Comment: Genotype-phenotype correlations in NF1: A case for routine genetic testing
NEUROLOGY
Campen, C. J., Greenwood, R. S.
2018; 90 (8): 380
Optic Pathway Gliomas in Neurofibromatosis Type 1
JOURNAL OF CHILD NEUROLOGY
Campen, C. J., Gutmann, D. H.
2018; 33 (1): 73–81
Abstract
Neurofibromatosis type 1 (NF1) is one of the most common brain tumor predisposition syndromes, in which affected children are prone to the development of low-grade gliomas. While NF1-associated gliomas can be found in several brain regions, the majority arise in the optic nerves, chiasm, tracts, and radiations (optic pathway gliomas; OPGs). Owing to their location, 35-50% of affected children present with reduced visual acuity. Unfortunately, despite tumor stabilization following chemotherapy, vision does not improve in most children. For this reasons, more effective therapies are being sought that reflect a deeper understanding of the NF1 gene and the use of authenticated Nf1 genetically-engineered mouse strains. The implementation of these models for drug discovery and validation has galvanized molecularly-targeted clinical trials in children with NF1-OPG. Future research focused on defining the cellular and molecular factors that underlie optic glioma development and progression also has the potential to provide personalized risk assessment strategies for this pediatric population.
View details for DOI 10.1177/0883073817739509
View details for Web of Science ID 000418190800005
View details for PubMedID 29246098
View details for PubMedCentralID PMC5739070
Abstract
To characterize the phenotype of pediatric Bickerstaff's brainstem encephalitis (BBE) and evaluate prognostic features in the clinical course, diagnostic studies, and treatment exposures.We systematically reviewed PubMed, Web of Science, and SCOPUS databases as well as medical records at the Lucile Packard Children's Hospital to identify cases of pediatric BBE. Inclusion required all of the following criteria: age ≤ 20 years, presence of somnolence or alterations in mental status at the time of presentation or developed within 7 days of presentation, ataxia, and ophthalmoplegia.We reviewed 682 manuscripts, identifying a total of 47 pediatric BBE cases. We also describe five previously unreported cases. The phenotype of these pediatric patients was similar to previously published literature. Sixty-eight percent of patients demonstrated positive anti-GQ1b antibody titers, yet the presence of these antibodies was not associated with longer times to recovery. Patients with neuroimaging abnormalities featured a longer median time to recovery, but this was not statistically significant (p = 0.124). Overall, patients treated with any form of immunotherapy (intravenous immunoglobulin, steroids, or plasmapheresis) demonstrated shorter median time to resolution of symptoms compared to supportive therapy, although this trend was not statistically significant (p = 0.277). Post-hoc t tests revealed a trend towards use of immunotherapy against supportive care alone (p = 0.174).Our study identified clinical, radiologic, and treatment features that may hold prognostic value for children with BBE. The role of immunotherapy remains under investigation but may prove of utility with further, randomized controlled studies in this rare disease.
View details for DOI 10.1007/s00415-017-8684-8
View details for Web of Science ID 000419777000019
View details for PubMedID 29177548
Abstract
To compare cerebral perfusion and diffusion in survivors of childhood posterior fossa brain tumor with neurologically normal controls and correlate differences with cognitive dysfunction.We analyzed retrospectively arterial spin-labeled cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) in 21 patients with medulloblastoma (MB), 18 patients with pilocytic astrocytoma (PA), and 64 neurologically normal children. We generated ANCOVA models to evaluate treatment effects on the cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, and cerebral white matter at time points an average of 5.7 years after original diagnosis. A retrospective review of patient charts identified 12 patients with neurocognitive data and in whom the relationship between IQ and magnetic resonance imaging variables was assessed for each brain structure.Patients with MB (all treated with surgery, chemotherapy, and radiation) had significantly lower global CBF relative to controls (10%-23% lower, varying by anatomic region, all adjusted P < .05), whereas patients with PA (all treated with surgery alone) had normal CBF. ADC was decreased specifically in the hippocampus and amygdala of patients with MB and within the amygdala of patients with PA but otherwise remained normal after therapy. In the patients with tumor previously evaluated for IQ, regional ADC, but not CBF, correlated with IQ (R(2) = 0.33-0.75).The treatment for MB, but not PA, was associated with globally reduced CBF. Treatment in both tumor types was associated with diffusion abnormalities of the mesial temporal lobe structures. Despite significant perfusion abnormalities in patients with MB, diffusion, but not perfusion, correlated with cognitive outcomes.
View details for DOI 10.1016/j.jpeds.2017.01.019
View details for PubMedID 28187964
Abstract
BACKGROUND AND PURPOSE:Neurofibromatosis type 1 is associated with increased risk for stroke, cerebral vasculopathy, and neurocognitive deficits, but underlying hemodynamic changes in asymptomatic children remain poorly understood. We hypothesized that children with neurofibromatosis type 1 have decreased cerebral blood flow.MATERIALS AND METHODS:Arterial spin-labeled CBF was measured in 14 children with neurofibromatosis type 1 (median age, 9.7 years; mean, 10.2 years; range, 22 months to 18 years) and compared with age-matched control subjects on 3T MR imaging. Three-dimensional pseudocontinuous spin-echo arterial spin-labeled technique was used. Measurements were obtained at cortical gray matter of bilateral cerebral hemispheres and centrum semiovale by use of the ROI method. Comparison by Mann-Whitney test was used, with Bonferroni-adjusted P values ≤.004 judged as significant.RESULTS:We identified 7 of 12 areas with significantly diminished arterial spin-labeled CBF in patients with neurofibromatosis type 1 compared with control subjects. These areas included the anterior cingulate gyrus (P = .001), medial frontal cortex (P = .004), centrum semiovale (P = .004), temporo-occipital cortex (P = .002), thalamus (P = .001), posterior cingulate gyrus (P = .002), and occipital cortex (P = .001). Among patients with neurofibromatosis type 1, there were no significant differences in these regions on the basis of the presence of neurofibromatosis type 1 spots or neurocognitive deficits.CONCLUSIONS:Reduced cerebral perfusion was seen in children with neurofibromatosis type 1, particularly in the posterior circulation and the vascular borderzones of the middle and posterior cerebral arteries.
View details for DOI 10.3174/ajnr.A3649
View details for Web of Science ID 000329848800034
View details for PubMedID 23764727
Abstract
Embryonal tumors are an aggressive subtype of high-grade, pediatric central nervous system (CNS) tumors often with dismal survival rates. The 5-year survival for highest-risk embryonal tumors may be as low as 10 %. We report feasibility and efficacy from our experience using intravenous (IV) cyclophosphamide concurrently with craniospinal radiation (CSI) in high-risk embryonal CNS tumors of childhood. Ten consecutive children (aged: 3.5-15.5 years, median: 10.2 years, six male) with high-risk embryonal tumors, including: large cell/anaplastic medulloblastoma (6), atypical teratoid rhabdoid tumor (1), and leptomeningeal primitive neuroectodermal tumor (3), were treated with IV cyclophosphamide 1 g/M(2) on days 1 and 2 of CSI. Following a median of 36 Gy CSI plus tumor boosts, adjuvant treatment consisted of 21 doses of oral etoposide (7) and alkylator based chemotherapy from five to eight cycles in all. Of the ten patients thus treated, six remain alive with no evidence of disease and four are deceased. Median survival was 3.3 years, with a 3-year progression-free survival of 50 % (5/10). Median follow-up was: 3.3 years (range: 5 months-12.9 years) in the five patients with progression, median time-to-progression was: 1.3 years (range: 1 month-3 years). Median follow-up in the patients without progression is 8.8 years (range: 3-12.9 years). Complications due to adjuvant chemotherapy were typical and included myelosupression (10), necessitating shortened duration of chemotherapy in three, and hemorrhagic cystitis (1). In high-risk embryonal CNS tumors, cyclophosphamide given concurrently with CSI is well tolerated. Early results suggest that a phase II trial is warranted.
View details for DOI 10.1007/s11060-012-0969-2
View details for Web of Science ID 000311208100017
View details for PubMedID 22941430
Abstract
The purposes of this study were to determine the incidence of neurovascular events as late complications in pediatric patients with brain tumor and to evaluate radiation as a risk factor.Patients were ascertained using the tumor database of a pediatric tertiary care center. Included patients had a primary brain tumor, age birth to 21 years, initial treatment January 1, 1993, to December 31, 2002, and at least 2 visits with neuro-oncology. Radiation exposure included: whole brain, whole brain plus a focal boost, or focal brain. The primary outcome was stroke or transient ischemic attack.Of 431 subjects, 14 had 19 events of stroke or transient ischemic attack over a median follow-up of 6.3 years. The incidence rate was 548/100 000 person-years. Overall, 61.5% of subjects received radiation, including 13 of 14 subjects with events. Median time from first radiation to first event was 4.9 years. The stroke/transient ischemic attack hazard ratio for any brain irradiation was 8.0 (95% CI, 1.05-62; P=0.045); for the circle of Willis, radiation was 9.0 (95% CI, 1.2-70; P=0.035); and for focal noncircle of Willis, radiation was 3.4 (95% CI, 0.21-55; P=0.38).The incidence of neurovascular events in this population is 100-fold higher than in the general pediatric population and cranial irradiation is an important risk factor. By defining the incidence of this late effect, physicians are better able to counsel parents regarding treatment, monitor patients at risk, and target a population for primary stroke prevention in future studies.
View details for DOI 10.1161/STROKEAHA.112.661561
View details for Web of Science ID 000310432800296
View details for PubMedID 22968468
View details for PubMedCentralID PMC3492057
Abstract
OPINION STATEMENT: Rates of regrowth after resection of subependymal giant cell astrocytoma (SEGA) are low, making surgical resection a successful and permanent therapeutic strategy. In addition to surgical resection of SEGAs, other treatment options now include medications and Gamma Knife™ therapy. Advising patients on medical versus surgical management of SEGAs is currently not easy. SEGAs have been reported to regrow if mTOR inhibitor therapy is stopped, raising the possibility that long-term medication may be required to prevent tumor growth and hydrocephalus. The question of regrowth following medication withdrawal will need to be addressed in more patients to help establish the optimal duration of therapy. The risks of surgery include acute morbidity and the permanent need for ventriculoperitoneal shunting, which must be balanced against the adverse effects of mTOR inhibitors, including immunosuppression (infections, mouth sores), hypercholesterolemia, and the need for chronic drug monitoring. Some additional benefits of mTOR inhibition in patients with tuberous sclerosis complex, however, may include shrinkage of angiofibromas and angiomyolipomas as well as a possible decrease in seizure burden. Recent reports of successful nonsurgical treatment of SEGAs are promising, and it is hoped that further specifics on dosing, duration, and long-term outcome will help patients and physicians to make informed therapeutic choices.Present treatment recommendations for SEGAs include routine surveillance neuroimaging and close clinical follow-up, paying particular attention to signs and symptoms of acute hydrocephalus. If symptoms arise, or if serial neuroimaging demonstrates tumor growth, neurosurgical intervention is recommended. When gross total resection is impossible, rapamycin and everolimus should be considered, but may not offer a durable response.
View details for DOI 10.1007/s11940-011-0123-z
View details for Web of Science ID 000292402500005
View details for PubMedID 21465222
View details for PubMedCentralID PMC3130084
