Extra-axial Cerebrospinal Fluid Research Articles

Extra-axial cerebrospinal fluid in high-risk and normal-risk children with autism aged 2–4 years: a case-control study

We previously showed, in two separate cohorts, that high-risk infants who were later diagnosed with autism spectrum disorder had abnormally high extra-axial cerebrospinal fluid (CSF) volume from age 6-24 months. The presence of increased extra-axial CSF volume preceded the onset of behavioural symptoms of autism and was predictive of a later diagnosis of autism spectrum disorder. In this study, we aimed to establish whether increased extra-axial CSF volume is found in a large, independent sample of children diagnosed with autism spectrum disorder, whether extra-axial CSF remains abnormally increased beyond infancy, and whether it is present in both normal-risk and high-risk children with autism. In this case-control MRI study, children with autism spectrum disorder or with typical development aged 2-4 years were recruited from the community to the UC Davis MIND Institute Autism Phenome Project, based in Sacramento, CA, USA. The autism spectrum disorder group comprised children with autism spectrum disorder who were either normal risk (ie, from simplex families) or high risk (ie, from multiplex families). Measurements of extra-axial CSF volume, brain volume, head circumference, sleep problems, and familial risk status were derived from MRI and behavioural assessments. We applied a previously validated machine learning algorithm based on extra-axial CSF volume, brain volume, age, and sex to the current dataset. Between July 20, 2007, and Dec 13, 2012, 159 children with autism spectrum disorder (132 male, 27 female) and 77 with typical development (49 male, 28 female) underwent MRI scans. The autism spectrum disorder group had an average of 15·1% more extra-axial CSF than controls after accounting for differences in brain volume, weight, age, and sex (least-squares mean 116·74 cm3 [SE 3·33] in autism group vs 101·40 cm3 [3·93] in typical development group; p=0·007; Cohen's d = 0·39). Subgroups of normal-risk (n=132) and high-risk (n=27) children with autism spectrum disorder had nearly identical extra-axial CSF volumes (p=0·78), and both subgroups had significantly greater volumes than controls. Both extra-axial CSF volume (p=0·004) and brain volume (p<0·0001) uniquely contributed to enlarged head circumference in the autism spectrum disorder group (p=0·04). Increased extra-axial CSF volume was associated with greater sleep disturbances (p=0·03) and lower non-verbal ability (p=0·04). The machine learning algorithm correctly predicted autism spectrum disorder diagnosis with a positive predictive value of 83% (95% CI 76·2-88·3). Increased extra-axial CSF volume is a reliable brain anomaly that has now been found in three independent cohorts, comprising both high-risk and normal-risk children with autism spectrum disorder. Increased extra-axial CSF volume is detectable using conventional structural MRI scans from infancy through to age 3 years. These results suggest that increased extra-axial CSF volume could be an early stratification biomarker of a biologically based subtype of autism that might share a common underlying pathophysiology. US National Institutes of Health.

A Novel Framework for the Local Extraction of Extra-Axial Cerebrospinal Fluid from MR Brain Images.

The quantification of cerebrospinal fluid (CSF) in the human brain has shown to play an important role in early postnatal brain developmental. Extr a-axial fluid (EA-CSF), which is characterized by the CSF in the subarachnoid space, is promising in the early detection of children at risk for neurodevelopmental disorders. Currently, though, there is no tool to extract local EA-CSF measurements in a way that is suitable for localized analysis. In this paper, we propose a novel framework for the localized, cortical surface based analysis of EA-CSF. In our proposed processing, we combine probabilistic brain tissue segmentation, cortical surface reconstruction as well as streamline based local EA-CSF quantification. For streamline computation, we employ the vector field generated by solving a Laplacian partial differential equation (PDE) between the cortical surface and the outer CSF hull. To achieve sub-voxel accuracy while minimizing numerical errors, fourth-order Runge-Kutta (RK4) integration was used to generate the streamlines. Finally, the local EA-CSF is computed by integrating the CSF probability along the generated streamlines. The proposed local EA-CSF extraction tool was used to study the early postnatal brain development in typically developing infants. The results show that the proposed localized EA-CSF extraction pipeline can produce statistically significant regions that are not observed in previous global approach.

Impact of extra-axial cerebrospinal fluid collection in frontal morphology after surgical treatment of scaphocephaly.

Background:Infants with sagittal suture synostosis often present a pathologic dilatation of subarachnoid spaces. The impact of such subarachnoid spaces’ enlargement in the morphology of the skull, especially on the forehead and on the surgical outcome, was analyzed.Methods:Children less than 6 months of age undergoing a surgical correction of the scaphocephaly with Renier's H technique between 2003 and 2008 were included in the study. In these patients, preoperative and postoperative fronto-occipital diameter (FOD), biparietal diameter (BPD), temporal width (TW), and naso-frontal angle (NFA) were measured. Cranial index (CI) and the difference between preoperative and postoperative CI (ΔCI) were calculated. Preoperative cranio-cortical width (CCW) was measured to analyze the subarachnoid spaces’ volumes. The children here considered were then divided into two groups: Group 1 with CCW within normal estimated value corrected for age and Group 2 with CCW larger than estimated normal value.Results:About 159 children were enrolled (72.3% male). CCW was larger than expected in 95 children (59.8%). A positive correlation between CCW and BPD (P ≤ 0.001) and a negative correlation between CCW and NFA (P ≤ 0.001) were found. When comparing the two groups, the mean age at preoperative computed tomography (CT) scan was 121 days in Group 1 and 110 days in Group 2. The mean age at operation was 130 days in Group 1 and 123 in Group 2. The mean age at postoperative examination (RX or CT scan) was 53.4 months in Group 1 and 51.8 months in Group 2. Preoperatively, the mean BPD, TW, and CI were significantly larger in Group 2 (P ≤ 0.01), whereas the NFA was significantly narrower (P = 0.03). Postoperative analysis showed that ΔCI was statistically different between the two groups (Group 1: 10%, Group 2: 7%; P < 0.04). The duration of follow-up period ranged between 19 and 129 months.Conclusion:Two main subtypes of forehead of infants with scaphocephaly may be distinguished. Indeed, the morphology of the forehead differs when a pathologic subarachnoid spaces’ enlargement is present preoperatively and it also affects the postoperative evolution. Such observation highlights the importance of evaluating whether subarachnoid spaces are enlarged when planning a surgical correction in isolated sagittal suture synostosis.

Neuroimaging findings in infantile Pompe patients treated with enzyme replacement therapy.

Recombinant human acid α-glucosidase (rhGAA) enzyme replacement therapy (ERT) has prolonged survival in infantile Pompe disease (IPD), but has unmasked central nervous system (CNS) changes. Brain imaging, consisting of computed tomography (CT) and/or magnetic resonance imaging (MRI), was performed on 23 patients with IPD (17 CRIM-positive, 6 CRIM-negative) aged 2-38months. Most patients had baseline neuroimaging performed prior to the initiation of ERT. Follow-up neuroimaging was performed in eight. Sixteen patients (70%) had neuroimaging abnormalities consisting of ventricular enlargement (VE) and/or extra-axial cerebrospinal fluid accumulation (EACSF) at baseline, with delayed myelination in two. Follow-up neuroimaging (n=8) after 6-153months showed marked improvement, with normalization of VE and EACSF in seven patients. Two of three patients imaged after age 10years demonstrated white matter changes, with one noted to have a basilar artery aneurysm. Mild abnormalities on brain imaging in untreated or newly treated patients with IPD tend to resolve with time, in conjunction with ERT. However, white matter changes are emerging as seen in Patients 1 and 3 which included abnormal periventricular white matter changes with subtle signal abnormalities in the basal ganglia and minimal, symmetric signal abnormalities involving the deep frontoparietal cerebral white matter, respectively. The role of neuroimaging as part of the clinical evaluation of IPD needs to be considered to assess for white matter changes and cerebral aneurysms.

Imaging in cutis laxa syndrome caused by a dominant negative ALDH18A1 mutation, with hypotheses for intracranial vascular tortuosity andwide perivascular spaces.

The autosomal dominant progeroid form of cutis laxa is a recently identified multiple congenital anomaly disorder characterized by thin, wrinkled skin, a progeroid appearance, intra-uterine growth retardation, postnatal growth restriction, psychomotor developmental delay, microcephaly, cataract, hypotonia and contractures. De novo heterozygous mutations in ALDH18A1 have been described in this condition. We present neuroimaging abnormalities in three patients. One patient had intracranial arterial and venous tortuosity, widened ventricular and extra-axial cerebrospinal fluid (CSF) spaces, wide perivascular spaces and increased T2 signal intensity in the cerebral white matter over time. The second patient had vascular tortuosity. The third patient had prominent ventricular and extra-axial cerebrospinal fluid (CSF) spaces on CT. We propose an embryological mechanism for the development of intracranial vascular tortuosity and discuss the anatomical basis of wide perivascular spaces in relation to this syndrome. Although we do not know the clinical implications of these cerebral vascular anomalies, we suggest inclusion of neuroimaging in the baseline evaluation of these patients.

Extra-axial cerebrospinal fluid spaces in children with benign external hydrocephalus: A case-control study.

Background The distinction between normal and pathological extra-axial cerebrospinal fluid (CSF) spaces is unclear, with the use of the term benign external hydrocephalus (BEH) not being well defined in clinical practice. This study aimed to establish a distribution of metrics of the subarachnoid space in a population of children diagnosed as normal, and investigate the clinical use of the term BEH. Methods A retrospective case-control study on magnetic resonance image scans was performed on 150 children diagnosed as normal and 10 children diagnosed with BEH. Measurements were taken in the axial plane for CSF width (CSFW), and interhemispheric width (IHW). Results Normal controls had a mean age of 11.1 ± 7.6 months (78 male, 72 female) and the BEH sample had a mean age of 10.6 ± 7.8 months (six male, four female). Mean CSFW was 7.96 ± 4.79 mm in the BEH sample compared to 4.58 ± 2.25 mm in the normal sample ( p < 0.05). Mean IHW was 6.30 ± 2.79 mm in the BEH sample compared to 3.89 ± 1.83 mm in the normal sample ( p < 0.05). However, a substantial overlap between the two distributions of CSFW was found, with 50% of BEH patients lying within a single standard deviation of the mean of normal individuals. Conclusion The absence of diagnostic criteria for BEH means reporting is variable. Patients being diagnosed with BEH who have no other clinical defects may represent the extreme of the normal population rather than a distinct clinical entity.

Cerebrospinal Fluid and Parenchymal Brain Development and Growth in the Healthy Fetus

Objective: The objective of this study was to apply quantitative magnetic resonance imaging to characterize absolute cerebrospinal fluid (CSF) development, as well as its relative development to fetal brain parenchyma in the healthy human fetus. Design: We created three-dimensional high-resolution reconstructions of the developing brain for healthy fetuses between 18 and 40 weeks' gestation, segmented the parenchymal and CSF spaces, and calculated the volumes for the lateral, third, and fourth ventricles; extra-axial CSF space; and the cerebrum, cerebellum, and brainstem. From these data, we constructed normograms of the resulting volumes according to gestational age and described the relative development of CSF to fetal brain parenchyma. Results: Each CSF space demonstrated major increases in volumetric growth during the second half of gestation: third ventricle (23-fold), extra-axial CSF (11-fold), fourth ventricle (8-fold), and lateral ventricle (2-fold). Total CSF volume was related to total brain volume (p < 0.01), as was lateral ventricle to cerebral volume (p < 0.01); however, the fourth ventricle was not related to cerebellar or brainstem volume (p = 0.18-0.19). Relevance: Abnormalities of the CSF spaces are the most common anomalies of neurologic development detected on fetal screening using neurosonography. Normative values of absolute CSF volume, as well as relative growth in comparison to intracranial parenchyma, provide valuable insight into normal fetal neurodevelopment. These data may provide important biomarkers of early deviations from normal growth, better distinguish between benign variants and early disease, and serve as reference standards for postnatal growth and development in the premature infant.

Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism

BackgroundWe previously reported that infants who developed autism spectrum disorder (ASD) had increased cerebrospinal fluid (CSF) in the subarachnoid space (i.e., extra-axial CSF) from 6 to 24 months of age. We attempted to confirm and extend this finding in a larger independent sample. MethodsA longitudinal magnetic resonance imaging study of infants at risk for ASD was carried out on 343 infants, who underwent neuroimaging at 6, 12, and 24 months. Of these infants, 221 were at high risk for ASD because of an older sibling with ASD, and 122 were at low risk with no family history of ASD. A total of 47 infants were diagnosed with ASD at 24 months and were compared with 174 high-risk and 122 low-risk infants without ASD. ResultsInfants who developed ASD had significantly greater extra-axial CSF volume at 6 months compared with both comparison groups without ASD (18% greater than high-risk infants without ASD; Cohen’s d = 0.54). Extra-axial CSF volume remained elevated through 24 months (d = 0.46). Infants with more severe autism symptoms had an even greater volume of extra-axial CSF from 6 to 24 months (24% greater at 6 months, d = 0.70; 15% greater at 24 months, d = 0.70). Extra-axial CSF volume at 6 months predicted which high-risk infants would be diagnosed with ASD at 24 months with an overall accuracy of 69% and corresponding 66% sensitivity and 68% specificity, which was fully cross-validated in a separate sample. ConclusionsThis study confirms and extends previous findings that increased extra-axial CSF is detectable at 6 months in high-risk infants who develop ASD. Future studies will address whether this anomaly is a contributing factor to the etiology of ASD or an early risk marker for ASD.

Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism

Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism

Brain Dysplasia Associated with Ciliary Dysfunction in Infants with Congenital Heart Disease

To test for associations between abnormal respiratory ciliary motion (CM) and brain abnormalities in infants with congenital heart disease (CHD) STUDY DESIGN: We recruited 35 infants with CHD preoperatively and performed nasal tissue biopsy to assess respiratory CM by videomicroscopy. Cranial ultrasound scan and brain magnetic resonance imaging were obtained pre- and/or postoperatively and systematically reviewed for brain abnormalities. Segmentation was used to quantitate cerebrospinal fluid and regional brain volumes. Perinatal and perioperative clinical variables were collected. A total of 10 (28.5%) patients with CHD had abnormal CM. Abnormal CM was not associated with brain injury but was correlated with increased extraaxial cerebrospinal fluid volume (P < .001), delayed brain maturation (P < .05), and a spectrum of subtle dysplasia including the hippocampus (P < .0078) and olfactory bulb (P < .034). Abnormal CM was associated with higher composite dysplasia score (P < .001), and both were correlated with elevated preoperative serum lactate (P < .001). Abnormal respiratory CM in infants with CHD is associated with a spectrum of brain dysplasia. These findings suggest that ciliary defects may play a role in brain dysplasia in patients with CHD and have the potential to prognosticate neurodevelopmental risks.

Diagnosis and Genetic Analysis of Glutaric Acidaemia Type I: Very rarely seen inborn error of metabolism.

Diagnosis and Genetic Analysis of Glutaric Acidaemia Type I: Very rarely seen inborn error of metabolism.

Neuroendoscopic treatment for hydrocephalus associated to midline arachnoid cysts in a series of nine pediatric patients.

Arachnoid cysts are extra-axial cerebrospinal fluid (CSF) collections surrounded by a membrane. Occasionally, hydrocephalus is associated due to a change in CSF circulatory dynamics. Neuroendoscopic treatment has been recommended for patients who develop symptoms resulting from the cyst location. We retrospectively evaluate the results in our series of 9 patients with hydrocephalus associated to midline arachnoid cysts treated endoscopically. Success was rated on a scale of five degrees of neuroendoscopical success. We performed endoscopic third ventriculostomy (ETV) in three cases; ETV was associated to ventriculocystostomy (VC) in three cases; ETV, VC and septostomy (SPT) were performed in one patient; neuroendoscopic Monro foraminoplasty (NEFPMO) plus SPT were associated in one case; last patient was performed ETV, VC and cystocysternostomy (CC). For first procedures, 6 patients completed permanent Success (grade I). In one case success was transitory (grade II) and required a second procedure (ETV). In one patient VC success and ETV failure implied partial success (grade III). One patient's early failure (grade V) required a second procedure (ETV + NEFPMO). Success in second procedures was grade I in both patients. Follow-up period was over 12 months and altogether success was grade I in 8/9 patients and grade III in 1/9 patients. Shunt independency went over 88%. Endoscopy allows a solution avoiding the implantation of cerebrospinal fluid shunt devices. When possible, we likely approach both, hydrocephalus and arachnoid cyst, with different endoscopic maneuvers in a single procedure. It is important to expand the usage of success classifications for combined procedures.

Incidental findings on preoperative computed tomography for nonsyndromic single suture craniosynostosis.

Although the diagnosis of nonsyndromic single suture craniosynostosis (NSSC) can usually be made by clinical examination, computed tomography (CT) is still commonly used in preoperative evaluation. This practice has been questioned in light of recent studies that document a small, but measurable, increased risk of malignancy from CT-associated radiation. The purpose of this study was to examine whether preoperative CT for patients with NSSC provided clinically important information beyond confirmation of craniosynostosis. We performed a retrospective analysis of all patients with NSSC undergoing cranial vault remodeling at our center from March 1999 to March 2011. Only patients with complete preoperative CT scans available for review were included. Staff pediatric neurosurgeons were blinded to patient diagnosis and official radiology report, analyzed the CT images, and documented the site of synostosis and any other findings. Of the 231 patients, 80 met the inclusion criteria. Sites of synostosis included sagittal (51 patients), coronal (17 patients), metopic (11 patients), and frontosphenoidal (1 patient). Clinical diagnosis correlated with radiographic site of fusion in all patients except the patient with frontosphenoidal synostosis. Incidental findings were documented in more than 50% of the patients including prominent extra-axial cerebrospinal fluid (n = 36, 45%), ventriculomegaly (n = 5, 6.25%), choroid fissure cyst (n = 2), cavum septum pellucidum (n = 2), Chiari malformation (n = 1), and prominent perivascular space (clinically nonsignificant finding, n = 1). Incidental findings required additional follow-up or management in 5 patients (6.25%). Our findings support the use of preoperative imaging in this population to identify intracranial anomalies that cannot be discerned by clinical examination. Whereas many findings were not clinically important, some required additional attention.

Role of post-decompressive hydrocephalus in patients with malignant cerebral infarction

The association between post-decompressive hydrocephalus and clinical neurological expression is still unclear. In order to investigate this relationship, the authors analyze series of ventricular morphology and level of consciousness at different clinical stages for patients accepting decompressive craniectomy (DC). From 2005 to 2011, 13 patients accepting DC under the diagnosis of malignant cerebral infarction were retrospectively evaluated in terms of ventricular frontal horn dilatation and level of consciousness, Glasgow Coma Scale score, at four different clinical stages: 1): pre-DC stage; 2): post-DC stage while stabilization; 3): post-cranioplasty stage; 4): post-shunt stage [for those with permanent cerebrospinal fluid (CSF) diversion]. All 13 patients had ventricular dilatation and two of them had extra-axial CSF collection. Restoration of ventricular dilatation was not observed in all patients after bone flap placement, but extra-axial CSF collection resorbed spontaneously. Four patients accepting permanent CSF diversion had no improvement over neurological expression. Otherwise, two of them complicated with subdural effusion after shunt placement. Decompressive craniectomy itself would lead to ventricular dilatation universally. There is no direct association between degree of ventriculomegaly and neurological expression. Permanent CSF diversion surgery as treatment for ventriculomegaly makes no clinical improvement with possible complications of overshunting.

Pontocerebellar hypoplasia type 2 and TSEN2: Review of the literature and two novel mutations

Pontocerebellar hypoplasias (PCH) represent a heterogeneous group of autosomal recessive neurodegenerative disorders characterized by hypoplasia of the cerebellum and pons, variable cerebral involvement, microcephaly, severe delay in cognitive and motor development, and seizures. Seven different subtypes have been reported (PCH1-7) and mutations in three genes, TSEN2, TSEN34 and TSEN54 encoding three of four subunits of the tRNA splicing endonuclease complex have been found to underlie PCH2, PCH4 and PCH5. PCH2 is characterized by cerebellar hypoplasia affecting the hemispheres more severely than the vermis, progressive cerebral atrophy and microcephaly, dyskinesia, seizures, and death in early childhood. We describe a male patient with progressive microcephaly, severe hypotonia, and myoclonic-tonic seizures. Brain MRI confirmed microcephaly with simplified cortical gyration and revealed hypoplasia of the brainstem, cerebellum and cerebellar vermis. Sequencing of the TSEN2 gene detected the novel missense mutation c.934G > A (p.G312R) on one allele and the first nonsense mutation c.691C > T (p.Q231*) on the second allele. Although the cytosine-to-thymine transition results in introduction of a premature stop codon in the majority of annotated TSEN2 transcript variants, it could represent a splice site mutation (c.517-3C > T) in variant 4. However, by RT-PCR analysis we did not identify mRNAs representing TSEN2 transcript form 4 in leukocyte-derived RNA of the patient and healthy individuals. The clinical phenotype of the patient is comparable with PCH2. However, we noticed decreased cerebral volume with increased extra-axial cerebrospinal fluid spaces and wide-open Sylvian fissures indicating cerebral immaturity that might be associated with the TSEN2 null allele. We conclude that the severity of pontocerebellar hypoplasia in the patient fits PCH2, while the large involvement of the cerebrum better corresponds to PCH4 demonstrating the phenotypic spectrum of PCH2 and 4. To establish a possible genotype–phenotype correlation, more individuals with biallelic TSEN2 mutations need to be investigated.

In Reply:

We thank De Bonis et al for their interest in our article.1 In our series of 17 patients who underwent decompressive hemicraniectomy (DH) for cerebrovascular accident-related, medically refractory increased intracranial pressure, a full standard hemicraniectomy was performed in 13 patients, whereas only 4 received large craniectomy flaps. Clinically significant hydrocephalus necessitating cerebrospinal fluid (CSF) diversion developed in none of the 14 survivors. Unfortunately, we are unable to provide the authors with the information that they request because exact measurements of the hemicraniectomy flaps, particularly the distance between their medial edge and the superior sagittal sinus, were difficult to determine in our retrospective study. However, it has been our standard practice to perform wide bony decompressions extending from the floor of the middle fossa laterally to within 1 to 2 cm of the sagittal suture medially and from the floor of the anterior fossa anteriorly to approximately 5 to 6 cm behind the pinna posteriorly.2 Therefore, we would expect that the vast majority of patients in our series had hemicraniectomy flaps extending to within 2.5 cm of the superior sagittal sinus. When analyzing the incidence of hydrocephalus after DH, it is important to distinguish between complications of the underlying cerebral insult and those resulting from the surgical procedure itself. This is particularly true in patients with head trauma and those with subarachnoid and/or intraventricular hemorrhage who are naturally prone to the development of hydrocephalus, regardless of whether DH is performed. For this reason, we have strived to eliminate these major confounding factors and exclude such patients from our analysis. We read the authors' recent article on posttraumatic hydrocephalus after decompressive craniectomy in patients with traumatic brain injury.3 Although we find the authors' hypothesis interesting in general, there are nonetheless several issues that merit discussion. Their patient cohort was particularly small, with only 26 survivors included in the final analysis. Such a small sample size is unlikely to have a high enough statistical power to allow firm conclusions regarding prognostic factors, particularly when a 6-variable multivariate analysis is performed. Moreover, numerical variables were not analyzed as such and instead were dichotomized using arbitrary cutoff values (30 d for cranioplasty, 40 yr for age, 162 cm2 for cranioplasty, and 25 mm for distance from midline). This raises significant concerns about the validity of their statistical analysis. Clinical examination was not included in the definition of hydrocephalus for many comatose patients, which may have significantly affected their results. In our series, in 2 patients, asymptomatic extra-axial CSF collections developed after DH, which resolved spontaneously after cranioplasty. We believe that such collections are the result of increased intracranial compliance after the removal of a large piece of cranium rather than an actual mismatch between CSF production and absorption.1 Most importantly, the presence of a statistically significant association between a DH extending close to midline and hydrocephalus is in no way proof of a causal relationship, particularly in severely head-injured patients. It is noteworthy that all but 2 of their patients had evidence of subarachnoid and/or intraventricular blood on computed tomography (Fisher grade 2). A major confounding factor was thus present in the absolute majority of patients, which makes it difficult to attribute the development of hydrocephalus to the surgical procedure itself. Is it possible that patients who underwent DH closer to the midline had more severe structural damage to the cerebral hemisphere on CT, which may account for their increased rate of posttraumatic hydrocephalus? This is definitely a possibility in the setting of a retrospective study that may be subject to all kinds of inherent biases. In conclusion, to establish a cause-and-effect relationship between DH and hydrocephalus, one has to study the incidence of the latter in patients undergoing DH for conditions not known to be associated with hydrocephalus (eg, ischemic stroke). Alternatively, a randomized, controlled trial comparing the incidence of hydrocephalus in severe traumatic brain injury survivors who underwent DH and those who did not may provide the answer. Until then, we have no reason to believe that DH is a risk factor for hydrocephalus, independently of the patient's underlying cerebral insult. Michel Bojanowski Ralph Rahme Montreal, Quebec

Decompressive Craniectomy Is Not an Independent Risk Factor for Communicating Hydrocephalus in Patients With Increased Intracranial Pressure

It was recently suggested that communicating hydrocephalus is an almost universal finding after hemicraniectomy and that early cranioplasty may prevent the need for permanent cerebrospinal fluid diversion in these patients. To conduct a study in an attempt to verify these findings. The medical records of all patients who underwent decompressive craniectomy for medically refractory elevated intracranial pressure between 2001 and 2009 were retrospectively reviewed. Patients with subarachnoid hemorrhage, intraventricular hemorrhage, or head trauma were excluded. Hydrocephalus was classified as internal or external and as clinically significant or asymptomatic. The patient population consisted of 17 patients, 8 men and 9 women, with a median age of 44 years (range, 27-53 years). Etiologies included malignant middle cerebral artery territory infarction in 12 patients, hemorrhagic transformation of ischemic cerebrovascular accident in 2 patients, dural sinus thrombosis in 2 patients, and hemorrhagic cerebrovascular accident in 1 patient. The extent of craniectomy ranged from a large bone flap in 4 patients to a standard hemicraniectomy in 13 patients. Two patients died and 1 was lost to follow-up during the acute stage. The remaining 14 patients underwent cranioplasty after a median interval of 21 days (range, 3-42 days). In none of these patients did clinically significant hydrocephalus develop requiring cerebrospinal fluid diversion. Asymptomatic extra-axial cerebrospinal fluid collections developed in 2 patients that resolved spontaneously after cranioplasty. Our results suggest that, contrary to some beliefs, hydrocephalus does not frequently occur after decompressive craniectomy.

Subdural Effusions with Hydrocephalus after Severe Head Injury: Successful Treatment with Ventriculoperitoneal Shunt Placement: Report of 3 Adult Cases

Background. Subdural collections of cerebrospinal fluid (CSF) with associated hydrocephalus have been described by several different and sometimes inaccurate terms. It has been proposed that a subdural effusion with hydrocephalus (SDEH) can be treated effectively with a ventriculoperitoneal shunt (V-P shunt). In this study, we present our experience treating patients with SDEH without directly treating the subdural collection. Methods. We treated three patients with subdural effusions and hydrocephalus as a result of a head injury. All the patients were treated with a V-P shunt despite the fact that there was an extra-axial CSF collection with midline shift. Results. In all of the patients, the subdural effusions subsided and the ventricular dilatation improved in the postoperative period. The final clinical outcome remains difficult to predict and depends not only on the successful CSF diversion but also on the primary and secondary brain insult. Conclusion. Subdural effusions with hydrocephalus can be safely and effectively treated with V-P shunting, without directly treating the subdural effusion which subsides along with the treatment of hydrocephalus. However, it is extremely important to make an accurate diagnosis of an SDEH and differentiate this condition from other subdural collections which require different management.

Comment re: Temozolomide Preferentially Depletes Cancer Stem Cells

To the Editor: Beier and colleagues (1), in contrast to previous studies (2–4), show that temozolomide depletes clonogenic and highly tumorigenic cells in glioblastoma cultures and reduces tumorigenicity in vivo. The in vivo studies, however, raise concerns. Tumor xenografts were measured on T2-weighted magnetic resonance images (MRI; TR/TE 4,000/73 ms). In Fig. 6A of their report, the hyperintense signal of the xenograft is similar to cerebrospinal fluid (CSF). At this TR/TE value, a glial tumor without necrotic or cystic areas is expected to be less hyperintense than CSF (Fig. 1A and B, arrow). Although the MRI appearance may depend on transplantation techniques, the hyperintense signal of the xenografts seems related to regressive phenomena (5). In Fig. 6A of ref. 1 (upper and lower left), the ventricles homolateral to the tumor are not compressed or displaced as expected (Fig. 1C and D); conversely, they seem slightly enlarged. Furthermore, the untreated xenograft in Fig. 6A of ref. 1 (upper left) shows an extra-axial CSF collection that does not favor the presence of an underlying mass lesion.Glioblastoma cancer stem cells (CSCs) are known to generate tumors in vivo that phenocopy the parent tumor, although vascularity and heterogeneity may be less prominent. In Fig. 6B and C of ref. 1, however, the xenografts lack glioblastoma features resembling foci of anaplastic astrocytoma, therefore suggesting that the grafted CSCs may have lost the grade of malignancy of parental glioblastoma.Pretreatment with temozolomide dose-dependently reduced the size of tumor xenografts irrespective of the O6 methylguanine-DNA methyltransferase (MGMT) status of the CSCs. Indeed, tumor size substantially decreased in mice injected with CSCs exposed to 50 μmol/L of temozolomide relative to the 5 μmol/L dose, as shown in Fig. 6A and B of ref. 1. However, Fig. 6D of ref. 1 shows that proliferation of R28 cells does not significantly differ between 5 and 50 μmol/L of temozolomide. Changing the interpretation of Beier and colleagues, we propose that early after implantation 50 μmol/L-temozolomide treatment had been more effective than 5 μmol/L but 12 weeks later the tumors proliferated with similar rates. Beier and colleagues show that temozolomide-treated CD133+ glioblastoma cells actually continue to proliferate in vitro. The same may happen when xenografting the cells. Obtaining any data on cell death would have been beneficial. Future studies are needed to fully understand the effects of temozolomide and other therapies on different tumor cell populations in this heterogenous disease.No potential conflicts of interest were disclosed.

Fetal Head Biometry Assessed by Fetal Magnetic Resonance Imaging following in utero Myelomeningocele Repair

Objective: To examine the impact of fetal myelomeningocele (MMC) repair on fetal head biometry and cerebrospinal fluid (CSF) spaces assessed by magnetic resonance imaging (MR) studies. Study Design: Axial measurements of intracranial structures were taken at defined anatomical landmarks. Pre- and postnatal head biometry data and CSF spaces obtained from in utero repaired MMC fetuses (n = 22) were compared to the pre- and postnatal measurements of MMC patients that underwent standard neurosurgical MMC repair after birth (n = 16) and a cohort of age-matched control patients (prenatal, n = 52; postnatal, n = 9). Results: In fetuses with MMC, initial MR scans showed an almost complete absence of supratentorial and posterior fossa CSF spaces. No differences in postnatal CSF spaces were found between controls and prenatally repaired MMC newborns. In fetuses with postnatal MMC repair, CSF spaces remained significantly reduced (p < 0.0001). The mean ventricular diameter (VD) increase in the postnatal repaired MMC group was significantly higher compared to the mean percentage of VD increase in the fetal repaired MMC group (6.4 vs. 4.2 mm; p = 0.02). Pre- and postnatal brain thickness measurements were significantly reduced in both MMC populations compared to age-matched normal values (p < 0.0001). In contrast to postnatally repaired patients, in utero repair fetuses showed significant reversal of hindbrain herniation and normalization of the posterior fossa CSF spaces. Conclusion: Mid-gestational repair of MMC promotes normalization of extra-axial CSF spaces. Due to progressive ventriculomegaly, brain thickness remains decreased in both prenatal repaired and age-matched non-repaired MMC patients when compared to age-matched normal values. Restoration of CSF volume in the posterior fossa after in utero repair is indicative of reversal of hindbrain herniation.