Brain abnormalities in children and adolescents with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a risk factor for vascular disease and stroke. The spectrum of brain injury and microstructural white matter abnormalities in children with CKD is largely unknown. METHODS: Cross sectional study at two North American pediatric hospitals. A cohort of 49 children, 29 with CKD, including renal transplant (mean age 14.4 ± 2.9 years; range 9-18), and 20 healthy controls (mean age 13.7 ± 3.1 years; range 9-18) had their conventional brain magnetic resonance images (MRIs) reviewed by one neuroradiologist to determine the prevalence of brain injury. Fractional anisotropy (FA) maps calculated from diffusion tensor imaging (DTI) were generated to compare white matter microstructure in CKD compared to controls, using tract-based spatial statistics (TBSS). RESULTS: Focal and multifocal white matter injury was seen on brain MRI in 6 children with CKD (21%). Relative to controls, CKD subjects showed reduced white matter fractional anisotropy and increased mean diffusivity and radial diffusivity in the anterior limb of the internal capsule, suggestive of abnormal myelination. CONCLUSION: Cerebral white matter abnormalities, including white matter injury, are under-recognized in pediatric CKD patients. Brain imaging studies through progression of CKD are needed to determine the timing of white matter injury and any potentially modifiable risk factors.

Phase II Weekly Vinblastine for Chemotherapy-Naïve Children With Progressive Low-Grade Glioma: A Canadian Pediatric Brain Tumor Consortium Study.

Purpose Vinblastine monotherapy has shown promising activity and a low-toxicity profile in patients with pediatric low-grade glioma (PLGG) who experienced treatment failure after initial treatment with chemotherapy and/or radiation. The aim of this study was to assess the activity of vinblastine in therapy-naïve children. Patients and Methods Patients < 18 years old with unresectable and/or progressive therapy-naïve PLGG were eligible. Vinblastine was administered once per week at a dose of 6 mg/m2 intravenously over a period of 70 weeks. Vision, quality of life, neurofibromatosis type 1 (NF1) status, and BRAF mutation/fusion status were also determined and correlated with outcome. Results Fifty-four patients were enrolled onto the study, with a median age of 8 years (range, 0.7 to 17.2 years). Most patients had chiasmatic/hypothalamic tumors (55.5%), and 13 patients (24.1%) had NF1. The most common histology was pilocytic astrocytoma (46.3%). Seventeen patients were diagnosed using radiologic criteria alone. Best response to chemotherapy was centrally reviewed with a response rate (complete, partial, or minor response) of 25.9%. Disease stabilization (complete, partial, or minor response or stable disease) was achieved in 47 patients (87.0%). Visual improvement was observed in 20% of patients with optic pathway glioma. Five-year overall survival and progression-free survival (PFS) rates were 94.4% (95% CI, 88.5% to 100%) and 53.2% (95% CI, 41.3% to 68.5%), respectively, for the entire cohort. Patients with NF1 had a significantly better PFS (85.1%; 95% CI, 68.0% to 100%) when compared with patients without NF1 (42.0%; 95% CI, 29.1% to 60.7%; P = .012). Age< 3 years or > 10 years was not associated with poor outcome. Treatment was well tolerated, and quality of life was not affected during treatment. In this trial, there was no correlation between BRAF alterations and outcome. Conclusion Vinblastine administered once per week is well tolerated in children with treatment naïve PLGG. Overall survival and PFS are comparable to current therapies, with a favorable toxicity profile and a maintained quality of life.

Pediatric thalamic tumors in the MRI era: a Canadian perspective.

BACKGROUND: Thalamic gliomas are rare. The natural history is unpredictable, and the optimal management of these tumors in children is poorly defined. The aim was to identify outcomes, prognostic factors, and response to various modalities of treatment in a relatively large population of pediatric thalamic tumors from many centers within a fairly homogeneous health care system. METHODS: We performed a Canadian multicenter retrospective review of pediatric thalamic tumors presenting during the MRI era (1989-2012). Radiology and pathology were reviewed by central independent reviewers. Paraffin shavings for RNA extraction were taken and tested for fusion events involving KIAA1549:BRAF. Tumors were classified as unilateral or bithalamic based on their origin on imaging. Univariate and multivariate analyses on factors influencing survival were performed. RESULTS: Seventy-two thalamic tumors were identified from 11 institutions. Females represented 53% of the study population, and the mean age at presentation was 8.9 years. Sixty-two tumors were unilateral and 10 bithalamic. Unilateral tumors had a greater propensity to grow inferiorly towards the brainstem. These tumors were predominantly low grade in comparison to bithalamic tumors which were high-grade astrocytomas. The 5-year overall survival was 61 ± 13% for unithalamic tumors compared to 37 ± 32% for bithalamic tumors (p = 0.097). Multivariate analysis indicated tumor grade as the only significant prognostic factor for unithalamic tumors. Six unilateral tumors, all low grade, were BRAF fusion positive. CONCLUSION: Unilateral and bilateral thalamic tumors behave differently. Surgical resection is an appropriate treatment option in unilateral tumors, most of which are low grade, but outcome is not related to extent of resection (EOR). Bilateral thalamic tumors have a poorer prognosis, but the occasional patient does remarkably well. The efficacy of chemotherapy and radiotherapy has not been clearly demonstrated. Novel therapeutic approaches are required to improve the prognosis for malignant unilateral thalamic tumors and bilateral thalamic tumors.

Failure of repeated cyclophosphamide pulse therapy in childhood cerebral X-linked adrenoleukodystrophy.

Childhood cerebral X-linked adrenoleukodystrophy (ALD) remains one of the most devastating neurological diseases of childhood. Cardinal features are inflammatory cerebral demyelination that coincides with an advancing zone of gadolinium enhancement on brain MRI. Therapeutic options, including the role of antiinflammatory therapy, are limited and poorly understood. We report the failure of repeated cyclophosphamide pulse therapy to halt the clinical progression or alter the gadolinium accumulation in two cases of childhood cerebral ALD.

Hemiplegic migraine, seizures, progressive spastic paraparesis, mood disorder, and coma in siblings with low systemic serotonin.

BACKGROUND: Serotonin has an important role in vascular resistance and blood pressure control, and a functional serotonin transporter polymorphism has been associated with migraine. Disturbances in serotonin metabolism have been associated with autism, depression, and myoclonus related conditions, but serotonin has far more functions in the body. Familial hemiplegic migraine is a rare autosomal dominant subtype of migraine with aura in which attacks are associated with hemiparesis. CASES: We present two siblings with hemiplegic migraine, depression, progressive spastic paraparesis, myelopathy, and spinal cord atrophy. One of the sisters presented with prolonged coma after a migraine episode. Both sisters were found to have low cerebrospinal fluid serotonin metabolite (5-hydroxyindoleacetic acid), low platelet serotonin levels, and diminished serotonin transport capacity. Their clinical symptoms improved on 5-hydroxytryptophan replacement therapy. Mutational analysis of the CACNA1A and ATP1A2 genes was negative. CONCLUSION: This is the first time that systemic serotonin deficiency has been described in familial hemiplegic migraine. We hypothesize that the deficiency of serotonin transport may be part of a complex cellular membrane trafficking dysfunction involving not only the serotonin transporter but also other transporters and ion channels.

The role of hypoxia-ischemia in term newborns with arterial stroke.

The role of generalized hypoxia-ischemia in the genesis of perinatal focal arterial stroke remains puzzling. Animal studies have demonstrated that hypoxia-ischemia may alter blood flow through the ductus venosus, thereby increasing the risk for placental emboli entering the cerebral circulation. A retrospective review was performed of clinical records of all term newborns admitted to a tertiary perinatal center between January 1995 and May 2007 with acute arterial stroke on neuroimaging during the first week of life. Newborns were classified into 2 groups on the basis of neuroimaging abnormalities: stroke alone, or stroke and nonfocal hypoxic-ischemic brain injury. A total of 62 newborns had focal or multifocal stroke, 36 with stroke alone and 26 with stroke with nonfocal hypoxia-ischemia. Multiple risk factors for hypoxia-ischemia occurred in most newborns in both groups. These data indicate that hypoxia-ischemia may play a role in the genesis of stroke in the term newborn with or without evidence of nonfocal hypoxic-ischemic brain injury on neuroimaging.

Occurrence of basal ganglia germ cell tumors without a mass.

OBJECTIVE: To report a case series in which basal ganglia calcifications without mass effect proved to be germ cell tumors. DESIGN: Case series. SETTING: Tertiary care hospital. PATIENTS: Four patients. INTERVENTIONS: Computed tomography, magnetic resonance imaging, positron emission tomography, biopsy, chemotherapy, and radiation therapy. MAIN OUTCOME MEASURES: Recognition of clinical syndrome and radiological features. RESULTS: All patients had progressive hemiparesis, and 1 patient also had frontal lobe dementia. Imaging demonstrated progressive asymmetric signal abnormality with basal ganglia calcification and associated brainstem atrophy. Fludeoxyglucose F 18-positron emission tomography showed hypometabolism in contrast to malignant glioma. CONCLUSION: Germ cell tumor should be considered in patients with an indolently progressive neurological course, particularly if basal ganglia calcification is present with or without enhancement, asymmetric brain atrophy, or a mass.

Therapy resistant neonatal seizures, linear vesicular rash, and unusually early neuroradiological changes: incontinentia pigmenti: a case report, literature review and insight into pathogenesis.

CASE PRESENTATION: A substance abusing G2P1 mother spontaneously delivered at term an appropriate for gestational age girl. Neonatal seizures appeared at 21 hours and empiric anticonvulsive and antimicrobial treatment was started. At 25 hours, first vesicles appeared. While routine evaluations remained normal, a head CT revealed multifocal ischemic injuries, and a later MRI showed multifocal petechiae and diffusion abnormalities in the corticospinal tracts. The clinical diagnosis of incontinentia pigmenti (stage 1) was secured by histopathology. Follow-up at 13 months showed global developmental delay. DISCUSSION: We discuss the unusually early bilateral, fronto-occipital corticomedullar ischemias (CT day 3). On the MR imaging (day 7) extensive symmetric cerebral corticomedullar destruction and diffusion sequences with corticospinal tracts abnormalities are seen, which then evolve (day 26) to extensive symmetric cerebral destruction. We review the literature, genetics, suspected pathophysiology and possible neonatal manifestation. CONCLUSION: Incontinentia pigmenti is rare and, therefore, diagnosis is frequently delayed. Nevertheless, in the setting of therapy refractory seizures, excluded infections, and linear vesicular rash, a high index of suspicion is needed. This is the first report of simultaneous corticomedullar involvement as early as the third day of life.

Early hypodensity on computed tomographic scan of the brain in an accidental pediatric head injury.

OBJECTIVE: Hypodensities on computed tomographic (CT) brain scans are thought to take at least 6 hours to become apparent after blunt head trauma. This finding, in conjunction with the later evolution of the hypodensities, is used in timing the injury in children with suspected non-accidental brain injury, in whom the history may be inaccurate. The purpose of this study is to report the occurrence of diffuse cerebral parenchymal hypodensities on CT scans performed within 5 hours of a well-defined accidental head injury. METHODS: A retrospective review was performed of five patients admitted to British Columbia Children's Hospital who had accidental head injury and who were identified as having diffuse cerebral hemispheric hypodensities on early CT scans. RESULTS: We present five patients (age range, 4 mo-14 yr) with well-documented accidental head injuries who demonstrated obvious and extensive CT brain scan cerebral hemispheric hypodensity from 60 minutes to 4.5 hours after trauma. All five patients presented with severe head injuries and immediate, unremitting coma, and all five progressed rapidly to brain death within 48 hours. CONCLUSION: It is unusual, but possible, to develop CT hypodensities as early as 1 hour after accidental head injury. In our small series of cerebral hemispheric hypodensity occurring less than 5 hours after trauma, all five patients had a uniformly fatal outcome. These observations may be important medicolegally in the assessment of the timing of head injury when the history of the trauma is not clear, as in children with suspected non-accidentally inflicted injury. It is inappropriate to generalize these findings to patients who are not unconscious immediately after a head injury, who regain consciousness after an injury before deteriorating, or who do not progress rapidly to brain death.

Spontaneous regression of cerebellar astrocytoma after subtotal resection.

CASE REPORT: The authors report a child in whom residual cerebellar astrocytoma after surgical resection was documented on serial computed tomography scans to undergo gradual complete regression spontaneously over a period of 11 years. In this case, the time course of regression has been well documented. CONCLUSION: The time course of regression may provide clues as to the underlying cause of this phenomenon.

Pediatric lateral sinus thrombosis: retrospective case series and literature review.

OBJECTIVE: A comparison between the literature and our management of pediatric patients presenting with otogenic lateral sinus thrombosis. DESIGN: A retrospective case series of five pediatric patients. SETTING: Four patients were treated at BC Children's Hospital, whereas the fifth patient was treated in New Westminster, BC. All were treated between 1994 and 2001. METHODS: A retrospective chart review was conducted with a literature review for otogenic lateral sinus thrombosis. MAIN OUTCOME MEASURES: Treatment success was based on resolution of acute infection and neurologic symptoms. RESULTS: Five patients, four males and one female, aged 2 to 14 years were reviewed. Three patients were treated successfully without mastoidectomy. One patient received a mastoidectomy that yielded no pus or granulation tissue within the mastoid cavity. One patient required a mastoidectomy after failure to respond to bilateral myringotomy and tympanostomy tube insertion. Although no pus was seen in the mastoid cavity, perisinus pus was found after unroofing the sigmoid sinus plate; free flow of blood was obtained on needle aspiration of the sinus, and the sinus was not surgically opened. CONCLUSION: The current literature states that the management of otogenic lateral sinus thrombosis includes high-dose intravenous antibiotics with a mastoidectomy and possible opening of the sinus. In our retrospective case series, three of five patients recovered completely without mastoidectomy, and a fourth had a mastoidectomy deemed to have been unnecessary. We conclude that intravenous antibiotics and insertion of a tympanostomy tube are sufficient treatment for selected cases of otogenic lateral sinus thrombosis. Mastoidectomy with possible opening of the sinus should be reserved for patients refractory to the above conservative treatment.

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.

Predicting stroke risk in pediatric moyamoya disease with xenon-enhanced computed tomography.

OBJECTIVE: To determine whether estimates of regional cerebral blood flow (rCBF) using xenon computed tomography (XeCT) in children with moyamoya disease can predict stroke risk before and after treatment. METHOD: Seven patients with moyamoya disease underwent 22 serial Xe computed tomographic scans. Estimates of rCBF were obtained at three computed tomographic levels by use of a 5-minute inhalation of 28% Xe. Acetazolamide challenge was performed in eight scans. For comparison of abnormal vessel distribution and areas of infarction, 17 intra-arterial digital subtraction angiograms, 47 computed tomographic scans, and 15 magnetic resonance imaging scans were available. Follow-up exceeded 36 months in all patients. Mean follow-up for the interventional group was 65.2 months (n = 5; range, 37-109 mo) and 38 months for the nonoperative patients (n = 2; 36 and 40 mo). RESULTS: Of six Xe computed tomographic scans obtained at diagnosis, four revealed regions of oligemia, augmented vertebrobasilar flow, and regions of carotid steal after acetazolamide. In the delay between diagnosis and treatment, three patients had strokes in ischemic areas identified by XeCT. Of the 10 posttreatment scans obtained from 4 patients, 2 revealed improved tissue perfusion with angiography confirming successful encephaloduroangiomyosynangiosis. In 2 others, XeCT performed 6 months posttreatment revealed improved perfusion without angiographic change, and angiography at 1 year revealed failed encephaloduroangiomyosynangiosis and new native collaterals. None of the patients with improved rCBF had new strokes. Eleven of 14 Xe computed tomographic scans were obtained within 30 days of angiography. Comparison of these studies demonstrates that regions of oligemia were confined to areas associated with vessel stenosis and little neovascularity or collateral pathways. CONCLUSION: XeCT, particularly with acetazolamide challenge, objectively quantifies rCBF. Our preliminary data suggest that it may permit assessment of stroke risk in children with moyamoya disease and may predict surgical outcome earlier than angiography.