Hypertensive Crisis With Optic Disc Edema and Cerebral White Matter Lesions

A 47‐year‐old black woman presented to the Kaiser Permanente Anaheim Hospital emergency department complaining of a 3‐month history of blurred vision and headache. Hypertension had first been diagnosed with her two pregnancies 21 and 10 years previously; each time it resolved postpartum. Approximately 7 years before admission, at age 40, sustained hypertension developed and medication was started. Four years previously, on hydrochlorothiazide and lisinopril, blood pressures (BPs) varied between 123/69 mm Hg and 152/100 mm Hg. Two years before admission, on hydrochlorothiazide, lisinopril, and atenolol, her serum creatinine was 1.0 mg/dL (normal, 0.6–1.1 mg/dL), a fasting glucose was 89 mg/dL (normal, 70–110 mg/dL), a urine dipstick was negative for protein, and an echocardiogram revealed moderate concentric left ventricular hypertrophy with an ejection fraction of 60%.

She became unemployed and lost health insurance for 2 years; she stopped taking medication. Three months previously the patient was hospitalized for headache and blurred vision with a BP of 293/190 mm Hg. Serum creatinines were 3.9–4.1 mg/dL, and a chest radiograph showed cardiomegaly. She was discharged 2 days later on metoprolol 25 mg b.i.d., furosemide 40 mg b.i.d., amlodipine 10 mg q.d., and doxazosin 2 mg q.d., with BPs of 140/75–95 mm Hg. New health insurance coverage was obtained with new employment. When headache and blurred vision recurred, the patient came to the emergency department. She stated that she had been compliant with her medications, but her son accompanying her expressed doubt.

The patient's BP was 258/170 mm Hg with a heart rate of 119 bpm. She was unable to walk without assistance due to symmetric bilateral lower extremity weakness, and visual acuity was limited to finger counting. Physical examination was significant for bilateral optic disc edema, morbid obesity, and an S₄ gallop. She was not confused. A chest radiograph showed cardiomegaly without evidence of heart failure. Hemoglobin was 9.8 g/dL (normal, 12–16 g/dL), blood urea nitrogen 46 mg/dL (normal, <19 mg/dL), creatinine 4.2 mg/dL, and there was 3+ protein and full field red blood cells on urinalysis. Following a 20 mg labetalol IV bolus, the patient received a 2 mg/min labetalol drip in the intensive care unit, and her BP came down to 162/94 mm Hg after 4 hours. Oral medications were then initiated. Additional work‐up included brain magnetic resonance imaging, (MRI) which revealed extensive confluent periventicular white matter lesions involving most of the centrum semiovale as well as the pons and thalamus, but did not reveal a stroke (Figure 1); a 24‐hour urine protein of 6417 g; and a renal ultrasound showing echogenic normal‐sized kidneys. Thyroid stimulating hormone level was 1.06 IU/mL (normal, 0.4–4.0 IU/mL), a 24‐hour urine‐free cortisol was 43 μg/24 hours (normal, 20–90 μg/24 hours), 24‐hour urine vanillylmandelic acid was 6 mg (normal, <7 mg), and a 24‐hour urine metanephrine collection was 126 μg (normal, 19–140 μg). Therefore, thyroid crisis and pheochromocytoma were ruled out. She was discharged 4 days later with a BP of 157/98 mm Hg on metoprolol 100 mg b.i.d., furosemide 40 mg b.i.d., and nifedipine sustained release 60 mg q.d. Retinal photographs were obtained on the day of discharge demonstrating cotton‐wool spots, hemorrhages, narrowed arterioles, hard exudates, and optic disc edema (Figure 2). On discharge, her visual acuity had improved and she was ambulatory with a walker.

Figure 1.

Brain magnetic resonance imaging inversion recovery sequence showing extensive white matter changes in a confluent periventricular distribution (left), also involving the brainstem (right)

Figure 2.

Retinal photograph revealing cotton‐wool spots, hemorrhages, optic disc edema, narrowed arterioles, and hard exudates consistent with grade II retinopathy representing malignant hypertension

DISCUSSION

On the basis of optic disc edema and severe BP elevation, this patient had a hypertensive emergency and received IV labetalol. Labetalol competitively blocks β‐adrenergic receptors in a nonselective manner as well as blocking α receptors. The β‐ to α‐blocking potency ratio is 3:1 for oral labetalol and 7:1 for IV labetalol. ¹ Unlike pure β‐adrenergic blocking agents, which reduce cardiac output, labetalol preserves cardiac output. ² It is particularly indicated for acute renal, cardiac, vascular, and neurologic injury in hypertensive crises, with beneficial effects in acute cardiac ischemia, reduction of shear force in the vasculature, and preservation of cerebral, renal, and coronary blood flow. ² Contraindications to labetalol include bronchoconstriction and heart block greater than first degree. Onset of action occurs within 2–5 minutes, with peak effect at 5–15 minutes; the duration of activity followed discontinuation is 2–4 hours. ² Bolus dosing followed by continuous infusion of labetalol permits controlled lowering of BP with a response rate of more than 85%. ³

Due to the combined α‐ and β‐adrenergic blocking actions, heart rate reductions on labetalol by IV infusion are only 3–4 bpm, and patients presenting with a hypertensive crisis already taking β blockers are as likely to respond as patients not on β blocker pretreatment. ³ Labetalol by continuous infusion is well tolerated. Its safety profile in one series of 59 patients is illustrated in Table I. In the current case, it was decided to reduce the diastolic pressure to 100–110 mm Hg over several hours, to reduce the chance of further decrease in renal function with more rapid BP lowering, and to hydrate the patient with IV normal saline at 100 mL/h. On the basis of her clinical appearance, tachycardia, and a history of recent poor oral intake, it was believed that she was dehydrated. Many patients in a hypertensive crisis are volume depleted as a consequence of pressure‐related diuresis ⁴ ; further volume depletion may worsen the hypertension ⁵ and lead to further end‐organ damage.

Table I.

Adverse Effects With IV Labetalol Reported in 59 Patients

Signs/Symptoms	Number of Patients
Nausea	8
Vomiting	4
Paresthesia*	6
Sweating	4
Flushing	2
Dizziness	2
Headache	2
Somnolence	2
Symptomatic hypotension	2
Arrhythmia: ventricular, premature ventricular contractions	2
*Scalp tingling in three, tingling of hand in one, burning sensation in the chest and groin in one, and in the temporal area of one. Reprinted with permission from Am J Med. 1983;75:95–102. 3

A recent review of hypertensive retinopathy reported that swelling of the optic disc as a manifestation of malignant hypertension is rarely seen as a result of improved control of hypertension in the general population. ⁶ However, the lack of health insurance for 45 million Americans ⁷ may lead to significant interruptions in medical care, as it did in the current case, and the occurrence of otherwise uncommon presentations of a common disease such as hypertension. In fact, a hypertensive crisis most commonly occurs in patients with a history of hypertension who have been on inadequate therapy or have not been taking their medication as prescribed. ⁸ Severe hypertension may cause exudative retinopathy occurring as result of the disruption of the blood‐retinal barrier, and may lead to necrosis of endothelial cells and exudation of blood and lipids. ⁶ The result is retinal ischemia. A higher prevalence of hypertensive retinopathy in blacks than whites is mostly explained by higher levels of BP in the black population. ⁹

Older classification systems of hypertensive retinopathy have been reviewed and critiqued and a new simpler categorization has been recommended (Table II). ¹⁰ , ¹¹ The World Health Organization has recommended that retinal hemorrhages and exudates, as manifestations of the disruption of the blood‐retinal barrier which may occur in response to severe BP elevation, define the category of “malignant hypertension.” ¹² Retinal hemorrhages originating from the nerve fiber layer and deeper layers result from necrosis of the capillary and precapillary arteriole walls. Hard exudates are yellow lipid residues of fluid which diffuse through the retina as another result of disruption of the blood‐retinal barrier. Figure 3 illustrates the prevalence of retinopathy lesions according to systolic BP. ¹³

Table II.

Hypertensive Retinopathy: Revised Classification

Grade I	Arteriolar narrowing, focal constriction, and arteriovenous nicking
Grade II	Hemorrhages and exudates, with or without disc edema
Reprinted with permission from J Clin Hypertens (Greenwich). 2000;2:194–197. 11

Figure 3.

Age‐adjusted prevalence of retinopathy lesions by systolic blood pressure (SBP) quartiles and sex: first quartile SBP, men up to 129 mm Hg, women up to 130 mm Hg; second quartile SBP, men 130–140 mm Hg, women 131–144 mm Hg; third quartile SBP, men 141–154 mm Hg, women 145–159 mm Hg; fourth quartile SBP, men ≥155 mm Hg, women ≥160 mm Hg. Reprinted with permission from Arch Ophthalmol. 1998;116:83–89. ¹³

The presence of papilledema is an “optional” feature of the exudative retinopathy of malignant hypertension ¹² because papilledema is an insensitive indicator of the severity of hypertension. ¹⁰ Hypertensive papilledema alone does not affect vision. Acute visual loss is due to exudates, macular involvement, and choroidal detachment, which may improve following treatment of the hypertensive emergency, though delayed blindness may occur. ¹⁴ Too rapid a reduction in BP as a result of overaggressive management of hypertensive crisis with exudative retinopathy can precipitate blindness as a result of optic nerve infarction; this scenario may be the most common cause of visual impairment associated with malignant hypertension. ¹⁴

This patient was nearly blind due to severe exudative retinopathy and was initially nonambulatory from leg weakness, without evidence of a stroke but with extensive white matter changes on a brain MRI. Signs of retinopathy are often associated with cerebral white matter lesions, ¹⁵ and the associated pathophysiology is probably explained by the shared anatomic, physiologic, and embryologic features of the cerebral and retinal circulations. ⁶ The 5‐year relative stroke risk among individuals with both hypertensive retinopathy and brain MRI lesions in the Atherosclerosis Risk in Communities study was 18.1 (95% confidence interval, 5.9–55.4) compared with individuals lacking either of these conditions. ¹⁵ Signs of exudative retinopathy in the Cardiovascular Health Study (retinal hemorrhage, microaneurysms, and cotton‐wool spots) had twice the relative risk of stroke as individuals with equivalent BP elevations lacking signs of exudative retinopathy. ¹⁶ These indicators of blood‐retinal barrier disruption, as opposed to lesser degrees of retinopathy, parallel changes in the cerebral circulation, heralding a higher stroke risk. Supportive findings were seen in population‐based studies in Japan and Wisconsin, where retinopathy was a marker of increased stroke risk independent of other cardiovascular risk factors. ¹⁷ , ¹⁸

Whereas hypertensive therapy may prevent the progression of white matter lesions on serial brain MRI examinations, established lesions generally do not regress ¹⁹ ; this was also the finding in the present case. Midbrain white matter change involvement was severe enough in this patient that a followup MRI was recommended to rule out a primary cerebral disorder. The confluence of the white matter injury and sparing of the corpus callosum, however, argued against primary demyelinating disease and was more consistent with ischemic injury. The MRI findings in this patient were believed to be chronic rather than acute. Involvement of almost the entire centrum semiovale placed the extent of this patient's white matter involvement at grade 7 on a scale of 0–9 described by Wong et al. ¹⁵ In combination with grade II changes of malignant hypertensive retinopathy, she was therefore in the highest stroke risk category. Despite the lack of improvement on a follow‐up imaging study, the patient became fully ambulatory within several days and her vision also improved. Her already high risk of stroke and end‐stage renal disease as well as other adverse cardiovascular events is further complicated by the risk posed by the possible recurrent loss of health insurance and lack of medication compliance.