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MODERN APPROACHES TO DIAGNOSTICS AND TREATMENT OF OPTIC
NEUROPATHY
Jalalova Dilfuza Zuhridinovna
Scientific supervisor.
Department of Ophthalmology, Samarkand State Medical University
Kasimov Turdali
Samarkand State Medical University, Department of Ophthalmology, 1st year clinical ordinator
https://doi.org/10.5281/zenodo.15072881
Abstract. Leber optic neuropathy is a genetic disease that causes progressive atrophy of
the optic nerve and loss of vision. The pathology occurs when a mutation in mitochondrial DNA
occurs, which is transmitted to children through the maternal line. The main symptom of the
disease is a sharp decrease in visual acuity from normal to light perception, which most often
occurs between the ages of 18 and 30. For diagnosis, ophthalmoscopy, OCT, and visual potential
tests are prescribed. The diagnosis can be confirmed using molecular genetic testing. Treatment
of Leber neuropathy includes neurometabolic drugs and long-term rehabilitation.
Keywords: Causes, Pathogenesis, Symptoms, Complications, Diagnostics, Treatment of
Leber's optic neuropathy, Conservative therapy, Experimental treatment, Rehabilitation,
Prognosis and prevention.
Introduction:
The disease is named after the German ophthalmologist Theodor Leber,
who first described 15 cases of sudden vision loss in patients from four families. The molecular
genetic basis of the disease was established in 1988 by the American biochemist D. Wallace.
Leber's hereditary optic neuropathy (LHON) occurs with a frequency of 1 case per 50
thousand people, but every ten thousandth person on the planet is a carrier of the mutation. In
Russia, the disease is more common among the population of Siberia. Men suffer from optic
neuropathy 5 times more often than women.
The disease develops as a result of mutations in mitochondrial DNA, which lead to a
disruption of the energy supply of the optic nerves and lead to their death. Up to 95% of cases are
associated with 3 types of hereditary anomalies: 3460G>A in the ND1 gene, 11778GC (ND6). The
mutation of the ND4 gene is the most common in clinical practice. Leber optic neuropathy can
also be caused by other variants of anomalies that are not well understood due to their rarity.
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Mitochondrial DNA mutations are characterized by complete penetrance, so some people
with an abnormal gene develop a pronounced clinical picture, while others remain asymptomatic
carriers throughout their lives. External triggers play a role in the development of the disease.
The most important of them are:
When the nucleotide sequence in mitochondrial DNA is disrupted, the structure of the
proteins encoded by these genes changes. Since Leber's optic neuropathy affects the ND genes
encoding proteins of complex I (NADH-ubiquinone reductase), the pathology occurs at the stage
of formation of ATP molecules. The cells of the nervous system are sensitive to the lack of energy
molecules, which leads to damage to the optic nerve.
The molecular basis of the disease is a decrease in ATP transport to the distal parts of the
axons, which leads to the initiation of apoptosis processes from the periphery. ATP deficiency is
most pronounced in the thin unmyelinated fibers that make up the optic nerve, therefore vision is
primarily affected in Leber's neuropathy. The development of pathology is facilitated by the
congenital multiplicity of axons in the optic nerve head and the special structure of the cribriform
plate.
Research methods and materials:
Leber's optic neuropathy is characterized by 3
successive stages: preclinical, acute, chronic (atrophic). The first stage is asymptomatic, but when
the patient is examined by an ophthalmologist for another reason, swelling of the optic nerve and
the appearance of telangiectasias in it are detected. The duration of this stage is not regulated, since
the disease is detected very rarely in the preclinical stage.
The acute stage of Leber's optic neuropathy most often occurs in young men aged 18 to 30
years. Patients complain of a sharp decrease in vision, similar to a central scotoma. Within 1-1.5
months, a person loses the ability to distinguish small objects, sometimes even counting fingers
up to a hundred, and only the sensation of light remains. Pathology affects both eyes
simultaneously or sequentially with an interval of 6-8 weeks.
After 6 months, the disease becomes chronic, when visual acuity is reduced to several
thousandths. During this period, nerve atrophy continues, after which the function of the eyeball
cannot be restored. The ophthalmological picture is characterized by pallor of the optic disc.
However, there are cases of reverse development of symptoms, when after some time patients
partially restore vision.
Extraocular manifestations are possible with optic neuropathy. Nerve damage can affect
more than just the optic tract, so some patients experience peripheral neuropathy, myopathy, and
muscular dystonia. If the disease manifests itself in early childhood, there is a risk of developing
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subacute necrotizing encephalomyopathy (Leigh syndrome). Sometimes, symptoms of NONLS
and MELAS syndrome overlap.
The main problem of Leber's neuropathy is loss of vision, which is especially difficult for
young patients. Against the background of blindness, severe depression develops, which can end
in suicide attempts. Since even partial restoration of vision does not occur in everyone, in the future
patients become disabled and are forced to undergo rehabilitation to adapt to new living conditions.
In some women, Leber's neuropathy occurs in the form of multiple sclerosis, with
alternating periods of exacerbation and remission. In such patients, vision loss alternates with
episodes of incomplete recovery of vision. It is characterized by the secondary development of
neurological symptoms in combination with blindness, known as Harding's disease. The pathology
is accompanied by foci of demyelination in the brain, which aggravates the clinical course.
Progressive vision loss is a reason for a comprehensive examination of the patient by an
ophthalmologist. Diagnostically important criteria: central scotoma, absence of pain syndrome,
the presence of similar symptoms in close relatives on the maternal line. The following tests are
used to confirm Leber's optic neuropathy:
Results:
Ophthalmoscopy. Fundus examination reveals swelling and waxy pallor of the
optic disc. Central disc excavation is within normal limits. In the early stages of the disease, retinal
hemorrhages are clearly visible during examination.
Visometry. It is impossible to assess visual acuity using standard tables, since this indicator
does not exceed 0.001. In practice, this corresponds to the ability to "count fingers near the face"
and distinguish silhouettes. In addition, perimetry is performed, which confirms the loss of central
visual fields.
Optical coherence tomography. Targeted examination of the macula of the retina shows
thinning and poor differentiation of all layers, flattening of the foveolar contour, and thickening of
the internal limiting membrane. OCT is the most informative method for diagnosing ON atrophy.
Visual acuity testing. Electrophysiological diagnostics of visual evoked potentials show a
decrease in nerve conduction in the preoptic area. The severity of these changes depends on the
degree of visual loss.
Molecular genetic testing. To confirm the diagnosis of Leber neuropathy, isolation of the
mitochondrial mutation is necessary. Patients are offered targeted testing for the 3 most common
point mutations and, if indicated, a multigene panel or complete mtDNA sequencing is performed.
In the acute stage, NONL should be differentiated from inflammatory diseases of the optic
nerve: retrobulbar neuritis, Devic optic myelitis, optic neuritis in rheumatic diseases. Ischemic
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optic neuropathy, which is characteristic of increased intraocular pressure, should be excluded.
The chronic stage of the disease is distinguished by compression of the optic nerve by tumors of
the orbit and chiasmatic-sellar region.
1.
Ophthalmological examination
2.
Ophthalmological examination
3.
Treatment of Leber's optic neuropathy
4.
Conservative therapy
Discussion:
For people with visual impairments, social and psychological adaptation is of
primary importance. The rehabilitation program consists of teaching independent movement,
spatial orientation, and self-care skills. All patients receive training in Braille, which allows them
to continue reading and studying. At the request of the person, labor rehabilitation and training in
skills (carving, music, sculpture) are carried out.
NONL with the 14484T>C mutation is considered prognostically favorable, with patients
having a chance of complete recovery of vision. The 3460G>A mutation has a very unfavorable
course and quickly leads to blindness. Anomaly 11778G<A has an intermediate prognosis. To
prevent the disease, patients with severe heredity are recommended to avoid provoking factors.
Conclusion:
In practical ophthalmology, there is no effective treatment regimen that would
improve the visual function of patients. Coenzyme Q10, levocarnitine, and cytochrome
preparations are prescribed as adjuvant and pathogenetic therapy. They are often combined into
"mitochondrial cocktails" to enhance their therapeutic effect. However, even long-term use of
drugs does not significantly affect clinical indicators.
Since drug therapy has not restored vision, scientists have placed great hopes in genetic
engineering technologies. Their essence is based on the transformation of mutant mitochondrial
DNA to a normal state in order to increase the ATP content in the axons of the visual pathway and
prevent nerve atrophy. Today, such methods are at the experimental stage, and some are
undergoing the first phase of clinical trials.
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