From the Retina-Vitreous Service (DS, BR, TPV, AR), Aravind Eye Hospital & Postgraduate Institute of Ophthalmology; and Lions Aravind Institute of Community Ophthalmology (NN), Madurai, Tamil Nadu, India.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Dhananjay Shukla, Aravind Eye Hospital & Postgraduate Institute of Ophthalmology, 1 Anna Nagar, Madurai 625 020, Tamil Nadu, India.
Hypertension affects about 1 billion people worldwide; about half of them remain unaware of their hypertensive status.1,2 The prognostic implications of hypertensive retinopathy (HTR) for the systemic disease status are probably more significant than the effects of hypertension on ocular fundus, as outlined in the Keith–Wagener–Barker classification of HTR.3 Treatment is considered to be most urgent for malignant hypertension, defined by the severity of retinopathy.3–5 The significance of disc edema as the traditional hallmark of grade 4 HTR and malignant hypertension has been challenged recently.6–9 Nonetheless, most of these studies ignore the implications of hypertensive choroidopathy for defining systemic disease status. We evaluated serous detachment of the macula, essentially a manifestation of hypertensive choroidopathy, as a marker of malignant hypertension.
Material and Methods
This observational case series included 14 consecutive outpatients with systemic hypertension and serous detachment of macula in one or both eyes, who presented with defective vision or headache at a tertiary eye care center. The ophthalmic evaluation included best-corrected visual acuity (BCVA) assessment, fundus examination and photography, and optical coherence tomography (Stratus OCT 3, Carl Zeiss Meditec., Dublin, CA). Subsequently, each patient underwent a detailed systemic examination by an in-house physician, who decided on further systemic investigations based on the clinical findings and patient history. Fluorescein angiography was not a mandatory investigation due to frequent systemic association of nephropathy.
The blood pressure was measured by the auscultatory method with a precalibrated mercury sphygmomanometer. The recordings were made with patients in a sitting position, and the arm was supported at the heart level, after 5 min of rest. At least two consecutive measurements, ≥1 min apart, were averaged. For this study, malignant hypertension was defined as severe hypertension (systolic BP ≥180 mm Hg and/or diastolic BP ≥110 mm Hg) associated with grade 3 or 4 HTR: bilateral retinal hemorrhages and exudates, with or without papilledema.7 HTR was graded as per Keith–Wagener–Barker classification, on a severity scale of 1 to 4.3 Overt nephropathy was determined to be present on the basis of urine albumin 1+ (30 mg/dL), blood urea > 40 mg/dL (14.28 mmol/L), and serum creatinine > 1.5 mg/dL (133 micromoles/L), as described before.10 Serous retinal detachment (SRD) of macula was considered to be present if the posterior surface of the sensory retina was elevated from the underlying retinal pigment epithelium (RPE), through a nonreflective cavity. Retinal edema was defined as internal hyporeflective areas within the retinal layers, with loss of foveal contour and increased central retinal thickness (>250 μ). The components of central macular thickness (edema and SRD) were graded as “−” if the component was absent, “+” if the component was present and constituted <50% of central macular thickness, and “++” when the component constituted 50% or more of the central macular thickness (Table).
Table: Maculopathy in Malignant Hypertension: Demographic and Clinical Profile
Patients with other ocular or systemic diseases likely to cause SRD (diabetic retinopathy, retinal vein occlusions and central serous chorioretinopathy; or thrombotic thrombocytopenic purpura, disseminated intravascular coagulopathy, pre-eclampsia, systemic lupus, etc.) or those with lens opacities incompatible with good-quality OCT scans were excluded from the study. Patients with evidence of raised intracranial pressure, and those having undergone cataract surgery within the previous 6 months were similarly excluded. OCT exclusion criteria included presence of vitreomacular traction, epimacular membrane, or thickened posterior hyaloid attached to the macula. All patients were informed about the urgency of strict control and monitoring of BP, regular follow-up with the physician, and the risk of cerebrovascular accidents. Informed consent was taken from the patients for the use of their clinical data. This study was approved by the Institutional Review Board.
Statistical analysis was performed using STATA version 10 software package (College Station, TX). The data were expressed as mean ± S.D. (median; range) for continuous variables and as numbers (percent) for categorical variables. Two proportions test was used to assess the difference between macular SRD and optic disc edema as correlates of malignant hypertension. The level of significance was set at 0.05. Snellen’s visual acuity was converted to the decimal scale for analysis.
Fourteen patients (two women) with HTR and macular SRD were evaluated in this study (Table). The mean age was 44.35 ± 15.5 years (median: 48.5 years; range: 25 to 65 years). The reported duration of hypertension varied from 2 to 20 years (mean: 12 years; median: 5 years). None of the patients were on regular treatment for hypertension. The mean BCVA at presentation was 6/12 (median: 6/12; range: 6/6 to 6/60). The salient fundus findings are shown in Figure 1: five patients had bilateral grade 4 HTR (Fig. 1A), 5 had bilateral grade 3 changes, whereas the remaining 4 had grade 4 retinopathy in one eye, and grade 3 in the fellow eye. In other words, optic disc edema in one or both eyes was observed in nine patients. OCT demonstrated a prominent SRD and varying degree of intra-retinal edema at macula in both eyes (Figs. 1B, D, F, and H) of all patients, except three: one had foveal atrophy, and two had normal foveal contours in their fellow eyes. The correlation of macular SRD (100%) with malignant hypertension was significantly stronger than the correlation of papilledema (64%) with malignant hypertension (P = .0132). Acute focal RPE lesions were visible in or around the posterior pole in six patients (10 eyes) (Fig. 1C). SRD was the predominant component of central macular thickness over macular edema in 16 eyes; in the remaining 9 eyes, both were of equal degree. Evidence of turbidity in the subretinal fluid, caused by leaked proteins and fibrin, was observed as hyperreflectivity of subretinal fluid on OCT in seven patients (11 eyes): bilaterally in four, and unilaterally in three (Figs. 1B, F, and H). A partial or complete macular star was visible in six patients (7 eyes).
Figure 1. Varied Clinical Associations of Serous Macular Detachment in Malignant Hypertension, with Corresponding Optical Coherence Tomograms (OCT). (A) Fundus View of Patient 2 Showing Grade 4 Hypertensive Retinopathy (disc Edema, Cotton Wool Spots, and Hemorrhages) with Serous Elevation and Hard Exudates at the Macula. (B) The Corresponding OCT (horizontal 5-mm Line Scan) Confirms the Presence of Macular Detachment. In Addition, Note the Outer Retinal Edema and Hyperreflectivity of Subretinal Fluid, Suggestive of Increased Turbidity Due to Protein and Fibrin Content. (C) In This Fundus Photograph (patient 7), Choroidopathy Is Evident as Focal Pigment Epithelial Lesions (arrowheads) as Well as Macular Detachment, Along with Grade 4 Hypertensive Changes. (D) Horizontal 10-mm OCT Scan Shows a Macular Serous Detachment (SRD) with Retinal Edema. (E) The Clinically Prominent Macular Serous Elevation (case 12) Is in Contrast with the Relatively Mild Hypertensive Retinopathy. (F) On OCT, the Macular Detachment Is as Severe as in Case 2, with Evidence of Subretinal Fluid Turbidity. (G) The Left Eye of Patient 13 Shows a Nasal Macular Star of Severe Hard Exudates. (H) Horizontal OCT Scan Shows Prominent Nasal Intraretinal Edema and Serous Detachment. The Hard Exudates (hyperechoic Dots) Are Evident Subretinally Too, Along with Weaker Echoes of Subretinal Protein/fibrin.
On systemic evaluation by the physician, all the 14 patients were found to have malignant hypertension. However, none could be labeled as hypertensive emergency (marked blood pressure elevation with acute target organ damage).1 The mean systolic pressure was 208.57 ± 32.78 mmHg (median: 205; range 160 to 270 mm Hg), and the mean diastolic pressure was 117.86 ± 14.2 mmHg (median: 120; range 90 to 140). Eight patients (57%) had overt nephropathy.
Follow-up varied from 1 to 30 months (median: 3 months; mean: 14 months); two patients died before review visits; two were lost to follow-up. Fundus examination showed regression of hypertensive changes with resolution of macular SRD in the remaining 10 patients over 10 to 40 days (mean: 18 days) (Fig. 2, A–H). The eyes with focal RPE lesions developed stippled hyper-pigmentation (Elschnig’s spots) on resolution of acute lesions (Fig. 3, A–D). Mean BCVA recovered to 6/9 (median: 6/9; range: 6/6 to 6/36). Optic disc developed pallor due to ischemic optic neuropathy in 2 eyes (2 patients) with poor visual recovery (6/18 and 6/36). Blood pressure readings recorded at the time of resolution of macular SRD were observed to be normalizing in all 10 patients (mean systolic pressure 152.14 ± 20.71 mm Hg; mean diastolic pressure: 89.56 ± 13.47 mm Hg).
Figure 2: (A–B) This 30-Year-Old Man (case 4) Presented with Grade 4 Hypertensive Retinopathy. Macular Star Was More Prominent in the Right Eye, and Macular Detachment Was Predominant in the Left; (C–D) Optical Coherence Tomogram (OCT) Confirmed the Clinical Impression. (E–F) Strict Blood Pressure Control Resulted in Resolution of the Disc Edema and Macular Thickening in Both the Eyes; Water-Tide Marks Were Visible Around the Left Optic Disc. (G–H) OCT Showed Normalized Foveal Contours in Both Eyes.
Figure 3: (A–B) This 25-Year-Old Woman (case 5) Developed Bilateral Grade 3 Hypertensive Retinopathy; Choroidopathy Was Manifest as Macular Detachments (more in the Right) and Focal Lesions of Retinal Pigment Epithelium (more in the Left; Arrowheads). Blood Pressure Was 200/130 mm Hg; the Patient Was not Pregnant. (C–D) A Month Later, with Stabilization of Blood Pressure, the Fundi Were Nearly Normal Except Focal Pigmentary Alterations Replacing the Acute Pale Lesions (Elschnig’s Spots). (E–F) OCT Showed Complete Resolution of Macular Elevation Bilaterally, Shown Here in the Right Eye.
Although uncommon, SRD has been reported with malignant hypertension as well as related systemic conditions like disseminated intravascular coagulopathy and thrombocytopenic purpura.11–15 Almost all the human studies of SRD in malignant hypertension have been isolated case reports. Hayreh reported a large experimental study (60 rhesus monkeys) with iatrogenically induced malignant hypertension, choroidopathy was observed in 30 monkeys, manifested as macular SRD in 22 (73%) of them.16 The previous largest human series of SRD in hypertension consisted of seven patients (11 eyes); all patients were young (19 to 40 years), with grade 3 or 4 HTR (9 and 5 eyes, respectively), and had excellent visual outcome. The local serous retinal detachments were observed bilaterally in four patients, and unilaterally in three. Remarkably, in contrast to Hayreh’s series, none of the eyes were reported to have a macular detachment; although many had a macular star.11 A macular star forms by the aggregation of macular hard exudates, a common finding in grade 3 to 4 HTR. A solitary human study has suggested an association been the macular star and (resolving) macular SRD.15 We concur that the macular star may be a sign of resolving macular edema as well as SRD. We found that the macular star associated with SRD in seven eyes of six patients, a finding that explains the gross discrepancy in incidence of macular SRD between the aforementioned animal16 and human11 studies. Indeed, the falsely low incidence of macular SRD in severe hypertension in the literature may be due to a lack of focus on choroidopathy as well as the shallow and flat nature of most macular SRDs,16 not clinically appreciated in the absence of OCT. On the other hand, all the reports of OCT in malignant hypertension mention the presence of macular SRD.17–19
It is possible that maculopathy in severe hypertension consists predominantly of serous detachment rather than intraretinal oedema.20 A serous detachment could explain why maculopathy in most of these cases resolves spontaneously with generally good visual prognosis in spite of the severity of retinopathy and systemic disease; except the eyes that develop ischemic optic neuropathy.20,21 Predominance of SRD over intraretinal edema in our and Dr. Hayreh’s series16 confirms a greater involvement of choroidal than retinal vessels in malignant hypertension. The intrinsic hyperreflectivity of the subretinal fluid, as observed in our series, probably reflects its plasmoid nature and presence of fibrin, another indicator of its choroidal origin.16,21 We endorse the observations of Dr. Hayreh that maculopathy in malignant hypertension is primarily a choroidopathy (fibrinoid necrosis of choroidal vessels), which in turn leads to ischemic breakdown of the outer blood–retinal barrier (RPE) and consequent retinal detachment. Intraretinal edema may occur due disruption of both/either outer or inner blood–retinal barrier, which occur independently.16,20 The independence of choroidopathy from retinopathy is highlighted in Figure 1, which shows SRD in combination with varying severity of retinopathy. Similar to previous large studies,11,16 we too observed that macular SRD may not be bilaterally symmetrical in malignant hypertension.
A new prognosis-oriented classification of HTR has been recently suggested, which essentially clubs the first two stages of Keith–Wagener–Barker classification to evolve three grades of HTR: mild, moderate, and severe.5 The patients with moderate retinopathy (essentially grade 3 HTR) are advised to undergo detailed investigations whereas those with severe retinopathy (disc edema, grade 4 HTR) warrant urgent management.5 This recommendation is not entirely in agreement with the WHO criteria as well as some recent studies, which view both grade 3 and 4 hypertensive changes as acute manifestations of blood–retinal barrier breakdown, occurring in continuum, and therefore both can be associated with malignant hypertension.6–9 We propose that the presence of SRD, especially at macula, may be a useful alternative indicator of a malignant stage in hypertensive patients (and consequently urgent treatment), especially in view of the equivocal value of disc edema. If carefully looked for, it may be found more commonly in patients with a malignant hypertension than currently reported, particularly in eyes with macular star. However, similar to other hypertensive fundus changes, SRD is also a transient phenomenon, institution of systemic control promptly resolves the macular elevation along with the retinal signs, as we also observed in our patients on follow-up visits.9,11–15,17,19,21 Therefore, although the presence of SRD with HTR may strongly reflect severity of hypertension, SRD may not always be observed in a patient with malignant hypertension.
We had a limited and variable follow-up of patients in this study, which focused on the cross-sectional association between SRD and malignant hypertension. The other limitations of this study were lack of fluorescein angiographic documentation of the macular status and the small sample size. These limitations also explain the relative paucity of acute focal RPE lesions in our series; the fresh lesions are faint and may be masked by the macular detachment and oedema.16 The small sample size also prevented a quantitative correlation of the macular SRD with the severity of hypertension; however, it was shown to be a significantly better marker for malignant hypertension than papilledema. To the best of our knowledge, this is first large case-series of OCT-documented serous macular detachments secondary to malignant hypertension in human eyes. It supports the concept that macular SRD — and by implication choroidopathy, an acute event — is common in malignant HT. This pilot study lacks the power to definitively comment on the predictive value of macular SRD for malignant hypertension, as a stand-alone marker or vis-à-vis papilledema. The proposed correlation needs to be confirmed in larger, longitudinal, comparative studies to better equip the physicians with key ophthalmic warning signals of the otherwise insidious course of this global disease.
- Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC report. JAMA. 2003;289:2560–2572. doi:10.1001/jama.289.19.2560 [CrossRef]
- Joshi V, Lim J, Nandkumar M. Prevalence and risk factors of undetected elevated blood pressure in an elderly Southeast Asian population. Asia Pac J Public Health. 2007;19:3–9. doi:10.1177/10105395070190020201 [CrossRef]
- Keith NM, Wagener HP, Barker NW: Some different types of essential hypertension: their cause and prognosis. Am J Med Sci1939;197:332–343. doi:10.1097/00000441-193903000-00006 [CrossRef]
- Dodson PM, Lip GY, Eames SM, Gibson JM, Beevers DG. Hypertensive retinopathy: a review of existing classification systems and a suggestion for a simplified grading system. J Hum Hypertens. 1996;10:93–98.
- Wong TY, Mitchell P. Hypertensive retinopathy. N Engl J Med. 2004;351:2310–2317. doi:10.1056/NEJMra032865 [CrossRef]
- Ahmed MEK, Walker JM, Beevers DG, Beevers M. Lack of difference between malignant and accelerated hypertension. British Medical Journal. 1986;292:235–237. doi:10.1136/bmj.292.6515.235 [CrossRef]
- Chatterjee S, Chattopadhyay S, Hope-Ross M, Lip PL. Hypertension and the eye: changing perspectives. J Hum Hypertens. 2002;16: 667–675. doi:10.1038/sj.jhh.1001472 [CrossRef]
- McGregor E, Christopher GI, Jay JL, Lever AF, Murray GD. Retinal changes in malignant hypertension. British Medical Journal. 1986; 292: 233–234. doi:10.1136/bmj.292.6515.233 [CrossRef]
- Beutler JJ, Koomans HA. Malignant hypertension: still a challenge. Nephrol Dial Transplant. 1997;12:2019–2023. doi:10.1093/ndt/12.9.2019 [CrossRef]
- Shukla D, Kolluru CM, Singh J, et al. Macular ischemia as a marker for nephropathy in diabetic retinopathy. Indian J Ophthalmol. 2004;52:205–210.
- De Venecia G, Jampol LM. The eye in accelerated hypertension II. Localized serous detachments of the retina in patients. Arch Ophthalmol. 1984;102:68–73.
- Sathish S, Arnold JJ. Bilateral choroidal ischaemia and serous retinal detachment in pre-eclampsia. Clin Experiment Ophthalmol. 2000;28:387–390. doi:10.1046/j.1442-9071.2000.00342.x [CrossRef]
- Isaacs TW, Acheson JF. Reversible visual failure due to exudative retinal detachments in a patient with uncontrolled systemic hypertension. J R Soc Med. 1994;87:557–558.
- Schartz H. Diagnostic challenges: retinal detachment in acute systemic hypertension. Retina. 1995;15:524–526.
- Noble KG. Hypertensive retinopathy simulating leber idiopathic stellate neuroretinitis. Arch Ophthalmol. 1997;115:1594–1595.
- Hayreh SS, Servais GE, Virdi PS. Fundus lesions in malignant hypertension VI. Hypertensive choroidopathy. Ophthalmology. 1986;93:1383–1400.
- Suzuki M, Minamoto A, Yamane K, Uka J, Aoki S, Mishima HK. Malignant hypertensive retinopathy studied with optical coherence tomography. Retina. 2005;25:383–384. doi:10.1097/00006982-200504000-00026 [CrossRef]
- Hammond S, Wells JR, Marcus DM, Prisant LM. Ophthalmoscopic findings in malignant hypertension. J Clin Hypertens (Greenwich). 2006;8:221–223. doi:10.1111/j.1524-6175.2005.04147.x [CrossRef]
- Olson JL, Prall FR, Ciardella AP. Bilateral foveal neurosensory detachment in hypertensive retinopathy demonstrated by optical coherence tomography. Eye. 2006;20:1370–1371. doi:10.1038/sj.eye.6702201 [CrossRef]
- Hayreh SS. Hypertensive fundus changes. In: Guyer DR, Yannuzzi LA, Chang S, Shields JA, Green WR eds. Philadelphia: Retina-Vitreous-Macula. WB Saunders: 1999;345–371.
- Scott IU, Flynn HW, Al-Attar L, Ganser GL, Aragon AV, Lam BL. Bilateral optic disc edema in patients with severe systemic arterial hypertension: clinical features and visual acuity outcomes. Ophthalmic Surgery, Lasers and Imaging. 2005;36:374–322.
Maculopathy in Malignant Hypertension: Demographic and Clinical Profile
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