Social Experiences of Turkish Parents Raising a Child With Apert Syndrome: A Qualitative Study.

OBJECTIVE: Apert syndrome is a rare and understudied craniofacial condition with regard to its psychosocial impact on children and their parents. Due to the lack of studies focusing solely on the social experiences of children and families with Apert syndrome, it is difficult to develop interventions and strategies to support well-being and positive adjustment for this particular population. This study addressed this gap by assessing the unique social experiences of parents who are raising their children with Apert syndrome including difficulties they face and strategies they use to cope with challenges. DESIGN: Descriptive qualitative study using thematic analysis. PARTICIPANTS: Participants included 21 parents of 12 children (aged 1-12 years) with Apert syndrome (9 couples, 2 fathers, and 1 mother) who were recruited from a pediatric neurosurgery unit in Turkey. RESULTS: The qualitative analysis yielded four main themes describing the experiences of parents including (1) social challenges; (2) coping with negative reactions; (3) promoting socialization and independence; and (4) sources of strength. CONCLUSIONS: Parents reported several challenges, including social stigmatization, and utilized a range of strategies to support both their own and their child's positive adaptation and resiliency, including the use of religion and reliance on their spouses for support. Results offer clinically relevant insights about the strengths and challenges of families coping with Apert syndrome.

Intraoperative Neuromonitoring of Motor-Evoked Potentials in Infants Undergoing Surgery of the Spine and Spinal Cord.

PURPOSE: The aim of this single-center prospective cohort study is to record reliable transcranial motor-evoked potentials (TcMEPs) and to determine their thresholds under inhalational anesthesia in infants undergoing spine and spinal cord surgery. METHODS: A total of 15 infants (age <12 months) with mean (SD) months: 5.82 ± 3.45 were included. The entry criteria were that the child should be no older than 1 year of age and undergoing a surgical procedure at the conus-cauda region. The patients were monitored with motor-evoked potentials (TcMEPs) and bulbocavernosus reflex. RESULTS: Transcranial motor-evoked potentials were recorded in all the patients in both upper and lower extremities in one muscle at least. All patients were monitored with a mean TcMEP threshold of 488.46 ± 99.76 V (range 310-740 V). The lowest threshold of TcMEPs was used to record the musculus abductor pollicis brevis mean of 315.15 ± 126.95 V (range 140-690 V) and the highest for musculus sphincter ani mean of 444.17 ± 138.54 V (range 206-700 V). CONCLUSIONS: Intraoperative neuromonitoring for spine and spinal cord procedures of the infant population requires higher TcMEP thresholds and train count. Most patients aged older than 6 months require significantly lower TcMEPs.

The Acute and Delayed Effects of Vagal Nerve Stimulation on an Absence Epilepsy Model in WAG/Rij.

AIM: Vagal nerve stimulation (VNS) is an effective method of treatment for epilepsy patients either unresponsive to medical therapy or not suitable for resective surgeries. We designed an experimental study on Wistar Albino Glaxo rats from Rijswijk (WAGRij) to investigate the effects of VNS on a non-convulsive epilepsy model. MATERIAL AND METHODS: The experiment was performed on six WAG/Rij rats, a validated strain for genetic absence seizures. The animals were underwent VNS and the effects were investigated on electroencephalography (EEG) recordings at 22, 24, 26 hours of stimulation and 15 days after the cessation, for duration of spike and wave complexes (SWC), the numbers, mean duration of SWC and frequencies in an hour. RESULTS: EEG recordings demonstrated that the mean duration of SWC was 353.1 seconds and the number of activity per hour was 62 at the baseline. There were statistically significant decreases in the total duration of SWC and the number of activities (61.8% and 78% decrease, respectively). There were no significant decreases in the mean duration of SWC and the frequencies. CONCLUSION: The acute stimulation of the vagal nerve caused a statistically significant decrease both in overall duration of SWC and the number of complexes in an hour. Moreover, the positive effects seemed to last even 15 days after the cessation of the stimulation. Further studies focusing on different stimulation parameters and delayed effects of the VNS on human absence seizures are warranted.

Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype.

BACKGROUND: Pediatric low-grade gliomas (PLGGs), the most frequent pediatric brain tumor, comprise a heterogeneous group of diseases. Recent genomic analyses suggest that these tumors are mostly driven by mitogene-activated protein kinase (MAPK) pathway alterations. However, little is known about the molecular characteristics inherent to their clinical and histological heterogeneity. METHODS: We performed gene expression profiling on 151 paraffin-embedded PLGGs from different locations, ages, and histologies. Using unsupervised and supervised analyses, we compared molecular features with age, location, histology, and BRAF genomic status. We compared molecular differences with normal pediatric brain expression profiles to observe whether those patterns were mirrored in normal brain. RESULTS: Unsupervised clustering distinguished 3 molecular groups that correlated with location in the brain and histological subtype. "Not otherwise specified" (NOS) tumors did not constitute a unified class. Supratentorial pilocytic astrocytomas (PAs) were significantly enriched with genes involved in pathways related to inflammatory activity compared with infratentorial tumors. Differences based on tumor location were not mirrored in location-dependent differences in expression within normal brain tissue. We identified significant differences between supratentorial PAs and diffuse astrocytomas as well as between supratentorial PAs and dysembryoplastic neuroepithelial tumors but not between supratentorial PAs and gangliogliomas. Similar expression patterns were observed between childhood and adolescent PAs. We identified differences between BRAF-duplicated and V600E-mutated tumors but not between primary and recurrent PLGGs. CONCLUSION: Expression profiling of PLGGs reveals significant differences associated with tumor location, histology, and BRAF genomic status. Supratentorial PAs, in particular, are enriched in inflammatory pathways that appear to be tumor-related.

DNA fragmentation simulation method (FSM) and fragment size matching improve aCGH performance of FFPE tissues.

Whole-genome copy number analysis platforms, such as array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays, are transformative research discovery tools. In cancer, the identification of genomic aberrations with these approaches has generated important diagnostic and prognostic markers, and critical therapeutic targets. While robust for basic research studies, reliable whole-genome copy number analysis has been unsuccessful in routine clinical practice due to a number of technical limitations. Most important, aCGH results have been suboptimal because of the poor integrity of DNA derived from formalin-fixed paraffin-embedded (FFPE) tissues. Using self-hybridizations of a single DNA sample we observed that aCGH performance is significantly improved by accurate DNA size determination and the matching of test and reference DNA samples so that both possess similar fragment sizes. Based on this observation, we developed a novel DNA fragmentation simulation method (FSM) that allows customized tailoring of the fragment sizes of test and reference samples, thereby lowering array failure rates. To validate our methods, we combined FSM with Universal Linkage System (ULS) labeling to study a cohort of 200 tumor samples using Agilent 1 M feature arrays. Results from FFPE samples were equivalent to results from fresh samples and those available through the glioblastoma Cancer Genome Atlas (TCGA). This study demonstrates that rigorous control of DNA fragment size improves aCGH performance. This methodological advance will permit the routine analysis of FFPE tumor samples for clinical trials and in daily clinical practice.

The value of sacral skin lesions in predicting occult spinal dysraphism in children with voiding dysfunction and normal neurological examination.

OBJECTIVE: The role of magnetic resonance imaging (MRI) in detecting occult spinal dysraphism (OSD) in children with voiding dysfunction and a normal neurological examination is still under debate. The aim of this study was to assess the correlation of sacral skin lesions with OSD detected on MRI, in a population of children with resistant lower urinary tract symptoms (LUTS). PATIENTS AND METHODS: A total of 114 children over 5 years of age with urinary tract infection (UTI) and/or LUTS and normal neurological examination were enrolled. All children underwent sacral neurological examination, urine analysis and cultures, renal/bladder ultrasound, voiding cystourethrogram and urodynamic examination. After a treatment period of 6 months, the patients were re-evaluated and spinal MRI was performed in 61 with ongoing LUTS or UTI. RESULTS: Nineteen of 61 children (31%) had cutaneous stigmas. MRI detected spinal abnormality in 2/42 children with a normal sacral examination in comparison to 7/19 children with an abnormal sacral finding (Chi-squared test, P < 0.005). The sensitivity and specificity of an abnormal sacral finding in predicting MRI abnormality were 0.76 and 0.77, respectively. Urodynamic parameters did not predict an abnormal spinal MRI. CONCLUSIONS: Abnormal sacral findings, but not urodynamic studies, are strong predictors of OSD. A normal sacral examination does not rule out OSD.

Ictal electrocardiographic changes in children presenting with seizures.

BACKGROUND: The aim of this study was to determine electrocardiographic changes in children during seizures. METHODS: We assessed heart rate changes, RR intervals and QT changes during 47 seizures in children. Consecutive QT and RR intervals were measured for 60 s before the seizures, during the seizures and 60 s after the seizures during video electroencephalography monitoring. RESULTS: There were 47 seizures in 18 patients. Five patients had generalized seizures and 13 patients had focal seizures. Twelve patients were male. The mean age during monitoring was 10.1 years (range 4 months-19 years). Ictal tachycardia was seen in every seizure. No ictal bradycardia was noted. There was only one dropped beat in a patient. The mean ictal heart-rate-corrected QT (QTc) interval was significantly higher than the postictal measurements (P= 0.005). Mean ictal QTc variation tended to increase during seizures and then decreased below the pre-ictal measurements in the postictal period. However these changes were statistically insignificant (P > 0.05). RR variance was significantly decreased during seizures compared to the postictal period and the standard deviation of the RR intervals was significantly decreased in the ictal period compared to the pre-ictal period (P= 0.014 and P= 0.001, respectively). CONCLUSION: Tachycardia is the main finding in seizures in children. Ictal bradycardia and cardiac arrhythmias are very rare despite being more frequent in adults with seizures.

Detection of KIAA1549-BRAF fusion transcripts in formalin-fixed paraffin-embedded pediatric low-grade gliomas.

Alterations of BRAF are the most common known genetic aberrations in pediatric gliomas. They frequently are found in pilocytic astrocytomas, where genomic duplications involving BRAF and the poorly characterized gene KIAA1549 create fusion proteins with constitutive B-Raf kinase activity. BRAF V600E point mutations are less common and generally occur in nonpilocytic tumors. The development of BRAF inhibitors as drugs has created an urgent need for robust clinical assays to identify activating lesions in BRAF. KIAA1549-BRAF fusion transcripts have been detected in frozen tissue, however, methods for FFPE tissue have not been reported. We developed a panel of FFPE-compatible quantitative RT-PCR assays for the most common KIAA1549-BRAF fusion transcripts. Application of these assays to a collection of 51 low-grade pediatric gliomas showed 97% sensitivity and 91% specificity compared with fluorescence in situ hybridization or array comparative genomic hybridization. In parallel, we assayed samples for the presence of the BRAF V600E mutation by PCR pyrosequencing. The data further support previous observations that these two alterations of the BRAF, KIAA1549 fusions and V600E point mutations, are associated primarily with pilocytic astrocytomas and nonpilocytic gliomas, respectively. These results show that fusion transcripts and mutations can be detected reliably in standard FFPE specimens and may be useful for incorporation into future studies of pediatric gliomas in basic science or clinical trials.

Basal ganglia location of subependymal giant cell astrocytomas in two infants.

Subependymal giant cell astrocytomas are benign tumors that constitute one of the primary features of tuberous sclerosis. Two infants with tuberous sclerosis had very unusual subependymal giant cell astrocytomas, confirmed on biopsy in one of the infants. In both cases, contrast-enhanced cranial magnetic resonance imaging suggested a calcified intra-axial mass with diffuse basal ganglia involvement extending into the lateral ventricle. Computed tomography confirmed calcification in both cases. The first patient had right temporal lobectomy for intractable epilepsy. Biopsy of the basal ganglia lesion in that case suggested subependymal giant cell astrocytoma. In infants, subependymal giant cell astrocytomas can present with unusual morphology and may feature diffuse basal ganglia involvement and severe calcification.

Microvessel density and vascular endothelial growth factor expression as predictors of childrens' survival from cerebellar medulloblastoma.

Cerebellar medulloblastoma is the most common malignant brain tumor of childhood. This neoplasm is highly vascular and has a high growth rate. We aimed to determine whether high microvessel density (MVD) and expression of vascular endothelial growth factor (VEGF) in medulloblastoma tissue is correlated with survival time in children with this tumor. Tissue from 32 cerebellar medulloblastomas in 14 girls and 18 boys was studied. The standard-risk group comprised patients older than 3 years, without metastases of medulloblastoma and a residual post-operative tumor with a surface area less than 1.5 cm(2). The patients assigned to a high-risk group had at least one of the following indicators: younger than 3 years, metastases, or a residual post-operative tumor with a surface area larger than 1.5 cm(2). For each tumor, MVD was determined and the expression of VEGF was assessed using immunohistochemical techniques. The 5-year survival rate for the 32 patients was 56.2%. Five-year survival rates were 70.6% and 40.0% for patients in the standard-risk and high-risk groups, respectively. The mean (+/-standard deviation, SD) MVD for all patients was 22.0+/-9.1 microvessels per 0.7 mm(2). There was no difference in the survival rate between the groups with above-average MVD and below-average MVD (66.7% and 50.0%, respectively). Testing revealed 7 tumors with VEGF expression and 25 without. The 5-year survival rates for these 2 groups were not significantly different (57.1% vs. 56.0%, respectively). The mean (+/-SD) MVD values for the VEGF-positive and VEGF-negative groups were not significantly different (19.1+/-6.5 vs. 22.9+/-9.7 microvessels per 0.7 mm(2), respectively, Mann-Whitney U-test=78.5, Z=-0.41, p=0.68). There were no significant correlations between risk groups and expression of VEGF or MVD. These results indicate that neither high MVD nor the expression of VEGF in tumor tissue predicts poor prognosis in children with cerebellar medulloblastoma.

Prevention of brisk hyperactive response during selective dorsal rhizotomy in children with spasticity: isoflurane versus sevoflurane maintenance anesthesia.

In children with spasticity, deep tendon reflexes are hyperactive and even stimulation of normal dorsal rootlets can produce exaggerated full-strength, single-twitch responses in the muscles they innervate. This phenomenon is called the brisk hyperactive response (BHR). The aim of this study was to compare the efficacy of 2 volatile anesthetics, isoflurane and sevoflurane, for suppressing the confounding effect of BHR during selective dorsal rhizotomy (SDR) in children with spasticity. The subjects were 54 consecutive children of American Society of Anesthesiology physical status III who were scheduled for SDR. After tracheal intubation, each child was randomly assigned to Group I (isoflurane; n=27) or Group S (sevoflurane; n=27). There was no significant difference between the mean operation times in Groups I and S (200+/-40 vs. 220+/-35 minutes, respectively; p=0.0559). Thirteen patients in Group I (48.1%) and 5 in Group S (18.5%) exhibited BHR during stimulation of the dorsal rootlets (odds ratio 4.086; p=0.0418). Three of these 18 patients (2 in Group I and 1 in Group S) experienced hypertension and tachycardia simultaneously with BHR (odds ratio 4.086; p=1.0). The results suggest that sevoflurane is more effective at preventing BHR and might be a better choice for anesthetic management of children with spasticity undergoing SDR.

Deep brain stimulation for Holmes' tremor related to a thalamic abscess.

BACKGROUND: Medical treatment is usually ineffective for Holmes' tremor, and surgery is the treatment of choice for many patients. Here we report the case of a 14-year-old girl who developed Holmes' tremor related to a thalamic abscess and was successfully treated with thalamic deep brain stimulation. CASE REPORT: The patient presented with left hemiparesis and headache and was hospitalized. Investigation revealed a thalamic abscess in the left cerebral hemisphere. The abscess was drained via stereotactic surgery and a course of antibiotic treatment was completed. Four months after treatment, the patient developed Holmes' tremor in her left upper extremity. When attempts at medical treatment with levodopa, clonazepam, and trihexyphenidyl all failed, an implant was placed and deep brain stimulation of the ventral intermediate nucleus of the thalamus was initiated. During 2.5 years of follow-up, her tremor diminished by 90%. CONCLUSION: This case demonstrates that medically resistant Holmes' tremor related to a thalamic lesion can be successfully treated with thalamic deep brain stimulation.

Primary meningeal osteosarcoma of the brain during childhood. Case report.

Primary meningeal osteosarcomas are rare tumors, with only 19 reported cases in the literature; only 4 of these, including the present case, are in pediatric patients. In this report, the authors present the case of an 8-year-old boy with a history of generalized tonic-clonic seizures who was found to harbor a meningeal osteosarcoma within the sylvian fissure. Initial working diagnoses included meningioma and glioma. After tumor enlargement and progressive symptoms, the patient underwent a large frontotemporal craniotomy and complete resection of the lesion, which recurred 6 and 12 months after the initial surgery and was surgically treated after each recurrence. The rarity of primary meningeal osteosarcomas can make their diagnosis difficult, and histopathological evaluation is mandatory for diagnosis. Because of their fast progression, they must be treated aggressively by means of surgery, chemotherapy, and radiotherapy.

Is the brain biopsy obligatory or not for the diagnosis of Schilder's disease? Review of the literature.

BACKGROUND: Schilder's myelinoclastic diffuse sclerosis (Schilder's disease) is a rare demyelinating disorder. Clinical features and neuroimaging findings of this disease might mimic an intra-cranial mass lesion including an abscess or a tumour. CASE REPORT: Clinical and radiological findings of two children with the diagnosis of Shilder's disease are reported, and the role of brain biopsy as a diagnostic tool is discussed.

New candidate chromosomal regions for chordoma development.

BACKGROUND: Chordomas are rare, slow growing, infiltrative tumors thought to arise from vestigial or ectopic notochord. Chordoma can occur along the axial skeleton, predominantly in the sphenooccipital, vertebral, and sacrococcygeal regions. Although most chordomas are sporadic, familial cases have also been reported. The most common molecular cytogenetic abnormalities in these tumors are monosomy of chromosome 1 and gain of chromosome 7. In addition, a variety of other chromosomal changes, which are associated with losses and gains of different chromosomes, have also been described in chordomas, such as 1q, 2p, 3p, 5q, 9p, 10, 12q, 13q, 17, and 20q. METHODS: In this study, using molecular cytogenetics (iFISH), we have studied 1p36, 1q25, 3p13-p14, 7q33, 17p13.1 (p53 gene locus), 2p13 (TGF-alpha locus), 6p12 (VEGF locus), and 4q26-q27 (bFGF/FGF2 locus) loci in chordoma tissues from seven patients with 7 primary tumors and 11 recurrences. RESULTS: We found that chromosomes 1p36, 1q25, 2p13, and 7q33 are affected in primary chordomas, and these aberrations persist in recurrences. However, the chromosome 6p12 aberration was seen only in primary chordomas, but not in recurrences, indicating that this locus may be associated with chordoma genesis. CONCLUSIONS: Our descriptive data from interphase FISH analyses suggest that future studies should incorporate a larger number of patients and should focus on identifying the candidate genes in chordoma pathogenesis. Such studies may use a whole-genomic approach, in addition to the regions identified in this study and others.

Atypical midline cleft with duplication of the metopic suture.

INTRODUCTION: In contrast to the common clefts of the lip, alveolus and palate, the atypical clefts of the face may come in myriad patterns of clinical expression and are often not easy to define. PURPOSE: In this report, a case of median craniofacial dysraphia is described. PATIENT: At presentation, the 3-month-old male patient had a bilateral complete cleft of the lip, alveolus and palate. The nose was wide and a horn was present on the nasal dorsum. 3-D CT AND MRI REVEALED: Duplication of the metopic suture ending at the wide anterior fontanel; orbital hypertelorism; midline cranial cleft ending just superior to the nasal dorsum; frontoethmoidal encephalocoele and holoprosencephaly. The presence of two metopic sutures was confirmed during surgery. CONCLUSION: The presented case carries the characteristics of the median cleft face syndrome. However, it differs from similar cases in two respects. First, the patient had two metopic sutures, one on either side of the cranial extension of the median cleft. Second, the patient had a bilateral cleft lip in contrast to the expected median cleft lip deformity.

Surgical treatment of polymicrogyria with advanced radiologic and neurophysiologic techniques.

INTRODUCTION: Coexistence of multiple seizure types, inclusion of the motor cortex in the epileptogenic zone, and poor delimitation of the abnormal cortex make most patients with polymicrogyria (PMG) unlikely candidates for epilepsy surgery (Guerrini R et al., Epilepsy and malformations of the cerebral cortex in Epileptic syndromes in infancy, childhood and adolescence, 2005). CASE REPORT: We present here a child with frontal PMG and intractable epilepsy evaluated with advanced magnetic resonance imaging (MRI) and neurophysiologic techniques. Diffusion tensor imaging and fiber tractography showed severe involvement of neighboring white matter tracts besides the cortex. The evaluation also included functional MRI, chronic subdural electroencephalogram monitoring, and intra-operative motor mapping. The patient had a decrease in seizure frequency and an increase in his developmental skills after the surgery. CONCLUSION: Advanced neuroradiologic and neurophysiologic techniques are required to provide an effective and safe resection of the epileptogenic cortex in cortical dysplasias.

Are myelodysplastic children receiving sufficient health care in Turkey? An analysis of the problems in primary management and their impact on neuro-urological outcome.

OBJECTIVE: To investigate the problems in the primary care of children with spina bifida and to analyze their impact on neuro-urological outcome in Turkey. Information from mothers about the disease, difficulties in getting medical services, availability and efficacy of prenatal ultrasound, and folic acid intake was also assessed. PATIENTS: A retrospective review of 476 children registered in the pediatric urology section of our institutional multidisciplinary spina bifida clinic between 1996 and 2005 was made. All children were assessed for the time of primary repair, time to first neuro-urological visit, and compliance to follow up. A phone interview was made with 166 mothers to obtain data regarding their educational status, supplementary folic acid intake before/during gestation, compliance to obstetric follow up, prenatal diagnosis and counseling, information about the importance of neuro-urological surveillance, and difficulties in neuro-urological follow up. RESULTS: Two-thirds of the mothers had an educational status of elementary school or lower. Phone interviews revealed inadequate obstetric follow up in 42% and a low prenatal diagnosis rate (49%) in those under regular follow up. Chart review revealed a significant delay in timing of primary surgical closure (mean 3 months and 2.9 years for open and closed lesions, respectively) and first neuro-urological follow-up visit (mean 1.8 years and 9.7 months after primary repair for open and occult lesions, respectively). Reasons for delayed closure were misguided advice of the nurse/midwife involved in delivery and inability to obtain tertiary health care. Socioeconomic inadequacy of the families and inefficacy of the health insurance system were the most important factors impairing follow up. CONCLUSIONS: Serious problems exist in the prevention, prenatal diagnosis and primary management of children with myelodysplasia in Turkey. As a consequence, neuro-urological follow up starts relatively late, which adversely affects the urological prognosis.

Does surgical release of secondary spinal cord tethering improve the prognosis of neurogenic bladder in children with myelomeningocele?

PURPOSE: The diagnostic criteria for secondary tethering of the spinal cord in children with prior closure of an open spinal defect are not well defined. Urological, neurological or orthopedic deterioration during followup remains the only strong indicator for the diagnosis of this condition. However, the outcome of untethering surgery cannot always be predicted. The aim of this study was to determine neurourological outcome after secondary untethering surgery in children with myelomeningocele. MATERIALS AND METHODS: Of 401 children with myelomeningocele followed at our multidisciplinary spina bifida clinic between 1996 and 2005, 56 (14%) were diagnosed with secondary tethering of the spinal cord (median age at diagnosis 4.1 years). The diagnosis was based on urological and neuro-orthopedic deterioration in 58% and 42% of children, respectively. Preoperative urological findings were compared with 6-month postoperative findings. RESULTS: Febrile urinary tract infection, upper tract dilatation and vesicoureteral reflux were preoperatively documented in 48.2%, 19% and 30% of the 56 children, respectively. At 6 months postoperatively urine cultures were sterile in 34% of patients and upper tract dilatation completely resolved in 45%. For all grades of vesicoureteral reflux complete resolution occurred in 47% of patients. Urodynamic parameters in terms of cystometric bladder capacity and detrusor leak point pressure substantially improved 6 months after untethering surgery (125 vs 170 ml and 69.1 vs 47.5 cm H2O, respectively, p < 0.05). Assessment of urodynamic findings in 19 children at 1 year failed to demonstrate a significant change in these parameters. A subgroup analysis according to patient age at untethering surgery revealed urodynamic improvement was more significant in children who were diagnosed and treated before age 7 years. CONCLUSIONS: Secondary tethering of the spinal cord is a major risk factor for urological and neurological deterioration in children with myelomeningocele. Close urological surveillance remains the most valuable tool in the early diagnosis. Our study shows that secondary untethering surgery may significantly improve urological outcome.