Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults

DEFINITIONS AND TERMINOLOGY — Hypertensive emergencies are acute, life-threatening conditions resulting from markedly increased blood pressure (BP), generally ≥180/120 mmHg (table 1), characterized by acute, ongoing target-organ damage [1-5]. In addition to the hypertensive emergencies that are discussed in detail elsewhere (see "Evaluation and treatment of hypertensive emergencies in adults"), two less common clinical syndromes induced by acute, severe hypertension include:

●Moderate to severe hypertensive retinopathy − Moderate to severe hypertensive retinopathy, corresponding to grades III and IV hypertensive retinopathy, is characterized by retinal hemorrhages, exudates, and papilledema (image 1) [6]. (See "Ocular effects of hypertension", section on 'Ocular diseases directly related to hypertension'.)

Severe hypertensive retinopathy was formerly called "malignant hypertension," a term that clinicians should avoid (although it is used for administrative purposes in the United States). Moderate hypertensive retinopathy was often referred to as "accelerated hypertension," but this term should likewise be avoided. Patients with moderate to severe hypertensive retinopathy frequently have acute hypertensive nephrosclerosis (formerly called "malignant nephrosclerosis"), although kidney biopsies are seldom performed.

Historically, papilledema was the hallmark of a more advanced condition (ie, "malignant hypertension") associated with a higher mortality (akin to having a malignancy). However, the advent of effective antihypertensive drug therapy has improved the prognosis and patients with severe hypertensive retinopathy have similar outcomes to those with moderate hypertensive retinopathy [7]. Thus, acute treatment of such patients is the same whether or not papilledema is present.

●Hypertensive encephalopathy − Hypertensive encephalopathy refers to the presence of signs and/or symptoms of cerebral edema caused by severe and/or sudden rises in BP. It is primarily a diagnosis of exclusion after other causes of central nervous system dysfunction are ruled out, and it characteristically responds dramatically to acute lowering of the mean arterial pressure, sometimes by as little as 10 to 15 percent. (See "Evaluation and treatment of hypertensive emergencies in adults", section on 'Neurologic emergencies'.)

MECHANISMS OF VASCULAR INJURY — With mild to moderate elevations in blood pressure (BP), the initial response is arterial and arteriolar vasoconstriction. This autoregulatory process both maintains tissue perfusion at a relatively constant level and prevents the increase in pressure from being transmitted to the smaller, more distal vessels [8].

With increasingly severe hypertension, however, autoregulation eventually fails (figure 1) [8]. The ensuing rise in pressure in the arterioles and capillaries leads to acute damage to the vascular wall. Disruption of the vascular endothelium then allows plasma constituents (including fibrinoid material) to enter the vascular wall, thereby narrowing or obliterating the vascular lumen. Within the brain, the breakthrough vasodilation from failure of autoregulation leads to the development of cerebral edema and the clinical picture of hypertensive encephalopathy [8].

The level at which fibrinoid necrosis occurs depends upon the chronic baseline BP (prior to the substantial increase in BP). Patients with chronic hypertension have arteriolar hypertrophy that minimizes the transmission of pressure to the capillary circulation. Grades III and IV hypertensive retinopathy are often associated with diastolic pressures above 120 mmHg. By comparison, hypertensive encephalopathy can be seen at diastolic pressures as low as 100 mmHg in previously normotensive patients with acute hypertension due to preeclampsia or acute glomerulonephritis; patients in whom autoregulation is impaired also may develop hypertensive injury at relatively mild degrees of hypertension [8].

In addition to protecting tissues against the effects of severe hypertension, autoregulation also maintains tissue perfusion during the treatment of hypertension via arterial and arteriolar vasodilation. Since flow is equal to pressure divided by resistance, parallel reductions in both parameters allow sufficient blood flow to be maintained. However, an excessive hypotensive response below the autoregulatory range can lead to ischemic symptoms (figure 1). The arteriolar hypertrophy induced by chronic hypertension means that hypoperfusion will occur at a higher BP than in normotensive subjects [8].

It has been suggested that factors other than the level of BP, particularly activation of the renin-angiotensin system, may contribute to the development of fibrinoid necrosis. Plasma renin activity is often increased in patients with grades III and IV hypertensive retinopathy, potentially mediated by both an initial natriuresis induced by the high pressure and renal vascular injury. The importance of the renin-angiotensin system in the vascular injury of severe hypertension has been demonstrated in transgenic rats [9]. In this study, rats prone to severe hypertension were treated with low-dose ramipril (5 mg/day) or no therapy. Ramipril significantly reduced the frequency of arteriolar fibrinoid necrosis, despite having no significant effect on BP, suggesting a role for the renin-angiotensin system independent of BP.

CLINICAL MANIFESTATIONS AND DIAGNOSIS — Moderate to severe hypertensive retinopathy and hypertensive encephalopathy most often occur in patients with longstanding, uncontrolled hypertension, many of whom have discontinued antihypertensive drug therapy [10]. Secondary hypertension, especially renovascular hypertension, is more common in patients with advanced hypertensive retinopathy than in hypertensive individuals without such funduscopic findings [11].

Clinical manifestations — In addition to marked elevation in blood pressure (BP), the major clinical manifestations of hypertensive retinopathy and encephalopathy include the following [3,4,12,13]:

●Patients with moderate to severe hypertensive retinopathy do not usually have visual symptoms, although 5 to 10 percent may have visual complaints. However, the ophthalmologic examination can reveal retinal hemorrhages and/or exudates (representing both ischemic damage and leakage of blood and plasma from affected vessels) and papilledema (image 1). Yet few non-ophthalmologists can distinguish moderate from severe retinopathy, and the value of funduscopy in hypertensive patients is unclear [14]. (See "Ocular effects of hypertension".)

●Neurologic symptoms are frequent in patients with severe hypertension [15]. Hypertensive encephalopathy, which is related to cerebral edema, is characterized by the insidious onset of headache, nausea, and vomiting, followed by nonlocalizing neurologic symptoms such as restlessness, confusion, and, if the hypertension is not treated, seizures and coma [12]. In contrast, patients with ischemic stroke or intracerebral hemorrhage typically present with abrupt and focal neurologic symptoms. However, such patients may occasionally have insidious and generalized neurologic symptoms and, because the treatment of ischemic stroke and intracerebral hemorrhage differs significantly from the treatment of hypertensive encephalopathy, diagnostic brain imaging is critical to distinguish the cause of neurologic symptoms. (See 'Diagnosis' below.)

●Patients with severe hypertensive retinopathy and/or hypertensive encephalopathy often have acute hypertensive nephrosclerosis, leading to acute kidney injury, hematuria, and proteinuria. Acute hypertensive nephrosclerosis is discussed elsewhere. (See "Evaluation and treatment of hypertensive emergencies in adults", section on 'Kidney emergencies'.)

Diagnosis — Hypertensive retinopathy is diagnosed by ophthalmologic examination of the eyes, with identification of retinal hemorrhages, exudates, and/or papilledema (image 1). (See "Ocular effects of hypertension".)

Hypertensive encephalopathy is a diagnosis of exclusion, confirmed retrospectively when neurologic symptoms improve after the BP is lowered into (but not beyond) the autoregulatory range (figure 1). However, cerebral imaging, particularly magnetic resonance imaging (MRI) with T₂-weighted images, may reveal edema of the white matter of the parieto-occipital regions, a finding consistent with hypertensive encephalopathy that is termed reversible posterior leukoencephalopathy syndrome [16]. When the MRI reveals primarily pontine abnormalities, the condition has been called hypertensive brainstem encephalopathy [17,18]. (See "Reversible posterior leukoencephalopathy syndrome".)

As noted above, ischemic stroke and intracerebral hemorrhage should usually be excluded in patients with severe hypertension and neurologic symptoms since treatment of these conditions differs from the treatment of hypertensive encephalopathy. Thus, in the presence of neurologic symptoms such as headache, nausea, and vomiting, followed by nonlocalizing symptoms such as restlessness, confusion, seizures, or coma, a computerized tomography (CT) or MRI scan of the brain should be obtained to exclude an acute ischemic stroke or hemorrhage, which are not routinely (or primarily) treated by reducing BP [19]. (See "Neuroimaging of acute stroke" and "Initial assessment and management of acute stroke", section on 'Blood pressure management' and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management' and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Blood pressure control'.)

TREATMENT

Goal of therapy — The initial aim of treatment in patients with moderate to severe hypertensive retinopathy and/or hypertensive encephalopathy is to rapidly lower the mean arterial pressure by approximately 10 to 15 percent in the first hour, and by no more than 25 percent compared with baseline by the end of the first day of treatment [12,13]. This level of blood pressure (BP) control will allow gradual healing of the necrotizing vascular lesions. More aggressive hypotensive therapy is both unnecessary and may reduce BP below the autoregulatory range, possibly leading to ischemic events (such as stroke or myocardial infarction) [20,21]. (See "Evaluation and treatment of hypertensive emergencies in adults", section on 'Neurologic emergencies'.)

Once BP is controlled, the patient should be switched to oral therapy, with the systolic pressure being gradually reduced to <130 mmHg and the diastolic pressure being gradually reduced to <80 mmHg over two to three months. The initial reduction in BP is often associated with a modest worsening of kidney function; this change, however, is typically transient as the vascular disease tends to resolve and kidney perfusion improves over one to three months [22], even among patients treated with angiotensin-converting enzyme (ACE) inhibitors, renin inhibitors, or angiotensin II receptor blockers (ARBs) [23]. Antihypertensive therapy should not be withheld in this setting unless there has been an excessive reduction in pressure. (See "Evaluation and treatment of hypertensive emergencies in adults", section on 'Kidney emergencies'.)

However, a change in medication may be required if the decline in kidney function only occurs after initiation of therapy with an ACE inhibitor, renin inhibitor, or ARB, which can interfere with renal autoregulation and produce acute kidney injury in patients with bilateral renal artery stenosis. (See "Renal effects of ACE inhibitors in hypertension".)

Choice of antihypertensive drug — Initial treatment of marked hypertension-associated moderate (ie, grade III, hemorrhages or exudates) to severe (ie, grade IV, papilledema) hypertensive retinopathy and/or hypertensive encephalopathy usually includes parenteral antihypertensive drug therapy administered in an intensive care unit. (See 'Parenteral antihypertensive therapy' below.)

After a suitable period (often 8 to 24 hours) of BP control at target in the intensive care unit, oral medications may be started and the initial intravenous therapy is tapered and discontinued.

In settings where parenteral antihypertensive drugs are unavailable, rapidly acting oral agents (such as sublingual captopril) may be used, although such medications may occasionally cause ischemic symptoms due to an unpredictable, excessive, and uncontrolled hypotensive response. (See 'Oral alternatives' below.)

Parenteral antihypertensive therapy — The parenteral antihypertensive agents most often used in the initial treatment of moderate to severe hypertensive retinopathy and/or hypertensive encephalopathy are briefly listed below [12,13]. A more detailed discussion about the pharmacology, dosing, and adverse effects of these agents is provided elsewhere (table 2). (See "Drugs used for the treatment of hypertensive emergencies".)

●Clevidipine – A short-acting dihydropyridine calcium channel blocker. It reduces BP without affecting cardiac filling pressures or causing reflex tachycardia. The initial dose is 1 mg/hour and the usual maximum dose is 21 mg/hour. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Clevidipine'.)

●Nicardipine – A dihydropyridine calcium channel blocker with arteriolar dilator effect, given as an intravenous infusion. The initial dose is 5 mg/hour and the usual maximum dose is 15 mg/hour. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Nicardipine'.)

●Fenoldopam – A peripheral dopamine-1 receptor agonist, given as an intravenous infusion. The initial dose is 0.1 mcg/kg per min and the dose is titrated at 15-minute intervals, depending upon BP response. Fenoldopam may be particularly beneficial in patients with kidney impairment. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Fenoldopam'.)

●Sodium nitroprusside – An arteriolar and venous dilator, given as an intravenous infusion. The initial dose is 0.25 to 0.5 mcg/kg per min and the usual maximum dose is 8 to 10 mcg/kg per min. The potential for cyanide and thiocyanate toxicity limits the prolonged use of nitroprusside, particularly in patients with acute or chronic kidney disease. (See "Drugs used for the treatment of hypertensive emergencies", section on 'Nitroprusside'.)

●Labetalol – An alpha and beta adrenergic blocker, given as an intravenous bolus or infusion. A 20 mg bolus is usually given initially, followed by 20 to 80 mg intravenously every 10 minutes to a total dose of 300 mg. Labetalol can also be given as a continuous infusion at 0.5 to 2 mg/min. Labetalol should not be used without prior adequate alpha blockade in patients with hyperadrenergic states (eg, cocaine-induced hypertension). (See "Drugs used for the treatment of hypertensive emergencies", section on 'Labetalol'.)

Oral alternatives — The use of oral antihypertensive agents as therapy for hypertensive emergencies is limited by slower onset of action and the inability to control both the rapidity and degree of BP reduction. However, such therapy may be useful in resource-limited settings when access to parenteral antihypertensive medications is lacking.

Rapid, unpredictable, and often substantial BP lowering can occur after either sublingual captopril (25 mg, single dose) or nifedipine (10 mg, single dose) [24]. Because sublingual nifedipine is minimally absorbed, swallowing nifedipine liquid (from a punctured capsule) is even faster, and perhaps even more dangerous.

The major risk of any oral agent used for hypertensive emergencies is ischemic symptoms (eg, angina pectoris, myocardial infarction, or stroke) due to an excessive and uncontrolled hypotensive response [25], usually due to lowering of BP to below the autoregulatory threshold. Thus, the use of oral agents should generally be avoided in the treatment of hypertensive emergencies if parenteral drugs are available (table 2).

PROGNOSIS — Even with effective antihypertensive therapy, most patients who have had moderate to severe hypertensive retinopathy and/or hypertensive encephalopathy have chronic and acute vascular damage and are at increased risk for coronary, cerebrovascular, and kidney disease. The magnitude of this problem was illustrated in a retrospective study that evaluated the kidney outcomes of 169 patients with grade III or IV hypertensive retinopathy [26]. Despite adequate antihypertensive therapy, progressive kidney function impairment occurred in 57 percent of patients after a mean follow-up of 53 months.

However, overall survival has improved markedly with the availability of antihypertensive medications. Historically, without therapy, one-year survival was only 10 to 20 percent [27]. With effective acute and chronic antihypertensive therapy, five-year survival rates of more than 70 percent are typical [12,13], with some studies reporting 90 percent survival at 40 to 52 months [28]. Patients with higher stages of chronic kidney disease tend to have a lower survival rate [26,29].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertension in adults".)

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●Basics topics (see "Patient education: High blood pressure emergencies (The Basics)")

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SUMMARY AND RECOMMENDATIONS

●Moderate to severe (grades III and IV) hypertensive retinopathy is characterized by retinal hemorrhages, exudates, and papilledema (image 1). (See 'Definitions and terminology' above.)

●Hypertensive encephalopathy refers to the presence of signs and/or symptoms of cerebral edema caused by a severe and/or sudden rise in blood pressure (BP). It is primarily a diagnosis of exclusion, after other causes of central nervous system dysfunction are ruled out, and it characteristically responds dramatically to acute lowering of the mean arterial pressure, sometimes by as little as 10 to 15 percent. (See 'Definitions and terminology' above.)

●Moderate to severe hypertensive retinopathy and hypertensive encephalopathy most often occur in patients with longstanding, uncontrolled hypertension, many of whom have recently discontinued antihypertensive drug therapy. (See 'Clinical manifestations and diagnosis' above.)

●In addition to marked elevation in BP, the major clinical manifestations include the following (see 'Clinical manifestations' above):

•Patients with moderate to severe hypertensive retinopathy do not usually have visual symptoms, but the ophthalmologic examination can reveal retinal hemorrhages and/or exudates (representing both ischemic damage and leakage of blood and plasma from affected vessels) and papilledema (image 1).

•Hypertensive encephalopathy, which is related to cerebral edema, is characterized by the insidious onset of headache, nausea, and vomiting, followed by nonlocalizing neurologic symptoms such as restlessness, confusion, and, if the hypertension is not treated, seizures and coma.

•Patients with severe hypertensive retinopathy and/or hypertensive encephalopathy often have acute hypertensive nephrosclerosis, leading to acute kidney injury, hematuria, and proteinuria.

●Hypertensive retinopathy is diagnosed by ophthalmologic examination of the eyes, with identification of retinal hemorrhages, exudates, and/or papilledema (image 1). (See 'Diagnosis' above.)

●Hypertensive encephalopathy is a diagnosis of exclusion, confirmed retrospectively when neurologic symptoms improve after the BP is lowered into the autoregulatory range. However, cerebral imaging, particularly magnetic resonance imaging (MRI) with T₂-weighted images, may reveal edema of the white matter of the parieto-occipital regions, a finding consistent with hypertensive encephalopathy that is termed "reversible posterior leukoencephalopathy syndrome." When the MRI reveals primarily pontine abnormalities, the condition has been called "hypertensive brainstem encephalopathy." Ischemic stroke and intracerebral hemorrhage should be excluded in patients with severe hypertension and neurologic symptoms since treatment of these conditions differs from the treatment of hypertensive encephalopathy. (See 'Diagnosis' above.)

●The initial aim of treatment in patients with moderate to severe hypertensive retinopathy and/or hypertensive encephalopathy is to rapidly lower the mean arterial pressure by approximately 10 to 15 percent in the first hour, and by no more than 25 percent compared with baseline by the end of the first day of treatment. (See 'Goal of therapy' above.)

●Initial treatment of marked hypertension-associated moderate to severe hypertensive retinopathy and/or hypertensive encephalopathy usually includes parenteral antihypertensive drug therapy administered in an intensive/critical care unit. After a suitable period (often 8 to 24 hours) of BP control at target in the intensive care unit, oral medications are usually given and the initial intravenous therapy is tapered and discontinued. (See 'Choice of antihypertensive drug' above.)