Clinical practice guidelines for glaucoma, 5th edition: preface

Glaucoma is the leading cause of blindness in Japan and the second leading cause of blindness worldwide after cataract. The number of patients with glaucoma is increasing with an aging society. The disease is irreversible, with complex pathogenesis. The treatment measures are diverse and the only treatment modality is reducing the intraocular pressure. As visual impairment affects an individual’s quality of life and quality of vision and causes great loss to social burden, we, the Japan Glaucoma Society, must unite in our efforts toward early detection and treatment of glaucoma, thereby preventing blindness.

The fifth edition of the Clinical Practice Guidelines for Glaucoma, edited by the Japan Glaucoma Society, has recently been published. This edition follows the first, second, third, and fourth editions in 2003, 2006, 2012, and 2017, respectively. Recent advances in the clinical practice of glaucoma have been remarkable, including several large-scale clinical trials, improved diagnosis with the introduction of OCT, increased number of eye drops and combination drugs, and the development of several minimally invasive surgical techniques, ranging from laser surgery to surgery at surgical theater. Keeping these developments in mind, we have decided to create a new edition three years since the last.

Moreover, the method of guideline development has evolved. The fourth edition of the guideline was developed for the first time in accordance with the Medical Information Distribution Service (MINDS) Clinical Practice Guidelines Development Manual. Although it can be time-consuming to assess and integrate the overall evidence from the recommended large-scale systematic reviews, the mission of the guideline is to communicate the most important points promptly and accurately during progress in glaucoma care. In addition to the “strength of recommendation” and “strength of evidence” presented in the fourth edition, this edition presents “clinical questions (CQs)” for more important clinical issues, and a systematic review was conducted, yielding a clearer guideline.

As with each edition, I would like to mention that some public sanctions may be imposed on practitioners for not following the recommendations of this guideline. As the official position of the Japan Glaucoma Society, we clearly state that “as with previous editions, these guidelines are positioned as a reference for therapists and do not bind the decision-making authority of therapists in providing individual treatment to patients.” Based on this understanding, we anticipate that this edition will be used by many people and contribute to the improvement of glaucoma care in Japan. We would like to express our sincere gratitude to Yoshiaki Kiuchi, the committee chairman, and to all those involved in the preparation of the fifth edition.

May 2021

Japan Glaucoma Society

Chairman Makoto Aihara

The following “strength of recommendation” and “strength of evidence” are provided for the evidence referred to in the contents of this guideline.

Strength of Evidence

  1. A.

    (Strong) Strong confidence in the estimated effect

  2. B.

    (Moderate) Moderate confidence in the estimated effect

  3. C.

    (Weak) Limited confidence in the estimated effect

  4. D.

    (Very weak) Little confidence in the estimated effect

Strength of Recommendation

  1. 1.

    Strong recommendation

  2. 2.

    Weak recommendation (suggestion)

Foreword

Glaucoma has always been one of the leading causes of blindness in Japan and is a condition of great social importance. In a detailed epidemiological study of glaucoma conducted between 2000 and 2002 (Tajimi Study), its prevalence among Japanese aged 40 years or above was 5.0%, and the estimated number of patients was 4.65 million based on the 2016 population statistics. Furthermore, in the same epidemiological study, the new detection rate of glaucoma was 89%, indicating that many potential glaucoma patients in Japan have yet to receive treatment. Optic neuropathy and visual field impairment in glaucoma are progressive and irreversible. Since glaucoma progresses gradually without the patient’s awareness, early detection and treatment of glaucoma are important to prevent or control the progression of the damage. In recent years, remarkable progress has been made in the diagnosis and treatment of glaucoma, and many new diagnostic and therapeutic modalities have been introduced into clinical practice, which increasingly diversified the diagnosis and treatment of glaucoma. However, it is not always easy to select the appropriate diagnostic and therapeutic measures for each case, to perform early diagnosis and treatment, and to manage the disease over a long period with consideration of quality of life or quality of vision. Additionally, a major problem is that there are many cases in which the progression of disability cannot be prevented or controlled despite employing various diagnostic and therapeutic alternatives. Recent technological innovations in medicine have emphasized the maintenance and improvement of treatment standards. Therefore, the necessity of establishing treatment guidelines to improve the quality of treatment has increased in recent years. Guidelines are also useful for communication between patients and medical practitioners, selecting treatment and sharing information, and team approach to health care. In the social background, there is a need to reduce medical costs through the efficient use of medical resources in response to the globalization of medicine and from the viewpoint of the medical economy, emphasizing the necessity of implementing guidelines as a norm. Against this backdrop, the Japanese Glaucoma Society published the Clinical Practice Guidelines for Glaucoma in 2003, as well as the subsequent revised editions in 2006, 2012, and 2017. This time, we have created the fifth edition that incorporates recent advances in medical care. The structure of this edition follows that of the fourth edition, with new descriptions added. The treatment section also presents recommendations based on a systematic search of articles using the MINDS method to formulate clinical questions. We anticipate that this book will be widely used and be effective as an aid in daily glaucoma care.

  • Medical treatment should be based on the discretion of the physician, and the physician should make the most appropriate diagnosis and treatment for each case. The Japan Glaucoma Society assumes no responsibility or liability for any legal issues that may arise from medical treatment administered with or without using these guidelines.

Chapter 1: Definition of Glaucoma

Glaucoma is a disease characterized by functional and structural abnormalities of the eye, with characteristic changes in the optic nerve and visual field, wherein optic neuropathy can be alleviated or suppressed by sufficiently lowering intraocular pressure (IOP).

Chapter 2 Classification of Glaucoma

Introduction

Glaucomatous optic neuropathy (GON) refers to damage to the optic nerve associated with glaucoma. Glaucoma can be classified according to anterior chamber angle findings, and other factors that may cause elevated IOP. Glaucoma is classified into three types: primary glaucoma, in which the elevated IOP cannot be attributed to any other disease; secondary glaucoma, in which elevated IOP results from other ocular diseases, systemic diseases, or drug use; and childhood glaucoma, in which elevated IOP occurs in childhood due to abnormal prenatal chamber angle development or other diseases or factors. Primary glaucoma is broadly classified into primary open-angle glaucoma (a disease concept that encompasses both conventional primary open-angle glaucoma and normal-tension glaucoma) and primary angle-closure glaucoma.

I. Primary glaucoma

  1. 1.

    Primary open-angle glaucoma (broad)

    Primary open-angle glaucoma (broad) is a disease concept that encompasses both*primary open-angle, where IOP is higher than the normal range, and normal-tension glaucoma. In clinical practice, primary open-angle glaucoma (broad) is divided into high IOP (primary open-angle glaucoma) and normal IOP (normal-tension glaucoma) groups. The upper normal limit of IOP is traditionally defined in western countries as an IOP of 21 mmHg. According to the Tajimi Study, an epidemiological study comprising Japanese patients, the upper limit of normal IOP, defined as mean±2 standard deviations, is 19.9–20.0 mmHg. Thus, it is reasonable to divide the Japanese population into two clinical types based on IOP of 20 mmHg: primary open-angle and normal IOP glaucoma. Primary open-angle glaucoma (broad) is a chronic progressive optic neuropathy with morphologic features of the optic nerve disc and retinal nerve fiber layer (RNFL) (enlarged disc cup and thinning of the rim, and RNFL defect) and without other diseases or congenital abnormalities. Although gonioscopy shows a normal open-angle, this does not exclude the presence of functional abnormalities in the chamber angle.

    *In some cases, primary open-angle glaucoma in the high IOP group is referred to as primary open-angle glaucoma (specific); however, in this guideline, primary open-angle glaucoma in the high IOP group is defined as primary open-angle glaucoma (broad) unless otherwise indicated.

    1. 1.

      Primary open-angle glaucoma

      This is a subtype of primary open-angle glaucoma (broad) in which IOP exceeds the statistically determined normal value during the developmental process of glaucomatous optic neuropathy, and an abnormal increase in IOP is strongly suspected to be involved in the development of optic neuropathy. As diurnal and seasonal variations in IOP are known to exist, IOP may not be abnormally high when it is only measured a few times.

    2. 2.

      Normal-tension glaucoma

      This is a subtype of primary open-angle glaucoma (broad) in which the IOP always remains within the statistically determined normal range during the developmental process of GON. IOP is involved in the development of optic neuropathy even when IOP is within the statistically normal range. However, owing to the diurnal and seasonal variations in IOP, it is not clear what defines the IOP of a patient. Clinically, there is no means of ascertaining the IOP of a patient when they do not visit the hospital. Even if the patient has low IOP during the examination, their IOP may increase at other times. It is common for IOP to fluctuate in the morning and evening during hospitalization and at different times in the outpatient clinic, and it is difficult to grasp whether IOP is always within the normal range.

      It is also common to see findings suggestive of factors independent of IOP, such as circulatory disturbances.

      Appendix 1: Ocular hypertension

      Patients with IOP above the statistically defined upper limits of normal; however, without abnormalities in the optic nerve or visual field

      Appendix 2: Preperimetric glaucoma (PPG)

      The term PPG refers to a condition in which there are abnormalities suggestive of glaucoma, such as glaucomatous optic nerve head and retinal nerve fiber defects on ophthalmoscopy and optical coherence tomography (OCT), but no visual field defects are seen on conventional automated static perimetry test.

  2. 2.

    Primary angle-closure glaucoma and precursor lesions

    1. 1.

      Primary angle-closure glaucoma (PACG)

      PACG is a disease in which elevated IOP results from (primary) angle closure induced by genetic background or age-related changes in anterior segment morphology, without other factors, and in which glaucomatous optic neuropathy has already occurred.

    2. 2.

      Primary angle-closure (PAC)

      PAC is a condition in which primary angle-closure causes elevated IOP or peripheral anterior synechia (PAS) but does not cause glaucomatous optic neuropathy. The name and etiology of this condition according to the speed of onset are the same as those of PACG.

    3. 3.

      Primary angle-closure suspect (PACS)

      PACS is a condition in which there is primary angle-closure but without elevated IOP, organic PAS, or GON. Conversely, only appositional angle closure is present.

      Some forms of PACG and PAC develop acutely and are collectively referred to as acute glaucoma attacks. In acute PACG and acute PAC, elevated IOP is often markedly high (40–80 mmHg), and symptoms such as decreased visual acuity, blurring of vision, glaucomatous halo, ocular pain, headache, nausea, vomiting, and diminished or absent light reflexes are common.

      *Primary angle-closure disease (PACD)

      Primary angle-closure glaucoma, primary angle-closure, primary angle-closure glaucoma suspect, acute primary angle-closure glaucoma, acute primary angle closure, and all precursor lesions of primary angle-closure glaucoma are collectively referred to as primary angle closure (PAC). This is confusingly like PAC, which is an angle closure condition with high IOP or PAS. A new term, PACD, is defined as the collective term for all primary angle-closure glaucoma and its precursor lesions.

      Primary angle-closure glaucoma and primary angle-closure are often caused by a combination of (i) relative pupillary block, (ii) plateau iris, (iii) lens factors, and (iv) behind the lens factors (such as ciliary body factors).

      Relative pupillary block is a condition in which anterior bowing of the iris caused by resistance to aqueous humor outflow between the iris and lens in the pupillary region leads to chamber angle obstruction. Plateau iris is an anomaly in iris morphology in which the root of the iris is bent anteriorly, resulting in chamber angle obstruction during mydriasis. The iris configuration itself is referred to as the plateau iris configuration, and the resulting elevated IOP and GON are referred to as plateau iris glaucoma or plateau iris syndrome. An increase in lens thickness owing to age-related changes is also involved in the formation of primary angle closure. The ciliary body, choroid, and vitreous body are involved as posterior lens factors.

II. Secondary glaucoma

Secondary glaucoma is a condition in which elevated IOP is caused by other ocular diseases, systemic diseases, or drug use. In accordance with the principle of defining glaucoma as a condition characterized by the presence of GON, the term ocular hypertension is used to refer to secondary glaucoma in the absence of GON. However, it is often challenging to determine the presence or absence of GON in secondary glaucoma because of the influence of causative diseases.

Secondary glaucoma is classified according to the mechanism of elevated IOP as follows.

  1. 1.

    Mechanism of elevated IOP in secondary open-angle glaucoma

    1. 1.

      The main locus of resistance to aqueous humor outflow is between the trabecular meshwork and the anterior chamber: neovascularization (open corner stage), heterochromatic iridocyclitis, and anterior chamber epithelial downgrowth.

    2. 2.

      The main locus of resistance to aqueous humor outflow is in the trabecular meshwork: steroids; exfoliation material; amyloid; uveitis; lens material; trauma; ophthalmic surgery (cataract surgery, vitrectomy, and corneal transplantation); intraocular foreign body; intraocular tumor; Schwartz syndrome; and iris pigment.

    3. 3.

      The main locus of resistance to aqueous outflow is posterior to the Schlemm’s canal: glaucoma accompanying increased pressure in the superior vena cava.

  2. 2.

    Mechanism of elevated intraocular pressure in secondary closure angle glaucoma

    1. 1.

      Due to pupillary block: bulging lens, lens dislocation, microphthalmia, and bulging iris due to posterior iris adhesion.

    2. 2.

      Direct angle obstruction caused by the anterior movement of the iris-lens due to causes other than pupillary block: bulging lens and lens dislocation.

    3. 3.

      Due to anterior movement of tissues located posterior to the lens: microphthalmia, after pan-retinal photocoagulation, intraocular tumors, posterior scleritis, ciliochoroidal detachment due to uveitis (Vogt-Koyanagi-Harada disease), malignant glaucoma, intraocular filling material, massive intraocular hemorrhage, and retinopathy of prematurity.

    4. 4.

      Due to peripheral anterior adhesion unrelated to anterior chamber depth: neovascularization (occluded angle stage), iridocorneal endothelial (ICE) syndrome, uveitis, surgery, and trauma.

III. Childhood glaucoma

The term childhood glaucoma refers to glaucoma resulting from a condition that develops in childhood. Although the term developmental glaucoma was used in the previous guidelines, the definition and classification have been substantially changed based on the recommendations of the World Glaucoma Association Consensus Conference [1]. However, the upper age limit for childhood glaucoma has not been clearly defined by international standards.

  1. 1.

    Diagnostic criteria for childhood glaucoma

    The diagnostic criteria for childhood glaucoma [1] are shown in Table 1. Due to the characteristics of pediatric glaucoma, testing under favorable conditions is challenging in many respects. Thus, the diagnostic criteria (Table 1) include findings other than IOP, such as corneal diameter expansion, ocular axial extension, Haab striae (Descemet’s membrane rupture lines) and disc cup enlargement.

  2. 2.

    Classification of childhood glaucoma

    Table 1 Diagnostic criteria for childhood glaucoma by the World Glaucoma Association (WGA)
    Full size table

    Childhood glaucoma is classified into primary and secondary, which is then further subdivided.

    Primary childhood glaucoma is classified as primary congenital glaucoma when ocular enlargement (buphthalmos) occurs owing to high IOP immediately after birth or during the early postnatal period resulting from severe goniodysgenesis and as juvenile open-angle glaucoma when the onset is delayed, does not cause ocular enlargement, and caused by mild goniodysgenesis.

    Secondary childhood glaucoma is classified into glaucoma associated with non-acquired ocular anomalies and glaucoma associated with non-acquired systemic disease or syndrome. Those caused by acquired factors such as trauma, steroids, uveitis, and retinopathy of prematurity are classified as glaucoma associated with acquired conditions. Additionally, glaucoma that develops after cataract surgery, which is more frequent among acquired factors, is classified separately as glaucoma following cataract surgery.

    1. 1.

      Primary congenital glaucoma (PCG)

      Diagnostic criteria

      • Goniodysgenesis (minor congenital iris formation abnormality may be present)

      • Meets diagnostic criteria for childhood glaucoma (generally associated with an ocular enlargement)

      • Further subdivided by age at onset

        1. 1.

          neonatal or newborn onset (0–1 month)

        2. 2.

          Infantile onset (1–24 months)

        3. 3.

          late onset or recognized late (above the age of 2 years)

      • In case of typical signs, the case is classified as PCG even if it stops spontaneously and the IOP decreases.

    2. 2.

      Juvenile open-angle glaucoma

      Diagnostic criteria

      • Pediatric glaucoma that develops after the age of 4 years

      • Without ocular enlargement

      • No congenital ophthalmic dysplasia or systemic disease

      • Open angle (normal corner angle findings)

      • Meets the diagnostic criteria for childhood glaucoma

    3. 3.

      Glaucoma associated with non-acquired ocular anomalies

      Diagnostic criteria

      • Ocular dysplasia present at birth with no apparent relationship to systemic findings

      • Meets the diagnostic criteria for childhood glaucoma

      Representative examples of non-acquired ocular anomalies

      Axenfeld-Rieger anomaly, Peters anomaly, congenital ectropion uveae, congenital iris hypoplasia, aniridia, persistent fetal vasculature, oculodermal melanosis (Nevus of Ota), posterior polymorphous dystrophy, microphthalmia, microcornea, and ectopia lentis.

    4. 4.

      Glaucoma associated with non-acquired systemic disease or syndrome

      Diagnostic criteria

      • Non-acquired systemic diseases associated with ocular findings from birth

      • Meets the diagnostic criteria for childhood glaucoma

      Typical examples of non-acquired systemic diseases

      Chromosomal disorders such as Down syndrome; connective tissue disorders (Marfan syndrome, Weill–Marchesani syndrome, Stickler syndrome); metabolic disorders (homocystinuria, Lowe syndrome, mucopolysaccharidosis); phakomatoses (neurofibromatosis, Sturge–Weber syndrome, Klippel–Trenaunay–Weber syndrome); Rubinstein–Taybi syndrome; and congenital rubella syndrome.

    5. 5.

      Glaucoma associated with acquired condition

      Diagnostic criteria

      • Glaucoma occurring after birth but not at birth and meets the diagnostic criteria for childhood glaucoma

      • Glaucoma after cataract surgery is excluded

      • Based on gonioscopy results

        1. 1.

          Open-angle (50% or more open)

        2. 2.

          Closure angle (less than 50% open or acute angle closure)

      Typical examples of acquired factors

      Uveitis; trauma (hyphema, angle recession, extopia lentis); steroids; tumor (benign/malignant, intraocular/orbital); and retinopathy of prematurity.

    6. 6.

      Glaucoma following cataract surgery

      Diagnostic criteria

      • Glaucoma that develops after cataract surgery and meets the diagnostic criteria

        1. 1.

          Congenital idiopathic cataract

        2. 2.

          Congenital cataract related to ophthalmic dysplasia or systemic disease without glaucoma

        3. 3.

          Acquired cataract without glaucoma

      • Based on gonioscopy results

        1. 1.

          Open-angle (50% or more open)

        2. 2.

          Closure angle (less than 50% open or acutely obstructed angle)

Chapter 3 Examination for glaucoma

I. Medical interview

The initial medical interview is a basic and important examination in the treatment of glaucoma. As the course of IOP, visual field, and optic nerve changes are important in glaucoma, it is essential to determine the diagnosis and management plan of glaucoma through a detailed interview based on the medical information provided by the previous physician.

The interview inquires the following:

  • Risk factors for glaucoma: high blood pressure, low blood pressure, diabetes, migraine, and sleep apnea syndrome [2, 3].

  • History of drug use, including steroids

  • History of systemic diseases, particularly chronic serious diseases, including cardiac and respiratory diseases

  • History of ocular disease, surgery, particularly refractive surgery, and trauma

  • Family history: eye disease, including glaucoma, visual impairment in blood relatives

  • Presence of drug allergies

  • Information on diagnosis and treatment, such as IOP, fundus, visual field, from other physicians

Basically, glaucoma has few subjective symptoms; however, it is important to interview patients regarding their subjective symptoms as misty vision, glaucomatous halo, ocular pain, headache, and hyperemia may suggest a history of acute glaucoma event.

  1. 1.

    Ocular pain

    When IOP rises markedly owing to an acute glaucoma event, strong intraocular pain is often felt suddenly. In general, strong intraocular pain is felt when IOP rises sharply from a normal level to a markedly high level. Intraocular pain may also be caused by corneal epithelium disorder or ciliary body irritation in uveitis.

  2. 2.

    Headache

    In an acute glaucoma attack, headache with nausea and vomiting is observed along with a sudden increase in IOP, accompanied by decreased visual acuity, photophobia, and glaucomatous halo.

  3. 3.

    Blurred vision

    In cases of corneal edema associated with markedly elevated IOP or secondary glaucoma due to uveitis, patients may notice blurring of vision.

  4. 4.

    Visual field defect

    In the early stages of glaucoma, patients are often unaware of visual field abnormalities, even when visual field abnormalities are detected using visual field testing. By the time patients become aware of visual field abnormalities, optic neuropathy or visual field damage may have already progressed considerably.

  5. 5.

    Hyperemia

    Hyperemia is noticed in acute glaucoma attacks as well as in various secondary glaucoma, such as those caused by uveitis, and neovascular and phacolytic glaucoma.

II. Slit‐lamp examination

Slit‐lamp examination is a basic examination in glaucoma treatment. This examination observes the corneal conjunctiva, anterior chamber, iris, and lens, and an auxiliary lens is used to observe the anterior chamber angle and fundus.

  1. 1.

    Corneal conjunctiva

    Corneal edema is observed when the IOP rises markedly owing to an acute glaucoma attack; however, in secondary glaucoma associated with corneal endothelial damage such as iridocorneal endothelial syndrome, corneal edema may be observed even when the IOP is within the normal range. In childhood glaucoma, rupture of Descemet’s membrane, called Haab’s line, may be observed as a tortuous ridge on the corneal endothelium due to ocular swelling associated with increased IOP. Additionally, keratic precipitate may be observed in glaucoma caused by uveitis, and spindle-shaped pigmentation (Krukenberg spindle) may be seen on the posterior surface of the cornea in pigmentary glaucoma and pigment dispersion syndrome.

  2. 2.

    Anterior chamber

    Although cells and flare in the anterior chamber are confirmed, screening of anterior chamber depth by slit-lamp examination is simple and useful, particularly in the diagnosis of angle closure glaucoma. The frequency of glaucoma with the shallow anterior chamber is known to be higher in Asians than in Caucasians [4, 5]. The van Herick technique estimates the width of the anterior chamber angle by comparing corneal thickness and peripheral anterior chamber depth. In plateau iris glaucoma, a narrow angle or angle closure is observed even though the central anterior chamber depth is almost normal. As such, evaluation of anterior chamber depth using slit-lamp examination alone is insufficient for diagnosis, and gonioscopy is essential.

    Van Herick technique

    The angle between the slit beam and the observation system of the slit-lamp examination is set at 60˚, and the slit beam is focused perpendicularly to the corneal limbus. The slit beam then enables comparison of the peripheral anterior chamber depth with corneal thickness to estimate the width of the anterior chamber angle.

    Grade 0: The cornea is in contact with the iris. The angle is closed.

    Grade 1: The anterior chamber depth is less than one-fourth of corneal thickness, and angle closure is likely

    Grade 2: The anterior chamber depth is one-fourth of the corneal thickness, and angle closure is possible

    Grade 3: The anterior chamber depth is one-fourth to one-half of the corneal thickness, and angle closure is unlikely

    Grade 4: The anterior chamber depth is greater than or equal to corneal thickness, and there is no angle closure

  3. 3.

    Iris

    The iris is generally flat or mildly anteriorly bowed. When the iris is markedly anteriorly bowed, the presence of a pupillary block is suspected. Abnormal findings of the iris include anterior adhesion of the iris to the cornea or the trabecular meshwork, posterior adhesion to the lens, neovascularization of the iris, iris atrophy, iris nodules, and exfoliation material on the pupillary margin.

  4. 4.

    Lens

    Lens abnormalities associated with glaucoma include abnormalities in the size and shape of the lens (swollen lens, spherophakia) and abnormalities in the position of the lens (dislocation, subluxation). Abnormalities in the position of the lens may be related to abnormalities in the ciliary body (congenital abnormalities, trauma, and exfoliation glaucoma). Abnormalities in lens position and increased lens thickness due to cataract progression may cause angle closure. In mature or hypermature cataracts, there may be concomitant development of phacolytic glaucoma due to leakage of lens material. In exfoliation glaucoma, the deposition of exfoliated material in the anterior surface of the lens may be observed only after mydriasis.

III. Intraocular pressure test

  1. 1.

    Intraocular pressure

    According to the results of a study of many cases, the distribution of IOP values skewed toward higher values and did not show a perfectly normal distribution [6]. The mean value (± standard deviation) of normal IOP indicated by Leydhecker was approximately 15.5 (±2.6) mmHg, and the statistically determined upper limit of normal IOP was approximately 21 mmHg. However, these values are based on the results of a survey of Caucasians. According to the distribution of IOP in the participants of the Tajimi Study, right IOP was 14.6 (±2.7) mmHg, and left IOP was 14.5 (±2.7) mmHg [7]. If normal IOP is defined as the mean ±2 × standard deviation, the upper limit of normal IOP is 19.9–20.0 mmHg. There is diurnal variation in IOP, which is generally higher in the morning; however, the pattern differs among individuals [8]. Additionally, there are seasonal variations in IOP, and it is known that IOP is generally higher in winter and lower in summer [9]. Factors related to IOP include age, sex, refraction, race, body position, exercise, blood pressure, eyelid pressure and eye movement, and various drugs affecting IOP fluctuation [10].

  2. 2.

    Tonometer

    With a few exceptions, tonometers deform the cornea and estimate the IOP before the deformation occurs. Therefore, IOP measurements are affected by biomechanical factors such as corneal thickness, the radius of curvature, stiffness, and viscosity [11]. IOP measurements after laser refractive surgery such as photorefractive keratectomy and laser in situ keratomileusis are prone to errors [11]. The tonometer is generally an applanation tonometer; however, in recent years a rebound tonometer has also been used.

    1. 1.

      Applanation tonometer

      A flat surface is pressed against the cornea, and the IOP is predicted from the force in which a certain area is flattened. This is represented in the Goldmann applanation tonometer. However, in general, the physical characteristics of the cornea for IOP measurements should be focused upon.

      The Goldmann tonometer is the most clinically accurate and standard tonometer used in the clinical treatment of glaucoma (1B). Bearing the same principle of measurement as that of the Goldmann tonometer, a Perkins tonometer is portable and equipped with the same tonometric prism.

      The non-contact tonometer measures IOP by flattening the cornea with an air jet. Although the measurement technique is simple, it is susceptible to the influence of pulse waves. Thus, the measurement should be repeated more than three times.

      Tonopen® is a portable tonometer that can measure IOP in sitting and supine positions. It is equipped with a pressure transducer at the tip.

    2. 2.

      Rebound tonometer

      The iCare® is a portable tonometer that allows the measurement of IOP without the need for ophthalmic anesthesia. A small probe is ejected towards the cornea. IOP is estimated from the bounce rate of the probe. Though the results match well with those of the Goldmann applanation tonometer, they are often slightly higher. The reliability of the measured values is also high; thus, this tonometer is also easy to use for IOP measurement in children [12]. If the tip is pointed downward, the probe will fall, and measurement cannot be taken. The iCare IC200 is designed so that it can be used in a downward position.

IV. Gonioscopy

  1. 1.

    Anterior chamber angle

    Gonioscopy is essential in the treatment of glaucoma (1A). It is important to correctly recognize the components of the angle, such as the Schwalbe’s line, trabecular meshwork, scleral spur, ciliary band, and angle vessels.

    1. 1.

      Schwalbe’s line

      Schwalbe’s line corresponds to the end of the Descemet’s membrane and is observed as a protruding ridge in the anterior chamber. Particularly in the eyes of a person with exfoliation glaucoma, a wavy and marked pigmentation may be observed anterior to the Schwalbe’s line, which is called the Sampaolesi's line.

    2. 2.

      Trabecular meshwork

      The trabecular meshwork and Schlemm’s canal are located between the Schwalbe's line and the scleral spur. The area from the center of the trabecular meshwork to the scleral spur side corresponds to the functional trabecular meshwork and may be observed as the pigmented zone. In exfoliation glaucoma, pigmentary glaucoma, and pigment dispersion syndrome, the trabecular meshwork is often markedly pigmented.

    3. 3.

      Scleral spur

      The scleral spur is observed as a white line between the ciliary band and the trabecular meshwork. The iris process is often observed on its surface. In some eyes with childhood glaucoma, the iris is anterior to the scleral spur, preventing observation of the scleral spur.

    4. 4.

      Ciliary band

      The ciliary band corresponds to the anterior surface of the ciliary body and is observed as a gray-black band. Dissection and widening of the ciliary band (angle recession) may be observed as traumatic changes.

    5. 5.

      Angle vessels

      Physiologically, blood vessels (capillary vessels) may be observed in the angle; however, the blood vessels show a regular course, such as concentric, or radial. Pathological neovascularization has an irregular, tortuous course, often with numerous branches, and may be accompanied by peripheral anterior iris adhesions. The presence of pathological neovascularization may be overlooked owing to the interruption of blood flow at high IOP.

    6. 6.

      Other angle findings

      Peripheral anterior iris synechia, nodules, hemorrhage, and angle pus may be observed.

  2. 2.

    Angle observation method

    There are two types of gonioscopy: the direct method, which uses a direct gonioscope and the indirect method, which uses an indirect gonioscope. Direct gonioscope includes Koeppe, Balkan, Swan–Jacob, and Hill lenses. In contrast, indirect gonioscope includes Goldmann and Zeiss 4-mirror lenses. For accurate diagnosis of angle closure, it is desirable to perform both static and dynamic gonioscopy. The direct-type gonioscope is placed on the cornea with the patient in a supine position, and the corner angle is observed using a hand-held slit-lamp microscope or an operating microscope. It is primarily used for pediatric and surgical patients.

    1. 1.

      Static gonioscopy

      Static gonioscopy is performed in a dark room with the light intensity of the slit-lamp microscope set at the lowest to prevent light from entering the pupillary region as well as to prevent applying pressure from the gonioscope. The test evaluates the degree of angle opening during spontaneous mydriasis in the primary position. This test cannot distinguish between non-synechial and synechial angle closure.

    2. 2.

      Dynamic gonioscopy

      This test is performed following static gonioscopy. The light intensity of the slit-light microscope is increased to induce pupillary constriction, and the corner angle is widened by applying mild pressure through the gonioscope or by tilting the eye position. In addition to the presence and extent of synechial angle closure, the test diagnoses the presence or absence of nodules and neovascularization.

    3. 3.

      Indentation gonioscopy

      This is a type of dynamic gonioscopy in which the central cornea is compressed and deformed by the gonioscope, causing the aqueous humor to push the surrounding iris backward and facilitating observation of the base of the angle. This test is performed when it is difficult to differentiate between non-synechial and synechial angle closure using conventional dynamic gonioscope owing to the extremely narrow angle.

  3. 3.

    Beneficial test equipment for auxiliary diagnosis

    The ultrasound biomicroscope is a diagnostic instrument that permits cross-sectional observation of the microstructure of the anterior segment, including the angle, iris, and part of the ciliary body, and has been reported to be useful in glaucoma treatment [13]. The anterior segment OCT is a diagnostic instrument that allows non-contact observation of the angle, and its resolution is superior to that of ultrasound biomicroscopy; however, it cannot detect the ciliary body.

  4. 4.

    Methods of noting angle findings

    The angle findings are noted using Shaffer’s classification [14], Scheie’s classification [15], and Spaeth’s classification [16]. The former two are commonly used in Japan.

    1. 1.

      Shaffer’s classification

      Grade 0: Angle closure is present (corner angle: 0˚)

      Grade 1: Angle closure probably occurs (angle of the corner: 10˚)

      Grade 2: Angle closure may occur (angle of angle: 20˚)

      Grade 3–4: Angle closure is unlikely (angle of angle: 20–45˚)

    2. 2.

      Scheie’s classification

      Grade 0: All parts of the angle can be observed, indicating wide open angle

      Grade I: A part of the ciliary band cannot be observed

      Grade II: The ciliary band cannot be observed

      Grade III: The posterior half of the trabecular meshwork cannot be observed

      Grade IV: All parts of the angle cannot be observed

V. Fundus examination

  1. 1.

    Optic nerve disc and retinal nerve fiber layer

    In the diagnosis of glaucoma, the detection of morphological changes in the optic nerve disc or RNFL is extremely important. The findings of optic nerve disc and RNFL damage are related to the stage of glaucoma; however, are often detected before the detection of visual field abnormalities. In normal-tension glaucoma, the detection of optic neuropathy by fundus examination is often the trigger for disease detection. Observation of optic nerve findings by fundus examination incorporates: (1) ophthalmoscopy, (2) slit-light microscopy using an auxiliary lens, (3) fundus photography, (4) red-free ophthalmoscopy, and (5) fundus three-dimensional image analysis.

    For further details, please refer to Supplementary Material 3, “Guidelines for Determination of Glaucomatous Optic Nerve Disc and Retinal Nerve Fiber Layer Changes,” which has been prepared separately (Figs. 1, 2, 3).

    Fig. 1
    figure 1

    Example (a) and schematic diagram (b) of the measurement of horizontal and vertical C/D ratio. Regardless of the slope of the disc or cuppings, the horizontal or vertical diameters are determined, and their ratios are taken

    Full size image
    Fig. 2
    figure 2

    Example (a) and schematic (b) of R/D ratio measurement

    Full size image
    Fig. 3
    figure 3

    Schematic diagram of disc-to-macula distance/disc diameter (DM/DD) ratio. Generally, this ratio is between 2.4 and 3.0.

    Full size image

VI. Visual field test

  1. 1.

    Visual field

    The visual field test is not only useful in the diagnosis of glaucoma but is also important for follow-up. Normal visual field has a horizontal oval shape and is approximately 60˚ in the superior and nasal directions, 70–75˚ in the inferior direction, and 100–110˚ in the temporal direction. There are two methods of visual field measurement: kinetic measurement and static measurement. It is desirable to evaluate the data in consideration of the learning effect and reliability (1B). The test results are affected by ptosis, refractive error, opacity of the optic media, pupil diameter, and aging.

  2. 2.

    Kinetic visual field

    In the kinetic visual field measurement using the Goldmann perimeter, the examiner moves the target and draws several isopters. When the examiner is skilled, highly accurate results can be obtained. It is difficult to detect early glaucomatous changes and slight sensitivity loss using dynamic visual field testing. It is useful for patients for whom static visual field testing is challenging.

  3. 3.

    Static visual field

    In general, static visual field measurement is more sensitive than kinetic visual field measurement in detecting visual field abnormalities in early glaucoma. Static visual fields are recommended in the treatment of glaucoma (1A). Humphrey and Octopus perimeters are widely used. There are two measurement programs: screening and threshold tests. The threshold test method is essential for the follow-up of glaucoma. Useful indices for evaluating the reliability of test results are the status of fixation, the frequency of false negatives and false positives, and short-term variability. The experience of the participant is also important, and the first test result is generally less reliable than subsequent results. The test results are shown as the measurement threshold, gray scale, total deviation, and pattern deviation. The measurement of the visual field within 30˚ is the standard, and the measurement of the visual field within 10˚ is also performed as appropriate.

    A minimum of five visual field measurements are required to determine progression. It is ideal to have more than five measurement points. The more frequent the measurements, the easier it is to determine progression. For patients with newly diagnosed glaucoma, it is recommended that measurements be taken as frequently as possible during the first two years [17] (2C).

  4. 4.

    Other visual field measurements

    Blue on yellow perimetry (short-wavelength automated perimetry: SWAP), frequency doubling technology (FDT), and flicker perimetry are reported to be useful for glaucoma diagnosis in the very early stage. It has been reported that SWAP, FDT, and flicker perimetry may be useful in the diagnosis of very early glaucoma [18].

  5. 5.

    Criteria for glaucomatous visual field abnormalities and progression judgment

    1. 1.

      Noting results of Humphrey perimeter

      1. 1.

        Confidence coefficient

        The three coefficients of false positive, false negative, and fixation loss indicate reliability. Many false positives indicate a lack of reliability. Many false negatives indicate that the patient does not understand the content of the test, or that the patient has lost concentration. Fixation loss also indicates a patient's lack of attention. It is an important indicator of the reliability of the results.

      2. 2.

        Grayscale

        It is a graphical shading display of numerical values. It is useful to grasp the pattern of visual field disorder roughly.

      3. 3.

        Total deviation

        It indicates the deviation from the normal value of the same age built into the machine.

      4. 4.

        Pattern deviation

        It is an index that subtracts the overall loss of sensitivity and brings out the local abnormality. It is useful when there is an overall loss of sensitivity due to opacity or mydriasis of the optic media such as cataract or corneal opacity.

      5. 5.

        Statistical index of visual field

        • Mean deviation, mean defect (MD): Difference in mean visual sensitivity from normal age-corrected participants.

        • Visual field index (VFI): An index similar to MD but weighted to the sensitivity of the central region.

        • Pattern standard deviation (PSD): The degree of unevenness of the visual field. It increases with localized loss of sensitivity.

        • Short-term fluctuation (SF): Standard deviation obtained by measuring the same measurement point two or more times during a single visual field test. This is used as an index of reproducibility of data.

        Corrected pattern standard deviation (CPSD): PSD minus the effect of SF.

      6. 6.

        Glaucoma hemifield test

        In glaucoma, there is often a difference in the degree of optic nerve neuropathy between the upper and lower retina, particularly in the early and middle stages. Thus, statistical analysis is performed between the upper and lower five clusters to make a judgment. The results are classified within normal limits, outside normal limits, borderline, general depression of sensitivity, and abnormally high sensitivity.

    2. 2.

      Criteria for glaucomatous visual field abnormalities [19]

      If any of the following criteria are met:

      In the pattern deviation probability plot, there are three or more points with p<5% adjacent to each other, except for the most peripheral inspection point, and one of these points has p<1%.

      PSD or CPSD of p<5%.

      Glaucoma hemifield test is outside normal limits.

    3. 3.

      Progress judgment

      During follow-up, visual field examination is necessary to estimate the presence and rate of progression of visual dysfunction, and multiple visual field examinations are necessary to determine progression from baseline [17] (1B).

      Two methods, event and trend analyses, are the mainstream methods for determining progression.

      1. 1.

        Event analysis: Two visual field test results are set as the baseline. The results of the baseline and subsequent tests are compared. A statistically significant worsening of three consecutive measurement points for two or more consecutive times is regarded as progression. Three or more deteriorations are considered more definite progression.

      2. 2.

        Trend analysis: This is a method to determine the degree of deterioration of MD and VFI per year by using linear regression equations. This method can be used by the program of the perimeter, and the electronic medical record system, or independent visual field management software.

Chapter 4

I. Principles of glaucoma treatment

  1. 1.

    Treatment aims to maintain the patient's quality of vision and quality of life

    The goal of glaucoma treatment is to maintain the quality of vision (QoV) and the associated quality of life (QoL) of patients [20]. QoV and QoL decrease with the progression of visual impairment such as visual field impairment due to glaucoma [21, 22]. Social, psychological, and economic burdens associated with treatment may also decrease QoL, and consideration needs to be given to the possibility [22] (1A).

  2. 2.

    The most reliable treatment is IOP reduction

    Currently, IOP reduction is the only reliable evidence-based treatment for glaucoma [23,24,25,26,27,28,29,30,31,32,33] (1A). The results of various randomized controlled trials and related studies support the idea that IOP lowering reduces both the onset and progression of glaucoma [25,26,27,28,29,30,31,32,33]. IOP lowering is effective regardless of the type or stage of glaucoma [25,26,27,28,29,30,31,32,33] (1A). In the treatment of IOP lowering, attention to IOP and its fluctuation is necessary [23,24,25,26,27,28,29,30,31,32,33] (1A). In addition to diurnal, seasonal, and positional variations, corneal properties also have a significant effect on IOP measurement. In addition to congenital differences in corneal thickness, it should be noted that IOP may increase or decrease owing to the influence of other diseases or refractive surgery.

    As new methods of treatment for non-IOP factors, therapies to improve blood flow to the optic disc and retina and neuroprotective therapies are receiving significant attention and are being tested. These may become innovative treatments in the future. Although some clinical trials have suggested significant visual field maintenance in addition to the IOP-lowering effect (2C) [34], there is currently no reliable evidence that so-called complementary or alternative therapies other than IOP lowering, Chinese herbal medicine, or supplements are effective in the treatment of glaucoma (Fig. 4).

    Fig. 4
    figure 4

    Flow chart. a Determination of disease type/stage of glaucoma b Static quantitative perimetry (automated perimeter) c Intraocular pressure-lowering treatment: Determination of target intraocular pressure [Primary open-angle glaucoma (broad definition)] d Intraocular pressure-lowering treatment: Basic policy for medical treatment [Primary open-angle glaucoma (broad definition)] e Treatment of primary angle-closure glaucoma f Treatment of acute primary angle-closure ・ acute primary angle-closure glaucoma

    Full size image
  3. 3.

    Treatment of the cause if there is a treatable cause

    If the cause of elevated IOP is treatable, the cause should be treated along with treatment for lowering IOP. These include iridotomy and lens extraction for glaucoma caused by pupillary blocks such as primary angle-closure glaucoma, anti-inflammatory treatment for glaucoma associated with uveitis, retinal photocoagulation for neovascular glaucoma, and discontinuation of corticosteroid administration for steroid-induced glaucoma.

  4. 4.

    Importance of early detection

    In glaucoma, whatever visual function is lost cannot be recovered. In many cases, glaucoma progresses slowly after long-term observation [35]. Even with adequate IOP-lowering therapy, some cases of glaucoma progression are known to occur, particularly in late-stage cases [36, 37]. Therefore, early detection and early treatment are important in glaucoma therapy [35,36,37] (1A).

  5. 5.

    Maximum effect with minimum necessary drugs

    The principle of drug therapy is to achieve the maximum effect with the minimum number of drugs and side effects. Thus, the mechanism of action, side effects, and contraindications of each drug must be comprehended.

  6. 6.

    Choice among drug, laser, and surgery; See FQ2

    IOP-lowering treatment for glaucoma includes drug therapy, laser therapy, and surgery. The effects and side effects, and advantages and disadvantages of each method of treatment should be considered, and the appropriate treatment should be selected according to the stage and type of disease of each patient [38,39,40,41]. In selecting a method of treatment, the decision should be made jointly by the physician and patient [38], considering not only the patient’s age and the severity of the disease, but also the possibility of continuing the treatment, financial burden, and appropriateness of adherence.

    Concomitant use of multiple drugs may lead to increased side effects and reduced adherence; therefore, careful consideration is warranted [40, 41] (1A). Although the use of a combination ophthalmic solution may be considered to improve adherence, in principle, it is advisable to start with a single drug for the first time (1B). In general, when multiple drugs are required to control IOP, other treatment methods such as laser therapy and surgery should be considered as viable alternatives.

  7. 7.

    Selection of individualized treatment

    Personalized glaucoma therapy aims to provide treatment that fulfills the needs and desires of individual patients. The choice of treatment is based on the level of IOP, the degree of fundus changes and visual field impairment, the effect of treatment, the patient’s quality of life, life expectancy, and the presence of risk factors [38] (1A). The diagnosis of the stage and type of glaucoma, prognosis, management plan, and the possibility of long-term treatment should be determined for each patient [38,39,40,41].

  8. 8.

    Deceleration of rate of progression

    Glaucoma management aims to slow the progression of visual field impairment by lowering IOP. Therefore, assessing the rate of progression of visual field impairment due to glaucoma is important [17, 42] in evaluating the management and treatment of patients, including whether the established target IOP is appropriate and whether the current treatment is enough.

  9. 9.

    Assessment of risk factors

    Risk factors related to the progression of glaucoma must be evaluated for treatment. The major risk factors for blindness are disease severity at detection and life expectancy [36]. Several studies have demonstrated that the most important prognostic factor for blindness is more severe visual field impairment at the time of detection [36, 37]. Therefore, more aggressive treatment should be administered in advanced cases [27, 36, 37] (1A). The following are the risk factors for the onset and progression of open-angle glaucoma and ocular hypertension. High baseline IOP [29] and mean IOP during the disease [26, 30] are associated with progression of visual field and optic neuropathy. Absolute IOP is strongly related to the progression of visual field impairment; however, IOP fluctuation is reported to be also related to the progression [17, 31,32,33,34,35,36,37,38,39,40,41,42,43]. It has been reported that patients with severe visual field impairment in one eye have a higher risk of progression in the other eye [44].

    • High IOP: high baseline IOP[30], high mean IOP during the course of the disease[27, 30], large IOP fluctuation[31]

    • Age

    • Family history

    • Large C/D ratio, small optic nerve rim area

    • Disc hemorrhage

    • Large β-zone of peripapillary chorioretinal atrophy (PPA)

    • Thin corneal thickness

    • Low corneal hysteresis

    • Low ocular perfusion pressure

    • Low diastolic and systolic blood pressure

    • Type 2 diabetes

    • Exfoliation syndrome

    • Poor drug adherence

II. Treatment practice

Since the majority of glaucoma cases have a chronic course, the glaucoma treatment described here covers primary open-angle glaucoma (broad), primary angle-closure glaucoma after iridotomy and lens extraction, and chronic secondary glaucoma. Glaucoma treatment aims to 1) control IOP, 2) maintain optic nerve and retina, and 3) maintain the visual field.

  1. 1.

    Understanding the baseline data

    The untreated status of each patient is important as baseline data. The IOP level without treatment is the IOP that causes optic nerve impairment, and this level is the IOP at which the damage is expected to progress further. It is necessary to determine the IOP level at the time of no treatment to judge treatment efficacy. Additionally, it is important to understand the fundus and visual field findings at the time of no treatment not only to determine the treatment policy but also to detect the progression of the impairment at an early stage and to promptly modify the treatment. Therefore, it is advisable to obtain baseline data such as IOP, angle, fundus, and visual field before initiating treatment, unless there is a particularly urgent need to start treatment, such as in late-stage cases.

  2. 2.

    Target intraocular pressure

    The goal of glaucoma treatment is to maintain QoV and QoL. However, because optic neuropathy is irreversible and progresses slowly, it takes a long period to determine the effect of treatment. Therefore, glaucoma should be treated by setting a target IOP level [17, 29, 30, 45,46,47] for each patient (see Flowcharts III to IV).

    1. 1.

      Setting target intraocular pressure

      It is challenging to determine the rate of progression of optic neuropathy and IOP at which it can be suppressed in advance. Therefore, when initiating treatment, a target IOP is set for each patient, considering risk factors such as glaucoma stage, IOP at no treatment, life expectancy and age, progression of visual field damage, family history, and status of the fellow eye (see Flowchart III) (1A). In general, the target IOP should be set lower in late-stage glaucoma cases owing to the greater impact on QoL if the disease progresses further. If the patient is anticipated to have a long-life expectancy, it is recommended that the target IOP be set lower and the progression is slowed down more aggressively because the treatment will be prolonged[27, 36, 37] (1B). The target IOP should be set according to each case, considering the risk of other eye conditions, family history, and other factors. In determining the stage and severity of glaucoma, it is important not only to evaluate functional changes due to visual field impairment, but also to evaluate structural changes including optic nerve disc depression.

      It has been proposed that the target IOP should be set according to the stage of glaucoma: 19 mmHg or less, 16 mmHg or less, and 14 mmHg or less for early, middle, and late stages, respectively [45]. However, this does not consider untreated IOP. Therefore, based on the results of various randomized controlled trials [25,26,27,28,29,30,31,32,33], it is recommended that a target be set as the percentage of IOP reduction from untreated IOP, 20% reduction from untreated IOP or 30% reduction from treated IOP (2B).

    2. 2.

      Assessment of progression and modification of target IOP

      The limitation of treatment with target IOP is that the validity of the initially set target IOP cannot be judged until the course progresses. In general, the appropriateness of the target IOP can be confirmed only when the progression of optic neuropathy is sufficiently suppressed. The target IOP is not absolute; some cases progress rapidly even if the target IOP is achieved, while others do not progress, or progress very slowly, even if the target IOP is not achieved. Therefore, the target IOP must be reevaluated and revised at the time of follow-up (1B). If structural or functional changes due to optic neuropathy progress and are judged to pose a risk of worsening QoV or QoL in the long-term prognosis, the target IOP must be revised to a lower value (1B). In contrast, if treatment has side effects or effects on QoL, it must be determined whether it is necessary to maintain the target IOP. Whether the current target IOP is necessary must be reconsidered if there is no progression over a long period. Often, untreated IOP can change over time. In cases where it is considered necessary and possible during treatment, the interruption of treatment and rechecking of untreated IOP must be considered. Since the target IOP is a means and not an end of treatment, it should be considered as a guideline for treatment (1B).

    3. 3.

      Glaucoma follow-up and progression judgment

      Fundus photographs and OCT can be used to determine progression based on structural changes (fundus findings). For a determination using fundus photography, photographs are taken and recorded at baseline and over time during follow-up. The depression, shape of the rim, and area of the RNFL defect are compared. Disc hemorrhage is considered a sign of progression, and if it is observed during follow-up, the need for enhanced treatment at that time will be examined (2B). The measurement of peripapillary RNFL thickness and macular inner retinal layer thickness using OCT can be used to quantitatively record fundus findings and to judge the progression of the disease based on the said findings (2B). Each OCT is equipped with a program to detect changes over time. However, it is important to note that the thickness measured using OCT is affected by various imaging conditions (displacement of the measurement position and image quality) and should not be taken for granted (2B). Additionally, it is difficult to detect further thinning in eyes with advanced glaucoma (floor effect); as such, OCT is suitable for relatively early stages of glaucoma, and visual field testing is primarily used to determine progression in advanced glaucoma (1C). The decrease in retinal superficial blood flow associated with glaucoma progression detected by OCT angiography is less sensitive to the floor effect than OCT measurement of the RNFL. As such, it may be more advantageous than OCT in determining progression in eyes with advanced glaucoma (2D). However, currently, a standardized utilization method has not been established in clinical practice.

      The progress of functional changes is judged using a visual field test. Typical methods include event and trend analyses using a static perimeter (see Chapter 3, Glaucoma Testing, IV Visual Field Testing). Trend analysis can determine not only the presence or absence of progression but also the rate of progression, which is useful for predicting the prognosis of visual function and evaluating the effect of treatment. The impact of visual field impairment on QoL varies depending on the area in the visual field [21], and the local progression, as well as the overall progression, must be evaluated (2B).

    The determination of progression in patients with advanced visual dysfunction due to glaucoma is limited despite fundus and visual field findings [37]. When static visual field tests are used, it is ideal to monitor the progress of the disease by using test methods appropriate for each case, for example, by measuring the visual field within the central 10° or increasing the optotype size, or evaluating the temporal residual visual field using kinetic visual field tests (2B).

  3. 4.

    Glaucoma and QoL

    Maintenance of quality of life is one of the most important goals associated with glaucoma care [21, 22]. The impairment of QoV due to glaucoma has profound impact on QoL. For example, it has been reported that as glaucoma progresses, the ability to drive, read, walk, and recognize faces decreases, cognitive function decreases, and the risk of falls and stumbling increases [21, 22]. Additionally, the progression of glaucoma itself makes it difficult to use eye drops and oral medicine, possibly leading to a decrease in the accuracy of treatment not only for glaucoma but also for other diseases. In contrast, the diagnosis of glaucoma, a chronic disease with the potential to lead to blindness, causes worry and anxiety in patients and their families, and may lead to a decrease in psychological QoL [22]. Social withdrawal owing to the decline in QoL is also an important issue. Side effects of treatment, financial burden, and time constraints may also negatively impact QoL [22].

    To maintain the patient’s QoL, not only the treatment of the disease but also the impact of our diagnosis and treatment on the patients and their families must be considered (2C).

  4. 5.

    Adherence in glaucoma drug therapy

    Adherence is defined as the willingness of the patient and the physician to participate in the decision-making process and to implement the treatment method. Since glaucoma is a progressive disease that often follows extremely chronic progress, requires long-term use of the ophthalmic solution and regular follow-up, and often has no subjective symptoms, maintaining adherence is greatly related to the success or failure of treatment [39,40,41].

    The adherence to glaucoma medication treatment is reported to be worse than that anticipated by physicians [41]. It has been reported that 40% of patients who are prescribed the ophthalmic solution for glaucoma in Japan drop out of treatment approximately one year after the start.

    This is a remarkable feature of glaucoma which is characterized by the lack of subjective symptoms, the lack of feedback on the effects of IOP treatment.　This can be the high burden of self-administered treatment using ophthalmic solution [48]. Poor adherence is one of the most important factors in the progression of glaucoma, and it is desirable to select drugs for treatment that are not only effective but also easy to adhere to (2B). When IOP control is inadequate or visual dysfunction progresses, it is necessary to reconfirm adherence (2B). Many factors contribute to poor adherence [39,40,41]. For example, problems in life and environment (problems in the patient’s life, and irregular lifestyle); problems in treatment (medical costs, side effects of drugs, and complicated treatment); problems on the part of the patient (complications of other diseases, lack of understanding of the disease); and problems on the part of the healthcare provider (lack of communication with the physician). To improve and maintain adherence, a cooperative relationship between the patient and medical professionals, including physicians, nurses, and certified orthoptists, is essential. To improve adherence, it is important to (1) fully explain the disease, purpose of treatment, methods, and side effects; (2) select the treatment method with the least burden and side effects; (3) customize treatment according to the patient’s lifestyle; (4) provide correct guidance for ophthalmic solution use; and (5) collect information from the patient regarding the status of adherence (2B). Currently, explanations and instructions are often communicated verbally. According to the 1st Questionnaire Survey on the Actual Conditions of Glaucoma Treatment conducted by the Japan Glaucoma Society in 2020 (published in September 2021 by the Japan Glaucoma Society, scheduled to be posted on the website), the average duration of explanation to patients is about 10 min for other eye diseases. In contrast, glaucoma takes an average of 15 min, which is still more time-consuming and labor-intensive than for other eye diseases. However, there is evidence that appropriate and enough guidance and management, such as document delivery, hospital visit management, and reminder notification, has significantly improved the treatment retention rate and treatment outcomes [49].

    Therefore, it is ideal to provide patient-specific written explanations and delivery to improve adherence and visit management and send notifications for sustainable long-term management. However, only approximately 1.4% of medical institutions that perform all these services are affiliated with glaucoma specialists. Although measures to improve adherence, including guidance for patients with glaucoma and long-term management, have been considered medical professionals shoulder a heavy burden and are not known to most people.

Chapter 5 Glaucoma drugs

I. Classification of Glaucoma Drugs (See Table 2 and Supplementary Data 2)

Table 2 Major glaucoma ophthalmic drugs and their characteristics
Full size table
  1. 1.

    Topically administered drugs

    1. 1.

      Prostanoid receptor-related drugs

      1. 1.

        Prostanoid FP receptor agonists (FP agonists)

      2. 2.

        Selective prostanoid EP2 receptor agonist (EP2 agonist)

    2. 2.

      β-adrenergic blockers (β-blockers)

      1. 1.

        Nonselective β-blockers

      2. 2.

        Selective β1-blocker

      3. 3.

        α1β-blocker

    3. 3.

      Carbonic anhydrase inhibitors (topical formulation)

    4. 4.

      α2-adrenergic agonist (α2agonist)

    5. 5.

      Rho-kinase inhibitor (ROCK inhibitor)

    6. 6.

      Parasympathomimetic drugs

    7. 7.

      α1-adregenic blocker (α1blocker)

    8. 8.

      Ion channel opener

    9. 9.

      Fixed-combination ophthalmic solutions

  2. 2.

    Systemic drugs

    1. 1.

      Carbonic anhydrase inhibitor (systemic formulation)

    2. 2.

      Hypertonic osmotic drugs

II. Drug selection

Prostanoid FP receptor agonists (FP agonists), which are prostanoid receptor-related drugs, are the most commonly used first-line drugs in open-angle glaucoma owing to their superior IOP-lowering effect and good tolerability in terms of frequency of ophthalmic administration and side effects [50] (1A). β-blockers and selective prostanoid EP2 agonist (EP2 agonist) may also be first-line drugs in terms of IOP-lowering efficacy and tolerability; however, contraindications and side effects should be considered. EP2 agonists, which have a novel mechanism of action different from that of FP agonists, were approved in September 2018 and are considered non-inferior to latanoprost in terms of lowering IOP. It is contraindicated in eyes with intraocular lenses and is not recommended for use in combination with FP agonists.

Second-line drugs include carbonic anhydrase inhibitor ophthalmic solution, α2 agonists, ROCK inhibitor, α1 blocker, ion channel opener, and parasympathomimetic drugs.

Combination ophthalmic solutions are useful for improving adherence in patients taking multiple drugs [51] (1B).

III Treatment trials and evaluation of IOP reduction

There are individual differences in the effects of drugs and daily and diurnal variations in IOP. When introducing ophthalmic medications, it is advisable to ascertain the baseline IOP, administer the medication to one eye, consider the relationship between the time of ophthalmic administration and the time of IOP measurement, determine the IOP lowering effect and side effects in the early stage of ophthalmic administration (single-eye trial), and confirm the effect before starting administration to both eyes [52] (2C). However, beta-blockers also have a slight IOP lowering effect in the untreated eye, which should be taken into consideration when evaluating the effect.

IV Considerations for concomitant use of drugs　(See FQ1 and FQ2)

  • If a drug is ineffective, is insufficiently effective, or causes drug resistance, the drug should be changed first, and single-agent therapy (monotherapy) should be pursued.

  • When the effect of a single drug (monotherapy) is inadequate, multidrug combination therapy (including fixed-combination ophthalmic solutions) should be used, considering the additional IOP lowering effect as well as side effects and contraindications.

  • The use of fixed-combination ophthalmic solutions should be considered to improve patient adherence and quality of life when multidrug therapy is followed.

  • Increasing the number or the amount of ophthalmic solutions beyond the prescribed regimen does not increase the IOP-lowering effect but increases side effects.

  • When multiple medications are required, other treatment alternatives such as laser therapy and incisional surgery should be considered in light of their efficacy in lowering IOP, side effects, and impact on adherence.

V. Combination therapy and fixed-combination ophthalmic solutions (1B)

A single bottle of ophthalmic solution (single agent) generally contains a single component drug; however, a single bottle of an ophthalmic solution containing two or more components is defined as a “fixed-combination ophthalmic solution.” In Japan, only two-component combination ophthalmic solutions are available.

When the effect of a single drug is insufficient, combination therapy should be used. The current candidates for use in combination with ophthalmic medications are prostanoid receptor-related drugs, β-blockers, carbonic anhydrase inhibitors, α2agonists, and ROCK inhibitor, based on the point of action and IOP lowering effect.

When prescribing concomitant medications, drugs with the same pharmacologic mechanism of action should not be selected. For example, two prostanoid receptor-related drugs or two β-blockers should not be used in combination. The newer EP2 and FP agonists, which have different intracellular signaling and outflow-promoting mechanisms, are also contraindicated in combination. Sympathomimetic drugs can be used in combination if the receptors that act on them are different. Although some combinations are pharmacologically unsuitable or have unsuitable mechanisms for lowering IOP, such as the combination of a prostanoid receptor-related agent that increases trans uveoscleral outflow and pilocarpine that decreases trans uveoscleral outflow, these combinations may lower IOP. When prescribing fixed-combination ophthalmic solutions, care should be taken to ensure that concomitant medications do not include drugs in the same family as the fixed-combination ophthalmic solution.

VI. Importance of instructions on the use of ophthalmic solutions and improving adherence (1B)

In glaucoma, a chronic disease with few subjective symptoms, adherence to ophthalmic treatment is extremely poor. No matter how well the prescription is given, the therapeutic drug will not be effective if not administered properly. The patient may think that they are administering the solution properly; however, use of multiple ophthalmic solutions without interval, several drops, or frequent blinking of the eyes may lead to decreased effectiveness and increased side effects. Poor adherence to using eye drops is associated with the progression of glaucoma [53, 54]. When prescribing IOP-lowering drugs, it is important to teach the correct method of ophthalmic administration (described below) to improve adherence by increasing intraocular transfer of the ophthalmic solution, thereby increasing efficacy, decreasing systemic transfer to reduce side effects, reducing local side effects, and ultimately achieving significant IOP reduction and tolerating side effects.

  • Hands should be washed before administering the ophthalmic solution

  • Caution must be exercised to not let the tip of the bottle touch the eyelashes

  • One drop should be used per ophthalmic solution

  • The patient should be instructed to gently close the eyelids and pressure should be applied to the lacrimal sac after administration

  • Any liquid around the eyes should be wiped off and any liquid on the hands should be washed off

  • When multiple ophthalmic solutions are used in combination, the interval between each administration should be at least 5 min

Chapter 6: Laser surgery

I. Laser iridotomy

  1. 1.

    Purpose

    This procedure aimed to release the pupillary block, relieve the pressure difference between the anterior and posterior chambers, and open the anterior chamber angle.

    1. 1.

      Indications

      This procedure is indicated for primary angle-closure glaucoma due to pupillary block, primary and secondary angle-closure glaucoma, or eyes with narrow angle in which relative pupillary block needs to be prevented (1B). It may be performed to eliminate the element of pupillary block in cases of suspected plateau iris (1C).

  2. 2.

    Preoperative preparation (2C)

    1. 1.

      An hour prior to surgery, 1–2% pilocarpine is administered to allow the iris to stretch and tense, facilitating penetration.

    2. 2.

      To prevent postoperative transient elevation of IOP, apraclonidine should be administered 1 h before and immediately after surgery [55].

    3. 3.

      If corneal edema is present, carbonic anhydrase inhibitor or hyperosmotic agent should be administered after the cornea becomes transparent.

    4. 4.

      The procedure is performed under topical anesthesia.

  3. 3.

    Contact lens

    Abraham and Wise contact lenses should be used for iridotomy.

  4. 4.

    Surgical technique and site (2D)

    The iridotomy contact lens is used to irradiate the periphery of the iris.

  5. 5.

    Laser settings (2C)

    1. 1.

      Nd:YAG laser iridotomy

      1. 1.

        Since the plasma generation energy differs depending on the device, the energy specified for the specific model is used.

      2. 2.

        The iris stroma should be focused upon rather than the iris surface.

      3. 3.

        To prevent iris hemorrhage, pre-irradiation of the planned penetration site using an argon laser may be performed [56].

    2. 2.

      Argon laser and Nd:YAG laser combination method

      This is a method to open a penetrated wound using an Nd:YAG laser after irradiating with a thermal coagulation laser, such as an argon laser. This method is recommended because the total amount of energy is smaller than that obtained with argon laser alone, and the bleeding is less than that when using the Nd:YAG laser alone (2C).

    3. 3.

      Thermocoagulation laser iridotomy, such as argon laser

      1. 1.

        Step one (the area around the planned penetration site should be irradiated and the iris should be stretched)

        Spot size: 200–500 μm

        Power: 200–600 mW

        Time: 0.2–0.6 s

      2. 2.

        Step two (penetration irradiation)

        Spot size: 50 μm

        Power: 1000–1500 mW

        Time: 0.02 s

        Upon successful penetration, pigment rises like an oil plume from the irradiated area, and further irradiation is administered to enlarge the perforation wound to a size (100–200 μm) enough to resolve the pupillary block.

  6. 6.

    Complications

    Laser iridotomy is associated with the following complications, of which bullous keratopathy is the most critical. The development of bullous keratopathy is thought to be related to the condition of the corneal endothelium and the total energy of laser irradiation. Preoperative assessment of the state of the corneal endothelium and avoidance of over-irradiation are essential (2C).

    • Ectopia pupillae

    • Anterior chamber hemorrhage

    • Corneal opacity

    • Bullous keratopathy

    • Postoperative iritis

    • Localized cataracts

    • Transient postoperative IOP elevation

    • Posterior synechia

    • Re-occlusion of perforated wound

    • Retinal mis-irradiation

  7. 7.

    Postoperative management (2D)

    1. 1.

      IOP should be measured 1–3 h after surgery to check for transient elevation of IOP.

    2. 2.

      Carbonic anhydrase inhibitor or hyperosmotic agent should be administered as needed.

    3. 3.

      Postoperative inflammation often resolves spontaneously; however, depending on the degree of inflammation, adrenal corticosteroids may be administered.

II. Laser trabeculoplasty

  1. 1.

    Purpose

    Improvement of aqueous humor outflow rate by laser irradiation of the trabecular meshwork.

  2. 2.

    Indication

    Primary open-angle glaucoma (broad), exfoliation glaucoma, pigmentary glaucoma, ocular hypertension, primary angle-closure glaucoma after laser iridotomy, and mixed-type glaucoma. (1B).

    In combination with or as an alternative to drug therapy.

  3. 3.

    Preoperative preparation [57] (1A)

    1. 1.

      To prevent a transient increase in IOP after surgery, apraclonidine should be administered 1 h before and immediately after surgery.

    2. 2.

      The procedure is performed under topical anesthesia.

  4. 4.

    Contact lens

    Indirect goniolens for laser coagulation

  5. 5.

    Surgical technique and site (2C)

    Argon laser (argon laser trabeculoplasty [ALT]), 532 nm Q-switch half-wave YAG laser (selective laser trabeculoplasty [SLT]) is used. In ALT, approximately 25 shots are applied to the trabecular pigment band around one-fourth to half of the anterior chamber angle at equal intervals per quadrant. In the SLT, the irradiation is performed at intervals that do not overlap with the trabecular meshwork from half to the entire circumference of the anterior chamber angle.

  6. 6.

    Laser setting (2C)

    Argon laser trabeculoplasty (ALT)

    • Argon laser

    • Spot size: 50 μm

    • Power: 400–800 mW (enough to achieve dye desorption without the appearance of small bubbles)

    • Time: 0.1 s

    Selective Laser Trabeculoplasty (SLT)

    • 532 nm Q-switched half-wavelength YAG laser

    • Spot size: 400 µm

    • Power: 0.4–1.2 mJ (reduce the power if small bubbles appear)

    • Time: 3 nanoseconds

  7. 7.

    Complications

    • Anterior chamber hemorrhage

    • Peripheral anterior synechia

    • Postoperative iritis

    • Elevated postoperative IOP

    • Corneal endothelial damage

  8. 8.

    Postoperative management (2D)

    1. 1.

      Measure IOP 1–3 h after surgery to check for transient IOP elevation.

    2. 2.

      Carbonic anhydrase inhibitor or hypertonic osmotic agent should be administered as needed.

    3. 3.

      Postoperative inflammation often resolves spontaneously, but depending on the degree of inflammation, adrenal corticosteroids may be administered.

III. Laser gonioplasty (Laser peripheral iridoplasty)

  1. 1.

    Purpose

    Thermal coagulation using a laser shrinks the iris periphery and opens the anterior chamber angle.

  2. 2.

    Indication [58]

    In patients with plateau iris, angle-closure glaucoma due to pupillary block in whom laser iridotomy cannot be performed owing to corneal opacity, primary open-angle glaucoma (broad) with a narrow anterior chamber angle as a pre-procedure for laser trabeculoplasty, or eyes treated with goniosynechialysis to prevent postoperative anterior synechia (1B).

  3. 3.

    Preoperative preparation (2C)

    1. 1.

      To prevent a transient increase in IOP after surgery, apraclonidine should be administered 1 h before and immediately after surgery.

    2. 2.

      The procedure is performed under topical anesthesia.

  4. 4.

    Lens

    Abraham contact lens for iridotomy, Wise contact lens, and Goldmann three-mirror are used.

  5. 5.

    Surgical technique and site (2D)

    Coagulation is performed in one or two rows of approximately 15 shots per quadrant in the periphery of the iris, either two or four quadrants.

  6. 6.

    Laser setting (Argon laser) (2C)

    Spot size: 200–500 μm

    Power: 200–400 mW

    Time: 0.2–0.5 s

  7. 7.

    Complications

    • Transient IOP elevation

    • Postoperative iritis

    • Ectopia pupillae

    • Corneal endothelial damage

  8. 8.

    Postoperative management (2D)

    1. 1.

      Measure IOP 1–3 h after surgery to check for transient IOP elevation.

    2. 2.

      Carbonic anhydrase inhibitor or hypertonic osmotic agents should be administered as needed.

    3. 3.

      Postoperative inflammation often resolves spontaneously; however, depending on the degree of inflammation, adrenal corticosteroids may be administered.

IV. Cyclophotocoagulation

  1. 1.

    Purpose

    There are two modes: one is continuous laser oscillation and the other is micro pulsed-wave oscillation with repeated on and off cycles. In the continuous oscillation mode, the laser destroys the ciliary processes and suppresses aqueous humor production to lower the IOP. Micropulse waves stimulate the cells in the pars plana of the ciliary body. An increase in the uveoscleral outflow may result in IOP reduction.

  2. 2.

    Indication

    Cyclodestructive procedure through a continuous wave is indicated for patients for whom other glaucoma surgeries, such as filtration surgery, are ineffective or not indicated. It can cause vision threatening complications and should be considered as a last alternative for lowering IOP. Trans-scleral, trans-pupillary, and trans-vitreous approaches are available. In the case of micropulse waves, they may be indicated early on as an addition to ophthalmic treatment; however, their role has not yet been fully investigated.

  3. 3.

    Preoperative preparation

    It is performed with retrobulbar anesthesia or sub-tenon anesthesia.

  4. 4.

    Surgical technique and site

    1. 1.

      Trans-scleral diode laser cyclocoagulation

      The ciliary body is coagulated using a coagulation probe placed 0.5–2.0 mm posterior to the limbus, and 15–20 shots are performed in half to three-fourth rounds per session.

    2. 2.

      Trans-scleral micropulse wave cyclocoagulation

      A probe for micropulse waves is placed 3 mm behind the limbus. The 3 o’clock and 9 o’clock directions are avoided, and the upper and lower hemispheres are irradiated four times for 20 s each (total of 80 s x 2).

  5. 5.

    Laser setting

    1. 1.

      Trans-scleral diode laser cyclocoagulation)

      Power: 2, 000 mW Time: 2 s

    2. 2.

      Trans-scleral micropulse wave cyclocoagulation

      Power: 2, 000 mW Time: 80 s x 2

  6. 6.

    Complications

    The following complications are assumed; however, complications from micropulse waves are reported to be more minor [66, 67].

    • Pain

    • Decreased visual acuity, loss of light perception

    • Low IOP, phthisis bulbi

    • Anterior chamber hemorrhage

    • Corneal disorders

    • Prolonged inflammation

    • Macular edema

    • Ciliary detachment

    • Vitreous hemorrhage

    • Mydriasis

    • Transient IOP elevation

  7. 7.

    Postoperative management

    1. 1.

      Anti-inflammatory and analgesic drugs should be administered to prevent pain.

    2. 2.

      For postoperative inflammation, corticosteroids should be administered.

    3. 3.

      IOP often increases again by single irradiation; therefore, IOP control is often achieved by several repeat irradiations.

V. Laser suture lysis

  1. 1.

    Purpose

    Increasing the filtration rate after trabeculectomy or other filtration surgeries.

  2. 2.

    Indication (1B)

    When it is judged that the amount of filtration is insufficient.

  3. 3.

    Preoperative preparation

    1. 1.

      Intraoperatively, the scleral flap should be sutured using nylon thread.

    2. 2.

      The procedure is performed under topical anesthesia.

  4. 4.

    Lens

    A laser suture lysis lens is used.

  5. 5.

    Surgical technique and site

    Thermocoagulation laser (red laser is preferred to avoid conjunctival burns). The conjunctiva is lightly compressed with the laser suture lysis lens, and the laser beam is focused on the sutures through the conjunctiva.

  6. 6.

    Laser setting (2D)

    Spot size: 50 μm

    Power: 100–300 mW

    Time: 0.1–0.2 s

  7. 7.

    Complications

    • Conjunctival burn, perforation

    • Overfiltration

  8. 8.

    Postoperative management

Check the status of IOP and filtration bleb.

Chapter 7: Incisional surgery

I. Indication

Incisional surgery is generally indicated in patients who failed to achieve adequate IOP reduction using other therapies (drug and laser therapies), those who are not indicated for other therapies owing to side effects or poor adherence, or in whom other therapies are considered inadequate to achieve adequate IOP reduction. Indications for surgery must be determined based on a comprehensive evaluation of each patient’s disease type, stage, knowledge of the disease, adherence, age, general condition, and the patient’s social background.

Additionally, all treatments, not limited to surgery, should be performed with the consent of the patient upon full explanation of the treatment method and the contingencies and complications associated with the treatment method.

II. Surgical technique

Currently, the most widely performed procedure for most types of glaucoma, including primary open-angle glaucoma (broad), is trabeculectomy. However, the technique should be selected after considering the response mechanism, long-term results, complications, and the type, stage, and previous surgical history of each patient. In recent years, surgeries called as minimally invasive glaucoma surgery or micro-invasive glaucoma surgery (MIGS) have been applied clinically, primarily for outflow pathway reconstruction, and are now performed earlier than trabeculectomy.

  1. 1.

    Filtration surgery

    A new aqueous humor outflow pathway is created between the anterior chamber and subconjunctival tissue by making a small hole in the scleral limbus. The most critical complication is late infection from the filtration bleb. Patients who have undergone filtration surgery, including trabeculectomy, should be fully informed of the risk of late infection. The probability of late infection after trabeculectomy with mitomycin C in Japanese patients was 2.2% at five years.

    1. 1.

      Trabeculectomy

      This technique adjusts the filtration rate by fabricating a scleral flap, excising the limbus tissue below the scleral flap, and suturing the scleral flap. It is currently the most common glaucoma surgery for most types of glaucoma, including primary open-angle glaucoma (broad). The antimetabolic agents, mitomycin C or 5-fluorouracil are used intraoperatively and postoperatively to inhibit scarring at the filtration site. Obisort® may also be used before performing the peripheral iridectomy required for the trabeculectomy procedure. Laser suture lysis and scleral massage are used to adjust postoperative IOP.

    2. 2.

      Tube shunt surgery (without a plate) [60]

      This is a filtration surgery using a mini-tube without a plate. The EX-PRESS® Glaucoma Filtration Device has been approved in Japan. The advantages of this device over trabeculectomy are that it is easier to insert, the size of the outflow tract can be standardized, and does not require iridectomy. It is contraindicated in patients with angle-closure glaucoma, uveitis, and metal allergy. MRI examinations up to three Tesla are considered safe as they do not cause deviation.

    3. 3.

      Tube shunt surgery (with plate) See CQ4[61,62,63]

      This is a filtration procedure using a long tube connected to a silicone plate. Three types of Baerveldt glaucoma implants (BG101-350, BG102-350, and BG103-250) and two types of Ahmed glaucoma valves (FP7 and FP8) have been approved in Japan. The BG101-350, BG103-250, FP7, and FP8 are implants inserted into the anterior chamber, while the BG103-250 and FP8 are used in children or patients with short axial length. BG102-350 is an implant that is inserted into the vitreous cavity. The BG102-350 implant is indicated for patients who have unsuccessful trabeculectomy with concomitant use of antimetabolites, those with severe conjunctival scarring due to previous surgery, those who are unlikely to achieve successful trabeculectomy or are technically unable to undergo other filtration procedures (1B). To prevent postoperative exposure of the tube to the outside of the eye, a patch material such as preserved sclera or preserved cornea must be used or the tube must be covered using an autologous lamellar scleral flap (1A).

    4. 4.

      Other filtration surgery

      Full-thickness filtering surgery creates a direct outflow channel from the anterior chamber to the subconjunctiva without creating a scleral flap. Compared with scleral flap filtration surgery such as trabeculectomy, it is more challenging to control the filtration volume and has more complications (shallow anterior chamber), and is currently indicated only in some extremely difficult cases (2C). Non-perforating trabeculectomy is a filtration surgery in which a portion of tissue is excised below the scleral flap to create an outflow tract that does not perforate the anterior chamber. It has fewer complications in the early postoperative period compared with trabeculectomy; however, it is less effective in lowering IOP than trabeculectomy [64, 65].

  2. 2.

    Physiological outflow pathway reconstruction

    1. 1.

      Trabeculotomy (ab externo method)

      After a conjunctival incision, a scleral flap is created, and the trabecular meshwork is incised to facilitate the outflow of aqueous humor into Schlemm’s canal. A trabeculotome is inserted into Schlemm’s canal identified under the scleral flap and rotated into the anterior chamber to incise the trabecular meshwork from the outside. A nylon thread is inserted into Schlemm’s canal instead of a trabeculotome to make a wider incision in the trabecular meshwork.

    2. 2.

      Trabeculotomy (ab interno method)

      This is a surgical procedure to promote the outflow of aqueous humor into Schlemm’s canal by incising or excising the trabecular meshwork under direct observation of the trabecular meshwork through a goniolens. The incision can be made with a metal hook or with a nylon thread inserted into Schlemm’s canal by anterior chamber angle manipulation. There are two methods of excision: one is by using a special knife with two blades, and the other is by using a Trabectome® handpiece to electrically incinerate the inner wall of Schlemm’s canal and the trabecular meshwork. However, since either incision or excision may cause anterior chamber angle damage and postoperative transient IOP elevation, the procedure should be performed by a surgeon with sufficient experience in anterior chamber angle surgery.

    3. 3.

      Intraocular drain in combination with cataract surgery

      When lens reconstruction surgery is performed, a stent is placed into Schlemm’s canal from the anterior chamber side under observation using a goniolens to lower IOP more than that achieved by lens reconstruction surgery alone. There are two types of stents for intraocular drainage: the first-generation iStent® and the second-generation iStent inject W®. Both have been reported to have stronger IOP-lowering effects than via cataract surgery alone [68, 69] (1A). Patients with early- to mid-stage open-angle glaucoma who also have a cataract are approved for cataract surgery in Japan. However, complications resulting from incorrect penetration or lumen occlusion have been reported. As such, the procedure should be performed by a surgeon with sufficient experience in anterior chamber angle surgery [70].

  3. 3.

    Surgery to eliminate the pupillary block

    Peripheral iridectomy

    Peripheral iridectomy is a procedure to relieve the pressure difference between the anterior and posterior chambers by removing the peripheral iris to address glaucoma caused by pupillary blocks such as primary angle-closure glaucoma. With the widespread use of laser iridotomy, incisional peripheral iridectomy is rarely performed.

  4. 4.

    Cyclodestructive procedure

    A procedure that lowers IOP by coagulating the ciliary body using a cryocoagulator or diathermy and suppressing aqueous humor production. Since laser devices are used for this purpose, the procedure has become less common. The procedure is painful and has many complications (phthisis bulbi), and is indicated only for refractory cases in which other treatments are ineffective.

Chapter 8 Glaucoma treatment by disease type

Introduction

Building a trusting relationship with the patient is the most important factor in the effective treatment of glaucoma (determination of treatment plan, change of treatment plan, implementation of treatment, and follow-up).

Additionally, the effects and side effects (complications) of each treatment method must be comprehended and a treatment method, whose advantages outweigh the negative effects on the patient’s visual function, general condition, and QOL, must be selected. It should be understood that the follow-up intervals during treatment may be shortened or prolonged depending on the status of intraocular pressure, optic nerve, and visual field of each patient, and uniform observation should not be performed. IOP measurement, perimetry, and ophthalmoscopy with image recording should be performed during follow-up.

I. Primary Glaucoma

  1. 1.

    Primary open-angle glaucoma

    Although the target IOP for treatment is determined according to the stage and condition of each patient (see Flowchart IV, Chapter 4), it should be remembered that this is only a rough estimate. Do not be satisfied that the target IOP has been achieved and neglect observation, or on the contrary, do not be obsessed with the target IOP value and overtreatment. A feasible plan should be determined to improve adherence according to the patient’s age, preferences, and degree of ocular damage, as well as the dose and cost [38].

    1. 1.

      Drug therapy

      1. 1.

        Drug therapy is the first-line treatment for primary open-angle glaucoma.

      2. 2.

        Drug therapy begins with monotherapy (single drug) using ophthalmic hypotensive drops. If the efficacy is not confirmed, the drug should be changed, and if the efficacy is not satisfactory, multiple drug combinations (including combination ophthalmic solution) should be used.

      3. 3.

        If possible, the IOP-lowering effect should be confirmed by comparing the IOP of one eye with that of the untreated eye, measuring the diurnal variation of IOP in the untreated and treated eyes, measuring the variation of IOP according to positional change, and confirming the stability of treatment efficacy. Prostanoid receptor-related drugs have excellent safety, efficacy, and resistance, and can be instilled once a day; therefore, unless there is a specific reason, they should be the first choice [71,72,73] (1A).

    2. 2.

      Laser trabeculectomy

      It is used as an alternative treatment for patients who are unable to achieve target IOP using drug therapy, those who cannot continue drug therapy for some reason, or who have poor adherence to using ophthalmic solutions [74] (2B).

    3. 3.

      Incisional Surgery (with additional postoperative medical treatment if necessary)

      1. 1.

        Filtration surgery (trabeculectomy with/without antimetabolites, non-perforated trabeculectomy, tube shunt surgery)

      2. 2.

        Reconstructive surgery of the aqueous humor outflow tract (trabeculotomy)

      3. 3.

        Minimally Invasive Glaucoma Surgery (MIGS)

        Currently, the most widely performed technique is trabeculectomy [50]. The postoperative IOP of trabeculotomy is higher than that of trabeculectomy, and is known to be in the upper 10 mmHg range when combined with postoperative glaucoma medication [75, 76]. However, it has fewer complications compared to those with trabeculectomy and does not require concomitant antimetabolites. As for non-penetrating trabeculectomy, the results are inferior to those of trabeculectomy with antimetabolites in terms of lowering IOP; however, sufficient evidence comparing the two procedures is lacking [77].

        It is currently recommended in Japan that tube shunt surgery with a plate should be used when trabeculectomy fails or is expected to fail (see Chapter 4, V).

      4. 4.

        Cyclodestructive procedure

        It is rarely necessary for the treatment of primary open-angle glaucoma (broad). Since it has a significant impact on the structure and function of the eye, it should be applied with meticulous consideration.

    4. 4.

      Observation of progress

      The follow-up interval should be set flexibly according to the status of the IOP, optic nerve, and visual field of each patient and should not be observed uniformly. Even after control of IOP is achieved, IOP measurement and ophthalmoscopy should be performed every one month for several months and perimetry at least once or twice a year. Fundus imaging records are also useful in monitoring the course of the disease. Disc hemorrhage, a risk factor for progression, is easier to detect on fundus images than on ophthalmoscopy [78] (2C).

      In filtration surgery, it is important to explain the risk of bleb-related infection to patients and instruct them to come to the clinic or hospital immediately if they have symptoms suggestive of infection, such as redness, lacrimation, blurred vision, or eye pain.

      (Appendix 1) Ocular hypertension: See CQ1

      The rate of conversion to primary open-angle glaucoma is only 1–2% per year. In a multicenter study conducted in the United States, patients with high IOP between 24 and 32 mmHg were randomly divided into a non-treatment group and a treatment group (to achieve an IOP of 24 mmHg or less with ophthalmic treatment) and observed over five years. The results showed that the incidence of visual field defects or optic neuropathy was significantly lower in the treatment group. However, the study did not examine whether this also applied to patients with IOP less than 24 mmHg [28]. Therefore, IOP that is slightly above the upper limit of normal does not necessarily indicate prompt necessity for initiation of any treatment. There is consensus that patients with repeated IOP in the upper 20 mmHg range or with risk factors such as family history of glaucoma (see Chapter 2) may be subjects for treatment with tolerable ophthalmic solutions (2C). The follow-up interval should be every one month for several months, and IOP should be monitored. In cases where the optic nerve and perimetry are confirmed to be normal and there are no risk factors for conversion to primary open-angle glaucoma, IOP, ophthalmoscopy, and perimetry are performed every 1–2 years without treatment [79].

      (Appendix 2) Preperimetric glaucoma: See CQ2

      In principle, the patient should be carefully followed without treatment. However, if the patient has risk factors for developing glaucomas, such as high IOP, high myopia, or a family history of glaucoma, or if abnormalities are detected by special or more precise perimetry tests or fundus three-dimensional image analyzers, initiation of the minimum necessary treatment should be considered [25].

  2. 2.

    Normal-tension glaucoma

    Regarding the target IOP for treatment, the results of a multicenter study in the United States reported that there was a significant difference in the progression of visual field impairment between the group that achieved an IOP reduction of 30% or more and the untreated group, indicating that IOP reduction is effective [17, 34, 80] (1B). However, it is unclear whether the reduction in IOP must be 30% or more. Additionally, it has been reported that filtration surgery was performed in more than half of the cases to achieve an IOP reduction of 30% or more, and that eventual postoperative cataract progression can reduce visual function [17, 34, 80].

    Treatment and follow-up are the same as for primary open-angle glaucoma, and prostanoid receptor-related drugs are the first choice (1B) [71]. Laser trabeculoplasty is assumed to have little effect on IOP reduction. In addition to IOP-lowering therapy, improvement of optic nerve blood flow and neuroprotective therapy are gaining attention. Recently, it has been reported that brimonidine maintains a visual field that does not correspond to its IOP-lowering effect [26, 81] (2B).

  3. 3.

    Primary angle-closure glaucoma

    1. 1.

      Primary angle-closure glaucoma and primary angle-closure due to relative pupillary block

      Release of the relative pupil block by laser iridotomy (or surgical peripheral iridectomy) [82] or lens extraction[83] is the fundamental treatment and the first choice of treatment (1A).

      Drug therapy is used to address high IOP that persists after removal of the pupillary block (residual glaucoma), to relieve symptoms and findings in cases of acute glaucoma attack, and to facilitate and enhance the safety of laser iridotomy and iridectomy. Since most cases are bilateral, if primary angle-closure glaucoma or primary angle closure is observed in one eye, preventative laser iridotomy [84] (1A) and lens extraction [85] (1A) is also performed for the other eye with a narrow angle.

      1. 1.

        Acute primary angle-closure glaucoma and acute primary angle closure

        1. i.

          Drug therapy

          1. A.

            Hyperosmotic drugs

            Although hyperosmotic drugs are the most effective agents for transiently reducing substantial IOP elevation, systemic side effects of such drugs must be considered, since a rapid increase in extracellular fluid volume may cause an increase in circulating plasma volume, placing a burden on the circulatory system and possibly causing pulmonary edema in patients with heart failure or pulmonary congestion. It should also be noted that the IOP-lowering effect of hyperosmotic drugs is temporary, and repeated administration with the expectation of sustained IOP reduction will only worsen the patient’s general condition.

            Mannitol: A 20% mannitol solution at 1.0–2.0 g/kg BW is administered intravenously over 30–60 min. The minimum IOP is reached in 60–90 min, and the reduction in IOP is sustained for 4–6 h. Since mannitol is excreted by the kidney, decreased excretion due to renal impairment may cause acute renal failure due to increased plasma osmolality and increased circulating plasma volume. Additionally, patients with acute glaucoma may already be dehydrated due to vomiting at the time of the attack, and the diuretic effect of mannitol may worsen the dehydration.

            Glycerol: Approximately 300–500 mL is intravenously administered for 45–90 min. The minimum IOP will be achieved 30–135 min after the start of infusion. The duration of the effect is approximately 5 h. Because glucose is produced during the metabolic process and each liter of glycerol contains 637 kcal of energy, caution should be exercised when administering this drug to patients with diabetes.

          2. B.

            Miosis

            Approximately 1% to 2% pilocarpine is instilled 2–3 times/h. When the pupillary sphincter is ischemic owing to high IOP, leading to the loss of pupillary light reflex (sphincter paralysis), frequent administration of parasympathomimetic agents is ineffective and will not produce miosis. Rather, this causes anterior rotation of the ciliary muscle, resulting in increased pupillary block. Additionally, administration of large doses of miotics may be absorbed intranasally and cause systemic side effects.

          3. C.

            Suppression of aqueous humor production

            1. a.

              10 mg/kg acetazolamide: i.v. or oral

            2. b.

              β-blocker ophthalmic solution

            3. c.

              α2 agonist ophthalmic solution

            4. d.

              αβ-blocker ophthalmic solution

            5. e.

              Carbonic anhydrase inhibitor ophthalmic solution

          4. D.

            Enhancement of aqueous humor outflow

            1. a.

              FP agonist ophthalmic solution

            2. b.

              α1-blocker ophthalmic solution

            3. c.

              α2 agonist ophthalmic solution

            4. d.

              αβ-blocker ophthalmic solution

          5. E.

            Anti-inflammation

            1. a.

              Steroid ophthalmic solution

        2. ii.

          Surgical therapy

          In an acute attack of primary angle-closure glaucoma or primary angle closure, there is a risk of corneal endothelial damage, or developing malignant glaucoma or choroidal bleeding. As such, it is desirable to reduce IOP before surgery.

          1. A.

            Laser iridotomy

            Laser iridotomy is effective in relieving pupillary block [82] (1A). Laser iridotomy should be performed when the cornea is sufficiently clear. Laser irradiation through an opaque cornea increases the risk of developing bullous keratopathy [86]. Therefore, in cases of corneal opacity, unreasonable laser irradiation must be avoided and the indication for surgical iridotomy should be considered. The development of bullous keratopathy after laser iridotomy is known to be more common in patients with corneal guttata, those with diabetes, those with a history of acute attack of primary angle closure (glaucoma), or those with decreased corneal endothelial cells.

          2. B.

            Surgical peripheral iridectomy

            Surgical peripheral iridectomy can be performed even when the eye has corneal opacity that makes laser irradiation difficult; however, it also carries risks associated with end ophthalmic surgery.

          3. C.

            Lens extraction

            Although lens extraction is effective in radically resolving pupillary block [83] (1A), it carries a higher risk of intraoperative complications compared to cataract surgery on eyes without an acute attack of primary angle closure (glaucoma). Lens extraction for primary angle closure, particularly in the acute phase, is prone to complications and should be performed by a skilled surgeon (1B).

      2. 2.

        Chronic primary angle-closure glaucoma

        As in acute primary angle-closure glaucoma and acute primary angle closure, removal of the pupillary block is the basis of treatment. Treatment of prolonged high IOP after resolution of the pupillary block (residual glaucoma) is similar to that for primary open-angle glaucoma and includes drug therapy, laser therapy, and surgery.

        1. A.

          Drug therapy

          A combination of medications should be used in accordance with primary open-angle glaucoma.

        2. B.

          Surgical therapy

          1. a.

            Laser iridectomy (or peripheral iridectomy)

            This procedure removes the pupillary block

          2. b.

            Lens extraction

            It has been reported that this procedure is effective for both the removal of the pupillary block and the opening of the iridocorneal angle. Furthermore, it is reported to lower IOP even when used alone [83] (1A). However, IOP-lowering effect is often limited in the case of extensive peripheral anterior synechiae of the iris.

          3. c.

            Aqueous humor outflow tract reconstruction (goniosynechialysis, trabeculotomy)

            Goniosynechialysis is indicated in cases of extensive peripheral anterior synechiae of the iris (more than 50% of the iridocorneal angle). Trabeculotomy is indicated in the area where the trabecular meshwork is open. It is also used to detach the peripheral anterior synechiae. Both techniques, when combined with lens extraction (including intraocular lens insertion), have been reported to more likely prevent re-synechialization at the surgical site and to have a more favorable effect on lowering IOP.

          4. d.

            Trabeculectomy

            It is indicated in cases of inadequate intraocular pressure control by medication, long-term presence of peripheral anterior synechiae, difficulty in dissecting peripheral anterior synechiae owing to difficulty in seeing through the corneal angle, or failed goniosynechialysis or trabeculotomy. It should be noted that complications such as flat anterior chamber and malignant glaucoma are not uncommon in narrow-angle eyes.

            (Appendix) Primary Angle-closure Suspect (PACS)

            There are varying opinions on the use of pupil unblocking surgery including laser therapy for primary angle-closure suspects because primary angle-closure glaucoma does not always develop in such eyes.

            However, surgery may be indicated for eyes that are positive for various stress-loading tests, for patients who cannot undergo periodic examinations, who cannot immediately visit an ophthalmologist at the time of an acute attack, who have a family history of primary angle-closure glaucoma, and who require frequent mydriatic tests to monitor fundus diseases such as diabetic retinopathy.

            Pupil block removal in patients with primary angle-closure suspects is a preventive treatment for the development of primary angle-closure glaucoma and primary angle closure; therefore, laser iridotomy is indicated rather than surgical peripheral iridectomy. Lens extraction is also effective in relieving pupillary blocks in patients who are eligible for cataract surgery.

    2. 2.

      Primary angle-closure glaucoma and primary angle-closure by a plateau iris mechanism

      1. 1.

        Drug therapy

        Miosis pulls the peripheral iris toward the center, opens the iridocorneal angle, and prevents the progression of iridocorneal angle closure [87] (2C). In the case of extensive peripheral anterior synechiae that provide less opportunity to lower IOP with miotic agents alone, drug therapy is performed to suppress aqueous humor production and promote aqueous humor outflow as in chronic primary angle-closure glaucoma after pupillary block removal.

      2. 2.

        Surgical therapy

        Laser gonioplasty (laser peripheral iridoplasty) can shrink the iris root and widen the distance between the root and the iridocorneal angle [88] (1B), but its long-term efficacy remains unknown. Iridectomy and laser iridotomy are effective only when the plateau iris accompanies a pupil block mechanism. Lens extraction is expected to widen the iridocorneal angle.

II. Secondary glaucoma

The priority in the treatment of secondary glaucoma is to treat the causative disease whenever possible. A treatment method should be planned based on underlying mechanisms of IOP elevation. The following is a list of treatment methods for frequently encountered secondary glaucoma.

  1. 1.

    Exfoliation glaucoma

    In exfoliation glaucoma, the progression of GON is reported to be more rapid than in primary open-angle glaucoma because of the large variation in IOP and preference among the elderly [89]; as such, aggressive IOP reduction is recommended(1B).

    1. 1.

      Drug therapy

      Drug therapy according to primary open-angle glaucoma.

    2. 2.

      Surgical therapy

      Filtration surgery and outflow tract reconstruction are effective. Conjunctive cataract surgery is sometimes performed because of preference among the elderly for exfoliation glaucoma. Laser trabeculoplasty and outflow tract reconstruction have been reported to produce greater IOP reduction than those for primary open-angle glaucoma [90] (1B).

  2. 2.

    Secondary glaucoma caused by uveitis (Posner-Schlossman syndrome, sarcoidosis, Behcet's disease, herpetic keratouveitis, cytomegalovirus endotheliitis, Vogt-Koyanagi-Harada disease, etc.)

    Although treatment of the primary disease is prioritized, it is often difficult to differentiate glaucoma due to long-term steroid use.

    1. 1.

      Treatment of the causative disease, anti-inflammatory therapy

    2. 2.

      Instillation, oral medication, and IV administration of IOP-lowering drugs

    3. 3.

      Surgical therapy

    Trabeculectomy (with antimetabolites) or tube shunt surgery is performed. However, in cases of possible steroid-induced glaucoma, outflow tract reconstruction may be chosen as a treatment. Laser trabeculoplasty is often ineffective.

  3. 3.

    Steroid-induced glaucoma

    Steroids are administered for a variety of diseases, including uveitis, macular edema, palpebral conjunctival disease, postoperative instillation, and systemic diseases; therefore, it is important to understand the relationship between steroids and increased intraocular pressure. In general, IOP decreases with the discontinuation of steroids.

    1. 1.

      Discontinuation of steroid medication (if possible)

    2. 2.

      Instillation, oral medication, and IV administration of IOP lowering drugs

    3. 3.

      Surgical therapy

      Filtration surgery and outflow tract reconstruction are effective. It has been reported that outflow tract reconstruction can achieve a greater reduction in IOP than for primary open-angle glaucoma [91] (1B). Laser trabeculoplasty has also been reported to be effective [77].

  4. 4.

    Neovascular glaucoma

    It is often caused by diabetic retinopathy, central retinal vein occlusion, or ocular ischemic syndrome. It is important to restore the ischemic condition caused by the primary disease.

    1. 1.

      Drug therapy

      Drug therapy is performed in accordance with primary open-angle glaucoma. The efficacy of intraocular administration of anti-vascular endothelial growth factor (VEGF) agents has been reported [92, 93] (2C). Atropine and steroid ophthalmic solutions are effective in reducing inflammation and pain (2C). Parasympathomimetic drugs are often ineffective and may cause worsening of the condition owing to disruption of the blood-aqueous humor barrier.

    2. 2.

      Surgical therapy

      Trabeculectomy (with antimetabolites) and tube shunt surgery are performed. Laser trabeculoplasty is not only ineffective but also harmful. The efficacy of non-penetrating trabeculectomy and aqueous humor outflow tract reconstruction (trabeculotomy) have not been confirmed. Preoperative intraocular administration of anti-VEGF agents has been reported to reduce intraoperative and postoperative complications [94] (2B).

  5. 5.

    Pigmentary glaucoma, or pigment dispersion syndrome

    Pigment dispersion caused by reverse pupillary block is thought to cause elevated IOP. GON that is due to pigment dispersion syndrome is called pigmentary glaucoma.

    1. 1.

      Drug therapy

      It is like primary open-angle glaucoma. However, mydriatic agents may cause pigment dispersion and worsen aqueous humor.

    2. 2.

      Surgical therapy

      Resolution of the reverse pupillary block by laser iridotomy and lens extraction can reduce the pigmentation caused by iris-lens contact and prevent irreversible damage to the trabecular meshwork [95] (2B). Laser trabeculoplasty is performed at lower power than usual because of the high degree of pigmentation in the trabecular meshwork. The IOP response is highly variable. Reconstructive surgery of the outflow tract and filtration surgery may be successful.

  6. 6.

    ICE syndrome

    Abnormal proliferation of corneal endothelial cells results in obstruction of the trabecular meshwork and increased IOP. It usually occurs in one eye.

    1. 1.

      Drug therapy

      It is like primary open-angle glaucoma but is treatment-resistant.

    2. 2.

      Surgical therapy

      Filtration surgery: When compared with primary open-angle glaucoma, the outcomes of trabeculectomy are inferior; therefore, tube shunt surgery with a plate may be an option.

  7. 7.

    Malignant glaucoma

    It is presumed that the anterior deviation of the vitreous body obstructs the iridocorneal angle, which is due to anterior rotation of the ciliary body or misdirection of aqueous humor into the vitreous cavity.

    1. 1.

      Drug therapy

      Pupillary dilation and ciliary relaxation with atropine ophthalmic solution. Topical or per oral IOP-lowering drugs are effective. Hyperosmotic ophthalmic solutions are often chosen to reduce the vitreous volume, but their therapeutic effect is temporary, and they should be considered as just a preoperative measure. In contrast, miotic drugs are contraindicated because they promote anterior protrusion of the ciliary body.

    2. 2.

      Surgical therapy

      In pseudophakic or aphakic eyes, anterior vitrectomy or capsulotomy with YAG laser or surgery is the treatment of choice [96] (2C). It is important to resolve the condition by vitrectomy with incision of the anterior vitreous membrane. In some cases, an iridectomy may be necessary to treat the most peripheral anterior vitreous membrane (2C). In phakic eyes, conjunctive lens extraction may be required (2C).

III. Childhood glaucoma

  1. 1.

    Primary congenital glaucoma (PCG)

    The first choice of treatment is surgery [1] (1B). This is because of the empirical fact that the pathogenesis of glaucoma is owing to abnormal development of the iridocorneal angle, which can be resolved surgically in many cases, and because it is difficult to confirm the efficacy and effectiveness of drug therapy in infants. Additionally, because the systemic pharmacokinetics of drug therapy for glaucoma differs between children and adults, rare and serious adverse effects in adults may occur in children and fetuses. Furthermore, adherence is also a major issue as drug therapy is dependent on the guardian because patients themselves are uncooperative. Therefore, drug therapy is used as an adjunct in the perioperative period or after surgical treatment [1] (1B).

    1. 1.

      Surgical therapy

      1. i.

        Principle

        Patients should be treated in a facility where physicians and medical staff with enough experience in pediatric ophthalmology and glaucoma treatment are always available. This is because reoperation is often necessary, follow-up is required for more than a year, and evaluation of visual development optimized by refractive correction and amblyopia treatment is necessary.

      2. ii.

        Trabeculotomy

        Compared with goniotomy, this procedure can be performed even when it is difficult to see through the cornea, but it requires the creation of conjunctival and scleral flaps[97], which may make the procedure difficult and reduce its effectiveness when filtration surgery is required in the future. In some cases of megalocornea, it is difficult to identify Schlemm's canal, and extensive surgical experience is required for the procedure. A 360-degree incision of the trabecular meshwork using a thread or an illuminated microcatheter is gradually being tried out.

      3. iii.

        Goniotomy

        It is indicated for patients with a clear cornea. A single corneal incision of 90 to 120 degrees can be made. Iridocorneal angle surgery can be approached from different locations up to three times and is considered effective [100].

        The choice between this technique and trabeculotomy depends on the experience of the surgeon. There are no prospective studies comparing goniotomy and trabeculotomy. Both techniques have similar success rates (70-90%) in PCG patients 3-12 months of age[101]. The cause of failure depends on the degree of underdevelopment of the iridocorneal angle and the degree of impairment of the iridocorneal angle structure due to overextension of the anterior segment.

      4. iv.

        Filtration surgery

        It is indicated in cases in which goniotomy or trabeculotomy has failed. It is important to keep in mind that PCG patients have thin sclera, making it difficult to create a scleral flap, and that there are many anatomical abnormalities in the iris and ciliary body. Moreover, in infants and young children, it is difficult to form a filtration bleb even with antimetabolites, or even if a filtration bleb is formed, patients are exposed to the risk of postoperative infection for the rest of their life. In general, long-term results are worse than those in adults, and the success rate after one year is at 50-87% [102,103,104].

      5. v.

        Tube shunt surgery with a plate

        In other countries, it has been used in cases in which conventional filtration surgery is ineffective [101], but there is still no clear evidence in Japan.

      6. vi.

        Cyclodestructive procedure

        This procedure is considered if IOP control could not be achieved with any of the above treatments [101].

    2. 2.

      Drug therapy

      Although a combination of drugs should be used in accordance with primary open-angle glaucoma, infants and young children should start with the lowest concentration possible, bearing in mind that the dosage (including that of ophthalmic solution) is highly relative to their body weight and body surface area. It should also be remembered that data on the safety and efficacy of any drug in infants and children have not been established. The effects of FP agonists are weaker in children than in adults [105, 106]. α2 agonists are contraindicated in children under two years of age owing to the occurrence of neuropsychiatric symptoms (1B).

  2. 2.

    Juvenile open-angle glaucoma

    This is childhood glaucoma that develops after the age of four and is characterized by a normal iridocorneal angle appearance and the absence of systemic diseases or ocular signs. In principle, the treatment is the same as that for primary open-angle glaucoma, but since there is a significant overlap with PCG in terms of abnormal iridocorneal angle formation and markedly high IOP, it is necessary to consider these factors when providing treatment.

    The rate of progression is higher with drug treatment than with surgical treatment [107]. It has been reported that there is no difference in efficacy between FP agonists and β-blockers [108].

  3. 3.

    Secondary childhood glaucoma

    The following is a list of representative diseases.

    1. 1.

      Axenfeld-Rieger anomaly

      The partial attachment of the peripheral iris to the posterior embryotoxon is a prerequisite for diagnosis. If there is a systemic abnormality, Axenfeld-Rieger syndrome is diagnosed, and the pediatrician should be asked to examine the patient for systemic symptoms. Autosomal dominant inheritance is common.

      Treatment is like that for PCG. If the iridocorneal angle is open and the trabecular meshwork is not widely covered by the surrounding iris, corneal angle surgery may be chosen, but the success rate is lower than that in PCG [109, 110]. Therefore, trabeculectomy or tube shunt with a plate may be the first choice when corneal angle surgery is ineffective.

    2. 2.

      Peters’ anomaly

      Congenital anomaly characterized by loss of endothelium in the center of the cornea, anterior adhesion of the iris, and cataract.

      Treatment is like that for PCG. However, only one-third of cases achieve good postoperative IOP [111, 112]. Because of corneal abnormalities, it is often difficult to obtain useful visual acuity.

    3. 3.

      Aniridia

      This syndrome is mainly characterized by iris hypoplasia due to abnormalities of the PAX6 gene and may be accompanied by macular hypoplasia. It is advisable to refer patients with sporadic aniridia to the department of pediatrics [113] for screening of Wilms' tumor until the age of six.

      Treatment is like that for PCG. To reduce photophobia and eye strain, the use of shaded glasses and the prescription of orthoptical contact lenses should be considered.

    4. 4.

      Sturge-Weber syndrome

      Elevated IOP is thought to be caused by primary goniodysgenesis, Schlemm’s canal atrophy, elevated superior scleral vein pressure, peripheral anterior synechiae formation, and increased permeability of the thinning vascular wall associated with choroidal hemangioma. It may be accompanied by an ipsilateral choroidal hemangioma, which may lead to serious complications such as superior choroidal hemorrhage or retinal detachment during and after surgical treatment [114].

      For congenital or infantile-onset cases, trabeculotomy or goniotomy is the treatment of choice. In older patients with elevated superior scleral venous pressure, drug therapy is the first choice [115, 116]. If drug therapy or outflow tract reconstruction is unsuccessful, trabeculectomy or tube shunt surgery with a plate should be considered.

    5. 5.

      Glaucoma after cataract surgery

      In cases that require cataract surgery during childhood, abnormalities in the development of the aqueous humor outflow tract may occur, which is thought to lead to increased IOP [117, 118]. Therefore, postoperative glaucoma can occur in patients with idiopathic congenital cataracts, cataracts related to ocular or systemic diseases, and complicated cataract. The risk is lifelong and occurs in both aphakic and pseudophakic eyes. It can occur in both open-angle and closed angle eyes. In some cases, the central cornea is thick [119], resulting in apparently high IOP.

      Treatment is like that for PCG. However, owing to poor surgical results, tube shunt surgery with a plate may be eventually necessary. In the case of an obstructed iridocorneal angle, the release of the pupillary block may be necessary.

Chapter 9 Results of a systematic review on glaucoma treatment

I Process of creation

We identified “medical practices of high importance” with respect to the treatment of glaucoma and set clinical questions (CQ) at a panel meeting. The guideline development group and the systematic review team collaborated to collect literature on the CQs. The results of multiple articles were integrated, the risk of bias was considered, and recommendations and their explanatory notes were developed. When there were not enough research papers to provide recommendations for CQs, they were designated as background questions (BQ) and future research questions (FQ).

Glossary of terms

Clinical Question (CQ)

The authors discuss topics that are difficult to judge in daily clinical practice, carry out quantitative and qualitative systematic reviews, and determine recommendations and strength of recommendations through voting at the recommendation meetings, and explain the contents of these reviews based on the points of discussion at recommendation meetings.

Background Question (BQ)

Details that are considered as standard treatment in the previous guidelines and should be adhered to by everyone including non-specialists, and details that are difficult to judge in daily clinical practice and should be treated as CQ, but only having old data with no prospect for new evidence to emerge in the future are also positioned as BQ.

Future Research Question (FQ)

Despite insufficient data to address as a CQ, the current view on the future important issues and possible CQs will be explained.

Systematic Review (SR)

A scientific study that uses a clear and well-designed scientific method to find, select, evaluate, and summarize the findings of separate, similar studies focused on a specific problem. It may or may not include a quantitative synthesis (meta-analysis) of the results from separate studies.

Randomized Controlled Trial (RCT)

A research method in which the target and treatment groups are randomly assigned and conducted in a double-blind manner. The results are highly reliable.

Prostanoid

Prostaglandins and thromboxane are collectively referred to as prostanoids. Omidenepag isopropyl, an EP2 receptor agonist, does not have a prostaglandin structure and is classified as a prostanoid.

Glaucoma treatment: BQ, FQ, and CQ summary

No.

Question

Summary and recommendation

Strength of recommendation

BQ

   

1

How do we perform drug therapy for primary open-angle glaucoma (POAG) during pregnancy, childbirth, and breastfeeding?

  

2

Postoperative management of trabeculectomy

  

FQ

   

1

Should additional drugs be administered when the effect of the first-line drug is insufficient?

  

2

When should surgery be considered as an option in the multimodal treatment of POAG?

  

3

Are treatments other than IOP reduction (neuroprotection, improved blood flow) helpful?

  

CQ

   

1

What are the criteria for starting treatment for ocular hypertension?

It is recommended that treatment be initiated in patients with ocular hypertension who have risk factors. Risk factors for the development of primary open-angle glaucoma from ocular hypertension include older age, large vertical C/D ratio, high IOP, large pattern standard deviation, thin central corneal thickness, and the appearance of optic nerve disc hemorrhage.

Treatment is strongly recommended in cases with risk factors

2

Is it recommended to treat preperimetric glaucoma (PPG) with normal intraocular pressure (IOP)?

We suggest that the initiation of treatment for PPG with normal IOP should be considered with careful follow-up and consideration of risk factors.

We weakly recommend performing the treatment.

3

Is glaucoma surgery recommended for patients with progression of visual field defects even when IOP is in the low 10 mmHg range with IOP-lowering medications?

We weakly recommend that trabeculectomy be performed for patients with progression of visual field defects despite IOP in the low 10 mmHg range with IOP-lowering medications.

We weakly recommend performing glaucoma surgery.

4

Is tube shunt surgery recommended instead of trabeculectomy?

When selecting both surgical procedures, it is important to consider the treated eye, the patient’s background, and the surgeon’s proficiency with the surgical procedure. It is not recommended to perform tube shunt surgery in place of trabeculectomy.

We weakly recommend not to perform tube shunt surgery.

5

Is steroid instillation recommended after trabeculectomy for POAG?

Local anti-inflammatory treatment, including steroid instillation, is recommended after trabeculectomy for POAG because it is advantageous for IOP control. There are insufficient research results to conclude whether it is effective in controlling surgical complications such as hyphema, transient IOP elevation, and shallow anterior chamber.

We strongly recommend administering steroid ophthalmic solution.

6

How long are antibiotic instillation and ointment therapy necessary after trabeculectomy?

It is recommended that antimicrobial ophthalmic solution and ointment be used continuously for some time after surgery. For the long term, antimicrobial ophthalmic solution and ointment should be used as appropriate according to the risk of bleb-related infection.

We strongly recommend implementing antimicrobial ophthalmic solutions and ointment therapy.

7

Is combined trabeculectomy with cataract surgery recommended for POAG?

Combined trabeculectomy with cataract surgery for POAG may be considered if cataract surgery is thought to be beneficial for improving visual function, although it may worsen the outcome of IOP adjustment.

We weakly recommend performing combined cataract surgery.

8

Is cataract surgery or laser therapy the first-line treatment for primary angle-closure glaucoma (PACG) and its precursor lesion, primary angle-closure (PAC)?

Cataract surgery is strongly recommended as the first-line treatment for PACG, and PAC. Lens extraction can be the first-line treatment regardless of the presence or absence of symptomatic cataracts. However, it is not an absolute first-line treatment and laser therapy should be selected according to the circumstances of each case. It should also be noted that the indication for treatment of PAC with normal intraocular pressure should be carefully considered.

We strongly recommend performing lens extraction.

9

Is therapeutic intervention necessary for PACS?

We recommend that therapeutic intervention for PACS should be based on the risk assessment of each case and should not be performed uniformly. Intervention is recommended for patients with PACS who are at high risk of progressing to acute primary angle-closure (APAC) or PACG.

PACS as a whole: We weakly recommend not to perform interventions uniformly. We strongly recommend intervention for APAC eyes.

Reading recommendations and commentary

Throughout the guideline

This guideline was revised with two goals in mind: (1) to update the descriptions in the fourth edition of the Clinical Practice Guidelines for Glaucoma published in May 2017 in accordance with subsequent advances in medical care (drug treatment and surgical treatment), and (2) to prepare the treatment section in accordance with the Minds Clinical Practice Guideline Development Manual 2017. The guideline development committee has been working on the revision of the guideline. The guideline development committee identified important clinical issues related to the treatment of glaucoma and addressed those that could be recommended as CQ. After conducting a systematic review (SR) of each CQ, important issues for which enough evidence could not be obtained were listed as FQ. BQ was added for items that were considered important, but for which no new research has been conducted or that should be known as a matter of course.

We reviewed articles collected on CQ to determine the strength of the evidence. The strength of recommendation was determined by estimating the balance of benefits and harm of the treatment method, the certainty of the evidence, and, whenever possible, the cost.

Presentation of recommendation

The modified Delphi method was used to determine the recommendations. Specifically, in the first round, the SR review team was selected from the councilors of the Japan Glaucoma Society for each CQ and evaluated individually. Based on the results obtained in the first round, we conducted another round of individual evaluation in a web conference attended by all the members of the committee, guideline development group, and SR team (second round), and determined the recommendations.

Strength of recommendation

The strength of the recommendation was determined based on the “certainty of the evidence,” “balance of benefit and harm,” “diversity of patient values and intentions,” and “economic perspective.” The following four categories are described below.

Strong recommendation to perform.

Weak recommendation to perform.

Strong recommendation to not perform.

Weak recommendation to not perform.

Strength of evidence for CQ

The retrieved literature was reviewed, and the strength of evidence was determined by considering the level of evidence for each article.

A (Strong): Strong confidence in the estimated value of the effect

B (Moderate): Moderate confidence in the estimated value of the effect

C (Weak): Limited confidence in the estimated value of the effect

D (Very weak): Little confidence in the estimated value of the effect

Explanatory note

The decision was made by using the informal consensus-building method with the supervisory committee members.

Process of recommendation creation

A summary of the process leading to the presentation of the recommendation based on the CQ is provided. The range of articles adopted is also described as necessary.

Summary of SR report

We describe the certainty and level of evidence of the papers discussed in the SR and explain how we reached our conclusions.

References

A list of references used in the SR is presented.

II Recommendation

BQ1 How do we perform drug therapy for PAOG during pregnancy, childbirth, and breastfeeding?

(Shiro Mizoue)

Generally, drug therapy for glaucoma should be discontinued during pregnancy, childbirth, and lactation.

Currently, there are no glaucoma medications for which safety has been established in pregnant women, fetuses, or nursing mothers [120]. Although IOP often decreases during pregnancy, laser therapy or surgery should be considered if IOP control worsens upon discontinuation of the drug.

In the categorization of risk to the human fetus, conducted by the U.S. Food and Drug Administration (FDA) based on the results of comparative studies and animal experiments [121] (Table 3), all drugs are classified as Category C except for brimonidine, which is classified as Category B [122]. In contrast, birth defects in Japan are said to be 1.7–2%; however, chromosomal abnormalities and internal factors account for most of the causes, and among other external factors, those caused by drugs account for 2–3% [123]. Furthermore, a recent report in Japan stated that there was no association between the use of glaucoma ophthalmic solution in pregnant women in early pregnancy and the incidence of adverse events in newborns. When glaucoma medication must be continued for unavoidable reasons, a drug with a high level of safety should be selected with enough informed consent.

Table 3 U.S. FDA pregnancy risk categories
Full size table

Theoretical hazards in the pharmacodynamics of glaucoma medication of concern to pregnant women include the myoconstrictive effects of prostanoid receptor -related drugs and impaired placental perfusion of pilocarpine [120].

Sympathetic β-blockers, brimonidine, and carbonic anhydrase inhibitors have been demonstrated to transfer to breast milk; however, the transfer of other drugs is unknown. It has been reported that sympathetic β-blockers in breast milk are concentrated to six times the plasma concentration; however, their effects on the infant remain unclear [125].

BQ2 Postoperative management of trabeculectomy

(Yasumasa Otori, Tetsuya Togano)

Trabeculectomy is a surgical procedure to open the limbus sclera and create a non-physiologic aqueous outflow tract from the anterior chamber to the subconjunctival space. The postoperative IOP is determined by the balance between the amount of aqueous humor production and the amount of outflow to the filtration bleb through the scleral flap. Whether or not the target IOP can be achieved by surgery depends on the adjustment of the filtration volume through the scleral flap in the early postoperative period and the suppression of subconjunctival tissue scarring that occurs over a long period. Therefore, postoperative management is as important a factor as a surgical technique in determining the surgical outcome. Additionally, postoperative complications are more frequent than in other surgeries, and it is necessary to learn how to address them.

In adding a section on postoperative management to these guidelines, some points should be considered. As with surgical techniques, the actual clinical practice reflects the experience and preferences of the surgeon; as such, there is no standardized method of postoperative management. Additionally, many of the management procedures are performed according to the postoperative condition. Specifically, they are decided after the fact, making it challenging to conduct clinical research with a high level of evidence, such as randomized clinical trials (RCT). Most of the reports on the efficacy and comparison of various postoperative management methods are single-center, retrospective studies. Therefore, due circumspection should be exercised when generalizing the results of these studies.

Furthermore, most of the studies on the effects of postoperative management methods on surgical outcomes have been conducted outside Japan. Since it has been reported that differences in scar formation owing to racial differences may affect surgical outcomes, due caution should be exercised against hastily applying foreign evidence to Japanese patients.

Early postoperative management

In trabeculectomy, scarring of the subconjunctival tissue occurs during the postoperative wound healing process. Concomitant use of Mitomycin C (MMC) suppressed the early excessive tissue reaction and increased the probability of long-term maintenance of the filtration bleb. However, the postoperative period of several months, during which scar formation progresses rapidly, is an important period for postoperative management as the outflow resistance of the scleral flap and the morphology of the filtration bleb change constantly, requiring appropriate and timely treatment. The main methods are described below.

  1. 1.

    Laser suture lysis (LSL) (1B)

    The scleral flap is sutured using multiple nylon sutures to restrict the filtration volume at the end of surgery. The filtration volume is increased gradually by transconjunctival laser suturing according to the postoperative IOP [127,128,129]. Adjustment of the filtration rate using LSL is recommended as a method to prevent excessive filtration in the early postoperative period.

    During LSL, a special contact lens is used to exclude conjunctival blood vessels, subconjunctival connective tissue, and hemorrhage and to enhance the visibility of the targeted sutures. The timing of postoperative LSL depends on the number of sutures and their strength and is often determined by the surgeon. It has been reported that the earlier the LSL is performed after surgery, the greater the reduction in IOP; however, there is a greater risk of excessive filtration. As postoperative scarring progresses, tissue adhesions around the scleral flap reduce the effectiveness of LSL. According to a past report, the effect of LSL decreases in 3 weeks to 1 month after surgery in trabeculectomy with MMC. Furthermore, the longer periods between surgery and LSL is associated with higher IOP in the long term after surgery. Therefore, it is necessary to examine the patient at appropriate intervals to avoid missing the timing of LSL [130, 131].

  2. 2.

    Scleral massage (1D)

    Scleral massage that enhances the aqueous outflow into the filtering bleb is an important technique in postoperative management. It can be performed by applying pressure to the eyeball with the fingers over the eyelid or by applying pressure directly near the scleral flap using a glass rod. Scleral massage during the examination is also useful to check the amount of outflow from the scleral flap and to determine the need for LSL. Scleral massage may also be performed to open outflow tracts that are obstructed by clotting or fibrin. Postoperative scleral massage may also be performed by the patient if the risk of excessive filtration is low. However, few studies compare the site, intensity, and frequency of scleral massage performed by the patient, and no recommended method has been established.

    The efficacy of scleral massage after the mid-postoperative period (3 months) has not yet been confirmed. Kane et al. reported that IOP decreased for a few hours after scleral massage. In contrast, in an RCT comparing patients who did/did not perform scleral massage on themselves at 3–216 months postoperatively, there was no difference in the amount of IOP change between the two groups at 6 months after the start of massage [133].

  3. 3.

    Postoperative subconjunctival injection of antimetabolites and anti-VEGF agents

    1. (a)

      5-Fluorouracil (5-FU)

      In an RCT of patients who did not receive intraoperative antimetabolites, postoperative IOP was significantly lower in the group that received a postoperative subconjunctival injection of 5-FU compared with the control group. However, it has not been investigated whether the adjuvant use of 5-FU with postoperative subconjunctival injection improves surgical outcomes in patients who received concomitant intraoperative MMC application, which is currently common. On the other hand, it should be noted that postoperative subconjunctival injection of 5-FU has been shown to increase the frequency of corneal epithelial damage and aqueous humor leakage.

    2. (b)

      Anti-vascular endothelial growth factor (anti-VEGF drug)

      The SR investigating the benefit of perioperative use of anti-VEGF drugs refers to four RCTs that compared anti-VEGF agents with MMC or no antimetabolites. The SR concludes that there is insufficient evidence to conclude that the use of anti-VEGF agents improves IOP reduction and surgical success rates [134].

  4. 4.

    Postoperative ophthalmic solution

    1. (a)

      Antibiotic ophthalmic solution

      Although much less frequent than in the late postoperative period, it has been reported that bleb-related infection can also occur in the early postoperative period (0.1–0.2%)[135, 136]. Once bleb infection develops, not only will it negatively affect the surgical outcome, but may also result in serious visual dysfunction due to endophthalmitis. Therefore, prophylactic administration of antibiotics is recommended; however, to date, there is no consensus on the type of drug, dosage regimen, and duration of administration. (For details, see CQ6, “How long is ophthalmic antibiotic therapy necessary after surgery?”).

    2. (b)

      Instillation of anti-inflammatory drugs (1B)

      Postoperative inflammatory response is thought to be a major factor in subconjunctival tissue scarring. To avoid excessive scarring and to form a functioning filtering bleb, corticosteroid instillation is recommended postoperatively. (For details, see CQ5, “How long is ophthalmic treatment with steroids necessary after surgery?”)

Early postoperative complications and how to address them

The frequency of early postoperative complications of trabeculectomy has been reported as 0.9–13% for the shallow anterior chamber, 5–14% for choroidal detachment, 2.7–11% for anterior chamber hemorrhage, and 3.4–14% for aqueous humor leakage from conjunctival wound [63, 76, 137, 138]. The frequency of postoperative complications such as hypotony maculopathy and bleb-related infection, which can cause visual dysfunction after 1 month postoperatively, has been reported to be 0.9–5% and 0.97–5%, respectively [63, 76, 137, 138].

  1. 1.

    Excessive filtration

    1. (a)

      In the absence of aqueous humor leakage from the conjunctiva, the cause of postoperative low IOP is excessive filtration from the scleral flap. In many cases, excessive filtration is associated with the shallow anterior chamber and choroidal detachment. The use of antimetabolites such as 5-FU and MMC increases aqueous humor leakage from the scleral flap. A common management strategy is to increase scleral flap sutures intraoperatively to reduce excessive filtration and to manage IOP postoperatively with the LSL.

    2. (b)

      In some cases, the disease improves spontaneously owing to scarring of the subconjunctival and periscleral tissues of the scleral flap; as such, the patient may be followed conservatively with atropine instillation and anti-inflammatory measures. In some cases, excessive filtration may be improved by applying a pressure bandage with gauze or other material to accurately compress the scleral flap.

    3. (c)

      It has been reported that transient postoperative low IOP does not affect long-term postoperative IOP. However, if low IOP persists and the sclera contracts, shortening the axial length of the eye [139], choroidal folds, macular folds, and retinal vascular tortuosity, and disc edema occur, resulting in hypotony maculopathy which causes serious deterioration of visual function. It has been reported that hypotony maculopathy is more common in myopic eyes of young individuals [140, 141].

    4. (d)

      Aggressive intervention for ocular hypotension associated with excessive filtration.

      1. ①

        Transconjunctival suturing of the scleral flap

        As a method of suppressing excessive filtration, suturing the scleral flap with a nylon thread directly over the conjunctiva has demonstrated long-term efficacy in treating hypotonic maculopathy [142, 143].

      2. ②

        Autologous blood injection

        Injection of autologous blood into and around the filtration bleb has been reported to improve hypotonic maculopathy [144,145,146]. However, it may cause a rapid increase in IOP.

      3. ③

        If ocular hypotension does not improve by the above methods, the conjunctiva should be reopened, and the scleral flap sutured under direct vision. If significant choroidal detachment has occurred, the fluid accumulated in the suprachoroidal space must be drained by scleral fenestration.

  2. 2.

    Adhesion of the scleral flap

    1. (a)

      Scleral flap adhesions during the early period are often due to intraoperative or postoperative hemorrhage or fibrin. If the sclerectomy area is clogged with clots as shown under gonioscopy, wait for the clots to dissolve. Excessive LSL may cause ocular hypotension when the clot dissolves.

    2. (b)

      If the scleral flap has adhered during the early period and the aqueous humor is not filtered through the subconjunctiva, needling is necessary to remove the adhesions by inserting a 25–27-gauge needle or microsurgical knife through the conjunctiva to lift the scleral flap.

  3. 3.

    Suprachoroidal hemorrhage

    Suprachoroidal hemorrhage should be suspected in cases of sudden onset of ocular pain, nausea, and loss of vision within a few days after surgery. In general, high IOP and shallow anterior chambers are present. Furthermore, massive choroidal detachment (hemorrhage) is excessively large, causing the retina to meet each other. The hemorrhage may be spontaneously absorbed, and it is advisable to wait for 7–10 days for the hemorrhage to liquefy before performing drainage of the suprachoroidal hemorrhage.

Mid-postoperative complications and how to address them

  1. 1.

    Needling for scarring starting from the mid-postoperative period

    1. (a)

      Needling of concomitant antimetabolites

      There is a report showing the efficacy of needling with an antimetabolite in cases where, despite the formation of a filtration bleb for some time after trabeculectomy, the bleb shrinks over time and the IOP rises again [148, 149].

    2. (b)

      Needling for encapsulated bleb

      When the filtration bleb is tall, dome-shaped, with thick walls and dilated vascular invasion, it is called encapsulated bleb which causes elevated IOP. It occurs in approximately 13% of trabeculectomy [150]. In an SR comparing the efficacy of needling for encapsulated bleb, there was no significant difference in IOP control between one-time needling without antimetabolites and drug treatment [151].

  2. 2.

    Aqueous humor leakage from an avascular filtration bleb

    1. (a)

      Aqueous humor leakage

      Aqueous humor leakage from the filtration bleb is a major risk factor for bleb-related infections; therefore, it is necessary to immediately control the leakage [152].

    2. (b)

      Resection of the avascular filtration bleb + conjunctival advancement

      In this method, the avascular filtration bleb with aqueous humor leakage is excised and the posterior normal conjunctiva and tenon’s capsule are anteriorly transposed [153]. There is also a report that tenon advancement using amniotic membrane was effective [154].

FQ1 Should additional drugs be administered when the effect of the first-line drug is insufficient?

(Megumi Honjo, Akira Sawada)

There are eight major categories of glaucoma ophthalmic solutions in widespread use today. (1) Prostanoid receptor-related drugs (FP receptor agonists and selective EP2 receptor agonists) (2) β-adrenergic blockers (β-blockers) (3) Carbonic anhydrase inhibitors (topical preparations) (4) α2-adrenergic agonists (α2-agonists) (5) ROCK inhibitors (6) Parasympathomimetic drugs (7) α1-adrenergic blockers (α1-blockers), and (8) ion channel openers. Clinically, these combinations have been used to establish drug therapy for glaucoma.

Of these, the category of drugs widely used as first-line drugs for the treatment of open-angle glaucoma worldwide is prostanoid receptor-related drugs owing to their superior IOP-lowering effect and favorable tolerability in terms of the number of drops and side effects [50]. Next, β-blockers may be selected as the first-line drug owing to their hypotensive effect and acceptability; however, contraindications and side effects should be considered. Second-line agents include carbonic anhydrase inhibitor ophthalmic solution, α2 agonists, ROCK inhibitors, α1-blockers, ion channel openers, nonselective adrenergic agonists, and parasympathomimetic drug. Additionally, combination ophthalmic solutions are useful for improving adherence when multiple drugs are used.

This FQ was based on the results of SR from case series and review articles. The SR for this FQ could not be performed at this time because of a lack of literature on ROCK inhibitors and EP2 receptor agonists immediately after their launch.

  1. 1.

    β-blocker as the first-line drug

    The superiority of FP receptor agonists over β-blockers in lowering IOP has been shown in many publications [155,156,157,158,159] and a change from timolol maleate to FP receptor agonists has been reported to have a greater effect in lowering IOP [160, 161].

    In contrast, a meta-analysis demonstrated that FP receptor agonists, nonselective adrenergic agonists, carbonic anhydrase inhibitors, and parasympathomimetic agonists lowered IOP [159]. However, the extent of IOP reduction is limited to 1–2 mmHg for single agents, except for the addition of FP receptor agonists [159].

  2. 2.

    FP receptor agonist as first-line drug

    A change from FP receptor agonists to other IOP-lowering drugs is not anticipated to further decrease IOP. In contrast, when considering changing from one FP receptor agonist to another, the change to bimatoprost should be considered. Although bimatoprost may have lower tolerability than other FP receptor agonists [162], there are some reports that bimatoprost is equivalent or slightly superior to other FP receptor agonists in lowering IOP when used as a single agent [162,163,164]. Among the four FP receptor agonists, the proportion of nonresponders was reported to be lower with bimatoprost [165]. However, it should be noted that there are reports from Japan that prostaglandin-associated periorbitopathy (PAP), in particular suprapalpebral sulcus deepening, has a high incidence which may affect IOP measurement and the prognosis of filtration surgery [166, 167].

    A meta-analysis showed that when a second drug is added to FP receptor agonists, β-blockers, nonselective adrenergic agonists, and carbonic anhydrase inhibitors lowered IOP [159]. However, the range of IOP reduction was similarly limited to about 1–1.5 mmHg.

  3. 3.

    Summary

    However, there are few reports of RCT, meta-analyses, and other evidence; as such, it is difficult to provide a concrete answer to the FQ concerning the addition of IOP-lowering drugs when the effect of first-line agents is inadequate. Other than FP receptor agonists, the range of IOP reduction with additional drugs was small (1–2 mmHg). Since there are many cases in which a sufficient decrease in IOP cannot be obtained with a single FP receptor agonist, to decrease IOP, it is ideal to continue developing new drugs, as well as accumulate evidence for ROCK inhibitors, often used as second-line drugs, and selective EP2 receptor agonists launched in 2019 and have been reported to be non-inferior to latanoprost and effective against latanoprost non-responders in clinical trials.

FQ2 When should glaucoma surgery be considered as an option in the multiple eye drops of primary open angle glaucoma including normal tension glaucoma?

(Tomoko Naito, Yoko Ikeda)

Glaucoma can be treated using eye drops, laser, or surgery to lower IOP. As a general rule, in primary open-angle glaucoma (POAG) including normal tension glaucoma (NTG) eye drops treatment should be initiated, and when multiple eye drops are required for IOP control, laser and surgical treatment should be considered as alternatives.

Glaucoma surgery should be considered when there is concern that the harm from concomitant use of multiple eye drops may outweigh the benefits. In general, eye drop with greatest IOP-lowering effect and the least side effects and the least prescribed number of eye drop time per one day are selected (first-line eye drop). Further, eye drops that are anticipated to have additional effects to the eye drops currently being used in terms of their mechanism of action may be added (second-line eye drop). Eye drops added thereafter (third-line eye drop and so on), are likely to have smaller IOP-lowering effect. In contrast, as the number of concomitant eye drops increase, there is a risk of increased side effects and decreased adherence. Therefore, we conducted a systematic literature review search focusing on the number of preoperative eye drops in POAG patients and investigated the stages and factors that may lead to concerns that the harm from multiple eye drops treatment outweighs the benefits.

It is important to note that most of the articles do not clarify whether the number of IOP-lowering eye drops is listed as the number of bottles or the number of eye drops’ agents and whether the fixed combination eye drops is listed as one or two agents after the launch of the fixed combination eye drops. In this report, all eye drops are listed as agents, which requires careful interpretation.

  1. 1.

    Number of IOP-lowering eye drops used in patients with POAG

    1. (a)

      POAG patients who underwent glaucoma surgery

      The average number of preoperative IOP-lowering eye drops in POAG patients was 3.1 or less for MIGS[170, 171] and 3.8 or less for trabeculectomy, suggesting that many patients would have chosen surgical treatment if a fourth-line eye drops had been added [172,173,174,175,176]. The European Glaucoma Society SR [1] states that if the combination of two eye drops does not sufficiently lower IOP, a change of eye drops, the addition of a third-line eye drops or laser therapy or surgery should be considered if possible. This recommendation may be followed in Europe and the United States. However, the number of preoperative eye drops was similar in the reports from Japan [175]and Taiwan [176], suggesting that, in general, when the addition of a fourth-line eye drops is necessary for IOP control, glaucoma surgery is considered as an alternative treatment.

    2. (b)

      POAG patients without previous glaucoma surgery

      Patients who have been successfully treated with four or more eye drops have not been included in studies of those undergoing surgery. In a 2003 survey at a university hospital, Ishizawa et al. reported that most of 265 eyes with glaucoma without previous surgery (POAG including NTG, exfoliation glaucoma) were treated with up to three IOP-lowering eye drops , while 8.3% were treated with four or more eye drops [177]. Shimizu et al. also reported similar results in a 2005 survey of university and affiliated hospitals [178]. Arai et al. in their 2016 survey of ophthalmology hospitals and clinics reported that 8.3% of 3,429 eyes of patients with POAG including NTG, including those who had undergone surgery, were prescribed four or more IOP-lowering eye drops [179]. Like the survey by Ishizawa et al., the majority of participants were given three or less eye drops [177], suggesting that the tendencies in prescription have not changed in the last 10 years.

  2. 2.

    Factors that may lead to consideration of surgery when a fourth additional eye drops is needed

    Adherence and persistence rates of eye drops, as well as the effect on trabeculectomy, were suggested.

    1. (a)

      Adherence and persistence rates in concomitant use of four eye drops

      The success of glaucoma treatment depends not only on the efficacy of the combination eye drop therapy but also on the patient’s ability to adhere to the ophthalmic dosing regimen for all eye drops. In a case-control study, Djafari et al. compared the dispensing records and medical records of 181 patients with open-angle glaucoma, ocular hypertension, or suspected glaucoma (number of eye drops used: 1–4) and reported that adherence decreased significantly as the number of eye drops increased [180]. In a case-control study, Neelakantan et al. reported that 29 patients with glaucoma (69% POAG, 31% another glaucoma) with inadequate IOP control with three eye drops had a significant reduction in efficacy (>20% IOP reduction from baseline with no change in treatment regimen) and safety (no side effects leading to discontinuation of eye drops and no need for surgery) after the addition of a fourth eye drops [181]. They reported that the cumulative Kaplan-Meier rates (success rate) of achieving both efficacy and safety were low (31% in 6 months, 14% in 1 year).

    2. (b)

      Effects of concomitant use of four eye drops on IOP lowering and trabeculectomy

Johnson et al. conducted a randomized controlled trial in which 1,400 POAG patients using 1 to 4 eye drops without prior glaucoma surgery (other than laser trabeculoplasty) were given a washout before MIGS [182]. Although IOP increased in the patient group with a greater number of eye drops, there was no significant difference in terms of IOP increase range between the group with three eye drops and that with four eye drops. As for the reason for these facts, it is suggested that the prescribed eye drops may not have been administered properly; i.e., poor adherence, or the effect of the additional eye drops may have been low. In a retrospective cohort study by Fendi et al., multivariate analysis was performed on 120 glaucoma eyes (POAG: 58 eyes, primary angle-closure glaucoma: 31 eyes, secondary glaucoma: 31 eyes) who underwent trabeculectomy [183]. The “use of four or more glaucoma eye dropsbefore surgery” has been revealed as one of the risk factors for poor outcomes.

In all reports, up to three IOP-lowering eye drops were commonly used, and four or more eye drops were remarkably less commonly used. In general, when IOP control is poor or the target IOP cannot be achieved even using a combination of three IOP-lowering eye drops (including fixed combination eye drops), treatment alternatives, including glaucoma surgery, should be considered.

In recent years, the advent of MIGS, fixed combination eye drops, preservative-free ophthalmic solutions, and new glaucoma treatments have been launched consecutively, and it is necessary to wait for future evidence to observe how the evidence to date will shift.

FQ3: Are treatments other than IOP reduction (neuroprotection, improved blood flow) helpful?

(Yu Yokoyama, Kazuko Omodaka)

There are several reports on IOP-independent neuroprotection in a variety of agents. However, it is difficult to determine the sufficiency of the results obtained in clinical studies to demonstrate neuroprotection. Sena et al. stated in a 2017 systematic review on neuroprotection for glaucoma treatment that at least 4 years of observation is required to determine a clinical neuroprotective effect. They also stated that RCTs that fall into this category were included in the literature search review [81]. However, at the time of this review, the only relevant report was the Low-pressure Glaucoma Treatment Study (LoGTS). This review concluded that the evidence shown in LoGTS was insufficient for proving a neuroprotective effect of brimonidine tartrate 0.2% ophthalmic solution.

Here, trials with a 2-year follow-up period were included for a broader review. Literature for trials on neuroprotection in the glaucoma treatment (including α2-adrenergic agonists, NMDA receptor antagonists such as memantine, calcium channel blockers, neurotrophic factors, antioxidants, ginkgo biloba extract, nitric oxide synthase inhibitors, and sleep apnea syndrome treatment) and trials examining improvement in ocular blood flow were searched. A literature search was conducted for the following studies. RCTs and non-English papers (except Japanese) that did not include functional assessment by static automated perimetry or structural assessment of the RNFL or ganglion cell layer as outcomes were excluded. If we included the study in which the effect of the treatment was evaluated in 4 or more follow-up periods, only three studies matched this inclusion criteria.

  1. 1.

    α2-adrenergic agonist

    The LoGTS was a multicenter, double-blind study in which 178 glaucoma patients with IOP of 21 mmHg or less were randomized to treatment with brimonidine tartrate 0.2% ophthalmic solution (α2 receptor agonist) or timolol maleate 0.5% ophthalmic solution (β-blocker) [34, 184,185,186]. The study reported 48-month results, and although the two drugs had comparable IOP-lowering effects, the brimonidine group significantly reduced the progression of visual field impairment in a survival analysis using the Kaplan-Meier method. This suggests that brimonidine tartrate 0.2% ophthalmic solution has a neuroprotective effect independent of IOP.

  2. 2.

    NMDA receptor antagonist

    Memantine is an NMDA receptor antagonist that suppresses excitotoxicity. Weinreb et al. reported a phase III study in which a total of 2298 patients with open-angle glaucoma were randomized to 20 mg, 10 mg oral memantine, or placebo on two separate occasions. Their progress was evaluated by Humphrey perimeter, FDT, and optic nerve disc stereography over 48 months [187]. This study did not confirm a consistent inhibitory effect of memantine on glaucoma progression.

  3. 3.

    Other neuroprotective treatments, blood flow improving drugs

    Citicoline (cytidine-5’-diphosphocholine) plays an important role in the maintenance of phospholipid components of cell membranes and is used as a drug to improve brain metabolism. A multicenter, randomized, double-blind study using this drug in patients with glaucoma has been reported [188]. Eighty patients with open-angle glaucoma who showed a tendency to progress despite IOP control to 18 mmHg were randomly assigned to citicoline ophthalmic solution or placebo and received three drops thrice daily. Glaucoma progression was significantly inhibited in Humphrey 10-2 visual field and RNFL thickness assessment by OCT for 3 years.

Antioxidants are also expected to have neuroprotective effects in glaucoma treatment, and two reports were included in this systematic review. One was an open-label, randomized, controlled trial comparing three groups: oral antioxidant supplements containing ω-3 fatty acids, oral antioxidant supplements without ω-3 fatty acids, and a control group; however, this study failed to demonstrate the efficacy of antioxidants [189]. The other was a 2-year, single-center, randomized, double-blind study using blackcurrant anthocyanins, which reported a significant reduction in progression of visual field impairment after 2 years in the blackcurrant anthocyanin group [190]. This study reported that the blackcurrant anthocyanin-treated group demonstrated improved blood flow in the optic nerve disc area when evaluated using Laser Speckle Flowgraphy. Another study reported that blackcurrant anthocyanins improved the reduction of endothelin-1 blood levels in patients with glaucoma, suggesting that blackcurrant anthocyanins may affect ocular circulation [191].

Several calcium antagonists have been studied as agents to improve ocular circulation, and neuroprotective effects have been reported [192, 193]. Among them, a study of oral nilvadipine in 33 patients with low IOP glaucoma evaluated ocular blood flow using laser Doppler and reported that oral nilvadipine improved ocular circulation.

It is known that some glaucoma ophthalmic solutions affect ocular blood flow. In a 5-year study of patients with POAG treated using timolol maleate 0.5% ophthalmic solution who received either dorzolamide hydrochloride 2% ophthalmic solution or brinzolamide hydrochloride 1% ophthalmic solution (in addition to timolol maleate 0.5% ophthalmic solution), the mean IOP reduction in both treatment groups was similar; however, the dorzolamide-timolol group had significantly less visual field impairment [194]. In a color Doppler study of retrobulbar blood flow, there was an increase in end-diastolic blood flow velocity and a decrease in vascular resistance in the same group, suggesting that these factors were involved in reducing the risk of progression.

Several drugs have been suggested to have neuroprotective effects independent of IOP; however, the number of long-term RCTs for each drug is extremely small. Considering the bias that exists in each trial, multiple trials are necessary to establish evidence. Neuroprotection independent of IOP is a promising field in glaucoma treatment, as the results of LoGTS [34, 184,185,186] have attracted attention. Further studies are needed to establish evidence-based neuroprotective therapy.

CQ1 What are the criteria for starting treatment for ocular hypertension?

(Kenji Inoue, Shinji Ohkubo)

Presentation of recommendation

As a criterion for initiating treatment in patients with ocular hypertension, it is recommended that treatment be initiated in those with risk factors.

Risk factors for developing primary open-angle glaucoma from ocular hypertension include older age, large vertical C/D ratio, high IOP, large pattern standard deviation (PSD), thin central corneal thickness (CCT), and occurrence of optic nerve disc hemorrhage.

Strength of recommendation

Treatment is strongly recommended in patients with risk factors.

Strength of evidence for CQ

☐ A (strong) ■ B (moderate) ☐ C (weak) ☐ D (very weak)

Background to the creation of the recommendations

We conducted a systematic literature search on the characteristics of patients who develop primary open-angle glaucoma from ocular hypertension. We performed SR focusing on two RCTs. The Ocular Hypertension Treatment Study (OHTS) was conducted at 22 centers in the United States [28, 195], and the European Glaucoma Prevention Study (EGPS) was conducted at 18 centers in Europe [196, 197]. In the OHTS, 1636 patients with ocular hypertension were divided into treatment and observation groups for 5 years of follow-up [28]. 1366 patients who were invited to continue in OHTS under the same protocol except that topical ocular hypotensive medication was made available to participants in the observation group as well for 13 years of follow-up [195]. The EGPS is a 5-year follow-up of 1081 patients with ocular hypertension divided into dorzolamide treatment and placebo groups [196, 197].

We adopted 10 prospective and retrospective cohort studies that examined RCTs [78, 198,199,200,201,202,203,204,205,206] based on OHTS. Additionally, two retrospective cohort studies comparing OHTS and EGPS were also adopted [207, 208]. It is important to clarify risk factors as criteria for initiating treatment in patients with ocular hypertension. Risk factors for developing POAG include older age, large vertical C/D ratio, high IOP, large PSD, thin CCT, and presence of disc hemorrhage [196, 198]. There was little evidence of increased adverse events associated with medication for IOP reduction [195]. Initiation of therapy is strongly recommended for patients with these risks.

Summary of SR report

In OHTS, the goal for the treatment group was to achieve an IOP of 24 mmHg and less with a reduction of at least 20% compared with baseline IOP. Firstly, a single agent treatment was started in the eye with the higher IOP. The medication was switched if the IOP reduction was less than 10% from baseline, and the medication was switched or added at the physician's discretion if the IOP reduction rate was between 10% and 20%. In the EGPS, patients were divided into dorzolamide-treated and placebo groups [197]. In the OHTS, the incidence of POAG was significantly lower at 5 years in the treatment group (4.4%) compared to the control group (9.5%) [28]. In the EGPS, there was no significant difference in the conversion to POAG between the dorzolamide group (13.4%) and control group (14.1%) [197]. the difference in results between the two studies may be since, in the OHTS, patients could change or add medications if the target IOP was not reached, whereas, in the EGPS, only dorzolamide ophthalmic solution was allowed. The results are summarized below, divided into the following sections: fundus, visual field changes, cost-effectiveness, and others.

  1. 1.

    Fundus

    A large vertical C/D ratio (Table 1) and the presence of optic nerve disc hemorrhage are risk factors for the development of primary open-angle glaucoma. A larger vertical C/D ratio increased the incidence of primary open-angle glaucoma in both OHTS and EGPS (Table 1) [196, 198]. Additionally, the incidence of primary open-angle glaucoma increased with a greater difference in left and right eyes in vertical C/D ratio in EGPS (Table 1) [196].

    According to the OHTS, the glaucoma conversion rate was highest in patients with a CCT of 555 μm or less and a vertical C/D ratio of >0.30 and <0.50 (26%/year). Patients with CCT >555 μm and ≤588 μm and vertical C/D ratio ≤0.30 had the lowest glaucoma transition rate (1%/year) [198]. In the EGPS, the glaucoma incidence was 52.7%/year in the group with a thin CCT and larger vertical C/D ratio. The incidence was 2.4%/year in the group with thicker CCT and smaller vertical C/D ratio.

    The presence of optic nerve disc hemorrhage was determined by stereo fundus photography performed once a year in OHTS. The cumulative incidence of primary open-angle glaucoma over 96 months was 13.6% and 5.2% in eyes that developed and did not develop optic nerve disc hemorrhage during follow-up, respectively [78]. The incidence of optic nerve disc hemorrhage in OHTS was 0.5% annually for an average of 13 years and 1.2% annually for an average of 6 years before and after the onset of primary open-angle glaucoma respectively [199]. Optic nerve disc hemorrhage was an independent predictor of progression to primary open-angle glaucoma in patients with ocular hypertension. Predictors of optic nerve disc hemorrhage are similar to those of primary open-angle glaucoma development in patients with ocular hypertension (older age, large vertical C/D ratio, and high IOP) [199]. The EGPS has not examined optic nerve disc hemorrhage.

    In a study of 68 cases in OHTS and EGPS controls who could undergo image analysis, OCT parameters (average thickness, superior average, inferior average, nasal average, and temporal average) were significantly correlated with the risk of POAG in patients with ocular hypertension over 5 years, whereas scanning laser polarimetry and Heidelberg Retinal Tomograph parameters were not significantly correlated with the risk of POAG [200].

  2. 2.

    Visual field changes

    A large PSD is a risk factor for the development of primary open-angle glaucoma (Table 1). A larger PSD was associated with an increased incidence of primary open-angle glaucoma in both OHTS and EGPS (Table 1) [197, 198]. In a 5-year study of the OHTS observation group, initiation of IOP lowering medication significantly reduced the rate of progression of visual field impairment [201].

    The rate of MD change (slope) in the study of OHTS that spanned over 10 years was significantly faster (P< 0.001) in eyes with POAG onset (n=359; -0.26±0.36 dB/year) than in eyes without (n=2250; -0.05±0.14 dB/year) [202]. In a study of 1618 OHTS cases, left-right asymmetry in the visual field threshold was associated with a 37% higher risk of developing POAG in the eye with the lower threshold (sensitivity). The left-right asymmetry in the visual field threshold is a better indicator of the development of POAG than MD, although not as good as PSD [203].

    In a report examining the rate of visual field change in 1379 OHTS patients with at least 10 reliable visual fields and at least 5 years of observation, eyes diagnosed with POAG due to visual field impairment changes alone (n = 74; -0.29 ± 0.31 dB/year) or eyes diagnosed with POAG due to optic nerve disc changes alone (n=158; -0.12 ± 0.19 dB/year) had significantly worse MD change rates than eyes with no POAG (P<0.001)[202]. Additionally, eyes with POAG diagnosed by both visual field impairment and optic nerve disc changes (n=127; -0.42 ± 0.46 dB/year) had a rapidly worse MD change than eyes with visual field impairment changes alone (P=0.017) or optic nerve disc changes alone (P<0.001) [202]. Patients with both visual field impairment and optic nerve disc changes should be more aware of the development of POAG.

  3. 3.

    Cost-effectiveness

    Currently, in Japan, the treatment of ocular hypertension is covered by insurance. However, no report has examined the cost-effectiveness of ocular hypertension treatment in Japan. Using a Markov model to estimate the costs and benefits of disease processes, the risk of developing POAG for each case was calculated based on the risk factors shown in OHTS, and four treatment strategies were used for OHTS cases: “Treat all (treat all cases),” “Treat ≥2% of risk (treat cases with ≥2% annual risk of developing POAG,” “Treat ≥5% of risk (treat cases with ≥5% annual risk of developing POAG), and “Treat no one (no treatment for all patients).” Because of the comparative examination, “Treat ≥2% (treat cases with ≥2% annual risk of developing POAG)” was the most cost-effective [204].

    The incremental cost-effectiveness ratio (ICER) of “treating all ocular hypertensive patients to prevent one case from progressing to POAG” was calculated to be $89,072 using OHTS cases. After a 5-year review of age, IOP, C/D, and CCT, the following conditions were found to be below the standard ICER of $50,000/ quality-adjusted life-year (QALY): ≥76 years old (average age of patients with ocular hypertension), average IOP of ≥29 mmHg, average CCT of ≤533 μm, and average C/D ratio of ≥0.6. Therefore, the results suggest that treating all patients with ocular hypertension is not cost-effective [205].

    However, cost-effectiveness cannot be applied directly because the medical insurance systems in the United States and Europe are different from the system in Japan.

  4. 4.

    Others

    Since the incidence of POAG increased with older age, higher IOP, and thinner CCT in both OHTS and EGPS, these items are risk factors for the development of POAG (Table 1) [196, 198]. The cumulative proportion of patients who developed POAG during 13 years of OHTS follow-up was 0.22 (95% confidence interval [CI] 0.19–0.25) in the observation group, which was higher than 0.16 (95% CI 0.13–0.19) in the medication group (P < 0.01) [195]. In a 5-year study of 1618 OHTS cases, for every 1 mmHg increase in left-right asymmetry in IOP, the risk of developing POAG increased by 17% [203]. When the risk prediction model derived from OHTS was validated in 126 patients with ocular hypertension, five risk factors (older age, larger vertical C/D ratio, higher IOP, larger PSD, and thinner CCT) were consistent with previous reports (6-year follow-up) [198]; however, a history of diabetes was also detected as a risk factor (hazard ratio [HR] 1.13 [0.40–3.18]) [206].

Patients that underwent at least two IOP measurements before POAG progression in OHTS and EGPS were classified by baseline IOP using latent class analysis to assess the interrelationship between baseline covariates, past IOP variability, and risk of POAG progression. We observed treatment status and baseline IOP to be important factors associated with higher risks. Although there were differences in the pattern of IOP variability between OHTS and EGPS, the risk factors for developing POAG were similar [207].

The risk of the OHTS observation group and the EGPS placebo group was assessed using a multivariate Cox proportional hazards model [208]. Cases that developed POAG were 9.3% in OHTS and 16.8% in EGPS, and the baseline risks in the two groups were age, IOP, CCT, vertical C/D ratio, and PSD. The risk rate can be calculated for each case by entering these items on the following website: [https://ohts.wustl.edu/risk/]

Owing to the small number of Asian participants in both the OHTS and EGPS trials, and because of the bias in each outcome in terms of race, subjects, and method, whether the results can be directly applied to Japanese subjects should be examined.

CQ2. Is treatment of preperimetric glaucoma (PPG) with normal IOP recommended?

Yasuyuki Suzuki, Hitomi Saito

Presentation of recommendation

Treatment initiation for preperimetric (PPG) with normal IOP should be considered alongside careful clinical follow-up and evaluation of risk factors.

Strength of recommendation

Treatment is weakly recommended.

Strength of evidence for CQ

☐ A (strong) ☐B (moderate) ■C (weak) ☐D (very weak)

Progress of the creation of the recommendation

Cohort studies, review articles, and expert descriptive articles with keywords such as PPG, glaucoma suspect, treatment, progression, quality of life, and cost-benefit analysis were searched. The efficacy of PPG treatment in reducing the onset and progression of the disease and cost-effectiveness (including psychological aspects and QoL) of treatment were examined as outcome measures. Since there were no RCTs that prospectively evaluated the efficacy of PPG treatment, the results of retrospective studies were primarily used to infer the evidence. Since PPG is not an independent disease concept but rather a continuum of early-stage primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG), findings of RCTs on NTG were interpreted to be generally applicable to PPG. Furthermore, because the present study was limited to the treatment of PPG with normal IOP, articles on ocular hypertension were excluded. However, reports that included both NTG and POAG were adopted.

Consequently, 14 studies were included for our review: 4 summarizing the natural history, progression, and treatment effects of PPG; 1 examining the QoL of patients with PPG; 2 examining changes in QoL and cost-effectiveness of glaucoma treatment (not limited to PPG); 2 examining the effectiveness of NTG treatment and risk factors for progression; 2 examining the effectiveness of NTG treatment and risk factors for progression; 3 examining the effects of topical medical treatment and laser treatment such as SLT for glaucoma; and 1 related to treatment adherence.

Summary of SR report

Progression of PPG

In a retrospective study of PPG with normal IOP, progression, which was defined as the appearance of structural changes or visual field abnormalities, was reported to be <60% at a mean observation period of 7 years [209]. When progression was defined only by the appearance of visual field abnormalities, the cumulative incidence of visual field abnormalities was reported to be 21.5% at 5 years, 40% at 10 years, 58.6% at 15 years, and 70.5% at 20 years[210]. Other studies including PPG with high IOP also reported that 40–60% of the patients showed structural changes or visual field abnormalities after an average observation period of 5–6 years, confirming that there is considerate number of eyes with PPG that progress over time [211, 212].

Risk factors for PPG progression and implications for treatment

Risk factors for progression of PPG have been pointed out in previous reports, including older age, presence of disc hemorrhage, poor PSD values at the time of initial examination, and abnormal OCT findings at the time of initial examination [209,210,211,212]. Furthermore, it has been reported that the higher the rate of IOP reduction, the more the progression from PPG to glaucoma with visual field abnormalities was suppressed, suggesting that it may be worthwhile to reduce IOP in PPG as well as in NTG [209, 212].

IOP-lowering therapy for OAG and NTG is well known to slow down visual field progression [80, 213]; therefore, it appears consistent that it would have a similar effect on PPG (the earliest stage of OAG). However, there are no reports with a high level of evidence on the treatment of PPG. Furthermore, PPG is not associated with subjective symptoms or reduced QoL [26]. Some PPG patients may not progress to perimetric glaucoma and others may have been misdiagnosed owing to false-positive tests or inadequate diagnosis. Therefore, initiation of treatment must be conducted with careful consideration.

Treatment alternatives and treatment-induced changes in QoL

As with POAG and NTG, the first choice of treatment for PPG is topical medical treatment. Although there have been no publications comparing the treatment of PPG among various types glaucoma treatment agents, it appears reasonable that the choice of treatment for PPG should be like that of POAG and NTG.

However, since PPG is a stage in which subjective symptoms and QoL reduction are still scarce as described above [26], QoL reduction due to treatment must also be taken into consideration. Since there were no studies that looked into changes in QoL due to treatment in patients with PPG, we reviewed those on POAG and found that there was no apparent decrease in QoL due to topical medical treatment. However, drugs with strong side effects should be avoided owing to low patient satisfaction [214, 215]. From the viewpoint of adherence, drugs that have strong side effects and require frequent instillation are not recommended, and it is ideal to provide treatment with as little patient burden as possible [216].

In addition to topical medical treatment, the efficacy and benefits of laser therapy such as selective laser trabeculoplasty (SLT) in early-stage glaucoma have been reported and may be an alternative for PPG treatment. An average IOP reduction of approximately 2 mmHg was observed after SLT treatment in patients with NTG. Additionally, in a report on POAG and ocular hypertension, patients were randomly assigned to either topical medical treatment or SLT groups and followed up for 3 years. As a result, 74% of patients in the SLT group did not require further glaucoma treatment during the observation period. Although SLT has not been reported to cause a decrease in QOL or any serious complications, considering that it is a form of surgical treatment, it is advisable to consult with patients in determining the optimal treatment plan [218].

Additionally, surgical treatment of early-stage patients is not recommended because of decreased QOL [214].

Cost-effectiveness analysis of treatment

Although there were no papers that analyzed the cost-effectiveness of PPG treatment, there are reports that treatment of early-stage glaucoma is cost-effective [219, 220] and PPG treatment may be considered to have a similar cost effect. Additionally, there is a report that SLT was more cost-effective in comparison with topical medical treatment for early-stage glaucoma patients.

However, it should be noted that earlier initiation of treatment may result in increased burden in terms of patient time and money, as well as increased health care costs.

Conclusion

Initiation of PPG treatment is weakly recommended. However, the level of evidence is weak because most of the evidence is inferred from studies on POAG and NTG. Clinically, treatment initiation should be determined at an individual level with careful follow-up of fundus, visual field and imaging findings along with evaluation of risk factors.

CQ3 Is glaucoma surgery recommended for patients with progressive visual field impairment even when IOP is in the low 10 mmHg range under topical antiglaucoma treatment?

(Kyoko Ishida, Tomomi Higashide)

Presentation of recommendation

In patients with progressive visual field impairment despite IOP in the low 10 mmHg range under topical ophthalmic treatment, trabeculectomy is weakly recommended. When visual field impairment progresses even at IOP levels in the low 10 mmHg range, factors related to IOP should first be thoroughly evaluated. Detect the possibility of high true IOP or high IOP variability by measuring central corneal thickness and diurnal variations of IOP. Trabeculectomy is anticipated to further lower IOP, reduce IOP variability more than drug therapy, and inhibit the progression of visual field impairment. Although there is a possibility of complications due to the surgery itself or postoperative hypotony, no studies are evaluating the decline in QOL associated with these complications. Consideration should be given to the risks associated with surgery and enough explanation should be given before surgery is considered.

Strength of recommendation

Surgical treatment is weakly recommended.

Strength of evidence for CQ

☐ A (strong) ☐ B (moderate) ■ C (weak) ☐ D (very weak)

Process of the creation of the recommendation

As there are no RCTs that have evaluated the effect of surgical or non-operative treatment on the progression of visual field impairment in patients with IOP in the low 10 mmHg range under topical antiglaucoma treatment, reviews, retrospective studies, and multicenter prospective studies of Japanese patients for risk factors were adopted.

Summary of SR report
  1. 1.

    Necessity of precise preoperative IOP evaluation and visual field evaluation

    A precise preoperative IOP and visual field evaluation is performed to confirm whether the visual field impairment progresses although the IOP is in the low 10 mmHg range with eye drops [221]. Bearing in mind the possibility that the true IOP is high or that there is a high IOP variability, adherence to glaucoma medication treatment should be confirmed. If possible, central corneal thickness, hysteresis, and diurnal variation of IOP should be evaluated. Furthermore, check for possible involvement of systemic progression factors (sleep apnea syndrome, blood flow abnormalities such as low diastolic blood pressure at night). If the progression of glaucoma is confirmed by multiple perimetries and IOP factors are strongly involved, trabeculectomy should be considered as a treatment method that can further lower IOP and reduces IOP variability [43].

  2. 2.

    IOP-lowering effect by surgery and complications

    In all these reports [222, 223], trabeculectomy (partially combined with cataract surgery) was performed for glaucoma that still progressed despite topical antiglaucoma treatment; however, there were no reports of preoperative mean IOP less than 13 mmHg. Shultz et al. performed surgery on 30 eyes with a mean preoperative IOP of 13.3 mmHg (mean number of eye drops: 2.5), and significantly lowered the mean IOP to 8.6 mmHg (mean number of eye drops: 0.6) at an average of 50 months after surgery [222]. Naito et al. operated on 17 eyes with a mean preoperative IOP of 13.9 mmHg (mean number of eye drops: 3.0) and significantly lowered the mean IOP to 8.1 mmHg (mean number of eye drops: 0.8) at a mean of 60 months after surgery [223]. In both studies, 68[222]–82% [223] and 52% [222] of patients achieved IOP reduction of 20% and 30%, and 68[222]–82% [223] of patients achieved postoperative IOP of ≤10 mmHg. In contrast, postoperative complications were observed in 53[222]–71% [223] of patients, including transient hypotony (30[222]–53% [223]), hypotony maculopathy (6[222]–18% [223]), cataract progression (44% [222]), and visual acuity loss of ≥0.1 unit of logMAR (18% [223]). However, trabeculectomy was effective in lowering the IOP to a single-digit level.

  3. 3.

    Effect of surgery on visual field maintenance

    According to the follow-up report [224] by Shultz et al. [222] and the report by Naito et al. [223] surgery reduced mean IOP by 35% and 42%, respectively, compared with preoperative IOP of 13.1[224] and 13.9 mmHg [223]. MD slope was -1.05 ± 0.66 (-0.25 ± 0.86) [224] and -0.91 ± 0.57 (-0.32 ± 0.57) dB/y [223] preoperatively (postoperatively), respectively, and the rate of progression was significantly suppressed by surgery. Additionally, MD slope improved in 92% of patients with postoperative IOP of <10 mmHg; however, it improved only in 20% of patients with IOP >10 mmHg [223].

A study was conducted involving 40 patients with progressive NTG with a mean preoperative IOP of 15.2 mmHg (mean number of eye drops: 3.0), which was lowered to 9.4 mmHg by trabeculectomy [225]. In this study, the rate of visual field progression according to two progression criteria (AGIS score and MD slope) was 4% and 9%, respectively, in patients who achieved 30% IOP reduction; 59% and 47% in patients who did not achieve 30% IOP reduction; 7% and 11% in patients who achieved 20% IOP reduction; and 75% in patients who did not achieve 20% IOP reduction. The progression rates of visual field impairment were 8% and 8% when postoperative IOP was less than 10 mmHg and 56% and 50% when IOP was greater than 10 mmHg, respectively [225].

All reports conclude that achieving a single-digit IOP with filtration surgery is effective in slowing the rate of visual field progression in NTG cases that progress at low IOP.

In another study [226], 60 NTG patients with MD slope progression before treatment were divided into three treatment groups (17 patients in the trabeculectomy group, 24 patients in the group that achieved ≥15% IOP reduction with FP receptor agonists, and 19 patients in the group that did not achieve IOP reduction with FP receptor agonists). Respective MD slopes were compared before and after treatment. Although there was no significant difference in pre-treatment IOP between the three groups, IOP significantly decreased from 14.7 to 9.1 mmHg (38% reduction) and MD slope significantly slowed from -0.86 ± 0.51 to -0.19 ± 0.20 dB/year in the trabeculectomy group. In the group that achieved ≥15% IOP reduction with FP receptor agonists, IOP significantly decreased from 14.7 to 11.7 mmHg (20% reduction) and MD slope improved from -0.52 ± 0.37 to -0.31 ± 0.30 dB/year before and after the intervention. In the group that did not achieve ≥15% IOP reduction with FP receptor agonists, IOP significantly decreased from 14.4 to 13.2 mmHg (8% reduction) before and after the intervention; however, MD slope did not improve from -0.40 ± 0.27 to -0.50 ± 0.65 dB/year before and after treatment.

As mentioned earlier, there are only a small number of retrospective reports of cases in which surgery was inevitably performed in actual clinical practice for patients whose condition progressed despite having low IOP (10 mmHg range) under topical antiglaucoma treatment. Therefore, the level of evidence is C owing to case selection bias. In the future, it will be necessary to conduct RCTs with the surgical and non-operative groups to determine the suppressive effect of trabeculectomy on loss of both visual field and QOL.

CQ4 Is tube shunt surgery recommended over trabeculectomy?

(Koji Nitta, Akira Matsuda)

Presentation of recommendation

It is recommended that the choice between the two techniques be based on the eye to be treated, the patient’s background, and the surgeon’s proficiency in the technique. Additionally, since there are differences in the characteristics of the Baerveldt glaucoma implant and the Ahmed glaucoma valve, it is important to select an implant that is appropriate for the situation of the affected eye.

Strength of recommendation

It is weakly recommended not to perform tube shunt surgery instead of trabeculectomy.

Strength of evidence for CQ

☐ A (strong) ☐ B (moderate) ■ C (weak) ☐ D (very weak)

Process of recommendation creation

Eleven English studies were selected after searching for comparative studies of tube shunt surgery and trabeculectomy as invasive glaucoma surgery [227,228,229,230,231,232,233,234], reviews including guidelines [235,236,237], case reports, and expert papers. The therapeutic effects of the two surgical procedures and their complications were examined.

Summary of SR report

Trabeculectomy is a useful technique for lowering IOP and is recommended as the initial treatment for patients with inadequate control of IOP by drug therapy or laser therapy or for severe cases. Tube shunt surgery has been performed for intractable glaucoma in which IOP cannot be controlled despite drug therapy and trabeculectomy; however, the range of indications for this procedure has been expanding in recent years. There was no significant difference in the results of IOP control between trabeculectomy and tube shunt surgery, and there was no significant difference in the incidence of serious complications that impair visual function. However, the frequency of complications associated with low IOP, and postoperative infection is higher in trabeculectomy, while implant exposure and corneal endothelial damage is higher in tube shunt surgery. In the SR on the CQ of the use of trabeculectomy versus tube shunt surgery, most of the participants in the study had POAG with high IOP, and the evidence for NTG, which is more common in Japanese, is insufficient.

  1. 1.

    Comparison of IOP lowering results

    Many studies have reported no significant difference in IOP control between trabeculectomy with MMC and tube shunt surgery [227,228,229]. There was no significant difference in IOP control in the 5-year results of the TVT study comparing trabeculectomy and Baerveldt implant insertion [227]. There was no significant difference in 3-year results in the PTVT study comparing trabeculectomy and Baerveldt implant (350 mm2) in the initial surgery. There was no significant difference in 3–4-year outcomes in a study comparing trabeculectomy with Ahmed glaucoma valve insertion. A meta-analysis of two studies comparing the 5-year outcomes of Ahmed and Baerveldt implants reported that the mean postoperative IOP of the Baerveldt implant was 13.2 mmHg, which was significantly lower (P<0.001) than the mean postoperative IOP of the Ahmed valve, which was 15.8 mmHg. There may be a difference in IOP control outcomes between the two implants [232].

  2. 2.

    Comparison of cumulative failure rates

    In the TVT study, the 5-year cumulative failure rate (≥21 mmHg or ≤20% IOP reduction, repeat glaucoma surgery, ≤5 mmHg IOP, loss of light vision) was 29.8%* in the tube shunt group and 46.9% in the trabeculectomy group. This suggests that failure is significantly higher in the trabeculectomy group (P=0.02, log-rank test). The cumulative failure rate (defined as in the TVT) based on the 3-year results of the PTVT study was 33%* in the tube shunt group and 28% in the trabeculectomy group, with no significant difference between the two groups [227, 228]. In an Ahmed-trabeculectomy comparison study, the cumulative success rate (within 5-21 mmHg or ≥15% IOP reduction, no repeat glaucoma surgery, and no loss of light perception after 41-52 months) was 69.8% in the Ahmed group and 68.1% in the trabeculectomy group. These results suggest that there was no significant difference between the two groups [229].

    *When comparing the TVT study and the PTVT study, the failure rate in the initial-surgery eye (PTVT) tube group, which is expected to give good results, is higher than that in the re-surgery eye (TVT). The study group believes that the younger age group and the higher proportion of black people may have an effect [231, 232].

  3. 3.

    Frequency of complications (corneal endothelial damage, suprachoroidal hemorrhage, retinal detachment, cataract, ocular hypotension, infection, strabismus, aqueous humor leakage, tube occlusion)

    In the 5-year results of the TVT study, there was no significant difference in the frequency of complications occurring after 1 month after surgery between the trabeculectomy group and the Baerveldt insertion group [227]. In contrast, there was a difference in the complications between the two groups. Corneal endothelial damage, eye movement disorder, and tube exposure were more common in the Baerveldt insertion group, while filtration bleb leakage, hypotony maculopathy, blebitis, and endophthalmitis were more common in the trabeculectomy group [227]. There was no difference between the two groups in the frequency of complications occurring after the first month after surgery in the 3-year results of the PTVT study [228]. In the Ahmed versus trabeculectomy study, there was no difference in the frequency of postoperative complications, but tube exposure was more common with Ahmed, and filtration bleb leakage and blebitis were more common with trabeculectomy (no significant difference) [229]. A meta-analysis of two studies comparing the 5-year postoperative outcomes of Ahmed valve and Baerveldt implants demonstrated a significantly higher incidence of ocular hypotension after Baerveldt implants (4.5%) compared with Ahmed valve (0.4%) (P=0.002) [233].

  4. 4.

    Postoperative visual acuity and visual field changes

    There were no significant differences in postoperative visual acuity or visual field changes between the two groups in the 5-year results of the TVT study and the results of the Ahmed versus trabeculectomy study (41–52 months) [229]. There was no significant difference in postoperative visual acuity at 3 years in the PTVT study [228].

  5. 5.

    Number of drugs used

    There was no significant difference between the 5-year results of the TVT study and the number of glaucoma drugs used by the two groups in the Ahmed-trabeculectomy comparison study [227]. In the 3-year results of the PTVT study, the number of glaucoma drugs used in the tube shunt surgery group was significantly higher than that in the trabeculectomy group.

  6. 6.

    Number of additional glaucoma surgeries

    The number of additional glaucoma surgeries in the 5-year results of the TVT study was significantly higher in the trabeculectomy group (P=0.025) [227]. No significant difference was noted in terms of the number of additional glaucoma surgeries in the 3-year PTVT study between the two groups [228].

  7. 7.

    Analysis of the quality of life and economic aspects of patients

    In the postoperative QoL assessment using the NEI VFQ-25 performed in the TVT study, there was no significant difference in subjective assessment of the QoL between the tube surgery group and the trabeculectomy group [233]. The average cost of glaucoma treatment simulated based on medical costs in the United States was $6,172 for conservative treatment, $10,075 for Baerveldt implant insertion, and $7,872 for trabeculectomy. Compared with conservative treatment, the cost per QALY was $8,289 for trabeculectomy and $13,896 for Baerveldt implant insertion, with the former being less expensive [234].

CQ5 Is steroid instillation recommended after trabeculectomy for primary open-angle glaucoma?

Atsuya Miki, Rumi Kawashima, Shunichi Usui

Presentation of recommendation

Local anti-inflammatory treatment, such as steroid instillation, is advantageous and recommended for IOP control after trabeculectomy for POAG. There are not enough research results to conclude whether it is effective in controlling surgical complications such as anterior chamber hemorrhage, transient elevation of IOP, and shallow anterior chamber.

Strength of recommendation

Instillation is strongly recommended.

Strength of evidence for CQ

☐ A (strong) ■ B (moderate) ☐ C (weak) ☐ D (very weak)

Process of recommendation creation

Based on the results of a systematic review of previous studies, anti-inflammatory treatment, such as steroid instillation, is recommended after trabeculectomy for POAG. Although some studies have shown no difference between steroid and nonsteroidal anti-inflammatory analgesic instillation, quantity and quality of evidence is not enough to replace the commonly administered steroids with nonsteroidal anti-inflammatory drugs. There is no evidence that the addition of treatments other than instillation results in better IOP reduction. No evidence-based conclusions have been drawn regarding the efficacy of postoperative steroid eye drops in reducing complications. Because the frequency of postoperative complications after trabeculectomy is not high, a much larger number of patients than in previous studies are needed to verify the complication-suppressing effect, which is a subject for future research.

Summary of SR report

Of the 140 candidate articles obtained from the literature search on the use of steroids after trabeculectomy for POAG, five RCTs were screened to be relevant to this CQ. Owing to the small number of reports and the variability in follow-up periods, designs, and outcomes among studies, a meta-analysis was not possible, and recommendations were made by considering the results of individual studies and current standards of practice.

In three studies from a same study group, postoperative IOP was significantly lower in the group using postoperative steroid instillation than in the group that did not use it [238,239,240]. The total frequency of complications (anterior chamber hemorrhage, transient IOP elevation, and shallow anterior chamber) was not significantly different between patients who used and did not use eye drops. There are some reports of differences in the incidence of anterior chamber hemorrhage between patients that did and did not use eye drops, but the number of cases is insufficient to draw definitive conclusions. Overall, currently, it is not possible to determine whether the use of steroid eye drops is effective in reducing complications of trabeculectomy.

Two RCTs of steroid instillation and nonsteroidal anti-inflammatory drug instillation was also reported [241, 242]. Neither of these studies showed a significant difference in IOP control between steroidal instillation and nonsteroidal anti-inflammatory drug instillation. These results suggest that nonsteroidal anti-inflammatory analgesic instillation may be used as a substitute for steroidal eye drops. However, these trials were all small studies with 10–20 patients in each group, which is insufficient considering the diverse background of glaucoma. Because these studies do not provide enough evidence to replace the currently widely used steroid instillation therapy with nonsteroidal anti-inflammatory drug instillation, further studies are needed. Furthermore, although steroids may be administered by other methods, such as local injection or systemic administration, there is insufficient evidence to make a recommendation on whether these methods improve IOP control for trabeculectomy.

In summary, postoperative anti-inflammatory treatment, such as steroid eye drops, is recommended to improve IOP control after trabeculectomy for POAG. Whether other drugs (nonsteroidal anti-inflammatory drug), or other administration methods (local injections or systemic administration), have the same or additional effects is not sufficiently evident to make a recommendation, and future studies are needed.

CQ6 How long is antibiotic instillation and ointment therapy necessary after trabeculectomy?

(Takehiro Yamashita, Kenji Nakamoto)

Presentation of recommendation

Antibiotic instillation and ointments should be used continuously for some time after surgery. For long-term use, antibiotic instillation and ointment application should be performed as appropriate according to the risk of bleb-related infection.

Strength of recommendation

Treatment is strongly recommended.

Strength of evidence for CQ

☐ A (strong) ☐ B (moderate) ■ C (weak) ☐ D (very weak)

Process of recommendation creation

Unlike other ophthalmic surgeries, trabeculectomy involves the creation of a filtration bleb; as such, there is a risk of bleb-related infection not only in the early postoperative period but also in the long-term postoperative period. This CQ was established because the transition from blebitis to endophthalmitis can cause critical visual dysfunction including blindness, and the long-term use of antibiotics is a major clinical concern.

We conducted a systematic literature search on the duration of antibiotic use after trabeculectomy. Because new quinolones are currently the main antibiotic agents used after ophthalmologic surgery, we selected articles with a high level of evidence that covered cases after 2000, when new quinolones were launched, owing to the nature of setting guidelines for the next several years. The only relevant studies were the four reports [243,244,245,246] that analyzed the use of antibiotic agents in 104 eyes with bleb-related infection in a nationwide survey of bleb-related infection conducted by the Japan Glaucoma Society. This study is a prospective, large-scale study of Japanese patients, in which most patients (40 of 42 eyes in the long-term use group) were using new quinolone antibiotics. It is highly reliable as it was evaluated by specialists of the Japan Glaucoma Society. In addition, a study was adopted on the risk factors for bleb-related infection that was published in the same study and followed patients for 5 years after surgery [244]. In the following text, unless otherwise cited, the results of this study of bleb-related infection will be described.

Early postoperative antibiotic use

Of the 104 eyes included in the study, none developed blebitis or endophthalmitis within 17 weeks after surgery. Although there is no detailed description of the duration of early postoperative antibiotic use in the article, the glaucoma surgeons who participated in the study generally performed antibiotic instillation continuously for 1–3 months after surgery. As a result, no postoperative infection occurred within 17 weeks after surgery. However, in a strict sense, the strength of the evidence is weak as the study did not allocate the period of postoperative antibiotic use, which makes it impossible to define a definite period.

Long-term postoperative antibiotic use

Although there are no RCTs of　long-term postoperative antibiotic use, a study of bleb-related infection showed that long-term use of antibiotic agents significantly delayed the onset of bleb-related infection compared with no use, and the effect of ointment was particularly large (the median time of postoperative onset of bleb-related infection was 3.9 years in the group without antibiotics, 6.4 years in the group with antibiotics, and 10.5 years in the group with ointment). These results suggest that long-term use of antibiotic agents is acceptable from the viewpoint of preventing bleb-related infection.

The main risk factor for bleb-related infection is leakage of aqueous humor from the filtration bleb [244]. Based on the clinical findings, the walls of the filtration bleb are thin, allowing aqueous humor to leak when raising the upper eyelid. Subjective symptoms include epiphora upon awakening. If these findings and symptoms are observed, the use of new quinolone ophthalmic ointment at bedtime should be considered.

Long-term use of antibiotics may lead to changes in the conjunctival microflora and the appearance of resistant bacteria. In a study of resistant strains toward new quinolone antibiotic agents on the surface of filtration bleb after trabeculectomy, there was no significant difference in culture positivity between eyes with and without long-term antibiotic use [245]. In 26 eyes with long-term use of new quinolone antibiotics, resistant bacteria were found in nine eyes, of which six were Staphylococcus epidermidis [246], which makes endophthalmitis less likely to become severe. Inadvertent use of antibiotic agents should be avoided from a medical economic point of view, and research with a high level of evidence regarding the use of postoperative antibiotic agents is awaited.

Q7 Is concomitant cataract surgery recommended when performing trabeculectomy for primary open-angle glaucoma?

(Shinki Chin, Katsuhiko Maruyama, Yasuhiro Shinmei)

Presentation of recommendation

Concomitant cataract surgery during trabeculectomy for primary open-angle glaucoma may be performed if lens reconstruction is thought to be beneficial for improving visual function, but this may worsen the outcome of intraocular pressure (IOP) adjustment.

Strength of recommendation

Concomitant cataract surgery is weakly recommended.

Strength of evidence for CQ

☐ A (strong) ☐ B (moderate) ☐ C (weak) ■ D (very weak)

Process of recommendation creation

This study was based on reports that compared the outcomes of trabeculectomy alone and simultaneous trabeculectomy and cataract surgery for primary open-angle glaucoma (POAG). As there are no randomized controlled trials (RCTs) or meta-analyses with a high level of evidence for this comparison, we adopted five prospective cohort studies [247,248,249,250,251] and five retrospective cohort studies [252,253,254,255,256]. In this study, trabeculectomy was compared to deep sclerectomy [247] and XEN® Gel Stent surgery [255], and the results were divided into two groups: trabeculectomy alone and simultaneous trabeculectomy and cataract surgery. The proportion of patients with POAG ranged from 34%–72.6% [247,248,249,250,251,252,253,254,255,256]; other glaucoma types, such as exfoliation glaucoma, were also included. Trabeculectomy also includes concomitant mitomycin C use [249,250,251, 253,254,255,256] and concomitant 5-fluorouracil use [248, 252]. Results of filtration surgery using devices that are difficult to obtain in Japan, such as XEN®, were excluded from the analysis.

　A structured report (SR) was conducted to assess the outcomes of IOP adjustment (postoperative IOP, eye drop score, and survival), incidence of complications, and improvement in visual acuity. Improvements in quality of vision (QoV) and quality of life (QoL) are also important outcomes for patients; however, there are no objective studies on them at present.

Summary of SR report

In previous reports of trabeculectomy alone and simultaneous trabeculectomy and cataract surgery, the preoperative background was likely to be different; moreover, there are no RCTs or meta-analyses with a high level of evidence for this comparison.

There were limitations in these reports. In the prospective cohort studies used in this study, all criteria for choosing single or simultaneous cataract surgery, such as visual acuity [248], patient preference, [249, 250] and choice of surgeon [251], were subjected to bias, and no studies randomly assigned the patients. In retrospective cohort studies, there was no uniformity in patient background. However, three out of ten reports showed that trabeculectomy alone was superior to simultaneous trabeculectomy and cataract surgery, in terms of postoperative IOP, ophthalmic score, and survival [248, 250, 252]. However, there are no reports showing that simultaneous cataract surgery with trabeculectomy is superior to trabeculectomy alone in terms of IOP reduction.

The postoperative complications of simultaneous cataract surgery with trabeculectomy were investigated in three papers [247, 249, 251], and the results showed no statistically significant difference between the two groups. We believe that the risk of complications from simultaneous cataract surgery and trabeculectomy is equivalent to that of surgery with trabeculectomy alone.

The effect of surgery on visual acuity is expected to be higher in the group of patients who have undergone simultaneous cataract surgery with trabeculectomy, which is mostly seen in selected patients with vision loss due to cataracts [248, 250, 251]. Three reports have shown this effect in the simultaneous cataract surgery group, and it is assumed to have contributed to the postoperative satisfaction of the patients.

Finally, we recommend simultaneous cataract surgery after careful consideration of the balance between benefits and risks. This is because simultaneous trabeculectomy and cataract surgery are expected to improve visual function through lens reconstruction, whereas trabeculectomy alone may require lens reconstruction as the cataract progresses.

  1. 1.

    Postoperative IOP

    Seven reports of postoperative IOP were reviewed. There have been reports of a strong IOP-lowering effect with trabeculectomy alone [247, 251, 254,255,256], as well as reports stating that there is no significant difference between trabeculectomy alone and simultaneous cataract surgery with trabeculectomy [248, 252]. However, there have been no reports of a strong IOP-lowering effect with simultaneous surgery. This suggests that simultaneous cataract surgery should not be performed in patients with POAG who do not undergo cataract surgery in the hope that lens extraction will lower IOP.

  2. 2.

    Instillation score

    Three studies evaluated the number of postoperative eye drops. One report showed that simultaneous cataract surgery resulted in the use of additional postoperative glaucoma eye drops [250], while the other two reports showed no statistically significant difference [251, 252]. No reports have shown that the instillation score was lower in simultaneous cataract surgery than in single surgery.

  3. 3.

    Survival rate

    Four reports included Kaplan-Meier survival analysis on the surgical outcomes, two of which reported a higher survival rate with a single surgery [250, 252] and two reported no statistically significant difference [247, 253]. However, the criteria for survival and the observation period differed among the reports, and it is challenging to make a unified evaluation; moreover, no report showed that the survival rate after simultaneous cataract surgery was better than that after single surgery.

  4. 4.

    Incidence of complications

    Three reports have been adopted for the statistical analysis of postoperative complications [247, 249, 251]. Cillino et al. [247] reported no significant difference in the frequency of anterior chamber hemorrhage, postoperative inflammation with fibrin deposition, ocular hypotension, flat anterior chamber, choroidal detachment between trabeculectomy alone and simultaneous trabeculectomy and cataract surgery. Inatani et al. [249] reported no significant difference in postoperative inflammation between the two groups using a laser flare cell meter at 2 and 4 weeks after surgery. Graf et al. [251] reported that intraoperative complications such as problems with scleral valve preparation were more common in the single surgery group than in the simultaneous surgery group; however, there was no difference in the frequency of postoperative complications such as ocular hypotension and aqueous humor leakage between the two groups. Simultaneous cataract surgery did not appear to have a significant effect on the degree of postoperative inflammation in trabeculectomy.

  5. 5.

    Improvement of visual acuity

    In patients with decreased visual acuity due to cataracts, it is expected that postoperative visual acuity would improve in the simultaneous cataract surgery group. Three reports have statistically compared postoperative visual acuity between the two groups [248, 250, 251], two of which reported statistically significant improvements in visual acuity in the simultaneous cataract surgery group compared with the single surgery group [248, 250].

For each of these endpoints, the level of evidence was set at D owing to the absence of RCTs or meta-analyses with a high level of evidence, a small number of cases in individual reports, and a serious risk of bias.

CQ8 Is lens extraction or laser therapy the first-line treatment for primary angle-closure glaucoma (PACG) and its precursor lesion, primary angle-closure (PAC)?

(Yasuo Kurimoto, Hiroshi Sakai, Satoshi Yoshimizu)

Presentation of recommendation

Lens extraction is strongly recommended as the first-line treatment for PACG and PAC. Lens extraction can be the first-line treatment regardless of the presence or absence of symptomatic cataracts. However, it is not an absolute first-line treatment, and laser therapy should be selected according to the circumstances of each case. It should also be noted that the indication for treatment of PAC with normal IOP should be carefully considered.

Strength of recommendation

We strongly recommend performing lens extraction.

Strength of evidence for CQ

■ A (strong) ☐ B (moderate) ☐ C (weak) ☐ D (very weak)

Process of recommendation creation

This examination is based on RCTs of lens extraction and laser peripheral iridotomy (LPI) for acute primary angle-closure, PACG, and primary angle-closure PAC. The most important outcomes were the degree of IOP reduction, treatment success rate, and adverse events associated with each procedure, as well as visual acuity, QoL, and medical costs.

Overall, LPI for PACG and PAC (precursor lesion) results in an enlarged anterior chamber angle; however, it has a lower success rate in IOP reduction, requires more postoperative ophthalmic drug therapy, and requires additional surgery. In the case of lens extraction, the angle opening is greater than in LPI, the success rate of IOP reduction is higher (approximately 90%) even in acute PAC (APAC, so-called acute glaucoma attack) eyes, the need for additional surgery is lower, the cost is lower than in LPI, and the quality of life per cost is higher. Although more than half of patients with APAC have good visual acuity (0.5 or better) after resolution of the attack, it is considered that upon careful consideration of the balance of benefits and harm, lens extraction can be performed to open the angle and lower IOP regardless of the presence or absence of symptomatic cataracts with visual loss. It is recommended that patients with PAC with high IOP, PACG, and APAC undergo lens extraction as the first-line treatment.

This CQ presents the superiority of LPI and lens extraction based on long-term outcomes and questions the choice of treatment in situations where both treatments are feasible, and does not limit the treatment of individual cases. For example, RCTs have not been performed in emergency LPI or laser gonioplasty (or argon laser peripheral iridoplasty) followed by lens extraction, and this recommendation does not imply that lens extraction is an absolute first-line treatment for all APAC, PACG, or PAC cases with high IOP. There are many situations in which laser therapy, including LPI, may be the initial treatment of choice depending on the circumstances of each case. Currently, LPI is listed as a treatment alternative in many national and regional guidelines (SR2, SR3, SR4). It should be noted that there are no RCTs that recommend LPI or lens reconstruction for PAC without high IOP, and the need for surgical treatment should be carefully considered.

Summary of SR report

PACG and PAC with high IOP are also treated with pharmacotherapy as initial therapy; however, the prognosis for long-term drug therapy is poor. In a retrospective case-control study conducted after the development of LPI, it was reported that more than half of patients with either chronic PACG or APAC developed uncontrolled IOP or developed recurrent attacks during long-term drug therapy. Considering these results, it is not ethical to conduct RCTs comparing drug therapy with surgery, and this has not been done in practice. LPI and lens extraction are the main first-line treatments, excluding initial treatment. In the SR for this CQ, RCTs directly comparing LPI and lens extraction for PACG, PAC, and APAC were selected. There were two RCTs for PACG or PAC and three RCTs for APAC. An RCT comparing LPI with lens extraction for primary angle closure suspect (PACS) was also identified. In one RCT for PACG or PAC, the latter was associated with a high IOP of ≥30 mmHg. Based on these studies, we examined treatment success rates, adverse events, effects on corneal endothelial cells, refractive error, visual acuity, visual field, QoL, QoV, and medical costs using anterior chamber angle morphology, IOP values, and IOP reduction as outcomes.

  1. 1.

    Improvement of anterior chamber angle morphology

    Primary angle closure disease (PACD) is a concept that encompasses PACG, PAC, and PACS. Overall, the characteristics of PACD eyes, such as the shallow anterior chamber, narrow angle, and angle closure, are improved by LPI and lens extraction, but more so by lens extraction. In PACD eyes, central anterior chamber depth and anterior chamber volume significantly improved with lens extraction than with LPI [258, 259]. Shaffer grade, which is a classification of the angle, is improved in LPI and lens extraction; [260, 261] however, it is significantly improved in lens extraction than in LPI [261]. There is a report that the degree of peripheral anterior synechiae (PAS) does not differ between LPI and lens extraction [260, 262], and another reporting that PAS is more common in LPI than in lens extraction [261]. It has been reported that lens vault, iris convexity, angle opening distance, and angle recess angle significantly improve in lens extraction than in LPI [258]. It is judged that the risk of non-directivity and bias was low and that the inconsistency was small. Therefore, the level of evidence was judged to be A.

  2. 2.

    IOP control

    It has been reported that postoperative IOP in PACD eyes is lower in lens extraction than in LPI eyes [258, 261, 262], or decreases only in lens extraction eyes [259]. In survival analysis of APAC with IOP control as the primary endpoint, it was reported that IOP control with lens extraction was very high (89.5% at 3 years and 96.7% at 18 months), while survival with LPI was significantly lower (50.0% at 3 years and 53.3% at 18 months). All five RCTs of PACD eyes describing IOP reported better IOP control with lens extraction than with LPI. It is judged that the level of evidence is A because of non-directivity, low risk of bias, and low inconsistency.

  3. 3.

    Need for additional medications and surgical therapy

    Three RCTs describing the postoperative drug therapy of LPI or lens extraction for PACG, APAC, and PAC with high IOP were retrieved [259, 261, 262]. In PACG or PAC with high IOP or APAC, the number of eye drops required for postoperative IOP control was significantly lower with lens extraction [261, 262] or decreased postoperatively only with lens extraction [261]. It is judged that the results are nondirective, with a low risk of bias and low inconsistency; as such, the level of evidence was judged to be A.

  4. 4.

    Adverse events

    Overall, the incidence of adverse events after LPI or lens extraction for PACD was low, and no serious events were reported during the observation period of up to 3 years. There were some reports of anterior chamber hemorrhage after LPI with YAG laser, rupture during lens extraction, shallow anterior chamber, malignant glaucoma, and corneal edema in both techniques after LPI or extraction; however, no differences were noted [259]. In the case of lens extraction for APAC, 12 cases of intraoperative corneal edema, seven cases of postoperative fibrin deposition, five cases of posterior cataract, one case of posterior capsule damage, and one case of iris hemorrhage were reported in 31 eyes, all of which were managed without sequelae [262]. There is one RCT examining the density of corneal endothelial cells, which is LPI after APAC or after lens extraction. There was no apparent decrease after surgery in both groups, and there was no difference between the two groups. There were few clinically problematic adverse events in both LPI and lens extraction in the reported cases collected in the SR. The risk of non-directivity and bias was judged to be low, and the inconsistency was judged to be low; as such, the level of evidence was judged to be A.

  5. 5.

    Refraction value, visual acuity, and visual field

    In RCTs of PACG or PAC with high IOP, refractive values significantly decreased from hyperopic to emmetropic after lens extraction [263]; however, refractive values were not statistically different from those of the LPI group [259]. Reports state that there is no difference in visual acuity between post-LPI or post-lens extraction [262]. There is a report of improvement in both procedures; however, there are two reports of significant improvement in visual acuity after lens extraction [259, 261] and stable visual acuity after lens extraction for 3 years [263]. It has been noted that in APAC eyes, half of the patients had visual acuity of 0.5 or better after the resolution of the attack, which may influence the discussion on the merits of lens extraction in eyes with good visual acuity [85]. Although there is one report stating that there is no difference in visual field parameters between post-LPI or post-lens extraction [262], this SR report was insufficient to examine visual field abnormalities.

  6. 6.

    QoL, QoV, and health care costs

    The only RCT to examine QoL, QoV, and medical costs was the EAGLE trial of PACG and PAC with high IOP. QoV was evaluated using the NEI-VFQ-25 and the glaucoma utility index, both of which showed that lens extraction was associated with higher and better visual outcomes. In terms of QoL, the European QoL5 questionnaire was used, and again, lens extraction was associated with a higher QoL. In terms of medical costs, the simple cost of lens extraction is higher in the early stages; however, in the long term (>3 years), the cost of lens extraction is likely to be lower in relation to the benefits obtained. Owing to differences in insurance systems, simple comparisons cannot be made; however, it is possible to estimate the costs based on insurance, and it is thought that non-directivity could be eliminated. Specifically, outpatient lens extraction costs 866 Euros (2,157 Euros for inpatient), whereas LPI costs 118 Euros. In contrast, under the Japanese insurance system, the cost of lens extraction is 121,000 yen (K282 lens extraction, one intraocular lens insertion, b, other 12, 100 points), whereas the cost of LPI is 66,200 yen (K270 iris photocoagulation, 6, 620 points).

CQ9 Is therapeutic intervention necessary for PACS?

(Yasuo Kurimoto, Hiroshi Sakai, Satoshi Yoshimizu)

Presentation of recommendation

We recommend that therapeutic intervention for PACS should be based on the risk assessment of each case and should not be performed uniformly. Intervention is recommended for patients with PACS who are at high risk of progressing to APAC or PACG, particularly for fellow eyes of APAC affected eyes.

Strength of recommendation

Overall PACS: We weakly recommend not to perform interventions uniformly.

Fellow eyes of APAC affected eyes: We strongly recommend intervention.

Strength of evidence for CQ

☐ A (strong) ■ B (moderate) ☐ C (weak) ☐ D (very weak)

Process of recommendation creation

In making the recommendations, we focused on the course of IOP, disease progression, anterior chamber angle morphology, and corneal endothelial cell density as adverse events in patients with and without therapeutic intervention for PACS. LPI was considered as a method of therapeutic intervention based on the search contents of the systematic review.

As a specific procedure, we excluded from the search results articles whose endpoints were inconsistent with the purpose of this CQ or those that reported only early results from the day after treatment to several weeks after treatment and reviewed the remaining articles. The literature related to an RCT from China called the ZAP trial, which compared PACS eyes with and without unilateral LPI treatment, included East Asians as in Japan, and had a long-term observation period of 6 years [265,266,267]. An RCT that followed corneal endothelial cell density for 3 years was also selected [268]. Another RCT, called the IMPACT study, was also selected; however, it was excluded from this CQ as it included both PACS and primary angle-closure, had a short observation period of 6 months, and included a Caucasian population [84].

As will be described later, there are other treatment alternatives for angle closure, such as lens extraction and laser gonioplasty, and although it is necessary to select an appropriate treatment alternative based on the diagnosis of the mechanism of angle-closure by imaging tests, it should be noted that this is not included in the discussion of this CQ because enough evidence has not been searched in systematic reviews.

Summary of SR report

Based on the search of systematic reviews, we reviewed the results of RCTs on LPI treatment for PACS.

In a Chinese report (ZAP trial) [265], PACS eyes were randomly assigned to LPI treatment in one eye and no treatment in the other eye, and followed for 6 years. The annual incidence rates were 4.19 and 7.97 per 1000 eyes (P=0.021). Although there was a significant difference between the two groups, the incidence rates were both very low. The number needed to treat (NNT) to prevent progression from PACS to PAC over 6 years was 44. The annual incidence of progression to PAC per 1000 eyes in the LPI and no treatment groups for each endpoint was 0.66 and 1.11 (P=0.480) for elevated IOP (>24 mmHg), 3.31 and 6.64 (P=0.024) for PAS, 0.22 and 1.11 (P=0.100) for APAC, APAC onset was much less frequent, and no significant difference was observed in this RCT. Although not an RCT, there was a previous report that 23% of patients progressed from PACS to PAC over a 5-year period [269]. However, the observation was made in 1995; therefore, there are differences with the current diagnostic criteria. As such, racial differences must be considered because the report was from South India [270].

Regarding anterior chamber angle morphology, the ZAP trial at 18 months reported that the angle widened after LPI treatment owing to resolution of pupillary block; however, it narrowed over time, and that narrowing progressed more rapidly in the untreated group [267].

Regarding corneal endothelial cell loss, which has been reported as an adverse event particularly in Japan, analysis of the ZAP trial showed that both groups showed age-related endothelial cell loss; however, there was no significant difference between the treated and untreated groups until 4.5 years [266]. At 6 years, there was a significant difference in the rate of loss; however, it was small (0.74%), and the authors concluded that it was not clinically significant [266]. In another RCT involving primarily Chinese participants, the follow-up period was 3 years, which was shorter than the RCT; however, there was no significant difference in the rate of endothelial cell loss between the treated and untreated groups [268]. Based on these results, we concluded that although LPI treatment did not result in a clinically clear decrease in corneal endothelial cells, it may have affected the long-term course of the disease.

No serious adverse events were reported in this ZAP trial [265], although mild anterior chamber hemorrhage, corneal injury, and transient IOP elevation were observed in association with LPI treatment.

Based on the low incidence of PAC progression and NNT in these RCTs, it is recommended that preventative LPI treatment should not be based solely on the fact that patients meet the current diagnostic criteria for PACS.

In contrast, therapeutic intervention is recommended for patients with PACS who are at high risk for progression to APAC or PACG. One of the high-risk conditions is the presence of APAC in the fellow eye. It is considered difficult to perform RCT because of ethical issues; however, referring to previous reports, 50% of patients with APAC developed it in the untreated fellow eye during observation. It has been reported that approximately one-third of them developed within 1 year [271]. In a Japanese report of PAC eyes followed up for more than 5 years with drug treatment alone, 26% of the APAC fellow eyes developed APAC [272]. Considering the high incidence of APAC and the rapid progression of symptoms once APAC develops, aggressive therapeutic intervention is recommended for APAC fellow eyes. However, there are cases of APAC fellow eyes in which the degree of angle closure differs between right and left eyes. In such cases, the indication for treatment should be considered after evaluating the degree of angle-closure using gonioscopy, imaging studies, and supplementary provocative tests. In a comparative study of the anterior segment configuration of APAC eyes and fellow eyes using anterior segment OCT, it was reported from Singapore that the shallow central anterior chamber depth was most strongly associated with the development of APAC, being 1.63 mm in APAC eyes and 1.91 mm in fellow eyes [273]. In a study with anterior segment OCT in Japanese PACD eyes, a central anterior chamber depth of <1.7 mm was reported as a morphologic risk for the development of APAC with a sensitivity of 82.4% and a specificity of 91.7% (area under the curve 0.931) [274] (this is one of the guidelines for the reduction of central anterior chamber depth in considering the risk of APAC, and does not mean the cutoff value for PACS intervention in this CQ).

As for risk factors for PAC progression, the multivariate results of the ZAP trial mentioned above pointed to allocation to LPI (P=0.023, HR 0.52), peripheral anterior chamber depth (P<0.001, HR 0.49: modified Van Herick grading 10% higher), central anterior chamber depth (P=0.013, HR 0.21: per 1mm increase), and age (P=0.015, HR 1.07) [265].

Additionally, social factors such as the accessibility of medical institutions at the time of APAC, the need for frequent mydriasis due to concurrent ocular fundus diseases, and the degree of patient understanding of the pathogenesis of PACS may also be helpful in determining therapeutic intervention.

This CQ discusses the significance of LPI treatment as a therapeutic intervention based on the results of a systematic review. However, because LPI is effective only for pupillary block mechanism, alternative treatments, such as lens extraction and laser gonioplasty, should be considered in eyes with other mechanisms (plateau iris, lens factor). It is important to evaluate not only the presence or absence of angle closure by gonioscopy but also the mechanism of angle closure using anterior segment OCT and ultrasound biomicroscopy.

Additionally, considering that the effect of lens extraction is stronger than that of LPI in opening the angle, and that lens extraction is effective in treating other mechanisms of angle closure besides pupillary block, lens extraction may be the initial treatment of choice in PACS eyes with symptomatic cataract or when imaging evaluation indicates a predominance of non-pupillary block mechanisms.

In summary, it is recommended that preventative LPI treatment should not be based solely on the fact that patients meet the current diagnostic criteria for PACS, but that therapeutic intervention is recommended for patients with PACS who are at high risk for progression to APAC or PACG.