Mental status changes attributable to arterial BP are most often seen with low, rather than high, BP and are due to impaired cerebral blood flow. Cerebral perfusion pressure (CPP), the pressure gradient that influences blood flow to the brain, is the difference between mean arterial pressure (MAP) and intracranial pressure (ICP) and is represented by the formula:

where CBF is cerebral blood flow and CVR is cerebrovascular resistance.

Cerebrovascular autoregulation maintains a constant blood flow over a wide range of CPP, due to changes in CVR. Thus, under normal conditions, moderate changes in CPP have little effect on CBF. An increase in CPP produces vasoconstriction, and a decrease produces vasodilation. Typically for adults, CPP ranges between 50 and 100 mm Hg, though some research suggests 70 to 90 mm Hg to be a more accurate number.^1-3 In chronically hypertensive individuals, the cerebral arterioles develop medial hypertrophy and lose their ability to dilate effectively at lower pressures.⁴ This can lead to decreased cerebral perfusion when systemic BP falls, even though BP may remain within a range that would provide adequate cerebral perfusion in patients without hypertension.

The mechanisms governing CBF autoregulation are controversial.⁵ Most likely, the autoregulatory vessel caliber changes are influenced by arterial smooth muscle and metabolic mechanisms.^6,7 Perivascular nerves and the vascular endothelium may also play a role.^8-10 CBF autoregulation typically operates when mean systemic BP (SBP) is between 50 and 150 mm Hg and can be modulated by sympathetic nervous activity and the renin-angiotensin system (RAS).²

Central nervous system (CNS) trauma or acute ischemic stroke may impair CBF autoregulation, leaving surrounding brain tissue vulnerable to over or underperfusion. Likewise, autoregulation may be lost in the setting of a space-occupying brain lesion such as a tumor or hematoma.¹¹ Autoregulation may be regained by hyperventilatory hypocapnia.¹² Patients with diabetes may have impaired CBF autoregulation, due to diabetic microangiopathy.¹³ In summary, cerebral autoregulation is a dynamic process affected by a patient’s medical condition and, in particular, previous BP control.

Hypertensive encephalopathy (HE) was first described by Oppenheimer and Fishberg in 1928 in the report of a patient with acute glomerulonephritis complicated by neurologic symptoms, convulsions, and severe hypertension.¹⁴ It is a descriptive term referring to reversible cerebral disorders associated with high blood pressure in the absence of cerebral thrombosis or hemorrhage.

Hypertensive encephalopathy occurs most frequently when diastolic BP exceeds 120 mm Hg in a patient with chronic hypertension.¹⁵ At this level of diastolic BP, cerebral autoregulation cannot effectively limit blood flow to the brain.¹⁶ Cerebral edema and microhemorrhages may occur. Clinically, headaches precede progressive deterioration in neurologic status. Hypertensive encephalopathy defines 16.3% of cases of hypertensive emergencies, more than intracranial hemorrhage (ICH) or aortic dissection.¹⁷ The syndrome is generally precipitated by a severe and rapid rise in BP. After BP reduction all signs and symptoms often resolve.

Two theories have been proposed to account for the clinical and radiologic abnormalities associated with HE. The first proposes that HE results from spasm of the cerebral vasculature in response to acute hypertension; in other words, excessive autoregulation leads to ischemia and edema particularly in the regions bordering the arterial blood supply.^18,19 A more recent hypothesis suggests the syndrome results from breakthrough of autoregulation.^20-22 This would result in interstitial extravasation of proteins and fluids, producing focal vasogenic edema in the peripheral vascular distribution of the involved vessel. Vascular injury, tissue ischemia, and the release of vasoconstrictive mediators worsen the condition.^23,24 Fibrinoid necrosis eventually occurs if the process is not interrupted. Figure 50-1 shows the renal arteriolopathy associated with hypertensive emergency, and Figure 50-2 shows changes associated with chronic hypertension.

Magnetic resonance imaging (MRI) may now allow for a rapid and more specific diagnosis of HE. In uncomplicated cases, brain MRI shows areas of cerebral edema predominately in posterior white matter.²⁵ Lesions may be symmetric or asymmetric. Although not diagnostic, the terms posterior reversible encephalopathy syndrome (PRES) or reversible posterior leukoencephalopathy syndrome (PLS) have been adopted for this neuroradiologic finding. Flair imaging is the most sensitive sequence with which to detect areas of cerebral edema. The lesions are hyperintense on T2-weighted imaging and flair, and iso- to hypo-intense on T1-weighted imaging.²⁶ Diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping shows the edema in HE to be vasogenic in origin.²⁵ Figure 50-3 demonstrates typical MR findings for hypertensive encephalopathy.

Some drugs are cerebral vasodilators and have the potential to impair autoregulation and raise ICP with systemic hypertension. This is seen most commonly with at least some calcium antagonists and hydralazine.^27,28 In particular, hydralazine has multiple cerebral hemodynamic effects. It raises ICP and, because of its effect to lower systemic pressure, reduces CPP. Subsequently, CBF may increase though not necessarily before cerebral underperfusion has occurred.²⁹

Angiotensin-converting enzyme (ACE) inhibitors improve autoregulation during hypotension, probably by reducing angiotensin II–dependent tone in cerebral resistance vessels. With chronic antihypertensive treatment, CBF autoregulation may return to normal. ACE inhibitors in particular, when given chronically, may maintain autoregulation at the lower limit of CPP. Apart from this example, it is uncertain if there is a class-specific beneficial pharmacologic effect of antihypertensive drugs directly on the cerebral circulation.

The development of uncontrolled hypertension associated with sudden discontinuation of antihypertensive medications has been described frequently in the medical literature and is referred to as discontinuation syndrome, acute post treatment syndrome, acute withdrawal syndrome, and rebound hypertension.^30-32 This syndrome has been reported to occur with clonidine, methyldopa, propranolol, and rarely with ACE inhibitors.^33-40 Of the medications mentioned, clonidine has been studied best in determining the mechanism responsible for rebound hypertension following discontinuation. Clonidine is a widely used antihypertensive drug that suppresses the sympathetic nervous system via a central mechanism by agonism of inhibitory α receptors. Sudden discontinuation of clonidine leads to rebound hypertension due to secretion of stored norepinephrine.⁴¹ This effect is amplified in patients also taking propranolol (and possibly other ß-adrenergic blockers) due to unopposed peripheral α receptor activation.⁴² Mirtazapine, which is a central α receptor blocker, was reported to produce extreme hypertension in a patient maintained on clonidine, presumably by blocking clonidine’s central effect.⁴³

Hypertension is associated with impaired cognition, particularly executive functions, and is believed to play a causal role in cognitive decline above and beyond its relationship to stroke.^44,45 Pathologic changes in the brain associated with hypertension include vascular remodeling, impairment of cerebral autoregulation, white matter lesions, unrecognized lacunar infarcts, and Alzheimer’s-like changes such as amyloid angiopathy and cerebral atrophy.⁴⁶ Hypertension appears to affect the subcortical white matter in particular and may affect a substantial volume of variably damaged tissue that is potentially salvageable through optimization of blood supply.

Based on the evidence above, it is probable that our patient has hypertensive encephalopathy in association with uncontrolled blood pressure, due to withdrawal of high-dose clonidine, with concurrent atenolol use. This case emphasizes the importance of educating patients about the adverse effects of abrupt discontinuation of antihypertensive agents, particularly clonidine.

Fairly strong evidence supports the deleterious effects of rapid reductions in BP in the early period following a stroke.^47-51 In patients with ischemic stroke, immediately beyond the area of infarction, the penumbra is at high risk for ischemia and infarct extension.^52,53 A number of factors about BP in patients with a stroke are worth emphasizing. First, BP frequently rises immediately following cerebral ischemia.^53,54 (Proposed mechanisms for increases in BP after stroke generally include excess sympatho-adrenal tone from direct neural injury,⁵³ altered parasympathetic function, catecholamine release, and cytokine activation.^55-58) BP typically begins to fall spontaneously within hours to days after stroke, without intervention.^55,59 As a result, medication-induced reductions in BP may lead to CPP below a level that allows adequate cerebral perfusion to the penumbra. Exacerbating this tendency, patients with a stroke typically have had long-standing HTN and, thus, an autoregulatory curve that is shifted to the right.