POSTERIOR REVERSIBLE

ENCEPHALOPATHY
SYNDROME
DR. SUMIT KAMBLE
SENIOR RESIDENT
DM NEUROLOGY,
GMC, KOTA

MODERATOR
DR. DILIP MAHESHWARI
ASSO. PROF. NEUROLOGY
HISTORICAL BACKGROUND
In 1897, Vaquez and Nobecourt pointed out the correlation of
toxemia of pregnancy and HTN

In1928, Oppenheimer and Fishberg introduced the term

hypertensive encephalopathy

In 1996, Hinchey and colleagues first described the clinical

condition- reversible posterior leukoencephalopathy( RPLE)

Semin Neurol 2011;31:202215

INTRODUCTION
Disorder of reversible subcortical vasogenic brain oedema in
patients with acute neurological symptoms (eg, seizures,
encephalopathy, headache, and visual disturbances) in the
setting of renal failure, blood pressure fluctuations, cytotoxic
drugs, autoimmune disorders, and pre-eclampsia or eclampsia.

Reversible posterior cerebral edema syndrome

Posterior leukoencephalopathy syndrome
Hyperperfusion encephalopathy
Brain capillary leak syndrome

Lancet Neurol 2015; 14: 91425

 Brain imaging usually reveals vasogenic oedema predominantly
involving the bilateral parieto-occipital regions.

PRES is caused by endothelial injury related to abrupt blood

pressure changes or direct effects of cytokines on the
endothelium, which leads to breakdown of the blood brain
barrier and subsequent brain oedema.

PRES is generally reversible, both radiographically and

clinically, and has a favourable prognosis.
PHYSIOLOGY OF CEREBROVASCULAR BLOOD FLOW

Cerebral blood flow autoregulation - cerebral circulation

normally maintains a constant cerebral blood flow, despite
changes in cerebral perfusion pressure

Largely driven by changes in cerebral arteriolar wall diameter,

which can be produced by several mechanisms, including
cerebrovascular pressure reactivity , chemical factors (eg,
carbon dioxide tension), and autonomic nervous system.

Lancet Neurol 2015; 14: 91425

 Blood pressure decreases - cerebral arteriolar vasodilation
occurs, preserving adequate blood flow and perfusion for
neuronal and glial needs.

Blood pressure increases arterioles constrict as a physiological

response to maintain a steadyand not increasingcerebral
blood flow.
 Endothelium regulates vascular tone by secreting a combination
of vasodilators (nitric oxide, prostacyclin, hydrogen sulfide, and
endothelium-derived hyperpolarising factor) and
vasoconstrictors (throm boxane A2, endothelin 1, and
angiotensin II).

With chronic HTN, the resistance arterioles undergo

proliferation of the muscular media adapting to the chronically
high perfusion pressures

This results in a shift of the autoregulation curve to the right

NORMAL CEREBRAL AUTOREGULATION
DYNAMICS OF CBF IN PTS WITH CHRONIC HTN
PATHOPHYSIOLOGY OF PRES
1. Cerebral Hyperperfusion- Rapidly developing hypertension
exceeds the upper limit of cerebral blood flow autoregulation
and causes hyperperfusion.

When the pressure rise is rapid and severe, the autoregulatory

response might be insufficient, hyperperfusion can occur, and
the bloodbrain barrier breaks down, allowing the interstitial
extravasation of plasma and macromolecules.

Posterior brain regions can be particularly susceptible to

hyperperfusion because little sympathetic innervation exists in
posterior fossa.
J Stroke Cerebrovasc Dis 2012; 21: 87382.
 Important factors that influence breakdown in the bloodbrain
barrier
1. Patients mean baseline blood pressure,
2. Proportional rise in blood pressure,
3. Rapidity with which the change takes place
 2. Cerebral Hypoperfusion - 1520% of patients with PRES
are normotensive or hypotensive and that, even among patients
who are hypertensive, less than 50% have a documented mean
arterial pressure above the usually quoted upper limit of
cerebral blood flow autoregulation (140150 mm Hg).

Endothelial dysfunction - from systemic toxic effects -

hypertension could be a reaction to insufficient brain perfusion
COMORBID CONDITIONS/TRIGGERS
Pregnancy-related conditions
1. Eclampsia
2. Hydatidiform mole

Major medical illness

1. Organ transplantation
2. Thrombotic thrombocytopenic purpura
3. Henoch-Schonlein purpura
4. Autoimmune inflammatory disease: systemic lupus, scleroderma,
Wegeners, periarteritis nodosa
5. Sepsis/systemic inflammatory response syndrome/multiple organ
failure
6. Alcohol and drug withdrawal
7. Hypomagnesemia, hypercalcemia, hypocholesterolemia
8. Renal failure
 Neurologic illness
1. Guillain-Barres syndrome
2. Spinal cord injury with autonomic dysreflexia
3. Head injury

Drugs that cause endothelial dysfunction

1. Immunosuppressant agents - Cyclosporine A
2. Chemotherapeutic agents, especially high-dose multidrug -
Tacrolimus (FK506), Cisplatin, Gemcitabine, Bevacizumab
3. Erythropoietin
4. Blood transfusion
5. Indinavir
6. Cytarabine
7. IVIg
CLINICAL FEATURES
Epidemiology
Age - 4 to 90 years, most cases occur in young to middle-aged
adults, mean age ranging across case series from 39 to 47 years

Female predominance

Acutely or subacutely, usually developing during several hours

or days.
Encephalopathy
severity from confusion, somnolence, and lethargy to coma
reported in 13 % to 90 % of cases

Seizure
Up to 92 % of cases
Secondary generalized seizures are common (5362 %) , rarely
focal (23 %-28 %)
Status epilepticus - 3 % to 13 %
Visual abnormalities
found in 26 % to 67 % of patients
blurred vision (7 -18 %)
visual neglect (4 -27 %)
homonymous hemianopsia (4 -20 %)
visual hallucinations (3 -5 %)
cortical blindness (8 -33 %)

Focal neurological signs

3-17% cases
hemiparesis or aphasia,

Myelopathic symptoms and signs (Am J Neuroradiol 2012; 33: 896903.)

PREVALENCE OF CLINICAL SYMPTOMS AND SIGNS
SYMPTOMS PREVALENCE

Encephalopathy 5080%

Seizure 6075%

Headache 50%

Visual disturbances 33%

Focal neurological deficit 1015%

Status epilepticus 515%

J Stroke Cerebrovasc Dis 2012; 21: 87382.

 DISTRIBUTION OF CLINICAL FEATURES IN COHORT STUDIES OF PRES

Clinical Features Hinchey Bartynski McKinney Lee Burnett

1996 2007(N=13 2007(N=76) 2008(N=36) 2010(N=79)
(N=13) 6)
Encephalopathy 10 (67 %) 39 (26 %) 10 (13 %) 34 (94 %) 76 (90 %)
Seizure 11 (73 %) 97 (71 %) 58 (76 %) 33 (92 %) 56 (70 %)
Headaches 8 (53 %) 39 (26 %) 3 (4 %) 19 (53 %) 26 (31 %)
Visual abnormalities 10 (67 %) 39 (26 %) 3 (4 %) 13 (36 %) 24 (29 %)
Nausea/vomiting 8 (53 %) 39 (26 %) NR NR NR

Focal neurological NR NR 2 (3 %) 1 (3 %) 14 (17 %)

signs
Acute hypertension 12 (80 %) 91 (67 %) NR NR 62 (78 %)

Annual Update in Intensive Care and Emergency Medicine 2011

DIAGNOSIS

Acute and subacute neurological symptoms in the appropriate

clinical context (ie, in the presence of pronounced hypertension,
blood pressure fluctuations, immuno suppression, autoimmune
disorders, renal failure, pre-eclampsia, or eclampsia).

Diagnosis of PRES is not mainly radiological; the clinical

context is crucial in making correct diagnosis.
IMAGING
Useful to exclude alternative diagnoses
Confirms diagnosis of PRES.

Computed tomography (CT):

Hypodensities in a suggestive
topographic distribution
MRI BRAIN
T1: hypo intense in affected regions

T1 C+ (Gd): patchy variable enhancement. It can be seen in ~35% of

patients, whether leptomeningeal or cortical pattern.

T2: hyperintense in affected regions

DWI: usually normal

ADC: signal increased in affected regions due to increased diffusion

GRE: may show hypointense signal in cases of haemorrhage

SWI: may show microhemorrhages in up to 50%

RADIOLOGICAL CHARACTERISTICS OF PRES

1. Holohemispheric watershed pattern (23 %)

watershed zone between the anterior and posterior cerebral
arteries and the middle cerebral artery
confluent vasogenic edema extends through the frontal, parietal,
and occipital lobes
2. Dominant parietal-occipital pattern (22 %)
previously thought to be typical of PRES
posterior part of the parietal and occipital lobes is
predominantly involved

Am J Neuroradiol 2012; 33: 896903.)

3. Superior frontal sulcus pattern (27 %)
Patchy edema predominates in the frontal lobes along the mid
to posterior aspect of the superior frontal sulcus.
parietal and occipital lobes are variably involved
4. Partial or Asymmetric Expression of the Primary Patterns
(27.9%)
Asymmetric abnormalities in the affected parietal or occipital
lobes.
ATYPICAL MRI FINDINGS IN POSTERIOR
REVERSIBLE ENCEPHALOPATHY SYNDROME
Edema can affect basal ganglia and brainstem in up to a third of
cases and the cerebellum in up to half

Restricted diffusion can be seen on MRI in 1530% of cases

Presence of restricted diffusion is generally associated with

irreversible structural injury and incomplete clinical recovery.

Am J Neuroradiol 2012; 33: 896903

 Enhancement is seen in about 20% of patients with PRES

Intracranial haemorrhage - 1025% of cases.

Intraparenchymal hemorrhage is the most common type and
sulcal subarachnoid haemorrhage is the second most common
type. About 1830% of patients with haemorrhage have both
types
DIFF ERENT TYPES OF INTRACRANIAL HAEMORRHAGE IN POSTERIOR
REVERSIBLE ENCEPHALOPATHY SYNDROME
ATYPICAL MRI FINDINGS IN POSTERIOR
REVERSIBLE ENCEPHALOPATHY SYNDROME
Axial T2 fluid-
attenuated inversion
recovery sequences
show predominant
(A) brainstem
(B) basal ganglia
(C) thalamus
(D) pontine
involvement
23 yr-old-male cocaine-induced malignant hypertension, presenting
with headaches, confusion and spinal cord syndrome
Radiological Hinchey Casey Bartynski McKinney Lee Burnett
Features 1996 (N=13) 2000 2007(N=136 2007(N=76) 2008(N=36) 2010(N=7
N = 16 9)

Bilateral 15 (100%) 11 (69%) 98 (72%) NR 36(100 %) NR

Asymmetric 10 (67 %) NR 21 (15 %) 2 (3 %) NR NR

Confluent NR 2 (13 %) 31 (23 %) 44 (58 %) 2 (13 %) 12(16 %)
Gray matter 4 (27 %) NR NR 22 (29 %) 16 (44 %) NR
Posterior > 14 (93 %) 15 (94 %) 30 (22 %) NR NR NR
anterior
Occipital 14 (93 %) NR 134 (99 %) 75 (99 %) NR NR

Parietal 13 (87 %) 8 (50 %) 134 (99 %) 75 (99 %) NR 50 (67 %)

Frontal 7 (47 %) 14 (88 %) 93 (68 %) 60 (89 %) 22 (61 %) 61 (81 %)

Temporal 9 (60 %) 16 (100 55 (40 %) 52 (68 %) NR 62 (83 %)
%)
Brainstem 2 (13 %) NR 17 (13 %) 14 (18 %) 21 (58 %) NR
Cerebellum 1 (7 %) NR 41 (30 %) 26 (34 %) 21 (58 %) NR
Basal ganglia 1 (7 %) 3 (19 %) 19 (14 %) 9 (12 %) NR NR
REGIONAL INVOLVEMENT BY PRES IN SERIES OF 136
PATIENTS

AJNR 2007;28:1302-07
DIFF ERENTIAL DIAGNOSES OF POSTERIOR REVERSIBLE
ENCEPHALOPATHY SYNDROME (PRES)

Infectious encephalitis
Fever
Peripheral leucocytosis
CSF pleocytosis
Positive CSF Gram stain or culture
Positive CSF microbial serology or PCR
Can be unilateral in brain imaging

Autoimmune or paraneoplastic encephalitis

History of malignancy or tumour
Antigen-specific antibody in serum or CSF
Can be unilateral in brain imaging
Lancet Neurol 2015; 14: 91425
Malignancy or tumour (lymphoma, gliomatosis cerebri,
metastatic disease)
Subacute-to-chronic clinical presentation
History of malignant tumour
History of unintentional weight loss
Abnormal CSF cytology
Absence of clinical and radiological resolution
Can be unilateral in brain imaging

CNS vasculitis
Often subacute clinical presentation
CSF pleocytosis
Cytotoxic oedema in non-PRES-like pattern
Progressive multifocal leukoencephalopathy
Subacute-to-chronic clinical presentation
Can be unilateral in brain imaging

Osmotic demyelination syndrome

History of rapid normalisation of sodium or glucose concentrations
Does not preferentially affect the parieto-occipital lobes
Characteristic central pontine signal abnormality in a bat-wing shape
Acute demyelinating encephalomyelitis
Usually a disorder affecting children
Preceded by viral or bacterial infection
Fever in 5075% of patients
Radiographically supratentorial lesions usually asymmetrical

Toxic leukoencephalopathy
History of illicit drug use
Positive drug or toxin screen
Symptoms progress for weeks
Magnetic resonance spectroscopy can show abnormally raised lactate and
decreased N-acetyl aspartate concentrations
Reversible cerebral vasoconstriction syndrome

Thunderclap headache
PRES quickly progresses over a few hours, complications may occur for
several days with the RCVS
Imaging PRES- Bilateral parieto-occipital lesions on MRI, typical for PRES
Imaging RCVS- classic pattern of string of beads on Angiography, at least
two narrowings per artery on two different cerebral arteries at brain magnetic
resonance angiography (MRA) or at conventional angiography
10% of cases there seems to be overlap between this syndrome and PRES
TREATMENT
General measures- aimed at maintaining ABC of the patient

Symptomatic therapy
Antihypertensives - reduce blood pressure by 25% within first
few hours.
Anticonvulsants

Correction/Removal of the underlying cause

Withdrawl of offending drug
Termination of pregnancy
PROGNOSIS
Brain lesions are reversible

Most studies- excellent short term and long term outcome

Symptoms usually seem to resolve in about 38 days (7590%)

while recovery of the MRI abnormalities takes longerseveral
days to weeks

Mortality (36%) - intracranial haemorrhage, posterior fossa

oedema with brainstem compression or acute hydrocephalus, or
marked diffuse cerebral oedema and increased global
intracranial pressure.
 Persistent neurological sequelae -1020%

Hyperglycaemia and time to control of the causative factor have

been also reported to be independently associated with poor
outcomes
Poor outcome may also be related to associated comorbidity
(sepsis) or intracerebral haemorrhage
 Recurrent PRES ~ 4% of cases

More common in patients with uncontrolled hypertension

compared with patients who have other causes compared with
patients who have other causes (ie, immunosuppressant
therapy).

1015% develop recurrent seizures in the first few years after

PRES
PAEDIATRIC POSTERIOR REVERSIBLE
ENCEPHALOPATHY SYNDROME
Incidence - 0.4%

Common causes- haematological disorders, kidney disease, or

those taking cytotoxic drugs after organ transplantation,
Glomerulonephritis, acute leukaemia, Henoch- Schonlein
purpura, and haemolytic uraemic syndrome

Clinical and radiological presentation appears to be similar to

that in adults
Mean blood pressure at presentation -140/85 mm Hg
AREAS OF UNCERTAINTY AND CONTROVERSY

Opposing pathophysiological hypothesis hypoperfusion /

hyperprfusion

Co-occurrence of neuromyelitis optica spectrum disorders and

PRES - role of aquaporin-4 channelopathy in its pathogenesis ?

Myelopathy or brainstem dysfunction

PRES can be also be diagnosed in the presence of normal brain

imaging ?
THANK YOU
REFERENCES
Posterior reversible encephalopathy syndrome: clinical and
radiological manifestations, pathophysiology, and outstanding
questions Lancet Neurol 2015; 14: 91425

Semin Neurol 2011;31:202215

Understanding Posterior Reversible Encephalopathy Syndrome

S. Legriel, F. Pico, and E. Azoulay. Annual Update in
Intensive Care and Emergency Medicine 2011

Posterior Reversible Encephalopathy Syndrome, Fundamental

Imaging and Clinical Features Am J Neuroradiol 2012; 33:
896903