Ординатура / Офтальмология / Учебные материалы / Retinal Vascular Disease Joussen Springer

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26 III

Table 26.2.2. Maternal and fetal complications of severe preeclampsia. (Adapted from [46])

I. Fetal complications

Preterm delivery (15 – 67 %)

Intrauterine growth restriction (10 – 25 %)

Perinatal death (1 – 2 %)

Hypoxia-induced CNS injury (< 1 %)

Long-term complications of preterm birth

II. Maternal complications

Disseminated intravascular coagulopathy (DIC)/HELLP (10 – 20 %)

Pulmonary edema/aspiration (2 – 5 %) Acute renal failure (1 – 5 %)

Abruptio placentae (1 – 4 %) Liver failure or hemorrhage (1 %) Eclampsia (< 1 %)

Stroke (rare)

Death (rare)

Long-term cardiovascular complications

vascular coagulopathy (DIC), pulmonary edema, left ventricular failure, acute renal failure, liver failure, placental abruption, and aortic dissection. In addition, recent studies have suggested an increased risk of coronary artery disease and cerebrovascular disease later in life for women with a history of PIH [25, 53].

Fetal complications of PIH include preterm delivery (with its associated short-term and long-term complications), intrauterine growth restriction, hypoxia-related CNS injury, and perinatal death.

26.2.4Ocular and Neurologic Manifestations

Essentials

PIH affects both the retinal and choroidal circulation

Retinal vascular manifestations of PIH III 26 resemble hypertensive retinopathy, and are

rarely associated with permanent loss of vision

Serous retinal detachments are a reflection of choroidal ischemia, and may occur in up to 1/3 of patients with severe preeclampsia or eclampsia.

Cerebral vasospasm and edema in the occipital lobes can lead to transient cortical blindness in PIH.

Visual disturbances are common in PIH, and have long been associated with the disease. The most common complaint is blurred vision. Other less frequent symptoms include scotomata, diplopia, photopsia, amaurosis, and chromatopsia. Visual symptoms are present in up to 25 % of patients with preeclampsia, and 50 % of patients with eclampsia [12].

The most common ocular finding associated with PIH is a retinopathy resembling hypertensive retinopathy (Fig. 26.2.1a). The earliest changes are focal constriction or spasm of the retinal arterioles. As the

condition progresses, this narrowing may become generalized. In early studies of preeclampsia, the incidence of focal retinal arteriolar abnormalities was reported to be anywhere from 30 % to 100 %. More recent studies suggest a much lower incidence of 5 % in preeclampsia and 30 % in pregnant women with chronic hypertension [42, 43]. The lower inci-

26 III dence is most likely attributable to improvements in the treatment of PIH, leading to a reduced incidence of more severe systemic disease. Vision loss secondary to retinal arteriolar spasm in PIH is rare, but has been reported [15, 47].

Other retinal manifestations of systemic hypertension, such as cotton-wool spots, intraretinal hemorrhages, retinal edema and optic nerve edema are usually seen only in more severe cases of PIH, and their presence in a patient with only mild preeclampsia should immediately raise suspicion for other coexisting systemic conditions, such as chronic hypertension and diabetes [26].

Less commonly in PIH, the retinal vascular system may be affected by vascular occlusive events. A Purtscher’s-like retinopathy developing after childbirth has been reported in patients with preeclampsia, and may be caused by complement-activated leukoembolus formation [4, 45]. Central retinal vein occlusion occurring 10 days post-partum in a patient with HELLP syndrome has been reported [18]. Transient unilateral vision loss, presumably from a thrombotic event, has also been reported in two patients with preeclampsia and antiphospholipid antibodies [6]. Finally, bilateral peripheral retinal neovascularization has been seen following PIH, which was attributed to microthrombus formation [5].

Choroidal involvement in PIH is marked by yel- low-white focal lesions at the level of the retinal pigment epithelium (RPE), serous retinal detachment, and Elschnig’s spots (small, isolated areas of hyperpigmentation with surrounding yellow or red halos). The serous detachments are often bullous, and usually bilateral (Fig. 26.2.1A). Although earlier studies estimated the incidence of serous retinal detachment at 1 % in severe preeclampsia and 10 % in eclampsia, a recent study by Saito and Tano [41] suggests a much higher incidence. The authors examined 71 women with severe preeclampsia or eclampsia within a few days of admission to the hospital, and found an incidence of serous retinal detachment of 32 %. Because 72 % of these detachments resolved within one week of initial examination, the authors suggested that prior studies underestimated the true incidence of retinal detachment, because patients were not examined within this short window of time.

Fluorescein angiography indicates that the choroidal manifestations of PIH are most likely a result

of choroidal ischemia and infarction [31, 41]. Delayed choroidal filling is seen in areas corresponding to the yellow-white RPE lesions, the shape and distribution of which reflect the lobular pattern of the choriocapillaris (Fig. 26.2.1B). Subretinal leakage of fluorescein is also observed. The limited histopathologic evidence suggests that Elschnig’s spots represent cicatricial change from infarction of the RPE and choriocapillaris [27].

Involvement of the occiptal cortex in PIH can lead to transient cortical blindness. Complete recovery of vision usually occurs within one week, even in cases with complete loss of light perception. Computed tomography (CT) imaging typically shows multiple low density, nonenhancing lesions in the occipital lobe, which are felt to represent areas of decreased perfusion secondary to arterial vasospasm or cerebral edema. Magnetic resonance (MR) imaging will show focal areas of increased signal. Transient diplopia from ischemic cranial neuropathies have also been reported [36].

26.2.5 Pathophysiology and Epidemiology

Essentials

PIH is a multisystem disorder of unknown etiology

The angiogenic factors VEGF and PlGF may play important roles in disease pathogenesis through their effects on vascular endothelial function

PIH-associated retinopathy results from the compensatory responses of the retinal and choroidal vasculature to elevated blood pressure, and ultimately, the failure of those compensatory systems.

PIH is a multisystem disorder of unknown etiology. At the simplest level, preeclampsia is a maternal response to placentation. A final common pathway in disease pathogenesis appears to be systemic endothelial dysfunction, manifested as increased vascular permeability, platelet aggregation, enhanced vascular sensitivity to angiotensin II and norepinephrine, and decreased production and activity of the vasodilators prostacyclin and nitric oxide [46].

Recent studies have suggested that soluble angiogenic factors may play an important role in the pathogenesis of endothelial cell dysfunction in PIH. In normal pregnancy, vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are released by uterine natural killer cells, resulting in significant increases in the maternal circulating levels of these factors. Increased levels of VEGF and

Although fluorescein and ICG are probably safe for use during pregnancy, confirmatory epidemiologic evidence is lacking. Therefore, their use should be limited to conditions in which the results would affect treatment decisions. A careful discussion with

26 III the patient about the risks, benefits and alternatives is necessary and informed consent should be obtained.

PIH has a generally benign natural history. A complete resolution of visual symptoms and abnormal fundus findings soon after delivery of the fetus occurs in the vast majority of patients. For this reason, extensive diagnostic evaluation beyond simple documentation of the funduscopic findings by chart drawing or fundus photography is probably not warranted.

There are no data in the literature to suggest that fluorescein angiography poses a significant risk to the fetus: increased rates of birth defects or fetal loss have not been observed in animal studies or reported in humans. However, sodium fluorescein does cross the placenta and enter the fetus, and no large epidemiologic studies have been published to confirm the safety of fluorescein angiography during pregnancy. In a survey of 424 retinal specialists, Halperin et al. [23] found that 77 % had never knowingly performed fluorescein angiography on a pregnant woman. As part of this study, the authors were able to gather outcome data from 116 pregnant women on whom fluorescein angiography had been performed. Four fetal or neonatal deaths were reported, 2 of which could clearly be attributed to other causes. Birth anomalies were reported in 2 children (undescended testicle and syndactyly). The authors concluded that there was no significantly increased risk of birth anomaly or fetal demise associated with the use of fluorescein angiography during pregnancy. Given the limited data, however, fluorescein angiography during pregnancy should probably be reserved for those conditions in which the results would affect treatment decisions, such as juxtafoveal choroidal neovascularization.

Evidence supporting the safety of indocyanine green (ICG) angiography during pregnancy is stronger. ICG does not cross the placenta at any measurable level, and ICG has been used extensively for non-ophthalmologic applications on pregnant women (in the study of hepatic blood flow and cardiac output), without any reported adverse maternal or fetal effects. Nonetheless, there remains widespread hesitation by retinal specialists to perform ICG angiography on pregnant patients. Of 520 retinal specialists surveyed by Fineman et al. [14], only 24 % felt ICG was safe to use during pregnancy. Of the remain-

ing respondents, 15 % felt ICG was unsafe, and 60 % were unsure.

It should be noted that both fluorescein and ICG are classified by the Food and Drug Administration as pregnancy category C, which means that safety during pregnancy is uncertain, due to insufficient data.

26.2.7 Treatment

Essentials

Specific treatment for the ocular manifestations of PIH is not generally indicated. Systemic treatment of PIH consists of antihypertensive therapy, magnesium sulfate, and early delivery of the fetus when indicated

As permanent visual loss is rare in PIH, specific treatments for the ocular manifestations of PIH are not generally indicated. Rather, treatment is directed at the underlying systemic disease, and patients with PIH should be under the care of a qualified obstetrician. Perhaps the most important role of the ophthalmologist is to recognize the ocular manifestations of PIH, so that the rare undiagnosed patient can be referred in a timely manner to the appropriate specialists. More commonly, the ophthalmologist is consulted to evaluate the vision complaints of a patient with a preexisting diagnosis of PIH. In these cases, the primary role is to provide reassurance to the patient that the vision will likely return to normal after delivery of the fetus.

The cure for PIH (with rare exceptions – [32]) is delivery of the fetus. In severe preeclampsia, preterm delivery by induction of labor or C-section must be considered. The obstetrician must weigh the risks to the health of the mother and fetus of continuing the pregnancy, against the risk to the fetus from the complications of prematurity. In general, severe preeclampsia is an indication for preterm induction of labor once the pregnancy reaches 34 weeks of gestation. Those with mild preeclampsia are induced at 38 weeks [46].

In the past, the degree of retinal vascular changes associated with preeclampsia was felt to be predictive of fetal mortality [17, 40] and was sometimes used as an indication for early delivery of the fetus [12]. In a prospective, controlled and masked study of 31 patients with preeclampsia and 25 control patients, Jaffe and Schatz [26] found that it was indeed possible to distinguish patients with severe preeclampsia from those with no disease or mild disease based solely on abnormal fundoscopic findings, which consisted of focal arteriolar constrictions, and

a reduction in the arteriole-to-venule ratio. Because the diagnosis of severe preeclampsia was already clinically obvious in these patients, however, the authors argued that the role of the ophthalmologist in guiding the management of preeclampsia is limited. Moreover, the study found that it was not possible reliably to distinguish patients with mild preeclampsia from those without disease. Therefore, the role of the ophthalmologist in routine screening for the disease is likewise limited. The authors have recommended that obstetricians measure Snellen acuity or perform Amsler grid testing as basic screening tests to identify those patients that need an ophthalmology consultation. Of course, the sensitivity and specificity of these screening measures is not clear, so perhaps the best advice is that visually symptomatic patients be examined and that patients who would have management altered if certain eye findings were seen be referred as well.

The mainstay of treatment for PIH is antihypertensive therapy. Because mild to moderate gestational hypertension has no clear effect on maternal or fetal outcomes, and because antihypertensive treatment does not reduce the risk of progression to preeclampsia, treatment is not generally indicated for mild to moderate gestational hypertension [1]. Treatment of mild gestational hypertension may also increase the risk for a small-for-gestational-age baby [51].

Severe gestational hypertension is associated with maternal and fetal morbidities that more closely resemble severe preeclampsia than mild preeclampsia. Therefore, it is recommended that both patients with severe gestational hypertension and patients with severe preeclampsia be admitted to the hospital for bedrest, monitoring and antihypertensive therapy (Table 26.2.4). Parenteral hydralazine, labetalol, sodium nitroprusside and short-acting oral nifedipine are the most common first-line medications for management of acute hypertension in pregnancy. For chronic management of PIH, oral methyldopa, labetalol, nifedipine, and thiazide diuretics are the drugs of choice. Furosemide, angiotensin-convert- ing enzyme inhibitors (ACE inhibitors), and angiotensin receptor blockers (ARBs) are all contraindicated during pregnancy, but may be used in the postpartum period. Furosemide has been associated with hypospadias. ACE inhibitors and ARBs are associated with numerous fetal complications, including intrauterine demise, renal dysgenesis, oligohydramnios, pulmonary hypoplasia, fetal growth restriction and neonatal renal dysfunction [46].

Parenteral magnesium sulfate is used for the treatment of eclamptic seizures, as it has been demonstrated to be superior to both phenytoin and diazepam in preventing recurrent eclamptic seizures, and in preventing maternal and fetal death [49]. Patients

Table 26.2.4. Indications for antihypertensive therapy in pregnancy. (Adapted from [10])

With thrombocytopenia or congestive heart failure:

SBP 160 mm Hg or

DBP 105 mm Hg or

MAP 125 mm Hg

II. Postpartum

Persistent elevations for at least 1 h:

SBP 160 mm Hg or

DBP 105 mm Hg or

MAP 125 mm Hg

on magnesium sulfate need to be monitored closely for signs of magnesium toxicity, which include hyporeflexia, decreased mental status, slurred speech, muscular paralysis, respiratory distress and cardiac arrest.

Numerous studies have been conducted over the years to evaluate various medications and dietary modifications that might reduce the rate and/or severity of preeclampsia. The data are insufficient to recommend anything except low dose aspirin, which may provide modest reductions in the risks of preeclampsia and fetal death [28]; and calcium supplementation, which may reduce the risk for those women at high risk for preeclampsia, and for those with low dietary calcium intake [3].

26.2.8 Clinical Course and Outcomes

Essentials

The visual symptoms and abnormal fundus findings associated with PIH generally resolve completely after delivery of the fetus

Permanent loss of vision related to PIH is rare, but has been reported

Most women with ocular manifestations of PIH make a full recovery without permanent loss of vision or other ocular sequelae of the disease. Focal and generalized arteriolar narrowing, the most common ocular manifestations of the disease, generally

resolve after delivery of the fetus and normalization of blood pressure.

Saito and Tano [41] published a relatively large case series of 31 patients with severe preeclampsia or eclampsia, who were determined to have abnormalities in the choroidal circulation, based on the presence of yellowish opaque RPE lesions (47 eyes), and/

26 III or serous retinal detachments (40 eyes). Of the retinal detachments, 72 % had completely resolved within 1 week of initial examination, and 97.5 % within 3 weeks. The RPE lesions completely resolved without scarring within 3 weeks of initial examination in 83 % of involved eyes. Persistent RPE mottling was observed in 8.5 % of involved eyes, and localized chorioretinal atrophy was observed in 8.5 % of eyes. None of the women in the study experienced any permanent measurable loss of vision. It should be noted that persistent RPE lesions from prior episodes of preeclampsia (Elschnig’s spots) may be mistaken for an inherited macular dystrophy [16].

Permanent vision loss secondary to PIH has been observed in rare cases. One cause is optic atrophy secondary to retinal arterial occlusion or direct ischemia to the optic nerve [8, 15, 32, 47]. Vision loss secondary to a Purtscher’s-like retinopathy developing after childbirth has also been reported in at least five patients with preeclampsia or gestational hypertension [4, 45]. This condition has also been seen in patients without preeclampsia, but with an underlying coagulopathy [19, 34].

In patients with cortical vision loss, full visual recovery is likewise the norm. Cunningham et al. [11] published a retrospective case series covering a 14-year period at Parkland Hospital, in which 15 patients with preeclampsia who developed associated cortical blindness were identified. In these patients, blindness persisted anywhere from 4 h to 8 days, but subsequently resolved in all. Persistent electroencephalographic abnormalities, however, have been measured in patients who have nonetheless experienced a full recovery of vision after cortical vision loss in PIH [20]. This suggests that persistent subclinical cortical dysfunction may occur.

Although abnormal fundoscopic, fluorescein angiographic and ICG angiographic findings usually resolve after delivery of the fetus and normalization of blood pressure, mild multifocal electroretinographic abnormalities may persist in areas with previous choroidal ischemia, despite otherwise normal measures of visual function [29]. This suggests that some degree of permanent damage to the retina can result from severe cases of PIH. The functional significance of this damage appears to be insignificant.

References

1.Abalos E, Duley L, Steyn DW, Henderson-Smart DJ (2001) Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 1:CD002252

2.American College of Obstetricians and Gynecologists (1996) Hypertension in Pregnancy. ACOG Tech Bull 219

3.Atallah AN, Hofmeyr GJ, Duley L (2002) Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 1:CD001059

4.Blodi BA, Johnson MW, Gass JD et al (1990) Purtscher’s-like retinopathy after childbirth. Ophthalmology 97:1654 – 1659

5.Brancato R, Menchini U, Bandell F (1987) Proliferative retinopathy and toxemia of pregnancy. Ann Ophthalmol 19: 182 – 183

6.Branch DW, Andres R, Kigre KB et al (1989) The association of antiphospholipid antibodies with severe preeclampsia. Obstet Gynecol 73:541 – 545

7.Brown MA, Lindheimer MD, de Sweit M et al (2001) The classification and diagnosis of the hypertensive disorders in pregnancy: a statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 20:IX–XIV

8.Carpenter F, Kave HL, Plotkin D (1953) The development of total blindness as a complication of pregnancy. Am J Obstet Gynecol 66:641 – 647

9.Chaiworapongsa T, Romero R, Espinoza J et al (2004) Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Am J Obstet Gynecol 190:1541 – 1547

10.Coppage KH, Sibai BM (2005) Treatment of hypertensive complications in pregnancy. Curr Pharm Design 11:749 – 757

11.Cunningham FG, Fernandez CO, Hernandez C (1995) Blindness associated with preeclampsia and eclampsia. Am J Obstet Gynecol 172:1291 – 1298

12.Dieckmann WJ (1952) The toxemias of pregnancy, 2nd edn. Mosby, St Louis

13.Einarsson JI, Sangi-Haghpeykar H, Gardner MO (2003) Sperm exposure and development of preeclampsia. Am J Obstet Gynecol 188:1241 – 1243

14.Fineman MS, Maguire JI, Fineman SW, Benson WE (2001) Safety of indocyanine green angiography during pregnancy: a survey of the retina, macula and vitreous societies. Am J Ophthalmol 119:353 – 355

15.Gandhi J, Ghosh S, Pillari VT (1978) Blindness and retinal changes with preeclamptic toxemia. NY State J Med 78: 1930 – 1932

16.Gass JDM, Pautler SE (1985) Toxemia of pregnancy pigment epitheliopathy masquerading as a heredomacular dystrophy. Trans Am Ophthalmol Soc 83:114 – 130

17.Gibson GG (1938) The clinical significance of the retinal changes in the hypertensive toxemias of pregnancy. Am J Ophthalmol 21:22

18.Gonzalvo FJ, Abecia E, Pinilla I et al (2000) Central retinal vein occlusion and HELLP syndrome. Acta Ophthalmol Scand 78:596 – 598

19.Greven CM, Weaver RG, Owen J, Slusher MM (1991) Protein S deficiency and bilateral branch retinal artery occlusion. Ophthalmology 98:33 – 34

20.Grimes DA, Ekbladh LE, McCartney WH (1980) Cortical blindness in preeclampsia. Int J Gynecol Obstet 17:601 – 603

21.Haig D (1993) Genetic conflicts in human pregnancy. Q Rev Biol 68:495 – 532

22.Hall G, Noble W, Lindow S, Masson E (2001) Long-term sexual co-habitation offers no protection from hypertensive disease of pregnancy. Hum Reprod 16:349 – 352

23.Halperin LS, Olk RJ, Soubrane G, Coscas G (1990) Safety of fluorescein angiography during pregnancy. Am J Ophthalmol 110:323 – 325

24.Harlow FH, Brown MA (2001) The diversity of diagnosis of preeclampsia. Hypertens Pregnancy 20:57 – 67

25.Haukkamaa L, Salminen M, Laivuori H et al (2004) Risk for subsequent coronary artery disease after preeclampsia. Am J Cardiol 93:805 – 808

26.Jaffe G, Schatz H (1987) Ocular manifestations of preeclampsia. Am J Ophthalmol 103:309 – 315

27.Klein BA (1968) Ischemic infarcts of the choroid (Elschnig spots). A cause of retinal separation in hypertensive disease with renal insufficiency. A clinical and histopathologic study. Am J Ophthalmol 66:1069 – 1074

28.Knight M, Duley L, Henderson-Smart DJ, King JF (2002) Antiplatelet agents for preventing and treating pre-eclamp- sia. Cochrane Database Syst Rev 2:CD000492

29.Kwok AK, Li JZ, Lai TY et al (2001) Multifocal electroretinographic and angiographic changes in pre-eclampsia. Br J Ophthalmol 85:111 – 112

30.Levine RJ, Maynard SE, Qian C et al (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672 – 683

31.Mabie WC, Ober RR (1980) Fluorescein angiography in toxaemia of pregnancy. Br J Ophthalmol 64:666 – 671

32.Matthys LA, Coppage KH, Lambers DS et al (2004) Delayed postpartum preeclampsia: an experience of 151 cases. Am J Obstet Gynecol 190:1464 – 1466

33.Maynard SE, Min JY, Merchan J et al (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. Clin Invest 111:649 – 658

34.Nelson ME, Talbot JF, Preston FE (1989) Recurrent multi- ple-branch retinal arteriolar occlusions in a patient with protein C deficiency. Graefes Arch Clin Exp Ophthalmol 227:443 – 447

35.Ness RB, Markovic, Harger G, Day R (2004) Barrier methods, length of preconception intercourse, and preeclampsia. Hypertens Pregnancy 23:227 – 235

36.Ober RR (2001) Pregnancy-induced Hypertension (pre- eclampsia-eclampsia). In: Ryan SJ (ed) Retina, 3rd edn, vol 2. Mosby, St Louis, pp 1393 – 1403

37.Oudejans CB, Mulders J, Lachmeijer AM et al (2004) The parent-of-origin effect of 10q22 in pre-eclamptic females coincides with two regions clustered for genes with down-

regulated expression in androgenetic placentas. Mol Hum Reprod 10: 589 – 598

38.Purkerson ML and Vekerdy L (1999) A history of eclampsia, toxemia and the kidney in pregnancy. Am J Nephrol 19: 313 – 319

39.Report of the National High Blood Pressure Education Program (2000) Working group report on high blood pressure

in pregnancy. Am J Obstet Gynecol 183:S1–S22

40. Sadowsky A, Serr DM, Landau J (1956) Retinal changes and III 26 fetal prognosis in the toxemias of pregnancy. Obstet Gyne-

col 8:426 – 431

41.Saito Y, Tano Y (1998) Retinal pigment epithelial lesions associated with choroidal ischemia in preeclampsia. Retina 18:103 – 108

42.Saito Y, Omoto T, Kidoguchi K et al (1990) The relationship between ophthalmoscopic changes and classification of toxemia in pregnancy. Acta Soc Ophthalmol Jpn 94:870 – 874

43.Schiotz I (1921) Über retinitis gravidarum et amaurosis eclamptica. Klin Mbl Augenheilk 67:1 – 136

44.Schreyer P, Tzadok J, Sherman DJ et al (1990) Fluorescein angiography in hypertensive pregnancies. Int J Gynecol Obstet 34:127 – 132

45.Shaikh S, Ruby AJ, Piotrowski M (2003) Preeclampsia-relat- ed chorioretinopathy with Purtscher’s-like findings and macular ischemia. Retina 23:247 – 250

46.Sibai B, Kupferminc M (2005) Pre-eclampsia. Lancet 365: 785 – 799

47.Somerville-Large LB (1950) A case of permanent blindness due to toxemia of pregnancy. Br J Ophthalmol 34:431 – 434

48.Sunness JS, Santos A (1999) Retinal disease in pregnancy. In: Guyer DR, Yannijzzi LA, Chan GS, Shields JA, Green WR (eds) Retina-vitreous-macula. Saunders, Philadelphia, pp 498 – 513

49.The Eclampsia Trial Collaborative Group (1995) Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 345:1455 – 1463

50.Trupin LS, Simon LP, Eskenazi B (1996) Change in paternity: a risk factor for preeclampsia in multiparas. Epidemiology 7:240 – 244

51.Von Dadelszen P, Magee LA (2000) Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet 355:87 – 92

52.Von Graefe A (1855) Über eine Krebsablagerung im Innern des Auges, deren Ursprung Sitz zwischen Sclera und Choroidera war. Albrecht von Graefes Arch Klin Ophthalmol 2:214 – 224

53.Wilson BJ, Watson MS, Prescott GJ et al (2003) Hypertensive diseases of pregnancy and risk of hypertension and stroke later in life: results from cohort study. BMJ 326:1 – 7

Core Messages

Complications of sickle cell disease result from vaso-occlusive disease

Packed sickle RBCs precede platelet fibrin thrombi and leukocytes

Activation of endothelial cells is seen along with subsequent expression of adhesion molecules such as ICAM-1, VCAM-1, E-selectin, and P-selectin

Inflammatory cytokines (TNF-, IL1-) are involved

Black sunbursts represent hyperplastic retinal pigment epithelium (RPE)

Vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) are involved in proliferative disease

27.1.1 Introduction

Sickle cell hemoglobinopathies all share the common feature of an abnormal globin chain, which leads to sickling of erythrocytes and obstruction of the microcirculation. Sickle vaso-occlusive events are insidious and affect virtually every vascular bed in the eye, often with visually devastating consequences. Vaso-occlusion most profoundly affects the retina, the light-sensitive tissue that lines the inside wall of the posterior aspect of the eye, because it is exquisitely sensitive to deprivation of oxygen. Even temporary vaso-occlusion, if longer than about 1.5 – 2 h, can result in permanent infarction of the retina. Most, if not all, of the complications of sickle cell disease in retina originate from the vasoocclusive processes. The pathological changes can be divided into nonproliferative and proliferative events.

27.1.2 Nonproliferative Changes

27.1.2.1Retinal Vessel Occlusions and Remodeling

Retinal occlusive events occur first and most often in the peripheral retina and only rarely cause loss of peripheral or side vision because of the extremely far peripheral location of the obstructed vessels, where the retina has little important function. Occlusions of the peripheral retinal microvasculature have been documented in HbSS subjects as early as 20 months of age (Fig. 27.1.1) [29]. Although retinal capillaries

and precapillary arterioles appear to be the initial site of occlusion early in life, larger-caliber vessels eventually become nonperfused with age (Fig. 27.1.2). The sites of occlusion in larger vessels are often at arteriovenous crossings as in Fig. 27.1.3. We have documented and examined sites of occlusion in retina by incubating the retinas for adenosine diphosphatase (ADPase) activity and then flatembedding them in the transparent polymer glycol methacrylate for serial sectioning. ADPase activity is only present in viable blood vessels, so sites of occlusion can be identified en bloc and sectioned (Figs. 27.1.1 – 27.1.4). Where vessels and ADPase activity end abruptly, sometimes hairpin-shaped loops will form. With repeated vaso-occlusive events in the peripheral retina over a prolonged time, centripetal recession of the most peripheral vascular arcades occurs away from the ora serrata and toward the equator. The end result is a totally ischemic peripheral retina (Fig. 27.1.2) [14].

Hairpin loops are short at sites of capillary and arteriolar occlusion (Fig. 27.1.1) and longer where major vessels end (Fig. 27.1.2). One channel of the loop is the original blood vessel lumen that became occluded and the second channel is a recanalization of the original wall of the occluded segment (Fig. 27.1.4). The recanalization appears to progress until the first viable branch of the original blood vessel is encountered and this branch then becomes the efferent channel or path for blood flow. Flow through the 360° turns must be awkward and one would imagine that hairpin loops might become subsequent sites of occlusion.