Hypertensive Encephalopathy
This 10 year old patient suffered from an acute, apparently transient illness characterized by headache, decreased alertness, and transient visual loss, with subsequent development of seizures. Her blood pressure was significantly elevated above normal levels for her age, and her symptoms resolved with anticonvulsant and antihypertensive treatment. Although an initial CT scan was reportedly unremarkable, a T2-weighted MRI study performed shortly after interhospital transfer demonstrated patchy, largely posteriorly located hyperintense lesions affecting white matter and the gray-white junction. A subsequent cerebral angiogram was normal. In the absence of findings suggesting an alternative cause, this presentation is characteristic of the potentially devastating syndrome of hypertensive encephalopathy, or acute posterior leukoencephalopathy. In this patient, the inciting cause of her illness is likely post-streptococcal glomerulonephritis, as suggested by the clinical and laboratory evidence of nephritis in association with markedly elevated anti-streptolysin O (ASO) and anti-DNase B titers.
Many disorders can produce acute, concomitant renal and cerebral dysfunction. In this case, an alternative diagnosis of systemic vasculitis was entertained, in view of multiple affected systems, cortical as well as white matter involvement, and an initial MRA suggested the possibility of a vasculopathy. However, a cerebral angiogram performed the following day was negative, mesenteric and renal arteriograms were likewise essentially normal, CSF examination did not show clear evidence of inflammation, and laboratory screens for several syndromes associated with vasculitic involvement were all negative. Together with the patient's rapid improvement on antihypertensive therapy, these findings make a diagnosis of vasculitis unlikely. Systemic lupus erythematosus can also produce acute renal dysfunction and meningocerebral involvement. In this patient, however, there was no history of polyarthralgias, inflammation of pleura or pericardium, malar rash, or constitutional evidence suggesting a pre-existing autoimmune disorder. Her ANA profile was negative, and a double-stranded DNA titer, which was weakly positive, does not in isolation confirm a diagnosis of lupus. Reduction in complement titers, noted in this patient, is seen not only in lupus but in other disorders such as post-streptococcal glomerulonephritis. Microangiopathic syndromes such as thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome, although frequently associated with renal and cerebral involvement, are unlikely in view of the patient's normal platelet counts, lack of clinical or laboratory evidence of diffuse hemolysis, lack of azotemia, and rapid improvement without specific immunotherapy. We also did not observe evidence of schistocytes on blood smears, which is characteristic of these disorders. Other post-streptococcal immune disorders (e.g., acute disseminated encephalomyelitis, Sydenham's chorea) may produce encephalopathy in association with a post-streptococcal glomerulonephritis, but would typically differ from this patient in MRI findings or in the clinical and MRI response to antihypertensive treatment. Again, the limited data from CSF examination did not suggest an immune-inflammatory process within the CNS. Frequently overlooked in patients with renal disease is the possibility of dehydration or renal loss of anticoagulant proteins predisposing to cerebral venous thrombosis. Venous thrombosis can present with bilateral, high-signal T2 changes on MRI, not conforming to a single arterial distribution, in association with headache and focal neurologic signs. However, the patient's MRI and cerebral angiogram did not show evidence of venous thrombosis. Malignant hypertension, as classically defined in the literature, may produce cerebral and renal dysfunction in addition to other evidence of end-organ damage (e.g., retinal changes, left-ventricular strain, schistocyte formation). Finally, occasional cases of posterior cerebral infarction from vascular occlusion may be associated with renal disease by a number of different intermediate mechanisms, but the onset of symptoms and signs is typically abrupt, and MRI findings would be expected to conform to a known vascular distribution, unlike the findings observed in this patient.
The causes of the syndrome of hypertensive encephalopathy, also known as reversible posterior leukoencephalopathy, are diverse. Common precipitants include acute elevations of blood pressure, acute renal decompensation, the peripartum period (eclampsia), and treatment with immunosuppressive drugs such as cyclosporine, FK-506 (tacrolimus), or mycophenolate derivatives. In one study of seven patients with this syndrome (none of whom were chronically hypertensive), the increase in arterial pressure resulting in hypertensive encephalopathy ranged from a low of 35% to a high of 62% over the patient's baseline. In all of these patients, the symptoms of hypertensive encephalopathy resolved completely after their blood pressure was satisfactorily controlled.
A 1996 study of 15 patients in Europe and the United States diagnosed with hypertensive encephalopathy, listed the most common clinical features as headache, altered alertness and behavior, seizures, and abnormalities of visual perception. A review of 52 cases of hypertensive encephalopathy in the pediatric population confirmed these four signs and symptoms as being most common in patients with this syndrome. In the latter study, fully 76% of the cases had at least three of the four listed signs and symptoms, although their severity varied considerably among cases. Alterations in alertness ranged from drowsiness and diminished spontaneity to frank stupor. Abnormalities of visual perception, ranging from blurred vision to frank cortical blindness, are almost always detectable. Seizures were most common near the onset of other neurologic symptoms, but could also develop at later times. Focal seizures typically generalized, and occurrence of multiple seizures was more common than isolated events.
The syndrome of hypertensive encephalopathy characteristically begins with a subacute prodromal period of altered alertness and activity. Lethargy and somnolence are often the first signs noted, with slowing of mental functions and confusion as the encephalopathy progresses. Increasing headache and visual blurring may also occur during this period, and frequently bring the patient to medical attention. This prodromal period is important to recognize as it marks an opportunity to minimize morbidity by initiating early treatment, and may help to differentiate hypertensive encephalopathy from other disorders. However, as previously noted, the syndrome of hypertensive encephalopathy can also become manifest by acute seizures without an obvious prodrome.
Findings suggesting hypertensive encephalopathy (reversible posterior leukoencephalopathy) are frequently absent on CT studies, and thus MR imaging has become the procedure of choice when this syndrome is suspected, both to detect the characteristic lesions and to screen for alternative causes. The most common abnormality on neuroimaging is evidence of edema involving the white matter in the posterior portions of the cerebral hemispheres, especially the parieto-occipital areas bilaterally. This is best seen using T2-weighted magnetic resonance imaging. All of 52 pediatric cases cited in one study had abnormal MRI findings. However, diffusion weighted MR imaging has not been shown to be useful in defining cases of hypertensive encephalopathy. In a recent report of seven patients with this syndrome, areas seen to be affected on conventional T2-weighted MR studies did not show high signal on diffusion-weighted images. Since diffusion-weighted imaging is most sensitive to increased water content with restricted diffusion (e.g., edema within cells), these findings suggest that the edema in hypertensive encephalopathy is not cytotoxic in nature but rather is vasogenic.
In many (but not all) patients with hypertensive encephalopathy (reversible posterior leukoencephalopathy), the calcarine and paramedian occipital lobe structures are relatively spared on neuroimaging. If present, this finding may help to distinguish hypertensive encephalopathy from bilateral infarctions of the posterior cerebral artery territory. Predominant involvement of white matter may also assist in this distinction. However, involvement of the gray-white junction, with edema extending into the cortex, may be more common than initial reports have suggested. Furthermore, lesions associated with this syndrome may not be limited to occipital areas of the brain, as changes in the brainstem, cerebellum, basal ganglia and frontal lobes have also been reported. Patients with hypertensive encephalopathy (reversible posterior leukoencephalopathy) undergoing follow-up imaging universally show improvement or complete resolution of imaging abnormalities, further suggesting that this syndrome is characterized by transient edema rather than infarction of the affected brain. Clinical improvement may precede resolution of MR imaging abnormalities. Although prompt treatment usually leads to resolution of symptoms, in some cases, neurologic dysfunction persists, suggesting that permanent injury can occur. Permanent injury may also result from intracerebral hemorrhage, especially in patients with thrombocytopenia or poorly controlled hypertension.
The pathogenesis of hypertensive encephalopathy is poorly understood, but it is thought that sudden elevations in systemic blood pressure exceed the autoregulatory capabilities of the brain vasculature. Failure of autoregulation then leads to regions of vasodilation and vasoconstriction with breakdown of the blood-brain barrier and focal transudation of fluid into the surrounding brain tissue. The frequent association of hypertensive encephalopathy with precipitating factors not normally responsible for blood pressure elevations, and the occasional occurrence of this syndrome in patients with only modest elevations of blood pressure, suggests that some other additional factor(s), either local or systemic, may be responsible for predisposing the cerebral vasculature to the effects of acute elevations in blood pressure. In this regard, attention has been focused on the selective vulnerability of watershed areas in the posterior circulation, which have been reported to exhibit increased sensitivity to normally circulating pressor agents, and deficiencies of locally produced vasodilating prostaglandins. Dysfunction of particular subtypes of endothelial cells has also been hypothesized to result in the vasospasm, blood-brain barrier breakdown, and loss of fluid from the intravascular compartment which is seen in hypertensive encephalopathy (reversible posterior leukoencephalopathy). However, the mechanism(s) leading to endothelial cell dysfunction in this syndrome are, at the present time, unclear.
Early diagnosis of the syndrome of hypertensive encephalopathy (reversible posterior leukoencephalopathy) is of the utmost importance, as it is generally regarded as reversible and readily treated by controlling the patient's blood pressure. It is also important to distinguish this syndrome from conditions which require different specific treatments (e.g., immunosuppression or anticoagulation), and from conditions in which aggressive lowering of blood pressure may be harmful (e.g., acute ischemic stroke). In the pediatric population, it is important to recognize that systolic blood pressures as low as 140 mm Hg, levels easily tolerated by most adults, can represent a serious hypertensive crisis. The potential reversibility of this syndrome, risk of permanent neurologic dysfunction if left untreated, and potential for diagnostic confusion with other serious disorders affecting the CNS mandate that a high index of clinical suspicion be maintained in patients presenting with neurologic symptoms associated with acute elevations of blood pressure, and that such patients be evaluated and treated on an emergency basis.
In other cases, we have occasionally observed a reluctance on the part of physicians to consider the possibility of hypertensive encephalopathy without demonstrated evidence of other end-organ damage attributable to elevated blood pressure (e.g., schistocytes on blood smear, evidence of retinal edema or papilledema, or left ventricular strain pattern on ECG). In view of the range of blood pressure values associated with this clinical syndrome, and the evidence for factors predisposing to selective vulnerability of the cerebral circulation to even modest acute elevations in blood pressure, this view can no longer be considered tenable.
This patient did very well, with treatment of her elevated blood pressure resulting in nearly immediate clinical improvement, and complete resolution of her symptoms within two days of her hospitalization. Long-term anticonvulsant therapy was not initiated, as her seizures were felt to result from a reversible process. A follow-up MR study demonstrated complete resolution of all radiographic abnormalities. It was felt by the clinical team that her hypertensive encephalopathy was secondary to transiently elevated systemic blood pressure, associated with post-streptococcal glomerulonephritis. No other cause of her illness was found which would require initiation of additional specific therapies.
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