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REVIEW ARTICLE J.C. Benson, A.A. Madhavan, J.K. Cutsforth-Gregory, D.R. Johnson, and C.M. Carr ABSTRACT SUMMARY: The Monro-Kellie doctrine is a well-accepted principle of intracranial hemodynamics. It has undergone few consequen- tial revisions since it was established. Its principle is straightforward: The combined volume of neuronal tissue, blood, and CSF is constant. To maintain homeostatic intracranial pressure, any increase or decrease in one of these elements leads to a reciprocal and opposite change in the others. The Monro-Kellie doctrine assumes a rigid, unadaptable calvaria. Recent studies have disproven this assumption. The skull expands and grows in response to pathologic changes in intracranial pressure. In this review, we outline what is known about calvarial changes in the setting of pressure dysregulation and suggest a revision to the Monro-Kellie doctrine that includes an adaptable skull as a fourth component. ABBREVIATIONS: IIH ¼ idiopathic intracranial hypertension; SIH ¼ spontaneous intracranial hypotension he Monro-Kellie doctrine has been a fundamental principle evidence of a nonrigid, adaptable calvaria in the setting of patho- Tof neurophysiology for .200 years. Its hypothesis is based logically elevated or reduced CSF pressure. on simple reasoning: Within a rigid calvarial vault, the total vol- ume of brain, CSF, and blood is constant. Any change in one of BACKGROUND these elements results in an opposing compensatory response by The Monro-Kellie doctrine underwent many early changes the other 2 components. On neuroimaging, the effects of this before achieving its current form. Alexander Monro, a Scottish doctrine are ubiquitous: Encephalomalacia leads to ex vacuo dila- doctor of impressive medical lineage, first proposed that a tion of an adjacent ventricle, an edematous and enlarged brain rigid skull contained an incompressible brain and a constant compresses ventricles and vessels, and CSF hypovolemia results amount of blood; ie, a steady input of arterial blood led to a in pituitary and venous engorgement. compensatory output in venous blood. In 1824, his student Multiple studies, however, now suggest that the Monro-Kellie George Killie de Leith provided postmortem evidence of this doctrine is due for further examination, particularly in the setting theory. Neither, however, mentioned CSF. Around the same of abnormal intracranial pressure. Both increased and decreased time, John Ambercrombie made similar observations in ani- intracranial pressure exerts downstream effects on the calvaria. mals; some early citations of this theorem were entitled the Increased pressure leads to calvarial thinning and pitting, while “Monro-Abercrombie doctrine.” decreased pressure leads to development of layering hyperostosis George Burrows first included CSF in this model, and it was along the inner table of the skull. These findings have substantial not until 1926 that Harvey Cushing neatly summarized the implications, both in terms of how we think of the Monro-Kellie Monro-Kellie doctrine as it is generally known today. According doctrine and potentially how pathologies of intracranial pressure to Cushing, the “three elements” (blood, nervous tissue, and are identified and treated. In light of these findings, we review the fluid) in the skull “must always remain the same in bulk....any history of the Monro-Kellie hypothesis and describe mounting increase in blood volume, for example, can only take place at the expense of one of the other elements.” Cushing considered the responsiveness of any reciprocal action to be prompt, “These Received August 27, 2022; accepted after revision October 5. 7 changes all take place rapidly—a matter of minutes.” From the Departments of Radiology (J.C.B., A.A.M., D.R.J., C.M.C.) and Neurology Of course, self-evident exceptions to this rule abound. A for- (J.K.C.-G.), Mayo Clinic, Rochester, Minnesota. eign body may enter the calvarial vault, displacing or decreasing Please address correspondence to John C. Benson, MD, Department of Radiology, Mayo Clinic, 723 6th St. SW, Rochester, MN 55902; e-mail: email@example.com all 3 native intracranial components. Many types of intracranial Indicates open access to non-subscribers at www.ajnr.org masses are not composed of brain, CSF, or blood (eg, abscesses, http://dx.doi.org/10.3174/ajnr.A7721 metastases, and granulation tissue). These exceptions do not 2 Benson Jan 2023 www.ajnr.org The closest proposed revision came from Mascarenhas et al, who per- formed a set of postmortem experi- ments in which they expanded a rubber balloon in a skull while measuring skull deformation. The results indicated that deformation was noted during increases and decreases in internal pressure. The authors consequently contended that the Monro-Kellie doctrine was, there- fore, invalid because it failed to acknowl- edge such deformational changes in the skull. Now there is convincing evidence of a more chronic type of elasticity of thecalvaria in responseto increases and decreases in intracranial pressure. Unlike the experiments of Mascarenhas et al, however, this elasticity manifests as changes in the thickness and shape of the calvarium, rather than transient deformations. Both types of changes represent adaptivity of the skull to expand or contract the calvarial vault in response to CSF pressure abnormal- ities. Below, we review in detail what is FIG 1. Sella expansion and skull base pitting in IIH. Sagittal CT image (A) ina 38-year-oldwoman currently known about such calvarial with pseudotumor cerebri demonstrates marked expansion of the osseous walls of the sella changes. (short solid arrows), with frank dehiscence posteriorly. Corresponding sagittal MR image (B) shows ﬂattening of the pituitary tissue along the ﬂoor of the sella (long solid arrow). Prominent pitting is also noted along the anterior margins of both middle cranial fossae (dashed arrows, C). Intracranial Hypertension 3D reconstruction image of an MRV (D) demonstrates smooth tapering of the bilateral transverse Intracranial hypertension was first sinuses (dashed ovals), compatible with IIH. described in 1893 by Heinrich Quincke, a disease he labeled “meningitis serosa” require a revision of the doctrine because they neither challenge attributed to alterations in CSF secretions. In 1904, Max Nonne the underlying mechanism on which the Monro-Kellie doctrine is first used the term pseudotumor cerebri (“false brain tumor”)to built nor change the primary assumption of a fixed-volume skull. describe this syndrome. Nonne’s intent was to propose a state of Our understanding of intracranial pressure dynamics has elevated intracranial pressure that was distinct from that related to become more nuanced since the inception of the doctrine. It is cerebral tumors: intercranial hypertension that followed a less sin- 11 12 now known, for example, that blood plays a much greater role in ister course. John Foley later offered the term “benign intracra- dictating intracranial pressure than CSF. The total intracranial nial hypertension.” in- and outflow of blood is approximately 700 mL/min, occupying These labels have become outdated. First, several other etiolo- 100–130 mL of intracranial volume at any time. CSF, conversely, gies of increased intracranial pressure have become known. Such is produced at only 0.35 mL/min, with a total volume of about 75 cases are referred to as secondary intracranial hypertension, mL. The cardiac cycle also dynamically influences intracranial reserving the term “primary pseudotumor cerebri” (also known an idiopathic intracranial hypertension [IIH]) for cases of crypto- pressure, with variations in arterial input during systolic and dia- genic elevated intracranial pressure. Next, the vision loss associ- stolic flow resulting in pulsatile brain movement, brain expansion ated with IIH has made the label “benign” inappropriate. and contraction, and intraventricular CSF flow. The etiologic mechanism for IIH remains unknown. Theories Although our understanding of intracranial pressure has become more refined, the Monro-Kellie doctrine has notably not generally fall into the categories of altered CSF hydrodynamics or been adjusted or revised. A few prior studies have proposed hindrances to venous outflow. The disorder represents a dys- minor updates regarding concepts such as tissue elasticity and function in the homeostatic regulatory role of the Monro-Kellie compliance and the dynamic nature of intracranial arterial and doctrine; the increase in $1 intracranial component is insuffi- 5 15 venous vascularity. None of these proposals have strayed far ciently balanced by a corresponding decrease in the others. from the tenets of the doctrine: 1) The 3 major constituents that On imaging, numerous sequelae of IIH have been well-estab- play a role in intracranial pressure homeostasis are blood, CSF, lished. The pituitary gland is typically flattened along the floor of the sella, thought to be related to downward herniation of an and brain parenchyma, and 2) the calvaria is rigid and has a fixed volume. arachnocele through the diaphragma sella. Ventricles are often AJNR Am J Neuroradiol 44:2–6 Jan 2023 www.ajnr.org 3 16 slitlike. Many findings have been reported in the orbits: flatten- calvarial expansion and/or thinning in the setting of IIH. To date, ing of the posterior sclera, distention of the perioptic subarach- no studies have shown that these calvarial changes affect patient noid space, tortuosity of the optic nerves, and intraocular outcomes. Still, IIH remains an evolving field. As our knowledge protrusion of the optic nerve. Most important, lateral transverse of this disorder continues to grow, it is possible that calvarial sinus stenosis is also common, likely mediated by and contribut- changes among some patients with IIH could affect treatment ing to increased intracranial pressure. strategies or could be used as a prognostic marker. Recent studies have demonstrated that remodeling of the calva- Intracranial Hypotension ria is common in the setting of chronic pseudotumor cerebri. In Spontaneous intracranial hypotension (SIH) is related to CSF vol- such patients, the elevated intracranial pressure can lead to enlarge- ume depletion. Although CSF leaks may be secondary to trauma ment of the sella turcica (Fig 1), as well as prominent arachnoid and iatrogenic causes such as surgery or lumbar punctures, intra- pits and/or arachnoid granulations. Meningoceles are also com- cranial hypotension by fiat is due to spontaneous spinal CSF mon, typically forming in the temporal bone (Fig 2). As Bialer et leaks. Like IIH, the intracranial sequelae of intracranial hypo- al noted, these findings are all biomechanically similar in that tension have been well-described on imaging. they increase the volume of the subarachnoid space, thereby at Even more so than intracranial hypertension, most of the intra- least conceptually decreasing intracranial pressure. Skull base ero- cranial sequelae of SIH can be explained by the conventional sion and meningocele formation can lead to the development of understanding of the Monro-Kellie doctrine. For example, the rel- CSF leaks. In some cases, encephaloceles in these locations may ative dearth of CSF results in pituitary enlargement (ie, opposite to also lead to epilepsy. 26,27 Beyond distinct areas of pitting, the skull itself becomes thinned IIH) and expansion of the dural venous sinuses. The dura 23 28 in IIH. A case-control study by Barke et al found both skull base engorges, leading to diffuse dural thickening and enhancement. thickness (P , .001) and calvarial width (P ¼ .024) to be signifi- In some patients, subdural fluid collections, either hygromas or 24 29 cantly smaller in patients with IIH than in controls. Rabbani et al hematomas, develop over the cerebral convexities. On the basis confirmed such findings, noting that while advancing age was typ- of the presence or absence of these findings, one can reliably pre- ically associated with increased calvarial thickness, increased dict the likelihood of a patient having SIH. Ultimately, SIH rep- age portended calvarial thinning in patients with IIH. These resents a disorder in which autoregulatory mechanisms are calvarial changes are in opposition to the conventional under- insufficient to compensate for the CSF loss, and other imaging standing of the Monro-Kellie doctrine. abnormalities reflect this breakdown. Specifically, the brain begins Except for CSF leaks and rare cases of epilepsy related to ence- to sag inferiorly, with effacement of the suprasellar and prepontine phaloceles, little remains known about the clinical relevance of cisterns and decreased mamillopontine distance. Despite the number of changes observed, most of the compensatory changes in SIH are related to hyperemia; other than the pituitary gland, the brain parenchyma is relatively unable to expand in response to CSF depletion. The same is true following treatment. Once a leak has been repaired, intracranial CSF vol- umehas been shown to increasesignifi- cantly over its hypotensive baseline. The brain volume in the posttreatment setting, 17,31 in contrast, remains the same. Thus, the maincompensatory actionfollowing CSF leak repair is a reciprocal reduction of intracranial blood volume. It is only recently that we have become aware of calvarial changes in the setting of SIH. Johnson et al first showed that patients with SIH were often observed to have a thickened cal- varia, often with a characteristic layered hyperostotic growth pattern along the inner table of the skull. In the setting of FIG 2. Skull pitting, meningoceles, and CSF leak in a patient who presented with rhinorrhea. Axial and coronal CT images (A and B) demonstrate substantial pitting along the anteromedial aspect long-standing SIH, the authors opined, of the left middle cranial fossa (dashed ovals, A and B), with complete opaciﬁcation of the left calvarial growth served as an addi- sphenoid sinus (asterisks), concerning for a CSF leak. Milder pitting is noted on the right (solid tional compensatory mechanism for arrows). Corresponding MR imaging (C and D)conﬁrms a meningocele protruding into the left the depleted intracranial CSF volume. sphenoid sinus (dashed ovals, C and D). MRV (not shown) noted smooth tapered stenoses involv- ing both transverse sinuses, and the patient was ultimately diagnosed with pseudotumor cerebri. Babcock et al confirmed such findings 4 Benson Jan 2023 www.ajnr.org 35 growth, Moseley et al noted, is primar- ily the inner table of the calvaria. Thus, the findings are analogous to the layer cake appearance seen in adult patients with SIH. The increased inner-to-outer table measurement is important because it helps distinguish these calvarial changes from those related to expansion of the diploic space (eg, sickle cell dis- ease or thalassemia). The clinical implications of these cal- varial findings are currently unknown. There are, however, some potential effects that have been considered. The presence of layer cake hyperostosis in patients with SIH, for example, leads to FIG 3. Example of layered calvarial thickening in a patient with SIH. Sagittal MR images (A)dem- onstrate classic ﬁndings of SIH, including pituitary enlargement, brain sag, and dural venous sinus a decrease in the volume of the calvarial engorgement. Axial CT image (B) in the same patient shows thickening of the bifrontal calvaria vault. Conceptually, this could reduce with characteristic layering related to preferential growth along the inner table of the skull the ability to normalize brain sag follow- (between straight arrows). ing CSF leak repair—that is, calvarial hyperostosis could impede the ability of brain to “un-sag” by acting as an unyielding intracranial barrier. Similarly, patients with SIH with layer cake skull changes might be at higher risk of rebound hypertension after leak repair because the tightened intracranial space could potentially lead to greater mass effect on the transverse sinuses. For now, these hypotheses remain concep- tual in nature, though studies on these topics are ongoing. Call For Revision Altogether, studies have convincingly FIG 4. Hyperostosis related to a CSF leak. Sagittal T1-weight images before (A) and after (B)the shown demonstrable changes in the cal- development and diagnosis of SIH, with 16 years between examinations. Multiple classic ﬁndings of SIH are seen, including brain sag (dashed oval) and herniation of the cerebellar tonsils through varia in the setting of pathologic condi- the foramen magnum (dashed arrow). The patient also developed substantial frontal-predomi- tions of intracranial pressure. The skull nant calvarial hyperostosis (between solid arrows), particularly along the inner table of the skull. expands in response to IIH and grows inward along its inner table in response to SIH. Skeptics might argue that these changes are outside the in a case-control study, noting that layered hyperostosis was realm of the Monro-Kellie doctrine because they represent adapt- present in 32% of patients with SIH but in only 5% of controls ive changes in response to a breakdown of pressure homeostasis. (P , .001; OR ¼ 11.58) (Fig 3). Most important, the study of It is clear, however, that the concept of a rigid calvaria, a funda- Babcock et al found no significant difference in the prevalence mental tenet upon which the doctrine is based, has been disproven of diffuse (nonlayered) hyperostosis between groups (P ¼ .465). multiple times. We should add a fourth component to the Thus, the “layer cake” type of hyperostosis is much more indica- Monro-Kellie hypothesis: a nonrigid calvaria that adjusts, albeit tive of intracranial hypotension (Fig 4). Although the expected slowly, to changes in intracranial pressure. location of this layer cake appearance was not discussed in detail in either publication, it is possible that these findings tend to be Disclosure forms provided by the authors are available with the full text and frontal-predominant, similar to benign hyperostosis frontalis PDF of this article at www.ajnr.org. interna. Specifically, the representative examples in the article by Babcock et al seem to suggest that such findings are at least REFERENCES prone to more substantial development along the frontal bone. 1. Mokri B. The Monro-Kellie hypothesis: applications in CSF vol- A similar phenomenon, termed “hyperostosis cranii ex vacuo” ume depletion. Neurology 2001;56:1746–48 CrossRef Medline has been described in chronic shunting of pediatric hydrocepha- 2. Rosenberg KI, Banik R. Pseudotumor cerebri syndrome associated 33,34 lus. 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American Journal of Neuroradiology – American Journal of Neuroradiology
Published: Jan 1, 2023
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