Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Retinal Disease_Wright, Spiegel, Thompson_2006
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United Cerebral Palsy Association 7 Penn Plaza, Suite 804
New York, NY 10001 800/USA-1UCP 212/268-6655
CHARGE Syndrome
CHARGE Accounts c/o Quota Club 2004 Parkade Blvd.
Columbia, MO 65202 314/442-7604
Chronic Illness
N.O.R.D.
National Organization for Rare Disorders P.O. Box 8923
New Fairfield, CT 06812 http://www.rarediseases.org
Magic Foundation
(Optic Nerve Hypoplasia) 1327 N. Harlem Ave. Oak Park, IL 60302 709/383-0808
http://www.magicfoundation.org
Parents of Chronically Ill Children 1527 Maryland St.
Springfield, IL 62702 217/522-6810
Deaf/Blind
John Tracy Clinic 806 West Adams Blvd
Los Angeles, CA 90007 800/522-4582
Hydrocephalus
Hydrocephalus Association 2040 Polk St., Box 342
San Francisco, CA 94109 415/776-4713
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Hydrocephalus Support Group c/o Kathy McGowan
6059 Mission Rd., #106 San Diego, CA 92108 619/282-1070
National Hydrocephalus Foundation 22427 S. River Rd.
Joliet, IL 60436 815/467-6548
Lawrence Moon Bardet Biedl Syndrome
Lawrence Moon Bardet Biedl Syndrome Network 18 Strawberry Hill
Windsor, CT 06095 203/688-7880
Marfan Syndrome
National Marfan Foundation 382 Main St.
Port Washington, NY 10050 516/883-8712
Mental Retardation
Association for Retarded Citizens of the U.S. 500 E. Border St., Suite 300
Arlington, TX 76010 817/261-6003
Neurofibromatosis
National Neurofibromatosis Foundation 141 Fifth Ave., Suite 7-S
New York, NY 10010 800/323-7938 212/460-8980
Visual Impairments
American Foundation for the Blind 15 West 16th St.
New York, NY 10011 800/AF-BLIND (232-5463) 212/620-2043
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American Printing House for the Blind 1839 Frankfort Ave.
P.O. Box 6085
Louisville, KY 40206-0085 502/895-2405
Association for Macular Diseases 210 East 64th St.
New York, NY 10021 212/655-3007
The Institute for Families of Blind Children P.O. Box 54700
Mailstop #111
Los Angeles, CA 90054-0700 323/669-4649
National Association for the Visually Impaired P.O. Box 317
Watertown, MA 02272-0317 800/562-6265
Fax: 617/972-7444
(Some areas have a state organization as well; NAPVI can direct the parent)
National Organization for Albinism and Hypopigmentation (NOAH)
155 Locust St., Suite 1816 Philadelphia, PA 19102 800/473-2310 215/545-2322
Parents and Cataract Kids (PACK) c/o Geraldine Miller
P.O. Box 73 Southeastern, PA 19399 215/352-0719
Retinoblastoma International 4650 Sunset Blvd., M.S. 88 Los Angeles, CA 90027 323/669-2299 www.retinoblastoma.net
New England Retinoblastoma Support Group
603 Fourth Range Road
Pembroke, NH 03275
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General Resources
The Family Resource Coalition 230 N. Michigan Avenue
Suite 1625, Dept. W Chicago, IL 60601
(Identification of parent support groups all over the country)
Reaching Out: A Directory of National Organizations Related to Maternal and Child Health
38th and R Streets, NW
Washington, DC 20057 202/625-8400
Team of Advocates for Special Kids 100 W. Cerritos Ave.
Anaheim, CA 92805 714/533-8275
Other National Toll-Free Numbers:
American Council of the Blind 800/424-8666 Better Hearing Institute 800/424-8576 Epilepsy Information Line 800/332-1000 Cystic Fibrosis Foundation 800/344-4823 Downs Syndrome 800/221-4602
Easter Seal Society 800/221-6827
Health Information Clearinghouse 800/336-4797 Spina Bifida 800/621-3141
Fragile X Foundation 800/835-2246 American Kidney Fund 800/835-8018
National Information Center for Orphan Drugs and Rare Disease 800/336-4797
Sickle Cell Association 800/421-8453
Retinitis Pigmentosa (RP) Association International 800/ 344-4877
Local School Districts or State Departments of Special Education
Search on the Internet for most current information.
4
Heritable Disorders of
RPE, Bruch’s Membrane,
and the Choriocapillaris
Arlene V. Drack
This chapter covers disorders characterized by ophthalmoscopically visible changes in structures deep to the neurosensory retina. A prominent component of many of these conditions is the accumulation of yellowish material within and beneath the retinal pigment epithelium (RPE) associated with a progressive loss of macular RPE cells. A number of toxic and inflammatory conditions can also cause dots and spots at the level of the RPE, but these conditions can usually be distinguished by history from those in this chapter and are considered elsewhere in this volume (Chapter 11). Choroideremia, gyrate atrophy, and some forms of congenital stationary night blindness are also associated with ophthalmoscopically visible abnormalities in structures beneath the photoreceptors. However, these diseases share some psychophysical, electrophysiological, and symptomatic features with the photoreceptor degenerations and are discussed in Chapter 5. Last, myopia (Chapter 12) can be associated with several abnormalities at the level of the RPE that can be ophthalmoscopically similar to the
entities discussed in this chapter.
The disorders discussed here are a source of distress for many ophthalmologists for a variety of reasons. Some of the conditions can cause legal blindness at a relatively young age while others usually have a very benign clinical course. Despite the descriptive nature of many of their names (e.g., butterfly dystrophy), it is often quite difficult to distinguish between them in individual patients using ophthalmoscopy alone. Several different terms have been used to describe each disorder in the
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literature, and there seem to be more different classification schemes than diseases themselves.
These difficulties notwithstanding, some of these entities are common enough that they are encountered from time to time in most general and pediatric ophthalmology practices and, so long as the ophthalmologist can provide a discussion of prognosis and risk of recurrence to the affected patient and their family, then the exact name attached to the condition is of little importance.
The main goal of this chapter is to provide the general or pediatric ophthalmologist with a practical approach to patients with these disorders that will allow most cases to be correctly diagnosed with a minimum of laboratory investigation and which allow the most serious errors in diagnosis and genetic counseling to be avoided. A secondary goal is to give the reader an appreciation of the history and genetic complexity of these diseases and their potential importance to our understanding of normal and pathological macular physiology.
HISTORICAL ORIGIN OF AN OPHTHALMOSCOPICALLY BASED NOMENCLATURE
Some of the diseases discussed in this chapter were recognized shortly after the introduction of the direct ophthalmoscope and were initially thought to be inflammatory. The familial nature of these conditions was clarified in the first decades of the twentieth century. Despite the variable expressivity of many of these disorders, the near-total reliance on the ophthalmoscope for diagnosis resulted in the evolution of a descriptive nomenclature that persists to the present day.
A tacit assumption in any system that classifies diseases on the basis of their ophthalmoscopic appearance is that lesions that look alike are similar in other ways; that is, for such a system to be clinically useful, a lesion’s appearance should have some relationship to its clinical behavior. This notion is often extended to include an expectation that similar-appearing diseases have similar pathophysiological mechanisms and even similar responses to therapy.
Unfortunately, such assumptions are frequently not valid and can cloud one’s thinking; this is especially true for the
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dystrophies discussed in this chapter as well as the heritable photoreceptor degenerations discussed in the next.
INEQUALITY BETWEEN OPHTHALMOSCOPIC APPEARANCE AND BIOCHEMICAL ABNORMALITY
The mechanical analogy depicted in Figure 4-1 is useful for understanding why ophthalmoscopically similar diseases can behave very differently. At the level of ophthalmoscopy, the retina is a “black box” whose individual molecular components cannot be visualized. Only the end result of the function or dysfunction of the parts can be seen, depicted in Figure 4-1 as a pair of clock hands that move as a result of the movement of the other parts. Note that an electrical generator is also connected at one point in the power train such that additional diagnostic information can be obtained by sampling the output of the generator.
In this system, loss of gears “a,” “b,” “c,” “d,” “e,” or “f” would result in an identical result: lack of movement of the
FIGURE 4-1. Mechanical analogy of inherited eye disease. The clock face on the right-hand side of the machine represents the function of the retina (or retinal pigment epithelium) as visualized by ophthalmoscopy. The meter at the top of the machine represents a detectable voltage produced by the generator connected to gear h. The various gears inside the machine correspond to specific components, all of which must be normal if the clock hands and the electric generator are to function normally.
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hands. Measurement of the voltage produced by the generator could distinguish between lesions proximal and distal to gear “c” but not between lesions in each group. An enlargement of gear “a” would make the hands move faster, and a reduction in size would make the hands move more slowly. Thus, lesions affecting the same part can look different to the observer while lesions affecting different parts can look the same. A nomenclature based upon clock movement would not correctly group the disorders according to the components actually affected.
In human beings, the situation is further complicated by the diploid nature of the genetic material. That is, there are potentially two different blueprints (genes) for each component—one inherited from each parent. Consider the situation in which each parent carries one inactive gene for “gear a.” Both parents are phenotypically normal because their normal gene for “gear a” is capable of directing the manufacture of a sufficient quantity of that gear that all their machines still work normally. In contrast, if one of their children inherits both defective genes, the child is not able to make “gear a” at all and none of his machines work, which is the situation for disorders with a recessive inheritance pattern.
If a parent has a gene for an enlarged “gear a,” some of the machines in that parent will have rapidly moving clocks that might be detectable clinically. Any child who inherits the gene for the enlarged gear would have a similar phenotype, the situation for dominantly inherited conditions. Note that this example illustrates that different defects in the same gene can cause phenotypes with different inheritance patterns.
Suppose a fraction of the population have genes that result in clock hands that are more fragile than the rest and that this fragility causes no problems so long as the rate of clock movement is normal. If a child with fragile clock hands inherits a large “gear a” from a parent, the outcome might be more severe than if his sibling with strong clock hands inherited it. Thus, the presence of other genes (the genetic background) can alter the effect of a disease-causing gene.
The ideal nomenclature for referring to defects in the machine depicted in Figure 4-1 would precisely describe each defect; for example, “gear ‘a’ missing” or “gear ‘a’ has 32 teeth with 50% fragile clock hands.” Molecular biology is making such a component-based nomenclature a reality for ophthalmic diseases. As discussed more fully in the next chapter (Chapter 5), some retinal diseases can now be diagnosed by identifying
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the precise genetic defect to the level of a single nucleotide, allowing patients with identical defects to be grouped for study even if they are seen by different investigators in different centers. Thus, within the past few years we have been able to ascertain whether such similar disorders as Stickler syndrome and Wagner syndrome are really the same genetic and biochemical disorder.
The advent of molecular biology holds great promise not only for the diagnosis and classification of heritable diseases but also for understanding the pathophysiology well enough to design effective therapy. To return to the mechanical analogy, one would be hard pressed to design an effective therapy knowing only that the clock hands did not move. Even worse, if the patient population consisted of patients with all possible gear abnormalities, one might statistically overlook the beneficial effect of replacing “gear a” in patients lacking that part because this treatment would have no benefit in the phenotypically identical patients with defects in other components.
After extolling the virtues of molecular biology, it is important to add that this new technology in no way lessens the importance of skillful clinical ophthalmology. On the contrary, for a molecular biologist to find a disease-causing gene, clinicians must first identify families affected with the disease and correctly diagnose various family members. Moreover, as different mutations are identified in patients with inherited diseases, it will be the correlation of a clinical phenotype with each mutation that will give molecular diagnosis real prognostic power. Last, even though the clinician may be aided by the availability of molecular diagnosis, he or she still must interpret the meaning of such tests for patients and their families.
GENERAL APPROACH TO PATIENTS WITH BILATERAL LESIONS OF THE POSTERIOR POLE
Table 4-1 gives a differential diagnosis of flecks, drusen, vitelliform lesions, atrophy, and pigment disruption affecting the posterior pole. There are several general questions that apply to patients who have such lesions which should be addressed before the individual disease entities are considered.
When a lesion of the posterior pole is discovered either incidentally or because the patient has visual complaints, a few bits
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TABLE 4-1. Differential Diagnosis of Flecks, Drusen, Vitelliform Lesions, Atrophy, and Pigment Disruption in the Posterior Pole.
1.Stargardt’s disease
2.Best’s vitelliform dystrophy
3.The pattern dystrophies
4.Drusen
5.North Carolina macular dystrophy
6.Sorsby’s macular dystrophy
7.Fenestrated sheen macular dystrophy
8.Crystalline macular dystrophy
9.Congenital stationary night blindness (see Chapter 5)
10.Inflammatory lesions of the retina and retinal pigment epithelium (see Chapter 11)
11.Toxic retinopathies (see Chapter 11)
12.Myopia (see Chapter 12)
13.Systemic diseases (see Chapter 13)
14.Cone dystrophies (see Chapter 5)
of historical data coupled with some features of the clinical examination can rule out a large number of entities from the differential diagnosis. First, are the lesions bilaterally symmetrical? Most heritable dystrophies affecting the posterior pole are quite symmetrical. Of course, one eye may have already progressed to a more atrophic stage than the other eye and thus the lesions might appear ophthalmoscopically different, but it is unusual for one macula to be totally normal while the other macula has an easily observable lesion. Unilateral lesions should lead one to seriously consider other diagnoses such as choroidal hemangiomas or nevi or the sequelae of trauma or inflammation. The next information to gather is a family history. One should ask whether any relatives have poor vision even with glasses, whether anyone has been unable to obtain or keep a driver’s license, or if any have been diagnosed with “macular degeneration.” The latter diagnosis is often given to patients with familial disorders of the posterior pole who manage to reach their fifth decade before coming to ophthalmologic attention. If any relatives have accompanied the patient to the clinic, it is wise to try to examine them as well. It is not uncommon to discover macular lesions similar to those in the patient in an asymptomatic relative.
One should ask whether the patient has any difficulty seeing with dim illumination. Good questions to assess a patient’s scotopic visual function include whether the patient has unusual difficulty finding his seat in a movie theater and whether they can see individual stars on a clear night. Strongly positive answers to these questions should suggest one of the photore-