Luis Vernaza Hospital, Department of Solid Organ and Tissue Transplantation, Guayaquil, Ecuador
Received date: April 13, 2017; Accepted date: April 21, 2017; Published date: April 22, 2017
Citation: Tobar P, Molina E, Benalcazar G (2017) Atypical Posterior Reversible Encephalopathy Syndrome Imaging on Liver Transplant Patients. J Liver 6:211. doi:10.4172/2167-0889.1000211
Copyright: © 2017 Tobar P, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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The Posterior Reversible Encephalopathy Syndrome (PRES) is a known clinical entity that presents as changes on neurological images (CT/MRI) with concomitant appearance of new onset neurological signs and symptoms. It complicates a diversity of diseases and the use of certain medication, mostly immunosuppressive, that should be taken into account when new clinical manifestations with neuroimaging changes appear on a immunosuppressed patient.
Case report: We report a case of a Liver Transplant recipient patient with Tacrolimus as main immunosuppression, that develops new onset neurological focalization signs and diffuse atypical changes on imaging (CT and MRI/MRA) not according to her signs and symptoms, which improve once the calcineurin inhibitors are remove from her medication scheme.
Conclusion: In any patient receiving calcineurin inhibitors the presence new onset changes on imaging and neurological manifestations, even if they are not the typical ones, imposes the ruling out of common infectious causes and the rotation of the immunosuppressive medication in expectance of improvement of the clinical picture, which support the diagnoses of PRES.
The earliest definition and description of the Posterior Reversible Encephalopathy Syndrome (PRES) was given on 1996 by Hinchey et al. . On this description it was described a diverse group of clinicalradiological findings such as: headache, paresis, visual disturbances, seizures and consciousness state alterations , in conjunction with radiological evidence of bilateral subcortical vasogenic edema that apparently was more common on the posterior areas of the brain. [1,3].
PRES has been diagnose within several contexts, it is considered a common comorbidity on hypertensive obstetric conditions such as preclampsia and eclampsia, renal diseases, autoimmune conditions, immunosuppressive therapy (calcineurin inhibitors) and hypertensive encephalopathy [4,5]. Tacrolimus and cyclosporin belong to the family of the calcineurin inhibitors and their mechanism of action relies on avoid the transcription of interleucin-2 (IL-2) [6,7], these medications have some adverse effects such as neurotoxicity, hypertension and nephrotoxicity [7,8]. These adverse effects at the same time are commonly found within the development of PRES without showing causality, which may be explained by the fact that most of the information we have about this pathology relies on observational retrospective studies [1-5].
The neurologic manifestations can present on an acute or sub-acute manner, between the most common ones and in a frequency order there can be observed encephalopathy which can vary from a mild confusion to stupor, seizures, which are generalized tonic-clonic on most of the cases even though partial crisis have been reported and there can be presence of status epilepticus, which has a worst prognosis; constant headache that the patient cannot localize, with poor analgesic response; visual alterations that go from blurry vision to cortical blindness depending on the affected area [9-12]. PRES is mostly reversible however there has been reports of some residual impairment on some patients, most of them due to large hemorrhages or infarctions, even though variables had been evaluated as predictors of the reversibility of this syndrome, it seems to be individualdependent.
Next we are describing the case of a patient recipient of liver transplant with cadaveric donor on immunosuppressive therapy with tacrolimus and subsequent development of PRES.
The patient is a 55 years old female previously diagnosed with primary biliary colangitis on cirrhotic decompensated phase, that was subject of orthotopic liver transplantation on June 2015, from a donor with cold ischemia time of 4 h 35 min, with a post-transplant stay of 7 days, without any immediate complication. The patient goes to the emergency service of the Luis Vernaza Hospital on January the 9th of 2016 with right hemiparesis of crural predominance, facial asymmetry, speech difficulties and holocraneal headache. At that moment the patient was 7 month after her liver transplant surgery without major organ complications. On the physical examination the patient seems oriented on time, space and person, with blood pressure of 100/80 mmHg and other vital signs within normal limits. Neurologic evaluation reveals right central facial paralysis, right hemiparesis with strength evaluation of 4/5 on upper limb and 2/5 on inferior limb. A blood sample is taken that shows serum creatinine of 1.4 mg/dL (Glomerular Filtration Rate by MDR4 of 41.49 mL/min/1.73 m2 ). A Computed Tomography without contrast is done where hypo densities are seen on white substance without previous hemorrhage or infarction signs; with these results a Magnetic Resonance Image(MRI) of the brain is ordered where there can be appreciated micro infarction on basal ganglia, semioval centers and radiate crown, periventricular leukoaraiosis and demyelination of basal ganglia on T2 and Diffusion Weighted Imaging (DWI) sequences (Figure 1). A Magnetic Resonance Angiography (MRA) of the Willis Polygone is realized where there is no evidence of stenosis, aneurism or arteriovenous malformations.
Two days posterior to the admission a lumbar puncture for Cerebrospinal Fluid (CSF) analysis is realized and Polymerase Chain Reaction (PCR) for Herpes virus, John Cunningham (JC) virus, Toxoplasma gondii and Mycobacterium tuberculosis are realized with negative results for all of them. At this moment Tacrolimus associated PRES is suspected, the patient was receiving 2 mg Orally (PO) Twice a Day (BID) with a serum dosage of 6.8 ng/ml; the immunosuppressant is changed to Cyclosporin at a 50 mg PO BID with serum dosage of 132 ng/ml. Despite the change in the immunosuppressive regimen the neurological manifestations persist, and the dose of cyclosporine is decreased to 25 mg PO BID and prednisone is added at a dose of 20 mg/d to avoid organ rejection.
On day 6 after admission the clinical manifestations persist and the neurological symptoms progress reducing the muscular strength on the upper limb to 1/5 on Daniel’s scale, there is instauration of diplopia with divergent strabismus and development of motor aphasia. Cyclosporin is totally suspended and immunosuppression is replaced with Azathioprine 50 mg +Prednisone 20 mg PO once a day. 48 h later the patient is reevaluated with improvement of the dysarthria and the right hemiparesis. Afterwards the patient remains hospitalized for a total of 20 days since her admission through emergency services with total resolution of her symptoms. Currently the patient remains asymptomatic, without any sequel and with current immunosuppressive treatment of Everolimus 0.5 mg PO once daily +Prednisone 5 mg PO once daily.
The physiopathology of PRES has not been clearly defined, actually there are several hypothesis that are widely debated between them the autoregulation of cerebral blood flow dysfunction associated with blood pressure rise that would cause damage to endothelium, that eventually causes fluid extravasation to the interstitial space, cytokine release and subcortical edema production . However on 25% of the cases there can be seen normal or low blood pressure  which suggests that there are individuals more susceptive to abrupt changes of blood pressure than from an elevation of it . Besides hypertension, there has been seen commonly a concomitant renal injury and rise on cellular damage markers such as lactate dehydrogenase (LDH) during PRES.
PRES is considered as the maximum extreme in the spectrum of the neurotoxicity caused by calcineurin inhibitors; this toxicity is thought to be caused by sympathetic stimuli alteration, induction of apoptosis of oligodendrocytes and nitric oxide production inhibition by endothelium .
Within the neurologic manifestations there has been described headache that can range from mild to severe, different degrees of visual impairment and partial to generalized seizures. However it is worth notice that the report of focalized neurologic signs range from 0-3%.
When using different imaging studies the MRI is preferred since it let us distinguish from other possible diagnoses, specially the sequence T2, DWI and FLAIR which let us classify the white matter edema in four different patterns described by Legriel et al. being the holohemispheric watershed pattern that courses with bilateral vasogenic edema of the frontal, parietal and occipital lobes. The superior frontal pattern presents edema on the superior sulci. The dominant parietal-occipital pattern that is the one classically described on the first PRES reports, which consist on edema of the parietal and occipital lobe on different degrees. And the partial or asymmetric expression of the primary patterns, where the partial form is the absence of edema on the parietal or occipital area and the asymmetric form that is characterized by the unilateral absence of edema in either of the two lobes previously described [12-15,4,9].
On a solid organ recipient transplant patients presenting with progressive neurological disease there are some common infectious etiologies we are obligated to rule out before thinking on pharmacological induced PRES, such as Herpes virus encephalitis, progressive multifocal leukoencephalopathy (PML) and cerebral toxoplasma reactivation. However, HSV encephalitis is more common on the first month after liver transplant and most of the time it presents with primary skin/mucosae characteristic lesions [16,17]. PML seems as a tentative option given the clinical picture, however this lesion is more common on HIV patients and with a negative PCR test on a CSF analysis, with a specificity of 95%, this diagnosis becomes unlikely . Finally cerebral toxoplasma reactivation would have presented as multiple ring lesions with preference for basal ganglia, once again, this infection is more prevalent on the HIV population and the CSF analysis gave back negative PCR results .
Other important factor is the time between the procedure/start of the immunosuppression and the onset of neurologic symptoms, in our case clinical manifestations starts 7 months after the procedure, the literature describes an early onset related with use of CNI in patients after liver transplantation (LTx) usually within 2-3 months posttransplant . despite this information a case of PRES occurring 13 months after LTx with CNI has been reported on 2005  and in a case series of 19 subjects shows 1 patient who develops symptoms after 14 months of treatment with tacrolimus .
Our patient is impossible to classify from an imaging point of view on any of the four MRI patterns and common infectious causes have been excluded. Finally due to the total clinical resolution after the treatment modification with withholding of the calcineurin inhibitors medication we reached and the PRES diagnosis.
Even though there is a clearly defined series of radiological signs and neurologic manifestations that usually present during PRES, it is important to remember that in any patient receiving calcineurin inhibitors, the presence of neurologic alterations de novo with changes on imaging studies as MR and the systematic evaluation and elimination of more common causes should raise the concern for PRES, since this is a potentially reversible etiology. In case there may be any doubt about the feasibility of the diagnosis a clinical improvement and a cleaning of the radiologic images posterior to the medication suspension should help support the diagnosis further.
The authors of this case report have no conflict of interest on respect of funding, affiliations or management that could be perceived as source of interest.
Original script: J Tobar, E Molina, G Benalcazar Script; Review: G Benalcazar. Imaging providing: L Rosales MD, Luis Vernaza Hospital Intervention Imaging department.