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Hugh J. L. Garton, John R. W. Kestle and James M. Drake

Object. In evaluating pediatric patients for shunt malfunction, predictive values for symptoms and signs are important in deciding which patients should undergo an imaging study, whereas determining clinical findings that correlate with a low probability of shunt failure could simplify management.

Methods. Data obtained during the recently completed Pediatric Shunt Design Trial (PSDT) were analyzed. Predictive values were calculated for symptoms and signs of shunt failure. To refine predictive capability, a shunt score based on a cluster of signs and symptoms was derived and validated using multivariate methods.

Four hundred thirty-one patient encounters after recent shunt insertions were analyzed. For encounters that took place within 5 months after shunt insertion (early encounters), predictive values for symptoms and signs included the following: nausea and vomiting (positive predictive value [PPV] 79%, likelihood ratio [LR] 10.4), irritability (PPV 78%, LR 9.8), decreased level of consciousness (LOC) (PPV 100%), erythema (PPV 100%), and bulging fontanelle (PPV 92%, LR 33.1). Between 9 months and 2 years after shunt insertion (late encounters), only loss of developmental milestones (PPV 83%, LR 36.7) and decreased LOC (PPV 100%) were strongly associated with shunt failure. However, the absence of a symptom or sign still left a 15 to 29% (early encounter group) or 9 to 13% (late encounter group) chance of shunt failure. Using the shunt score developed for early encounters, which sums from 1 to 3 points according to the specific symptoms or signs present, patients with scores of 0, 1, 2, and 3 or greater had shunt failure rates of 4%, 50%, 75%, and 100%, respectively. Using the shunt score derived from late encounters, patients with scores of 0, 1, and 2 or greater had shunt failure rates of 8%, 38%, and 100%, respectively.

Conclusions. In children, certain symptoms and signs that occur during the first several months following shunt insertion are strongly associated with shunt failure; however, the individual absence of these symptoms and signs offers the clinician only a limited ability to rule out a shunt malfunction. Combining them in a weighted scoring system improves the ability to predict shunt failure based on clinical findings.

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Abhaya V. Kulkarni, James M. Drake, Derek C. Armstrong and Peter B. Dirks

Object. The goal of this study was to determine and compare imaging correlates in pediatric patients who underwent successful or failed endoscopic third ventriculostomies (ETVs). To this end, the authors measured ventricular size changes and the presence of cerebrospinal fluid (CSF) flow void in both groups of children following ETV.

Methods. Images obtained in children with hydrocephalus immediately before and at least 30 days after having undergone ETV were reviewed by four independent observers (two blinded and two nonblinded). Each observer independently measured the frontal and occipital horn ratio ([FOR], a reliable and valid measure of ventricular size) and provided a subjective assessment of the presence of a flow void at the ETV site, the degree of periventricular edema, and the amount of CSF over the cerebral hemispheres.

There were 29 children whose mean age was 6.6 years at the time of ETV and who had a mean postoperative follow-up period lasting 1.6 years. Postoperatively, the mean reduction in ventricular size (as measured using the FOR) was 7% (95% confidence interval [CI] 3–11%) in cases that were deemed failures (eight patients) and 16% (95% CI 12–20%) in clinically successful cases (21 patients). This reduction was significantly greater in cases of clinical success compared with those that were deemed failures (p = 0.03, t-test). There were no substantial differences between blinded and nonblinded assessments. Flow void was present in 94% of successes and absent in 75% of failures (p = 0.01, Fisher's exact test). The other subjective assessments were not significantly different between the groups of successes and failures.

Conclusions. Ventricular size appears to be somewhat reduced in both groups of patients who underwent clinically successful and failed ETV; however, the reduction is significantly greater among clinically successful cases. The presence of a flow void also appears to correlate with clinical success and its absence with clinical failure.

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Abhaya V. Kulkarni, Laurence E. Becker, Venita Jay, Derek C. Armstrong and James M. Drake

✓ Primary cerebellar glioblastomas multiforme are exceedingly rare in children. The authors therefore retrospectively characterized the clinical behavior and pathological features of these tumors. A review of the database at the Hospital for Sick Children, Toronto, Canada revealed four patients with cerebellar tumors that displayed significant pleomorphism, hypercellularity, mitoses, and necrosis with pseudopalisading. The authors performed a detailed clinical, radiological, histological, and immunohistochemical analysis of the tumors in these four children (three boys and one girl; average age at presentation 7 years; range 21 months–15 years). Magnetic resonance imaging and computerized tomography most commonly revealed a large lesion with minimal edema, inhomogeneous contrast enhancement, and a discrete border. Tumor resection was subtotal in one patient and gross total in three patients. Immunostaining of the tumor cells with antisera to glial fibrillary acidic protein and vimentin was positive in varying degrees. Initial adjuvant therapy consisted of local radiation only (one patient), chemotherapy only (one patient), and radiation and chemotherapy (one patient). One patient received no adjuvant therapy. Tumor recurrence was documented in all patients: two local recurrences (at 3.5 and 7 months), one spinal recurrence (at 14 months), and one local recurrence with ventricular and spinal spread (at 8 months). Ultimately, three of the four patients developed leptomeningeal tumor spread. Patient follow up ranged from 8 to 17 months (mean 12.5 months). Three patients were dead at last follow up with a mean survival of 15 months.

The prognosis for patients with cerebellar glioblastomas is extremely poor, and the tumor has a tendency for cerebrospinal fluid dissemination. The optimal management of patients harboring of these difficult-to-treat tumors, including the role of craniospinal radiation and chemotherapy, has not yet been achieved.

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Yuzuru Tashiro and James M. Drake

Intellectual impairment has been related to alteration of neuronal innervation in the following regions: cholinergic basal forebrain nuclei (Ch1–Ch6, learning and memory), dopaminergic ventral tegmental area (emotional control), and noradrenergic locus ceruleus (cognition). Recent studies have implicated neuronal injury in the pathogenesis of hydrocephalus.

Object. The authors used immunohistochemical techniques to investigate functional injury in these regions in animals with progressive hydrocephalus, following shunt placement for cerebrospinal fluid (CSF) drainage.

Methods. Hydrocephalus was induced in 20 Wistar rats by intracisternal injection of 0.05 ml of 25% kaolin solution. Four control animals (Group 1) received the same volume of saline. Ventriculoperitoneal shunts were inserted in eight rats at 2 and 4 weeks after kaolin injection and the animals were killed at 8 weeks (Group 2). The other 12 hydrocephalic animals were killed at 2, 4, and 8 weeks without undergoing shunt placement (Group 3). Immunoreactive (IR) neurons to choline acetyltransferase (ChAT) in Ch1–Ch6, tyrosine hydroxylase (TH) in the ventral tegmental area, and dopamine B-hydroxylase (DBH) in the locus ceruleus, as well as IR projection fibers in the terminal areas, were compared between groups. The number of ChAT- and TH-IR neurons in rats with and without shunt placement was counted for quantitative analysis. The number of ChAT-IR neurons was progressively reduced during the development of hydrocephalus in Ch1, Ch2, Ch3, and Ch4 (p < 0.05). Tyrosine-hydroxylase-immunoreactive neurons were also reduced in number, and demonstrated decreased projection fibers and terminals. Early shunting (at 2 weeks) restored ChAT and TH immunoreactivity to control levels, but late shunting (at 4 weeks) did not (p < 0.05). The DBH—IR neurons in the locus ceruleus were remarkably compressed by the dilated fourth ventricle, and diminished immunoreactivity was observed in the terminal areas. Shunt placement for CSF also restored the immunoreactivity in this system.

Conclusions. These findings indicate that a progressive functional injury occurs in the cholinergic, dopaminergic, and noradrenergic systems as a result of hydrocephalus. This may contribute to intellectual impairment and might be prevented by early treatment with shunt placement.

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Yuzuru Tashiro, Shushovan Chakrabortty, James M. Drake and Toshiaki Hattori

✓ The authors investigated functional neuronal changes in experimental hydrocephalus using immunohistochemical techniques for glutamic acid decarboxylase (GAD) and two neuronal calcium-binding proteins: parvalbumin (PV) and calbindin D28K (CaBP).

Hydrocephalus was induced in 16 adult Wistar rats by intracisternal injection of a kaolin solution, which was confirmed microscopically via atlantooccipital dural puncture. Four control rats received the same volume of sterile saline. Immunohistochemical staining for GAD, PV, and CaBP, and Nissl staining were performed at 1, 2, 3, and 4 weeks after the injection. Hydrocephalus occurred in 90% of kaolin-injected animals with various degrees of ventricular dilation. In the cerebral cortex, GAD-, PV-, and CaBP-immunoreactive (IR) interneurons initially lost their stained processes together with a concomitant loss of homogeneous neuropil staining, followed by the reduction of their total number. With progressive ventricular dilation, GAD- and PV-IR axon terminals on the cortical pyramidal cells disappeared, whereas the number of CaBP-IR pyramidal cells decreased, and ultimately in the most severe cases of hydrocephalus, GAD, PV, and CaBP immunoreactivity were almost entirely diminished. In the hippocampus, GAD-, PV-, and CaBP-IR interneurons demonstrated a reduction of their processes and terminals surrounding the pyramidal cells, with secondary reduction of CaBP-IR pyramidal and granular cells. On the other hand, Nissl staining revealed almost no morphological changes induced by ischemia or neuronal degeneration even in the most severe cases of hydrocephalus.

Hydrocephalus results in the progressive functional impairment of GAD-, PV-, and CaBP-IR neuronal systems in the cerebral cortex and hippocampus, often before there is evidence of morphological injury. The initial injury of cortical and hippocampal interneurons suggests that the functional deafferentation from intrinsic projection fibers may be the initial neuronal event in hydrocephalic brain injury. Although the mechanism of this impairment is still speculative, these findings emphasize the importance of investigating the neuronal pathophysiology in hydrocephalus.

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Yuzuru Tashiro, Shushovan Chakrabortty, James M. Drake and Toshiaki Hattori

The authors investigated functional neuronal changes in experimental hydrocephalus using immunohistochemical techniques for glutamic acid decarboxylase (GAD) and two neuronal calcium-binding proteins: parvalbumin (PV) and calbindin D28K (CaBP).

Hydrocephalus was induced in 16 adult Wistar rats by intracisternal injection of a kaolin solution, which was confirmed microscopically via atlantooccipital dural puncture. Four control rats received the same volume of sterile saline. Immunohistochemical staining for GAD, PV, and CaBP and Nissl staining were performed at 1, 2, 3, and 4 weeks after the injection. Hydrocephalus occurred in 90% of kaolin-injected animals with various degrees of ventricular dilation. In the cerebral cortex, GAD-, PV-, and CaBP-immunoreactive (IR) interneurons initially lost their stained processes together with a concomitant loss of homogeneous neuropil staining, followed by the reduction of their total number. With progressive ventricular dilation, GAD- and PV-IR axon terminals on the cortical pyramidal cells disappeared, whereas the number of CaBP-IR pyramidal cells decreased, and ultimately in the most severe cases of hydrocephalus, GAD, PV, and CaBP immunoreactivity was almost entirely diminished. In the hippocampus, GAD-, PV-, and CaBP-IR interneurons demonstrated a reduction of their processes and terminals surrounding the pyramidal cells, with secondary reduction of CaBP-IR pyramidal and granular cells. On the other hand, Nissl staining revealed almost no morphological changes induced by ischemia or neuronal degeneration even in the most severe cases of hydrocephalus.

Hydrocephalus results in the progressive functional impairment of GAD-, PV-, and CaBP-IR neuronal systems in the cerebral cortex and hippocampus, often before there is evidence of morphological injury. The initial injury of cortical and hippocampal interneurons suggests that the functional deafferentation from intrinsic projection fibers may be the initial neuronal event in hydrocephalic brain injury. Although the mechanism of this impairment is still speculative, these findings emphasize the importance of investigating the neuronal pathophysiology in hydrocephalus.

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Marcia C. da Silva, James M. Drake, Claude Lemaire, Albert Cross and Ursula I. Tuor

✓ The authors studied the effects of hydrocephalus on the high-energy phosphate metabolism of the brain and the impact of ventriculoperitoneal (VP) shunting on these changes in an experimental model of hydrocephalus. High-energy phosphate metabolism was analyzed using in vivo magnetic resonance (MR) imaging and 31P MR spectroscopy. Hydrocephalus was produced in 34 1-week-old kittens by cisternal injection of 0.05 ml of a 25% kaolin solution. Sixteen litter mates were used as controls. A VP shunt with a distal slit valve was implanted in 17 of the 34 hydrocephalic animals 10 days after induction of hydrocephalus. Both MR imaging and 31P MR spectroscopy were obtained 1 and 3 weeks after either kaolin or distilled water injection. Untreated hydrocephalic animals had marked dilatation of the lateral ventricles and periventricular edema. Magnetic resonance spectroscopy showed a significant decrease in the energy index ratio of phosphocreatine (PCR): inorganic phosphate (PI) and an increase in the PI:adenosine triphosphate (ATP) ratio. There was a direct correlation between the decrease in the energy index and ventricular size. Compared with preoperative scans, shunted animals showed no periventricular edema, and the ventricles decreased in size. Also, PCR:PI and PI:ATP ratios were within the levels of controls. This study suggests that neonatal hydrocephalus results in a mild hypoxic/ischemic insult that is treatable by VP shunting.

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Paul D. Chumas, James M. Drake, Marc R. Del Bigio, Marcia Da Silva and Ursula I. Tuor

✓ The metabolic changes in neonatal hydrocephalus that lead to permanent brain injury are not clearly defined, nor is the extent to which these changes can be prevented by a cerebrospinal fluid shunt. To clarify these processes, cerebral glucose utilization was examined using [14C]2-deoxyglucose autoradiography in 1-month-old kittens, kaolin-induced hydrocephalic littermates, and hydrocephalic kittens in which a ventriculoperitoneal shunt had been inserted 10 days after kaolin injection. The hydrocephalic kittens showed thinning of the cerebral mantle and an anterior-to-posterior gradient of enlargement of the ventricular system, with a ventricle:brain ratio of 24% for the frontal and 35% for the occipital horns compared with control (< 0.5%) and shunted (< 5%) animals. White matter in hydrocephalic animals was edematous. Myelination was delayed in the periventricular region and in the cores of the cerebral gyri.

Glucose utilization in hydrocephalic and shunted animals was unchanged from control animals in all gray-matter regions examined. However, in hydrocephalic animals, the frontal white matter exhibited a significant increase in glucose utilization (25 µmol • 100 gm−1 • min−1) in the cores of gyri compared with normal surrounding white-matter values (14.8 µmol • 100 gm−1 • min−1). Very low values (mean 4 µmol • 100 gm−1 • min−1) were found in areas corresponding to severe white-matter edema, and these areas were surrounded by a halo of increased activity (24 µmol • 100 gm−1 • min−1). In contrast, cytochrome oxidase activity in white matter was homogeneous. Shunting resulted in restoration of the cerebral mantle thickness, a return to normal levels of glucose utilization in the white matter, and an improvement in myelination.

It is suggested that the areas of increased glucose utilization seen in the white matter represent anaerobic glycolysis which, if untreated, progresses to infarction. The pattern of this increased glucose utilization matches that of expected myelination and, during this period of high energy demand, white matter may be susceptible to the hypoperfusion associated with hydrocephalus.

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Paul D. Chumas, Marc R. Del Bigio, James M. Drake and Ursula I. Tuor

✓ It has recently been reported that pretreatment with a single dose of dexamethasone (0.1 mg/kg) 24 hours before hypoxia in 7-day-old rat pups is protective against an hypoxic-ischemic insult (unilateral carotid artery occlusion followed by 3 hours of hypoxia in 8% O2). The authors now examine whether pretreatment 6 hours before insult is equally effective and compare other agents potentially suitable for prophylaxis in neonatal hypoxia-ischemia, including the calcium antagonists flunarizine (30 mg/kg pretreatment), nimodipine (0.5 mg/kg pretreatment), and the 21-aminosteroid U-74389F (10 mg/kg pre- and posttreatment). For each active agent, there was also a vehicle-treated control group.

Comparison of the mean area of ipsilateral infarction on brain coronal sections showed that there was no statistically significant difference between the various control groups (mean area of infarction 66% ± 4%). Pretreatment with dexamethasone 6 hours prior to hypoxia offered complete protection with no infarction. A beneficial effect was seen following pretreatment with flunarizine (mean area of infarction 33.6% ± 7.8%), although this degree of damage was still significantly different from that seen with dexamethasone pretreatment. Pretreatment with nimodipine or U-74389F offered no protection (mean area of infarction 77.5% ± 4% and 59% ± 10%, respectively). Unlike findings in adult animals and clinical studies, the current studies show that dexamethasone may have a role in the treatment of neonatal hypoxia-ischemia and deserves reappraisal.