The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.

Thromboembolic toxicity observed with concurrent trametinib and lenalidomide therapy.

The event-free survival of pediatric low-grade gliomas is poor, and patients often require multiple treatment strategies. While MEK and RAF inhibitors are efficacious in early-phase trials, not all patients respond, and many experience progression following completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. We report our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system tumors. Two of four patients using this combination therapy experienced severe thromboembolic events, necessitating discontinuation of therapy. This combination requires further investigation, and we urge caution if used.

Prevalence of cerebral sinovenous thrombosis in abusive head trauma.

BACKGROUND: Cerebral sinovenous thrombosis (CSVT) has been proposed in legal settings to be an atraumatic mimic of abusive head trauma (AHT). OBJECTIVE: The objective of this study was to determine the prevalence of CSVT and subdural hemorrhage (SDH) in a large AHT population. MATERIALS AND METHODS: This retrospective cohort study measured the prevalence of CSVT and SDH on magnetic resonance venograms in 243 patients diagnosed with AHT at a single center. We also reported additional intra- and extracranial injuries, head injury severity and length of hospital stay. RESULTS: Among 243 patients diagnosed with AHT, 7% (16/243) had CSVT. SDH was present in 94% (15/16) of the CSVT cases. Cytotoxic edema and subarachnoid hemorrhage were in 88% (14/16) and 69% (11/16) of the CSVT cases, respectively. Extracranial signs of abuse were also in 100% (16/16) of the patients with CSVT. Critical to maximal head injury severity (abbreviated injury scale >=5) was in 75% (12/16) of the CSVT population vs. 33% (82/243) in the total AHT population. Length of hospital and pediatric intensive care unit stay was greater in those with CSVT (10 vs. 21.9 and 3.5 vs. 7.3 days). CONCLUSION: These findings suggest that CSVT is uncommon in AHT and is associated with additional traumatic injuries and greater injury severity.

Response assessment in paediatric intracranial ependymoma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Response criteria for paediatric intracranial ependymoma vary historically and across different international cooperative groups. The Response Assessment in the Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, neuro-radiologists, radiation oncologists, and neurosurgeons, was established to address both the issues and the unique challenges in assessing the response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric ependymoma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric ependymoma to clinical trial therapy. For areas in which data were scarce or unavailable, consensus was reached through an iterative process. RAPNO response assessment recommendations include assessing disease response on the basis of changes in tumour volume, and using event-free survival as a study endpoint for patients entering clinical trials without bulky disease. Our recommendations for response assessment include the use of brain and spine MRI, cerebral spinal fluid cytology, neurological examination, and steroid use. Baseline postoperative imaging to assess for residual tumour should be obtained 24-48 h after surgery. Our consensus recommendations and response definitions should be prospectively validated in clinical trials.

Methionine synthase deficiency: Variable clinical presentation and benefit of early diagnosis and treatment.

Methionine synthase deficiency (cblG complementation group) is a rare inborn error of metabolism affecting the homocysteine re-methylation pathway. It leads to a biochemical phenotype of hyperhomocysteinemia and hypomethioninemia. The clinical presentation of cblG is variable, ranging from seizures, encephalopathy, macrocytic anemia, hypotonia, and feeding difficulties in the neonatal period to onset of psychiatric symptoms or acute neurologic changes in adolescence or adulthood. Given the variable and nonspecific symptoms seen in cblG, the diagnosis of affected patients is often delayed. Medical management of cblG includes the use of hydroxocobalamin, betaine, folinic acid, and in some cases methionine supplementation. Treatment has been shown to lead to improvement in the biochemical profile of affected patients, with lowering of total homocysteine levels and increasing methionine levels. However, the published literature contains differing conclusions on whether treatment is effective in changing the natural history of the disease. Herein, we present five patients with cblG who have shown substantial clinical benefit from treatment with objective improvement in their neurologic outcomes. We demonstrate more favorable outcomes in our patients who were treated early in life, especially those who were treated before neurologic symptoms manifested. Given improved outcomes from treatment of presymptomatic patients, cblG warrants inclusion in newborn screening.

Isolated lesions of the suprasternal notch in pediatric patients.

BACKGROUND: Palpable masses of the head and neck are a common indication for imaging in the pediatric population. Midline lesions of the infrahyoid neck, particularly lesions isolated to the suprasternal notch, are not well studied. OBJECTIVE: To delineate the histopathological and imaging spectrum of masses that occur within and isolated to the suprasternal notch. MATERIALS AND METHODS: A retrospective study was performed to identify patients with an isolated lesion of the suprasternal notch that had available pathological diagnoses. Available imaging was reviewed and characterized by fellowship-trained pediatric radiologists and compared by descriptive statistics to the final pathological diagnoses. RESULTS: Eighteen masses isolated to the suprasternal notch with available pathological diagnoses were identified. Of these, congenital epithelial inclusion cysts were diagnosed in 14 patients (77.8%) with dermoid cysts comprising 11 of those (61.1%) and epidermoid cysts accounting for 3 (16.7%). The most common imaging appearance was a cystic or pseudosolid appearance without vascularity. CONCLUSIONS: Isolated resected lesions of the suprasternal notch in pediatric patients are most frequently dermoid/epidermoid cysts, with a differential diagnosis including other less common entities.

Visualization of the Anal Dimple by Fetal MRI: Is It Feasible?

INTRODUCTION: The aim of this study was to determine the feasibility of fetal MRI in identifying the normal anal dimple (AD) and compare it with prenatal ultrasound (US). METHODS: Retrospective review of 130 patients with both fetal MRI and US. The gestational age (GA) was stratified into four groups: (1) 16 to 21 weeks-6 days; (2) 22 to 27 weeks-6 days; (3) 28 to 33 weeks-6 days; and (4) 34 weeks and beyond. Steady-state free precession (SSFP) and single shot fast spin echo (SSFSE) axial T2 MRI and transverse US images of the fetal perineum were analyzed, and visualization of the AD was determined. Clinical indication, gender, single versus multiple gestation, best MRI sequence where it was seen, and postnatal AD information were recorded. RESULTS: The AD was visualized in 125/130 fetal MRIs, and visualization was independent of GA (p 0.230). US visualized the AD in 67/130 cases, and the best GA for visualization was in group 3 (p < 0.001). There was no difference in AD visualization between SSFSE and SSFP sequences (p 0.167). CONCLUSION: Prenatal visualization of the AD by MRI is feasible and superior to US, independent of GA. Adding AD visualization to routine screening prenatal US and MRI may increase recognition of anorectal malformation.

"Growing cerebellum" requiring operative decompression following perinatal ventriculoperitoneal shunting.

INTRODUCTION: While cases of acquired Chiari I malformation following ventriculoperitoneal shunting for posthemorrhagic hydrocephalus have been reported, true disproportionate cerebellar growth is rare, with no previous cases requiring posterior fossa decompression reported. CLINICAL PRESENTATION: We present a premature neonate who underwent ventriculoperitoneal shunt placement for suspected posthemorrhagic hydrocephalus. He subsequently developed a symptomatic Chiari I malformation with volumetric measurements demonstrating disproportionate growth of the cerebellum. He did not demonstrate thickening of the supratentorial or posterior fossa cranium. The patient underwent an extradural posterior fossa decompression, with resolution of symptoms. OUTCOME AND CONCLUSIONS: We review the extant literature regarding the development of Chiari malformation type I as a manifestation of craniocerebral disproportion (CCD) following shunt placement for posthemorrhagic hydrocephalus of prematurity. Most previous reports reflect a mechanism that includes underdevelopment of the intracranial posterior fossa (or supratentorial) volume. The case presented in this report, as well as one additional case, indicates that there may exist a variant mechanism, characterized by rapid growth of the cerebellum itself, in the absence of one of the rare syndromes associated with primary macrocerebellum. While this case was effectively managed with extradural posterior fossa decompression, previous reports indicate that supratentorial cranial expansion procedures are preferable in some cases. As such, pediatric neurosurgeons should be able to distinguish the patterns of craniocerebral disproportion when considering treatment options for these patients. Further investigation regarding these uncommon patients may better describe the underlying mechanisms.

Neuroimaging of retinal hemorrhage utilizing adjunct orbital susceptibility-weighted imaging.

Retinal hemorrhages are an integral part of the evaluation of abusive head trauma (AHT). Timely detection of retinal hemorrhage not only facilitates the diagnosis of AHT, but has the potential to prevent further abuse to the child and the siblings and to identify the abuser. The gold standard for diagnosing retinal hemorrhage is a dilated fundoscopy exam, which requires pharmacological dilation. As such, there is a small percentage of patients for whom the dilated fundoscopy exam might be delayed. Evolving literature suggests that MRI, specifically susceptibility-weighted imaging (SWI), of the orbits might provide an alternative diagnostic tool for noninvasively detecting retinal hemorrhages, particularly when there is a delay in administering the dilated fundoscopy exam. In this paper we review the utility of SWI for detecting retinal hemorrhages in abusive head trauma, including discussion of diagnostic limitations and future research.

Visualization of the fetal anus by prenatal ultrasound for the diagnosis of anorectal malformations: is it feasible?

PURPOSE: The goal of this study was to determine the feasibility of identifying the anal dimple (AD) on routine prenatal ultrasound. Using the presence, absence, appearance, and location of the anal dimple as an indirect sign for possible underlying anorectal malformations (ARM), we hypothesize that evaluation of the anal dimple as part of the fetal anatomic survey may increase the sensitivity in detecting less severe ARMs. METHODS: In a prospective longitudinal observational study, pregnant women who underwent prenatal ultrasound (US) at the Colorado Fetal Care Center between January 2019 and 2020 were enrolled. The variables recorded included gestational age, singleton versus multiple pregnancy, gender of the fetus, visualization of the AD, and reason for non-visualization of the AD. RESULTS: A total of 900 ultrasounds were performed, evaluating 1044 fetuses, in 372 different pregnant women. Gestational ages ranged from 16 to 38 weeks. The AD was visualized in 612 fetuses (58.6%) and not seen in 432 (41.4%). The two most common reasons for non-visualization were extremes in gestational age (n = 155; 36%) and fetal position (n = 152; 35.3%). The optimal gestational age range for AD visualization was 28-33 weeks + 6 days, with 78.1% visualization rate. CONCLUSION: Visualization of the anal dimple by ultrasound is feasible and may aid in the detection of less severe ARMs, ultimately impacting pregnancy management and family counseling. The optimal timing for anal dimple visualization is late second and third trimester.

Subpial Hemorrhage of the Neonate.

Background and Purpose- Subpial hemorrhage of the neonate is a rare stroke subtype reported in few case series. Birth trauma and coagulopathy are commonly proposed etiologies. We evaluated our subpial hemorrhage of the neonate patient cohort to expand current understanding Methods- Cases of subpial hemorrhage of the neonate were identified by keyword searches of the institutional database. The medical records and magnetic resonance imagings were reviewed. Results- Seventeen cases were identified. Assisted delivery occurred in 12% of cases, and acute coagulation abnormalities occurred in 77%. Subpial hemorrhage of the neonate was located in the temporal lobe in 82%, with cytotoxic edema and medullary vein congestion and thrombosis subjacent to the hemorrhages in 100% and 76% of cases, respectively. Neurological disability was present in 44% of survivors. Three patients had chronic coagulation abnormalities. Conclusions- In our cohort, clinical findings supporting a potential relationship with birth trauma were infrequent. The imaging findings suggest a nonarterial, deep venous pattern of hemorrhagic ischemia.

A novel acceptor stem variant in mitochondrial tRNATyr impairs mitochondrial translation and is associated with a severe phenotype.

Genetic defects in mitochondrial DNA encoded tRNA genes impair mitochondrial translation with resultant defects in the mitochondrial respiratory chain and oxidative phosphorylation system. The phenotypic spectrum of disease seen in mitochondrial tRNA defects is variable and proving pathogenicity of new variants is challenging. Only three pathogenic variants have been described previously in the mitochondrial tRNATyr gene MT-TY, with the reported phenotypes consisting largely of adult onset myopathy and ptosis. We report a patient with a novel MT-TY acceptor stem variant m.5889A>G at high heteroplasmy in muscle, low in blood, and absent in the mother's blood. The phenotype consisted of a childhood-onset severe multi-system disorder characterized by a neurodegenerative course including ataxia and seizures, failure-to-thrive, combined myopathy and neuropathy, and hearing and vision loss. Brain imaging showed progressive atrophy and basal ganglia calcifications. Mitochondrial biomarkers lactate and GDF15 were increased. Functional studies showed a deficient activity of the respiratory chain enzyme complexes containing mtDNA-encoded subunits I, III and IV. There were decreased steady state levels of these mitochondrial complex proteins, and presence of incompletely assembled complex V forms in muscle. These changes are typical of a mitochondrial translational defect. These data support the pathogenicity of this novel variant. Careful review of variants in MT-TY additionally identified two other pathogenic variants, one likely pathogenic variant, nine variants of unknown significance, five likely benign and four benign variants.

Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease.

Hydrogen sulfide, a signaling molecule formed mainly from cysteine, is catabolized by sulfide:quinone oxidoreductase (gene SQOR). Toxic hydrogen sulfide exposure inhibits complex IV. We describe children of two families with pathogenic variants in SQOR. Exome sequencing identified variants; SQOR enzyme activity was measured spectrophotometrically, protein levels evaluated by western blotting, and mitochondrial function was assayed. In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure. After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging. She died shortly after. Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex. Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation. Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13. The resulting p.Glu213Lys change disrupts hydrogen bonding with neighboring residues, resulting in severely reduced SQOR protein and enzyme activity, whereas sulfide generating enzyme levels were unchanged. In family B, a boy had episodes of encephalopathy and basal ganglia lesions. He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels. SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure. In conclusion, SQOR deficiency represents a new, potentially treatable, cause of Leigh disease.

COVID-19: A primer for Neuroradiologists.

The potential for central nervous system (CNS) involvement in coronavirus disease 2019 (COVID-19) is a matter of grave concern and there is a relevant body of evidence in the basic sciences to support this possibility. A neuroradiologist should be aware of the potential mechanisms involved in the neuropathogenesis of this virus, as we begin to see cases with abnormal brain scans emerging from all parts of the world.

Utility of image fusion software in identifying shunt malfunction.

PURPOSE: Pediatric shunt malfunction occurs frequently and is important to recognize due to the high associated morbidity and mortality. Although neuroimaging plays a crucial role in the diagnosis, it remains imperfect. We sought to identify the effect of image fusion software in predicting shunt malfunction. METHODS: A total of 248 rapid shunt series brain MRIs performed between 2013 and 2017 were compared with prior neuroimaging for changes in ventricular size by two methods: radiology report and Brainlab fusion. Shunt malfunction was defined by an operative report confirming malfunction within 72 h of neuroimaging. The two methods were compared by logistic regression models, with sensitivity and specificity subsequently calculated. RESULTS: Shunt malfunction was identified in 40 cases (16.1%). Imaging report demonstrated a lower Akaike information criterion than the Brainlab fusion and is therefore a better fitting model. While sensitivity is similar for the two models, 0.94 (0.90 to 0.97, 95% CI) for imaging report, and 0.95 (0.91 to 0.98, 95% CI) for Brainlab, the specificity was significantly different, 0.50 (0.37 to 0.63, 95% CI) and 0.33 (0.24 to 0.44, 95% CI) respectively. CONCLUSIONS: Our data indicate that an increased ability to detect subtle changes in ventricular size does not translate to improved accuracy, but instead leads to decreased specificity, and therefore an overdiagnosis of shunt malfunction in children with normally functioning shunts. While imaging continues to play a prominent role in the identification of shunt malfunction, neurosurgical clinical evaluation remains crucial to the final diagnosis.

How to read a fetal magnetic resonance image 101.

Accurate antenatal diagnosis is essential for planning appropriate pregnancy management and improving perinatal outcomes. The provision of information vital for prognostication is a crucial component of prenatal imaging, and this can be enhanced by the use of fetal MRI. Image acquisition, interpretation and reporting of a fetal MR study can be daunting to the individual who has encountered few or none of these examinations. This article provides the radiology trainee with a general approach to interpreting a fetal MRI. The authors review the added value of prenatal MRI in the overall assessment of fetal wellbeing, discuss MRI protocols and techniques, and review the normal appearance of maternal and fetal anatomy. The paper concludes with a sample template for structured reporting, to serve as a checklist and guideline for reporting radiologists.

Imaging of fetal ventriculomegaly.

Fetal ventriculomegaly is the most common central nervous system abnormality detected by prenatal imaging. It has a high association with other anomalies. Etiologies and prognoses for fetal ventriculomegaly range from normal outcomes to significant neurodevelopmental sequelae. In this paper, we review the development, terminology, pathogenesis, imaging and prognosis of fetal ventriculomegaly.

Age-associated hippocampal volume changes in childhood arterial ischemic stroke.

PURPOSE: Recent evidence suggests that recovery from secondary neurodegeneration following arterial ischemic stroke (AIS) may be related to age at injury and site of occlusion. We conducted a study of hippocampal volume (HCV) in a cohort of pediatric patients with middle cerebral artery (MCA) territory AIS to determine whether HCV would be preserved in younger children as compared to older children. METHODS: This single-center, HIPAA-compliant retrospective study was approved by the institutional review board. The medical records of 149 children treated for AIS between 2000 and 2016 were reviewed for inclusion criteria: unilateral MCA territory AIS and availability of high-resolution T1-weighted MR imaging at both acute and chronic time periods. Manual segmentation was utilized to measure stroke-side HCV, contralateral HCV, hemispheric volumes, and stroke volume on each scan. To correct for variable brain size, HCV measurements were ratio normalized. Patients were divided into two age-at-stroke groups: younger (30 days-9 years old) and older (> 9-18 years old). Analysis was performed using Fisher's test or Student's t test. RESULTS: The MR imaging of 19 children (9 younger, 10 older) was analyzed. At follow-up, the average stroke-side HCV increased by 10.9% in the younger group and decreased by 6.3% in the older group (P = 0.010); this between-group difference remained significant even when ratio normalized (P = 0.003). The total brain volume-adjusted acute stroke size between groups was not statistically different (P = 0.649). CONCLUSIONS: In children with AIS, younger age is associated with the relative preservation of HCV, which could reflect differences in age-related plasticity.

Differentiating presacral masses in anorectal malformations and isolated sacrococcygeal teratomas.

PURPOSE: Presacral masses associated with anorectal malformations (ARM) are most frequently dermoid or teratomas. Sacrococcygeal teratoma (SCT), in isolation, is a different condition. There are limited data comparing the two. The aim of this study was to compare presacral masses associated with ARM and isolated SCTs. METHODS: A retrospective review was performed from 1979 to 2018. Patients with presacral masses and associated ARM (n = 39) were identified and compared to patients with isolated SCTs (n = 32). RESULTS: Those with presacral mass and ARM had a lower proportion of immature and mixed teratomas by pathology and a longer time to mass resection. They had higher percentages of sacral anomalies (76% versus 9%), tethered cord (50% versus 6%), and other anomalies (51% versus 9%). For long-term bowel function, patients with presacral mass and ARM were more likely to be fecally incontinent and require enemas (59% versus 11%). Regarding isolated SCTs, 4% recurred with a time to recurrence of 7 months. CONCLUSIONS: Compared to patients with isolated SCT, patients with presacral mass and ARM had lower grade tumors. In addition, they had a higher proportion of sacral defects and other congenital defects, as well as worse bowel function outcomes.

Imaging of congenital central nervous system infections.

Congenital central nervous system (CNS) infections are a cause of significant morbidity and mortality. The recent Zika virus outbreak raised awareness of congenital CNS infections. Imaging can be effective in diagnosing the presence and severity of infection. In this paper we review the clinical presentations and imaging characteristics of several common and less common congenital CNS infections.