Opportunistic infections and organ‐specific diseases in HIV‐1‐infected children: a cohort study (1990–2006)

Objectives

Highly active antiretroviral therapy (HAART) has dramatically changed the natural history of HIV infection in children, but there are few studies in the literature about the incidence of clinical manifestations after HAART in this population, compared with adults. The aim of this study was to describe the influence of the widespread use of HAART on the development of opportunistic infections and organ‐specific diseases in HIV‐infected children.

Methods

An observational study of a cohort of 366 vertically HIV‐infected children followed from 1990 to 2006 was carried out. According to the main antiretroviral protocol used, three calendar periods (CPs) were defined and compared: CP1 (1990–1996: no patients on HAART), CP2 (1997–1999: <60% on HAART) and CP3 (2000–2006: >60% on HAART).

Results

Children experienced a progressive increase in CD4 T cell count (P<0.05) and a decrease in HIV viral load from 1996 onwards (P<0.05). Similarly, rates of death, AIDS, opportunistic infections (bacteraemia, candidosis, cryptosporidiosis and bacterial pneumonia) and organ‐specific diseases (wasting syndrome, thrombocytopenia, cardiomyopathy, lymphoid interstitial pneumonia and HIV‐associated encephalopathy) were lower in CP2 and CP3 than in CP1.

Conclusions

This study provides evidence of improved clinical outcomes in HIV‐infected children over time and shows that mortality, AIDS, opportunistic infections and organ‐specific diseases declined as HAART was progressively instituted in this population.

     

Dynamic changes of ictal high-frequency oscillations in neocortical epilepsy: using multiple band frequency analysis

PURPOSE: To characterize the spatial and temporal course of ictal high-frequency oscillations (HFOs) recorded by subdural EEG in children with intractable neocortical epilepsy. METHODS: We retrospectively studied nine children (four girls, five boys; 4-17 yr) who presented with intractable extrahippocampal localization-related epilepsy and who underwent extraoperative video subdural EEG (1000 Hz sampling rate) and cortical resection. We performed multiple band frequency analysis (MBFA) to evaluate the frequency, time course, and distribution of ictal HFOs. We compared ictal HFO changes before and after clinical onset and postsurgical seizure outcomes. RESULTS: Seventy-eight of 79 seizures showed HFOs. We observed wide-band HFOs ( approximately 250 Hz, approximately 120 electrodes) in six patients either with partial seizures alone (three patients) or with epileptic spasms (three patients). Three patients with partial seizures that secondarily generalized had wide-band HFOs ( approximately 170 Hz) before clinical onset and sustained narrow-band HFOs (60-164 Hz) with electrodecremental events after clinical onset ( approximately 28 electrodes). In four postoperatively seizure-free patients, more electrodes recorded higher-frequency HFOs inside the resection area than outside before and after clinical seizure onset. In five patients with residual seizures, electrodes recorded more HFOs that were of higher or equal frequency outside the surgical area than inside after clinical onset. CONCLUSION: For partial seizures alone and epileptic spasms, more electrodes recorded only wide-band HFOs; for partial seizures that secondarily generalized, fewer electrodes recorded wide-band HFOs, but in these seizures electrodes also recorded subsequent sustained narrow-band ictal HFOs. Resection of those brain regions having electrodes with ictal, higher HFOs resulted in postsurgical seizure-free outcomes.     

Epilepsy surgery in the first 3 years of life: A Canadian survey

Objective:   To determine the clinical characteristics, surgical challenges, and outcome in children younger than 3 years of age undergoing epilepsy surgery in Canada.
Methods:   Retrospective data on patients younger than age 3 years who underwent epilepsy surgery at multiple centers across Canada from January 1987 to September 2005 were collected and analyzed.
Results:   There were 116 patients from eight centers. Seizure onset was in the first year of life in 82%, and mean age at first surgery was 15.8 months (1–35 months). Second surgeries were done in 27 patients, and a third surgery in 6. Etiologies were malformations of cortical development (57), tumor (22), Sturge-Weber syndrome (19), infarct (8), and other (10). Surgeries comprised 40 hemispheric operations, 33 cortical resections, 35 lesionectomies, 7 temporal lobectomies, and one callosotomy. There was one surgical mortality. The most common surgical complications (151 operations in 116 patients) were infection (17) and aseptic meningitis in 13. Of 107 patients with seizure outcome assessed more than one year postoperatively, 72 (67.3%) were seizure free (Engel I), 15(14%) had >90% improvement (Engel II), 12 had >50% improvement (Engel III), and 8 did not benefit from surgery (Engel IV). Development improved in 55.3% after surgery.
Conclusion:   Epilepsy surgery in children younger than 3 years of age is relatively safe and is effective in controlling seizures. Very young age is not a contraindication to surgery in children with refractory epilepsy, and early surgery may impact development positively.     

Pathology type does not predict language lateralization in children with medically intractable epilepsy

Purpose: We examined potential differences in the effects of pathology type on language lateralization in pediatric epilepsy. Methods: We examined findings from intracarotid sodium amobarbital procedure (IAP/Wada) in a large consecutive sample of children with refractory epilepsy. Subjects were assigned to one of three pathology groups: developmental (n = 28), acquired (n = 26), and tumor (n = 20); groups were compared for language lateralization. Results: Rates of atypical language lateralization did not differ across groups. Greater than half of the subjects with left hemisphere insults and seizure onset before 6 years of age had atypical language lateralization, independent of pathology type. Discussion: Atypical language lateralization may occur in the context of developmental, acquired, and/or tumor pathology.     

Epigenetic regulation of glial fibrillary acidic protein by DNA methylation in human malignant gliomas

Glial fibrillary acidic protein (GFAP) is an intermediate filament expressed in glial cells that stabilizes and maintains the cytoskeleton of normal astrocytes. In glial tumors, GFAP expression is frequently lost with increasing grade of malignancy, suggesting that GFAP is important for maintaining glial cell morphology or regulating astrocytoma cell growth. Most permanent human glioma cell lines are GFAP negative by immunocytochemistry. Given that the GFAP gene is not mutated in human glioma specimens or glioma cell lines, we considered epigenetic mechanisms, such as promoter methylation, as a cause of silencing of GFAP in these tumors. In this study, we treated known GFAP-negative glioma cell lines with 5-aza-2'-deoxycytidine to examine GFAP promoter hypermethylation. Additionally, we performed bisulfite sequencing on primary glioma samples and glioma cell lines and showed an inverse relationship between GFAP promoter methylation status and GFAP expression. Using a gene reporter assay with the GFAP promoter cloned upstream of a luciferase gene, we showed that methylation of the GFAP promoter downregulates the expression of the luciferase gene. Our results suggest that epigenetic silencing of the GFAP gene through DNA methylation of its promoter region may be one mechanism by which GFAP is downregulated in human gliomas and glioma cell lines.     

Initial management of childhood brain tumors: neurosurgical considerations

Intracranial tumors are the most common solid tumors in children. The infratentorial compartment will be the primary site for 60% to 70% of these tumors, including astrocytomas, medulloblastomas, and ependymomas. Several technological advancements have increased our knowledge of the cell biology of pediatric brain tumors, facilitated earlier diagnosis, and improved neurosurgical resections while minimizing neurological deficits. These in turn have not only improved the survival of children with brain tumors but also their quality of life. Current management strategies in most cases rely on surgery coupled with adjuvant therapies, including radiation therapy and chemotherapy. The vulnerability of the immature brain to adjuvant therapies creates many challenges for the treating physician. We review current diagnostic and therapeutic approaches and outcome for children harboring the most common pediatric brain tumors: astrocytomas (low-grade and high-grade glioma), ependymoma, medulloblastoma, and craniopharyngioma. The emphasis will be on the neurosurgical management of children with these tumors.     

Oncogene amplification in medulloblastoma: analysis of a case by comparative genomic hybridization and fluorescence in situ hybridization

We describe amplification of the MYCC oncogene in a medulloblastoma with aggressive clinical behavior. The patient was a six year old boy who underwent gross total surgical excision of a cerebellar tumor. Despite chemotherapy and total neuraxis radiation, the clinical course was one of relentless progression, with extensive subarachnoid spread and death within eight months of presentation. The pathological features were consistent with the recently described, "large cell variant" of medulloblastoma. Tumor cells exhibited large vesicular nuclei, prominent nucleoli and strong immunoreactivity for synaptophysin. Polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) assay revealed no evidence of MYCN amplification or 1p deletion in the tumor. FISH analysis revealed evidence of MYCC amplification in the 20- to 30-fold range. Comparative genomic hybridization (CGH) revealed regions of gains and amplification in three locations, with gains of chromosome 7, amplification of 8q24 (corresponding to the MYCC locus) and gains of the long arm of chromosome 17 (suggestive of isochromosome 17q). While conventional karyotypic analysis was not successful in the present case, CGH provided invaluable information about gene amplification and losses/gains of chromosomes and chromosomal regions. Thus, CGH is a powerful technique applicable to frozen or paraffin-embedded material which helps to ascertain the presence of gene amplification even without prior knowledge of the gene to be tested.     

Advances and challenges of nanotechnology-based drug delivery systems

The ability to deliver highly efficient therapeutic compounds specifically to diseased sites is crucial for effectively treating all human illnesses. Unfortunately, conventional therapeutic strategies require unnecessarily high systemic administration due to non-specific biodistribution and rapid metabolism of free drug molecules prior to reaching their targeted sites. Using the tools of nanotechnology, drug delivery systems within the nanometer size regime can be developed to alter both pharmacological and therapeutic effects of drug molecules. Due to their small size, these novel DDS offer superior advantages, such as altered pharmacokinetic behaviour and improved payload, over traditional large-scale systems. In addition, the relative ease in modifying their surface chemistry permits the attachment of targeting and therapeutic molecules for specific therapeutic applications. Finally, complex nanostructures can be assembled using different building blocks with multiple functionalities ranging from targeting, detecting, imaging and therapeutic capabilities.     

Fractionated stereotactic radiotherapy for acoustic neuroma: single-institution experience at The Princess Margaret Hospital

BACKGROUND: The clinical outcome and toxicity of fractionated stereotactic radiotherapy (FSRT) was assessed for acoustic neuroma in 60 patients treated in a single institution. METHODS: Between October 1996 and February 2005, 60 patients received FSRT for acoustic neuroma (AN). The mean total dose applied was 50 Gy in single daily 2-Gy fractions over 5 weeks. The median irradiated tumor volume was 4.9 cm(3) (range, 0.3-49.0 cm(3)). The median follow-up period was 31.9 months. RESULTS: FSRT was well tolerated in all patients. The 5-year actuarial local control rate was 96.2% (95% CI: 91.1%-100.0%). Five-year actuarial progression-free survival was 92.8% (95% CI: 84.8%-100.0%). The overall hearing preservation rate was 77.3%. Five of 6 patients with initial cranial nerve V (CNV) numbness remained stable post-FSRT. Two of 3 patients with baseline trigeminal neuralgia improved with the remaining patient stable. All 3 patients with nonsurgically related facial nerve weakness either improved or achieved stability in function. There were no cases of new cranial nerve toxicity post-FSRT. CONCLUSIONS: FSRT for the treatment of AN is safe, effective, and well tolerated. FSRT should thus be considered as an effective alternative treatment modality when compared with microsurgical resection or single fraction stereotactic radiosurgery.