Overview
Unlike the peripheral nervous system (PNS), in which axonal injury leads to regeneration, injury to axons of central nervous system (CNS) neurons is irreversible, and usually leads to death of the cell body. The optic neuropathies, which are the main focus of this chapter, almost always involve injury to the retinal ganglion cell (RGC) axon. Etiologies include glaucoma, ischemia, compression, inflammation and demyelination, transection, infiltration, and papilledema ( Box 42.1 ). Each of these involves axonal injury that ultimately leads to varying degrees of ganglion cell death.
| Disease | Clinical features | Genetics | Epidemiology | Treatment | Prognosis |
|---|---|---|---|---|---|
| Glaucoma |
| Family history important, and several known genes, e.g., myocilin (MYOC) for primary and juvenile open-angle glaucoma; optineurin (OPTN) for primary open-angle glaucoma; CYP1B1 for congenital glaucoma |
Risk factors
| Lowering of IOP | Many patients progress despite lowering of IOP |
| Optic neuritis |
| Similar to those of multiple sclerosis (MS), e.g., HLA complex (HLA-DR2 haplotype) |
Risk factors
|
|
|
| Papilledema |
| Dependent on disease causing elevated intracranial pressure |
|
|
|
| Arteritic anterior ischemic optic neuropathy |
| Sporadic |
Risk factors
|
|
|
| Nonarteritic anterior ischemic optic neuropathy |
| Sporadic |
Risk factors
| No proven treatment |
|
| Compressive optic neuropathy |
| Dependent on cause of disease | Risk factors
| Removal or reduction of compressive mass by surgery, radiotherapy, or chemotherapy |
|
| Traumatic optic neuropathy |
| None | Up to 5% of indirect head injuries may have a traumatic optic neuropathy | No treatment shown to be superior to observation alone | Spontaneous improvement may occur, but prognosis often poor, especially if no light perception at onset |
| Infiltrative optic neuropathy |
| Dependent on cause of disease | Risk factors Granulomatous disease (e.g., sarcoidosis), neoplasms (leukemia, lymphomas, metastases), optic nerve glioma | Treatment of underlying disease | Dependent on disease process |
Glaucoma ( Chapter 19 , Chapter 20 , Chapter 21 , Chapter 22 , Chapter 23 , Chapter 24 , Chapter 25 , Chapter 26 , Chapter 27 , Chapter 28 , Chapter 29 ) is the most common of all of the optic neuropathies, ischemic optic neuropathy ( Chapters 41 and 43 ) is the most common acute optic neuropathy in older persons, and optic neuritis ( Chapter 37 ) is most common in the young. Compressive etiologies include neoplasms, aneurysms, and enlargement of extraocular muscles in thyroid-associated orbitopathy. Transection of the optic nerve may be partial or complete, and can occur with trauma such as bullet or knife wounds, or iatrogenically, e.g., during resection of a tumor. Infiltration of the optic nerve may involve neoplasm (e.g., gliomas or metastases) or inflammation (e.g., sarcoidosis) and usually results in a combination of compressive, inflammatory, and ischemic damage to the optic nerve. Papilledema is caused by increased intracranial pressure and the pathological mechanism of disease involves disrupted axonal transport.
Clinical background
Historical development
The quest to understanding the mechanisms behind axonal degeneration began in the mid-1800s with the works of Augustus Waller. In 1850, he demonstrated that axons could undergo a compartmentalized degenerative process. By transecting frog hypoglossal and glossopharyngeal nerves, he noted that the distal axonal fragments (those separated from the cell soma) underwent a “curdling” and disorganization, and in 1856 noted a similar observation following transection of the rabbit optic nerve. This type of axonal degeneration has been termed “wallerian degeneration.” Since this time, more and more evidence has shown that axons undergo a compartmentalized degenerative process, using mechanisms distinct from those causing the degeneration and death of the cell soma. Clinically, this has arisen parallel to the perception that certain CNS diseases may be considered “axogenic” diseases, or arising primarily from injury to the neuronal axon, whereas others may be considered “somagenic” diseases, which, in contrast, arise primarily from injury to the cell soma.
In neuro-ophthalmic disease, the RGC body and its axon are the main targets of pathology, and just as in the rest of the CNS, the concept of somagenic versus axogenic disease applies. Diseases primarily affecting the RGC layer (somagenic diseases) are usually retinopathies, and result from injuries including ischemia, excitotoxicity, autoimmune processes, thermal and photic injury, storage diseases, neoplastic processes, nutritional deprivation, and toxins. Axogenic diseases of the optic nerve and the mechanisms underlying their pathophysiology are the subject of this chapter.
Key symptoms and signs
Diseases characterized by optic nerve axonal injury are associated with abnormal visual acuity, color vision, visual field, and optic nerve head color and morphology. Ischemic, traumatic, compressive, infiltrative, inflammatory, infectious, toxic, and nutritional optic neuropathies are often associated with decreased visual acuity early in the course of disease because of significant involvement of RGCs sending axons via the papillomacular bundle. Open-angle glaucoma, papilledema, and optic disk drusen affect the papillomacular bundle much later on, thereby not initially causing reduction in visual acuity. Similarly, color vision is variably affected. Color vision loss, which usually affects the red–green axis, occurs late in glaucomatous optic neuropathy.
Optic nerve excavation and pallor, which reflect the effect of chronic loss of RGC axons, are elements that can help distinguish the various optic neuropathies. Histologically, excavation represents loss of all tissue and thus leads to the creation of an empty space, or cup, surrounded by axon-containing tissue, called the rim. Pallor is caused by axonal loss, but occurs in the presence of remaining viable glial tissue. This glial tissue takes the place of the space that would otherwise increase the size of the excavation, producing instead a pale area. In glaucoma, the morphology of the excavation is almost pathognomonic, although other optic neuropathies may have significant excavation ( Table 42.1 ). Pallor of the neuroretinal rim is eventually seen in most nonglaucomatous optic neuropathies. On the other hand, cupping in the absence of pallor is typical of glaucomatous optic neuropathy. This rule is not without exception, however, as end-stage glaucoma may be associated with a pale rim (see Chapter 44 ).
| Glaucoma |
| Compressive optic neuropathies (sometimes) |
| Methanol optic neuropathy |
| Arteritic anterior ischemic optic neuropathy |
| Shock optic neuropathy |
| Dominant optic neuropathy |
| Leber’s hereditary optic neuropathy |
| Periventricular leukomalacia |
Visual field abnormalities help to differentiate the optic neuropathies. Optic neuropathies that are caused by more anterior or optic nerve head damage usually give rise to defects that follow the RGC axon distribution pattern in the retina, or nerve fiber bundle defects. Glaucoma is the best known of these, and typically causes arcuate scotomas, nasal steps, and temporal wedges. Other neuropathies which may cause similar types of visual field changes include papilledema and optic disk drusen. In the beginning stages, papilledema may give rise to an enlarged blind spot that is refractive (due to elevation of the peripapillary retina). This is followed by nasal steps, arcuate visual field defects, and concentric constriction of the visual field. Nonarteritic anterior ischemic optic neuropathy typically gives rise to altitudinal field defects, mostly inferiorly, which may also cross the horizontal meridian and involve fixation and are therefore not strictly nerve fiber bundle defects. Optic neuropathies due to axonal injury posterior to the optic nerve head, yet anterior to the chiasm, frequently produce central scotomas or diffuse visual field loss. Included in this category are optic neuritis, compressive, infiltrative, toxic and nutritional optic neuropathies, as well as Leber’s hereditary optic neuropathy and autosomal-dominant optic neuropathy.
Epidemiology
See Box 42.1 .
Genetics
See Box 42.1 .
Diagnostic workup
The diagnosis of many axonal injuries of the optic nerve can be made on the basis of neuro-ophthalmic history and examination. Neuroimaging is typically the first step when the diagnosis is not otherwise apparent, especially when there is optic nerve edema, pallor of the neuroretinal rim, central visual field loss, or visual field loss that respects the vertical meridian. Examination of the blood or cerebrospinal fluid and other imaging techniques are determined based on the specific clinical syndrome.
Differential diagnosis
See Box 42.1 .
Treatment and prognosis
Treatment and prognosis depend on specifics of the optic neuropathies. There are no proven treatments for nonarteritic anterior ischemic optic neuropathy, congenital and hereditary optic neuropathies, most traumatic optic neuropathies, and compressive optic neuropathy other than decompression of the instigating mass. Lowering the intraocular pressure has been proven to decrease the rate of progression of glaucomatous optic neuropathy. Patients with optic neuritis will recover vision more quickly when treated with intravenous corticosteroids, but the final visual outcome is the same as with placebo. Intravenous and oral corticosteroids may stop progression or save the unaffected eye in arteritic anterior ischemic optic neuropathy.
Pathology
The mechanisms responsible for optic neuropathies reflect different types of axonal injury. Major underlying causes include ischemia, demyelination, inflammation, compression, transection, glaucoma, infiltration, and papilledema. Two or more of these factors may be involved in one optic nerve disease. For example, both demyelination and inflammation are implicated in the pathogenesis of optic neuritis or other active lesions in multiple sclerosis. In multiple sclerosis, demyelination is thought to lead to loss of axonal trophic support, whereas inflammatory mechanisms may lead to either direct (immunologic attack) or indirect (through cytokines and proteolytic enzymes) axonal injury. In glaucoma, increased intraocular pressure is thought to lead to mechanical deformations of axons, disrupted axonal transport, and microvacular ischemia.
On a microscopic level, mitochondrial dysfunction, disruption of axonal conduction, disruption of axonal transport, and axonal transection can each result from the different types of axonal injury and contribute to the pathogenesis of the various optic neuropathies ( Box 42.2 ). Ultrastructurally, the first sign of axotomy-induced axonal degeneration includes a rounding and swelling of the axolemma, occurring in the first 12–24 hours following injury in rats and up to 7 days for humans. This is followed by calcium entry into the cell, the subsequent activation of calcium-dependent proteases (calpains), and activation of the ubiquitin proteosome system. These processes ultimately lead to the degradation of microtubules and neurofilaments, contributing to axonal disassembly. Wallerian degeneration demonstrates multiple dense bodies, neuroaxonal spheroids, and retraction balls at the sites of axonal transaction. Blockage of extracellular calcium channels or inhibition of the ubiquitin-proteasome system is enough to delay the processes of axonal degeneration. The importance of calcium in mediating axonal degeneration cannot be overemphasized; increasing extracellular calcium concentrations alone (in the absence of axotomy) is sufficient to cause axonal degeneration in mouse dorsal root ganglia cultures.
| Optic neuropathy | Pathogenesis |
|---|---|
| Glaucoma |
|
| Optic neuritis |
|
| Papilledema | Intra-axonal edema causing abnormalities in axonal transport |
| Arteritic anterior ischemic optic neuropathy | Occlusion of posterior ciliary arteries and infarction of optic nerve head |
| Nonarteritic anterior ischemic optic neuropathy | Decreased perfusion |
| Compressive optic neuropathies | Conduction block, ischemia, demyelination, and axonal transection |
| Traumatic optic neuropathies | Transection, avulsion, hemorrhage (direct injury) or stretch, compression (indirect injury) |
| Infiltrative optic neuropathies | Infiltration, compression of optic nerve |
The pathological end-stage of axonal optic neuropathy is optic atrophy, and this is discussed in Chapter 44 , as well as in the pathophysiology section, below.
Etiology
A variety of risk factors have been associated with optic nerve axonal injuries, including age, sex, race, family history, ocular morphology, systemic disease, nutritional factors, exposure to toxins, and possibly other environmental factors (see Box 42.2 and individual chapters for specifics). For example, optic neuritis and Leber’s hereditary optic neuropathy are more common in the young, whereas glaucoma and ischemic optic neuropathy are more prevalent in older individuals. Optic neuritis and arteritic anterior ischemic optic neuropathy are more common in women and Leber’s hereditary optic neuropathy is more common in men. Examples of ocular morphology risk factors include a greater incidence of glaucoma in myopic individuals and of nonarteritic anterior ischemic optic neuropathy in those with small, crowded optic nerve heads. Systemic disease risk factors include neurofibromatosis (optic gliomas), thyroid disease (compressive optic neuropathy), and many more. Genetic risk factors are profound in hereditary optic neuropathies, e.g., Leber’s hereditary optic neuropathy and dominant optic atrophy, but play an important role in glaucoma, optic neuritis, and disk drusen. Some studies have demonstrated that genetics may also play a role in the ischemic optic neuropathies.
Pathophysiology
As discussed above, the optic neuropathies generally arise from some form of injury to retinal ganglion axons. In some cases, the site of injury is obvious, e.g., traumatic optic neuropathies. In other cases, e.g., glaucoma, there is less direct evidence that the initial sites of injury are the RGC axons within the optic nerve head. Several studies have demonstrated that early injury occurs at the lamina cribrosa in glaucoma. Additional findings, including focal notching of the disk and splinter hemorrhages, have also helped to pinpoint the optic disk as the initial site of injury. More recent evidence from the DBA/2J mouse model of glaucoma confirms the axonal locus of injury.
The effects of the axonal injury are numerous, not only on the optic nerve and RGCs, but also on other cells. The concept of axonal degeneration has recently been reviewed ( Figure 42.1 ). This section discusses some of the major consequences of axonal injury, focusing on the following: (1) effects on the RGC body; (2) wallerian degeneration of the axon distal to the injury site; (3) retrograde degeneration proximal to the injury site; (4) effects on other neurons; and (5) effects on nonneuronal cells. There are numerous other effects, e.g., excitability, axonal conduction, and particularly changes in the dendritic arborization, which are areas of active study.
