Clinical manifestations

Presentation and course

Hypertension-induced neurologic signs and symptoms can be broadly divided into either focal deficits associated with chronic hypertension (eg, lacunar stroke or hypertensive basal ganglia hemorrhage) or diffuse cerebral dysfunction related to acute hypertension, which is described as “hypertensive encephalopathy.”

Patients with hypertensive encephalopathy most commonly present with headache, altered mental status—ranging from mild confusion to coma, nausea, vomiting, visual changes, and seizures. Headache is the most common symptom, occurring in greater than 75% of patients with hypertensive encephalopathy (08). Gradual onset of morning headaches accompanied by nausea and vomiting is typical, and symptoms may progress to stupor, coma, and death if left untreated.

Visual disturbances are also common, even in absence of funduscopic abnormalities (28). The presence of cortical visual symptoms remains a helpful diagnostic feature corresponding to occipital lobe involvement. Retinal or optic disc ischemia and papilledema may be present in some patients with visual complaints (03), but more often, the fundi are unremarkable, and the visual symptoms relate to involvement of the occipital lobe involvement (35; 02).

Typical visual symptoms may range from a nonspecific blurriness with normal acuity to color blindness, visual field defects, impairment of facial recognition (prosopagnosia), parietal lobe dysfunction with visual neglect, cortical blindness, denial of blindness (Anton syndrome), and visual hallucinations. Periodic alternating gaze deviation and nystagmus have also been reported when vasogenic edema involves the cerebellum (31).

The level of blood pressure elevation that will result in hypertensive encephalopathy is variable. However, a rapid rise in blood pressure in a previously normotensive patient is more likely to result in manifestations of hypertensive encephalopathy than a similar elevation in a chronically hypertensive patient; thus, a moderate elevation in blood pressure can be sufficient to produce the syndrome and should raise suspicion in the appropriate clinical context (38).

Acute renal failure leading to hypertension and volume overload as well as medication nonadherence are common precipitants. Use of mineralocorticoids, erythropoietin (10), or MAO-inhibitors, withdrawal of clonidine, and abuse of drugs with phencyclidine and cocaine all have been reported to cause hypertensive encephalopathy (19).

The condition may also be precipitated by Cushing disease, pheochromocytoma, and scleroderma (43; 51). One case report described cortical blindness in a patient with untreated malignant hypertension in the setting of undiagnosed pheochromocytoma (40). There have been two case reports of patients with SARS-CoV-2 infection developing seizures or headaches in the context of hypertension and later found to have posterior predominant white matter changes, which is consistent with the syndrome of hypertensive encephalopathy/PRES. Although the significance of hypertension in these cases is unclear, both patients had elevated blood pressures at the time of symptom onset, and one responded well to verapamil, which has both vasodilatory and blood pressure lowering properties (12; 17). Another study looking at two case reports of patients with COVID-19 demonstrated that these patients may be susceptible to encephalopathy resulting from hypertension and that this may prolong ventilator time (29). It has been postulated that hypertension and, specifically, blood pressure variability, which is exacerbated by COVID-19’s effect on renin-angiotension-aldosterone system, results in endothelial dysfunction and hypertensive encephalopathy (54).

Hypertensive encephalopathy may also occur in the pediatric population. In these cases, a secondary cause for hypertension is often discovered. For example, one retrospective study found that elevated blood urea nitrogen (BUN) levels were independently associated with hypertensive encephalopathy, possibly suggesting that kidney injury and resultant BUN elevation makes children more susceptible to vascular autoregulation dysfunction (55). Another case report described hypertensive encephalopathy as the presenting symptom of a rare autosomal dominant disorder called homozygous familial hypercholesterolemia, which affects low-density lipoprotein receptor genes (33).

These cases of severe “brainstem hypertensive encephalopathy” are important to recognize because a decompressive ventriculostomy (01) and cerebellar resection (06) may be lifesaving, although some may respond well to antihypertensive medication (49).

Prognosis and complications

Early recognition of hypertensive encephalopathy followed by prompt lowering of blood pressure will most often result in clinical recovery, usually within hours to several days, but sometimes the recovery is slower. Complete resolution of the MRI signal changes is often delayed, sometimes taking several weeks or months (42).

Delayed recognition and treatment of the clinical syndrome, on the other hand, may lead to permanent neurologic deficits or even death. Complications include cerebral hemorrhage and infarction. Overzealous lowering of blood pressure during the acute phase may also result in permanent neurologic deficit due to ischemic stroke, especially in border zone territories (18).

Rarely, the vasogenic edema that arises from endothelial cell dysfunction may be extreme enough to result in intracranial pressure crisis, which may progress to herniation if not immediately addressed (20). As such, transorbital sonography for noninvasive measurement of the optic nerve sheath diameter has been suggested as a way to noninvasively identify raised intracranial pressure (30).

In extreme cases, obstructive hydrocephalus may occur due to brainstem edema, causing compression of the cerebral aqueduct or fourth ventricle. Emergent ventriculostomy may be necessary (01).

Clinical vignette

A 38-year-old woman with systemic lupus erythematosus had a several-year history of hypertension. Two weeks after she was discharged from the hospital, after successful treatment of peritonitis related to her dialysis, she was readmitted, complaining of several days of headaches, nausea, unsteadiness of gait, and intermittent visual blurriness. On the morning of the admission, she had a seizure. Examination revealed elevated blood pressure of 200/140 mm Hg. She was edematous, confused, and drowsy. Her neck was supple, and her visual fields were full. Her fundi were remarkable for bilateral disc swelling and arteriolar narrowing without frank hemorrhages. An MRI revealed bilateral occipital high-intensity signal changes near the occipital pole on T2-weighted and FLAIR sequences. On further questioning, she stated that she had not been taking her antihypertensive medications due to financial hardship since her discharge from the hospital. Brief treatment with intravenous nitroprusside, followed by reinstitution of her oral blood pressure medications, resulted in rapid clinical improvement to her baseline, and she was discharged on the fourth hospital day.

Biological basis

Etiology and pathogenesis

Failure to clearly separate the pathologic changes of chronic hypertension and acute hypertensive encephalopathy has delayed understanding of the pathogenesis of both. In addition, only few cases of acute hypertensive encephalopathy undergo brain biopsy as a diagnostic investigation, so the range of pathologic changes accompanying the disorder cannot be studied comprehensively.

In general, the pathophysiology of hypertensive encephalopathy can be regarded as failure of cerebral autoregulation from sudden elevation of blood pressure that results in endothelial injury and vasogenic edema. Persistent damage to small vessels leads to vessel stenosis and decreased vessel reactivity; in turn, there is a decrease in hemodynamic reserve with impaired autoregulation (48). Normally, cerebral perfusion is maintained despite fluctuations in systemic blood pressure by adjustment of arteriolar caliber. Acute hypertensive encephalopathy represents a failure of cerebral blood flow regulation beyond the autoregulatory range (47).

Using a mouse model developed for studying hypertension and vascular dementia, researchers have found MRI evidence of T2-hyperintense lesions in the cortical watershed and posterior white matter that resemble the changes humans have with hypertensive encephalopathy. Histopathology of these animals demonstrates severe blood-brain barrier disruption, white matter vacuolization, and microbleeds that are predominantly posterior (24). Additionally, the hematologic data demonstrate thrombocytopenia and is suggestive of thrombotic microangiopathy. TTP-HUS and thrombotic microangiopathy have been observed to concurrently occur in patients with hypertensive encephalopathy; however, it is uncertain if thrombotic microangiopathy plays a role in the pathogenesis of hypertensive encephalopathy or if these are merely two coincidental consequences of malignant hypertension (11).

Preferential posterior cerebral involvement in this syndrome may be due, in part, to decreased sympathetic innervation in the vertebrobasilar artery territory in contrast to more robust sympathetic innervation in the carotid system (14). More effective vasoconstriction of the carotid arterial territory results in reduction of distal perfusion pressure during malignant hypertension, whereas decreased sympathetic innervation in the vertebrobasilar distribution allows for higher capillary pressure that may overwhelm the autoregulatory limit. Distal border zone or watershed regions may be more vulnerable in hypertensive encephalopathy, but the reason is unclear (22).

Epidemiology

The exact prevalence and incidence of hypertensive encephalopathy is unknown. Data from 1981 suggest that less than 1% of an estimated 60 million Americans with hypertension will have a hypertensive crisis (21). An even smaller portion of this group will have hypertensive encephalopathy. Data from a hospital in Ontario that tracked all visits to the emergency department for hypertension from 2002 to 2012 (total number of more than 200,000 visits) found that only 7.8% of visits resulted in hospitalization, and of those, less than 1% were ultimately diagnosed with hypertensive encephalopathy (36). In contrast, other studies suggest a higher incidence. An accurate estimate remains difficult due to poorly defined diagnostic criteria, variable and often limited clinical manifestations, arbitrarily defined upper limits of blood pressure, and lack of neuroradiologic documentation. Although hypertensive encephalopathy may occur at any age, it is more common in the second to fourth decades of life, in part due to higher prevalence of eclampsia and nephritis.

Prevention

The best means of preventing hypertension encephalopathy is blood pressure control, usually with antihypertensive medications. For patients on immunosuppressant treatment known to cause PRES or RPLS, blood pressure should also be closely tracked as these patients often develop clinical and radiographic changes of posterior reversible leukoencephalopathy in the context of concomitant hypertension (26).

Differential diagnosis

Confusing conditions

The most common symptoms of hypertensive encephalopathy—headache, nausea, and visual complaints—are nonspecific; thus, the differential diagnosis for this presentation initially can and should be broad. In patients with acute onset of headache and hypertension, subarachnoid hemorrhage or intraparenchymal hemorrhage must be considered. Patients with a more subacute presentation should be evaluated for venous sinus thrombosis or idiopathic intracranial hypertension.

Funduscopic abnormalities and proteinuria should be sought, but these may not be present. Gradual symptom onset over several days accompanied by significant blood pressure elevation and followed by rapid improvement after lowering of blood pressure are important in supporting hypertensive encephalopathy. Frequently, however, the lack of pathognomonic clinical features and absence of diagnostic laboratory or radiologic abnormalities make hypertensive encephalopathy a diagnosis of exclusion.

An MRI appearance of predominantly posterior cerebral white matter lesions with mild or absent hypertension should prompt investigation of the other etiologies of posterior reversible encephalopathy, such as eclampsia or exposure to immunomodulatory or chemotherapeutic agents, such as cyclosporine, methotrexate, interferon alpha, cisplatinum, tacrolimus, and vascular endothelial growth factor inhibitor bevacizumab (16).

Depending on the clinical context, the differential also includes posterior cerebral artery territory infarction, venous infarcts, intracranial tumors, osmotic myelinolysis, vasculitis, and such infectious or inflammatory disorders as progressive multifocal leukoencephalopathy, multiple sclerosis, or acute disseminated encephalomyelitis.

Associated or underlying disorders

By definition, hypertension must be present to make a diagnosis of hypertensive encephalopathy. Common precipitants of acute hypertensive crisis include acute or chronic renal failure with volume overload, medications that may induce hypertension (eg, MAO-inhibitors, vasopressors, clonidine withdrawal), or drugs of abuse (eg, cocaine, methamphetamines).

As discussed above, posterior reversible encephalopathy syndrome and eclampsia likely share a common pathophysiology of failed cerebral autoregulation and endothelial dysfunction.

Diagnostic workup

Routine blood tests, urine analysis, and urine toxin screens will help to assess renal function and exclude exogenous toxins that may be associated with hypertensive encephalopathy.

Imaging studies with CT or MRI scans are particularly helpful in suspected cases, often revealing bilateral, posterior cortical, and white matter lesions that extend beyond a posterior cerebral artery territory. A T2-weighted or fluid-attenuated inversion-recovery MRI scan is particularly helpful in disclosing the full extent of the signal abnormality (05). The relative absence of mass effect or pathologic contrast enhancement helps to differentiate hypertensive encephalopathy from a tumor or an abscess. Bilateral posterior cerebral artery distribution infarction can be excluded by the frequent sparing of calcarine and paramedian occipital lobe structures in hypertensive encephalopathy. T2 changes found most often represent vasogenic edema without ischemia or infarct, as evidenced by the absence of diffusion restriction on MRI (45).

Although posterior lesions are the most common distribution identified, anterior lesions have also been reported and confirmed by biopsy demonstrating white matter necrosis and micro-hemorrhage with no evidence of vasculitis (25). MRI may also reveal a central variant pattern with preferential involvement of brainstem, thalami, and periventricular white matter (07; 46).

Spinal fluid examination in patients with hypertensive encephalopathy is nondiagnostic. It is often obtained in non-classic cases to rule out alternative diseases such as encephalitis, malignancy, and vasculitis. Despite the frequent appearance of cerebral swelling and edema in patients with hypertensive encephalopathy, Datar and colleagues demonstrated that among patients diagnosed with posterior reversible leukoencephalopathy (84% of whom were hypertensive), the median opening pressure was 17 mmHg (normal is less than 20 mmHg). Mild elevation in the CSF protein was seen in the majority of cases, with a median total protein level of 58 mg/dL (normal is less than 35 mg/dL). On univariate analysis, vasogenic edema involving the thalamus, cerebellum, brainstem, and basal ganglia was associated with higher CSF protein level. In addition, there was a direct correlation between CSF protein level elevation and the extent of vasogenic edema on brain MRI scan (09). Lymphocytic pleocytosis is unusual, and neutrophilic pleocytosis is distinctly rare (37). Its presence should suggest a separate underlying infectious or inflammatory disorder.

EEG recordings in patients with hypertensive encephalopathy and reversible cerebral vasoconstriction syndrome or posterior reversible leukoencephalopathy are frequently abnormal, but the findings are nondiagnostic, ranging from slowing of the background activity to epileptiform transients in up to 80% of patients (50).

Management

Hypertensive encephalopathy represents one of the true hypertensive emergencies, the others being progressive myocardial ischemia, aortic dissection, and renal insufficiency. Prompt but gradual lowering of the mean arterial pressure by approximately 25% (or diastolic to 110 to 120 mmHg) over several minutes to a couple of hours is warranted in most hypertensive emergencies (15). Parenteral antihypertensive agents should be first line as oral agents do not have the ability to be titrated in a time urgent fashion. In chronic, poorly controlled patients, higher diastolic levels should be targeted. Further lowering of the blood pressure to normal levels is a reasonable approach over ensuing weeks for long-term management. Careful blood pressure monitoring is necessary because treatment-induced stroke may occur (32).

Patients should be evaluated for signs of increased intracranial pressure with noninvasive modalities like transorbital ultrasonography, transcranial dopplers, or pupillometry. If there is a concern for severe intracranial hypertension, invasive intracranial pressure monitoring may be needed to guide treatment.

Outcomes

With blood pressure management, most patients with hypertensive encephalopathy will recover with accompanying normalization of the MRI findings over days to weeks. However, delay in treatment may result in hemorrhage or, less commonly, ischemia. Although blood pressure control is necessary, as a result of the pathologic cerebral vasoregulation and pressure-dependent cerebral perfusion, abrupt blood pressure control may result in ischemia, especially in border-zone areas (32).

Special considerations

Pregnancy

Although eclampsia has long been recognized to cause a similar clinical syndrome as hypertensive encephalopathy, it was not until 1935 that Volhard suggested “eclamptic uremia” might have the same underlying pathophysiology as hypertensive encephalopathy (53). Advanced neuroimaging confirmed the similarities in the radiographic findings: mainly posterior-predominant vasogenic areas of vasogenic edema, which are reversible with treatment of eclampsia.

Thus, hypertensive encephalopathy and the encephalopathy of (pre)eclampsia likely share a common pathogenesis of endothelial dysfunction and failure of cerebral vasculature autoregulation. Pathologic studies support this shared mechanism of disease and have demonstrated cerebral edema and petechial hemorrhages, especially in the parieto-occipital and occipital lobes. Microscopically, these petechiae are ring hemorrhages around capillaries and precapillaries that are occluded by fibrinoid material (13).

Like posterior reversible leukoencephalopathy, there are primarily two theories that might explain the encephalopathy of eclampsia. In the first, circulating endogenous cytokines damage renovascular networks, resulting in the abrupt onset of hypertension. This theory posits that it is the change in blood pressure and perfusion pressure that drives pathology (04). Alternatively, endogenic cytotoxins caused by eclampsia may drive endothelial dysfunction and disrupt vascular integrity triggering fluid extravasation and edema formation (34). As described above, it is hypothesized antiangiogenic factors such as sFlt-1 (soluble vascular endothelial growth factor receptor 1) and sEng (soluble endoglin) trap circulating vascular endothelial growth factor and transforming growth factor Beta resulting in endothelial dysfunction and vasogenic edema in multiple organ systems, including the brain (27).

Treatment is aimed at prompt lowering of blood pressure and expedited delivery of the fetus to prevent seizures and further neurologic complications. If treatment is not delayed, then clinical and radiographic changes are most often reversible.