On-site CAD templates reduce surgery time for complex craniostenosis repair in infants: a new method.

INTRODUCTION: The surgical correction of craniostenosis in children is a time-consuming and taxing procedure. To facilitate this procedure, especially in infants with complex craniostenosis, we refined the computer-aided design and manufacturing technique (CAD/CAM) based on computed tomography (CT)-generated DICOM data. We used cutting guides and molding templates, which allowed the surgeon to reshape and fixate the supraorbital bar extracorporeally on a side table and to control the intracorporal fit without removing the template. METHOD AND PATIENTS: To compare our traditional concept with the possibility of preoperative virtual planning (PVP) technique, the surgical treatment and courses of 16 infants with complex craniostenosis following fronto-orbital advancement (FOA) (age range 8-15 months) were analyzed in two groups (group 1: traditional, control group n = 8, group 2: CAD/CAM planned, n = 8). RESULTS: While in both groups, the head accurately reshaped postoperatively during the follow-up; the CAD group 2 showed a significantly shorter operating time with a mean of 4 h 25 min compared with group 1 with a mean of 5 h 37 min (p = 0.038). Additionally, the CAD group 2 had a significantly lower volume of blood loss (380 ml vs. 575 ml mean, p = 0.047), lower blood transfusion volume (285 ml vs. 400 ml mean, p = 0.108), lower fresh frozen plasma (FFP) volume (140 ml vs. 275 ml mean, p = 0.019), shorter stay in the pediatric intensive care unit (PICU) (3 vs. 5 days mean (p = 0.002), and shorter total length of hospital stay (6 days vs. 8 days mean, p = 0.002). CONCLUSION: CAD/CAM cutting guides and templates offer optimizing operative efficiency, precision, and accuracy in craniostenosis surgery in infants. As shown in this single-center observational study, the use of on-site templates significantly accelerates the reconstruction of the bandeau. The virtual 3D planning technique increases surgical precision without discernible detrimental effects.

Optimized surgical treatment for normal pressure hydrocephalus: comparison between gravitational and differential pressure valves.

OBJECTIVES: In idiopathic normal pressure hydrocephalus (NPH) ventriculoperitoneal (VP) shunt insertion is the method of choice to improve cardinal symptoms such as gait disturbance, urge incontinence and/or dementia. With reduced compliance, the brain of the elderly is prone for overdrainage complications. This was especially true with the use of differential pressure valve implantation. The present study compares clinical outcome and complication rates after VP shunt insertion with differential pressure valves in the early years and gravitational valves since 2005. METHODS: The authors reviewed patients treated at our institution for NPH since 1995. Differential pressure valves were solely used in the initial years, while the treatment regimen changed to gravitational valves in 2005. Clinical improvement/surgical success rates as well as complications were compared between the two groups. RESULTS: Eighty-nine patients were enrolled for the present study. Mean age at the time of surgery was 73.5 ± 6.3 years. Male patients predominated with 73, compared with 16 female patients. Median follow-up time was 28 ± 26 months. Date of last follow-up was 1st October 2013. Forty-nine patients received a gravitational valve, while 40 were treated with differential pressure valves. In the gravitational group a significant improvement was observed after shunt insertion for gait disorder, cognitive impairment and urge incontinence (p < 0.0001, resp. p = 0.004), while a significant change in the differential pressure group was only seen for gait disorder (p = 0.03) but not for cognition or urinary incontinency (p > 0.05). The risk of hygroma as a sign of shunt overdrainage requiring surgical intervention was significantly higher in the differential pressure group (5 versus 0 in the gravitational group). CONCLUSIONS: Patients with NPH treated with gravitational valves in the present cohort showed a more profound improvement in their initial symptoms, including gait disorder, cognitive impairment and urinary incontinency without the risk of overdrainage complications requiring surgical intervention when compared with patients who received differential pressure valves in previous years.

[Hydrocephalus in childhood : causes and imaging patterns]. / Hydrozephalus im Kindesalter : Ursachen und bildmorphologische Darstellung.

CLINICAL ISSUE: Causes and imaging patterns of hydrocephalus differ depending on the age of the patient. Traditionally, hydrocephalus was classified into non-communicating and communicating hydrocephalus but more recent classifications also take the site of occlusion and the etiology into account. DIAGNOSTICS: For the diagnostic work-up computed tomography (CT), sonography and magnetic resonance imaging (MRI) are available and MRI is the method of choice for children and adolescents as it allows determination of the cause and location of a possible obstruction. In the first 12-18 months sonography allows evaluation of the lateral ventricles and the third ventricle and CT is usually only chosen in children in emergency situations and/or if no other modality is available. PERFORMANCE: We retrospectively evaluated a population of 785 children and adolescents (426 males aged 0-17 years) referred for MRI between April 2009 and March 2012 due to headaches, somnolence, concentration difficulties or developmental delay. Among these 80 (49 male) met the MRI criteria for hydrocephalus, 75 (46 male) had non-communicating hydrocephalus and 5 (3 male) communicating hydrocephalus. Of the patients 24 (15 male) had posthemorrhagic aqueductal stenosis, 16 (8 male) intracranial tumors, 9 (6 male) Chiari II malformations, 5 (4 male) other congenital malformations including malformations of the Dandy Walker spectrum, 9 (3 male) idiopathic aqueductal stenosis, 7 (5 male) arachnoidal cysts and 10 (8 male) other disorders, such as post-infections, macrocephaly cutis marmorata telangiectatica congenita (M-CMTC) syndrome, mesencephalic arteriovenous malformation (AVM), Langerhans cell histiocystosis. PRACTICAL RECOMMENDATIONS: It is important to take the age of the patient and the imaging pattern into account and to exclude tumors when reporting MR images of children with hydrocephalus.

Congruence and discrepancy of interictal and ictal EEG with MRI lesions in focal epilepsies.

OBJECTIVE: To compare the occurrence and localization of interictal epileptiform discharges (IEDs) and epileptic seizure patterns (ESPs) with the localization of MRI lesions. METHODS: We retrospectively analyzed the EEG and MRI data of a series of patients with focal epilepsies that had been studied from 1991 to 2009. RESULTS: In patients with temporal lesions, the localization of IEDs was most congruent (58.6% with IEDs exclusively over the lesional lobe and 29.7% with a majority of temporal IEDs). This differed (p < 0.001) from frontal lesions (27.5% with exclusively frontal IEDs, 24.6% with a majority of frontal IEDs). In parieto-occipital lobe lesions, only 12.1% had IEDs exclusively over the lesional lobe compared to 48.5% with no parieto-occipital IEDs at all. Patients with central lesions often lacked any IEDs (54.5%, p < 0.001). The occurrence and localization of ESPs also differed between the regions. They were most congruent in temporal lesions (63.5% of patient had ESPs only over the lesional lobe, 23.4% had the majority of ESPs over the lesional lobe), which differed from frontal and parieto-occipital lesions (37.7% and 30.3% of patients with ESPs only over the lesional lobe). Patients with central lesions had ESPs very frequently only outside the lesional lobe (63.6%). Surgery outcome did not differ between the regions. CONCLUSIONS: The occurrence and localization of interictal and ictal EEG findings differs vastly for lesions in different brain regions. These findings should be used to carefully weigh the results from EEG studies particularly in patients with extratemporal epilepsies considered for epilepsy surgery.

Expression of BARHL1 in medulloblastoma is associated with prolonged survival in mice and humans.

Medulloblastoma is the most common malignant brain tumor in childhood, and development of targeted therapies is highly desired. Although the molecular mechanisms of malignant transformation are not fully understood, it is known that medulloblastomas may arise from cerebellar granule neuron precursors. The homeodomain transcription factor Barhl1 is known to regulate migration and survival of granule cell precursors, but its functional role in medulloblastoma is unknown. We show here that the expression of BARHL1 is significantly upregulated during human cerebellar development and in human medulloblastoma samples as compared with the normal adult cerebellum. We also detected high levels of Barhl1 expression in medulloblastomas of Math1-cre:SmoM2 mice, a mouse model for Sonic hedgehog-associated medulloblastomas that we developed previously. To investigate Barhl1 function in vivo during tumor development, we generated Barhl1(-/-)Math1-cre:SmoM2 mice. Interestingly, tumors that developed in these mice displayed increased mitotic activity and decreased neuronal differentiation. Moreover, survival of these mice was significantly decreased. Similarly, low expression of BARHL1 in human medulloblastoma cases was associated with a less favorable prognosis for patients. These results suggest that the expression of Barhl1 decelerates tumor growth both in human and in murine medulloblastomas and should be further investigated with respect to potential implications for individualized therapeutic strategies.

Decompensated hydrocephalus causing syringomyelia and tetraparesis: a case report.

OBJECTIVE: Various causes for the development of syringomelia are discussed. The influence of hydrocephalus upon syringomyelia is rarely reported and its role remains unclear. MATERIAL AND METHODS: We report a young female patient with shunt dysfunction and consequent syrinx development after child delivery. RESULTS: The patient showed rapid clinical deterioration after delivery. Treatment was shunt revision and reconstitution of CSF flow in the posterior fossa. After surgery, the patient showed regressive syringomyelia going along with a quick and pronounced clinical improvement. CONCLUSION: Development of syringomyelia can be caused by CSF flow disorders and hydrocephalus and may be aggravated by increased intra-abdominal pressure.

Reversible dementia and corresponding CSF alterations due to intraspinal lumbosacral metastasis of a prostate carcinoma.

We report, for the first time, how intraspinal carcinoma metastasis can cause reversible dementia accompanied by distinct cerebrospinal fluid (CSF) alterations. A 73-year-old male patient who suffered from rapidly progressive dementia and gait disturbance showed marked abnormalities of CSF tau protein, amyloid beta(1-42), and prostate-specific antigen. A lumbosacral, intraspinal metastasis from a prostate carcinoma was found, and after microsurgical removal, CSF alterations normalized and the clinical symptoms regressed. This case illustrates how malignant tumors can disturb brain function via indirect mechanisms.

Interstitial iodine-125 radiosurgery alone or in combination with microsurgery for pediatric patients with eloquently located low-grade glioma: a pilot study.

PURPOSE: The optimal therapeutic management of children with World Health Organization grade I and II gliomas not accessible to complete resection is poorly defined. Radical surgical resection is the first-line treatment for large hemispheric tumors, whereas interstitial iodine-125 radiosurgery (IRS) might be an attractive treatment concept for selected patients with small (tumor diameter in the range of 4 cm) and circumscribed tumors in any location of the brain. Precise high-dose application, maximal sparing of surrounding normal tissue, and the absence of long-term complications have been reported to be the hallmark of IRS. Therefore, the therapeutic impact and the risk of IRS alone or in combination with microsurgery (in case of larger tumor volumes) were prospectively examined. METHODS: Seven boys and four girls were included (mean age, 6.8 years; range, 11 months to 16 years). IRS (after stereotactic biopsy) was considered to be indicated for circumscribed tumors with a diameter in the range of 4 cm (four cases). For larger tumors, a combined microsurgical/radiosurgical approach was preferred (seven patients). Temporary iodine-125 seeds were used exclusively (tumor dose calculated to the boundary, 54 Gy; dose rate, 10 cGy/h). Tumor location was hypothalamic/suprasellar in four, lobar in three, deep (thalamus and pineal gland) in two, and within the brain stem in two children. Treatment effects of IRS were estimated according to the MacDonald criteria. RESULTS: A complete response after IRS was seen in four patients, and a partial response was seen in seven patients (median follow-up, 31.5 months). There was no perioperative morbidity after microsurgery and/or IRS, and no radiogenic complications occurred during the follow-up period. Five patients experienced an improvement in their deficits, and no deterioration in neurological/endocrine function was seen in any of the patients at the time of last follow-up evaluation. CONCLUSION: IRS alone or in combination with microsurgery (in the case of larger tumors) is a safe, effective, and minimally invasive treatment strategy for eloquently located pediatric low-grade gliomas and deserves further prospective evaluation.

Inducible expression of p57KIP2 inhibits glioma cell motility and invasion.

To examine the role of p57KIP2 in human malignant glioma cells, we studied its expression in a panel of human malignant glioma specimens by western blot and immunohistochemical analysis. To determine the effects of p57KIP2 expression on the phenotype of glioma cells, we analyzed two inducible stably transfected p57KIP2 expressing glioma cell lines. Expression of p57KIP2 was induced in U373 and U87 malignant glioma cells with doxycycline using the tetracycline repressor system. A phagokinetic track assay on gold particles was used to investigate differences in cell migration between p57KIP2 expressing and non-expressing control cells. The effects of the extracellular matrix (ECM) on U373 motility was determined in p57+ and p57-cells on surfaces coated with 5 microg/cm2 of fibronectin, laminin, type I and type IV collagens. The invasion of p57+ and p57- glioma cells across BD Biocoat Matrigel invasion chambers was then determined. p57KIP2 was weakly expressed in 4/6 glioblastoma (GBM) specimens by western blot. By immunohistochemistry, p57KIP2 immunoreactivity was positive in 8/40 GBMs, and was primarily nuclear in location. The motility of U373 glioma cells was significantly reduced after p57KIP2 induction. The presence of ECM proteins did not further alter the motility of p57+ and p57- glioma cells. The results of the invasion chamber assay showed that p57+ cells exhibited a 35% reduction in their invasive capacity as compared to p57- cells. These data suggest that p57KIP2 is expressed in at least some malignant gliomas. Inducible expression of 57KIP2 in cell lines deficient in this cyclin-dependent kinase inhibitor reduces their otility and invasiveness.

Fatal ethibloc embolization of vertebrobasilar system following percutaneous injection into aneurysmal bone cyst of the second cervical vertebra.

A 4-year-old boy developed progressive neck pain and an expansile osteogenic lesion of C2; the diagnosis was an aneurysmal bone cyst. An image-guided biopsy with 3D CT planning was performed followed by Ethibloc injection into the aneurysmal bone cyst. Subsequent CT and MR images demonstrated embolization material in the vertebrobasilar system, and the patient died of brain stem and cerebellar infarction 23 hours after the intervention. The course of events and technical considerations are discussed.

Recurrent spinal cord astrocytoma with intraventricular seeding.

PATIENT: We report on an unusual case of a recurrent and progressive spinal pilocytic astrocytoma with metastatic spreading to the hypothalamus in a 14-year-old boy. TREATMENT AND RESULTS: The patient underwent resection of an intramedullary atypical pilocytic astrocytoma classified as WHO grade II at the level of Th11/12 in 1997 and received local photon beam irradiation. Three years later, a second operation was necessary for a recurrent tumour at the same level. Seventeen months later, a second recurrent tumour with spinal seeding as well as an intracranial tumour in the third ventricle and hypothalamus was detected. He was shunted for an occlusive hydrocephalus and a stereotactic biopsy of the hypothalamic lesion was performed. The tumour was classified as anaplastic pilocytic astrocytoma (WHO grade III). He received chemotherapy with ifosfamide, cisplatin and etoposide (HIT-GBM-C-protocol), craniospinal radiation, and is still alive 60 months after the first operative intervention without neurological deficits.

Surgical resection of gliomas WHO grade II and III located in the opercular region.

BACKGROUND: Surgery in the opercular region especially in the dominant hemisphere impose a major challenge for the neurosurgeon due to the close vicinity to functional important motor and speech areas. The purpose of the present study is to analyse on a homogenous patient group pre- and postoperative functional deficits with regard to different speech qualities (e.g. aphasia, apraxia), and to correlate these data with MR and intraoperative monitoring results. METHOD: Fourteen patients with suspected low grade astrocytomas in the opercular region consecutively treated by surgery were eligible for this study (histology revealed 3 WHO grade III tumours). Degree and duration of postoperative deficits were retrospectively evaluated according to tumour location and boundaries on MR, intraoperative neuromonitoring results and extent of tumour resection. FINDINGS: Postoperatively, 8 patients showed speech or language disturbances, in 4 patients combined with motor deficits mainly of the contralateral upper extremity. Fifty percent of the neuropsychologically tested patients exhibited speech apraxia while the other 50% had a true aphasic syndrome. Recovery of the latter deficits was in general faster and more complete. The severity and duration of postoperative deficits was in good correlation with the distance of the resection margin to the next positive stimulation point(s), and a distance of more than 0.5 cm proved to avoid major impairments. The distribution of functional important stimulation points in relation to the tumour extension was not predictable, and -- unexpectedly -- up to 50% of these sites were found overlaying the tumour. INTERPRETATION: Surgery for WHO grade II and III gliomas in the opercular region can result in speech apraxia or an aphasic syndrome with or without concomitant motor deficits. Intraoperative cortical electrical stimulation is essential in resecting tumours in the opercular region to avoid permanent morbidity.

Rapid formation of a multi-compartment neonatal arachnoid cyst.

A 3-day-old term infant born via vaginal delivery presented with irritability and tachypnoea. Cranial ultrasound, CT and MRI demonstrated a massive left temporal arachnoid cyst extending into the anterior and posterior fossa as well as the suprasellar area. In utero ultrasounds at 9.5, 19 and 32 weeks of gestation had been normal. Endoscopic exploration revealed that all cyst components were communicating, and a cystoperitoneal shunt was inserted with rapid resolution of symptoms and cyst decompression. Arachnoid cysts may develop rapidly in utero and may not be associated with underlying brain hypoplasia. Attempts at rapid and maximum decompression may be reasonable in this setting.

Molecular genetic investigations in the CCM1 gene in sporadic cerebral cavernomas.

OBJECTIVE: Cerebral cavernous malformations (CCM) occur in familial and sporadic forms that cannot be distinguished by phenotype. Mutations in Krit1, a gene located at the CCM1 locus on chromosome 7q21, account for the majority of familial CCM cases. The authors investigated the role that mutations at the CCM1 locus play in sporadic cavernomas and the prevalence of occult familial forms among symptomatic cavernomas. METHODS: The authors screened the DNA of cavernomas and adjacent normal brain tissue of 72 consecutive patients treated at the Neurosurgical Department/Ludwig-Maximilian University for mutations in Krit1. Eight of the patients had been suspected to have a mutation at CCM1, as they showed multiple cavernomas or clinically familial forms. RESULTS: None of the patients showed a mutation at the CCM1 site, either in cavernomas or in normal brain tissue. CONCLUSION: Mutations in Krit1 are seldom a cause of sporadic cavernomas.

Invasiveness in vitro and biological markers in human primary glioblastomas.

Invasion of spheroids from 20 human primary glioblastomas into precultured fetal rat brain tissue in culture has been studied and quantified. Between 30 and 98 percent of the normal brain tissue was destroyed by invading glioma cells within 4 days. The degree of invasion did not correlate with patient survival. A slightly higher invasiveness and shorter survival was seen in tumors with EGF receptor overexpression, and the opposite pattern was found for tumors with a TP53 mutation. The degree of invasiveness in vitro was far higher than would be expected from the dynamics of clinically observed tumor spread. This suggests that mechanisms suppressing invasion may be operative in the normal brain; alternatively the differences may be due to a higher permissiveness of the fetal brain tissue for invasion in vitro.

A case history of glioma progression.

Low-grade diffuse astrocytomas have an intrinsic tendency for malignant progression but the factors determining the kinetics of this process are still poorly understood. We report here the case of a male patient who developed a fibrillary astrocytoma at the age of 33 years and who underwent six surgical interventions over a period of 17 years without radiotherapy or chemotherapy. The first three biopsies spanned a period of 11 years and led to the diagnosis of low-grade, diffuse astrocytoma (WHO grade II), with a growth fraction (MIB-1 labeling index) of 2.3-3.7%. The fourth to sixth biopsies showed histological features of anaplastic astrocytoma (WHO grade III), with growth fractions between 5.0 and 10.5%. The fraction of gemistocytic neoplastic astrocytes also increased, from 0.3% in the first biopsy to 17.5% in the last biopsy and preceded the increase in proliferative activity and transition to anaplastic astrocytoma. The fraction of tumor cells immunoreactive to BCL-2 increased from 0.3% to 8.2%. A p53 mutation in codon 273 (CGT-->TGT, Arg-->Cys) was identified in the first biopsy and persisted throughout the course of the disease. However, the fraction of cells with p53 protein accumulation increased significantly during progression, from 3.2% in the first biopsy to 13.7% in the last. The absence of additional genetic alterations (PTEN mutations, loss of chromosome 10 and 19q) may be responsible for the slow progression and lack of glioblastoma features even after a 17-year disease duration.

Genetic profile of the giant cell glioblastoma.

Giant cell glioblastoma is a rare glioblastoma variant characterized by the presence of large, bizarre, multinucleated giant cells. This glioblastoma subtype develops clinically de novo after a short clinical history and contains a high frequency of p53 mutations. In this study, we screened a series of 18 giant cell glioblastomas for additional genetic alterations. PCR-SSCP followed by DNA sequencing revealed PTEN mutations in 5 of 15 tumors (33%). Of these, two mutations were located in exon 5, two mutations in exon 6, and one mutation each in exons 1 and 9. Four mutations were point mutations and two mutations were deletions. One neoplasm contained two PTEN mutations (exons 5 and 6). None of the giant cell glioblastomas showed a homozygous deletion of PTEN orp16, or amplification of MDM2. Immunohistochemically, MDM2 overexpression was either not observed or detected in only a minor fraction of tumor cells. Differential PCR revealed EGFR amplification in only one of 17 tumors (6%). These results indicate that giant cell glioblastomas occupy a hybrid position, sharing with primary (de novo) glioblastomas a short clinical history, the absence of a less malignant precursor lesion and a 30% frequency of PTEN mutations. With secondary glioblastomas that develop through progression from low-grade astrocytomas, they have in common a younger patient age at manifestation and a high frequency (>70%) of p53 mutations.

PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas.

Loss of heterozygosity (LOH) on chromosome 10 is the most frequent genetic alteration associated with the evolution of malignant astrocytic tumors and it may involve several loci. The tumor suppressor gene PTEN (MMAC1) on chromosome 10q23 is mutated in approximately 30% of glioblastomas (WHO Grade IV). In this study, we assessed the frequency of PTEN mutations in primary glioblastomas, which developed clinically de novo, and in secondary glioblastomas, which evolved from low-grade (WHO Grade II) or anaplastic astrocytomas (WHO Grade III). Nine of 28 (32%) primary glioblastomas contained a PTEN mutation and an additional case showed a homozygous PTEN deletion. This indicates that after overexpression/amplification of the EGF receptor, loss of PTEN function is the most common alteration in primary glioblastomas. In this series, 5 of 28 (18%) primary glioblastomas showed both a PTEN mutation and EGFR amplification. In contrast, only 1 of 25 (4%) secondary glioblastomas contained a PTEN mutation, and none of them showed a homozygous PTEN deletion. The secondary glioblastoma with a PTEN mutation developed from an anaplastic astrocytoma that already carried the mutation. The observation that secondary glioblastomas have a p53 mutation as a genetic hallmark but rarely contain a PTEN mutation supports the concept that primary and secondary glioblastomas develop differently on a genetic level.