European Journal of Cardiovascular Medicine

Posterior Reversible Encephalopathy Syndrome (PRES) also referred to as Reversible posterior cerebral edema syndrome, hyper perfusion encephalopathy, Posterior leukoencephalopathy syndrome, Brain capillary leak syndrome is a clinical-radiographic syndrome was first described by Hinchey  in 1996 ¹.Subacute in onset, it has varied neurological features ranging from headache, loss of consciousness, seizures, visual disturbances and focal neurological deficits. It is often found to be associated with a number of conditions like malignant hypertension, pregnancy induced hypertension, antineoplastic treatments, cytotoxic and immunosuppressive drugs and certain autoimmune conditions.² Because of its varied presentation as well as its association with a number of conditions, this rather newer entity in the spectrum of hypertensive encephalopathy patients is becoming more commoner than usual due to increased awareness not only among neurologists but  also among other clinicians who are crucial in having a high index of suspicion to identify this syndrome. Management of patients with hypertensive emergencies and hypertensive encephalopathy which can range from mild neurological deficits to coma and seizures is often in done the multidisciplinary ICUs and knowledge about this condition and risk factors is essential to intensivists who are the primary care givers in these areas.

Though reversibilityis a hallmark feature,long term sequalae can be present if diagnosis and treatment is delayed which further stresses the importance of its early recognition.

Here we have 5 cases admitted with varied presentations and etiologies to our multidisciplinary ICU over a period of 1 year.

A retrospective analysis of 5 patients who were admitted to an adult MICU and diagnosed with PRES over a 1‑year period from 2021 to 2022 was done.

Demographic data like Age and Gender, past medical history, symptoms at presentation and other neurological symptoms including like Seizures, Headache, Visual disturbances, GCS with any Focal neurological deficit if any was noted. The peak blood pressure during the course, any requirement of ventilator, the radiological findings in CT and MRI was also noted. The patient’s status at discharge, MRI after recovery if any, outcome at 90 days were also followed up.

Index:- GTCS –generalized tonic clonic seizures POG-period of gestation, MPGN-membranoproliferative glomerulonephritis, LSCS-lower segment caesarean section , CKD –chronic kidney disease, MHD-maintenance haemodialysis ,TTP- thrombotic thrombocytopenic purpura, LRTI- lower respiratory tract infection, CXR-chest X ray ,MMF-mycophenolate mofetil

Image 1-T2 FLAIR showing an ill -defined high signal in the right occipital lobe-atypical presentation of PRES (Case 5)

Image 2 DWI image showing a subtle restricted diffusion in the right occipital lobe-maybe due to edema(case 5)

Image 3 –T2 FLAIR image showing ill -defined high signal changes in the right frontal lobe (case1)

Image 4 –DWI showing subtle restricted diffusion in the right frontal lobe(case1 )

Image 5 and 6 –T2 FLAIR images showing bilateral symmetrical hyperintensitites involving the frontal lobes, centrum semiovale and bilateral occipital lobes (case 3)

Over a period of 1‑year, we identified 5 patients diagnosed with PRES [Table 1]. Out of these patients, three patients were eclampsia of pregnancy, one diagnosed case of IgA nephropathy on conservative management, andanother patient of immune complex mediated glomerulonephritis on treatment with mycophenolate mofetil and being conservatively managed for the same.

 The patients were in the middle age group range from 20 to 42 years. Accelerated hypertension was present in all five patients with systolic blood pressure ranging between 170-200 and diastolic pressures ranging between 90-110 mm of Hg.

Presenting features varied, as shown in the table, as per the primary condition of the patient. Only one patient was referred in view of generalised tonic clonic seizures while the rest of the patients developed seizures during the course of stay in the hospital.

Three patients complained of headache and it was found to be prior to seizure onset. Only one patient had sudden loss of vision after seizure onset .Two patients required ventilation for airway protection and one patient required reintubation in view of respiratory distress.

INVESTIGATIONS

CT scan was the primary imaging done in all five patients and was normal in four. MRI was done in all patients and diagnosis of PRES was established. All patients except one had more than one areas of the brain involved mainly occipital and parietal. The MRI showed bilateral symmetrical involvement in four cases exception being in case 5 where asymmetrical right sided involvement was noted along with FLAIR showing diffusion restrictions.

TREATMENT

Patients with PRES secondary to pregnancy related hypertension recovered faster as compared to those with background of chronic hypertension. At the time of ICU discharge all patients had better control of pressures and no focal neurological deficit.

One of the patients with pregnancy related PRES had a complicated course with persistent thrombocytopenia and required multiple platelet transfusions and was evaluated and found to have Thrombotic thrombocytopenic purpura(TTP), treated with steroids and plasmapheresis, she also developed septicaemia with pan resistant klebsiella treated with teicoplanin and polymyxin.Both the patients with underlying autoimmune disease had chronic hypertension and renal involvement, and were being managed conservatively for renal involvement were initiated on Haemodialysis and immunosuppressants.

OUTCOME AND FOLLOW UP

On the 90 day follow- up we found that all the patients were stable and the IgA nephropathy patient was on maintenance haemodialysis and off immunosuppressants while the patient with immune complex mediated glomerulonephritis was on immunosuppressant’s and required maintenance haemodialysis while the 3 female patients were continuing their routine life and patient with TTP advised for 6 monthly follow-up.

PRES is a clinico radiological entity with varied clinical presentations and severity with a female preponderance. Seizures was reported to be the most common feature (80%) in literature and all the patients reported here had seizures. There is a propensity of recurrence of seizures especially generalized tonic clonic type. Involvement of the occipital lobe has been found to be associated with recurrence of seizures ^5. Our patient who had recurrence of seizures too had hyperintensities in the occipital lobe on neuroimaging.

Another common presentation in PRES are the visual disturbances which were reportedly seen in 39% of patients in one study ⁶. The symptoms can present as various types of visual field deficits, blurred vision, visual neglect, hallucinations and cortical blindness. The ocular examination and fundoscopic examination in patients with PRES are often normal, although a few may reveal papilledema along with nonspecific haemorrhages and exudate ⁷.An important finding in patients with ocular complaints is that all of them had a history of hypertension ^8. In our cases, one patient had visual loss and another patient blurring of vision. Both of them had hypertension correlating well with the available literature.

Headache is one more frequently reported manifestation of PRES, often patients describe it as a dull intractable headache or thunderclap headache ⁹. Postpartum headache has been described as a recurrent syndrome associated with PRES ⁵. In our case series two of our patients had headache preceding seizure onset.

PRES has been associated with an array of general conditions like hypertension, sepsis, solid organ transplantation, eclampsia and pre-eclampsia, renal failure, malignancy (solid organ and haematological), bone marrow transplantation. Autoimmune disorders linked with PRES are rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease and scleroderma. Some toxins have also been reported to be linked to PRES like Lysergic acid diethylamide (LSD), scorpion poison, and cocaine. Several cytotoxic and immunosuppressive medications also have known to be associated with development of PRES like gemcitabine. Tacrolimus, sirolimus, mycophenolate and cisplatin amongst others ¹⁰. Few cases with Covid –19 related PRES also have been reported ^5. In the above reported cases, our patients had eclampsia, uncontrolled hypertension in chronic kidney disease which could be the cause of PRES in them. PRES associated with IgA nephropathy have been reported in medical literature ¹¹, and we also report a similar case here. We also had a case of TTP with PRES which presented like postpartum eclampsia. TTP associated with PRES is a rare presentation and such cases have been reported ^{12, 13}. We also report a case of PRES linked with mycophenolate mofetil, similar presentations have been found in literature ¹⁴.

 PRES has been described as a disorder caused by dysregulated perfusion of the brain, leading to the development of in reversible vasogenic oedema. Various hypothesis have been proposed explaining the cerebral vasculature dysregulation in PRES, but there was no exclusive theory to substantiate development of vasogenic oedema in all associated causes .Thus, multiple mechanisms contributing to development of PRES, including excessive hypertension, impaired cerebral autoregulation causing cerebral hyper perfusion and endothelial dysfunction.¹⁰The posterior circulation was more susceptible to hyper perfusion as it has less sympathetic innervation to counter reflex parasympathetic vasodilation .Patients with PRES commonly have acute fluctuations in blood pressure, but it is not known whether these are the cause or a secondary effect of the syndrome.Endothelial dysfunction may result, either directly or as a downstream effect, from the secretion of cytokines, including tumour necrosis factor alpha, interleukin-1, interferon gamma and vascular endothelial growth factor.⁵

As pregnancy has effects on perivascular innervations by mechanisms not yet proven, especially in pial vessels, in which nerve hypertrophy is produced. Thus, implying that neurotransmitters may have a part in hypertensive intolerance that results in the development of PRES. Angiogenic factors can reduce endothelial dysfunction, thereby preventing pathogenesis of PRES. VEGF and PIGF are antiangiogenic factors found to be elevated in pregnancy, thereby predisposing pregnant patients to endothelial dysfunction. While preeclampsia-eclampsia treatment is achieved by delivery of foetus, but for unknown reasons, PRES has been found to develop in the postpartum period ¹⁵. In our case no 2 reported here, she had developed PRES in the postpartum period, correlating with the available literature.

PRES is often a diagnosis of exclusion. No specific criteria have been defined for diagnosis. The presence of acute onset of neurological symptoms, fluctuations in blood pressure, and features of vasogenic oedema on neuroimaging and clinical history of comorbidities or triggering factors of PRES should help us make a diagnosis. Fugate et al ¹⁶ have proposed the following criteria for diagnosis –

-neurological symptoms of acute onset

- (focal) vasogenic oedema on neuroimaging

-reversibility of clinical and/or radiological findings

Neuroimaging is of utmost importance in diagnosis. Both CT and MRI brain are helpful. CT scans generally show vasogenic oedema with a bi -hemispheric distribution, but MRI is more sensitive showing hyper intense lesions in T2-weighted or fluid-attenuated inversion recovery (FLAIR) sequences ². MRI diffusion-weighted imaging usually confirms vasogenic oedema with absence of restricted diffusion. ² The bilateral cortical–subcorticalvasogenic oedema has been observed to have three anatomical patterns seen in about 70% of patients: a dominant parietal-occipital pattern, a holohemispheric watershed pattern; and superior frontal sulcus pattern.A central-variant (brainstem) pattern has also been identified, affecting the brainstem, basal ganglia posterior limb of the internal capsule, cerebellum and periventricular regions, but has no cortical or subcortical involvement.PRES may rarely even involve the spinal cord.Temporal and frontal lobe involvement can occur in up to 75% of cases,but in practice, these patterns are commonly mixed. PRES with such combined patterns is actually more common than PRES with isolated parietal-occipital involvement ¹⁷. In the cases reported here, all of our patients had posterior occipital hyper intensities on MRI. CT imaging did not show any abnormality in our cases with exception of case 2 where, parietal and occipital changes were observed in CT. In our patients CT was done first due to hemodynamic instability and only once patient was stabilized MRI was done.

Management of PRES includes supportive care and includes treatment of underlying cause like hypertension. Once clinician suspects PRES, patient should be carefully monitored and shifted to ICU especially if patient has hypertension, seizures, encephalopathy and low GCS. Blood pressure control is essential, antihypertensives should be commenced at the earliest. The current recommendations are to reduce the MAP in an initial rate of not more than 20-25% within the first 2 hours, as a rapid reduction of the MAP can worsen the brain dysfunction by decreasing perfusion ¹⁵. Thus, an intravenous short acting drug that permits easy titration would be the best pharmacologic therapy in this context like labetalol, nicardipine, nitroglycerine. Continuous administration in an infusion of these antihypertensive drugs under hemodynamic monitoring to avoid any fluctuations in blood pressure is the standard goal of management in these patients.

Preeclampsia-eclampsia related PRES management requires supportive treatment and definitive treatment which consists of prompt delivery. General supportive measures like blood pressure control, prevention and/or treatment of seizures must be the main goals. In the setting of eclampsia, magnesium sulphate is known to be the drug of choice as compared with other anticonvulsant agents with proven decreased maternal mortality, diminishing recurrence of seizure episodes as well as improvement in foetal outcome.

Anticonvulsants like lorazepam, phenytoin, phosphenytoin and levetiracetam has been used. The optimal duration of treatment of these patients with antiepileptic drugs is still unclear. General practice is to taper the anticonvulsive medication as soon as the patient is asymptomatic and stop once the imaging lesions have fully reversed ².

Identifying the triggering aetiology and subsequent treatment of the same along with general supportive care like maintenance of airway, intubation, antibiotics for sepsis, dyselectrolytemia correction, dialysis if needed amongst others are also important in managing this condition.Prognosis is generally good and the majority of patients will have a complete clinical recovery, although complete radiographic resolution may not occur in all. Complete recovery is reported in 75–90% of cases, and most patients will recover within a week, though in some patients, recovery occurs over a longer interval and neurological sequelae have been reported in 10–20% of patients ⁵.

All our patients recovered with no neurological complications and were subsequently discharge and follow-up had no complications, only one patient who had CKD but on conservative management was now requiring maintenance haemodialysis but this seems to be unrelated to development of PRES.

TAKE HOME MESSAGE

PRES is cliniconeuro-radiological acute event that adds to morbidity of patients. It must be promptly recognized especially in the high-risk groups. Intensivists should have high degree of suspicion and with neuroimaging early diagnosis and initiation of treatment can improve morbidity and outcomes.

• PRES is now a known complication in eclampsia and preeclampsia patients and hence should be kept in mind in obstetric patients.
• Chronic kidney disease patients who are hypertensive can be at risk of developing PRES.
• Often a diagnosis of exclusion, all other known causes have to be ruled out before concluding the diagnosis.Neuroimaging will help confirm the diagnosis.
• Multidisciplinary teams should be involved in diagnosing and managing the condition.

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