Even if the EP attracted the attention of researchers long ago [18–20], few authors have made in-depth studies of the development, morphological features and pathological aspects of this structure in humans. Among these, Del Bigio , in a recent review, summarizes the current knowledge of the biology and pathology of the EP in mammalian brains. In particular, the author underlines that the EP has potential barrier functions at the brain-CSF interface, including the upregulation of 'protective' proteins that might prevent re-entry of harmful metabolites from the CSF back into the brain. The presence of motile cilia is important to carry out this role.
Narita et al.  demonstrated that primary cilia in EP may function as chemosensors, thus playing an important role in regulating the homeostasis of the central nervous system. The EP also has transport systems and distinct enzymes that are able to remove endogenous and exogenous toxins from the nervous system [23–25]. The activity of tanycytes, the nonciliated ependymal cells characterized by basal processes penetrating into the brain parenchyma and frequently reaching small blood vessels, could be included in this context . The connections made by the tanycytes from the CSF to neural capillaries raise the possibility that they may play some role in sampling the biochemical constituents of both compartments, thereby allowing the uptake and transport of substances into and out of the CSF, so influencing neuronal activity. The participation of tanycytes in chemoreception is, however, a function limited to fetal life. Tanycytes, in fact, represent a transitional cell during human fetal development and not a distinct population. They gradually mature into common ependymal cells following loss of the basal processes .
In this study, direct investigation of the ventricular and spinal cord EP in a wide set of fetal and infant deaths (78 cases), victims of both unexplained and explained death, firstly allowed us to delineate the dynamic sequence of morphological and biological steps occurring in human EP development from gestational week 17. We observed that the ependymal lining is fully differentiated by approximately 32 to 34 weeks of gestation, which is several weeks later than reported by Del Bigio  and a few weeks before the estimation by Spassky et al.  that EP maturation occurs during the first postnatal week. In early fetal life ventricular EP showed a pseudostratified cytoarchitecture, including many tanycytes and ciliated cells together with strong GFAP and TUNEL immunoreactivity, whereas in late fetal life and in the first postnatal months it is formed by a single layer of cuboidal or columnar cells that are rarely immunopositive.
Additionally, this study identified a wide spectrum of pathological changes of the EP in a large proportion of sudden death victims. These prevalently included: desquamation or denudation; glial clusters and vacuolation in the SVZ beneath a discontinuous EP; chains of radial glial cells, particularly in SIDS victims; reactive gliosis and heterotopic neurons inside and over the EP edge.
Glial nodules rise from sequestration of EP diverticuli penetrating into the parenchyma. It is not clear what role these invaginations of the EP might have, and this topic merits further investigation. The subependymal vacuolation could be related to ependymal cell loss. The discontinuous lining may not be able to perform its function in regulating the transport of fluid, ions and small molecules between the CSF and the cerebral parenchyma, and thus may contribute to subependymal edema and the formation of vacuoles that could be interpreted as segregation of the excessive fluid.
The so-called 'radial glial cells' are generally recognized as elongated astrocytes with long processes arranged in small chains that run across the neuropil perpendicularly to the EP line. Experimental studies in mice demonstrated that a subpopulation of radial glia serves as progenitors of new ependymal cells during development . So, we can interpret the chains of radial glial cells associated with EP disruptions observed in SIDS victims as an attempt to reconstruct an intact border between the brain parenchyma and the ventricular cavity.
The heterotopic presence of single intraependymal and supraependymal neurons observed in SIDS is more difficult to understand. It has long been well known that some neuronal elements send their processes to the CSF. Using silver impregnation methods, Parent  demonstrated that several serotonergic axons of neurons belonging to the raphé nuclei terminate in the ventricular surface of the EP entering the CSF. Similarly, long basal processes from neurons of the arcuate nucleus in mammals are able to run into the subependymal neuropil reaching the ventricle . These neurons represent a component of the so-called 'CSF-contacting neuronal system' , which is an important nonsynaptic signal transmission in the brain. Three peculiar types of CSF-contacting neurons have been recognized: intraependymal neurons, which line the walls of ventricles and of the central canal of the spinal cord; supraependymal cells, which are subjacent to the ependyma; and distal CSF-contacting neurons, whose body is in the parenchyma of the brain and whose processes extend into the CSF in the ventricle system .
The same brainstem nucleus can include neurons with intraventricular processes modulating their activity according to the composition of the ventricular CSF, as well as neurons that work according to the composition of the intercellular fluid. The connection between the two types of neurons may lead to the detection of differences between the two fluids, so coordinating a nonsynaptic transmission. Nevertheless, we cannot exclude that single cells belonging to the first group of neurons may dedifferentiate, migrate outside their original localization and directly establish contact with the CSF of the ventricle. These heterotopic neuronal cells could, at last, represent newly generated neurons in the SVZ. In the mouse brain, in fact, the SVZ represents a neurogenic stem cell niche that controls neurogenesis and gliogenesis [34–36]. In this regard, a subpopulation of SVZ astrocytes has been identified as comprising stem cells that are able to generate neuroblasts, although it is not yet known exactly how intercellular communication regulates SVZ neurogenesis .
In any case, the EP lesions are generally irreversible and, regardless of the type of alteration, the damaged EP may not be able to perform its primary function as a protective barrier between the brain and the CSF, selectively removing noxious substances from the nervous system [23–25]. We suggest that many of the EP alterations that we observed in this study are indicative of prenatal injury that could induce dysfunctions in the control of vital functions, like the developmental abnormalities of other nuclei and/or structures of the brainstem and cerebellum that we have reported in previous work [13–15].
Experimental studies have demonstrated that in pathological situations, such as viral infections, destruction of the EP is the main outcome [3, 37, 38]. Chronic brain hypoxia/ischemia in rats rapidly allows EP cells to reacquire a radial glia phenotype in SVZ [39–41]. Rothstein and Levison  confirmed that in conditions of cerebral hypoxia the EP and SVZ cells are most vulnerable and easily undergo extensive damage.
In our view cigarette smoke is the main factor involved in human EP alterations in unexplained fetal and infant death. In fact, a very high percentage (68%) of SIUD/SIDS victims with EP developmental alterations had a smoker mother. The work by Bajanowski et al.  supports this hypothesis. These authors reported a high concentration of cotinine, the major oxidative metabolite of nicotine, in the CSF of SIDS victims with smoker mothers. During pregnancy, about 80 to 90% of the inhaled nicotine is absorbed systemically, as assessed using 14C-nicotine . Most of the constituents of tobacco smoke, in particular nicotine and carbon monoxide, are able to pass through the placental-fetal barrier. By chromatography, Malkawi et al.  detected significant concentrations of cotinine primarily in CSF samples from newborn babies of smoker mothers, indicating that it rapidly permeates through the blood-brain barrier.
In conclusion, we feel able to say that noxious agents passed from the mother to fetus cause damage to the EP before other autonomic nervous system centers. Therefore, the EP, being the nervous system structure primarily showing structural and/or functional abnormalities in these conditions, should be examined in-depth first in victims of sudden fetal or infant death with smoker mothers.