ZOLLINGER’S ATLAS OF SURGICAL OPERATIONS

The classic surgical atlas, more comprehensive than ever!

A  Doody's Core Title for 2017!

For more than half-a-century, Zollinger’s Atlas of Surgical Operations has been the gold-standard reference for learning howto perform the most common surgical procedures using safe, well-established techniques. The tenth edition continues this tradition of excellence. The atlas covers gastrointestinal, hepatobiliary, pancreatic, vascular, gynecologic, and additional procedures, including hernia repair, vascular access, breast procedures, sentinel lymph node biopsy,thyroidectomy, and many more. The illustrations in this atlas have withstood the test of time. They allow you to visualize both the anatomy and the operation, making the book useful as a refresher or for learning the steps of a particular procedure.

The tenth edition of Zollinger’s Atlas of Surgical Operations expands the content to include 19 new operations. Each chapter contains beautifully rendered line drawings with color highlights that depict every important action you must consider while performing the operation. Each chapter also includes consistently formatted coverage of indications,preoperative preparation, anesthesia, position, operative preparation, incision and exposure, procedure, closure, and postoperative care.

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Postterm Pregnancy | Ricardo Side

Postterm Pregnancy 

• Author: Aaron B Caughey, MD, PhD, MPH; Chief Editor: David Chelmow, MD

Overview

Postterm pregnancy is defined as a pregnancy that extends to 42 0/7 weeks and beyond.^[1] The reported frequency of postterm pregnancy is approximately 3-12%.^{[1, 2]} However, the actual biologic variation is likely less since the most frequent cause of a postterm pregnancy diagnosis is inaccurate dating.^{[3, 4, 5, 6]} Risk factors for actual postterm pregnancy include primiparity, prior postterm pregnancy, male gender of the fetus, and genetic factors.^{[7, 8, 9, 2, 1]}

Laursen et al studied monozygotic and dizygotic twins and their subsequent development of prolonged pregnancies. They found that maternal but not paternal genetic factors influenced the rate of postterm pregnancies and accounted for the etiology in as many as 30% of these pregnancies.^[10] A more recently described risk factor is obesity, which appears to increase the risk of pregnancies progressing beyond 41 or 42 weeks of gestation.^{[11, 12, 13]}

Although the last menstrual period (LMP) has been traditionally used to calculate the estimated due date (EDD), many inaccuracies exist using this method in women who have irregular cycles, have been on recent hormonal birth control, or who have first trimester bleeding. In particular, women are more likely to be oligo-ovulatory than polyovulatory, so cycles longer than 28 days are not uncommonly seen.^[4] If such a cycle is 35 days instead of 28 days, a second trimester ultrasound will not be powerful enough to redate the pregnancy. Thus, not only the LMP date, but the regularity and length of cycles must be taken into account when estimating gestational age.

Ultrasonographic dating early in pregnancy can improve the reliability of the EDD; however, it is necessary to understand the margin of error reported at various times during each trimester. A calculated gestational age by composite biometry from a sonogram must be considered an estimate and must take into account the range of possibilities.

Estimation range varies. For example, crown-rump length (CRL) is 3-5 days, ultrasonography performed at 12-20 weeks of gestation is 7-10 days, at 20-30 weeks is 2 weeks, and after 30 weeks is 3 weeks. Thus, a pregnancy that is 35 weeks by a 31-week ultrasound could actually be anywhere from 32 weeks to 38 weeks (35 wk +/-3 wk). If the calculated ultrasonographic gestational age varies from the LMP more than the respective range of error, it is used instead to establish the final EDD. The importance of determining by what method a pregnancy is dated cannot be overemphasized because this may have significant consequences if the physician delivers a so-called term pregnancy that is not or observes a so-called term pregnancy that is very postterm.

When determining a management plan for an impending postterm pregnancy (>40 wk of gestation but < 42 wk), the 3 options are (1) elective induction of labor, (2) expectant management of the pregnancy, or (3) antenatal testing. Each of these 3 options may be used at any particular time during this 2-week period.

Note that if the pregnancy is at risk for an adverse outcome from an underlying condition, either maternal or fetal, inducing labor may proceed without documented lung maturity. Also, an elective induction of labor may proceed at or after 39 weeks of gestation in the absence of documented lung maturity provided that 36 weeks have elapsed since documentation of a positive human chorionic gonadotropin (+hCG) test finding, 20 weeks of fetal heart tones have been established by a fetoscope or 30 weeks by a Doppler examination, or 39 weeks' gestation have been established by a CRL or by an ultrasound performed before 20 weeks of gestation consistent with dates by the patient's LMP.

Perinatal outcomes in postterm pregnancies

Recent studies have shown that the risks to the fetus^{[14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26]} and to the mother^{[23, 27, 28, 29, 30, 31, 32, 33]} of continuing the pregnancy beyond the estimated date of delivery is greater than originally appreciated.

Risks have traditionally been underestimated for 2 reasons. First, earlier studies were published before the routine use of obstetric ultrasonography and, as a result, likely included many pregnancies that were not truly postterm. As noted above, such a misclassification bias would artificially lower the complication rates of pregnancies designated postterm and increase the complication rates in those designated term, resulting in a diminution in the difference between term and postterm pregnancies.

The second issue relates to the definition of stillbirth rates. Traditionally, stillbirth rates were calculated using all pregnancies delivered at a given gestational age as the denominator. However, once a fetus is delivered, it is no longer at risk of intrauterine fetal demise, and use of this denominator has traditionally underestimated the risk of stillbirth. The appropriate denominator is not all deliveries at a given gestational age, but ongoing (undelivered) pregnancies.^{[18, 19, 33]} In one retrospective study of more than 170,000 singleton births, for example, Hilder et al demonstrated that the stillbirth rate increased 6-fold (from 0.35-2.12 per 1,000 pregnancies) when the denominator was changed from all deliveries to ongoing (undelivered) pregnancies.^[16]

Fetal and neonatal risks

Antepartum stillbirths account for more perinatal deaths than either complications of prematurity or sudden infant death syndrome.^[17] Perinatal mortality (defined as stillbirths plus early neonatal deaths) at 42 weeks of gestation is twice that at 40 weeks (4-7 vs 2-3 per 1,000 deliveries, respectively) and increases 4-fold at 43 weeks and 5- to 7-fold at 44 weeks.^{[15, 16, 17]} These data also demonstrate that, when calculated per 1000 ongoing pregnancies, fetal and neonatal mortality rates increase sharply after 40 weeks.^[16]

Cotzias et al calculated the risk of stillbirth in ongoing pregnancies for each gestational age from 35-43 weeks.^[17] The risk of stillbirth was 1 in 926 ongoing pregnancies at 40 weeks’ gestation, 1 in 826 at 41 weeks, 1 in 769 at 42 weeks, and 1 in 633 at 43 weeks. Uteroplacental insufficiency, asphyxia (with and without meconium), intrauterine infection, and anencephaly all contribute to excess perinatal deaths, although postterm anencephaly is essentially nonexistent with modern obstetrical care.^[34]

A number of key morbidities are greater in infants born to postterm pregnancies as well as pregnancies that progress to and beyond 41 0/7 weeks gestation including meconium and meconium aspiration, neonatal acidemia, low Apgar scores, macrosomia, and, in turn, birth injury. For example, since postterm infants are larger than term infants, with a higher incidence of fetal macrosomia (defined as estimated fetal weight ≥ 4,500 g)^[35] , they are, in turn, at greater risk for other complications.^{[36, 37]} Such complications associated with fetal macrosomia include prolonged labor, cephalopelvic disproportion, and shoulder dystocia with resultant risks of orthopedic or neurologic injury.

Approximately 20% of postterm fetuses have fetal dysmaturity (postmaturity) syndrome, which describes infants with characteristics of chronic intrauterine growth restriction from uteroplacental insufficiency.^[38] These pregnancies are at increased risk of umbilical cord compression from oligohydramnios, nonreassuring fetal antepartum or intrapartum assessment, intrauterine passage of meconium, and short-term neonatal complications (such as hypoglycemia, seizures, and respiratory insufficiency).

Meconium aspiration syndrome refers to respiratory compromise with tachypnea, cyanosis, and reduced pulmonary compliance in newborns exposed to meconium in utero and is seen in higher rates in postterm neonates.^[39] Indeed, the 4-fold decrease in the incidence of the meconium aspiration syndrome in the United States from 1990-1998 has been attributed primarily to a reduction in the postterm delivery rate^[21] with very little contribution from conventional interventions designed to protect the lungs from the chemical pneumonitis caused by chronic meconium exposure, such as amnioinfusion^{[40, 41]} or routine nasopharyngeal suctioning of meconium-stained neonates.^[42]

Postterm pregnancy is also an independent risk factor for neonatal encephalopathy^[43] and for death in the first year of life.^{[16, 17]}

While much of the work above has been conducted in postterm pregnancies. Some of the fetal risks such as presence of meconium, increased risk of neonatal acidemia, and even stillbirth have been described as being greater at 41 weeks of gestation and even at 40 weeks of gestation as compared with 39 weeks’ gestation.^{[22, 23]} For example, in one study, the rates of meconium and neonatal acidemia both increased throughout term pregnancies beyond 38 weeks of gestation. In addition to stillbirth being increased prior to 42 weeks of gestation, one study found that the risk of neonatal mortality also increases beyond 41 weeks of gestation.^[44] Thus, 42 weeks does not represent a threshold below which risk is uniformly distributed. Indeed, neonatal morbidity (including meconium aspiration syndrome, birth injury, and neonatal acidemia) appears to be the lowest at around 38 weeks and increase in a continuous fashion thereafter.^[45]

While preterm delivery is a well-established risk factor for cerebral palsy, a recent study suggested that delivery at 42 weeks or later is also associated with increased risk (RR 1.4, 95% CI, 1.2-1.6 when compared with delivery at 40 weeks’ gestation).^[46]

Maternal risks and mode of delivery

The maternal risks of postterm pregnancy are often underappreciated. These include an increase in labor dystocia (9-12% vs 2-7% at term), an increase in severe perineal injury (3^rd and 4^th degree perineal lacerations) related to macrosomia (3.3% vs 2.6% at term) and operative vaginal delivery, and a doubling in the rate of cesarean delivery (14% vs 7% at term).^{[18, 27, 28, 29]} The latter is associated with higher risks of complications such as endometritis, hemorrhage, and thromboembolic disease.^{[28, 47]}

In addition to the medical risks, the emotional impact (anxiety and frustration) of carrying a pregnancy 1-2 weeks beyond the estimated due date should not be underestimated. In a randomized, controlled trial of women at 41 weeks of gestation, women who were induced would desire the same management 74% of the time, whereas women with serial antenatal monitoring only desired the same management 38% of the time.^[48]

Similar to neonatal outcomes, maternal morbidity also increases in term pregnancies prior to 42 weeks of gestation. Such complications as chorioamnionitis, severe perineal lacerations, cesarean delivery rates, postpartum hemorrhage, and endomyometritis all increase progressively after 39 weeks of gestation.^{[23, 30, 31, 32, 21]}

Timing of Delivery

The first decision that must be made when managing an impending postterm pregnancy is whether to deliver. In certain cases (eg, nonreassuring surveillance, oligohydramnios, growth restriction, certain maternal diseases), the decision is straightforward. In these high-risk situations, the time at which the risks of remaining pregnant begin to outweigh the risks of delivery may come at an earlier gestational age (eg, 39 weeks of gestation). However, frequently several options can be considered when determining a course of action in the low-risk pregnancy. The certainty of gestational age, cervical examination findings, estimated fetal weight, patient preference, and past obstetric history must all be considered when mapping a course of action.

The main argument against a policy of routine induction of labor at 41 0/7 to 41 6/7 weeks has been that induction increases the rate of cesarean delivery without decreasing maternal and/or neonatal morbidity. Some of the studies that failed to show a reduction in fetal/neonatal morbidity were diluted by poorly dated pregnancies that were not necessarily postterm. In addition, the potential for increasing the risk for cesarean delivery with a failed induction is far less likely in the era of safe and effective cervical ripening agents.

To date, more than 10 studies have been published of elective induction of labor, many of them at 41 weeks of gestation.^{[49, 34, 50, 51, 52, 53]} The preponderance of the evidence from these studies, including meta-analyses, find that not only is rate of cesarean delivery not increased in women who were randomized to routine induction of labor, but also more cesarean deliveries were performed in the noninduction groups, and the most frequent indication was fetal distress. Even with multiple studies, very few neonatal differences have been demonstrated. However, the reduction in meconium is statistically significant and the rate of neonatal mortality is lower.

In summary, routine induction at 41 weeks of gestation does not increase the cesarean delivery rate and may decrease it without negatively affecting perinatal morbidity or mortality. In fact, both the woman and the neonate benefit from a policy of routine induction of labor in well-dated, low-risk pregnancies at 41 weeks' gestation. Because it is associated with a lower rate of adverse outcomes, including shoulder dystocia and meconium aspiration syndrome, this policy may also prove to be more cost-effective.^[54]

A policy of routine induction at 40 weeks' has few benefits, and there are multiple reasons not to allow a pregnancy to progress beyond 42 weeks.

Prior to 41 weeks of gestation, the evidence becomes more scant with only 3 small, non-US, randomized, controlled trials comparing elective induction of labor to expectant management of pregnancy.^[52] However, elective induction of labor is increasingly being used as a management strategy.^{[55, 56]} While this management may be reasonable in a practice that allows 48 hours or more for the management of the latent phase and the first stage of labor overall, in a setting where induction of labor is called a failure after 18-24 hours, it will likely further increase the cesarean delivery rate

Prevention of Postterm Pregnancy

As noted above, the most decisive way to prevent postterm pregnancy is induction of labor prior to 42 weeks’ gestation. However, since complications rise during 40 and 41 weeks' gestation and both clinicians and patients are concerned about the risks of induction of labor, it is perceivably better for women to go into spontaneous labor at 39 weeks of gestation on their own. Several minimally invasive interventions have been recommended to encourage the onset of labor at term and prevent postterm pregnancy, including membrane stripping, unprotected coitus, and acupuncture.

Stripping or sweeping of the fetal membranes refers to digital separation of the membranes from the wall of the cervix and lower uterine segment. This technique, which likely acts by releasing endogenous prostaglandins from the cervix, requires the cervix to be sufficiently dilated to admit the practitioner’s finger. Although stripping of the membranes may be able to reduce the interval to spontaneous onset of labor, a reduction in operative vaginal delivery, cesarean delivery rates, or maternal or neonatal morbidity has not been consistently proven.^{[57, 58, 59]}

Unprotected sexual intercourse causes uterine contractions through the action of prostaglandins in semen and potentially release of endogenous prostaglandins similar to stripping of the membranes. Indeed, prostaglandins were originally isolated from extract of prostate and seminal vesicle glands, hence their name. Despite some conflicting data, it appears that unprotected coitus may lead to the earlier onset of labor, reduction in postterm pregnancy rates, and less induction of labor.^{[60, 61, 62]}

In a small randomized trial that attempted to address this question, women were randomized to a group advised to have coitus versus a control group that was not. In this study, the women advised to have coitus did so more often (60% vs 40%), the difference in the rate of spontaneous labor was not measurable in this underpowered study.^[63] Similarly, the efficacy of acupuncture for induction of labor cannot be definitively assessed because of the paucity of trial data; this requires further examination.^{[64, 65]}

Cervical Ripening and Intrapartum Management

Once the decision to deliver a patient has been made, the management of the labor induction depends on the clinical setting, and a brief review of cervical ripening agents and potential complications of induction of labor is appropriate. A comprehensive review of all available methods for cervical ripening, indications, contraindications, and dosing is beyond the scope of this article.

As many as 80% of patients who reach 42 weeks' gestation have an unfavorable cervical examination (ie, Bishop Score < 7). Many options are available for cervical ripening. The different preparations, indications, contraindications, and multiple dosing regimes of each require practitioners to familiarize themselves with several of the preparations.

Prostaglandin E2 gel and suppositories for vaginal application were used extensively until the late 1990s when many pharmacies stopped manufacturing them because of the advent of commercially available and less labor-intensive preparations. Currently available chemical preparations include prostaglandin E1 tablets for oral or vaginal use (misoprostol), prostaglandin E2 gel for intracervical application (dinoprostone cervical [Prepidil]), and a prostaglandin E2 vaginal insert (dinoprostone [Cervidil]). Cervidil contains 10 mg of dinoprostone and has a lower constant release of medication than Prepidil. In addition, this vaginal insert device allows for easier removal in the event of uterine hyperstimulation.

Many studies have compared the efficacy and risks of various prostaglandin cervical ripening agents. Rozenburg et al performed a randomized trial comparing intravaginal misoprostol and dinoprostone vaginal insert in pregnancies at high risk of fetal distress. They found that both methods were equally safe for the induction of labor and misoprostol was actually more effective.^[66]

Another method for ripening the cervix is by mechanical dilation. These devices may act by a combination of mechanical forces and by causing release of endogenous prostaglandins. Foley balloon catheters placed in the cervix, extra-amniotic saline infusions, and laminaria have all been studied and have been shown to be effective.

Regardless of what method is chosen for cervical ripening, the practitioner must be aware of the potential hazards surrounding the use of these agents in the patient with a scarred uterus. In addition, the potential for uterine tachysystole and subsequent fetal distress requires that care be taken to avoid using too high a dose or too short a dosing interval in an attempt to get a patient delivered rapidly. Care should also be taken when using combinations of mechanical and pharmacologic methods of cervical ripening.

Once an induction of labor has begun, watch for the major potential complications associated with inductions beyond 41 weeks' gestation and have a plan for dealing with each. Complications include the presence of meconium, macrosomia, and fetal intolerance to labor.

The further the pregnancy progresses beyond 40 weeks, the more likely it is that significant amounts of meconium will be present. This is due to increased uteroplacental insufficiency, which leads to hypoxia in labor and activation of the vagal system. In addition, the presence of a smaller amount of amniotic fluid increases the relative concentration of meconium in utero.

Traditionally, saline amnioinfusion and aggressive nasopharyngeal and oropharyngeal suctioning at the perineum were used to decrease the risk of meconium aspiration syndrome. Recent studies contradict this standard practice. Fraser et al performed a prospective, randomized, multicenter study evaluating the risks and benefits of amnioinfusion for the prevention of meconium aspiration syndrome.^[41] They concluded that in clinical settings, which have peripartum surveillance, amnioinfusion of thick meconium-stained amniotic fluid did not decrease the risk of moderate-to-severe meconium aspiration syndrome, perinatal death, or other serious neonatal disorders compared with expectant management. In addition, other recent studies have shown that deep suctioning of the airway at the perineum does not effectively prevent meconium aspiration syndrome, contrary to popular belief.

Fetal macrosomia can lead to maternal and fetal birth trauma and to arrest of both first- and second-stage labor. Because the risk of macrosomia increases throughout term and postterm pregnancies, one of the most important parts of the delivery plan is being prepared for shoulder dystocia in the event that this unpredictable, anxiety-provoking, and potentially dangerous condition arises. To prepare such an event, experienced clinicians should be present at the delivery, a stool/step next to the delivery bed should be placed to help with suprapubic pressure, and the maneuvers to reduce the shoulder dystocia should be reviewed.

Finally, intrapartum fetal surveillance in an attempt to document fetal intolerance to labor before it leads to acidosis is critical. Whether continuous fetal monitoring or intermittent auscultation is used, interpretation of the results by a well-trained clinician is of paramount importance. If the fetal heart rate tracing is equivocal, fetal scalp stimulation and/or fetal scalp blood sampling may provide the reassurance necessary to justify continuing the induction of labor. If the practitioner cannot find reassurance that the fetus is tolerating labor, cesarean delivery is recommended.

Summary

The management of postterm pregnancies is complicated and fraught with complex issues. The decision of whether to induce labor or to proceed with expectant management with or without antepartum fetal surveillance is not taken lightly. Data support inducing labor at 41 weeks' gestation in an accurately dated, low-risk pregnancy, regardless of cervical examination findings. This strategy, although not without its critics, averts the need for antepartum fetal surveillance and does not increase the cesarean delivery rate; in fact, it may decrease the cesarean delivery rate.

Neovascular Glaucoma | Ricardo Side

Neovascular Glaucoma 

• Author: Jacqueline Freudenthal, MD; Chief Editor: Hampton Roy Sr, MD

Background

Neovascular glaucoma (NVG) is classified as a secondary glaucoma. First documented in 1871, historically, it has been referred to as hemorrhagic glaucoma, thrombotic glaucoma, congestive glaucoma, rubeotic glaucoma, and diabetic hemorrhagic glaucoma. Numerous secondary ocular and systemic diseases that share one common element, retinal ischemia/hypoxia and subsequent release of an angiogenesis factor, cause NVG. This angiogenesis factor causes new blood vessel growth from preexisting vascular structure. Depending on the progression of NVG, it can cause glaucoma either through secondary open-angle or secondary closed-angle mechanisms. This is accomplished through the growth of a fibrovascular membrane over the trabecular meshwork in the anterior chamber angle, resulting in obstruction of the meshwork and/or associated peripheral anterior synechiae.

NVG is a potentially devastating glaucoma, where delayed diagnosis or poor management can result in complete loss of vision or, quite possibly, loss of the globe itself. Early diagnosis of the disease, followed by immediate and aggressive treatment, is imperative. In managing NVG, it is essential to treat both the elevated intraocular pressure (IOP) and the underlying cause of the disease.

Pathophysiology

Retinal ischemia is the most common and important mechanism in most, if not all, cases that result in the anterior segment changes causing NVG. Various predisposing conditions cause retinal hypoxia and, consequently, production of an angiogenesis factor.

Several angiogenesis factors have been identified as potential agents causing ocular neovascularization. Recent studies suggest that vascular endothelial growth factor (VEGF) might play a central role in angiogenesis.

Once released, the angiogenic factor(s) diffuses into the aqueous and the anterior segment and interacts with vascular structures in areas where the greatest aqueous-tissue contact occurs. The resultant growth of new vessels at the pupillary border and iris surface (neovascularization of the iris [NVI]) and over the iris angle (neovascularization of the angle [NVA]) ultimately leads to formation of fibrovascular membranes. The fibrovascular membranes, which may be invisible on gonioscopy, accompany NVA and progressively obstruct the trabecular meshwork. This causes secondary open-angle glaucoma.

As the disease process continues, the fibrovascular membranes along the NVA tend to mature and contract, thereby tenting the iris toward the trabecular meshwork and resulting in peripheral anterior synechiae and progressive synechial angle closure. Elevated IOP is a direct result of this secondary angle-closure glaucoma.

Epidemiology

Frequency

United States

Incidence of NVG is rare.

Mortality/Morbidity

Treatment of NVG is difficult. Maintaining visual acuity in patients with NVG also is difficult.

Age

NVG is more prevalent in elderly patients.

History

A careful and detailed ocular and systemic history is imperative in diagnosing both neovascular glaucoma (NVG) and the underlying problem causing it.

Physical

A complete ocular examination of both eyes, particularly of the posterior segment, will almost certainly provide the etiology of neovascularization. Of the 3 most common causes of NVG, ocular ischemic syndrome presents as a diagnostic dilemma and, thus, deserves special mention.

The typical clinical presentation of NVG is the same regardless of the underlying cause. The typical clinical presentation can be divided into the following 2 stages: the early stage and the advanced stage. These stages generally follow each other in progression, and the early stage is subdivided further into rubeosis iridis and secondary open-angle glaucoma.

Early stage (rubeosis iridis)

• Normal IOP
• Presence of tiny, neovascular, dilated capillary tufts at pupillary margin
• High magnification on slit lamp (to view earliest finding in NVG)
• NVI (irregular, nonradial vessels usually not in the iris stroma)
• NVA (can occur with or without NVI)
• Careful gonioscopy in all eyes at high risk for NVG even without pupillary and iris involvement
• Poorly reactive pupil
• Ectropion uvea

Early stage (secondary open-angle glaucoma)

• Elevated IOP
• NVI continuous with NVA
• Proliferation of neovascular tissue over the angle
• Fibrovascular membranes (develop circumferentially across the angle, blocking the trabecular meshwork)

Advanced stage

In this stage, secondary angle-closure glaucoma is characterized by some or all of the following:

• Acute severe pain, headache, nausea, and/or vomiting
• Photophobia
• Reduced visual acuity (counting fingers to hand motion)
• Elevated IOP (≥ 60 mm Hg)
• Conjunctival injection
• Corneal edema
• Plus/minus hyphema
• Aqueous flare
• Synechial angle closure
• Severe rubeosis
• Distorted, fixed, mid-dilated pupil and ectropion uveae
• Retinal neovascularization and/or hemorrhage
• Optic nerve cupping (possibly)

Ocular ischemic syndrome

Ocular ischemic syndrome occurs in the presence of more than 90% of patients with carotid artery stenosis, but it can occur as a result of aortic arch disease (eg, syphilis, Takayasu arteritis, dissecting aneurysm), in which case the presentation may be bilateral.

Symptoms include a dull periocular/periorbital pain that can be secondary to the ischemia and/or NVG.

Signs include the following:

• Vision can vary from 20/20 to no light perception.
• Midperipheral intraretinal hemorrhage (in contrast to diabetic retinopathy and CRVO where the hemorrhage is mostly situated in the posterior pole)
• IOP can be elevated secondary to NVG, decreased secondary to ciliary body hypoperfusion, or normal as a result of both processes.
• Other signs include corneal decompensation, iritis, iris atrophy, cataract, and spontaneous pulsations of the central retinal artery.
• Intravenous fluorescein angiogram will demonstrate prolonged choroidal filling and increased arteriovenous transit time.

Causes

Relatively frequent causes of NVG include the following:

• Central retinal vein occlusion (CRVO)
• Proliferative diabetic retinopathy
• Carotid artery occlusive disease (CAOD)

Less frequent causes of NVG include the following:

• Branch retinal vein occlusion
• Central retinal artery occlusion (CRAO)
• Intraocular tumor
• Chronic retinal detachment
• Secondary to intraocular lens (uveitis-glaucoma-hyphema [UGH] syndrome)
• Chronic or severe ocular inflammation
• Endophthalmitis
• Sickle cell retinopathy
• Retinopathy of prematurity
• Radiation retinopathy
• Eales disease
• Coats disease
• Carotid-cavernous fistula
• Ocular ischemic syndrome/carotid insufficiency
• Takayasu disease
• Giant cell arteritis
• Anterior segment ischemia (ie, previous extraocular muscle surgery)
• Trauma
• Metastatic intraocular malignant lymphoma^[1]

Imaging Studies

• Intravenous fluorescein angiogram and electroretinography (ERG) to assess retinal ischemia
• B-scan ultrasound
• Optical coherence tomography^[2] - Images observed per grade of neovascular glaucoma

Grades are as follows:

• Grade 1: No modification
• Grade 2: A slightly hyper-reflective linear iris secondary to neovascularization
• Grade 3: A thickened hyper-reflective iridocorneal angle with possible iridocorneal synechiae
• Grade 4: Closed iridocorneal angle associated with iris contraction and uveae ectropion

Medical Care

General principles for treating patients with neovascular glaucoma (NVG) include the following:

• Identifying the underlying etiology is fundamental in the management of NVG.
• CRVO, diabetic retinopathy, CAOD, and CRAO require systemic workup and appropriate intervention to prevent further complications.
• The management of NVG is approached through the following 4 stages that reflect the progression of the disease: prophylactic treatment, early-stage treatment, advanced-stage treatment, and end-stage treatment.

Prophylactic treatment

Most patients are either at high risk for developing NVI/NVG or have early NVI with normal IOP. Prevention of NVG is the single most important aspect in its management.

Reducing the amount of viable retina is known to inhibit and even to reverse new vessel proliferation in the anterior segment. The mainstay in prevention is retinal ablation achieved via panretinal photocoagulation (PRP) or cryophototherapy because of media opacities (ie, corneal edema, cataract, vitreous hemorrhage) or other patient factors. Other treatment options in this stage include goniophotocoagulation.

PRP can be delivered in the following 3 ways: slit lamp delivery system, indirect laser, or endolaser at time of vitrectomy.

The amount of PRP required varies. The Diabetic Retinopathy Study (DRS) guidelines recommend 1200-1500 burns, with a spot size of 500 µm to be applied to the peripheral retina. Many retina specialists recommend 1500-2000 burns, with a spot size of 500-800 µm, using a wide-angle fundus contact lens (eg, Rodenstock). The types of laser include argon, krypton (better with media opacities and retinal hemorrhages), and diode (same utility as krypton laser).

To begin, a 360° peritomy is performed with isolation of the 4 recti muscles. A 2.5-mm retinal cryoprobe is used to create cryoapplication burns just anterior to the equator. Three spots are placed between each rectus muscle. Two additional rows of application are performed posterior to the first so that the third row is just outside the major vascular arcades. In total, 32 cryoapplications are performed under direct visualization. The probe tip remains in contact with the sclera until 70° has been maintained for 5-10 seconds. This procedure causes considerable inflammation, and complications (eg, tractional and exudative retinal detachment, vitreous hemorrhage) can occur.

Goniophotocoagulation, another laser therapy, is performed directly to NVI before the development of NVG. Its role in management of NVG is unclear, and it has not proven to be beneficial in preventing synechial closure of angle or advanced NVG.

All patients should undergo fluorescein angiography to delineate nonischemic CRVO from ischemic CRVO. Virtually no patients with nonischemic CRVO develop NVG. Overall incidence of NVG is 40% for an ischemic CRVO. NVI and NVG can appear from 2 weeks to 2 years. More than 80% of patients with NVI/NVG present within the first 6 months. Of patients with nonischemic CRVO, 15% can convert to ischemic CRVO within 8 months. The strongest predictors of NVI/NVG following CRVO include extensive retinal capillary nonperfusion of intravenous fluorescein angiography (IVFA), extensive retinal hemorrhages, short duration of occlusion, and male sex. In the Central Retinal Vein Occlusion Study, PRP was indicated for IVFA confirmed ischemic CRVO if development of 2 clock hours of NVI occurred or any NVA was present.^[3] No benefit occurred when prophylactic PRP was performed prior to the development of NVI or NVA when frequent follow-up care was provided.

Prophylactic PRP still is recommended by many retinal specialists before the development of NVI or NVA, especially in case of the following: clear extensive capillary nonperfusion, extensive systemic vascular disease, patient who is monocular, and/or noncompliance or poor follow-up results. Preoperative care is fundamental for all types of cataract surgery, capsulotomy, and vitreous surgery.

For patients with diabetic retinopathy, ensure frequent follow-up care and tight glycemic control. If proliferative diabetic retinopathy exists, then complete PRP is recommended as treatment.

Early-stage treatment

This stage is characterized by the development of a fibrovascular membrane across some or all of the angle, obstructing the trabecular meshwork, and an increase in IOP.

With secondary open-angle glaucoma, treatment is identical to prophylactic treatment and includes PRP (filler PRP if already performed initially), panretinal cryotherapy, and medical therapy.

The most important medical therapy for this stage includes topical atropine 1% to decrease ocular congestion and topical steroids (eg, prednisolone [Pred Forte, Inflamase Forte]) to decrease inflammation. Standard antiglaucoma medications to treat secondary open-angle glaucoma are recommended. Other agents include topical beta-blockers (eg, levobunolol [Betagan], timolol [Timoptic]), topical brimonidine (Alphagan), topical carbonic anhydrase inhibitor (eg, dorzolamide [Trusopt], brinzolamide [Azopt]), and oral carbonic anhydrase inhibitor (eg, acetazolamide [Diamox]). Topical pilocarpine is contraindicated because it may increase inflammation. The role of topical latanoprost (Xalatan) is unclear in the treatment of early NVG.

The successful use of photodynamic therapy with verteporfin directed at the iris and the angle to obliterate neovascularization and to reduce IOP has been reported.

Advanced-stage treatment

This stage is characterized by synechial closure of the angle and secondary angle-closure glaucoma.

PRP is still the initial and most important treatment, both to prevent further NVI/NVA and angle closure and to prepare the eye for surgical intervention (see Surgical Care). Surgical intervention is indicated in eyes with potential for useful vision.

Medical therapy is indicated, with topical atropine and steroids being the most important agents. Antiglaucoma medications, topical beta-blockers, and carbonic anhydrase inhibitors are also recommended. The role of topical brimonidine and latanoprost in advanced disease is unclear. Topical pilocarpine and echothiophate iodide are contraindicated (may cause increased inflammation and hyperemia). Oral glycerol and intravenous mannitol are recommended only if IOP is elevated symptomatically.

Anti-VEGF therapy

Antivascular endothelial growth factor is frequently used for various conditions in which VEGF release is induced in response to retinal ischemia. It is still under study as an adjunct^[4] or alternative treatment for NVG. Anti-VEGFs such as bevacizumab (Avastin), pegaptanib sodium (Macugen), and ranibizumab (Lucentis) block angiogenic factors that promote the formation of new vessels, reversing the neovascularization process. The initial use of anti-VEGF agents for the treatment of retinal neovascularization has been expanded to include other pathology such as neovascular glaucoma.^[5] The quantity of growth factors in the aqueous decrease after intraocular injection of anti-VEGFs, decreasing further progression of angular damage secondary to IOP increments.^[6] However, other investigators have reported a lack of efficacy of intravitreal bevacizumab in the treatment of neovascularization of theiris and iridocorneal anglebut support its use for diabetic retinopathy and central vein occlusion.^[7]

Several studies propose the use of anti-VEGF agents with traditional treatments such as panretinal photocoagulation (PRP), with or without additional surgery and vary in the timing, combination, and place of injection (intracameral or intravitreal, or both simultaneously). The most frequent recommendation by various authors for treatment is the adjunct combination of intravitreal bevacizumab/panretinal photocoagulation for the treatment of neovascular glaucoma (NVG) instead of PRP alone or as alternative treatment when visibility of the posterior segment is difficult due to opacities of the media (eg, hemorrhage).^[8]

Although intravitreal, and less commonly intracameral, delivery of anti-VEGF agents is preferred for the management of NVG, several authors describe different protocols of treatment according to the stage of disease and the possible underlying cause as standardized guidelines of NVG treatment with anti-VEGFs have not yet been established.

Several reports about the favorable response to intravitreal anti-VEGF agents in NVG have been published. In a review of 26 original papers between 2006 and August 2008, efficacy and safety of the procedure in 127 eyes was analyzed in a series of cases: None had been performed in a clinical randomized controlled assay. The efficacy calculated in the sample was 68.7%, and the recurrence rate was 18.6% at 4.2 months of follow-up. Ophthalmic complications were under 0.78%, and no systemic complications were found.^[9]

Intravitreal bevacizumab is the most frequent anti-VEGF adjunct treatment used for NVG due to the lower cost. Systematic review of the efficacy and safety of intravitreal bevacizumab (IVB) in the treatment of neovascular glaucoma (NVG) establishes bevacizumab is well tolerated, effectively stabilizes INV activity, and controls IOP in patients with INV when used alone and at an early-stage of NVG.^[10]

Randomized clinical trials are now being reported. Intraocular doses described for treatment with bevacizumab are 1 mg/0.05 mL, 1.25 mg/0.05 mL, or 2.5 mg/0.05 mL, according to the stage and recurrence of NVG.

In a case of ocular ischemic syndrome, a single injection of intravitreal bevacizumab (1.25 mg/0.05 mL injection) detained all signs of neovascularization just one day after injection but failed to control IOP.^[11]

Postintravitreal injection of a single dose of bevacizumab (1.25 mg) promotes quick response of pain relief 1 week postinjection;^[12] this safely facilitates further surgical intervention to lower IOP when treating refractory NVG.

End-stage treatment

This stage is characterized by complete angle closure by peripheral anterior synechiae with no remaining useful vision.

The primary goal of treatment in this stage is pain control. Medical therapy includes topical atropine 1% and steroids. If corneal decompensation occurs, use a bandage contact lens. Cyclodestructive procedures are performed if medical therapy fails to provide symptomatic relief. With cyclocryotherapy, the IOP-lowering effect is achieved by destroying secretory ciliary epithelium and/or reducing blood flow to the ciliary body. It is indicated as a last resort only if relief of pain is the main goal. In a large series, 34% of eyes achieved IOP of less than 25 mm Hg; however, 34% of eyes became phthisical and 57% of eyes lost all light perception. Other complications include sympathetic ophthalmia and anterior segment ischemia.

With Nd:YAG laser transscleral cyclophotocoagulation, 2 approaches, contact and noncontact, are used. In the contact approach, one study reported a 40% decrease in IOP to less than 19 mm Hg in eyes with NVG. In the noncontact approach, out of 27 eyes with NVG, only 15% achieved satisfactory IOP control.

The results of diode laser transscleral cyclophotocoagulation are similar to Nd:YAG cyclophotocoagulation.

Direct laser cyclophotocoagulation is performed under direct observation using the argon laser. Two approaches, transpupil or with endoscopy, are used. Its role in NVG management is secondary. Success in controlling IOP is limited (may have less inflammation and pain versus cyclocryotherapy).

Retrobulbar alcohol injection is indicated after all medical and surgical options have been explored and the patient does not want an enucleation. Complications include external ophthalmoplegia and blepharoptosis. Enucleation is indicated only if intractable pain is not relieved by any other treatment modality.

Surgical Care

Surgical care is indicated in patients with remaining useful vision. Preoperative care is fundamental to the postoperative success of any surgical intervention.

• With surgical care, ensure that adequate PRP is completed to reduce vasoproliferative stimulus. Atropine and steroids are indicated to decrease inflammation, and antiglaucoma medication is indicated to decrease IOP. Wait approximately 3-4 weeks to allow the eye to quiet down.
• Surgical modalities include trabeculectomy with or without an antifibrotic agent and valve implant surgery.
• Trabeculectomy with the antifibrotic agents mitomycin-C and 5-fluorouracil (5-FU) is one modality. Trabeculectomy in NVG has a significant failure rate. Using standard trabeculectomy (without antifibrosis), an IOP of less than 25 mm Hg on one medication or less has been reported to occur in 67-100% of patients in 3 studies. Using injections of 5-FU subconjunctivally in the postoperative period, the surgical success has been reported to be 68% over 3 years. Inject 0.1 mL of 5 mg/mL 5-FU subconjunctivally either superiorly above the bleb or inferiorly (just above the lower fornix). Mitomycin-C used intraoperatively has been shown to be more effective than 5-FU in routine trabeculectomies. No significant follow-up studies exist on the use of mitomycin-C with trabeculectomy in NVG.
• A retrospective cohort study from January 1994 to March 2007 of 101 eyes found that the prognostic factors for failure of trabeculectomy with MMC for NVG were younger age and previous vitrectomy in patients with NVG, having a fellow eye with NVG in patients with disease caused by diabetic retinopathy, and persistent proliferative membrane and/or retinal detachment after vitrectomy.^[13]
• Valve implant surgery is another modality and is indicated when trabeculectomy fails or extensive conjunctival scarring exists, thereby preventing a standard filtering procedure. Molteno, Krupin, and Ahmed valve implants commonly are used. One large series using the Krupin valve reported 79% of eyes with NVG had a 67% success rate in controlling IOP (< 24 mm Hg) with mean follow-up of 23 months. Long-term results are mixed. Using the Molteno implant, 60 eyes with NVG achieved a satisfactory IOP (< 21 mm Hg) and maintenance of visual acuity over 5 years of only 10.3%. If combined with the need for vitrectomy, consideration of pars plana tube-shunt insertion may reduce anterior segment complications.
• Complications include postoperative hypotony with associated complications, blockage of internal fistula, blockage of external filtration site (fibrosis of the filtering bleb), and corneal endothelial loss.
• Adjunct anti-VEGF therapy
• In a short case series, the use of intracamerular bevacizumab prior to trabeculectomy with MMC improved NVG.^[14]
• The postoperative inhibition of angiogenesis after glaucoma surgery has also been described. Possible routes of bevacizumab administration are subconjunctival application during trabeculectomy, postoperative needling, or intravitreal injection during a filtrating procedure.^[15]
• Bevacizumab has also been injected into the silicone oil in eyes with neovascular glaucoma after vitrectomy for advanced diabetic retinopathy with favorable outcomes.^[16]
• Intravitreal bevacizumab is useful to safely and effectively implant an aqueous shunting tube in eyes with severe NVG and intractable IOP, in addition to postoperative panretinal photocoagulation that reduces the recurrence of neovascular activity improving the success rate of aqueous shunting surgery.^[17]

·         Medication Summary

·         The most important medications include a regimen of topical steroids and atropine. Antiglaucoma medications include both topical and oral agents.

·         Cycloplegic drugs

·         Class Summary

·         Paralyze ciliary muscle, preventing ciliary muscle spasm; provide pain relief; and decrease ocular congestion.

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·         Atropine ophthalmic (Isopto, Atropair, Atropisol)

·          

·         Acts at parasympathetic sites in smooth muscle to block response of sphincter muscle of iris and muscle of ciliary body to acetylcholine, causing mydriasis and cycloplegia.

·         Steroidal anti-inflammatory

·         Class Summary

·         Decreases ocular inflammation.

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·         Prednisolone acetate 1% (Pred Forte)

·          

·         Treats acute inflammations following eye surgery or other types of insults to eye. Decreases inflammation and corneal neovascularization. Suppresses migration of polymorphonuclear leukocytes and reverses increased capillary permeability. In cases of bacterial infections, concomitant use of anti-infective agents is mandatory; if signs and symptoms do not improve after 2 days, reevaluate patient. Dosing may be reduced, but advise patients not to discontinue therapy prematurely.

·         Alpha2-adrenergic agonists

·         Class Summary

·         Decrease IOP by reducing aqueous humor production.

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·         Brimonidine (Alphagan)

·          

·         Selective alpha2-receptor that reduces aqueous humor formation.

·         Carbonic anhydrase inhibitors

·         Class Summary

·         By slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport, it may inhibit carbonic anhydrase in the ciliary processes of the eye. This effect decreases aqueous humor secretion, reducing IOP.

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·         Dorzolamide hydrochloride 2.0% (Trusopt)

·          

·         Used concomitantly with other topical ophthalmic drug products to lower IOP. If more than one ophthalmic drug is being used, administer drugs at least 10 min apart. Reversibly inhibits carbonic anhydrase, reducing hydrogen ion secretion at renal tubule and increasing renal excretion of sodium, potassium bicarbonate, and water to decrease production of aqueous humor.

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·         Acetazolamide (Diamox, Diamox Sequels)

·          

·         Inhibits enzyme carbonic anhydrase, reducing rate of aqueous humor formation, which, in turn, reduces IOP. Used for adjunctive treatment of chronic simple (open-angle) glaucoma and secondary glaucoma and preoperatively in acute angle-closure glaucoma when delay of surgery desired to lower IOP.

·         Prostaglandins

·         Class Summary

·         Used to reduce IOP in patients who are intolerant or resistant to other IOP-lowering medications. They are contraindicated in glaucomas in which inflammation is a prominent ocular finding.

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·         Bimatoprost (Lumigan)

·          

·         Prostaglandin analog that selectively mimics effects of naturally occurring substances, prostamides. Exact mechanism of action unknown but believed to reduce IOP by increasing outflow of aqueous humor through trabecular meshwork and uveoscleral routes.

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·         Travoprost ophthalmic solution (Travatan)

·          

·         Prostaglandin F2-alpha analog and selective FP prostanoid receptor agonist. Exact mechanism of action unknown but believed to reduce IOP by increasing uveoscleral outflow.

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·         Unoprostone ophthalmic solution (Rescula)

·          

·         Prostaglandin F2-alpha analog and selective FP prostanoid receptor agonist. Exact mechanism of action unknown but believed to reduce IOP by increasing uveoscleral outflow and facilitating conventional outflow through the trabecular meshwork

·         Beta-adrenergic blockers

·         Class Summary

·         The exact mechanism of ocular antihypertensive action is not established, but it appears to be a reduction of aqueous humor production.

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·         Levobunolol (AKBeta, Betagan)

·          

·         Nonselective beta-adrenergic blocking agent that lowers IOP by reducing aqueous humor production.

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·         Timolol maleate 0.5% (Timoptic, Timoptic XE, Blocadren)

·          

·         May reduce elevated and normal IOP, with or without glaucoma, by reducing production of aqueous humor.

Further Outpatient Care

• Ophthalmologists should provide long-term follow-up care for patients with neovascular glaucoma (NVG), closely monitoring for any worsening in the patient's condition.
• Intensity of follow-up care is related to the conditions predisposing the patient to the development of NVG (ie, CRVO, diabetic retinopathy).

Complications

• Complications include uncontrolled glaucoma, hyphema, and loss of vision.

Prognosis

• Generally, NVG carries a very guarded prognosis. Prognosis is highly dependent on the following 2 factors: prevention and treatment of NVG early in its course and the underlying disease process.

Patient Education

• Patients with NVG must be educated about the disease process and its poor prognosis.
• For excellent patient education resources visit eMedicineHealth's Eye and Vision Center and Diabetes Center. Also, see eMedicineHealth's patient education articles Glaucoma Overview, Glaucoma FAQs, Glaucoma Medications, and Diabetic Eye Disease.