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. 2020 Dec 16;10(1):22013.
doi: 10.1038/s41598-020-78880-4.

An update to the Monro-Kellie doctrine to reflect tissue compliance after severe ischemic and hemorrhagic stroke

Anna C J Kalisvaart  1 , Cassandra M Wilkinson  1 , Sherry Gu  2 , Tiffany F C Kung  2 , Jerome Yager  3 , Ian R Winship  2   4 , Frank K H van Landeghem  2   5 , Frederick Colbourne  6   7
Affiliations

An update to the Monro-Kellie doctrine to reflect tissue compliance after severe ischemic and hemorrhagic stroke

Anna C J Kalisvaart et al. Sci Rep. .

Abstract

High intracranial pressure (ICP) can impede cerebral blood flow resulting in secondary injury or death following severe stroke. Compensatory mechanisms include reduced cerebral blood and cerebrospinal fluid volumes, but these often fail to prevent raised ICP. Serendipitous observations in intracerebral hemorrhage (ICH) suggest that neurons far removed from a hematoma may shrink as an ICP compliance mechanism. Here, we sought to critically test this observation. We tracked the timing of distal tissue shrinkage (e.g. CA1) after collagenase-induced striatal ICH in rat; cell volume and density alterations (42% volume reduction, 34% density increase; p < 0.0001) were highest day one post-stroke, and rebounded over a week across brain regions. Similar effects were seen in the filament model of middle cerebral artery occlusion (22% volume reduction, 22% density increase; p ≤ 0.007), but not with the Vannucci-Rice model of hypoxic-ischemic encephalopathy (2.5% volume increase, 14% density increase; p ≥ 0.05). Concerningly, this 'tissue compliance' appears to cause sub-lethal damage, as revealed by electron microscopy after ICH. Our data challenge the long-held assumption that 'healthy' brain tissue outside the injured area maintains its volume. Given the magnitude of these effects, we posit that 'tissue compliance' is an important mechanism invoked after severe strokes.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Scatter plots of animal lesion size and cortical thickness in experiments 1 (a, d), 2 (b, e), and 3 (c, f) with representative sections of ICH (collagenase model; g), MCAO (intraluminal suture occlusion model; h) and HIE (Vannucci–Rice model; i). Maximum hematoma area was quantified in experiment 1 (a), whereas total lesion volume in was quantified in experiments 2 (b) and 3 (c). SHAM animal lesion volume data were not added as there were no signs of injury in any of the sham operated rats in these experiments. Cortical thickness (d–f) was measured from the cingulum to layer II of the cortex bilaterally in each animal, **p < 0.01 versus respective SHAM controls. Scatterplots were made using GraphPad Prism version 8.4.3 for macOS, GraphPad Software, San Diego, California USA, www.graphpad.com.
Figure 2
Figure 2
In experiment 1, neuron soma volume (a, c, e, g) and density (b, d, f, h) were analyzed with unbiased stereology on days 1, 3, and 7 following striatal ICH or sham operation. Astrocyte soma volume was also analyzed on day 1. Areas assessed in all animals included in CA1 (a, b, i), CA3 (c, d), S1 (e, f), and contralateral striatum (g, h, j). Ipsilateral striatum was not assessed as it was largely destroyed by the ICH, as expected. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 versus respective SHAM controls. Scatterplots were made using GraphPad Prism version 8.4.3 for macOS, GraphPad Software, San Diego, California USA, www.graphpad.com.
Figure 3
Figure 3
Representative sections and images demonstrating locations of regional sampling for the Fluoro-jade C positive cell counts as a marker of neuronal death in CA1, (a–c; 1.78 ± 2.89 on D1, 1.93 ± 1.15 for D3, 2.33 ± 1.97 for D7, versus 1.79 ± 1.18 for SHAMs), S1 (d–f; 3.14 ± 2.9 on D1, 1.14 ± 0.83 on D3, 2.33 ± 1.43 on D7, versus 1.5 ± 1.68 for SHAMs), and the perihematoma zone (PHZ; g–i) after ICH. A representative example of the hematoma size is delineated by the dotted black line (g). Representative images in CA1 were taken at 20 × objective magnification (b), while those in S1 were taken at 40 × (e). PHZ representative images (h) were taken at 20 × and 40 × objective magnification respectively to better demonstrate the extent of cells positive for FJC + stain, with the approximate area in which the higher magnification image was taken marked by a box on the lower magnification image. ****p < 0.0001 versus SHAM controls. Figure and scatterplots were made using GraphPad Prism version 8.4.3 for macOS, GraphPad Software, San Diego, California USA, www.graphpad.com.
Figure 4
Figure 4
In experiment 2, contralateral neuron soma volume and density were analyzed 24 h following MCAO in CA1 (a, b), S1 (c, d), and the dorsal striatum (e, f). *p < 0.05, **p < 0.01 versus SHAMs. Scatterplots were made using GraphPad Prism version 8.4.3 for macOS, GraphPad Software, San Diego, California USA, www.graphpad.com.
Figure 5
Figure 5
Representative transmission TEM images of hippocampal layer CA1 area in Experiment 4, in SHAM (a–h) and striatal ICH groups (i–p) at 24 h post-stroke. The asterisks identify the presence of the small intranuclear vacuoles that appear with relatively rare frequency in SHAMs. Solid arrows identify normal and intact myelinated axons, while non-solid arrows mark well-defined, narrow rough endoplasmic reticulum. Arrowhead symbols ( <) indicate intact healthy-looking mitochondria with well-defined and packed cristae, and the # symbol denotes Golgi apparatus, which looks structurally normal. In ICH rats, asterisks mark large intranuclear vacuoles that are spread throughout the nucleus, both contralaterally and ipsilaterally (j–l, n, p). Solid arrows indicate instances of axonal damage; signs of injury include thinning interrupted, unravelling, or “smudged” myelin accompanied by dilated periaxonal spaces (o, p). Mitochondria both within such axons and the cell soma are denoted by arrowhead symbols, and appeared to be extremely edematous, containing disorganized and interrupted cristae, with some in transitive stages of lysosomal degeneration (l, o, p). The hashtag symbol denotes a disrupted and edematous Golgi apparatus (p), and the non-solid arrow denotes rough endoplasmic reticulum that are swollen and distended (j, l). At low magnification, CA1 pyramidal cells in the ICH group have noticeably crenated nuclear and plasma membranes, with extremely dense cytoplasmic and nuclear contents, which we posit is the result of tissue compliance. In layer CA1, cells in the SHAM group have a characteristic ovoid shape with taught, intact membranes. Figure was made using GraphPad Prism version 8.4.3 for macOS, GraphPad Software, San Diego, California USA, www.graphpad.com.
Figure 6
Figure 6
A plot of the D1 effect size (average % difference vs. SHAMs ± 95% CI of difference) for cell volume and density (a) across every brain region assessed in experiment 1, along with the overall experimental average effect size for each endpoint (highlighted). The traditional Munro-Kellie model of ICP compliance asserts that once a mass is added to the brain (whether that be edema and/or a hematoma), CSF and vascular blood are redirected to reduce rising ICP (b, c). In our proposed modification, the increase in neuronal packing density and reduction in cell volume that we observed in both ICH and MCAO kick in as ICP rises, aiding in compliance and reducing the required displacement of vascular blood and CSF (e), especially after large strokes (f). This may aid in avoiding secondary ischemic injury due to reduced cerebral blood flow, and potentially helps prevent transforaminal herniation. Lastly, representative cresyl violet images of hippocampal layer CA1 in both ipsilateral ICH-D1(d) and SHAM (g) tissue are shown to illustrate the tissue compliance phenomenon. Cresyl violet images were taken at 40 × magnification, and cranium diagrams (derivative of Creative Commons Licence CCO Public Domain image: https://commons.wikimedia.org/wiki/File:Human_skull_no_text_no_color.svg) were put together in Adobe Photoshop (version 21.2.1) and are not to anatomical scale. Figure was made using GraphPad Prism version 8.4.3 for macOS, GraphPad Software, San Diego, California USA, www.graphpad.com.
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