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M. E. Iliev, J. Danias, H.-R. Widmer, T. Mittag, D. Goldblum; Do Chronic, Intermittent Elevations of Intracranial Pressure (ICP) Lead to Glaucomatous Optic Nerve Damage? (An Experimental ICP Model of Normal-Tension Glaucoma (NTG) in the Rat). Invest. Ophthalmol. Vis. Sci. 2007;48(13):3281.
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The mechanism of neuronal loss in NTG is poorly understood. Intraocular pressure (IOP)-independent factor involvement is suspected. We hypothesized that subclinical fluctuations of ICP may play a role, by causing intermittent mechanical compression, shear forces and reperfusion phenomena at the level of lamina cribrosa (site of the ICP/IOP gradient). We strived to develop a rat model of intermittently raised ICP and determine retinal ganglion cell (RGC) loss in these animals.
A permanent cannula to the lateral ventricle was implanted in the brain of adult, male, Brown-Norway rats, allowing hydrostatic fluctuation of ICP via an external saline reservoir. Experimental animals (N=16) were subjected (under isoflurane anesthesia) to a procedure of ICP fluctuations (20 consecutive cycles of 3 min elevation / 3 min baseline) twice a week. Sham controls (N=7) received the same procedure, but ICP was kept throughout the time at baseline level. A third group (N=5) was observed without cannulation or manipulation (normal control). IOP was measured in some animals with TonoPen under anesthesia and during ICP procedures. After a mean of 10 procedures (5-6 weeks), rats were observed for either 3 or 20 weeks, at which time RGCs were retrogradely labeled with Fluorogold. RGC density in retinal flat-mounts was evaluated by a masked observer and graded semi-quantitatively in 0.5 increments from 5.0 (completely normal) to 0.0 (severely damaged).
IOP under anesthesia was: 6.5±2.1, 8.3±2.7, 6.4±1.4 mmHg for the three groups respectively, p>0.05 ANOVA). During the periods of ICP elevation, IOP remained stable. No significant change in behaviour, food or water intake was registered. RGC density was scored 2.8±1.6 in the experimental group (n=32 eyes); 4.5±1.0 in the sham control group (n=14 eyes), and 4.6±0.8 in the normal control group (n=10 eyes) (p<0.001, ANOVA of ranks). The experimental group score was significantly lower than that of both other groups (p<0.01, Bonferroni).
Intermittent, short-term elevations of ICP cause no change in the general status and behaviour of rats. However, despite no change in the IOP, they do cause a significant loss of RGCs compared to the controls. The results support the novel hypothesis that subclinical fluctuations of ICP may play a pathogenic role in glaucoma, especially in NTG.
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