Epstein–Barr virus encephalitis in a renal allograft recipient diagnosed by polymerase chain reaction on cerebrospinal fluid and successfully treated with ganciclovir

Robert MacGinley1, Paul B. Bartley2, Theo Sloots3 and David W. Johnson1

1 Departments of Renal Medicine and 2 Microbiology, Princess Alexandra Hospital 3 Molecular Diagnostic Research Unit, Department of Microbiology, Royal Brisbane Hospital, Brisbane, Australia

Sir,

Epstein–Barr virus (EBV) encephalitis has been reported rarely in the context of solid-organ and bone-marrow transplantation [1]. We report a case of a renal transplant recipient who developed EBV encephalitis following OKT3 therapy for acute allograft rejection. The diagnosis was expedited by the detection of EBV DNA in the cerebrospinal fluid (CSF) by nested polymerase chain reaction (PCR). Moreover, clinical recovery and clearance of CSF EBV DNA appeared to follow the institution of parenteral ganciclovir treatment.

Case.

A 43-year-old woman with end-stage renal failure secondary to diabetic nephropathy received a renal allograft from her fraternal twin in 1989. Her post-transplant course was uncomplicated. She was initially treated with a combination of cyclosporin, prednisolone and azathioprine for 1 year, at which time the steroid was discontinued. In March 1999, the patient was treated with a 7-day course of OKT3 for biopsy-proven, steroid-refractory, acute renal allograft rejection precipitated by cyclosporin non-compliance.

Eleven days after completion of OKT3, the patient developed confusion, nausea, vomiting and fevers to 39°C. There were no focal neurological signs or meningism. She had a mild lymphopenia, but no atypical lymphocytes. A chest X-ray was normal and cultures of blood and urine were sterile. Computed tomography and magnetic resonance imaging of the brain were both normal. An electroencephalogram was consistent with a diffuse encephalopathy. Lumbar puncture revealed a mononuclear CSF pleocytosis with subsequently negative bacterial and fungal cultures (Table 1Go). The patient was treated empirically with intravenous ampicillin and ceftriaxone, but became obtunded within 48 h. EBV DNA was detected in the CSF by nested PCR. Her serological responses were consistent with reactivation of a recent (within 2–4 months) primary EBV infection (Table 1Go). Parenteral ganciclovir (5 mg/kg/day, adjusted for renal function) was added and resulted in an improvement in her level of consciousness within 72 h. The antibacterials were stopped and the patient was continued on ganciclovir monotherapy for 21 days, followed by oral valacyclovir (500 mg b.d.) for 3 months. The patient's symptoms were completely resolved by day 13 and repeat CSF examination at 1 month revealed clearance of EBV DNA. The patient has remained asymptomatic for 5 months after cessation of valacyclovir.


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Table 1. Results of EBV serology and CSF studies

 

Comments.

Reports of EBV encephalitis are exceedingly rare in the context of solid-organ transplantation [1], and may be partly explained by inherent difficulties in diagnosing such a condition in immunocompromised patients. Routine CSF studies and central nervous system imaging modalities do not demonstrate specific diagnostic features. Moreover, although the diagnosis may be suspected in the appropriate epidemiological context of an EBV seroconversion, serological testing may be unreliable in the setting of immunosuppression.

The presence of EBV DNA in this patient's CSF during an encephalitic illness and its clearance after recovery strongly suggests a diagnosis of EBV encephalitis. The diagnostic utility of nested PCR analysis of CSF to find EBV DNA is best established in HIV-infected patients where its presence in CSF is predictive of primary central nervous system lymphoma [2,3]. One post-mortem study of EBV encephalitis has described a strong correlation between the presence of EBV DNA in brain tissue and CSF [2]. It is likely that it will be applicable to the solid-organ transplant recipients but prospective clinical studies are lacking.

The prompt reversal of clinical deterioration in the present case by the institution of ganciclovir also suggests a therapeutic role for this antiviral agent. Although there is no high level clinical evidence that antiviral therapy is efficacious in EBV encephalitis, there has been one previous report of successful treatment with ganciclovir in a bone marrow transplant recipient [4].

In conclusion, the possibility of EBV infection should be considered in immunocompromised patients presenting with encephalitis, particularly if they have recently received anti-thymocyte immunoglobulin therapy and/or are known to be EBV-seronegative. The diagnosis can be made by PCR detection of EBV DNA in CSF and/or an appropriate serological response. Antiviral therapy with ganciclovir appeared to be effective in this case.

References

  1. Kim SC, Jang HJ, Han DJ. Acute disseminated encephalomyelitis after renal transplantation in patients with positive Epstein–Barr virus antibody. Transplant Proc1998; 30: 3139[ISI][Medline]
  2. 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 HIV-infected patients. AIDS1996; 9: 951–958[ISI]
  3. Merelli E, Bedin R, Sola P et al. Encephalomyeloradiculopathy associated with Epstein–Barr virus: primary infection or reactivation? Acta Neurol Scand1997; 96: 416–420[ISI][Medline]
  4. Dellemijn PL, Brandenburg A, Niesters HG et al. Successful treatment with ganciclovir of presumed Epstein–Barr meningo-encephalitis following bone marrow transplant. Bone Marrow Transplant1995; 16: 311–312[ISI][Medline]




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