Intraventricular infusion of hyperosmolar dextran induces hydrocephalus: a novel animal model of hydrocephalus

Abstract

Background: Popular circulation theory of hydrocephalus assumes that the brain is impermeable to cerebrospinal fluid (CSF), and is therefore incapable of absorbing the CSF accumulating within the ventricles. However, the brain parenchyma is permeable to water due to the presence of specific ion channels as well as aquaporin channels. Thus, the movement of water into and out of the ventricles may be determined by the osmotic load of the CSF. If osmotic load determines the aqueous content of CSF in this manner, it is reasonable to hypothesize that hydrocephalus may be precipitated by pathologies and/or insults that produce sustained elevations of osmotic content within the ventricles.

Methods: We investigated this hypothesis by manipulating the osmotic content of CSF and assaying the development of hydrocephalus in the rat brain. This was achieved by continuously infusing artificial CSF (negative control; group I), fibroblast growth factor (FGF2) solution (positive control; group II) and hyperosmotic dextran solutions (10 KD and 40 KD as experimental solutions: groups III and IV) for 12 days at 0.5 muL/h. The osmolality of the fluid infused was 307, 664, 337 and 328 mOsm/L in Groups I, II, III and IV, respectively. Magnetic resonance imaging (MRI) was used to evaluate the ventricular volumes. Analysis of variance (ANOVA) with pairwise group comparisons was done to assess the differences in ventricular volumes among the four groups.

Results: Group I had no hydrocephalus. Group II, group III and group IV animals exhibited significant enlargement of the ventricles (hydrocephalus) compared to group I. There was no statistically significant difference in the size of the ventricles between groups II, III and IV. None of the animals with hydrocephalus had obstruction of the aqueduct or other parts of CSF pathways on MRI.

Conclusion: Infusing hyperosmolar solutions of dextran, or FGF into the ventricles chronically, resulted in ventricular enlargement. These solutions increase the osmotic load in the ventricles. Water influx (through the choroid plexus CSF secretion and/or through the brain) into the ventricles to normalize this osmotic gradient results in hydrocephalus. We need to revise the popular theory of how fluid accumulates in the ventricles at least in some forms of hydrocephalus.

Figure 1

Representative examples of MRI images of animals after 12 days of infusion of artificial CSF (negative control), FGF-2 (positive control), 10 KD and 40 KD dextran (experimental) solutions. Note that the ventriculomegaly produced by FGF-2, 10 KD and 40 KD dextrans were similar.

Figure 2

Box plot showing the ventricular volumes in μL for the different infusion groups. The center line of the boxplot is the median value with the upper and the lower margins of the box representing the upper quartile (75^th percentile) and the lower quartile representing (25^th percentile). The upper and lower fences represent the value equal to 1.5 times the difference between the lower and upper quartiles (interquartile ratio). The outliers are represented by a mark outside the box plot. Note that all the infusions resulted in enlarged ventricles except for ACSF, and were significantly different from the ACSF group (I vs II p = 0.002, I vs III p = 0.009, and I vs IV p = 0.023). Note: Two outlying symbols represent ventricular size of animals in the ACSF and 10 KD dextran group that were much larger than the rest of the group.

Figure 3

T2-weighted MRI of animal with hydrocephalus induced by 10 KD dextran. Note the periventricular edema (arrow top row last figure from the left) in the corpus callosum and external capsule and the patent cerebral aqueduct (arrow labeled Aq). Note that the ventricular enlargement was asymmetric with the larger ventricle on the side of infusion.