Introduction
Blockage of the cerebrospinal fluid (CSF) circulation in experimental and human hydrocephalus results in a rise in intraventricular pressure with dilation of the lateral ventricles, alterations on the fine structure of choroid plexus, and disruption of the ependymal lining. Cerebrospinal fluid is infused into the white matter through the damaged ependyma, and causes severe periventricular edema, ependyma and periventricular white matter, cortical brain edema, parenchymal destruction, micro- and macrovascular changes, derangement of brain development, formation of cystic cavities, and reactive changes of glial cells. The subependymal white matter shows enlargement of extracellular space, edematous and degenerative changes in neurons, especially in axons and myelin sheath, edematous changes of glial cells, reactive astrocytosis and phagocytosis [1,6,9,10,14,30,34-36,38,40,41,43,46-49,52,56,57,63, 78,79,83,85,86,89,93,101-103,114].
Since the pioneering work of Struck and Hemmer [97] very few studies have been dedicated to explore the cortical gray matter alterations in human hydrocephalus. This aspect is basically important if we consider that CSF traverses the entire cerebral parenchyma as earlier demonstrated by Milhorat and Hammock [72]. Earlier electron microscopic studies of the gray matter have demonstrated enlarged extracellular space in murine hydrocephalus and human normal pressure hydrocephalus [5,70]. Takeuchi and Murakami [103] described two types of congenital hydrocephalus induced in rats by X-irradiation in utero. Castejón [2] found degenerative changes of neurons and glial cells in infant patients with congenital hydrocephalus and Chiari malformation type II. Weller et al. [110] studied the inflammatory reaction in infected cerebrospinal fluid shunts in hydrocephalic patients. Oka et al. [5] described the angioarchitecture in experimental rat hydrocephalus. Richardson [91] examined congenital hydrocephalus associated to other developmental abnormalities. Glees and Voth [46], Glees et al. [47], Glees and Hasan [48] earlier described the pathlogical changes in infant hydrocephalus. Miyazawa and Sato [75,76] reported learning disability and impairment of synaptogenesis in HTx-rats. Jones et al. [5-59] confirmed that the cerebral cortex is severely distorted in congenital hydrocephalus in the HTx-rats, in a mutant mouse, and in infantile hydrocephalus. Kriebel et al. [62] studied the microstructure of cortical neuropil before and after decompression in experimental infantile hydrocephalus. Sada et al. [2] found underdevelopment or immaturity of blood-brain barrier in hydrocephalic HTx-rat brain. Harris et al. [51] reported dendritic damage in hydrocephalic HTx-rats. Boillat et al. [7,8] analyzed the damage of cortical pyramidal neurons in control, hydrocephalic and shunted HTx-rats. Shoesmith et al. [94] reported relative impairment of extracellular fluid movement through the cerebral cortex of young hydrocephalic rats. Aolad et al. [3] found extensive cell death in mice following X-irradiation. Del Bigio et al. [35-37,39] demostrated myelination delay and proteolitic damage in immature rats with kaolin-induced hydrocephalus. Ding et al. [43,44] showed neuron tolerance during hydrocephalus, extensive axon and neuropil degeneration, and that neuron death was not a mayor pathological change. Del Bigio et al. [36] and Del Bigio [38] found in chronic hydrocephalus destruction of white matter. Aoyama et al. [4] found swollen and fragmented axons in experimental hydrocephalus. Castejón [10-24] described the electron microscopic changes of nerve cell organelles, and nerve cell death in congenital hydrocephalus. Khan et al. [60] observed astroglial/microglial reaction in kaolin-induced hydrocephalus. Aliev et al. [2] reported severe edema in a murine model of congenital hydrocephalus. Aoyama et al. [4] reported neuronal damage in experimental hydrocephalus. Humphreys et al. [53] reported cerebral mantle disruption in human fetal hydrocephalus in kaolin-induced hydrocephalus. Voelz et al. [107] described in rat kaolin-induced hydrocephalus the dynamic of CSF circulation. Del Bigio and Enno [32] found reduced extracellular space in kaolin-induced rat hydrocephalus. Goto et al. [50] described defects in oligodendrocyte development, axonal damage, and subsequent hydrocephalus in Fin-deficient mouse.
The present review describes the fine structural alterations of human hydrocephalic cerebral cortex and correlates some results with those reported in experimental hydrocephalus in animal models. Experimental hydrocephalus investigations in animal models help to better understand the pathogenetic mechanisms of human hydrocephalus. Intracellular edema of hydrocephalic nerve cells
In pyramidal and non-pyramidal neurons, moderate to severe swelling of intraneuronal compartment revealed by plasma membrane fragmentation, variable degrees of enlargement of rough endoplasmic reticulum and perinuclear cistern, and wide communications between the nucleoplasm and cytoplasmic matrix are constantly found. A degranulated rough endoplasmic reticulum also is observed [24]. The intracellular edema is prominent at the level of the smooth Golgi flattened stacked cisterns, which appear extremely dilated and fragmented [23]. The mitochondria exhibit also a wide spectrum of morphological changes ranging from light to moderate and severe swelling [13]. Lysosomes show damage of their limiting plasma membrane, and appear surrounded by areas of cytoplasmic focal necrosis (Figs. 1-3) [19].
The hydropic changes of nuclear and cytoplasmic matrix induce an increased electron lucent aspect of nerve cells, which acquired a watery appearance. These edematous changes and the degranulated rough endoplasmic reticulum could be correlated with the impairment of protein synthesis, reduced cerebral glucose and oxygen metabolism, and changes in the levels of neurotransmitters reported in the hydrocephalic cerebral cortex [31,51,64,74,90]. Edematous changes have also been earlier observed in the experimental rabbit hydrocephalus at the level of the white matter [109]. Boillat et al. [7,8] earlier analyzed the damage of rat cortical pyramidal neurons, showing cluster organization, fewer mature dendrites, infrequent synapses, degenerative changes, vacuolated cytoplasm, dilated Golgi and endoplasmic reticulum, distorted mitochondria, and single ribosomes in hydrocephalic HTx-rats. The edematous and degenerative changes of cerebral cortex in human hydrocephalus appeared to be initially of a mechanical origin due to the high cerebrospinal fluid pressure, and secondarily to the increased interstitial edema, ischemic process, and oxidative stress [22].
In addition to the neuronal edema there is also an associated ischemic process. The role of ischemia in neonatal brain injury was suggested by Del Biggio et al. [34]. According to Jones et al. and Jones and Anderson [55,59], and Harris et al. [51], there is a progressive reduction in energy metabolites, which leads to cell swelling with decreased osmolytes and neurotransmitters. Jones et al. [55] found significant increase in water, Na+ and Cl– content in rat infant hydrocephalus. Hydrocephalic edema also is associated with oxidative stress. According to Socci et al. [96], there is evidence that oxidative stress is associated with the pathophysiology of inherited hydrocephalus in the HTx-rat model.
Pathology of myelinated axons
Earlier microscopic studies of experimental hydrocephalus show damage of axons and myelin sheath at the subependimal white matter [43,63,70,77,83,84, 111-113]. Myelinated axons are not observed in the gray matter of neonate patients with congenital hydrocephalus, especially in those patients between 10 days and 3 months of age [22]. A myelination delay in the cerebral white matter of immature rats with kaolin-induced hydrocephalus was earlier reported by Del Bigio et al. [35]. Del Bigio and Zhan [37] reported axonal injury in the corpus callosum one week in kaolin-induce hydrocephalus. These authors described axonal damage four weeks after severe ventriculomegaly. Electron microscopic changes of dendrites and dendritic spines in congenital hydrocephalus
The immature hydrocephalic cerebral cortex neuropil in neonate patients with congenital hydrocephalus shows irregularly beaded shaped, and swollen and vacuolated dendritic processes with elongated and dark mitochondria. Some of them exhibit lamellipodic and filopodic processes, and endocytic vesicle formation at the limiting plasma membrane [22]. These dendrites exhibit mushroom, stubby and filiform types of dendritic spines making asymmetric synaptic junctions [14,18]. Some dendritic processes show fragmented plasma membrane and disrupted microtubules in areas of severe brain edema (Fig. 4).
Hydropic dendritic deterioration has been reported in feline-infantile hydrocephalus by Kriebel and McAllister [62]. Harris et al. [51] found a decreased in the total length of dendritic tree in the infant HTx-rats. McAllister et al. [69] reported dendritic varicosities and spine loss as the most striking dendritic alterations in experimental induced hydrocephalus in newborn rats.
In patients with congenital hydrocephalus and Chiari malformation, a variety of swollen spine shapes are found [14]: mushroom type-, filopodic and lanceolate spines. In the immature neuropil of these neonate and hydrocephalic patients, some spines appear axonless or unattached, and others making asymmetric axodendritic synaptic contacts. The immature spines exhibit mostly an elongated neck with several microtubules. Unattached or axonless elongated spines, presumably represent a compensatory mechanism to navigate in the widened extracellular space of the immature neuropil to reach axons farther away. These spines exhibit an edematous head, a disrupted actin-like network, dilated profiles of smooth endoplasmic reticulum, swollen clear and dense mitochondria, and clusters of free ribosomes. Such alterations are due to dendrotoxicity [18]. Synaptic plasticity and synaptic degeneration features in congenital hydrocephalus
In human congenital hydrocephalus few inmmature axodendritic and axosomatic synapses are observed in infant patients ranging from 1 to 6 months of age (Fig. 5). Synaptic plasticity in mature synapses is mainly characterized by the presence of activated flat and invaginated axodendritic and axospinodendritic asymmetric synaptic contacts showing synaptic vesicles anchored to the presynaptic membrane, and short or large synaptic active zones [20]. Tsubokawa et al. [106] also found impaired hippocampal synaptic plasticity in the experimental chronic hydrocephalus.
The swollen and degenerated axodendritic and axosomatic synaptic contacts observed in areas of moderate and severe hydrocephalic edema exhibit enlargement of few synaptic vesicles, and lack of pre- and post synaptic densities. In addition, isolated and swollen presynaptic endings with few or numerous synaptic vesicles, disruption of limiting plasma membrane, and without postsynaptic partners are observed. Megaspines up to 2.86 µm in lenght are observed in Chiari malformation making mature axodendritic junctions with one or two synaptic active zones, and exhibiting a dilated spine apparatus (Fig. 6). Synaptic degeneration and synaptic disassembly occur in elevated intracranial pressure-hydrocephalus (Fig. 7). Phagocytic astrocytes appear engulfing the degenerated synapses. Hydrocephalic edema and ischemia, oxidative stress, increased calcium concentration, activation of NMDA receptors, and disturbance of ion homeostasis are apparently related with the synaptic plasticity and synaptic degenerative changes observed in human hydrocephalus [20,21].
The damage of nerve cell processes and synaptic contacts indicates nerve cell circuit alterations in the hydrocephalic cortex, which might explain some clinical and neurobiological symptoms, such as decline in intellectual functions and learning disabilities, motor deficits, and seizures observed in infant hydrocephalic patients [20,22,46,48,76].
Learning disability and impairment of synaptogenesis in HTx-rats with arrested shunt-dependent hydrocephalus have been also reported by Miyasawa and Sato [76]. Besides, changes of synaptic related proteins (SVP-38 and debrins), and of synaptogenesis have been earlier reported by Suda et al. in congenitally HTx-rats [98,99]. Reactive changes and phagocytic activity of neuroglial cells
Two distinct morphological types of astrocytes: Glycogen rich- and glycogen-depleted astrocytes have been found in human congenital hydrocephalus in perineuronal, interfascicular and perivascular localization (Fig. 8) [16]. These findings suggest astrocytic glycogen mobilization during anoxic and ischemic conditions, revealing the important contribution of astrocytes on neuronal survival under conditions of energy substrate limitations. Astroglial cells might perform several energy-dependent functions that may aid neuronal and oligodendroglial cell survival in pathological conditions, such as congenital hydrocephalus [16].
At the level of cortical gray matter neuropil, the astrocyte cells show notable edematous changes and phagocytic activity. Gliosis and microgliosis have been reported to be a common and persistent feature in the white matter of hydrocephalic brain [67-73]. Reactive changes in astrocytes and oligodendroglial cells in kaolin-induced rat hydrocephalus have been described by Klinge et al. [61]. According to Mangano et al. [67], microglial cells constitute one important element in the gliosis that accompanies hydrocephalus.
In the edematous human cortical gray matter, the oligodendroglial cells exhibit in certain regions a normal structural pattern, and in severely edematous areas moderate and remarkably hydropic changes and phagocytic activity [12]. Pathology of blood-brain barrier
The capillary wall shows evident signs of blood-brain barrier dysfunction characterized by increased endothelial vesicular and vacuolar transport (Fig. 9), closed and open interendothelial junctions, thin and fragmented basement membrane with areas of focal thickening, and discontinuous perivascular astrocytic end-feet [22,27].
In severely edematous areas with presence of disrupted neuropil, the perivascular space is notably enlarged and the capillaries appeared floating as isolated structures. They show tight or partially open endothelial junctions, increased vesicular and vacuolar transendothelial transport, and swollen and disrupted basement membrane (Fig. 10). Our findings in human hydrocephalus favor the idea of an interendothelial route either for edema formation or resolution in human hydrocephalic cerebral cortex [22,27]. Nakagawa et al. [80] also reported widening of interendothelial clefts between the tight junctions in capillaries of the subependymal and subcortical white matter in hydrocephalic rats, and postulated the possibility of a paracellular route for hydrocephalic edema resolution. In this context, human hydrocephalus differs from the hy-3 mouse neonatal hydrocephalus [70], in which a normal operating blood-brain barrier is suggested by the presence of intact interendothelial tight junctions, no indication of increased pinocytotic activity, and perivascular astrocytes of apparently normal submicroscopic morphology.
Okuyama et al. [86] also have reported a disturbed microcirculation in congenitally hydrocephalic brain, especially at the level of endothelial cells of capillaries and venules in the periventricular edematous region. Glees et al. [48] studying the microvasculature in hydrocephalic human infants have postulated a possible role of endothelial pinocytotic vesicle as a transcellular route for hydrocephalic edema resolution, and considered that CSF or edema fluid is absorbed into the vascular system via a transendothelial pathway. Increased pinocytotic transport also occurs in traumatic human brain edema [25,26]. Since both traumatic and high pressure hydrocephalic human brain edema initially have a common mechanical origin, the reactivity and behavior of endothelial cells are apparently the same in both nosological entities. Hasan and Glees [52] have postulated a possible role of perivascular pericytes and juxtavascular phagocytes in hydrocephalic edema resolution. In an early publication [107] we have reported that pericytes also exhibit remarkable edematous changes, increased vesicular and vacuolar transport, formation of transient transpericytal channels, and tubular structures in human brain edema associated to brain trauma, tumor and congenital malformations. Presence of myelin figures
Numerous myelin figures are observed in nerve cells and astrocytes in human congenita hydrocephalus, suggesting that the pressure exerted by the interstitial edema, and the anoxic ischemic conditions of brain parenchyma induce the concentrically arrangement of nerve cell cytomembranes [22]. Apparently these concentric lamellar formations are conformational changes induced by the high pressure exerted by the non-circulating cerebrospinal fluid present in the dilated extracellular space upon the immature plasma membranes, which have distinct macromolecular composition, characterized by changes in integral membrane proteins, cholesterol domains, and in certain carbohydrates residues and anionic sites [100]. Myelin figures could be considered markers of nerve cell degeneration, and nerve cell death. The cerebrospinal fluid edema associated to hydrocephalus
The hydrocephalix cerebral cortex neuropil formed by an intricate complex of neuronal and neuroglial cell processes shows notable enlargement of the electron lucid extracellular space located among these processes (Figs. 3, 4, 6, 8-10), which is occupied by a non-proteinaceous and non-circulating CSF. The enlargement of extracellular space is more evident than the dilation of intracellular space. Lacunar extracellular spaces are constantly found at the meeting point of three or four nerve cell processes. The pressure of the non-circulating CSF induces separation, indentation and rupture of nerve cell processes [22,28]. Similar observations were earlier reported by Struck and Hemmer [97] and Foncin et al. [45] in the gray matter of human hydrocephalus. Such observations could also be correlated with previous studies on experimental and human congenital hydrocephalus, in which enlargement of the periventricular subependymal space has been widely reported [41,70,71,78,109,110]. Kriebel et al. [62] also found edematous extracellular space in experimental infant hydrocephalus. The increased extracellular space of the human hydrocephalic cortical neuropil suggests the establishment of a transparenchymal route for fluid absorption through the cortical capillaries [22,70,71].
The penetration of CSF induces edematous and degenerative changes in the neighboring neurons, neuroglial cells and synaptic regions [15,17,19,20,22]. The damage of the gray matter results from both hydrostatic forces and biochemical alterations induced by the extracellular pooling of CSF, and also by the expansion forces or stretching effects produced by the ventricular enlargement. Nerve cell death in human hydrocephalus
In human congenital hydrocephalus, nerve cells undergo a coexisting oncotic and apoptotic process, characterized by cytoplasmic and plasma membrane blebbing, remarkably swollen mitochondria and endoplasmic reticulum canaliculi and cisterns, dense nucleoplasm with a condensed chromatin, formation of apoptotic bodies, and increased number of perichromatinic granules [17]. According to Majno and Joris [66] and Trump et al. [105], these features have been characterized as oncosis. Both types of combined nerve cell death are considered as leading to necrosis. This later conceptualized as the changes that occur after nerve cell death [17]. Although apoptosis and necrosis are mediated through distinct pathways, in human hydrocephalus we have found a continuum oncosis, apoptosis and necrosis, depending of the severity of cerebrospinal fluid edema, the age of the patients, and the moderate or severe anoxic-ischemic conditions involved. The oligodendroglial cells appear in some cases exhibiting a normal structure (Fig. 11), and undergoing mainly apoptosis (Fig. 12) featured by nuclear chromatin condensation and formation of cytoplasmic apoptotic bodies. Oligodendrocytes also exhibit oncosis featured by enlarged and disrupted perinuclear cistern widely communicated with the vacuolated endoplasmic reticulum, and the dilated extracellular space, suggesting that the oncotic cell death is due to the high pressure exerted by the interstitial hydrocephalic edema or probably occurring in areas with milder or severe forms of ischemic damage (Fig. 13). The astrocytes also show apoptosis only (Fig. 14), or a combined oncotic and apoptotic cell death [17] featured by strong chromatin condensation, disrupted swollen cytoplasm and fragmented limiting plasma membranes. These hybrid forms of astrocyte cell death lead to necrosis (Fig. 15). In congenital hydrocephalus, neurons suffer a clear apoptotic process characterized by chromatin condensation and formation of typical apoptotic bodies. Necrotic neurons show fragmentation and dissolution of cytoplasm, and mitochondria, Golgi complex and lysosome degeneration.
In congenital hydrocephalus and Chiari malformations we are dealing with immature brains, where oncosis, apoptosis and necrosis also occur as a continuum, as previously described by Martin [68] in inmmature brain parenchyma. In these cases the nerve cell populations exhibit high vulnerability, and support the hypothesis of Portera-Cailliau et al. [88] that excitotoxic neuronal death in the immature brain is not an uniform event but rather overlapped morphological processes, with a distinct phenotype of neurodegeneration. Autophagic cell death has not been reported until now in human hydrocephalus.
The nerve cell death in congenital hydrocephalus is related with the severity of brain edema, anoxic-ischemic conditions of brain parenchyma, oxidative stress, glutamate excitotoxicity, calcium overload, and caspase dependent and independent mechanisms [11,17,105].
In relationship with nerve cell death in experimental hydrocephalus, Naruse and Keino [81] earlier described abnormal apoptosis inducing hydrocephalus. Del Bigio and Zhang [37] found nerve cell death in kaolin-induced rat hydrocephalus. Mori et al. [77] reported neuronal and oligodendrocyte cell death in the thalamus of hydrocephalic HTx-rats. More recently, Nonaka et al. [82] postulated a molecular mechanism related with accumulation of tau protein that induces neuronal death in the cerebral cortex of compensated HTx-rat hydrocephalus. Concluding remarks
Hydrocephalic nerve cells exhibit intracellular edema characterized by dilation of endoplasmic reticulum canaliculi and perinuclear cistern. Some degranulated areas of rough endoplasmic reticulum, edema and degenerative changes of Golgi apparatus, variable degrees of mitochondrial swelling, lysosomal damage, and fragmented limiting plasma membrane are observed. These edematous changes and the degranulated rough endoplasmic reticulum could be correlated with the impairment of protein synthesis, reduced cerebral glucose and oxygen metabolism, and changes in the levels of neurotransmitters reported in the hydrocephalic cerebral cortex. Myelination delay and axonal and oligodendroglial cell damage are reported in both human and experimental hydrocephalus. Damage of myelinated axons is found in the white matter. Myelinated axons are not observed in some neonate patients. The dendrites show edematous changes, irregularly beaded shaped, vacuolization and elongated dark mitochondria. A variety of swollen spine shapes are found such as mushroom type, filopodic and lanceolate spines. Some spines appear axonless or unattached, and others are making asymmetric axodendritic synaptic contacts. Signs of synaptic plasticity and synaptic degeneration are observed. Megaspines also are distinguished. The damage of nerve cell processes and synaptic contacts indicates nerve cell circuit alterations in the hydrocephalic cortex, which might explain some clinical and neurological symptoms, such as decline in intellectual functions and learning disabilities, motor deficits, and seizures observed in infant hydrocephalic patients. Hydrocephalic edema and ischemia, oxidative stress, increased calcium concentration, activation of NMDA receptors, and disturbance of ion homeostasis are apparently related with the synaptic plasticity and synaptic degenerative changes observed in human hydrocephalus. Astrocyte cells show notable edematous changes and phagocytic activity. Glycogen rich- and glycogen depleted astrocytes are found in congenital hydrocephalus. These latter findings suggest astrocytic glycogen mobilization during anoxic and ischemic conditions, revealing the important contribution of astrocytes on neuronal survival under conditions of energy substrate limitations. The capillary wall shows evident signs of blood-brain barrier dysfunction characterized by increased endothelial vesicular and vacuolar transport, closed and open interendothelial junctions, thin and fragmented basement membrane with areas of focal thickening, and discontinuous perivascular astrocytic end-feet. The perivascular space is notably dilated and widely communicated with the enlarged extracellular space in the neuropil. The increased extracellular space of the human cortical neuropil suggests the establishment of a transparenchymal route for fluid absorption through the cortical capillaries. In human congenital hydrocephalus, non-pyramidal neurons and astrocytes undergo a coexisting oncotic cell death and apoptotic process leading to necrosis. Oligodendrocyte cells exhibit mainly oncotic cell death. The nerve cell death in congenital hydricephalus is related with the severity of brain edema, anoxic-ischemic conditions of brain parenchyma, oxidative stress, glutamate excitotoxicity, calcium overload, and caspase dependent and independent mechanisms. Acknowledgement
This paper has been carried out from a subvention obtained of CONDES-LUZ. Zulia University, Maracaibo, Venezuela.
References
1. Akai K, Uchigasaki S, Tanaka U, Komatsu A. Normal pressure hydrocephalus. Neuropathological study. Acta Pathol Jpn 1987; 37: 97-110.
2. Alliev G, Miller JP, Leifer DW, Obrenovich MG, Shenj JC, Smith MA, Lamanna JE, Perry G, Lust DW, Cohen AR. Ultrastructural analysis of a murine model of congenital hydrocephalus produced by overexpression of transforming growth factor beta 1 in the central nervous system. J Submicrosc Cytol Pathol 2006; 200: 85-91.
3. Aolad HM, Inouye M, Darmanto W, Hayasaka S, Murata Y. Hydrocephalus in mice following X-irradiation at early gestational stage: possibly due to persistent deceleration of cell proliferation. J Radiat Res 2000; 41: 213-226.
4. Aoyama Y, Kinoshita Y, Yokota A, Hamada T. Neuronal damage in hydrocephalus and its restoration by shunt insertion in experimental hydrocephalus: a study involving the neurofilament-immunostaining method. J Neurosurg 2006; 104: 322-329.
5. Aoyama Y, Kinoshita Y, Yolota A, Hamaga T. Neuronal damage in hydrocephalus and its restoration by shunt insertion in experimental hydrocephalus: a study involving the neurofilament-immunostaning method. J Neurosurg 2006; 104: 297-298.
6. Bannister Carys M, Chapman SA. Ventricular ependyma of normal and hydrocephalic subjects: a scanning electronmicroscpic study. Develop Med Child Neurol 1980; 22: 725-735.
7. Boillat CA, Harris NG, Kaiser GL, Jones HC. Electron microscopy of the cerebral cortex in control, hydrocephalic and shunted H-Tx rats. Eur J Pediatr Surg 1993; 1: 30-31.
8. Boillat CA, Jones HC, Kaiser GL, Harris NG. Ultrastructural changes in the deep cortical pyramidal cells of infant rats with inherited hydrocephalus and the effect of shunt treatment. Exp Neurol 1997; 147: 377-388.
9. Bryan JH, Hughes RL, Bates TJ. Brain development in hydrocephalic-polydactyl, a recessive pleioroic mutant in the mouse. Virchows Arch Pathol Anat Histol 1977; 374: 205-214.
10. Castejón OJ, Acurero G. Traumatic axolemmal and cytoskeletal derangement in myelinated axons of human oedematous cerebral cortex and loss of consciousness. An electron microscopic study using cortical biopsies. J Submicrosc Cytol Pathol 2005; 36: 285-293.
11. Castejón OJ, Arismendi, GJ. Nerve cell nuclear and nucleolar abnormalities in the human oedematous cerebral cortex. An electron microscopic study using cortical biopsies. J Submicrosc Cytol Pathol 2004; 36: 273-283.
12. Castejón OJ, Castejón HV, Castellano A. Oligodendroglial cell damage and demyelination in infant hydrocephalus. An electron microscopy study. J Submicrosc Cytol Pathol 2001; 33: 33-40.
13. Castejón OJ, Castejón HV. Structural patterns of injured mitochondria in human oedematous cerebral cortex. Brain Injury 2004; 18: 1107-1126.
14. Castejón OJ, Castellano A, Arismendi G. Transmission electron microscopy of cortical dendritic spines in the human oedematous cerebral cortex. J Submicrosc Cytol Pathol 2004; 36: 181-191.
15. Castejón OJ, Castellano A, Arismendi GJ, Medina Z. The inflammatory reaction in human traumatic oedematous cerebral cortex. J Submicrosc Cytol Pathol 2005; 37: 43-52.
16. Castejón OJ, Diaz M, Castejón HV, Castellano A. Glycogen-rich and glycogen-depleted astrocytes in the oedematous human cerebral cortex associated with brain trauma, tumours and congenital malformation: an electron microscopy study. Brain Injury 2002; 16: 109-132.
17. Castejón OJ, Arismendi GJ. Nerve cell death types in the edematous human cerebral cortex. J Submicrosc Cytol Pathol 2006; 38: 21-36.
18. Castejón OJ, Arismendi GJ. Morphological changes of dendrites in the human edematous cerebral cortex. A transmission electron microscopic study. J Submicrosc Cytol Pathol 2003; 35: 395-413.
19. Castejón OJ. Lysosome abnmormalities and lipofucsin content of nerve cells of oedematous human cerebral cortex. J Submicrosc Cytol Pathol 2004; 36: 263-271.
20. Castejón OJ. Synaptic plasticity and synaptic degeneration in human congenital hydrocephalus. J Pediatr Neurol 2006; 6: 99-107.
21. Castejón OJ. Synaptic plasticity in the oedematous human cerebral cortex. J Submicrosc Cytol Pathol 2003; 35: 177-179.
22. Castejón OJ. Transmission electron microscope study of human hydrocephalic cerebral cortex. J Submicrosc Cytol Pathol 1994; 26: 29-39.
23. Castejón OJ. Ultrastructural pathology of Golgi apparatus of nerve cells in human brain edema associated to brain congenital malformations, tumours and trauma. J Submicrosc Cytol Pathol 1999; 31: 203-213.
24. Castejón OJ. Ultrastructural pathology of neuronal membranes in the oedematous cerebral cortex. J Submicrosc Cytol Pathol 2004; 36: 167-179.
25. Castejón OJ. Increased vesicular and vacuolar transport in traumatic human brain edema. A combined electron microscopy and theoretical approach. J Submicrosc Cytol 1984; 16: 359-369.
26. Castejón OJ. Submicroscopic changes of cortical capillary pericytes in human perifocal brain edema. J Submicrosc Cytol 1984; 16: 601-618.
27. Castejón OJ. Blood-brain barrier alterations in human congenital hydrocephalus and Arnold-Chiari malformation. Folia Neuropathol 2009; 47: 11-19.
28. Castejón OJ. The extracellular space in the edematous human cerebral cortex: an electron microscopic study using cortical biopsies. Ultrastuct Pathol 2009; 33: 102-111.
29. Castejón OJ. The congenital human hydrocephalus and the interstitial brain edema. In: Electron Microscopy of Human Brain Edema. Astrodata, Maracaibo 2009; pp. 267-276.
30. Choi BH, Kim RC, Peekham NH. Hydrocephalus following prenatal methylmercury poisoning. Acta Neuropathol (Berl) 1988; 75: 325-330.
31. Chovannes GI, Mcallister JP, Lamperti AA, Saloto AG. Truex RC. Monoamine alterations during experimental hydrocephalus in neonatal rats. Neurosurgery 1988; 22: 86-91.
32. Del Biggio MR, Enno TL. Effect of hydrocephalus on rat brain extracellular compartment. Cerebrospinal Fluid Res 2008; 5: 12 (Abstract).
33. Del Bigio MR. Cellular damage and prevention in childhood hydrocephalus. Brain Pathol 2004; 14: 317-324.
34. Del Bigio MR, da Silva MC, Drake JM, Tour UI. Acute and chronic cerebral white matter damage in neonatal hydrocephalus. Can J Neurol Sci 1994; 21: 299-305.
35. Del Bigio MR, Kanfer JN, Zhang YW. Myelination delay in the cerebral white matter of immature rats with kaolin-induced hydrocephalus is reversible. J Neuropathol Exp Neurol 1997; 56: 1053-1066.
36. Del Bigio MR, Wilson MJ, Enno T. Chronic hydrocephalus in rats and humans: white matter loss and behaviour changes. Ann Neurol 2003; 53: 337-346.
37. Del Bigio MR, Zhang YW. Cell death, axonal damage, and cell birth in the immature rat brain following induction of hydrocephalus. Exp Neurol 1998; 154: 157-169.
38. Del Bigio MR. Neuropathological changes caused by hydrocephalus. Acta Neuropathol 1993; 85: 573-585.
39. Del Bigio MR. Calcium-mediated proteolytic damage in white matter of hydrocephalic rats? J Neuropathol Exp Neurol 2000; 59: 946-954.
40. Del Bigio, M, Bruni JE, Fewer HD. Human neonatal hydrocephalus. An electron microscopic study of the periventricular tissue. J Neurosurg 1985; 63: 56-63.
41. Dickson DW, Huroupian DS, Thal LJ, Lantos G. Gliomatosis cerebri presenting with hydrocephalus and dementia. Am J Neuroradiol 1988; 9: 200-202.
42. Diggs J, Price AC, Burt AM, Flow WJ, McKanna JA, Novak GR, James AE Jr. Early changes in experimental hydrocephalus. Invest Radiol 1986; 21: 118-121.
43. Ding Y, McAllister JP 2nd, Yao B, Yan N, Canady AI. Axonal damage associated with enlargement of ventricles during hydrocephalus: a silver impregnation study. Neurol Res 2001; 23: 581-587.
44. Ding Y, McAllister JP 2nd, Yao B, Yan N, Canady AI. Neuron tolerance during hydrocephalus. Neuroscience 2001; 106: 659-667.
45. Foncin JF, Redondo A. Lebeau J. Le cortex cerebral des malades atteints d’hydrocephalie a pression normale. Etude ultrastructurale. Acta Neuropathol (Berlin) 1976; 34: 353-357.
46. Glees P, Hasan M, Voth D, Schwarz M. Fine structural features of the cerebral microvaculature in hydrocephalic human infants: correlated clinical observations. Neurosurg Rev 1989; 12: 315-321.
47. Glees P, Hasan M. Ultrastructure of human cerebral macroglia and microglia: naturing and hydrocephalic frontal cortex. Neurosurg Rev 1990; 13: 231-242.
48. Glees P, Voth D. Clinical and ultrastructural observations of maturing human frontal cortex. Part I. Biopsy material of hydrocephalic infants. Neurosurg Rev 1988; 11: 273-278.
49. Gopinath G, Bhatia R, Gopinath, PG. Ultrastructural observations in experimental hydrocephalus in the rabbit. J Neural Sci 1979; 43: 333-344.
50. Goto J, Tezuka T, Nakazawa T, Sagara H, Yamamoto T. Loss of Finn tyrosine kinasa on the C57TB/6 genetic bacground causes hydrocephalus with defects in ologodendrocyte development. Mol Cell Neurosci 2008; 38: 203-212.
51. Harris NG, Plant HD, Inglis BA, Briggs RW, Jones HC. Neurochemical changes in the cerebral cortex of treated and untreated hydrocephalic rat pups quantified with in vitro 1H-NMR spectroscopy. J Neurochem 1997; 68: 305-312.
52. Hasan M, Glees P. The fine structure of human cerebral perivascular pericytes and juxtavascular phagocytes: Their possible role in hydrocephalic edema resolution. J Hirnforsch 1990; 31: 237-249.
53. Humphreys P, Muzumdar, DP, Sly LE, Michaud J. Focal cerebral mantle disruption in fetal hydrocephalus. Pediatr Neurol 2007; 36: 236-243.
54. James AE, Flor WJ, Novack GR, Ribas JL, Parker JL. Sickel WL. The ultrastructural basis of periventricular edema: preliminary studies. Radiology 1980; 135: 747-750.
55. Jones HC, Anderson RW. Progressive changes in cortical water and electrolyte content at three stages of rat infantile hydrocephalus and the effect of shunt treatment. Exp Neurol 1998; 154: 126-136.
56. Jones HC, Bucknall, RM, Harris NG. The cerebral cortex in congenital hydrocephalus in the HTx-rat: a quantitative light microscope study. Acta Neuropathol (Berl) 1991; 82: 217-224.
57. Jones HC, Dack S, Ellis C. Morphological aspects of the development of hydrocephalus in a mouse mutant (SUMS/NP). Acta Neuropathol 1987; 72: 268-276.
58. Jones HC, Harris NG, Rocca JR, Andersohn RW. Progressive tissue injury in infantile hydrocephalus and prevention/reversal with shunt treatment. Neurol Res 2000; 21: 89-86.
59. Jones HC, Harris NG, Rocca JR, Anderson RW. Progressive changes in cortical metabolites at three stage of infantile hydrocephalus studied in vitro NMR spectroscopy. J Neurotrauma 1997; 14: 587-602.
60. Khan OH, Enno TL, Del Bigio MR. Brain damage in neonatal rats following kaolin induction of hydrocephalus. Exp Neurol 2006; 200: 311-320.
61. Klinge P, Mühlendyck A, Lee S, Lüdemann W, Groos S, Samii M, Brinker T. Temporal and regional profile of neuronal and glial cellular injury after induction of kaolin hydrocephalus. Acta Neurochir Suppl 2002; 81: 275-277.
62. Kriebel RM, Shab AB, McAllister JP 2nd. The microstructure of cortical neuropil before and after decompression in experimental infantile hydrocephalus. Exp Neurol 1993; 119: 89-98.
63. Lawson RB, Raimondi JA. Hydrocephalus-3, a murine mutant. I. Alterations in fine structure of choroid plexus and ependyma. Surg Neurol 1973; 1: 115-128.
64. Lovely TJ, Mc Allister JP, Miller DW, Lamperti AA, Wolfson BJ. Effects of hydrocephalus and surgical decompression in cortical norepinephrine levels in neonatal cats. Neurosurg 1989; 24: 43-52.
65. Madhavi C, Jacob M. Light and electron microscopic structure of choroids plexus in hydrocephalic guinea pig. Indian J Med Res 1995; 101: 217-224.
66. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 1995; 146: 3-15.
67. Mangano FT, McAllister JP 2nd, Jones HC, Jhonson MJ, Kriebel RM. The microglial response to progressive hydrocephalus in midel of inherited aqueductal stenosis. Neurol Res 1998; 20: 697-704.
68. Martin LJ. Neuronal cell death in nervous system development, disease, and injury. Int J Mol Med 2001; 7: 455-478.
69. McAllister JP, Maugans TA, Shah MV, Truex RC Jr. Neuronal effects of experimentally induced hydrocephalus in newborn rats. J Neurosurg 1985; 63: 776-783.
70. McLone DG, Bondareff W, Raimondi AJ. Hydrocephalus-3, a murine mutant. II. Changes in the brain extracellular space. Surg Neurol 1973; 1: 233-242.
71. McLone DG, Bondareff W, Raimondi AJ. Brain edema in the hydrocephalic hy-3 mouse: submicroscopic morphology. J Neuropathol Exp Neurol 1971; 30: 627-637.
72. Milhorat TH, Hammock MK. Isotope ventriculography. Arch Neurol 1971; 5: 1-8.
73. Miller JM, McAllister JP 2nd. Reduction of astrogliosis and microgliosis by cerebrospinal shunting in experimental hydrocephalus. Cerebrospinal Fluid Res 2007; 4: 5 (Abstract).
74. Miyaoka M, Ito M, Wada M, Sato K, Ishii S. Measurement of local cerebral utilization before and after V-P shunt in congenital hydrocephalus in rats. Metab Brain Dis 1988; 3: 125-132.
75. Miyazawa T, Sato K. Hippocampal synaptogenesis in hydrocephalic HTx- rats using a monoclonal anti-synaptic vesicle protein antibody. Brain Dev 1994; 16: 432-436.
76. Miyazawa Y, Sato K. Learning disability and impairment of synaptogenesis in HTx-rats with arrested shunt-dependent hydrocephalus. Childs Nerv Syst 1991; 7: 121-128.
77. Mori F, Tanji, K, Yoshida Y, Wakabayashi K. Thalamic retrograde degeneration in the congenitally hydrocephalic rat attributable to apoptotic cell death. Neuropathology 2002; 22: 186-193.
78. Mori K, Raimondi AJ. Submicroscopic changes in the periventricular white matter of hydrocephalic Ch mouse. Arch Jap Chirurg 1975; 4: 159-168.
79. Nakada J, Oka N, Nagahori T, Endo S, Takaku A. Changes in the cerebral vascular bed in experimental hydrocephalus: an angio-architectural and histological study. Acta Neurochir 1992; 114: 43-50.
80. Nakagawa J, Cervós-Navarro J, Artigas J. A possible paracellular route for the resolution of hydrocephalic edema. Acta Neuropathol (Berl) 1984; 64: 122-128.
81. Naruse I, Keino H. Apoptosis in the developing CNS. Prog Neurobiol 1995; 47: 135-155.
82. Nonaka Y, Miyajima M, Ogino I, Nakajima M, Arai H. Analysis of neuronal cell death in the cerebral cortex of H-Tx rats with compensated hydrocephalus. J Neurosurg Pediatrics 2008; 1: 68-74.
83. Nyber-Hansen R, Torvick A, Bhatia R. On the pathology of experimental hydrocephalus. Brain Res 1975; 95: 343-350.
84. Ogata J, Hochwald GM, Cravioto H, Ransohoff J. On the pathology of experimental hydrocephalus. Brain Res 1972; 31: 454-463.
85. Oka N, Nakada J, Endo S, Takaku A. Angioarchitecture in experimental hydrocephalus. Pedriat Neurosci 1985; 12: 294-299.
86. Okuyama T, Hashi K, Sasaki S, Sudo K, Kurokawa Y. Changes in the cerebral microvasculature in congenital of the inbred rats LEW/Jms: Light and electron microscopic examination. Surg Neurol 1987; 27: 338-342.
87. Perez-Figares JM, Jiménez AJ, Perez-Martín M, Fernández-Llebrez P, Cifuentes M, Riera P, Rodrigues, S, Rodrigues EM. Spontaneous congenital hydrocephalus in the mutant mouse hyh. Changes in the ventricular system and the subcommissural organ. J Neurophathol Exp Neurol 1998; 57: 188-202.
88. Portera-Cailliau C, Price DL, Martin LJ. Excitotoxic neuronal death in the immature brain is an apoptosis-necrosis morphological continuum. J Comp Neurol 1997; 378: 70-87.
89. Price DL, James E, Sperber E, Strecker EP. Communicating hydrocephalus. Arch Neurol 1976; 33: 15-24.
90. Richards HK, Bucknall RM, Jones HC, Pickard JD. The uptake of (14C) deoxyglucose into brain of young rats with inherited hydrocephalus. Exp Neurol 1989; 103: 194-198.
91. Richardson RR. Congenital genetic murine (ch) hydrocephalus. A structural model of cellular dysplasia and isorganization with the molecular locus of deficient proteoglycan synthesis. Childs Nerv Syst 1985; 1: 87-99.
92. Sada Y, Morkki T, Kuwahara S, Yamane T, Hara H. Immunohistochemical study on blood-brain barrier in congenitally hydrocephalic HTx-rat brain. Zentralbl Pathol 1994; 140: 289-298.
93. Shimizu A, Koto M. Ultrastructure and movement of the ependymal and tracheal cilia in congenitally hydrocephalic WIC-Hyd rats. Childs Nerv Syst 1992; 8: 25-32.
94. Shoesmith CL, Buist R, Del Bigio MR. Magnetic resonance imaging study of extracellular fluid tracer movement in brains of immature rats with hydrocephalus. Neurol Res 2000; 22: 111-116.
95. Shuman CS, Bryan JH. Comparative quantitative ultrastructural studies of the choroidal epithelium of hydrocephalic (ppy/hpy) and normal mice, and the effect of stress induced by water deprivation. Anat Anz 1991; 173: 33-44.
96. Socci DJ, Bjugstad KB, Jones HC, Patisapu JV, Arendash GW. Evidence that oxidative stress is associated with the pathophysiology of inherited hydrocephalus in the HTx-rat model. Exp Neurol 1999; 155: 109-117.
97. Struck G, Hemmer R. Elektronenmikroskopische Untersuchungen der menschlichen Hirnrinde beim Hydrocephalus. Arch Psych Z Neurol 1964; 206: 17-27.
98. Suda K, Sato K, Miyazawa T, Arai H. Changes of synapse-related proteins (SVP-38 and drebrins) during development of brain in congenitally hydrocephalic HTx-rats with and without early placement of ventriculoperitoneal shunt. Pediatr Neurosurg 1994; 20: 50-56.
99. Suda K, Sato K, Takeda N, Miyazawa T, Arai H. Early ventriculoperitoneal shunt-effects on learning ability and synaptogenesis of the brain in congenitally hydrocephalic HTx-rats. Childs Nerv Syst 1994; 10: 19-23.
100. Surchev L, Dontchev V, Ichev K, Dolapchieva S, Boshilova-Pastirova A, Vankova M, Kirazov E, Vassileva E, Vendov L. Changes in the neuronal plasma membrane during synaptogenesis. Cell Mol Biol (Noisy Le Grand) 1995; 41: 1073-1080.
101. Suzuki F, Handa J, Maeda T. Effects of congenital hydrocephalus on serotonergic input and barrel cytoarchitecture in the developing somatosensory cortex of rats. Childs Nerv Syst 1992; 8: 18-24.
102. Takei F, Shapiro K, Hirano A, Kohn I. Influence of the rate of ventricular enlargement on the ultrastructural morphology of the white matter in experimental hydrocephalus. Neurosurgery 1987; 21: 645-650.
103. Takeuchi IK, Murakami U. Two types of congenital hydrocephalus induced in rats by X-irradiation in utero: electron microscopic study on the telencephalic wall. J Anat 1979; 128: 693-708.
104. Torvik A, Stenwig AE. The pathology of experimental obstructive hydrocephalus. Electron microscopic observations. Acta Neuropathol 1977; 38: 21-26.
105. Trump BF, Berezesky IK, Chang SH, Phelps PC. The pathways of cell death: oncosis, apoptosis, and necrosis. Toxicol Pathol 1997; 25: 82-88.
106. Tsubokawa T, Katayama Y, Kawamata T. Impaired hippocampal plasticity in experimental chronic hydrocephalus. Brain Injury 1988; 2: 19-30.
107. Voelz K, Kondziella D, von Rautenfeld DB, Brinker T, Lüdeman WA. Ferritin tracer study of compensatory spinal CSF outflow pathways in kaolin-induced hydrocephalus. Acta Neuropathol (Berl) 2007; 113: 569-575.
108. Volpe JJ. Intraventricular hemorrhage and brain injury in the premature infant. Neuropathology and pathogenesis. Clin Perinatol 1989; 16: 361-386.
109. Weller RO, Mitchell J, Griffin RL, Gardner MJ. The effects of hydrocephalus upon the developing brain. Histological and quantitative studies of the ependyma and subependyma in hydrocephalic rats. J Neurol Sci 1978; 36: 383-402.
110. Weller RO, Mitchell J, Griffin RL. Cerebral ventriculitis in the hydrocephalic mouse: a histological and scanning electron microscope study. Acta Neuropathol (Suppl) 1981; 7: 160-161.
111. Weller RO, Shulman K. Infantile hydrocephalus: clinical, histological, and ultrastructural study of brain damage. J Neurosurg 1972; 36: 255-265.
112. Weller RO, Wisniesky H, Shulman K, Terry RD. Experimental hydrocephalus in young dogs: histological and ultrastructural study of brain tissue damage. J Neuropathol Exp Neurol 1971; 30: 613-626.
113. Wozniak M, McLone DG, Raimondi AJ. Micro- and macrovascular changes as the direct cause of parenchymal destruction in congenital murine hydrocephalus. J Neurosurg 1975; 43: 535-545.
114. Yoshida Y, Koya G, Tamayama K, Kumanishi T, Abe S. Histopathology of cystic cavities in the cerebral white matter of HTx rats with inherited hydrocephalus. Neurol Med Chir 1990; 30: 229-233.
