Central adrenal insufficiency following traumatic brain injury: a missed diagnosis in the critically injured.

BACKGROUND: High-dose steroid administration is no longer recommended in the treatment of acute traumatic brain injury (TBI) as it failed to prove beneficial in improving patients' outcome. However, a masked benefit of steroid administration in TBI management was that it provided corticosteroid replacement therapy in patients with TBI-related central adrenal insufficiency. CASE PRESENTATION: We report the case of a 12-year-old boy who suffered a severe TBI from a motor vehicle accident that resulted in complete deficiency of anterior pituitary function. Central adrenal insufficiency was not ruled out by a near normal response to a low-dose ACTH test performed on D11. CONCLUSION: Consideration should be given to the empirical treatment of TBI pediatric patients with stress doses of corticosteroids if injury to the hypothalamus or pituitary gland is possible until a formal assessment of the hypothalamic-pituitary-adrenal axis can be made.

Does optic nerve sheath diameter on MRI decrease with clinically improved pediatric hydrocephalus?

INTRODUCTION: Serial change in ventricular size is recognized as an imperfect indicator of ongoing hydrocephalus in children. Potentially, other radiographic features may be useful in determining the success of hydrocephalus interventions. In this study, optic nerve sheath diameter (ONSD), optic nerve tortuosity, and optic disk bulging were assessed as indicators of hydrocephalus control in children who underwent endoscopic third ventriculostomy (ETV) or posterior fossa tumor resection. METHODS: Sixteen children underwent ETV or tumor resection for treatment of hydrocephalus. T2-weighted axial magnetic resonance images of the orbit were obtained, and the ONSD was measured posterior to the optic globe, pre- and post-intervention. Evidence of optic disk bulging and optic nerve tortuosity was also assessed. Ventricular size was estimated using the frontal and occipital horn ratio (FOR). RESULTS: There was a significant reduction in the ONSD post-ETV (n = 9) and after tumor resection (n = 7). Average preoperative ONSD was 6.21 versus 5.71 mm postoperatively (p = 0.0017).There was also an 88% (p = 0.011) and 60% (p = 0.23) reduction in optic disk bulging and tortuosity, respectively. The FOR normalized in the tumor resection group but not the ETV group. After intervention, all patients showed improvement in signs and symptoms of hydrocephalus. CONCLUSION: In our study population, ONSD decreased in response to measures to reduce hydrocephalus. Optic disk bulging also appears to resolve. Serial reduction in ONSD, and optic disk bulging may be indicators of improved hydrocephalus following pediatric neurosurgical interventions.

Expanding the clinical phenotype of the mitochondrial m.13513G>A mutation with the first report of a fatal neonatal presentation.

Diagnosis of mitochondrial disease is often a challenge because of the extreme heterogeneity of the clinical phenotype and the variety of underlying gene defects. Insight into the range of clinical phenotypes associated with a particular mitochondrial DNA mutation will facilitate better recognition of patients at risk by focused gene testing. We present a family affected by the mitochondrial m.13513G>A (p.D393N, ND5) mutation, illustrating a previously unreported degree of clinical heterogeneity, varying from mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) in a 10-year-old female, to a fatal neonatal course with metabolic acidosis and hypotonia in a younger sister, to absence of medical problems in the mother. The mutation loads ranging from 66% in the deceased neonate to 30% in the female with MELAS and 7% in the asymptomatic mother, correlated with severity of the clinical phenotype. The importance of proactive collection and storage of appropriate samples during the diagnostic work-up of an acutely ill or deceased neonate, allowing subsequent mitochondrial investigations, is hereby illustrated.

Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas--possible role of Cannabis inhalation.

INTRODUCTION: Spontaneous regression of pilocytic astrocytoma after incomplete resection is well recognized, especially for cerebellar and optic pathway tumors, and tumors associated with Neurofibromatosis type-1 (NF1). The purpose of this report is to document spontaneous regression of pilocytic astrocytomas of the septum pellucidum and to discuss the possible role of cannabis in promoting regression. CASE REPORT: We report two children with septum pellucidum/forniceal pilocytic astrocytoma (PA) tumors in the absence of NF-1, who underwent craniotomy and subtotal excision, leaving behind a small residual in each case. During Magnetic Resonance Imaging (MRI) surveillance in the first three years, one case was dormant and the other showed slight increase in size, followed by clear regression of both residual tumors over the following 3-year period. Neither patient received any conventional adjuvant treatment. The tumors regressed over the same period of time that cannabis was consumed via inhalation, raising the possibility that the cannabis played a role in the tumor regression. CONCLUSION: We advise caution against instituting adjuvant therapy or further aggressive surgery for small residual PAs, especially in eloquent locations, even if there appears to be slight progression, since regression may occur later. Further research may be appropriate to elucidate the increasingly recognized effect of cannabis/cannabinoids on gliomas.

Trametinib therapy for children with neurofibromatosis type 1 and life-threatening plexiform neurofibroma or treatment-refractory low-grade glioma.

PURPOSE: To describe a series of children with extensive PNF or treatment refractory PLGG treated on a compassionate basis with trametinib. METHODS: We report on six patients with NF-1 treated with trametinib on a compassionate basis at British Columbia Children's Hospital since 2017. Data were collected retrospectively from the patient record. RAPNO and volumetric criteria were used to evaluate the response of intracranial and extracranial lesions, respectively. RESULTS: Subjects were 21 months to 14 years old at the time of initiation of trametinib therapy and 3/6 subjects are male. Duration of therapy was 4-28 months at the time of this report. All patients had partial response or were stable on analysis. Two patients with life-threatening PNF had a partial radiographic response in tandem with significant clinical improvement and developmental catch up. One subject discontinued therapy after 6 months due to paronychia and inadequate response. The most common adverse effect (AE) was grade 1-2 paronychia or dermatitis in 5/6 patients. There were no grade 3 or 4 AEs. At the time of this report, five patients remain on therapy. CONCLUSION: Trametinib is an effective therapy for advanced PNF and refractory PLGG in patients with NF-1 and is well tolerated in children. Further data and clinical trials are required to assess tolerance, efficacy and durability of response, and length of treatment required in such patients.

Effect of chorioamnionitis on brain development and injury in premature newborns.

OBJECTIVE: The association of chorioamnionitis and noncystic white matter injury, a common brain injury in premature newborns, remains controversial. Our objectives were to determine the association of chorioamnionitis and postnatal risk factors with white matter injury, and the effects of chorioamnionitis on early brain development, using advanced magnetic resonance imaging. METHODS: Ninety-two preterm newborns (24-32 weeks gestation) were studied at a median age of 31.9 weeks and again at 40.3 weeks gestation. Histopathological chorioamnionitis and white matter injury were scored using validated systems. Measures of brain metabolism (N-acetylaspartate/choline and lactate/choline) on magnetic resonance spectroscopy, and microstructure (average diffusivity and fractional anisotropy) on diffusion tensor imaging were calculated from predefined brain regions. RESULTS: Thirty-one (34%) newborns were exposed to histopathological chorioamnionitis, and 26 (28%) had white matter injury. Histopathological chorioamnionitis was not associated with an increased risk of white matter injury (relative risk: 1.2; p = 0.6). Newborns with postnatal infections and hypotension requiring therapy were at higher risk of white matter injury (p < 0.03). Adjusting for gestational age at scan and regions of interest, histopathological chorioamnionitis did not significantly affect brain metabolic and microstructural development (p > 0.1). In contrast, white matter injury was associated with lower N-acetylaspartate/choline (-8.9%; p = 0.009) and lower white matter fractional anisotropy (-11.9%; p = 0.01). INTERPRETATION: Histopathological chorioamnionitis does not appear to be associated with an increased risk of white matter injury on magnetic resonance imaging or with abnormalities of brain development. In contrast, postnatal infections and hypotension are associated with an increased risk of white matter injury in the premature newborn.

White matter injury in term newborns with neonatal encephalopathy.

White matter injury (WMI) is the characteristic pattern of brain injury detected on magnetic resonance imaging in the premature newborn. Focal noncystic WMI is increasingly recognized in populations of term newborns. The aim of this study was to describe the occurrence of focal noncystic WMI in a cohort of 48 term newborns with encephalopathy studied with magnetic resonance imaging at 72 +/- 12 h of life, and to identify clinical risk factors for this pattern of injury. Eleven newborns (23%; 95% CI 11-35) were found to have WMI (four minimal, three moderate, and four severe). In 10 of the 11 newborns, the WMI was associated with restricted diffusion on apparent diffusion coefficient maps. An increasing severity of WMI was associated with lower gestational age at birth (p = 0.05), but not lower birth weight. Newborns with WMI had milder encephalopathy and fewer clinical seizures relative to other newborns in the cohort. Other brain injuries were seen in three of the 11 newborns: basal nuclei predominant pattern of injury in one and cortical strokes in two. These findings suggest that WMI in the term newborn is acquired near birth and that the state of brain maturation is an important determinant of this pattern of brain injury.

Clinical, radiologic and pathologic features and outcome following surgery for cervicomedullary gliomas in children.

INTRODUCTION: Surgical resection is generally recommended for cervicomedullary tumors, but morbidity of resection may be significant. This study sought to identify MRI characteristics that might predict morbidity and extent of resection. MATERIALS AND METHODS: A retrospective review was performed of MRI findings, histopathology, extent, and morbidity of resection in cervicomedullary gliomas undergoing resection during 1985-2008. RESULTS: Of 78 brainstem tumors, nine cervicomedullary tumors undergoing resection were identified: two pilocytic astrocytomas, two gangliogliomas, and five grade II astrocytomas. Mean age was 6.3 years (range 1.7-11.2 years). Initial treatment was surgery in seven: biopsy (1), <25% resection (4), and 25-50% resections (2). Bulbar worsening occurred in five of six patients with interposed areas of non-enhancement versus one of three patients without interposed non-enhancing tissue (P = 0.014). Additionally, bulbar worsening occurred in five of five patients with a poorly defined tumor/brainstem interface and abnormal low T1 signal extending beyond obvious tumor into the brainstem versus one of four with a well-defined tumor margin (P = 0.008). Following chemo- or radiotherapy, the definition of the brainstem/tumor interface improved. In four patients undergoing surgery after chemo/radiotherapy, more extensive resections were achieved without neurologic worsening: >80% in three and 30% in one. CONCLUSION: A less aggressive initial surgical approach, supplemented by postoperative chemotherapy, designed to preserve brainstem function, is proposed for patients with interposed non-enhancing tissue continuous with normal cervical cord or medulla and/or a poorly defined ventral tumor/brainstem interface with abnormal low T1 signal extending beyond obvious tumor into the brainstem.

Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex I deficiency.

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1. Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G > A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts. Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.

Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex 1 deficiency.

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1. Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G>A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts. Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.

Ocular overelevation in adduction in craniosynostosis: is it the result of excyclorotation of the extraocular muscles?

PURPOSE: We sought to determine whether radiological evidence supports excyclorotation of the extraocular muscle cone as a cause of overelevation in adduction in children with craniosynostosis. METHODS: This was a retrospective case series of 40 patients with craniosynostosis. Ophthalmic findings were assessed for incomitant vertical strabismus in particular excessive elevation in adduction. Computed tomography and magnetic resonance imaging scans were reviewed. Those scans with adequate coronal imaging of their orbits to assess the position and angulation of the horizontal extraocular muscles were identified, and the degree of rotation of the muscles formally measured along with aged matched controls. These groups were analyzed for the association between presence of overelevation in adduction and degree of excyclorotation of the extraocular muscle cone. RESULTS: The identified updrift on adduction that mimics inferior oblique muscle overaction was present in 63% (25/40) of patients. Imaging that permitted accurate measurement of the muscles positions was available in 10 of the 40 patients. Of these 10, 8 had the updrift, and 7 of these 8 (88%) demonstrated more excyclorotation than their aged matched controls. Comparison of scan measurements of patients revealed a significant difference in degree of excyclorotation (mean difference = 16.2, 95% confidence interval 6.2-31.5; P = 0.006) between patients with and without excess elevation in adduction. CONCLUSION: Overelevation in adduction is significantly associated with excyclorotation of the extraocular muscle cone in children with craniosynostosis. We demonstrate a simple method to assess for the excyclorotation. Our findings support the importance of imaging of the orbits in these children before strabismus surgery.

Radiological prevalence of superior and posterior semicircular canal dehiscence in children.

OBJECTIVE: Establishing the prevalence of semicircular canal dehiscence in a pediatric population using temporal bone CT imaging. STUDY DESIGN: Retrospective analysis of all temporal bone CT scans during a 5-year period (2007-2012). METHODS: CT scan images were reformatted in the plane of the canals and assessed by two independent reviewers with a third to resolve disagreement. Detailed chart review was performed for those found to have dehiscence. Superior and posterior canals were classified as "dehiscent", "possibly dehiscent", "thin" or "normal" for each case. RESULTS: 649 temporal bones were assessed from 334 children (under 18 years of age). The prevalence rate of superior canal dehiscence (SCD) was 1.7% (3.3% of individuals). Posterior canal dehiscence (PCD) was present in 1.2% (2.1% of individuals). There were no cases of bilateral SCD, and one case of bilateral PCD. Age under 3 years was associated with a higher prevalence of thinning but not dehiscence. Congenital inner ear malformation was not related to a higher probability of dehiscence. The superior petrosal sinus was associated with the SCD in three cases (27.3%). Retrospective chart review highlighted possible vestibular symptoms in 3/11 patients with SCD (27.3%). CONCLUSIONS: This forms the largest pediatric study of canal dehiscence to date. This study's prevalence rate is significantly lower than previous reports. The identified association with overlying venous structures may reflect the etiological process involved. The occurrence in children supports the hypothesis of a congenital predisposition for development of canal dehiscence syndrome.

Cerebellar vermian atrophy after neonatal hypoxic-ischemic encephalopathy.

BACKGROUND AND PURPOSE: Although pathologic evidence of cerebellar injury due to birth asphyxia is well described, neuroimaging evidence is sparse. The primary purpose of this retrospective study was to evaluate the early and late imaging findings in the cerebellum of patients who had neonatal hypoxic-ischemic encephalopathy with thalamic edema shown by neonatal CT. The secondary aims were to validate thalamic edema shown by neonatal CT as a marker of thalamic injury and to assess the late cerebral cortical abnormalities associated with neonatal thalamic edema. METHODS: Fifty-five neonates with thalamic edema shown by CT performed when patients were 3 days old were identified from a cohort of full-term neonates with hypoxic-ischemic encephalopathy. Twenty-six of the 55 underwent follow-up neuroimaging. All sonograms, CT scans, and MR images of the brains of the 55 neonates were retrospectively reviewed by two pediatric neuroradiologists. The examinations were reviewed for evidence of hemorrhage, edema, atrophy, and CT attenuation or MR signal intensity abnormalities in the cerebellum, basal ganglia, and cerebral cortex. The neonatal autopsy findings in four cases were reviewed separately by a pediatric neuropathologist. RESULTS: Of the 55 neonates with thalamic edema shown by neonatal CT, 28 (51%) had thalamic edema with diffuse cerebral cortical edema, and 27 (49%) had thalamic edema without diffuse cortical edema. The cerebellar vermes appeared normal on all neonatal sonograms, CT scans, and MR images. However, atrophy of the cerebellar vermis was found in 12 (46%) of 26 patients by use of follow-up studies (95% CI, 27-65%). One of the 12 patients also had cerebellar hemispheric atrophy. Cerebellar vermian atrophy was shown at follow-up in eight (67%) of 12 patients who had neonatal thalamic edema with cortical sparing, compared with four (29%) of 14 patients who had thalamic edema with diffuse cortical edema. The difference did not reach statistical significance. The thalami appeared abnormal on follow-up neuroimages in 25 of 26 cases. Different patterns of cortical atrophy were observed on the images of patients who had thalamic edema with cortical sparing compared with those obtained in patients who had thalamic edema with cortical involvement. CONCLUSION: Cerebellar vermian atrophy is a frequent finding on follow-up images of patients in whom neonatal CT showed hypoxic-ischemic encephalopathy with abnormal thalami.

MRI findings in infants with infantile spasms after neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: To evaluate the predominant pattern of brain injury and the anatomic areas of injury in children with infantile spasms following neonatal hypoxic-ischemic encephalopathy. METHODS: A nested case-control study of infantile spasms in children with term neonatal hypoxic-ischemic encephalopathy was performed. All patients had T1/T2-weighted magnetic resonance imaging with diffusion-weighted imaging performed on the third day of life. Using a validated scoring system, the magnetic resonance imaging was classified as: normal, watershed, basal ganglia/thalamus, total, or focal-multifocal. Two study investigators scored additional anatomic areas of injury (cortical extent, levels of the brainstem, hypothalamus) on T1/T2-weighted magnetic resonance imaging and diffusion-weighted imaging blinded to the outcome. The predominant pattern of brain injury and anatomic areas of injury were compared between patients who developed infantile spasms and randomly selected controls. RESULTS: Eight patients who developed infantile spasms were identified among a cohort of 176 term newborns with hypoxic-ischemic encephalopathy (4.5%). There were no significant differences in the perinatal and neonatal course between newborns who developed infantile spasms and controls who did not. The development of infantile spasms after neonatal hypoxic-ischemic encephalopathy was significantly associated with basal ganglia/thalamus and total brain injury (P = 0.001), extent of cortical injury greater than 50% (odds ratio = 11.7, 95% confidence interval = 1.1-158.5, P = 0.01), injury to the midbrain (odds ratio = 13, 95% confidence interval = 1.3-172, P = 0.007) and hypothalamic abnormalities (P = 0.01). CONCLUSIONS: The development of infantile spasms after hypoxic-ischemic encephalopathy is associated with injury to the basal ganglia and thalami on neonatal magnetic resonance imaging, particularly when extensive cortical injury and/or injury to the midbrain is present.

Ophthalmic complications of otitis media in children.

PURPOSE: To evaluate the outcome of ophthalmic complications in children with otitis media. METHODS: The records of children with ophthalmic complications arising from otitis media who presented to the British Columbia Children's Hospital between August 2006 and March 2008 were reviewed retrospectively. RESULTS: Of 1,400 patients presenting to the emergency department for otitis media during the study period, 7 with ophthalmic complications were identified (age range, 1-11 years). All patients had abducens nerve palsy on presentation. Other notable ophthalmic complications included papilledema, Horner syndrome, and proptosis. Extracranial and intracranial complications included mastoiditis, petrositis, parapharyngeal abscess, hydrocephalus, epidural abscess, and cerebral venous thrombosis, including cavernous sinus thrombosis in 2. Of the 7 patients, 6 were treated with surgery, including myringotomy and tube placement (6 patients) and mastoidectomy (3 patients). All patients were initially anticoagulated and received intravenous antibiotics. Satisfactory final visual outcomes and stereopsis ranging from 40 to 100 seconds were achieved in all patients. CONCLUSIONS: Ophthalmic complications of otitis media in children are likely to include abducens palsy. All patients in our series required anticoagulation and intravenous antibiotics. Most required otolaryngologic surgery, but none required strabismus surgery, and all patients had satisfactory visual and ocular motility outcomes.

Third ventricular shape: a predictor of endoscopic third ventriculostomy success in pediatric patients.

OBJECT: The criteria for identifying patients in whom endoscopic third ventriculostomy (ETV) provides control of hydrocephalus remain in evolution. In particular, it is not clear when ETV would be effective if intraventricular obstruction is not found preoperatively. The authors postulated that 1) displacement of the third ventricle floor inferiorly into the interpeduncular cistern and displacement of the lamina terminalis anteriorly into the lamina terminalis cistern could predict clinical success of ETV, and 2) improvement in these displacements would correlate with the success of ETV. METHODS: Magnetic resonance imaging in 38 consecutive patients treated between 2004 and 2010 was reviewed to assess displacement of the lamina terminalis and third ventricular floor prior to and following ETV. Displacements of the floor and lamina terminalis were judged qualitatively and quantitatively, using a newly created index, the Third Ventricular Morphology Index (TVMI). The association between the aforementioned morphological features and clinical success of ETV was analyzed. RESULTS: Ninety-six percent of patients in whom the authors preoperatively observed displacement of the lamina terminalis and the third ventricular floor were successfully treated with ETV. Displacements of the third ventricular floor and lamina terminalis, as judged qualitatively, correlated with the clinical success of ETV. The TVMI correlated with the qualitative assessments of displacement. Postoperative decrease in the TVMI occurred in the majority of successfully treated patients. Changes in third ventricular morphology preceded changes in other measures of third and lateral ventricular volume following ETV. CONCLUSIONS: Assessment of third ventricular floor and lamina terminalis morphology is useful in predicting clinical success of ETV and in the follow-up in treated patients. The TVMI provided a quantitative assessment of the third ventricular morphology, which may be useful in equivocal cases and in research studies.