**Author details**

Purificación Ballester, Pilar Zafrilla, Raúl Arcusa, Alejandro Galindo\*, Begoña Cerdá and Javier Marhuenda Faculty of Health Sciences, Pharmacy Department, Catholic University of Murcia, Murcia, Spain

\*Address all correspondence to<EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


*Edited by František Pollák and Peter Markovič*

*Brand Management* discusses several issues of marketing management within the limits of marketing communication. Chapters address such topics as Internet marketing, the transition from offline to online in the process of building brand equity, standardization versus adaptation of brand elements in international markets, and "living" the brand.

ISBN 978-1-80355-999-5

Brand Management

Published in London, UK © 2022 IntechOpen © zefart / iStock


*3.1.3. Horizontal gene transfer*

Horizontal gene transfer is reported as the main source of evolution of pathways in bacteria [123, 124]. Sequencing results of genomes from different bacterial strains have revealed the presence of acquired genes in mosaic like fashion throughout bacterial genomes. Their presence varies from almost negligible (*Rickettsia prowazekii* and *Mycobacterium genitalium*) to about 17% (in *Synechocystis* strain) [123]. Plasmids also play a major role in carrying catabolic genes during horizontal gene transfer [125]. Transposons are also known to facilitate the catabolic gene transfer processes [126].


**6. Conclusion**

The HAART has as one of its major collateral effect the lipodystrophy syndrome. There is necessity of more studies to deep into physiopathology of this syndrome; and metabolic and cardiovascular complications secondary to HAART. Dyslipidemia stands out as one of the most prevalent metabolic changes in patients with HIV, what makes it essential to feasibility of research in therapeutic care to clarifying of the clinical management. It is noted that nutritional guideline and/or hypolipidemic use, when have there been acceptance to treatment, takes place improvements of the lipid profile, can also there be normalization of those levels, in particular of the triglyceride levels. However, the adherence neither always takes place, what difficult the management of those patients.


Childhood Glaucoma and Medical Treatment: An Up to Date

*Antonio Greco, Marco Giuseppe Leto, Andrea Greco, Riccardo Merli and Agostino Salvatore Vaiano*

### **Abstract**

Successful treatment of paediatric glaucoma presents many challenges, with IOP control as the first but not the only priority. In paediatric cases medical therapy may play different roles: it could be an important resource for preparing patients for surgical intervention through clearing cornea, it may help control IOP postoperatively or it may be the initial and often the mainstay pillar for clinical management. Besides inadequate IOP reduction, multiple factors conspire against the success of long term medical therapy in paediatric glaucoma: the difficulties with long term adherence, more than in adults, adequate ascertainment of drug-induced side effects and potential adverse systemic effect of protracted therapy among others. Many medications are available for glaucoma management but many of them still carry a warning that "safety and efficacy in paediatric patients have not been established". An "Up to date" of medical options for childhood glaucoma is the core aim of this chapter, hoping it could be useful for the daily clinical decision process.

**Keywords:** juvenile glaucoma, childhood glaucoma, glaucoma, paediatric glaucoma, therapeutic management, primary congenital glaucoma

### **1. Introduction**

Treatment of paediatric glaucoma presents many challenges, with IOP control being the first but not the only priority. In paediatric cases, medical therapy may play different roles: it could be an important tool for preparing patients for surgical intervention by clearing the cornea, it may help control IOP post-operatively or it may be the initial step and often the mainstay of clinical management. In addition to inadequate IOP reduction, multiple factors conspire against the success of longterm medical therapy in paediatric glaucoma: these include, among other things, the difficulty of ensuring long-term patient compliance, which is a problem in children more so than in adults, and inadequate assessment of drug-induced side effects and potential adverse systemic effects of protracted therapy. Indeed, as pointed out in a review by Samant et al. in 2016 "the goal of medical therapy for glaucoma in children should be to achieve target IOP while minimizing side effects and maximizing compliance" [1]. The core aim of this chapter is to provide an "update" of medical options for childhood glaucoma, in the hope that it might be useful for everyday clinical decision making.

### **2. Definition, classification and epidemiology**

Childhood glaucoma is a rare, heterogeneous group of diseases characterised by progressive ganglion cell loss, as in adult forms. Often vision-threatening, these diseases present special challenges in terms of diagnosis and management: the clinical presentation of glaucoma varies with the age of onset and the severity of IOP elevation and clinical examination, as well as the administration of drugs, may be exceedingly difficult. Several classifications of paediatric glaucoma have been proposed: differences are based on the chosen criteria, such as anatomical parameters, the age of onset, the presence/absence of associated systemic disorders and hereditary factors. Most classifications distinguish between primary and secondary glaucoma. Although this classification system is far from ideal, it is the one most commonly used, also because our somewhat limited knowledge today precludes a more meaningful conceptual classification.

The classification approved by the *European Glaucoma Society* is the following:

According to a US population-based survey published in 2013, the incidence of paediatric glaucoma was 2.29 per 100,000 residents, and secondary glaucoma was the predominant type [3].

PCG occurs more frequently (1:1250–1:70,000) in Eastern Europe, in the Middle East, within the Roma population and in southern India, where parental consanguinity may play a role in the increased incidence [4–8].

There is no clear sex or racial-ethnic predisposition to PCG (except where consanguinity or a small population size may play a role).

Most PCG cases occur sporadically; only 10–40% of cases are familial, usually with autosomal recessive inheritance and variable penetrance [4–12]. Thus far, two main causative genes have been reported: the CYP1B1 gene, on the GLC3A locus, and the LTBP2 gene, possibly on the GLC3C locus [13–16].

### **3. Clinical features**

PCG commonly presents bilaterally (65–85% of cases) [17, 18] although significant IOP elevation may occur in only one eye in 25–30% of cases. Several ocular

### *Childhood Glaucoma and Medical Treatment: An Up to Date DOI: http://dx.doi.org/10.5772/intechopen.100579*

features, with the exception probably of those emerging from gonioscopy, are not unique to PCG, as they may be a part of any childhood glaucoma occurring during the first few years of life. For example, it is common to observe, in all forms of glaucoma, an enlarged cornea (megalocornea, defined as a cornea wider than 13 mm in children) and high long axis-related myopia; these findings are attributable to the effect of an uncontrolled IOP on a more distensible eye in children than in adults. Stretching of the infant eye is not limited to the cornea and may involve the whole globe (AC angle structures, sclera, ONH) [19].

Infants with PCG usually undergo ophthalmologic evaluation because the paediatrician or the parents have noticed one or more of the following classic symptoms (triad): epiphora, photophobia (which results from corneal oedema and is manifested by the child hiding his/her face when exposed to bright light or even just light in severe cases) and blepharospasm, which may be considered as another sign of photophobia. Other symptoms and signs that may manifest themselves include lack of eye contact, facial birthmarks, pupillary abnormalities and nystagmus, but these account for less than 2.3% of symptoms at first presentation [20]. The severity of presenting signs and symptoms varies among infants, probably as a function of the magnitude and duration of IOP elevation.

In children with glaucoma onset after 1 year of age, fewer signs and symptoms may occur due to decreased eye expansibility.

IOP measurement in an infant or child should ideally be performed in the doctor's office so as to avoid causing trauma to the child, also because performing tonometry on an uncooperative child will invariably produce falsely elevated readings, which are not useful for the diagnosis of PCG or follow-up of an already diagnosed PCG. Handheld devices such as the Perkins, Tono-Pen and I-Care tonometers are useful in the case of babies, whereas in the case of more collaborative children older than 3 years of age a Goldmann applanation tonometer can be used. Infants with PCG commonly present with unanaesthetised IOPs in the range of 30–40 mmHg, although occasionally values above or below this range occur [9]. As in adults, the target pressures depend on the details of the particular case, although, as shown by G. Sinha et al. an IOP greater than 30 mmHg will result in a greater visual field loss. The most common visual field defect in PCG is arcuate scotoma, according to G. Sinha et al. [21, 22].

Measuring IOP under anaesthesia is sometimes necessary but should be combined, for the sake of convenience, with an overall assessment of the whole eye/eyes (optic nerve photographs, axial length and gonioscopy). When IOP is measured during general anaesthesia, account must be taken of the possible variations due to the anaesthetics used; the effect of the latter may be dose- and/or time-dependent:

Many paediatric anaesthesiologists routinely use inhalational agents (halogenated agents like isoflurane and sevoflurane) before obtaining intravenous access and placing an airway device. They are known to decrease IOP by suppressing the diencephalon, which has a direct effect on IOP [23]. Park et al. found a mild to moderate IOP decrease 3 min after administration of halogenated agents. Propofol, an intravenously administered sedative agent used commonly for maintenance, may cause a sharp IOP drop [24].

In the case of ketamine—which has been used routinely for procedural sedation in children [25]—the effects on IOP have not been so clearly determined: some suggest an increasing effect on IOP [26], probably by virtue of an increase in extraocular muscle (EOM) tone, whereas others report no effect [27, 28]. Another drug causing an IOP increase is succinylcholine; the increase is usually transient, with a peak at 20–30 s postinjection, and it is due to drug-induced EOM contraction as in the case of ketamine [29].

### *Vision Correction and Eye Surgery*

Midazolam is an anxiolytic and sedative often used as a preoperative medication in children. Most studies show no significant effect of midazolam on IOP [30]. Further information is given in the table below (**Table 1**).

In 2017 Mikhail et al [30]. identified a few rules for obtaining an accurate IOP measurement during an examination under anaesthesia (EUA):

The role of central corneal thickness (CCT) evaluation in children as opposed to adults has yet to be determined: in several children with PCG, the CCT has shown to be smaller than in other children [34], but eyes with aniridia have a thicker central cornea than normal, as do eyes with aphakia, particularly those with aphakic glaucoma [33, 35–41].

Gonioscopy provides vital anatomic information about the mechanism of glaucoma in a given eye. The structures composing the angle in a healthy infant appear slightly different from those in a healthy adult eye: Schwalbe's line is less distinct, the trabecular meshwork (TM) is less pigmented and the junction between the scleral spur and ciliary body is less clear. In PCG infants the iris usually has an insertion that is more anterior to the TM, while the angle is usually avascular; anomalous iris vessels may also be seen as loops branching from the major arterial circle (MAC) (the so-called Loch Ness monster phenomenon) and the other structures seems to be covered by a translucent veil known as the Barkan membrane [42–45].

An evaluation of the optic nerve head (ONH) is of central importance also in paediatric glaucomatous patients, not only for the purpose of diagnosis but also for assessing the response to therapy; associated fundus abnormalities may sometimes help confirm the glaucoma type (for example a stalk in persistent foetal vasculature, foveal hypoplasia in aniridia or choroidal hemangioma in Sturge Weber syndrome). Like adults with glaucoma, children with PCG have an increased cup-to-disk (CD) ratio, but unlike in the case of the former, in children the cup enlarges circumferentially [46]. Cupping proceeds more rapidly in infants than in adults and it is reversible—though there are exceptions to the rule—if the pressure is lowered

*Childhood Glaucoma and Medical Treatment: An Up to Date DOI: http://dx.doi.org/10.5772/intechopen.100579*

### **Table 1.**

*Data drawn from [31].*

*Relationship between IOP and anesthesia (drugs and related procedures).*

sufficiently, thanks to the high resilience of ONH connective tissue and the elasticity of the lamina cribrosa in children [47]. An improvement in ONH appearance does not necessarily lead to a visual field gain.

### **4. Medical management: general considerations**

Although childhood glaucoma often requires surgery as soon as possible, goniotomy, trabeculotomy etc., medical therapy may in any case play different roles, e.g. in preparing patients awaiting surgery—according to data from the British Infantile and Childhood Glaucoma (BIG) Eye Study, 81% of PCG subjects had medication before an operation—and aiding in the management of IOP postoperatively, and it may be the initial and often the mainstay therapy for juvenile open-angle glaucoma and other secondary forms of glaucoma, such as those occurring in aphakia or with uveitis. In children with glaucoma, medical therapy is used more often in the management of secondary glaucoma rather than the primary congenital form; however, IOP is successfully controlled (the goal being to reach a pressure less than or equal to 21 mmHg) through the administration of drugs alone in only 32% of patients with the congenital form, while the same target is reached in 86% of cases with a secondary childhood glaucoma, according to data from the BIG Eye Study [2]. Multiple factors conspire against the success of long-term medical therapy in paediatric glaucoma: the difficulty of ensuring longterm adherence to treatment protocols, a bigger problem in children than in adults, inadequate assessment of drug-induced side effects and potential adverse systemic effects of protracted therapy, among others.

A large variety of drugs are available for intraocular pressure control but little is known regarding their use in the paediatric population; there is scarce evidence, especially as regards the latest prostaglandin analogues (tafluprost), or none at all, as in the case of the newest Rho kinase inhibitors. This is partly due to the

secondary role covered by medical therapy in children and partly to greater difficulties in conducting prospective studies due both to ethical issues and to intrinsic difficulties in their evaluation. Moreover, changes in the European regulatory framework were introduced in 2007 (Official Journal of the European Union, Regulation (EU) No. 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use) with the aim of ensuring that paediatric medicines were subject to research of high quality; this changed the clinical and pharmaceutical practice of prescribing medicines to children in Europe.

At present, few data are available from prospective clinical trials on the efficacy and safety of a defined therapeutic scheme for the medical management of paediatric glaucoma; to our best knowledge, the Glaucoma Italian Paediatric Study (GIPSy) is the only interventional study where a predefined therapeutic scheme seemed to be effective in the management of PCG (the sample included patients in whom IOP was insufficiently controlled after a single surgical procedure) [48].

This review provides an overview of the latest evidence available in the literature for every category of drug used in paediatric glaucoma treatment, as well as the more promising prospects in this field.

### **5. Carbonic anhydrase inhibitors**

### **5.1 Specific Drugs: Carbonic anhydrase inhibitors**

Carbonic anhydrase inhibitors reduce the secretion of the hydrogen ion and increase the excretion of bicarbonate, potassium, sodium, and water, which in turn decreases aqueous humour secretion [49].

They are metabolised in the liver by cytochrome P450 and afterwards excreted principally with urine. They are the only class of anti-glaucoma drugs available for both oral and topical administration, but to date none have been licenced for use in glaucomatous children. Oral intake also produces slight diuresis.

Systemic CAIs are usually administered in addition to a topical treatment, but their side effects limit their use. The recurrence of side effects in the paediatric population has not been clearly determined due both to the wide spectrum of their manifestations and the lack of prevalence studies in this particular group. According to Moore and Nischal, they occur in more than 40% of cases: headache, dizziness, paraesthesia, asthenia, nausea, epistaxis and hypersensitivity reactions (including urticaria, angioedema and bronchospasm), just to mention a few. Although in adults the risk of aplastic anaemia has been reported to increase with higher intakes, this does not seem to be the case in children [50]. Metabolic acidosis may occurs in infants and toddlers; its manifestations include rapid breathing, poor feeding and poor weight gain and may be somewhat ameliorated with oral sodium citrate and citric acid oral solution (Bicitra, 1 mEq/kg/day) [9].

In 2010 Sharan et al*.* retrospectively evaluated the weight gain in 22 patients who had been taking acetazolamide orally for three months at least; the purpose was to detect the real impact on growth of the intake of CAIs, growth retardation being the largest complaint made by several paediatric ophthalmologists. According to their results "acetazolamide does not cause significant weight changes in cases of pediatric glaucoma" [51].

In patients aged 1 month to 12 years acetazolamide is well tolerated when administered orally with food or milk three or four times daily (dosage 10–20 mg/kg, maximum daily dosage 750 mg); in teenagers the recommended daily dosage is 0.5–1 g [20, 50]. According to Portellos et al., the mean IOP reduction with systemic therapy

was approximately 35%, compared with 25% for topical therapy [52]. In a series of 22 paediatric glaucoma patients aged 8 months to 15 years, a combined administration of topic and systemic CAIs was reported to reduce IOP further than when either drug was used alone [20]. Oral or intravenous CAI administration is contraindicated in patients with meiopragic kidneys, hypokalaemia or hyponatraemia or metabolic acidosis. Allergy to sulfa drugs should be evaluated due to hypersensitivity cross-reactions.

Topical CAIs, such as dorzolamide, are an effective alternative to oral acetazolamide, as they are well tolerated and have a greater IOP-lowering effect in children than in adults [20]. In one study the effectiveness of brinzolamide was compared to that of levobunolol in children with glaucoma younger than 6 years of age; both drugs were well tolerated, but a greater efficacy of brinzolamide was shown in patients with glaucoma associated with systemic disorders (e.g. Sturge-Weber syndrome) or ocular abnormalities than in patients with primary congenital glaucoma [52]. Dorzolamide should be avoided in children with a compromised cornea due to the risk of irreversible corneal decompensation [53].

### **5.2 Beta-adrenergic antagonists**

Since the introduction of timolol in 1978, B-blockers have played a central role in glaucoma treatment. Controlling aqueous humour production is the main purpose of this class of drugs: the influence of these agents on aqueous formation may be related to inhibition of the catecholamine-stimulated synthesis of cAMP, as has been demonstrated in rabbit studies [54, 55].

The drugs belonging to this group can be split into different categories according to the presence or the absence of selectivity for a specific adrenergic sub-receptor type and the presence or the absence of an intrinsic sympathomimetic activity (ISA) [further information is shown below in **Table 2**].

There have been a number of studies concerning the treatment of paediatric glaucoma with timolol. In many cases, timolol was added as an adjunct to other IOPreducing drugs the children were already taking for their glaucoma; only a few studies evaluated the effect of timolol alone [56–60]. As noted by Plager et al. in 2009*, "*published works were not, for the most part randomized, masked clinical studies" [61].

Timolol is commercially available at 0.1, 0.25 and 0.5% concentrations in aqueous and gel-forming solution.

The drop in IOP seems to be between 20 and 25% [56, 57, 59–63], even though different types of paediatric glaucoma may respond differently (or not at all) [63, 64]: for example, in a double-masked, randomised study comparing a 0.5% levobetaxolol suspension to a 1% brinzolamide suspension, J.T. Whitson et al. found the former drug to be more efficacious in subjects with primary congenital glaucoma and less efficacious in secondary glaucomas, especially in aphakic glaucoma, which was the prevalent type in that study [54]. According to Boger and Walton, timolol provides a good or at least modest benefit in patients with several categories of glaucoma including, primary congenital glaucoma, aniridia and congenital rubella syndrome [60]. A betaxolol-based treatment was reported by Awad et al. to be a successful therapy for a patient with Sturge-Weber syndrome, especially in combination with the administration of dipivefrin or pilocarpine [65].

The incidence of systemic side effects reported in the literature varies from 0 to 18% [58–62]; the most frequently recurring ocular side effects are tearing and eye itching, whose prevalence has been determined as 2% and 4% respectively [59]. The most severe systemic adverse effects in children receiving topical B-blockers like timolol include asthma attacks, bradycardia and apnoeic spells (the latter in neonates) (cf. **Figure 1**) [58–62, 67]. In children, plasma timolol levels reach higher values than in adults [1], probably due to the smaller volume of distribution for the drug. That is

*Childhood Glaucoma and Medical Treatment: An Up to Date DOI: http://dx.doi.org/10.5772/intechopen.100579*

### **Table 2.**

*Data drawn from the text.*

*Indications, side effects and warnings for main drugs used in the management of paediatric glaucoma.*

### **Figure 1.**

*Simplified scheme showing the origin of systemic effects of B-blockers after local ocular administration. CYP2D6 is a member of the cytochrome P450 superfamily and it plays a primary role in the metabolism of about 25% of the commonly prescribed drugs, including timolol and related compounds. Adapted from [66].*

why it is reasonable to begin with 0.25% drops (the lowest concentration is preferred in order to reduce systemic side effects) [68, 69], except in children with a history of asthma or bradycardia; upon the first administration on an outpatient basis, children should be kept under observation for 1 or 2 h. Less frequent systemic side effects are hallucinations, light-headedness, depression, fatigue, diarrhoea and masking of symptoms of hypoglycaemia in children with diabetes mellitus [54, 70]. In 2007, T. Nieminen et al. reported that using a timolol hydrogel formulation in adults once daily resulted in lower plasma levels compared to when a timolol solution was used twice daily [66].

Other B-blockers available for clinical use in children are betaxolol (0.25% suspension and 0.5% solution, twice daily), levobunolol (0.5%, twice daily) and carteolol (1 and 2%, twice daily) [1].

Betaxolol, as a relatively cardioselective beta-adrenergic blocker, should be preferred in patients with a history of asthma, as it is less likely to trigger acute asthma attacks (which may also present just as coughing), although this finding has been confirmed in published studies that have investigated adults.

In children as in adults, CAI drugs, administered either orally or topically, have an additive effect when administered together with B-blockers compared to B-blockers alone [20, 61]. The two greatest limitations in using B-blockers in paediatric glaucoma seem to be the risk of apnoea developing in neonates—a lifethreatening situation—and tachyphylaxis after long-term administration, which causes a loss of efficacy as in adults [46].

### **5.3 Adrenergic agonists**

Both alpha-adrenergic and beta-adrenergic receptors, as parts of the sympathetic nervous system, play a major role in regulating aqueous humour production and dynamics. The pharmacological development of this class of drugs was based on the observation that topical administration of clonidine (an antihypertensive agent) also lowered IOP [71]. The discovery of clonidine's ability to penetrate the blood-brain barrier, thus causing significant systemic hypotensive episodes, even after topical administration alone, limited its clinical use and led to research aimed at developing agents selective for a specific sub-receptor type (alpha 2), now available for clinical use: brimonidine and apraclonidine.

Their mechanism of action consists in reducing humour aqueous production; moreover, these agents have only a slight, if any, effect on blood-aqueous barrier permeability [72, 73]. Speculations have been made regarding a possible role played by these agents in regulating the facility of outflow through the trabecular meshwork, given the presence of alpha 2A-adrenergic receptors in the latter, but there is no supporting evidence [74, 75].

However, there are few published data suggesting optimal dosing schedules for paediatric patients and, as observed by M. Lai Becker et al. in 2009: "because these drugs are instilled into the eye, dosing is uncontrolled, and a child may inadvertently receive a higher-than-intended dose per unit body weight. In addition, systemic absorption through the conjunctiva may be more rapid and complete in children than adults" [76]. So despite their greater selectivity or their effectiveness, shown in adults, in bringing about an IOP reduction, these drugs are relegated to a secondary (secondor third-line) role in paediatric glaucoma control because of their potential systemic side effects, including hypothermia, dizziness, agitation, ataxia, drowsiness, coma, apnoea, hypotension, hypertension, bradycardia, respiratory depression, respiratory failure, and even death, especially when combined with topical beta-blockers [77–82].  Most of the time, the adverse events occur within a few hours of administration of the drops. There has been a great deal of speculation about the reasons for the increased sensitivity to brimonidine in infants; their small

size, their lesser ability to metabolise and excrete drugs, their immature blood-brain barrier or their increased receptor sensitivity seem to be the most likely [81, 83, 84].

According to data collected from different studies, it seems that the frequency of side effects increases with low weight (<20 kg) and very young age (<6 y.o.) [81, 85, 86].

Neither of the two commercially available alpha2-adrenergic agonists, apraclonidine and brimonidine, have been approved by the U.S. FDA.

There has been much speculation about naloxone, an opiate antagonist, and its role in treating alpha2-adrenergic agonist poisoning; the data in the literature are contradictory: some authors have reported efficacy [87–89], whereas others were disappointed with the results [90, 91].

In 2009 M. Lai Becker et al. conducted an interesting retrospective study in order to determine the recurrence of and trends in side effects and the actual role of naloxone as an antidote in cases of poisoning by brimonidine. They retrieved and examined data on all brimonidine exposures in children aged 0–5 years between 1997 and 2005 from the *American Association of Poison Control Centers' Toxic Exposure Surveillance System* (TESS) database and the *US Food and Drug Administration's Medwatch Adverse Events Reporting System* (AERS). Out of 753 reports to both authorities, they selected 200 cases involving children aged 5 years or younger, 185 from the TESS database and 15 from the AERS; there was no overlapping among the selected cases. Of 176 unintentional paediatric poisonings recorded in the TESS database, 73 children were observed at home and 103 were seen at a health care facility; 28 were hospitalised and 11 received naloxone; of the reports included in the AERS database, all the children concerned were hospitalised. In the latter system 13 (86.7%) of 15 cases involved ocular exposures and presumably adverse events occurred during therapeutic use of the drug. By contrast, only 17 (9.2%) cases from the former database involved ocular exposures. According to TESS data, 2-year-old children were most vulnerable to brimonidine poisoning.

The authors concluded that "Infants and children aged 5 years and younger can experience serious cardiovascular and neurologic toxicity after inadvertent exposure to brimonidine-containing eye drops, and medical evaluation of such cases seems prudent. Although naloxone was recommended in 10% of serious brimonidine intoxications, its role and efficacy remain unclear" [76].

### **5.4 Cholinergic stimulators**

The use of these drugs, often called simply miotics, has been largely supplanted by the administration of other medications and their use in the treatment of childhood glaucoma, as in the adult form, have a limited value. The IOP reduction they bring about is generally poor, probably due to the abnormal insertion of the ciliary muscle into the trabecular meshwork, a frequent finding in paediatric glaucomatous patients [92, 93]. Pilocarpine is used to achieve and maintain miosis before and after surgical procedures (in goniotomy or trabeculotomy, miosis is important for keeping the angle wide and thereby aiding in protecting the crystalline lens from injury during the procedure) except in cases of uveitic glaucoma [94].

Ecothiopate iodide (EI or phospholine iodide) is a "stronger" miotic than pilocarpine, because it is a long-acting cholinesterase inhibitor; in children it may be used in the management of accommodative esotropia [95]. In 2016 M. Samant et al. mentioned a recent study where EI was used in aphakic glaucoma patients and determined a significant reduction in IOP [2, 96]. In most of the patients in the cited study, this drug was given as an additional IOP-lowering agent and the mean duration of treatment was 3.5 years. In their review M. Samant et al. noted that the study failed to discuss the significant side effects of EI in both children and adults;

the most recurrent side effects are ocular pemphigoid—induced with long-term use of this drug (minimum 6 years)—bronchospasm, cystoid macular oedema, and prolongation of anaesthetic agents, specifically succinylcholine, which have been reported to cause post-anaesthesia apnoea [2].

### **5.5 Prostaglandin analogues**

Prostaglandin analogues (PGA) are prodrugs that become biologically active after being hydrolysed by corneal esterase. These drugs lower IOP by increasing outflow via the uveoscleral pathway and, to a variable extent, decreasing outflow resistance through a mechanism that has not been fully determined. It is thought that the ocular hypotensive prostaglandin analogues bind to various prostaglandin receptors, triggering a cascade of events that leads to matrix metalloproteinase activation. The increase in the volume of aqueous flow is probably due to the remodelling of the ciliary body, trabecular meshwork and probably also of the scleral extracellular matrix, as a result of the action of the metalloproteinases. Several studies have shown that a topical prostaglandin analogue-based therapy results in an increase in the space between the muscle fascicles within the human ciliary body, which is thought to be the primary location of uveoscleral outflow [97–100].

These agents are all administered once daily, preferably in the evening; another undoubtable advantage is represented by the extremely rare occurrence of systemic side effects [101, 102]: there is only one case report in the literature, as observed by Samant et al. in 2016, of abundant sweat secretion over the entire body in a child with coexisting glaucoma and aniridia within 1–2 h of latanoprost application [103]. However, prostaglandin analogues have numerous local side effects including a possible change in iris colour (particularly in patients with mixed-colour irides) [104], blepharitis, ocular irritation and pain, darkening, thickening and lengthening of eyelashes and transient punctate epithelial erosion. Less common are eyelid oedema and rash and, more rarely, darkening of palpebral skin has been reported [105].

The relationship between prostaglandin analogues and development of cystoid macular oedema (CME) in adults is still a matter of debate: several authors did not find any causative connection [106, 107], also after an uncomplicated phacoemulsification [108, 109], but there are also many important studies providing evidence of a role of a prostaglandin-based therapy in altering the blood-retinal barrier [110, 111] and consequently in CME determination. There is ample evidence in the literature of an already existing impairment of the blood-aqueous barrier in patients with glaucoma [112–116], suggesting that being glaucomatous is in itself likely to represent a risk factor for developing CME, especially after interventions like phacoemulsification [117]. As long as there is a lack of prospective studies, the debate on prostaglandin and the connection with CME in adults will continue. To the best of our knowledge, no prevalence or incidence studies analysing this connection in paediatric samples have been carried out.

Strong evidence based on reproducible data from challenge-dechallenge-rechallenge studies has attested to a connection between anterior uveitis and prostaglandin analogue use [118, 119]. Interestingly, patients with glaucoma and previous anterior uveitis do not seem to be more at risk of topical prostaglandin-induced uveitis [120]. In a recent review focusing on drug-induced uveitis, the authors associate the concomitant use of corticosteroids and/or other immunomodulatory agents with the reduction in the risk of side effects from prostaglandins [121].

In a review published in 2007, Moore and Nischal [50] wrote: "[…] it is suggested that they [prostaglandin analogues—ed.] should not be used within 5 min of the use of thimerosal-containing preparations." However, a search in the literature

database reveals nothing about a possible bad interaction between thimerosal and prostaglandin analogues.

Various different types of prostaglandins are available for clinical use: latanoprost, travoprost, bimatoprost and tafluprost; despite this variety, latanoprost still accounts for more than 65% of prostaglandin analogue prescriptions [2].

The authors of several studies evaluating the effectiveness of prostaglandin analogues and prostamide medications judged them to be less effective in children than in adults with open-angle glaucoma [65, 122–126]. But not all data are in agreement with this assessment: in the *Glaucoma Italian Paediatric Study* (*GIPSy*), the authors found, in a relatively long-term follow-up (3 years), that PGA was efficacious in 57.6% of cases, with a mean IOP reduction of 9.7 mmHg with latanoprost as a monotherapy [46]. In 2013 L. Chang et al., who analysed the database of the Paediatric Glaucoma Service of Moorfields Eye Hospital, observed that PGA and prostamide were as effective in lowering IOP as beta-blockers (the median percentage IOP-lowering effect of PGA and beta-blockers used in monotherapy was −17.2% and − 17.7%, respectively) [127, 128]. A prospective, randomised, double-masked multicentre study was conducted in 2011 by T. Maeda-Chubachi et al., who compared the efficacy of latanoprost 0.005% and timolol 0.5% (0.25% for patients aged <3 years) in a sample of children with glaucoma (both primary and non-primary forms were included); they found the former drug to be either more effective than the latter or similarly effective (mean IOP reduction 7.2 mmHg for latanoprost and 5.7 for timolol), with a greater effectiveness of latanoprost in patients with a non-primary congenital form of glaucoma [129].

These contradictions in the data probably arise because the IOP-lowering effect of glaucoma drugs might sometimes be masked in patients with a more aggressive form of the disease, but they might also be due to the fact that a wide spectrum of clinical pictures is included under the heading of paediatric glaucoma and different glaucomas may respond to treatment in different ways.

Latanoprost has been the subject of several studies and has shown excellent results in lowering IOP in JOAG and aphakic glaucoma, while poorer efficacy has been found in paediatric glaucoma associated with other ocular disorders or in the primary form [129–131].

In 2017 Journal of AAPOS published a study comparing the efficacy of travoprost and timolol in a paediatric population (age range 2 months to less than 18 years) with different forms of glaucoma or ocular hypertension. Out of the 157 patients included in the study (mean age 9.6 years), 77 received travoprost and 75 timolol; the patients were evaluated at 2 weeks, 6 weeks, and 3 months after treatment. The efficacy of both drugs showed to be comparable, with a mean IOP drop of −5.4 mmHg for travoprost and − 5.3 mmHg for timolol [132, 133].

To the best of our knowledge, there do not exist any studies evaluating the effectiveness of bimatoprost or tafluprost in a paediatric sample.

### **5.6 Rho kinase inhibitors**

The Rho kinase (ROCK) signalling pathway is involved in several cellular events (cell proliferation, cytoskeleton modulation) and in the human eye it has been identified as an important regulator of trabecular meshwork outflow.

In December 2017, the FDA approved netarsudil for the treatment of elevated intraocular pressure (IOP) caused by open-angle glaucoma or ocular hypertension. It is the first drug of this class. Approval was based on 2 phase III clinical trials (Rocket 1 and Rocket 2), with 1167 patients enrolled, where the effect of netarsudil was compared to that of timolol. Patients were randomised to receive netarsudil once daily (Rocket 1 and Rocket 2) or b.i.d. (Rocket 2 only). Treatment with

netarsudil once daily produced clinically and statistically significant reductions of IOP from the baseline value (*P* < 0.001) and was not inferior to timolol [134].

In glaucoma patients with the primary congenital form, the trabecular meshwork is often anomalous not only in terms of its functional properties, but also in its anatomic configuration, so this class of drugs will probably not have any application in clinical practice. Their action on cell proliferation and on cytoskeleton modulation must be considered, so it is impossible to rule out in any case that Rho kinase inhibitors might properly treat these glaucoma forms. This is only a speculative consideration that does not find any support in the literature and their role in both paediatric and adult glaucoma remains to be seen.

### **6. Discussion**

Medical therapy may play different roles in the management of paediatric glaucoma: it may be a useful instrument for preparing patients for surgical interventions—such as goniotomy, through clearing of the cornea—it may help to control IOP post-operatively and it may be the initial and often the mainstay therapy for juvenile open-angle glaucoma and other secondary forms of glaucoma such as those occurring in aphakia or with uveitis.

According to the main international guidelines, such as the World Glaucoma Association's "Medical Management of Glaucoma in Infants and Children*"*, carbonic anhydrase inhibitors are considered as first-line drugs for proper IOP control in children. Their importance is also due to the fact that CAI inhibitors may be administered topically and orally, though systemic administration might give rise to some major side effects such as dizziness, paraesthesia, epistaxis and hypersensitivity reactions (including urticaria, angioedema, bronchospasm), just to mention a few, while metabolic acidosis may represent a worrying risk in toddlers. Another concern regards the influence of CAIs on weight gain and consequently subsequent growth in this latter group of patients, but there is no evidence to support this fear.

Timolol and others B-blockers play a central role in the treatment of both paediatric and adult glaucoma patients. Several pieces of evidence show that B-blocker therapy provides a good or at least modest benefit in patients with several categories of paediatric glaucoma, including the primary congenital form, aniridia and congenital rubella syndrome. In view of children's smaller volume of distribution, it is probably advisable to use the lowest concentration solution, as severe systemic adverse effects, including asthma attacks, bradycardia and apnoeic spells—life threatening situations—may otherwise occur. That is why it is reasonable to exclude children with a history of asthma or bradycardia and to keep children under observation for 1 or 2 h children at the first administration in an outpatient setting.

Prostaglandin analogues and prostamide medications are commonly judged to be less effective in children than in adults with open-angle glaucoma and in several prominent outpatient paediatric clinics like Moorfields, they are recommended as a secondline therapy. However, several recent studies have shown an excellent result in terms of lowering IOP in JOAG and aphakic glaucoma; indeed, these drugs proved to be more effective than B-blockers or similarly effective, while the poorest efficacy was found in paediatric glaucoma associated with other ocular disorders or in the primary form.

Latanoprost is by far the most widely prescribed PGA and has also been studied in a paediatric sample; to the best of our knowledge, there do not exist any studies evaluating the efficacy of bimatoprost or tafluprost in a paediatric patient.

Brimonidine and apraclonidine, alpha-adrenergic agonists, are relegated to a secondary role in paediatric glaucoma control because of their potential severe systemic side effects, including hypothermia, coma, apnoea, hypotension,

*Childhood Glaucoma and Medical Treatment: An Up to Date DOI: http://dx.doi.org/10.5772/intechopen.100579*

hypertension, bradycardia, respiratory depression, respiratory failure, and even death, especially if combined with topical beta-blockers. It seems that the frequency of adverse side effects increases with low weight (<20 kg) and a very young age (<6 y.o.).

There has been much speculation surrounding the opiate antagonist naloxone and its role in treating alpha2-adrenergic agonist poisoning. The data in the literature are contradictory, and a large study on this subject conducted by M. Lai Becker et al. [76] in 2009 did not reach a definitive conclusion as to its efficacy.

Miotics occupy a marginal role in the management of paediatric glaucoma and they are primarily used to achieve and maintain miosis before and after surgical procedures in order to protect lenses from accidental injuries.

Rho kinase (ROCK) inhibitors represent the newest class of drugs used for managing glaucoma; their role in paediatric glaucoma remains to be seen.

Even children whose glaucoma is well controlled through therapy require lifelong follow-up. Loss of IOP control may occur months or even decades after initial successful control and may be asymptomatic in older children or young adults; progressive myopia, progressive optic nerve cupping or an increase in corneal size constitute indirect signs of inadequate IOP control.

### **Author details**

Antonio Greco\*, Marco Giuseppe Leto, Andrea Greco, Riccardo Merli and Agostino Salvatore Vaiano Ophthalmology Department, Santa Croce and Carle Hospital, Cuneo, Italy

\*Address all correspondence to<EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Passo MS, Palmer EA, et al. Plasma timolol in glaucoma patients. Ophthalmology. 1984;**91**(11): 1361-1363

[2] Samant M, Medsinge A, Nischal KK. Pediatric glaucoma: Pharmacotherapeutic options. Pediatric Drugs. 2016;**18**:209-219

[3] Papadopoulos M, Cable N, Rahi J, Khaw PT, BIG Eye Study Investigators. The British infantile and childhood glaucoma (BIG) eye study. Investigative Ophthalmology & Visual Science. 2007;**48**(9):4100-4106

[4] Fung DS, Roensch MA, Kooner KS, Cavanagh HD, Whitson JT. Epidemiology and characteristics of childhood glaucoma: Results from the Dallas glaucoma registry. Clinical Ophthalmology. 2013;**7**:1739-1746

[5] Gencik A, Gencikova A, Ferak V. Population genetical aspects of primary congenital glaucoma. I. Incidence, prevalence, gene frequency, and age of onset. Human Genetics. 1982;**61**(3):193-197

[6] Gencik A. Epidemiology and genetics of primary congenital glaucoma in Slovakia. Description of a form of primary congenital glaucoma in gypsies with autosomal-recessive inheritance and complete penetrance. Developments in Ophthalmology. 1989;**16**:76-115

[7] MacKinnon JR, Giubilato A, Elder JE, Craig JE, Mackey DA. Primary infantile glaucoma in an Australian population. Clinical & Experimental Ophthalmology. 2004;**32**(1):14-18

[8] Sarfarazi M, Stoilov I, Schenkman JB. Genetics and biochemistry of primary congenital glaucoma. Ophthalmology Clinics of North America. 2003;**16**(4):543-554, vi

[9] Tamcelik N, Atalay E, Bolukbasi S, Çapar O, Ozkok A. Demographic features of subjects with congenital glaucoma. Indian Journal of Ophthalmology. 2014;**62**(5):565-569

[10] Alanazi FF, Song JC, Mousa A, Morales J, Al Shahwan S, Alodhayb S, et al. Primary and secondary congenital glaucoma: Baseline features from a registry at King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. American Journal of Ophthalmology. 2013;**155**(5):882-889

[11] Dandona L, Williams JD, Williams BC, Rao GN. Population based assessment of childhood blindness in southern India. Archives of Ophthalmology. 1998;**116**(4):545-546

[12] Liu B, Huang W, He M, Zheng Y. An investigation on the causes of blindness and low vision of students in blind school in Guangzhou. Yan Ke Xue Bao. 2007;**23**(2):117-120

[13] Westerlund E. Københavns Universitet. Clinical and Genetic Studies on the Primary Glaucoma Diseases. Copenhagen: Nyt Nordisk Forlag; 1947. p. 207

[14] Stoilov I, Akarsu AN, Alozie I, et al. Sequence analysis and homology modeling suggest that primary congenital glaucoma on 2p21 results from mutations disrupting ether the hinge region or the conserved core structures of cytochrome P4501B1. American Journal of Human Genetics. 1998;**62**(3):573-584

[15] Chitsazian F, Tusi BK. Elahi E et al CYP1B1 mutation profile of Iranian peimary congenital glaucoma patients and associated haplotypes. The Journal of Molecular Diagnostics. 2007;**9**(3):382-393

[16] Narooie-Nejad M, Paylakhi SH, Shojaee S, et al. Loss of function

*Childhood Glaucoma and Medical Treatment: An Up to Date DOI: http://dx.doi.org/10.5772/intechopen.100579*

mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma. Human Molecular Genetics. 2009;**18**(20):3969-3977

[17] Ali M, McKibbin M, Booth A, et al. Null mutations in LTBP2 cause primary congenital glaucoma. American Journal of Human Genetics. 2009;**84**(5):664-671

[18] Duke-Elder S. Congenital deformities. System of Ophthalmology. Vol 3 (pt2). ST Louis: CV Mosby; 1969

[19] Hoskins HD, Shaffer RN. Evaluation tachniques for congenital glaucomas. Journal of Pediatric Ophthalmology and Strabismus. 1971;**8**:81-87

[20] de Luise VP, Anderson DR. Primary infantile glaucoma (congenital glaucoma). Survey of Ophthalmology. 1983;**28**(1):1-19

[21] Walton DS. Diagnosis and treatment of glaucoma in childhood. In: Epstein DL, editor. Chandlers and Grant's Glaucoma. 3rd ed. Philadelphia, PA: Lea & Febiger; 1986

[22] Sinha G, Patil B, Sihota R, et al. Visual field loss in primary congenital glaucoma. Journal of AAPOS. 2015;**19**(2):124-129. DOI: 10.1016/j. jaapos.2014.12.008

[23] Samuels B, Hammes N, Johnson P, Shekhar A, McKinnon S, Allingham R. Dorsomedial/perifornical hypothalamic stimulation increases intraocular pressure, intracranial pressure and the translaminar pressure gradient. Investigative Ophthalmology & Visual Science. 2012;**53**(11):7328-7335

[24] Park JT, Lim HK, Jang KY, Um DJ. The effects of desflurane and sevoflurane on the intraocular pressure associated with endotracheal intubation in pediatric ophthalmic surgery. Korean Journal of Anesthesiology. 2013;**64**(2):117-121

[25] Barclay K, Wall T. Intra-ocular pressure changes in patients with glaucoma. Anaesthesia. 1994;**49**:159-162

[26] Green S, Roback M, Kennedy R, Al E. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Annals of Emergency Medicine. 2011;**57**:449-461

[27] Yoshikawa K, Murai Y. The effect of ketamine on intraocular pressure in children. Anesthesia and Analgesia. 1971;**50**(2):199-202

[28] Ausinsch B, Graves S, Munson E, Al E. Intraocular pressures in children during isoflurane and halothane anesthesia. Anesthesiology. 1975;**42**(2):167-172

[29] Peuler M, Glass D, Arens J. Ketamine and intraocular pressure. Anesthesiology. 1975;**43**(5):575-578

[30] Metz HS, Venkatesh B. Succinylcholine and intraocular pressure. Journal of Pediatric Ophthalmology and Strabismus. 1981;**18**(1):12-14

[31] Mikhail M, Sabri K, Levin AV. Effect of anesthesia on intraocular pressure measurement in children. Survey of Ophthalmology. 2017

[32] Dillon JB, Gunter R, Abarwala Taylor DB. Action of succinylcholine on extraocular muscles and intraocular pressure. Anesthesiology. 1957;**18**(1):44-49

[33] Bordon A, Katsumi O, Hirose T. Tonometry in pediatric patients: A comparative study among Tono-pen, Perkins, and Schiötz Tonometer. Journal of Pediatric Ophthalmology and Strabismus. 1995;**32**:373-377

[34] Langham M. The aqueous outflow system and its response to autonomic receptor agonists. Experimental Eye Research. 1977;**25**(Suppl):311-322

[35] Henriques MJ, Vessani RM, Reis FA, et al. Corneal thickness in congenital glaucoma. Journal of Glaucoma. 2004;**13**(3):185-188

[36] Muir KW, Duncan L, Enyedi LB, et al. Central corneal thickness in children: Stability over time. American Journal of Ophthalmology. 2006;**141**(5):955-957

[37] Brandt JD, Caruso LA, Budenz DL. Markedly increased central corneal thickness: An unrecognized finding in congenital aniridia. American Journal of Ophthalmology. 2004;**137**(2):348-350

[38] Muir KW, Duncan L, Enyedi LB, et al. Central corneal thickness: Congenital cataracts and aphakia. American Journal of Ophthalmology. 2007;**144**(4):502-506

[39] Simon JW, O'Malley MR, Gandham SB, et al. Central corneal thickness and glaucoma in aphakic and pseudophakic children. Journal of AAPOS. 2005;**9**(4):326-329

[40] Simsek T, Mutluay AH, Elgin U, et al. Glaucoma and increased central corneal thickness in aphakic and pseudophakic patients after congenital cataract surgery. British Journal of Ophthalmology. 2006;**90**(9):1103-1106

[41] Tai TY, Mills MD, Beck AD, et al. Central corneal thickness and corneal diameter in patients with childhood glaucoma. Journal of Glaucoma. 2006;**15**(6):524-528

[42] Barkan O. Pathogenesis of congenital glaucoma: Gonioscopic and anatomic observation of the angle of the anterior chamber in the normal eye and in congenital glaucoma. American Journal of Ophthalmology. 1955;**40**(1):1-11

[43] Papadopoulos M, Edmunds B, Chiang M, Mandal A, Grajewski AL, Khaw PT. Glaucoma surgery in children. In: Weinreb RN, Grajewski A, Papadopoulos M, Grigg J, Freedman S, editors. Childhood Glaucoma WGA

Consensus Series—9. Amsterdam: Kugler Publications; 2013. pp. 95-134

[44] Faschinger C, Hommer A. Gonioscopy. Berlin Heidelberg: Springer; 2012. pp. 25-30

[45] Choplin NT, Lundy DC. Atlas of Glaucoma. 2nd ed. CRC Press; 2007

[46] Gupta V, James MK, Singh A, Kumar S, Gupta S, Sharma A, et al. Differences in optic disc characteristics of primary congenital glaucoma, juvenile and adult onset open angle glaucoma patients. Journal of Glaucoma. 2014;**26**. Epub ahead of print

[47] Krishnadas R, Ramakrishnan R. Congenital glaucoma—A brief review. Journal of Current Glaucoma Practice. 2008;**2**(2):17-25

[48] Quaranta L, Biagioli E, Oddone F, Weinreb RN, et al. The glaucoma Italian pediatric study (GIPSy): 3-year results. Journal of Glaucoma. 2018;**27**:856-863

[49] Scuderi G, Regine F, et al. Comparative efficacy of acetazolamide and apraclonidine in the control of intraocular pressure following phacoemulsification. Ophthalmologica. 2006

[50] Moore W, Nischal KK. Pharmacologic management of glaucoma in childhood. Pediatric Drugs. 2007;**9**(2)

[51] Sharan S, Dupuis A, Hébert D. The effect of oral acetazolamide on weight gain in children. Canadian Journal of Ophthalmology. 2010;**45**:41-45

[52] Portellos M, Buckley EG, Freedman SF. Topical versus oral carbonic anhydrase inhibitor therapy for pediatric glaucoma. Journal of AAPOS. 1998;**2**(1):43-47

[53] Sabri K, Levin AV. The additive effect of topical dorzolamide and systemic acetazolamide in pediatric *Childhood Glaucoma and Medical Treatment: An Up to Date DOI: http://dx.doi.org/10.5772/intechopen.100579*

glaucoma. Journal of AAPOS. 2006;**10**(5):464-468

[54] Whitson JT, Roarty JD, Vijaya L, Robin AL, Gross RD, Landry TA, et al. Efficacy of brinzolamide and levobetaxolol in pediatric glaucomas: A randomized clinical trial. Journal of AAPOS. 2008;**12**(3):239-246

[55] Konowal A, Morrison JC, et al. Irreversible corneal decompensation in patients treated with topical dorzolamide. American Journal of Ophthalmology. 1999;**128**(6):774-776

[56] Bartels SP, Roth HO, Jumblatt MM, et al. Pharmacological effects of topical timolol in the rabbit eye. Investigative Ophthalmology and Visual Science. 1980;**19**(10):1189-1197

[57] Nathanson JA. Adrenergic regulation of intraocular pressure: Identification of beta 2-adrenergicstimulated adenylate cyclase in ciliary process epithelium. Proceedings of the National Academy of Sciences of the United States of America. 1980;**77**(12):7420-7424

[58] Hoskins HD Jr, Hetherington J Jr, Magee SD, Naykhin R, Migliazzo CV. Clinical experience with timolol in childhood glaucoma. Archives of Ophthalmology. 1985;**103**:1163-1165

[59] Zimmerman TJ, Kooner KS, Morgan KS. Safety and efficacy of timolol in pediatric glaucoma. Survey of Ophthalmology. 1983;**28**(Suppl):S262-S264

[60] Boger WP, Walton DS. Timolol in uncontrolled childhood glaucomas. Ophthalmology. 1981;**88**:253-258

[61] Boger WP III. Timolol in childhood glaucoma. Survey of Ophthalmology. 1983;**28**(Suppl):259-261

[62] McMahon CD, Hetherington J Jr, Hoskins HD Jr, Shaffer RN. Timolol and pediatric glaucomas. Ophthalmology. 1981;**88**:249-252

[63] Plager DA, Whitson JT, Netland PA, et al. Betaxolol hydrochloride ophthalmic suspension 0.25% and timolol gel-forming solution 0.25% and 0.5% in pediatric glaucoma: A randomized clinical trial. Journal of AAPOS. 2009;**13**:384-390

[64] Muir KW, Jin J, Freedman SF. Central corneal thickness and its relationship to intraocular pressure in children. Ophthalmology. 2004;**111**:2220-2223

[65] Enyedi LB, Freedman SF. Latanoprost for the treatment of pediatric glaucoma. Survey of Ophthalmology. 2002;**47**(Suppl):S129-S132

[66] Nieminen T et al. Ophthalmic timolol: Plasma concentration and systemic cardiopulmonary effects. Scandinavian Journal of Clinical and Laboratory Investigation. 2007;**67**:237-245

[67] Olson RJ, Bromberg BB, Zimmerman TJ. Apneic spells associated with timolol theraoy in a neonate. American Journal of Ophthalmology. 1979;**88**(1):120-122

[68] Turach ME, Aktan G, Idil A. Medical and surgical aspects of congenital glaucoma. Acta Ophthalmologica Scandinavica. 1995;**73**(3):261-263

[69] Coppens G, Stalmans I, Zeyen T, Casteels I. The safety and efficacy of glaucoma medication in the pediatric population. Journal of Pediatric Ophthalmology and Strabismus. 2009;**46**(1):12-18

[70] Awad AH, Mullaney PB, Al-Mesfer S, Zwaan JT. Glaucoma in Sturge-Weber syndrome. Journal of AAPOS. 1999;**3**:40-45

[71] Krieglstein GK, Langham ME, Leydhecker W. The peripheral and central neural actions of clonidine in normal and glaucomatous eyes. Investigative Ophthalmology & Visual Science. 1978;**17**(2):149-158

[72] Lee DA, Topper JE, Brubacker RF. Effect of clonidine on aqueous humor flow in normal human eyes. Experimental Eye Research. 1984;**38**(3):239-246

[73] Gharagozloo NZ, Relf SJ, Brubacker RF. Aqueous flow is reduced by the alpha-adrenergic agonist, apraclonidine hydrochloride (ALO 2145). Ophthalmology. 1988;**95**(9):1217-1220

[74] Stamer WD, Huang Y, Seftor RE, et al. Cultured human trabecular meshwork cells express functional alpha 2A adrenergic receptors. Investigative Ophthalmology & Visual Science. 1996;**37**(12):2426-2433

[75] Toris CB, Gleason ML, Camras CB, et al. Effects of brimonidine on aqueous humor dynamics in human eyes. Archives of Ophthalmology. 1995;**113**(12):1514-1517

[76] Lai Becker M, Huntington N, Woolf AD. Brimonidine tartrate poisoning in children: Frequency, trends, and use of naloxone as an antidote. Pediatrics. 2009;**123**:e305

[77] Klein-Schwartz W. Trends and toxic effects from pediatric clonidine exposures. Archives of Pediatrics & Adolescent Medicine. 2002;**156**(4):392-396

[78] Spiller HA, Klein-Schwartz W, Colvin JM, Villalobos D, Johnson PB, Anderson DL. Toxic clonidine ingestion in children. The Journal of Pediatrics. 2005;**146**(2):263-266

[79] Carlsen JO, Zabriskie NA, Known YH, et al. Apparent central nervous system depression in infants after the use of topical brimonidine. American Journal of Ophthalmology. 1999;**128**(2):255-256

[80] Korsch E, Grote A, Seybold M, et al. Systemic adverse effects of topical treatment with brimonidine in an infant with secondary glaucoma. European Journal of Pediatrics. 1999;**158**(8):685

[81] Enyedi LB, Freedman SF. Safety and efficacy of brimonidine in children with glaucoma. Journal of AAPOS. 2001;**5**(5):281-284

[82] Mungan NK, Wilson TW, Nischal KK, et al. Hypotension and bradycardia in infants after the use of topical brimonidine and beta-blockers. Journal of AAPOS. 2003;**7**(1):69-70

[83] Kiryazov K, Stefova M, Iotova V. Can ophthalmic drops cause central nervous system depression and cardiogenic shock in infants? Pediatric Emergency Care. 2013;**29**(11):1207-1209

[84] Walters G, Taylor RH. Severe systemic toxicity caused by brimonidine drops in an infant with presumed juvenile xanthogranuloma. Eye. 1999;**13**(Pt 6):797-798

[85] Al-Shahwan S, AL-Torbak AA, Turkmani S, et al. Side-effect profile of brimonidine tartrate in children. Ophthalmology. 2005;**112**:2143-2148

[86] Bowman RJ, Cope J, Nischal KK, et al. Ocular and systemic side effects of brimonidine 0.2% eye drops (Alphagan) in children. Eye. 2004;**18**:24-26

[87] Tenenbein M. Naloxone in clonidine toxicity. American Journal of Diseases of Children. 1984; **138**(11):1084

[88] Fiser DH, Moss MM, Walker W. Critical care for clonidine poisoning in toddlers. Critical Care Medicine. 1990;**18**(10):1124-1128

*Childhood Glaucoma and Medical Treatment: An Up to Date DOI: http://dx.doi.org/10.5772/intechopen.100579*

[89] Romano RJ, Dinh A. A 1000-fold overdose of clonidine caused by a compounding error in a 5-year-old child with attentiondeficit/hyperactivity syndrome. Pediatrics. 2001;**108**(2):471-472

[90] Banner W, Lund ME, Clawson L. Failure of naloxone to reverse clonidine toxic effects. American Journal of Diseases of Children. 1983;**137**(12):1170-1171

[91] Wedin GP, Richardson SL, Wallace GH. Clonidine poisoning in children. American Journal of Diseases of Children. 1990;**144**(8):853-854

[92] Walton DS. Primary congenital open angle glaucoma: A study of the anterior segment abnormalities. Transactions of the American Ophthalmological Society. 1979;**77**:746-768

[93] Kolker AE, Hetherington J Jr. Congenital glaucoma. In: Becker Shaffer's Diagnosis and Therapy of the Glaucomas. 5th ed. St. Louis, MO: CV Mosby; 1983. pp. 317-369

[94] Chandler PA, Grant WM. Glaucoma. 2d ed. Philadelphia, PA: LEA & Febiger; 1979

[95] Reddy RH. Echothiophate iodide: Its use in accomodative esotropia (high Ac/A ratio). Indian Journal of Ophthalmology. 1982;**30**:225

[96] Kraus CL, Trivedi RH, Wilson ME. Intraocular pressure control with echothiophate iodide in children's eyes with glaucoma after cataract extraction. Journal of AAPOS. 2015;**19**(2):116-118 e1

[97] Woessner JF Jr. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. The FASEB Journal. 1991;**5**(8):2145-2154

[98] Weinreb RN, Kashiwagi K, Kashiwagi F, et al. Prostaglandins increase matrix metalloproteinase release from human ciliary smooth muscle cells. Investigative Ophthalmology & Visual Science. 1997;**38**(13):2772-2780

[99] Kashiwagi K, Jin M, Suzuki M, et al. Isopropyl unoprostone increases the activities of matrix metalloproteinases in cultured monkey ciliary muscle cells. Journal of Glaucoma. 2001;**10**(4):271-276

[100] Ocklind A. Effect of latanoprost on the extracellular matrix of the ciliary muscle. A study on cultured cells and tissue sections. Experimental Eye Research. 1998;**67**(2):179-191

[101] Yanovitch TL, Enyedi LB, Schotthoeffer EO, Freedman SF. Travoprost in children: Adverse effects and intraocular pressure response. Journal of AAPOS. 2009;**13**(1):91-93

[102] Alm A, Grierson I, Shields MB. Side effects associated with prostaglandin analog therapy. Survey of Ophthalmology. 2008;**53**(Suppl. 1):S93-S105

[103] Schmidtborn F. Systemic sideeffects of latanoprost in a child with aniridia and glaucoma. Ophthalmology. 1998;**95**(9):633-634

[104] Brown S. Increased iris pigment in a child due to latanoprost. Archives of Ophthalmology. 1998;**116**(12):1683-1684

[105] Schumer RA, Camras CB, Mandhal AK. Putative side effects of prostaglandin analogs. Survey of Ophthalmology. 2002;**47**(Suppl. 1):S219-S230

[106] Miyake K, Ibaraki N. Prostaglandins and cystoid macular edema. Survey of Ophthalmology. 2002;**47**(Suppl. 1):S203-S218

[107] New topical drugs for open angle glaucoma. BNF 11.6. Drugs and

Therapeutics Bulletin. 2003. Available from: http://www.dtb.org.uk [Accessed: 21 February 2006]

[108] Chu CJ, Johnston RL, Buscombe C, Sallam AB, Mohamed Q, Yang YC, et al. Risk factors and incidence of macular edema after cataract surgery; a database study of 81984 eyes. Ophthalmology. 2016;**123**:316-323. Available from: http://www.aaojournal.org/article/ S0161-6420(15)01146-X/pdf [Accessed: 08 June 2017]

[109] Walkden A, Porter LF, Morarji J, Kelly SP, Sioras E. Pseudophakic cystoid macular edema and spectral-domain optical coherence tomography– detectable central macular thickness changes with perioperative prostaglandin analogs. JCRS. 2017;**43**(8):1027-1030

[110] Moroi SE, Gottfredsdottir MS, Schteingart MT, et al. Cystoidmacular edema associated with latanoprost therapy in a case series of patients with glaucoma and ocular hypertension. Ophthalmology. 1999;**106**:1024-9.20

[111] Warwar RE, Bullock JD, Ballal D. Cystoid macular edema andanterior uveitis associated with latanoprost use. Experienceand incidence in a retrospective review of 94 patients. Ophthalmology. 1998;**105**:263-268

[112] Kuryshova NI, Vinetskaia MI, Erichev VP, et al. Permeability of blood-aqueous humor barrier in primary open-angle glaucoma. Vestnik Oftalmologii. 1998;**114**(1):10-13

[113] Bleich S, Roedl J, Von Ahsen N, et al. Elevated homocysteine levels in aqueous humor of patients with pseudoexfoliation glaucoma. American Journal of Ophthalmology. 2004;**138**(1):162-164

[114] Nguyen NX, Kuchle M, Martus P, et al. Quantification of blood-aqueous barrier breakdown after

trabeculectomy: Pseudoexfoliation versus primary open-angle glaucoma. Journal of Glaucoma. 1999;**8**(1):18-23

[115] Schumacher S, Nguyen NX, Kuchle M, et al. Quantification of aqueous flare after phacoemulsification with intraocular lens implantation in eyes with pseudoexfoliation syndrome. Archives of Ophthalmology. 1999;**117**(6):733-735

[116] Kong X, Liu X, Huang X, et al. Damage to the blood-aqueous barrier in eyes with primary angle closure glaucoma. Molecular Vision. 2010;**16**:2026-2032

[117] Wendel C, Zakrzewski H, Carleton B, Etminan M, Mikelberg FS. Association of post-operative topical prostaglandin analog or beta-blocker use and incidence of pseudophakic cystoid macular edema. Journal of Glaucoma. 2018;**27**(5):402-406

[118] Fechtner RD, Khouri AS, Zimmerman TJ, et al. Anterior uveitis associated with latanoprost. American Journal of Ophthalmology. 1998;**126**:37-41

[119] Warwar RE, Bullock JD, Ballal D. Cystoid macular edema and anterior uveitis associated with latanoprost use. Experience and incidence in a retrospective review of 94 patients. Ophthalmology. 1998;**105**:263-268

[120] Chang JH, McCluskey P, Missotten T, et al. Use of ocular hypotensive prostaglandin analogues in patients with uveitis: Does their use increase anterior uveitis and cystoid macular oedema? The British Journal of Ophthalmology. 2008;**92**:916-921

[121] Moorthya RS, Moorthyd MS, Cunningham ET Jr. Drug-induced uveitis. Current Opinion in Ophthalmology. 2018;**29**(6):588-603

[122] Enyedi LB, Freedman SF, Buckley EG. The effectiveness of *Childhood Glaucoma and Medical Treatment: An Up to Date DOI: http://dx.doi.org/10.5772/intechopen.100579*

latanoprost for the treatment of pediatric glaucoma. Journal of AAPOS. 1999;**3**:33-39

[123] Yang CB, Freedman SF, Myers JS, et al. Use of latanoprost in the treatment of glaucoma associated with Sturge-Weber syndrome. American Journal of Ophthalmology. 1998;**126**:600-602

[124] Ong T, Chia A, Nischal KK. Latanoprost in port wine stain related paediatric glaucoma. The British Journal of Ophthalmology. 2003;**87**:1091-1093

[125] Altuna JC, Greenfield DS, Wand M, et al. Latanoprost in glaucoma associated with Sturge-Weber syndrome: Benefits and side-effects. Journal of Glaucoma. 1999;**8**:199-203

[126] Urban B, Bakunowicz-Lazarczyk A, Mrugacz M, et al. The effectiveness of latanoprost for the treatment of pediatric glaucoma. Klinika Oczna. 2004;**106**: 243-244

[127] Chang L, Ong EL, Bunce C, et al. A review of the medical treatment of pediatric glaucomas at Moorfields Eye Hospital. Journal of Glaucoma. 2013;**22**:601-607

[128] Weinreb RN, Araie M, Susanna R, et al., editors. Medical management of glaucoma in infants and children. In: Medical Treatment of Glaucoma. Consensus Series 7. Chapter. Amsterdam, The Netherlands: World Glaucoma Association Kugler Publications; 2010. pp. 267-271

[129] Maeda-Chubachi T, Chi-Burris K, Simons BD, Freedman SF, Khaw PT, et al. Comparison of latanoprost and timolol in pediatric glaucoma: A phase 3, 12-week, randomized, double-masked multicenter study. Ophthalmology. 2011;**118**(10):2014-2021. DOI: 10.1016/j. ophtha.2011.03.010. Epub 2011 Jun 16

[130] Black AC, Jones S, Yanovitch TL, Enyedi LB, Stinnett SS, Freedman SF. Latanoprost in pediatric glaucoma– pediatric exposure over a decade. Journal of AAPOS. 2009;**13**(6):558-562

[131] Uva MG, Avitabile T, Reibaldi M, Bucolo C, Drago F, Quaranta L, et al. Long-term efficacy of latanoprost in primary congenital glaucoma. Eye. 2014;**28**(1):53-57

[132] Maeda-Chubachi T, Chi-Burris K, Simons B, Bremond-Gignac D, Freedman S, Khaw PT, et al. Impact of age, diagnosis, and history of glaucoma surgery on outcomes in pediatric patients treated with latanoprost. Journal of Glaucoma. 2013;**22**(8):614-619

[133] Dixon ER, Landry T, Venkataraman S, Gustafson N, Salem C, Bradfield Y, et al. A 3-month safety and efficacy study of travoprost 0.004% ophthalmic solution compared with timolol in pediatric patients with glaucoma or ocular hypertension. Journal of AAPOS. 2017;**21**(5):370-374.e1

[134] Serle JB, Katz LJ, McLaurin E, Heah T, Ramirez-Davis N, et al. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure: Rho kinase elevated IOP treatment trial 1 and 2 (ROCKET-1 and ROCKET-2). American Journal of Ophthalmology. 2018;**186**:116-127

### **Chapter 4**


*3.3. BRDF for Specular Flakes*

The expansion in scattering order (1) works in the accurate approach and in the LTE. In most cases, the first-order term is the principal one and the latter ones are secondary corrections to it. Therefore, if we take the first-order calculated using the accurate approach and the second and other orders calculated using the LTE, we shall give a decent approximation

$$\begin{array}{rcl} f\_1 &=& f\_1 + f\_2^{(LTE)} + f\_3^{(LTE)} + \cdots \\ &=& f\_1 + \left( f^{(LTE)} - f\_1^{(LTE)} \right) \end{array}$$

For vertically homogeneous paint, the equation for the first-order BRDF (2) becomes

$$f\_1(v, u) = t\_F(v) t\_F(u) \\ f\_1(v', u') \int\_0^H a(v', u', z) \, dz'$$

It is valid for both the LTE and the accurate approach. The pre-integral factor is the same for both approaches. The attenuation is different: (4) for the LTE and (8) for the accurate approach. So

$$f\_1(v, u) = f\_1^{(LTE)}(v, u) \frac{A|\_{\text{accumate}}}{A|\_{LTE}} \tag{14}$$

where

$$A \equiv \int\_0^H a\left(v', u', z\right) dz$$

Therefore, the final approximation to the full (all orders) BRDF becomes

$$f \approx f^{(LTE)} + \left(\frac{A|\_{\text{acurate}}}{A|\_{LTE}} - 1\right) f\_1^{(LTE)}(v, u) \tag{15}$$

For the LTE method, the integral of attenuation (4) is

$$A\_{LTE} = \frac{1 - e^{-2DSH}}{2DS} \tag{16}$$

While for the accurate model, according to (8),

$$\begin{array}{rcl} A & \equiv & \int\_0^H a(v', u', z) dz \\ & \approx & \frac{2}{c} \int\_0^{\frac{\epsilon M}{2}} e^{-2c^{-1}(1-t)(2\overline{\text{D}}\overline{\text{S}}Z - (1-t)a(Z))} dZ \\ & = & 2\rho H \int\_0^{\frac{1}{2\rho}} e^{-4(1-t)\rho F(\zeta - \frac{(1-t)}{\overline{\pi}}\widetilde{a}(\zeta))} d\zeta \end{array} \tag{17}$$

where ∼

$$\begin{array}{rcl} \mathfrak{a}(\zeta) & \equiv & \frac{\pi}{2c\rho F}\mathfrak{a}(Z) \\ \zeta & \equiv & \frac{Z}{cH\rho} = \frac{Z}{R} \\ \rho & \equiv & c^{-1}r \\ r & \equiv & \frac{\overline{R}}{H} \\ \overline{R} & \equiv & \sqrt{\overline{S}/\pi} \\ F & \equiv & \overline{D}\overline{S}H \end{array}$$

The *F* is a sort of a concentration parameter like PVC. It can be named PAC (pigment area concentration) because by definition *F* is the total area of flakes in the paint layer of the unit area. *R* is the effective mean radius, and *r* ≡ *R*/*H* is the relative effective radius. *A* is determined just by the three parameters *ρ*, *F* and *H* and depends on the directions *v* and *u* only through *ρ* which is inversely proportional to *c* = *c*(*v* , *u* ).

The integral (17) can be calculated only numerically.

The functions *γm* and *α* are determined solely by the distribution of flake area. Thus, they can be pre-calculated in advance and re-used for all color channels and all BRDF points (i.e., for all combinations of the directions of incidence and illumination) because it is only *c* that depends on these directions and *t* which depends on the color channel.


3.4.3. Temporary Bias Error Correction

Special event bias may occur with persistent multiple error events even after the application of the error correction models mentioned above, as shown in Figure 10. Special event bias is defined as a sudden change in the amount of power over a quarter of the maximum load happening in a two-or-more-hour period. The evidence of such occurrences is significant in most demand load data. A classic example is the Korean research institute (KEPRI) building demand load data used in our case study analysis. In the dataset, the total number of such occurrences was 91 over a 553-day period.

**Figure 10.** Special event bias.

Although it is sudden, the occurrence of special event bias is significant in a given period. From Figure 11, the duration of the sudden bias is logarithmic in time. The highest magnitude of the bias lasts for the first few hours and monotonically decreases with time to the nominal value. In this study, we compensated for these sudden changes in the demand load forecast with a temporal bias error correction model. The procedure for the error compensation is similar to the permanent bias error correction, except for the required input data and error correction formula. The occurrence distribution and occurrence duration distribution are shown in Figures 12 and 13, respectively.

**Figure 11.** Special event occurrence.

**Figure 12.** Special event load fluctuation distribution.

**Figure 13.** Special duration distribution.

Actual data for the previous3h(*T*) was utilized to estimate the error for compensation. The formulation of the correction model, as defined in Equation (17), is to correct the average quantum of the special event, learned for one hour until the power remains zero. An initial correction value, α, is an average of the event values that occurred in the past. With the KEPRI demand dataset, α was estimated as 312.6 KW. Considering that temporary bias error correction is a model for accident events, the average elapsed period, *T*, was set to be 3.5 h, which is the average time required to identify an event.

$$
\hat{y}\_t = \alpha (1 - e^{-\frac{T-t}{\delta^5}}) \tag{17}
$$


**1. Introduction**

To help address continuing environmental and public health degradation, most governments adhere to international energy policies with regard to the use of biofuels. The increased environmental concerns, depletion of petroleum, public health and socioeconomic challenges have driven research to develop alternative fuels from renewable resources that are cheaper and environmentally acceptable.

In the last years, the use of alternative fuels has been shown to reduce emissions without negative effects on engine performance. There are also some studies that demonstrate an increase in particle emission with the use of biofuels. However, the literature reviewed here found noticeable decrease in particle emissions and smoke opacity with the use of biofuels. Indeed, many studies have been conducted to characterize and better understand biofuel proprieties related to particle emission.

The particles emitted by combustion of vehicle engines can be distributed in different ranges of size and number of particles. The particle size distributed in the range covering the nano‐ particles (particles smaller or equal to 100 nm) has a greater toxic potential compared with a larger particle. Studies suggest that exposure to nanoparticles causes serious damage to health, such as lung inflammation, asthma, chronic obstruction of arteries and lungs, cell death, obstruction and accumulation in the olfactory bulb, access to brain damage, tumor necrosis, oxidative stress, neural effects, heart problems, and even death.

Particles emitted from combustion of vehicle engines can also be of different chemical and toxicological proprieties. The chemical composition of particle emission is directly related to the burned fuel and vehicular exhaust condition, and may affect its toxicity. Studies suggest that the higher the organic carbon composition is, the higher damage of particle emitted will be to health.

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Conscious about this subject, there is now considerable research and investment on the kind of fuel and biofuel to develop and promote fuels able to minimize the toxicity and particle emissions from vehicular exhausts. Thus, the viability of using biofuels, its impact on public health and environment, and the impact of biodiesel burning on particle emissions from vehicular exhaust, can be better understood.