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

Abstract

BackgroundPopular 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.MethodsWe 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 μL/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.ResultsGroup 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.ConclusionInfusing 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.

“Compensated hyperosmolarity” of cerebrospinal fluid and the development of hydrocephalus

“…5 and 6). We can say that it is obvious that a long-term (7 days) increase in CSF osmolarity leads to the development of hydrocephalus, as was observed in rats (Krishnamurthy et al, 2009). However, while increased osmolarity in rats led to an equal development of hydrocephalus in the whole ventricular system, in our experiments hydrocephalus predominantly developed in the RLV (Figs.…”

“…water) in the CSF system. It has recently been proposed that development of hydrocephalus (Krishnamurthy et al, 2009;Orešković and Klarica, 2011) and the change in CSF volume is caused by changes in blood or CSF osmolarity (Hochwald et al, 1974;Wald et al, 1976;Orešković et al, 2002;Maraković et al, 2010;Jurjević et al, 2012) and that elevated CSF osmolarity should be considered as one of the most important factors in excessive CSF/water accumulation. We have also presumed that the greatest responsibility for the maintenance of CSF iso-osmolarity is the rapid extraction of water from the bloodstream into the osmotically loaded CSF space, and that extracted water would consequently cause an accumulation of fluid, increase in ICP and the development of hydrocephalus.…”

“…It is well documented that osmotic gradients play a significant part in the regulation of brain water and CSF volume (Hochwald et al, 1974;Wald et al, 1976;Orešković et al, 2002;Maraković et al, 2010;Jurjević et al, 2012). Because of this, it has been presumed that without significant obstruction or stenosis of the CSF system, all pathological processes in which an increase of CSF osmolarity (the osmotic load of CSF) takes place should lead to an increase in CSF volume, and consequently should cause hydrocephalus (Krishnamurthy et al, 2009;Orešković and Klarica 2010; what speaks in favor the most recent multiinstitutional studies of hydrocephalus as a consequence of hemispherectomy surgery for medically intractable epilepsy treatment (Lew et al, 2013).…”

“…The term "compensated hyperosmolarity" represents the time period when CSF hyperosmolarity has already disappeared but the effect of hyperosmolarity still persists in the CSF system. Since we assume that hydrocephalus often develops over a prolonged period (Orešković and Klarica, 2011), and the fact that hydrocephalus was experimentally produced in rats by means of chronic hyperosmolar infusion (Krishnamurthy et al, 2009), the development of hydrocephalus was studied in cats through subchronic micro-volume infusion of hyperosmolar solution into the right lateral ventricle (RLV).…”

Development of hydrocephalus and classical hypothesis of cerebrospinal fluid hydrodynamics: Facts and illusions

“…The increase in CSF osmolarity as a reason for the development of hydrocephalus was shown on rats by a chronic (12 days) intraventricular infusion of hyperosmolar substances (Krishnamurthy et al, 2009). The hyperosmolar fluid was infused by a microcatheter connected to an Alzet osmotic minipump inserted through the needle track into the lateral ventricle.…”