A Porcine Model of Hydrocephalus Induced by Gamma Knife Irradiation
Authors: John Duncan III, Ilias Caralopoulos, Georg Noren, Edward Stopa, Gerald Silverberg, Petra Klinge, John Donahue, Michael Park, Miles Miller and Conrad Johanson
Background
The Leksell Gamma Knife® has been used for several decades as a
relatively non-invasive, highly effective and precise therapeutic
tool for brain disorders ranging from tumours to vascular
malformations. It has a very benign side effect profile. To date
many animal hydrocephalus models have been surgically or chemically
invasive. Our exploratory model uses Gamma Knife to induce a lesion
with the aim of increasing CSF outflow resistance at the cerebral
aqueduct.
Materials and Methods
A 3 month old female domestic pig (Sus domestica) was
housed with an age- and sex-matched pig serving as a non-radiated
control. Anaesthesia was induced with tiletamine/zolazepam
and xylazine and maintained with isoflurane. After securing a
modified human stereotactic head frame to the pig, the coordinates
of the cerebral aqueduct were determined by MRI. A single maximum
dose of 200 Gy was delivered to the aqueductal lumen using the 4 mm
collimators of a Leksell Gamma Knife® Model C. MRI studies with
gadolinium were performed at 4, 8 and 12 weeks post-radiosurgery.
At 12 weeks, the brains of both animals were extracted for gross
and microscopic analysis.
Results
Marked enlargement of the third and lateral ventricles, most
pronounced in the posterior horns of the lateral ventricles, was
visible on imaging through 12 weeks (Evans ratio >0.3, FOHR
>0.5). Lesional oedema, visualized with FLAIR, was maximal at 4
weeks and decreased through 12 weeks. Minimal contrast enhancement
was visible at 4 and 8 weeks and resolved by 12 weeks. Subependymal
FLAIR hyperintensity lining the lateral ventricles was present at 4
weeks. On dissection, the aqueductal lumen of the irradiated pig
was smaller than the control's. The transverse and especially
rostro-caudal dimensions of the lateral ventricles were noticeably
greater. The only clinical abnormalities were a gaze palsy
consistent with the site of the oedema, a compensatory head tilt
and a slight gait disturbance. Weight gain, grooming and behaviour
were comparable to the control.
Conclusions
The striking ventriculomegaly, restricted lesion and benign
clinical course indicate that our non-life threatening porcine
hydrocephalus model is promising. The early periventricular FLAIR
hyperintensity is consistent with increased resistance to CSF
outflow. The minimal contrast enhancement indicates a temporary
limited breakdown of the Blood Brain Barrier. The persistent
hydrocephalus at twelve weeks despite the near resolution of the
MRI abnormalities suggests potential for a long-term model with
physiologic similarity to human late-onset aqueductal stenosis and
applications in the development of therapeutic devices.
Supported by Medtronic.
Dept. of Clinical Neurosciences, Alpert Medical School at
Brown University, 593 Eddy Street, Providence, Rhode Island, 02903
USA
E-Mail: Ilias_Caralopoulos@brown.edu
