Optic Nerve

Introduction

The two optic nerves carry the axons of retinal ganglion cells (RGCs), and along these axons transmit all of the visual information from the inner retina ( Chapter 23 ) to the brain ( Chapter 29, Chapter 30, Chapter 31 ). Thus, diseases that affect the optic nerve commonly cause vision loss. The retina and optic nerve are developmentally an outgrowth of the forebrain, and, like other white matter tracts of the central nervous system (CNS), the optic nerve does not repair itself after most types of injury. Thus, blindness from optic nerve injury or degenerative disease is typically irreversible. This chapter reviews the principal aspects of optic nerve anatomy, development, and physiology, and discusses the pathologic changes at the molecular and cellular levels in the context of clinical disease.

Retinal ganglion cell axons within the nerve fiber layer

RGC axons begin at the RGC bodies in the inner layer of the retina. Although most neurons in this layer are RGCs and the layer is commonly referred to as the ganglion cell layer , in humans approximately 3 percent of cells in the central retina and up to 80 percent in the peripheral retina may be other cell types, primarily displaced amacrine cells. In addition, studies in mammals have demonstrated a few displaced RGCs located in the inner nuclear layer. As discussed in Chapter 23 , the RGCs receive input from bipolar cells and amacrine cells, and project their axon towards the vitreous, whereupon they turn approximately 90° and project towards the optic nerve head in the nerve fiber layer . The nerve fiber layer is not quite radially arranged around the optic nerve head (optic disk), as axons near the center of our visual field course away from the fovea, and then towards the optic disk, entering in the superior and inferior portions of the disk ( Fig. 28.1 ). This interesting anatomy prevents axons from crossing the high-sensitivity fovea, where they might otherwise scatter light and degrade visual acuity. The axons from more peripheral RGCs are more superficial (vitread) to those arising from less peripheral ganglion cells ( Fig. 28.2 ). In addition, there is strict segregation of those fibers arising from RGCs located superior to the temporal horizontal meridian (raphe) and those fibers arising from RGCs located inferior to the horizontal raphe. Because of this segregation, visual field defects corresponding to injury to RGC axons typically have stereotyped patterns, e.g. superior or inferior nasal steps, temporal wedges, or arcuate scotomas. These are called nerve fiber bundle defects, and with other visual field defects are covered in more detail in Chapter 35 . The nerve fiber layer can be measured using various modalities in human eyes ( Box 28.1 ).

Intrascleral optic nerve

The optic nerve itself is considered to begin at the optic nerve head which, when viewed through the front of the eye, is observed as the optic disk . There is an approximately 1-mm component of optic nerve within the intrascleral part of the globe, which includes the lamina cribrosa ( Fig. 28.3 ). Once at the optic disk, ganglion cell axons turn away from the vitreous and dive into the optic disk towards the brain. Axons arising from more peripheral RGCs are peripheral within the optic nerve head. The optic disk contains the nerve fibers around its edge, the neuroretinal rim , and the central cup which does not contain RGC axons. The cup-to-disk ratio may range from 0 to 1.0, depending on natural variation in the size of the disk, and whether there is less than a full complement of axon fibers, for example as a result of damage from glaucomatous optic neuropathy (see below).

Intraorbital optic nerve

The optic nerve extends approximately 30 mm from the globe to the optic canal. The straight-line distance from the back of the globe to the optic canal is much less (the exact amount depending on individual orbital depth), with the excess optic nerve laxity allowing for free movement of the globe during eye movements. Excessive proptosis stretches the optic nerve tautly, resulting in some cases in direct injury to or even avulsion of the nerve itself. Beginning behind the globe, the nerve is ensheathed by the layered meninges extending from the brain, bathing the optic nerve in cerebrospinal fluid and providing vascular support along the length of the nerve (see below).

The retinotopic segregation of RGC axons (topographic correspondence of optic nerve fibers to retinal location), particularly the segregation between axons arising from the superior and inferior retina, is gradually lost as the axons course through the nerve ( Fig. 28.3 ). There is only moderate retinotopy in the initial segment of the optic nerve. The retinotopy decreases distally, and then becomes ordered vertically for eventual nasal decussation near the chiasm. The loss of retinotopy is not absolute, because the fibers from the nasal (but not temporal) macula continue to be located centrally within the nerve over a considerable distance. Fibers from large RGCs are less retinotopically organized than those from smaller ganglion cells. Although studies in humans are difficult to do ante-mortem, post-mortem studies of nerves with specific visual field defects demonstrate similar findings, while post-mortem studies of developing fetuses and adult eyes also show loss of retinotopy within the transition from the optic nerve head to the nerve. Within the orbit, the optic nerve travels within the muscle cone formed by the superior rectus, lateral rectus, inferior rectus, and medial rectus muscles. Tumors within the cone are common sources of compression of the optic nerve, or compressive optic neuropathy . Examples of these tumors include cavernous hemangioma, hemangiopericytoma, fibrous histiocytoma, lymphoma, and schwannoma. In addition, enlargement of the muscles themselves, particularly the inferior rectus and/or the medial rectus in Grave's ophthalmopathy, may also compress the optic nerve.

The optic canal

The optic nerve enters the cranium via the optic canal, a 5–12 mm passage which lies immediately superonasal to the superior orbital fissure. The optic canal contains some axons of sympathetic neurons destined for the orbit, as well as the ophthalmic artery. The latter lies immediately inferolateral to the optic nerve itself, covered in dura. At the distal end of the canal, there is a half-moon-shaped segment of dura which overhangs the optic nerve superiorly, and thereby lengthens the canal by a few millimeters. As in the intraorbital portion of the optic nerve, within the canal, and immediately posterior to the optic canal, meningeal tissue ensheathes the optic nerve. Benign tumors of the meninges, or meningiomas, are frequent causes of compressive optic neuropathies in these locations. Small tumors within the canal itself, where there is very little free space, may lead to compressive optic neuropathy without a radiographically visible tumor.

Intracranial optic nerve and the optic chiasm

Once the nerve has entered the cranium, there is a highly variable (8–19 mm, mean of 12 mm) length of nerve until the chiasm is reached. The length of the chiasm itself is approximately 8 mm. The intracranial optic nerve and chiasm are immediately above the planum sphenoidale and sella turcica, the latter of which contains pituitary gland. There is approximately 10 mm between the inferior part of the nerve and the superior part of the pituitary. Tumors of the pituitary which increase in size enough to compress the chiasm may therefore cause compressive optic neuropathy.

At the optic chiasm, RGC axons from the temporal retina remain ipsilateral, and those from the nasal retina cross the chiasm and course towards the contralateral brain. The ratio of fibers which cross versus those which do not cross is anatomically 53 : 47 and functionally 52 : 48. This small difference between the number of crossing and non-crossing fibers is commonly reported to be responsible for the relative afferent pupillary defect seen in disorders of the optic tract, in which an afferent pupillary defect is seen contralateral to the injured tract (see Chapter 25 ), but could also reflect the fact that some fibers from specialized cells within the retinal responsible for the pupillary reflex may cross from the temporal retina into the contralateral optic tract.

The optic tract and lateral geniculate nucleus

Although the optic nerve anatomically ends at the chiasm, RGC axons continue within the optic tract until the lateral geniculate nucleus, superior colliculus, pretectal nuclei, or hypothalamus (see below). Circuitry and processing by these targets are discussed in Chapter 25, Chapter 29 .

Axons

There are no other neuronal cell bodies within the optic nerve, making it a pure white matter tract of the central nervous system. Although the optic nerve itself may contain other small nerves, particularly tiny peripheral nerves (branches of the trigeminal system) which carry pain sensation or control vascular tone, the vast majority of the optic nerve is composed of the approximately 1,200,000 axons of the retinal ganglion cells. Optic nerve axons are collected in fascicles, which are separated by pia-derived septa. The number of fascicles ranges from approximately 50 to 300, being maximal immediately retrobulbar and at the optic canal. The mean axon diameter is slightly less than 1 µm, with a unimodal distribution skewed to the left. The mean diameter may decrease during aging, either through loss of large-diameter axons, or from a general, aging-induced atrophy. Compared with the optic tract, there is relatively little segregation of axons by size within the optic nerve, except for a tendency for finer axons to be located inferocentrotemporally.

There is variability of axonal diameter and myelin thickness from the retina to the brain. Studies in the ferret show that the diameters of the largest axons increase as the distance from the retina increases. The diameter of individual axons is regulated by multiple factors, including oligodendrocytes and activity, increases during development, and correlates with local accumulation of specifically phosphorylated neurofilament proteins.

Oligodendrocytes and myelin

Conduction of nerve impulses down the axons in the optic nerve depends on the presence of myelin, a fatty multilaminated structure which insulates each axon and greatly increases the speed and efficiency of conduction (discussed below). The retrolaminar optic nerve is completely myelinated under non-pathological circumstances ( Fig. 28.4 ). There are non-myelinated axons of the peripheral nervous systems within the adventitia of the central retinal artery and non-myelinated and myelinated Schwann cells around peripheral axons of the outer dura. Each axon is myelinated with several lamellae of myelin bilayers, with the number of lamellae varying from axon to axon but in strict proportion to the diameter of the axon. Individual oligodendrocytes elaborate an average of 20–30 processes per cell, each of which myelinates 150–200 µm of axon length.

Oligodendrocytes and axons regulate each other during development and throughout adulthood. Oligodendrocytes depend on the presence of axons for their survival, and for production of myelin proteins. Axons regulate oligodendrocyte survival and proliferation, and thus their number, through expression of specific signaling proteins and through axonal electrical activity, controlling oligodendrocyte number to match the number of axons. Conversely, axons are signaled by oligodendrocytes to regulate axon number and diameter, and to prevent axon sprouting or branching in the optic nerve. Later, in the adult, oligodendrocytes and myelin are partially responsible for inhibition of axon regeneration after optic nerve damage or degeneration (see below).

Astrocytes

Astrocytes, named for their stellate appearance, are ubiquitous glial components of the central nervous system, and function in white matter tracts like the optic nerve to regulate ionic and energy homeostasis. Astrocytes are highly efficient at transporting potassium, and increases in the level of extracellular potassium as a result of repolarization are buffered by astrocytes. Their ability to accumulate glycogen may allow them to serve as an energy source for the optic nerve in the absence of glucose (e.g. ischemia), by shuttling lactate to adjacent axons. Astrocytes form the glial-limiting membrane, and their processes are concentrated at the nodes of Ranvier and in contact with nearby capillaries. This positions the astrocyte to play a role in transportation of substances between the local circulation and the axons; in inducing endothelial cells to form the blood–brain barrier; and perhaps in signaling blood vessels to dilate or constrict according to local metabolic needs. Astrocytes also mediate connectivity between optic nerve axons and the adjacent connective tissues, such as the pial septa, the adventitia of the central retinal artery and vein, and the pia in a layer named the glial mantle of Fuchs.

Interestingly, the most common intrinsic tumor of the optic nerve is an astrocytoma, or optic nerve glioma. This is usually a low-grade tumor of well-differentiated astrocytic cells that appear hair-like, or “pilocytic.” Pilocytic astrocytomas are usually seen in childhood, and have a favorable prognosis. They are also commonly seen in association with neurofibromatosis. Rarely, more malignant neoplasms of astrocytic origin develop in adults. These resemble the higher-grade astrocytic neoplasms found elsewhere in the central nervous system, and are usually fatal.

Microglia

Microglia, a type of resident macrophage, are an important cellular component of the optic nerve. Although their origin was debated for decades, they have been shown experimentally to be of peripheral, bone marrow origin, and are not derived from the neuroectoderm that yields neurons, astrocytes, and oligodendrocytes. Microglia share several markers with macrophages, with both having Fc receptors (for immunoglobulin), C3 receptors (for complement), binding of Griffonia isolectin B4, and antigenicity for F4/80 and ED1 monoclonal antibodies. In the human optic nerve, microglia can be seen at 8 weeks after conception, when they are relatively undifferentiated. Microglia become more differentiated during fetal development, going from tuberous to amoeboid to a ramified morphology. They are associated with axon bundles, but not necessarily with blood vessels, and are found in both the nerve parenchyma and its meninges. Nerve and meningeal microglia are similar ultrastructurally except for vacuoles and endoplasmic reticulum in the former. This may be due to their phagocytosis of dying axons during development. Microglia share several characteristics of immune capacities of macrophages. By phagocytosing extracellular material, degradation within intracellular compartments can occur. This may be followed by antigen presentation on the cell surface. In combination with certain histocompatibility antigens, this presented antigen can cause stimulation of T lymphocytes and subsequent immune system activation (see below).

Meninges and meningothelial cells

The optic nerve is covered with three layers of meninges, dura, arachnoid, and pia. The meninges can also be divided up into pachymeninges (dura) and leptomeninges (arachnoid and pia). The outermost dura is a thick fibrovascular tissue, which is in immediate contiguity with the sclera, periorbita, and the dural layer of the lining of the cranial contents. The middle arachnoid layer is a loose, thin, fibrovascular tissue. The innermost pia is a thin, tightly adherent layer with extensions into the nerve itself forming the pial septae, through which the fascicles of ganglion cell axons course. In the optic canal, there are numerous trabeculae connecting the dura through the arachnoid to the pia, which reduce the free space of the nerve sheath in this area.

The space between the dura and arachnoid is the subdural space, while the space between the arachnoid and pia is the subarachnoid space. The subdural space around the optic nerve is small, and is not in communication with the intracranial subdural space. The subarachnoid space, on the other hand, is in communication with the intracranial subarachnoid space. The optic nerve subarachnoid space ends anteriorly within a blind pouch just before the optic disk. This extension of the subarachnoid space from the brain into the orbit explains why elevated intracranial pressure may cause compression of the optic nerve via elevating the hydraulic pressure. There is an appreciable pressure within the subarachnoid space, measuring from 4 to 14 mmHg.

Meningothelial cells may have several functions, including wound repair and scarring, phagocytosis, and collagen production. The meningeal vessels include pericytes and endothelial cells, which form tight junctions. Macrophages and mast cells are also found in the meninges. The role of these and other resident cells in meningeal inflammations is only speculative.

Optic nerve head

Studies of histological sections and of corrosion casting of the vessels themselves have added greatly to our understanding of the optic nerve blood supply ( Fig. 28.5 ). The ophthalmic artery provides the major vascular supply to the inner retina and optic nerve. The central retinal artery branches off of the intraorbital ophthalmic artery, and enters the optic nerve during approximately 12 mm behind the globe. In the retina, RGC bodies and the nerve fiber layer are supplied by capillary branches derived primarily from the central retinal artery arising out of the optic nerve head. As it branches on the optic disk into the retinal arterioles, the central retinal artery provides partial perfusion of the superficial optic disk via small capillaries. Along the optic nerve itself, however, the central retinal artery provides minimal perfusion of the nerve through which it courses.

In contrast, branches of the medial and lateral short posterior ciliary arteries, originating from the ophthalmic artery, provide the major blood supply to the optic nerve head, as well as the choroid. Their branches perfuse the optic nerve, both anteriorly via direct branches and posteriorly via a retrograde arteriolar investiture of the optic nerve (see below). Anastomoses of posterior ciliary artery branches form the circle of Zinn-Haller, which contributes significant perfusion to the optic nerve head. In addition, there are contributions from recurrent choroidal arterioles to the prelaminar and laminar optic nerve head, and contributions from recurrent pial arterioles to the laminar and retrolaminar optic nerve head. A clinical implication of the common posterior ciliary arterial source of the choroid and deep optic nerve head is that they will fluoresce simultaneously during the earliest phase of fluorescein angiography, before the retinal arterioles transit dye.

Unlike the choroidal vessels, which have fenestrated endothelial cells, optic nerve vessels have non-fenestrated endothelial cells with tight junctions, surrounded by pericytes. Optic nerve vessels therefore share the same blood–nerve barrier characteristics as the blood–brain barrier. Only a restricted number of molecules can cross the blood–nerve barrier. For example, gadolinium enhancement on magnetic resonance imaging is not seen unless there is some pathological process within the optic nerve that would disrupt the blood–nerve barrier, e.g. inflammation. Another major difference between choroidal and optic nerve head vessels is that only the latter can autoregulate, i.e. maintain approximately constant blood flow despite most changes in intravascular or intraocular pressure. Thus there is compensation of perfusion for a wide range of intraocular pressures in normal individuals. A dysregulation in optic nerve head autoregulation, and any ischemia that would follow, may contribute to the pathophysiology of glaucoma (see below).

Intraorbital optic nerve and optic canal

The intraorbital optic nerve is perfused primarily by the pial circulation, which branches off of the ophthalmic artery either directly or indirectly via recurrent branches of the short posterior ciliary arteries. The pia sends penetrating vessels into the intraorbital optic nerve along the fibrovascular pial septae, from which a capillary network extends into neural tissue (axons and glia). Similarly, the intracanalicular optic nerve is perfused by up to three branches of the ophthalmic artery, namely a medial collateral, lateral collateral, and ventral branch, which perfuse the pial surface and then penetrate the nerve. An important clinical implication of the pial supply relates to optic nerve sheath meningiomas. If a surgeon strips the meningioma away from the nerve, then the pia will be removed as well, resulting in loss of the blood supply to the nerve, and possible infarction and blindness. Another clinical correlation is related to the small amount of free space within the canal, when occupied by blood from shearing of the delicate vessels there, this may result in a sight-threatening compressive hematoma (and see below).

Intracranial optic nerve, chiasm, and optic tract

The intracranial optic nerve and chiasm are perfused by the internal carotid artery and its branches, primarily the anterior cerebral, anterior communicating, and the superior hypophyseal artery. The posterior chiasm may also be perfused by branches of the posterior communicating artery. The optic tract is predominantly perfused by branches of the posterior communicating and anterior choroidal arteries. Similar to the intraorbital and intracanalicular optic nerve, the blood supply occurs via small pial penetrating vessels. However, there is no dura or arachnoid surrounding the optic nerve posterior to the optic canal, and thus the risk of infarction is not from stripping a tumor off the nerve, but from inadvertent detachment of the fine vessels during surgical manipulation.