Pseudopapilledema and association with idiopathic intracranial hypertension

Purpose

Diagnosing idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, can be challenging in children. Diagnosis is based on lumbar puncture, opening pressures, and appearance of the optic disk. Misdiagnosis of papilledema, a typical finding, may lead to unnecessary treatments and procedures. We report 52 children over a 6-year period to better identify the true incidence of pseudopapilledema and other factors that may confound the diagnosis of IIH.

Methods

A retrospective chart review approved by the Institutional Review Board was performed. Fifty-two children under the age of 21 referred to us based on suspected IIH or papilledema from 2007 to 2013 are included in this study. Patients were assessed by a pediatric ophthalmologist and a neurosurgeon.

Results

Fifty-two children were initially diagnosed with IIH and/or papilledema; 26 diagnoses were revised to pseudopapilledema after pediatric ophthalmological review. Out of those 26 patients with pseudopapilledema, 14 had undergone lumbar punctures, 19 had MRIs, 9 had CTs, and 12 were taking medications—these medications were discontinued upon revision of the diagnoses. The difference in the CSF opening pressure between children diagnosed with true IIH (32.7 cm H₂O) and children diagnosed with pseudopapilledema (24.7 cm H₂O) was statistically significant.

Conclusions

IIH diagnosis is heavily reliant on the appearance of the optic disk. Pediatric ophthalmological assessment is essential to carefully examine the optic disk and prevent further unnecessary investigation and treatments. Close communication between pediatricians, ophthalmologists, and neurosurgeons can avoid invasive procedures for children who do have pseudopapilledema, and not IIH or associated papilledema.     

End-stage liver disease developing with the use of methotrexate in heterozygous α1-antitrypsin deficiency

We report a case of cirrhosis developing in a man who was heterozygous for α₁-antitrypsin deficiency and who was receiving methotrexate for severe rheumatoid arthritis. The α₁-antitrypsin phenotype PiMZ has been associated with cryptogenic cirrhosis. Our patient had no biochemical or histologic evidence of chronic liver disease during the first year of receiving methotrexate. We postulate that the PiMZ state may result in enhanced susceptibility to methotrexate-induced hepatic toxicity and should be screened for if liver function abnormalities occur during methotrexate therapy.     

Strength and Sterility of Stock and Diluted Carprofen Over Time

Carprofen, a nonsteroidal antiinflammatory drug, is a commonly used analgesic for laboratory animals. The manufacturer labeling indicates the stock bottle may be stored and used for up to 28 d under refrigeration. However, institutional guidelines may vary in how long diluted carprofen solutions can be stored before they must be discarded. When administered to laboratory rodents, small volumes of the stock solution are diluted to provide accurate dosing and ease of administration. Because carprofen is formulated for use in companion animals (for example, dogs) and comes in larger volume multidose vials, the majority of carprofen at our institution is discarded before it can be used. In this study, we evaluated the amount of target ingredient present (strength), sterility, and endotoxin levels of both stock and diluted carprofen when stored in a variety of containers and at multiple temperature settings for up to 180 d, mimicking facets of typical use in laboratory animal research and medicine. We demonstrated that when refrigerated and stored in sterile vials, stock and diluted carprofen can be kept and used for up to 180 d while retaining strength and sterility. For short-term use, diluted carprofen can also be stored for up to 60 d at room temperature in conical tubes. These results will help establish scientifically justified storage conditions for carprofen to ensure that these agents remain appropriately potent and sterile for therapeutic use in laboratory animals.

Preclinical research involving animal models must be designed and performed to maximize animal welfare and the benefit to harm ratio while minimizing pain, distress and research variability. A common component of most preclinical research involves evaluating novel test articles for use in treating disease or using experimental compounds to either modify an animal’s pathophysiology or induce disease. In addition to the experimental compounds, therapeutic drugs may be administered for anesthesia, analgesia, or treatment of disease. Experimental test articles and therapeutic drugs are generally administered to laboratory animals (primarily rodents) by a parenteral route (subcutaneous, intraperitoneal, intravenous, intrathecal) rather than orally. The use of Food and Drug Administration (FDA)-approved drugs manufactured under Good Manufacturing Practice conditions is recommended, especially if the drugs can be used without dilutions or modifications. During product development, manufacturers determine the compound’s chemical and physical stability, packaging integrity, sterility, and expiration date based on recommended storage conditions. However, FDA approved drugs are not routinely labeled for small animals, rodents, or exotic species; thus, dilutions of manufactured drugs are often necessary to achieve the correct dose and an appropriate volume for safe administration. The Guide for the Care and Use of Laboratory Animals (8th ed.)⁷ and USDA policies state that whenever possible, pharmaceutical grade drugs should be used to minimize unwanted side effects or toxicities. According to the Guide, “if a non-pharmaceutical grade chemical or substance must be used to meet scientific goals or if a human or veterinary pharmaceutical grade product is unavailable then consideration should be given to the grade, purity, sterility, pH, pyrogenicity, osmolality, stability, site and route of administration, formulation, compatibility, and pharmacokinetics of the chemical or substance to be administered, as well as animal welfare and scientific issues relating to its use.”⁷ The United States Pharmacopeia (USP) publishes standards, guidelines for tests and procedures, monographs and reference standards for drugs, biologics, and compounding preparations (sterile and nonsterile) in their USP-National Formulary used by the FDA and state pharmacy boards to enforce and regulate nonsterile and sterile preparation compounding, adulteration, and misbranding of drugs. The USP National Formulary (USP-NF) is composed of general chapters; chapter numbers below 1000 are legally enforceable standards referenced by the FDA; and chapters above 1000 are generally used for informational guidance although they may be enforced in some countries.^4,20Regarding sterile pharmaceutical compounding in human and veterinary medicine, the USP General Chapter <797> Pharmaceutical Compounding – Sterile Preparations (a legally enforceable standard) must be followed when enforced by regulatory agencies or professional boards. The provisions include strict engineering processes regarding clean room requirements, airborne particle sampling, microbial monitoring, cleaning and disinfectant procedures, training, and development of quality assurance program. Per USP <797>, a compounded sterile preparation must state a beyond-use date (BUD) after which the preparation must not be stored, transported, or administered and therefore, must be discarded. A BUD is different from an expiration date, which is assigned by the manufacturer and is based upon rigorous analytical stability testing, specific for the formulation, dosage container, and storage conditions.²¹ Although USP General Chapter <797> standards are not a mandatory requirement for all preclinical research (unless required by the state board of pharmacy or other regulatory agency), the chapter’s components align with the use of nonpharmaceutical grade compounds as described in the Guide. The use of product-specific quantitative strength assays (e.g. HPLC), validated stability-indicating methods, sterility testing per USP <71> and bacterial endotoxin testing per USP <85> can be used to best determine optimal storage or beyond-use dating for compounded or diluted preparations. For instance, the USP <71> sterility criteria require a minimum use quantity depending on container size, and a 2-wk incubation of sample in growth media to determine if contamination is present. Utilization of such practices will ensure that laboratory animals receive experimental compounds and clinical therapeutics that are free from contamination and have the required potency to achieve a therapeutic clinical response until the storage or beyond-use date is reached.Carprofen, a nonsteroidal antiinflammatory drug, is one of the most commonly used analgesic compounds at our institution. When administered to mice, the stock solution is diluted from 50 mg/mL to 0.5 to 1 mg/mL to allow accurate dosing. Per USP guidelines for multidose vials, manufacturer labeling for injectable carprofen indicates that the stock vial should be maintained under refrigeration for up to 28 d once the vial stopper is punctured. Because carprofen is formulated for use in companion animals (for example, dogs) and comes in larger unit volumes (20 mL), the majority of carprofen become outdated before it can be used, requiring disposal and thus leading to waste and reduced cost-efficiency. In efforts to promote chemical and physical stability and reduce contamination in pharmaceutical formulations or preparations, research institutes should develop guidelines or policies for storing diluted aliquots of carprofen, including the amount of time that aliquots may be kept under various storage conditions (refrigeration, room temperature, or freezing). However, product-specific scientific data to support such recommendations is often sparse and must be extrapolated from methods outlined in USP <795>, or empirical beyond-use dates as indicated in USP <797> may be necessary. Moreover, default beyond-use dates in absence of quantitative or stability-indicating testing can be very restrictive, as indicated in USP <797>, requiring disposal of larger quantities of an unused drug that is normally manufactured in larger volume containers, yet must be diluted or used in smaller volumes in an animal research setting.This study was designed to evaluate carprofen (undiluted and diluted) for strength and sterility when stored in a variety of sterile containers and at multiple temperature settings over time. This storage was performed in conjunction with frequent manipulation intended to mimic common laboratory animal research and medicine usage. Results from this study will provide veterinarians and institutional animal care and use committees with additional information for determining appropriate beyond-use dates for this commonly used analgesic to ensure that the compound remains potent and sterile for therapeutic use.     

Use of Single-Item Self-Rated Health Measure to Identify Frailty and Geriatric Assessment-Identified Impairments Among Older Adults with Cancer

BackgroundPoor self-rated health (SRH) is a known predictor of frailty and mortality in the general population; however, its role among older adults with cancer is unknown. We evaluated the role of SRH as a potential screening tool to identify frailty and geriatric assessment (GA)-identified impairments.Materials and MethodsAdults ≥60 years diagnosed with cancer in the UAB Cancer & Aging Resilience Evaluation (CARE) registry underwent a GA at the time of initial consultation. We measured SRH using a single-item from the Patient-Reported Outcomes Measurement Information System global health scale and dichotomized responses as poor (poor, fair) and good (good, very good, and excellent). We evaluated the diagnostic performance of SRH in measuring frailty, and GA impairment (≥2 deficits among a set of seven GA domains). We examined the impact of SRH with survival using a Cox model adjusting for confounders, exploring the mediating role of frailty.ResultsSix hundred and three older adults with cancer were included, with a median age of 69 years. Overall, 45% (n = 274) reported poor SRH. Poor SRH demonstrated high sensitivity and specificity for identifying frailty (85% and 78%, respectively) and GA impairment (75% and 78%, respectively). In a Cox regression model, poor SRH was associated with inferior survival (HR = 2.26; 95% CI 1.60-3.18) after adjusting for confounders; frailty mediated 69% of this observed relationship.ConclusionSelf-rated health may be used as a screening tool to identify older adults with cancer with frailty and GA impairments. Poor SRH is associated with inferior survival, which is mediated by frailty.     

Influence of hydration and mechanical characterization of carious primary dentine using an ultra-micro indentation system (UMIS)

The conditions under which mechanical properties of dentine are tested influence the values recorded. The aims of this study were to examine the effect of hydration on the mechanical properties of primary carious dentine and to provide information on changes in hardness and modulus of elasticity change caused by the demineralizing caries process in dentine. Three primary molar teeth with untreated carious dentine were prepared for nano-indentation tests under both wet and dry conditions. Further tests were conducted on eight primary molars with untreated carious dentine under hydrated conditions. The mechanical properties of dehydrated carious dentine increased approximately 10-fold for hardness and 100-fold for the modulus of elasticity compared with hydrated dentine. The hardness and elastic modulus of the carious primary dentine deteriorated progressively toward the lesion cavity floor, ranging from 0.001 to 0.52 GPa and from 0.015 to 14.55 GPa, respectively, and could be fitted to a simple linear relationship when plotted in logarithmic scale vs. distance. The total depth of dentine affected was around 1100 microm parallel to the tubule direction. This depth was significantly greater than observed subjectively, implying that the demineralization process is more advanced than might be suspected on simple clinical examination.