Posterior reversible encephalopathy syndrome is a rare and serious neurologic adverse effect of calcineurin inhibitors. The pathophysiology of this clinical entity is still unclear. Impaired cerebral autoregulation and endothelial dysfunction are thought to be the main pathologic processes. Imaging shows the syndrome to be characterized by vasogenic edema or cytotoxic edema in parietal and occipital areas of the brain. With regard to clinic presentation, headache, diminished visual acuity, cortical blindness, altered consciousness, seizures, and hallucinations can be seen. It is known that the clinical presentation is improved when calcineurin inhibitors are stopped early. Here, we present and evaluate a case of a cortical blindness that developed in a 36-year-old patient who had been using tacrolimus after renal transplant and who returned to health after 1 week of hospitalization.
Key words : Cortical blindness, Emergency department, Kidney transplant
Although posterior reversible encephalopathy syndrome (PRES) has been known as an increasingly recognized syndrome since 1996, there are few reports on its presentation with regard to emergency medicine. So far, the pathophysiology of PRES is unclear, but there are some theories that stand out. The first of these is a theory of impaired cerebral vascular autoregulation caused by rapidly devel-oping hypertension due to parieto-occipital area hyperperfusion, which is weaker in terms of sympathetic innervation of the brain, and vasogenic edema due to protein leakage and fluid extravasation.1-3 Another theory that causes this clinical condition is ischemia, which develops as a secondary response to vasospasm.4 The latest theory holds endothelial dysfunction responsible, which is similar to the development of eclampsia.5,6
Although the syndrome frequently affects the posterior area of the brain, it is known that it can also involve other areas, including the frontal lobe and cortex, and presents with related clinical conditions. Although defined as reversible, status epilepticus, intracranial hemorrhage, which may occur as a complication in the disease process, can cause significant morbidity and mortality.7
With regard to the causes of PRES, autoimmune diseases (such as thrombotic thrombocytopenic purpura, Wegener granulomatosis, and systemic lupus erythematosus), hypertension, sepsis, multiple organ dysfunction, and cytotoxic drug use have also been reported.1,2 Calcineurin inhibitors, such as cyclosporine and tacrolimus, are the most implicated immunosuppressants of PRES in the literature along with high-dose steroid therapy and sirolimus. Patients with PRES may present with vision disorders, encephalopathy, headache, and decreased visual acuity and cortical blindness.
A 36-year-old female patient who had 13 years of dialysis for chronic renal failure and had undergone deceased-donor renal transplant about 6 weeks earlier was admitted to the emergency department with complaints of progressive loss of vision and headache. The patient showed no changes in consciousness and no seizures during examination. She was using prednisolone, mycophenolate mofetil, valganciclovir, and tacrolimus.
The patient’s general condition was good, conscious, fully oriented, and cooperative on her examination. Her blood pressure level was 155/91 mm Hg, heart rate was 108 beats/minute, respiration rate was 20 breaths/minute, and fingertip oxygen saturation was 98%. Cardiovascular exam-ination showed no murmurs, but bilateral pretibial edema was seen. Abdominal examination showed no defense or rebound. We heard no abnormalities in lungs during pulmonary auscultation of the respiratory system. During neurologic examination, Glasgow coma scale showed 15/15, and bilateral light reflex was normal. However, both eyes of the patient were shown to be mydriatic. On visual acuity examination, she only could perceive an intense light from a distance of 15 cm. Bilateral optical disc boundaries were faintly shown during eye examination. Muscle strength was detected to be fully functional bilaterally in both the upper and lower extremities.
The patient’s complete blood count and bio-chemistry analysis were as follows: white blood cell count of 8.1 × 103/mm3, hemoglobin level of 9.7 g/dL, hematocrit of 28.7%, platelet count of 155 × 103/mm3, neutrophil count of 6.9 × 103/mm3 (85.5%), urea level of 44 mg/dL, creatinine level of 1.22 mg/dL, sodium level of 140 mmol/L, potassium level of 4 mmol/L, total calcium of 7.6 mmol/L, international normalized ratio of 1.1, glucose level of 121 mg/dL, total protein of 5.8 g/dL, and albumin of 3.77 g/dL.
Cranial computed tomography (CT) was per-formed first (Somatom Definiton AS Plus, Siemens; Erlangen, Germany). The patient’s cranial CT imaging (Figure 1) showed no intracranial hemorrhage or space-occupying lesions to explain this clinical situation. The patient then underwent fluid-attenuated inversion recovery imaging (1.5 T, Magnetom-Avanto, Siemens Healthcare) and diffusion-weighted magnetic resonance imaging. Fluid-attenuated inversion recovery images showed multiple cortical and subcortical high signal intensities, especially bilaterally in the parieto-occipital lobes and slightly bilaterally in the cerebellar cortical areas (Figure 2). Diffusion-weighted magnetic resonance images showed that most of the lesions had a high signal, and apparent diffusion coefficient (ADC) maps demonstrated decreased signal intensity in both occipital areas, representing cytotoxic edema (Figure 3).
Because of the imaging findings and clinical story of the patient, we considered PRES, resulting in treatment for blood pressure control and having the patient stop tacrolimus intake. The patient also required consultation with neurology, which noted that symmetrical involvement in both posterior brain areas and progressive loss of vision were related to PRES. The patient was hospitalized in our transplant department.
Another diffusion-weighted magnetic resonance imaging examination, which was taken on day 8 after visual improvement, showed diffusion restrictions of the bilateral occipital region to be regressed (Figure 4). On day 9 of hospitalization, she was discharged with full recovery.
The underlying physiopathology of PRES with undetermined origin has been thought to be due to impaired vascular autoregulation, resulting in increased endothelial permeability and cerebral edema.2,5 This syndrome can be a rare adverse effect of immunosuppressive agent use, with diagnosis by characteristic neuroimaging findings that accompany neurologic findings. Although an association between nontoxic doses of tacrolimus and symptoms has been shown,8 no clear correlation has been found,9,10 leading to the conclusion that therapeutic doses of tacrolimus may cause encephalopathy.1 It has also been shown that individuals with ABCB1 gene polymorphism in the liver are predisposed to calcineurin-related neurotoxicity.11
During clinical examinations, it is important to exclude metabolic, neurologic, and infectious causes that may cause headache, focal neurologic deficits, or altered consciousness. In addition, hypertension, hypocholesterolemia, hypomagnesemia, and high-dose use of methylprednisolone have been shown to worsen the neurologic adverse effects of calcineurin inhibitors even when tacrolimus serum levels are within a normal range.12 Although electrolyte levels in our patients were within the normal range, electrolyte disturbances are a common problem after kidney transplant, and a high level of calcineurin inhibitors can worsen allograft functions, showing raised potassium and calcium levels. Calcineurin inhibitors strongly affect serum electrolyte levels; therefore, electrolyte levels should be monitored closely in these patients.13
Occipital white matter appears to be uniquely susceptible to the neurotoxic effects of calcineurin inhibitors. Injury to both the major and minor vascular structures may cause hypoperfusion or ischemia and local secondary toxicity in the white matter.12 Hyperintense lesions are seen in fluid-attenuated inversion recovery imaging and T2-weighted sequences in neuroimaging. However, it is not possible to distinguish whether these lesions are caused by cytotoxic or vasogenic edema on T2-weighted imaging. Therefore, ADC mapping should also be performed to exclude the glare effects of T2-weighted images. Diagnostic findings in ADC mapping include cytotoxic edema, which is more common in the occipital, parietal, frontoparietal, and inferior temporo-occipital areas, and white matter lesions in regions that indicate irrigated areas of major branches of the cerebral arteries.14
In transplant recipients, severe hypertension has been shown to be directly associated with the development of PRES.14 Because the risk of seizure development is significantly increased with this syndrome, it is critical to recognize the possible increased mortality and morbidity with status epilepticus early and to maintain strict blood pressure follow-up during hospitalization and in the emergency department.2 In the presence of auto-immune diseases such as underlying systemic lupus erythematosus and thrombotic thrombocytopenic purpura, oral and/or intravenous antihypertensive treatments may be insufficient to control blood pressure; therefore, treatment methods other than conventional treatments, including plasmapheresis, should be considered.15 In our patient, recovery without sequelae was achieved with discontinuation of tacrolimus, a calcineurin inhibitor, administration of an oral antihypertensive medication (amlodipine) for blood pressure control, and seizure observation.
The most common presentation of PRES, which is rarer with immunosuppressant agents such as tacrolimus, is seizures, encephalopathy, headache, and visual disturbances.6 Including this syndrome, which can result in recovery without sequelae with interventions such as interruption of tacrolimus use and close blood pressure control, in early differential diagnosis and imaging should be considered in specific groups (posttransplant, immunosuppressant use) when patients present with changes in con-sciousness.
DOI : 10.6002/ect.2018.0193
From the Cerrahpasa Medical Faculty, Istanbul University Cerrahpasa, Istanbul,
Turkey; and the 2University of Health Sciences, Haseki Training and Research
Hospital, Istanbul, Turkey
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Fatih Çakmak, İstanbul University Cerrahpasa-Cerrahpasa Medical Faculty, Emergency Medicine Department, Koca Mustafa Paşa Mahallesi, Cerrahpaşa Caddesi No:53, 34096 Fatih/İstanbul, Turkey
Phone: +90 532 6539947
Figure 1. Computed Tomography Showing No Intracranial Hemorrhage
Figure 2. Fluid-Attenuated Inversion Recovery Magnetic Resonance Imaging
Figure 3. Diffusion-Weighted Magnetic Resonance Images and Apparent Diffusion Coefficient Mapping at Presentation
Figure 4. Diffusion-Weighted Magnetic Resonance and Apparent Diffusion Coefficient Mapping Images at Follow-up