Posterior Reversible Encephalopathy Syndrome
Introduction
Posterior Reversible Encephalopathy Syndrome (PRES) is a radiological finding
of non-specific etiology. PRES has been associated with many underlying etiologies but
the primary pathological end-point is brain edema.
History
The term posterior reversible leukoencephalopathy syndrome was first used in
1996 by Hinchey et al. to describe a syndrome characterized by an association between
the clinical symptoms of altered mental status, headache, seizures, blurred vision and the
neuroimaging findings of posterior leukoencephalopathy 2. This name became a
misnomer after it was observed that gray matter could also involved and the name was
changed to posterior reversible encephalopathy syndrome 2. The syndrome has also been
known by many names including occipital-parietal encephalopathy, reversible posterior
leukoencephalopathy (RPLS), hyperperfusion encephalopathy, and brain capillary leak
syndrome 1,3.
Epidemiology
There is no good data to available to give an estimate of the incidence of PRES 3.
Age does not appear to be a risk factor as PRES has been reported in patients from age 2
to 90 years old 3. PRES has been associated with patients that have particular underlying
clinical problems including 2:
 Hypertensive encephalopathy
 Preeclampsia/eclampsia/HELLP syndrome
 Immunosuppressive/cytotoxic medication use
 Renal disease
 Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome
 High-dose steroid therapy
 Liver failure
 Endocrine dysfunctions
 Electrolyte abnormalities
 Bone marrow transplantation
 Massive blood transfusion/EPO use
 Porphyria
 Various other causes
Pathophysiology
The basic mechanism of RPL is brain edema without infarction 1. There are three
different theories as to the underlying cause of the brain edema. The first is the cytotoxic
theory, and the second is the vasogenic theory 1. These two theories can be seen as two
parts of a dichotomy. The third theory meanwhile belongs in a separate class and
proposes that in some cases PRES can be caused by medications that damage the blood
brain barrier.
Cytotoxic Theory
The precursor event of PRES in the cytotoxic theory is a sudden increase in blood
pressure above what is “normal” for the patient 1. This sudden increase causes cerebral
vascular damage and the vasculature reacts by vasoconstriction 1. It is this
vasoconstriction that causes hypoxic damage to the brain parenchyma and therefore brain
edema 1. Cerebral angiography in cases of PRES has shown vasoconstriction of the
posterior and middle cerebral arteries which supports this theory 1. Yet, this
vasoconstriction has not been seen consistently 1. The complete reversibility of
radiographic changes with control of blood pressure is also not compatible with the
cytotoxic edema resulting from vasospasm and ischemia proposed by this idea 1.
Vasogenic Theory
The vasogenic theory of PRES relies on our understanding of the autoregulation
of cerebral vasculature. Autoregulation by the cerebral vessels is essential in maintaining
cerebral perfusion. Cerebral autoregulation is effective when the mean arterial pressure
(MAP) remains between 60-120 mmHg. The normal autoregulatory response to
increasing MAP is cerebral vasoconstriction. A sudden rise in blood pressure can
overcome the abilities of cerebral autoregulation to accommodate it 1.
At a higher MAP instead of the normal response of vasoconstriction, there is
arteriolar vasodilatation, endothelial dysfunction, capillary leakage and a disruption of the
blood-brain barrier 1,2. This leads to extravasation within the extracellular space,
particularly in the white matter, which is less tightly packed. The rate of elevation of
blood pressure seems to be important and the cerebral vasculature of patients with
chronic hypertension can withstand higher blood pressures without dysfunction than
patients with acute increases in blood pressure from lower baseline levels 3. For those
with chronic hypertension, blood pressures are usually required to be above 250/110 mm
Hg to cause symptoms 4.
It is curious that it is the posterior brain that is associated with PRES. The
territory supplied by the posterior cerebral circulation may be more vulnerable to RPL
because the posterior cerebral and vertebrobasilar arteries both have less sympathetic
innervation than other parts of the cerebral circulation 1. This may translate into less
capacity to withstand an acute increase in blood pressure by sympathetic mediated
vasoconstriction 1.
Evidence for the vasogenic theory comes from phase contrast angiography studies
of flow in carotid and basilar arteries documenting an elevation in cerebral blood flow at
high MAP, implying a breakdown of autoregulation 1. But the primary dysfunction in
PRES is seen in the posterior cerebral areas. Light microscopy studies of RPL patients
have shown edematous white matter consistent with vasogenic cerebral edema 1.
Medication Induced Disruption of the Blood Brain Barrier
A third proposal to account for some cases of PRES expounds on the role of the
cytotoxic medications that these patients are sometimes taking. These drugs may have a
direct toxic effect on the cerebral vascular endothelium that leads to endothelial
dysfunction, capillary leakage and vasogenic edema 2. This theory is useful because not
all cases of PRES have been associated with concurrent hypertension 2. PRES has also
occurred in these patients even at “nontoxic” levels of these cytotoxic drugs 2. In a similar
manner, other conditions such as sepsis, renal failure and electrolyte imbalance may
predispose to RPL by first damaging the blood-brain barrier and thereby leading to
vasogenic edema at MAP levels that would normally be within the range that is well
tolerated 1.
Clinical Presentation
RPL characteristically presents as a headache, altered mental status, seizures and
visual disturbances with or without accelerated hypertension 1. Multiple seizures are more
common than single seizures 2. Visual problems may include hemianopsia, visual neglect
or cortical blindness 2.
An examination of the patient’s eyes is the most useful portion of the physical
exam to confirm a suspicion of PRES 4. Ophthalmoscopy may reveal retinal arteriolar
spasm, papilledema, retinal hemorrhages and retinal exudates 4.
Diagnosis
The major differential diagnosis of RPL is ischemic stroke 1. Differentiating
between the two is essential since in RPL good blood pressure control is mandatory for
treatment, whereas ischemic stroke is often treated with permissive hypertension 1.
A complete differential diagnoses includes 2:
 CNS vasculitis
o Granulomatous angiitis
o Systemic lupus erythematous
o Polyarteritis nodosa
 Acute or subacute neurological disease
o Ischemic stroke
o Progressive multifocal leukoencephalopathy
o Acute disseminated encephalomyelitis
o Infective encephalitis
o Cerebral venous thrombosis
o Cerebral autosomal dominant arteriopathy with stroke and ischemic
leukoencephalopathy (CADASIL)
 Mitochondrial disease
o Mitochondrial encephalomyopathy, lactic acidosis and stroke-like
episodes (MELAS)
o Myoclonic epilepsy and ragged red fibers syndrome (MERRF)
 CNS collagen disease
 Hypoglycemia/hyponatremia
 Infectious etiologies
Lumbar puncture
A lumbar puncture is sometimes done because of the clinical presentation of
headache and visual symptoms. An LP is generally not helpful but may show normal or
elevated CSF pressure and protein 4.
Imaging
The diagnosis of RPL is made by imaging regardless of the underlying cause of
PRES 2. MRI is both the favored modality and gold standard for diagnosis 1,2. Edema due
to PRES is seen on an MRI as an increased signal on T2 and FLAIR in the occipital and
posterior parietal lobes 1. The involved areas are usually bilateral and symmetrical 1.
Fluid-attenuated inversion recovery (FLAIR) sequences should be performed when PRES
is suspected because they significantly improve the ability to make the diagnosis 2. RPL
lesions are seen particularly well on FLAIR because FLAIR nulls of the signal from
ventricular and subarachnoid CSF which makes cerebral edema more prominent 1.
Radiographic changes generally appear in the region of the posterior circulation 1.
Grey matter is involved in 94% of cases 1. In a case series of 15 patients described by
Hinchey et al. 60% had involvement of the anterior hemisphere 1. Other areas such as the
brainstem, thalamus, and cerebellum may be involved in 56% of patients 1. Also noted
has been a sparing of the calcerine fissure and paramedian occipital lobe structures 1. This
can be used to distinguish RPL from a bilateral posterior cerebral artery infarction 1.
Computed tomography can also be used to image PRES and may show areas of
low attenuation in the posterior white matter 1.
Treatment
Blood Pressure Control
Treatment of RPL primarily consists of early control of elevated blood pressure if
present 1. Blood pressure control results in complete resolution of symptoms in most
cases 1. The goal is a reduction of MAP by 20-25% within first 1-2 hours or a reduction
of diastolic to 100mmHg 1. Blood pressure control is usually obtained using intravenous
nicardipine, labetalol or nimodipine 2. Second line agents include sodium nitroprusside,
hydralazine and diazoxide 2. Angiotensin converting anzyme (ACE) inhibitors are
avoided in patients with hypovolemia, underlying renal artery stenosis or patients that are
pregnancy 1.
Treat of Underlying Cause
Also essential is to treatment is the withdrawal or reduction of dosing of any
medications that may have caused the RPL 1. Underlying renal failure should be
addressed 1. Plasmapheresis may be indicated in patients with Thrombotic
Thrombocytopenic Purpura 1. In pregnancy, delivery of the baby is the treatment of
choice 1.
Seizures
The treatment of any accompanying seizures with done with anticonvulsants such
as lorazepam or diazepam 2. The disappearance of seizures usually corresponds with the
disappearance of radiographic abnormalities and long-term antiepileptic therapy is not
required 1.
Prognosis
The term RPL has been stated to be a misnomer because the syndrome is not
always reversible to the extent of full recovery even with adequate therapy 2.
Also, changes in the brain are not necessarily localized to the posterior region of the brain
and may also encompass changes in the areas supplied by the anterior and middle
cerebral arteries 1. Involvement beyond the posterior circulation may a poor prognostic
indicator and seen in more severe cases 1. Radiographic predictors of poor outcome
include gadolinium enhancement, hemorrhage and infarction 1. Also, extensive
abnormalities seen in T2 are predictive of worse prognosis 1.
As a general rule, seizures disappear with radiographic abnormalities 1. There
have been case reports of hypertensive encephalopathy later followed by chronic epilepsy
2
. Usually though, complete neurological recovery can be expected in most patients
within 2 weeks 1.
References
1. Stott V.L. Reversible Posterior Leukoencephalopathy Syndrome: A Misnomer
Reviewed. Internal Medicine Journal 2005; 35:83-90
2. Servillo G. Posterior Reversible Encephalopathy Syndrome in Internsive Care
Medicine. Intensive Care Med (2007) 33:230-236
3. Neill, Terry. Reversible Posterior Leukoencephalopathy Syndrome. UpToDate.
Sept 17, 2007.
4. Aminoff, Michael. Clinical Neurology 6th Edition. Lange 2005.