Initial detachment of the mouse oocyte from the zona pellucida is mediated by metallopeptidase activity†.

The fully grown mammalian oocyte is tightly attached to its extracellular matrix shell, the zona pellucida (ZP), but the oocyte detaches from the ZP shortly after ovulation is signaled. The mechanism by which the oocyte detaches from the ZP is unknown. Because ZP proteins are initially secreted as transmembrane proteins, we hypothesized that attachment of the oocyte to the ZP is mediated by transmembrane ZP proteins and that detachment occurs when these proteins are cleaved by peptidases. To identify potential candidates for the type of peptidase, we used mouse oocyte transcriptome data sets to identify candidate peptidases localized to the exterior of the oocyte. Screening with a set of small molecule inhibitors that broadly target the families of peptidases represented by the candidates, we found that only inhibitors of the M10 and M12 families of metallopeptidases prevented detachment. Using more selective inhibitors indicated that detachment was prevented by an inhibitor, GI254023X, developed to be selective for ADAM10 in the M12 family but not by those considered selective for the M10 family or for other M12 metallopeptidases expressed in oocytes. Using an antibody that binds to an epitope just distal to the likely cleavage site of murine ZP3 showed that this site was gradually lost from the oocyte surface during the period when detachment occurs and that inhibiting metallopeptidase activity prevented the loss of this epitope. Taken together, these results indicate that detachment of the oocyte from the ZP is mediated by a metallopeptidase.

Latent Class Analysis to Classify Injury Severity in Pediatric Traumatic Brain Injury.

Heterogeneity of injury severity among children with traumatic brain injury (TBI) classified by the Glasgow Coma Scale (GCS) makes comparisons across research cohorts, enrollment in clinical trials, and clinical predictions of outcomes difficult. The present study uses latent class analysis (LCA) to distinguish severity subgroups from a prospective cohort of 433 children 2.5-15 years of age with TBI who were recruited from two level 1 pediatric trauma centers. Indicator variables available within 48 h post-injury including emergency department (ED) GCS, hospital motor GCS, Abbreviated Injury Score (AIS), Rotterdam Score, hypotension in the ED, and pre-hospital loss of consciousness, intubation, seizures, and sedation were evaluated to define subgroups. To understand whether latent class subgroups were predictive of clinically meaningful outcomes, the Pediatric Injury Functional Outcome Scale (PIFOS) at 6 and 12 months, and the Behavior Rating Inventory of Executive Function at 12 months, were compared across subgroups. Then, outcomes were examined by GCS (primary) and AIS (secondary) classification alone to assess whether LCA provided improved outcome prediction. LCA identified four distinct increasing severity subgroups (1-4). Unlike GCS classification, mean outcome differences on PIFOS at 6 months showed decreasing function across classes. PIFOS differences relative to the lowest latent class (LC1) were: LC2 2.27 (0.83, 3.72), LC3 3.99 (1.88, 6.10), and LC4 11.2 (7.04, 15.4). Differences in 12 month outcomes were seen between the most and least severely injured groups. Differences in outcomes in relation to AIS were restricted to the most and less severely injured at both time points. This study distinguished four latent classes that are clinically meaningful, distinguished a more homogenous severe injury group, and separated children by 6-month functional outcomes better than GCS alone. Systematic reporting of these variables would allow comparisons across research cohorts, potentially improve clinical predictions, and increase sensitivity to treatment effects in clinical trials.

A ten-year retrospective evaluation of acute flaccid myelitis at 5 pediatric centers in the United States, 2005-2014.

BACKGROUND: Acute flaccid myelitis (AFM) is a severe illness similar to paralytic poliomyelitis. It is unclear how frequently AFM occurred in U.S. children after poliovirus elimination. In 2014, an AFM cluster was identified in Colorado, prompting passive US surveillance that yielded 120 AFM cases of unconfirmed etiology. Subsequently, increased reports were received in 2016 and 2018. To help inform investigations on causality of the recent AFM outbreaks, our objective was to determine how frequently AFM had occurred before 2014, and if 2014 cases had different characteristics. METHODS: We conducted a retrospective study covering 2005-2014 at 5 pediatric centers in 3 U.S. regions. Possible AFM cases aged ≤18 years were identified by searching discharge ICD-9 codes and spinal cord MRI reports (>37,000). Neuroradiologists assessed MR images, and medical charts were reviewed; possible cases were classified as AFM, not AFM, or indeterminate. RESULTS: At 5 sites combined, 26 AFM cases were identified from 2005-2013 (average annual number, 3 [2.4 cases/100,000 pediatric hospitalizations]) and 18 from 2014 (12.6 cases/100,000 hospitalizations; Poisson exact p<0.0001). A cluster of 13 cases was identified in September-October 2014 (temporal scan p = 0.0001). No other temporal or seasonal trend was observed. Compared with cases from January 2005-July 2014 (n = 29), cases from August-December 2014 (n = 15) were younger (p = 0.002), more frequently had a preceding respiratory/febrile illness (p = 0.03), had only upper extremities involved (p = 0.008), and had upper extremity monoplegia (p = 0.03). The cases had higher WBC counts in cerebrospinal fluid (p = 0.013). CONCLUSION: Our data support emergence of AFM in 2014 in the United States, and those cases demonstrated distinctive features compared with preceding sporadic cases.

Ability of the PILOT score to predict 6-month functional outcome in pediatric patients with moderate-severe traumatic brain injury.

PURPOSE: To assess the Pediatric Intensity Level of Therapy (PILOT) score alone and in combination with Emergency Department (ED) GCS and Rotterdam score of initial head CT to predict functional outcomes in children with traumatic brain injury (TBI). METHODS: Children (n=108) aged 31months-15years with moderate to severe TBI were prospectively enrolled at two sites. The ability of PILOT, ED GCS, and Rotterdam scores to predict the 6-month Pediatric Injury Functional Outcome Scale (PIFOS) was evaluated using multivariable regression models with enrollment site, age, and sex as covariates. RESULTS: PILOT total (sum) score was more predictive of PIFOS (R2=0.23) compared to mean (R2 = 0.20) or peak daily PILOT scores (R2=0.11). PILOT total score predicted PIFOS better than ED GCS (R2=0.01) or Rotterdam score (R2=0.06) and was similar to PILOT, ED GCS, and Rotterdam score combined. PILOT total score performed better in patients with intracranial pressure monitors (n=30, R2=0.28, slope=0.30) than without (n=78, R2=0.09, slope=0.36). CONCLUSIONS: The PILOT score correlated moderately with functional outcome following TBI and outperformed other common predictors. PILOT may be a useful predictor or moderator of functional outcomes. LEVEL OF EVIDENCE: Prognosis study, Level II.

Recognition and Management of Acute Flaccid Myelitis in Children.

BACKGROUND: In 2014-2015, several regions of the United States experienced an outbreak of acute flaccid myelitis in pediatric patients. A common, unique feature was disease localization to the gray matter of the spinal cord. METHODS: We report 11 children, ages 13 months to 14 years (median 9 years), in the Intermountain West who presented with extremity weakness (n = 10) or cranial neuropathy (n = 1) of varying severity without an apparent etiology. RESULTS: All children experienced acute paralysis, and 10 had symptoms or signs that localized to the spinal cord. Maximum paralysis occurred within 4 days of onset in all patients. All had spinal gray matter lesions consistent with acute myelitis detected by magnetic resonance imaging; no single infectious cause was identified. Despite therapy with intravenous immunoglobulin, corticosteroids, or plasma exchange, nine of 10 (90%) children had motor deficits at follow-up. CONCLUSIONS: Recognition of this disorder enables clinicians to obtain appropriate imaging and laboratory testing, initiate treatment, and provide families with accurate prognostic information. In contrast to other causes of acute flaccid paralysis in childhood, most children with acute flaccid myelitis have residual neurological deficits.

Combined MRI and MRS improves pre-therapeutic diagnoses of pediatric brain tumors over MRI alone.

INTRODUCTION: The specific goal of this study was to determine whether the inclusion of MRS had a measureable and positive impact on the accuracy of pre-surgical MR examinations of untreated pediatric brain tumors over that of MRI alone in clinical practice. METHODS: Final imaging reports of 120 pediatric patients with newly detected brain tumors who underwent combined MRI/MRS examinations were retrospectively reviewed. Final pathology was available in all cases. Group A comprised 60 subjects studied between June 2001 and January 2005, when MRS was considered exploratory and radiologists utilized only conventional MRI to arrive at a diagnosis. For group B, comprising 60 subjects studied between January 2005 and March 2008, the radiologists utilized information from both MRI and MRS. Furthermore, radiologists revisited group A (blind review, time lapse >4 years) to determine whether the additional information from MRS would have altered their interpretation. RESULTS: Sixty-three percent of patients in group A were diagnosed correctly, whereas in 10% the report was partially correct with the final tumor type mentioned (but not mentioned as most likely tumor), while in 27% of cases the reports were wrong. For group B, the diagnoses were correct in 87%, partially correct in 5%, and incorrect in 8% of the cases, which is a significant improvement (p < 0.005). Re-review of combined MRI and MRS of group A resulted 87% correct, 7% partially correct, and 7% incorrect diagnoses, which is a significant improvement over the original diagnoses (p < 0.05). CONCLUSION: Adding MRS to conventional MRI significantly improved diagnostic accuracy in preoperative pediatric patients with untreated brain tumors.

Magnetic resonance imaging features of complex Chiari malformation variant of Chiari 1 malformation.

BACKGROUND: Complex Chiari malformation is a subgroup of Chiari 1 malformation with distinct imaging features. Children with complex Chiari malformation are reported to have a more severe clinical phenotype and sometimes require more extensive surgical treatment than those with uncomplicated Chiari 1 malformation. OBJECTIVE: We describe reported MR imaging features of complex Chiari malformation and evaluate the utility of craniometric parameters and qualitative anatomical observations for distinguishing complex Chiari malformation from uncomplicated Chiari 1 malformation. MATERIALS AND METHODS: We conducted a retrospective search of the institutional imaging database using the keywords "Chiari" and "Chiari 1" to identify children imaged during the 2006-2011 time period. Children with Chiari 2 malformation were excluded after imaging review. We used the first available diagnostic brain or cervical spine MR study for data measurement. Standard measurements and observations were made of obex level (mm), cerebellar tonsillar descent (mm), perpendicular distance to basion-C2 line (pB-C2, mm), craniocervical angle (degrees), clivus length, and presence or absence of syringohydromyelia, basilar invagination and congenital craniovertebral junction osseous anomalies. After imaging review, we accessed the institutional health care clinical database to determine whether each subject clinically met criteria for Chiari 1 malformation or complex Chiari malformation. RESULTS: Obex level and craniocervical angle measurements showed statistically significant differences between the populations with complex Chiari malformation and uncomplicated Chiari 1 malformation. Cerebellar tonsillar descent and perpendicular distance to basion-C2 line measurements trended toward but did not meet statistical significance. Odontoid retroflexion, craniovertebral junction osseous anomalies, and syringohydromyelia were all observed proportionally more often in children with complex Chiari malformation than in those with Chiari 1 malformation. CONCLUSION: Characteristic imaging features of complex Chiari malformation, especially obex level, permit its distinction from the more common uncomplicated Chiari 1 malformation.

White matter lesions in children and adolescents with migraine.

BACKGROUND: The etiology and clinical importance of white matter lesions in migraine remain poorly understood. To understand these issues more fully, we reviewed the brain magnetic resonance imaging scans of pediatric patients and assessed the relationships between white matter lesions, migraine type, patent foramen ovale, and right-to-left shunting. METHODS: The magnetic resonance imaging scans of a cohort of children (n = 89) and adolescents, ages 6 to 18 years, who participated in a study of migraine and patent foramen ovale were reviewed. All children in the cohort had undergone saline contrast transthoracic echocardiography and transcranial Doppler studies. RESULTS: White matter lesions were detected in 15 of the 89 patients (17%). White matter lesions were small (<5 mm) in the majority (10/15; 66%). We observed no relationship between the presence of white matter lesions and (1) migraine type (six patients with white matter lesions among 35 with migraine with aura [17%] vs. nine with white matter lesions among 54 without aura [17%]; P = 1.0); (2) patent foramen ovale (five with white matter lesions among 35 with patent foramen ovale [14%] vs. 10 with white matter lesions among 54 without patent foramen ovale [19%]; P = 0.77); or (3) shunt size (two large shunts in 15 with white matter lesions [13%] vs. nine large shunts among 72 without white matter lesions [13%]; P = 1.0). CONCLUSIONS: These results indicate that small white matter lesions are not infrequent in children and adolescents with migraine. However, no relationships between white matter lesions and migraine type, patent foramen ovale, or degree of right-to-left shunting were observed.

Utility of neuroradiographic imaging in predicting outcomes after neonatal extracorporeal membrane oxygenation.

BACKGROUND: The need for routine neuroimaging after extracorporeal membrane oxygenation (ECMO) and the optimal radiographic study remains unclear. We sought to evaluate the correlation between findings on head ultrasound (HUS) and magnetic resonance imaging (MRI) and determine the association of these findings to neurodevelopmental outcome. METHODS: A retrospective review was performed (2003-2010) to identify neonates who had a MRI after ECMO. Each MRI was reviewed by a single pediatric neuroradiologist. Neurodevelopmental data was collected from the high-risk neonatal follow-up clinic. RESULTS: Fifty neonates had a MRI (venoarterial 37, venovenous 13) after ECMO. HUS was abnormal in 24%, whereas MRI was abnormal in 62%. All infants with an abnormal HUS had an abnormal MRI, but an additional 50% of patients with a normal HUS had an abnormal MRI. Venoarterial ECMO was significantly associated with an abnormal MRI. Follow-up data was available for 26 neonates. The only predictor of abnormal neurodevelopment was the need for supplemental tube feeds at discharge. CONCLUSIONS: MRI identified significantly more abnormalities compared to routine HUS after neonatal ECMO. However, neither MRI nor HUS findings correlated with early neurodevelopmental outcome. Feeding ability at discharge was the overall best predictor of neurologic impairment in survivors.

Diffuse intrinsic pontine glioma-current status and future strategies.

INTRODUCTION: Diffuse intrinsic pontine gliomas which constitute 15% of all childhood brain tumors are inoperable and response to radiation and chemotherapy has not improved long-term survival. Due to lack of newer effective therapies, mean survival after diagnosis has remained less than 12 months. Trials investigating chemotherapy and/or radiation have proven disappointing. As biopsy of these tumors are rarely performed due to the high eloquence of the brain stem, information about the pathology and biology remains elusive hindering development of novel biologic agents. Poor access of most chemotherapeutic agents to these tumors due to the blood-brain barrier continues to undermine therapeutic efficacy. Thus, to date, we remain at a virtual standstill in our attempts to improve the prognosis of children with these tumors. METHODS: An extensive review of the literature was performed concerning children with diffuse brain stem gliomas including clinical trials, evolving molecular biology, and newer therapeutic endeavors. CONCLUSION: A pivotal approach in improving the prognosis of these tumors should include the initiation of biopsy and encouraging families to consider autopsy to study the molecular biology. This will help in redefining this tumor by its molecular signature and profiling targeted therapy. Continued advances should be pursued in neuroimaging technology including identifying surrogate markers of early disease progression. Defining strategies to enhance local delivery of drugs into tumors with the help of newer surgical techniques are important. Exhaustive research in all these aspects as a multidisciplinary approach could provide hope to children with these fatal tumors.

Infarction of an extralobar pulmonary sequestration in a young child: diagnosis and excision by video-assisted thoracoscopy.

A 4-year-old male presented with abdominal pain. A computed tomography scan of the abdomen was negative, but a pleural effusion and mass was noted in the lower left thorax. Video-assisted thoracoscopic surgery revealed the mass to be a rare case of extralobar pulmonary sequestration that had undergone infarction.

Radiology of metastatic spine cancer.

Radiologic imaging is an essential component of current spinal cancer diagnosis and treatment algorithms and is used for cancer diagnosis,determination of tumor extent for treatment planning, and subsequent assessment of therapy efficacy on follow-up.

Sciatic nerve sarcoidosis: utility of magnetic resonance peripheral nerve imaging and treatment with radiation therapy.

Sarcoidosis may involve both the central and peripheral nervous system, although peripheral nerve manifestations are usually seen late in the disease. In this report, the authors describe a case of sarcoidosis in a 22-year-old woman who presented with a foot drop. Although results of conventional lumbar magnetic resonance (MR) imaging were normal, MR peripheral nerve imaging of the thigh showed a mass in the sciatic nerve indicating tumor. An intraoperative biopsy sample revealed noncaseating granulomas consistent with sarcoid. The patient was treated with steroid drugs to control the manifestations of her disease but exhibited early signs of femoral bone necrosis, which required discontinuation of the steroids. She was then treated with local radiation therapy. At her 2-year follow-up visit the patient demonstrated relief of her symptoms and improvement on MR peripheral nerve imaging. This case demonstrates that sarcoidosis may present with peripheral nerve manifestations. The appearance of a diffusely swollen nerve on MR imaging should prompt clinicians to include sarcoidosis in the differential diagnosis and plan surgery accordingly. Patients who are not responsive to or who are unable to tolerate medical therapy may be treated with radiation therapy.

Panhypopituitarism as an initial manifestation of primary central nervous system non-Hodgkin's lymphoma.

OBJECTIVE: To report an unusual case of primary central nervous system non-Hodgkin's lymphoma in which the initial manifestation was panhypopituitarism. METHODS: We present a retrospective case review and discuss similar cases from the literature. RESULTS: A 64-year-old woman with nausea, vomiting, diarrhea, and peripheral and periorbital edema was found to have panhypopituitarism. Magnetic resonance imaging showed minimal enlargement of the pituitary, and a transsphenoidal biopsy of the pituitary was nondiagnostic. Months later, abnormalities of extraocular movements developed. Repeated imaging and a second transsphe-noidal biopsy did not reveal the ultimate diagnosis. When further neurologic signs and symptoms subsequently developed, a right temporal open craniotomy was performed. It was not until this procedure, the patient's third biopsy, that the cause of her illness was discovered to be diffuse large cell lymphoma. CONCLUSION: Although idiopathic panhypopituitarism is a relatively common clinical entity, it remains a diagnosis of exclusion. The development of associated neurologic signs should prompt the clinician to initiate a new search for an underlying cause. This case underscores the protean manifestations of central nervous system lymphoma, both endocrine and neurologic, and the difficulties that may be encountered in attempts to establish a diagnosis.

Magnetoencephalographically directed review of high-spatial-resolution surface-coil MR images improves lesion detection in patients with extratemporal epilepsy.

PURPOSE: To determine whether (a) interictal magnetoencephalographic (MEG) epileptiform activity corresponds to anatomic abnormalities at magnetic resonance (MR) imaging, (b) high-spatial-resolution MR imaging depicts lesions in regions without MEG spike activity, (c) MEG-directed review of high-spatial-resolution MR images enables detection of abnormalities not apparent on conventional MR images, and (d) MEG information results in a greater number of diagnosed lesions at re-review of conventional MR images. MATERIALS AND METHODS: Twenty patients with neocortical epilepsy were evaluated with MEG, conventional brain MR imaging with a head coil, and high-spatial-resolution MR imaging with either a surface coil (n = 17) or a high-spatial-resolution birdcage coil (n = 3). Abnormal MEG foci were compared with corresponding anatomic areas on conventional and high-spatial-resolution MR images to determine the presence (concordance) or absence (discordance) of anatomic lesions corresponding to foci of abnormal MEG activity. RESULTS: Forty-four epileptiform MEG foci were identified. Twelve foci (27%) were concordant with an anatomic abnormality at high-spatial-resolution MR imaging, and 32 foci (73%) were discordant. Results of high-spatial-resolution MR imaging were normal in eight patients, and 23 lesions were detected in the remaining 12 patients. Twelve lesions (52%) were concordant with abnormal MEG epileptiform activity, and 11 (48%) were discordant (ie, there was normal MEG activity in the region of the anatomic abnormality). At retrospective reevaluation of conventional MR images with MEG guidance, four occult gray matter migration lesions that had initially been missed were observed. An additional patient with MEG-concordant postoperative gliosis was readily identified with high-spatial-resolution MR images but not with conventional MR images. CONCLUSION: Review of MEG-localized epileptiform areas on high-spatial-resolution MR images enables detection of epileptogenic neocortical lesions, some of which are occult on conventional MR images.