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Antiviral Therapy 2013; 18:257–261 (doi: 10.3851/IMP2451) Case report Successful treatment of Epstein–Barr virus encephalitis in the setting of HIV-associated neurocognitive disorder: a diagnostic and therapeutic challenge Janine M Trevillyan1*, Andrew A Mahony1, Catriona McLean2,3, Jennifer F Hoy1,4 Infectious Diseases Department, Alfred Hospital, Melbourne, Australia Anatomical Pathology Department, Alfred Hospital, Melbourne, Australia 3 Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia 4 Department of Infectious Diseases, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia 1 2 *Corresponding author e-mail: [email protected] We report a challenging case of HIV-associated neurocognitive disorder with superimposed Epstein–Barr virus (EBV) encephalitis. The patient presented with an abnormal MRI brain scan, and EBV DNA that was detected in the cerebrospinal fluid and brain biopsy, which also demonstrated histopathological findings consistent with the diagnosis. This occurred on the background of a 12-month period of gradual cognitive decrease secondary to HIV-associated dementia. Invasive testing was required to reach the diagnosis in this case, highlighting the importance of thorough investigation of neurological impairment in HIV-positive patients. Clinicopathological recovery was achieved through optimization of antiretroviral therapy and use of valganciclovir. Introduction We present the case of a 48-year-old woman with an acute deterioration in neurological function secondary to Epstein–Barr virus (EBV) encephalitis on the background of a 12-month period of intermittent neurological symptoms and mild cognitive impairment caused by HIV-associated neurocognitive disorder (HAND). We believe this is the first published case of its kind and highlights the importance of thorough investigation of neurological symptoms in HIV-infected patients. Management with antiviral therapy targeted at both EBV and HIV is explored. Case details The patient was diagnosed with HIV in 1989 and commenced antiretroviral therapy (ART) in 1994. She had a CD4+ T-cell nadir of 209 cells/µl. She transitioned through multiple antiretroviral regimens as the result of significant side effects, including pancreatitis, rash, angioedema and lipodystrophy. Despite excellent CD4+ T-cell recovery, except for a short period in 1997, she failed to maintain full virological suppression and, at the time of onset of this illness, was receiving didanosine, ©2013 International Medical Press 1359-6535 (print) 2040-2058 (online) AVT-12-CR-2572_Trevillyan.indd 257 lamivudine and ritonavir-boosted atazanavir, with a CD4+ T-cell count of 833 cells/µl and a peripheral HIV viral load of 700 copies/ml (range over previous 5 years of 0–1,250 copies/ml). She had no other significant medical history or previous AIDS-defining illnesses and was known to be EBV immunoglobulin-G-positive from 1991. Prior to this presentation, she worked full time in a care provision capacity, smoked 10–15 cigarettes per day and drank small amounts of alcohol. In the 12 months leading up to her acute hospital admission, she was seen by her specialist infectious diseases physician and reported intermittent fluctuating neurological symptoms characterized by daytime somnolence, anxiety, short-term memory impairment and episodes of transient asymmetrical upper limb tremor and paraesthesia that interfered significantly with hand function. The symptoms progressed until she was unable to maintain full-time employment. As part of a detailed work-up, she underwent an MRI brain scan, which demonstrated on T2-weighted images non-specific discrete areas of high-signal abnormality diffusely throughout both cerebral hemispheres (Figure 1A). Possible differential diagnoses raised included demyelinating 257 15/03/2013 15:46:38 JM Trevillyan et al. conditions, cerebral vasculitis or gliomatosis cerebri. The patient was reviewed by a neurologist; at that time, there were self-reported improvements in her cognitive deficits and no objective neurological findings elicited. Thus, an approach of close observation and monitoring was adopted. At this stage, she was reluctant to alter her currently well-tolerated antiretroviral regiment despite persisting low-level HIV viraemia. Figure 1. Axial flair MRI brain images A B C D (A) MRI at first presentation: diffuse patchy signals predominantly affecting white matter. (B&C) MRI at time of hospital admission: progression of extensive white matter signal change, now globally affecting the cerebral hemispheres and cerebellum bilaterally. (D) MRI at 12 months follow-up: moderate resolution of the supratentorial white matter hyperintensities with resolution of the cerebellar signal abnormality (not shown). 258 AVT-12-CR-2572_Trevillyan.indd 258 ©2013 International Medical Press 15/03/2013 15:46:40 EBV encephalitis in the setting of HIV-associated neurocognitive disorder There was a significant resurgence in symptoms 6 months later. She was the driver in a single-car lowspeed motor vehicle accident (during which no major injuries were sustained) and became progressively ataxic, leading to a number of unprovoked falls. Family members reported increasing impulsiveness and disorientation with episodes of dysarthria and lower limb weakness, prompting hospital admission. Her neurological examination now demonstrated a fine tremor with slowed coordination and truncal ataxia. There was a progressive worsening of the lower limb findings with subtly increased tone and hyper-reflexia bilaterally. She underwent a lumbar puncture and cerebrospinal fluid (CSF) sampling, which demonstrated an elevated total protein count of 1.13 g/l and a reactive lymphocytosis (24×106 cells/l). The HIV viral load in the CSF was 7,000 copies/ml and a real-time PCR (RT-PCR) for EBV was positive. Culture for bacterial and fungal pathogens was negative, as was PCR testing for polyomaviruses, herpes simplex viruses 1 and 2, varicella zoster virus, cytomegalovirus, human herpesvirus-6 and Tropheryma whippeli. There was no detectable cryptococcal antigen. Repeat MRI brain scan (Figure 1B and 1C) demonstrated progressive extensive, asymmetrical and confluent white matter changes in the cerebral hemispheres and cerebellum bilaterally. The ART regimen was changed to maximize peripheral viral control and CSF drug penetration. Given her extensive treatment experience and known archived resistance mutations, she commenced a regiment of lamivudine, raltegravir, etravirine and ritonavir-boosted darunavir (twice daily). Genotyping (ViroSeq®) subsequently showed major protease inhibitor (D30N and N88D) and reverse transcriptase mutations (M41L, E44D, D67N, T69D, V118I, M184V, L210W, T215Y and K219Q). Although the radiological findings were felt to be consistent with a viral encephalopathy, the presence of EBV by PCR in the CSF (with its known associations with primary central nervous system lymphoma), the tempo of the illness and the unusual pattern of neurological findings mandated a brain biopsy to rule out underlying malignancy. Histopathologically, this demonstrated a florid reactive meningoencephalitis and leukoencephalitis, which was not consistent with a diagnosis of HAND. EBV immunoperoxidase studies demonstrated scattered positively reactive cells, and EBV PCR on the tissue samples was also positive (Figure 2A, 2B and 2C). Immunoperoxidase studies and PCR for other infectious aetiologies, including herpes simplex virus, varicella zoster virus, cytomegalovirus and polyomaviruses, as well as culture for Cryptococcus, were negative. No evidence of lymphoma was found. She commenced oral valganciclovir 900 mg twice daily and over the following 2 weeks made a significant Antiviral Therapy 18.2 AVT-12-CR-2572_Trevillyan.indd 259 recovery with improved memory, mood and complete resolution of physical findings, including balance and coordination. Subjectively, there were increased energy levels and appetite, and, objectively, she recorded improved scores on formal neuropsychological testing. One month into therapy her peripheral HIV viral load was <50 copies/ml, with a CD4+ T-cell count of 968 cells/ml. Repeat lumbar punctures showed a normalization of total protein, an absence of EBV DNA on PCR and durable HIV suppression within the CSF. There has been a slow improvement in imaging findings on serial MRI brains to date (Figure 1D). She completed a 6-month course of valganciclovir and, following 12 months post-completion of therapy, is living independently at home with only minor residual neurocognitive deficits, predominantly short-term memory impairment. Discussion Despite the high EBV seroprevalence in the community [1], EBV encephalitis is rare, with neurological complications estimated to occur in 0.7–7.3% of all cases of acute EBV infection [2]. In HIV-infected patients, it has been thought that the detection of EBV DNA in the CSF is both a sensitive and specific marker of primary central nervous system lymphoma (PCNSL) [3]. However, with increasing awareness and availability of PCR testing, EBV DNA has been detected within the central nervous system of patients with a wide variety of clinical presentations [4]. In fact, although the sensitivity for PCNSL may indeed be as high as 97%, as initially reported, the specificity has been shown to be much lower in a number of studies [5–7]. Detection of high levels of EBV DNA in the CSF of patients with concurrent low peripheral plasma levels is consistent with intracerebral EBV reactivation and, in the setting of clinical symptoms and CSF lymphocytosis, supports the diagnosis of viral encephalitis. Intrathecal EBV replication is often detected in the presence of other infectious pathogens and diagnoses, and, although this interaction is yet to be fully explained, it raises the possibility that latent intracerebral EBV infection can be reactivated by concurrent viral (including HIV) and bacterial infections, leading to poorer outcomes in some instances [4,8]. Aciclovir, ganciclovir and valganciclovir have each been successfully used in a variety of clinical settings for the treatment of EBV infections [9–12]. Ganciclovir has been shown to decrease the quantitative EBV PCR in the CSF of HIV-infected patients, but this has not been correlated with clinical outcomes [13]. In 2007, Katramados et al. [14] described the case of a 39-year-old woman with well-controlled HIV presenting with progressive neurological signs, an abnormal 259 15/03/2013 15:46:40 JM Trevillyan et al. Figure 2. Photomicrographs showing the histopathology of cerebral biopsy A B C (A) CD3 immunoperoxidase studies: numerous small reactive T-cells are present. (B) Representative slice of white matter demonstrating florid perivascular lymphocytic cuffing with reactive microglia and macrophage infiltration; consistent with leukoencephalitis. (C) Epstein–Barr virus (EBV) latent membrane protein immunoperoxidase studies; fine cytoplasmic EBV immunoreactive granules within glial cells suggests EBV infection of cells. Hematoxylin and eosin staining, original magnification ×400. MRI and EBV DNA detectable in the CSF. As in our case, a brain biopsy demonstrated diffuse lympho- and plasma-cytic infiltration with mononuclear perivascular cuffing. With no change in ART, the patient made a full recovery, with one episode of relapse, following treatment with intravenous ganciclovir. Our patient’s rapid clinical deterioration, abnormal MRI brain scan and positive EBV PCR in the CSF and brain tissue, along with the histopathological findings, support the diagnosis of EBV encephalitis. The CSF lymphocyte count (24×109 cells/l) was lower than expected for an acute viral encephalitis but does not exclude the diagnosis and may have been affected by HIV coinfection. Our case is unique in that the encephalitis occurred in the setting of chronic HAND. Prior to her acute hospital admission, she was documented to have had a slow 12-month decline in 260 AVT-12-CR-2572_Trevillyan.indd 260 multiple domains of higher cognitive function, associated with persistent HIV viraemia and non-specific imaging findings: all consistent with a diagnosis of HAND [15]. It has been suggested that the optimal treatment for HAND includes antiretroviral agents with enhanced central nervous system penetration. In particular, agents such as abacavir, zidovudine, ritonavir-boosted protease inhibitors and nevirapine are commonly recommended [16]. However, clinical studies have not demonstrated consistent improvement in neurological function when patients are changed to these agents [17]. In our case, the decision was made to change her regimen because of persisting low grade viraemia (both peripherally and within the CSF). In combination with EBV-targeted antiviral therapy, this led to a significant and sustained clinical recovery. ©2013 International Medical Press 15/03/2013 15:46:42 EBV encephalitis in the setting of HIV-associated neurocognitive disorder Conclusions 7. EBV encephalitis is rare and has not previously been reported in the setting of HAND. This case highlights the importance of a thorough investigation of neurological impairment in HIV-positive patients and proposes the use of both antiviral and antiretroviral agents in this setting. 8. 9. 10. Disclosure statement JFH has served on advisory boards for Gilead Sciences, ViiV Healthcare, Janssen Cilag and Merck, Sharp & Dohme. Her institution has received research support from Merck, Sharp & Dohme and Gilead Sciences, and honoraria for speaking or chairing engagements from Gilead Sciences and Janssen Cilag. All other authors declare no competing interests. 2. 3. 4. 5. 6. 12. 13. References 1. 11. Morris MC, Edmunds WJ, Hesketh LM, et al. Seroepidemiological patterns of Epstein-Barr and herpes simplex (HSV-1 and HSV-2) viruses in England and Wales. J Med Virol 2002; 67:522–527. Silverstein A, Steinberg G, Nathanson M. Nervous system involvement in infectious mononucleosis. The heralding and-or major manifestation. Arch Neurol 1972; 26:353–358. Cinque P, Vago L, Dahl H, et al. Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated opportunistic diseases of the central nervous system in HIVinfected patients. AIDS 1996; 10:951–958. Martelius T, Lappalainen M, Palomaki M, Anttila VJ. Clinical characteristics of patients with Epstein Barr virus in cerebrospinal fluid. BMC Infect Dis 2011; 11:281. Corcoran C, Rebe K, van der Plas H, Myer L, Hardie DR. The predictive value of cerebrospinal fluid Epstein-Barr viral load as a marker of primary central nervous system lymphoma in HIV-infected persons. J Clin Virol 2008; 42:433–436. Ivers LC, Kim AY, Sax PE. Predictive value of polymerase chain reaction of cerebrospinal fluid for detection of Epstein-Barr virus to establish the diagnosis of HIV-related primary central nervous system lymphoma. Clin Infect Dis 2004; 38:1629–1632. 14. 15. 16. 17. Wang J, Ozzard A, Nathan M, et al. The significance of Epstein-Barr virus detected in the cerebrospinal fluid of people with HIV infection. HIV Med 2007; 8:306–311. Kelly MJ, Benjamin LA, Cartwright K, et al. Epstein-Barr virus coinfection in cerebrospinal fluid is associated with increased mortality in Malawian adults with bacterial meningitis. J Infect Dis 2012; 205:106–110. Adams LA, Deboer B, Jeffrey G, Marley R, Garas G. Ganciclovir and the treatment of Epstein-Barr virus hepatitis. J Gastroenterol Hepatol 2006; 21:1758–1760. Chadaide Z, Voros E, Horvath S. Epstein-Barr virus encephalitis mimicking clinical and electroencephalographic characteristics of herpes simplex encephalitis. J Med Virol 2008; 80:1930–1932. Kogelnik AM, Loomis K, Hoegh-Petersen M, Rosso F, Hischier C, Montoya JG. Use of valganciclovir in patients with elevated antibody titers against human herpesvirus-6 (HHV-6) and Epstein-Barr virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. J Clin Virol 2006; 37 Suppl 1:S33–S38. MacGinley R, Bartley PB, Sloots T, Johnson DW. EpsteinBarr virus encephalitis in a renal allograft recipient diagnosed by polymerase chain reaction on cerebrospinal fluid and successfully treated with ganciclovir. Nephrol Dial Transplant 2001; 16:197–198. Bossolasco S, Falk KI, Ponzoni M, et al. Ganciclovir is associated with low or undetectable Epstein-Barr virus DNA load in cerebrospinal fluid of patients with HIVrelated primary central nervous system lymphoma. Clin Infect Dis 2006; 42:e21–e25. Katramados AM, Sripathi N, Brar I, Mitsias PD. Intravenous ganciclovir consistently induces remission of persistent Epstein-Barr encephalitis in an HIV-1-infected patient. AIDS 2007; 21:778–780. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007; 69:1789–1799. Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 2008; 65:65–70. Sacktor N, Tarwater PM, Skolasky RL, et al. CSF antiretroviral drug penetrance and the treatment of HIV-associated psychomotor slowing. Neurology 2001; 57:542–544. Accepted 23 July 2012; published online 6 November 2012 Antiviral Therapy 18.2 AVT-12-CR-2572_Trevillyan.indd 261 261 15/03/2013 15:46:43