Posterior Reversible Encephalopathy Syndrome and Other Cerebrovascular Syndromes
Sara K. Rostanski
Fawaz Al-Mufti
Claire S. Riley
Joshua Z. Willey
POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME
The posterior reversible encephalopathy syndrome (PRES) has been evolving as a clinical entity for the last 10 years. Several terms have now been used interchangeably to define PRES, including reversible posterior leukoencephalopathy syndrome (RPLS), or by naming the underlying clinical cause. PRES is now recognized as a clinicoradiologic syndrome rather than a distinct disease entity with multiple different etiologies, which share several common features with the reversible cerebral vasoconstriction syndrome.
EPIDEMIOLOGY
Limited data exist to describe the epidemiology of this condition. The literature has mostly been centered around case reports and case series.
PATHOBIOLOGY
Disorders that cause PRES have in common cerebral injury due to failure of the cerebral vasculature to adapt to changes in blood pressure or cerebral hemodynamics or an excessive vascular reactivity in cerebral arterioles. The hallmark clinical entities that most often cause PRES are hypertensive encephalopathy and eclampsia (see also Chapter 124). A focal process that may share some features of this condition is cerebral hyperperfusion syndrome occurring after carotid endarterectomy. In patients with chronic hemodynamic failure, distal arterioles tend to dilate to reduce cerebral vascular resistance; in clinical scenarios of a sudden increase in cerebral blood flow, these maximally dilated cerebral arteries may not be able to adapt further to changes in cerebral blood flow, leading to cerebral edema and hemorrhage. In addition to impaired autoregulation in the face of hypertension and hyperperfusion, in many cases, PRES is also associated with abnormal capillary permeability in the brain and large-vessel proximal vasoconstriction detectable by angiography. Up to 87% of patients with PRES have diffuse vasoconstriction if studied with angiography, hence, PRES and reversible cerebral vasoconstriction syndrome (discussed later) often overlap and are felt in many cases to share a common pathogenesis. The result is vasogenic edema that preferentially affects the posterior hemispheres of the brain and the white matter more than the gray matter. Interspersed in this picture are scattered microinfarcts and microhemorrhages. The most severe cases can manifest as massive global cerebral edema with transtentorial herniation or larger infarcts or hemorrhages.
CLINICAL FEATURES
The clinical syndrome associated with PRES is dependent on the underlying cause, although regardless of underlying etiology, common clinical symptoms include headache, seizures, loss of visual acuity including blindness, nonlocalizing confusion, and somnolence (Table 43.1). The neurologic examination will not reveal localizing findings on the mental status, although cases of cortical blindness and Balint syndrome may occur due to involvement of the occipital lobes (Fig. 43.1). Other described findings include visual field cuts, loss of visual acuity, papilledema, and mild hemiparesis. More prominent bulbar and cerebellar symptoms have been described in case series where the pathology is restricted to the brain stem. A larger variety of clinical syndromes, which can be localized anywhere in the cerebral hemisphere occurs in the context of severe cases with cerebral infarction or hemorrhage. PRES leading to edema primarily involving the brain stem has also been described (Fig. 43.2).
TABLE 43.1 Approximate Frequency of Clinical Features of Posterior Reversible Encephalopathy Syndrome | ||||||||||||||
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DIAGNOSIS
Neuroimaging is essential in the diagnosis of this condition, with magnetic resonance imaging (MRI) providing greater clinical information than computed tomography (CT). The “classical” description in this condition is white matter hyperintensities seen on fluid-attenuated inversion recovery (FLAIR) sequences representing vasogenic edema (see also Chapter 21). The FLAIR changes have a predilection to occipital lobes and adjacent posterior temporal and parietal regions and are not typically associated with cerebral microhemorrhages, infarction, or involvement of gray matter structures. A hallmark of this condition is that these clinical findings improve with treatment of the underlying condition, along with the cerebral vasogenic edema. To some degree, however, the term posterior reversible encephalopathy syndrome may be a misnomer, as in several cases, the changes seen clinically or on imaging are neither posterior predominant nor reversible. Common underlying predisposing conditions include hypertensive emergency/malignant hypertension, eclampsia, and medication toxicity (notably FK-506 in prevention of transplant organ rejection). Table 43.2 describes a variety of underlying etiologies for PRES.
The differential diagnosis of PRES includes conditions which have a predilection for causing bilateral involvement of the hemispheres, particularly the white matter, or that affect watershed
regions between the major vascular territories. These include progressive multifocal leukoencephalopathy, encephalitis, vasculitis, and watershed infarction from cardiac arrest, among others.
regions between the major vascular territories. These include progressive multifocal leukoencephalopathy, encephalitis, vasculitis, and watershed infarction from cardiac arrest, among others.
 FIGURE 43.1 Magnetic resonance FLAIR image of posterior reversible encephalopathy syndrome on admission (A) and 2 weeks after stopping inciting medication (B). |
TREATMENT
Management of PRES begins with a careful review of medications and discontinuation of any potential inciting agent. Patients with PRES require the symptomatic measures usually taken in the intensive care unit (ICU). The need for upper airway protection should be evaluated continuously in patients with marked consciousness impairment or seizure activity.
Control of hypertensive emergency, if present, is an important part of the symptomatic management. The aim is not to normalize the blood pressure but rather to decrease the mean arterial pressure (MAP) by 20% to 25% within the first 2 hours and to bring the blood pressure down to 160/100 mm Hg within the first 6 hours. More rapid blood pressure reduction is not recommended because it can aggravate the cerebral perfusion pressure alterations and promote ischemia. Continuous infusion of intravenous (IV) antihypertensive agents is preferred to allow for precise blood pressure control within a tight range. The most commonly used agents include labetalol, nicardipine, or clevidipine if available (see Table 38.3).
Antiepileptic treatment should be initiated on an emergency basis for treatment of clinical or electrographic seizures or status epilepticus (see also Chapter 6). All comatose patients should undergo 48 hours of surveillance continuous electroencephalogram (EEG) monitoring in the ICU given the high risk of nonconvulsive seizures. Active seizures should be treated with a full loading dose of lorazepam 0.1 mg/kg IV. Once controlled, patients should be loaded with an IV anticonvulsant such as phenytoin 20 mg/kg IV, followed by 300 mg daily, or valproic acid, 45 mg/kg, followed by 500 mg IV every 6 hours. Refractory status epilepticus after treatment with a full loading dose of a benzodiazepine and IV antiepileptic agent should be treated with midazolam infusion (0.2 mg/kg IV load, followed by a starting dose of 0.2 mg/kg/h), which mandates continuous EEG monitoring and endotracheal intubation.
Patients with PRES due to eclampsia should also be started on magnesium infusion (1 to 2 g/h targeting a serum magnesium level of 2.0 to 3.5 to 4 mmol/L) [Level 1].1 Magnesium infusion is also recommended for any PRES patient with hypomagnesemia.
REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME
In 2007, the term reversible cerebral vasoconstriction syndrome (RCVS) was proposed to encompass several previously described miscellaneous cerebral vasculitic disorders, which included
Call-Fleming syndrome, thunderclap headache-associated vasoconstriction, postpartum angiopathy, migraine angiitis, and cerebral vasospasm caused by cocaine, amphetamines, sumatriptan, and other serotonergic and sympathomimetic drugs.
Call-Fleming syndrome, thunderclap headache-associated vasoconstriction, postpartum angiopathy, migraine angiitis, and cerebral vasospasm caused by cocaine, amphetamines, sumatriptan, and other serotonergic and sympathomimetic drugs.
 FIGURE 43.2 FLAIR images of posterior reversible encephalopathy syndrome presenting with prominent brain stem involvement (A-D). Nine days later, the lesions had significantly resolved (E-H). |
RCVS is characterized by a monophasic course of diffuse segmental constriction of cerebral arteries that resolves spontaneously within weeks to months. Although the angiographic findings may be indistinguishable from primary angiitis of the central nervous system (PACNS), RCVS is not a chronic condition that requires long-term immunosuppression. RVCS is not a form of vasculitis because vessel wall inflammatory infiltrates do not occur, although the angiographic findings are similar. The cerebrospinal fluid (CSF) is normal, and the clinical course tends to be benign given the marked and extensive angiographic abnormalities that can occur.
EPIDEMIOLOGY
Due to the lack of epidemiologic studies, the true incidence of RCVS has not been estimated. Since 2007, there has been a surge in the number of RCVS-related publications likely due to increased awareness.
PATHOBIOLOGY
Other than vasoconstriction, there is no known unifying pathologic mechanism that underlies RCVS because it is a syndrome rather than a distinct disease entity. An aberrant sympathetic response of cerebral vasculature is one of the preferred hypotheses resulting in an unpredictable and short-lived failure of normal regulation of cerebral arterial tone. This leads to segmental vasoconstriction and vasodilatation in small cerebral vessels, often triggering thunderclap headaches due to stretching of vasa nervorum within the vessel walls.
RCVS appears to be an intrinsic process that can be triggered by a wide variety of pharmacologic and physical stimuli (Table 43.3). Different precipitating factors, including vasoconstrictive drug exposure (serotonergic or adrenergic agents), recreational drugs, and postpartum state are associated with RCVS in around 50% of cases. Head injuries and neurosurgical interventions have also been associated with RCVS.
PRES occurs in a substantial proportion of patients with RCVS. Hence, a shared pathophysiology between these two overlapping syndromes is highly probable. Severe forms of RCVS are likely to lead to PRES. In the past, it is likely that many of the cases termed central nervous system vasculitis and benign angiitis of the central nervous system may have actually referred to RCVS.
CLINICAL FEATURES
RCVS affects mainly women, with a mean age at onset of 40 years. In over 80% of cases, patients present with a sudden onset of single or recurrent thunderclap headaches. These headaches differ from those associated with aneurysmal subarachnoid hemorrhage (SAH) because they are usually short lived and intermittent, whereas SAH causes unremitting headaches that persist for days with prominent meningismus. Seizures occur and transient focal deficits in the form of visual, sensory, dysphasic, or motor deficits occur in
approximately 20% of patients at some point during the course of the illness, either alone or in combination. The focal deficits usually last minutes to hours but in some cases are persistent and associated with focal infarction. Blood pressure surges occur in 40% of patients; it is unclear if these elevations are related to the primary condition or are a reaction to pain or neurologic injury. Rupture or reperfusion injuries involving small leptomeningeal arteries may cause convexity SAHs.
approximately 20% of patients at some point during the course of the illness, either alone or in combination. The focal deficits usually last minutes to hours but in some cases are persistent and associated with focal infarction. Blood pressure surges occur in 40% of patients; it is unclear if these elevations are related to the primary condition or are a reaction to pain or neurologic injury. Rupture or reperfusion injuries involving small leptomeningeal arteries may cause convexity SAHs.
TABLE 43.2 Etiologies of Posterior Reversible Encephalopathy Syndrome | ||||||||||||||||||||||||||||||||||
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DIAGNOSIS
Calabrese et al. have proposed diagnostic criteria for RCVS that encompass clinical, radiographic, and CSF findings. Because RCVS can mimic PACNS, differentiation is crucial because management is extremely different (Table 43.4). Basic hematologic and metabolic tests, including ESR and liver and renal function tests, are typically normal in RCVS. Tests to rule out CNS vasculitis should be performed as delineated in Table 42.3, but in addition, urine toxicology screens and urinary concentrations of vanillylmandelic acid and 5-hydroxyindoleacetic acid should be measured if pheochromocytoma is suspected.
TABLE 43.3 Precipitants of Reversible Cerebral Vasoconstriction Syndrome | ||||||||||||||
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A normal CSF profile is the rule, although mild abnormalities in the CSF can be present when subarachnoid or intracerebral hemorrhages exist. If the white blood cell count exceeds 10 cells/µL or the protein concentration exceeds 80 mg/dL, analysis of CSF should be repeated after a few weeks to ensure that these abnormalities have normalized.
Up to 50% of patients had a normal initial CT or MRI scan despite the presence of diffuse vasoconstriction on concomitant cerebral
angiography. By the end of the clinical course, 80% of patients eventually develop lesions on MRI. Common findings include convexity SAH, small discrete intracerebral hemorrhages, and infarcts.
angiography. By the end of the clinical course, 80% of patients eventually develop lesions on MRI. Common findings include convexity SAH, small discrete intracerebral hemorrhages, and infarcts.
TABLE 43.4 Summary of Critical Elements for the Diagnosis of Reversible Cerebral Vasoconstriction Syndrome | |||||||
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Digital subtraction angiography (DSA) is he preferred method for demonstrating multifocal segmental vessel constriction. As is the case with PACNS, CT and magnetic resonance angiography (MRA) do not have sufficient resolution of the distal vasculature to demonstrate small-vessel “beading,” although they can demonstrate spasm of the larger proximal vessels (Fig. 43.3). Findings on angiography maybe dynamic, with repeat scans demonstrating resolution of some abnormalities and new vasoconstriction of others. Initial angiography might be normal if performed very early in the course of the disease. Repeat angiography is sometimes useful if the diagnosis remains unclear days to weeks after the performance of an initial study. The onset of headache and cortical SAH may precede the development of vasospasm on vascular imaging, and indeed, elevated flow velocities on transcranial Doppler may predict the small minority of patients who are at risk for developing subsequent ischemic stroke due to severe vasospasm.
TREATMENT
Treatment of RCVS is largely supportive; there are no proven effective pharmacologic agents that can reverse the vasoconstriction, although nimodipine 60 mg every 4 hours, verapamil 60 mg every 6 hours, and magnesium sulfate 1 to 2 g/h IV have all been tried. Prospective and retrospective studies indicate that nimodipine 60 mg every 4 hours may help reduce the frequency and severity of headaches, but there is no evidence that it affects vasospasm or outcome. Management focuses on discontinuation or avoidance of precipitating agents, pain control, blood pressure control, antiepileptic drugs for seizure control, and admission to an ICU of neurologic monitoring in severe cases. Steroids are not indicated, as they do not seem to prevent clinical deterioration and may be harmful with regard to side effects such as immunosuppression, hyperglycemia, and psychosis. Intra-arterial vasodilators and balloon angioplasty have been used in severe cases.
 FIGURE 43.3 Multifocal beading of the cerebral vasculature, characteristic of reversible cerebral vasoconstriction syndrome. (From Neil WP, Dechant V, Urtecho J. Pearls and oy-sters: reversible cerebral vasoconstriction syndrome precipitated by ascent to high altitude. Neurology. 2011;76:e7-e9.) |
OUTCOME
RCVS is generally considered a monophasic, self-limiting condition with a good long-term prognosis. Headaches usually resolve within 3 weeks, and no new symptoms occur more than 1 month after presentation. The angiographic and parenchymal findings typically resolve within 12 weeks. Less than 5% of patients develop fulminant disease with multiple strokes and global cerebral edema. The vast majority of patients make a complete functional recovery. The case fatality rate is less than 1%.
FIBROMUSCULAR DYSPLASIA
Fibromuscular dysplasia (FMD) is a noninflammatory, nonatherosclerotic arteriopathy of medium-sized vessels of unknown cause. Although it can affect any vascular bed, the renal and cervicocranial carotid and vertebral arteries are most commonly involved.
EPIDEMIOLOGY
Cervicocranial FMD is a rare condition, with one autopsy study citing an overall prevalence of 0.02%. Rates for renovascular FMD are higher, with prevalence estimates of up to 4% shown in several studies. In confirmed FMD cases, renal involvement is generally seen in up to 65% of cases, with cerebrovascular involvement in 25% to 30% of cases. In a series of 1,100 FMD patients, women were twice as frequently affected as men with Caucasians disproportionately affected. The mean age of diagnosis in patients with cerebrovascular involvement is 50 years, older than for renovascular involvement. Approximately 10% of cases are felt to be familial. Diagnosis is frequently delayed, with up to 9 years elapsing from initial symptoms to diagnosis.
PATHOBIOLOGY
There are three types of FMD, characterized by arterial layer of involvement: intimal fibroplasia, medial dysplasia, and adventitial fibroplasia. Intimal fibroplasia occurs in up to 10% of cases and results from accumulation of abnormal subendothelial mesenchymal cells, which project into the vessel lumen. This commonly results in areas of smooth, focal stenosis or long tubular stenosis. Adventitial fibroplasia, where the fibrous adventitia is replaced by collagen, is very rare.
Medial dysplasia is the most common, with three distinct subtypes recognized: medial fibroplasia, perimedial fibroplasia, and medial hyperplasia. Medial fibroplasia is the most common and accounts for up to 80% of cases.
The main histologic hallmark is disruption of smooth muscle cells, which are replaced by fibroblasts and collagen. There is frequently secondary disruption of the internal elastic lamina, which may lead to aneurysm formation. The alternating areas of medial disruption give rise to the commonly seen “string of beads” radiographic appearance, where areas of stenosis are admixed with dilated areas that are of larger caliber than the original vessel. Perimedial fibroplasia results from abnormal collagen deposition between the media and adventitia, leading to areas of stenosis with preserved internal elastic lamina. Radiographic appearance may be similar to medial fibroplasia, but the “beads” are of smaller diameter than the original vessel.
Although the etiology is unknown, FMD is associated with a variety of diseases including alpha-1 antitrypsin deficiency, Marfan syndrome, and Alport syndrome. Given the female preponderance, hormonal links have been posited, although evidence is lacking. Ischemia at the level of the vasa vasorum has been suggested as a possible underlying factor, although this remains unproven.
CLINICAL FEATURES
Cervicocranial FMD is frequently an incidental finding and rates of neurologic symptoms vary. Neurologic complications mainly arise due to ischemic or hemorrhagic symptoms that result from stenosis, thrombosis, dissection, or aneurysmal formation. Carotid-cavernous fistulas have also been described. Severe stenosis can cause distal hypoperfusion. Thrombotic occlusion of a stenotic vessel or distal embolism can lead to hemispheric ischemic symptoms. SAH can result from intracranial aneurysm rupture. Spontaneous cervical dissection can also occur, and headache, dizziness, carotidynia, pulsatile tinnitus, and Horner syndrome are all symptoms commonly seen with cervicocranial FMD. Dissection may be more common in Asian populations.
DIAGNOSIS
The gold standard for diagnosis remains catheter-based angiography. Noninvasive imaging modalities such as Doppler ultrasound and MRA may also detect FMD, but because lesions most commonly occur in the middle to distal carotid artery near C1-C2, adequate visualization with Doppler may be limited. Based on the underlying histology, a string of beads appearance due to medial fibroplasia is most commonly seen. Aneurysmal dilatation and areas of smooth tubular stenosis may also be present (Fig. 43.4). When cervicocranial disease is discovered, intracranial vessels should be imaged to evaluate for aneurysms and renal vessels for renovascular disease that may predispose to hypertension. The main differential diagnoses to consider are vasculitis and atherosclerotic disease.
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