Posterior reversible leukoencephalopathy syndrome (PRES)

PRES, posterior reversible leukoencephalopathy syndrome, hypertensive encephalopathy, reversible posterior cerebral oedema syndrome and hyperperfusion encephalopathy are all terms used to describe the same neuroradiology findings, which might be caused by a variety of totally different pathological processes. But, all those processes end up causing white matter oedema in a bilateral (usually posterior) distribution, which shines with an obvious increased signal intensity on an  MRI T2-weighted image. The management for most of these conditions is the same (i.e. nothing specific) and the intensivist is invariably left in an unsatisfying position of the coma babysitter, waiting for this supposedly reversible condition to turn the corner so the patient can be extubated.

This condition has never come up in the first twenty or so years of the CICM Part II written exam until a relatively recent radiology question (Question 14.1 from the first paper of 2016). The college presented us with a T2-weighed MRI image which clearly demonstrated increased signal intensity in the posterior white matter. The history was given as "headache, confusion and blurred vision followed by a generalised tonic-clonic seizure" on the background of immunosuppression; the CSF was unremarkable. This was an ulcerative colitis patient who had been given infliximab recently, which is apparently a classical associatuion ( Zamvar et al, 2009). That time, 66% of the candidates were able to answer to a passing mark or better. PRES appeared again in Question 10 from the second paper of 2018, but this time with a full 10-mark SAQ asking for details about risk factors, clinical features, differential diagnoses, radiological findings and management. 

Because this condition is something of an esoteric unicorn, the time-poor candidate is advised to steer clear of such magnum opus articles as the luxuriously detailed 2008 review by Walter Bartynski (Part 1 or Part 2). Something like the LITFL half-page or the Radiopedia entry will probably suffice. Otherwise, one risks joining this author in a swamp of unnecessary brain-cluttering detail. In any case, the Bartynski papers have been chopped up and boiled to form the summary below, which hopefully retains some of their educational value. Maximal attention was paid to the radiological features and risk factors, because this is what the college wanted in the answer to Question 14.1.

Definition of PRES

Say, you have an unconscious person. Under what circumstances can one decide to call their coma PRES? Well, there are actually no specific diagnostic criteria which must be met in order to make this diagnosis. Typically, there is a constellation of characteristic features:

• Altered level of consciousness, ranging from confusion to coma
• Headache
• Seizures
• Visual symptoms (usually, blindness or hemianopia)
• Neuroradiology findings
• Exclusion of other pathology (eg. encephalitis or stroke)
• Acute onset, and reversibility over days or weeks
• Hypertension

The UpToDate authors courageously refuse to give us any guidance, "in the appropriate clinical setting, clinicians should recognize the neurologic syndrome... and order a brain MRI". A recent article by Fugate and Rabenstein (Lancet, 2015) offers a bunch of features which are compatible with the diagnosis, but nothing in the way of actual diagnostic criteria. Most authors struggle to define the syndrome, and it is still known by multiple synonyms (eg. hypertensive encephalopathy), but not everybody agrees that these are in fact synonyms (but rather separate radiologically similar conditions). In short, it's a mess.

Pathophysiology of PRES

The current "popular theory" for how this happens is the hypertension-failed autoregulation-hyperperfusion theory. It can be summarised in point form:

• The upper limit of cerebral bloodflow autoregulation is about 150-160 mmHg (higher by up to 30mmHg in cases of chronic hypertension)
• Beyond that limit, increasing blood pressure drives an increased blood flow
• As the pressure increases, arterioles passively dilate
• The permeability of these vessels increases as their endothelial cells are forced apart
• Increased hydrostatic pressure within injured vessels causes a migration of fluid out of the circulatory compartment and into the brain parenchyma

This theory is supported by the following observations:

• Most PRES patients have hypertension at presentation
• Treatment of hypertension seems to be associated with symptom improvement
• Vasogenic cerebral oedema is readily induced by hypertension in animal models (a bunch of hypertensive cats - MacKenzie et al, 1976)
• Neuroradiology findings in affected patients are consistent with oedema

The theory has the following major holes in it:

• Many (up to 50%!) of PRES patients are not hypertensive at presentation. Hypertension is not an essential feature of this disorder.
• Many people out in the community have horrific uncontrolled hypertension and they never develop PRES. For instance, the occasional cocaine binge will result in sustained peaks of extreme hypertension, which will not be associated with PRES.
• Nobody has ever convincingly demonstrated hyperperfusion in PRES brains.
• The degree of oedema does not correlate with the severity of hypertension
• Some sort of systemic process is usually associated with PRES (eg. pregnancy, immunosuppressant therapy, autoimmune disease), but this theory does not explain this association

Risk factors and associations

PRES is almost exclusive to significant systemic conditions. It is associated with something major going on in the rest of the body. Classical associations include the following list (borrowed from Bartynski's Table 1):

• Solid organ transplant
• Bone marrow transplant
• Graft vs. host disease following allogenic BMT
• Immunosuppressant therapy, especially cyclosporine and tacrolimus
• Pregnancy (particularly, pre-eclampsia)
• Cancer chemotherapy, specifically cytarabine, cisplatin, gemcitabine and bevacizumab
• Autoimmune disease, particularly scleroderma, SLE, polyarteritis nodosa and Wegener's granulomatosis
• Sepsis and septic shock, specially when associated with MOSF

Biological processes commonly associated with PRES therefore include the following:

• Immune system activation
• T-cell hyperactivity
• Endothelial cell activation (surface-marker expression, etc)
• Endothelial injury
• Systemic vasoconstriction
• Systemic organ hypoperfusion

The UpToDate article gives an even larger list of "associated conditions", which adds the following:

• TTP / HUS
• Cryoglobulinaemia
• Chronic kidney diseases
• Porphyria
• Blood transfusion
• Contrast media exposure

Miscellaneous associations listed by Bartynski are also offered here as an interesting word salad

• Hypomagnesemiai
• Hypercalcemia
• Hypocholesterolemia
• Intravenous immunoglobulin
• Guillain-Barré syndrome
• Ephedra overdose
• Erythropoietin use
• Triple-H therapy
• Tumor lysis syndrome
• Hydrogen peroxide
• Dimethyl sulfoxide stem cells

Differential diagnosis

From UpToDate, a series of plausible differentials is:

• Eclampsia
• Cerebral oedema due to hypertensive encephalopathy
• Reversible cerebral vasoconstriction syndrome
• Ischaemic stroke (posterior circulation)
• Cerebral venous thrombosis
• Encephalitis (infectious, paraneoplastic or autoimmune)
• CNS malignancy, eg. lymphoma
• Acute demyelinating encephalomyelitis (ADEM)

This is probably relevant to the main thrust of Question 6 from the first paper of 2020, which basically asked "HSV encephalitis: how is this not PRES?". The specific answer called for "clinical manifestations, aetiology, treatment and complications". For the purpose of maintaining at least some semblance of attachment to exam relevance, the answer to this question is transformed into a table and presented below. The specific information regarding HSV encephalitis are derived from an excellent article by Bradshaw & Ventakesan (2016), which somehow happens to protrude through the Springer paywall.

PRES vs. HSV encephalitis

HSV encephalitis	PRES
Pathophysiology / aetiology
Viral illness Transmitted along an axon from the ganglion of the trigeminal nerve, where it lays dormant Pathophysiology is inflammatory and (Bradshaw et al, 2016) Characterised by the development of inflammatory cerebral oedema  Exhibits tropism for the orbitofrontal and mesiotemporal lobe	Hypertensive disorder Hypertension, followed by failed autoregulation, followed by hyperperfusion As the result of hypertension, permeability of cerebral vessels increases Vasogenic cerebral oedema results
Clinical manifestations
Historical features and symptoms (Sili et al, 2014) Subacute course (>24 hrs) Headache Altered mental status initially Abnormal behaviour Progressively worsening level of consciousness Features on examination Focal signs are possible Fever Seizures CSF biochemistry CSF pleocytosis, mainly lymphocytic Elecated CSF protein HSV PCR positive Radiology/neurophysiology Contrast-enhancing lesions on MRI Evidence of lost grey-white differentiation on CT EEG findings (non-pathognomic)	Historical features and symptoms Headache Visual disturbance Altered mental status Features on examination Blindness Hypertension Seizures CSF biochemistry (Ellis, 2019) CSF pleocytosis Mildly elevated protein Radiology/neurophysiology MRI evidence of oedema Oedema is symmetric (bilateral) Posterior occipital or parietal distribution (but this is not essential): in fact three major anatomical patterns of distribution exist: holohemispheric superior frontal sulcal primary parietal-occipital Nonspecific EEG findings
Treatment
IV aciclovir 10 mg/kg q8h for 14–21 days Foscarnet is a second option	Aggressive control of blood pressure Give antiepileptics if seizures were a presenting problem. Stop the causative drug or arrest the causative process (eg. eclampsia)
Complications
Decreased level of consciousness Seizures, status epilepticus Development of NMDA receptor antibodies	Hypertensive complications (Fischer et al, 2017) Intracranial haemorrhage (eg subarachnoid or intraparenchymal) Status epilepticus Persistent neurological sequelae are rare Persisting epilepsy may occur

Radiological features

The images below were stolen from the 2012 article by Swarnalatha et al, where the PRES was associated with renal failure. These are the same T2 weighted MRI images which I used to replace the college's own pictures from Question 14.1 from the first paper of 2016. 

The characteristic radiology features listed below were blended from those offered by Radiopedia and those listed by Bartynski.

• Oedema is symmetric (bilateral)
• Posterior occipital or parietal distribution (but this is not essential): in fact three major anatomical patterns of distribution exist:
  • holohemispheric
  • superior frontal sulcal
  • primary parietal-occipital

MRI findings with different imaging sequences:

• T1: hypointense 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%

In case the reader is wondering whether it is valuable to commit this list of abbreviations to memory, they may refer to Question 2 from the first paper of 2019, where the MRI features of PRES were asked about (for 20% of the mark). The examiners complained of "poor knowledge in this area with many factual errors"  which suggests that they absolutely did expect their trainees to have this information available for immediate recall.

ICU management for PRES

Apart from waiting patiently until the condition resolves, what else can the intensivist realistically offer?
Not much.

• Aggressively control the blood pressure.
• Give antiepileptics if seizures were a presenting problem.
• Stop the causative drug.
• Deliver the baby (in eclampsia).
• Protect the patient from the horrors of ICU stay by attentive FASTHUGish supportive care