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Neurologic Complications in Children with Enterovirus 71 Infection

Enterovirus Encephalomylitis 

Update of Enterovirus Infection in Infants and Children

The human enteroviruses are ubiquitous, enterically transmitted viruses that cause a wide spectrum of both common and uncommon illnesses among infants and children. In temperate climates, enterovirus infections occur mainly in the summer and fall. We will discuss enteroviruses other than polioviruses. Enteroviruses are members of the family Picornaviridae. The genus Enterovirus is now divided into five major groups: polioviruses, group A coxsackieviruses, group B coxsackiviruses, echoviruses and (newer) enteroviruses.

Enteroviruses are shed in the upper respiratory tract for 1-3 weeks and in the feces for up to 8 weeks after primary infection. The fecal-oral route is thought to be the predominant mode of enterovirus transmission, although some exceptions occur including coxsackie A21, which is spread mainly by respiratory secretions, and enterovirus 70, which is shed in tears and spread via fingers and fomites.

CLINICAL DISEASE

The majority of enterovirus infections in children are asymptomatic.

NONFOCAL, ACUTE FEBRILE ILLNESS

Prospective studies have shown that the nonpolio enteroviruses are a common cause of fever without an apparent focus among infants seen in the emergency room. During the summer and fall, enteroviruses account for at least 53-63% of these cases. A study in New York showed that infants born during the Enterovirus season acquired an enterovirus infection during the first 3 months of life, and 21% of the infected infants were hospitalized. Fever often is the sole finding,although some infants will also have irritability, lethargy, poor feeding, vomiting, diarrhea, exanthems, or sings of upper respiratory tract infection. Upon evaluation, approximately half of enterovirus-infected infants will have aseptic meningitis, although there are no clinical features that distinguish those with meningitis before performing the lumbar puncture. Infants with enterovirus-induced fever recover within 2-10 days without complications.

VIRAL MENINGITIS

A recently completed study in Baltimore has confirmed that more than 90% of community-acquired cases of viral meningitis are caused by the group B coxsackievirus and echoviruses. Coxsackie serotypes B2 and B5, and echovirus 4,6,9,11,16 and 30 are the most frequently implicated as causative agents of aseptic meningitis. The least associated, causing fewer than 5% of cases are the group A coxsackievirus. Naturally occurring (wild type) polioviruses were an important cause of viral meningitis (often called onparalytic poliomyelitis? before the control and ultimate eradication of poliomyelitis in the US. Therefore, it is not surprising that rare cases of viral meningitis are now attributed to the attenuated (oral polio vaccine) polioviruses.

Viral meningitis associated with oral polio vaccine occurs among both recipients of OPV and among children who appear to have acquired infection by contact with an OPV vaccinee. Only a minority of infants younger than 3 months with aseptic meningitis will have clinical manifestations of neurologic disease. Ten percent have acute CNS complications such as seizures, obtundation, or increased intracraneal pressure.

ENCEPHALITIS

The enteroviruses account for approximately 10% to 20% of cases of frank encephalitis of proven viral etiology. The group A coxsackieviruses have been conspicuous among the agents isolated from infants and children with focal enteroviral encephalitis.

MYELITIS

The nonpolio enteroviruses rarely cause a syndrome of acute motor weakness and paralysis that is clinically and pathologically indistinguishable form poliomyelitis, although myelitis caused by the nonpolio enteroviruses is less severe, muscle weakness is less likely to persist and bulbar involvement is less common. Enterovirus 71 is known to have been responsible for large outbreaks of acute paralysis involving hundreds of individuals, mostly children.

MYOPERICARDITIS

The cardiomyotropic nature of the group B coxsackieviruses has been recognized since they were first discovered; they account for one third to one half of all cases of sporadic, acute myopericarditis, and for virtually all cases reported to have occurred during epidemics.

The pathophysiology of group B coxsackievirus myopericarditis has been well studied; viral replication in the myocardium peaks within 3-7 days, depending on the route of infection, and persists for 7-10 days in immunocompetent hosts, and longer in those with compromise. Physically active adolescents and young adults may have the highest risk; males have at least twice the risk of females.

Enteroviral myopericarditis is clinically indistinguishable from disease caused by other cardiotropic viruses, including adenoviruses, influenza A virus, and mumps virus. Two-thirds of patients report a febrile upper respiratory tract infection preceding symptoms of frank myocarditis, which may include fever, substernal chest pain, exercise intolerance and dyspnea. A pericardial friction rub is present in 35-80% of cases, and gallop rhythm or other signs of ventricular failure in about 20%. Echocardiography confirms the diagnosis.

OPHTHALMIC INFECTION

Acute hemorrhagic conjunctivitis (AHC) is a highly contagious infection characterized by eye pain, eyelid swelling, and subconjuntival hemorrhages. Two enterovirus serotypes have been responsible for widespread epidemics of AHC that have occurred throughout the tropics. AHC is transmitted directly form person to person via fingers and fomites.

NEONATAL INFECTIONS

• Neonates are at risk of serious and sometimes fatal disease resulting from enterovirus infection acquired during the perinatal period. This unique susceptibility, which extends to about 10 days of age, is based in part on the immunologic immaturity of the human infant, and in part on other host factors.
• The echoviruses and group B coxsackieviruses are responsible for the great majority of neonatal infections. Neonates acquire the infection vertically from their mothers; the outcome of neonatal infection is strongly influenced by the presence or absence of passively acquired maternal antibody specific for the infecting enterovirus serotype. Thus, the timing of maternal infection in relation to development of maternal IgG antibody, and delivery of the infant, may be the most critical factor in determining the outcome of neonatal enterovirus infection.
• Although a wide range of clinical disease has been reported to occur in neonates, including nonspecific febrile illnesses, exanthems, and aseptic meningitis, the most severe manifestations which are usually limited to infants younger than 10 days, are myocarditis with or without encephalitis, hepatitis, and pneumonia. Neonatal myocarditis which is usually caused by group B coxsackievirus serotypes 2-5, presents with the abrupt onset of respiratory distress, tachycardia, cyanosis, temperature instability, arrythmias, hepatomegaly, and signs of poor peripheral circulation.
• Unlike older patients, infants often have concomitant meningoencephalitis, pneumonia, hepatitis, pancreatitis, or adrenalitis. Mortality among infants with myocarditis alone is generally reported to be 30-50%. Neonatal hepatitis is also associated to echovirus 11, and other echoviruses. Initially nonspecific signs and symptoms appear during the first week of life, lethargy, poor feeding, apnea, and jaundice. Progression to a severe hypocoagulability state occurs within 2-3 days, marked by echymoses and prolonged bleeding at puncture sites, progressive anemia and severe prolongation of PT and PTT, and extremely elevated serum transaminase levels. Bleeding into the skin, lungs, GI tract, renal medullae and brain ventricles is characteristic.
• Mortality is 80% even after heroic replacement therapy with PRBC, platelets, and FFP. Signs and symptoms such as extreme lethargy, seizures, hemiparesis, flaccid paralysis, and coma define the more serious form of meningoencephalitis that often accompanies myocarditis or hepatitis. Lesions found in the brain consist of perivascular infiltration with mononuclear cells and PMN in the cerebrum, cerebellum, pons, medulla and spinal cord. Echovirus serotypes 6, 9, and 11 are responsible for a small number of case reports of perinatal pneumonitis.
• Some of the cases have been characterized by the onset of symptoms within hours of birth, indicating prenatal exposure and by a high mortality rate. The severity of disease and poor outcome has raised interest in the use of immune globulin for treatment of neonatal enterovirus infection. Anecdotal reports describe successful outcomes after the administration of IVIG (1g/ kg) and maternal plasma to echovirus 11-infected infants with hepatitis; but results are too small to assess the clinical benefit.

ENTEROVIRUSES AND DIABETES MELLITUS

• No proven association between enterovirus infection and IDDM in children exists. However, an extensive body of epidemiologic, clinical and experimental data has accumulate during the past 30 years that provide suggestive and intriguing links between the human enteroviruses, especially the group B coxsackieviruses and IDDM.
• The observation that new onset of IDDM cases occurs in seasonal patterns, and sometimes in clusters or small outbreaks, if often cited as evidence for the role of viral disease in the pathophysiology of IDDM. Recent studies do not support this.
• The pathophysiology of the process by which enteroviruses might cause or contribute to IDDM is highly conjectural. The irect hit?theory of acute enterovirus infection of the pancreatic islets or surrounding acinar tissue derives support form postmortem isolation of coxsackievirus serotypes B4 and B5 form pancreatic tissue of children dying of ketoacidosis as their initial manifestation of IDDM.
• Although acute infection may cause diabetes in some cases, this concept conflicts with studies demonstrating that the majority of children with IDDM have humoral anti-islet cell antibodies at diagnosis, which may be related to a past viral insult, a genetic predisposition or both.

DIAGNOSIS

• The lab diagnosis is traditionally based on isolation of virus in cell culture, which can be applied to all types of clinical specimens, is relatively sensitive, and yields an isolate that can be further serotyped for clinical or epidemiologic purposes. However, it takes about 3-7 days, it is expensive and not readily available.
• The recent introduction of PCR-bases methods has markedly improved the speed and sensitivity of clinical enterovirus detection. Most of the reported experience is limited to testing CSF specimens where the sensitivity of PCR in confirmed or suspected cases of enteroviral meningitis ranges form 66% to greater than 90%, compared with the 35-40% yield of generally achievable with cell culture.
• Experience with clinical specimens other than CSF is limited.