User:ETYL27/Exercise and cerebral palsy

Peripheral ulcerative keratitis (PUK) is a group of destructive inflammatory diseases involving the peripheral cornea in human eyes. The symptoms of PUK include pain, redness of the eyeball, photophobia, and decreased vision accompanied by distinctive signs of a destructive lesion of the juxta-limbal corneal stroma and possible corneal perforation. The causes of this disease are broad, ranging from injuries, contamination of contact lenses, to association with other systemic conditions. The majority of PUK is mediated by local or systemic immunological processes, which can lead to inflammation and eventually tissue damage. The most common diagnostic tests are reviewing the history of ocular infections and a complete ophthalmic examination. Two major treatments are the use of medications such as corticosteroids or other immunosuppressive agents and surgical resection of conjunctiva.

The corneal epithelium consists of five to six layers of cells with a total thickness of around 0.52mm^[1]. The cornea thickens to 0.65mm towards the periphery of the corneal^[1]. Stroma, which accounts for 90% of the corneal thickness^[1], refers to the middle layer between epithelium and endothelium. Stroma in the peripheral cornea serves as a transition zone between cornea and sclera. It is supplied by limbal vasculature deriving from capillaries at the periphery of cornea^[1]. Diffusion of various molecules occurs from these capillaries in the peripheral cornea to the central cornea. With limited diffusion, there is a higher concentration of Langerhans cells, IgM, and factor C1 of the complement cascade^[1][2].  

Any kind of inflammatory stimulus present in the peripheral cornea results in neutrophil recruitment and activation of both classical and alternative pathways of immune response, namely the humoral and cell-mediated autoimmune responses, leading to the production of antigen-specific antibodies to combat foreign antigens. However, antigen-antibody complexes formed may deposit in the vascular endothelium and activate complements leading to severe local inflammation^[3]. Under this circumstance, inflammatory cells, including neutrophils and macrophages, enter the peripheral cornea. These inflammatory cells release enzymes protease and collagenases, potentially disrupting the corneal stroma^[3]. The additional release of cytokines, for example, interleukin-1, from these cells further accelerates the process of stromal destruction^[2].

The physical signs of PUK are easily visible in the eyes, with the lesion of the juxta-limbal corneal presented in a crescent shape usually^[4]. Common reasons for destruction are stromal degradation and epithelial defects on the inflammatory cells. There would be a change in conformation of the peripheral cornea, which depends on the severity of corneal thinning accompanied by the possibility of concealing perforation^[5]. The formation of an oval-shaped ulcer at the margin of the cornea is also a sign^[4].

Symptoms of PUK include pain, redness, tearing, increased sensitivity to bright light, impaired or blurred vision, and lastly, the feeling of foreign objects trapped in the eyes^[6].

There are several causes for PUK. Injury is one of the possible causes, in which any kind of scratches by sharp or hard objects on the surface of the cornea. The scratched area forms an opening in the cornea, allowing microorganisms to access the cornea and lead to infection^[2].

Contamination of contact lenses is another cause as fungi, bacteria and parasites, microscopic parasite acanthamoeba, in particular, could inhabit the surface of the carrying case of the contact lens^[7]. When placing the contact lens to one’s eyes, invisible microorganisms may contaminate the cornea resulting in PUK. An extended period of wearing contact lenses could also cause damage on the cornea surface, allowing the entry of microorganisms to the cornea^[7].

Other than contamination of contact lenses, contamination occurring in water could also cause PUK. Especially in places like the ocean, rivers, lakes and hot tubs, massive amounts of bacteria, fungi, and parasites exist^[3]. When there is an injury on the cornea surface, coming into contact with contaminated water could transfer unwanted microorganisms into the cornea resulting in PUK. Virus and bacteria are sources of infection to the cornea. Herpes virus and bacteria that cause gonorrhea are some examples^[8].

There are several associations of PUK to ocular and systemic diseases^[2][6][9]. Rheumatoid arthritis (RA),  Wegner’s granulomatosis (WE), and Polyarteritis Nodosa (PAN) are the most common systemic conditions^[6]. Approximately 50% of PUK are associated with collagen vascular disease, in which RA is the most common category^[2][9]. Around 34-42% of PUK patients suffer from RA^[6]. Apart from RA, WG is a rare autoimmune disease associated with PUK. It causes vasculitis of the upper and lower respiratory tracts, and it also affects multiple organs, including eyes^[6]. Without timely initiation of systemic therapy, WG patients will suffer from conjunctival and scleral inflammations^[6]. The inflammation will eventually cause corneal thinning and worsen PUK^[6]. PAN is another autoimmune disease^[9] in which the body’s immune system attacks small and medium-sized arteries of its own by mistake^[6]. PUK is one of the predominant ocular inflammatory manifestations of PAN^[6].  

Mooren’s ulcer is a common form of PUK^[6]. One classification of Mooren’s ulcer, based on the clinical presentation, includes unilateral mooren’s ulcer, bilateral aggressive mooren’s ulcer, and bilateral indolent mooren’s ulcer^[6]. Unilateral mooren’s ulcer, meaning ulcer of one eye, mainly affects elderly above 60 years old. Rapid onset with redness and severe pain of the affected eye and either slow or extremely quick progression are some typical characteristics of unilateral mooren’s ulcer^[6]. Bilateral aggressive mooren’s ulcer is prevalent in Indian between age 14 to 40^[6]. The common presentation includes the appearance of lesions in one eye, followed by the development of lesions in another eye^[6]. Finally, bilateral indolent mooren’s ulcer is common in patients of at least 50-year-old^[6]. It usually progresses slowly and causes little or no pain^[6].

Other classification methods also exist. The first one is classifying Mooren’s ulcers based on clinical presentation and prognosis into two categories^[9]. The first type is usually presented unilaterally, accompanied by symptoms ranging from mild to moderate^[9]. Therefore it has a more effective response to treatment. In contrast, type II appears in a bilateral manner, with severe symptoms and poor outcome of treatment^[9]. The second classification is based on severity^[9]. Grade I refers to corneal thinning, grade II describes impending corneal perforation, and corneal perforation with a diameter greater than 2mm is grade III^[9].

Pathogenesis of PUK involves various local and systemic factors. Hence many investigative modalities are available for diagnosing specific clinical scenarios. Evaluation includes history and physical examination^[2][10], followed by systemic review^[10]. Since PUK may be the initial or presenting features of other underlying diseases, it is necessary to obtain a thorough history regarding any previous history of ocular infections, contact lens usage, other medication, or surgery^[2]. An ophthalmic examination helps identify whether it is due to local pathogenesis^[2]. Physical examinations allow more understanding of the underlying systemic process^[2].

A standard testing procedure includes hematological investigations, immunological testing, followed by chest X-ray. Hematological investigations are blood tests estimating hemoglobin, total white blood cell count, platelet count, erythrocyte sedimentation rate and viscosity^[10]. Other common body checks include renal and liver function tests and urinalysis^[10]. The selection of immunological testings for various markers is based on clinical history and examination.  Possible markers are antinuclear antibodies, anti-rheumatoid antibodies, and antibodies to cyclic citrullinated peptides^[10]. Finally, a chest X-ray helps distinguish whether there are complications, such as pulmonary diseases, due to systemic conditions associated with PUK^[10].

Ocular infections are one of the common causes of PUK. Bacteria, viruses, and fungi are microorganisms that may cause PUK^[10]. To detect the causative microorganism, doctors usually collect samples before the commencement of therapy and send them to laboratories^[10]. Laboratory personnel then perform smear examination, inoculate the samples on culture media, and perform serological testing^[10]. Serological testing is an antibody test providing information on PUK etiology^[10]. The diagnosis of PUK due to systemic conditions requires a combination of hematological and serological testing, together with imaging techniques like radiography and CT scanning^[10].

Various PUK therapies are of different objectives, for example, inflammation control, halting of disease progression, stroma repairment, avoidance of secondary complications, and vision restoration^[11]. A thorough understanding of PUK and different therapies is the key to success. Medical and surgical treatments are two major approaches to manage PUK.

As for medical therapy, there are several types of drugs available for PUK. Topical corticosteroids usually serve as therapy for milder unilateral cases of RA-associated PUK^[2]. Systemic corticosteroids in the form of an oral dose are the acute management of more severe cases^[2]. However, there are side effects with prolonged usage of oral corticosteroids. Immunosuppressive agents, such as azathioprine, cyclophosphamide, and methotrexate ^[2][9], have demonstrated efficacy in treating inflammatory eye diseases, including PUK^[2]. The combined therapy of systemic corticosteroids up to 100mg/day and immunosuppressive agents are used for severe cases of PUK^[2]. Biological agents, such as anti-tissue necrosis factors (anti-TNF), is a well-established treatment of systemic inflammatory diseases^[2]. Infliximab and Adalimumab are TNF blockers for treating RA-associated PUK^[2]. However, the high cost and uncertainty of long-term side effects are the possible drawbacks.

In terms of surgical treatment, conjunctival resection is a common procedure. Conjunctival resection can temporarily remove local inflammatory mediators and collagenases^[2] and therefore slow down the disease progression. Other surgical management includes corneal gluing, or keratoplasty procedures^[9]. Corneal transplantation is a management option when there is severe corneal melting or perforation although one possible disadvantage is the risk of rejection^[9].

Surgical treatment helps maintain the integrity of the globe, but it is usually complementary because it alone cannot influence the underlying immunological process^[2]. Therefore, medical and surgical treatments are commonly used in conjunction.

One classification method PUK patients use whether they are infectious or noninfectious. Their treatments are also different. Selection of the right targeted antimicrobial therapy for infectious PUK bases on clinical judgement and culture results^[11].  For example, the appropriate treatment for bacterial infections is antibiotics, such as fluoroquinolones^[11]. As for Mooren’s ulcers, 56% of unilateral PUK and 50% of bilateral PUK in one eye showed recovery with intensive topical steroids^[11]. Only 18% of patients with bilateral ulcers occurring simultaneously in both eyes show improvements with topical steroids alone; therefore a combination of systemic steroids and immunosuppressive agents should be given in early courses of management^[11]. Corticosteroids are the first line of therapy, but side effects may arise from long-term usage. Moreover, conjunctival resection can also be performed to temporarily remove local inflammatory mediators, followed by the use of immunosuppressants^[11].