Rapidly Progressive and Fatal EBV-Related Encephalitis in a Patient with Advanced HIV-1 Infection at Presentation: a Case Report and Review of the Literature

NEW MICROBIOLOGICA , 33 , 275-280, 2010

Rapidly progressive and fatal EBV-related encephalitis in a patient with advanced HIV-1 infection at presentation: a case report and review of the literature

Ennio Polilli 2, Federica Sozio 1, Elena Mazzotta 1, Augusta Consorte 1, Francesco Di Masi 1, Adriana Agostinone 1, Monica Tontodonati 1, Luana Cosentino 2, Giustino Parruti 1 1Infectious Disease Unit, “Spirito Santo” Hospital, Pescara, Italy; 2Clinical Pathology Unit, “Spirito Santo” Hospital, Pescara, Italy

SUMMARY

Epstein-Barr virus (EBV) has been associated with primary central nervous system lymphoma and other EBV-relat - ed malignancies in HIV infected patients, and detection of EBV DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) has been demonstrated to be a good marker of PCNSL. Conversely, EBV has been rarely associated with encephalitis in HIV patients. Here we describe for the first time the case of an HIV-infected, late presenter Caucasian man, diagnosed with a rapidly progressive diffuse encephalitis at presentation. A very high viral load for EBV was detected in CSF by PCR. The patient died 12 days after the onset of encephalitis in spite of supportive, an - tiviral and antiretroviral therapy. Our experience would suggest that in profoundly immunosuppressed HIV patients EBV may cause severe encephalitis in the absence of lymphoproliferative disorders.

KEY WORDS: HIV, Late-presenter, EBV, Encephalitis

Received December 23, 2009 Accepted February 03, 2010

INTRODUCTION have been described as related to Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6) and Human immunodeficiency virus (HIV) infected mixed herpes virus infections (Martínez et al ., individuals are known to be at higher risk of de - 2007). veloping severe central nervous system (CNS) in - EBV is a B-lymphotropic virus that was initially fections caused by herpes viruses as well as her - associated with a variety of lymphoid malig - pes virus-related malignancies, although a more nances in immune-compromised patients, as favorable course of such conditions has been Burkitt’s lymphoma, Hogkin’s disease, B-cell lym - more recently reported for patients treated with phoma, primary central nervous system lym - highly active antiretroviral therapy (HAART) phoma (PCNSL), as well as with CNS infections (Kennedy et al ., 2005; Martínez et al ., 2007; as encephalitis, meningo-encephalitis and Serraino et al ., 2005). Guillain-Barré syndrome (Serraino et al ., 2005; In HIV patients, cytomegalovirus (CMV) is the Domachowske et al ., 1996; Takahashi et al ., 2005; most frequently identified cause of CNS infec - Kleinschmidt-DeMasters et al ., 2008). tions among herpes viruses, while fewer cases Detection of EBV DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) has been demonstrated to be a good marker of PC - Corresponding author NSL in HIV patients in several studies Giustino Parruti, MD, PhD (Bossolasco et al ., 2002; De Luca et al ., 1995). Infectious Disease Unit Pescara General Hospital Indeed, the detection of EBV DNA by PCR in CSF Via Fonte Romana, 8 - 65124 Pescara, Italy from HIV-infected patients with PCNSL has a E-mail: [email protected] very high diagnostic sensitivity, approximating 80 276 E. Polilli, F. Sozio, E. Mazzotta, A. Consorte, F. Di Masi, A. Agostinone, M. Tontodonati, L. Cosentino, G. Parruti to 100% in recent series (Bossolasco et al ., 2002; HHV6, HHV8, CMV, JC virus and Mycobacteria. De Luca et al ., 1995; Cinque et al ., 1996). EBV Cultures for Cryptococcus were negative. HIV vi - was undetectable in most patients without PC - ral load in the CSF was 261,000 cp/mL. EBV DNA NSL in such series. and other herpes viruses were not amplified from While the presence of EBV DNA in CSF has been parallel peripheral blood samples. related with later development of PCNSL in some A first brain magnetic resonance imaging (MRI) studies (Al-Shahi et al ., 2000; Brink et al ., 1998), scan showed an apparently normal pattern. others failed to demonstrate an increased risk of Antiviral therapy with i.v. aciclovir was soon es - developing PCNSL in patients with detectable tablished at standard doses, without benefit. EBV DNA in CSF (Tachikawa et al ., 1999; Wang Three days later, therefore, an association of i.v. et al ., 2007). ganciclovir and foscarnet was started at standard This report describes the case of an HIV-infected doses. man, who was diagnosed with HIV infection and In spite of that, the patient rapidly progressed to AIDS due to Pneumocystis jiroveci pneumonia a state of light coma, difficult to awaken. A sec - and soon after presented a rapidly progressive ond MRI brain scan with and without contrast and lethal deterioration of consciousness, which medium was again normal, without any evidence was related to a high EBV viral load in CNS, in of organic lesions, while EEG monitoring docu - the absence of any other evidence of CNS infec - mented a worsening of bioelectric patterns. tion, apart from HIV. On the tenth day HAART was started (lopinavir, The patient died 12 days after the onset of signs LPV; stavudine, d4T; lamivudine, 3TC), without of encephalitis in spite of prompt introduction of any improvement. A few days later the patient HAART and combined treatment with ganciclovir showed progressive focal neurological involve - and foscarnet. ment (strabismus and a coarse tremor), deepen - ing in his state of coma and necessitating reloca - tion at an intensive care unit. A third MRI scan CASE REPORT could not be therefore be undertaken. Thirteen days after admission, the patient died due to car - The patient, a 40-year-old heterosexual diac arrest, in spite of any attempt at resuscita - Caucasian, came to our attention for the first time tion. Autoptic examination was not granted. in February, 2008, transferred from another Institute due to worsening dyspnea not respon - sive to antibiotics. Severe pulmonary interstitial DISCUSSION disease was molecularly diagnosed by real-time PCR as Pneumocystis Jiroveci pneumonia. HIV The rapid and irreversible neurological progres - infection was documented for the first time; CD4 sion of our patient is of relevance, as it may rep - T-cell count was 56 mm 3 and HIV viral load was resent the first evidence of rapidly progressive 555,000 cp/mL. and lethal EBV-related encephalitis in an HIV pa - Treatment with i.v. cotrimoxazole was effective tient. Indeed, his fatal course occurred in the ab - in controlling fever and dyspnea, but on the third sence of any evidence of other causative agents day the patient showed rapidly worsening sleepi - of encephalitis in his CSF and in spite of combi - ness in the absence of focal neurological deficits nation antiviral therapy for EBV and HAART, and/or any sign of peripheral neuropathy. A brain whereas treatment with cotrimoxazole controlled CT scan with and without contrast medium did his presentation pneumonia. Indeed, HIV itself not reveal any obvious organic damage, while a was amplified from CSF at high titer. first EEG showed diffuse slow discharge, consis - Our patient, however, did not present any of the tent with severe encephalopathy. clinical characteristics which have been report - Routine CSF analysis was normal, with no cellu - ed for HIV-related meningo-encephalitis: he was lar sediment, and a modest increase in CSF pro - a late presenter, with very low CD4 T-cell counts teins. Real Time PCR on CSF, however, amplified in his peripheral blood, did not present any sign EBV DNA at a high titer (11,230 cp/mL), while it of meningitis, and no cellular sediment was de - was negative for pathogens such as HSV1-2, tected on CSF (Villar Del Saz et al ., 2008). Rapidly progressive and fatal EBV-related encephalitis 277

Furthermore, pneumonia due to Pneumocystis Katramados et al . reported a possible case of jiroveci was his presenting condition, followed by EBV-related encephalitis in a HIV patient treated rapid deterioration of his mental state and late with HAART and a relatively preserved immune appearance of focal neurological signs after the system (Katramados et al ., 2007). In this case, the start of HAART with a lopinavir-based regimen, patient experienced early partial clinical im - which may well have rapidly controlled HIV repli - provement and a clinical relapse of encephalitis cation in CSF (Letendre et al ., 2007). For this rea - during maintenance therapy with oral valganci - son, we felt that the diagnosis of HIV-related clovir. The authors reported a favorable course meningo-encephalitis was not likely on a clinical after restoring therapy with intravenous ganci - basis, although a concurrent role of HIV cannot clovir and suggested that restoration of immune be excluded. Serial electroencephalographic eval - control induced by HAART may have prevented uations showed patterns of severe encephalopa - development of PCNSL, thus inducing an un - thy, with progressively diffuse lateralizing epilep - usual clinical expression of persistent EBV in - tiform discharges, in the absence of any neuro - fection, that is recurrent encephalitis. Our expe - radiologic evidence of brain damage or PCNSL rience would therefore suggest for the first time on serial MRI scans. A causative role for EBV was the occurrence of EBV-related encephalitis in an therefore supported by its very high titer in CSF, advanced, severely immunosuppressed patient at as well by the absence of other known pathogens presentation of HIV infection, without any sign of such as HSV1-2, CMV, HHV-6, VZV, JC virus, lymphoma. HHV-8, Cryptococcus and Mycobacteria In spite of association therapy with i.v. gancy - (Landgren et al ., 1994; Cinque et al ., 2003). clovir and foscarnet and the early start of HAART, Interestingly, EBV was not amplified on a paral - a rapid worsening of encephalitis with progres - lel peripheral blood sample drawn at the time of sion to status epilepticus ensued. This was un - CSF sampling, adding to the causative role of its likely to be due to the emergence of viral resist - reactivation in CSF (Pedneault et al ., 1992; Volpi, ance, a well-known phenomenon with other her - 2004). pes viruses in HIV-infected patients (Astriti et al ., Most members of the herpesviridae family with 2006; Field et al ., 1994) as well as in HIV infect - CNS tropism have been associated with sporadic ed patients chronically treated for other EBV-re - cases of encephalitis, causing a wide spectrum of lated infections, as in the case of oral hairy leuko - clinical manifestations (Aberle et al ., 2002; plakia (Walling et al ., 2003). Quereda et al ., 2000). Patients with an impaired The rapid worsening of the clinical state of our immune system, and especially patients with HIV patient, however, with the ensuing of focal signs, infection, have been reported at increased risk suggested us that further sampling of CSF might (Kennedy et al ., 2005). Analysis of CSF by PCR be unwise. Failure of antiviral therapy in our pa - for herpes viruses proved useful in establishing tient might have been rather related to uncon - an accurate diagnosis and to monitor the effica - trollable reactivation of EBV during his state of cy of antiviral therapy in these patients (Frías et advanced immune suppression, as evidenced by al ., 2001). a high titer by quantitative PCR, possibly favor - To our knowledge, few reports of EBV-related en - ing clinically irreversible EBV-related brain in - cephalitis have been published in HIV-infected jury. patients (Hirsch et al ., 1998; Katramados et al ., Indeed, 2 sequential brain MRI scans did not re - 2007; Cubo et al ., 2007). EBV infections of CNS veal any evidence of brain damage in our patient. were usually reported without recurrences and/or Acute encephalitis associated with EBV infection, long-term sequelae (Fujimoto et al ., 2003). In a however, has been frequently reported in the ab - recent report, the presence of EBV-DNA in CSF sence of abnormalities at neuroimaging (Shian was not associated with more advanced im - et al ., 1996). munosuppression in HIV patients without a di - Available reports of MRI findings are limited, and agnosis of PCNSL (Wang et al ., 2007). Indeed, the describe lesions involving the basal ganglia, brain - use of HAART may protect these patients from stem and cerebral cortex (Shian et al ., 1996; Ono developing PCNSL even in the presence of EBV et al ., 1998; Angelini et al ., 2000), consistent with (Astriti et al ., 2006). In a recent communication, the late events observed in our patient, for whom 278 E. Polilli, F. Sozio, E. Mazzotta, A. Consorte, F. Di Masi, A. Agostinone, M. Tontodonati, L. Cosentino, G. Parruti a third MRI scan could not be performed at the also indebted to Mr. Paolo De Cono for assistance time when focal signs ensued. Normal brain MRI with laboratory assays. scans, however, have also been reported in cases Dr. E. Polilli was funded by an educational grant of other viral encephalitis (Misra et al ., 2008). The from the “Fondazione onlus Camillo de Lellis per majority of patients with herpes simplex en - l’Innovazione e la Ricerca in Medicina”, Pescara, cephalitis have positive findings at inferomedial Italy. temporal lobes, but some 10% of them have nor - mal MRI scans (Domingues et al ., 1998). Furthermore, normal MRI scans in 6 advanced HIV patients with CMV encephalitis have been re - REFERENCES lated to a possible lack of sensitivity of standard ABERLE S.W., P UCHHAMMER -S TÖCKL E. (2002). Diagnosis MRI neuroimaging (Clifford et al ., 1996). Finally, of herpesvirus infections of the central nervous sys - abnormal findings in HHV-6 related encephalitis, tem. J. Clin. 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