Jul. 09, 2021
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Epstein-Barr virus is a ubiquitous herpes virus associated with infectious mononucleosis. Neurologic complications due to acute Epstein-Barr virus infection include acute encephalitis, cerebellar ataxia, cranial nerve palsies, and Guillain-Barré syndrome. Studies also show a high seropositivity of Epstein-Barr virus among patients with multiple sclerosis.
• Epstein-Barr virus is a herpes virus associated with infectious mononucleosis.
• Neurologic symptoms can be seen with infectious and postinfectious complications of Epstein-Barr virus.
• The role of Epstein-Barr virus infection in multiple sclerosis is an area of intense research, but a causal relationship has not been definitively demonstrated.
Discovered in 1964 from lymphoma cells of the jaw, Epstein-Barr virus has since been implicated in a variety of disease processes, both benign and malignant (10). The virus was discovered by Anthony Epstein, Yvonne Barr, and colleagues upon studying lymphoma from the jaw of central African children, which was found by surgeon Denis Burkitt (05). Epstein and colleagues discovered the first virus that could cause cancer. Years later, Epstein-Barr virus was found to be the culprit of infectious mononucleosis, also known as glandular fever (15). The virus belongs to the herpesviridae family, and the origin of the word herpes comes from the Latin word herpein, which means literally “to creep, move slowly”. It is one of the most common viruses among humans. It is implicated in a variety of diseases such as nasopharyngeal carcinoma, hairy cell leukoplakia, Burkitt lymphoma, lymphomas in the immunocompromised, and primary CNS lymphomas. The following discussion will concentrate on neurologic manifestations of Epstein-Barr virus.
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, symptoms begin as fever, pharyngitis, lymphadenopathy (especially of the occipital and cervical nodes), splenomegaly (with risk of splenic rupture 0.1%-0.5% spontaneously or after trauma), leukocytosis with atypical lymphocytes, and hepatocellular dysfunction with a possible subsequent jaundice (02).
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 (11; 38; 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 (19) and is also associated with Alice in Wonderland syndrome, which is an encephalopathy characterized by visual hallucinations and perceptual distortions of objects and body parts, also known as metamorphopsia (24). Findings from fMRI studies show that metamorphopsia is linked to functional impairment of the occipital cortex and over activation of specific parietal regions (04).
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 (32). Epstein-Barr virus may cause an acute myelitis, but this is more common in immunocompromised patients. 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 (37). Symptoms may include paresthesias, extremity weakness, and loss of sphincter control (30).
Epstein-Barr virus infection has also been associated with peripheral nervous system syndromes, including mononeuropathies, autonomic neuropathies, polyradiculopathies, and brachial plexus neuropathies. Hottenrott described a case of Epstein-Barr virus causing a lumbrosacral radiculitis with radicular pain in an immunocompetent patient (18). Mechanisms of brachial plexus neuropathy from Epstein-Barr virus include brachial plexopathy from acute virus infection, which is often associated with lymphadenopathy, and a post-infectious brachial neuritis following infection (08).
Guillain-Barré syndrome is known to be associated with multiple antecedent infections, the most common being Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae. All 4 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 of how antibodies are produced to gangliosides (21). Miller Fisher syndrome, a variant of Guillain-Barré syndrome, can be caused 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 (06). It is thought that the pathophysiological mechanism of Epstein-Barr virus-induced Miller Fisher syndrome is similar to that of the cross-reactivity theory with Epstein-Barr virus and Guillain-Barré syndrome.
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 multiple sclerosis patients, with lower rates being found in non-multiple sclerosis patients of the same age range (01). Studies also suggest that a previous history of infectious mononucleosis is a risk factor for multiple sclerosis (14). 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 rescue them from apoptosis, thereby allowing them to act as antigen-presenting cells that activate CD4+ T cells and lead to chronic inflammation (34; 26). Other hypotheses describe a “2-hit” phenomenon implicating multiple factors that allow inflammatory cells to migrate into the CNS in the presence of Epstein-Barr virus infection (13). 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 (25; 09). The etiology of multiple sclerosis has yet to be fully understood, and the role of Epstein-Barr virus in its pathogenesis remains controversial.
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 (17). Brain tissue staining showed both measles and Epstein-Barr virus antigenic material. It is thought 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 (40) as well as primary CNS lymphomas in immunocompetent and immunocompromised patients (29; Grommes and DeAngelis 2017).
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 manifest with raised intracranial pressure and death. In children, it can be associated with subsequent developmental delay, and some adults have been reported to 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 (Grommes and DeAngelis 2017). 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.
Epstein-Barr virus is a human herpes virus, also known as human herpesvirus 4. The virus is unique in that it infects B lymphocyte cells 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 heavily through saliva, as well as many other bodily fluids, and viral entry is likely through the oropharynx.
It is speculated that the pathophysiology of neurologic complications may involve Epstein-Barr virus entering nerve tissue through infected B lymphocytes. Pathologic studies have shown perivascular lymphocytic infiltrates, parenchymal edema, microglial proliferation, and demyelination (07).
Epstein-Barr virus is a ubiquitous virus, with an estimate of 95% of adults globally being seropositive (28). The ability of the virus to establish latency and reactivation after initial infection, along with mild clinical symptoms in most infected individuals, allows for the ubiquity of the virus. In developed countries, children often seroconvert by the age of 3 or 4 years. Primary infection occurs at younger ages in lower socioeconomic settings, whereas primary infection occurs at older ages in regions with higher socioeconomic settings (16).
Vaccines to prevent complications like lymphoma are being developed, yet an animal model is still needed before a vaccine strategy can be implemented (31). 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.
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, and many other organisms (19).
Epstein-Barr virus may be involved in the progressive neuronal degeneration observed in people living with HIV. It is theorized that presence of ongoing Epstein-Barr viral replication leads to aberrant immune activity that promotes HIV-associated neuronal injury in the central nervous system. This has been suggested by the presence of Epstein-Barr virus DNA in CSF in 18% of a cohort of people living with HIV as well as its association with higher levels of HIV RNA in the CSF and an up to 3 times higher rate of pleocytosis in these participants (27).
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 antibody 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. Glucose level is normal. Epstein-Barr virus antibodies have been seen in the CSF of Epstein-Barr virus encephalitis (23). Quantitative CSF polymerase chain reaction in Epstein-Barr virus infections have shown a lower viral load in patients with post-infectious complications and a higher viral load in patients with primary encephalitis (39).
Epstein-Barr virus polymerase chain reaction in CSF can be positive in patients with primary CNS lymphoma (20). However, this is not always possible to establish, and negative polymerase chain reaction does not exclude primary CNS lymphoma (20). Therefore, the detection of Epstein-Barr virus can be supportive of the diagnosis of primary CNS lymphoma, but not definitive.
Epstein-Barr virus 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 (36). Latent infection can be reactivated in the setting of activation of the immune system, and, as such, its detection has to be interpreted carefully (35).
Management of Epstein-Barr viral infections includes supportive care and symptomatic treatment. Neurologic complications of acute virus infection can be treated with acyclovir (22). Acyclovir inhibits viral replication with a highly favorable therapeutic index (Pagano and Whitehurst 2018). Ganciclovir has also been shown to inhibit replication but has greater toxicity; however, antiviral agents are ineffective against latent infection (Pagano and Whitehurst 2018). In people living with HIV, primary central nervous system lymphoma has been shown to improve with antiretroviral therapy; it may be combined with methotrexate or whole-brain radiotherapy where appropriate (03).
Christina M Marra MD
Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.See Profile
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