Aridon, P.

D'Amelio, M.

LO RE, M.

Mazzola, M.

Quintini, G.

Ragonese, P.

Savettieri, G.

Talamanca, S.

Terruso, V.

ARIDON, Paolo

RAGONESE, Paolo

MAZZOLA, Maria Antonietta

LO RE, Marianna

TALAMANCA, Simona

TERRUSO, Valeria

D'AMELIO, Marco

SAVETTIERI, Giovanni

Quintini, G

Archivio istituzionale della ricerca - Università di Palermo

CASE REPORTReversible posterior leukoencephalopathy syndromein a patient with thrombotic thrombocytopenic purpuraPaolo Aridon • Paolo Ragonese • Maria Antonietta Mazzola •Gerlando Quintini • Marianna Lo Re • Simona Talamanca •Valeria Terruso • Marco D’Amelio • Giovanni SavettieriReceived: 21 February 2010 / Accepted: 24 November 2010 Springer-Verlag 2010Abstract Thrombotic thrombocytopenic purpura (TTP)is an autoimmune disorder characterised by fever, micro-angiopathic haemolytic anaemia, renal insufficiency, andthrombocytopenia. Neurological involvement, a prominentcomponent of TTP, is characterised by a variety of brainlesions which include reversible cerebral oedema or mag-netic resonance imaging (MRI) features of reversibleposterior leukoencephalopathy syndrome (RPLS). TTP isfrequently associated with deficiency of the von Wille-brand factor-cleaving protease, ADAMTS13.Here, we report a case of TTP with severe acuteencephalopathy. Posterior leukoencephalopathy and brain-stem oedema with triventricular hydrocephalus wereobserved on MRI. The low activity of ADAMTS13 was notobserved and ADAMTS-13 antibodies were absent. Neu-rological symptoms and patient’s condition were com-pletely resolved by plasma exchange therapy in addition tohigh dose of methylprednisolone.Keywords Reversible posterior leukoencephalopathy Thrombotic thrombocytopenic purpura  ADAMTS-13 Plasma exchangeIntroductionPosterior reversible leukoencephalopathy syndrome (RPLS)is a recently proposed clinico-neuroradiological entitypresenting with a variety of neurological features [1].These, although potentially devastating, are reversible onprompt diagnosis and appropriate treatment. Delayeddiagnosis can lead to long-term neurological disability [2].A relatively symmetrical pattern of involvement, typicallyin the subcortical white matter and occasionally in thecortex of the posterior circulation area of the brain is evi-dent on magnetic resonance imaging (MRI) studies [1].Common causes of RPLS are hypertensive encephalopa-thy, eclampsia, cyclosporin-A neurotoxicity, and uremicencephalopathy. Although the majority cases of RPLS areassociated with hypertensive disorders, it has also beendescribed in normotensive patients in association withthrombotic thrombocytopenic purpura (TTP) [3].Case reportA previously healthy 53-year-old Caucasian man wasadmitted in an emergency department for the rapid onset ofdisturbances of gait, dizziness, urinary incontinence andlethargy. The pulse rate was 80 beats/min, temperature38C and blood pressure was 260/180 mmHg, partiallydecreased by administered nitroprusside, furosemide andclonidine.White and red blood cells count and haemoglobin werenormal (7.5 9 103/ll, 5.55 9 106/ll, 15.7 g/dl). Plateletcount (86.0 9 103/ll), LDH (642 mg/dl), serum creatinine(1.90 mg/dl), and urea (53 mg/dl) were out of normalrange. A brain CT scan showed an enlargement of thelateral and third ventricles. The day after, the patientP. Aridon  P. Ragonese  M. A. Mazzola  M. Lo Re S. Talamanca  V. Terruso  M. D’Amelio  G. Savettieri (&)Biomedicina Sperimentale e Neuroscienze Cliniche (BIONEC),University of Palermo, Via Gaetano La Loggia 1,90129 Palermo, Italye-mail: gsavetti@tin.itG. QuintiniU.O. di Ematologia, Azienda Ospedaliera UniversitariaPoliclinico Paolo Giaccone dell’Universita` degli Studi diPalermo, Palermo, Italy123Neurol SciDOI 10.1007/s10072-010-0465-4started complaining weakness in lower limbs, mentalconfusion and impaired attention and because of worseningof symptoms he was admitted to our department. He waslethargic and neurological examination showed hyperre-flexia and pathological reflexes in all four limbs. Anelectroencephalogram (EEG) was characterised by markedslowness in the left posterior hemisphere without evidenceof epileptic activity.MRI of the brain revealed abnormal signal bilaterally inthe white matter of cerebral and cerebellar hemisphereswith the involvement of midbrain and cerebellar peduncles(Fig. 1a). A triventricular hydrocephalus, presumablycaused by brainstem oedema, was observed.A lumbar puncture revealed a limpid and uncolouredcerebrospinal fluid (CSF) with normal cell count (0.8/mm3) and a barely elevated total protein concentration(77 mmg/dl, normal value\40 mg/dl) with positive Pandyreaction. Polymerase chain reaction assay of Epstein–Barrvirus (EBV)-DNA, Herpes simplex virus (HSV)-DNA,Cytomegalovirus (CMV)-DNA was negative. CSF cultureshad no bacterial, viral and fungal growth.After 2 days from admission, laboratory findingsrevealed a platelet count of 58.0 9 103/ll. Lactate dehy-drogenase (LDH): 562 mg/dl (normal 200–480 mg/dl);serum creatinine: 3.04 mg/dl (normal 0.67–1.17 mg/dl);urea: 106 mg/dl (normal 10–50 mg/dl); bilirubin level:1.42 mg/dl (normal 0.3–1.1 mg/dl); AST: 38 U/l (max.37 U/l); GGT: 72 U/l (normal 8–61 U/l); rheumatoid fac-tor: 106 IU/ml; coagulation profile, complement C3 andC4: normal.The results of serological tests for acute infection withcytomegalovirus, Epstein–Barr virus, Herpes simplexvirus, and Herpes zoster virus were negative. Serologicaltests of antibodies to hepatitis B and C virus and humanimmunodeficiency virus were also negative.Tests for serum antibodies, including anticardiolipin,perinuclear anti-neutrophil cytoplasmatic antibodies (pAN-CA), cytoplasmic anti-neutrophil cytoplasmatic antibodiesFig. 1 T2-weighted axial andT1-weighted sagittal sectionMRI. a Two days after theadmission to our department:hyperintensity in the bilateralwhite matter of cerebral andcerebellar hemispheres withinvolvement of midbrain andcerebellar peduncles, b after2 weeks, c 3 months later:almost complete resolution ofabnormal signal on MRINeurol Sci123(cANCA), antinuclear antibody (ANA), anti-double stran-ded DNA antibody (dsDNA), anti-smooth muscle antibodies(anti-SM), anti-smooth muscle-ribonucleoprotein (anti-SMRNP), anti-Sjo¨gren’s syndrome A (anti-SSA) and anti-Sjo¨gren’s syndrome B (anti-SSB) were negative.A 5-day regimen of high-dose intravenous administra-tion of methylprednisolone (1 g/day) was started andwithin a week, an improvement of confusion and atten-tional difficulties was observed.A diagnosis of RPLS in a patient with TTP was sug-gested by a second platelet count of 40.0 9 103/ll, thepresence of schistocytes in the peripheral blood smear, inaddition to acute renal failure, confusion and other neuro-logical symptoms, and MRI features. A blood sample ofthe patient was sent to a reference laboratory for ADAM-TS-13 assays. The patient was transferred to the haema-tology division. More details regarding clinical andtherapeutic aspects of this recovery are reported elsewhere[4]. Briefly, a prompt plasma exchange therapy was started,with daily exchanges of one plasma volume while steroidtherapy was continued. After eight daily plasma exchangewithout complete remission, an additional immunosup-pressive treatment with rituximab (at a standard dosage of375 mg/m2) was administered weekly for 4 weeks. Thistreatment was continued despite ADAMTS-13 activity was100% and no antibodies against ADAMTS-13 weredetected. The platelet count was normalised and the neu-rological status improved progressively. The patientbecame totally normal after 3 months and a brain MRIshowed nearly complete resolution of brainstem oedemaand the T2 signal changes (Fig. 1c). Six months later, hisneurological examination was normal. Twenty-four monthslater, no relapses have been observed and the patient is stillhealthy.Discussion and conclusionRPLS, also known as posterior reversible encephalopathysyndrome (PRES), is a clinical condition characterised byan acute or subacute onset of neurological symptoms(headache, altered mental status, confusion, and drowsi-ness), visual disturbance (hemianopsia, visual neglect, andcortical blindness), seizures associated with imaging find-ings of reversible cortical and subcortical vasogenic brainedema [5]. Eclampsia, hypertensive emergency, renalfailure, autoimmune diseases and immunosuppressivetherapy are common precipitating factors in RPLS [6].The endothelial injury and the following release offactors promoting platelet activation and hyaline micro-thrombi formation in addition to blood–brain barrier injuryare the most important pathophysiologic mechanisms forTTP-associated RPLS [3]. These factors could causehypoperfusion leading to stroke or, on the contrary, cere-bral micro-haemorrhages due to thrombocytopenia andhypertension [7].We present a patient with TTP, elevated blood pressureand posterior vasogenic oedema on MRI consistent withposterior leukoencephalopathy. The course of these MRI-featured lesions permitted us to define it as reversible.Plasma exchange represents the first treatment of TTPpatients with or without ADAMTS-13 deficiency. Thesetwo groups differ in the frequency of relapses. In fact,patients without ADAMTS-13 deficiency almost neverrelapse, on the contrary, about 50% of the patients withADAMTS-13 deficiency suffer relapse within 2 years [8].In our patient, in addition to the methylprednisolone,plasma exchange was started when the diagnosis of TTPwas done, and as previously reported by other authors[9, 10], a rapid improvement of haemolysis and a nor-malization of platelet count were seen.This case shows the importance of the recognition andprompt treatment of patient with TTP and furtherstrengthens the evidence that, even if the demonstration ofplasma level of ADAMTS-13 and its antibodies are diag-nostic, the absence of this diagnostic test justify thebeginning of therapy without waiting the test results.Acknowledgments We thank the reviewers for their careful readingof the manuscript and helpful comments and Melanie Flynn fordetailed and insightful corrections.Conflict of interest The authors certify that there is no current orpotential conflict of interest in relation to this article.References1. Lee VH, Wijdicks EF, Manno EM, Rabinstein AA (2008) Clin-ical spectrum of reversible posterior leukoencephalopathy syn-drome. Arch Neurol 65:205–2102. Pratap JN, Down JF (2008) Posterior reversible encephalopathysyndrome: a report of a case with atypical features. Anaesthesia63:1245–12483. Bakshi R, Shaikh ZA, Bates VE, Kinkel PR (1999) Thromboticthrombocytopenic purpura: brain CT and MRI findings in 12patients. Neurology 52:1285–12884. Caramazza D, Quintini G, Abbene I, Coco LL, Malato A, DiTrapani R, Saccullo G, Pizzo G, Palazzolo R, Barone R, MazzolaG, Rizzo S, Ragonese P, Aridon P, Abbadessa V, Siragusa S(2010) Rituximab for managing relapsing or refractory patientswith idiopathic thrombotiv thrombocytopenic purpura–haemo-lytic uraemic syndrome. Blood Transfus 8(3):203–2105. Burrus TM, Wijdicks EF, Rabinstein AA (2009) Brain lesions aremost often reversible in acute thrombotic thrombocytopenicpurpura. Neurology 73:66–706. Pula JH, Eggenberger E (2008) Posterior reversible encephalop-athy syndrome. Curr Opin Ophthalmol 19:479–4847. Bas DF, Oguz KK, Topcuoglu MA (2008) Atypical reversibleposterior leukoencephalopathy syndrome in thrombotic throm-bocytopenic purpura. Intern Med 47(21):1931–1934Neurol Sci1238. Sadler JE (2008) Von Willebrand factor, ADAMTS13, andthrombotic thrombocytopenic purpura. Blood 112:11–189. Sarode R (2009) Atypical presentations of thrombotic thrombo-cytopenic purpura: a review. J Clin Apher 24:47–5210. Brunskill SJ, Tusold A, Benjamin S, Stanworth SJ, Murphy MF(2007) A systematic review of randomized controlled trials forplasma exchange in the treatment of thrombotic thrombocyto-penic purpura. Transfus Med 17:17–35Neurol Sci123

Reversible posterior leukoencephalopathy syndrome in a patient with thrombotic thrombocytopenic purpura

Paolo Aridon

Paolo Ragonese

Maria Antonietta Mazzola

Gerlando Quintini

Marianna Lo Re

Simona Talamanca

Valeria Terruso

Marco D’Amelio

Giovanni Savettieri

Crossref

Neurological Sciences

https://iris.unipa.it/retrieve/handle/10447/54452/28291/Reversible%20posterior%20leukoencephalopathy%20syndrome.pdf

Reversible posterior leukoencephalopathy syndrome in a patient with thrombotic thrombocytopenic purpura

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