Epidemiology and Risk Factors. Epstein-Barr virus (EBV) is a human B-lymphotropic virus, the causative agent of infectious mononucleosis. The major route of transmission of EBV is through saliva, and EBV infects the epithelial cells of the oropharynx and adjacent structures as well as those of the uterine cervix. Epithelial cells may play a major role in the persistence of EBV by allowing chronic viral replication and release of infectious particles throughout the lifetime of a virus-infected host. Eighty to 90 percent of children in developing countries are seropositive for EBV between 2 and 3 years of age. By the third decade, nearly 100 percent of adults have EBV serum antibodies.
Pathogenesis and Pathophysiology. EBV is a lymphotropic virus that selectively infects B lymphocytes. B lymphocytes are infected by EBV during their passage through the chronically EBV-infected oropharyngeal epithelium. EBV has the unique biological property of being able to induce dysregulated activation and growth of a subpopulation of the infected B cells that then grow continuously as lymphoblastoid cell lines that secrete immunoglobulins. '143] ,  Central nervous system invasion by infected B lymphocytes appears to be important in the pathogenesis of central nervous system disease. 'id
Clinical Features and Associated Findings. Infectious mononucleosis is the only known disease caused by acute EBV infection. The neurological complications of infectious mononucleosis include meningoencephalitis, Guillain-Barre syndrome, cerebellitis, transverse myelitis, cranial nerve palsies of which the most common is a seventh nerve palsy, and a variety of optic nerve abnormalities (papilledema, optic neuritis, retrobulbar neuritis). EBV infection is almost universally associated with primary central nervous system lymphomas in patients with AIDS.'wi Persistent viral activity or reactivation of EBV has been studied in the etiology of chronic fatigue syndrome.
Infectious Mononucleosis. The term infectious mononucleosis was first used in 1920 to describe the clinical findings of medical students attending Johns Hopkins University who had the typical clinical picture of this disease associated with atypical mononuclear cells. 'W The clinical course of infectious mononucleosis is characterized by a 7- day prodromal illness followed by a 4-day to 3-week acute illness characterized by fever, headache, malaise, pharyngitis, cervical lymphadenopathy, and mononuclear leukocytosis with atypical lymphocytes. Splenic and hepatomegaly may be present with transient hepatic dysfunction. [i43] , The neurological complications of infectious mononucleosis
include the Guillain-Barre syndrome, an aseptic meningitis or encephalitis of which nonfebrile seizures are a common presenting manifestation, and cranial nerve palsies, the most common of which is an isolated or bilateral facial nerve palsy. '146 Overall, meningoencephalitis is the most common neurological complication, whereas transverse myelitis is the least common.
CNS Lymphoma. EBV is detectable from a majority of primary central nervous system lymphomas in AIDS patients and to a lesser degree from primary CNS lymphomas in immunocompetent individuals.'^ The clinical presentation is that of progressive personality changes, seizures, and signs of increased intracranial pressure.'^]
Chronic Fatigue Syndrome. Chronic fatigue syndrome is characterized by debilitating fatigue accompanied by a variety of symptoms including cognitive difficulty, myalgias, and arthralgias.
Differential Diagnosis. The diagnosis of infectious mononucleosis is based on a positive heterophil antibody test, the appearance of atypical lymphocytes in the blood at 1 to 4 weeks after onset of disease, and/or by changes in EBV-specific antibodies. An acute infection is documented by detection of antiviral capsid antigen (VCA) titers of 1:320 or higher, the presence of anti-D (i.e., diffuse component of EBV-induced early antigen complex), or EBV VCA IgM antibodies and the absence of antibodies to virus-associated nuclear antigen (anti-EBNA IgG). In acute and convalescent paired sera, fourfold or greater increments in anti-VCA or anti-D titers, or a late decrease in anti-VCA titers or loss of anti-D titers, and the appearance of antibodies to virus-associated nuclear antigen (anti- EBNA IgG) denote a recent infection. Anti-VCA titers peak early and then decline to persistent lower levels. Anti- D responses and virus-specific IgM antibodies are present for only a few weeks. Anti-EBNA antibodies appear late in convalescence and persist for life. Wi In patients in whom neurological complications of infectious mononucleosis are suspected, the combination of serological tests and PCR performed on cerebrospinal fluid for the EBV DNA genome is recommended. If PCR for EBV DNA on CSF is negative, an acute EBV infection can be documented by evidence of positive IgM antibody titers to the viral capsid antigen early in the disease course, with a fourfold decrease in IgG antibody titers to the viral capsid antigen corresponding to a fourfold or greater increase in antibody to Epstein-Barr nuclear antigen between the acute and convalescent sera. A distinction between latent and symptomatic EBV infection cannot be made based strictly on positive results of PCR on CSF for EBV DNA. W
The diagnosis of primary CNS lymphoma is based on CT or MRI evidence of a focal enhancing mass lesion or lesions, and typically an unsuccessful response to antitoxo- plasma therapy, because the neuroimaging appearance of Toxoplasma gondii encephalitis and primary CNS lymphoma is similar. The gold standard for the diagnosis has been brain biopsy; however, the polymerase chain reaction technique is both sensitive and specific in making the diagnosis. EBV DNA was detected by PCR in the CSF from seven of eight patients with primary CNS lymphoma diagnosed by brain biopsy (87.5 percent sensitivity) but in none of the 11 controls with brain mass lesions (100 percent specificity). W] Although there are reports of patients with chronic fatigue syndrome and high antibody titers to viral capsid antigen and early antigen of EBV, to date there is no scientific evidence that the reactivation of EBV is involved in the chronic fatigue syndrome. 
Management. Although there are no EBV antiviral agents, ganciclovir is known to inhibit EBV replication in vitro, and there are a few reports of successful treatment of EBV meningoencephalitis with ganciclovir in transplant recipients.  Primary CNS lymphoma is treated with radiation therapy.
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