A Lumped Parameter Model Suggests That Infusion Studies Overestimate the Cerebrospinal Fluid Outflow Resistance in Normal Pressure Hydrocephalus

Abstract

Background/objectives: Cerebrospinal infusion studies indicate that cerebrospinal fluid outflow resistance (R_out) is elevated in normal pressure hydrocephalus (NPH). These studies assume that the cerebrospinal formation rate (CSF_fr) does not vary during the infusion. If the CSF_fr were to increase during the infusion then the R_out would be overestimated. Previous estimates of the CSF_fr in NPH have suggested a low figure. More recent estimates of the CSF_fr suggest that it is increased, indicating it probably varies with measurement technique. This would bring the estimation of R_out into doubt. A previous paper using a lumped parameter model suggested the CSF_fr could vary with the capillary transmural pressure (TMP) in this disease, suggesting a possible solution to this problem. The current study investigates the possibility that the intracranial pressure manipulation occurring during an infusion study may vary the capillary TMP and CSF_fr.

Methods: A lumped parameter model previously developed to describe the hydrodynamics of NPH was modified to investigate the effect of CSF pressure manipulation during infusion studies and to describe how the CSF_fr could vary depending on the technique used.

Results: The model indicates the capillary transmural pressure is normal in NPH and increases during an infusion study. CSF drainage at the end of an infusion study similarly increases the capillary TMP and, presumably, the CSF_fr by increasing the interstitial fluid production.

Conclusions: The model suggests that infusion studies and draining CSF increases the CSF_fr in NPH compared to earlier techniques. Allowing for an increase in the CSF_fr suggests that infusion overestimates the R_out by between 23 and 33%. This study indicates that further research may be required into the utility and accuracy of infusion studies and their ability to diagnose NPH.

Keywords: blood–brain barrier; cerebral blood flow; cerebrospinal fluid formation rate; glymphatic; infusion study; normal pressure hydrocephalus.

Figure 1

Results of modelling changes to blood flow in NPH. (A) Shows the normal findings. Note. ICP: intracranial pressure; mm: millimetres of mercury; mL: millimetres; NPH: normal pressure hydrocephalus. (B) Shows the baseline NPH findings; the red area indicates an increase in resistance in the artery and vein cuff and the green indicates decreased resistance in the veins. (C) Shows the findings in NPH following an instantaneous increase in blood flow back to normal, with the green area showing a reduction in resistance in the arteries and veins and the red area showing an increase in the outflow cuff resistance. (D) Indicates the findings in NPH following a reduction in blood flow of 40% below normal with increased resistance in the arteries. The red areas indicate increased resistance compared to the normal. (A,B) have been reproduced from [14] under a CC BY 4.0 commons licence.

Figure 2

Modelling of changes to ICP in NPH. (A) shows the baseline NPH findings, as seen above in Figure 1B. Red depicts increased resistance and green lower resistance compared to normal. (B) shows the findings in NPH following an infusion study, with the green area highlighting a reduction in resistance in the capillaries and veins and the red area showing an increase in the arteries and outflow cuff compared to normal. (C) shows the findings in NPH following CSF drainage to lower the ICP to zero. The outflow cuff resistance is abolished, reducing the venous and capillary pressure, but the ICP has a greater reduction, leading to an increase in capillary TMP. Red depicts increased resistance and green lower resistance compared to normal. Note, TMP: transmural pressure. (A) has been reproduced from [14] under a CC BY 4.0 commons licence.

Figure 3

Vascular changes in NPH compared to the cerebral blood flow. (A) A graph of the four calculated capillary transmural pressures vs. the cerebral blood flow for the four studies obtained from the initial modelling. The red dot is the baseline finding in NPH. Note, increasing the CBF above baseline increased the capillary TMP, while decreasing the CBF did the opposite in a linear fashion. (B) A graph of the four calculated venous volumes vs. the cerebral blood flow for the four studies obtained from the initial modelling. The red dot is the baseline finding in NPH. Note, increasing the CBF above baseline increased the venous volume and decreasing the CBF did the opposite in a quadratic fashion.

Figure 4

Relationship between the capillary transmural pressure and ICP in NPH. A graph of the change capillary transmural pressure vs. ICP from the data obtained from the second modelling study. The red dot indicates the NPH baseline. The graph is a complex polynomial function but the capillary TMP increases to an identical value at either extreme of the ICP change. The capillary TMP will remain close to the baseline if the ICP is not changed by much either way.