Reminder of important clinical lesson

Posterior reversible encephalopathy syndrome:
the importance of early diagnosis
Rute Teotónio,1 Dina Marmoto,2 Cristina Januário,1 Conceição Bento1
1

Department of Neurology, Hospitais da Universidade de Coimbra, Coimbra, Portugal
Department of Radiology, Hospitais da Universidade de Coimbra, Coimbra, Portugal

2

Correspondence to Dr Rute Teotónio, rute.teotonio@gmail.com

Summary
A 14-year-old boy was submitted to cardiac transplant due to a dilated cardiomyopathy. On the fourth day of immunosuppression
(corticosteroids, mycophenolate mofetil and tacrolimus), he developed right focal seizures and drowsiness. Blood pressure was in the
normal range and laboratory findings in cerebral spinal fluid and blood were unremarkable, with drugs in non-toxic levels. The EEG showed
a slow background rhythm more pronounced on the right and a seizure onset in the right occipital region. MRI revealed a diffuse
hyperintense subcortical white-matter lesion on fluid attenuated inversion recovery, with lesser involvement of left temporal–occipital
region. There was no enhancement with gadolinium and MRI diffusion-weighted imaging was consistent with vasogenic oedema.
Tacrolimus was stopped with regression of MRI abnormalities and clinical recovery. Posterior reversible encephalopathy associated with
tacrolimus is a rare but potentially serious complication of solid organ transplants. A prompt diagnosis and correct treatment is essential
to avoid irreversible brain damage.

BACKGROUND
Posterior reversible encephalopathy syndrome (PRES) is a
newly recognised brain disorder, first codified as a single
name syndrome by Hinchey et al.1 Classically characterised
by extensive and symmetric white-matter abnormalities
suggestive of vasogenic oedema in the posterior regions of
the cerebral hemispheres, it may also commonly involve
other cerebral areas (frontal and temporal lobes) as well as
cerebellum, brain stem and the basal ganglia. The clinical
findings tend to evolve rapidly and are usually diverse. The
typical clinical features include seizures, headache, nausea,
vomiting, altered mental status, visual disturbance and
focal neurological deficits.2–6 PRES is often associated with
abrupt increase in blood pressure, autoimmune disorders,
renal disease and cytotoxic or immunosuppressive therapy.
We present a case of PRES caused by tacrolimus. In doing
so, we want to highlight the differential diagnosis and possible aetiopathogenesis underlying this condition. We also
want to stress the importance of neuroimaging in the
establishment of a prompt diagnosis and correct treatment. Finally we intend to discuss the possible relation
between tacrolimus doses and use of concomitant drugs in
the development of PRES.

CASE PRESENTATION
A 14-year-old boy with chronic heart failure and pulmonary hypertension due to a post viral dilated cardiomyopathy was admitted to our hospital in September 2008 for
a cardiac transplant. After surgery he received prednisone,
mycophenolate mofetil and tacrolimus for initial
immunosuppression. At that time itraconazol, mycostatin
and cefuroxime were also administrated as prophylaxes
against opportunistic infection.
The course was uneventful for 1 week, but on day 8
after surgery and day 4 after immunosuppression, he
BMJ Case Reports 2012; doi:10.1136/bcr-2012-006852

became lethargic and sleepy. The neurological examination
showed a decreased level of consciousness with a left
extensor plantar response. On the next day he started
focal seizures with secondary generalisation. He experienced multiple episodes of eye deviation to the left and
clonic movements of the left limbs followed by a generalised tonic–clonic seizure. Blood pressure remained within
normal range values.

INVESTIGATIONS
Laboratory findings including ionogram, liver and renal
functions were normal. Cerebral spinal fluid (CSF) examination was unremarkable (glucose 79 mg/dl; white blood
cells 1.0/mm3; proteins 53 mg/dl) with negative PCR analysis for John Cunningham virus and serology for Herpes
simplex 1 and 2. Plasma levels of tacrolimus were always
maintained within the therapeutic range (5.7–15.3 ng/ml)
(normal values 5–20 ng/ml).
On the brain CT scan, we could see a linear image of
hyperdensity on the left precentral sulcus with a subcortical hypodensity on the inferior frontal gyros (figure 1).
A conventional 1.5 tesla-MRI was performed 5 days
after presentation. It revealed an asymmetric and discrete
cortical–subcortical signal increase on fluid attenuated
inversion recovery (FLAIR)-weighted images, in the left
precentral and postcentral gyros, frontal poles and parietal
lobes, with no paramagnetic enhancement (figure 2).
The EEG performed after the first seizure showed an
asymmetric background, slower on the right hemisphere.
Multiple seizures were recorded, all beginning on the right
occipital lobe.
Seven days after, the EEG showed slow activity mainly
in the posterior regions and bilateral occipital epileptic
activity.
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extension to frontal poles. There was no enhancement
after administration of gadolinium, and MRI diffusionweighted imaging (DWI) was consistent in establishing
that they represented vasogenic oedema (figure 3).

DIFFERENTIAL DIAGNOSIS
The differential diagnosis included various acute neurological conditions such as stroke, cerebral venous thrombosis,
encephalitis and progressive multifocal leucoencephalopathy
(PML). CSF examination helped us to exclude an infection,
namely encephalitis or PML. A vascular aetiology was also
ruled out by brain MRI and DWI (no restriction in water
molecules diffusion). These imaging studies allowed us to
understand the vasogenic and not ischaemic nature of the
white-matter lesions.
Figure 1 CT imaging demonstrates hyperdensity in the left
precentral sulcus and surrounding discrete hypodensity.

The MRI performed at that time, revealed diffuse and
extensive hyperintense subcortical white-matter lesions on
FLAIR-weighted images, spanning both hemispheres, with
lesser involvement of temporal and occipital left lobes and

TREATMENT
Tacrolimus was discontinued and cyclosporine and
azathioprine were introduced. Two days after tacrolimus
withdrawal, the boy was no longer stuporous, although
he remained mildly confused and with visual hallucinations. A 1.5 tesla-MRI was performed 20 days after tacrolimus withdrawal. It showed an almost complete
regression of signal changes (figure 4). The symptoms

Figure 2 Brain MRI imaging (fluid attenuated inversion recovery sequence), demonstrates hyperintense, linear, cortical–subcortical
lesions, in the parietal and frontal lobes, with frontal pole extension.
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Figure 3 Brain MRI imaging (fluid attenuated inversion recovery, diffusion-weighted imaging and postcontrast T1-weighted images),
demonstrates extensive vasogenic oedema, with subcortical white-matter hyperintense lesions, affecting on both sides, the occipital,
parietal and frontal lobes. It seemed to be present at the vascular anastomotic border zones. There is no restricted diffusion, and no
enhancement after gadolinium.
gradually cleared and 30 days after admission, the neurological examination had no abnormalities. He was then
discharged in a good clinical condition.

perceived, but some occipital spikes were identified. The
1.5 tesla-MRI was performed 6 months after admission
and showed a complete resolution of the former whitematter signal changes (figure 5).

OUTCOME AND FOLLOW-UP
One month after discharge he visited our outpatient
clinic. He was seizure-free, with no complaints and with
a normal neurological examination. The EEG performed
at that time showed a normal background activity with
scarce bilateral temporo-occipital delta waves.
In a second visit, the boy complained of poorer performance at school. A neuropsychological assessment was
done and a multifocal and mild cognitive impairment
associated with a left frontal and right hippocampal dysfunction was revealed. An EEG was repeated 5 months
after discharge and the initial slow activity was no longer

Figure 4 Brain MRI imaging (fluid attenuated inversion
recovery), showed almost complete resolution of the vasogenic
oedema.
BMJ Case Reports 2012; doi:10.1136/bcr-2012-006852

DISCUSSION
Although the disorders that can predispose to PRES are
multiple and well identified (box1), the precise mechanisms underlying this condition are not clearly known.
Some hypotheses have been postulated, but the issue is
still controversial.7 One hypothesis, favoured by the
majority of the authors, is the hypertension–hyperperfusion theory. According to this theory, a rapid rise in blood
pressure may lead to loss of normal brain blood flow autoregulation. This disturbance would promote dilatation of
cerebral arterioles, opening up of endothelial tight junctions and cerebral oedema by leakage of plasma into extracellular space.8
Alternatively, others have proposed that PRES would
result from vasospasm secondary to sudden and severe
rise in blood pressure. The subsequent ischaemic damage
would induce cytotoxic oedema followed by extracellular
oedema. Although angiographic and single-photon

Figure 5 Normal brain MRI imaging (fluid attenuated inversion
recovery).
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Box1 Conditions associated with posterior
reversible encephalopathy syndrome
1. Uncontrolled essential hypertension
2. Secondary hypertension
▸ Renal failure with hypertension
▸ Acute glomerulonephritis
3. Toxemia of pregnancy (eclampsia/pre-eclampsia)
4. Infection/sepsis
5. Post-transplantation
▸ Allogeinec bone marrow transplantation
▸ Solid organ transplantation
6. Drugs
▸ Ciclosporin
▸ Tacrolimus
▸ Interferon-ɑ
▸ Fludaribine
▸ Cisplatin
▸ Gemcitabine
▸ Ifosfamide
▸ Intravenous immunoglobulins
▸ Erythropoietin
7. Auto-immune disease
▸ Systemic lupus erythematosous
▸ Wegener’s
▸ Polyarteritis nodosa
▸ Scleroderma
▸ Behçet’s syndrome
8. Others
▸ Thrombotic–thrombocytopaenic purpura
▸ Haemolytic uraemic syndrome
▸ AIDS
▸ Acute intermittent porphyria
▸ Hyponatraemia, hypomagnesaemia, hypercalcaemia

emission CT studies performed during the symptomatic
period were consistent with vasospasm, the uncommon
infarction seen in this syndrome does not favour a relevant cerebral ischaemia.9
In basal conditions the sympathetic nervous system
preserves cerebral blood flow by modifying vascular tone
if sudden change of blood pressure occurs. The anterior
cerebral circulation is controlled in part by adrenergic sympathetic nerve supply from superior cervical ganglion
along the carotid arteries, whereas posterior circulation
depends on the sympathetic chain via vertebrobasilar
arteries. The sympathetic nerve supply of the posterior
circulation is rather deficient when compared with the
anterior one. Consequently, a poor autoregulation of
blood flow occurs in the posterior regions with a predominance of oedema in these areas.
However, a moderate-to-severe hypertension is encountered in only 70–80% of patients with PRES.7 10 Is not
uncommon that patients with PRES and eclampsia/preeclampsia, allogeneic bone marrow transplantation, infection/sepsis or immune suppression therapy have normal
or minimally elevated blood pressure that does not reach
the level of cerebral autoregulation failure. It seems that
an endothelial dysfunction must be implicated in PRES,
especially in cases without hypertension.11 Concerning
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immunosuppressive agents such as tacrolimus, a probable
direct toxic effect on neurons with axonal swelling and a
direct capillary endothelial injury causing a blood-barrier
breakdown may explain the clinical and radiological findings. Seizures associated with PRES may also increase
lactate levels and serum CO2 with a subsequent increase
in vascular permeability.12
The not uncommon association between autoimmune
disorders and PRES also supports a possible inflammatory
underlying mechanism. Inflammatory cytokines induced
by activated monocytes and lymphocytes could provoke
endothelial dysfunction with subsequent fluid and protein
leakage to the interstitium.3
In PRES, brain MRI imaging typically demonstrates
focal or confluent regions of symmetric vasogenic oedema,
most commonly in the parietal and occipital lobes.13–16
Confluence of the lesions may develop as the extent of
the oedema increases. The PRES imaging pattern tends to
reflect the watershed nature of this condition. Three
hemispheric pattern variants can be usually identified: a
holohemispheric, a superior frontal sulcal and a dominant
parietal–occipital. There are incomplete expressions
( partial or asymmetric) of the three primary variants.
These patterns reflect the junctional expression between
distal hemispheric branches of major cerebral arteries
(anterior, middle and posterior cerebral arteries).10 17
The MRI presentation of the disease, in our patient,
strengthens the holohemispheric watershed pattern of
PRES.
Of note, a low proportion of patients show a cytotoxic
oedema component instead of vasogenic oedema. The
analysis of albumin levels of 28 patients with classical
PRES showed that patients with vasogenic oedema had
significantly decreased serum albumin levels compared
with those with cytotoxic oedema, suggesting that low
serum albumin levels may be involved in the development
of vasogenic oedema in PRES.18
A prompt diagnosis and treatment are crucial as an
adequate intervention usually leads to complete recover
within hours (12–24 h) to days.5 Nevertheless, imaging findings may persist for weeks, even when a clinical improvement is achieved earlier. A late recognition and/or incorrect
treatment can cause irreversible brain damage and even
death. A delayed correction of the causative agent or
removal of the offending drug can induce prolonged brain
ischaemia and infarction. Ischaemic changes on DWI/apparent diffusion coefficient and involvement of large brain areas
are predictors of poor prognosis. In case of hypertension, the
aim should be to decrease mean blood pressure by 20%
within the first hour or to obtain normal mean arterial
blood pressure between 105 and 125 mm Hg.12 19
Intravenous labetalol is preferred by many physicians for its
short duration of action. Calcium channel blockers can also
be an effective option as they reduce arterial muscle contractility, inhibiting arterial vasospasm.19
It is known that the incidence of tacrolimus-induced
PRES is nearly 1.6%, with an onset approximately
61 days after the initiation of the immunosuppressive
drug.20 Interestingly, in our case the onset of PRES
occurred much earlier, only 4 days after tacrolimus introduction, with serum levels always within the therapeutic
range. We question ourselves if this reflects an individual
susceptibility to the development of PRES or if it may
BMJ Case Reports 2012; doi:10.1136/bcr-2012-006852

be related to the effect of multiple drugs since our
patient was on several medications that are known to be
potentially associated with PRES. Previous reports of
PRES related to tacrolimus have noted that this kind of
neurotoxicity is not uncommonly seen with non-toxic
levels.21 Of note, in series of a paediatric population
with kidney transplantation or end-stage renal disease
that developed PRES, all children under calcineurin inhibitors presented drug levels within therapeutic range.22
In our view, this should raise the possibility of children
being more susceptible to develop neurotoxic side effects
with lower doses of tacrolimus. It is important remember that PRES may not be necessarily the same for
children as for adults. Risk factors for its occurrence in
the younger population might be different and should be
further investigated.

Learning points
▸ Posterior reversible encephalopathy syndrome (PRES)
can complicate a large number of medical conditions,
such as immunosuppressive therapy.
▸ Clinical features include headache, nausea, vomiting,
seizures, confusion, visual disturbance and focal
neurological deficits.
▸ Gold standard imaging study is brain MRI that usually
shows bilateral and subcortical diffusion-weighted
imaging and apparent diffusion coefficient maps should
always be performed when the possibility of PRES is
raised in order to confirm the typical vasogenic
oedema seen in this condition.
▸ The aetiopathogenesis is not fully understood yet.
Vasogenic oedema, vasospasm and direct toxic effect
are some possible implicated mechanisms.
▸ A prompt diagnosis and treatment are essential, as a
permanent damage can be expected in a delayed
correction of the causative condition or removal of the
offending drug.

Competing interest None.
Patient consent Obtained.

BMJ Case Reports 2012; doi:10.1136/bcr-2012-006852

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2012;10.1136/bcr-2012-006852, Published XXX
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