Francois Magendie was born in 1783. Under the influence of his father, an ardent republican, and a physician, his education was subjected to the mixture of enlightenment and confusion, which marks the time following the French Revolution. His Paris medical school underwent changes in curricula which make present-day medical education appear superlatively conservative.
In 1809, Magendie made his debut in academic medicine with a criticism of the inexactness of the science of physiology, and from thence onwards was an exponent of the experimental method. He also criticised the established practice of medicine and championed the natural ability of patients to cure themselves despite the physicians. He was, throughout his active career, opinionated, and intolerant of discussion, but withal, judicious, and very enlightened.
Magendie became well known in England from the controversy over whether it was he or Charles Bell who first described the separate motor and sensory functions of the spinal nerves.
In 1821, Magendie founded the "Journal de Physiologie Experimentale" and his observations upon the cerebrospinal fluid (CSF) first appeared in this. The 1825 volume contained a description of the fluid in the cranial cavity communicating with that in the spinal canal, and the 1827 volume describes the "ouverture arrondie" between the two posterior (inferior) cerebellar arteries which now bears Magendie's name. At that time, he conjectured that the fluid in the ventricles was renewed by a flux and reflux through the foramen, having observed that it was formed on the surface of the pia mater.
The influence of respiration upon reflux through the foramen is described in the 1828 edition of the journal and the hydraulic functions of the CSF suggested. The 1836 edition of Magendie's "Precis elementaire Physiologie" contains a full description of the ventricular system and subarachnoid spaces, the movement of the brain with cardiac pulsation, and the formation of CSF both by the pia mater and the choroid plexuses of the ventricles. The CSF is regarded as protecting the brain and floating it, a concept which is also developed in the "Lecons sur les functions et les maladies du systeeme nerveaux" published in 1839. Thus the initial observations of the 1820s and 30s became the basis for the quite elaborate concept of CSF physiology contained in his well-known book "Recherches physiologiques et cliniques sur le liquide cephalorachidien de cerebrospinal" published in 1842.
It is over a hundred and fifty years since Magendie published his observations and it is appropriate to re-consider his foramen in the light of modern knowledge in order to reach some further understanding of its particular function.
MorphologyThe openings in the lateral recesses of the fourth ventricle were described by Luschka in 1854 (1) and, in 1875, Key and Retzius examined 100 human brains for these structures and found: the midline foramen was present in 97, and the lateral foramina in 97 (2). In 1886 Wilder confirmed the lateral and midline foramina in man and pointed out that the cat lacked a foramen of Magendie (3). Blake, in 1900, made extensive observations on the occurrence of the midline foramen (or metapore as it is sometimes called) in the animal kingdom, and concluded that it is present in man and three species of Old World Monkey, but not in other mammals or birds (4).
The technical difficulties involved in the preparation of the hind brain for anatomical study of the CSF system are formidable, and classical textbooks of zoology and comparative morphology throughout the first half of the twentieth century remained rather non-committal on this subject. In 1967, however, Coben reported absence of a foramen of Magendie in the dog, cat, rabbit and goat (5), and Cammermeyer, in 1971, reported on the comparison of median and caudal apertures in the fourth ventricle roof in rodents and primates (6). In 1979, the author, following an extensive study of the comparative morphology of the CSF system, reported and tabulated the findings (7). From these studies it was concluded that:
The development of neurosurgery during the first half of the twentieth century made the intra-operative observation of the metapore in man relatively commonplace, and it is seen as providing a direct view into the lower end of the fourth ventricle upon gently separating the cerebellar tonsils. The lateral foramina are less easily visualised and require exploration of the posterior fossa in the relatively confined space of the cerebello-pontine angle; in the normal angle the lateral foramen is seen containing a tuft of freely protruding choroid plexus between the cerebellum and the middle cerebellar peduncle. Neuro-radiological procedures have made the visualisation of these structures even easier; they are clearly seen in computerised tomograms (CT scans) or magnetic resonance images (MRI scans) obtained from patients without pathology in the posterior fossa.
EmbryologyThe embryology of the roof of the hindbrain has been the subject of many observations and much debate. The fenestrations seen in the amphibians are not present in tadpoles, studied by the same light microscopy methods, but appear at the time of metamorphosis. Studies using scanning and transmission electron microscopy, however, have shown that a few inter ependymal pores are present in the late embryonic (7-10mm) stage in Rana pipiens, and they increase rapidly throughout the larval tadpole stage until the adult appearance is present at metamorphosis (8). Most of the early twentieth century studies on mammal embryos failed to find a metapore other than in anthropoids, and only detected lateral foramina in the later stages of development (9), findings confirmed in more recent studies (10).
Initial observations on human foetal material suggested that the metapore appeared in the fifth month (129mm crown-rump length) (11), but later it was clearly described in 26mm and 20mm embryos, but not found to be present in a 17mm embryo (12). Further observations confirmed attenuation of the roof of the developing hindbrain in the 20mm (7 week) embryo in areas just rostral and caudal to the choroid plexus fold (13); the appearance was of deficiencies surrounded by cells staining positively with Periodic Acid Schiff reagent (PAS). The rostral area (sometimes termed area membranacea superior) became a thick intact structure again by the 32mm (8 week) stage, but the metapore was clearly apparent in the caudal area (area membranacea inferior) from this stage onwards. The lateral foramina are not present until much later in human foetal development.
Injection experimentsVarious injection techniques used in the study of the morphogenesis of the roof of the fourth ventricle have, in addition to demonstrating continuity between internal and external CSF compartments in some animals, raised the question of the mechanism of development of the metapore. Some early studies, in which pig embryos were examined by infusing through the spinal canal a solution of potassium ferricyanide and ammonium citrate at a pressure of 50 mm water, and observing the distribution of the infusion by precipitation with acid (Prussian Blue reaction), showed an increased permeability of the hindbrain roof at a stage which coincided with attenuation of the ependyma both rostral and caudal to the choroid plexus fold in the fourth ventricle roof. It was assumed that this permeability was the result of increased intraventricular pressure from CSF secretion by the choroid plexuses, which were apparent at the same developmental stage, and the concomitant vacuolisation of the mesenchyme surrounding the hindbrain was thought to be from the same cause, thereby creating the definitive subarachnoid space. The author produced no actual evidence for such CSF production and circulation in the embryo, but deduced from the observations in the pig that the attenuation of the hindbrain roof in human embryos at a similar stage is caused by the pressure of intra-ventricular CSF. He was careful to state that he had no evidence that the areas of permeability became actual foramina in the roof of the hindbrain (14).
Later authors, using the same ferricyanide infusion technique, demonstrated permeability of the roof of the hindbrain in chick embryos at 7 days (rostral area) and 8 days (caudal area) that coincided with choroid plexus development and the appearance of the subarachnoid space (15). In a similar study of rabbit, guinea pig, rat, and mouse embryos, the same workers again identified attenuated areas in the hindbrain roof, but they remained impermeable to the solution (16). A series of studies of intraventricular pressure in the developing chick noted the significant drop in the recordings which accompanied the appearance of fenestration in the hindbrain roof and concluded that this was caused by the development of the metapore rather than vice versa (17,18).
The original studies using freshly prepared human embryos referred to above (13), showed, by injection of isotonic dextran sulphate solution (molecular weight 6000-7000) in a 20 mm embryo, and by intraventricular injection of particulate carbon black suspension (less than 0.1 micrometer in size) in 43, 55, and 68mm embryos, free communication between the fourth ventricle and the developing subarachnoid space through the metapore. In these studies, the appearance of the PAS positive ring around the developing metapore (see above) was interpreted as indicative of an active metabolic process involved in the development of the metapore rather than a passive disruption from raised intraventricular pressure. A more recent study of human embryos (19) showed the subarachnoid space to appear first in the region ventral to the mid- and hindbrain prior to the development of the choroid plexus, and the appearance of subarachnoid spaces dorsal to the attenuated hindbrain roof occurred at a later stage. It was also found that the subarachnoid space appeared in abnormal embryos with a frank encephaloschisis that communicated the ventricular system directly with the exterior, thus indicating that the development of the subarachnoid space is likely to be independent of bulk flow from the ventricles.
The interpretation of the development of continuity between the internal and external CSF as an active process independent of bulk flow and pressure is a tenable view, and has the corollary that the midline foramen of Magendie, or metapore, present in man and anthropoids, is a specific development which facilitates ease of bulk flow between the compartments in these bipeds.
PhysiologyWhen Cushing gave the Cameron Lectures in 1925 (20), he found enough evidence from the work of his colleagues, and from his own observations on his surgical cases, to put forward the concept of the 'cerebrospinal circulatory sector' consisting of: CSF production by the choroid plexuses, its flow through the ventricular system, foramina of the fourth ventricle, and subarachnoid space, to the sites of absorption by the arachnoid villi protruding into the cerebral and spinal venous sinuses. The emphasis thereafter was upon the pressure gradients and flow patterns of this 'Third Circulation' and its obstruction and distortion by tumours and other pathological processes.
In the mid-twentieth century, perfusion and clearance studies demonstrated the barrier between the systemic circulation and the CSF such that ions and small molecules could pass relatively easily into the latter, whereas larger molecules were excluded. Studies with the electron microscope demonstrated the relatively tight intercellular junctions in the epithelial lining of the cerebral and choroid plexus microvasculature comprising what became known as the blood brain barrier (21, 22). Radioisotope studies not only confirmed these dynamic exchanges between the cerebral circulation and CSF, but also, by the use of larger ‘tagged’ molecules, confirmed Cushing’s concept of a third circulation from the choroid plexuses of the ventricles to the villi of the arachnoid granulations within the cerebral and spinal venous sinuses (23,24). The emphasis of these studies was on the physiology of the CSF in relationship to ionic and molecular exchange between functioning neurones and the cerebro-vascular circulation across the various intercellular junctions between them; the CSF was presented as the sump or as a kind of lymphatic flow for the central nervous system. These aspects of CSF physiology were researched particularly by Davson and co-workers, and collated in their publications (25,26,27,28).
The technique of CSF pressure monitoring has demonstrated not only the overall pressure gradients which determine bulk flow (29,30), but also the pulsatile nature of the flow pattern (31,32) as originally observed by Francois Magendie. The to and fro' movement of CSF which he observed to occur through his foramen, and which is easily confirmed by direct observation through the intact cisterna magna in animal preparations, and during operations on patients, can now be seen and analysed most fully by dynamic studies using MRI techniques (33). It remains to be seen whether or nor they bear any relationship to backward and forward movement of the subjects.
SignificanceThe evolution of the CSF system from a closed ventricular system to one with an internal and external compartment, limited by the well-defined arachnoid membrane, and communicating through the foramina of the fourth ventricle roof, must be seen primarily as a complex reservoir which maintains the extra- cellular space of the central nervous system essential to its specialised neurological functions. However, the complex relationship of the evolution of the rhombencephalic foramina to, firstly, terrestrial as opposed to aquatic life, and, secondly, to the adoption of the upright posture, when the midline metapore, or Foramen of Magendie, predominates over the lateral openings, may suggest that these foramina are associated with forward motion in the biped.
The bulk flow and turnover of the CSF system is a relatively slow affair, taking some twelve to twenty four hours, but the foramina permit a rapid exchange between the ventricular compartment, with its low capacitance, and the relatively high capacitance subarachnoid space. The foramina are situated posteriorly, giving egress to the cisterna magna, and the extensive spinal subarachnoid space with its relationship to the low-pressure venous system. Rapid forward movement of the head and contained brain, accompanied by rapid posterior displacement of CSF through the Foramen of Magendie, may add an hydraulic form of cushioning to the buoyancy provided by the CSF system, and thereby reduce impacts and cerebral concussion.
Clinical ImplicationsAbnormalities of the CSF system, such as the effects of inflammation, trauma, and impinging tumours, in addition to congenital malformations, all tend to cause distortions of CSF compartment and obstructions to CSF flow, with the accumulation of CSF under pressure, which we know as hydrocephalus. Of particular interest is the well-described dilation of the supra-pineal recess which accompanies chronic hydrocephalus. Diagnosis and elucidation of pathology is by MRI. Relief of hydrocephalus by removal of specific obstruction is relatively rare, and, more commonly, CSF is shunted to another body compartment. The outcome of such procedures is limited by the relative crudity of the hydro-dynamics of the various devices used, and the risk of infection.
Various intracranial by-pass procedures have been practiced over the years (34) and the use of the neuro-endoscope more recently has greatly facilitated these. The current practice is to make the opening in the posterior aspect of the floor of the third ventricle, thus leading the CSF posteriorly, into the pre-pontine cistern. Some 20-40 percent of such procedures fail(35). It would be reasonable to consider making the third ventriculostomy through another region of the third ventricle, such as the suprapineal recess, thus creating egress into a region of greater capacitance, as appurtains for the Foramen of Magendie in normal CSF outflow.
References