A novel model of acquired hydrocephalus for evaluation of neurosurgical treatments

Abstract

Background Many animal models have been used to study the pathophysiology of hydrocephalus; most of these have been rodent models whose lissencephalic cerebral cortex may not respond to ventriculomegaly in the same way as gyrencephalic species and whose size is not amenable to evaluation of clinically relevant neurosurgical treatments. Fewer models of hydrocephalus in gyrencephalic species have been used; thus, we have expanded upon a porcine model of hydrocephalus in juvenile pigs and used it to explore surgical treatment methods. Methods Acquired hydrocephalus was induced in 33–41-day old pigs by percutaneous intracisternal injections of kaolin (n = 17). Controls consisted of sham saline-injected (n = 6) and intact (n = 4) animals. Magnetic resonance imaging (MRI) was employed to evaluate ventriculomegaly at 11–42 days post-kaolin and to plan the surgical implantation of ventriculoperitoneal shunts at 14–38-days post-kaolin. Behavioral and neurological status were assessed. Results Bilateral ventriculomegaly occurred post-induction in all regions of the cerebral ventricles, with prominent CSF flow voids in the third ventricle, foramina of Monro, and cerebral aqueduct. Kaolin deposits formed a solid cast in the basal cisterns but the cisterna magna was patent. In 17 untreated hydrocephalic animals. Mean total ventricular volume was 8898 ± 5917 SD mm3 at 11–43 days of age, which was significantly larger than the baseline values of 2251 ± 194 SD mm3 for 6 sham controls aged 45–55 days, (p < 0.001). Past the post-induction recovery period, untreated pigs were asymptomatic despite exhibiting mild-moderate ventriculomegaly. Three out of 4 shunted animals showed a reduction in ventricular volume after 20–30 days of treatment, however some developed ataxia and lethargy, from putative shunt malfunction. Conclusions Kaolin induction of acquired hydrocephalus in juvenile pigs produced an in vivo model that is highly translational, allowing systematic studies of the pathophysiology and clinical treatment of hydrocephalus.

Acquired hydrocephalus is associated with neuroinflammation, progenitor loss, and cellular changes in the subventricular zone and periventricular white matter

“…In the induced pigs, ventriculomegaly was prominent throughout the whole ventricular system, with communication between the ventricles but restricted flow into the subarachnoid space [ 50 ]. The expansion of the ventricles was especially pronunced in the body of the lateral ventricles.…”

“…These changes were detected in the PVWM adjacent to the body of the lateral ventricles; thus, the multifactorial mechanism of stretch, compression, edema, or hypoxia may be playing an important role in the myelin destruction [ 9 ]. Futures studies, including cognitive testing [ 49 , 50 ] and diffusion MRI, will be carried out to elucidate the consequences of the PVWM damages.…”

“…Hydrocephalus was induced in juvenile female pigs ( Sus scrofa domesticus ), aged 33–43 days old, via a kaolin injection. Females were used because they exhibit more exploratory behavior than males [ 49 ], and thus were more amenable to the cognitive assessments we have reported previously [ 50 ]. Animals were separated into two cohorts: (1) to study the neuropathology in the tissue (hydro group, n = 7; and sham control group n = 6), and (2) to analyze inflammation in the CSF (hydro group, n = 10; sham control group, n = 6).…”

“…There were three additional cases of pigs injected with kaolin that did not develop hydrocephalus after 12–48 days of induction (n = 3). Ventriculomegaly was determined as 2 standard desviation from the sham control volume mean[ 50 ]. These “kaolin-injected, non-hydrocephalic” pigs were used to analyze the microglial reaction cause by hydrocephalus, and not by the kaolin per se.…”

Testing and Validation of Reciprocating Positive Displacement Pump for Benchtop Pulsating Flow Model of Cerebrospinal Fluid Production and Other Physiologic Systems

“…Alternatively, animal studies are often used to investigate CSF dynamics and to provide insights into the healthy and pathological conditions of living organisms. However, limitations of in-vivo measurements, dramatic differences between humans and animals, and the lack of control over flow dynamics leave a clear need for testing and evaluation of current modes of treatments [18]. Furthermore, simulating CSF production rate, pulsations and amplitudes might provide valuable insights into the healthy and diseased states with significant diagnostic potential.…”