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The central nervous system pressure histogram in hydrocephalus and hydromyelia
Accepted Manuscript The Intracranial Pressure Histogram in Hydrocephalus and Hydromyelia HF Williams PII: DOI: Reference:
S0306-9877(17)30294-3 http://dx.doi.org/10.1016/j.mehy.2017.07.024 YMEHY 8634
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
15 April 2017 18 July 2017
Please cite this article as: H. Williams, The Intracranial Pressure Histogram in Hydrocephalus and Hydromyelia, Medical Hypotheses (2017), doi: http://dx.doi.org/10.1016/j.mehy.2017.07.024
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The Intracranial Pressure Histogram in Hydrocephalus and Hydromyelia Author; H F Williams Address; 19 Elibank Road, London SE9 1QQ United Kingdom Phone; 00442088509600 Email; [email protected] Grants; nil
Introduction This work proposes that the pressure histogram for central nervous system (CNS) pressure, that is local to any brain or spinal cavity, is a determinant of filling. This forms part of a unifying hypothesis that has been introduced in previous publications [1],[2],[3]. The brain ventricles are unique because they fill in physiological situations by active secretion or by low pressure from inside the cavity. Active secretion comes from the choroid plexus. Low pressure is a sub-atmospheric suction force that has relevance because brain membranes are semipermeable, allowing osmotic and hydrostatic forces to act on water molecules. Other cavities tend to fill by only one of these mechanisms, with dual mechanisms reflecting the importance of cerebrospinal fluid (CSF) volume to CNS physiology. Active secretion and low pressure result in watery rather than protein rich fluid accumulation, which distinguishes them from those due directly to inflammation or lymphatic obstruction. Cranial and chest cavity filling can be compared as a means of illustrating the disease processes. When venous pressures are within the normal range, low pressure filling can be physiological. Negative chest pressure maintains lung expansion, causes air to enter the lungs and fluid to enter the pleural space so that it can be drained by lymphatics that cover the lung surfaces, providing immune surveillance. Abnormal chest cavity
filling often occurs with lung parenchyma congestion onto which negative pressure is imposed, as for example with left ventricular failure. The magnitude of the low pressure suction force in the chest can be greatly enhanced by airway obstruction, such as laryngospasm. This may lead to acute lung edema as fluid enters the interstitial, alveolar and pleural spaces. The mechanism in these acute cases is also described as a state of reduced venous flow in the lung parenchyma, onto which negative pressure is imposed [4],[5]. It is proposed that the amount of time spent at low pressure in the CNS, the magnitude of the low pressures and tissue turgor local to the cavity influence filling. The ventricle pressure is reflected by intracranial pressure (ICP) histogram otherwise known as a pressure time curve (PTC). Physiological levels of venous flow and hydrostatic pressure allow fluid balance between compartments and tissues, imbalance of these pressures may lead to hydrocephalus and hydromyelia. Principles that underpin the hypothesis have been described in the previous companion work [3], and include that; Pressure, as measured in the CNS, relates to the presence of region fluid outflow from and around the space being measured, rather than the volume it occupies. During peaks or troughs of pressure there may be slow venous flow (high pressure) in the parenchyma, which represents venous insufficiency.
Hyperemia in response to intermittent ischemia (when compliance is low) can increase parenchyma water content. Increased pulsatility within the arterial tree in hydrocephalus demonstrates the potential for a hyperemic response to hypoxic stress. Hydrocephalus is caused by conditions that narrow the CNS compliance curve. The most influential of these conditions in developmental forms of hydrocephalus is restriction of the posterior fossa. Hydrocephalus is a disorder of water balance that can lead to increasing CNS pressure by means of aqueduct stenosis and hindbrain herniation. Previous ideas are not repeated here, however it is important to stress that the sequence of events for naturally occurring hydrocephalus is for ventricle enlargement due to an abnormal increase in ventricle CSF volume, followed by attenuation of the aqueduct. The aqueduct is usually not fully stenosed by the presence of hydrocephalus, showing variable levels of narrowing. Aqueduct stenosis results from pressure on the midbrain from the enlarged lateral ventricles [6],[7],[8],[9].This includes cases of spina bifida and X linked hydrocephalus where aqueduct stenosis is traditionally considered to result from aqueduct stenosis [10],[11]. Evidence for this mechanism has accumulated over a period of more than 50 years, and is not adequately recognised, as idiopathic stenosis is still sometimes stated to be an acceptable cause of hydrocephalus [12]. This theory takes an opposing view by proposing that an aqueduct is
needed as part of the ventricular system and narrows in the presence of enlarged ventricles thereby assisting in reduction of choroid plexus secretion. When the aqueduct is blocked net choroid secretion can cease [13], indicating that choroid plexus secretion responds to ICP rather than causes it. The aqueduct which is positioned downstream of the choroid becomes narrowed as a part of a system that aims to resolve a high pressure illness. Clinical and experimental evidence indicate that choroid plexus tissue is sensitive to pressure and regulated by sympathetic nerves [14],[15]. When intraventricular pressure is low, as happens with an external drain, the choroid may secrete large volumes [16]. The hypothesis is consistent with the finding that choroid plexus removal is not an effective treatment for established hydrocephalus, although it can be beneficial in the neonate. This is because the profile of pressure that results in hydrocephalus in the neonate involves episodes of low pressure where choroid secretion can contribute to net CSF volume. Choroid plexectomy can be successful if it is done early in life [17],[18],[19]. It can moderate filling before the acquired obstructions of hydrocephalus become established. These acquired obstructions can mould and damage brain tissue when they cause reduced flow. By slowing the disease progression with cautery there may be time for adaptations to elevated pressure, particularly in the venous and aquaporin systems [20]. There will also be time for vault expansion to accommodate enlarged ventricles and allow patency to the aqueduct. If the plexectomy is delayed, the filling mechanism may lead to more severe brain deformities.
These obstructions include hind brain herniation. Depletion of parenchyma volume and vault expansion may allow stabilisation of the disease because the requirement for arterial blood over a period of time decreases and because of alleviation of pressure on the midbrain and hindbrain. These two changes facilitate communication between CSF spaces which enable the spaces to contribute to CNS compliance [1],[2]. Concepts of disease progression are represented in fig 1. The Pressure Histogram It is proposed that a CNS pressure histogram or curve, which can be constructed from a continuous pressure measurement taken from a CNS space or cavity, can assist in overcoming the difficulty of understanding the relationships between venous pressure and hydrocephalus. This is because it links venous pressure and filling with symptoms. The hypothesis concludes that hydrocephalus arises when negative pressure is imposed on parenchyma which is in a state of venous insufficiency. A histogram or curve is described by mode, skew and pressure range. A positive skew refers to curves with a mode to the left of the median and an elongation of the tail to the right, and negative skew describes an opposite asymmetry. An ICP histogram array demonstrates intraventricular pressure over time by placing histograms in sequence. An example is given in Fig. 2 for a patient who demonstrated a rise in ICP after cardiopulmonary arrest [21]. Interventions
caused a temporary moderation of mode pressure followed by a steady rise as further efforts failed. When IVP and arterial pressure is represented over time it can indicate prognosis. This has been demonstrated for 428 patients following head injury, as shown in fig. 3. This diagram shows the probability of survival after head injury as ICP and arterial blood pressure influence cerebral perfusion [22]. These works show that there is a relationship between IVP over time and prognosis that relates to cerebral blood supply. There are principles of interpretation of the ICP histogram that are of importance to the hypothesis. These include that mode pressure of the histogram is a function of flow within the CNS. Mode relates to intracranial anatomy on a microscopic and macroscopic level, reflecting the ability of the spaces to behave in a fluid-like manner by dispersing pressure that is generated by fluid movement. In other words it reflects the compliance of the system. Compliance requires that gravitational forces are facilitating outflow of venous blood from the CNS. There are two means by which venous outflow of blood from the CNS spaces in impeded. These are retrograde venous flow towards the CNS and Starling resistance. Starling resistance is pressure in a vessel as the walls are pressed together due to the weight of both the walls and the surrounding tissue. When venous pressure is low in the neck due to gravity with upright posture some veins collapse and become Starling resistors, and others remain open. Susceptibility to collapse reflects vessel wall thickness, the structural support
available to the vein from surrounding tissue, the magnitude of the gravitational force and venous pressure. Starling resistance allows negative (suction) force at the subarachnoid space of the vault which helps to keep the brain inside the cranium when upright, in a similar way to the negative pleural pressure which allows the lungs to remain inflated. Retrograde venous flow towards the spine when upright enables CSF buoyancy in the spinal space. These two mechanisms contribute to support for the parenchyma, especially to the hindbrain, preventing brain herniation through the foramen magnum due to gravity. The most important advance that this work makes on previous ideas in this series is that in the presence of elevated mode pressure there is an increased likelihood of intermittent episodes of low pressure in CSF space, especially those that are gravitationally above the heart. This tendency can be enhanced with physical movement. As the mode shifts to the right, the left skew for intracranial and cerebral cistern pressure may be extended and made more prominent when any suction force is applied. This concept is supported by the observations of Janney who described enhanced skew as mode pressure rises in a study of 13 cases with differing intracranial pathologies, although details of the individuals were not given [23]. This is happening because fluctuations in pressure when imposed on a state of elevated pressure will occur beyond the zone of CNS compliance, especially if there are fixed obstructions.
A simplified representation of potential variability in the intraventricular PTC in the absence of pathology is illustrated in Fig 4. Resting recumbent and resting head down profiles for a single individual are shown alongside a curve generated by activity with upright posture. Head down posture causes the highest mode IVP because cerebral venous outflow is slowed by retrograde pressure and the intracranial space then communicates with the high pressure veins. In health, there is not a large left skew with head down posture because there is no increase in the amount of fixed obstruction to the cerebral compartment and physical movements are often limited. Resting profiles are narrower than the curve in activity. This is because venous pressure fluctuations are imposed on the CNS as the body moves. The more vigorous the movement, the broader will tend to be the PTC. The PTC for any region of the CNS will vary as movement related changes are imposed on gravitational influences. This physical movement in combination with any reduced compliance tends to increase mode pressure if it increases parenchyma water content and it also therefore contributes to the skew. Fixed obstructions to flow such as skull base abnormality will be a prime cause of broadening of the PTC, in either or both direction in response to routine daily activity [3]. Upright posture facilitates low cerebral pressure which is necessary for capillary flow in brain parenchyma, as in other body tissues. Further proposals
New proposals in this work include that; Cavity filling, including ventricles, subarachnoid spaces, cysts and hydromyelia cavities relates to the PTC in that anatomical region. The PTC that maintains hydrocephalus (CSF accumulation driven by intermittent parenchyma ischemia) can arise from and be sustained by a profile with high, low or normal mode CSF pressure. Hydrocephalus has a physiological role. Although hydrocephalus can be self-perpetuating by causing obstruction it can also be self-limiting by moderating a labile pressure profile. The histogram in hydrocephalus Diseases that directly cause venous hypertension sometimes lead to hydrocephalus; examples include superior vena cava thrombosis [24] and surgeries for congenital cardiac defects [25]. No correlation has been found between large vessel venous pathology and hydrocephalus. This will be due to the presence of venous adaptations over time in the form of anastomoses that develop in response to elevated pressure, and also because large vessel pressure does not correlate with parenchyma venule pressure. The importance of venous competence for the brain is illustrated by the separation of craniopagus twins, where a staged approach to surgery to the major cerebral veins reduces the risk of morbidity and mortality [26],[27]. Damage to veins can cause acute
intracranial hypertension in the early post-operative phase, and hydrocephalus may be a later complication. Small vessel venous pressure can be linked to hydrocephalus by measuring CSF cavity pressure, although this relationship is complicated by the digression of ventricle and parenchyma pressure at the point that pressure becomes low [3]. This is also true in the lungs as mentioned previously. Brain tissue pressure studies have not thus far utilised negative pressure, however the idea of tissue being subject to increased pressure when the ‘local vascular reservoir has been squeezed out’ has been used to describe brain tissue response to pressure [28]. It is just as valid to propose that tissue is subject to increase pressure when vessels are ‘sucked’ out as when they are squeezed. Negative pressure in the CNS is not brought about by the absence of compression; rather it is the presence of a suction force. The concept of low pressure as a cause of ischemia is important, as it means that pressures at either end of a labile profile may interrupt small vessel flow and thereby increases CNS parenchyma water content [3]. Thus venous insufficiency can be present at either end of a histogram, especially but not exclusively, when the curve is abnormally wide. This means that hydrocephalus or hydromyelia that may benefit from surgery that alleviates parenchyma pressure can be caused by profiles with high, low or normal mode CSF pressure. Elevated mode pressure tends to improve absorption of CSF and water back into the circulatory system [29]. Accompanying an elevation, there may be resolution of a high pressure illness with or without a filling mechanism, as shown in fig 1.
The shape of the PTC in the cerebral ventricles that is typical of established hydrocephalus with upright posture is illustrated in Fig.5. A more normal profile for intraventricular pressure over a similar time period would show a slightly narrower base and lower mode. Time spent at the extremes of the curve, indicated by the arrows. can generate intermittent ischemia. The negative skew demonstrates time that leads to CSF space filling. The left skew will be more prominent when upright and within a gravitational field but not necessarily completely eliminated when recumbent. Likewise the elevation of mode IVP in hydrocephalus will be more prominent when lying down and may not be eliminated when upright. This concept anticipates an interaction of pressure effects illustrated in Fig. 4 and Fig. 5. A pattern of the PTC that emerges from a low pressure filling mechanism and leads to symptoms and then compensates by loss of parenchyma is illustrated by means of a hypothetical array shown in Fig 6. Where hydrocephalus results from a high pressure illness Curves a. and b. would be of a similar shape to that shown, but would be positioned on the right side of the x axis rather than on the left as shown. Any position of curve on the x axis could give rise to curve c so long as it meets the requirements of venous insufficiency combined with episodes of negative pressure. It is proposed that cavity filling causing pressure to rise leads to the phase of Curve c. It is possible for the disease to compensate, and this will lead to a more normal shape and position of curve; this is shown by the transition to d. The transition from Curve c. to d. is possible with surgery.
Ischemia with movement is important for hydrocephalus rather than ischemia at rest. Ischemia at rest becomes progressively more significant as mode pressure becomes high and threatens life, as with ICH following trauma or brain haemorrhage. This difference can make eclampsia, altitude sickness and other ICH conditions particularly dangerous. High venous pressure in the parenchyma caused by relatively rapid changes in parenchyma water content and venous drainage will cause a different set of symptoms than those for patients that can tolerate an imperfect venous system whilst moving around. Obstructions occur by degree, are affected by movement, and are not a present or absent property of an individual. The more fixed in terms of anatomy, the greater will be the potential effect on the filling mechanism. A potential cause of variable pulsatility profiles relates to differences the dimensions of the subarachnoid CSF spaces. Differences that are difficult to demonstrate on an individual basis may have an influence on compliance and therefore the risk of developing hydrocephalus or hydromyelia. This assertion is supported by evidence from study of the subarachnoid space flow in Chiari malformation [30]. Brain inflammation with edema and breakdown of cellular function may result in hydrocephalus as a complication during illness or recovery. CNS parenchyma is contained within stiff boundaries that are made less stiff, when considering the dynamic situation, by the presence of interconnected CSF spaces. These CSF spaces amplify the available venous drainage channels at any moment in
time. Parenchyma edema causes problems for arterial supply in the brain more readily than in other organs because of the bone constraints. With a primary edema the possible outcomes include full recovery, death or a degree of morbidity related to infarction and or hydrocephalus. There is evidence that a diffuse change in the brain parenchyma with minor head injury can reduce cerebral compliance with impaired venous flow [30]. Minor changes are usually recoverable, however when inflammation is severe the PTC may shift significantly to the right and lesions such as arachnoid adhesions may occur which exacerbate obstruction. A delay between the high pressure illness and symptoms attributable to hydrocephalus may occur, and the length of time is highly variable. An ICP histogram has been reported to assist in the management of hydrocephalus in a single case [31]. In this instance, histograms demonstrate the difference between an approximately normal ICP histogram and another that shows elevated mode and a left skew. In this case a 12 year old child underwent removal of a large epithelialised thoraco-lumbar myelomeningocele sac. Pre and postoperative IVP profiles were measured to determine whether surgery might lead to the need for a shunt. Before surgery, there was higher mode pressure with a small prominence of the left side of the curve. After surgery, mode pressure was lowered and there was a reduction in the number of lower pressure readings, there was also an increase in higher pressure pulsations resulting in a
right skew. The histograms have been reproduced in previous works [3],[32]. It was suggested by the authors that the thoraco-lumbar sac had performed the function of a ‘shock absorber’ to the CNS. It is proposed here that this concept is correct, and that whilst dampening of the highest pressures had occurred, due to the presence of the sac, there had been time for cerebral adaptations to raised mode pressure. This prevented an excess increase in ventricle and skull size that could have happened if repair had been undertaken prior to suture closure. It is also proposed that the repair of the sac resulted in an improvement in CSF flow around the foramen magnum by improving the buoyancy in the spinal space [32]. Both histograms were consistent with the child not needing a shunt; however the profile with the higher mode pressure in the preoperative phase was a feature of a child in whom the epithelialised sac was gradually enlarging. The operation was done to help the child achieve a sitting position which has become difficult because the sac had reached ‘baseball’ size [31]. Measurements made in the region of the lumbar spine of the patient, rather than the head, would have shown a different change in pressure profiles than that arising from the ventricles which is shown in this case. The challenge to CNS blood supply from exertion was stressed in the first publications in this series and this assertion is supported by recent evidence [33]. The hypothesis has progressed to proposing that venous pulsatility caused by skeletal muscle activity in the physiological range is essential to CNS
physiology, aiding blood flow and physiological water distribution [3]. One study of jaw movement and brain blood flow provides support for this concept [34]. A case study of a single patient with aqueduct stenosis who developed symptoms of raised pressure with exercise also supports this concept [35]. Third ventriculostomy for this individual was reported to resolve the exertional symptoms. More evidence of the mechanism of this phenomenon is needed. It is proposed that the quantity of extra parenchymal water volume generated by episodes of ischemia can be reabsorbed over the course of a 24 hour period; however when filling is occurring frequently, spaces will tend to enlarge and venous volume will be displaced. When excess water is delivered into the CNS it is distributed into areas with the greatest compliance including any potential space such as a membrane defect or the central cord canal [3], and compartments that have been created surgically [36]. The histogram in Hydromyelia Cranial spaces can moderate extremes of pressure more easily than the spinal space in Chiari malformation because of the adaptability of the choroid and the advantages for cerebral compliance afforded by gravity. Spinal pressure is intrinsically labile with movement due to the capacitance of spinal veins [2]. The labile venous volume combined with retrograde venous flow towards the spine, contributes to the explanation for the occurrence of hydromyelia with foramen magnum obstruction, without there necessarily being a clinically
obvious hydrocephalus. The pressure histogram that generates cervical hydromyelia cavities will tend to show a lower and more labile profile than with lesions in that originate in the lower thoracic and lumbar region. Hydromyelia cavities may stabilise or improve if CSF flow at the foramen magnum can be improved surgically. Evidence indicates that this alleviates tonsil herniation [37], which strongly implicates low pressure with the formation of cervical cavities. Obstruction to CSF flow at the foramen magnum prevents the flow of CSF into the spinal compartment with upright posture; this leads to a suction force on the hindbrain. It is proposed that as cervical cavities enlarge, mode cervical spine pressure rises which gradually alleviates some of the negative pressure. In the fetus, hindbrain herniation is caused by physical movement in the presence of a restricted posterior fossa [32]. Amniotic fluid pressure reduces the impact of gravity on the hindbrain via the spinal defect, and prevents Starling resistance around the skull. When anatomy is normal and CSF and venous blood can flow freely around the hindbrain, there is little suction force on the fetal hindbrain. When low spinal pressure in the fetus is caused by skeletal muscle movement the hindbrain is vulnerable to herniation. A spinal defect does not reduce mode pressure. These concepts are complex and will be discussed in more detail in a forthcoming work. When open to atmospheric pressure there may be severely detrimental ischemia in the region of the placode due to the lack of CSF buoyancy. Encouraging a natural epithelialisation of the
spinal defect before birth, whilst maintain amniotic fluid pressure may be a better surgical approach than other forms of prenatal placode surgery. The physiological Role of Hydrocephalus. The reason that Starling principles apply within the CNS space is the requirement for a certain volume of CSF for parenchyma health. CSF is needed because of gravity and the need for a skull and spinal column. High and low IVP represent time spent away from the compliant zone. The expansion of fluid volume in response to low pressure will usually be returning CSF volume towards compliance and restoring buoyancy for brain tissues. With an abnormally narrow compliance curve due to skull base malformation, the increased CSF volume provides the stimulus for reduction of choroid secretion, vault expansion, improved collateral flow, sacrifice of parenchyma tissue, and aquaporin adaptations. There may be delay in closure of the fontanelles or spontaneous rupture of the floor of the third ventricle. These changes lead to transient or long standing improvement in compliance and may decrease in parenchymal blood requirements. It is important that the growth of neural tissue and its bone encasements fit together so that neural tissue is able to receive adequate amounts of arterial blood at all times. Abnormally labile pulsatility related to exertion is not sustainable. One of the many purposes of the lateral ventricles is to apply pressure to the parenchyma of the vault so that its blood flow can be promoted in physiological states [3]. Vault and ventricle
enlargement provide skull space, that if conditions are physiological, the brain can then ‘grow into’. Development can be delayed when compliance of the cranium is insufficient for adequate arterial supply. This facilitates a situation where the parenchymal volume is reduced and ischemia with physical movement is of little significance to symptoms, although higher functions may be impaired. It can alleviate pressure on the brain stem and ‘buy some time’ in the process of optimising function. Damage to the cortex and a large head is a better outcome in terms of the future of the individual than brain edema, ICH and brain herniation, which is an alternative outcome in the presence of cerebral venous insufficiency. Normal Pressure Hydrocephalus For many hydrocephalic disorders, the more closely the CSF resembles normal fluid the more physiological is the process, although disease states may emerge. An exception to this is normal pressure hydrocephalus, where the disease, according to the concepts of this hypothesis, represents the breakdown of fluid balance mechanisms that had previously been effective for a period either after a brain insult or as part of normal CNS function. One example of such a breakdown of normal physiology is the increased brain stiffness with aging that may restrict blood flow in the parenchyma. An association between abnormal brain stiffness and normal pressure hydrocephalus has been observed [38]. Ascites caused by cirrhosis gives a pathological analogy for the process of
venous hypertension and cavity filling caused by increased parenchyma stiffness. Results from magnetic resonance elastography of the brain and liver support these assertions [39]. Some of the other mechanisms outlined in this work that may be acting in combination with changes in elasticity allow for heterogeneous causes for NPH. Venous pressure in the parenchyma that results from increase in brain stiffness may not be fully reflected in the PTC because CSF may flow more freely than venous blood in the supratentorial spaces when the brain becomes stiff. This may increase the appearance of ‘normality’ within the pressure profile of some symptomatic patients. Draining ascites does not greatly improve portal hypertension. If brain stiffness is acting with other compliance variables in normal pressure hydrocephalus then shunt response will also vary. The greater the obstructive component the greater will be the shunt response. Conclusion The theory accords with concepts promoted by Rekate, in that it proposes that hydrocephalus is an obstructive process and venous insufficiency in isolation causes brain edema. Hydrocephalus is in part, by definition, a disease where blood supply to the parenchyma improves with removal of CSF from enlarged spaces, so that according to this hypothesis, a negative skew and elevated mode should form part of the profile of the disease in treatment responsive cases. This relationship needs further exploration.
Author’s contributions This is the work of one author Conflicts of interest I declare that no funding was received and that no conflict of interest arises from this work.
References [1] Williams H. The venous hypothesis of hydrocephalus Medical Hypotheses 2008, 70:743-747. [2] Williams H. A unifying hypothesis for hydrocephalus, Chiari malformation, syringomyelia, anencephaly and spina bifida. Cerebrospinal Fluid Research 2008;5:7. [3] Williams H. A unifying hypothesis for hydrocephalus and the Chiari malformations part two: The hydrocephalus filling mechanism. Medical Hypotheses 2016;94:30–39 [4] Udeshi A, Cantie S M, Pierre E. Post obstructive pulmonary edema. Journal Critical Care 2010;25:538.e1-5. [5] Krodel D J, Bittner E A, Abdulnour R, Brown R, Eikermann M. Case Scenario: Acute Postoperative Negative Pressure Pulmonary Edema Anesthesiology 2010; 113:200-207. [6] Williams B. Is aqueduct stenosis a result of hydrocephalus? Brain 1973;96:399-412. [7] McMillan J J, Williams B. Aqueduct stenosis, Case review and discussion. Journal of Neurology, Neurosurgery, and Psychiatry 1977;40:521-532.
[8] Borit A. Communicating hydrocephalus causing aqueductal stenosis Neuropaediatrie, 1976 - thieme-connect.com [9] Masters C L. Pathogenesis of the Arnold-Chiari malformation: the significance of hydrocephalus and aqueduct stenosis Journal of Neuropathology and Experimental Neurology 1978;37:56–74. [10] Landrieu P, Inane J N, Ferriére G, Lyon G. Aqueductal stenosis in Xlinked hydrocephalus: a secondary phenomenon. Developmental Medicine and Child Neurology 1979;21:637–642. [11] Barkovich A J, Newton T H. MR of aqueduct stenosis: evidence of a broad spectrum of tectal distortion. American Journal of Neuroradiology 1989;10:471476 [12] Cinalli G, Spennato P, Nastro A, ALiberti F, Trischitta V, Ruggiero C, Mirone G, Cianciulli E. Hydrocephalus in aqueductal stenosis. Child's Nervous System 2011, 27:1621 [13] M. Klarica Orešković D, Božić B, Vukić M, Butković V, Bulat M. New experimental model of acute aqueductal blockage in cats: effects on cerebrospinal fluid pressure and the size of brain ventricles. Neuroscience 2009;158:1397–1405. [14] Owman C, Lindvall M. Sympathetic nervous control of CSF production in normal and hydrocephalic animals, and its relationship to cerebral blood volume
and intracranial pressure. Intracranial pressure V. Springer-Verlag Berlin. Ishii S, Nagai H, Brock M (Ed).1883:10-28. [15] Auer L. M, Sayama I. Johansson B. B, Leber K. Sympathoadrenergic modulation of cerebral blood volume during increased ICP. Intracranial pressure V Springer-Verlag Berlin. Ishii S, Nagai H, Brock M (Ed) 1983:342347. [16] Phi J H, Shin C H, Wang K, Park S, Kim S. Catastrophic electrolyte imbalance caused by excessive production and overdrainage of cerebrospinal fluid in an infant with choroid plexus papilloma. Childs Nervous System 2011;27:1153-1156. [17] Pople I K, Ettles D. The role of endoscopic choroid plexus coagulation in the management of hydrocephalus. Neurosurgery 1995;36:698–702. [18] Di Rocco C, Iannelli A. Poor outcome of bilateral congenital choroid plexus papillomas with extreme hydrocephalus. European Neurology 1997;37:33-37. [19] Warf B C, Campbell J W. Combined endoscopic third ventriculostomy and choroid plexus cauterization as primary treatment of hydrocephalus for infants with myelomeningocele: long-term results of a prospective intent-to-treat study in 115 East African infants. Journal of Neurosurgery Pediatrics 2008;2:310– 316.
[20] Abreu-Rodrıguez I, Silva R, Martins A, Soveral G, Toledo-Aral J, LopezBarneo J, Echevarria M. Functional and transcriptional induction of aquaporin-1 gene by hypoxia; analysis of promoter and role of Hif-1a. PLoS ONE 2011; 6(12): e28385. doi:10.1371/journal.pone.0028385 [21] Tsutsumi H, Nishiyama T, Aruga H, Toyooka H, Mii K, Tsuzuki M, Manaka S, K. Takakura. Usefulness of ICP histogram and ICP histogram array in ICP monitoring. Intracranial pressure V Springer-Verlag, Berlin. Ishii S, Nagai H Brock M (Ed) 1983:135-139. [22] Marmarou A., Anderson R.L., Ward J.D., Choi S.C., Young H.F. Impact of ICP instability and hypotension on outcome in patients with severe head trauma. Journal Neurosurgery 1991;75:S59-S66. [23] Janny P, Jouan J.P, Janny L, Gourgand M, Gueit U.M. A statistical approach to longterm monitoring of intracranial pressure Intracranial Pressure Vol I. Springer-Verlag Berlin. Brock et al (Ed) 1972:59-64 [24] McLaughlin J F, Loeser J D, Roberts T S. Acquired hydrocephalus associated with superior vena cava syndrome in infants. Childs Nervous System 1997;13:59-63. [25] Dillon T, Berman Jr W, Yabek S M, Seigel R, Akl B, Wernly J. Communicating Hydrocephalus: A Reversible Complication of the Mustard
Operation with Serial Hemodynamics and Long-term Follow-up. The Annals of Thoracic Surgery 1986;41:146-149. [26] Walker M, Browd S R. Craniopagus twins: embryology, classification, surgical anatomy and separation. Childs Nervous System 2004;20:554-566. [27] Staffenberg D A, Goodrich J T. Separation of craniopagus conjoined twins with a staged approach. Journal of Craniofacial Surgery 2012;23:2004-2010. [28] Brock M, Furuse M, Weber R, Hasuo M, Dietz H. Brain tissue pressure gradients Intracranial Pressure II. Springer, Berlin. Lundberg N., Pontén U., Brock M. (Eds) 1975;215-220. [29] McLone D G. Consensus: modelling of hydrocephalus. Child's Nervous System 1994;10:24–28 [30] Pahlavian S. H, Loth F, Luciano M, Oshinski J, Martin B A. Neural tissue motion impacts cerebrospinal fluid dynamics at the cervical medullary junction: A patient-specific moving-boundary computational model. Annals of Biomedical Engineering 2015;43:2911-2923. [31] Pomschar A, Koerte I, Lee S, Laubender R P, Straube A, Heinen F, ErtlWagner B, Alperin N. MRI evidence for altered venous drainage and intracranial compliance in mild traumatic brain injury. PLoS ONE 2013;8(2): e55447. doi:10.1371/journal.pone.0055447
[32] Linder M, Nichols J, Sklar F H. Effect of meningomyelocele closure on the intracranial pulse pressure. Child’s Brain 1984;11:176-182. [33] Williams H. Questioning the rationale and conduct of the management of myelomeningocele study. Medical Hypotheses 2011;77:101–105. [34] Seifert T, Secher N H. Sympathetic influence on cerebral blood flow and metabolism during exercise in humans. Progress in Neurobiology 2011;95:406– 426. [35] Hasegawa Y, Ono T, Hori K, Nokubi T. Influence of human jaw movement on cerebral blood flow. Journal of Dental Research 2007;86:64-68. [36] Yamada S M, Matsuno A, Yamada S, Running-induced headaches in aqueductal stenosis patient. Surgical neurology.org 2012 [37] Frassanito P, Massimi L, Caldarelli M, Tamurrini G, Di Rocco C. Complications of delayed cranial repair after decompressive craniectomy in children less than 1 year old. Acta Neurochirurgica 2012;154:927-933. [38] Duddy M J, Williams B. Hindbrain migration after decompression for hindbrain hernia: A quantitative assessment using MRI. British Journal of Neurosurgery 1991;5:141-152. [39] Fattahi N, A. Arani A, Perry A, Meyer F, Manduca A, Glaser K, Senjem M L, Ehman R L, Huston J. MR Elastography demonstrates increased brain
stiffness in normal pressure hydrocephalus. American Journal of Neuroradiology 2016;37:462-467. [40] Klatt D, Hamhaber U, Asbach P, Braun J, Sack I. Noninvasive assessment of the rheological behavior of human organs using multifrequency MR elastography: a study of brain and liver viscoelasticity. Physics in Medicine and Biology 2007; 52:7281-94.
Fig.1 Representation of the three dimensional surface of estimated outcome probability versus the proportion of intracranial pressure (ICP) measurement greater than 20mmHg and the proportion of blood pressure measurements less than 80mmHg. The effect of hypotension is evident from the front to back sloping of the surface and the impact of ICP elevation is apparent from the left to right sloping of the surface. Reproduced from Fig. 4 Marmarou A, Eisenberg H Foulkes M. et al. Impact of ICP instability and hypotension on outcome in patients with severe head injury. J Neurosurg 1991;75:S59-S66 (with permission: Journal of neurosurgery publishing group) Fig.2
ICP histogram array. Each successive line starting at the bottom is an ICP distribution curve measured for six hours. The case is a 21-year old male after cardiopulmonary resuscitation. ICP gradually increased after successful resuscitation and decreased transiently in response to treatment, and again increased until brain death. Reproduced from Fig.3 Tsutsumi H, Nishiyama T, Aruga H. et al. Usefulness of ICP histogram and ICP histogram array in ICP monitoring Intracranial pressure V Springer-Verlag, Berlin. Ishii S, Nagai H Brock M (Ed) 1983:135-139. (with permission; Springer-Verlag, Berlin) Fig.3 Representation of intracranial pressure response to posture and activity. Each curve represents a period of continuous monitoring. Curve a. is generated in response to activity such as running. Curve b. is recumbent and at rest. Curve c. is generated by head down posture with rest. Fig.4 The pressure time curve (ICP histogram) in hydrocephalus. The case illustrates symptomatic cases amenable to treatment. Mode pressure is raised and there is a negative skew. Elevated mode pressure indicates poor venous drainage and may be associated with ischemia particularly at the extremes of pressure. The left skew represents episodes of low or negative pressure in the continuous profile
and indicates that filling of the cavity is occurring over the period that the measurement is taken. Fig.5 A hypothetical array of curves demonstrating pressure with time during the evolution of a high cervical spine syringomyelia (hydromyelia) cavity. Transition through the array shows the initiating problem of low pressure in the high cervical spine region followed by the formation of a cavity with symptoms, the transition to curve d. occurs with successful surgical decompression of the skull base or with loss or parenchyma after a prolonged illness.
Fig. 6 The relationship between pressure and time for a 12 year old child before and after myelomeningocele repair. Time (%) versus ICP (mmHg) before and after meningomyelocele closure. ICP data were averaged over 3 min intervals. Reproduced from Fig. 1. Linder M, Nichols J, Sklar F. Effect of meningomyelocele closure on the intracranial pulse pressure. Childs Brain 1984;11:176–182 (with permission; S. Karger AG, Basel).
Reduced compliance and a filling mechanism
Adaptation and nearly normal (or normal variant) neural and venous anatomy
Initially non- progressive PTC
Abnormal anatomy including large head, aqueduct stenosis, hindbrain hernia and benign external hydrocephalus ,
Higher risk of complications including hydromyelia, scoliosis, headaches and cognitive impairment
Progressive disease with symptoms and signs
Shunting/third ventriculostomy/choroid cauterisation/venous stenting/hindbrain decompression
Stabilisation Vulnerability to normal pressure hydrocephalus and adult onset hydromyelia (syringomyelia)
Treatment failures and morbidity including infection, seizures, pain syndromes, hydromyelia, recurrent episodes of hydrocephalus, brainstem or cerebella r symptoms, bladder and other autonomic dysfunction, restricted head size and intracranial hypertension/shunt dependency
Progressive Failure of treatment
Partial response to treatment
Rise in pressure
0
10
20
ICP mmHg
30
40
50
Probability death/vegetative p=1.0
1.0
1.0
p (BP <80mmHg) p (ICP >20mmHg)
0.0
c Time
b a
Pressure mmHg: arbitrary scale
Time mode pressure: symptoms
left skew: filling mechanism
Pressure: arbitrary scale
PTC with time
d c
b
a Pressure: arbitrary scale
Hypothetical histogram array for a hydromyelia cavity in the high cervical spine
S0306-9877(17)30294-3 http://dx.doi.org/10.1016/j.mehy.2017.07.024 YMEHY 8634
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
15 April 2017 18 July 2017
Please cite this article as: H. Williams, The Intracranial Pressure Histogram in Hydrocephalus and Hydromyelia, Medical Hypotheses (2017), doi: http://dx.doi.org/10.1016/j.mehy.2017.07.024
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The Intracranial Pressure Histogram in Hydrocephalus and Hydromyelia Author; H F Williams Address; 19 Elibank Road, London SE9 1QQ United Kingdom Phone; 00442088509600 Email; [email protected] Grants; nil
Introduction This work proposes that the pressure histogram for central nervous system (CNS) pressure, that is local to any brain or spinal cavity, is a determinant of filling. This forms part of a unifying hypothesis that has been introduced in previous publications [1],[2],[3]. The brain ventricles are unique because they fill in physiological situations by active secretion or by low pressure from inside the cavity. Active secretion comes from the choroid plexus. Low pressure is a sub-atmospheric suction force that has relevance because brain membranes are semipermeable, allowing osmotic and hydrostatic forces to act on water molecules. Other cavities tend to fill by only one of these mechanisms, with dual mechanisms reflecting the importance of cerebrospinal fluid (CSF) volume to CNS physiology. Active secretion and low pressure result in watery rather than protein rich fluid accumulation, which distinguishes them from those due directly to inflammation or lymphatic obstruction. Cranial and chest cavity filling can be compared as a means of illustrating the disease processes. When venous pressures are within the normal range, low pressure filling can be physiological. Negative chest pressure maintains lung expansion, causes air to enter the lungs and fluid to enter the pleural space so that it can be drained by lymphatics that cover the lung surfaces, providing immune surveillance. Abnormal chest cavity
filling often occurs with lung parenchyma congestion onto which negative pressure is imposed, as for example with left ventricular failure. The magnitude of the low pressure suction force in the chest can be greatly enhanced by airway obstruction, such as laryngospasm. This may lead to acute lung edema as fluid enters the interstitial, alveolar and pleural spaces. The mechanism in these acute cases is also described as a state of reduced venous flow in the lung parenchyma, onto which negative pressure is imposed [4],[5]. It is proposed that the amount of time spent at low pressure in the CNS, the magnitude of the low pressures and tissue turgor local to the cavity influence filling. The ventricle pressure is reflected by intracranial pressure (ICP) histogram otherwise known as a pressure time curve (PTC). Physiological levels of venous flow and hydrostatic pressure allow fluid balance between compartments and tissues, imbalance of these pressures may lead to hydrocephalus and hydromyelia. Principles that underpin the hypothesis have been described in the previous companion work [3], and include that; Pressure, as measured in the CNS, relates to the presence of region fluid outflow from and around the space being measured, rather than the volume it occupies. During peaks or troughs of pressure there may be slow venous flow (high pressure) in the parenchyma, which represents venous insufficiency.
Hyperemia in response to intermittent ischemia (when compliance is low) can increase parenchyma water content. Increased pulsatility within the arterial tree in hydrocephalus demonstrates the potential for a hyperemic response to hypoxic stress. Hydrocephalus is caused by conditions that narrow the CNS compliance curve. The most influential of these conditions in developmental forms of hydrocephalus is restriction of the posterior fossa. Hydrocephalus is a disorder of water balance that can lead to increasing CNS pressure by means of aqueduct stenosis and hindbrain herniation. Previous ideas are not repeated here, however it is important to stress that the sequence of events for naturally occurring hydrocephalus is for ventricle enlargement due to an abnormal increase in ventricle CSF volume, followed by attenuation of the aqueduct. The aqueduct is usually not fully stenosed by the presence of hydrocephalus, showing variable levels of narrowing. Aqueduct stenosis results from pressure on the midbrain from the enlarged lateral ventricles [6],[7],[8],[9].This includes cases of spina bifida and X linked hydrocephalus where aqueduct stenosis is traditionally considered to result from aqueduct stenosis [10],[11]. Evidence for this mechanism has accumulated over a period of more than 50 years, and is not adequately recognised, as idiopathic stenosis is still sometimes stated to be an acceptable cause of hydrocephalus [12]. This theory takes an opposing view by proposing that an aqueduct is
needed as part of the ventricular system and narrows in the presence of enlarged ventricles thereby assisting in reduction of choroid plexus secretion. When the aqueduct is blocked net choroid secretion can cease [13], indicating that choroid plexus secretion responds to ICP rather than causes it. The aqueduct which is positioned downstream of the choroid becomes narrowed as a part of a system that aims to resolve a high pressure illness. Clinical and experimental evidence indicate that choroid plexus tissue is sensitive to pressure and regulated by sympathetic nerves [14],[15]. When intraventricular pressure is low, as happens with an external drain, the choroid may secrete large volumes [16]. The hypothesis is consistent with the finding that choroid plexus removal is not an effective treatment for established hydrocephalus, although it can be beneficial in the neonate. This is because the profile of pressure that results in hydrocephalus in the neonate involves episodes of low pressure where choroid secretion can contribute to net CSF volume. Choroid plexectomy can be successful if it is done early in life [17],[18],[19]. It can moderate filling before the acquired obstructions of hydrocephalus become established. These acquired obstructions can mould and damage brain tissue when they cause reduced flow. By slowing the disease progression with cautery there may be time for adaptations to elevated pressure, particularly in the venous and aquaporin systems [20]. There will also be time for vault expansion to accommodate enlarged ventricles and allow patency to the aqueduct. If the plexectomy is delayed, the filling mechanism may lead to more severe brain deformities.
These obstructions include hind brain herniation. Depletion of parenchyma volume and vault expansion may allow stabilisation of the disease because the requirement for arterial blood over a period of time decreases and because of alleviation of pressure on the midbrain and hindbrain. These two changes facilitate communication between CSF spaces which enable the spaces to contribute to CNS compliance [1],[2]. Concepts of disease progression are represented in fig 1. The Pressure Histogram It is proposed that a CNS pressure histogram or curve, which can be constructed from a continuous pressure measurement taken from a CNS space or cavity, can assist in overcoming the difficulty of understanding the relationships between venous pressure and hydrocephalus. This is because it links venous pressure and filling with symptoms. The hypothesis concludes that hydrocephalus arises when negative pressure is imposed on parenchyma which is in a state of venous insufficiency. A histogram or curve is described by mode, skew and pressure range. A positive skew refers to curves with a mode to the left of the median and an elongation of the tail to the right, and negative skew describes an opposite asymmetry. An ICP histogram array demonstrates intraventricular pressure over time by placing histograms in sequence. An example is given in Fig. 2 for a patient who demonstrated a rise in ICP after cardiopulmonary arrest [21]. Interventions
caused a temporary moderation of mode pressure followed by a steady rise as further efforts failed. When IVP and arterial pressure is represented over time it can indicate prognosis. This has been demonstrated for 428 patients following head injury, as shown in fig. 3. This diagram shows the probability of survival after head injury as ICP and arterial blood pressure influence cerebral perfusion [22]. These works show that there is a relationship between IVP over time and prognosis that relates to cerebral blood supply. There are principles of interpretation of the ICP histogram that are of importance to the hypothesis. These include that mode pressure of the histogram is a function of flow within the CNS. Mode relates to intracranial anatomy on a microscopic and macroscopic level, reflecting the ability of the spaces to behave in a fluid-like manner by dispersing pressure that is generated by fluid movement. In other words it reflects the compliance of the system. Compliance requires that gravitational forces are facilitating outflow of venous blood from the CNS. There are two means by which venous outflow of blood from the CNS spaces in impeded. These are retrograde venous flow towards the CNS and Starling resistance. Starling resistance is pressure in a vessel as the walls are pressed together due to the weight of both the walls and the surrounding tissue. When venous pressure is low in the neck due to gravity with upright posture some veins collapse and become Starling resistors, and others remain open. Susceptibility to collapse reflects vessel wall thickness, the structural support
available to the vein from surrounding tissue, the magnitude of the gravitational force and venous pressure. Starling resistance allows negative (suction) force at the subarachnoid space of the vault which helps to keep the brain inside the cranium when upright, in a similar way to the negative pleural pressure which allows the lungs to remain inflated. Retrograde venous flow towards the spine when upright enables CSF buoyancy in the spinal space. These two mechanisms contribute to support for the parenchyma, especially to the hindbrain, preventing brain herniation through the foramen magnum due to gravity. The most important advance that this work makes on previous ideas in this series is that in the presence of elevated mode pressure there is an increased likelihood of intermittent episodes of low pressure in CSF space, especially those that are gravitationally above the heart. This tendency can be enhanced with physical movement. As the mode shifts to the right, the left skew for intracranial and cerebral cistern pressure may be extended and made more prominent when any suction force is applied. This concept is supported by the observations of Janney who described enhanced skew as mode pressure rises in a study of 13 cases with differing intracranial pathologies, although details of the individuals were not given [23]. This is happening because fluctuations in pressure when imposed on a state of elevated pressure will occur beyond the zone of CNS compliance, especially if there are fixed obstructions.
A simplified representation of potential variability in the intraventricular PTC in the absence of pathology is illustrated in Fig 4. Resting recumbent and resting head down profiles for a single individual are shown alongside a curve generated by activity with upright posture. Head down posture causes the highest mode IVP because cerebral venous outflow is slowed by retrograde pressure and the intracranial space then communicates with the high pressure veins. In health, there is not a large left skew with head down posture because there is no increase in the amount of fixed obstruction to the cerebral compartment and physical movements are often limited. Resting profiles are narrower than the curve in activity. This is because venous pressure fluctuations are imposed on the CNS as the body moves. The more vigorous the movement, the broader will tend to be the PTC. The PTC for any region of the CNS will vary as movement related changes are imposed on gravitational influences. This physical movement in combination with any reduced compliance tends to increase mode pressure if it increases parenchyma water content and it also therefore contributes to the skew. Fixed obstructions to flow such as skull base abnormality will be a prime cause of broadening of the PTC, in either or both direction in response to routine daily activity [3]. Upright posture facilitates low cerebral pressure which is necessary for capillary flow in brain parenchyma, as in other body tissues. Further proposals
New proposals in this work include that; Cavity filling, including ventricles, subarachnoid spaces, cysts and hydromyelia cavities relates to the PTC in that anatomical region. The PTC that maintains hydrocephalus (CSF accumulation driven by intermittent parenchyma ischemia) can arise from and be sustained by a profile with high, low or normal mode CSF pressure. Hydrocephalus has a physiological role. Although hydrocephalus can be self-perpetuating by causing obstruction it can also be self-limiting by moderating a labile pressure profile. The histogram in hydrocephalus Diseases that directly cause venous hypertension sometimes lead to hydrocephalus; examples include superior vena cava thrombosis [24] and surgeries for congenital cardiac defects [25]. No correlation has been found between large vessel venous pathology and hydrocephalus. This will be due to the presence of venous adaptations over time in the form of anastomoses that develop in response to elevated pressure, and also because large vessel pressure does not correlate with parenchyma venule pressure. The importance of venous competence for the brain is illustrated by the separation of craniopagus twins, where a staged approach to surgery to the major cerebral veins reduces the risk of morbidity and mortality [26],[27]. Damage to veins can cause acute
intracranial hypertension in the early post-operative phase, and hydrocephalus may be a later complication. Small vessel venous pressure can be linked to hydrocephalus by measuring CSF cavity pressure, although this relationship is complicated by the digression of ventricle and parenchyma pressure at the point that pressure becomes low [3]. This is also true in the lungs as mentioned previously. Brain tissue pressure studies have not thus far utilised negative pressure, however the idea of tissue being subject to increased pressure when the ‘local vascular reservoir has been squeezed out’ has been used to describe brain tissue response to pressure [28]. It is just as valid to propose that tissue is subject to increase pressure when vessels are ‘sucked’ out as when they are squeezed. Negative pressure in the CNS is not brought about by the absence of compression; rather it is the presence of a suction force. The concept of low pressure as a cause of ischemia is important, as it means that pressures at either end of a labile profile may interrupt small vessel flow and thereby increases CNS parenchyma water content [3]. Thus venous insufficiency can be present at either end of a histogram, especially but not exclusively, when the curve is abnormally wide. This means that hydrocephalus or hydromyelia that may benefit from surgery that alleviates parenchyma pressure can be caused by profiles with high, low or normal mode CSF pressure. Elevated mode pressure tends to improve absorption of CSF and water back into the circulatory system [29]. Accompanying an elevation, there may be resolution of a high pressure illness with or without a filling mechanism, as shown in fig 1.
The shape of the PTC in the cerebral ventricles that is typical of established hydrocephalus with upright posture is illustrated in Fig.5. A more normal profile for intraventricular pressure over a similar time period would show a slightly narrower base and lower mode. Time spent at the extremes of the curve, indicated by the arrows. can generate intermittent ischemia. The negative skew demonstrates time that leads to CSF space filling. The left skew will be more prominent when upright and within a gravitational field but not necessarily completely eliminated when recumbent. Likewise the elevation of mode IVP in hydrocephalus will be more prominent when lying down and may not be eliminated when upright. This concept anticipates an interaction of pressure effects illustrated in Fig. 4 and Fig. 5. A pattern of the PTC that emerges from a low pressure filling mechanism and leads to symptoms and then compensates by loss of parenchyma is illustrated by means of a hypothetical array shown in Fig 6. Where hydrocephalus results from a high pressure illness Curves a. and b. would be of a similar shape to that shown, but would be positioned on the right side of the x axis rather than on the left as shown. Any position of curve on the x axis could give rise to curve c so long as it meets the requirements of venous insufficiency combined with episodes of negative pressure. It is proposed that cavity filling causing pressure to rise leads to the phase of Curve c. It is possible for the disease to compensate, and this will lead to a more normal shape and position of curve; this is shown by the transition to d. The transition from Curve c. to d. is possible with surgery.
Ischemia with movement is important for hydrocephalus rather than ischemia at rest. Ischemia at rest becomes progressively more significant as mode pressure becomes high and threatens life, as with ICH following trauma or brain haemorrhage. This difference can make eclampsia, altitude sickness and other ICH conditions particularly dangerous. High venous pressure in the parenchyma caused by relatively rapid changes in parenchyma water content and venous drainage will cause a different set of symptoms than those for patients that can tolerate an imperfect venous system whilst moving around. Obstructions occur by degree, are affected by movement, and are not a present or absent property of an individual. The more fixed in terms of anatomy, the greater will be the potential effect on the filling mechanism. A potential cause of variable pulsatility profiles relates to differences the dimensions of the subarachnoid CSF spaces. Differences that are difficult to demonstrate on an individual basis may have an influence on compliance and therefore the risk of developing hydrocephalus or hydromyelia. This assertion is supported by evidence from study of the subarachnoid space flow in Chiari malformation [30]. Brain inflammation with edema and breakdown of cellular function may result in hydrocephalus as a complication during illness or recovery. CNS parenchyma is contained within stiff boundaries that are made less stiff, when considering the dynamic situation, by the presence of interconnected CSF spaces. These CSF spaces amplify the available venous drainage channels at any moment in
time. Parenchyma edema causes problems for arterial supply in the brain more readily than in other organs because of the bone constraints. With a primary edema the possible outcomes include full recovery, death or a degree of morbidity related to infarction and or hydrocephalus. There is evidence that a diffuse change in the brain parenchyma with minor head injury can reduce cerebral compliance with impaired venous flow [30]. Minor changes are usually recoverable, however when inflammation is severe the PTC may shift significantly to the right and lesions such as arachnoid adhesions may occur which exacerbate obstruction. A delay between the high pressure illness and symptoms attributable to hydrocephalus may occur, and the length of time is highly variable. An ICP histogram has been reported to assist in the management of hydrocephalus in a single case [31]. In this instance, histograms demonstrate the difference between an approximately normal ICP histogram and another that shows elevated mode and a left skew. In this case a 12 year old child underwent removal of a large epithelialised thoraco-lumbar myelomeningocele sac. Pre and postoperative IVP profiles were measured to determine whether surgery might lead to the need for a shunt. Before surgery, there was higher mode pressure with a small prominence of the left side of the curve. After surgery, mode pressure was lowered and there was a reduction in the number of lower pressure readings, there was also an increase in higher pressure pulsations resulting in a
right skew. The histograms have been reproduced in previous works [3],[32]. It was suggested by the authors that the thoraco-lumbar sac had performed the function of a ‘shock absorber’ to the CNS. It is proposed here that this concept is correct, and that whilst dampening of the highest pressures had occurred, due to the presence of the sac, there had been time for cerebral adaptations to raised mode pressure. This prevented an excess increase in ventricle and skull size that could have happened if repair had been undertaken prior to suture closure. It is also proposed that the repair of the sac resulted in an improvement in CSF flow around the foramen magnum by improving the buoyancy in the spinal space [32]. Both histograms were consistent with the child not needing a shunt; however the profile with the higher mode pressure in the preoperative phase was a feature of a child in whom the epithelialised sac was gradually enlarging. The operation was done to help the child achieve a sitting position which has become difficult because the sac had reached ‘baseball’ size [31]. Measurements made in the region of the lumbar spine of the patient, rather than the head, would have shown a different change in pressure profiles than that arising from the ventricles which is shown in this case. The challenge to CNS blood supply from exertion was stressed in the first publications in this series and this assertion is supported by recent evidence [33]. The hypothesis has progressed to proposing that venous pulsatility caused by skeletal muscle activity in the physiological range is essential to CNS
physiology, aiding blood flow and physiological water distribution [3]. One study of jaw movement and brain blood flow provides support for this concept [34]. A case study of a single patient with aqueduct stenosis who developed symptoms of raised pressure with exercise also supports this concept [35]. Third ventriculostomy for this individual was reported to resolve the exertional symptoms. More evidence of the mechanism of this phenomenon is needed. It is proposed that the quantity of extra parenchymal water volume generated by episodes of ischemia can be reabsorbed over the course of a 24 hour period; however when filling is occurring frequently, spaces will tend to enlarge and venous volume will be displaced. When excess water is delivered into the CNS it is distributed into areas with the greatest compliance including any potential space such as a membrane defect or the central cord canal [3], and compartments that have been created surgically [36]. The histogram in Hydromyelia Cranial spaces can moderate extremes of pressure more easily than the spinal space in Chiari malformation because of the adaptability of the choroid and the advantages for cerebral compliance afforded by gravity. Spinal pressure is intrinsically labile with movement due to the capacitance of spinal veins [2]. The labile venous volume combined with retrograde venous flow towards the spine, contributes to the explanation for the occurrence of hydromyelia with foramen magnum obstruction, without there necessarily being a clinically
obvious hydrocephalus. The pressure histogram that generates cervical hydromyelia cavities will tend to show a lower and more labile profile than with lesions in that originate in the lower thoracic and lumbar region. Hydromyelia cavities may stabilise or improve if CSF flow at the foramen magnum can be improved surgically. Evidence indicates that this alleviates tonsil herniation [37], which strongly implicates low pressure with the formation of cervical cavities. Obstruction to CSF flow at the foramen magnum prevents the flow of CSF into the spinal compartment with upright posture; this leads to a suction force on the hindbrain. It is proposed that as cervical cavities enlarge, mode cervical spine pressure rises which gradually alleviates some of the negative pressure. In the fetus, hindbrain herniation is caused by physical movement in the presence of a restricted posterior fossa [32]. Amniotic fluid pressure reduces the impact of gravity on the hindbrain via the spinal defect, and prevents Starling resistance around the skull. When anatomy is normal and CSF and venous blood can flow freely around the hindbrain, there is little suction force on the fetal hindbrain. When low spinal pressure in the fetus is caused by skeletal muscle movement the hindbrain is vulnerable to herniation. A spinal defect does not reduce mode pressure. These concepts are complex and will be discussed in more detail in a forthcoming work. When open to atmospheric pressure there may be severely detrimental ischemia in the region of the placode due to the lack of CSF buoyancy. Encouraging a natural epithelialisation of the
spinal defect before birth, whilst maintain amniotic fluid pressure may be a better surgical approach than other forms of prenatal placode surgery. The physiological Role of Hydrocephalus. The reason that Starling principles apply within the CNS space is the requirement for a certain volume of CSF for parenchyma health. CSF is needed because of gravity and the need for a skull and spinal column. High and low IVP represent time spent away from the compliant zone. The expansion of fluid volume in response to low pressure will usually be returning CSF volume towards compliance and restoring buoyancy for brain tissues. With an abnormally narrow compliance curve due to skull base malformation, the increased CSF volume provides the stimulus for reduction of choroid secretion, vault expansion, improved collateral flow, sacrifice of parenchyma tissue, and aquaporin adaptations. There may be delay in closure of the fontanelles or spontaneous rupture of the floor of the third ventricle. These changes lead to transient or long standing improvement in compliance and may decrease in parenchymal blood requirements. It is important that the growth of neural tissue and its bone encasements fit together so that neural tissue is able to receive adequate amounts of arterial blood at all times. Abnormally labile pulsatility related to exertion is not sustainable. One of the many purposes of the lateral ventricles is to apply pressure to the parenchyma of the vault so that its blood flow can be promoted in physiological states [3]. Vault and ventricle
enlargement provide skull space, that if conditions are physiological, the brain can then ‘grow into’. Development can be delayed when compliance of the cranium is insufficient for adequate arterial supply. This facilitates a situation where the parenchymal volume is reduced and ischemia with physical movement is of little significance to symptoms, although higher functions may be impaired. It can alleviate pressure on the brain stem and ‘buy some time’ in the process of optimising function. Damage to the cortex and a large head is a better outcome in terms of the future of the individual than brain edema, ICH and brain herniation, which is an alternative outcome in the presence of cerebral venous insufficiency. Normal Pressure Hydrocephalus For many hydrocephalic disorders, the more closely the CSF resembles normal fluid the more physiological is the process, although disease states may emerge. An exception to this is normal pressure hydrocephalus, where the disease, according to the concepts of this hypothesis, represents the breakdown of fluid balance mechanisms that had previously been effective for a period either after a brain insult or as part of normal CNS function. One example of such a breakdown of normal physiology is the increased brain stiffness with aging that may restrict blood flow in the parenchyma. An association between abnormal brain stiffness and normal pressure hydrocephalus has been observed [38]. Ascites caused by cirrhosis gives a pathological analogy for the process of
venous hypertension and cavity filling caused by increased parenchyma stiffness. Results from magnetic resonance elastography of the brain and liver support these assertions [39]. Some of the other mechanisms outlined in this work that may be acting in combination with changes in elasticity allow for heterogeneous causes for NPH. Venous pressure in the parenchyma that results from increase in brain stiffness may not be fully reflected in the PTC because CSF may flow more freely than venous blood in the supratentorial spaces when the brain becomes stiff. This may increase the appearance of ‘normality’ within the pressure profile of some symptomatic patients. Draining ascites does not greatly improve portal hypertension. If brain stiffness is acting with other compliance variables in normal pressure hydrocephalus then shunt response will also vary. The greater the obstructive component the greater will be the shunt response. Conclusion The theory accords with concepts promoted by Rekate, in that it proposes that hydrocephalus is an obstructive process and venous insufficiency in isolation causes brain edema. Hydrocephalus is in part, by definition, a disease where blood supply to the parenchyma improves with removal of CSF from enlarged spaces, so that according to this hypothesis, a negative skew and elevated mode should form part of the profile of the disease in treatment responsive cases. This relationship needs further exploration.
Author’s contributions This is the work of one author Conflicts of interest I declare that no funding was received and that no conflict of interest arises from this work.
References [1] Williams H. The venous hypothesis of hydrocephalus Medical Hypotheses 2008, 70:743-747. [2] Williams H. A unifying hypothesis for hydrocephalus, Chiari malformation, syringomyelia, anencephaly and spina bifida. Cerebrospinal Fluid Research 2008;5:7. [3] Williams H. A unifying hypothesis for hydrocephalus and the Chiari malformations part two: The hydrocephalus filling mechanism. Medical Hypotheses 2016;94:30–39 [4] Udeshi A, Cantie S M, Pierre E. Post obstructive pulmonary edema. Journal Critical Care 2010;25:538.e1-5. [5] Krodel D J, Bittner E A, Abdulnour R, Brown R, Eikermann M. Case Scenario: Acute Postoperative Negative Pressure Pulmonary Edema Anesthesiology 2010; 113:200-207. [6] Williams B. Is aqueduct stenosis a result of hydrocephalus? Brain 1973;96:399-412. [7] McMillan J J, Williams B. Aqueduct stenosis, Case review and discussion. Journal of Neurology, Neurosurgery, and Psychiatry 1977;40:521-532.
[8] Borit A. Communicating hydrocephalus causing aqueductal stenosis Neuropaediatrie, 1976 - thieme-connect.com [9] Masters C L. Pathogenesis of the Arnold-Chiari malformation: the significance of hydrocephalus and aqueduct stenosis Journal of Neuropathology and Experimental Neurology 1978;37:56–74. [10] Landrieu P, Inane J N, Ferriére G, Lyon G. Aqueductal stenosis in Xlinked hydrocephalus: a secondary phenomenon. Developmental Medicine and Child Neurology 1979;21:637–642. [11] Barkovich A J, Newton T H. MR of aqueduct stenosis: evidence of a broad spectrum of tectal distortion. American Journal of Neuroradiology 1989;10:471476 [12] Cinalli G, Spennato P, Nastro A, ALiberti F, Trischitta V, Ruggiero C, Mirone G, Cianciulli E. Hydrocephalus in aqueductal stenosis. Child's Nervous System 2011, 27:1621 [13] M. Klarica Orešković D, Božić B, Vukić M, Butković V, Bulat M. New experimental model of acute aqueductal blockage in cats: effects on cerebrospinal fluid pressure and the size of brain ventricles. Neuroscience 2009;158:1397–1405. [14] Owman C, Lindvall M. Sympathetic nervous control of CSF production in normal and hydrocephalic animals, and its relationship to cerebral blood volume
and intracranial pressure. Intracranial pressure V. Springer-Verlag Berlin. Ishii S, Nagai H, Brock M (Ed).1883:10-28. [15] Auer L. M, Sayama I. Johansson B. B, Leber K. Sympathoadrenergic modulation of cerebral blood volume during increased ICP. Intracranial pressure V Springer-Verlag Berlin. Ishii S, Nagai H, Brock M (Ed) 1983:342347. [16] Phi J H, Shin C H, Wang K, Park S, Kim S. Catastrophic electrolyte imbalance caused by excessive production and overdrainage of cerebrospinal fluid in an infant with choroid plexus papilloma. Childs Nervous System 2011;27:1153-1156. [17] Pople I K, Ettles D. The role of endoscopic choroid plexus coagulation in the management of hydrocephalus. Neurosurgery 1995;36:698–702. [18] Di Rocco C, Iannelli A. Poor outcome of bilateral congenital choroid plexus papillomas with extreme hydrocephalus. European Neurology 1997;37:33-37. [19] Warf B C, Campbell J W. Combined endoscopic third ventriculostomy and choroid plexus cauterization as primary treatment of hydrocephalus for infants with myelomeningocele: long-term results of a prospective intent-to-treat study in 115 East African infants. Journal of Neurosurgery Pediatrics 2008;2:310– 316.
[20] Abreu-Rodrıguez I, Silva R, Martins A, Soveral G, Toledo-Aral J, LopezBarneo J, Echevarria M. Functional and transcriptional induction of aquaporin-1 gene by hypoxia; analysis of promoter and role of Hif-1a. PLoS ONE 2011; 6(12): e28385. doi:10.1371/journal.pone.0028385 [21] Tsutsumi H, Nishiyama T, Aruga H, Toyooka H, Mii K, Tsuzuki M, Manaka S, K. Takakura. Usefulness of ICP histogram and ICP histogram array in ICP monitoring. Intracranial pressure V Springer-Verlag, Berlin. Ishii S, Nagai H Brock M (Ed) 1983:135-139. [22] Marmarou A., Anderson R.L., Ward J.D., Choi S.C., Young H.F. Impact of ICP instability and hypotension on outcome in patients with severe head trauma. Journal Neurosurgery 1991;75:S59-S66. [23] Janny P, Jouan J.P, Janny L, Gourgand M, Gueit U.M. A statistical approach to longterm monitoring of intracranial pressure Intracranial Pressure Vol I. Springer-Verlag Berlin. Brock et al (Ed) 1972:59-64 [24] McLaughlin J F, Loeser J D, Roberts T S. Acquired hydrocephalus associated with superior vena cava syndrome in infants. Childs Nervous System 1997;13:59-63. [25] Dillon T, Berman Jr W, Yabek S M, Seigel R, Akl B, Wernly J. Communicating Hydrocephalus: A Reversible Complication of the Mustard
Operation with Serial Hemodynamics and Long-term Follow-up. The Annals of Thoracic Surgery 1986;41:146-149. [26] Walker M, Browd S R. Craniopagus twins: embryology, classification, surgical anatomy and separation. Childs Nervous System 2004;20:554-566. [27] Staffenberg D A, Goodrich J T. Separation of craniopagus conjoined twins with a staged approach. Journal of Craniofacial Surgery 2012;23:2004-2010. [28] Brock M, Furuse M, Weber R, Hasuo M, Dietz H. Brain tissue pressure gradients Intracranial Pressure II. Springer, Berlin. Lundberg N., Pontén U., Brock M. (Eds) 1975;215-220. [29] McLone D G. Consensus: modelling of hydrocephalus. Child's Nervous System 1994;10:24–28 [30] Pahlavian S. H, Loth F, Luciano M, Oshinski J, Martin B A. Neural tissue motion impacts cerebrospinal fluid dynamics at the cervical medullary junction: A patient-specific moving-boundary computational model. Annals of Biomedical Engineering 2015;43:2911-2923. [31] Pomschar A, Koerte I, Lee S, Laubender R P, Straube A, Heinen F, ErtlWagner B, Alperin N. MRI evidence for altered venous drainage and intracranial compliance in mild traumatic brain injury. PLoS ONE 2013;8(2): e55447. doi:10.1371/journal.pone.0055447
[32] Linder M, Nichols J, Sklar F H. Effect of meningomyelocele closure on the intracranial pulse pressure. Child’s Brain 1984;11:176-182. [33] Williams H. Questioning the rationale and conduct of the management of myelomeningocele study. Medical Hypotheses 2011;77:101–105. [34] Seifert T, Secher N H. Sympathetic influence on cerebral blood flow and metabolism during exercise in humans. Progress in Neurobiology 2011;95:406– 426. [35] Hasegawa Y, Ono T, Hori K, Nokubi T. Influence of human jaw movement on cerebral blood flow. Journal of Dental Research 2007;86:64-68. [36] Yamada S M, Matsuno A, Yamada S, Running-induced headaches in aqueductal stenosis patient. Surgical neurology.org 2012 [37] Frassanito P, Massimi L, Caldarelli M, Tamurrini G, Di Rocco C. Complications of delayed cranial repair after decompressive craniectomy in children less than 1 year old. Acta Neurochirurgica 2012;154:927-933. [38] Duddy M J, Williams B. Hindbrain migration after decompression for hindbrain hernia: A quantitative assessment using MRI. British Journal of Neurosurgery 1991;5:141-152. [39] Fattahi N, A. Arani A, Perry A, Meyer F, Manduca A, Glaser K, Senjem M L, Ehman R L, Huston J. MR Elastography demonstrates increased brain
stiffness in normal pressure hydrocephalus. American Journal of Neuroradiology 2016;37:462-467. [40] Klatt D, Hamhaber U, Asbach P, Braun J, Sack I. Noninvasive assessment of the rheological behavior of human organs using multifrequency MR elastography: a study of brain and liver viscoelasticity. Physics in Medicine and Biology 2007; 52:7281-94.
Fig.1 Representation of the three dimensional surface of estimated outcome probability versus the proportion of intracranial pressure (ICP) measurement greater than 20mmHg and the proportion of blood pressure measurements less than 80mmHg. The effect of hypotension is evident from the front to back sloping of the surface and the impact of ICP elevation is apparent from the left to right sloping of the surface. Reproduced from Fig. 4 Marmarou A, Eisenberg H Foulkes M. et al. Impact of ICP instability and hypotension on outcome in patients with severe head injury. J Neurosurg 1991;75:S59-S66 (with permission: Journal of neurosurgery publishing group) Fig.2
ICP histogram array. Each successive line starting at the bottom is an ICP distribution curve measured for six hours. The case is a 21-year old male after cardiopulmonary resuscitation. ICP gradually increased after successful resuscitation and decreased transiently in response to treatment, and again increased until brain death. Reproduced from Fig.3 Tsutsumi H, Nishiyama T, Aruga H. et al. Usefulness of ICP histogram and ICP histogram array in ICP monitoring Intracranial pressure V Springer-Verlag, Berlin. Ishii S, Nagai H Brock M (Ed) 1983:135-139. (with permission; Springer-Verlag, Berlin) Fig.3 Representation of intracranial pressure response to posture and activity. Each curve represents a period of continuous monitoring. Curve a. is generated in response to activity such as running. Curve b. is recumbent and at rest. Curve c. is generated by head down posture with rest. Fig.4 The pressure time curve (ICP histogram) in hydrocephalus. The case illustrates symptomatic cases amenable to treatment. Mode pressure is raised and there is a negative skew. Elevated mode pressure indicates poor venous drainage and may be associated with ischemia particularly at the extremes of pressure. The left skew represents episodes of low or negative pressure in the continuous profile
and indicates that filling of the cavity is occurring over the period that the measurement is taken. Fig.5 A hypothetical array of curves demonstrating pressure with time during the evolution of a high cervical spine syringomyelia (hydromyelia) cavity. Transition through the array shows the initiating problem of low pressure in the high cervical spine region followed by the formation of a cavity with symptoms, the transition to curve d. occurs with successful surgical decompression of the skull base or with loss or parenchyma after a prolonged illness.
Fig. 6 The relationship between pressure and time for a 12 year old child before and after myelomeningocele repair. Time (%) versus ICP (mmHg) before and after meningomyelocele closure. ICP data were averaged over 3 min intervals. Reproduced from Fig. 1. Linder M, Nichols J, Sklar F. Effect of meningomyelocele closure on the intracranial pulse pressure. Childs Brain 1984;11:176–182 (with permission; S. Karger AG, Basel).
Reduced compliance and a filling mechanism
Adaptation and nearly normal (or normal variant) neural and venous anatomy
Initially non- progressive PTC
Abnormal anatomy including large head, aqueduct stenosis, hindbrain hernia and benign external hydrocephalus ,
Higher risk of complications including hydromyelia, scoliosis, headaches and cognitive impairment
Progressive disease with symptoms and signs
Shunting/third ventriculostomy/choroid cauterisation/venous stenting/hindbrain decompression
Stabilisation Vulnerability to normal pressure hydrocephalus and adult onset hydromyelia (syringomyelia)
Treatment failures and morbidity including infection, seizures, pain syndromes, hydromyelia, recurrent episodes of hydrocephalus, brainstem or cerebella r symptoms, bladder and other autonomic dysfunction, restricted head size and intracranial hypertension/shunt dependency
Progressive Failure of treatment
Partial response to treatment
Rise in pressure
0
10
20
ICP mmHg
30
40
50
Probability death/vegetative p=1.0
1.0
1.0
p (BP <80mmHg) p (ICP >20mmHg)
0.0
c Time
b a
Pressure mmHg: arbitrary scale
Time mode pressure: symptoms
left skew: filling mechanism
Pressure: arbitrary scale
PTC with time
d c
b
a Pressure: arbitrary scale
Hypothetical histogram array for a hydromyelia cavity in the high cervical spine