Spatial Atlas for Mapping Vascular Microcalcification Using 18F-NaF PET/CT: Application in Hyperphosphatemic Familial Tumoral Calcinosis.

BACKGROUND: Vascular calcification causes significant morbidity and occurs frequently in diseases of calcium/phosphate imbalance. Radiolabeled sodium fluoride positron emission tomography/computed tomography has emerged as a sensitive and specific method for detecting and quantifying active microcalcifications. We developed a novel technique to quantify and map total vasculature microcalcification to a common space, allowing simultaneous assessment of global disease burden and precise tracking of site-specific microcalcifications across time and individuals. METHODS: To develop this technique, 4 patients with hyperphosphatemic familial tumoral calcinosis, a monogenic disorder of FGF23 (fibroblast growth factor-23) deficiency with a high prevalence of vascular calcification, underwent radiolabeled sodium fluoride positron emission tomography/computed tomography imaging. One patient received serial imaging 1 year after treatment with an IL-1 (interleukin-1) antagonist. A radiolabeled sodium fluoride-based microcalcification score, as well as calcification volume, was computed at all perpendicular slices, which were then mapped onto a standardized vascular atlas. Segment-wise mCSmean and mCSmax were computed to compare microcalcification score levels at predefined vascular segments within subjects. RESULTS: Patients with hyperphosphatemic familial tumoral calcinosis had notable peaks in microcalcification score near the aortic bifurcation and distal femoral arteries, compared with a control subject who had uniform distribution of vascular radiolabeled sodium fluoride uptake. This technique also identified microcalcification in a 17-year-old patient, who had no computed tomography-defined calcification. This technique could not only detect a decrease in microcalcification score throughout the patient treated with an IL-1 antagonist but it also identified anatomic areas that had increased responsiveness while there was no change in computed tomography-defined macrocalcification after treatment. CONCLUSIONS: This technique affords the ability to visualize spatial patterns of the active microcalcification process in the peripheral vasculature. Further, this technique affords the ability to track microcalcifications at precise locations not only across time but also across subjects. This technique is readily adaptable to other diseases of vascular calcification and may represent a significant advance in the field of vascular biology.

Infigratinib, a selective FGFR1-3 tyrosine kinase inhibitor, alters dentoalveolar development at high doses.

BACKGROUND: Fibroblast growth factor receptor-3 (FGFR3) gain-of-function mutations are linked to achondroplasia. Infigratinib, a FGFR1-3 tyrosine kinase inhibitor, improves skeletal growth in an achondroplasia mouse model. FGFs and their receptors have critical roles in developing teeth, yet effects of infigratinib on tooth development have not been assessed. Dentoalveolar and craniofacial phenotype of Wistar rats dosed with low (0.1 mg/kg) and high (1.0 mg/kg) dose infigratinib were evaluated using micro-computed tomography, histology, and immunohistochemistry. RESULTS: Mandibular third molars were reduced in size and exhibited aberrant crown and root morphology in 100% of female rats and 80% of male rats at high doses. FGFR3 and FGF18 immunolocalization and extracellular matrix protein expression were unaffected, but cathepsin K (CTSK) was altered by infigratinib. Cranial vault bones exhibited alterations in dimension, volume, and density that were more pronounced in females. In both sexes, interfrontal sutures were significantly more patent with high dose vs vehicle. CONCLUSIONS: High dose infigratinib administered to rats during early stages affects dental and craniofacial development. Changes in CTSK from infigratinib in female rats suggest FGFR roles in bone homeostasis. While dental and craniofacial disruptions are not expected at therapeutic doses, our findings confirm the importance of dental monitoring in clinical studies.

Characterization of Oral Health Status in Chilean Patients with X-Linked Hypophosphatemia.

X-Linked Hypophosphatemia (XLH) is the most common cause of inherited hypophosphatemic rickets. Dental involvement, including spontaneous abscesses and/or fistulae, is an important part of the disease and has not been completely defined, especially in cohorts from developing countries. To describe oral health status in a cohort of Chilean patients with XLH and explore its correlation with biochemical presentation and treatment, we conducted a cross-sectional observational study of patients with PHEX mutation-confirmed XLH. All patients had an oral clinical exam, radiographic evaluation; clinical and biochemical data were obtained to determine their association with oral features. Twenty-six patients were included, 77% adults and 23% children. Most adults (89%) had past or current dental pulp pathology (abscesses and/or fistulae). Pulpal chamber enlargement and radiolucent apical lesions were common radiological features (94 and 74%, respectively). In children, abscess and/or fistulae were also common (33%). Caries index, which was determined by dmft/DMFT, was higher than the Chilean national average. Early and long-term therapy with phosphate and activated vitamin D was associated with lower carious index and attachment loss. XLH patients frequently present with high pulpal involvement and carious index. Conventional therapy was associated with lower carious index and attachment loss. These data highlight the importance of early and periodical dental care in order to prevent dental damage and assure a good quality of oral health for XLH patients.

Sport-related Concussion Clinical Profiles: Clinical Characteristics, Targeted Treatments, and Preliminary Evidence.

Sport-related concussion (SRC) is a heterogeneous injury that involves varied symptoms and impairment that presents a significant clinical challenge to sports medicine professionals. In response to this challenge, clinical researchers have proposed clinical profiles or subtype models for assessing and treating athletes with SRC. One such model emphasizes five concussion clinical profiles including cognitive/fatigue, vestibular, ocular, migraine, and anxiety/mood. Sleep is a common modifier that co-occurs across these clinical profiles. A combination of medical history, risk factors, injury information, clinical characteristics, and assessment outcomes can inform each clinical profile. Preliminary data involving 236 patients from a concussion specialty clinic indicate that the migraine (26%) and anxiety/mood (24%) profiles are the most common, with vestibular and ocular profiles combined representing more than one third (35%) of clinical profiles. Findings also support several relationships among different clinical profiles including vestibular and migraine, suggesting that many athletes present with multiple clinical profiles. Targeted, active treatments for each profile are discussed.

Fibrous Dysplasia and Medication-Related Osteonecrosis of the Jaw.

PURPOSE: Osteonecrosis of the jaw (ONJ) is an established side effect of intravenous bisphosphonates and other antiresorptive medications. Although bisphosphonates are frequently prescribed for patients with the skeletal disorder fibrous dysplasia (FD), there are no reports of ONJ in this population. This has led some to conclude that patients with FD are at low risk for the development of bisphosphonate-related ONJ. PATIENTS AND METHODS: Patients were evaluated as part of a longstanding FD natural history study at the National Institutes of Health. RESULTS: Of 76 patients with FD who were treated with bisphosphonates, 4 developed ONJ (5.4%). Three patients developed ONJ in areas of FD-affected bone and 1 in an area of normal bone. All 4 patients had features known to be associated with ONJ in the general population, including long-term high-dose intravenous bisphosphonate treatment, periodontal and endodontic infections, and dentoalveolar surgical procedures. CONCLUSIONS: These cases establish ONJ as a potential complication of bisphosphonate treatment in patients with FD. The presence of established risk factors for ONJ in this group of patients with FD suggests that high-risk patients could be identified before the development of ONJ. Clinicians should use caution in prescribing bisphosphonates to patients with FD and should do so only for established indications.

Bone density and fractures in autosomal dominant hyper IgE syndrome.

PURPOSE: Autosomal Dominant Hyper IgE Recurrent Infection Syndrome (AD-HIES) is caused by mutations in STAT3 and characterized by eczema, recurrent bacterial infections, and skeletal and connective tissue abnormalities. To further understand the minimal trauma fractures of AD-HIES, we examined bone mineral density (BMD) and laboratory markers of bone turnover. METHODS: Patients with AD-HIES enrolled in a prospective natural history study were examined with dual x-ray absorptiometry (DEXA) scans and laboratory studies of bone metabolism. The number of fractures was recorded as well as clinical features of AD-HIES including scoliosis and retained primary teeth. Patients on medications with skeletal effects, including bisphosphonates, were examined separately. RESULTS: Twenty-three AD-HIES children (6-18 years) and 33 AD-HIES adults (21-50 years) not receiving bone-active drugs were studied. Fourteen of the 23 children (61%) had histories of minimal trauma fractures, as did 26 of the 33 adults (79%). Osteopenia or osteoporosis was found in 79% of children and adults. Only radial BMD correlated with the qualitative occurrence of fractures but it did not correlate with the numbers of fractures. Markers of bone metabolism did not correlate with minimal trauma fractures or BMD. Patients on bone-active medications had improved BMD, but still sustained fractures. CONCLUSIONS: Minimal trauma fractures and decreased BMD are common in AD-HIES. Low radial BMD is associated with fractures, but hip and spine BMD are not. Treatment with bisphosphonates increased BMD but its role in fracture prevention remains undefined.

Anticipated effects of burosumab treatment on long-term clinical sequelae in XLH: expert perspectives.

X-linked hypophosphatemia (XLH) is a rare, progressive, genetic disease with multisystem impact that typically begins to manifest in early childhood. Two treatment options exist: oral phosphate in combination with active vitamin D ("conventional therapy") and a fully human monoclonal anti-FGF23 antibody, burosumab. The clinical benefit of conventional therapy in adults is limited, and poor tolerance and complications are common. Burosumab was first approved as a treatment for XLH in 2018 and its disease-modifying benefits in clinical trials in children suggest burosumab treatment could also alter the disease course in adults. Without long-term clinical data on multiple XLH-related sequelae available, the results of an elicitation exercise are reported, in which eight global experts in XLH posited how long-term treatment with burosumab is anticipated to impact the life course of clinical sequelae in adults with XLH. Based on their clinical experiences, the available evidence and their disease understanding, the experts agreed that some long-term benefits of using burosumab are likely in adults with XLH even if they have a misaligned skeleton from childhood. Burosumab treatment is anticipated to reduce the incidence of fractures and halt the progression of clinical sequelae associated with conventional therapy. While the trajectories for established dental abscesses are not expected to improve with burosumab treatment, dental abscess development may be prevented. Starting treatment with burosumab in childhood to increase the likelihood of an aligned skeleton and continuation into and throughout adulthood to maintain euphosphatemia may optimize patient outcomes, although future real-world investigation is required to support this hypothesis.

Emerging Role of 18F-NaF PET/Computed Tomographic Imaging in Osteoporosis: A Potential Upgrade to the Osteoporosis Toolbox.

Osteoporosis is a metabolic bone disorder that leads to a decline in bone microarchitecture, predisposing individuals to catastrophic fractures. The current standard of care relies on detecting bone structural change; however, these methods largely miss the complex biologic forces that drive these structural changes and response to treatment. This review introduces sodium fluoride (18F-NaF) positron emission tomography/computed tomography (PET/CT) as a powerful tool to quantify bone metabolism. Here, we discuss the methods of 18F-NaF PET/CT, with a special focus on dynamic scans to quantify parameters relevant to bone health, and how these markers are relevant to osteoporosis.

Risk assessment for consumer exposure to toluene diisocyanate (TDI) derived from polyurethane flexible foam.

Polyurethanes (PU) are polymers made from diisocyanates and polyols for a variety of consumer products. It has been suggested that PU foam may contain trace amounts of residual toluene diisocyanate (TDI) monomers and present a health risk. To address this concern, the exposure scenario and health risks posed by sleeping on a PU foam mattress were evaluated. Toxicity benchmarks for key non-cancer endpoints (i.e., irritation, sensitization, respiratory tract effects) were determined by dividing points of departure by uncertainty factors. The cancer benchmark was derived using the USEPA Benchmark Dose Software. Results of previous migration and emission data of TDI from PU foam were combined with conservative exposure factors to calculate upper-bound dermal and inhalation exposures to TDI as well as a lifetime average daily dose to TDI from dermal exposure. For each non-cancer endpoint, the toxicity benchmark was divided by the calculated exposure to determine the margin of safety (MOS), which ranged from 200 (respiratory tract) to 3×10(6) (irritation). Although available data indicate TDI is not carcinogenic, a theoretical excess cancer risk (1×10(-7)) was calculated. We conclude from this assessment that sleeping on a PU foam mattress does not pose TDI-related health risks to consumers.

Applications of Artificial Intelligence in 18F-Sodium Fluoride Positron Emission Tomography/Computed Tomography:: Current State and Future Directions.

This review discusses the current state of artificial intelligence (AI) in 18F-NaF-PET/CT imaging and the potential applications to come in diagnosis, prognostication, and improvement of care in patients with bone diseases, with emphasis on the role of AI algorithms in CT bone segmentation, relying on their prevalence in medical imaging and utility in the extraction of spatial information in combined PET/CT studies.

Radiofrequency ablation combined with liposomal quercetin to increase tumour destruction by modulation of heat shock protein production in a small animal model.

PURPOSE: To investigate the effect of heat shock protein (HSP) modulation on tumour coagulation by combining radiofrequency (RF) ablation with adjuvant liposomal quercetin and/or doxorubicin in a rat tumour model. METHODS: Sixty R3230 breast adenocarcinoma tumours/animals were used in this IACUC-approved study. Initially, 60 tumours (n=6, each subgroup) were randomised into five groups: (1) RF alone, (2) intravenous (IV) liposomal quercetin alone (1 mg/kg), (3) IV liposomal quercetin followed 24 h later with RF, (4) RF followed 15 min later by IV liposomal doxorubicin (8 mg/kg), (5) IV liposomal quercetin 24 h before RF followed by IV liposomal doxorubicin 15 min post-ablation. Animals were sacrificed 4 or 24 h post-treatment and gross coagulation diameters were compared. Next, immunohistochemistry staining was performed for Hsp70 and cleaved caspase-3 expression. Comparisons were performed by using Student t-tests or ANOVA. RESULTS: Combination RF-quercetin significantly increased coagulation size compared with either RF or liposomal quercetin alone (13.1±0.7 mm vs. 8.8±1.2 mm or 2.3±1.3 mm, respectively, P<0.001 for all comparisons). Triple therapy (quercetin-RF-doxorubicin) showed larger coagulation diameter (14.5±1.0 mm) at 24 h than quercetin-RF (P=0.016) or RF-doxorubicin (13.2±1.3 mm, P=0.042). Combination quercetin-RF decreased Hsp70 expression compared with RF alone at both 4 h (percentage of stained cells/hpf 22.4±13.9% vs. 38.8±16.1%, P<0.03) and 24 h (45.2±10.5% vs. 81.1±3.6%, P<0.001). Quercetin-RF increased cleaved caspase-3 expression at both 4 h (percentage of stained cells/hpf 50.7±13.4% vs. 41.9±15.1%, P<0.03) and 24 h (37.4±7.8% vs. 33.2±6.5%, P=0.045); with, triple therapy (quercetin-RF-doxorubicin) resulting in the highest levels of apoptosis (45.1±10.7%) at 24 h. Similar trends were observed for rim thickness. CONCLUSIONS: Suppression of HSP production using adjuvant liposomal quercetin can increase apoptosis and improve RF ablation-induced tumour destruction. Further increases in tumour coagulation can be seen including an additional anti-tumour adjuvant agent such as liposomal doxorubicin.

Experimental testing of the variable rotated elastic parabolic equation.

A series of laboratory experiments was conducted to obtain high-quality data for acoustic propagation in shallow water waveguides with sloping elastic bottoms. Accurate modeling of transmission loss in these waveguides can be performed with the variable rotated parabolic equation method. Results from an earlier experiment with a flat or sloped slab of polyvinyl chloride (PVC) demonstrated the necessity of accounting for elasticity in the bottom and the ability of the model to produce benchmark-quality agreement with experimental data [J. M. Collis et al., J. Acoust. Soc. Am. 122, 1987-1993 (2007)]. This paper presents results of a second experiment, using two PVC slabs joined at an angle to create a waveguide with variable bottom slope. Acoustic transmissions over the 100-300 kHz band were received on synthetic horizontal arrays for two source positions. The PVC slabs were oriented to produce three different simulated waveguides: flat bottom followed by downslope, upslope followed by flat bottom, and upslope followed by downslope. Parabolic equation solutions for treating variable slopes are benchmarked against the data.

A Cross-Sectional Cohort Study of the Effects of FGF23 Deficiency and Hyperphosphatemia on Dental Structures in Hyperphosphatemic Familial Tumoral Calcinosis.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disorder caused by mutations in FGF23, GALNT3, KLOTHO, or FGF23 autoantibodies. Prominent features include high blood phosphate and calcific masses, usually adjacent to large joints. Dental defects have been reported, but not systematically described. Seventeen patients with HFTC followed at the National Institutes of Health underwent detailed clinical, biochemical, molecular, and dental analyses. Studies of teeth included intraoral photos and radiographs, high-resolution µCT, histology, and scanning electron microscopy (SEM). A scoring system was developed to assess the severity of tooth phenotype. Pulp calcification was found in 13 of 14 evaluable patients. Short roots and midroot bulges with apical thinning were present in 12 of 13 patients. Premolars were most severely affected. µCT analyses of five HFTC teeth revealed that pulp density increased sevenfold, whereas the pulp volume decreased sevenfold in permanent HFTC teeth compared with age- and tooth-matched control teeth. Histology revealed loss of the polarized odontoblast cell layer and an obliterated pulp cavity that was filled with calcified material. The SEM showed altered pulp and cementum structures, without differences in enamel or dentin structures, when compared with control teeth. This study defines the spectrum and confirms the high penetrance of dental features in HFTC. The phenotypes appear to be independent of genetic/molecular etiology, suggesting hyperphosphatemia or FGF23 deficiency may be the pathomechanistic driver, with prominent effects on root and pulp structures, consistent with a role of phosphate and/or FGF23 in tooth development. Given the early appearance and high penetrance, cognizance of HFTC-related features may allow for earlier diagnosis and treatment. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Do liposomal apoptotic enhancers increase tumor coagulation and end-point survival in percutaneous radiofrequency ablation of tumors in a rat tumor model?

PURPOSE: To characterize effects of combining radiofrequency (RF) ablation with proapoptotic intravenous liposome-encapsulated paclitaxel and doxorubicin on tumor destruction, apoptosis and heat-shock protein (HSP) production, intratumoral drug accumulation, and end-point survival. MATERIALS AND METHODS: R3230 mammary adenocarcinomas (n = 177) were implanted in 174 rats in this animal care committee-approved study. Tumors received (a) no treatment, (b) RF ablation, (c) paclitaxel, (d) RF ablation followed by paclitaxel (RF ablation-paclitaxel), (e) paclitaxel before RF ablation (paclitaxel-RF ablation), (f) RF ablation followed by doxorubicin (RF ablation-doxorubicin), (g) paclitaxel followed by doxorubicin without RF ablation (paclitaxel-doxorubicin), or (h) paclitaxel before RF ablation, followed by doxorubicin (paclitaxel-RF ablation-doxorubicin). Tumor coagulation area and diameter were compared at 24-96 hours after treatment. Intratumoral paclitaxel uptake with and without RF ablation were compared. Immunohistochemical staining revealed cleaved caspase-3 and 70-kDa HSP (HSP70) expression. Tumors were randomized into eight treatment arms for Kaplan-Meier analysis of defined survival end-point (3.0-cm diameter). RESULTS: Paclitaxel-RF ablation increased tumor coagulation over RF ablation or paclitaxel (mean, 14.0 mm ± 0.9 [standard deviation], 6.7 mm ± 0.6, 2.5 mm ± 0.6, respectively; P < .001). Paclitaxel-RF ablation-doxorubicin had similar tumor coagulation (P < .05), compared with paclitaxel-RF ablation, at 24 and 96 hours. Mean intratumoral paclitaxel accumulation for paclitaxel-RF ablation (6.76 µg/g ± 0.35) and RF ablation-paclitaxel (9.28 µg/g ± 0.87) increased over that for paclitaxel (0.63 µg/g ± 0.25, P < .001). Paclitaxel substantially increased apoptosis and decreased HSP70 expression at coagulation margin. Mean end-point survival for paclitaxel-RF ablation-doxorubicin (56.8 days ± 25.3) was greater, compared with that for paclitaxel-RF ablation or RF ablation-paclitaxel (17.6 days ± 2.5), RF ablation-doxorubicin (30.3 days ± 4.9, P < .002), or paclitaxel-doxorubicin (27.9 days ± 4.1, P < .001). CONCLUSION: Selecting adjuvant liposomal chemotherapies (paclitaxel, doxorubicin) to target cellular apoptosis and HSP production effectively increases RF ablation-induced tumor coagulation and end-point survival, and combined multidrug approach results in even better outcomes. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100500/-/DC1.

Regional changes in corneal thickness and shape with soft contact lenses.

PURPOSE: To investigate the influence of soft contact lenses on regional variations in corneal thickness and shape while taking account of natural diurnal variations in these corneal parameters. METHODS: Twelve young, healthy subjects wore four different types of soft contact lenses on four different days. The lenses were of two different materials (silicone hydrogel or hydrogel), designs (spherical or toric), and powers (3.00 or -7.00 diopter). Corneal thickness and topography measurements were taken before and after 8 h of lens wear and on 2 days without lens wear, using the Pentacam HR system. RESULTS.: The hydrogel toric contact lens caused the greatest level of corneal thickening in the central (20.3 +/- 10.0 microm) and peripheral cornea (24.1 +/- 9.1 microm) (p < 0.001) with an obvious regional swelling of the cornea beneath the stabilizing zones. The anterior corneal surface generally showed slight flattening. All contact lenses resulted in central posterior corneal steepening, and this was weakly correlated with central corneal swelling (p = 0.03) and peripheral corneal swelling (p = 0.01). CONCLUSIONS: There was an obvious regional corneal swelling apparent after wear of the hydrogel soft toric lenses because of the location of the thicker stabilization zones of the toric lenses. However, with the exception of the hydrogel toric lens, the magnitude of corneal swelling induced by the contact lenses over the 8 h of wear was less than the natural diurnal thinning of the cornea over this same period.

Tear film surface quality with soft contact lenses using dynamic-area high-speed videokeratoscopy.

OBJECTIVES: To evaluate the performance of the dynamic-area high-speed videokeratoscopy technique in the assessment of tear film surface quality with and without the presence of soft contact lenses on eye. METHODS: Retrospective data from a tear film study (Kopf et al., J Optom. 2008;1:14-21) using basic high-speed videokeratoscopy, captured at 25 frames per sec, were used. Eleven subjects underwent tear film analysis conducted in the morning, midday, and evening on the first and seventh day of 1 week of no lens wear. Five of the 11 subjects then completed an extra week of hydrogel lens wear, followed by a week of silicone hydrogel lens wear. Analysis was performed on a 6-sec period of the interblink recording. The dynamic-area high-speed videokeratoscopy technique uses the maximum available area of Placido ring pattern reflected from the tear interface and eliminates regions of disturbance because of shadows from the eyelashes. A value of tear film surface quality was derived using image-processing techniques based on the quality of the reflected ring pattern orientation. RESULTS: The group mean tear film surface quality and the standard deviations for each of the conditions (bare eye, hydrogel lens, and silicone hydrogel lens) showed a much lower coefficient of variation than that of previous methods (average reduction of approximately 92%). Bare eye measurements from the right and left eyes of 11 individuals showed high correlation values (Pearson correlation r = 0.73, P<0.05). Repeated measures ANOVA across the 6-sec period of measurement in the normal interblink period for the bare eye condition showed no statistically significant changes. However, across the 6-sec interblink period with both the contact lenses, statistically significant changes were observed (P<0.001). Overall, wearing hydrogel and silicone hydrogel lenses caused the tear film surface quality to worsen compared with that of the bare eye condition (repeated measures ANOVA, P<0.0001 for both the hydrogel and silicone hydrogel). CONCLUSIONS: The results suggest that the dynamic-area method of high-speed videokeratoscopy was able to distinguish and quantify the subtle, but systematic worsening of tear film surface quality in the interblink interval in contact lens wear. It was also able to clearly show a difference between bare eye and contact lens wearing conditions.

Sports concussion: management and predictors of outcome.

Interest in sports concussion has grown widely in the last two decades among laypersons and medical professionals. Significant contributions of evidence-based research have led to a better understanding of this multifaceted, but still often elusive, injury. This information has transformed all aspects of concussion management, from on-field evaluation through return-to-play guidelines. The aim of this article is to highlight important research regarding predictors of outcome and treatment protocols. This research has been the basis of the paradigm shift from traditional concussion grading scales to individualized care. Today, concussion management requires a patient-centered approach with individualized assessment, including risk factor analysis, neurocognitive testing, and a thorough symptom evaluation.

Sport-Related Concussion Evaluation and Management.

Concussion is a challenging and controversial medical diagnosis that can test even the most seasoned practitioner. Knowledge on this topic is ever evolving. It was not so long ago that grading guidelines were based on loss of consciousness and amnesia. Medicine has seen a renaissance of discovery over the past 20 years in concussion evaluation and management. A PubMed search for "concussion" between 1990 and 2000 produced just over 1000 articles and that same search including the last 18 years expands to over 10,000 publications. The most recent knowledge and recommendations are discussed based on the published evidence.