Neurol Sci (2008) 29:163–167 DOI 10.1007/s10072-008-0929-y C A S E R E P O RT A case of posterior reversible encephalopathy during polyarteritis nodosa vasculitis Lorenzo Stanzani • Laura Fusi • Antonella Gomitoni • Mauro Roncoroni • Paolo Villa • Giampiero Grampa Received: 14 December 2007 / Accepted in revised form: 30 May 2008 © Springer-Verlag 2008 Abstract Posterior reversible encephalopathy is a distinctive syndrome associated with different diseases and drugs. Disease evolution is frequently favorable with an adequate treatment. Damage typically involves parietal-occipital lobes even if a more anterior diffusion has been described. Here, we report the case of a woman affected by Polyarteritis Nodosa, who suddenly complicated with decreased consciousness and seizures, during an acute hypertensive state. MRI imaging showed increased T2 and FLAIR signal in posterior regions. Her neurological evolution was positive, according to arterial pressure correction, although the systemic vasculitis was still ongoing, hence affecting final prognosis. Keywords PRES · PAN · Brain MRI · Pathogenesis prognosis L. Stanzani (쾷) · L. Fusi · A. Gomitoni · M. Roncoroni · P. Villa · G. Grampa Unità Operativa di Neurologia, Presidio Ospedaliero di Saronno Azienda Ospedaliera “Ospedale di Circolo” di Busto Arsizio Piazzale Borella 1, 21047 Saronno, Italy e-mail: lorestan@libero.it Introduction Posterior reversible encephalopathy syndrome (PRES) typically presents with headache, decreased alertness, seizures, visual loss including cortical blindness, as a consequence of a white matter edema, involving brain parietaltemporal-occipital regions. The term PRES is misleading as it is not always reversible and an early recognition of the condition is mandatory to prevent permanent brain damage. PRES encompasses disorders such as hypertensive encephalopathy (including eclampsia), renal, liver and hematological diseases, but it is also associated with cyclosporin treatment and other immunosuppressant or immunomodulant drugs [1, 2]. Although the underlying mechanism is incompletely understood, the main hypothesis holds that acute high blood pressure overwhelms cerebral vessels autoregulation leading to vasodilatation and vasogenic edema without infarction. Occipital brain regions are supposed to be more susceptible to PRES as a result of minor sympathetic innervation of vertebrobasilar and posterior cerebral arteries [3]. Drug-associated PRES is supposed to develop from direct cytotoxic damage on vascular endothelium, inducing vasospasm, coagulation cascade activation, and bloodbrain barrier disruption [1, 2, 4]. CT scan shows hypodense areas in the posterior white matter, whereas cerebral edema is seen as increased T2weighted MRI signal. The involvement is usually bilateral, sometimes diffused to anterior regions, cerebellum, and brainstem [1, 2]. Early diagnosis of PRES is essential, because blood pressure reduction, withdrawal or tapering of any offending medication, and use of anticonvulsants are the main tools to generate improvement or complete resolution of clinical and radiological abnormalities [1, 2]. In this report, we present a case of PRES occurring in a woman during an acute hypertensive state presumably 164 related to a Polyarteritis Nodosa renal involvement. Direct vasculitic CNS damage linked to PAN is not uncommon, but a transient cerebral injure as happens in PRES, is rather an atypical expression for this kind of vasculitis. Case report An HCV-positive, 52-year-old woman was admitted to the Internal Medicine Department of our hospital for a progressive gait impairment associated with fever, asthenia, malaise, and purpura. Before hospitalization, she underwent 2 months IFNa and ribavirine therapy, which was interrupted for intolerance. At entry she showed an areflexic hypotonic tetraparesis, with main distal involvement. The trunk control was maintained and she was able to walk only for short distances. Routine laboratory tests revealed increased inflammatory parameters with a complement consume and the presence of mixed (type II) cryoglobulines. Immunological work-up did not detect other autoantibodies except for rheumatoid factor. Proteinuria was in the range of nephrotic syndrome, although renal function was still satisfactory. Neurophysiologic study showed a marked axonaldemyelinating sensory-motor polineuropathy. CSF examination was normal and oligoclonal bands were absent. Antigangliosides antibodies were negative. Brain MRI evidenced only a few small hyperintense signals, in the left corona radiata, left thalamus, and in frontal subcortical area, without contrast enhancement, whose origin was presumably lacunar infarcts. Spinal cord MRI was negative. The diagnosis of a cryoglobulinemic vasculitis with polineuro- Neurol Sci (2008) 29:163–167 pathic injury was formulated and plasma-exchange and steroid treatment were started. In the following days, clinical condition complicated with headache, and initial mild hypertension was treated with diuretics. The patient showed a progressive confusion and lethargy until became stuporous, with a secondary generalized seizure. She underwent a cerebral CT scan that showed a diffuse hypodensity involving bilateral occipital lobes, up to temporal and parietal regions. At admittance in the Neurology Department blood pressure was 200/110 mmHg: values resulted constantly elevated for the following 5 days, even though pharmacological treatment was strengthened. Subsequently, a cerebral MRI with angioMRI was performed excluding arterials or venous thrombosis, but confirming a wide posterior encephalopathy: abnormalities were seen on T2weighted imaging, with little corresponding on T1 and without Gadolinium enhancement (Fig. 1). Coagulation and neoplastic screening were negative. Antiedemic and antihypertensive therapies began to be effective after a few days, while patient clinical conditions improved: she gradually recovered consciousness and the vision was restored from a cortical blindness up to a visual blurring, until a final complete regression. Successive cerebral MRI witnessed a progressive resolution of posterior encephalopathy in a period of 17 days, with only persistence of those minute hyperintense signals described in the first MRI (Fig. 2). Unfortunately, a different systemic disease was still ongoing: renal function worsened, abdomen pain and diarrhea were persistent, and an initial acrocianosis converted to distal necrosis; hence the woman was moved again to the Internal Medicine Department. Electrolytes showed severe Fig. 1 T2-weighted brain MRI images show a wide cortico-subcortical area of hyperintense signal, confirming the presence of edema from the occipital lobes to more anterior regions. An occipital and parietal white matter signal abnormality spreads to frontal subcortical region on the left and to external capsula on the right. All these alterations were seen on T2-weighted imaging, with little corresponding on T1 and without Gadolinium enhancement Neurol Sci (2008) 29:163–167 165 Fig. 2 A complete resolution of posterior encephalopathy was obtained in a period of 17 days, with a progressive reduction of T2-weighted hyperintense signals. More anterior regions were the first to ameliorate, while occipital and parietal subcortical white matter edema slowly waned. Only two focal hyperintense signals are still present, in the left thalamus and in frontal subcortical area, without contrast enhancement. They may be due to infarcts, frequently described in PAN cerebral involvement. These alterations were already present in the first MRI, executed before PRES occurred imbalance. Her neurological condition was newly complicated by a generalized seizure with following normal consciousness restored. Anticonvulsant prophylaxis was started successfully. CT scan was negative for PRES relapse and no more MRIs were performed. Since her evolution was atypical for a cryoglobulinemic syndrome, she execut- ed a skin and muscle biopsy: the former was not informative, while the latter showed a myositis with inflammatory perivascular infiltrates and fibrinoid necrosis focal areas. Moreover, she underwent an abdominal and renal selective angiography (Fig. 3) that demonstrated the presence of multiple numerous small aneurysms involving renal, Fig. 3 Abdomen angiography demonstrated the presence of multiple numerous microaneurysm involving renal, mesenteric, gastric, gastroduodenal, and intrahepatic arterial branches. The figure represents a selective angiogram of superior mesenteric artery that illustrates the occurrence of aneurysm involving some intestinal and right colic branches 166 mesenteric, gastric, and hepatic arterial branches. This angiographic pattern, together with muscle biopsy and clinical history, fitted the diagnosis of Polyarteritis Nodosa (PAN). Despite high-dose steroid treatment, with associated cycles of intravenous immunoglobulines and cyclophosphamide, the disease course was never successfully modified. The woman died 7 months after hospital admittance. Discussion This patient represents a complicated case of PRES, successfully managed until resolution of cerebral involvement, although the final fatal evolution has been dramatically striking. The most likely mechanism was that PAN caused an accelerated renal hypertension presumably leading to the posterior encephalopathy. Actually, development of PRES is strongly associated with the rate of pressure increase, more than absolute arterial levels. This is especially significant in normotensive individuals, since a pre-existing condition of chronic hypertension seems to induce adaptive vascular changes that lower the probability of hypertensive emergency [3]. In this case report, the role of acute hypertension is enforced by the fact that once blood pressure was corrected, PRES reverted. Moreover, this patient was not affected by arterial hypertension before hospitalization. The diagnosis of PAN was quite difficult until gastrointestinal injury became manifest in association with renal failure, arterial hypertension, and polineuropathy. Other putative vasculitic disorders (SLE, Wegener’s granulomatosis, rheumatoid arthritis) were considered less probable according to the overall clinical feature and considering that abdominal angiographic findings were highly suspect but not completely specific for PAN [5]. The initial diagnostic trouble was also probably related to the presence of overlapping cryoglobulinemic syndrome (HCV infection, mixed type II cryoglobulines, complement consume, purpura, polineuropathy, nephropathy), whose role remains obscure in evaluating the progress of this case. Cerebral cortical and subcortical infarcts are quite common radiological findings during PAN [6], but intracranial hemorrhage may also occur [7]. A review by Provenzale about neuroradiological findings in PAN has remarkably sustained the small peripheral infarction origin of most cerebral lesions, even though one described case presents clinical features suggestive for posterior encephalopathy (visual disturbance, seizures). MRI illustrated bilateral parietal, left frontal, cerebellar, and brain stem T2-weighted lesions with a normal cerebral angiography [6]. Majority of these lesions are certainly of ischemic origin, but posterior ones might be interpreted in a different way, considering also the presence of visual deficit. Unfortunately, no data are known about radiological and clinical follow-up that are diriment for a final diagnosis of PRES. Neurol Sci (2008) 29:163–167 In our case, a cerebral angiography was initially planned, but afterwards was believed unnecessary: MRI complete reversibility persuaded us about the idea of a putative hypertensive encephalopathy, secondary to a vasculitic nephropathy, making less convincing the hypothesis of a CNS vasculitis. As we considered acute arterial hypertension as the trigger for inducing PRES, we also presume that the failure of cerebral vasodilator responses occurred during this encephalopathy might be combined to a sort of vasculitic effect on vessels. Patients with this kind of systemic inflammatory disease commonly show impaired endothelial activity, with reduced nitric oxide synthesis, exposing their circulation to autoregulation breakthrough [8, 9]. On this particular landscape, a sudden pressure increase might easily overcome vessels’ compensatory mechanisms based on paracrine/autocrine release of vasodilators molecules, altering endothelial permeability and developing cerebral edema. This kind of modification might be mostly dysfunctional and not necessarily involving definitive changes in vessels structure, so to be reversible when the main cause is removed. In case of vasculitis, pharmacological suppression of inflammation is required to restore endothelial function [8]. This aspect represents a contradictory debating point about immunomodulant treatment as an adjunctive therapeutic tool in those PRES eventually associated to inflammatory diseases. Steroids have powerful antiedemic and immunosuppressant effects, but PRES might be precipitated by this kind of drug [1, 10], because hypertension and fluid retention are common adverse events potentially behaving as predisposing factors for PRES. Intravenous immunoglobulins have also been associated to PRES, possibly linked either to a transient hyperviscosity syndrome or an arterial vasospasm [1, 11]. Moreover, many immunosuppressive therapies (cyclophosphamide, cyclosporin, tacrolimus) have been reported to cause a presumed cytotoxic posterior encephalopathy [1, 4]. According to these data, correction of each eventual major cause of PRES is mandatory, but immunomodulant therapy should be started carefully only when cerebral vessels autoregulation has been restored with evidence of edema reduction. Finally, PRES reversibility appears to be also influenced by localization of brain lesions, because brainstem or deep white matter involvements are related to a less favorable evolution compared to typical cortical and subcortical lesions [12], like those in our case report. In fact, final complete cerebral integrity was achieved, but our patient had inexorably a fatal evolution. 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