Impaired folate 1-carbon metabolism causes formate-preventable hydrocephalus in glycine decarboxylase-deficient mice.

Ventriculomegaly and hydrocephalus are associated with loss of function of glycine decarboxylase (Gldc) in mice and in humans suffering from non-ketotic hyperglycinemia (NKH), a neurometabolic disorder characterized by accumulation of excess glycine. Here, we showed that ventriculomegaly in Gldc-deficient mice is preceded by stenosis of the Sylvian aqueduct and malformation or absence of the subcommissural organ and pineal gland. Gldc functions in the glycine cleavage system, a mitochondrial component of folate metabolism, whose malfunction results in accumulation of glycine and diminished supply of glycine-derived 1-carbon units to the folate cycle. We showed that inadequate 1-carbon supply, as opposed to excess glycine, is the cause of hydrocephalus associated with loss of function of the glycine cleavage system. Maternal supplementation with formate prevented both ventriculomegaly, as assessed at prenatal stages, and postnatal development of hydrocephalus in Gldc-deficient mice. Furthermore, ventriculomegaly was rescued by genetic ablation of 5,10-methylene tetrahydrofolate reductase (Mthfr), which results in retention of 1-carbon groups in the folate cycle at the expense of transfer to the methylation cycle. In conclusion, a defect in folate metabolism can lead to prenatal aqueduct stenosis and resultant hydrocephalus. These defects are preventable by maternal supplementation with formate, which acts as a 1-carbon donor.

Did Ibn Zuhr (Avenzoar) Postulate Before Vesalius That Liquid Collects in Ventricles in the Hydrocephalus?

OBJECTIVE: This study aimed to present and evaluate the part of Avenzoar's Liber Teisir that pertains to hydrocephalus. Avenzoar was an Andalusian physician prominent in the history of medicine because of the broadness of his observations and original methods. His most important work is recognized to be the Al-Taysir fi al-Mudawat wa al-Tadbir (On Preventive Regimen and Treatment), and its Latin version, Alteisir scilicet regiminis et medelae, which was in use for centuries in Europe. METHODS: The Arabic (Rabat, Morocco, in 1991) and Latin (Venice, Italy, in 1530) versions of Avenzoar's work were perused, relevant sections were separately translated into English, and both translations were then compared. An English version was prepared and is given in our results. RESULTS: The location of liquid collection was described as the anterior ventricles of the brain and around the brain. CONCLUSIONS: Avenzoar might have noted one of the earliest records on the clinical state called idiopathic adult hydrocephalus and postulated liquid collection in the ventricles of the brain in hydrocephalus before Vesalius.

Nimodipine treatment does not benefit juvenile ferrets with kaolin-induced hydrocephalus.

Prior research on 3-week hydrocephalic rats showed that behavioral deficits and white matter damage could be reduced by treatment with Ca2+ channel blocker nimodipine. We hypothesized that treatment with nimodipine would be also beneficial to young ferrets with kaolin-induced hydrocephalus. Hydrocephalus was induced at 14 days of age and animals were treated either with vehicle, low dose nimodipine (3.2 mg/kg/day), or high dose nimodipine (16 mg/kg/day) for 2 weeks from 38 to 52 days age. Hydrocephalic ferrets developed progressive ventriculomegaly, behavioral changes, and in some cases cortical blindness. These changes were not ameliorated by nimodipine. Histological examination showed damage in periventricular white matter, corpus callosum thinning, axonal damage, reactive astroglial changes, and suppressed cell proliferation compared to non-hydrocephalic controls. Treatment with nimodipine was not beneficial for any of the pathological changes mentioned above; only low dose nimodipine treatment was associated with normalized content of glial fibrillary acidic protein, despite larger ventricles. We conclude that young hydrocephalic ferrets experience behavioral impairments and structural brain damage that are not consistently improved by intermittent nimodipine treatment. Continuous delivery should be considered in further preclinical studies.

Hyperbaric oxygen therapy reduces astrogliosis and helps to recovery brain damage in hydrocephalic young rats.

PURPOSE: We investigated the possible beneficial effects that hyperbaric oxygen therapy could offer in different brain structures affected by ventriculomegaly in pup rats submitted to experimental hydrocephalus. METHODS: Seven-day-old Wistar rats were submitted to hydrocephalus by intracisternal injection of 10% kaolin into the cisterna magna. The animals were divided into four groups: control (n = 5); control with HBOT (3ATA/2 h/day) (n = 5); untreated hydrocephalic (n = 10); hydrocephalic treated with HBOT (3ATA/2 h/day) (n = 10). The treatment with HBOT was performed daily for 14 days post-induction of hydrocephalus. To evaluate the response to treatment, behavioral tests (open field, Morris water maze, and activity monitor) were performed. After 14 days, the animals were euthanized, and the brain was removed for histological (hematoxylin-eosin and solochrome-cyanine) and immunohistochemical (GFAP and Ki-67) studies. RESULTS: The hyperbaric treatment, although not causing changes in ventricular enlargement, resulted in a significant improvement in the behavioral performance (p = 0.0001), with greater agility and exploration of the environment, preservation of spatial memory, and greater learning capacity (p = 0.0001). Through the immunohistochemical study, the astrocytic activity (glial fibrillary acidic protein) in the corpus callosum (p = 0.0001) and in the germinative matrix (p = 0.0033) was significantly reduced as compared to that in the H group. CONCLUSION: The results suggest that hyperbaric treatment bettered the behavioral performance and offered benefits to the structures affected by the ventricular increase helping to recover the brain damages. In this way, the HBOT it can be considered an adjuvant therapy for the treatment of hydrocephalus.

Semiquantitative analysis of hypothalamic damage on MRI predicts risk for hypothalamic obesity.

OBJECTIVE: Excessive weight gain frequently occurs in patients with hypothalamic tumors and lesions leading to hypothalamic obesity (HO). METHODS: Digital brain magnetic resonance imaging (MRI) and clinical outcomes were studied retrospectively in a single center, including 45 children with postoperative lesions in the sellar region (41 craniopharyngiomas, 4 with Rathke's cleft cysts), ∼5 years post-surgery, mean age 13.9 years. Four standard sections covering hypothalamic areas critical to energy homeostasis were used to assess lesions and calculate a hypothalamic lesion score (HLS); the association with HO was examined. RESULTS: Compared to subjects who did not develop HO (n = 23), subjects with HO (n = 22) showed more frequently lesions affecting the third ventricular floor, mammillary bodies, and anterior, medial (all P < 0.05), and most importantly posterior hypothalamus (P < 0.01). The HLS correlated significantly with BMI z-score changes 12 and 30 months post-surgery, even after adjusting for potential confounders of gender, age at surgery, surgery date, surgery BMI z-score, hydrocephalus, and residual hypothalamic tumor (r = 0.34, P = 0.03; r = 0.40, P = 0.02, respectively). Diabetes insipidus was found to be an endocrine marker for HO risk. CONCLUSIONS: The extent of damage following surgery in the sellar region can be assessed by MRI using a novel scoring system for early HO risk assessment.

Camellia sinensis neuroprotective role in experimentally induced hydrocephalus in Wistar rats.

PURPOSE: This study tested possible neuroprotective effects of Camellia sinensis-extracted polyphenols in experimental hydrocephalus in young rats. METHODS: Seven-day-old Wistar rats were used in this study. Pups were subjected to hydrocephalus induction by 20 % kaolin intracisternal injection. The polyphenol was administered intraperitoneally for 9 or 20 days from the induction of hydrocephalus. Clinical observations and behavioral tests were performed once a day. The animals, deeply anesthetized, were sacrificed by cardiac perfusion with saline 10 or 21 days after induction of hydrocephalus and their brains were removed. Preparations were made for histological analysis by hematoxylin and eosin, solochrome-cyanine, and immunohistochemistry for GFAP. RESULTS: Histopathological analysis showed that animals treated with the polyphenol for 9 consecutive days displayed reduction on astrocyte activity on the corpus callosum and external capsule, shown by GFAP immunostaining. They also displayed thicker and myelinated corpus callosum, exhibiting a more intense solochrome-cyanine blue staining. CONCLUSION: Although these results demonstrate a possible neuroprotective effect at the initial onset of the disease, additional studies should be performed to obtain an effective and safe therapy for deeper studies in clinical trials.

Bilateral thalamic lesions.

OBJECTIVE: Bilateral thalamic lesions are rare and relatively obscure neoplasms. We present our experience with nine cases of bilateral thalamic lesions and attempt to analyse them in the background of available literature. MATERIALS AND METHODS: Retrospective analyses of the case records of 9 cases of bilateral thalamic lesions treated in our department since January 2002, which have a minimum of 1 year follow-up. RESULTS: The study group included four males and five females with a mean age of 14.6 years (5 years to 29 years). Seven of these patients had radiological evidence of bilateral thalamic lesions at presentation and 2 patients had involvement of the opposite thalamus at a later stage of the disease. All patients except one presented with raised intracranial pressure symptoms. Focal motor deficits (4/9), behavioral and memory disturbances (3/9) were the other major presenting symptoms. Biopsy confirmation was possible in six patients and histopathology was suggestive of low grade fibrillary astrocytoma in all six patients. Seven patients required CSF diversion procedure for associated hydrocephalus. Eight of our nine patients underwent radiotherapy. On last follow-up, 3 patients were clinically stable with images suggestive of arrested disease, four patients had evidence of progressive disease both clinically and radiologically and there were two recorded cases of mortality. CONCLUSION: Primary bilateral thalamic lesions have characteristic neuroradiological properties and are distinct from unilateral thalamic tumours with bilateral progression. Almost all of these lesions on histology prove to be gliomas but decompressive surgery is seldom feasible. Surgical intervention is limited to biopsy and CSF diversion for hydrocephalus. Bilateral thalamic lesions remain unresponsive to adjuvant therapy and generally carry a poor prognosis.

Neuropathology and structural changes in hydrocephalus.

In the context of spina bifida, hydrocephalus is usually caused by crowding of the posterior fossa with obstruction to cerebrospinal fluid flow from the forth ventricle, and less often by malformation of the cerebral aqueduct. Enlargement of the cerebral ventricles causes gradual destruction of periventricular white matter axons. Motor, sensory, visual, and memory systems may be disturbed through involvement of the long projection axons, periventricular structures including the corpus callosum, and the fimbria-fornix pathway. Secondary changes occur in neuronal cell bodies and synapses, but there is minimal death of neurons. The clinical syndrome of hydrocephalic brain dysfunction is thus due to subcortical disconnection. Some of the brain dysfunction is reversible by shunting, probably through restoration of cerebral blood flow and normalization of the extracellular environment. However, destroyed axons cannot be restored.

Addressing a folate imbalance in fetal cerebrospinal fluid can decrease the incidence of congenital hydrocephalus.

Fetal-onset hydrocephalus (HC), which affects between 1:500 and 1:5000 live human births, results from unequal production and drainage of cerebrospinal fluid (CSF) and is associated with abnormal development of the cerebral cortex leading to severe neurological deficits. We previously found that in the hydrocephalic Texas rat, the CSF of affected fetuses induced a cell cycle arrest in neural progenitor cells. Here, we show that alterations in folate metabolism in the CSF of the developing cerebrum are likely responsible for this effect. We identified 3 folate enzymes in the CSF and demonstrate that low levels of one of these, 10-formyltetrahydrofolate dehydrogenase, are associated with HC in the hydrocephalic Texas rat. Therefore, we tested whether supplementation with specific folate species would improve developmental outcome. After daily administration of a combination of tetrahydrofolic and 5-formyltetrahydrofolic acids to pregnant dams, there was a significant reduction in the incidence of HC and improved brain development. By contrast, supplementation with folic acid increased the incidence of congenital HC in this model. These results indicate the complexities of folate metabolism in the developing brain and suggest that folate imbalance leading to HC in the hydrocephalic Texas rat fetuses can be treated with maternal folate supplementation using specific folate metabolites and combinations thereof.

Papillary tumor of the pineal region: a case report.

We report a case of papillary tumor of the pineal region (PTPR) and describe the morphological, immunohistochemical, and neuroimaging findings. A 43-year-old man presented with signs of increased intracranial pressure and upward gaze palsy. Magnetic resonance (MR) imaging demonstrated a heterogeneously enhanced mass in the pineal region and obstructive hydrocephalus. Proton MR spectroscopy revealed increased choline and decreased N-acetyl aspartate peaks with a slightly increased lactate peak. Minimum apparent diffusion coefficient value was 0.60 x 10(-3) mm2/s. Positron emission tomography showed significantly increased [18F]fluorodeoxyglucose uptake at the site of the lesion. He underwent total resection of the pineal region mass, resulting in resolution of the symptoms. The tumor consisted of columnar and cuboidal cells, with papillary growth pattern. Immunohistochemical staining showed positive reaction for neuron-specific enolase, S-100 protein, and vimentin. Ki-67 labeling index (LI) was 13.1%. These features were consistent with PTPR. Postoperatively, the patient received radiochemotherapy, and maintenance chemotherapy at our outpatient clinic, and was doing well without tumor recurrence 1 year after the surgery. Although the morphological features agree with those in the original description of the PTPR, the Ki-67 LI and radiologic findings suggest the malignant nature and the necessity for adjuvant therapy.

Mesencephalic ependymal cysts: treatment under pure endoscopic or endoscope-assisted keyhole conditions.

OBJECT: Primary intracranial ependymal cysts are extremely rare. Similar to congenital intraparenchymal cysts in the mesencephalon they usually occur with symptoms of an occlusive hydrocephalus or symptoms like Parinaud syndrome, dizziness, or gait disturbance. The objective of this study was to evaluate the surgical methods for the treatment of these cysts and the clinical outcome of the patients. METHODS: The authors present the clinical records of 8 patients who were treated in their department for symptomatic mesencephalic ependymal cysts in the past 10 years. The patient age ranged from 22 to 60 years with a mean age of 44 years. In 4 cases the authors performed a suboccipital infratentorial supracerebellar approach by using endoscope-assisted microsurgery. The other 4 patients underwent a pure endoscopic procedure over a frontal bur hole trepanation. RESULTS: Four patients became symptom free, and the remaining 4 improved significantly after a mean follow-up duration of 38.5 months (range 5-119 months). One patient underwent 2 operations: first a ventriculocystostomy and 4 months later endoscopic third ventriculostomy because of recurrent hydrocephalus. In 1 case a second surgery was necessary because of a wound infection. In all of the patients an adequate fenestration of the cyst was achieved. CONCLUSIONS: A symptomatic mesencephalic ependymal cyst is an indication for neurosurgical intervention. These cysts can be treated successfully and most likely definitively by a pure endoscopic or endoscope-assisted keyhole neurosurgical technique. There were no morbid conditions or death due to the procedures in this group of 8 patients. Therefore, the authors regard these surgical procedures to be good alternatives to treatments such as shunt placement or stereotactic aspiration of the cysts.

Bimedial rectus hypermetabolism in convergence spasm as observed on positron emission tomography.

A 52-year-old man developed vertical gaze palsy, convergence spasm, and convergence-retraction nystagmus due to glioblastoma of the right thalamus. 18F-fluorodeoxyglucose positron emission tomography (PET) inadvertently demonstrated markedly increased metabolism in the medial rectus muscles. The hypermetabolism indicates active contraction of these extraocular muscles due to excessive convergence drive attributed to inappropriate activation or disrupted inhibition of convergence neurons by the diencephalic lesion.

Prognostic significance of third ventricle dilation in spontaneous intracerebral hemorrhage: a preliminary clinical study.

OBJECTIVE: Although numerous factors have been described that predict outcome after spontaneous intracerebral hemorrhage (ICH), very little is know about the role of hemorrhagic dilation of the third ventricle in development of hydrocephalus and prognosis. The objective of this study was to investigate whether the presence of hemorrhagic third ventricle dilation after ICH would predict development of hydrocephalus and outcome. METHODS: We identified the patients with spontaneous ICH treated with external ventricular drainage (EVD) in this retrospective study. Computerized tomography (CT) was performed at admission within 24 hours of onset and retrospectively analysed to determine lesion size and location, status of third and fourth ventricle and frontal horn index (FHI). Glasgow coma scale (GCS) score, mean arterial pressure (MAP), etiology and demographic data were obtained from medical records. Outcome was determined using modified Rankin score at month 3. Patients with and without third ventricle dilation were compared in terms of hydrocephalus (FHI > 0.38), initial GCS score, age and MAP, and analyses were performed to determine whether third ventricle dilation was a predictor of poor outcome. RESULTS: Of the 22 patients studied, all had thalamic or basal ganglia hemorrhage with intraventricular hemorrhage (IVH) and all are treated with external ventricular drainage (EVD). Of the 22 patients, 12 had third ventricle dilation (width > or = 10 mm) and ten patients had non-dilated third ventricle (width < 10 mm). Patients with third ventricle dilation had lower GCS scores (7.4 +/- 1.8 versus 9.7 +/- 2.1, p < 0.005) and had higher FHI (0.46 +/- 0.06 versus 0.38 +/- 0.02, p < 0.005) as compared to patients with non-dilated third ventricle. The differences in age (59.5 +/- 9.4 versus 59.2 +/- 11.2) and MAP (128.3 +/- 16.0 versus 130.5 +/- 13.6) of the patients were not significant statistically. Sixty-six percent of patients (8/12) with third ventricle dilation and 60% of patients (6/10) with normal third ventricle were dead 6 months post-operation and mortality rate did not differ significantly. DISCUSSION: Although the roles of various factors are well described in the prognosis of spontaneous ICH, little is known about the role of third ventricle dilation. Based on our results, we concluded that third ventricle dilation is a poor prognostic factor.

Effects of congenital hydrocephalus on the hypothalamic gonadotrophin-releasing hormone system.

OBJECT: Despite the investigations that have linked hydrocephalus to reproductive system abnormalities, no researchers have attempted to identify the pathophysiological mechanism of this relationship. Because the role of the hypothalamic gonadotrophin-releasing hormone (GnRH) system in the regulation of reproductive functions is well established, the authors used immunohistochemical and radioimmunoassay (RIA) techniques to determine the morphological and biochemical effects of hydrocephalus on the hypothalamic GnRH system. METHODS: Hypothalamic GnRH levels, fiber density, and cell types were studied in 21- and 50-day-old control and congenitally hydrocephalic Texas rats. Results of RIA indicated a significant (8.4%) increase in GnRH in 21-day-old hydrocephalic rats (9.17 +/- 0.64 pg/ng total protein) compared with that in controls (0.97 +/- 0.74 pg/ng total protein). In addition, the 50-day-old hydrocephalic animals had a significantly higher level of GnRH compared with age-matched controls (20.4 pg/ng compared with 1.88 +/- 2.1 pg/ng total protein). This increase was accompanied by changes in the fiber appearance and a shift from low GnRH producing cells to high GnRH producing cells in the hydrocephalic animals; however, there was no significant difference in the fiber density between the control and hydrocephalic animals at 21 days. In addition, poor neurological scores correlated with the severity of hydrocephalus. CONCLUSIONS: These results demonstrated that hypothalamic GnRH levels are significantly affected by fetal-onset hydrocephalus and that the mechanisms responsible for these effects may take place at the cellular rather than the gross structural level. Furthermore, they suggest that impairments in the GnRH system may be protracted in neonates and infants with hydrocephalus, and thus may be overcome by relatively early treatment with ventricular diversion. However, the clinical implications of GnRH perturbations in shunt-dependent patients must await a forthcoming study in shunted animals.

[Effect of salvianolic acid B on brain energy metabolism and hydrocephalus of cerebral ischemia in mice at different time].

Mice pathological model of acute cerebral ischemia was established. In order to observe the effect of salvianolic acid B (Sal B) on brain energy metabolism and hydrocephalus in the brain of mice at different ischemic times, the energy charge (EC), content of phosphocreatine (PCr), level of lactic acid (Lac), activity of Na+ -K+ -ATPase, brain index and water content of brain were measured at 6, 12, 18, 24, and 30 min, separately after ligating bilateral common carotid arteries in mice. NIH mice were randomly divided into sham-operated group (sham), cerebral ischemia group (ischemia), Sal B-treated group (Sal B) and nimodipine-collated group (Nim). At 6 min after cerebral ischemia, EC, content of PCr and activity of Na +-K -ATPase began to decrease, while level of Lac, brain index and water content of brain increased gradually. However, Sal B (22.5 mg x kg(-1) improved pathophysiological changes at different ischemic times. Especially at 30 min after cerebral ischemia in Sal B group, EC (P < 0.01), content of PCr (P < 0.01 and activity of Na+ -K+ -ATPase ( < 0.05) increased significantly. Meanwhile, level of Lac (P < 0.01, brain index (P < 0.01) and water content of brain (P < 0.05) were lower obviously than those of cerebral ischemia group. Sal B could alleviate hydrocephalus by the improvement of energy metabolism in mice with acute cerebral ischemia, that provides scientific evidence that Sal B can be used for the clinical application of ischemic diseases.

X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia.

We describe a family with an X-linked dominant chondrodysplasia. Four males and six females were affected through four generations. Identification of skeletal abnormalities and hydrocephaly during the pregnancy of three male fetuses led to termination of the pregnancies. A fourth affected male died at 6 days of life. The four patients had chondrodysplasia, hydrocephaly, and facial features with microphthalmia. Radiographs showed severe platyspondyly and various bone abnormalities including a distinctive metaphyseal cupping of the metacarpals, metatarsals, and phalanges. The affected females were less affected and showed small stature, sometimes associated with body asymmetry and mild mental retardation. This condition appears to be a previously unrecognized X-linked dominant chondrodysplasia.

Primary intra-axial leiomyosarcoma with obstructive hydrocephalus in a young dog.

A female Chihuahua dog aged 2 months had a 3-week history of progressive neurological signs (abnormal behaviour, disorientation, left-sided circling, and incessant whimpering). Necropsy revealed a primary leiomyosarcoma in the midline of the posterior thalamus with secondary obstructive hydrocephalus of the lateral ventricles. Grossly, an infiltrative, grey-white tumour had partly invaded the third ventricle. Histologically, the tumour formed hypercellular, interlacing bundles of neoplastic spindle cells with blunt-ended nuclei. Neoplastic cells were strongly immunoreactive for vimentin and both muscle-specific and alpha-smooth muscle actin; MIB-1 immunoreactivity indicated a proliferative index of up to 5%. Leiomyosarcoma should be included in the differential diagnosis for primary brain tumours and hydrocephalus in young dogs.

Surgical considerations regarding giant dilations of the perivascular spaces.

OBJECT: Dilations of brain perivascular spaces (PVSs), also known as Virchow-Robin spaces, are routinely identified on magnetic resonance imaging studies of the brain and recognized as benign normal variants. Giant dilations occur only rarely and can be easily misdiagnosed as central nervous system tumors. The relevant surgical literature was reviewed to help establish indications for surgical intervention in these typically benign lesions. METHODS: Giant dilations of the PVSs in 12 patients who had undergone surgery for several different indications were identified. Both clinical and radiographic presentations of these patients were reviewed along with the surgical procedures. CONCLUSIONS: Dilations of the PVSs can become giant lesions that may necessitate surgical intervention to relieve mass effect or hydrocephalus. The relationship of these lesions to neurological symptoms such as tremor and seizures remains unclear.

Thalamic retrograde degeneration in the congenitally hydrocephalic rat is attributable to apoptotic cell death.

Congenitally hydrocephalic HTX rats develop ventricular dilatation with extensive damage of the cerebral white matter. Recently, we have reported that neuronal cell death also occurs in the thalamus of HTX rats. To investigate the mechanism underlying this thalamic degeneration in these animals, we carried out a histopathological study of the brain at different phases of postnatal development. Eosinophilic neurons with condensed chromatin or fragmented nuclei were observed in the thalamus from postnatal day 17 onward. The incidence of cell death in the thalamus increased with the progression of hydrocephalus. Ultrastructurally, thalamic neurons occasionally had apoptotic features including nuclear chromatin condensation and marginalization. Immunohistochemically, single-stranded DNA-positive neuronal nuclei were found in the thalamus. They were also positively stained with the TUNEL method. Marked loss of myelin and axons with many TUNEL-positive oligodendrocytes were found in the cerebral white matter. These findings suggest that the neuronal cell death observed in the thalamus in hydrocephalic HTX rats is retrograde degeneration due to extensive damage of axons in the cerebral white matter and that the thalamic retrograde degeneration is attributable to apoptotic cell death.

Gliomatosis cerebri: pitfalls in diagnosis.

We report two young patients with obscure presentations of gliomatosis cerebri. Initial CT scanning was inconclusive and in one case showed intraventricular haemorrhage, a feature not previously described. Magnetic resonance imaging was required to show the lesions with greater definition; however, in both cases, a biopsy was needed to confirm the diagnosis.