A unifying hypothesis for hydrocephalus, Chiari malformation, syringomyelia, anencephaly and spina bifida
© Williams; licensee BioMed Central Ltd. 2008
Received: 19 September 2007
Accepted: 11 April 2008
Published: 11 April 2008
This work is a modified version of the Casey Holter Memorial prize essay presented to the Society for Research into Hydrocephalus and Spina Bifida, June 29th 2007, Heidelberg, Germany. It describes the origin and consequences of the Chiari malformation, and proposes that hydrocephalus is caused by inadequate central nervous system (CNS) venous drainage. A new hypothesis regarding the pathogenesis, anencephaly and spina bifida is described.
Any volume increase in the central nervous system can increase venous pressure. This occurs because veins are compressible and a CNS volume increase may result in reduced venous blood flow. This has the potential to cause progressive increase in cerebrospinal fluid (CSF) volume. Venous insufficiency may be caused by any disease that reduces space for venous volume. The flow of CSF has a beneficial effect on venous drainage. In health it moderates central nervous system pressure by moving between the head and spine. Conversely, obstruction to CSF flow causes localised pressure increases, which have an adverse effect on venous drainage.
The Chiari malformation is associated with hindbrain herniation, which may be caused by low spinal pressure relative to cranial pressure. In these instances, there are hindbrain-related symptoms caused by cerebellar and brainstem compression. When spinal injury occurs as a result of a Chiari malformation, the primary pathology is posterior fossa hypoplasia, resulting in raised spinal pressure. The small posterior fossa prevents the flow of CSF from the spine to the head as blood enters the central nervous system during movement. Consequently, intermittent increases in spinal pressure caused by movement, result in injury to the spinal cord. It is proposed that posterior fossa hypoplasia, which has origins in fetal life, causes syringomyelia after birth and leads to damage to the spinal cord in spina bifida. It is proposed that hydrocephalus may occur as a result of posterior fossa hypoplasia, where raised pressure occurs as a result of obstruction to flow of CSF from the head to the spine, and cerebral injury with raised pressure occurs in anencephaly by this mechanism.
The current view of dysraphism is that low central nervous system pressure and exposure to amniotic fluid, damage the central nervous system. The hypothesis proposed in this essay supports the view that spina bifida is a manifestation of progressive hydrocephalus in the fetus. It is proposed that that mesodermal growth insufficiency influences both neural tube closure and central nervous system pressure, leading to dysraphism.
Hydrocephalus involves degrees of raised central nervous system (CNS) pressure and extracellular fluid accumulation. It is thought to result from many unrelated disease processes. The relationship between hydrocephalus and spina bifida has been the subject of prolonged debate. The Chiari I malformation is related to posterior fossa hypoplasia and causes spinal injury in syringomyelia by obstruction to cerebrospinal fluid (CSF) flow at the foramen magnum [1, 2]. The Chiari II malformation is found in association with spina bifida and is thought by many to be unrelated to Chiari I, with neural injury and reduced posterior fossa size caused by failure of neural tube closure and its consequences, including toxicity caused by exposure to amniotic fluid [3, 4]. It is proposed that there is an alternative explanation for the varied manifestations of anencephaly and spina bifida that represents a combination of defective neural tube closure and hydrocephalus in the fetus. The hypothesis argues that:
Hydrocephalus progresses because of venous insufficiency. This occurs with all primary abnormalities that cause a pathological increase in CNS pressure.
Hindbrain herniation is caused by an abnormal cranio-cervical pressure gradient or hindbrain compression resulting from posterior fossa hypoplasia. These mechanisms frequently act together to give rise to the Chiari malformations.
Chiari malformations cause obstruction to CSF flow that elevates CNS pressure and damages neural tissue by ischemic and mechanical forces.
Chiari-related syringomyelia, spina bifida and anencephaly form a spectrum of disease related to restricted growth of the posterior fossa.
The terms pressure and volume may often be used interchangeably when describing CNS pressure, because pressure depends upon volume . The hypothesis depends upon the relationship between pressure and volume, which includes the phenomenon of compliance. Compliance enables a volume increase to occur in the intrathecal CNS space without causing a pressure increase , and occurs when a corresponding amount of venous blood is displaced. Compliance affects the ability of the CNS to accommodate volume fluctuations that occur with movement and so avoid ischemia.
In a relaxed subject with normal compliance, small volume fluctuations caused by blood flow will not be detected by overall pressure measurement. As compliance is reduced, minor volume fluctuations may result in measurable pulsations and physical movement will cause the greatest pressure fluctuations and peaks. The elevation of CSF pressure in normal pressure hydrocephalus  and in hydrocephalic children observed during continuous pressure monitoring  supports the hypothesis. Reduction of pulsatility of CSF pressure following cranial expansion as a treatment for hydrocephalus  is also consistent with the proposed theory.
The mechanism of extracellular fluid accumulation
It is proposed that when compliance is reduced:
Venous volume increase with postural movements will cause delay of venous and arterial flow in the parenchyma.
At peaks of pressure, vessels in the parenchyma of the brain or spinal cord may be sufficiently compressed to result in ischemia.
Continuous unidirectional flow in venous plexus vessels is not essential, venous blood may be diverted via anastamoses to lower resistance vessels whereas continuous flow in parenchymal vessels is necessary to provide oxygen. Full compliance benefits flow in all vessels [5, 19]. The autonomic nervous system, by controlling vessel diameter and flow, is known to influence extracellular fluid volume in many tissues, with filtration or absorption taking place in venules depending on local circumstances . Autonomic regulation of flow in CNS vessels is likely to influence the rate of filtration into the parenchyma. If, however, autoregulation is unable to compensate for the effect of venous pressure fluctuations, extracellular fluid will accumulate causing reduction in compliance. Consequently, venous outflow will be further compromised and hydrocephalus will progress. Ischemia is likely to be a part of the pathological process with a hyperemic response enhancing filtration of fluid into the parenchyma. Volume increases that do not cause ischemia are accommodated, but progressive volume increase will cause ischemia at peaks of CNS pressure.
The observation that removing CSF from patients with symptomatic normal pressure hydrocephalus improves both arterial supply and venous drainage  supports the hypothesis proposed here. It is suggested that artificial increase in cranial pressure by balloon insufflation inside a lateral ventricle mimics the mechanism for progression of hydrocephalus. In this model, intracranial pressure is intermittently raised  in a manner that is comparable to that which will occur with movement in the presence of any cause of loss of compliance. Signs of a hyperemic response may have been observed during direct measurement of CNS pressure following pressure increase with movement in Chiari I . Experimentally induced foramen magnum blockage has lead to subjective observations of venous insufficiency in the cord , and the effect of pressure on venous flow, causing localised oedema that resolves with improved perfusion of veins may be seen during surgery .
Chiari I and II malformations are characterised by degrees of hindbrain herniation. Adults with Chiari I malformation have a reduced posterior fossa size, relative to head size [12, 24–26], providing evidence for posterior fossa restriction as a cause of cerebellar herniation. Cerebellar herniation is a feature of posterior fossa restriction with known causes, for example craniosynostosis . The familial tendency for Chiari I indicates that there are genetic determinants for posterior fossa growth [28, 29]. Chiari II is characterised by a hypoplastic posterior fossa with compression of hindbrain structures . Associated bone abnormalities in the face, provide additional evidence of a primary maldevelopment of bone as part of the malformation . Facial and posterior fossa bones have common embryological origins and their responsiveness to fibroblast growth factor suggests that they have related growth mechanisms . The greater incidence of Chiari I and II in females supports the view that posterior fossa size is genetically determined, with males having larger posterior fossa CSF spaces than females, so that restriction of posterior fossa size leads to hindbrain herniation more readily in females than males.
Spinal CSF and venous blood provide buoyancy to the central nervous system , maintaining the position of the hindbrain. The phenomenon of coning in response to lumbar puncture illustrates how hindbrain herniation can occur in response to loss of spinal fluid volume. The use of lumboperitoneal shunts is associated with cerebellar herniation , and is likely to be related to loss of CSF from the spinal compartment. Reduction of posterior fossa CSF space may also cause an abnormal cranio-spinal pressure gradient by retaining CSF in the head, which would otherwise be free to move through the foramen magnum. Direct measurement of pressure in the presence of Chiari I support the hypothesis that low CSF pressure may cause the cerebellar tonsils to be drawn into the spine . It is suggested here that this may occur when venous blood leaves the spinal venous plexus so that excessively free drainage from the spinal plexus may also contribute to hindbrain herniation. In these instances, hindbrain symptoms may predominate over those caused by raised spinal pressure. In animal studies the hindbrain descends following creation of an artificial spina bifida lesion , and may elevate following intrauterine repair . This allows for the common assertion that low spinal pressure contributes to the hindbrain herniation of Chiari II.
It is proposed that hydrocephalus is an oedema of the central nervous system. Rapidly developing venous insufficiency leads to increase in parenchyma water content and slower processes lead to increase in water that is distributed between the parenchyma and larger extracellular spaces. Symptoms, signs and morphology of hydrocephalus will depend upon the pathology that causes the pressure increase, the rate of fluid accumulation, and the developmental stage at which hydrocephalus develops. Compliance and therefore hydrocephalus, is influenced by:
The internal dimensions of CNS bones
Fontanelles and surgically created bone defects
The presence of any space occupying lesion
Free flow of CSF around the CNS
The integrity of CNS veins and central venous pressure
Growth and atrophy of neural tissue
Autonomic regulation of blood pressure and flow
Fluid flows down pressure gradients from areas of higher to lower pressure . The passage of fluid into the ventricles and subarachnoid spaces represents flow to an area of lower mean pressure than the parenchyma. Maximal CSF pressures are achieved during physical movement and arterial pressures will tend to exceed this. Movement of tracers from the subarachnoid space to the parenchyma has been demonstrated to occur rapidly  and might appear to contradict this theory. If movement of fluid occurs along perivascular channels, such movement might depend upon the amplitude of the arterial pulse and the energy that it imparts . According to the proposed hypothesis rapid accumulation of fluid would tend to remain in the parenchyma. Slow accumulation that occurs with intermittent periods of relaxation, when CSF pressure falls, would encourage fluid flow into CSF spaces.
Ventricle size is not a good indicator of intracranial pressure. Lateral ventricle size is determined by ventricle wall tension, brain turgor and the ability of CSF to flow through the aqueduct and fourth ventricle. Small ventricles may be found with raised, normal, or low intracranial pressure if CSF can exit the head . Brain oedema may lead to small ventricles if CSF can pass into the spine. Fluid accumulation in the parenchyma will increase brain turgor and cause it to resist ventricle enlargement  whereas tension in the ventricle walls will exert a force on brain tissue, favouring enlargement of the ventricles. Wall tension is proportional to the internal radius of the cavity , as well as fluid pressure. Pressure waves generated by venous volume fluctuation in the spine may influence lateral ventricle wall tension without the requirement for flow , so physical movement may maintain or increase ventricle size when posterior fossa CSF pathways are patent. In chronic cases of raised intracranial pressure there will be atrophy related to ischemia, causing the brain to shrink. The posterior fossa CSF spaces and the aqueduct will remain open, giving the clinical presentation of normal pressure hydrocephalus. Rapid pressure increase will tend to cause obstructions to CSF flow. When the overall volume occupied by the brain increases with space occupying lesions, enlarged ventricles, or oedema, there may be obstruction of CSF flow at the aqueduct . This is due to the narrowness of the aqueduct and its compressibility in comparison to the ventricles. As overall brain (including fluid) volume increases, CSF may be displaced from the subarachnoid spaces into the spine and the hindbrain may be displaced towards the foramen magnum. This may enhance the rate of intracerebral pressure increase by preventing the normal to and fro flow movement of CSF across the foramen magnum  that facilitates CNS venous drainage. These two major obstructive effects on CSF flow will contribute to the self-perpetuating nature of hydrocephalus, minor obstructions will also be detrimental.
A balance between brain turgor and ventricle pressure may occur, this is a feature of normal health and is also illustrated by cases where normal lateral ventricle size may occur with raised pressure and papilloedema. Alternatively, very rapid increase in ventricle pressure may cause symptoms of raised CNS pressure, with little time for the development of clinically detectable oedema of the optic nerve. A phenomenon of reactive enlargement of the ventricles following lumbar puncture has been observed in the presence of cerebral oedema . In these cases a decrease in overall CNS pressure with lumbar puncture allows improved venous drainage, water passes out of the oedematous brain and CSF may then move out of the spine into the cranial cavity as venous blood enters the spinal venous plexus. If the ventricles are small or obstructed and intracranial pressure is high the patient's condition will be critical. This will be indicated by obliteration of subarachnoid CSF spaces.
There are many disease processes that can lead to a state of CNS venous insufficiency by causing an increase in arterial supply, filtration of fluid into the parenchyma or venous pressure. An incomplete list includes CNS infection, hypoxia with altitude, carbon monoxide poisoning, water intoxication, renal impairment, obesity, and anaemia. Hydrocephalus may be caused by abnormalities of CSF production in the choroid plexus or absorption at the arachnoid granulations. That cardiac failure is an infrequent cause of hydrocephalus  may be an illustration of the efficiency of normal autoregulation of CNS extracellular fluid volume. Restriction of internal bone space through multiple suture craniosynostosis with a normally developing brain will tend to cause hydrocephalus  by compressing venous channels and CSF spaces. Single lambdoid suture fusion will be associated with raised pressure , because of the relative importance of posterior fossa size to ventricle emptying and foramen magnum flow. Direct and indirect measurements of venous pressure demonstrate variable correlation with hydrocephalus because pressure  and venous drainage  are dynamic processes. Current methods of quantifying these pressures are not representative of fluctuation with time.
Syringomyelia and spina bifida have been described as part of a disease continuum, with more severe manifestations in the fetus . The mechanism for neural injury in the original theory had a requirement for hydrocephalus with CSF flow from the head into the cord parenchyma via the fourth ventricle. Hydrocephalus is not always present in the two conditions and fluid flow from the fourth ventricle into spinal cord cavities in syringomyelia is uncommon. It is proposed that the disease continuum relates to posterior fossa hypoplasia that causes reduced CNS compliance before or after birth.
Anencephaly and Spina Bifida
Features of spina bifida that need to be addressed for a unifying hypothesis to be plausible include:
The nature of progressive neural injury
An association with hydrocephalus
A higher incidence of Chiari malformation in females
The relationship between the level and severity of the lesion
Small head size in the fetus
Intrauterine growth retardation
Syringomyelia after birth
The more severe the mesodermal impairment, the more hypoplastic the posterior fossa will tend to be, with earlier and greater potential for separation of the spinal and cerebral CSF spaces and subsequent neural injury. Anencephaly represents the highest and most severe lesion. A more normal posterior fossa size will lead to more normal cerebral development. If posterior fossa size is not significantly restricted and a small deficit in the vertebrae occurs, a meningocele will tend to result at any level. The effect of timed dosing of vitamin A in the creation of neural tube defects adds strength to the argument that abnormal mesodermal growth at different stages may result in different morphological features. This teratogen results in more frequent anencephaly when given early in gestation and more frequent spina bifida if dosing is delayed . There will, according to this theory, be a tendency for higher lesions to be more severe, which accords with some observations on spina bifida [54, 55].
In anencephaly and spina bifida, early neural development may be relatively normal , with progressive damage during gestation. Posterior fossa restriction occurs at an early stage with progressive hindbrain herniation [57, 58]. It is suggested that any movement may cause mechanical force on neural tissue. Fetal cardiac movement is present from five post-menstrual weeks, trunk movements are detectable from seven weeks and the fetus is active by ten weeks . It is proposed that disturbances in blood flow, accumulation of CSF and stretching forces act on tissue, which lacks mechanical support of the mesoderm. As fetal movement becomes stronger forces will be magnified around an open lesion, but the whole CNS may be affected. Widening of the whole vertebral column may be found in anencephaly, suggesting severe distending forces  and vertebral widening is found in the cervical spine with syringomyelia suggesting a mild distending force during growth .
Excessive pressure in the head or spine as a result of posterior fossa hypoplasia may be viewed as a progressive process occurring during or after gestation. In the fetus impairment to CSF flow may adversely influence neuronal migration . Animal studies demonstrate that ischemia damages developing neural tissue and neurobehavioural abnormalities, such as memory deficits may result from such injury . Abnormalities of migration have been described in human neurospheres transplanted into rat cerebral cortex following ischemic injury . Such studies give clues as to the possible origin of complex cerebral abnormalities that may be found in anencephaly and spina bifida.
Acute worsening of obstructive hydrocephalus after birth has been observed with spina bifida . Repair of the spinal lesion may increase CNS pressure, whereas loss of CSF from a lesion may be beneficial for the fetus as gestation progresses in circumstances where CSF tends to accumulate. Breathing air and expansion of the thorax will increase capacitance in pulmonary vessels and reduce thoracic pressure . This will tend to improve CNS venous drainage and lower CNS pressure. Improved venous drainage may contribute to the low CSF pressure found in normal neonates . It may also encourage herniation of the hindbrain due to lowering of pressure in the spinal venous plexus. Loss of brain turgor associated with weight loss that tends to occur in the neonatal period  may also contribute to ventricle enlargement. These factors in combination will tend to favour foramen magnum obstruction, whereas taping of CSF in the neonatal period may avert an obstruction to CSF flow.
Abdominal growth tends to be reduced in fetuses with open spina bifida as gestation progresses . If degrees of CNS hypoxia are a feature of spina bifida that also progresses during gestation then it is possible that this pattern of abnormal abdominal growth would be expected. One mechanism for accommodating a chronic increase in central nervous system pressure may be decreased cardiac output  suggesting a mechanism for growth retardation. Areas of brain that are most damaged in anencephaly are also the most susceptible to ischemia in chronic hydrocephalus [72, 73]. The relative preservation of basal brain structures in anencephaly will relate to their blood supply. Cervical meningoceles are sometimes found, but are not associated with significant CSF obstruction at the foramen magnum and neural development appears to be normal . Support for a theory of ischemic damage in spina bifida has been obtained from histological observations on the spine, movement analysis of neonates with spina bifida, [75, 76] and the presence of metabolites associated with ischemia in the CSF of affected neonates .
A hypothesis to unify all causes of hydrocephalus is possible by considering the effects of physical movement on CNS pressure when compliance is reduced. The hypothesis argues that hydrocephalus is a self-perpetuating problem caused by loss of compliance and also causing loss of compliance by the accumulation of excessive extracellular fluid which may obstruct CSF flow. The hypothesis allows for the suggestion that a combination of cranial expansion and relief of obstruction to CSF flow, including plastic surgery to the posterior fossa, may reduce the necessity for some shunt procedures. Continuous pressure monitoring during activity causing reversible ischemia would provide direct evidence for the proposed mechanism of hydrocephalus and if this predicted effect could be demonstrated, tests for reversible ischemia may be of diagnostic use. An absence of reversible ischemia would suggest a compensated phase of the disease lacking the potential for a favourable surgical outcome.
Chiari malformations are primarily caused by congenital posterior fossa hypoplasia sufficient to cause obstruction to CSF flow, which damages the CNS. Abnormal mesodermal growth leads to abnormalities of central nervous system pressure. The manifestations of Chiari related syringomyelia, spina bifida and anencephaly form a spectrum of disease. If fetal posterior fossa CSF flow can be improved there is the potential for reducing the impact of Chiari malformation before birth.
I am grateful to Queen Elizabeth Hospital Woolwich for extensive library assistance. The work of many authors has contributed to the formulation of ideas presented in this essay; it has not been possible to recognise all of these contributions. I am grateful to Dr S Demonchaux, Dr J Dickson, Dr H Jones, Prof T Kohl, Prof K Nicolaides and Dr JMS Pearce.
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