Ординатура / Офтальмология / Английские материалы / The Retina and its Disorders_Besharse, Bok_2011

stimulus, and a mean voxel intensity underneath the area without the stimulus. For any particular tissue layer, a time series of this plotted data is expected to show no change in the area without stimulus, and some change in the stimulated area, if there is a change to be observed. The hypothesis is that some layers will show change after stimulus while other layers will not. After the above mentioned normalizations, it appears that an increase larger than the noise level may occur in the inner outer segment region. The decay time for the change (20–30 min) is on the order of the time that the subject observed a persistent after image.

Although the experimental protocol differs from published protocols of studies performed in vitro in rabbit and in vivo in mouse, the key results are consistent in location and type of change. These, however, could not be convincingly repeated and are therefore presented as an illustration of the techniques used rather than an established observation. Furthermore, the results reported here were only observable in the data after several normalizations. These normalizations are logical, but should be applied with caution. Hence, measuring intrinsic optical signals with OCT in an awake human is challenging. Much needs to be done to deliver both clinically and neurologically significant results. Finally, and probably most importantly, because there is currently a lack of understanding of the physiology that produces intrinsic optical signals, it is difficult to search for the signal using the correct stimulus and measurement protocols. It seems likely that doing more work in vitro and with animal models where CCD camera techniques have been highly successful will help identify parameters that are most likely to yield a strong and relevant signal.

Conclusion

Currently, commercial fourth generation 3D ophthalmic OCT systems seem to have a significant diagnostic impact in daily clinical routine as well as novel therapeutic trials. After introducing 3D visualization of the healthy and pathologic human retina, the emphasis now shifts toward filtering out proper biomarkers from this significantly increased amount of information for improved diagnostic decisions. In this respect, it is at the moment not obvious where retinal OCT is heading. Recent developments in OCT technology significantly improved its potential for successful biomedical and clinical applications. These will also be important prerequisites for functional OCT extensions like Doppler OCT, polarization sensitive OCT, and optophysiology.

Despite several proof-of-principle demonstrations of significantly improved state-of-the-art retinal OCT imaging performance sound clinical studies on larger, properly selected patient cohorts are necessary to demonstrate the improved clinical impact and therefore verify the increased

technological effort of these novel improvements in retinal OCT modalities.

Acknowledgments

The author wants to acknowledge all members of the biomedical imaging group at the School of Optometry and Vision Sciences, Cardiff University, Alan C. Bird and Catherine A. Egan, Medical Retina Service, Moorfields, London, United Kingdom. Financial and equipment support by the following institutions is also acknowledged: Cardiff University, FP6-IST-NMP-2 STREPT (017128), Action Medical Research (AP1110), DTI (1544C), European Union project FUN OCT (FP7 HEALTH, contract no. 201880); FEMTOLASERS GmbH, Carl Zeiss Meditec Inc., Maxon Computer GmbH, Multiwave Photonics.

See also: Adaptive Optics; Primary Photoreceptor Degenerations: Retinitis Pigmentosa; Primary Photoreceptor Degenerations: Terminology; Rod and Cone Photoreceptor Cells: Inner and Outer Segments; Secondary Photoreceptor Degenerations: Age-Related Macular Degeneration; Secondary Photoreceptor Degenerations.

Further Reading

Bizheva, K., Pflug, R., Hermann, B., et al. (2006). Optophysiology: Depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography. Proceedings of the National Academy of Sciences of the United States of America

103: 5066–5071.

Choma, M. A., Sarunic, M. V., Yang, C. H., and Izatt, J. A. (2003). Sensitivity advantage of swept source and Fourier domain optical coherence tomography. Optics Express 11: 2183–2189.

de Boer, J. F., Cense, B., Park, B. H., et al. (2003). Improved signal-to- noise ratio in spectral-domain compared with time-domain optical coherence tomography. Optics Letters 28: 2067–2069.

Drexler, W. and Fujimoto, J. G. (2008). Optical Coherence Tomography: Technology and Applications. New York: Springer.

Drexler, W., Morgner, U., Ghanta, R. K., et al. (2001). Ultrahighresolution ophthalmic optical coherence tomography. Nature Medicine 7: 502–507.

Drexler, W., Morgner, U., Kartner, F. X., et al. (1999). In vivo ultrahighresolution optical coherence tomography. Optics Letters 24: 1221–1223.

Fercher, A. F., Hitzenberger, C. K., Drexler, W., Kamp, G., and Sattmann, H. (1993). In-vivo optical coherence tomography.

American Journal of Ophthalmology 116: 113–115.

Fernandez, E. J., Hermann, B., Povazay, B., et al. (2008). Ultrahigh resolution optical coherence tomography and pancorrection for cellular imaging of the living human retina. Optics Express 16:

11083–11094.

Fujimoto, J. G., Brezinski, M. E., Tearney, G. J., et al. (1995). Optical biopsy and imaging using optical coherence tomography. Nature Medicine 1: 970–972.

Huang, D., Swanson, E. A., Lin, C. P., et al. (1991). Optical coherence tomography. Science 254: 1178–1181.

Huber, R., Wojtkowski, M., and Fujimoto, J. G. (2006). Fourier Domain Mode Locking (FDML): A new laser operating regime and applications for optical coherence tomography. Optics Express 14: 3225–3237.

Leitgeb, R., Hitzenberger, C. K., and Fercher, A. F. (2003). Performance of fourier domain vs. time domain optical coherence tomography.

Optics Express 11: 889–894.

Povazˇay, B., Hofer, B., Torti, C., et al. (2009). Impact of

enhanced resolution, speed and penetration on three-dimensional retinal optical coherence tomography. Optics Express

17: 4134–4150.

Schuman, J. S., Puliafito, C. A., and Fujimoto, J. G. (2004). Optical Coherence Tomography of Ocular Disease. Thorofare, NJ: Slack.

Srinivasan, V. J., Adler, D. C., Chen, Y., et al. (2008). Ultrahigh-speed optical coherence tomography for three-dimensional and en face

imaging of the retina and optic nerve head. Investigative Ophthalmology and Visual Science 49: 5103–5110.

Swanson, E. A., Izatt, J. A., and Hee, M. R. (1993). In-vivo retinal imaging by optical coherence tomography. Optics Letters 18: 1864–1866.

Tumlinson, A., Hermann, B., Hofer, B., et al. (2009). Techniques for extraction of depth resolved in vivo human retinal intrinsic optical signals with optical coherence tomography. Japanese Journal of Ophthalmology 53(4): 315–326.

Unterhuber, A., Povazˇay, B., Hermann, B., et al. (2005). In vivo retinal optical coherence tomography at 1040 nm-enhanced penetration into the choroid. Optics Express 13: 3252–3258.

Glossary

Apoptosis – A genetically determined process of cell death that is marked by the fragmentation of nuclear DNA, occurs under both pathological and physiological conditions (known as programmed cell death).

Gadolinium – An element of the rare earth family of metals (atomic symbol Gd) used as a paramagnetic contrast agent in magnetic resonance imaging.

Isoelectric focusing – The most sensitive method for protein separation in serum and CSF using agarose gel electrophoresis.

Multiple sclerosis – A chronic autoimmune inflammatory demyelinating disease affecting the central nervous system (CNS) (synonym: encephalomyelitis disseminata).

P100 latency – The time it takes for the signal from the retina to reach the occipital cortex in the brain.

Plasmapheresis (plasma exchange) –

A technology for removing pathologic plasma constituents from anticoagulated whole blood by a machine and returning the rest to the donor, usually with saline solution and albumin.

Snellen chart – Chart that contains rows of standardized letters, numbers, or symbols routinely used to assess visual acuity at a distance of 20 feet.

Visual evoked potential – A diagnostic test that measures alterations in the speed of responses to visual events. The patients watch a black-and-white checkerboard and an electroencephalogram (EEG) measures occipital cortex responses.

Definition

Optic neuritis (Latin – neuritis nervi optici) is defined as an inflammation of the optic nerve causing a relatively rapid onset of visual failure. Inflammation may occur in the portion of the nerve within the globe (neuropapillitis or anterior optic neuritis) or in the most commonly involved portion behind the globe (retrobulbar neuritis or posterior optic neuritis).

Optic Nerve Anatomy

(3–16 mm). The diameter of the nerve increases from 1 mm at the intraocular point, 3–4 mm in the orbit, to 4–7 mm within the cranial cavity. The orbital section of the optic nerve has a slightly sinuous shape to allow for movements of the eyeball. As part of the brain, the optic nerve is surrounded by meninges. The outer dural sheath and inner arachnoid sheath merge with the sclera. Between the arachnoid sheath and pial sheath lies a cerebrospinal fluid (CSF)-filled space. The optic nerve consists mainly of fibers derived from the ganglion cells of the retina. The fibers emanating from the nasal part of each retina cross over to the other side in the optic chiasm. The nerve fibers originating in the temporal part of the retina do not cross over. From there, the mixed fibers from the two nerves become the optic tract passing through the thalamus and turning into the optic radiation until they reach the visual cortex located in the occipital cortex of the brain.

Immunopathogenesis

An early event in the development of inflammation is considered to be the activation of circulating autoreactive T lymphocytes by factors such as infection, superantigen stimulation, or effects of reactive metabolites or metabolic stress. Activated T lymphocytes interact with the venule endothelium surface to harm and break down the blood–brain barrier. Upregulation of vascular cell adhesion molecules (e.g., intercellular adhesion molecule-1 (ICAM-1)) increases vascular permeability and enables migration of T cells, B cells, and macrophages into the central nervous system (CNS). The activated antigenspecific T cells appear to develop a Th1-dominant profile with production of proinflammatory cytokines (e.g., IL-2, IFNg, and TNFa). These cytokines exacerbate the inflammation resulting in further recruitment of pathogenic inflammatory cells, which play a direct role in demyelination. Other factors such as demyelinating antibodies, proinflammatory cytokines, and other soluble mediators contribute to myelin and axonal injury. Also the humoral immunity with autoreactive B-lymphocyte expansion with IgG production plays a relevant role in autoimmune inflammation. Despite significant research

progress in this field, the antigen driving the putative cascade of autoimmune inflammation has not been identified, leaving a substantial gap in the understanding of pathogenesis.

Epidemiology

Optic neuritis typically affects young adults with a mean age of 30–35 years. The majority of patients are female. The annual incidence of optic neuritis ranges from 1.4 to 6.4 new cases per 100 000 population. The prevalence is estimated to be 115 per 100 000 population.

Etiology

Various diseases and conditions may cause optic neuritis. The first description of a relationship of optic neuritis to multiple sclerosis (MS) came from Buzzard in 1893. Nowadays, MS is recognized to be the most common etiology for optic neuritis. Up to 50% of MS patients will develop an episode of optic neuritis.

Some other causes of optic neuritis include inflammation of vessels supplying the optic nerve, infectious diseases (e.g., viral encephalitis, sinusitis, meningitis, HIV, tuberculosis, and syphilis) and autoimmune disorders (e.g., lupus erythematosus). Toxic agents can clearly influence optic nerve and retinal function. Among the common offenders are tobacco and alcohol. Drugs (e.g., salicylates, digitalis, amiodaron, and some antibiotics) can also damage the optic nerve. Rarely, tumor metastasis to the optic nerve, diabetes, pernicious anemia, Graves’ disease, and trauma lead to optic neuritis.

Some people, especially children, develop optic neuritis following a viral illness such as mumps, measles, or a cold.

Symptoms

Optic neuritis typically presents with a triad of symptoms: loss of vision, dyschromatopsia, and pain during eye movements. The major symptom is vision loss, which occurs over a period of 3–5 days and generally improves within 2–8 weeks. The visual deficit varies from a small central or paracentral scotoma to complete blindness. The initial attack is unilateral in 70% of adult patients and bilateral in 30%. Both eyes are affected with equal regularity. The visual symptoms are usually described as blurring or fogging of vision. Interestingly, some patients become aware of a unilateral visual disturbance by accident when, for some reason, the unaffected eye is covered.

Many patients with optic neuritis may lose some of their color vision in the affected eye, called dyschromatopsia. The colors appear slightly washed out compared to

the other eye. In the majority of cases, patients experience tenderness in the eye, which is associated with pain at rest or on eye movement. In some cases, pain on eye movement precedes the visual loss. Positive visual phenomena, such as a sensation of sparks and flashes of light induced by certain eye movements, occur infrequently.

Symptoms of optic neuritis include one or more of the following:

reduced visual acuity (near or far)

pain on eye movement

central scotoma

dyschromatopsia or impaired color vision

impaired contrast sensitivity

afferent pupillary defect, and

headache

Diagnosis

Optic neuritis can usually be diagnosed from a patient’s history, clinical examination, visual-evoked potentials (VEP), CSF investigation and observations from magnetic resonance imaging (MRI).

Clinical Examination

Despite the wide use of MRI and electrophysiological techniques, the diagnosis of optic neuritis depends on accurate clinical assessment. The medical history should also be assessed to determine if exposure to toxins such as lead or methanol may have caused the visual disturbance. Patients with optic neuritis typically contact an ophthalmologist first. A complete visual examination, including a visual acuity test, color vision test, and visualization of the retina and optic disc by indirect ophthalmoscopy, should be performed. However, frequently there is no abnormal appearance of the optic disk during ophthalmoscopy. Occasionally, there may be hyperemia of the optic disk and distension of the large retinal veins. At later stages the margins of the optic disk are blurred and papilledema can be found. Clinical signs such as impaired pupil response may be apparent during an eye examination, but in some cases the eye may appear normal. Central field defects predominate in patients with optic neuritis.

Visual Evoked Potential

VEP is a noninvasive technique to detect pathological changes of the visual system during optic neuritis and is used as a routine clinical test. Commonly used visual stimuli are flashing lights or patterns (e.g., checker boards) on a video screen. The main interest in electrophysiological findings for optic neuritis focus on the so-called P100 latency and VEP amplitude. During the acute phase of the

N145

N75

P100

Right

N145

N75

Left P100

Figure 1 VEP from a 25-year-old woman with a 4-day history of acute right-sided optic neuritis. VEP shows a decrease in amplitude in the affected right eye. VEP amplitude consists of potentials originating in different parts of the brain (N75: area 17; P100: area 18, 19 and partially 17; N145: area 18 and 19).

disease, a decrease in the VEP amplitude, caused by a conduction block of inflamed optic nerve fibers, is a common pathological feature (Figure 1). The depression of the VEP amplitude correlates with the visual acuity and is associated with the degree of atrophy. The prolongation of P100 latency is the main characteristic in the chronic phase and persists over years in up to 70% of patients who suffer from optic neuritis.

Magnetic Resonance Imaging

The principal use of MRI is the evaluation of patients when optic neuritis is the first demyelinating disease event. In a typical case, if accurate clinical assessment has been done, MRI is not required to diagnose and distinguish optic neuritis from other common optic neuropathies. However, the patients with other pathologies such as ischemic or acute compressive optic neuropathy due to a cerebral aneurysm or pituitary tumor may not have the typical features that distinguish these disorders from optic neuritis. In these situations, MRI, when performed with the appropriate examination technique, can make a relevant contribution to the differential diagnosis. The small size and mobility of the optic nerve and artifacts caused by surrounding CSF and orbital fat are technically challenging in optic nerve imaging. Significant progress has been made in developing fat and CSF-suppressed highresolution imaging. Use of these sequences increases the sensitivity in detecting inflammatory demyelination and optic nerve atrophy. Symptomatic lesions can be detected with sensitivities of 95% in fat-saturated fast spin-echo (FSE) imaging and 94% for the enhancing lesion on fatsaturated T1-weighted imaging following intravenous (IV) gadolinium administration (Figure 2). The abnormal gadolinium enhancement of the affected optic nerve indicates a blood–optic nerve barrier breakdown and is a consistent feature of acute optic neuritis.

Figure 2 (a) Axial and (b) coronal T1-weighted magnetic resonance images after the IV application of gadolinium.

(c) Coronal T2-weighted image from a 25-year-old woman with a 4-day history of acute right-sided optic neuritis demonstrating optic nerve swelling (arrow: diseased optic nerve; arrowhead: demyelinated cerebral lesion).

Cerebrospinal Fluid

CSF analysis is of great relevance to detect an inflammatory process in the brain. The diagnostic sensitivity of single parameters in CSF diagnostics depends on the quality of the applied techniques, especially with isoelectric focusing, and does not have a worldwide standard, such as MRI. In optic neuritis related to MS, typical changes are present in the CSF: slight pleocytosis (max. 50 leucocytes/ml), intrathecal (within the meningeal sheath) IgG production, and additional oligoclonal IgG bands, which are not present in the simultaneously examined serum. The so-called MRZ reaction (intrathecal synthesis of

antibodies against measles, rubella, and varicella-zoster) has a higher diagnostic specificity and is suggested in a European consensus report. Before the use of brain MRI, the detection of CSF pleocytosis and oligoclonal IgG bands provided paraclinical evidence of the dissemination of lesions and met the criteria for the diagnosis of laboratory-supported MS in isolated optic neuritis.

In other autoimmune disorders (e.g., lupus erythematosus and neurosarcoidosis) the cell count is moderately elevated. Verification of oligoclonal IgG bands can be achieved in up to 70% of the cases.

CSF abnormalities in optic neuritis resulting from a viral infection are not specific concerning number of cells, differential cell count, and total protein content and depend particularly on the stage of the disease.

Optical Coherence Tomography

OCT is a relatively new, noninvasive and easy-to-use technology that quantifies the thickness of the peripapillary retinal nerve fiber layer (RNFL), fovea, and macula in real time with highly refined resolution. Originally developed to investigate retinal axonal loss in glaucoma patients, OCT demonstrated a significant reduction of mean RNFL thickness in patients with optic neuritis. Hence, OCT may be useful for observing occult neurodegeneration and monitoring the efficacy of potential neuroprotective therapies in optic neuritis. Serial clinical studies in optic neuritis correlating MRI, clinical, and electrophysiological data are required to establish the use of OCT as an in vivo biomarker for axonal loss.

Differential Diagnosis

The differential diagnosis can be divided into several pathophysiological categories: inflammatory/autoimmune diseases, infectious diseases, genetic/hereditary disorders, neoplastic disease, and other demyelinating diseases. Errors in the diagnosis can be minimized if strict clinical criteria are applied and the neurologist is alert to discrepancies in the clinical picture presented (e.g., absence of pain, age of onset, and failure to remit). Also the character of visual symptoms and the type of field defect give additional important information. A slowly progressive unilateral visual failure should always suggest the possibility of compressive etiology. A central field defect can occur with a tumor but, with time, will extend to the periphery. Interestingly, spontaneous improvement in vision may occur in this case. Pain on eye movement is not confined to optic neuritis and can occur in optic nerve glioma, meningioma, and aneurysm. Any of the fundoscopic changes found in optic neuritis may be reproduced by compressive or infiltrative lesions. In such cases, MRI will significantly contribute to the correct diagnosis. The various vascular optic neuropathies generally affect a

different age group from optic neuritis and tend to have a poor prognosis.

When both eyes are involved in optic neuritis, simultaneously or sequentially, the disorder must be distinguished from Devic’s disease, Leber’s hereditary optic neuropathy, nutritional/toxic amblyopia, and functional blindness. Devic’s disease, neuromyelitis optica, is characterized by a combination of transverse myelitis and optic neuritis occurring within a finite period of time from each other, typically within weeks. Clinically, the disorder usually has monophasic presentation. The identification of serum anti-aquaphorin-4 antibodies should be helpful for differential diagnosis. Of the hereditary disorders, Leber’s optic neuropathy causes optic atrophy with acute or subacute visual loss. This disorder is maternally transmitted and can be diagnosed through genetic testing. In optic neuropathies caused by toxic agents, the overlap of the visual symptoms with those due to optic neuritis is minimal. It often presents as a painless, progressive, bilateral, and symmetrical visual disturbance. Optic nerve pallor is often found in the ophthalmologic examination. Vision loss can be presented as a symptom of Lyme borreliosis optic neuropathy, syphilis, HIV-associated optic neuropathies, and other infectious disorders. In these cases optic nerve involvement tends to be bilateral and MRI and CSF examinations should show a reliable distinction.

Treatment

Treatment of optic neuritis depends on the underlying cause. In a MS-related episode of optic neuritis a course of IV methylprednosolone followed by oral steroids has been found to be helpful. No treatment is also a viable option. The optic neuritis treatment trial (ONTT) has shown that high dose IV steroids (250 mg prednisone every 6 h for 3 days) followed by oral prednisone (1 mg kg 1 d 1 for 11 days) accelerated visual recovery but did not have any impact on the 6-month and 1-year visual outcome compared with a placebo. An interesting finding of this study was that patients who received IV corticosteroids followed by oral corticosteroids had a temporarily reduced risk of development of a second demyelinating event consistent with MS compared with those who received an oral placebo or treatment with oral corticosteroids only. Oral prednisone has been found to increase the likelihood of recurrent episodes of optic neuritis, and is not recommended for treating the disorder. Patients with severe optic neuritis, who do not respond sufficiently to corticosteroids, can undergo escalating immunotherapy with plasma exchange within 1 month of the first symptoms. In clinical trials up to 60% of patients with optic neuritis had functional improvement after 5 plasmapheresis sessions with an exchange volume of 3000 ml. Long term prophylactic immunomodulatory

therapy with interferon-beta or glatiramer acetate is recommended in patients when optic neuritis is an event of demyelinating disease with a presence of further demyelinated brain lesions shown on the MRI.

Vision loss caused by viral or bacterial infection usually resolves itself once the virus/bacteria are treated. For herpes virus infection the IV treatment with aciclovir (10 mg kg 1 every 8 h for 14 days) is recommended. In cases of borrelia infection with neurological symptoms, patients should undergo a treatment session with doxycycline 200 mg d 1 for 14–21 days. Optic neuritis resulting from toxin damage may improve once the source of the toxin is removed.

Neuroprotective Treatment Strategies

The increasing importance of axonal damage as a major substrate of clinical disability in autoimmune inflammation has led to ongoing research in developing treatment strategies that inhibit degeneration of axons and protect the neuronal cell body from apoptotic cell death. The hypothesis of achieving neuroprotective effects as a secondary phenomenon resulting from the treatment of inflammation and autoimmunity is supported by studies showing close association of axonal damage and inflammation. However, the elimination of the inflammatory component does not necessarily stop the disease progression. MRI studies showed that treatment with methylprednisolone did not limit ongoing lesion lengthening triggered by an episode of optic neuritis nor did it prevent optic nerve atrophy. A detrimental effect of corticosteroids on retinal ganglion cells (RGCs) has even been described in experimental optic neuritis. The effects of cytokines and trophic factors (e.g., erythropoietin, ciliary neurotrophic factor) on neuronal apoptosis appear to be limited; despite preventing neuronal apoptosis, these substances failed to improve visual acuity due to severe and ongoing degeneration of optic nerve fibers in autoimmune optic neuritis. For this reason, anti-inflammatory/ immunomodulatory therapies should be combined with primary neuroprotective agents. The potential neuroprotective substances are still in the experimental stage of development, and controlled clinical trials are needed to prove the efficacy and tolerance of these agents.

Prognosis

The vision loss associated with optic neuritis is usually temporary. Spontaneous remission occurs within 2–8 weeks. The majority of patients (65–80%) recover visual acuity of 20/30 (on the Snellen chart) or better. Long-term prognosis depends on the underlying cause of the condition. If a viral infection has triggered the episode,

it frequently resolves itself with no aftereffects. If optic neuritis is associated with MS, future episodes are common. Thirty-three percent of optic neuritis cases recur within five years. Each recurrence results in less recovery and worsening vision. There is a strong association between optic neuritis and MS. According to the latest literature, the probability of developing MS within 15 years after onset of optic neuritis is 50% and strongly related to the presence of lesions on a baseline non- contrast-enhanced magnetic resonance image of the brain.

See also: IOP and Damage of ON Axons; Non-Invasive Testing Methods: Multifocal Electrophysiology; Optical Coherence Tomography; Retinal Ganglion Cell Apoptosis and Neuroprotection.

Further Reading

Andersson, M., Alvarez-Cermeno, J., Bernardi, G., et al. (1994). Cerebrospinal fluid in the diagnosis of multiple sclerosis: A consensus report. Journal of Neurology, Neurosurgery, and Psychiatry 57: 897–902.

Beck, R. W. and Gal, R. L. (2008). Treatment of acute optic neuritis:

A summary of findings from the optic neuritis treatment trial. Archives of Ophthalmology 126: 994–995.

Buzzard, T. (1893). Atrophy of the optic nerve as a symptom of chronic disease of the central nervous system. British Medical Jornal 2: 779–784.

Diem, R., Sa¨ttler, M. B., and Ba¨hr, M. (2007). Neurodegeneration and protection in autoimmune CNS inflammation. Journal of Neuroimmunology 184: 27–36.

Hickman, S. J. (2007). Optic nerve imaging in multiple sclerosis. Journal of Neuroimaging 17: 42S–45S.

Hickman, S. J., Brierley, C. M. H., Brex, P. A., et al. (2002). Continuing optic nerve atrophy following optic neuritis: A serial MRI study.

Multiple Sclerosis 8: 339–342.

Kahle, W., Leonhardt, H., and Platzer, W. (2002). Color Atlas and Textbook of Human Anatomy, 4th edn. Stuttgart: Thieme.

Maier, K., Kuhnert, A. V., Taheri, N., et al. (2006). Effects of glatiramer acetate and interferon-beta on neurodegeneration in a model of multiple sclerosis: A comparative study. American Journal of Pathology 169: 1353–1364.

Maurer, K. and Eckert, J. (1999). Praxis der Evozierten Potentiale.

Stuttgart: Enke.

Perkin, G. D. and Rose, F. C. (1979). Optic Neuritis and Its Differential Diagnosis. Oxford: Oxford University Press.

Poser, C. M. and Brinar, V. V. (2007). The accuracy of prevalence rates of multiple sclerosis: A critical review. Neuroepidemiology 29: 150–155.

Sergott, R. C., Frohman, E., Glanzman, R., and Al-Sabbagh, A: OCT in MS Expert Panel (2007). The role of optical coherence tomography in multiple sclerosis: Expert panel consensus. Journal of the Neurological Sciences 263: 3–14.

The Optic Neuritis Study Group (2008). Multiple sclerosis risk after optic neuritis. Archives of Neurology 65: 727–732.

Trapp, B. D., Peterson, J., Ransohoff, R. M., et al. (1998). Axonal transection in the lesions of multiple sclerosis. New England Journal of Medicine 338(5): 278–285.

Wingerchuk, D. M. and Lucchinetti, C. F. (2007). Comparative immunopathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis. Current Opinion in Neurology 20: 343–350.

A P Adamis, University of Illinois, Chicago, IL, USA

ã 2010 Elsevier Ltd. All rights reserved.

Glossary

Angiogenesis – The formation of new vessels from differentiated vasculature.

Chemoattractant – A chemical agent that induces cell migration (chemotaxis) toward the agent. Embryogenesis – The phase of prenatal development involved in the establishment of the basic body form.

Hypoxia – A decrease below normal in the oxygen levels of a tissue.

Ischemia – Local loss of blood supply, with concomitant hypoxia, due to mechanical obstruction or degeneration of blood vessels. Neovascularization – Proliferation of blood vessels in tissues not normally containing them or proliferation of blood vessels of a different kind than usual.

Uveitis – Inflammation of the uveal tract, which includes the iris, ciliary body, and choroid. Vasculogenesis – Blood vessel formation occurring de novo from embryonic endothelial precursor cells (angioblasts).

Introduction

Research into the physiological development of the retinal vasculature and various ocular neovascular diseases has led to a deeper understanding of the molecular and cellular mechanisms underlying normal and pathological retinal vascularization. During embryogenesis, the developing retina is initially supplied by the hyaloid vasculature, which is then supplanted by a vascular plexus that originates at the optic nerve head and spreads peripherally. Subsequent remodeling and pruning leads to the formation of two additional parallel networks in the nerve fiber and inner plexiform layers, together with a circular avascular zone at the fovea.

Two basic mechanisms, vasculogenesis and angiogenesis, underlie the formation of new blood vessels; their relative contribution to the formation of the superficial retinal vasculature is a focus of some disagreement. Vasculogenesis, the differentiation of blood vessels from angioblasts, has been proposed as the mechanism for the formation of primary retinal vascular plexus, with deeper

layers developing by angiogenesis; in contrast, it has been argued that all three vascular layers develop through angiogenesis, the formation of new vessels from differentiated vasculature. This process involves both sprouting from differentiated tip cells as well as intussusception, the splitting of existing vessels. The question as to the importance of vasculogenesis ultimately depends on the cellular identity of retinal precursors, and it is possible that some of the discrepancies may reflect species differences among mammals.

With respect to pathological retinal neovascularization, there is general agreement that angiogenesis is the driving mechanism. Many retinal neovascular conditions are associated with ischemia, with the resultant hypoxia leading to the upregulation of proangiogenic molecules. Depending on the particular disease, different pathophysiological mechanisms lead to a common endpoint of local ischemia and neovascularization. In central retinal vein occlusion, ischemia is a direct result of venous blockage. In proliferative diabetic retinopathy (PDR), the mechanism is more complex; the accumulation of polyols, reactive oxygen intermediates, and advanced glycation end products results in inflammation accompanied by retinal leukostasis leading to vascular injury, capillary blockage, and dropout. A third mechanism for ischemia-mediated neovascularization is seen in retinopathy of prematurity (ROP) in which premature birth interrupts the normal retinal vascular development; not only is postnatal tissue oxygen significantly higher than in utero but the effects are compounded by the use of oxygen therapy as well. Ultimately, these high oxygen levels lead to an increased rate of vascular pruning with ischemia-mediated increases in vascular endothelial growth factor (VEGF) levels and the resultant rebound aberrant neovascularization, which can be accompanied by retinal detachment. Finally, it should be noted that not all pathological retinal neovascularization is related to hypoxia since it is also observed in inflammatory conditions such as severe uveitis.

Promoters and Inhibitors of Angiogenesis

Over the past two decades, the identification and study of modes of action of proangiogenic and antiangiogenic factors have yielded an extensive list in both categories (see Table 1). While much of this work has been directed to developing treatments for cancer, considerable progress has also been made in elucidating the importance of these factors in ocular neovascular diseases. This article

Transforming growth factor-b (TGF-b)

Vasculostatin Vasostatin (calreticulin

fragment)

Reproduced from: Angiogenesis Foundation. Understanding angiogenesis. List of known angiogenic growth factors. Available at: http://www.angio.org/understanding/content_understanding. html.

Table 2 Actions of VEGF in promoting angiogenesis

. Endothelial cell mitogen

. Endothelial cell survival factor

. Chemoattractant for bone marrow-derived endothelial cells

. Chemoattractant for monocyte lineage cells

. Inducer of synthesis of endothelial nitric oxide synthase and consequent elevation of nitric oxide, itself a promoter of angiogenesis

. Inducer of synthesis of enzymes promoting blood vessel extravasation

Matrix metalloproteinases Plasminogen activator

examines the evidence for those molecules whose roles are best understood in the context of pathological retinal angiogenesis.

Promoters of Angiogenesis

Vascular endothelial growth factor

VEGF (also known as VEGF-A) is a 45-kDa homodimeric glycoprotein that is the most potent known promoter of angiogenesis. It exists in a variety of isoforms and acts as a ligand for two receptor tyrosine kinases: VEGF receptor-1 (VEGFR1) and VEGF receptor-2 (VEGFR2). As a key regulator of angiogenesis, VEGF has a variety of proangiogenic actions (Table 2). Given the importance of ischemia in many retinal neovascular diseases, it is of particular relevance that retinal expression of VEGF is upregulated by hypoxia. In addition, it is an extremely potent known promoter of vascular permeability, 50 000 times stronger than histamine, thereby contributing to the edema that is often a central factor in vision loss.

The importance of VEGF in pathological retinal neovascularization has been established from both clinical and preclinical studies. The clinical work is correlative, demonstrating that ocular VEGF levels are increased in diseases such as diabetic retinopathy (DR), diabetic macular edema (DME), ROP, neovascular glaucoma, and retinal vein occlusion and in choroidal neovascular membranes from eyes of patients with age-related macular degeneration (AMD). With respect to the preclinical work, elevations of VEGF, whether by laser-induced retinal vein occlusion, direct injection, or transgenic approaches, all have proved capable of inducing ocular neovascularization.

Moreover, VEGF elevation has also been shown to be necessary for the neovascular response since blocking VEGF signaling prevents blood vessel growth. The approaches employed in these experiments have included the use of anti-VEGF antibodies or fragments thereof, an anti-VEGF aptamer, VEGFR fusion proteins, a nonangiogenic isoform of VEGF, antisense oligonucleotides, and small interfering RNAs. This work already has resulted in the clinical approval of two agents for the treatment of

AMD, pegaptanib and ranibizumab. Additionally, bevacizumab, a monoclonal antibody related to ranibizumab, increasingly is being used off-label for the treatment of AMD and other ocular neovascular diseases while VEGFTrap, a fusion protein combining components of both VEGFR1 and VEGFR2, currently is being examined in a phase 3 trial as a treatment for AMD.

Studies have further demonstrated that ocular neovascular diseases such as AMD and DR bear many hallmarks of an inflammatory process, with VEGF acting as a proinflammatory cytokine. Genetic studies have revealed that the risk of AMD is strongly correlated with polymorphisms of several components of the complement cascade. In addition, retinal leukostasis is believed to be important in the capillary dropout characteristic of DR, leading to the development of ischemia. Furthermore,

while the molecular mechanisms involved in ischemiamediated ocular neovascularization remain to be fully elucidated, the influx of inflammatory cells, including monocytes/macrophages (Figure 1) and neutrophils, is important for its development. Both of these cell types release VEGF. Since VEGF acts as a chemoattractant for macrophages while upregulating the expression of intercellular adhesion molecule-1 (ICAM-1), a molecule that promotes leukocyte adhesion, on influx of these inflammatory cells provides an inherent positive-feedback mechanism promoting neovascularization.

In detailed studies of VEGF action, the VEGF165 isoform proved to be especially active as an inflammatory cytokine, since it was highly expressed during ischemiamediated neovascularization. VEGF165 was also more potent than VEGF121, another common isoform, both

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