Expanding the phenotype of CRB2 mutations - A new ciliopathy syndrome?

Recessive CRB2 mutations were recently reported to cause both steroid resistant nephrotic syndrome and prenatal onset ventriculomegaly with kidney disease. We report two Ashkenazi Jewish siblings clinically diagnosed with ciliopathy. Both presented with severe congenital hydrocephalus and mild urinary tract anomalies. One affected sibling also has lung hypoplasia and heart defects. Exome sequencing and further CRB2 analysis revealed that both siblings are compound heterozygotes for CRB2 mutations p.N800K and p.Gly1036Alafs*43, and heterozygous for a deleterious splice variant in the ciliopathy gene TTCB21. CRB2 is a polarity protein which plays a role in ciliogenesis and ciliary function. Biallelic CRB2 mutations in animal models result in phenotypes consistent with ciliopathy. This report expands the phenotype of CRB2 mutations to include lung hypoplasia and uretero-pelvic renal anomalies, and confirms cardiac malformation as a feature. We suggest that CRB2-associated disease is a new ciliopathy syndrome with possible digenic/triallelic inheritance, as observed in other ciliopathies. Clinically, CRB2 should be assessed when ciliopathy is suspected, especially in Ashkenazi Jews, where we found that p.N800K carrier frequency is 1 of 64. Patients harboring CRB2 mutations should be tested for the complete range of ciliopathy manifestations.

Malignant transformation in pediatric spinal intramedullary tumors: case-based update.

BACKGROUND: In children, intramedullary spinal cord neoplasms are rare. These are typically low-grade neuroepithelial tumors, most commonly astrocytomas, ependymomas, and gangliogliomas. Malignant transformation, while common in recurrent adult low-grade gliomas, is an unusual event in pediatric low-grade neoplasms, specifically in intramedullary spinal cord tumors. ILLUSTRATIVE CASES: We report two cases of malignant transformation in low-grade neuroepithelial tumors of the pediatric intramedullary spinal cord. Two children with intramedullary tumors, one with a WHO grade I ganglioglioma and one with a low-grade astrocytoma, were treated surgically, diagnosed histologically, and followed through the course of their disease. Both patients' tumors transformed to higher grades without prior irradiation or chemotherapy, and without a genetic predisposition to tumorigenesis. DISCUSSION: Malignant transformation can occur in low-grade intramedullary neoplasms in children. This is a novel documented event for pediatric intramedullary spinal cord tumors and a rare event for all pediatric low-grade neuroepithelial tumors without induction by irradiation. A survey of the relevant literature reveals an underwhelming number of studies focusing on malignant transformation in children's CNS tumors relative to adults. Further investigation into molecular mechanisms of pediatric low-grade neoplasms may reveal more aggressive tumor sub-variants predisposed to malignant degeneration.

Diffusion tensor imaging in hydrocephalus: initial experience.

PURPOSE AND BACKGROUND: Diffusion tensor imaging (DTI) is an MR imaging-based technique that provides an in vivo tool for visualization of white matter tracts. In this preliminary study, we used this technique to investigate the diffusion characteristics of white matter tracts in patients with hydrocephalus before and after surgery and compared them with age-matched volunteers. MATERIALS AND METHODS: Seven patients with different types of acute hydrocephalus (defined by acute clinical signs of increased intracranial pressure and imaging evidence of enlarged ventricles) underwent MR imaging including a DTI protocol before and after surgery for shunt placement/revision or ventriculostomy. Eight age-matched healthy subjects served as a control group. The DTI was acquired in a clinical setting that included 6 gradient directions with a b value of 1000 s/mm(2). RESULTS: Before surgery, in fiber systems lateral to the ventricles (corona radiata), the diffusion parallel to the fibers was increased (+10%) and the diffusion perpendicular to the fibers was decreased (-25%) in all patients, resulting in an overall increase in the fractional diffusion anisotropy (FA, +28%). Following surgery, the FA values approached those of control values in all except 1 patient. In the corpus callosum, the presurgery FA values in patients with hydrocephalus (HCP) were lower than those of control values, and no significant changes were seen following surgery. CONCLUSIONS: DTI can distinguish the compression characteristics of white matter before and after surgery in patients with HCP. At the acute stage of the disease, DTI characteristics point to white matter compression as a possible cause of the observed changes.

Fetal intracranial hemorrhage (fetal stroke): does grade matter?

OBJECTIVE: To determine if the severity of antenatally diagnosed hemorrhagic fetal brain insults and fetal stroke detected by ultrasound and magnetic resonance imaging (MRI) predicts postnatal neurodevelopmental prognosis. METHODS: The in-utero presentation and postnatal neurodevelopmental outcome of sonographically detected subdural hematoma or fetal stroke presenting as intraventricular hemorrhage (IVH) or intraparenchymal brain hemorrhage were investigated. RESULTS: Of 33 fetuses diagnosed with hemorrhagic brain lesions, 17 were electively terminated and two suffered intrauterine fetal demise. Thirteen were liveborn, seven by Cesarean delivery and six by spontaneous vaginal delivery. One case was lost to follow-up. Eight neonates had moderate to severe neurological deficit by a mean age of 35 (range, 6-96) months. One died at 2 months of age. These nine were diagnosed with Grade III-IV IVH in utero. Four neonates had normal neurological outcome by a mean age of 41 (range, 30-48) months; these four were diagnosed with subdural hematoma (n = 1) or Grade I-II IVH (n = 3) in utero. Fourteen cases were followed up with MRI, which confirmed ultrasound findings in 10 (71%) cases. In three (21%) cases MRI diagnosis was more accurate and the severity of grading was greater than that obtained on ultrasound imaging. Unilateral left hemispheric lesions were much more common than right-sided lesions (13 vs. 1, respectively). CONCLUSIONS: An antenatal sonographic diagnosis of fetal stroke with IVH Grade III-IV or with brain parenchymal involvement appears to be associated with poor neurological outcome. MRI may contribute to the accuracy of diagnosis, particularly in Grade II and III lesions. Left-sided unilateral lesions are more common than right-sided ones.

Progression of terminal syrinx in occult spina bifida after untethering.

OBJECT: The association of spinal dysraphism and terminal syringomyelia is a well-known entity, and untethering with or without syrinx drainage is usually the surgery of choice. However, progression of the previously existing syrinx after an untethering procedure is an uncommon course. The objective of this study was to discuss the diagnostic, surgical, and follow-up consequences of such an occurrence. METHODS: Four children with occult spina bifida associated with terminal syrinx at the time of initial presentation are included in this study. After the primary releasing procedure, all developed enlargement of the syrinx. Two of them were operated on for placement of a syringo-subarachnoid shunt, while the other two were followed up conservatively. One of the shunted patients also had a second releasing procedure. CONCLUSION: Progression of the pre-existing terminal syrinx after the primary untethering procedure should be kept in mind even in the absence of overt neurological progression.

Repeat endoscopic third ventriculostomy: is it worth trying?

OBJECT: The goal of this study was to evaluate the safety, efficacy, and indications for repeat endoscopic third ventriculostomies (ETV). METHODS AND RESULTS: We reviewed the records of 20 patients who had undergone repeat ETV from 1987 to 1999. Their ages ranged from 8 months to 53 years (mean 17 years). The primary etiologies of hydrocephalus were: primary aqueductal stenosis (9 cases), tumor (5), Chiari malformation (2), prior infection (2), prior intraventricular hemorrhage (1), and blocked foramen of Monro (1 patient). The interval between the first and second ETVs ranged from 8 days to almost 6 years (mean 12.8 months). The intraoperative findings at repeat surgery were: occlusion of the primary orifice by scar (10 cases), virginal floor of the third ventricle (5 cases), pinhole ventriculostomy (3 cases), incompletely penetrated membrane (1 case), and blood clot occluding the orifice (1 case). The follow-up period ranged from 3 to 47 months (median 20 months). Repeat ETV was successful in 13 patients (65%). These patients did not require further shunting or other procedures during follow-up. Seven patients (35%) required placement of a shunt after repeat ETV. Several complications were observed in 1 patient (5%), including seizures, elevated ICP, bilateral pulmonary edema, and cardiac arrhythmia. This patient ultimately recovered fully; the ETV was successful, and the patient did not require a shunt. CONCLUSIONS: Based on the experience of this group of patients, repeat ETV is as effective and as safe as a primary ETV procedure, and should be attempted in selected patients.

Application of the orbito-cranial approach in pediatric neurosurgery.

OBJECTIVE: This study evaluates the benefits of and indications for the orbito-cranial approach (OCA) in pediatric patients. METHODS AND RESULTS: The authors report their recent experience of using the OCA in 9 pediatric patients, 6 boys and 3 girls. The patients' ages ranged from 3 to 17 years (mean 9.6+/-5.16 years). Follow-up periods varied between 6 and 21 months (mean 12.6+/-5.9 months). Five patients were operated on for craniopharyngiomas, 2 for chiasmatic-hypothalamic astrocytomas, 1 for a recurrent hypothalamic gangliocytoma, and 1 for a hypothalamic hamartoma. In 7 cases a neuronavigation system (BrainLab) was utilized. The lesions were removed totally in 5 patients, near-totally in 1, subtotally in 2, and partially in 1 patient. An average increase of 30% in the area of vertical exposure significantly decreased the need for brain retraction. There was no mortality in this series. The only complications connected with the surgical approach were transient subgaleal cerebro-spinal fluid collections in 7 of 9 children and a subgaleal-peritoneal shunt placement in another patient. CONCLUSIONS: Our experience with this series of patients suggests that the OCA is as safe and beneficial in pediatric patients as it is in adults. It facilitates tumor removal by providing shorter access to and better exposure of the suprasellar area, thereby minimizing brain retraction.

Morphometric study of the midsagittal MR imaging plane in cases of hydrocephalus and atrophy and in normal brains.

BACKGROUND AND PURPOSE: Midsagittal morphologic changes often aid in the diagnosis of hydrocephalus. Stretching and upward displacement of the corpus callosum, widening of third ventricular recesses, and decreased mammillopontine distance have been described as indicating the possibility of hydrocephalus. Quantitative studies are scarce. We performed retrospective, quantitative analysis to verify and quantify changes in midline morphology that might differentiate hydrocephalus and ventriculomegaly due to atrophy. METHODS: Sagittal MR imaging studies of 22 patients with hydrocephalus and 32 patients with atrophy were analyzed, as were 42 studies with normal findings. The studied parameters included mammillopontine and mammillocommissural distances, callosal height at two points, and the distances between the lines passing through the chiasm (chiasmal line) and the edge of the callosal splenium. Various angles between the chiasmal line and surrounding structures were measured. Similar measurements were done with the line passing through the third ventricular floor segment anterior to the mammillary bodies (third ventricular line). RESULTS: In hydrocephalus, mammillopontine distance decreased, mammillocommissural distance increased, the third ventricular floor segment was concave in most cases, and the chiasmal line rotated clockwise. These changes were not seen in atrophy. Callosal height was increased in hydrocephalus significantly more than in atrophy. CONCLUSION: Specific changes of the midsagittal plane in hydrocephalus, some of which have not been described previously, can be observed and quantified, which might aid in differentiating this condition from atrophy.

Ascites following ventriculoperitoneal shunting in children with chiasmatic-hypothalamic glioma.

OBJECT: Optic pathway gliomas in children can involve the optic nerve, chiasm, and hypothalamus. This uncommon, slowly growing tumor can cause hydrocephalus, which usually requires placement of a ventriculoperitoneal (VP) shunt. Symptomatic ascites may occasionally develop as a complication of the VP shunt procedure. The purpose of this study was to assess the risk factors associated with CSF ascites in children with optic pathway gliomas. METHODS: Twenty-two children (ages 4 months to 20 years) with chiasmatic-hypothalamic optic gliomas participated in this study. Four children were diagnosed with a chiasmatic glioma, 7 with a hypothalamic glioma, and 11 with a glioma involving both the optic chiasm and hypothalamus. Twelve children (55%) developed hydrocephalus and required VP shunt placement. Of the 12 shunted children, 4 (33%) developed CSF ascites. The incidence of ascites was not associated with infection, tumor metastasis, or multiple shunt revisions. There was no correlation with the size of the tumor. All 4 children with ascites had tumor involving the optic chiasm or optic nerve. None of the 5 children with pure hypothalamic glioma who underwent VP shunt placement have developed ascites. Among the 7 children suffering from chiasmatic or optic nerve gliomas who developed hydrocephalus, the risk of developing ascites as a complication of VP shunt placement was 57% (4/7). Ventriculoatrial (VA) shunt was the treatment of choice for children with VP shunt-induced ascites. After placement of a VA shunt the ascites subsided. The children did not develop further complications. CONCLUSION: We conclude that glioma involving the optic chiasm or nerve is associated with a high risk of developing ascites following VP shunt placement. VA shunt may be the treatment of choice for children with chiasmatic or optic nerve gliomas who require a CSF diversion procedure.

Huge acoustic neurinomas presenting in the late stage of pregnancy. Treatment options and review of literature.

BACKGROUND: Even though vestibular schwannomas rarely present during pregnancy, symptoms may appear or worsen particularly in this period. The clinical picture may include tinnitus, hearing abnormalities, and in large tumors, brain-stem and cerebellar compression with involvement of additional cranial nerves. Large vestibular schwannomas (also known as Acoustic Neurinomas) present a great challenge in peripartum management of both the mother and the fetus. MATERIAL AND METHOD: We present a case of a 24-year old woman, with headache, papilledema, ataxia, and multiple cranial nerve weakness, diagnosed in the 35th week of pregnancy. MRI demonstrated a huge vestibular schwannoma compressing the brainstem and causing obstructive hydrocephalus. RESULT: In the presence of high intra-cranial pressure a ventriculo-peritoneal shunt was first inserted, enabling delay of tumor surgery until after delivery. A successful elective cesarean section followed at 37 weeks, and radical tumor surgery was performed a week later. Maternal and fetal outcome were excellent. DISCUSSION: The options, sequence and timing of the neurosurgical and obstetrical interventions are discussed. Other reports of large vestibular schwannomas that presented during pregnancy are reviewed. Advances in neurosurgery, neuroradiology, neuroanesthesiology and obstetrics are highlighted, and their impact on outcome is discussed in comparison to the poor results reported in the past. Emphasis is made on the importance of early diagnosis, that necessitates high-index of suspicion by the obstetrician, in any pregnant woman presenting abnormal neurological signs. CONCLUSION: We conclude that with a cooperative team approach, maternal and fetal prognosis can today be excellent, even in cases of large vestibular schwannomas diagnosed in the late stage of pregnancy.

A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injury in mice.

Brain injury induces disruption of the blood-brain barrier, edema, and release of autodestructive factors that produce delayed neuronal damage. NAPSVIPQ (NAP), a femtomolar-acting peptide, is shown to be neuroprotective in a mouse model of closed head injury. NAP injection after injury reduced mortality and facilitated neurobehavioral recovery (P < 0.005). Edema was reduced by 70% in the NAP-treated mice (P < 0.01). Furthermore, in vivo magnetic resonance imaging demonstrated significant brain-tissue recovery in the NAP-treated animals. NAP treatment decreased tumor necrosis factor-alpha levels in the injured brain and was shown to protect pheochromocytoma (PC12 cells) against tumor necrosis factor-alpha-induced toxicity. Thus, NAP provides significant amelioration from the complex array of injuries elicited by head trauma.

Fibrous connective tissue lesion mimicking a vestibular schwannoma: case report.

OBJECTIVE AND IMPORTANCE: Cerebellopontine angle fibromas are rare pathological entities that can mimic the presentation of vestibular schwannomas (VSs). Diagnosis of these benign lesions, however, is important, because treatment options may be different. The clinical, radiological, and intraoperative features of these unusual lesions of the cerebellopontine angle are discussed, with review of the relevant literature. CLINICAL PRESENTATION: A 41-year-old man presented with recurrent episodes of diminished hearing on the left side, accompanied by facial ticks and pain on the same side. Magnetic resonance imaging and computed tomographic scans revealed a 1.5-cm, primarily intracanalicular lesion, suggesting a left VS. INTERVENTION: The lesion was partially removed through a retrosigmoid suboccipital craniotomy. Its intraoperative appearance and hard fibrotic consistency differed from the classic features of VSs. The pathological findings indicated nontumoral fibrous connective tissue. The lesion exhibited no features of inflammation or fat and was also negative for S-100 staining. Follow-up magnetic resonance imaging scans demonstrated a small residual lesion, which exhibited shrinkage in subsequent magnetic resonance imaging studies. The painful ticks disappeared and facial nerve weakness improved postoperatively. CONCLUSION: Although cerebellopontine angle fibromas may present similar radiological features, their clinical presentation may be somewhat different from that of typical VSs. If a fibroma is suspected, radiosurgery should be avoided; limited surgery may be considered as an option for patients experiencing symptoms. Because fibromas may be intraoperatively noted to be fibrotic and vascular, radical removal may not be easy or justified. After the final diagnosis has been reached, conservative treatment of the residual lesion may be the best option.

Cyst wall enhancement in pilocytic astrocytoma: neoplastic or reactive phenomena.

Cystic pilocytic astrocytomas (CPA) consist of a mural nodule and an accompanying cyst, which may prominently enhance on MRI after contrast administration. This raises the question whether an enhanced wall represents a tumor and thus should be resected together with the solid nodule, as radical tumor surgery is associated with better prognosis. Until now, no systematic histopathological examinations of cyst walls have been reported in correlation with MRI, intraoperative appearance and postoperative clinical and MRI follow-up. We present 3 patients with CPAs and brightly enhanced cyst walls on MRI. Because of the benign, transparent appearance of the cyst wall intraoperatively, it was biopsied but not resected, and only radical removal of the nodule and its immediate surroundings was performed. Separate specimens taken from the cyst wall showed no tumor. MRI performed annually, up to 48-56 months after surgery showed no recurrence of the cyst or the tumor. In such cases of CPA, we suggest that enhancement of cyst walls may represent reactive rather than tumoral tissue, and may be left intact without risking worse prognosis. Mechanisms leading to cyst wall enhancement and the optimal surgical treatment are discussed.

Increasing chronic subdural hematoma after endoscopic III ventriculostomy.

OBJECT: Endoscopic III ventriculostomy (ETV) is an effective and a rather safe treatment for noncommunicating hydrocephalus secondary to aqueductal stenosis and other obstructive pathologies. Though not devoid of risk, ETV is increasingly replacing shunt operations, and it prevents related complications, including overdrainage. METHODS: We report a rare case of a large chronic subdural hematoma (ChSDH) after ETV in a patient with aqueductal stenosis. Three weeks after he was shunted elsewhere, he presented to us with clinical symptoms of intracranial hypotension and overdrainage. ETV was performed and the shunt removed uneventfully. On routine postoperative MRI a few weeks later, a large ChSDH was noted, the patient being totally asymptomatic. Since the ChSDH grew significantly, causing a mass effect on the follow-up MRI, it was finally drained. Large and increasing ChSDHs have previously been reported secondary to overdrainage after shunt placement, but not after ETV. CONCLUSIONS: We conclude that though rare, a ChSDH may evolve even after ETV, if there is a substantial decrease in previously elevated intracranial pressure.

[Folic acid use by pregnant women in Israel for preventing neural tube defects].

Spina bifida and anencephaly are the most common, serious malformations in neural tube defects (NTD). Randomized trials in the last 2 decades have demonstrated that folic acid, 0.4 mg/d, reduces the incidence of NTD by more than 50%. We investigated the use of folic acid and multivitamins containing folic acid in childbearing women. Of 221 women interviewed, 67 (30%) regularly took pills containing 0.4 mg folic acid. Women with higher educational levels were more likely to take multivitamins with folic acid than were the less educated (p = 0.05). Of the women who took folic acid, only 5 (7.5%) used separate folic acid tablets, before and during their pregnancy. The rest used multivitamins containing folic acid. The 5 women who took folic acid separately were college-educated and nonreligious, and they took multivitamins in addition (p > 0.05). Of the women interviewed, 58 (26.2%) were Bedouin of the Negev. 24 (41.4%) of them took pills containing folic acid on a regular basis. This percentage is higher than that in the Jewish women in the study who took folic acid for prevention of NTD (17%; p = 0.038). Most of the women took folic acid after the first trimester. Only a minority took daily periconceptional folic acid. Multivitamins containing 0.4 mg of folic acid were more popular than folic acid tablets alone. This study emphasizes the need for continuing efforts to increase consumption of folic acid and awareness of its benefits among women of childbearing age.

Epidural hematoma in infants: a different entity?

BACKGROUND: Epidural hematoma (EDH) in infants may be difficult to diagnose. The mechanism of injury and the clinical presentation are different from those in older children. We characterized the clinical and radiologic parameters of EDH in infants and correlated them with outcome. Because there are no optimal prognostic tools or clear guidelines to perform computed tomography in this unique population, a new approach of neurotrauma scoring is suggested. METHODS: Eleven infants (<2 years old) operated on for EDH were studied. Children's Glasgow Coma Scale (CCS) score was applied, and diagnosis was confirmed by computed tomography. RESULTS: Age was 13+/-5 months. Seven infants (63.6%) fell from less than 1 m. CCS score on admission was 10.7+/-3.9. Five infants (45%) were unconscious, yet two (18.2%) had CCS scores of 15. Pupillary abnormalities were found in two infants and lateralizing signs in five infants. Eight infants (72.7%) had subgaleal hematomas. Mortality and morbidity were 9% each. CONCLUSION: We suggest that a Trauma Infant Neurologic Score be used when dealing with EDH in infants. Lateralizing signs, pupillary abnormalities, mechanism of trauma, and scalp injuries should be included because these are objective relevant parameters.

Giant lateral sinus pericranii. Case report.

A case of giant lateral sinus pericranii, which presented in a patient during early childhood as a soft, collapsible mass and gradually grew until it reached 13 x 9 cm when the patient was 36 years of age, is reported. The patient underwent successful surgery and the lesion was totally excised. The results of diagnostic tests (computerized tomography scanning, magnetic resonance imaging, cerebral angiography, and sinusography) and surgery-related problems are presented and discussed.

Spinal echinococcal cyst: treatment using computerized tomography-guided needle aspiration and hypertonic saline irrigation. Case report.

A multilocular extradural cervical spinal hydatid cyst that causes severe spinal cord compression and quadriplegia is relatively rare and difficult to treat. In a patient with this disorder, computerized tomography-guided needle aspiration of the cyst loculations and irrigation using hypertonic saline eliminated the need for emergency surgery and provided complete resolution of the patient's quadriplegia. The subsequent course of the disease was controlled by treatment with albendazole. Magnetic resonance imaging performed 4 months after the procedure demonstrated collapsed cysts and absence of spinal cord compression.