Treatment of Stargardt's disease: the impossible became possible. Stargardt's disease and yellow-spotted fundus Stargardt's disease treatment

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Definition

Stargardt's disease (Stargardfs disease) is a degenerative macular disease, which is characterized by the presence of separate, yellow fish-shaped spots at the level of the retinal pigment epithelium. Currently, Stargardt's disease (Stargardfs disease) and fundus flavimaculatus (yellow-spotted fundus) are considered as variants of the same disease. The term fundus flavimaculatus is mainly used when characteristic spots appear, scattered throughout the fundus. When the localization of such foci is limited to the posterior pole and the process is accompanied by macular atrophy, this condition is described as Stargardt's disease.

Epidemiology and etiology

Age. The disease usually manifests itself in the first or second decade of life.

Floor. Both sexes get sick with equal frequency.

Genetics. Stargardt's disease is usually inherited in an autosomal recessive manner, although cases of dominant inheritance have been described. The gene for autosomal recessive Stargardt's disease is located on the chromosome

1. This gene encodes the ATP-binding transport protein (ABCR), which is expressed in the inner segments of the rods, but not in the retinal pigment epithelium. A homozygous mutation in the gene (ASTP / ABC) causes the appearance of fundus flavimaculatus.

Anamnesis

Typically, children with Stargardt's disease are referred to an ophthalmologist because of a gradual visual impairment that parents notice or that is detected on eye exams at school.

Clinical signs

In the initial stages of the disease, visual acuity is little changed, but in the later stages it decreases significantly. The only initial clinical sign may be the disappearance of the foveal reflex. At some point in the course of the disease, the appearance of individual yellowish "fish-like" spots localized at the level of the retinal pigment epithelium is noted. The macula may be involved in the process or remain unaffected (Fig. 6-9, A, B). With the progression of the disease, the perifoveal spotting of the retinal pigment epithelium becomes more distinct.

Rice. 6-9. Stargardt's disease.
A. Multiple, isolated, yellow "fish-like" spots (one such spot is shown in the enlarged image) are localized at the level of the retinal pigment epithelium and are distributed throughout the posterior pole of the left eye.
B. The photo of the fluorescein angiogram shows a dark background of the choroid, there is a “fenestrated” hyperfluorescence of spots in the macular region and changes in the retinal pigment epithelium. (Retina Slide Collection, Wills Eye Hospital. Philadelphia, Pennsylvania, compiled by Dr Tamara Vrabec and Or Gordon Byrnes.)

Rice. 6-10. Stargardt's disease.
A. Advanced Stargardt disease with wrought bronze macula.
B. The corresponding fluorescein angiogram shows a central zone of hypofluorescence (accumulation of the retinal pigment epithelium) surrounded by a ring of hyperfluorescence (atrophy of the retinal pigment epithelium). There is a dark or "silent" choroid (fluorescence blockade).
B. Stargardt's disease with a bull's-eye pattern in the macula. Compare with fig. 6-5, D. The appearance of "forged bronze" in the macula is noted (enlarged image). (Reproduced with permission from Dr. Eric Shakin and the Retina Slide Collection. Wills Eye Hospital. Philadelphia. Pennsylvania, compiled by Dr. Tamara Vrabec and Dr. Gordon Byrnes.)

Rice. 6-11. Stargardt's disease.
A. Severe geographic loss of the retinal pigment epithelium in the central macular region in a patient with advanced Stargardt's disease. Visual acuity decreased to 20/200.
B. On the corresponding fluorescein angiogram, unevenly located zones of hypofluorescence and hyperfluorescence are observed, with a clear rim of hyperfluorescence in the area of geographic atrophy of the retinal pigment epithelium. Outside the macula, a dark choroid is clearly visible.

Rice. 6-12. Stargardfs disease, electron micrograph. An electron micrograph shows enlarged retinal pigment epithelium cells due to intracellular accumulation of a lipofuscin-like substance. (Published with permission from Dr. Ralph Eagle. Wills Eye Hospital. Philadelphia, Pennsylvania.)

There may be atrophy of the pigment epithelium in the form of a "bull's eye", especially noticeable on fluorescein angiography. In the advanced stage of the disease, the macula acquires a classic “forged bronze” appearance due to atrophy of the retinal pigment epithelium in the central regions (Fig. 6-10, A-B and 6-11, A, B). Histopathological examination in the cells of the retinal pigment epithelium reveals an accumulation of pathological lipofyscin-like substance (Fig. 6-12).

Differential Diagnosis

Cone dystrophy. Reduced vision is observed with a normal picture of the fundus in a child.

Bull's-eye maculopathy. Such changes occur with the toxic effect of chloroquine. Batten's disease, a benign concentric annular macular degeneration.

Diagnostics

Fields of view. Central scotoma usually occurs, but paracentral scotoma and annular scotoma may also occur, especially in the early stages of the disease.

Color vision. There is a slight dyschromatopsia for red and green colors.

Dark adaptometry. Dark adaptation is slow.

Fluorescent angiography. Features that help confirm a diagnosis of Stargardfs disease include a dark or "silent" choroid; irregularly shaped, asymmetric hyperfluorescent spots that do not correspond exactly to ophthalmologically visible spots; and hyperfluorescence ("fenestrated" defect) in the form of "bull's eye" in the macula.

Electroretinography. Usually normal, but may be reduced with an increase in the number of peripheral lesions and the spread of atrophy.

Electrooculography: as a rule, slightly changed.

Prognosis and treatment

Most patients maintain an average level of visual acuity (20/70 to 20/200) in at least one eye. There is no effective treatment for Stargardt's disease.

S.E. Avetisova, V.K. Surguch

Stargardt's dystrophy occurs as a result of the transmission of a pathological gene that encodes the synthesis of the ATP carrier protein to light-sensitive retinal cells. Due to a lack of energy, these formations die off with the forcing of a dark spot in the field of vision or incorrect perception of the color gamut, as well as the shape of surrounding objects. Treatment consists of supportive care to slow the progression of symptoms.

The disease usually manifests itself in childhood or adolescence.

Etiology

Stargardt's disease is inherited and is transmitted in an autosomal dominant or recessive manner. The occurrence of retinal dystrophy does not depend on gender. In this case, there is a violation of protein synthesis, which is involved in the transport of ATP to the macular zone. This phenomenon provokes the death and disruption of the functional activity of light-sensitive cells, which is caused by a lack of energy transport to them from the choroid. There is also an accumulation of trans-retinal protein, which turns into lipofuscin, which has a toxic effect on the retina. The protein is a product of the breakdown of rhodopsin, and in the process of disease progression, its restoration is disrupted. With a dominant type of inheritance, the disease proceeds much easier.

Varieties

With the central type of pathology, the spot covers the object to which the gaze is directed.

Stargardt degeneration, depending on the location of the focus of the pathological process on the retina, can be of the following types:

Central. It is manifested by the loss of the main zone of the visual field and the appearance of scotoma at the point of gaze fixation.
Peripheral. It is characterized by the appearance of a dark spot on the side of the point of focus of the gaze.
Mixed.

Main symptoms

Stargardt's syndrome is characterized by the occurrence of such clinical signs in a patient:

poor vision of black and white objects;
damage to both eyes;
violation and misperception of colors;
the appearance of a central or peripheral scotoma;
complete blindness caused by atrophy of the optic nerve.

Diagnostic methods

To check the correctness of the diagnosis, the doctor performs an ophthalmoscopy.

It is possible to identify that a patient has Stargardt's macular degeneration by the presence of clinical signs characteristic of this pathology. To confirm the diagnosis, it is recommended to perform ophthalmoscopy, where a ring on the retina with reduced pigmentation is found. Also, pathological inclusions are determined on the macula. When color perception is detected, red-green deuteranopia is observed, when one color is seen by the patient as completely different. Electrography shows a decrease in the transmission of nerve impulses. It is also recommended to perform fluorescein angiography, which reveals a dark choroid. Perform a biopsy of the macula area with subsequent histological examination. The diagnosis is confirmed by the accumulation of a large amount of lipofuscin in the biopsy specimen. The final diagnosis is made after molecular genetic analysis and the detection of a defective gene.

DEFINITION

Stargardt's disease is a degeneration of the macular area of the retina that begins in PES and manifests as a bilateral decrease in visual acuity at the age of 10-20 years.

ICD-10 CODE

H35.5 Hereditary retinal dystrophies.

CLASSIFICATION

Four forms of Stargardt's disease are distinguished depending on the localization of the pathological process: in the macular region, on the middle periphery (fundus flavimaculatus), in the paracentral region, as well as a mixed form with localization in the center and on the periphery.

ETIOLOGY

Currently, with the help of genetic studies, it has been proven that Stargardt's disease and yellow-spotted fundus are phenotypic manifestations of the same disease with an autosomal recessive, rarely autosomal dominant form of inheritance.

Positional cloning determined the main locus of the ABCR gene for Stargardt's disease, which is expressed in photoreceptors. ABCR is a member of the ATP-binding cassette transporter superfamily. In the autosomal dominant type of inheritance of Stargardt's disease, the localization of mutated genes on chromosomes 13q and 6q14 was determined; association analysis in locus mapping for central and peripheral forms of Stargardt's disease.

PATHOGENESIS

In RPE there is an intensive accumulation of lipofuscin. It weakens the oxidative function of lysosomes, increases the pH of RPE cells, which leads to a violation of the membrane integrity.

CLINICAL PICTURE

With the central form of Stargardt's dystrophy, as the process develops, the ophthalmoscopic picture of the macular region has a different appearance: from "broken metal" to "bull's eye", "forged bronze" and atrophy of the choroid.

The bull's-eye phenomenon is seen ophthalmoscopically as a dark center surrounded by a broad ring of hypopigmentation, usually followed by another ring of hyperpigmentation. The retinal vessels are not changed, the ONH is pale on the temporal side, which is associated with atrophy of nerve fibers in the papillomacular bundle. Foveolar reflex and macular elevation (umbo) are absent.

The presence of yellowish-white spots in the posterior pole of the eye in the retinal pigment epithelium of various sizes, shapes and configurations is a characteristic feature of the yellow-spotted fundus (fundus flavimaculatus). Over time, the color, shape, size of these spots may change. Initially yellowish spots with well-defined edges may become gray with indistinct borders or disappear after a few years.

DIAGNOSTICS

Anamnesis

The time of onset of the disease (in childhood or adolescence) can play an important role in its diagnosis.

Laboratory research

Histologically, an increase in the amount of pigment in the central zone of the fundus, atrophy of the adjacent RPE, a combination of atrophy and hypertrophy of the pigment epithelium are noted. Yellow spots are represented by lipofuscin-like material.

Instrumental Research

Perimetry in all patients with Stargardt's disease reveals relative or absolute central scotomas of various sizes, depending on the timing and spread of the process from early childhood or adolescence. With a yellow-spotted fundus, no changes in the macular region are noted, the field of view may not be changed.

The form of color anomaly in most patients with a central localization of the process is like deuteranopia, red-green dyschromasia, or more pronounced.

With a yellow-spotted fundus, color vision may not be changed. Spatial contrast sensitivity in Stargardt's dystrophy is significantly changed in the entire range of spatial frequencies with a significant decrease in the medium and its complete absence in the region of high spatial frequencies - "pattern-cone dystrophy". Contrast sensitivity (on- and off-activity of the cone system) is absent in the central region of the retina within 6-10 degrees.

ERG and EOG. Macular ERG decreases already in the initial stages of the central form of Stargardt's dystrophy and is not recorded in the advanced stages.

In the initial stages of the fundus flavimaculatus ganzfeld ERG and EOG remain within the normal range: in the advanced stages, the cone and rod components of the ERG decrease, which becomes subnormal, and the EOG parameters also change. Patients with this form have no symptoms. Visual acuity, color vision, field of view are within normal limits. Dark adaptation may be normal or slightly reduced.

On FAG, with a typical "bull's eye" phenomenon, against a normal background, zones of "absence", or gynofluorescence, with visible choriocapillaries, "dark", or "silent" choroid are found. The absence of fluorescence in the macular region is explained by the accumulation of lipofuscin, which shields fluorescein. Areas with hypofluorescence may become hyperfluorescent, which corresponds to a zone of RPE atrophy.

Differential Diagnosis

The similarity of the clinical picture of various degenerative diseases of the macular region makes it difficult to diagnose. The differential diagnosis of Stargardt's disease should be made with familial drusen, fundus albipunctatus, Kandori retinal spots, dominant progressive foveal dystrophy, cone, cone-rod, and rod-cone dystrophy, juvenile retinoschisis, vitelliform macular dystrophy, and acquired drug-induced dystrophies (eg, chloroquine retinopathy).

DEFINITION

Stargardt's disease is a degeneration of the macular area of the retina that begins in PES and manifests as a bilateral decrease in visual acuity at the age of 10-20 years.

ICD-10 CODE

H35.5 Hereditary retinal dystrophies.

CLASSIFICATION

ETIOLOGY

PATHOGENESIS

In RPE there is an intensive accumulation of lipofuscin. It weakens the oxidative function of lysosomes, increases the pH of RPE cells, which leads to a violation of the membrane integrity.

CLINICAL PICTURE

DIAGNOSTICS

Anamnesis

The time of onset of the disease (in childhood or adolescence) can play an important role in its diagnosis.

Laboratory research

Instrumental Research

The form of color anomaly in most patients with a central localization of the process is like deuteranopia, red-green dyschromasia, or more pronounced.

ERG and EOG. Macular ERG decreases already in the initial stages of the central form of Stargardt's dystrophy and is not recorded in the advanced stages.

Differential Diagnosis

- a hereditary disease of the retina, which is manifested by dystrophic changes in its macular zone and leads to loss of central vision. The onset of the disease occurs in childhood or adolescence. Patients present with central scotomas and color vision disorders. The progression of Stargardt's disease leads to complete blindness. Diagnosis is carried out using ophthalmoscopy, fluorescein angiography and retinal EFI. For treatment, injection therapy (vitamins, antioxidants, angioprotectors), physiotherapy, revascularization operations are performed, and a method of autologous tissue therapy is being developed.

General information

Another name for Stargardt's disease - juvenile macular degeneration - reflects the essence of the disease: it begins at a young (juvenile) age and is characterized by damage to the macula - the receptor apparatus of the visual analyzer. The disease was described by the German ophthalmologist Karl Stargardt at the beginning of the 20th century as a congenital lesion of the macular region of the eye, which was inherited in one family. Typical ophthalmoscopic signs of Stargardt's disease are polymorphic: "atrophy of the choroid", "bull's eye", "broken (forged) bronze". Pathogenetic name of the pathology - “yellow-spotted retinal abiotrophy" - reflects changes in the fundus area.

In 1997, geneticists discovered a mutation in the ABCR gene that disrupts the production of a protein that is supposed to carry energy to photoreceptor cells. Inferiority of the ATP transporter leads to the death of photoreceptors in the retina. Various types of hereditary macular degeneration occur in 50% of cases of eye pathology. Of these, Stargardt's disease accounts for about 7%. The nosological form is diagnosed with a frequency of 1:10,000 and is characterized by a progressive course. Bilateral eye pathology begins at a young age (from 6 to 21 years) and leads to severe consequences, up to complete loss of vision. The disease has a social significance, because it leads to disability at a young age.

Causes of the development of Stargardt's disease

Inheritance does not depend on the gender of the patient and parents. Pathology is transmitted mainly by an autosomal recessive type, that is, the inheritance of the pathology is not associated with sex (autosomal - associated with non-sex chromosomes) and is not always transmitted to the future generation (recessive inheritance). According to the latest data from geneticists, the pathology of a gene can also be transmitted according to the dominant type. With a dominant type of inheritance of defects in the gene - the controller of the synthesis of the ATP transporter protein - the disease proceeds more easily and rarely leads to disability. Most of the receptor cells of the macula (top) of the macula of the fundus are functioning. In patients with a dominant type of inheritance, the disease proceeds with a minimum of manifestations. Patients remain able to work and can even drive vehicles.

The main cause of macular cell degeneration is that they suffer from energy deficiency. The gene defect leads to the synthesis of an incomplete protein that transports ATP molecules through the cell membrane of the macula - the center of the retina, in which the graphic and color image is focused. There are no blood vessels in the area of the macula. The cone cells are powered by ATP carrier proteins from the nearby choroid (choroid). Proteins transport ATP molecules through the membrane into cone cells.

Under normal conditions, photoreceptor rhodopsin absorbs a photon of light, transforming into trans-retinal and opsin. Then, trans-retinal, under the influence of the energy of ATP, which is brought by carrier proteins, is converted into retinal, which combines with opsin. This is how rhodopsin is restored. When a gene is mutated, a defective carrier protein is formed. As a result, the restoration of rhodopsin is disrupted and trans-retinal accumulates. It turns into lipofuscin and has a direct toxic effect on cone cells.

Classification of Stargardt's disease

Types of the disease depend on the prevalence of the zone of damage to the macula. In ophthalmology, the following forms of Stargardt's disease are distinguished: central, pericentral, centroperipheral (mixed). In the central form, cells in the center of the macula are affected. This is expressed in the loss of central vision. The patient develops a central scotoma (from the Greek "skotos" - darkness). The central zone falls out of sight. The patient sees an image with a dark spot at the point of gaze fixation.

The pericentral form is characterized by the appearance of a scotoma away from the point of fixation. A person is able to focus his gaze, but notices dropouts in one of the sides from the center of the field of view in the form of a crescent. Over time, the scotoma takes the form of a dark ring. The centro-peripheral form starts from the center and rapidly spreads to the periphery. The dark spot grows and completely covers the field of view.

Symptoms of Stargardt's disease

Manifestations of the disease begin at the age of 6-7 years. All patients, regardless of the type of inheritance, have central scotomas. With a favorable course, scotomas are relative: the patient sees bright objects with clear contours and does not distinguish objects with a weak color gamut. Many patients have a violation of color vision of the type of red-green dyschromasia, in which a person sees light green as dark red. At the same time, some patients do not notice changes in the perception of colors.

In the initial phase of the disease, the boundaries of peripheral vision do not change; with progression, the central scotomas expand, which leads to complete blindness. Simultaneously with the appearance of loss of central vision, its sharpness decreases. In the final stage of Stargardt's disease, the optic nerve atrophies. The person loses his sight completely. There are no changes in other organs, both in the initial and in the terminal stages of the disease.

Diagnosis of Stargardt's disease

The disease begins in childhood - this is one of the main signs for differential diagnosis. With the help of ophthalmoscopy, a wide ring of reduced pigmentation is found that surrounds the dark center. Around the pale ring, the next ring of hyperpigmented cells is noted. The painting is reminiscent of "bull's eye" or "wrought bronze". Foveolar reflex is negative. Macular elevation is not defined. When examining the macula, yellowish-white spots of various sizes and configurations are noted. Over time, the boundaries of the inclusions are blurred, the spots acquire a gray tint or completely disappear.

During perimetry in Stangardt's disease, positive or negative (the patient does not feel them) central scotomas are noted. With the central form of the disease, red-green deuteranopia develops. The peripheral form is not characterized by a violation of color perception. Spatial contrast sensitivity changes over the entire range: it is absent in the high frequency region (in the central region up to 6-10 degrees) and decreases in the medium frequency region.

In the initial stage of the disease, there is a decrease in macular electrography in the central form of dystrophy. With further progression, electrical potentials are not recorded. When dystrophy is located in the middle peripheral zone, normal electrography and electrooculography are noted in the initial stage. Then the values of the cone and rod components of electroretinography are reduced to subnormal. The disease is asymptomatic - without impaired visual acuity and color perception. The boundaries of the visual field are within the normal range. Dark adaptation is slightly reduced.

With the help of fluorescein angiography against the background of the "bull's eye" zones of hypofluorescence are not detected, capillaries, "silent" or "dark" choroid are visible. In areas of atrophy, hyperfluorescent areas of retinal pigment epithelium cells are visible. Histological examination in the central zone of the fundus determines an increased amount of pigment - lipofuscin. There is a combination of hypertrophied and atrophied pigment epithelial cells.

Molecular genetic analysis allows you to notice a gene mutation before the onset of the manifestations of the disease. To detect nucleotide substitutions, real-time PCR is performed using several DNA probes - "molecular beacons". Differential diagnosis of Stargardt's disease is carried out with acquired drug-induced dystrophies, Kandori retinal spots, familial drusen, juvenile retinoschisis, dominant progressive foveal, cone, cone-rod and rod-cone dystrophy.

Treatment and prognosis of Stargardt's disease

There is no etiological treatment. As a general auxiliary treatment, parabulbar injections of taurine and antioxidants, the introduction of vasodilators (pentoxifylline, nicotinic acid), and steroid drugs are used. Vitamin therapy is carried out to strengthen blood vessels and improve blood supply (vit. groups B, A, C, E). Physiotherapeutic methods of treatment are shown: drug electrophoresis, ultrasound, retinal laser stimulation. The method of revascularization of the retina is used by transplanting a bundle of muscle fibers into the area of the macula. A pathogenetic regenerative ophthalmic technology of autologous tissue therapy is being developed using stem cells from the patient's adipose tissue.

Stargardt's disease begins at an early age and quickly leads to visual impairment. In rare cases, with a dominant type of inheritance, vision falls slowly. Patients are advised to observe an ophthalmologist, take vitamin complexes and wear sunglasses.