries might benefit from adjunctive steroids.

as anticipated by the authors of the Cochrane review, the two large clinical trials in adults with bacterial meningitis in low-income countries showed conflicting results. in a trial conducted in malawi, adjunctive steroids did not reduce morbidity or mor-tality.8 in a trial of adolescents and adults (aged >14 years) with bacterial meningi tis in vietnam, the intention-to-treat analysis

of all patients showed that adjunctive ste-roids did not reduce the risk of death at 1 month, or the risk of death or disability at 6 months.9 only a subset analysis of patients with microbiologically confirmed bacterial meningitis, representing 69% of the total cohort, revealed benefits from adjunctive steroids, which were confined to patients with Gram-positive etiology. Given that the most common microbiologically con-firmed etiology of meningitis in vietnam was Streptococcus suis, questions remained about the generalizability of even this subset benefit, since this cause of meningitis is rare outside asia.

the conflicting evidence from these two trials supported the idea that the effects of adjunctive steroids differ among geographic locales. the new findings prompted van de Beek et al. to conduct an updated meta- analysis.1 this analysis included five ran-domized, double-blind, placebo- controlled trials of adjunctive dexamethasone for bac-terial meningitis published since 2001 in which individual raw patient data were available. the five trials included the two aforementioned adult trials in malawi and

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‘‘In middle-income and low-income countries, meningitis is the fourth leading cause of disability’’

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vietnam, an adult trial conducted in western europe, and pediatric trials from south america and malawi. in total, the authors analyzed original data from 2,029 patients. the salient conclusion of this meta-analysis was that dexamethasone did not improve survival (either with or without improve-ment in hearing loss or neuro logical mor-bidity). the only benefit observed among survivors was a reduction in hearing loss. Further analyses of predefined subgroups of patients with similar bacterial causes, Hiv status, age or pre- dexamethasone antibiotic treatment revealed no benefits of adjunctive dexa methasone for any particular subgroup.

this new meta-analysis had several strengths, including the methodo logical rigor of the five individual trials, the avail-ability of individual participant data, clini-cally relevant outcomes, and prespecified subgroups. the main limitation of the analysis was that the reported tests for hetero geneity between the studies (includ-ing some that revealed heterogeneity) were constrained by the data collected.10 First, examination of the effect of Hiv status was limited by the fact that even in the malawi studies Hiv testing was not performed on all patients, and participants were assigned Hiv status on the basis of local epidemiological patterns (all untested malawian adults were characterized as likely to be Hiv positive, but malawian children were not character-ized unless they were Hiv tested). second, malnutrition, a relevant host factor for clini-cal response to infection and adverse out-comes, was not assessed in all patients, and was categorized according to local commu-nity prevalence. third, although an attempt was made to stratify meningitis severity on the basis of level of consciousness (mea-sured with a combination of two different scoring systems), the timing of mental status assessment was not standardized. meningitis is a rapidly progressing disease, so defining a precise baseline time for clinical assess-ment of conscious ness (for example, at initial triage, when antib iotics were admin-istered, or when steroids or placebo were administered) is crucial if the results are to be generalizable. last, bacterial meningitis is usually a systemic as well as a nervous system infection, and other key clinical data such as blood pressure or blood lactate could have revealed an important hetero-geneity that was otherwise not detected in the meta-analysis.

what are the implications of these find-ings for the clinician who needs to decide

whether or not to administer adjunctive steroids to a patient with bacterial men-ingitis? we believe that the consistently demon strated benefits of steroids in trials of patients with bacterial meningitis in higher-income countries with greater access to care warrants use in that setting. adverse events with steroids are infrequent in all trials. in lower-income countries, where delayed recog nition of disease and Hiv infection might preclude a benefit of steroids, attempts should be made to improve access to effective antibiotics. one overriding theme that emerges from over three decades of effort and debate, however, is that adjunc-tive steroids will not have a major impact on the public health burden of bacterial meningitis globally, particularly in the underserved areas that harbor a dispropor-tionate share of the morbidity and mortality associated with this condition. investigators, clinicians, pharmaceutical companies, public health officials, foundations and govern-ment organizations must, therefore, channel their efforts into enhancing the affordabil-ity of, and access to, effective conjugated vaccines worldwide.

Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, PO Box 208022, New Haven, CT 06520‑8022, USA (V. Quagliarello). Department of Medicine, Carter‑Harrison Research Building (MR6), 345 Crispell Drive, University of Virginia Health System, Charlottesville, VA 22908, USA (W. M. Scheld).

Correspondence to: V. Quagliarello vincent.quagliarello@yale.edu

doi:10.1038/nrneurol.2010.132

Competing interestsThe authors declare no competing interests.

1. Hsu, H. e. et al. effect of pneumococcal conjugate vaccine on pneumococcal meningitis. N. Engl. J. Med. 360, 244–256 (2009).

2. Murray, D. J., Lopez, A. D., Mathers, C. D. & stein, C. The Global Burden of Disease 2000 project: aims, methods and data sources. World Health Organization [online], http:// www.who.int/healthinfo/paper36.pdf (2001).

3. van de Beek, D. et al. Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data. Lancet Neurol. 9, 254–263 (2010).

4. Quagliarello, v. J. & scheld, w. M. Treatment of bacterial meningitis. N. Engl. J. Med. 336, 708–716 (1997).

5. van de Beek, D., de Gans, J., Tunkel, A. R. & wijdicks, e. F. Community acquired bacterial meningitis in adults. N. Engl. J. Med. 354, 44–53 (2006).

6. Tauber, M. G., Khayam-Bashi, H. & sande, M. A. effects of ampicillin and corticosteroids on brain water content, cerebrospinal fluid pressure, and cerebrospinal fluid lactate levels in experimental pneumococcal meningitis. J. Infect. Dis. 151, 528–534 (1985).

7. van de Beek, D., de Gans, J., Mcintyre, P. & Prasad, K. Corticosteroids for acute bacterial meningitis. Cochrane Database of Systematic Reviews, issue 1. Art. no.: CD004405. doi:10.1002/14651858.CD004405.pub2 (2007).

8. scarborough, M. et al. Corticosteroids for bacterial meningitis in adults in sub-saharan Africa. N. Engl. J. Med. 357, 2441–2450 (2007).

9. Mai, n. T. et al. Dexamethasone in vietnamese adolescents and adults with bacterial meningitis. N. Engl. J. Med. 357, 2431–2440 (2007).

10. Kent, D. M. & Lindenauer, P. K. Aggregating and disaggregating patients in clinical trials and their subgroup analyses. Ann. Intern. Med. 153, 51–52 (2010).

PArkInSon DISeASe

Deep brain stimulation versus best medical therapy for PDMatthew A. Brodsky and John G. Nutt

A new study indicates that deep brain stimulation (DBS) plus best medical therapy markedly improves quality of life of patients with advanced Parkinson disease compared with best medical therapy alone. The frequency of serious adverse events related to DBS was similar to that reported in other DBS trials, underscoring the need for careful patient selection and counseling for this invasive therapy.

anybody who has seen a video clip of a patient with Parkinson disease (PD) sitting in a chair with tremor and unable to stand up and walk cannot fail to be amazed when, after the patient’s deep brain stimulation

(DBs) is turned on, the tremor disappears and the patient stands and walks without difficulty. evidence of this dramatic tran-sition from severe parkinsonism to near normality demonstrates how effective this

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