The Ventriculus Terminalis and Filum Terminale of the Human Spinal Cord BEN H. CHOI, MD, PHD, RONALD C. KIM, MD, MICHIYASU SUZUKI, MD,* AND WONSICK CHOE, MD Serial sections of the conus medullaris and the filum terminale of 23 randomly selected human spinal cords were studied by light and electron microscopy, and following immunoperoxidase staining for glial fihrillary acidic protein (GFAP), vimentin, neuron-specific enolase (NSE), amyloid fi protein, and S-100 protein. The intradural portion of the filum contains bundles of GFAP-positive glial fibers, scattered silver- and NSE-positive neurons, segments of peripheral nerve, blood vessels, fibrous connective tissue, and fat. Glial cell clusters varying from five to 100 cell layers thick at times constitute the bulk of the filum. The periependymal glial cells possess moderate amounts of eosinophilic cytoplasm and relatively uniform round to ovoid nuclei containing evenly distributed chromatin. They are distributed diffusely with no specific pattern of organization, although some of them showed a tendency to form acinar structures. A minority of the glial cells showed GFAP immunoreactivity, and some were immunoreactive for vimentin. Electron microscopy demonstrated the presence of periependymal cells showing cilia, microvilli, and the formation of intercellularjunctional complexes, as well as cells containing bundles of glial filaments within the cytoplasm. Degenerated NSE-positive neurons and degenerated neurites resembling neuritic plaques were also demonstrated. However, immunoperoxidase staining for amyloid fi protein was negative in these structures. Thus, the filum terminale is endowed with an abundance of glial cells and neurons and is not simply a fibrovascular tag. Periependymal glial cells in the filum terminale should not be mistaken for neoplasm. The presence of neuropil with profuse astroglial and neuronal components within the filum terminale suggests a possible functional role for these structures. HUM PATHOL 23:916-920. Copyright 0 1992 by W.B. Saunders Company
The tail end of the spinal cord is generally neglected during routine autopsy examination. Therefore, accurate information concerning normal structural details of the filum terminale or the ventriculus terminalis is generally not available. The ependyma-lined central canal of the filum terminale forms a cystic dilatation at the lower end of the conus medullaris to become the ventriculus terminalis of the spinal cord. It may disappear and reappear at a lower level, and often is surrounded by large clusters of glial cells. The ventriculus terminalis is present in the spinal cord of all adults and From the Division of Neuropatholob~,Department of Pathology, University of California, Irvine, CA. Accepted for publication Octohel 1.5, 1991. *I-‘rr.wxtadcbr.ts: Departnwnt of Ncwrosurgery, Tohoku University, Sendai, Japan. Supported in pal-t by National Institutes of Health grant no. ES 02928 to Dr Choi. Kq ruorfl.~ filurn terrninale, ventl-ic-ulus trrnlinalis, spinal cord, glial c-ells. Address correspondence and reprint requests to Ben H. Choi, MD, PhD, Department of Pathology, University of California, Irvine, CA 92717. Copyright 0 1992 hy W.B. Saunders Contpany 0046-8177/92/2308-0014$5.00/O
children. For reasons as yet unknown, this region is frequently the seat of both glial and nonglial neoplasms.‘,’ Furthermore, difficulties may arise when one is confronted with a cellular lesion originating from this area without a thorough knowledge of the normal histology of this region. Although the filum terminale was at one time thought to be composed simply of a vascular attachment of the spinal cord to the coccyx,” histologic studies later demonstrated the presence of neural tissue within it.“.” The filum terminale extends from the lower end of the conus medullaris toward the coccyx for approximately 15 cm in its intradural portion. Although embryologic studies regarding the formation of the filum terminale in humans were described in detail by Kunitomo” and Streeter,” the normal histology of this region was detailed only in brief descriptions by Harmeier” and Tarlov.” For this reason, we undertook morphologic and immunocytochemical studies of serially sectioned COITUS medullaris and filum terminale of 20 randomly selected human adult spinal cords with no known spinal cord disease. Contrary to general assumptions, this structure is not simply a fibrovascular tag but is endowed with an abundance of cellular and extracellular elements that may play significant roles in spinal cord pathophysiology. MATERIALS
AND METHODS
The filmn terminale from each of 23 randomly selected individuals, fixed in formalin and embedded in paraffin, was examined. As shown in Table 1, the majority of cases came from elderly adults 50 years or older, but there were also two cases from 15- and 1 &year-old patients. Serial longitudinal sections extending from the cmus medullaris to the end of the intradural portion of the filum terminale were subjected Luxol fast blue-cresyl violet, Bielto hematoxylin-eosin, schowsky, and periodic acid-Schiff‘stains. In selected samples, congo red staining was carried out. Immurloperoxidase staining for glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), amyloid /3 protein, factor VIII, vimentin, keratin, and S-100 protein was also applied. In addition, samples fixed in Karnovsky’s fluid were embedded in epon and thin sections of selected samples were examined with a Philips EM 400 electron microscope.
RESULTS The
ventriculus
terminalis
is formed
by cystic dis-
tension of the central canal at the lower end of medullaris. The ependyma-lined central canal appear and reappear in the lower portions lum terminale. Microscopically, the filum 916
the conus may disof the fiterminale
FILUM TERMINALE
TABLE 1.
OF SPINAL CORD (Choi et al)
Age and Sex of the Patients
Patient No.
Case No.
Sex
Age (yr)
1 2 3 4 5 6 7 8 9 10 I1 12 13 14 15 16 17 18 19 20 21 23
147-85 157-85 195-95 217-85 71-86 228-85 204-85 273-85 275-85 281-85 33-86 54-86 61-86 70-86 71-86 73-86 126-86 133-86 175-86 218-86 175-87 141-87 5862-87
M M M M M M M M F M M M M M M F M M M M M F M
77 65 56 68 69 71 71 81 85 50 40 58 61 62 69 55 49 69 56 72 70 18 15
29
its course contained longitudinally disposed argyrophilic neuritic processes and GFAP-positive astroglial processes. Although the cellular elements were localized mostly around the central canal near the center of the filum, there was no distinct histologic pattern to indicate organization into either grey or white matter. Thick-walled blood vessels were noted along the outer surface of the filum. Endothelial cells showed strong immunoreactivity for factor VIII. Occasional clusters of NSE-positive ganglion cells and peripheral nerve fibers showing immunoreactivity for S-100 protein also were noted in the outer portions of the filum. The most impressive and significant microscopic finding was the presence of clusters of glial cells varying from five to more than 100 cell layers thick (Figs 1 and 2). In many samples the bulk of the filum was almost entirely composed of clusters of glial cells, often extending out toward the surface of the filum. These relatively uniform cells bore round to ovoid dark nuclei measuring 7 to 15 pm in diameter. The nuclear chromatin was evenly distributed and no mitotic figures were noted. Cytoplasm was eosinophilic and often relatively abundant (Fig 2). In some areas periependymal cells appeared to form acinar structures (Fig 2). Occasionally, scattered corpora amylacea were also noted among irregularly disposed cells. As shown in Fig 3, some of the periependymal cells near the central canal were strongly positive for GFAP. Many of them extended longitudinally oriented, GFAP-positive processes (Fig 3b). Scattered ependymal cells also exhibited GFAP immunoreactivity within their cytoplasm and processes (Fig 3a). However, most of the irregularly disposed periependymal cells were negative for GFAP, although some of them were strongly immunoreactive for GFAP in the cell bodies and processes (Fig 3~). Bielschowsky staining demonstrated the presence of scattered silver-positive throughout
917
plaques composed of degenerating neurites and neuronal cell bodies (Fig 4). These plaques resembled those observed in Alzheimer’s disease. The majority of patients over the age of 50 years showed the presence of these structures in some parts of the filum. However, the filum terminale obtained from the 15-year-old boy and the 18-year-old woman only showed thickened neurites; plaque-like structures were not observed. Both NSEand silver-positive neuronal cell bodies showing varying degrees of degeneration were also present among clusters of glial cells (Fig 4). Immunoperoxidase staining using polyclonal antibodies against amyloid /3protein was negative in these structures. Congo red staining demonstrated a positive reaction in blood vessel walls in some cases, but the plaque-like structures were negative for amyloid. In many areas degeneration characterized by vacuolization and mucoid change was noted among cellular and extracellular elements. In contrast to other regions of the central nervous system, the ependyma-lined central canal of the filum often was apposed directly to the underlying fibrous connective tissue. The fibrous tissue was frequently hyalinized. Electron microscopy demonstrated scattered periependymal cells showing the presence of cilia (Fig 5), microvilli (Fig 6), and junctional complexes (Figs 5 and 6). Astrocytes filled with bundles of intermediate filaments within the cytoplasm and processes were also numerous (Fig 7). Degenerating neurites and neuronal cell bodies with clusters of dense bodies were also frequently identified (Fig 8). However, structures resembling paired helical filaments were not demonstrated. Figure 9 shows the gross appearance of the ventriculus terminalis and filum terminale from an 18-year-old woman. DISCUSSION In humans the ventriculus terminalis grows and enlarges at the expense of the grey substance at the upper end of the cavity as the tail end of the spinal cord is being absorbed.” The absorption of the tail is completed when the human embryo reaches a length of 30 mm in crown-rump length. At this stage the coccygeal end of the spinal cord undergoes marked regressive changes with grossly evident cavity formation. There is no further regression beyond the 30-mm stage, but growth and development thereafter accompany the general growth of the central nervous system.” The ventriculus does not attain its maximal dimensions until after the first 2 years of postnatal life. Thus, it is not simply a dilated central canal but a cavity at the lower end of the conus medullaris that develops and grows along with the rest of the central nervous system. Occasionally, a remnant of the ventriculus may form a gelatinous mass on top of the filum terminale that may be mistaken for a cystic tumor.’ The physiologic role of the ventriculus terminalis is not clear; nevertheless, it is found in the conus medullaris and filum terminale of all children and adults, including human fetuses of more than 22 mm in crownrump length.’ It has been speculated by some investi-
FIGURE 1. A large cluster of periependymal glial cells. An arrow points to the ependymal lining of the ventriculus terminalis. The cells are relatively uniform, measuring from 10 to 15 pm in diameter, and contain round to ovoid nuclei with evenly distributed chromatin. No mitotic figures are noted. The eosinophilic cytoplasm is scanty to moderate. The majority of the glial cells were negative for either GFAP or NSE (72~year-old man). (Hematoxylin-eosin stain; magnification X86.)
FIGURE 3. lmmunoperoxidase staining for GFAP. (a) Note GFAP-positive ependymal and periependymal cells. Arrows point to GFAP immunoreactivity within the cytoplasmic processes of ependymal cells lining the central canal of the tilum (18.year-old woman). (Hematoxylin counterstain; magniftcation X430.) (b) Note the numerous GFAP-positive cells extendinglongitudinalprocesses(arrows).AlsonotethepresenceofGFAPnegative cells (arrowheads) (15-year-old boy). (Hematoxylin counterstain; magnification X430.) (c) The majority of the periependymal cells are not immunoreactive for GFAP (‘). There were also occasional astrocytes showing GFAP immunoreactivity within the cytoplasm and processes (arrow) (62.year-old man). (Hematoxylin counterstain; magnification X215.)
FIGURE 2. Higher magnification of periependymal glial cells showing a cluster of cells (arrow) lined up to suggest the formation of an acinar structure. All contain moderate amounts of eosinophilic cytoplasm (arrowhead). Only a few scattered cells were GFAP positive (not shown) (15-year-old boy). (Hematoxylin-eosin stain: magnification X430.)
FIGURE 4. Bielschowsky stain showing degenerated neurites and neuritic plaque-like structures. (a and b) Photomicrographs showing thickened and degenerated neurons and neurites forming plaque-like structures (empty arrows) resembling those seen in Alzheimer’s disease (72.yearold man). (Magnification X215.) (c) Higher magnification showing an examDIe of the neuritic Dlaaue-like structures CemDtv arrow) within the ftlum terminale of an 83-year-old woman. Note thickening and fragmentation of silver-positive neuronal cell bodies and neurites (arrowhead) (56~year-old man). (Bielschowsky stain; magnification X860.) (d) Higher magnification to show neuritic plaque-like structure (empty arrow) formed by degenerating neurons and neurites within the ftlum terminale (55 year-old woman). (Magnification X860.) (e) Higher magnitication of neuritic plaque-like structure formed by clusters of thickened and degenerated neurites (arrow) and cell bodies (62.year-old man). (Magnification X860.)
FILUM TERMINALE
OF SPINAL CORD (Choi et al)
FIGURE 5. Electron micrograph of a periependymal glial cell showing the presence of cilium (arrow) and junctional complex formation between the cells (arrowhead). A small arrow points to anchoring filaments for the cilium (40~year-old man.) (Magnification X 15,400.)
FIGURE 7. Electron micrograph of periependymal glial cell showing bundles of glial filaments (arrows) within the cytoplasm and processes. Note also the presence of glycogen granules within the cytoplasm (81~year-old man.) N, nucleus. (Magnification x20,000.)
that the ventriculus terminalis is where Reissner’s fiber (RF) terminates with the accumulation of neurosecretory substance.‘-” Published studies suggest that RF, a thread-like structure extending from the lower end of the subcommissural organ of the epithalamus to the ventriculus terminalis of the spinal cord of all but a few vertebrates,’ is a secretory product of the subcommissural organ.“-” It also has been suggested that RF may pass through gaps in the ependymal lining of the filum terminale to reach the periependymal loose tissue and possibly the subarachnoid space.” Suggestions regarding the physiologic role of RF have included (1) a mechanoreceptor function for the circumventricular organs and the choroid plexus to indicate variations in cerebrospinal fluid pressure,‘” (2) a vehicle by which the subcommissural organ can exert one of its functions, such as regulation of the quality of the cerebrospinal fluid,17 and (3) a source for an endogenous peptide.” One of the main objectives of this report is to emphasize the fact that the abundance of glial cells in the conus medullaris and filum terminale may be a feature characteristic of the normal filum and that it should not be confused with the presence of a true neoplasm in this region. Although these cells are diffusely dispersed with no specific pattern, some showed a tendency to form acinar structures demonstrating a tendency toward ependymal differentiation. Electron microscopy clearly
showed the presence of many cells with ependymal differentiation containing cilia, microvilli, and intercellular junctional complexes. However, there were many other cells with immunocytochemical and ultrastructural characteristics indicative of astrocytic differentiation, including the presence of bundles of glial filaments and immunoreactivity for GFAP. An interesting finding was the presence of degenerated neurites and neuronal cell bodies forming neuritic plaque-like structures resembling those observed in Alzheimer’s disease in many of our cases. We have carried out extensive immunocytochemical studies using polyclonal antisera for amyloid P protein, but failed to show positive staining in these structures. Congo red staining was also negative. Electron microscopy failed to show the presence of the paired helical filaments characteristic of neurofibrillary tangles in Alzheimer’s disease. It appears that the plaque-like structures simply represent an interesting degenerative feature of the filum terminale, particularly in older individuals. None of the material studied came from patients suffering from Alzheimer’s disease. The filum terminale in the frog also contains astroglial cells as the dominant cell type.‘” It is interesting to note in this context that for many years investigators used the filum terminale of the frog as a source of astroglial preparations to study the transport of ions and amino acids within glial cells.20~21As shown in Fig 3a, some of the ependymal cells of the central canal of the filum also showed immunoreactivity for GFAP within
gators
FIGURE 6. Electron micrograph of a periependymal glial cell showing the presence of microvilli (arrow) and junctional complex formation (arrow head) (65year-old man.) (Magnification x 15.400.)
FIGURE 8. Electron micrograph showing clusters of degenerating neuronal processes (68~year-old man). (Magnification x20.000.)
HUMAN PATHOLOGY
Volume 23, No. 8 (August
FIGURE 9. Gross photograph of the Mum terminale (empty arrow) with an engorged blood vessel running along the lateral surface. The small arrow points to the ventriculus terminalis at the lower end of the conus medullaris of the spinal cord (18year-old woman).
the cytoplasm and periependymal glial processes. Viewed in the context of the radial glial origin of macroglial cell types, includin 5 ast,rocytes, oligodendrocytes, and ependymal cells, 22-2J it 1s not surprising to find a mixture of these cell types and the expression of transitional features among the periependymal glial cells of the filum terminale. Ependymomas account for the majority of gliomas arising in the region of the conus medullaris and filum terminale, and myxopa illary ependymomas occur exclusively in this region. 1X826 The microscopic components of myxopapillary ependymomas closely resemble those seen in the normal filum terminale. They are frequently highly vascularized and show myxomatous degeneration of the stroma. Whether the presence of a large number of glial cells within the filum terminale plays a role in the genesis of neoplasms in this region remains unknown. However, the presence of neuropil with its neuronal and glial elements within the filum terminale, particularly the profuse astroglial components, suggests a possible functional role for these constituents in spinal cord pathophysiology.
Jann
Arkvmwledgvvuxt. The authors thank Teresa Espinosa, Geddes, and Paul Amodei for technical support.
REFERENCES 1. Sonnehd PI., Scheithauer
BW, Onofrio BM: Myxopapillary ependymoma. A clinicopathologic and immunocytochemical study of77 cases. Cancer 56:883-893, 1985
1992)
2. Specht CS, Smith TW, DeGirolami L’, cl al: Myxcq~apillar~ ependymoma of the filum terminale. A light and electron microscopic study. Cancer 58:310-317, 1986 ‘3. Tarlov IM: Structure of the filum terminale. Arch Neural Pspchiatry 40:1-IT. 1938 4. Harmeier J: The normal histology of the intradural filum terminate. .4rch Neural Psychiatry 29:308-3 16, 1933 5. Kunitomo K: Development and Reduction of the Tail and of the Caudal End of the Spinal Cord. Contribution to Embryology. Carnegie Institution of Washington 8: 16 l-l 98, 19 18 6. Streeter GL: Factors involved in the formation of the filum terminale. Am J Anat 25:1-12. 1919 7. Kernohan JW: The ventriculus terminalis: Its growth and development. J Comp Neurol 38: 107-l 25, 1924 8. Wislocki GB, Leduc EH, Mitchell AJ: On the ending of Reissner’s fiber in the filum terminal of the spinal cord. J Comp Neural 104:493-517, 1956 9. Tulsi RS: Reissner’s fiber in the sacral cord and filum terminale of the possum Tn’cho.rurus vulpeculu: A light, scanning, and electron microscopic study. J Comp Neural 21 1: 1 I-20, 1982 10. Rodriguez S, Hein S, Yulis R, et al: Reissner’s fiber and the wall of the central canal in the lumbo-sacral region of the bovine spinal cord. Cell Tissue Res 240:649-662, 1985 1 I. Diederen JHB: Influence of light and darkness on the subcommissural organ of Ram hmpomriu L. A cytological and autoradiographical study. 2 Zellforsch 111:379-403, 1970 12. Sterba G, Ermisch A, Freyer K, et al: Incorporation of sulphur”” into the subcommissurdl organ and Reissner’s fibre. Nature 216:514-517, 1967 13. Hofer H, Meinel W, Erhardt H: Electron microscopic study on the origin and formation of Reissner’s fibre in the subcommissural organ of Cebus apelh (primates, Platyrrhini). Cell Tissue Res 205:295301, 1980 14. Sterba G, Kiessig C, Naumann W, et al: The secretion of the subcommissurdl organ. A comparative immunocytochemical investigation. Cell Tissue Res 226:427-439, 1982 15. Rodriguez EM. Oksche A, Hein S, et al: Comparative immunocytochemical study of the subcommissural organs. Cell Tissue Res 237:427-441, 1984 16. Woollam DHM, Collis P: Reissner’s fibre in the rat: A scanning and transmission electron microscope study. J Anat I3 1: I35143, 1980 17. Weindle A, Schinko 1: Evidence by scanning electron microscopy foi- ependymdl secretion into the cerebrospinal fluid and formation of Reissner’s fibre by the subcommissural organ. Brain Res 88:319-324, 1975 18. Sterba G, Klein W, Naumann W, et al: lmmunocytochentic~tl investigation of the subcommissural organ in the rat. Cell Tissue Res 218:659-662, 1981 19. Chesler M, Nicholson C: Organization of the filum terminale in the frog. J Comp Neural 239:431-444, 1985 20. Glusman S, Oacgeci N, Gonzalez R, et al: The filum terminale of the frog spinal cord, a non transformed glial preparation. 1. Morphology and uptake of y-aminobutyrir acid. Brain Res 172:259-276, 1979 2 1. Ritchie T, Packev DJ, Trachtenberg MC, et al: K+ induced ion and water movements m the frog spinal cord and filum terminale. Exp Neural 71:356-369, 1981 22. Choi BH: Radial glia of developing human fetal spinal cord: Golgi, immunohistochemical and electron microscopic study. Dev Brain Res l:249-267, 1981 23. Choi BH, Kim RC, Lapham LW: Do radial glia give rise to both astroglial and oligodendroglial cells? Dev Brain Res 8: 11 O-130, 1983 24. Choi BH, Kim RC: Expression of glial fibrillaty acidic protein in immature oligodendroglia. Science 223:407-409. 1984 25. Choi BH, Kim RC: Expression of glial fibrillary acidic pl-otein by immature oligodendroglia and its implications. J Neuroimmunc,1 8:215-2:35, 1985 26. Kernohan JW: Primary tumors of the spinal cord and intrddurdl filun~ termmale, in Penfield W (ed): Cytology and Cellulat Pathology of the Nervous System, vol 3. New York, NY, Paul B. Hoeber, 1932, pp 993-1025
The tail end of the spinal cord is generally neglected during routine autopsy examination. Therefore, accurate information concerning normal structural details of the filum terminale or the ventriculus terminalis is generally not available. The ependyma-lined central canal of the filum terminale forms a cystic dilatation at the lower end of the conus medullaris to become the ventriculus terminalis of the spinal cord. It may disappear and reappear at a lower level, and often is surrounded by large clusters of glial cells. The ventriculus terminalis is present in the spinal cord of all adults and From the Division of Neuropatholob~,Department of Pathology, University of California, Irvine, CA. Accepted for publication Octohel 1.5, 1991. *I-‘rr.wxtadcbr.ts: Departnwnt of Ncwrosurgery, Tohoku University, Sendai, Japan. Supported in pal-t by National Institutes of Health grant no. ES 02928 to Dr Choi. Kq ruorfl.~ filurn terrninale, ventl-ic-ulus trrnlinalis, spinal cord, glial c-ells. Address correspondence and reprint requests to Ben H. Choi, MD, PhD, Department of Pathology, University of California, Irvine, CA 92717. Copyright 0 1992 hy W.B. Saunders Contpany 0046-8177/92/2308-0014$5.00/O
children. For reasons as yet unknown, this region is frequently the seat of both glial and nonglial neoplasms.‘,’ Furthermore, difficulties may arise when one is confronted with a cellular lesion originating from this area without a thorough knowledge of the normal histology of this region. Although the filum terminale was at one time thought to be composed simply of a vascular attachment of the spinal cord to the coccyx,” histologic studies later demonstrated the presence of neural tissue within it.“.” The filum terminale extends from the lower end of the conus medullaris toward the coccyx for approximately 15 cm in its intradural portion. Although embryologic studies regarding the formation of the filum terminale in humans were described in detail by Kunitomo” and Streeter,” the normal histology of this region was detailed only in brief descriptions by Harmeier” and Tarlov.” For this reason, we undertook morphologic and immunocytochemical studies of serially sectioned COITUS medullaris and filum terminale of 20 randomly selected human adult spinal cords with no known spinal cord disease. Contrary to general assumptions, this structure is not simply a fibrovascular tag but is endowed with an abundance of cellular and extracellular elements that may play significant roles in spinal cord pathophysiology. MATERIALS
AND METHODS
The filmn terminale from each of 23 randomly selected individuals, fixed in formalin and embedded in paraffin, was examined. As shown in Table 1, the majority of cases came from elderly adults 50 years or older, but there were also two cases from 15- and 1 &year-old patients. Serial longitudinal sections extending from the cmus medullaris to the end of the intradural portion of the filum terminale were subjected Luxol fast blue-cresyl violet, Bielto hematoxylin-eosin, schowsky, and periodic acid-Schiff‘stains. In selected samples, congo red staining was carried out. Immurloperoxidase staining for glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), amyloid /3 protein, factor VIII, vimentin, keratin, and S-100 protein was also applied. In addition, samples fixed in Karnovsky’s fluid were embedded in epon and thin sections of selected samples were examined with a Philips EM 400 electron microscope.
RESULTS The
ventriculus
terminalis
is formed
by cystic dis-
tension of the central canal at the lower end of medullaris. The ependyma-lined central canal appear and reappear in the lower portions lum terminale. Microscopically, the filum 916
the conus may disof the fiterminale
FILUM TERMINALE
TABLE 1.
OF SPINAL CORD (Choi et al)
Age and Sex of the Patients
Patient No.
Case No.
Sex
Age (yr)
1 2 3 4 5 6 7 8 9 10 I1 12 13 14 15 16 17 18 19 20 21 23
147-85 157-85 195-95 217-85 71-86 228-85 204-85 273-85 275-85 281-85 33-86 54-86 61-86 70-86 71-86 73-86 126-86 133-86 175-86 218-86 175-87 141-87 5862-87
M M M M M M M M F M M M M M M F M M M M M F M
77 65 56 68 69 71 71 81 85 50 40 58 61 62 69 55 49 69 56 72 70 18 15
29
its course contained longitudinally disposed argyrophilic neuritic processes and GFAP-positive astroglial processes. Although the cellular elements were localized mostly around the central canal near the center of the filum, there was no distinct histologic pattern to indicate organization into either grey or white matter. Thick-walled blood vessels were noted along the outer surface of the filum. Endothelial cells showed strong immunoreactivity for factor VIII. Occasional clusters of NSE-positive ganglion cells and peripheral nerve fibers showing immunoreactivity for S-100 protein also were noted in the outer portions of the filum. The most impressive and significant microscopic finding was the presence of clusters of glial cells varying from five to more than 100 cell layers thick (Figs 1 and 2). In many samples the bulk of the filum was almost entirely composed of clusters of glial cells, often extending out toward the surface of the filum. These relatively uniform cells bore round to ovoid dark nuclei measuring 7 to 15 pm in diameter. The nuclear chromatin was evenly distributed and no mitotic figures were noted. Cytoplasm was eosinophilic and often relatively abundant (Fig 2). In some areas periependymal cells appeared to form acinar structures (Fig 2). Occasionally, scattered corpora amylacea were also noted among irregularly disposed cells. As shown in Fig 3, some of the periependymal cells near the central canal were strongly positive for GFAP. Many of them extended longitudinally oriented, GFAP-positive processes (Fig 3b). Scattered ependymal cells also exhibited GFAP immunoreactivity within their cytoplasm and processes (Fig 3a). However, most of the irregularly disposed periependymal cells were negative for GFAP, although some of them were strongly immunoreactive for GFAP in the cell bodies and processes (Fig 3~). Bielschowsky staining demonstrated the presence of scattered silver-positive throughout
917
plaques composed of degenerating neurites and neuronal cell bodies (Fig 4). These plaques resembled those observed in Alzheimer’s disease. The majority of patients over the age of 50 years showed the presence of these structures in some parts of the filum. However, the filum terminale obtained from the 15-year-old boy and the 18-year-old woman only showed thickened neurites; plaque-like structures were not observed. Both NSEand silver-positive neuronal cell bodies showing varying degrees of degeneration were also present among clusters of glial cells (Fig 4). Immunoperoxidase staining using polyclonal antibodies against amyloid /3protein was negative in these structures. Congo red staining demonstrated a positive reaction in blood vessel walls in some cases, but the plaque-like structures were negative for amyloid. In many areas degeneration characterized by vacuolization and mucoid change was noted among cellular and extracellular elements. In contrast to other regions of the central nervous system, the ependyma-lined central canal of the filum often was apposed directly to the underlying fibrous connective tissue. The fibrous tissue was frequently hyalinized. Electron microscopy demonstrated scattered periependymal cells showing the presence of cilia (Fig 5), microvilli (Fig 6), and junctional complexes (Figs 5 and 6). Astrocytes filled with bundles of intermediate filaments within the cytoplasm and processes were also numerous (Fig 7). Degenerating neurites and neuronal cell bodies with clusters of dense bodies were also frequently identified (Fig 8). However, structures resembling paired helical filaments were not demonstrated. Figure 9 shows the gross appearance of the ventriculus terminalis and filum terminale from an 18-year-old woman. DISCUSSION In humans the ventriculus terminalis grows and enlarges at the expense of the grey substance at the upper end of the cavity as the tail end of the spinal cord is being absorbed.” The absorption of the tail is completed when the human embryo reaches a length of 30 mm in crown-rump length. At this stage the coccygeal end of the spinal cord undergoes marked regressive changes with grossly evident cavity formation. There is no further regression beyond the 30-mm stage, but growth and development thereafter accompany the general growth of the central nervous system.” The ventriculus does not attain its maximal dimensions until after the first 2 years of postnatal life. Thus, it is not simply a dilated central canal but a cavity at the lower end of the conus medullaris that develops and grows along with the rest of the central nervous system. Occasionally, a remnant of the ventriculus may form a gelatinous mass on top of the filum terminale that may be mistaken for a cystic tumor.’ The physiologic role of the ventriculus terminalis is not clear; nevertheless, it is found in the conus medullaris and filum terminale of all children and adults, including human fetuses of more than 22 mm in crownrump length.’ It has been speculated by some investi-
FIGURE 1. A large cluster of periependymal glial cells. An arrow points to the ependymal lining of the ventriculus terminalis. The cells are relatively uniform, measuring from 10 to 15 pm in diameter, and contain round to ovoid nuclei with evenly distributed chromatin. No mitotic figures are noted. The eosinophilic cytoplasm is scanty to moderate. The majority of the glial cells were negative for either GFAP or NSE (72~year-old man). (Hematoxylin-eosin stain; magnification X86.)
FIGURE 3. lmmunoperoxidase staining for GFAP. (a) Note GFAP-positive ependymal and periependymal cells. Arrows point to GFAP immunoreactivity within the cytoplasmic processes of ependymal cells lining the central canal of the tilum (18.year-old woman). (Hematoxylin counterstain; magniftcation X430.) (b) Note the numerous GFAP-positive cells extendinglongitudinalprocesses(arrows).AlsonotethepresenceofGFAPnegative cells (arrowheads) (15-year-old boy). (Hematoxylin counterstain; magnification X430.) (c) The majority of the periependymal cells are not immunoreactive for GFAP (‘). There were also occasional astrocytes showing GFAP immunoreactivity within the cytoplasm and processes (arrow) (62.year-old man). (Hematoxylin counterstain; magnification X215.)
FIGURE 2. Higher magnification of periependymal glial cells showing a cluster of cells (arrow) lined up to suggest the formation of an acinar structure. All contain moderate amounts of eosinophilic cytoplasm (arrowhead). Only a few scattered cells were GFAP positive (not shown) (15-year-old boy). (Hematoxylin-eosin stain: magnification X430.)
FIGURE 4. Bielschowsky stain showing degenerated neurites and neuritic plaque-like structures. (a and b) Photomicrographs showing thickened and degenerated neurons and neurites forming plaque-like structures (empty arrows) resembling those seen in Alzheimer’s disease (72.yearold man). (Magnification X215.) (c) Higher magnification showing an examDIe of the neuritic Dlaaue-like structures CemDtv arrow) within the ftlum terminale of an 83-year-old woman. Note thickening and fragmentation of silver-positive neuronal cell bodies and neurites (arrowhead) (56~year-old man). (Bielschowsky stain; magnification X860.) (d) Higher magnification to show neuritic plaque-like structure (empty arrow) formed by degenerating neurons and neurites within the ftlum terminale (55 year-old woman). (Magnification X860.) (e) Higher magnitication of neuritic plaque-like structure formed by clusters of thickened and degenerated neurites (arrow) and cell bodies (62.year-old man). (Magnification X860.)
FILUM TERMINALE
OF SPINAL CORD (Choi et al)
FIGURE 5. Electron micrograph of a periependymal glial cell showing the presence of cilium (arrow) and junctional complex formation between the cells (arrowhead). A small arrow points to anchoring filaments for the cilium (40~year-old man.) (Magnification X 15,400.)
FIGURE 7. Electron micrograph of periependymal glial cell showing bundles of glial filaments (arrows) within the cytoplasm and processes. Note also the presence of glycogen granules within the cytoplasm (81~year-old man.) N, nucleus. (Magnification x20,000.)
that the ventriculus terminalis is where Reissner’s fiber (RF) terminates with the accumulation of neurosecretory substance.‘-” Published studies suggest that RF, a thread-like structure extending from the lower end of the subcommissural organ of the epithalamus to the ventriculus terminalis of the spinal cord of all but a few vertebrates,’ is a secretory product of the subcommissural organ.“-” It also has been suggested that RF may pass through gaps in the ependymal lining of the filum terminale to reach the periependymal loose tissue and possibly the subarachnoid space.” Suggestions regarding the physiologic role of RF have included (1) a mechanoreceptor function for the circumventricular organs and the choroid plexus to indicate variations in cerebrospinal fluid pressure,‘” (2) a vehicle by which the subcommissural organ can exert one of its functions, such as regulation of the quality of the cerebrospinal fluid,17 and (3) a source for an endogenous peptide.” One of the main objectives of this report is to emphasize the fact that the abundance of glial cells in the conus medullaris and filum terminale may be a feature characteristic of the normal filum and that it should not be confused with the presence of a true neoplasm in this region. Although these cells are diffusely dispersed with no specific pattern, some showed a tendency to form acinar structures demonstrating a tendency toward ependymal differentiation. Electron microscopy clearly
showed the presence of many cells with ependymal differentiation containing cilia, microvilli, and intercellular junctional complexes. However, there were many other cells with immunocytochemical and ultrastructural characteristics indicative of astrocytic differentiation, including the presence of bundles of glial filaments and immunoreactivity for GFAP. An interesting finding was the presence of degenerated neurites and neuronal cell bodies forming neuritic plaque-like structures resembling those observed in Alzheimer’s disease in many of our cases. We have carried out extensive immunocytochemical studies using polyclonal antisera for amyloid P protein, but failed to show positive staining in these structures. Congo red staining was also negative. Electron microscopy failed to show the presence of the paired helical filaments characteristic of neurofibrillary tangles in Alzheimer’s disease. It appears that the plaque-like structures simply represent an interesting degenerative feature of the filum terminale, particularly in older individuals. None of the material studied came from patients suffering from Alzheimer’s disease. The filum terminale in the frog also contains astroglial cells as the dominant cell type.‘” It is interesting to note in this context that for many years investigators used the filum terminale of the frog as a source of astroglial preparations to study the transport of ions and amino acids within glial cells.20~21As shown in Fig 3a, some of the ependymal cells of the central canal of the filum also showed immunoreactivity for GFAP within
gators
FIGURE 6. Electron micrograph of a periependymal glial cell showing the presence of microvilli (arrow) and junctional complex formation (arrow head) (65year-old man.) (Magnification x 15.400.)
FIGURE 8. Electron micrograph showing clusters of degenerating neuronal processes (68~year-old man). (Magnification x20.000.)
HUMAN PATHOLOGY
Volume 23, No. 8 (August
FIGURE 9. Gross photograph of the Mum terminale (empty arrow) with an engorged blood vessel running along the lateral surface. The small arrow points to the ventriculus terminalis at the lower end of the conus medullaris of the spinal cord (18year-old woman).
the cytoplasm and periependymal glial processes. Viewed in the context of the radial glial origin of macroglial cell types, includin 5 ast,rocytes, oligodendrocytes, and ependymal cells, 22-2J it 1s not surprising to find a mixture of these cell types and the expression of transitional features among the periependymal glial cells of the filum terminale. Ependymomas account for the majority of gliomas arising in the region of the conus medullaris and filum terminale, and myxopa illary ependymomas occur exclusively in this region. 1X826 The microscopic components of myxopapillary ependymomas closely resemble those seen in the normal filum terminale. They are frequently highly vascularized and show myxomatous degeneration of the stroma. Whether the presence of a large number of glial cells within the filum terminale plays a role in the genesis of neoplasms in this region remains unknown. However, the presence of neuropil with its neuronal and glial elements within the filum terminale, particularly the profuse astroglial components, suggests a possible functional role for these constituents in spinal cord pathophysiology.
Jann
Arkvmwledgvvuxt. The authors thank Teresa Espinosa, Geddes, and Paul Amodei for technical support.
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