A Successfully Treated Case of Posterior Ischemic Optic Neuropathy That Developed during Antihypertensive Therapy for Hypertensive Emergency

Abstract

A 33-year-old woman developed hypertensive emergency (268/168 mmHg) with renal failure and hypertensive retinopathy. Four hours after the initiation of antihypertensive therapy with the continuous infusion of nicardipine, her blood pressure (BP) decreased to 168/84 mmHg; however, the patient developed blindness. She was diagnosed with posterior ischemic optic neuropathy (PION). Her BP was maintained at approximately 175/90 mmHg until her vision improved. Olmesartan was initiated on day 13, and her BP decreased to approximately 135/95 mmHg without the re-exacerbation of vision loss. Although the prognosis of PION is poor, its early diagnosis and gradual antihypertensive therapy may help preserve the patient's vision.

Introduction

Hypertensive emergency is a life-threatening condition that is characterized by severe hypertension and acute and progressive target-organ damage in the heart, brain, large blood vessels, kidneys, and eyes and requires urgent antihypertensive therapy (1). The prognosis of hypertensive emergency has recently improved due to the development of effective antihypertensive drugs, particularly renin-angiotensin system (RAS) inhibitors (2).

Posterior ischemic optic neuropathy (PION) is a rare cause of visual impairment, and its prognosis is poor (3). It is caused by ischemia of the optic nerve and may develop during antihypertensive therapy, particularly when the rate of reduction in blood pressure (BP) is excessive (4,5).

We herein report a case of PION that developed during antihypertensive therapy for hypertensive emergency and was successfully treated by increasing target BP levels until symptoms resolved.

Case Report

A 33-year-old Chinese woman visited her local ophthalmologist with decreased vision in the right eye. The patient had severe hypertension and was diagnosed with hypertensive retinopathy. She was referred to our department and admitted for hypertensive emergency with a BP of 268/168 mmHg, renal dysfunction, and heart failure symptoms. She had come to Japan for work at 20 years old. At approximately the same time, she underwent phototherapy for psoriasis. At 23 years old, she had given birth to a healthy infant with no history of preeclampsia or gestational hypertension, and there were no abnormalities on urine or blood tests during pregnancy. She did not undergo medical checkups after delivery, and her renal function and BP were not followed up. There was a family history of end-stage renal disease on hemodialysis in her maternal aunt; however, detailed information was not obtained.

On admission, the patient was awake and alert. Her height was 164 cm, body weight 89.6 kg, and body mass index 33.3 kg/m². A physical examination showed bilateral mild lower leg edema, of which the patient was unaware. An ophthalmologic examination revealed that the best-corrected decimal visual acuity (BCVA) was 0.7 (20/29 Snellen fraction) in the right eye and 1.2 (20/17 Snellen fraction) in the left eye, and the fundus showed multiple hard and soft exudates, retinal hemorrhaging, and normal optic discs in both eyes (Fig. 1A). Blood tests showed a serum creatinine level (sCr) of 4.2 mg/dL and blood urea nitrogen level of 37.0 mg/dL (Table). Plasma renin activity and the plasma concentration of aldosterone were 14 ng/mL/h (normal range 0.3-2.9 ng/mL/h) and 253 pg/mL (normal range 29.9-159 pg/mL), respectively. A urinalysis showed nephrotic-range proteinuria and glomerular hematuria. Electrocardiography revealed left ventricular hypertrophy. Cardiac enlargement (cardiothoracic ratio of 62.9%) with congestion was noted on chest X-ray. Cardiac echocardiography showed diffuse myocardial hypertrophy and enlargement of the inferior vena cava. Simple abdominal computed tomography revealed slightly atrophic bilateral kidneys with irregular surfaces (8.8×5.0 cm for the right kidney and 9.5×4.9 cm for the left kidney).

Figure 1.

Fundus photography. A: Fundus on admission showing multiple hard and soft exudates, retinal hemorrhaging, and normal optic discs in both eyes. B: Fundus findings did not show obvious changes at the onset of blindness.

Table.

Laboratory Findings on Admission.

Tests	Patient's results (normal range)
<Peripheral blood>
White blood cell count (/μL)	11,180 (3,300-8,600)
Red blood cell count (×104/μL)	373 (435-555)
Schistocytes (%)	<1 (<1)
Hemoglobin (g/dL)	10.1 (13.7-16.8)
Platelet count (×104/μL)	22 (15.8-34.8)
<Blood chemistry>
Total protein (g/dL)	6.0 (6.6-8.1)
Albumin (g/dL)	3.1 (4.1-5.1)
Aspartate aminotransferase (U/L)	27 (13-30)
Alanine aminotransferase (U/L)	26 (10-42)
Lactate dehydrogenase (U/L)	498 (124-222)
Total bilirubin (mg/dL)	1.0 (0.4-1.5)
Uric acid (mg/dL)	8.2 (3.7-7.8)
Blood urea nitrogen (mg/dL)	37.0 (8-20)
Creatinine (mg/dL)	4.2 (0.65-1.07)
Sodium (mEq/L)	140 (138-145)
Potassium (mEq/L)	3.8 (3.6-4.8)
Chloride (mEq/L)	105 (101-108)
<Serology>
C-reactive protein (mg/dL)	0.75 (0-0.14)
Immunoglobulin G (mg/dL)	1,181 (861-1747)
Immunoglobulin A (mg/dL)	375 (93-393)
Immunoglobulin M (mg/dL)	138 (33-183)
Complement component 3 (mg/dL)	126 (73-138)
Complement component 4 (mg/dL)	39.3 (11-31)
50% hemolytic complement activity (U/mL)	>65 (29-47)
Antinuclear antibody	<40 (<40)
Brain natriuretic peptide (pg/mL)	499.3 (0-18.4)
Plasma renin activity (ng/mL/h)	14 (0.3-2.9)
Plasma aldosterone concentration (pg/mL)	253 (35.7-240)
<Urinalysis>
Occult blood	(3+)
Protein (g/gCr)	3.84
N-acetyl-β-D-glucosaminidase (IU/gCr)	21.7 (0.9-2.4)
β-2-microglobulin (μg/gCr)	167.8 (4-180)
<Sediments>
Red blood cells (/high-power field)	20-29

The patient was treated according to the therapeutic strategy for hypertensive emergency described in the guidelines, namely, a reduction in systolic BP (SBP) by no more than 25% within 1 hour, and if it remained stable, further reductions to 160/100 mmHg within 2 to 6 hours and then to normal during the next 24 to 48 h (6,7). Treatment was started with the continuous intravenous infusion of nicardipine at 2 mg/h; however, the administration of a higher dose (10 mg/h) was required to achieve the target BP. Oral amlodipine was also initiated to reduce the dose of intravenous nicardipine because the long-term administration of high-dose intravenous nicardipine may cause phlebitis.

Four hours after the start of the continuous intravenous infusion of nicardipine, sudden and painless bilateral (right-dominant) vision loss occurred at a BP of 168/84 mmHg (Fig. 2). Visual acuity was no light perception in the right eye, and BCVA was 0.05 (20/400) in the left eye. Brain magnetic resonance imaging (MRI) showed posterior reversible encephalopathy lesions in the brain stem and bilateral nucleus (Fig. 3); however, these lesions did not explain the rapid loss of vision. Brain MRI did not reveal any other lesions, such as cerebral infarction, to explain eye symptoms. The event occurred in the late evening, and the patient was examined by the ophthalmologist the next morning. PION was suspected because fundus findings did not show obvious changes at the onset of blindness (Fig. 1B). Follow-up brain MRI on day 3 did not reveal any new lesions. Therefore, the patient was diagnosed with nonarteritic PION because of the lack of evidence for autoimmune diseases, such as a fever and an elevated C-reactive protein level, and previous findings suggested that ischemic optic neuropathy (ION) might develop during the treatment of hypertensive emergencies.

Figure 2.

Clinical course. Visual acuity is expressed by the best-corrected decimal visual acuity. The administration rate of nicardipine infusion is expressed using the maximum administration rate each day. SBP: systolic blood pressure, DBP: diastolic blood pressure, c.i.v.: continuous intravenous infusion, p.o.: per os, NLP: no light perception, RE: right eye, LE: left eye

Figure 3.

Magnetic resonance imaging was performed at the onset of vision loss. Axial fluid-attenuated inversion recovery shows high-signal areas in the pons (A) and bilateral nucleus basalis (B, arrowheads).

After the development of PION, the target SBP was set at 170 to 179 mmHg to maintain blood flow to the optic nerve. The patient's vision gradually improved to a BCVA of 0.3 (20/67) in the right eye and 0.9 (20/22) in the left eye on day 8, and the target BP was reduced with caution. On day 9, the oral administration of nifedipine CR was initiated to reduce the dose of intravenous nicardipine, and thereafter nicardipine administration was stopped on day 12. On day 13, olmesartan was started. On day 17, the patient was discharged from the hospital with a BP of approximately 135/95 mmHg and no re-exacerbation of vision loss.

Her renal function deteriorated with a peak sCr of 6.30 mg/dL during antihypertensive therapy but improved to sCr 3.13 mg/dL at the time of discharge. In parallel with antihypertensive therapy, the cause of hypertension was examined. Imaging studies and endocrinological evaluations were performed; however, the precise cause of secondary hypertension, such as primary aldosteronism or renal artery stenosis, could not be determined. In addition, there was no evidence of autoimmune diseases, including systemic lupus erythematosus and scleroderma, which exhibit renal insufficiency and severe hypertension. The patient was presumed to have developed hypertensive emergency complicated with chronic kidney disease (CKD) based on CT findings showing slightly atrophic kidneys. Although chronic glomerulonephritis or hereditary kidney diseases were suspected based on the urinalysis findings on admission and her family history, a definitive diagnosis for the cause of CKD was not reached because the patient was not willing to undergo a renal biopsy or genetic testing.

Her BCVA improved to 1.0 (20/20) in the right eye and 1.5 (20/13) in the left eye, and the sCr gradually decreased to 2.50 mg/dL at the 6-month follow-up.

Discussion

The most common cause of sudden painless vision loss is vascular insufficiency, such as central retinal artery occlusion, ION, and retinal vein occlusion (8). Acute-onset vision loss requires an urgent ophthalmologic consultation, and a funduscopic examination is crucial for distinguishing among these conditions (8). ION is a disease caused by circulatory disturbances in the arteries that feed the optic nerve (3) and is classified into anterior ischemic optic neuropathy and PION based on the location of the infarction. Furthermore, ION is classified into two types: the arteritis type (e.g., giant-cell arteritis) and nonarteritis type, and this differentiation is important for the selection of a treatment strategy. ION in the present case was classified as nonarteritic PION.

Hypertensive emergency is a life-threatening condition that requires the immediate initiation of treatment; however, rapid BP reduction needs to be avoided because it may cause ischemic organ injury, such as cerebral or cardiac ischemia (1,9). In hypertensive emergencies, severe mechanical injury from hypertension causes vascular autoregulatory failure associated with susceptibility to further ischemic injury during antihypertensive therapy (1). Therefore, an appropriate BP-lowering rate has been described in the guidelines to prevent ischemic injury during antihypertensive therapy (6,7). There is a similar autoregulatory system to maintain blood flow in the eye, and severe hypertension may disrupt the autoregulation of optic nerve circulation (10). Therefore, antihypertensive therapy may cause ION when the BP drops below the autoregulation range (4,5).

Case reports have described the development of ION during the treatment of hypertensive emergencies (4,5,11-14). The majority of patients showed extremely high BP before antihypertensive therapy and a rapid BP reduction to the normal range within 24 hours of treatment initiation. A later onset case of ION that developed approximately 36 hours after the initiation of antihypertensive therapy was previously reported (4) but showed hypotension with an SBP ＜100 mmHg, suggesting that the degree of BP reduction is also an important risk factor for the development of ION. The present case developed ION even though antihypertensive therapy was attempted based on the guidelines (6,7). This may be explained by the diastolic BP (DBP) at the onset being below the target level recommended by the guidelines, while the SBP was within the acceptable range. A previous study reported that a low DBP and SBP were associated with the risk of ION, indicating that not only the SBP but also the DBP influence the ocular blood flow (15). Therefore, controlling the SBP and DBP is important when treating hypertensive emergencies. Further studies are warranted to establish a safer antihypertensive strategy for the prevention of ION.

Once ION develops, there is no specific treatment, and its prognosis is dismal (1,16). However, if ION occurs during antihypertensive therapy due to relative hypotension, efforts to maintain the blood flow in the ocular and optic nerves may improve its prognosis. Previous case reports showed that the attenuation of antihypertensive therapy was effective, similar to the present case (11,12). Saline infusion or even vasopressors were used for relative hypotension after antihypertensive therapy.

The present case showed increased RAS activity. A vicious cycle of RAS activity plays an important role in the pathogenesis of hypertensive emergency, namely, severe hypertension causes endothelial injury to renal vessels leading to renal ischemia, and this induces the overactivation of RAS and further elevations in BP (9). RAS inhibitors, such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs), are useful as therapeutic agents to break this vicious cycle, and the efficacy of RAS inhibitors for hypertensive emergency has been reported (2,17). However, RAS inhibitors need to be initiated with caution, as they may cause a rapid reduction in BP and subsequent ischemia of the end organs in this condition (9,13). Our patient was treated with continuous infusion of nicardipine for more than 10 days to maintain the BP within 170-179 mmHg and, thus, perfusion of the optic nerve. ARBs were withheld until eye symptoms improved because of concerns regarding a rapid BP reduction and the difficulties associated with maintaining BP within the target range. The administration of 10 mg of olmesartan was initiated after vision improved; however, its effects were insufficient to withdraw intravenous nicardipine. The dose of olmesartan was not increased to avoid a reduction in intraglomerular pressure. Diuretics were also avoided as an antihypertensive treatment, as they may activate RAS, leading to the exacerbation of this clinical condition. Nifedipine CR was added as an oral anti-hypertensive drug to withdraw intravenous nicardipine, as calcium blockers, which do not directly inhibit RAS and do not markedly reduce the intraglomerular pressure, appeared to be safe under this clinical condition. However, since the safety and efficacy of the combined use of Ca blockers were not fully investigated, another class of anti-hypertensive drugs, such as α or β blockers, may be an alternative for reducing the dose of Ca blockers.

In summary, we encountered a patient who developed PION during treatment for hypertensive emergency despite antihypertensive therapy being performed according to the guidelines. Although there is no clear evidence for strategies to prevent PION during the treatment of hypertensive emergencies, the rapid normalization of the BP should be avoided. An early diagnosis and accurate BP control to maintain blood flow in the ocular and optic nerves may effectively restore vision.

The authors state that they have no Conflict of Interest (COI).