Marks, Lisa A.

Background: Lymphovenous anastomosis (LVA) is a microsurgical treatment for lymphedema of the lower extremity (LEL). This study systematically reviews the most recent data on outcomes of various LVA techniques for LEL in diverse patients. Methods: A comprehensive literature search was conducted in the Ovid MEDLINE, Ovid EMBASE, and Scopus databases to extract articles published through June 2021. Studies reporting data on objective postoperative improvement in lymphedema and/or subjective improvement in quality of life for patients with LEL were included. Extracted data comprised demographics, number of patients and lower limbs, duration of symptoms before LVA, surgical technique, duration of follow-up, and objective and subjective outcomes. Results: A total of 303 articles were identified and evaluated, of which 74 were ultimately deemed eligible for inclusion in this study, representing 6260 patients and 2554 lower limbs. The average patient age ranged from 22.6 to 76.14 years. The duration of lymphedema before LVA ranged from 12 months to 11.4 years. Objective rates of improvement in lymphedema ranged from 23.3% to 100%, with the greatest degree of improvement seen in patients with early-stage LEL. Conclusions: LVA is a safe and effective technique for the treatment of LEL of all stages. Several emerging techniques and variations may lead to improved patient outcomes.

Background: Combined PD-1/PD-L1 and CTLA-4 immune checkpoint inhibition for the has been shown to produce superior results in the treatment of malignant melanoma when compared to monotherapy. However, patients with intracranial disease were excluded from these studies given their poor prognosis. Objective: The objective of this study was to critically assess current evidence supporting the co-administration of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of melanoma brain metastases. Methods: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-oncology. Results: A recent, open-label, non-comparative randomized phase II trial was selected for critical appraisal. This trial evaluated the efficacy and safety of nivolumab alone or in combination with ipilimumab in 79 adult patients with untreated, asymptomatic melanoma brain metastases. The rates of the primary outcome (intracranial response at ≥12 wk) in the primary endpoint cohort were 46% for cohort A (combination therapy) and 20% for cohort B (nivolumab monotherapy). No treatment related deaths were observed in the study. Grade 4 adverse events occurred in 9% of patients in cohort A and none in cohort B. Conclusions: Co-administration of ipilimumab and nivolumab as first-line therapy is effective in the treatment of asymptomatic melanoma brain metastases, with an acceptable safety profile.

Background: Functional movement disorders (FMD, aka psychogenic movement disorders) are very common and frequently chronic and disabling. Despite this, there is a paucity of evidence-based treatment to manage and alleviate these conditions. Specialized physical therapy (PT), involving sequential motor relearning and redirecting attention, has shown promise as a therapeutic intervention for motor symptoms. Methods: The objective of this study was to critically assess current evidence regarding specialized PT compared with usual care in improving motor symptoms among patients with FMD. This was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, and content experts in the fields of physical medicine and rehabilitation, physical and occupational therapy, psychiatry, and psychology. Results: A randomized controlled feasibility trial was identified and selected for critical appraisal. This study randomized 60 patients with FMD to a 5-day specialized outpatient PT program or to general outpatient PT referral, and measured patient-reported and clinician-measured outcomes. At 6 months, 72% of patients in the intervention group had a good outcome compared with 18% of control group patients. Patients in the specialized outpatient PT program had significantly better outcomes in 3 Short-Form 36 (SF36) domains (d=0.46 to 0.79) and multiple other scales of physical and social function as well as clinician-measured outcomes. The intervention resulted in 0.08 additional quality-adjusted life years in a cost-effective manner. Conclusions: Current evidence suggests that in patients with FMD, specialized PT improves motor symptoms in a clinically significant, sustained, and cost-effective manner. This promising intervention warrants further investigation and replication.

Background: Stroke is a leading cause of disability worldwide. Selective serotonin reuptake inhibitors are often prescribed following stroke due to high rates of depression. Interest in selective serotonin reuptake inhibitor use for poststroke motor and functional recovery was generated after the publication of the Fluoxetine for motor recovery after acute ischemic stroke (FLAME) trial in 2011, which showed improved motor recovery in ischemic stroke patients with moderate to severe motor deficits. The objective of this study was to critically assess current evidence regarding the use of fluoxetine compared with placebo for poststroke functional recovery. Methods: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario and question, literature search, critical appraisal, results, evidence summary, commentary, and clinical bottom line conclusions. Participants included consultant and resident neurologists, medical librarian, clinical epidemiologists, and content experts in the field of cerebrovascular neurology and physical medicine and rehabilitation. Results: A randomized, placebo-controlled clinical trial was selected for critical appraisal. This trial compared the functional outcomes of subjects poststroke receiving fluoxetine versus placebo. There was no significant difference in functional outcome measured by the Modified Rankin Scale between the 2 groups. Prespecified secondary analysis showed significantly decreased rates of depression in the fluoxetine group, but significantly increased rates of bone fracture. Conclusion: Among patients with stroke, early initiation of fluoxetine did not result in improved functional recovery. Lower rates of depression were observed in the fluoxetine-treated group; however these patients experienced higher rates of bone fracture.

AbstractAimTo identify the appropriate methods of synovial fluid (SF) specimen storage, manipulation and handling for crystal associated arthritides (CAA) diagnosis.MethodA systematic literature review was conducted using 5 medical databases to identify diagnostic studies assessing SF specimen handling for calcium pyrophosphate (CPP) and monosodium urate (MSU) crystals identification. All included studies were rated for quality using the Quality Assessment of Diagnostic Accuracy Studies 2.ResultsFifteen studies, including 2 non‐English language manuscripts, were included. Eight studies examined both types of crystals, while 3 studies examined CPP and 4 studies examined MSU crystals only. Overall, MSU crystals were more stable over time compared to CPP crystals. MSU stability was generally independent of time, preservative and temperature. CPP crystals deteriorated with time and were more stable if refrigerated. Ethylenediaminetetraacetic acid (EDTA) was a suitable preservative. Re‐examining an initially negative SF sample at 24 hours facilitated detection of additional cases. Very few studies had an overall low risk of bias and applicability.ConclusionMonosodium urate crystals remain stable over time independent of storage time, temperature and preservative. CPP crystals are mostly stable for 24‐48 hours but can deteriorate with time. Overall, SF crystal examination should ideally be done within 24‐48 hours. They may be stored at room temperature without any preservative. Otherwise, refrigeration (4°C/39°F) and EDTA preservation is reasonable. Stored SF re‐examination, at 24 hours, helps identify a small number of additional MSU and CPP cases. Centrifugation techniques allow better and easier crystal identification, particularly CPP. Most studies were of unclear or low quality.

Objectives To address concerns related to the safety profile of both Food and Drug Administration (FDA)–approved and non‐FDA‐approved intranasal corticosteroid (INCS) use in the pediatric population. Data Source Systematic review of MEDLINE, PubMed, and EMBASE databases using comprehensive search strategy, including all INCS formulations and adverse events. The study design was developed using Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Additional sources were identified from study references of relevant articles. Review Methods A structured literature search was conducted. Extracted data included age, population size, study design, drug (dosage, route, and frequency), presence of hypothalamic‐pituitary‐adrenal (HPA) axis suppression, ocular symptoms, and growth velocity adverse events. Results A total of 33 studies met inclusion criteria. The studies included use of INCS as nasal sprays and drops. There were no persistent abnormalities noted in cortisol level or intraocular pressure change. Growth velocity reduction was reported in 3 of 10 randomized trials. Meta‐analysis of epistaxis and headache showed no significant difference in the incidence of headache or epistaxis when FDA‐approved INCSs were compared to placebo, with a relative risk of 1.12 (95% CI, 0.77‐1.63; P =. 56) and 0.84 (95% CI, 0.60‐1.18; P =. 32), respectively. Meta‐analysis was not performed for growth velocity, HPA axis suppression, and ocular change. Conclusions INCSs in FDA‐approved routes of administration are generally safe to use in the pediatric population. Use of non‐FDA‐approved INCS drops may increase risk of iatrogenic Cushing’s syndrome. Growth velocity reduction, HPA axis suppression, and visual changes due to INCS are uncommon.

Background: Noninvasive neuromodulation devices have been used for a variety of headache disorders, including cluster and migraine, since recently being cleared by the Federal Drug Administration. Although these devices have been touted as low-risk options for improved headache control, the data behind actual efficacy endpoints remain unclear. Objective: To critically assess current evidence regarding the efficacy of the noninvasive vagus nerve stimulator (nVNS) device for acute migraine management. Methods: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of headache. Results: A randomized, double-blind, sham-controlled clinical trial was selected for critical appraisal. In this trial, the primary endpoint (pain freedom at 120 min after use of nVNS for first acute migraine attack) was not met when compared with sham device (30.4% for nVNS vs. 19.7% for sham; P=0.067). However, there were statistically significant differences found for various secondary endpoints favoring nVNS, such as pain freedom rates at 30 and 60 minutes, pain relief at 120 minutes, and mean percentage pain score reduction rates at 60 and 120 minutes. Conclusions: When comparing nVNS with sham, no statistically significant differences were found with regards to the primary endpoint of pain freedom at 120 minutes, although differences were found with various secondary endpoints and post hoc analysis. nVNS is likely a safe alternative to medications.

ObjectivesTo address concerns related to the safety profile of both Food and Drug Administration (FDA)–approved and non–FDA‐approved intranasal corticosteroid (INCS) use in the adult population.Data SourceSystematic review of MEDLINE, PubMed, and EMBASE databases using a comprehensive search strategy including all INCS formulations and adverse events. The study design was developed using Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Additional sources were identified from study references of relevant articles.Review MethodsA structured literature search was conducted. Each study was graded for level of evidence using the Oxford Centre for Evidence‐Based Medicine. Extracted data included population size, study design, drug (dosage, route, and frequency), presence of hypothalamus pituitary axis suppression, ocular symptoms, and treatment‐related adverse events.ResultsA total of 60 studies met inclusion criteria. The studies included use of INCS as metered nasal sprays, drops, injections, aerosols, and irrigations. There were no persistent abnormalities in cortisol level or intraocular pressure change. Meta‐analysis of epistaxis showed a significantly increased risk in the FDA‐approved treatment group in comparison with control (risk ratio 1.56; 95% confidence interval, 1.13‐2.14; P =. 007).ConclusionsOverall, it appears that the use of both FDA and published non‐FDA application of INCS are safe in the adult population. Meta‐analysis demonstrated an increased risk of epistaxis in patients using INCS compared with placebo. Otherwise, there was no significant difference between in adults in the treatment group and placebo group. As an important caveat, the interpretation of safety of nonstandard INCS is restricted to delivery methods and dosages published in the literature.

Objectives (1) To perform a systematic literature review to evaluate associations between post‐dural puncture headache (PDPH) and opening pressure (OP), closing pressure (CP), and volume of cerebrospinal fluid (V) removed. (2) To perform a case‐control study to evaluate pressure‐volume index (PVI) as a novel risk factor for PDPH. Background According to the International Classification of Headache Diagnoses, 3rd Edition (ICHD‐3), the diagnosis of PDPH requires documentation of intracranial hypotension. However, this remains an unproven concept. Methods A systematic literature review was conducted, searching Cochrane Database of Systematic Reviews, Ovid EMBASE, OVID MEDLINE, Scopus, and Web of Science. Study inclusion required a comparison of headache incidence following a LP as a function of OP, CP, and/or V. A retrospective, case‐control study with 1:1 matching was conducted utilizing ICHD‐3 criteria. Patients with factors that could influence CSF pressure were excluded. Results In our case‐control study, we did not identify a paired difference in either median (95% CI) elastance (0.05 [−0.09, 0.11], P = .503) or PVI (4.53 [−7.98, 19.97], P = .678). We identified 22 references, evaluating V (n = 14), OP (n = 11), and/or CP (n = 4). There was no convincing evidence for an association of PDPH with either OP or CP. A minority of studies documenting an association with V included patients with high‐volume CSF removal, and/or stratified patients by the timing of the headache onset. Conclusions The overall risk of PDPH does not appear to be influenced by OP, CP, V or PVI. PDPH may be related to V in instances of high‐volume removal, and depend on the timing of outcome assessment. Future revision of criteria should consider the existence of immediate and delayed PDPH subtypes, and not presume intracranial hypotension as a mandatory feature.