Adjunctive agents for nerve blocks/local injections in the treatment of zoster-associated pain: A systematic review based on levels of evidence

Adjunctive pharmacological agents are extensively used in the treatment of patients with schizophrenia. This cross-sectional study examined the prevalence of the use of adjunctive agents, the extent to which their use conforms with Schizophrenia Patient Outcomes Research Team (PORT) recommendations for adjunctive pharmacological treatment and the relationship of conformance with treatment recommendations to demographic and clinical variables and to symptoms and level of function. Outpatients with schizophrenia (N=344) underwent an extensive interview, and their medical records were reviewed. Data on demographic and clinical characteristics, medications, and role functioning were collected. More than two-thirds of the outpatients received antiparkinsonian agents, and 50% received an adjunctive agent other than an antiparkinsonian agent. Fifty-four (15.7%) outpatients received two or more non-anti-parkinsonian adjunctive agents. Rates of conformance with the PORT treatment recommendations for the use of adjunctive agents ranged from 49% to 65%, depending on the type of agent. Ethnicity and diagnosis were the only two patient characteristics that were consistently related to conformance with PORT treatment recommendations. The treatment recommendation for adjunctive mood stabilizers was the only recommendation for which conformance was related to multiple measures of patients' symptoms and level of function. Adjunctive agents are widely used in the pharmacological treatment of patients with schizophrenia, but there is a limited relationship between use of these agents in conformance with treatment recommendations and measures of symptoms and level of function. Longitudinal, prospective studies are needed to demonstrate the clinical utility of adjunctive agents.

BACKGROUND: Acute zoster-related pain affects more than 90% of patients with acute herpes zoster. While nerve blocks with local anesthetics and steroids are commonly used to manage acute postoperative and chronic pain, their efficacy and safety in treating acute herpes zoster remain underexplored. OBJECTIVES: Our systematic review and meta-analysis aimed to evaluate the efficacy and safety of various nerve blocks for managing acute herpes zoster. STUDY DESIGN: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. METHODS: A comprehensive search of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials was conducted to identify studies of patients with acute herpes zoster who received nerve blocks. Study quality was assessed using risk-of-bias tools for randomized and nonrandomized studies. The primary outcome was analgesic efficacy; secondary outcomes included postherpetic neuralgia (PHN) incidences, analgesic consumption, and adverse events. RESULTS: Thirteen studies (9 RCTs, n = 815; 4 observational studies, n = 253) were included. Nerve blocks administered were paravertebral blocks (PVB), erector spinae plane (ESP) blocks, epidural blocks, and intercostal nerve blocks. The meta-analysis, which included 6 RCTs, indicated that at 4 weeks postprocedure, nerve blocks significantly reduced Visual Analog Scale pain scores. The blocks also reduced the need for acetaminophen and pregabalin compared with the control group. However, no differences in Visual Analog Scale pain scores were observed at 12 weeks. Both PVB and ESP blocks significantly decreased the PHN incidences at 3 and 6 months postprocedure. Five studies demonstrated that ultrasound-guided ESP blocks significantly reduced pain severity, duration, and the incidence of PHN without notable adverse events. Eight studies found PVBs to be effective in reducing pain scores and PHN incidences, though adverse events such as dizziness, drowsiness, and pain at the injection site were reported. Four observational studies comparing epidural or intercostal nerve blocks with other techniques provided weak evidence for their use. LIMITATIONS: Our study’s limitations include its small sample size with only 6 RCTs, significant heterogeneity in study designs, and variations in the interventions. Subjectivity in measuring pain and the lack of blinding introduces potential bias. Additionally, limited evidence on intercostal and epidural blocks for acute herpes zoster highlights the need for more high-quality RCTs. CONCLUSION: In conclusion, nerve blocks with local anesthetics and steroids provide effective analgesia, reduce analgesic consumption, and lower PHN incidences in patients with acute thoracic herpes zoster. We recommend an ESP block due to its safety profile, while a PVB may offer similar analgesic benefits but with a higher risk. Further high-quality studies are necessary to confirm these findings. KEY WORDS: Herpes zoster, nerve block, acute zoster-related pain, postherpetic neuralgia, erector spinae plane block, paravertebral block, systematic review, meta-analysis

Post-herpetic neuralgia (PHN) is a chronic neuropathic pain condition that persists 3months or more following an outbreak of shingles. Shingles, also known as acute herpes zoster, is associated with the reactivation of the dormant varicella zoster virus in an individual who has experienced chicken pox. PHN is associated with persistent and often refractory neuropathic pain. Patients may experience multiple types of pain including a constant deep, aching, or burning pain; a paroxysmal, lancinating pain; hyperalgesia (painful stimuli are more painful than expected); and allodynia (pain associated with typically non-painful stimuli). The pharmacological treatment of PHN may include a variety of medications including alpha-2 delta ligands (gabapentin and pregabalin), other anticonvulsants (carbamazepine), tricyclic antidepressants (amitriptyline, nortriptyline, doxepin), topical analgesics (5% lidocaine patch, capsaicin) tramadol, or other opioids. The considerable side effect profiles of the commonly used oral medications often limit their practical use, and a combination of both topical and systemic agents may be required for optimal outcomes. Physicians and other treatment providers must tailor treatment based on the response of individual patients.

Postherpetic neuralgia (PHN) is a chronic neuropathic pain condition that lasts 3 months or more after an outbreak of shingles. Herpes zoster, especially acute herpes zoster, is associated with the reactivation of the inactivated varicella zoster virus in individuals who have had chickenpox. PHN is associated with persistent and often refractory neuropathic pain. Patients may experience several types of pain, including deep pain, intolerable pain, burning, paroxysmal pain, stabbing pain, hyperalgesia, and allodynia. Pharmacological treatment of PHN may include a variety of drugs, including alpha-2 delta ligands (gabapentin and pregabalin), other anticonvulsants (carbamazepine), tricyclic antidepressants (amitriptyline, nortriptyline, doxepin), topical analgesics (5% lidocaine patch, capsaicin) tramadol, or other opioids. The sizeable side effect profile of commonly used oral drugs often limits their practical use, and a combination of topical and systemic agents may be required for optimal results. Doctors and other care providers must adapt treatment based on individual patient responses.

Incidence and Risk of Postherpetic Neuralgia after Varicella Zoster Virus Infection in Hematopoietic Cell Transplantation Recipients: Hokkaido Hematology Study Group

Botulinum toxin type A is widely utilized for both therapeutic and aesthetic purposes, yet concerns regarding its immunogenicity have raised issues related to treatment failure and adverse reactions. This review aims to evaluate the immunogenicity of commercially available botulinum toxin type A products across various clinical indications and identify the risk factors associated with antibody formation. A comprehensive search of electronic databases was conducted to find studies that investigated the immunogenicity of botulinum toxin type A in patients treated for different conditions. The studies were classified based on the Oxford Center for Evidence-Based Medicine's evidence hierarchy. The overall incidence of neutralizing antibody formation with botulinum toxin type A treatment is relatively low. However, it varies depending on the indication and is influenced by factors such as the frequency of injections and the cumulative dose. The total cumulative dose and the number of treatment cycles are critical factors in determining the risk of developing antibodies against botulinum toxin type A. This literature review highlights that the immunogenicity of botulinum toxin type A products differs across indications, with repeated injections posing a significant risk for the formation of neutralizing antibodies. The findings underscore the need for further research to better understand antibody formation mechanisms and to develop strategies that minimize their impact on treatment efficacy.

Neuraxial and sympathetic blocks in herpes zoster and postherpetic neuralgia: An appraisal of current evidence

Neuropathic pain includes postherpetic neuralgia (PHN), painful diabetic neuropathy (PDN), and trigeminal neuralgia, and so on. Although various drugs have been tried to treat neuropathic pain, the effectiveness of the drugs sometimes may be limited for chronic intractable neuropathic pain, especially when they cannot be used at an adequate dose, due to undesirable severe side effects and the underlying disease itself. Botulinum toxin type A (BoNT-A) has been known for its analgesic effect in various pain conditions. Nevertheless, there are no data of nerve block in PHN and PDN. Here, we report two patients successfully treated with ultrasound-guided peripheral nerve block using BoNT-A for intractable PHN and PDN. One patient had PHN on the left upper extremity and the other patient had PDN on a lower extremity. Due to side effects of drugs, escalation of the drug dose could not be made. We injected 50 Botox units (BOTOX®, Allergan Inc., Irvine, CA, USA) into brachial plexus and lumbar plexus, respectively, under ultrasound. Their pain was significantly decreased for about 4–5 months. Ultrasound-guided nerve block with BoNT-A may be an effective analgesic modality in a chronic intractable neuropathic pain especially when conventional treatment failed to achieve adequate pain relief.

Herpes zoster represents the reactivation of latent varicella-zoster virus located in the dorsal root ganglion. The virus multiplies and migrates to the skin surface producing a characteristic, usually painful, pustular eruption. Severe pain during the acute phase of herpes zoster has been associated with a higher risk of developing postherpetic neuralgia. Sympathetic ganglion block and somatic nerve block have been used for patients in the acute phase of herpes zoster to alleviate pain and prevent postherpetic neuralgia. Sympathetic nerve block appears to achieve these goals by blocking the profound sympathetic stimulation that is a result of the viral inflammation of the nerve and ganglion. However, they require repeated local anesthetic injections to relieve the symptoms of acute herpes zoster as well as to prevent the occurrence of postherpetic neuralgia. Pulsed radiofrequency has been proposed as safe, nondestructive treatment method. We present a case of acute herpes zoster that was managed with pulsed radiofrequency treatment. The results were satisfactory. (Korean J Anesthesiol 2007; 52: 586~90)

Herpes zoster and post-herpetic neuralgia showed an increasing incidence during past two decades. Most of herpes zoster and post-herpetic neuralgia patients suffered from pain, anxiety, and depression. Fire needle combined with cupping is becoming a popular way to relieve the pain caused by herpes zoster and decrease the incidence of post-herpetic neuralgia. In this study, we aim to investigating the efficacy and safety of fire needle combined with cupping for the treatment of acute herpes zoster and postherpetic neuralgia (PHN). The literature search will be carried out in following databases: PubMed/MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Chinese Biomedical Literature Database and Wanfang Data. Published and unpublished controlled trials compared fire needle combined with cupping to other treatments for acute herpes zoster or PHN will be included. Data from eligible studies will be extracted by 2 independent reviewers. Different scales will be used to assess the risk of bias based on the study design. Pain intensity and PHN are primary outcomes. The final effect size will be reported using 95% confidence interval at 0.05 significance level. This review will provide certain evidence to compare the efficacy and safety of combined acupuncture and cupping with guideline recommended drug or nerve block therapy for the treatment of herpes zoster and post-herpetic neuralgia. It will potentially provide more clinical suggestions and guidelines for health care professionals, policymakers, and researchers.

Levels of Evidence and the Journal of Hand Surgery

Evidence-based medicine is "the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients."1 This becomes complicated when busy health care providers are faced with the task of summarizing "the current best evidence." Systematic reviews, such as those published by the Cochrane Collaboration,2 serve this purpose by appraising and distilling the daunting amount of information available. These reviews are commonly attached to a level of evidence, which gauges the confidence of estimates reported by existing studies. Thus, levels of evidence pertain to the knowledge generated by the summative collection of research on a specific topic. Although the evidence base can come from a single study, more often it is the final step of a long scientific journey, in which experts collect, appraise, and summarize the findings of several individual studies using a specific, standard methodology.1 Different systems to define hierarchy of evidence have been proposed by renowned groups including the pioneer Cochrane Collaboration,2 the Oxford Centre for Evidence-Based Medicine (OCEBM),3 the US Preventive Task Force,4 and the Evidence-Based Practice Center (EPC) program of the US Agency for Healthcare Research and Quality.5 The recently launched Grades of Recommendation, Assessment, Development, and Evaluation (GRADE)6 system follows a detailed stepwise process to rate evidence and to determine the strength of recommendations in systematic reviews, health technology assessments, and clinical practice guidelines. According to the GRADE group Web site, more than 50 organizations have endorsed their system, including the World Health Organization, the American College of Physicians, the American College of Chest Physicians, the American Endocrine Society, the American Thoracic Society, the Canadian Agency for Drugs and Technology in Health, and the UK's National Institute for Health and Clinical Excellence. The British Medical Journal encourages authors of clinical guidelines to use the GRADE system.7 The Cochrane Collaboration has also adopted the principles of the GRADE system for evaluating the quality of evidence for outcomes reported in systematic reviews.8 Yet, a systematic review is not always available; thus, how will busy health care providers manage the formidable volume of information that becomes available everyday? "How does the article I read today change (or not) what I will recommend to my patients tomorrow?" To address this imperative, several scientific journals have recently adapted grading systems to assess the level of evidence of individual articles in an effort to provide guidance to their readers.9–12 This year, The Journal of Trauma joined the discourse by requiring authors to assign levels of evidence to their own clinically oriented studies. As detailed previously, the existing grading systems (e.g., GRADE) were originally designed to rate the summative body of evidence and not the level of evidence in individual articles. The grading of evidence in individual studies is a middle step in determining the hierarchy of evidence and comprises a judgment regarding the confidence and uncertainty emanating from a particular study. Several aspects of the investigation are examined, including, but not limited to appropriate design to address well-formulated research questions, appropriately measured outcomes, assessment of inferential error, risk of bias, and control of confounding. The results of this appraisal will inform the reader about the level of uncertainty of the study's findings and how much it adds to the existing knowledge in that topic. As part of the process of assessing the overall level of evidence, the GRADE system rates the evidence from individual studies into one of four categories ranging from high to very low (Table 1).13 Study design is the GRADE's critical measure to classify the quality of the evidence: for therapeutic studies, randomized clinical trials (RCTs) always start as High and observational studies as Low. From this starting point, evidence may be downgraded or upgraded through the evaluation of several specific domains as follows: (1) risk of bias, (2) imprecision, (3) inconsistency, (4) indirectness, (5) publication bias, (6) effect size, (7) existence of dose-response pattern, and (8) effect of plausible confounding on findings (Table 2). When the study addresses diagnostic accuracy, however, a slightly different classification applies.14TABLE 1: GRADE Quality Assessment CriteriaTABLE 2: Factors That May Decrease or Increase the Quality of EvidenceGRADE is a somewhat complicated system, which, as its own authors recognize, involves an element of subjectivity.15 In addition, there is the negative connotation created by classifying a study as low quality, a term which could be construed as lack of scientific rigor on the part of the authors. As the PRISMA authors wisely put it, "quality is often the best the authors have been able to do," and recommended the term risk of bias instead.16 Quality should be assessed when accepting or rejecting a manuscript for publication, whereas the evidence level of individual studies involves judging a study's level of uncertainty and risk of bias. Rather than introducing a new term (such as risk of bias), with which readers and authors may not be familiar, we propose to use the established nomenclature "evidence level of individual studies" (ELIS). Consensus statements such as the GRADE system and the OCEBM guidelines can serve as the basis upon which to build a standard to assess ELIS. The proposed ELIS system retains study design as a major factor in the classification but recognizes that each type of clinical question (therapeutic, diagnostic accuracy, etc.) demands different types of study designs. The proposed ELIS framework (Table 3) is heavily based on the previous groundbreaking work from the GRADE workgroup, the OCEBM 2009 and 2011 guidelines, and the Journal of Bone and Joint Surgery's adaptation of OCEBM's materials, which have been well accepted by the scientific community and shown to have acceptable reliability.17,18 The determination of ELIS involves three steps.TABLE 3: Proposed Evidence Level of Individual Studies (ELIS)ELIS STEP 1: DEFINE STUDY TYPE Therapeutic and care management studies evaluate a treatment efficacy, effectiveness, and/or potential harm, including comparative effectiveness research and investigations focusing on adherence to standard protocols, recommendations, guidelines, and/or algorithms. Prognostic and epidemiologic19 studies assess the influence of selected predictive variables or risk factors on the outcome of a condition. These predictors are not under the control of the investigator(s). Epidemiologic investigations describe the incidence or prevalence of disease or other clinical phenomena, risk factors, diagnosis, prognosis or prediction of specific clinical outcomes, and investigations on the quality of health care. Diagnostic tests or criteria 20 studies describe the validity and applicability of diagnostic tests/procedures or of sets of diagnostic criteria used to define certain conditions (e.g., definition of adult respiratory distress syndrome, multiple organ failure, or postinjury coagulopathy). Economic and value-based evaluations focus on which type of care management can provide the highest quality or greatest benefit for the least cost. Several types of economic evaluation studies exist, including cost-benefit, cost-effectiveness, and cost-utility analyses. More recently, Porter21,22 proposed value-based health care evaluations, in which value was defined as the health outcomes achieved per dollar spent. Systematic reviews and meta-analyses (SR/MA) evaluate the body of evidence on a topic; meta-analyses specifically include the quantitative pooling of data. Guidelines are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances.23 ELIS STEP 2: DEFINE THE RESEARCH DESIGN Table 3 reflects a different hierarchy of designs for each of the previously mentioned study types. For therapeutic studies, RCTs remain the paragon of biomedical research, and other treatment study designs will still rank lower than level I evidence. This is because the processes used to conduct RCTs minimize the risk of confounding factors influencing the results. As a result, the findings generated by RCTs are likely to be closer to the true effect than the findings generated by other research methods. Prognostic studies allow for more flexibility in study design, with cohort prospective studies with preestablished hypotheses generating less uncertainty and consequently stronger evidence than those of case-control designs. It is important that we clearly define case-series versus comparative, cohort versus case-control, and prospective versus retrospective studies. Case-series studies evaluate a group of patients submitted to a type of care/procedure/test without a suitable comparison group. A comparison group can be a group of patients with similar characteristics who received a different type of care/procedure/test or, alternatively, the investigator can compare the same group of patients before and after an intervention. It is not difficult to realize that the lack of a comparator makes us less confident in the evidence and less likely to adopt the new procedure. Of course, if this is an innovative treatment of a lethal disease for which there is no available treatment, we may adopt it even with low confidence for lack of better options. The urgency to adopt the new treatment, however, does not change the fact that our confidence is still low and that further research will be crucial to increase our confidence level. Once we determine that there is a comparator group, we can define whether this is a cohort or case-control study. The fundamental difference between these two designs lies on when the investigators determine the exposure/risk factor and the outcome.3 In case-control studies, the outcome is determined first and the exposure/risk factor/intervention later. For example, Wu et al.24 used a case-control design to compare the bone mineral density of 87 elderly patients with hip fractures to 87 elderly patients without hip fractures and found it to be significantly lower in the first group. In cohort studies, investigators define first the exposure/risk factor and then assess their outcome of interest. For example, Lin et al. enrolled a cohort of 217 elderly patients with hip fractures in their study and evaluated a risk factor defined as body mass index ratio between the greater trochanter and the femoral neck. In case-control studies, a group with the outcome (the "cases") is compared with a group without the outcome but otherwise similar (the "controls") regarding something that happened to them before they experienced the outcome. In cohort studies, a group of patients with at least one common characteristic (the "cohort") is assessed for the development of outcome(s). This distinction can get confusing when the authors compare, for example, survivors to nonsurvivors regarding a specific risk factor. In this case, readers will know that the study is a cohort if both survivors and nonsurvivors were consecutive patients with a common risk factor (e.g., trauma). To make things more confusing, a case-control study is sometimes a later offspring of a well-planned cohort study, as in the case-control study by Shaz et al.25 on postinjury coagulopathy. Although some of the most important medical discoveries were done through case-control studies,26 this design has several limitations that place it lower on the evidence hierarchy. These include, but are not limited to, potential for bias in the selection of the control group and uncontrolled confounding in the assessment of the risk factor/exposure. In this proposed ELIS, the terms prospective and retrospective refer to the intention underlying data collection, rather than when data were actually retrieved. If the data were compiled to answer a predefined set of research questions, then this is a prospective study, regardless of whether data were accrued concurrently with care or after the fact through records review. Conversely, the use of data to answer a question unrelated to the original question for which the data were gathered is a retrospective analysis. Some clinical databases are prospectively planned to answer a broad set of predetermined questions (e.g., the Denver MOF database constructed to assess early risk factors for postinjury multiple organ failure).27 Information recorded for other purposes (e.g., medical records, operating room registries, claims data) can only produce a retrospective analysis. Disease registries (e.g., trauma registries) are a point of contention because data collection occurs concurrently with care (commonly reported as "data were prospectively collected" or "patients were prospectively included into a registry"). The major strength of these registries lies on the quality of the data collected because factors such as recall bias and missing data are less likely. Yet, they can generate both prospective studies of preestablished outcomes and retrospective studies when used for not preestablished outcomes. Why is this distinction (retrospective vs. prospective) important in establishing the ELIS? It is important because retrospective studies are more subject to biases (e.g., relevant variables may not have been included or were measured using different methods) that decrease our confidence in their results. Furthermore, retrospective multiple unplanned comparisons increase the potential of a type I error, as explained in greater detail later in this article. ELIS STEP 3: ASSESS THE STRENGTHS AND LIMITATIONS OF THE STUDY THAT WILL AFFECT THE UNCERTAINTY OF THE RESULTS The next step in determining the ELIS recognizes that all research designs, even RCTs, are more or less limited by confounding, bias, inadequate sample size and statistical power, heterogeneity of included populations, differences between control and study groups, missing data, loss to follow up, and so on. All these factors affect the uncertainty around study outcomes. We combined some of the GRADE-defined factors (Table 2) with the earlier OCEBM table (Table 4) to modify the ELIS.TABLE 4: Oxford Center for Evidence-Based Medicine Levels of Evidence (March 2009)To define the magnitude of effect, we assessed the size of the relative risk (RR) within the context of disease severity. Thus, for a moderately severe condition (with low-to-moderate morbidity/mortality), a large effect was defined as a high RR (>5 or <0.2), whereas for more severe diseases, only a moderate-to-large RR (2–5 or 0.2–0.5) was required. The statistical power of the study is a critical aspect in determining ELIS. It is usually easier to first define the situations where statistical power is not important: once the study detects a significant difference for an a priori stated hypothesis, the issue of statistical power is irrelevant. When investigators conduct multiple unplanned comparisons, then the potential for type I error (the error of finding a difference when in fact there is not one, usually set at <0.05) increases. Statistical power becomes relevant when no significant difference is detected and we want to gauge the type II error (the error of not finding a difference when in fact there is one). When this happens, authors may declare "failure to detect a significant difference" and should provide the statistical power for detecting the observed (or predetermined) difference (generally accepted as adequate when >80%). This is often the case when assessing whether randomization was successful and the two RCT groups do not show statistical differences; or for secondary outcomes for which the study was not powered. In an alternative scenario, which is becoming more common with the popularity of comparative effectiveness studies, the authors may aim at declaring bioequivalence or noninferiority. In this case, power must be determined with as much rigor as we usually determine significance, thus requiring levels greater than 90%. Of course, akin to the well-known p < 0.05, statistical power levels are arbitrary and should reflect the specific topic of the study. Studies of lethal conditions without a known treatment may require lower confidence levels (e.g., p < 0.10 or p < 0.15) to establish a significant difference or lower statistical power to declare noninferiority whereas investigations of low morbidity/mortality conditions with established treatments may require higher power or confidence levels. Furthermore, differences can be statistically significant and clinically meaningless. In sum, statistical power and confidence are functions of the clinical question being answered by the study, not after-the-fact considerations. Other ELIS modifiers were included in two sets of "negative criteria" at the bottom of Table 3. One set is for general types of studies and includes confounding, bias, loss to follow-up, missing data, and heterogeneity of the populations. We contemplated using dose-response as factor, as recommended by the GRADE group, but decided that this was a difficult element to define in the instructions for authors. Especially in trauma and acute care, assessment of dose-response patterns can be complicated by survivorship bias.28 Instead, we encourage our reviewers to take dose-response gradients into consideration on a case-by-case basis. As mentioned previously, heterogeneity of populations must be taken into consideration when appraising a study, particularly multi-institutional studies (even when RCT is the design), studies including condition(s) caused by different pathogenic mechanisms (e.g., patients with sepsis, patients with critical illness), and national and international disease registries. Heterogeneity is also a major concern in SR/MA; thus, this element was incorporated to the second set of negative criteria, specific to SR/MA. A final note refers to procedures to ensure the quality, integrity, and internal validity of collected data. Especially when studies deal with large data sets recorded by multiple abstractors, we strongly encourage authors to describe, albeit briefly, these procedures (e.g., 10% of the records were reabstracted, and intrarater reliability was assessed by the κ statistic). For diagnostic studies, the consistent use of a "gold" standard is typically the defining factor. When all patients with a specified condition are submitted both to the test (or set of diagnostic criteria) under investigation and the "gold" standard, the result is a powerful design. Uncertainty arises when only a group of patients with the specified condition (e.g., patients who are more severely injured, "at the attending physician's discretion") is submitted to the "gold" standard test. The quality of the "gold" standard is, of course, a pivotal issue. We are all aware that, often, there are no ideal standards, capable of a precise discrimination between outcomes. In addition, the consistent application of the "gold" standard is sometimes neither ethical (e.g., submit all patients with abdominal pain to endoscopy and biopsy) nor possible (e.g., autopsy for all fatalities). Yet, although unavoidable, this is a limitation that affects our confidence in the results; thus, it must be reflected in the ELIS. ELIS AND STANDARDIZED REPORTING The ELIS can only be assessed if all essential elements are included in the report. The article must contain all necessary information for the study to be replicated by others, including sampling, refusal and attrition rates, randomization methods (in the case of RCTs), confounding control, risk adjustment, potential for bias, and statistical analysis. For that purpose, following standardized reporting guidelines (CONSORT, PRISMA, etc.) is pivotal. The Enhancing the Quality and Transparency Of health Research (EQUATOR) group's Web site29 is an excellent source of standardized reports, and we recommend it to authors submitting articles to the Journal of Trauma. This ELIS classification does not reflect the scientific rigor or research integrity of the study. A study that is essentially flawed because it did not follow rigorous scientific methodology does not bring new knowledge, and consequently, the likelihood of publication should be very low. With ELIS, we propose to gauge some of the uncertainty of a study's results, which will frame its application to current practice. In addition, the ELIS must be used in conjunction with the PICO framework's determination of similarity, that is, whether the patients [P], interventions [I], comparators [C], and outcomes [O] in the trial are similar enough to justify application of the trial results to the provider's patient population.30 It is understandable that an author would not like to define his/her study as "low evidence." Presenting level II or III evidence, however, should not be regarded as demeaning. Specific areas in health and health care, such as trauma, impose immense difficulties and moral dilemmas to the implementation of RCTs. Study designs reflect the realities of diverse settings and ethical imperatives.1 In a recent editorial, Vincent comments on the limitations of RCTs in the intensive care unit population and highlights the importance of considering other study designs in the challenging intensive care unit environment.31 Yet, recognizing these difficulties does not change the level of uncertainty associated with specific study designs, limited risk adjustment, and high risk of bias. Thus, our proposed ELIS system does not intend to define the merit of a study but rather to convey its level of uncertainty. In addition, we propose a new framework for the Discussion section, in which the authors place their results in context and explain the ELIS of their study. We invite authors to use the Discussion section to assist health care providers in answering the question stated at the beginning of this article: "How does the article I read today changes (or not) what I will recommend to my patients tomorrow?" We encourage authors to describe how the study contributes to existing knowledge about the topic and provide guidance on how results should be used by their readers in their current clinical practice using the PICO framework. As appropriate, investigators should also propose new studies likely to increase the level of evidence of existing research. In sum, we have proposed a system to appraise the level of uncertainty of individual studies tailored to the needs of surgical studies, especially those dealing with emergent care. We look forward to feedback from our readership. DISCLOSURE The authors declare no conflicts of interest.

This month we are introducing something new to the Journal, which I hope will add to the enjoyment for you, the readers. I have on a few occasions mentioned the importance of evidence-based approaches in urology. In addition, we have frequently heard the chairman of the various guideline committees describing the levels of evidence for their decisions. I have often felt that the level of evidence supplied by a paper should be printed after the abstract of the printed paper in our Journal, to help the readers formulate their ideas as to the value of the paper, and to help the guideline committees with their decision-making [1]. I would also refer you to an excellent comment which appeared in last month’s issue of the BJU International on this topic, by Dahm and Preminger [2]. They address several issues relating to such a policy and it is helpful to use their comment as an introduction because it explains much of our thinking behind it. For example, the decision as to the levels of evidence will be made by Mark Emberton, a newly appointed Associate Editor, who has appropriate training in these methods. The rating only provides a rough guide to the quality of the study and it is not intended to represent a decision that cannot be argued or defended by authors or readers. In fact, we would very much welcome your input on this; please write to us to let us know what you think of the idea, and whether you agree with our decisions. My idea to provide levels of evidence for each paper, echoed by Dahm and Preminger [2], is to act as a helpful aid to the reader, not as an attempt to sit in public judgement on authors or their work. Even papers with the highest quality of evidence might have limited clinical relevance, and in the field of urological surgery it might not be possible to carry out a randomized clinical trial on a particular surgical technique that might actually be of the highest clinical importance. It is important to bear both of these ideas in mind. I have included the Oxford Centre for Evidence-based Medicine ‘Levels of Evidence’ to follow this editorial comment, and this will appear at the end of each Journal issue in the future as a ‘ready-reckoner’. We have introduced this level-of-evidence rating in this month’s issue, but not on every paper because many have already appeared on-line in their final form. It will therefore be gradually introduced for every paper over the coming months. I hope you will approve of it. OXFORD CENTRE FOR EVIDENCE-BASED MEDICINE: LEVELS OF EVIDENCE (MAY 2001) A: consistent level 1 studies B: consistent level 2 or 3 studies or extrapolations from level 1 studies C: level 4 studies or extrapolations from level 2 or 3 studies D: level 5 evidence or troublingly inconsistent or inconclusive studies of any level ‘Extrapolations’ are where data are used in a situation which has potentially clinically important differences from the original study situation. Permission received from the Oxford Centre for Evidence-based Medicine to reproduce Levels of Evidence Model. Levels of Evidence produced by Bob Phillips, Chris Ball, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes.

Orthopaedic surgeons, like all physicians, must make clinical decisions based on the best available evidence. This evidence comes from individual clinical experience and external sources1. Although clinical experience is left to the physician, the medical and surgical literature provides the best external evidence. To facilitate the process of determining the best evidence to answer a clinical question, The Journal of Bone & Joint Surgery assigns level of evidence (LOE) ratings to all clinical articles. Since 20032, The Journal has used a hierarchical rating system based on the recommendations of the Centre for Evidence-Based Medicine (CEBM) in Oxford, United Kingdom, to rank articles according to the study design used to answer the primary research question3. In 2011, the CEBM updated its recommendations. After robust internal and external discussion, The Journal has decided to keep pace with the CEBM and has updated our LOE …

Varicella zoster virus (VZV) reactivation results in zoster, which may be complicated by postherpetic neuralgia, myelitis, meningoencephalitis, and VZV vasculopathy. This review highlights the clinical features, laboratory abnormalities, imaging changes, and optimal treatment of each of those conditions. Because all of these neurological disorders produced by VZV reactivation can occur in the absence of rash, the virological tests proving that VZV caused disease are discussed. After primary infection, VZV becomes latent in ganglionic neurons along the entire neuraxis. With a decline in VZV-specific cell-mediated immunity, VZV reactivates from ganglia and travels anterograde to the skin to cause zoster, which is often complicated by postherpetic neuralgia. VZV can also travel retrograde to produce meningoencephalitis, myelitis, and stroke. When these complications occur without rash, VZV-induced disease can be diagnosed by detection of VZV DNA or anti-VZV antibody in cerebrospinal fluid and treated with intravenous acyclovir. Awareness of the expanding spectrum of neurological complications caused by VZV reactivation with and without rash will improve diagnosis and treatment.