The pia mater: a comprehensive review of literature
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- Adeeb, N., Mortazavi, M.M., Deep, A. et al. Childs Nerv Syst (2013) 29: 1803. doi:10.1007/s00381-013-2044-5
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The pia mater has received less attention in the literature compared to the dura and arachnoid maters. However, its presence as a direct covering of the nervous system and direct relation to the blood vessels gives it a special importance in neurosurgery.
A comprehensive review of the literature was conducted to study all that we could find relating to the pia mater, including history, macro- and microanatomy, embryology, and a full description of the related structures.
The pia mater has an important anatomic position, rich history, complicated histology and embryology, and a significant contribution to a number of other structures that may stabilize and protect the nervous system.
KeywordsPia materDenticulate ligamentFilum terminaleLinea splendens
The first known description of the meninges can be traced back to the Edwin Smith Papyrus, which dates to Dynasties 16–17 of the second intermediate period of ancient Egypt. However, the description in this papyrus is limited to what is believed to be the dura mater. The Greek philosopher Aristotle, in the fourth century B.C., described two layers of the meninges, the stronger one near the bone of the skull and the finer one enclosing the brain. His descriptions were based on animal dissections. In the third century B.C., Herophilus and Erasistratus confirmed the findings of Aristotle in humans, in the first known human dissection in ancient history, done in Alexandria. Erasistratus was the first to use the term meninges (singular meninx, meaning “membrane”). In the second century A.D., Galen of Pergamon translated and added to the earlier descriptions of Herophilus and Erasistratus, and he used the terms pacheia and lepte to describe the outer thick and the inner thin layers, respectively. He found that the lepte covers and strengthens the brain and binds the vessels it encloses. During the Islamic Golden Age, the meninges were observed and named by an anonymous Muslim physician as umm al-dimagh (the mother of the brain). This was later subdivided by Haji Abbas into umm al-ghalida (the hard mother) and umm al-raqiqah (the thin mother). By the twelfth century A.D., the Italian monk Stephen of Antioch translated and described these two Arabic terms into Latin as dura (hard) mater and pia (pious) mater. Some authors believe that the use of pia is a misnomer and should have been replaced by tenue (thin), but Stephen chose the term pia, which has persisted. The term mater is derived from ma- (from matru, meaning mother), and the suffix -ter indicates the state of being. The arachnoid was first described by Herophilus in the third century B.C., but the first introduction and detailed description of this term is attributed to Frederick Ruysch, a Dutch anatomist, in 1699. Some authors use the term pachymeninx in regard to the dura mater and the term leptomeninx (or leptomeninges) in regard to the arachnoid and pia maters collectively [1–4]. Although the exact function of the pia mater is not clear, it does cover and potentially protects the brain. Moreover, via its specializations (denticulate ligaments, filum terminale), it affords some degree of stabilization of the spinal cord. These specialized parts of the pia and its overall “coating” of the central nervous system afford protection to the child's nervous system. Moreover, the pia via its perivascular space allows diffusion of solutes below 200 Å in diameter between the interstitial space and cerebrospinal fluid, thereby allowing for movement of metabolites and playing a role in the blood brain barrier [5, 6].
In both the cranium and spine, the pia is separated from the overlying arachnoid by the subarachnoid space and cisterns. This space is traversed by networks of fine, continuous, sheet-like trabeculae that link the arachnoid and pia mater and divide the subarachnoid space into compartments. It consists of a collagen core surrounded by a leptomeningeal layer that becomes continuous with the surface of the pia mater and blood vessels in the subarachnoid space at the sites of attachments .
In their book, Key and Retzius divided the spinal pia mater into two parts, the intimal and the epipial layers . The external, epipial, or intermediate leptomeningeal layer is mainly present in the spinal cord. It represents a vascular layer with almost a uniform thickness that consists of a network of collagenous fibers. The superficial fibers show an irregular arrangement, compared to the circular arrangement of the deeper fibers around the spinal cord. On each side of the spinal cord, this layer thickens and covers the collagenous core of the denticulate ligaments, as described earlier. Ventral to the anterior median fissure, it thickens and gives rise to the linea splendens, forming the sheath of longitudinal fibers around the anterior spinal artery. Along its course, this layer also dips into the anterior median fissure and is interrupted at the sites of entry and emergence of the spinal nerve rootlets, around which it forms a round margin. The subarachnoid blood vessels lie in between the strands of the epipial layer before entering the substance of the spinal cord. In the brain, the epipial layer only surrounds the medulla oblongata. Fine trabeculae were also found in the subarachnoid space of the brain, the spinal cord anchoring larger vessels in the space to the pia and arachnoid.
The underlying, avascular intimal or reticular layer closely invests the spinal cord and the brain throughout all their contours. This layer is composed of reticular and elastic fibers. In the spinal cord, it follows the anterior median fissure and the posterior median septum. It also gives rise to incomplete septae, which project into the white matter at irregular intervals from the periphery of the cord. In the brain, this layer closely invests the gyri and dips into the sulci. Fine septae were also found to pass into the brain for a short distance, mainly at the site of entry or emergence of the blood vessels. Before their entry, smaller blood vessels lie directly on the intimal layer [12, 13]. The pia mater rests on the basement membrane of the glial limitans, from which it is only separated by a subpial space. This space contains collagen bundles, fibroblast-like cells, and blood vessels [8, 13].
Although the VR space is separated from the subarachnoid space, some substances may still easily pass between the two of them. This explains the extension of certain pathological conditions, e.g., infections, from the subarachnoid space. This fluid-filled space also manifested certain types of macrophages, unrelated to pathological conditions, which have more activity than neural microglial cells. Other functions of the perivascular space include its role as a conduit for the CSF to reach the draining lymphatics .
Early investigations regarding the development of the meninges proposed a common origin from the neural tube ectoderm. However, this had been opposed by later authors starting with Schwann  in 1839. His , in 1865, described an origin from a mesenchymal tissue surrounding the neural tube, a theory that was accepted by later authors. This mesenchymal tissue was later named meninx primitiva (or primitive meninx) by Salvi  in 1898. This layer was further divided by two cellular condensations proposed by His  into endomeninx (or secondary meninx) and ectomeninx. The former contributes to the leptomeninx, while the latter contributes to the pachymeninx (or dura mater). However, the mesenchymal characteristics of the meninx primitiva have been questioned by some investigators and were later found to consist of different cells of various sources, including mesodermal and ectodermal cells. Other authors believed that the dura mater develops from the mesenchymal layer and the leptomeninges develop from the neural tube ectodermal cells, mainly neural crest cells .
In 1986, O'Rahilly and Müller  found that the perimedullary tissue (meninx primitiva) surrounds the neural tube almost entirely, except at the area of direct contact between the future spinal cord with the notochord and at the roof of the future brain. This tissue consisted of two layers: the inner layer, which gives rise to the future leptomeninges, and an outer layer, which gives rise to the pachymeninx. Two condensations were found to arise at the outer and inner parts of the outer layer. The outer condensation contributes to the skeletogenous layer of the future scalp, and the inner condensation contributes to the dural limiting layer. From the inner layer of the mesenchyme, signs of the pia mater are seen early in human development. It was found to closely invest the neural tube and adhere to the supplying blood vessels. In the same layer as well, leptomeningeal meshwork and spaces can also be seen, which gradually give rise to the future subarachnoid space. Within this space, numerous trabeculae were found to link the developing pia mater and dura mater [3, 23]. According to Haymaker and Adams, the denticulate ligaments are the first of the spinal meninges to differentiate from the primary meninx .
Structure originating from pia mater
The function of the denticulate ligaments is still not very clear. In earlier literature, the function of these ligaments was thought to be for stabilizing the spinal cord. Thus, it was assumed that they may tether the cord in various pathological conditions. However, later studies on the denticulate ligaments revealed that a wide range of movement is allowed before these ligaments become taut. Movements were tested in cranial–caudal, anterior–posterior, and lateral directions, and there was a wider range of movements as the spinal cord descended, which is expected as the denticulate ligaments become thinner. However, even with the wide range of movements allowed, the denticulate ligaments still provided means of limitation, as a cut or avulsion of the ligaments will further increase the cord's mobility, mainly in the cranial–caudal axis [26, 29].
Histological studies of the denticulate ligament have shown that it consists of a dense collagenous core that is thicker laterally. On its medial end, this core adheres to the subpial collagen, and at its lateral end, it fuses with the dural collagen. This fibrous core is surrounded by a leptomeningeal layer that is continuous with the cellular layer of the pia mater and arachnoid [24, 27, 28].
Lumbar intrathecal ligaments
In an experimental study on 56 cadavers, Kershner et al.  described the presence of lumber intrathecal ligaments. These ligaments (average of 18 per specimen) were found in the cauda equina, below the first lumber vertebra, but not below the second sacral intervertebral foramen. In most cases, these ligaments attached the dorsal spinal roots to the surrounding dura mater and sometimes bound the ventral roots to the dorsal roots in a longitudinal or vertical manner. Histological examination showed a fibrous core consisting mainly of collagen bundles and, to a lesser degree, elastin. Fibroblasts were scattered along the length of the ligament and were more densely found near sites of attachment. This core is surrounded by leptomeningeal cells that become continuous with the pia mater of the spinal roots. The broad-based attachments at both sides, along with their histological characteristics, contribute to the fact that the intrathecal ligaments need a greater force to disrupt the arachnoid. The similarities between these ligaments and the denticulate ligaments suggest that the intrathecal ligaments represent remnants from fetal development of the denticulate ligaments .
Dorsal and dorsolateral septae that arise from the partially fenestrated intermediate (or epipial) leptomeningeal layer have been found traversing the subarachnoid space in almost all the areas of the spinal canal . The epipial layer is considered as the outer layer of the pia mater [12, 19] and is discussed in further details below.
The filum terminale
In their description of the filum terminale externum in 15 adult cadavers (age 57 to 90 years), Tubbs et al. found that the length of the filum terminale externum in all the specimens ranged from 7 to 10.5 cm (mean, 8 cm) and with a mean width of 1 mm. In none of the specimens did tension applied on the extradural compartment result in any movement of the intradural compartment . The mean length of the extradural part was similar to that measured by Rauber . In Tarlov's experiment study, however, the length of this part in newborns and adults was 2.2 and 7.5 cm, respectively .
In 1892, Tourneux  mentioned that at the transition between the conus medullaris and the filum, the central canal flattens and continues within the filum as far as the vicinity of the dural cul-de-sac. He also mentioned the presence of medullary nerve cells, which also decrease in number until they totally disappear 1 mm below the dural sac. These findings were confirmed by Rauber  in 1909, who added that the medullary nerve cells were observed clinging to the sides of the filum. In 1933, Harmeier  described the microscopic characteristic of the intradural filum terminale. Large collections of the ependymal cells were found in certain places without definite arrangement and in other places surrounding irregular cavities. Excessive numbers of corpora amylacea were also found beneath the pia mater and also scattered throughout the filum. Ganglion cells were also found at the periphery, and neuroblasts were scattered within the tissue. Axons were also described extending all the way down, and myelin was abundant in the proximal half of the filum. As the filum terminale internum progresses downward, the amount of nerve tissue decreases gradually until it becomes confined as a peripheral thin layer .
Tarlov's  description of the microscopic anatomy of the filum terminale was more detailed. He found that at the transition between the conus medullaris and the filum, the difference between anterior and posterior horns, becomes gradually less pronounced with lack of demarcation of the gray and white maters. Nerve cells still can be seen, mainly within the first 3 cm of the intradural portion of the filum terminale. These nerve cells were occasionally large, multipolar cells. Some of these cells exhibit degenerative changes. Tracts of nerves fibers could also be seen continuing within the filum and gradually becoming less pronounced to attain a peripheral position in the filum. In the periphery, they become surrounded by Schwann cells and endoneurium and occasionally contain nerve cells. Many of these fibers were myelinated. The central canal may disappear and reappear again within the filum, and it may also reach the dorsal border of the filum. In certain cases, the central canal bifurcates to form various numbers of outpouchings, which appear as multiple cavities in cross section. Large numbers of glial cells are present within the intradural portion of the filum, and most of the time, these constitute the main bulk of the filum. These glial cells are similar to those found in the central nervous system and consist of ependymal cells, astrocytes, oligodendrocytes, and microglial cells. These cells are assumed to play their expected function and are present mainly within the cranial part of the filum terminale and disappear caudally. The ependymal cells were the most abundant and the last to disappear of all the interstitial cells, as they extend as far as the first 2 cm of the extradural part of the filum. Ependymal cells assume many shapes, surround the cavities, and are scattered in many parts of the filum. Corpora amylacea were also described, and they represent the most common form of the degeneration products within the filum . These structures are covered by the connective tissue sheath described above.
At the site of transition between the intradural and extradural portions, the filum becomes surrounded by arachnoid and dural layers. The arachnoid surrounds bundles of nerve fibers and the central portion of the filum. The cuboidal cells of the arachnoid at this level project into the fibrous stroma of the dural layer. Caudally, these become applied as a sheath with flattened lining cells that gradually disappear. The nerve fiber bundles become surrounded by the dural layer, which forms the epineurium. However, within the few first centimeters, all nerve fibers acquire a perineurium and an epineurium. Myelinated and non-myelinated nerve fiber bundles become less conspicuous gradually as they migrate laterally to their foramina of exit until they finally disappear. Small bundles of nerve fibers, however, were described along the entire course of the filum terminale. The filum finally blends with the periosteum on the dorsum of the coccyx. Psammoma bodies were found at the junction between the two parts of the dura, mainly in older subjects . According to Tubbs et al0 no glial or ependymal cells rests were found in this part of the filum, and a variable number of smooth muscle bundles were embedded within the fibrous stroma .
Reissner's fiber, named after the German anatomist Ernst Reissner (1824–1878), is a pretentious thread present in the central canal of most vertebrates, mainly the lesser vertebrates. It extends from the caudal end of the subcommissural organ of the epithalamus, through the lumen of the cerebral aqueduct, fourth ventricle, and central canal of the spinal cord into the rostral part of the filum terminale where it expands into an irregular, terminal, hyaline mass. Beyond the point where the fiber terminates, the filum contains an empty lumen extending caudally for a short distance . The function of this fiber was proposed to be related to control of the flexure and pose of the body .
Blood supply of the filum terminale is mainly provided by a single artery, the artery of the filum terminale. It arises from the bifurcation of the anterior arterial spinal axis at the level of the conus medullaris. It then descends on the ventral surface of the filum and becomes progressively smaller. It gives rise to smaller arterioles, and no arterial vascularization is usually observed on the dorsal surface. Venous drainage occurs by the vein of the filum terminale, which also travels along the ventral surface of the filum terminale behind the artery. It has an almost constant caliber, which is larger than the arterial caliber. At the level of the conus medullaris, it continues with the anterior spinal vein. No veins were observed on the dorsal surface of the filum. Microscopically, small veins, venules, small arteries, arterioles, and capillaries spread in apparently uniform fashion within the filum, both in the central region and in the periphery .
The pia mater has an important anatomic position, rich history, complicated histology and embryology, and a significant contribution to a number of other structures that may stabilize and protect the nervous system of the child.