Structural Components of the BNB

The BNB delimits the endoneurial microenvironment of the peripheral nervous system (PNS), a space that extends from the proximal root attachment zones of cranial and spinal nerves to the distal sensory and motor end-organs. Numerous studies in a variety of species, including rats, mice, rabbits, cats, dogs, humans, and frogs have demonstrated that nerve fascicles and the endoneur-ial compartment therein are anatomically circumscribed by a connective tissue ensheathment within which and through which travel the anastomosing plexuses of the vasa nervorum. With a few important exceptions that may be a consequence of the

2.1. Spinal Roots absence of lymphatic capillaries (1), entry into and exit from the endoneurial microenvironment is tightly regulated.

The connective tissues ensheathing the peripheral nerves merge with the meninges of the central nervous system (CNS) at the subarachnoid angle (4) (Fig. 1). Here the dense irregularly arranged collagen fibers and scattered fibroblasts of the dura mater blend with the epineurium, the outermost covering of peripheral nerves that binds fascicles together, while the arachnoid layer merges with the outer lamellae of the perineurium, the multilayered cellular investment of nerve fascicles that circumscribe the endoneurial space (4, 5). The inner layers of the perineurium are reflected onto the nerve roots as the root sheath. The outer root sheath is reminiscent of the pia mater (6) and consists of loosely arranged cell layers with intermittent junctional contacts, allowing communication between the subarachnoid and intercellular spaces, and containing collagen and small elastic fibers (4). The inner cell layers of the root sheath are closely opposed and contain squamous cells with a polygonal outline (5) and a basal lamina that is intermittent except for that which separates the innermost cells from the endoneurium of the root (4).

From the subarachnoid angle to the attachment zones, spinal roots traverse the subarachnoid space (Fig. 1). As noted above, the cellular layers of the inner root sheath are a centrally directed continuation of a portion of the perineurium that ends as an open-ended tube in the vicinity of the root attachment zone (6). In this region, continuity between the CSF-containing subarachnoid space and the endoneurium of the roots via pial tissue space has been demonstrated ultrastructurally (6). The continuity between subarachnoid and endoneurial extracellular spaces represents a pressure-driven egress pathway for CSF, which is a source of endoneurial fluid. The root attachment zones contain the regions where rootlets are connected to the spinal cord. The structural basis for the interface between CNS and PNS parenchyma is the glia limitans, the CNS surface-limiting membrane composed of astrocytic foot processes that is subjacent to the pia mater and crosses each rootlet at its point of attachment to the spinal cord (reviewed by Fraher (7)). The glia limitans thickens as it crosses the rootlets and the interdigitating, layered astrocytic foot processes become perforated by channels that contain either individual myelinated fibers or groups of unmyelinated axons. CNS and PNS tissues interpenetrate in the rootlets or spinal cord surface forming transition zones with a length of rootlet containing both tissues (7). Central to the glia limitans in the transitional zone, myelinated fibers are ensheathed by oligodendrocytes, while peripheral to it, myelinated fibers are ensheathed by Schwann cells and unmyelinated fibers by Remak cells. The abrupt change in ensheathment at the glia limitans is in marked contrast to the

SPACE

DANIEL MIZISIN 09

Fig. 1. The relationship of peripheral nerve and spinal root connective tissue ensheathments to the meningeal coverings of the spinal cord are shown. The outermost connective tissue of peripheral nerve, the epineurium (EP), is continuous with the outermost meningeal covering, the dura mater (DM). At the subarachnoid angle (SA ), the perineurium (P), the multilayered connective tissue ensheathment that defines nerve fascicles, divides, with the innermost layers continuing on to become the inner layers of the root sheath (RS ) and the outermost layers merging with the arachnoid layer (A ). As the dorsal and ventral spinal roots pass through subarachnoid space, some of the arachnoid layer is reflected onto the root sheath at the subarachnoid angle, becoming the outermost layers of this connective tissue ensheathment. At the root attachment zone (RAZ), the pia mater (PM) of the spinal cord is reflected onto the spinal root and merges with the outer layers of the root sheath, while the glia limitans continues across the attachment zone to form the interface between the central and peripheral nervous systems. The innermost layers of the root sheath terminate on the spinal root side of the glia limitans. At the dorsal and ventral root attachment zone, continuity between the subarachnoid space and endoneu-rium of the spinal roots (arrows) has been demonstrated ultrastructurally (modified from (4)).

SPACE

DANIEL MIZISIN 09

Fig. 1. The relationship of peripheral nerve and spinal root connective tissue ensheathments to the meningeal coverings of the spinal cord are shown. The outermost connective tissue of peripheral nerve, the epineurium (EP), is continuous with the outermost meningeal covering, the dura mater (DM). At the subarachnoid angle (SA ), the perineurium (P), the multilayered connective tissue ensheathment that defines nerve fascicles, divides, with the innermost layers continuing on to become the inner layers of the root sheath (RS ) and the outermost layers merging with the arachnoid layer (A ). As the dorsal and ventral spinal roots pass through subarachnoid space, some of the arachnoid layer is reflected onto the root sheath at the subarachnoid angle, becoming the outermost layers of this connective tissue ensheathment. At the root attachment zone (RAZ), the pia mater (PM) of the spinal cord is reflected onto the spinal root and merges with the outer layers of the root sheath, while the glia limitans continues across the attachment zone to form the interface between the central and peripheral nervous systems. The innermost layers of the root sheath terminate on the spinal root side of the glia limitans. At the dorsal and ventral root attachment zone, continuity between the subarachnoid space and endoneu-rium of the spinal roots (arrows) has been demonstrated ultrastructurally (modified from (4)).

continuity of myelinated and unmyelinated axons across this surface-limiting membrane, which defines the most proximal region of the endoneurial microenvironment.

The vasculature of the spinal roots has been examined in alkaline phosphatase preparations and shown to have large, more sparsely distributed vessels comparable to spinal cord white matter as well as most of the more distal portions of the peripheral neuraxis (8). Capillary density is greater in sensory ganglia and spinal cord gray matter (8), which is in line with the greater metabolic demands of nerve-cell-body-containing nervous tissue (9). The vessels in the spinal roots are permeable to morphological tracers of various molecular weights (9). The structural basis of tracer permeability in endoneurial vessels of spinal roots appears to be fenestrations in endothelial cells as well as open interen-dothelial clefts (10).

2.2. Peripheral Nerves Nerve trunks are ensheathed by two distinct types of connective tissue: epineurium and perineurium. The epineurium is the outermost connective tissue and consists of irregularly arranged collagen fibers, scattered fibroblasts and occasional clusters of adipocytes. The epineurium surrounds mono-fascicular nerves or loosely binds fascicles of multi-fascicular nerves together and contains the outermost portion of the intrinsic component of the vasa nervorum. The epineurial vasculature is an anastomosing vascular plexus fed by radicular vessels that connect to the extrinsic component of the vasa nervorum, which are segmental regional vessels that approach the nerve trunk at multiple levels (11). The epineurial arterioles and venules are large longitudinally oriented vessels that are evident superficially in the nerve trunk as well as in the deeper regions between fascicles. Extravasation of a variety of morphological tracers has been observed in the epineurial vascu-lature and attributed to diffusion through both open interen-dothelial clefts and fenestrated vessels (9).

The perineurium circumscribes the endoneurium in concentric cellular layers, each one cell thick. In larger nerve fascicles, the perineurium consists of as many as 15 cellular layers, with fewer layers in smaller fascicles and only one cell layer in the vicinity of sensory and motor end-organs. Perineurial collagen fibrils, which are smaller in diameter than those in the epineurium (12), are interposed in the extracellular space between cell layers arranged in circular, longitudinal and oblique bundles along with occasional elastic fibers (9) and likely provide the perineurium with its passive compliance properties. Perineurial cells are flattened squamous cells with a serrated polygonal border considered by some to be epithelial cells (5, 13) but later shown to have a fibroblast origin (14). As in the root sheath, perineurial cells lack a polarized architecture and are bounded on both sides by basal laminae (15, 16), which distinguishes perineurial cells from epineurial and endoneurial fibroblasts. In addition to abundant caveolae, filaments and dense bodies have been observed in the perineurial cells of mouse sciatic nerve, suggesting a contractile capacity (17) and possibly representing the structural basis for active compliance properties of the perineurium. Within a sleeve, tight junctions join perineurial cells together, while desmosomes and gap junctions are occasionally observed linking cells in adjacent layers together (18). These tight junctions, particularly those of the innermost sleeves, provide a barrier to the diffusion of various larger molecular weight tracers and restrict diffusion of low molecular weight tracers (19).

Anastomotic connections between the epineurial and perineurial vascular plexuses occur at various levels in the perineu-rium, with the longitudinally oriented vessels penetrating the cellular layer gradually in an oblique fashion before connecting to the endoneurial plexus (11). Single perineurial layers accompany these penetrating vessels as they enter the endoneurium and represent a restricted site of continuity between the epineurial and endoneurial spaces (18). The oblique penetration of the perineurial vasculature leaves these vessels vulnerable to compression when the endoneurial fluid pressure is increased (20). The endoneurial vascular plexus and the obliquely penetrating perineurial vessels comprise a fascicular vascular unit, a system of longitudinally oriented vessels that remains intact when an individual fascicle is isolated (11). Endoneurial vessels consist of a network of arterioles, capillaries and venules that are sparsely distributed as are vessels of the spinal cord white matter and roots. The arterioles are thin-walled with a fragmentary internal elastic membrane (8). The diameters of the continuous, nonfenestrated capillaries are larger than the diameters of capillaries found in adjacent skeletal muscle (6-10 vs. 3-6 mm) (8). The larger size and unusually complete pericyte investment of endoneurial capillaries are features shared with endoneurial postcapillary venules, although the presence of tight junctions and alkaline phosphatase activity distinguish these vessels (8). In contrast to leaky endoneurial vessels in new-borne mouse sciatic nerve, tight interendothe-lial junctions in adult endoneurial vessels represent the structural basis for restricted permeability to vascular tracers of various molecular weights including Evans Blue albumin and fluorescein isothiocyanate (9, 21-23), while open interendothelial gaps distinguish these vessels from the consistently tight vessels in most regions of the brain (8).

2.3. DRG and other The connective tissue capsule surrounding sensory and other

Ganglia ganglia is continuous with the ensheathment of peripheral nerves with an outer epineurium surrounding an inner perineurium. The perineurial cellular lamellae of ganglia are bounded by a basal lamina on both sides and have numerous tight junctions and des-mosomes, as well as occasional gap junctions (9, 24). Interposed between the cellular layers are collagen-containing extracellular spaces. The 2-4 cellular lamellae of the perineurium of the superior cervical ganglion act as a diffusion barrier, with the innermost layers preventing transperineurial movement of larger molecular weight tracers (24). In contrast to the perineurium and the endoneurial vessels of the distal nerve trunk, the endoneurial vasculature of cranial, spinal, and autonomic ganglia is permeable to a variety of low and high molecular weight tracers (24, 25). As in endoneurial vessels of the spinal roots, blood-borne tracer is extravasated through open interendothelial clefts, as well as through vessels with fenestrated endothelia, within minutes of injection (24).

2.4. Sensory and As nerve fascicles become smaller and approach sensory and

Motor End-Organs motor end-organs, the number of surrounding perineurial layers decrease to a single layer (5, 18). The decrease in the number of perineurial layers occurs by the termination of the innermost layer or by loss of the innermost layer as it accompanies nerve fibers separating from the parent fascicle, in which case tight junctions ensure an effective seal between the branching sleeve and the remaining perineurial layers (18). Whether single perineurial layers maintain their ensheathment as individual fibers reach sensory and motor end-organs has been a subject of controversy. Some maintain that a complete perineurial investment is continuous with the capsules of sensory organs, such as Meissner's, Krause's, and Pacinian corpuscles and also covers the motor end plate (5, 13). Others have provided ultrastructural evidence that the perineurial layer ends just before reaching the motor end plate, providing an open-ended termination with continuity between epineurial and endoneurial space (18). While ultrastructural evidence is lacking, there is likely an open-ended perineurial sleeve for the naked nerve endings of the intraepidermal innervation (5). The open-ended perineurial sleeve of motor and epidermal nerves provides distal continuity of the endoneurial microenvironment with the surrounding extracellular tissue space and may ensure maintenance of proximodistal endoneurial fluid flow (EFF) by providing distal drainage sites.

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

This guide will help millions of people understand this condition so that they can take control of their lives and make informed decisions. The ebook covers information on a vast number of different types of neuropathy. In addition, it will be a useful resource for their families, caregivers, and health care providers.

Get My Free Ebook


Post a comment