Learning and Attention Deficit/Hyperactivity Disorders as Risk Factors for Prolonged Concussion Recovery in Children and Adolescents.

OBJECTIVE: Examine pre-existing learning disorders (LD) and attention deficit/hyperactivity disorders (ADHD) as risk factors for prolonged recovery and increased symptomology following pediatric mild traumatic brain injury (mTBI). METHODS: We conducted a retrospective cohort study of children/adolescents (5-17 years) with mTBI who presented to a Children's Minnesota Concussion Clinic between April 2018 and March 2019. Differences across strata of pre-existing conditions (present vs. absent) in time to recovery measures were estimated via Kaplan-Meier and Cox proportional hazards analyses and differences in symptom trajectories were examined via linear mixed-effects regression models. Regression models were adjusted for age, sex and other confounders. RESULTS: In our cohort of 680 mTBI patients, those with LD (n = 70) or ADHD (n = 107) experienced significantly longer median durations of symptoms (58 and 68 days, respectively) than those without (43 days). Accordingly, LD was significantly associated with delayed symptom recovery (adjusted hazard ratio (aHR) = 1.63, 95% CI: 1.16-2.29), return to school (1.47, 1.08-2.00), and return to physical activity (1.50, 1.10-2.04). Likewise, ADHD was associated with delayed recovery (1.69, 1.28-2.23), return to school (1.52, 1.17-1.97) and physical activity (1.55, 1.19-2.01). Further, patients with LD or ADHD reported, on average, significantly more concussion symptoms and higher vision symptom scores throughout recovery versus those without. There was no evidence that concussion or vision symptom recovery trajectories varied over time between those with/without LD or ADHD (joint P-interactions > 0.05). CONCLUSION: Pre-existing LD and ADHD are risk factors for prolonged and more symptomatic mTBI recovery in youth. These results can inform clinical concussion management and recovery expectations.

Concussion symptomology and recovery in children and adolescents with pre-existing anxiety.

OBJECTIVE: To examine pre-existing anxiety disorders as a risk factor for increased concussion symptomology and prolonged recovery in children and adolescents. METHODS: In this retrospective cohort study, we abstracted medical record data for 637 children/adolescents (5-17 years) presenting to three tertiary concussion clinics between April 2018 and March 2019. Primary outcomes were mean concussion symptom and vision symptom severity scores measured at clinic visits. Linear mixed-effects regression models were employed to investigate differences in average symptom load, vision symptom score and symptom recovery trajectories across anxiety strata, adjusted for random effects (time), age and sex. Secondary outcomes, time to concussion symptom recovery and time to return to academics and sports, respectively, were examined via log-rank tests and multivariable Cox regression. RESULTS: Among 637 eligible concussion patients, 155 (24%) reported pre-existing anxiety. On average, patients with anxiety reported an additional 2.64 (95% CI 1.84 to 3.44) concussion symptoms and 7.45 (95% CI 5.22 to 9.68) higher vision symptom severity scores throughout recovery versus those without, after adjusting for age and sex. There was no evidence that concussion or vision symptom trajectories varied over time between those with/without anxiety after accounting for baseline dissimilarities in symptom scores (all pinteraction >0.05). Anxiety was significantly associated with delayed symptom recovery (adjusted HR 3.34, 95% CI 2.18 to 5.12), return to school (adjusted HR 2.01, 95% CI 1.59 to 2.53) and return to physical activity (adjusted HR 1.88, 95% CI 1.49 to 2.37). CONCLUSIONS: Pre-existing anxiety disorders were associated with more severe symptomology and prolonged recovery after concussion in children and adolescents. These results can be referenced by providers to manage patients' recovery expectations.

Circulating microparticle proteins obtained in the late first trimester predict spontaneous preterm birth at less than 35 weeks' gestation: a panel validation with specific characterization by parity.

BACKGROUND: We have previously shown that protein biomarkers associated with circulating microparticles proteins (CMPs) obtained at the end of the first trimester may detect physiologic changes in maternal-fetal interaction such that the risk of spontaneous preterm delivery ≤35 weeks can be stratified. OBJECTIVES: We present here a study extension and validation of the CMP protein multiplex concept using a larger sample set from a multicenter population that allows for model derivation in a training set and characterization in a separate testing set. MATERIALS AND METHODS: Ethylenediaminetetraacetic acid (EDTA) plasma was obtained from 3 established biobanks (Seattle, Boston, and Pittsburgh). Samples were from patients at a median of 10-12 weeks' gestation, and the CMPs were isolated via size-exclusion chromatography followed by protein identification via targeted protein analysis using liquid chromatography-multiple reaction monitoring-mass (LC-MRM) spectrometry. A total of 87 women delivered at ≤35 weeks, and 174 women who delivered at term were matched by maternal age (±2 years) and gestational age at sample draw (±2 weeks). From our prior work, the CMP protein multiplex comprising F13A, FBLN1, IC1, ITIH2, and LCAT was selected for validation. RESULTS: For delivery at ≤35 weeks, the receiver operating characteristic (ROC) curve for a panel of CMP proteins (F13A, FBLN1, IC1, ITIH2, and LCAT) revealed an associated area under the ROC curve (AUC) of 0.74 (95% CI, 0.63-0.81). A separate panel of markers (IC1, LCAT, TRFE, and ITIH4), which stratified risk among mothers with a parity of 0, showed an AUC of 0.77 (95% CI, 0.61-0.90). CONCLUSION: We have identified a set of CMP proteins that provide, at 10-12 weeks gestation, a clinically useful AUC in an independent test population. Furthermore, we determined that parity is pertinent to the diagnostic testing performance of the biomarkers for risk stratification.

Evaluation of proteomic biomarkers associated with circulating microparticles as an effective means to stratify the risk of spontaneous preterm birth.

BACKGROUND: The analysis of circulating microparticles in pregnancy is of revolutionary potential because it represents an in vivo biopsy of active gestational tissues. OBJECTIVE: We hypothesized that circulating microparticle signaling will differ in pregnancies that experience spontaneous preterm birth from those delivering at term and that these differences will be evident many weeks in advance of clinical presentation. STUDY DESIGN: Utilizing plasma specimens obtained between 10 and 12 weeks' gestation as part of a prospectively collected birth cohort in which pregnancy outcomes are independently validated by 2 board-certified maternal-fetal medicine physicians, 25 singleton cases of spontaneous preterm birth ≤ 34 weeks were matched by maternal age, race, and gestational age of sampling (±2 weeks) with 50 uncomplicated term deliveries. Circulating microparticles from these first-trimester specimens were isolated and analyzed by multiple reaction monitoring mass spectrometry for potential protein biomarkers following previous studies. Markers with robust univariate performance in correlating spontaneous preterm birth were further evaluated for their biological relevance via a combined functional profiling/pathway analysis and for multivariate performance. RESULTS: Among the 132 proteins evaluated, 62 demonstrated robust power of detecting spontaneous preterm birth in a bootstrap receiver-operating characteristic curve analysis at a false discovery rate of < 20% estimated via label permutation. Differential dependency network analysis identified spontaneous preterm birth-associated coexpression patterns linked to biological processes of inflammation, wound healing, and the coagulation cascade. Linear modeling of spontaneous preterm birth using a multiplex of the candidate biomarkers with a fixed sensitivity of 80% exhibited a specificity of 83% with median area under the curve of 0.89. These results indicate a strong potential of multivariate model development for informative risk stratification. CONCLUSION: This project has identified functional proteomic factors with associated biological processes that are already unique in their expression profiles at 10-12 weeks among women who go on to deliver spontaneously ≤ 34 weeks. These changes, with further validation, will allow the stratification of patients at risk of spontaneous preterm birth before clinical presentation.

Circulating microparticle proteins predict pregnancies complicated by placenta accreta spectrum.

Placenta accreta spectrum (PAS) is characterized by abnormal attachment of the placenta to the uterus, and attempts at placental delivery can lead to catastrophic maternal hemorrhage and death. Multidisciplinary delivery planning can significantly improve outcomes; however, current diagnostics are lacking as approximately half of pregnancies with PAS are undiagnosed prior to delivery. This is a nested case-control study of 35 cases and 70 controls with the primary objective of identifying circulating microparticle (CMP) protein panels that identify pregnancies complicated by PAS. Size exclusion chromatography and liquid chromatography with tandem mass spectrometry were used for CMP protein isolation and identification, respectively. A two-step iterative workflow was used to establish putative panels. Using plasma sampled at a median of 26 weeks' gestation, five CMP proteins distinguished PAS from controls with a mean area under the curve (AUC) of 0.83. For a separate sample taken at a median of 35 weeks' gestation, the mean AUC was 0.78. In the second trimester, canonical pathway analyses demonstrate over-representation of processes related to iron homeostasis and erythropoietin signaling. In the third trimester, these analyses revealed abnormal immune function. CMP proteins classify PAS well prior to delivery and have potential to significantly reduce maternal morbidity and mortality.

Late first trimester circulating microparticle proteins predict the risk of preeclampsia < 35 weeks and suggest phenotypic differences among affected cases.

We hypothesize that first trimester circulating micro particle (CMP) proteins will define preeclampsia risk while identifying clusters of disease subtypes among cases. We performed a nested case-control analysis among women with and without preeclampsia. Cases diagnosed < 34 weeks' gestation were matched to controls. Plasma CMPs were isolated via size exclusion chromatography and analyzed using global proteome profiling based on HRAM mass spectrometry. Logistic models then determined feature selection with best performing models determined by cross-validation. K-means clustering examined cases for phenotypic subtypes and biological pathway enrichment was examined. Our results indicated that the proteins distinguishing cases from controls were enriched in biological pathways involved in blood coagulation, hemostasis and tissue repair. A panel consisting of C1RL, GP1BA, VTNC, and ZA2G demonstrated the best distinguishing performance (AUC of 0.79). Among the cases of preeclampsia, two phenotypic sub clusters distinguished cases; one enriched for platelet degranulation and blood coagulation pathways and the other for complement and immune response-associated pathways (corrected p < 0.001). Significantly, the second of the two clusters demonstrated lower gestational age at delivery (p = 0.049), increased protein excretion (p = 0.01), more extreme laboratory derangement (p < 0.0001) and marginally increased diastolic pressure (p = 0.09). We conclude that CMP-associated proteins at 12 weeks' gestation predict the overall risk of developing early preeclampsia and indicate distinct subtypes of pathophysiology and clinical morbidity.

Lateralizing language with magnetic source imaging: validation based on the Wada test.

PURPOSE: Magnetoencephalography (MEG)/magnetic source imaging (MSI) is a noninvasive functional neuroimaging procedure used to localize language-specific regions in the brain. The Wada test, or intracarotid amobarbital procedure (IAP), is the gold standard in determining speech/language lateralization for presurgical planning, although it is invasive and associated with morbidity. The purpose of this study is to provide further validation on the use of MSI for presurgical language lateralization by comparing results against the IAP. METHODS: The sample consisted of 35 patients with epilepsy and/or brain tumor undergoing presurgical evaluation at the Minnesota Epilepsy Group. All patients received both an IAP and MSI to determine hemispheric language dominance. For MSI, a 148-channel MEG system was used to record activation of language-specific cortex by an auditory word-recognition task. RESULTS: The MSI and IAP were concordant in determining language in the hemisphere to be treated in 86% of the cases with sensitivity and specificity values of 80% and 100%, respectively. CONCLUSIONS: The results from this study are consistent with prior research findings comparing functional neuroimaging procedures to the IAP in determining language lateralization in presurgical patients. The current study provides an important replication and support for Papanicolaou et al.'s findings in 2004 using a consecutive clinical sample from a different institution. An unusually high rate of atypical IAP language cases in this sample and differences between the two procedures are believed to explain the noted discrepancies. MSI is a viable noninvasive alternative to the IAP in the presurgical determination of language lateralization.

State-of-the-art of serum testosterone measurement by isotope dilution-liquid chromatography-tandem mass spectrometry.

BACKGROUND: The recent interest of clinical laboratories in developing serum testosterone assays based on isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) stems from the lack of accuracy of direct immunoassays. In this study, we assessed the accuracy and state of standardization (traceability) of 4 published ID-LC-MS/MS procedures in a method comparison with an ID-gas chromatography (GC)-MS reference measurement procedure listed in the database of the Joint Committee for Traceability in Laboratory Medicine. METHODS: The study used 58 specimens from different patient categories. Each specimen was measured in triplicate (ID-LC-MS/MS) and quadruplicate (ID-GC-MS) in independent runs. RESULTS: The testosterone concentrations by ID-GC-MS were 0.2-4.4 nmol/L (women), 0.2-2.0 nmol/L (hypogonadal man), and 10.1-31.3 nmol/L (normogonadal men). For ID-GC-MS, the CV was nearly constant, with a median of 1.0%; for ID-LC-MS/MS, it was concentration-dependent, with a median of up to 8%. Weighted Deming regression gave mean slopes, intercepts, and correlation coefficients of 0.90-1.11, -0.055-0.013 nmol/L, and 0.993-0.997, respectively. The % difference plot showed between 7% and 26% of the results outside a total error limit of 14%, with median deviations from ID-GC-MS between -9.6 and 0.4%. CONCLUSIONS: This study demonstrated fairly good accuracy and standardization of the tested ID-LC-MS/MS procedures. Performance differences between procedures were evident in some instances, due to improper calibration and between-run calibration control. This emphasizes the need for thorough validation, including traceability, of new ID-LC-MS/MS procedures.

Mass spectrometric and physiological validation of a sensitive, automated, direct immunoassay for serum estradiol using the Architect.

BACKGROUND: Measurement of estradiol (E(2)) plays a critical role in the diagnosis and clinical management of reproductive disorders. The challenge for all currently available direct methods for measuring E(2) is to provide accuracy and precision across a wide dynamic range. METHODS: We describe the development and multi-site performance evaluation of a direct E(2) assay on the Architect i2000. Assay performance and method comparisons were performed by testing specimens from men, healthy women with regular menstrual cycles, and post-menopausal women using the Architect assay and isotope dilution, gas chromatography-mass spectrometry (ID/GC-MS). Reference intervals were established by testing prospectively collected daily blood draws from 42 healthy women, 72 postmenopausal women and 101 males. RESULTS: No unexpected cross-reactivity or interference was observed for over 40 compounds tested. Recovery was 100+/-10% in the presence of estrone and estriol. Functional sensitivity (%CV<20%) was <15 pg/ml.(1) The imprecision of the assay was <7.1% (total CV), <2.5%, and <2.3% for control sera containing 45, 190, and 600 pg/ml estradiol, respectively. The assay had a correlation of y=1.033 x+0.3156, r(2)=0.99, n=131 compared to ID/GC-MS. Reference intervals for the current Architect Estradiol assay are reported. CONCLUSIONS: Format changes resulted in dramatic improvement in the performance and accuracy of this direct, fully automated assay. The assay is standardized by ID/GC-MS. The assay is clinically useful for serum concentrations from 15 to >4000 pg/ml.

Psychogenic non-epileptic seizures.

Psychogenic non-epileptic seizures (PNES) are diagnosed in at least 10-40% of the patients seen for long-term monitoring of epilepsy, and it is no surprise that patients with PNES are often treated for epilepsy. Given the substantial economic costs and mental health burden of misdiagnosis, it is imperative to establish early identification, correct diagnosis, and effective treatment of PNES in order to provide the greatest opportunity for remission of events, improved psychological functioning, and social-vocational outcome. This article outlines an informed, practical approach to diagnosing this common condition and provides a summary of factors, based on medical history and semiology, that may suggest PNES. We discuss also the issues of communicating the diagnosis to the patient and making treatment recommendations which should ideally be coordinated using a multi-disciplinary team approach, involving the disciplines of neurology, psychiatry, psychology, social work, and nursing.

Reversible dementia: a case of cryptococcal meningitis masquerading as Alzheimer's disease.

A 70-year-old man presented to us in 1994 with a three-year history of worsening dementia. With the exceptions of a Mini-Mental State exam score of 20 and an inability to tandem walk, his physical and neurological examinations were normal. His past medical history revealed that in 1992 he had been evaluated at another institution for memory impairment and bifrontal headaches. A spinal tap had been done in 1992 showing elevated protein, reduced glucose, and a pleocytosis; his CSF fungal culture and cryptococcal antigen test were negative. He subsequently was lost to follow-up, and although his headaches had resolved, his mental status had continued to worsen. In 1994 his CSF cryptococcal antigen was positive, and his CSF fungal culture grew C. neoformans. He gradually improved with treatment for cryptococcal meningitis (CM). With the exception of mild memory impairment, in 2003 he and his family thought that his mental status had returned to normal. This case emphasizes that: 1) CM should always be kept in the differential diagnosis of dementia; 2) CM may be extremely insidious and difficult to diagnose; and 3) if one is to rule out unequivocally all possible reversible causes of dementia, one should perform a spinal tap.

Treatment outcome in patients with mesial temporal sclerosis.

The long-term prognosis of pharmacological therapy in patients with mesial temporal sclerosis (MTS) is generally considered poor. On the contrary, successful surgical therapy is frequently reported. We performed a retrospective case record survey of patients with MTS in a comprehensive epilepsy center between 1993 and 1999 in order to develop treatment strategies. The time period allowed access to high-resolution qualitative magnetic resonance imaging (MRI) and a minimum of 1-year outcome assessment. Eighty-three patients with intractable partial epilepsy with MRI and electroencephalograph (EEG) abnormalities and seizure semiology consistent with temporal lobe epilepsy were identified. Thirty-six patients were treated pharmacologically and surgically and 47 patients received only pharmacotherapy. The number of patients who became seizure free was in total 37 (45%); in the surgical group 26 and in the non-surgical group 11. The proportions of seizure-free patients in each group were 72% (surgical) and 23% (non-surgical). Clinical factors such as age, gender, lesion side, previous medical history, duration of illness, seizure frequency and IQ did not correlate to prognosis. A good seizure outcome was associated with early age of seizure onset, low number of previously used antiepileptic drugs (AEDs) and surgical treatment. There is a better long-term outcome in patients with MTS receiving surgical therapy in comparison with medical therapy.

WMS-III performance in epilepsy patients following temporal lobectomy.

We examined performances on the Wechsler Memory Scale-3rd Edition (WMS-III) among patients who underwent temporal lobectomy for the control of medically intractable epilepsy. There were 51 right (RTL) and 56 left (LTL) temporal lobectomy patients. All patients were left hemisphere speech-dominant. The LTL and RTL patients were comparable in terms of general demographic, epilepsy, and intellectual/attention factors. Multivariate analyses revealed a significant crossover interaction (p <.001), with the RTL group scoring significantly lower on the visual than auditory indexes while the LTL group scored significantly lower on the auditory than visual memory indexes. Within-group pairwise analyses revealed statistically significant auditory versus visual index score comparisons (all p <.001) for both surgical groups. Discriminant analysis (p <.001) identified Verbal Paired Associates I, Faces I, and Family Pictures II to significantly discriminate RTL and LTL patients, with an overall correct classification rate of 81.3%. Our findings suggest that the WMS-III is sensitive to modality-specific memory performance associated with unilateral temporal lobectomy.