Prevention of ophthalmological diseases in children against the background of certain intestinal pathologies

Alina A. Stadnik, Diana A. Tebueva, Milagros T. Gashimova, Angelina E. Doronina, Asiyat E. Batyrova, Ilia I. Zakharov. Prevention of ophthalmological diseases in children against the background of certain intestinal pathologies. Cardiometry; Issue No. 30; February 2024; p. 85-91; DOI: 10.18137/cardiom-etry.2024.30.8591; Available from: issues/no30-february-2024/рrevention-ophthalmological-dis-eases-children

The preservation of vision since childhood is an important area of work for any specialist in the field of ophthalmology. For this reason, the appointment of regular preventive examinations for children is extremely important. However, it must be remembered that the occurrence of ophthalmic pathologies in children may be associated with various factors, one of which is diseases of the digestive system. In particular, diseases of the digestive system can lead to a violation of the normal absorption of nutrients in the intestine, which leads to a deficiency of essential vitamins and minerals: for example, vitamin A plays a key role in maintaining eye health. In addition, various diseases of the digestive system can be accompanied by inflammatory processes and stress for the body, which has a negative impact on overall health. If the group of diseases in question has an autoimmune nature, then, in general, it can cause systemic changes in the body that affect various organs, including the eyes. Thus, the purpose of this study is to determine the directions of prevention of ophthalmic diseases in children against the background of certain pathologies of the digestive organs.

MATERIALS AND METHODS

In the process of writing the study, an analysis of theoretical and practical work was carried out within the framework of the topic raised. The works of clinicians were reviewed, individual medical histories were analyzed, and the experience of specialists in the field of ophthalmology, gastroenterology and pediatrics was systematized. Comparative, comparative and analytical research methods have been used in the work.

RESULTS

Inflammatory bowel diseases (IBD) are usually chronic in nature and mainly affect the gastrointestinal tract. Such diseases include Crohn’s disease (CD), ulcerative colitis (UC) and unclassified IBD (IBD-H). They may be associated with conditions affecting some

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other organs, which leads to the so-called extra-intestinal manifestations of IBD. According to research by specialists, extra-intestinal manifestations of IBD can affect approximately 10% to 40% of patients [1].

Ocular manifestations of IBD have been detected since the first descriptions of Crohn’s disease in 1925 and are one of the most common types of extra-intestinal manifestations of IBD, affecting approximately 2-6% of adult patients. Among the most common pathologies, experts note acute anterior uveitis and episcleritis [2]. Cases of retinal vasculitis, retrobulbar neuritis, keratopathy, orbital myositis and granulomatous dacryoadenitis have also been reported. It is believed that ophthalmic extra-intestinal manifestations of IBD is more common in CD than in UC, and they are usually associated with other extra-intestinal manifestations of IBD, such as musculoskeletal and skin manifestations. Sometimes they can precede the onset of intestinal disease [3].

Ophthalmological manifestations in children with IBD are not widely discussed in the literature. Experts note that their overall prevalence is lower in comparison with adults and ranges from 0.7% to 1.8% [4]. A number of studies have indicated a significant prevalence (from 6% to 23%) of asymptomatic uveitis (i.e., subclinical active intraocular inflammation detected only by slit lamp examination) in pediatric patients with IBD [5]. Some researchers consider it necessary to conduct periodic eye screening in children with IBD, but clear recommendations on this issue have not been noted.

Chronic diseases of the gastrointestinal tract have a multifactorial etiology, which is complex and not fully understood. The group of these diseases includes Crohn’s disease, ulcerative colitis and other pathologies. Intestinal inflammation occurs as a result of exposure to genetic, local, immunological and environmental factors. Individual specialists who conducted an associative study of the nature of the occurrence of inflammatory diseases of the gastrointestinal tract identified 50 genetic mutations predisposing carriers to the development of early IBD [6]

Symptoms of inflammatory bowel disease include diarrhea, abdominal pain, weight loss and fatigue [7]. However, ulcerative colitis in patients can provoke, on the contrary, constipation, and pain can be concentrated in the lower left quadrant of the abdomen. Crohn’s disease has symptoms such as pain in the lower right quadrant, nausea and vomiting [8].

In general, the localization of clinical manifestations of inflammatory bowel diseases occurs directly in the gastrointestinal tract (GI tract), however, their extra-intestinal manifestations may also occur, capable of affecting any organ. These can be disorders of the musculoskeletal system, as well as pathologies of the skin, mucous membranes and eyes. At the same time, the frequency of extra-intestinal manifestations of various inflammatory bowel diseases varies. Thus, it is noted in the literature that the most common pathologies that occur against the background of the development of inflammatory bowel diseases are arthritis, erythema nodosum, gangrenous pyoderma and uveitis.

Ophthalmological complications in patients with inflammatory bowel diseases can be either primary or secondary, or accidental. Most often, primary complications occur after exacerbations of IBD, experts note that such complications can be eliminated through systemic treatment. Among the primary complications are scleritis, choroiditis and keratopathy. The most common secondary complications are cataracts, which may occur as a result of corticosteroid therapy, as well as dry eye syndrome, which occurs due to hypovitaminosis A, which, in turn, may occur in the case of postresection syndrome of the short intestine.

A special group consists of accidental complications – they can occur in the general population regardless of the effect of IBD on their nature. Experts refer conjunctivitis to such accidental complications. The researchers point out that patients suffering from certain ophthalmological disorders (anterior uveitis, episcleritis or scleritis) have a higher risk of being diagnosed with IBD in the future than the corresponding patients without these symptoms. Accordingly, specialists in the field of ophthalmology should recommend their patients to undergo preventive examinations in order to detect IBD early. [9].

Episcleritis, the most common ocular complication associated with IBD, is an indicator of disease activity [10]. This self-limiting condition affects female patients more often. The limitation of the inflammatory process occurs due to the radially oriented superficial episcleral vessels of the tenon capsule. Episcleritis can be either simple or nodular. Its clinical features are sudden discomfort, lacrimation with or without photophobia, as well as mild to moderate pain in the eyeball. This disease is characterized by two forms – sectoral (rarely diffuse) redness of the episclera, or a red node arising from the episclera, in which vasoconstrictors are indicated. In this disease, visual acuity is not impaired, and there are no changes in the reaction of the pupils to light or corneal damage [11]. Most often, the main effective method of therapy is anti-inflammatory treatment of IBD. Unlike episcleritis, scleritis, a potentially blinding inflammation of the sclera, is much less common among patients with IBD (usually in 1% of cases) [12].

One of the most common eye complications in patients with IBD is uveitis. This condition can negatively affect visual acuity and even cause blindness [13]. A typical manifestation of uveitis in patients with IBD is acute anterior uveitis, a non-granulomatous type of uveitis (observed in 5% of patients with IBD), which is usually bilateral and persistent. The strongest independent risk factor for uveitis in patients with CD or UC is the coexistence of other EIM, mainly arthritis and erythema nodosum. In addition, the treatment of uveitis sometimes requires the use of immunosuppressants in patients with inflammatory bowel diseases. This confirms the idea that uveitis can be considered as a marker of the severe course of the disease.

Keratopathy associated with scleritis usually occurs in the same area as, or directly adjacent to, active scleritis. This condition can manifest itself in several clinical forms, the severity of which can vary from mild to severe. Their proper differentiation is important because they require different procedures and have a different prognosis. It is important to make the correct diagnosis and start treatment in order to prevent complications such as significant visual impairment or perforation. Clinical types of peripheral keratopathy associated with scleritis include peripheral ulcerative keratitis (PUC), stromal keratitis, and peripheral corneal thinning.

Peripheral ulcerative keratitis (PUC) is a consequence of an inflammatory disease of the peripheral part of the cornea, most often its manifestations are an epithelial defect and progressive melting of the corneal stroma with thinning of the affected area. Symptoms of the disease include pain, redness, photophobia and decreased vision. At the same time, the loss of vision due to PUC can be critical due to corneal scarring. This pathology is usually associated with systemic diseases, the most common of which are rheumatoid arthritis. It is also believed that PUC is a consequence of systemic lupus erythematosus, nodular polyarteritis, etc. However, experts report cases of this disease against the background of Crohn’s disease, although general statistics indicate that eye damage in this pathology occurs only in 10% of cases, the most common manifestations of ophthalmological pathologies are anterior uveitis and episcleritis [14].

The researchers note that ophthalmic diseases in adulthood can result from the development of gastrointestinal non-infectious pathologies that began to develop in childhood. So, as an example, we consider the case of a 32-year-old patient with a history of Crohn’s disease (diagnosed at the age of 16) seeking emergency ophthalmological care. Upon treatment, the patient experienced bilateral pain in her eyes. Upon examination in the emergency department, a bilateral PUC was found with corneal perforation associated with iris prolapse. A comprehensive examination showed that the patient also had severe extra-intestinal manifestations of Crohn’s disease, resistant to most available treatments. Experts have concluded that PUC requires timely diagnosis and aggressive treatment (of ocular and systemic diseases) to prevent related complications and vision loss. In the considered clinical case, the therapy of PUC was difficult due to an exacerbation against the background of taking medications of the underlying disease. Accordingly, it can be concluded that one of the reasons influencing the development of ophthalmic disease in the patient was the development of Crohn’s disease. The causes of this disease have not been precisely established, however, the influence of infection (mycobacteria, viruses), toxic substances, food, certain medications, genetic predisposition and autoimmune aggression are considered among the likely ones. Consequently, reducing the risk of developing gastrointestinal diseases of a non-infectious nature in childhood will reduce the likelihood of developing complex ophthalmological pathologies in the patient in the future and increase the effectiveness of their treatment [15].

Other forms of corneal lesions are infiltrates and scarring, which can occur in all layers of the cornea: epithelium, stroma and endothelium. They do not reduce visual acuity when they are located outside the visual axis. One study showed a decrease in corneal parameters, such as a smaller corneal thickness in all patients with IBD and a decrease in tear production in patients with CD. Corneal thinning and dry eye syndrome (DES) can also be aggravated by immunosuppressive therapy and anti-inflammatory drugs such as 5-aminosalicylic acid [16].

Although eye damage in patients with IBD usually affects the front of the eye, there are reports of cases and series of cases of other ocular manifestations [17]. These include inflammatory orbit syndrome (da-cryoadenitis, ptosis of the eyelids, ulcers on the edges of the eyelids, orbital myositis and pronounced ocular myasthenia gravis), retinal vasculitis (central serous chorioretinopathy, serpiginous chorioretinopathy, acute macular neuroretinopathy and macular edema), retinal vascular occlusion, retinal neovascularization, optic neuritis and pseudotumor of the brain.

Episcleritis as a benign disease rarely requires any special treatment, but it can be a sensitive indicator of an exacerbation of IBD, since these two conditions tend to manifest simultaneously. In most patients with IBD, episcleritis resolves with effective control of intestinal inflammation [18]. TNF-α inhibitors (mainly infliximab) have been shown to be effective in cases of relapses associated with IBD [19].

On the contrary, uveitis can occur regardless of the exacerbation of intestinal disease and have an insidious and persistent course. Therefore, immediate and intensive therapy is required to avoid potential complications such as glaucoma, striated keratopathy, persistent hypotension, refractory macular edema, chronic eye pain and ocular tuberculosis.

As for children’s patients, in this case, experts indicate that ocular symptoms occur in 0.3–13% of all cases of IBD; 1.6–5.4% in cases of UC; and 3.5–6.8% in cases of CD [20]. Ophthalmological disorders can occur both in the case of the manifestation of the disease itself, and be associated with taking medications. The most common ocular manifestations in patients with IBD include episcleritis (2-5%) and anterior uveitis (0,5–3,5%) [21]. Uveitis was the most common complication in children with IBD. The prevalence of episcleritis in children is usually lower than in adults, but it can be underestimated due to the possibility of asymptomatic uveitis. Children with CD may be at increased risk of developing this disease [22]. It is believed that exacerbation of episcleritis is associated with outbreaks of IBD, its relief occurs against the background of effective therapy of intestinal inflammation. However, the progression of anterior uveitis occurs independently of the activity of IBD. Experts also point out that sometimes this may be the first manifestation of intestinal disease [23].

Eye damage in IBD is a rare extra-intestinal manifestation, but it can be crucial because of poten- 88 | Cardiometry | Issue 30. February 2024

tial complications that threaten vision if not treated quickly and accurately. In addition, episcleritis in IBD is an important indicator of the activity of intestinal disease. Uveitis may precede symptoms from the gastrointestinal tract, so it is very important to ask the patient about other problems (fever, abdominal pain, weight loss or diarrhea). Ophthalmological examination should be recommended to all patients with IBD, since asymptomatic inflammation of the eye tissues is possible. Patients should be informed about the side effects of prolonged use of corticosteroids on the part of the eyes, such as cataracts and glaucoma. Moreover, some anti-inflammatory drugs used in the treatment of IBD can cause side effects from the eyes. A collaborative approach is needed in the management of such patients.

DISCUSSION

Since ophthalmological pathologies that occur in childhood can cause the development of serious eye diseases when the patient grows up, experts note the need for early prevention of not only the occurrence of eye pathologies in general, but also IBD, which can cause such pathologies. In this regard, recent studies have noted the need to influence the human microbiome as a whole. Some researchers today emphasize the existence of the gut-eye axis, where intestinal microbes can alter the immunity of the eye [24]. Accordingly, changes in the microbial composition of the intestine may be associated with various eye diseases, including age-related macular degeneration, uveitis, diabetic retinopathy, dry eye syndrome and glaucoma [25].

The use of probiotics and prebiotics is proposed as a preventive measure in this context. Probiotics are living microorganisms that have a beneficial effect on the host’s body when consumed in sufficient quantities [26]. To date, several anti-inflammatory commensal microbes are considered possible probiotics, including strains belonging to Streptococcus, Enterococcus, Bacillus, Pediococcus, Escherichia coli and Leuconostoc. However, commonly used probiotic formulations usually contain lactobacilli and bifidobacteria, which often change in some gastrointestinal and extra-intestinal disorders [27]. Reported direct or indirect benefits associated with probiotic consumption include reduction of gastrointestinal inflammation and secretion of proinflammatory cytokines, inhibition of pathogen growth, improvement of epithelial barrier integrity, and increased SCFA production [28].

By interacting with the immune system of the mucous membrane, probiotics induce the production of IgA, bacteriocins and defensins, which are then secreted into the lumen of the mucous membrane and enhance the host’s immunity. Based on these benefits, probiotics are considered a potential treatment for various diseases, including intestinal bowel syndrome, ulcerative colitis, etc.

Dry eyes is another eye disease that leads to inflammation of the eyes, for the treatment of which probiotics are considered [29]. In this regard, taking IRT5 (a probiotic mixture consisting of Lactobacillus reuteri, Lactobacillus acidophilus, Lactobacillus Casei, Streptococcus termophilus and Bifidobacterium bifidum) proved effective in restoring tear secretion in NOD. B10.H2b mice (an established model of autoimmune dry eye syndrome) [30].

Other eye diseases in which the anti-inflammatory and antioxidant effects of probiotics may benefit are glaucoma and AMD. In glaucoma, taking fermented corn emulsion rich in lactic acid bacteria can weaken the clinical signs of the disease by reducing intraocular pressure, preventing loss of ganglion cells and protecting against gliosis [31].

In general, the results of preclinical studies are promising. However, insufficient clinical data highlights the need for large cohort randomized controlled trials to confirm the preventive and therapeutic role of probiotics in the context of eye diseases.

Prebiotics are indigestible carbohydrate substances rich in fiber that serve as food for GM and benefit the host. Examples of prebiotics include, but are not limited to, galactooligosaccharides, fructans, inulin, oligosaccharides derived from glucose, and starch [32]. Given their ability to selectively promote the growth of beneficial anti-inflammatory bacteria compared to their anti-inflammatory counterparts, prebiotics have been considered as a preventive or therapeutic treatment for various pathologies, including Crohn’s disease, skin allergies and cardiovascular diseases and neurological disorders.

To date, the combined use of probiotics and prebiotics (so-called symbiotics) has been successful in reducing the clinical symptoms and parameters of inflammation (i.e., C-reactive protein (CRP), hf-CRP and the calculated erythrocyte sedimentation rate). a patient with uveitis.

Fecal microbiota transplantation (FMT) consists in transferring fresh or frozen fecal material from healthy donors into the patient’s intestine to restore eubiosis [33]. This type of therapy is currently being considered for the treatment of primary infections of Clostridium difficile, Crohn’s disease, and intestinal syndrome. The positive effects of FMT include restoration of eubiosis, reduction of inflammation, increase in the number of SCFAs and prevention of disruption of the integrity of the intestinal epithelial barrier [34]. Among the various approaches modulating the microbiota to date, probiotics are the most promising in the context of eye diseases.

CONCLUSIONS

Childhood is a period when it is very important to monitor the health of a child, since diseases that occur in the first years of life can later develop into chronic ailments and cause the development of other, more serious pathologies. The human body is a single system in which all processes are interconnected. In this regard, it is extremely important to understand the need to reduce the risk of developing inflammatory bowel diseases (IBD), which not only negatively affect the functioning of the gastrointestinal tract, but also contribute to the development of ophthalmological diseases in children. Experts have determined that exposure to the human microbiome through the use of probiotics and prebiotics can both effectively reduce the level of inflammation of the intestinal tract, and prevent or reduce the degree of development of various ophthalmological diseases. Accordingly, preventive measures related to the use of probiotics and prebiotics will allow specialists in the field of ophthalmology to increase the effectiveness of specialized therapy for eye diseases by reducing the negative effect of IBD on the child’s body.