Posterior reversible encephalopathy syndrome—Insight into pathogenesis, clinical variants and treatment approaches

AUTREV-01720; No of Pages 7 Autoimmunity Reviews xxx (2015) xxx–xxx

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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev

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Article history: Received 3 May 2015 Accepted 12 May 2015 Available online xxxx

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Keywords: Posterior reversible leucoencephalopathy syndrome Hypertensive encephalopathy Cerebral edema Seizures Immune dysregulation Acute vertigo Tinnitus

Department of Clinical Immunology, Sapienza University of Rome, Viale dell'Università, 37, 00161 Rome, Italy Organi di Senso Department University, Sapienza University of Rome, Viale del Policlinico, 151, 00161 Rome, Italy

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Posterior reversible encephalopathy syndrome is a rare clinicoradiological entity characterized by typical MRI findings located in the occipital and parietal lobes, caused by subcortical vasogenic edema. It was first described as a distinctive syndrome by Hinchey in 1996. Etiopathogenesis is not clear, although it is known that it is an endotheliopathy of the posterior cerebral vasculature leading to failed cerebral autoregulation, posterior edema and encephalopathy. A possible pathological activation of the immune system has been recently hypothesized in its pathogenesis. At clinical onset, the most common manifestations are seizures, headache and visual changes. Besides, tinnitus and acute vertigo have been frequently reported. Symptoms can be reversible but cerebral hemorrhage or ischemia may occur. Diagnosis is based on magnetic resonance imaging, in the presence of acute development of clinical neurologic symptoms and signs and arterial hypertension and/or toxic associated conditions with possible endotheliotoxic effects. Mainstay on the treatment is removal of the underlying cause. Further investigation and developments in endothelial cell function and in neuroimaging of cerebral blood flow are needed and will help to increase our understanding of pathophysiology, possibly suggesting novel therapies. © 2015 Published by Elsevier B.V.

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Introduction . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . Aetiopathogenesis . . . . . . . . . . Symptomatology . . . . . . . . . . . 4.1. Ophthalmological findings . . . 4.2. Inner ear disease . . . . . . . 4.3. Clinical course . . . . . . . . . Histopathology . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . 6.1. MRI findings . . . . . . . . . 6.2. Additional diagnostic procedures 6.3. Differential diagnosis . . . . . Prognosis . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . .

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Guido Granata a, Antonio Greco b,⁎, Giannicola Iannella b, Granata Massimo a, Alessandra Manno b, Ersilia Savastano b, Giuseppe Magliulo b

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Posterior reversible encephalopathy syndrome—Insight into pathogenesis, clinical variants and treatment approaches☆

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Abbreviations: Posterior reversible leucoencephalopathy syndrome, PRES; mean arterial pressure, MAP; nitric oxygen, NO; tumor necrosis factor, TNF; interferon, IFN; cell adhesion molecule, CAM; magnetic resonance, MR; transfusion-related acute lung injury, TRALI; vascular endothelial growth factor, VEGF; ear nose and throat, ENT; vestibular evoked miogenic potentials, VEMPs; magnetic resonance imaging, MRI; apparent diffusion coefficient, ADC; diffusion-weighted imaging, DWI; electroencephalography, EEG; computed tomography, CT; cerebrospinal fluid, CSF; central nervous system, CNS; acute disseminated encephalomyelitis, ADEM. ☆ All authors declare no conflicts of interest, grants or other founding supports. ⁎ Corresponding author at: M.D. Via Rome 00, Italy. Fax: +39 0649976826. E-mail addresses: [email protected] (G. Granata), [email protected] (A. Greco), [email protected] (G. Iannella), [email protected] (G. Massimo), [email protected] (A. Manno), [email protected] (E. Savastano), [email protected] (G. Magliulo).

http://dx.doi.org/10.1016/j.autrev.2015.05.006 1568-9972/© 2015 Published by Elsevier B.V.

Please cite this article as: Granata G, et al, Posterior reversible encephalopathy syndrome—Insight into pathogenesis, clinical variants and treatment approaches, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.05.006

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2. Epidemiology

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The incidence of PRES is unknown, incidence is moderately higher in females than in males. The male:female ratio is 0.8:1 [3,5]. The mean age at presentation is 44 years with an extended age range of 14 to 78 years [3]. Comorbid conditions in PRES are usually present, including hypertension (53% of the reported clinical cases), kidney disease (45%), malignancy (32%), dialysis dependency (21%), and transplantation (24%) (Table 1) [2,3].

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3. Aetiopathogenesis

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The putative pathophysiology on posterior encephalopathy is that of failed cerebral autoregulation with development of brain edema. At least four theories have been postulated explaining cerebral dysregulation [5] (Fig. 1); according to the “vasogenic” theory an increased systemic blood pressure could overcome cerebral autoregulation leading to increased cerebral mean arterial pressure (MAP). This might lead to hyperperfusion, increased capillary hydrostatic pressure, vasodilation and vasogenic edema. Increased cerebral arterial pressure might also lead to disruption of the physiological blood–brain barrier with extravasation of plasma through the tight junctions in the surrounding brain parenchyma leading to cerebral edema [5 26–29]. Several studies underline how cerebral vessels in the posterior circulation are more

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4. Symptomatology

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Clinically PRES is characterized by seizures, headache, vomiting, amaurosis, hemianopsia, coma, aphasia, decreased level of consciousness, dysarthria, ataxia, dizziness, hemiparesis and various other focal neurologic symptoms and signs (Fig. 2) [2–5,9–11,39]. Despite commonest symptoms are seizures, headache and visual changes, ear nose and

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Posterior reversible leucoencephalopathy syndrome (PRES) is a clinicoradiological syndrome, first described by Hinchey et al. in 1996 [1]. Hypertension has often been emphasized as a common feature of all PRES associated conditions. The most common clinical manifestations of PRES are headache, nausea and vomiting, altered mental status, decreased alertness, seizures, cortical blindness and other visual abnormalities, and transient motor deficits [2–11]. Besides, tinnitus and acute vertigo may accompany the other neurologic symptoms and signs due to the typical autoregulation deficit of the posterior cerebral circulation [12–14]. The main finding in neuroimaging is posterior white matter edema, often with symmetrical involvement of the parietal and occipital lobes due to vascular cerebral dysregulation. Nevertheless PRES can be associated with several conditions, including acute or chronic renal failure, blood transfusion, organ transplant, infection, autoimmune disorder, immunosuppression, and puerperal eclampsia [2]. The presence of this disease in such normo- or hypo-tensive patients has made possible to hypothesize a pathological activation of immune system in its pathogenesis, besides the previous entirely ‘vasogenic’ theory. Since the first descriptions of PRES in the 1996, several reports reported a possible autoimmune etiology of this disease [5,6,15–25].

prone to hypertension-related damage than anterior vessels richer in sympathetic neural innervation [22]. Vasogenic theory doesn't appear exhaustive in normo- or hypo-tensive patients or in conditions not associated with hypertension such as autoimmune disease, septic shock, and malignancy. According to the “cytotoxic” theory toxins or chemokines (from endogenous synthesis) or chemotherapy, immunosuppressive or immunomodulatory therapy (exogenous) once released in the bloodstream might be responsible for endothelial dysfunction and cerebral edema; both endotoxins (lipopolysaccharide) and esotoxins (peptidoglycan and lipoteichoic acid from gram-positive cell wall) can lead to endothelial injury promoting the release of endothelin-1 and immune activation [5,21]. The “immunogenic” theory emphasizes the role of the immune system via T-cell activation, cytokine release and subsequent increased endothelial permeability and vasogenic edema [5]. Endothelial cell activation with the release of mediators such as histamine, free radicals, nitric oxygen (NO), bradykinin and arachidonic acid representing the primum movens of local immune system activation [30]. All these changes result in vascular instability with vasoconstriction and downstream hypoperfusion. Blood–brain barrier dysfunction thus occurs, leading to cerebral edema [31]. Immune response to infection is a wide-complex process involving several systemic events. Chemokines such as tumor necrosis factor (TNF)-alpha, interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon (IFN)-γ lead to T-lymphocyte activation and subsequent leukocyte increased adherence and activation [16,30,32–35]. Leukocyte trafficking increases via the release of adhesion molecules such as intercellular adhesion molecule [ICAM]-1, P-selectin, E-selectin, and cell adhesion molecule (CAM)-1 [36]. Subsequent leukocyte activation besides inflammatory cytokines such as TNF-alpha and IL-1 upregulates potent vasoconstrictor (such as endothelin-1) mRNA production and stimulates its release from endothelial cells. Upregulation of endothelial surface antigens and the release of endothelin-1 affect the local vascular tone finally leading to vasospasm and ischemia [37]. This hypothesis is supported by studies involving catheter angiography, magnetic resonance (MR) angiography, and MR perfusion imaging, which show cerebral hypoperfusion [15,38]. According to the “neuropeptide” theory release of potent vasoconstrictors, such as endothelin-1, prostacyclin, and thromboxane A2, might lead to vasospasm and ischemia and subsequent cerebral edema [5]. From the observation of several cases of PRES that occurred during or after blood transfusion, Zhen-Yu Zhao et al. [17] speculated that the pathophysiology of PRES might be similar to transfusion-related acute lung injury (TRALI). TRALI is defined clinically as acute noncardiogenic lung injury occurring within 6 h of the transfusion of any blood product. According to this theory in patient with chronic severe anemia or other first predispositions cell signaling activation with release of vascular endothelial growth factor (VEGF) increases endothelial permeability. The blood transfusion represents thus the “second hit” to activate neutrophils and exacerbate dysfunction of the vascular endothelium. While in TRALI the only organ involved is the lung, in PRES the disruption of the blood–brain barrier leads to leakage of brain–capillary resulting in vasogenic edema in the brain. It was emphasized that an allergic reaction is possibly associated with the development of PRES in some cases [17]

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9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Table 1 Prevalence of comorbid conditions described in PRES.

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Hypertension Acute or chronic renal failure Organ transplant Malignancy Infection Dialysis dependency Autoimmune disorder Puerperal eclampsia Immunosuppression/chemotherapy

53 45 40 32 25 21 11 11 5

Please cite this article as: Granata G, et al, Posterior reversible encephalopathy syndrome—Insight into pathogenesis, clinical variants and treatment approaches, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.05.006

102 103 104 105 106 107 108 109 110 111 112 113 Q3 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152

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throat (ENT) symptoms like vertigo tinnitus are frequently reported. Hearing loss has never been reported in the literature, however, this condition may be present in the early stages although hidden by the more serious neurological symptoms. Symptoms often manifest with a

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Fig. 1. At least four theories have been postulated explaining failed cerebral autoregulation with development of brain edema and posterior encephalopathy. According to the “vasogenic” (1) theory an increased systemic blood pressure overcomes cerebral autoregulation leading to increased capillary hydrostatic pressure and disruption of the physiological blood–brain barrier, extravasation of plasma and cerebral edema. According to the “cytotoxic” theory (2) toxins such as eso/endo-toxins and cytotoxic or immunosuppressive agents are responsible for endothelial dysfunction. Endothelial injury is mediated by releasing of chemokines (such as endothelin-1) and immune activation leading to cerebral edema. The “immunogenic” theory (3) emphasizes the role of the immune system via T-cell activation, citochine release and subsequent increased endothelial permeability and vasogenic edema. Endothelial cell activation with the release of mediators such as histamine, free radicals, nitric oxygen, bradykinin and arachidonic acid results in blood–brain barrier dysfunction, leading to cerebral edema. According to the “neuropeptide” theory (4) the release of vasoconstrictors, such as prostacyclin, endothelin-1 and thromboxane A2, leads to vasospasm and ischemia and subsequent cerebral edema.

sudden onset, but they can also develop in several days [2–5,9–11,39]. At clinical onset, the most common manifestations are seizures. Disease onset is heralded by seizures in approximately 90% of case record and seizures are usually generalized or rapidly developing with progression from focal type to generalized seizures [2,3,5,10,11,39,40]. None of the symptoms is mandatory for the diagnosis of PRES, even hypertension is not essential to the syndrome and cases with normal or low blood pressure are described; rather than absolute blood pressure level, a rapid increase in pressure from a previous lower level seems to bring the highest risk of developing PRES. Consciousness alteration ranges from drowsiness to confusion, and can progress to stupor and coma. Visual abnormalities range from blurred vision, hemianopsia, visual neglect, and visual hallucinations to cortical blindness [2,3,5,9–11,39].

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4.1. Ophthalmological findings

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Usually there are no ophthalmological findings; papilledema seems 177 to be very uncommon with the exception of cases accompanied by 178 overt malignant hypertension [5]. 179

Fig. 2. Frequency (%) of posterior reversible encephalopathy syndrome signs and symptoms.

4.2. Inner ear disease

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The inner ear is supplied by the vertebrobasilar system through the internal auditory artery, which is usually a branch of the anterior inferior cerebellar artery. Within the internal auditory canal, the internal auditory artery irrigates the ganglion cells, nerves, dura, and arachnoid membranes and divides into two main branches, the common cochlear

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Please cite this article as: Granata G, et al, Posterior reversible encephalopathy syndrome—Insight into pathogenesis, clinical variants and treatment approaches, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.05.006

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Although the majority of symptoms can be reversible in few hours or days, usually in 3–8 days [8], depending also in the timing of recognition and establishing of the proper treatment, cerebral hemorrhage or ischemia may occur leading to irreversible neurological deficits or death [1–3,5,6,25].

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5. Histopathology

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The majority of autopsies performed at the early stages describe vasogenic edema surrounding reactive astrocytes, macrophages and lymphocytes [19,51]; fibrinoid necrosis of the vessel wall, microinfarcts and hemorrhages are described at a later stage of disease [52,53]. Commonly the lesions described are located bilaterally in the posterior vessels and in the cerebral parenchyma but involvement of the anterior circulation is described [53].

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6. Diagnosis

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6.2. Additional diagnostic procedures

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In patients with suspected PRES, diagnostic procedures, in addition to those described above, are often performed. Electroencephalography (EEG) findings in patients with suspected PRES can indicate the presence of encephalopathy, typically with the presence of focal sharp waves. Computed tomography (CT) study can be useful in ruling out acute infarct or hemorrhagic stroke [58]. When performed, brain biopsy may reveal edema and microangiopathy described above. Data from lumbar puncture and liquor examination are not common in literature. Zhen-Yu Zhao et al. [17] report the presence of cerebro spinal fluid (CSF) pleocytosis in a case suggesting that PRES can be accompanied by brain inflammation.

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6.3. Differential diagnosis

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ischemia occurs, diffusion restriction is observed [3]. Fluid-attenuated inversion recovery imaging increases the ability to detect subtle lesions while supplemental diffusion-weighted imaging and apparent diffusion coefficient (ADC) map images can be useful in distinguish vasogenic edema from cytotoxic edema; ischemic lesions display hyper-intensity on diffusion-weighted imaging (DWI) while PRES lesions display hypointensity [4,22,23,55–57]. Atypical pictures are hyperintensities located in the deep gray matter or in frontal and temporal lobes [3,4,22,23, 54–56]. Other atypical pictures have been described: edema can be located significantly in frontal lobes, between the main cerebral arteries or along the superior frontal sulcus; at the basal ganglia or in the brainstem [7,39]. MRI findings can be reversible in several days or weeks but permanent injury, hemorrhage into lesions, and unilaterality can also be seen [54]. Complete resolution of imaging abnormalities is found in 72% of cases within a mean of 6 weeks of follow-up [8].

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and anterior vestibular arteries [14,41–43]. Considering that the inner ear usually requires high-energy metabolism and that the internal auditory artery is an end artery with minimal collateral circulation from the otic capsule, the labyrinth could be especially vulnerable to increased capillary hydrostatic pressure, vasodilation and vasogenic edema [43]. In patients with PRES the presence of an autoregulation deficit of the posterior cerebral circulation could result in damage to the macula receptors of the saccule and utricle with the appearance of vestibular symptoms. Labyrinthine damage in patients with PRES could be very similar to that shown in patients with anterior inferior cerebellar artery infarction that reported isolated recurrent vertigo, fluctuating hearing loss, or tinnitus (as initial symptoms one to ten days prior to permanent infarction) [14,43]. Furthermore, there is a considerable evidence to suggest that hearing and vestibular function can be influenced by autoimmune processes [13,14]. A number of systemic autoimmune disorders including hearing loss and vertigo as part of their constellation of symptoms have been reported [12,13,44–46]. Autoimmune inner ear disease probably accounts for less than 1% of all cases of balance disorders, but its incidence is often overlooked due to the absence of a specific diagnostic test [12,47,48]. The Caloric Test and the Vestibular Evoked Miogenic Potentials (VEMPs) could be useful to determine the type and location of the labyrinth damage and could be well executed at the resolution of the acute symptoms [49,50]. The possible appearance of a hearing loss is usually neglected in patients with PRES. There are at least two possible explanations. First, patients may not be aware of their hearing loss during seizures, headache, vomiting and vertigo. Second, no clinician included the audiogram as a routine diagnostic tool for the hearing loss evaluation in patients with PRES. Finally because the several neurological conditions do not allow to perform a correct pure-tone audiometry.

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6.1. MRI findings

7. Prognosis

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Typical MRI findings are symmetric reversible T2 high signal intensities located in the occipital and parietal lobes, caused by subcortical vasogenic edema as clarified by diffusion weighted imaging (Fig. 3) [7]. Most lesions do not enhance on T1-weighted images. When cerebral

Most cases of PRES improve with a prompt, proper treatment and the majority of symptoms can be reversible after few hours or days; however cerebral hemorrhage or ischemia can occur and irreversible neurological deficits or death are reported [1–3,5,6,25].

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Magnetic resonance imaging (MRI) is considered the crucial diagnostic test in the presence of acute development of clinical neurologic symptoms and signs and arterial hypertension and/or toxic associated conditions with possible endotheliotoxic effects [2]. Commonest symptoms are seizures, headache and visual changes; although the onset is usually sudden symptoms may also develop in several days. Acute hypertension is associated with the majority of cases, but is not necessary for the diagnosis.

Despite its presumed rarity, PRES is considered as a differential diagnosis in various neurological, psychiatric and ophthalmological disorders, as well as ENT conditions (Table 2) and is often misdiagnosed. Severe neurological conditions such as encephalitis, reversible cerebral vasoconstriction syndrome, posterior circulation stroke, cerebral venous sinus thrombosis, reversible cerebral vasoconstriction syndrome, primary central nervous system (CNS) vasculitis and primary CNS vasculitis need to be considered as possible diagnoses [5,59–61]. Moreover tinnitus and dizziness in patients with PRES should always be differentiated from vestibular dysfunction due to infarcts of the anterior inferior cerebellar artery territory. [14,43,62]. Although the clinical picture of PRES is not specific, an early MRI leads to the correct diagnosis in most cases although misinterpretation of the MRI may lead to diagnoses of infarction, paraneoplastic demyelinating disorder or acute disseminated encephalomyelitis (ADEM). The presentation may be so acute as to suggest a stroke, especially a posterior circulation stroke with basilar syndrome; patients may have visual loss, nausea, and ataxia both in PRES and posterior stroke although posterior stroke is not usually heralded by seizures. Differentiation between the two conditions is essential to avoid delay in treatment considering that guidelines for ischemic stroke do not recommend treatment for mild to moderate hypertension [63–65]; echo planar DWI and the corresponding ADC map may help differentiating between cerebral infarction and PRES although cases of PRES characterized by cytotoxic edema may show radiological pictures similar to infarction with hyperintensity on DWI and low signal on correspondent ADC [4,22,23,54–57,66].

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Please cite this article as: Granata G, et al, Posterior reversible encephalopathy syndrome—Insight into pathogenesis, clinical variants and treatment approaches, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.05.006

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Please cite this article as: Granata G, et al, Posterior reversible encephalopathy syndrome—Insight into pathogenesis, clinical variants and treatment approaches, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.05.006

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Fig. 3. Magnetic resonance images of posterior reversible encephalopathy syndrome demonstrating multiple regions of cortical and subcortical increased T2 signal, predominantly involving the posterior and paramedian parietal and occipital lobes. Diffusion-weighted imaging was obtained: diffusion restriction is observed. Lesions do not enhance on T1-weighted images.

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Vascular Posterior circulation stroke Cerebral venous sinus thrombosis Intracerebral hemorrhage Stenosis of the intracranial or extracranial vessels Primary CNS vasculitis Reversible cerebral vasoconstriction syndrome Infectious Acute disseminated encephalomyelitis Encephalitis

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Degenerative Metabolic encephalopathy Malignant hypertension Pontine encephalopathy Progressive multifocal leukoencephalopathy Creutzfeldt–Jakob disease Cancer-related Chemotherapy-related demyelinating disorder Paraneoplastic demyelinating disorder Radiation necrosis Leptomeningeal disease Gliomatosis cerebri Cerebral metastases Cerebral edema

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or chronic renal failure, blood transfusion, infection, autoimmune disorder, chemotherapy treatment, immunosuppressant treatment, eclampsia, and malignancy. Acute hypertension is associated with the majority of cases, but is not necessary for the diagnosis. To the state of current knowledge the possibility of an autoimmune etiopathogenesis is increasingly considered and should be always evaluated in each patient with PRES. Commonest symptoms are seizures, headache and visual changes; Acute vertigo is a symptom reported many times and a labyrinthine damage should be investigated during the initial phase of the disease, although, its appearance may be hidden by other neurological symptoms. We believe that a suspected hearing loss requires performing a pure tone audiometry as soon as the patient's clinical conditions permit. From the first description of the syndrome by Hinchey et al. in 1996 [1], improvement in imaging and physician awareness led to increase in the case reports and to an earlier diagnosis. It must be underlined that although the majority of symptoms can be reversible, cerebral hemorrhage or ischemia can occur with development of irreversible neurological deficits or death; therefore early recognizing and prompt therapy are crucial in reducing the risk of longstanding neurologic sequelae. In patients with clinical presentation suggestive of PRES, RMI should be performed as soon as possible. Further investigation and developments in endothelial cell function and in neuroimaging of cerebral blood flow are needed and will help to increase our understanding of pathophysiology, possibly suggesting novel therapies.

Table 2 Differential diagnosis of PRES.

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340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363

364 365 • Posterior reversible encephalopathy syndrome is a rare disease char- 366 acterized by typical MRI findings located in the occipital and parietal 367

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It must be underlined that PRES syndrome has to be treated early, aggressively, and for a sufficiently long time to prevent relapses. An early diagnosis is the first important step to achieve effective treatment. Mainstay on the treatment is removal of the underlying cause; lowering of the blood pressure is mandatory, when hypertension is measured [5]. Lowering of high blood pressure could be achieved with a careful tapering of corticosteroids when these are implicated. According to general hypertensive crisis guidelines, hypertension in PRES should be managed aiming at a partial reduction of blood pressure; sudden drops in blood pressure must be avoided [63–65]. For what concerns acute treatment, a reduction of 20% seems to be reasonable [5]. In our experience, the best management is in an intensive/subintensive care unit with continuous blood pressure monitoring and intravenous antihypertensive medication. Volume control is often a significant factor in managing blood pressure, particularly in cases of PRES occurring in patient under chronic dialysis; dialytic treatment might help restore adequate blood pressure in selected cases [67]. If eclampsia or pre-eclampsia is diagnosed, supplementation with magnesium sulfate is indicated [68–72]; a prompt delivery of the fetus might be needed [5]. In the case of pheochromocytoma related hypertension, antihypertensive treatment should consider nitroprusside and phentolamine [73–75]; magnesium sulfate also seems to have specific effect for pheochromocytoma [74]. Aggravation of PRES with nitroglycerin has been described and this drug should therefore be avoided [75,76]. Antiepileptic agents to be preferred to control seizures are IV agents that can be rapidly loaded, such as intravenous benzodiazepines; second line anticonvulsants could be phenobarbital and phenytoin [6,15]. In patients with continuing seizure activity despite intravenous benzodiazepines and phenobarbital/ phenytoin should be considered the infusion of titrated doses of midazolam, propofol, or thiopental until remission of the clinical seizure activity [6,15].

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9. Conclusions

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PRES is a clinicoradiological syndrome characterized by endotheliopathy of the posterior vasculature of the brain, with the development of brain–blood barrier disruption. Many “associations” have been described, including hypertensive encephalopathy, acute

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lobes, caused by subcortical vasogenic edema. • Pathophysiology is not clear, it is known that it is an endotheliopathy of the posterior cerebral vasculature leading to failed cerebral autoregulation, posterior edema and encephalopathy; autoimmune pathogenesis should be considered. • The most common manifestations are seizures, headache and visual changes; vertigo, tinnitus and hearing loss may occur in the early stages of the disease. • Posterior reversible encephalopathy syndrome has to be treated early, aggressively, and for a sufficiently long time to prevent relapses. Mainstay on the treatment is removal of the underlying cause; lowering of the blood pressure is mandatory, when hypertension is measured.

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