Clinical manifestations

Presentation and course

Young children and young adults have a predilection for symptomatic infections, with severity ranging from mild to fulminant life-threatening complications. Infectious mononucleosis due to Epstein-Barr virus is one of the most common causes of prolonged illness in adolescents and young adults in Western societies. Infection is often spread by saliva in teens and young adults, designating infectious mononucleosis as the “kissing disease”. After an incubation period of 4 to 7 weeks, a typical triad of fever, pharyngitis, lymphadenopathy (especially of the occipital and cervical nodes) begins. Other clinical features may include splenomegaly, mononuclear leukocytosis, and hepatocellular dysfunction rarely presenting with jaundice (38).

Epstein-Barr virus has been associated with multiple neurologic complications including acute encephalitis, meningitis, acute cerebellar ataxia, myelitis, Guillain-Barré syndrome, cranial nerve palsies, neuropsychiatric syndromes, mononeuropathies, and acute disseminated encephalomyelitis (17; 49; 02). Meningitis and encephalitis are the most common complications of acute Epstein-Barr virus infection, with encephalitis being less frequent than meningitis. The initial symptoms of meningitis are severe headache and neck stiffness. Encephalitis may present with coma, seizures, delirium, or focal neurologic deficits before infectious mononucleosis is apparent. Epstein-Barr virus encephalitis may also present with ataxia due to cerebellitis (24) and is also associated with Alice in Wonderland syndrome (AIWS), which is an encephalopathy characterized by visual hallucinations and perceptual distortions of objects and body parts, also known as metamorphopsia (28). It remains the commonest infectious cause of Alice in Wonderland syndrome, and although the pathophysiology remains controversial, local cerebral edema and ischemia similar to that shown in migraine-associated Alice in Wonderland syndrome have been postulated (42). Findings from fMRI studies show that metamorphopsia is linked to functional impairment of the occipital cortex and over activation of specific parietal regions (07).

Acute disseminated encephalomyelitis is a post-infectious immune-mediated syndrome presenting with encephalopathy and focal neurologic deficits, with lesions often seen in both the brain and spinal cord. Epstein-Barr virus may be the antecedent infection, and diagnosis is based on a reactive Epstein-Barr virus IgM serology (37). Epstein-Barr virus may cause an acute myelitis, but this is more common in immunocompromised patients through local reactivation of the virus (52). It is an inflammatory myelopathy, with lymphocytic pleocytosis and elevated protein concentration in the CSF as well as abnormal hyperintensity on MRI of cervical and thoracic spinal cord segments (46). Symptoms may include paresthesias, extremity weakness, and loss of sphincter control (35).

Epstein-Barr virus infection has also been associated with peripheral nervous system syndromes, including cranial neuropathies and polyradiculopathies (11). Hottenrott described a case of Epstein-Barr virus causing a lumbosacral radiculitis with radicular pain in an immunocompetent patient (23). Mechanisms of brachial plexus neuropathy from Epstein-Barr virus include acute virus infection, which is often associated with lymphadenopathy, and a post-infectious brachial neuritis (14).

Guillain-Barré syndrome is associated with multiple antecedent infections, the most common being Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae. All four of these infections associated with Guillain-Barré syndrome cause the formation of antibodies that cross-react with glycoconjugate proteins on peripheral nerves. Epstein-Barr virus, cytomegalovirus, and Mycoplasma pneumoniae can also form cold agglutinins that bind to carbohydrate antigens on glycoconjugate proteins, which is a similar mechanism to how antibodies are produced to gangliosides (26). Miller Fisher syndrome, a variant of Guillain-Barré syndrome, can be precipitated by Epstein-Barr virus infection as shown in a case report of a 14-year-old boy with bilateral cranial nerve dysfunction, limb hyporeflexia, and positive anti-GQ1b antibodies (10). The pathophysiological mechanism of Epstein-Barr virus-induced Miller Fisher syndrome is likely similar to that of the cross-reactivity theory with Epstein-Barr virus and Guillain-Barré syndrome (03).

A considerable amount of research has been carried out to investigate the association between Epstein-Barr virus and multiple sclerosis; however, a causal relationship has not been definitively demonstrated. Seropositivity for Epstein-Barr virus is as high as 100% in some study cohorts of patients with multiple sclerosis, with lower rates being found in patients without multiple sclerosis of the same age range (01). Risk of multiple sclerosis following Epstein-Barr virus infection is suggested in a longitudinal analysis of a cohort of adults with multiple sclerosis (04; 47). There are multiple hypotheses on the mechanism of the pathogenesis of Epstein-Barr virus leading to multiple sclerosis. Pender’s hypothesis proposes that the virus infects “forbidden” memory B cells that are active against host CNS epitopes and rescues them from apoptosis, thereby allowing them to act as antigen-presenting cells that activate CD4+ T cells and lead to chronic inflammation (40; 30). Other hypotheses describe a “two-hit” scenario that allows inflammatory cells to migrate into the CNS in the presence of Epstein-Barr virus infection (19). However, most studies conducted to investigate this subject have failed to show the presence of Epstein-Barr virus within multiple sclerosis lesions, which has led to controversy about the theories and a persistent lack of evidence of causality (29; 15; 47). The etiology and pathogenesis of multiple sclerosis is complex and heterogenous, and it has yet to be fully understood; thus, the role of Epstein-Barr virus in its pathogenesis remains unclear (05).

Although subacute sclerosing panencephalitis is classically known as a consequence of measles infection, there have been a few cases reported that include Epstein-Barr virus as a factor. Hochberg and colleagues described a case of a 13-year-old girl who died of subacute sclerosing panencephalitis during an acute mononucleosis infection (22). Brain tissue staining showed both measles and Epstein-Barr virus antigenic material. One hypothesis is that decreased cellular immunity from acute mononucleosis may be responsible for activation of latent measles virus. Epstein-Barr virus has also been implicated in nasopharyngeal cancer (51) as well as primary CNS lymphomas in immunocompetent and immunocompromised patients (34; 18).

Prognosis and complications

Epstein-Barr virus encephalitis is often self-limiting and is relatively benign compared to other herpes encephalitides (02). Rarely, the clinical course is complicated by cerebral edema, which can cause raised intracranial pressure and death. In children, it can be associated with subsequent developmental delay, and some adults show persistence of neuropsychiatric disorders after resolution of the acute illness (02). Similarly, Epstein-Barr virus myelitis is often complicated by permanent sequelae, with limited resolution of limb paresis. The prognosis of primary CNS lymphoma associated with Epstein-Barr virus among people living with HIV improves with the use of effective antiretroviral therapy. The prognosis in immunocompetent patients depends on many factors, and predictive scores such as the International Extranodal Lymphoma Study Group (IELSG) score and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score can be used to stratify patients’ prognoses (18). Prognostic factors generally include the age of the patient (with older age being associated with poorer outcomes) and occurrence of adverse events associated with mass effect from the tumor itself.

Compared to other viruses such as hepatitis E virus, cytomegalovirus and Epstein-Barr virus cause milder forms of Guillain-Barré syndrome with better neurologic outcomes, and full recovery is usually around six months post-onset (13).

Biological basis

Etiology and pathogenesis

Epstein-Barr virus is a human herpes virus, also known as human herpesvirus 4. The virus is unique in that it infects B lymphocytes and epithelial cells through binding to CD21 and cellular integrins, respectively. The virus can exist in a latent phase or a lytic phase, with neurologic complications occurring in both phases. The virus is spread through saliva, as well as many other bodily fluids, and viral entry is likely through the oropharynx.

The pathophysiology of neurologic complications may involve Epstein-Barr virus entering nerve tissue through infected B lymphocytes. Pathologic studies show perivascular lymphocytic infiltrates, parenchymal edema, microglial proliferation, and demyelination in the central nervous system (12). Other studies show that altered gene expression of Epstein-Barr virus-infected B lymphocytes leads to increased trafficking of these cells into the central nervous system (48). Overcoming barriers to central nervous system entry in this manner has been implicated in pathological changes that lead to diseases such as primary central nervous system lymphoma and multiple sclerosis (48; 43).

Epidemiology

Epstein-Barr virus is a ubiquitous virus, with an estimate of 95% of adults globally being seropositive (33). The ability of the virus to establish latency and reactivate after initial infection, along with mild clinical symptoms in most infected individuals, allows for the ubiquity of the virus. In developing countries, children often seroconvert by the age of 3 or 4 years (45). Primary infection occurs at younger ages in lower socioeconomic settings, whereas primary infection occurs at older ages in regions with higher socioeconomic settings (21).

Prevention

Vaccines to prevent complications like lymphoma are being developed, yet an animal model is still needed before a vaccine strategy can be implemented (36). Persons with known infectious mononucleosis are advised to avoid activities that include exchanging saliva, such as kissing or sharing utensils. To prevent the life-threatening complication of splenic rupture in those with infectious mononucleosis, contact sports are strictly prohibited during acute infection.

Differential diagnosis

Confusing conditions

The differential diagnosis for a mononucleosis-like illness other than Epstein-Barr virus includes cytomegalovirus, acute HIV, human herpesvirus 6, toxoplasmosis, and anicteric hepatitis. As for other neurologic complications, encephalitis can be caused by Epstein-Barr virus; herpes simplex virus; a number of arboviruses; and numerous other bacteria, viruses, fungi, and parasites. Cerebellar ataxia in children is often caused by a post-infectious process, including Epstein-Barr virus, Mycoplasma pneumoniae, varicella zoster virus, as well as other organisms (24).

Associated or underlying disorders

Epstein-Barr virus may be involved in the progressive neuronal degeneration observed in people living with HIV. One theory is that the presence of ongoing Epstein-Barr viral replication in the central nervous system leads to aberrant immune activity that promotes HIV-associated neuronal injury (32). This hypothesis is supported by the observation that 18% of a cohort of people living with HIV had Epstein-Barr virus DNA in cerebrospinal fluid. In addition, those with detectable Epstein-Barr virus DNA in the CSF had higher levels of HIV RNA in the cerebrospinal fluid and a rate of pleocytosis up to three times higher (32).

Diagnostic workup

Epstein-Barr infections cause a peripheral lymphocytosis with greater than 10% atypical lymphocytes. Heterophile antibodies are IgM antibodies that agglutinate sheep or horse erythrocytes; they were used diagnostically more frequently in the past as they are less specific than the current Epstein-Barr virus-specific antibody assays used today. Viral serologies are helpful in determining acute versus latent Epstein-Barr virus infection. The presence of viral capsid antigen IgM and IgG antibodies in the absence of antibodies to virus-associated nuclear antigen is evidence of a current or recent Epstein-Barr virus infection. A reactive viral capsid antigen IgG and Epstein-Barr virus-associated nuclear antigen IgG with a nonreactive viral capsid antigen IgM is indicative of a previous infection.

In meningitis and encephalitis caused by Epstein-Barr virus, there is a CSF lymphocytic pleocytosis with the protein concentration being normal or elevated and glucose levels are normal. Diagnosis is made through detection of antibodies or detection of Epstein-Barr virus DNA in CSF by polymerase chain reaction, or both findings (52). Quantitative CSF polymerase chain reaction in Epstein-Barr virus infections have shown a lower viral load in patients with postinfectious complications and a higher viral load in patients with primary encephalitis (50).

Detection of CSF Epstein-Barr virus DNA by polymerase chain reaction can also be seen in patients with primary CNS lymphoma (25). This is not always possible to establish, and negative polymerase chain reaction does not exclude primary CNS lymphoma (25). However, the predictive value of the CSF Epstein-Barr virus PCR in people living with HIV/AIDS in the correct clinical settings can be very high.

Given the high seroprevalence of Epstein-Barr virus, particularly in adults greater than 40 years of age (45), Epstein-Barr virus can sometimes be detected a false positive or can sometimes be a “bystander” identified during the infectious workup of certain pathologies and may not actually be the causative organism of the pathology being investigated (44; 09). Latent infection can be reactivated in the setting of activation of the immune system, and, as such, its detection has to be interpreted carefully (41).

Management

Management of Epstein-Barr viral infections includes supportive care and symptomatic treatment. Neurologic complications of acute virus infection can be treated with acyclovir (27). Acyclovir inhibits viral replication with a highly favorable therapeutic index (39). Ganciclovir also inhibits replication but has greater toxicity; however, antiviral agents are ineffective against latent infection (39). In people living with HIV, primary central nervous system lymphoma may respond to antiretroviral therapy; it may be combined with methotrexate or whole-brain radiotherapy where appropriate (06).