Posterior reversible encephalopathy syndrome, Hypertension, Preeclampsia, Vasogenic oedema
The Posterior Reversible Encephalopathy Syndrome (PRES) is a neurological disorder of subacute onset characterized by varied neurological symptoms, like headache, impaired visual acuity or visual field deficits, disorders of consciousness, confusion, seizures, and focal neurological deficits. In a majority of patients,the clinical presentation includes elevated arterial blood pressure up to hypertensive emergencies, or hypotension. Neuroimaging, in particular magnetic resonance imaging, frequently shows a distinctive parieto-occipital pattern with a symmetric distribution of changes reflecting vasogenic edema. PRES frequently develops in the context of cytotoxic medication, eclampsia, sepsis, renal disease or autoimmune disorders.
The syndrome was first described in 1996 by Hincheyn and colleagues who reported on a series of 15 patients with neurological signs and symptoms including headache, seizures, visual disturbance and other focal neurological deficits.
We are going to present 3 of them with different presentation in different subsets.
Case Scenario 1 :
R D a 13-year-old boy presented with h/o sudden onset of dizziness followed by altered sensorium of one episode lasting for few minutes while he was playing with his friends. During admission, his blood pressure was 140/80, but he was conscious and oriented. He was admitted in general ward, on that night he had one episode of (Generalized Tonic clonic Seizure) GTCS, and he became unconscious, he was shifted to intensive care unitwith blood pressure 200/120, when he regained his consciousness fully after 2 hours, he complained of loss of vision in both eyes, his hearing was normal and he was following command, but he lost perception of light. Immediately ophthalmoscopy was done, no abnormality detected. He had persistently raised blood pressure 160/90 instead of antihypertensive medication (amlodipine). A CT brain done on that day which reveals poorly marginated hypodensity in bilateral paritooccipital region, MRI brain done next day reveals restricted diffusion in bilateral posterior parietal and occipital region with these regionsshowing T2 & Flair hyperintensity mainly in subcortical white matter. Over next three days he regained his vision, and after controlling blood pressure he completely recovered without any residual neuro deficit. He was diagnosed having paragnglionoma on later date, blood pressure was well controlled and didn't have any further episode known to me till now since 2010.
Figure : 1 CT of R. D.
Figure : 2 MRI of R. D.
Case Scenario 2 :
R. F. a 23-year-old, primigravida (P0+0) her antenatal period was uneventful. Her EDD was in April 2014. She was normotensive, and was having normal weight gain throughout the pregnancy. Her antenatal blood report was Hb 9.9gm%, TSH 2.5, PPBS 102mg/dl, urine R/E -WNL, FBS 86mg/dl. TORCH investigations showed Toxoplasma IgM +ve 1.2, Rubella IgG+ve 1.75, IgM+ve1.85, HIV -ve. USG on 21.11.13 showed triplet changes lie. She had no other contributory risk factor. Family history was non-contributory. She was on regular antenatal checkup. From latter half of 2nd trimester, her BP was increasing and she was put on Labetalol 100 mg thrice daily and nifedipine10mg thrice daily. She was admitted on 31st week and underwent LSCS under spinal anesthesia at 31 weeks 3 days (23.2.14). After postoperative period she complained of frontal headache which was constricting in nature suggestive of post spinal headache. Her BP was increasing slightly and she was on good hydration, analgesic and antihypertensive medications. After 6 hours she developed severe headache with visual blurring followed by GTCS type of convulsion followed by postictal confusion. Her BP again went up and was measured to be 200/110. A provisional diagnosis of postpartum eclampsia was made. Injection Midazolam and Injection Magnesium sulfate were started. But second episode of GTCS occured at 7:45 pm on that first postoperative day. She was shifted to ICU, and convulsion managed with Levetiracetam Injection. Blood pressure managed with GTN Infusion and magnesium sulfate. Her reports in ICU Hb- 12gm%, CRP negative, TLC 18500, Platelet 120000, Procalcitonin negative, urine for RE albumin trace, urine for C/S no growth. ANAnegative, urea creatinine, electrolyte, calcium, and magnesium all WNL. Fundoscopy did not reveal any papilledema. CT scan was normal.
On MRI brain done on second postoperative day showed a diffuse hyper intensity in T2 and FLAIR is noted in bilateral parieto-temporal and occipital cortex and sub cortical white matter along with hyper intensity in bilateral frontal cortex. Thalamus, basal ganglia, brain stem and cerebellum are normal. Sulci and sylvian fissure are effaced suggestive of PRES. The patient stabilized on the third postoperative day. Her neurological symptoms are completely resolved by sixth postoperative day. She was discharged with antihypertensive and anticonvulsant. She was on follow-up in neurology OPD for last 6 months and living a completely neurological ailment free life.
Case Scenarios 3 :
Mrs. P. M., non-hypertensive lady had uneventful pregnancy undergone caesarian section in some other hospital and was discharged on 4th postoperative day, she developed recurrent episodes of generalized seizure with altered sensorium at home and was shifted to the hospital, where she was detected having normal blood pressure and normal electrolytes with normal CT scan of brain and was treated with Levetiracetam on next day she was referred to our hospital as she developed hypotension, hypotension treated with noradrenalin infusion. On admission, she was conscious but disoriented, afebrile, normotensive, CSF revealed raise protein (204mg/dl) with cell count 3 cells/ml. CRP and procalcitonin was negative, serum sodium, calcium and magnesium was normal but LDH was raised, EEG revealed intermittent diffuse slowing at 1-2 Hzfor 2-3 seconds, no spikes or sharp waves, suggestive of mild diffuse encephalopathy or postictal slowing. CEMRI brain reveals - ill-defined hyperintensity in bilateral posterior parietal, temporal and occipital cortex. She recovered over next two days repeat CSF shows normal protein with normal cell count. She recovered and followed up at OPD without any further episode of neurological symptoms. Repeat MRI after one month was normal.
Figure : 3 MRI of Mrs P. M.
In all the three cases presented here had episodes of altered sensorium with convulsion, with complete recovery of the neurological symptoms. A diagnosis of PRES (Posterior Reversible Encephalopathy Syndrome) was made in all the 3 cases.
The global incidence of PRES is unknown. The only epidemiological data come from retrospective studies of patients seen between 1988 and 2008 [2-8]. PRES has been reported in patients aged 4 to 90 years, although most cases occur in young to middle-aged adults, the mean age ranging across case series from 39 to 47 years. There is a marked female predominance. Many patients with PRES have comorbidities, which may be severe conditions, such as bonemarrow or solid organ transplantation, chronic renal failure, and chronic hypertension.
FIG : 1 Pathogenesis of PRES
The pathogenesis of PRES remains unclear, but it appears to be related to disordered cerebral autoregulation and endothelial dysfunction.
Autoregulatory failure -- Normal autoregulation maintains constant cerebral blood flow over a range of systemic blood pressure, by means of arteriolar constriction and dilatation[9,10]. As the upper limit of cerebral autoregulation is exceeded, arterioles dilate and cerebral blood flow increases in a pressure-passive manner with rises in systemic blood pressure. The resulting brain hyper perfusion, particularly in arterial border zones, may lead to breakdown of the blood brain barrier allowing extravasation of fluid and blood products into the brain parenchyma.
The rate of blood pressure elevation is likely to be important.Children appear particularly vulnerable to PRES at lower blood pressures than adults[11,12].
Cerebral ischemia -- In severe cases, it has been postulated that disordered cerebral autoregulation may lead to reactive focal vasoconstriction, thereby resulting in local hypoperfusion, cytotoxic edema, and cerebral infarction. It is also possible that the cerebral infarctions, which uncommonly occur in PRES, could result from compression of microcirculation from the mass effect of vasogenic edema. Some patients, have demonstrable vasoconstriction on radiologic imaging. Radionuclide studies have demonstrated perfusion deficits in some patients with PRES[15,16].
Endothelial cell dysfunction - In preeclampsia, markers of endothelial cell dysfunction (lactate dehydrogenase, abnormal red blood cell morphology) typically arise prior to the clinical syndrome and correlate better with the extent of cerebral edema than do blood pressure changes[17-19]. More specific markers of endothelial dysfunction include fibronectin, tissue plasminogen activator, thrombomodulin, endothelin-1, and, in particular, von Willebrand factor[19-21]. Trophoblastic cytotoxic factors originating from a poorly perfused fetal unit may provide the initial stimulus. Markers of endothelial cell dysfunction have also been reported in patients with PRES in other clinical settings including chronic renal failure, lupus nephritis, and hemolytic uremic syndrome.
Other mechanisms -- In some clinical settings, uremia, sepsis, hypomagnesemia, and other metabolic disturbances have been noted. These factors may mediate their effects on the vascular endothelium or other sites of vasogenic control. Fluid overload may also contribute to cerebral edema in some patients.
The combination of acute hypertension and endothelial damage results in hydrostatic edema, a specific form of vasogenic edema characterized by the forced leakage of serum through capillary walls and into the brain interstitium, which if severe enough, will be radiographically evident. Unregulated vascular injury to blood-brain barrier endothelium leads to edema, protein extravasation, and fibrinoid necrosis. The cortex, structurally more tightly packed than the white matter, resists accumulation of edema, hence predilection of abnormalities to be seen in the white matter.
The primary involvement of posterior brain regions is not well understood. One possibility involves the regional heterogeneity of the sympathetic innervation of the intracranial arterioles, which has been shown to protect the brain from marked increases in blood pressure. A histochemical study revealed a greater concentration of adrenergic nerves around pial and intracerebral vessels in the anterior circulation than posteriorly.
Table 1 : Condition at risk for PRES
Table 2: Differential diagnosis of Cerebral MRI finding in patient with white matter abnormalities mimicking PRES
Table 3 : Diagnostic tools and Findings
The treatment of PRES is symptomatic.As no specific therapeutic strategy is currently available management of the underlying disease or pathology leading to PRES development is of major importance. Management of hypertensive episodes and maintenance of normal blood pressure is an essential component of PRES treatment[23,24]. However, there is no evidence, based on prospective controlled studies, that strict blood pressure control limits neurologic injury, or results in a regression of clinical or imaging findings. Preferred antihypertensive drugs per se is based on general recommendations for the management of hypertensive crisis or hypertensive emergency. A reduction of blood pressure levels by 25% from baseline values is recommended. Administration of antihypertensive drugs under hemodynamic monitoring should be considered. Anticonvulsive treatment is frequently required. There is no general recommendation for the use of specific drugs. Moreover, the optimal duration of antiepileptic drug treatment is unclear. Usually, anticonvulsive medication can be tapered off as early as the patient is asymptomatic and the imaging lesions have fully reversed. Immunosuppressive or cytotoxic medication may be responsible for the neurological manifestations. It is still a matter of controversy whether tapering off or immediate discontinuation of the triggering agent is required, or whether reducing the dosage with strict control of serum levels within the therapeutic range is sufficient.
In patients with PRES associated with systemic lupus erythematosus, active disease was found as the initiating trigger and intensification of immunosuppressive therapy was suggested to control neurological manifestations. As magnesium levels are found to be reduced in a high number of patients with PRES, coupled to its known prophylactic anticonvulsive and vasodilating effects, hypomagnesemia should be avoided and serum levels be maintained in the high normal range. In case of cerebral vasospasm or cerebral vasoconstriction, treatment of the vasospasm may be started at an early stage.
Prognosis and Outcome :
Most of the cases of PRES is completely reversible but prognosis depends on the underlying precipitating cause. PRES may be complicated by other factors and neurological sequel may persists. Singer and colleagues observed a complete resolution of neurological signs and symptoms in 84% of cancer patients with PRES. In 81% of cases, neuroimaging findings were reversible on follow-up MRI or CT scans. Mortality rate in their cohort was reported to be 19%. However, no death was directly associated with PRES. Heo and colleagues reviewed 102 cases of PRES and found long-term epilepsy in four patients. In contrast, Kastrup et al. described a cohort of 49 patients, 38 of them presenting with seizures during the acute phase. At followup none of their patients suffered from persisting epilepsy.
Future directions :
Findings on cerebral perfusion in PRES patients are conflicting, since hyper perfusion as well as decreased perfusion have been reported after PRES[31,32]. Future neuroimaging studies should focus on angiographic imaging and perfusion patterns to characterize cerebral hemodynamics during PRES that may vary depending on etiological aspects or disease progress. Further, non-invasive continuous monitoring of the cerebrovascular autoregulation may aid in the optimal hemodynamic management and the definition of individual blood pressure targets maintaining a constant cerebral blood flow within the limits of cerebral autoregulation.
PRES associated clinical features are reversible in majority of cases, disease severity and complications depends on underlying disease. Treatment is mostly symptomatic, prognosis depends on underlying disease. [Abbreviations: ANA - Anti nuclear antibody, CADASIL-Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CRP- C Reactive Protein DWI- Diffusion weighted image, FLAIR- Fluid Attenuated Inversion Recovery Gd- Gadolinium, GMD grey matter disease, MELASMitochondrial myopathy encephalopathy lactic acidosis and stroke-like episodes syndrome, TSH - Thyroid stimulating hormone, WMD - White matter disease, WNL - Within Normal Limit] Authors hereby declares there was no conflict of interest in this article.
Dr. Prabuddha Mukhopadhyay and Dr. Aparajita Das have written this article with referencing. Dr. Mukhopadhyay and Dr. Soumen Bhat collected those patient data.