Clinical features

Most humans acquire herpes simplex virus type 1 by oral transmission during childhood [Chayavichitsilp et al., 2009; Corey and Spear, 1986]. Primary herpes simplex virus infections are frequently asymptomatic, although some children experience vesicular pharyngitis or gingivostomatitis, a condition associated with fever, diminished oral intake, drooling, and herpetic lesions of the face and mouth. By contrast, herpes simplex virus type 2, usually acquired by sexual contact, causes genital lesions in young adults [Corey and Wald, 2009]. In children, herpes simplex virus-induced neurologic infections can be due to primary or reactivated infections, whereas most herpes simplex virus-induced disease after age 30 years, whether due to herpes simplex virus type 1 or type 2, reflects reactivated infection.

Neonatal herpes simplex virus infection, most often due to herpes simplex virus type 2, can be categorized as (1) skin, eyes, and mouth disease; (2) disseminated disease; or (3) encephalitis, affecting approximately 43 percent, 23 percent, and 34 percent of herpes simplex virus-infected infants, respectively [Corey and Wald, 2009; Kimberlin, 2004; Malm, 2009; Whitley et al., 1988]. Neonatal herpes simplex virus disease usually begins with nonspecific clinical features (poor oral intake, behavioral change, or fever), as early as the first day of life, but more often in the second or third weeks [Kimberlin, 2004; Koskiniemi et al., 1989]. Neonatal herpes simplex encephalitis produces focal or generalized seizures, paralysis, apnea, and lethargy or coma [Bale and Miner, 2005; Kimberlin, 2004; Koskiniemi et al., 1989; Malm, 2009; Whitley et al., 1988]. Herpes simplex encephalitis in neonates can be accompanied by pneumonitis, hepatitis, or disseminated intravascular coagulopathy, but one-third of infants with neonatal herpes simplex virus encephalitis have disease restricted to the CNS [Koskiniemi et al., 1989]. Approximately two-thirds of infants have a vesicular rash. The infection can be rapidly fatal, with multiorgan system failure, or be associated with apnea, impaired bulbar function, and intractable seizures. Approximately 5 percent of infants infected with herpes simplex virus acquire the virus in utero and display a relatively characteristic pattern of physical signs consisting of microcephaly, cataracts, intracranial calcifications (Figure 81-4), intrauterine growth retardation, and vesicular rash or other skin lesions [Grose, 1994; Hutto et al., 1987; Koch et al., 2009].

Fig. 81-4 Unenhanced computed tomography scan of an infant with congenital herpes simplex virus infection.

The scan reveals dense thalamic and periventricular calcifications (dark arrows), an additional periventricular density that may be calcium or hemorrhage (white arrow), and abnormal cerebral parenchyma.

(From Souza IE, Bale JF. The diagnosis of congenital infections: Contemporary strategies. J Child Neurol 1995;10:271.)

In older children or adolescents, herpes simplex encephalitis, typically herpes simplex virus type 1, begins nonspecifically with headache, fever, malaise, vomiting, and behavioral changes [Hsieh et al., 2007]. Focal neurologic signs, such as hemiparesis, dysphasia, or visual field defects, appear subsequently in most patients. Seizures affect approximately 40 percent of patients with biopsy-confirmed herpes simplex encephalitis; seizures can be generalized but are more often partial [Whitley et al., 1982]. Focal abnormalities reflect the predilection of herpes simplex virus for infecting frontotemporal brain regions, but other areas of the brain can be affected [Leonard et al., 2000]. The clinical course of herpes simplex encephalitis can be rapidly progressive, with coma and intractable seizures, or indolent, with memory loss and behavioral disturbances.

In addition to causing necrotizing encephalitis, herpes simplex virus has been linked to Bell’s palsy by detecting herpes simplex virus type 1 DNA in facial nerve tissues or in the geniculate ganglia [Burgess et al., 1994]. Herpes simplex virus also has been associated with primary or recurrent aseptic meningitis (Mollaret meningitis) [Bergström et al., 1990]. Common clinical manifestations of herpes simplex virus-associated aseptic meningitis include fever, photophobia, vomiting, and headache, but children with herpes simplex virus-induced meningitis usually lack herpetic lesions of the skin or mucosal surfaces [Rathore et al., 1996]. Although children with herpes simplex virus type 1 meningitis can recover uneventfully without therapy [Rathore et al., 1996], acyclovir therapy should be administered. Herpes simplex virus infection also has been associated with a necrotizing myelopathy in childhood, although it more commonly occurs in adults with reactivated herpes simplex virus infections [Ellstein-Shturman et al., 1976].

Diagnosis

Neonates with herpes simplex virus infections may have elevated serum transaminases, direct hyperbilirubinemia, and laboratory features of disseminated intravascular coagulopathy [Kimberlin, 2004; Koskiniemi et al., 1989]. The CSF in neonatal herpes simplex encephalitis reveals a lymphocytic pleocytosis and elevations of the protein content; the CSF glucose can be normal or mildly low. MRI and CT usually reveal diffuse edema during the acute stage, and later exhibit atrophy, parenchymal calcification, or cystic encephalomalacia [Tien et al., 1993; Vossough et al., 2008]. MRI can reveal a “watershed” distribution of abnormalities [Vossough et al., 2008]. EEGs are frequently abnormal in infants with encephalitis, revealing slow background activity and paroxysmal discharges that occasionally are periodic [Mikati et al., 1990].

Herpes simplex virus infection of the newborn can be confirmed by isolating virus from CSF, skin lesions, or mucosal surfaces of the eye, oropharynx, or rectum, or by detecting herpes simplex virus DNA in CSF or serum by using PCR. In a retrospective analysis of CSF samples accumulated by the National Institutes of Health–Collaborative Antiviral Study Group, herpes simplex virus DNA was detected by PCR in the CSF of 93 percent of the infants with disseminated infection, 76 percent of infants with encephalitis, and only 24 percent of infants with skin-eyes-mouth disease [Kimberlin et al., 1996].

Because older infants, children, and adolescents with herpes simplex virus encephalitis rarely have systemic signs of infection, neurodiagnostic and CSF PCR studies have major roles in establishing the diagnosis [Mitchell et al., 1997; Whitley and Lakeman, 1995; Whitley et al., 1982]. MRI may indicate unilateral or bilateral abnormalities consisting of T2 prolongation in the temporal lobe or insula, and enhancement of the insula, temporal cortex, and cingulate gyrus on T1-weighted, gadolinium-enhanced images [Schroth et al., 1987; Tien et al., 1993]. Focal abnormalities involving other cortical regions, including parietal or occipital lobes, can be observed, however, in atypical cases of herpes simplex encephalitis [Schlesinger et al., 1995]. EEGs, abnormal in approximately 80 percent or more of patients, reveal focal or diffuse slowing and epileptiform discharges that can be periodic and lateralizing.

In National Institutes of Health–Collaborative Antiviral Study Group studies of adults, herpes simplex virus DNA was detected in the CSF of 98 percent of patients with biopsy-proven herpes simplex virus encephalitis, whereas only 6 percent of biopsy-negative patients had herpes simplex virus DNA in CSF [Lakeman and Whitley, 1995]. These results, as well as results from other laboratories, indicate that the sensitivity and specificity of PCR in herpes simplex virus encephalitis of children or adolescents exceed 90–95 percent [Mitchell et al., 1997; Read et al., 1997]. None the less, clinicians must use caution when interpreting the results of CSF PCR studies for herpes simplex virus, especially when negative. Full courses of acyclovir may be necessary when clinical features, especially MRI findings, are compatible with herpes simplex virus encephalitis but CSF PCR studies are negative.

Treatment and outcome

Infants with herpes simplex virus infections should receive acyclovir, 20 mg/kg every 8 hours for 14 days in skin and mucous membrane infections, and 20 mg/kg every 8 hours for 21 days in disseminated infections or encephalitis [Bale and Miner, 2005; James et al., 2009; Kimberlin et al., 2001b; Whitley et al., 1986, 1991a, b]. CSF PCR should be obtained at 21 days in the latter infants, and if the PCR remains positive for herpes simplex virus DNA, acyclovir should be continued for another 7 days. Children with herpes simplex virus encephalitis should be treated with 20 mg/kg every 8 hours for 21 days, and adolescents can receive 1500 mg/m² for 21 days. Potential side effects include tremulousness, hematuria, and reversible nephropathy. The drug is very well tolerated, although complete blood counts and serum creatinine levels should be monitored during prolonged courses of acyclovir. Although favorable outcome after neonatal or childhood herpes simplex virus infections correlates with the early initiation of acyclovir, sequelae are common, even after appropriate medical management.

All acyclovir-treated infants with skin, eye, and mouth infections with herpes simplex virus survive, and nearly all such infants have no long-term sequelae of their infections, other than the propensity to have recurrent herpetic skin lesions [Kimberlin et al., 2001a]. As many as 30 percent of the infants with disseminated neonatal herpes simplex virus infections die, however, despite appropriate therapy, and 20–30 percent of the survivors have sequelae ranging from mild (speech delay or mild motor delay) to severe (spastic quadriparesis or severe developmental delay). Neonates with encephalitis have less than 10 percent mortality, but approximately 40 percent of the surviving infants have severe sequelae, despite acyclovir therapy [Kimberlin et al., 2001b]. Infants who survive herpes simplex virus encephalitis can have permanent pseudobulbar palsy with mutism and feeding difficulties (Figure 81-5). Infants with congenital herpes simplex virus infections generally have poor prognoses [Grose, 1994; Hutto et al., 1987]. Potential sequelae of herpes simplex virus encephalitis in children and adolescents consist of partial and generalized seizure disorders, developmental delay, cerebral palsy, language and memory dysfunction, behavioral abnormalities, and motor deficits [Hsieh et al., 2007; Kimberlin et al., 2001a, b; Whitley et al., 1991b].

Fig. 81-5 Unenhanced computed tomography scan of a young child who survived herpes simplex virus encephalitis.

The scan reveals cerebral atrophy and destructive changes of the insular cortex bilaterally. Despite treatment with acyclovir, the infant sustained extensive damage to both opercular areas and manifested severe pseudobulbar palsy.

Relapse or persistence of symptoms in herpes simplex virus encephalitis, associated with fever, lethargy, headache, and movement disorder, can develop despite appropriate initial management and acyclovir therapy [Barthez-Carpentier et al., 1995; Gutman et al., 1986]. Such children require repeat CSF PCR studies for herpes simplex virus, MRI, repeat treatment with acyclovir, and corticosteroid therapy if imaging results suggest acute disseminated encephalitis. Because of the substantial morbidity associated with neonatal and childhood herpes simplex virus encephalitis, on-going studies are evaluating the role for prolonged suppressive therapy with acyclovir in neonates with herpes simplex virus infections [James et al., 2009; Kimberlin, 2004].

Clinical features

Infection with cytomegalovirus, a ubiquitous member of the herpesvirus family, has been associated with several childhood neurologic conditions, including intrauterine infection; infantile spasms; Guillain–Barré syndrome; and encephalitis, myelitis, or retinitis in immunosuppressed hosts, especially persons with AIDS [Bale, 1999; McCutchan, 1995]. Approximately 1 percent of infants excrete cytomegalovirus at birth, and the virus is acquired steadily thereafter throughout life. Young children who attend daycare centers, adults who have contact with young children, and persons with multiple sexual partners acquire cytomegalovirus at annual rates of 8–25 percent or more, considerably higher than the background infection rates of 2–5 percent per year [Demmler, 1991; Murph and Bale, 1988]. Children acquire cytomegalovirus by contact with persons who shed cytomegalovirus in urine or saliva, and by transfusion of blood products or transplantation of organs from cytomegalovirus-seropositive donors [Demmler, 1991].

At birth, 0.4–2.5 percent of newborns shed cytomegalovirus in urine or saliva, indicating congenital infection [Demmler, 1991; Malm and Engman, 2007]. Approximately 90 percent of cytomegalovirus-infected infants are asymptomatic at birth. Although sensorineural hearing loss develops subsequently in 7–10 percent of these infants [Fowler et al., 1997], they rarely have other CNS complications. The remaining 10 percent of infants with congenital cytomegalovirus infection have hepatomegaly, splenomegaly, jaundice, petechial or purpuric skin rash, intrauterine growth retardation, microcephaly, or chorioretinitis [Boppana et al., 1997; Demmler, 1991; Malm and Engman, 2007].

Cytomegalovirus has been linked to infantile spasms, usually in infants with intrauterine infection. Immunocompetent children or adolescents with cytomegalovirus infections can have a mild, self-limited encephalitis [Studahl et al., 1992] or Guillain–Barré syndrome. The latter disorder begins with paresthesias and causes weakness that usually begins in the lower extremities. Affected children can have bilateral facial paresis, respiratory failure, or cardiac dysrhythmias. Symptoms of a cytomegalovirus-induced mononucleosis syndrome [Horwitz et al., 1986] – malaise, low-grade fever, or headache – may precede or accompany the onset of Guillain–Barré syndrome.

Patients immunocompromised by AIDS, malignancy, transplantation, or immunosuppressive therapy are at risk for cytomegalovirus-induced retinitis, encephalitis, myelopathy, and Guillain–Barré syndrome-like disorders. Given the demographics of AIDS, most reported patients with cytomegalovirus retinitis, encephalitis, or myelitis are adults between the ages of 20 and 50 years [Holland et al., 1994; Jacobson, 1997]. Immunocompromised infants or children, especially those with HIV infection, are at risk for retinitis, colitis, pneumonitis, and CNS complications of cytomegalovirus infections [Darin et al., 1994].

Diagnosis

The diagnosis of intrauterine cytomegalovirus infection can be established by assaying urine or saliva using the shell vial cell culture method. PCR can detect cytomegalovirus DNA in urine, saliva, or serum, but the shell vial assay is sensitive and cost-effective [Demmler et al., 1988]. Cytomegalovirus DNA can also be detected by PCR analysis of dried blood spots obtained from newborn infants, but the sensitivity of this detection method does not exceed that of urine or saliva assay [Atkinson et al., 2009]. Common, nonspecific laboratory features of congenital cytomegalovirus infections include thrombocytopenia, direct hyperbilirubinemia, and elevated serum transaminases [Demmler, 1991].

CT scans reveal intracranial calcifications (Figure 81-6) in 25–50 percent of symptomatic infants [Boppana et al., 1997; Pass et al., 1980]. Hydranencephaly, atrophy, lissencephaly, schizencephaly, and cerebellar hypoplasia also can accompany congenital cytomegalovirus infections [de Vries et al., 2004; Iannetti et al., 1998], and white-matter abnormalities are commonly seen when congenitally infected infants undergo brain MRI [van der Knapp et al., 2004]. Approximately 50 percent of symptomatic infants have abnormal auditory-evoked responses, indicating sensorineural hearing loss [Boppana et al., 1997; Pass et al., 1980; Rivera et al., 2002].

Fig. 81-6 Unenhanced computed tomography scan of an infant with symptomatic congenital cytomegalovirus infection.

The scan reveals multiple calcifications (circles) and pachygyric/lissencephalic cortical dysplasia (arrow).

Infection in older infants or children can be established by isolating cytomegalovirus from urine, saliva, or circulating leukocytes; by detecting cytomegalovirus-specific antigens in circulating leukocytes; or by detecting cytomegalovirus DNA in CSF, serum, or urine [Clifford et al., 1993]. Some patients with cytomegalovirus infection have elevated serum transaminases or hematologic abnormalities, such as leukopenia, anemia, or thrombocytopenia. CT or MRI may reveal abnormalities of the brain or spinal cord consisting of demyelination or inflammation involving cortical or periventricular regions [Miller et al., 1997].

Treatment and outcome

Infants who survive symptomatic intrauterine cytomegalovirus infections often have permanent neurodevelopmental sequelae consisting of mental retardation, seizure disorders, behavioral disturbances, visual impairment, and sensorineural hearing loss [Boppana et al., 1997; Malm and Engman, 2007; Pass et al., 1980]. Because hearing loss can be progressive, even after silent, intrauterine cytomegalovirus infection, infants with known congenital cytomegalovirus infection require serial audiometry at frequent intervals during infancy and childhood [Fowler et al., 1997]. Infants with abnormal CT scans are more likely to have adverse neurodevelopmental outcomes [Boppana et al., 1997; Noyola et al., 2001].

Although intrauterine cytomegalovirus infection cannot currently be prevented by vaccination, recent studies suggest that a vaccine based on glycoprotein B, a major immunogenic protein of human cytomegalovirus, can reduce the risk of maternal infection [Pass et al., 2009]. Ganciclovir, an antiviral drug closely related to acyclovir, provides some benefit to infants with congenital cytomegalovirus disease. A controlled trial of ganciclovir indicated that prolonged courses of ganciclovir, 10–12 mg/kg/day for 42 days, can improve hearing outcomes [Kimberlin et al., 2003]. Based on these encouraging data, ganciclovir should be considered for infants with congenital cytomegalovirus disease, given the high risk of sensorineural hearing loss in such infants. Bone marrow suppression and line infections can be potential adverse effects of prolonged intravenous therapy. Studies of oral therapy, using the prodrug valganciclovir, are on-going.

Immunocompromised children with invasive cytomegalovirus disease, especially retinitis, should receive ganciclovir, beginning with 5 mg/kg intravenously twice daily for approximately 14 days. Long-term maintenance therapy, using 5–10 mg/kg/day, is required in persons with cytomegalovirus retinitis and HIV infection [Jacobson, 1997]. Complete blood counts and renal function should be monitored frequently. Outcome of acquired cytomegalovirus infection depends greatly on the immunocompetence of the infected host. Patients who are immunosuppressed by AIDS or transplantation have increased risks of death during systemic or CNS cytomegalovirus infections. By contrast, most children with normal immune systems generally recover from acquired cytomegalovirus infections without lasting sequelae. The prognosis of cytomegalovirus-induced Guillain–Barré syndrome in immunocompetent children is comparable with that of Guillain–Barré syndrome resulting from other causes.

Clinical features

Varicella zoster virus, the cause of chickenpox (varicella) and shingles (zoster), has been associated with several neurologic conditions in children, including acute ataxia, myelitis, stroke, postherpetic neuralgia, Bell’s palsy, Ramsay Hunt syndrome, aseptic meningitis, encephalitis, congenital varicella syndrome, and Reye’s syndrome [Gilden, 2004; Weller, 1983]. These conditions can affect immunocompetent or immunocompromised hosts, although immunosuppressed hosts, such as patients with HIV/AIDS or hematologic malignancies, have greater risks of severe, invasive varicella zoster virus infections. Certain conditions, such as varicella-induced ataxia or Reye’s syndrome (rarely seen, currently), occur almost exclusively in immunocompetent children.

Chickenpox, the illness associated with primary varicella zoster virus infection, peaks among children between the ages of 5 and 9 years and occurs more often in winter months. The virus spreads by aerosolization and respiratory transmission; children are contagious during the interval encompassing 2 days before and 5 days after the onset of the chickenpox rash. The incubation period averages 14 days. After primary infection, the virus enters a latent stage in sensory ganglia and can reactivate, causing zoster or shingles [Gilden, 2004]. Consequently, zoster more commonly affects the elderly or persons with immunocompromising conditions. Zoster can occur, however, in otherwise healthy children or adolescents [Guess et al., 1985]. Less than 0.1 percent of otherwise healthy children with chickenpox experience neurologic complications. Acute cerebellar ataxia, the most common complication, begins approximately 10 days after the onset of the rash, although ataxia preceding the rash or after varicella vaccination has been reported [Sunaga et al., 1995]. Truncal ataxia, dysmetria, vomiting, and irritability are common clinical features. The ataxia, often maximum at onset, frequently inhibits independent ambulation, and nystagmus can be present [Connolly et al., 1994]. The precise pathogenesis of ataxia after varicella, although presumed to be immune-mediated, has not been fully elucidated.

Other varicella zoster virus-related neurologic complications are uncommon. Reye’s syndrome, a now-rare disorder characterized by pernicious vomiting, coma, and increased intracranial pressure, can be prevented by avoiding aspirin therapy in children or adolescents with chickenpox or influenza. Varicella encephalitis, another rare complication of either varicella or zoster, usually appears 3–7 days after the onset of the rash and produces headache, fever, seizures, coma, or paralysis [Gilden, 2004; Hausler et al., 2002]. Myelitis causes urinary retention or incontinence, paraparesis, and sensory abnormalities [Rosenfeld et al., 1993]. Ramsay Hunt syndrome, an uncommon complication of zoster in childhood, consists of acute facial palsy, pain, unilateral hearing loss, and occasionally other cranial palsies in association with zoster of the ear or neck [Grose et al., 2002]. Children infrequently have postherpetic neuralgia.

Stroke [Askalan et al., 2001; Miravet et al., 2007; Sebire et al., 1999] or, rarely, herpes zoster ophthalmicus [Gilden, 2004; Leis and Butler, 1987] has been reported in children after varicella. Usually occurring within 4–8 weeks of varicella or zoster infection, these disorders produce focal deficits, headache, lethargy or somnolence, and occasionally seizures. The pathogenesis of stroke in these pediatric cases appears to reflect vasculopathy mediated by varicella zoster virus, as occurs in herpes zoster ophthalmicus and delayed infarction, a potential complication of varicella zoster virus reactivation in adults [Hilt et al., 1983]. The intrauterine varicella syndrome affects approximately 2–3 percent of the offspring of women who have chickenpox during their first or second trimesters of pregnancy [Alkalay et al., 1987; Brunnell, 1992; Grose, 1994]. The characteristics of this disorder include intrauterine growth retardation, cicatricial skin lesions in a dermatomal distribution, eye abnormalities (chorioretinitis, cataracts, optic atrophy), limb hypoplasia, and neurologic abnormalities (hydrocephalus, microcephaly, seizures, or Horner’s syndrome) [Alkalay et al., 1987; Grose, 1994].

Diagnosis

Children or adolescents with neurologic conditions associated with varicella zoster virus have CSF abnormalities consisting of a lymphocytic pleocytosis and elevated protein content. Approximately 50 percent of children with ataxia after varicella have a lymphocytic pleocytosis, although the total leukocyte count and protein content rarely exceed 100 cells/mm³ and 40 mg/dL, respectively [Connolly et al., 1994]. Varicella zoster virus infection is suspected when characteristic skin lesions are present and confirmed by detecting infectious virus in skin lesions or varicella zoster virus-specific antibodies or varicella zoster virus DNA in CSF using PCR [Gilden, 2004; Kido et al., 1991]. Some adults and, presumably, some children or adolescents with varicella zoster virus-related neurologic complications lack cutaneous manifestations of varicella zoster virus [Gilden, 2004]. This is especially true when remote complications of varicella zoster virus, such as childhood stroke, occur [Askalan et al., 2001].

The results of neuroimaging studies vary, depending on the disorder and immune status of the child. Children with ataxia or encephalitis after varicella often have normal imaging studies, although MRI occasionally can detect edema or white-matter lesions compatible with demyelination. Occasionally, features suggesting acute disseminated encephalitis are observed. MRI indicates focal cerebral or cerebellar lesions in children with stroke [Leis and Butler, 1987; Sunaga et al., 1995], and hydrocephalus, cortical atrophy, hydranencephaly, or intracranial calcifications in infants with congenital varicella zoster virus embryopathy [Alkalay et al., 1987; Grose, 1994].

Treatment and outcome

Children with varicella zoster virus-related ataxia recover without antiviral or corticosteroid therapy [Connolly et al., 1994], indicating that conservative management of these children is warranted. Virtually all children with varicella-induced ataxia recover completely within 8 weeks of onset, although behavioral disturbances can persist longer. Children or adolescents with encephalitis or myelitis should receive acyclovir, 1500 mg/m²/day in three equally divided doses for at least 10 days, especially if immunocompromised by HIV/AIDS, solid organ or stem-cell transplantation, or chemotherapy [Gilden, 2004]. Children with Ramsay Hunt syndrome also may benefit from acyclovir.

Corticosteroid therapy (e.g., intravenous methylprednisolone) should be considered in children or adolescents with myelitis, acute disseminated encephalitis, or stroke secondary to varicella zoster virus vasculitis. Outcome of varicella-related stroke in children seems to be more favorable than the outcome in adults. Infants with intrauterine infections have variable outcomes, with high rates of permanent neurodevelopmental sequelae [Grose, 1994]. Varicella can be prevented by vaccination, suggesting that certain neurologic complications also may be preventable.

Clinical features

Epstein–Barr virus, the cause of infectious mononucleosis, has been associated with several neurologic disorders of children and adults, including encephalitis, Guillain–Barré syndrome, optic neuritis, Bell palsy, acute ataxia, chronic daily headaches, acute chorea, and “Alice in Wonderland” syndrome [Connelly and DeWitt, 1994; Doja et al., 2006; Volpi, 2004]. Epstein–Barr virus, transmitted by contact with oral secretions, commonly infects children before the age of 5 years, children and adolescents after age 10 years, and young adults. Most primary infections are asymptomatic, although infected individuals can experience infectious mononucleosis, an illness associated with fever, malaise, headache, sore throat, lymphadenopathy, splenomegaly, and rash [Sumaya and Ench, 1985a].

Epstein–Barr virus encephalitis accounts for 5 percent of cases of acute encephalitis and produces fever, headache, altered consciousness, and seizures, including acute status epilepticus [Connelly and DeWitt, 1994; Doja et al., 2006; Domachowske et al., 1996]. In the National Institutes of Health–Collaborative Antiviral Study Group studies, Epstein–Barr virus was the most common infectious agent mimicking herpes simplex virus encephalitis [Whitley et al., 1989]. “Alice in Wonderland” syndrome, another cerebral manifestation of Epstein–Barr virus infection, causes personality changes and illusions of distorted size, shape, or distance (metamorphopsia) [Liaw and Shen, 1991].

Other neurologic conditions attributed to Epstein–Barr virus, such as optic neuritis [Frey, 1973], Guillain–Barré syndrome, acute hemiplegia, and acute ataxia [Connolly et al., 1994], lack unique, distinguishing features that allow the clinical diagnosis of Epstein–Barr virus infection. The association of Epstein–Barr virus with these disorders often has been established retrospectively by serologic studies and exclusion of other potential causative factors. The lymphoproliferative syndrome associated with Epstein–Barr virus in transplant patients may cause seizures or altered sensorium as a consequence of intracranial mass lesions or lymphomatous meningitis [Boyle et al., 1997].

Diagnosis, treatment, and outcome

Children with Epstein–Barr virus infection frequently have elevated serum transaminases and hematologic abnormalities, including thrombocytopenia, leukopenia, and an atypical lymphocytosis [Sumaya and Ench, 1985a]. A positive heterophil response supports recent Epstein–Barr virus infection, although children younger than 4 years frequently have false-negative results [Sumaya and Ench, 1985b]. The diagnosis of Epstein–Barr virus infection can be established specifically by a serologic panel that assays Epstein–Barr virus-specific antibody responses to viral capsid, early, and nuclear antigens [Sumaya, 1985]. Acute infection is suggested by the presence of viral capsid antigen IgM or IgG and the absence of Epstein–Barr nuclear antigen IgG [Sumaya and Ench, 1985b]. Epstein–Barr virus infection of the CNS also can be diagnosed by detecting Epstein–Barr virus DNA in CSF [Landgren et al., 1994; Volpi, 2004].

EEG may demonstrate slowing or epileptiform discharges during acute Epstein–Barr virus encephalitis or in the “Alice in Wonderland” syndrome. Neuroimaging studies occasionally can be abnormal (Figure 81-7) [Bale, 1999; Domachowske et al., 1996; Baskin and Hedlund, 2007]. Current antiviral medications generally have minimal effect on CNS infections due to Epstein–Barr virus, although ganciclovir has been used with success during systemic and CNS Epstein–Barr virus infections [Adams et al., 2006]. Although most children with Epstein–Barr virus encephalitis recover completely with supportive care, severe CNS damage can occur and may have permanent neurodevelopmental sequelae (Figure 81-8) [Domachowske et al., 1996].

Fig. 81-7 T2-weighted magnetic resonance image from a child with Epstein–Barr virus encephalitis.

The scan reveals bilateral areas of T2 prolongation (arrows) reminiscent of acute disseminated encephalomyelitis.

(From Bale JF, Andersen RA, Grose C. Magnetic resonance imaging of the brain in childhood herpesvirus infections. Pediatr Infect Dis J 1987;6:644.)

Fig. 81-8 T1-weighted magnetic resonance image from a child with neurologic sequelae from Epstein–Barr virus encephalitis.

The image shows cystic encephalomalacia and gliosis.

Clinical features

Members of the picornavirus family, especially the enteroviruses, are important potential causes of neurologic infections worldwide. Although paralytic poliomyelitis has been eliminated from nearly all regions of the world, nonpolio enteroviruses continue to be associated with a spectrum of neurologic disease that includes aseptic meningitis, acute ataxia, acute hemiplegia, opsoclonus-myoclonus, encephalitis, Guillain–Barré syndrome, and poliolike paralysis [Alexander et al., 1994; Chen et al., 2001; Huang et al., 1999; Rorabaugh et al., 1993; Sawyer, 2002]. The last case of wild poliomyelitis in the United States occurred in 1979 (see Figure 81-1), and the World Health Organization has certified that the Americas, Europe, and the western Pacific regions are free of polio [CDC, 1994a, 2004b]. The numbers of wild poliovirus infections have declined dramatically from approximately 350,000 cases worldwide in 1988, the year in which the World Health Organization established the global eradication initiative, to approximately 1700 in 2008 [CDC, 2009a]. Eradicating poliomyelitis from the four remaining endemic locations (Afghanistan, India, Nigeria, and Pakistan) remains the objective of the World Health Organization [CDC, 2009a]. Before the use of the inactivated poliovirus vaccine for the complete childhood immunization series, vaccine-related poliomyelitis occurred occasionally in the United States [CDC, 1997b]; vaccine-associated poliomyelitis continues to be observed in countries relying upon the live oral polio vaccine [CDC, 2009b].

Spread by the fecal–oral route, the nonpolio enteroviruses, coxsackieviruses, and echoviruses produce several distinct systemic syndromes, including pharyngitis, herpangina, gastroenteritis, hand-foot-and-mouth syndrome, neonatal sepsis, and neurologic disorders. Data from the CDC indicate that approximately 10 million or more cases of nonpolio enteroviral infections occur annually in the United States [CDC, 2000]. More than 10,000 cases of nonpolio enterovirus aseptic meningitis are reported to the CDC annually [Sawyer, 2002]; outbreaks of aseptic meningitis appear sporadically in association with several echovirus serotypes, including 9, 13, 18, and 30 [CDC, 2006].

Aseptic meningitis, the most common neurologic manifestation of nonpolio enteroviral infection, appears epidemically during the late summer and early fall, although cases can be observed throughout the year. Affected children have fever, irritability, headache, photophobia, nausea, vomiting, meningeal signs, and other signs of enteroviral disease, including diarrhea, abdominal discomfort, and a maculopapular or petechial rash [Rorabaugh et al., 1993; Sawyer, 2002]. Signs of aseptic meningitis in a young infant may be remarkably subtle, consisting only of fussiness or poor oral intake. Fever is an inconsistent feature.

Occasionally, children with nonpolio enteroviral infections have an acute encephalitic presentation with fever, seizures, somnolence, coma, or focal deficits [Fowlkes et al., 2008]. Such children may have focal clinical, EEG, or neuroimaging abnormalities that resemble herpes simplex encephalitis. Children with acute opsoclonus-myoclonus, a syndrome more commonly associated with occult neural crest tumors, have involuntary, chaotic eye movements and random myoclonus of the extremities. Enterovirus 71, in addition to being associated with encephalitis and aseptic meningitis, causes an acute neurologic disorder with unilateral or bilateral flaccid paralysis that can resemble poliomyelitis or Guillain–Barré syndrome [Alexander et al., 1994; Chen et al., 2001; Huang et al., 1999]. Several other nonpolio enteroviruses have been linked to acute poliomyelitis-like syndromes.

Children with poliomyelitis have a biphasic illness; the initial, nonspecific phase consists of fever, malaise, vomiting, or diarrhea; the second, neurologic phase consists of aseptic meningitis or paralytic disease, usually more severe in the lower extremities [CDC, 1997b]. Mild or inapparent poliovirus infections greatly exceed the number of paralytic cases. Although the pathogenesis of their condition remains uncertain, persons with paralytic poliomyelitis may experience muscle pain, weakness, and fatigue after many years, a condition that has been labeled postpolio syndrome [Windebank et al., 1991].

Infants with nonpolio enteroviral infections can have a disseminated illness that resembles bacterial sepsis or herpes simplex virus infection. Clinical features of this condition include fever, respiratory distress, seizures, lethargy, shock, or disseminated intravascular coagulopathy; cardiomyopathy can complicate neonatal enteroviral infections, especially those due to coxsackieviruses, and be fatal in some infants [Verma et al., 2009]. During community enteroviral outbreaks, numerous young infants acquire enteroviruses, usually asymptomatically. Children with agammaglobulinemia can have a persistent, often fatal, neurologic condition caused by chronic nonpolio enterovirus infection of the CNS [Mease et al., 1981; Wilfert et al., 1977]. Patients with this rare disorder exhibit a dermatomyositis-like disorder and neurologic signs, which may include seizures, mental status changes, hemiparesis, and headache.

Diagnosis

Infants with disseminated enteroviral infections can have leukocytosis, elevated serum transaminases, and thrombocytopenia, whereas infants or children with aseptic meningitis have mild CSF changes, consisting of a lymphocytic pleocytosis and protein elevation [Negrini et al., 2000], and, occasionally, laboratory abnormalities consistent with the syndrome of inappropriate antidiuretic hormone secretion. The diagnosis of enteroviral infection can be established by isolating enteroviruses from CSF or stool or throat swabs, or by detecting enteroviral RNA in stool, serum, or CSF by using reverse transcription PCR [Hamilton et al., 1999; Sawyer, 2002; Schlesinger et al., 1994]. Imaging studies are normal in nonpolio enterovirus aseptic meningitis. Children with progressive nonpolio enterovirus infections have progressive cortical atrophy (Figure 81-9).

Fig. 81-9 Axial T2-weighted magnetic resonance image from a child with agammaglobulinemia and presumed progressive nonpolio enterovirus encephalopathy.

The image shows ventriculomegaly and diffuse cortical atrophy.

Treatment and outcome

In most instances, children with enteroviral CNS infections require supportive care only. Children with severe nonpolio enteroviral infections have been treated with pleconaril, a novel antiviral drug with some efficacy against several RNA viruses, although controlled trials suggest that pleconaril therapy is associated with only modest shortening of enteroviral disease-related symptoms [Abzug et al., 2003; Desmond et al., 2006; Sawyer, 2002]. Children with agammaglobulinemia and persistent echovirus infections may improve during immunoglobulin replacement therapy [Mease et al., 1981]. Infants with enteroviral aseptic meningitis recover uneventfully [Bergman et al., 1987], whereas the outcome in infants with myocarditis or children with encephalitis or enterovirus 71 infections can be less favorable [Sawyer, 2002]. Persistent enterovirus infections in children with agammaglobulinemia are often fatal, despite therapy with intravenous immunoglobulin and the available antiviral drugs.

Clinical features

Rubella virus causes neurologic dysfunction during acute childhood infection and in the offspring of women who are infected with rubella virus during the first trimester. These complications are rare in the United States and other regions with compulsory vaccination against rubella virus (Figure 81-10). Before vaccine licensure in 1969, rubella epidemics occurred at 6- to 9-year intervals, and during the last major pandemic in the mid-1960s, 20,000 cases of congenital rubella syndrome were reported. Between 10 and 20 percent of adults living in regions with compulsory immunization remain susceptible to rubella, however, and outbreaks of rubella and congenital rubella syndrome [Panagiotopoulos and Georgakopoulou, 2004] indicate that the rubella virus continues to pose a real threat in many regions of the world [Spika et al., 2003]. Rarely, maternal reinfection with rubella virus causes fetal infection [Robinson et al., 1994].

Fig. 81-10 Data regarding the incidence of rubella and congenital rubella syndrome in the United States from 1966 to 1992.

The data, as reported to the Centers for Disease Control and Prevention, show the dramatic decline in rubella and congenital rubella syndrome (CRS). The inset depicts the resurgence of congenital rubella syndrome that was observed in the early 1990s. Cases of rubella reported to the National Notifiable Diseases Surveillance System per 100,000 population; cases of congenital rubella reported to the National CRS Registry per 100,000 live births.

(From Rubella and congenital rubella syndrome – United States. MMWR Morb Mortal Wkly Rep 1994;43:391, 397.)

Rubella virus produces fever, coryza, lymphadenopathy of the posterior auricular and occipital nodes, and a maculopapular rash involving the face and trunk. Rare neurologic complications after acquired rubella virus infection consist of headache, seizures, or Guillain–Barré syndrome. The clinical features of intrauterine rubella virus infection, recognized first by Gregg in 1941, include cataracts, congenital heart disease, sensorineural hearing loss, microcephaly, intrauterine growth retardation, hepatosplenomegaly, petechial rash, osteopathy, jaundice, and pneumonitis [Bale, 2009; Dudgeon, 1975]. Sequelae relate directly to the gestational timing of maternal infections, with severe defects common before 12 weeks, when the risk of congenital rubella syndrome approaches 90 percent [Ueda et al., 1979]. By contrast, maternal infections after 24 weeks of gestation tend to be benign.

Diagnosis

The diagnosis of rubella virus infection can be established serologically by isolating the rubella virus from urine or nasopharyngeal secretions, or by detecting rubella virus RNA in CSF or other fluids by using reverse transcription PCR [Bosma et al., 1995]. Direct hyperbilirubinemia, elevated serum transaminases, and thrombocytopenia are potential laboratory abnormalities after intrauterine infection. Imaging of infants with congenital rubella syndrome reveals cerebral atrophy, intracranial calcifications, periventricular cysts, or leukomalacia [Yamashita et al., 1991].

Treatment and outcome

At present, therapy for rubella virus infections, including intrauterine infection, consists of supportive care. Survivors of intrauterine rubella virus infection have high rates of sequelae affecting vision, hearing, cardiac function, and intellect [Forrst et al., 2002; Givens et al., 1993]. Potential delayed sequelae of congenital rubella syndrome include endocrinopathies (diabetes mellitus, thyroid dysfunction, and growth hormone deficiency), progressive hearing loss, glaucoma, vascular abnormalities, and postrubella panencephalitis [Sever et al., 1985; Townsend et al., 1975]. Congenital rubella syndrome can be prevented by compulsory immunization programs.

Clinical features

Japanese encephalitis, a mosquito-borne virus endemic throughout much of eastern Asia, causes as many as 50,000 cases of encephalitis each year, usually in children younger than 15 years of age [CDC, 1993b, 2009g]. Disease activity peaks from May to October, although some countries, such as Indonesia, Malaysia, and India, experience cases year-round. The virus is maintained in a bird–vertebrate cycle involving Culex mosquitoes, domestic pigs, and wading birds [CDC, 1993b, 2009g]. Children with Japanese encephalitis have an abrupt, fulminant illness with fever, convulsions, and coma [Kumar et al., 1990]. Headache, vomiting, increased muscle tone, breathing irregularities, and occasionally focal neurologic deficits are additional clinical manifestations [Kumar et al., 1990]. The prodromal phase is less than 24 hours long in most children with Japanese encephalitis, but occasionally exceeds 7 days.

Diagnosis

The diagnosis of Japanese encephalitis can be confirmed by isolating the virus from CSF or brain tissue, detecting serologic responses to the virus, or detecting Japanese encephalitis virus RNA in CSF using reverse transcription PCR [Meiyu et al., 1997]. MRI can reveal bilateral lesions of the thalami or basal ganglia [Kalita and Misra, 2000; Kumar et al., 1997].

Treatment and outcome

Mortality rates for Japanese encephalitis range from 8 to 40 percent; 40–60 percent of the survivors have neurologic sequelae consisting of mental retardation, seizure disorders, motor deficits, or subtle behavioral and intellectual abnormalities [Kumar et al., 1993; Ooi et al., 2008]. An inactivated Japanese encephalitis virus vaccine prevents infection. The vaccine has an 80 percent efficacy after two doses [CDC, 1993b]; adverse reactions occur at a rate of approximately 15 per 100,000 doses [Berg et al., 1997; Takahashi et al., 2000]. Widespread immunization programs in Japan and other Asian nations have reduced the annual incidence of Japanese encephalitis by 90 percent or more [Arai et al., 2008].

Clinical features

St. Louis encephalitis virus, a mosquito-borne virus endemic to the midwestern United States, occasionally causes epidemics of aseptic meningitis, encephalitis, and influenza-like illness, often involving older adults in urban or suburban areas. The 1975 epidemic, the largest to date, affected more than 2000 persons [Creech, 1977]. The attack rates and disease severity of St. Louis encephalitis virus infections, similar to those of West Nile virus, increase with advancing age [Meehan et al., 2000]. The virus is maintained in a cycle involving Culex mosquitoes and pigeons, sparrows, doves, and other birds [Johnson, 1998].

Clinical syndromes associated with St. Louis encephalitis virus infection include nonspecific febrile illnesses, aseptic meningitis, and encephalitis, although most infections are asymptomatic [Creech, 1977]. After an incubation period of 21 days, children with St. Louis encephalitis may have a biphasic illness, with low-grade fever, diarrhea, vomiting, and malaise preceding the neurologic signs and symptoms [Kaplan et al., 1978]. In patients with encephalitis, representing approximately two-thirds of symptomatic infections, headache, vomiting, fever, neck stiffness, and lethargy or agitation begin abruptly. Tremor can be present; focal neurologic findings are infrequent, at least among reported adult cases. Fever may reach 41°C and can persist 7 or more days. Clinical improvement usually begins within 7–10 days of disease onset.

Diagnosis, Treatment, And Outcome

The CSF reveals a pleocytosis in most patients with St. Louis encephalitis. Neuroimaging studies are normal or nonspecifically abnormal, and EEGs may indicate diffuse slowing. The diagnosis can be established by detecting serologic responses in serum or CSF [Monath et al., 1984] or by nucleic acid amplification methods [CDC, 2009g]. Treatment consists of supportive care. Mortality, ranging from 8 to 20 percent [Creech, 1977; Meehan et al., 2000], is highest among persons older than age 50 years. Potential sequelae include seizures, parkinsonism, and intellectual deficits.

Clinical Features

First identified in Uganda in 1937, West Nile virus later appeared in Egypt and Israel in the 1950s [Marberg et al., 1956]. Beginning in the mid-1990s, human outbreaks became more frequent and severe, causing meningitis, encephalitis, and fatalities among persons living in Israel, Algeria, and Romania [Hubalek and Halouzka, 1999]. In 1999, cases of West Nile virus infection occurred in the United States, marking the first appearance of the virus in the Western hemisphere. An encephalitis outbreak in the New York City metropolitan area, linked to a West Nile virus strain closely related to a strain identified in Israel in 1998, caused seven deaths among adults [Lanciotti et al., 1999; Nash et al., 2001].

In 2000, West Nile virus activity was detected in 12 states surrounding New York State, but by the end of 2001, 27 states and the District of Columbia reported the presence of West Nile virus [Petersen et al., 2002]. West Nile virus spread rapidly among North American birds and mosquitoes, and led to a massive human outbreak in 2003 that affected nearly 10,000 inhabitants of states from New York to California (Figure 81-11). Only two western states (Oregon and Washington) did not report West Nile virus activity in that year [CDC, 2004a, c]. The epidemic continued, and by late 2009, nearly 30,000 cases of human disease due to West Nile virus had been reported to the CDC [CDC, 2009d].

Fig. 81-11 A map of the United States showing Centers for Disease Control and Prevention data regarding human West Nile virus cases in 2003.

This was the peak year of West Nile virus activity in the United States in the last decade.

(From the Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/ncidod/dvbid/westnile/mapsactivity/surv&control03maps.htm. Accessed November 15, 2009.)

West Nile virus is maintained in a bird–mosquito cycle, involving rural and urban wild birds and Culex and Aedes mosquitoes; humans represent dead-end hosts in most instances, although human-to-human transmission by organ transplantation and blood transfusion can occur [CDC, 2005a]. Asymptomatic human infections with West Nile virus outnumber symptomatic cases by approximately 5 to 1 [CDC, 2004c]. Neurologic manifestations, including meningitis, encephalitis, myelitis, poliolike illness, and others, occur in approximately 1 of every 150 infected persons [CDC, 2009d]. Adults constitute the majority of cases. After an incubation period of 2–14 days, systemic symptoms of fever, malaise, headache, nausea, and vomiting occur in symptomatic infections. Of symptomatic patients, 50 percent have a maculopapular rash and lymphadenopathy. To date, most patients with the neurologic complications of West Nile virus infections have been older than age 25 years.

Approximately 60 percent of persons with West Nile virus-induced neurologic disease have encephalitis [Sejvar et al., 2003]. Encephalitis can begin with the usual systemic prodrome, or more abruptly, with high fever and coma [Campbell et al., 2002]. Typical abnormalities in West Nile virus encephalitis include altered mental status, coma, diffuse muscle weakness (proximal greater than distal), respiratory paralysis, and hyporeflexia. Tremor, myoclonus, and parkinsonian features are additional components of the acute illness [Sejvar et al., 2003]. Less common neurologic manifestations of West Nile virus infection include aseptic meningitis, myelitis, optic neuritis, and Guillain–Barré syndrome [Campbell et al., 2002; Sejvar et al., 2003]. Involvement of the anterior horn cells can produce a poliomyelitis-like disorder with asymmetric paralysis of the upper or lower extremities [Li et al., 2003; Sejvar, 2004]. This disorder produces clinical, histopathologic, and electrophysiologic abnormalities comparable to those of classic poliomyelitis [Sejvar, 2004]. Although patients with West Nile virus-induced meningitis and encephalitis gradually recover, patients with limb paralysis usually have permanent deficits [Li et al., 2003; Sejvar et al., 2003].

A single case report indicates that West Nile virus can be transmitted to the fetus, causing intrauterine infection of the CNS [CDC, 2002]. In late 2002, an infant was born to a woman who had experienced meningoencephalitis during her pregnancy. At birth, the infant was found to have bilateral chorioretinitis and cystic encephalomalacia. A subsequent epidemiological study that evaluated the outcomes of West Nile virus infections during the pregnancies of 71 women identified no additional cases of congenital West Nile virus infections [O’Leary et al., 2006], indicating that congenital West Nile virus infection is an uncommon event.

Diagnosis, treatment, and outcome

Laboratory abnormalities include mild anemia and peripheral leukocytosis or leukopenia. The CSF of West Nile virus encephalitis resembles that of most arboviral infections, consisting of a mild, lymphocytic pleocytosis (30–100 cells/mm³), elevated protein content (80–100 mg/dL), and normal glucose content. Cranial CT is normal, whereas MRI can reveal leptomeningeal enhancement, periventricular inflammation, or abnormalities of the spinal cord [Campbell et al., 2002]. The diagnosis of West Nile virus infection can be confirmed by serologic studies that detect neutralizing antibodies to the virus in acute or convalescent serum samples or West Nile virus-specific IgM in serum or CSF. West Nile virus-specific IgM persists in serum for at least 16 months in more than half of infected persons [Campbell et al., 2002]. Infected patients experience brief periods of viremia, but infectious virus is rarely isolated from serum or CSF. Reverse transcription PCR can be used to detect West Nile virus in clinical samples [Lanciotti and Kersat, 2001]. A CDC protocol guides the evaluation of infants with suspected intrauterine West Nile virus infection [CDC, 2004f].

Therapy for the neurologic complications of West Nile virus infection currently consists of supportive care, with close observation for respiratory decompensation. Ribavirin possesses activity against the West Nile virus in vitro, but there are no controlled trials on which to base management decisions. There were 264 deaths among the 9862 cases reported to the CDC in 2003, corresponding to a mortality rate of approximately 2.7 percent [CDC, 2009d]. Deaths have been more common among the elderly. Approximately one-third of survivors have permanent sequelae affecting cognition, behavior, or motor function.

Clinical features

La Crosse virus, a California serogroup virus maintained in the wild through a mosquito–vertebrate animal cycle, causes encephalitis, known as La Crosse encephalitis, among children living in the midwestern and eastern United States. Before the emergence of West Nile virus in the United States, La Crosse encephalitis represented the most common arthropod-borne encephalitis in America (see Figure 81-3), accounting for approximately 70–100 reported cases among children per year [CDC, 2009i; McJunkin et al., 2001; Rust et al., 1999]. Nonspecific clinical features, consisting of fever, vomiting, headache, abdominal pain, and malaise, begin 3–7 days after exposure to the virus. Neurologic features appear 2–4 days later and consist of seizures (60 percent), lethargy or coma (50 percent), and focal deficits (20 percent) [McJunkin et al., 2001; Rust et al., 1999]. Neurologic symptoms usually resolve during the subsequent week.

Diagnosis

Laboratory findings include a peripheral leukocytosis (often with a neutrophil predominance) and mixed CSF pleocytosis ranging from 10 to 500 leukocytes/mL in approximately 90 percent of children. EEGs can be diffusely or focally slow, whereas CT and MRI are usually normal. The diagnosis of California encephalitis can be established serologically using IgM capture assays of serum or CSF [McJunkin et al., 2001]. The diagnosis also has been established by brain biopsy [McJunkin et al., 1997], but invasive diagnostic procedures are rarely necessary. Reverse transcription PCR can detect the RNA of California group viruses [Kuno et al., 1996].

Treatment and outcome

Because most cases of La Crosse encephalitis are mild, and current antiviral agents, with the possible exception of ribavirin [McJunkin et al., 1997], lack anti-California encephalitis virus activity, therapy consists of supportive care. Focal EEG or clinical manifestations of La Crosse encephalitis mimic herpes simplex virus and necessitate acyclovir therapy while awaiting the results of microbiologic studies. Most children with California encephalitis recover completely, although residual behavioral changes, seizure tendencies, or EEG abnormalities have been reported in 10–15 percent of children with proven California encephalitis [Balkhy and Schreiber, 2000; Grabow et al., 1969; McJunkin et al., 2001; Rust et al., 1999].

Clinical features

Despite the availability of the measles vaccine, a safe and effective live-virus preparation, measles remains a major worldwide public health concern [CDC, 1997d; Henao-Restrepo et al., 2003; WHO, 2009a]. Measles virus spreads via the respiratory route, with contagion highest during the prodromal catarrhal stage that precedes the rash. Before vaccine availability, measles typically caused disease in infants and young children during the winter and spring. Symptoms of measles infection include fever, cough, coryza, and conjunctivitis, beginning approximately 12 days after exposure in susceptible persons. The characteristic maculopapular exanthem appears on the face and spreads centrifugally to involve the trunk and extremities.

Neurologic complications of measles conform to three distinct disorders:

Measles encephalomyelitis, an immune-mediated disorder with an incidence of approximately 1 case per 1000 cases of measles, begins within 7 days after the onset of the measles rash [Johnson et al., 1984], and children younger than 10 years constitute most cases. Clinical manifestations include headache, irritability, somnolence, coma, and seizures, although some children have ataxia, choreoathetosis, or focal deficits [Johnson et al., 1984]. Subacute measles encephalopathy, first reported in the 1970s [Murphy and Yunis, 1976], begins 1–7 months after measles infection or immunization in an immunocompromised host, often a child with acute leukemia [Mustafa et al., 1993]. Altered consciousness and generalized or focal seizures, including epilepsia partialis continua, are typical clinical signs; 15–40 percent of patients have hemiparesis, hemiplegia, ataxia, aphasia, or visual symptoms [Mustafa et al., 1993].

Subacute sclerosing panencephalitis, a rare disorder in areas with measles immunization programs, begins 5–10 years after measles infection and usually affects young children at an average age of 7 years at disease onset [Anlar et al., 2001; Campbell et al., 2005; Garg, 2008; Honarmand et al., 2004; Modlin et al., 1979]. The disorder displays relatively stereotyped clinical stages, beginning with insidious declines in behavior and cognition that may mimic a psychiatric disorder. Myoclonus, a prominent component of the next phase of subacute sclerosing panencephalitis, involves the extremities, trunk, or head, and generalized or focal seizures may begin concurrently [Risk and Haddad, 1979]. As the disorder progresses, speech and intellectual function deteriorate; myoclonus intensifies; and other neurologic abnormalities, such as choreoathetosis, bradykinesia, or rigidity, appear. The typical course ends in debility, coma, and death. Approximately half of patients have chorioretinitis and visual impairment; a small proportion of subacute sclerosing panencephalitis cases begin in adulthood [Singer et al., 1997], or have atypical features with rapid deterioration and death [Silva et al., 1981].

Diagnosis

The diagnosis of measles encephalomyelitis can be established by detecting measles virus IgG titer elevations in acute and convalescent serum, or measles-specific IgM in serum or CSF. Measles virus also can be detected in clinical samples by using reverse transcription PCR [Shimizu et al., 1993]. Brain MRI may reveal white-matter lesions compatible with acute demyelination. In subacute measles encephalopathy, the CSF, although usually normal, may reveal a lymphocytic pleocytosis. EEGs typically reveal focal or generalized slowing or epileptiform discharges. Cranial CT is usually normal, but brain MRI can detect nonspecific changes involving the cortex, white matter, or deep nuclei (Figure 81-12) [Chen et al., 1994]. Paramyxovirus particles or measles virus RNA can be detected in brain tissue.

Fig. 81-12 T1-weighted magnetic resonance image from an immunocompromised child with measles encephalitis.

The image reveals diffuse cortical atrophy; patchy, hypointense areas at the gray–white matter interface; and subtle basal ganglia calcifications.

The pathogenesis of subacute sclerosing panencephalitis, although still obscure, reflects defective replication of the measles virus in neural tissues [Garg, 2008]. Patients with subacute sclerosing panencephalitis have elevated CSF immunoglobulin levels, oligoclonal bands, and increased IgG synthesis rates, indicating massive production of measles-specific IgG. High CSF titers of measles-specific IgG establish the diagnosis of subacute sclerosing panencephalitis, and measles virus RNA can be detected in CSF or plasma by reverse transcription PCR [Nakayama et al., 1995]. EEGs show bilaterally synchronous spike-wave or slow-wave bursts that assume a suppression-burst pattern over time. MRI commonly exhibits T2 prolongation of subcortical and periventricular white matter and eventually cortical atrophy (Figure 81-13) [Lum et al., 1986; Anlar et al., 1996].

Fig. 81-13 T2-weighted magnetic resonance image from an adolescent with subacute sclerosing panencephalitis.

The image shows demyelination and early cortical atrophy.

Treatment and outcome

Treatment of measles encephalomyelitis consists of supportive care. Outcome varies, ranging from complete recovery to survival with impaired intellectual function, motor deficits, or death. Although one report suggests transient improvement after ribavirin therapy [Mustafa et al., 1993], most children with subacute measles encephalopathy die or have severe neurologic sequelae. Subacute sclerosing panencephalitis progresses to death in 1–3 years in most cases, although some patients have extended plateau phases, either spontaneously or coincident with inosine pranobex (inosiplex; isoprinosine) therapy [Garg, 2008; Risk and Haddad, 1979; Yalaz et al., 1992]; intraventricular or intravenous ribavirin has also been used with uncertain benefits [Campbell et al., 2005]. A multinational trial indicated that approximately 35 percent of patients with subacute sclerosing panencephalitis stabilize during inosine pranobex therapy, but this study found no added benefit from interferon-alpha [Gascon, 2003].

Clinical features

Before vaccine licensure, mumps virus infection accounted for most cases of aseptic meningitis and mild encephalitis in the United States and many other regions. More than 150,000 cases of mumps were reported in the United States in 1968, with aseptic meningitis in 10 percent and encephalitis in 0.2 percent, whereas fewer than 2000 cases of mumps were reported in 1993, a 99 percent decrease [CDC, 1995b]. By the early 1980s, mumps meningoencephalitis had disappeared in many regions of the world [Koskiniemi et al., 1991]. However, large numbers of people remain susceptible to mumps virus infection, even in regions with compulsory immunization programs. In 2006, more than 6500 persons, predominantly between the ages of 18 and 24 years, and living in eight midwestern states of the USA, contracted mumps [Dayan et al., 2008], an outbreak attributed to vaccine failure.

Clinical features appear 2 weeks after acquisition and consist of anorexia, malaise, and low-grade fever; parotitis is a cardinal clinical feature. One-third or more of mumps virus infections are asymptomatic. Aseptic meningitis or encephalitis, heralded by headache, vomiting, and high fever, is associated with stiff neck, somnolence, and, occasionally, seizures, coma, or focal deficits [Koskiniemi et al., 1983]. Additional neurologic complications of mumps include acute cerebellar ataxia and hydrocephalus secondary to mumps virus-induced ependymitis [Bray, 1972].

Diagnosis, treatment, and outcome

CSF pleocytosis is common in patients with mumps virus meningitis or encephalitis. CSF protein content is usually normal, and the glucose content can be slightly reduced [Koskiniemi et al., 1983]. The diagnosis can be confirmed by detecting mumps virus-specific IgM or IgG. EEGs in children with encephalitis may reveal generalized or focal slowing. Children require supportive care; most recover completely.

Clinical features

Dreaded since antiquity, rabies poses a threat to individuals in many regions of the world, especially in the developing countries of Africa and Asia, where the incidence of 1 in 100,000 to 1 million inhabitants corresponds to approximately 50,000 deaths annually [Fishbein and Robinson, 1993; Plotkin, 2000; WHO, 2009b]. In these regions, unvaccinated domestic dogs transmit most rabies virus infections to humans, and children constitute most human rabies cases. By contrast, human and animal rabies has been eradicated in a few regions as a result of quarantine and vaccination of domestic animals [CDC, 1997a; Johnson, 1998]; for example, rabies does not exist in Hawaii.

In the continental United States, rabies remains endemic in certain wild animals, including raccoons, skunks, foxes, and bats. In the northeastern states, the number of infected raccoons has increased steadily since the 1970s [CDC, 1997a, 2009j; Fishbein and Robinson, 1993; Rupprecht et al., 1995]; in 2008, there were 6841 cases of animal rabies reported to the CDC [CDC, 2009j]. This epizootic constitutes a potential health hazard and an economic burden for postexposure prophylaxis; the cost of human rabies detection, control, and prevention in the United States now exceeds $300 million annually. The CDC receives reports of 1–3 indigenous cases of human rabies annually in the United States. Many cases have no apparent history of animal bites and have been linked by molecular analysis to the rabies virus strain carried by the insectivorous silver-haired bat [CDC, 2009j].

After a variable incubation period, averaging 20–60 days, human rabies begins with chills, fever, headache, sore throat, malaise, nausea, or abdominal pain [Johnson, 1998; Plotkin, 2000; WHO, 2009b]. Pain or itching corresponding to the site of inoculation is common. Neurologic symptoms and signs begin thereafter; symptoms and signs are cerebral in 80 percent and Guillain–Barré syndrome-like in the remainder. Patients with cerebral symptoms have marked behavioral changes, with agitation, hypersalivation, delirium, and opisthotonic posturing [WHO, 2009b]. Hydrophobia, present in 20–50 percent of patients, produces spasms of the laryngeal muscles, diaphragm, and accessory respiratory muscles, which can lead to respiratory arrest and death. Seizures ensue in many cases. Eventually, patients with rabies encephalitis lapse into a fatal coma. Rabies-induced Guillain–Barré syndrome-like disease produces bulbar dysfunction, facial diplegia, and, often, respiratory arrest [Chopra et al., 1980]. Cardiac dysrhythmias and irreversible coma are additional causes of death in paralytic cases.

Diagnosis

Because of its rarity in the United States and Canada, human rabies is often unsuspected [Noah et al., 1998; CDC, 2009j], especially during the early, nonspecific phase. Consequently, rabies usually is identified at postmortem examination. Premortem diagnosis can be established by immunofluorescence examination of skin from the nape of the neck, detection of rabies virus antibody in CSF or serum (assuming the patient was not vaccinated previously), or isolation of rabies virus from saliva or CSF [Plotkin, 2000; Smith, 1996]. Reverse transcription PCR can be used to detect rabies virus and determine the molecular profile and animal origin of the rabies virus strain. CSF may be normal or reveal nonspecific changes, with a mixed or lymphocytic pleocytosis and mild protein elevation [Chopra et al., 1980; Plotkin, 2000]. CT is normal; MRI can demonstrate signal abnormalities of the basal ganglia or thalami [Awasthi et al., 2001].

Treatment and outcome

Nearly all persons with symptomatic rabies die, despite supportive care, and only two survivors with “good” neurologic status have been reported in the medical literature over the past four decades [Wilde et al., 2008]. In a highly publicized and therapeutically important case, an unvaccinated teenager treated aggressively with ribavirin, amantadine, and drug-induced coma survived, with moderate neurological sequelae consisting of choreoathetosis, dysarthria, and a gait disorder [Willoughby et al., 2005]. Children with suspected or possible rabies exposures, including anyone with exposure to live or dead bats, should receive postexposure prophylaxis in accordance with CDC and local public health guidelines [CDC, 2009k], taking into account the animal species and the nature of the exposure. All postexposure treatment should begin with immediate and thorough cleansing of the wound with soap and water [Plotkin, 2000]. Bites are more likely to transmit the virus than scratches or other encounters [Fishbein and Robinson, 1993].

Because of the strong epidemiologic relationship between bat rabies strains and human rabies, prophylaxis should be administered after contact with bats, unless testing of the bat proves negative for rabies [CDC, 2009k]. Human-to-human transmission of rabies virus has been reported after corneal and organ transplantation [CDC, 2004e; Houff et al., 1979], but transmission by body fluids has not been described. None the less, persons with suspected rabies should be maintained in strict isolation to minimize contact with rabies virus-contaminated fluids and to reduce the number of health-care workers who require postexposure prophylaxis. An average of 54 persons (family members and health-care workers) per patient have required postexposure prophylaxis after contact with U.S. human rabies cases [Noah et al., 1998].

Clinical features

Cases of AIDS in children first appeared in the early 1980s before the causative agent, HIV-1, was identified [Falloon et al., 1989]. Early cases of childhood AIDS were linked to blood transfusions, hemophilia requiring factor replacement, or having a parent with AIDS or an AIDS-related condition. Subsequently, most HIV-1 infections in infants and children were linked to mothers harboring HIV-1. The offspring of untreated, HIV-1-infected women have a 15–30 percent risk of acquiring the virus, whereas current combination antiretroviral treatment and management strategies in HIV-1-infected mothers and their infants can reduce the risk of perinatal transmission to 2 percent or less [American Academy of Pediatrics, 2009; CDC, 1994b; Connor et al., 1994; Havens and Waters, 2004].

By the late 1980s, AIDS cases had been identified in more than 100 countries or territories, and the total number of AIDS cases worldwide rose nearly exponentially from approximately 12,000 cases in 1984 to more than 100,000 cases by the end of that decade. Although the rates of HIV-1 infection have plateaued or declined since in the United States and other regions, HIV-1 infection remains a major threat to the world’s population [De Cock et al., 2000; UNAIDS, 2002; WHO, 2008]. Currently, more than 90 percent of new HIV-1 infections occur among persons living in Asia and Africa (Figure 81-16), and the number of people living with HIV/AIDS globally remains enormous – approximately 33 million in 2007 [WHO, 2008]. The World Health Organization data indicate that approximately 7500 persons (approximately 1000 of these being children) acquire HIV-1 infection each day, corresponding to approximately 3 million persons with new HIV infections in 2007 [WHO, 2008]. More than 20 million infants, children, and adults have died since the first cases of AIDS were identified in 1981.

Fig. 81-16 AIDS mural on a school building in rural Namibia.

Infants infected with HIV-1 vertically can become symptomatic after the third month of life, manifesting hepatomegaly, lymphadenopathy, failure to thrive, interstitial pneumonitis, opportunistic infections (especially with Pneumocystis jiroveci [formerly, Pneumocystis carinii] or cytomegalovirus), or neurologic disease [Falloon et al., 1989]. The severity and spectrum of the clinical manifestations are modified substantially, however, by antiparasitic, antiviral, and antiretroviral therapies. In some children, HIV-1 infection can remain dormant, and 10 or more years may elapse before the symptoms of HIV-1 infection appear. Before current combination antiretroviral therapies, a child infected vertically with HIV-1 had a 50 percent probability of severe HIV/AIDS-related disease by age 5 years [Barnhart et al., 1996].

Neurologic complications were noted among adults early in the AIDS epidemic, and by the mid-1980s, similar disorders were reported in children [Belman et al., 1985; Epstein et al., 1985]. These early reports emphasized the dramatic, progressive decline in motor and intellectual skills in HIV-1-infected children, sometimes coinciding with the appearance of opportunistic infections with cytomegalovirus, P. jiroveci, Toxoplasma gondii, or other microorganisms. Early studies suggested that HIV-1-associated progressive encephalopathy developed in approximately 50 percent of children with advanced HIV-1 disease, whereas improved antiretroviral therapies have modified substantially the natural history of encephalopathy in HIV-1-infected children [Belman, 2002; Patel et al., 2009]. In utero exposure to HIV-1 without evidence of perinatal infection does not adversely affect early neurologic development [Belman et al., 1996].

Before the availability of effective antiretroviral therapies, infants and children with HIV-1 encephalopathy exhibited progressive motor dysfunction, cognitive abnormalities, developmental delay, and acquired microcephaly [Belman et al., 1985, 1986; Epstein et al., 1985]. Typical neurologic findings, attributable to the direct CNS effects of HIV-1, consist of apathy, dementia, ataxia, hyperreflexia, weakness, seizures, or myoclonus. Current antiretroviral therapies prevent or delay the onset of certain HIV-1-related neurologic complications [Gavin and Yogev, 1999; Belman, 2002; Patel et al., 2009]. HIV-1 invades the CNS early after intrauterine or postnatal infection and displays tropism for microglia/macrophages and astrocytes; microglia and macrophages are the principal reservoirs of HIV-1 infection within the CNS [Epstein and Gendelman, 1993; Epstein and Sharer, 1994]. Certain CNS cell populations, including neurons and oligodendrocytes, contain few or no HIV-1 nucleic acids, indicating that HIV-1 causes dysfunction and apoptosis of such cells through perturbations of proinflammatory cytokines, excitotoxins, and CNS neurotransmitters [Epstein and Sharer, 1994; Mitchell, 2006]. CNS disease, either due directly to HIV-1 or caused indirectly through opportunistic infections, reflects the degree of immunodeficiency [Belman, 2002] and the viral load of infected children.

Additional disorders linked directly to HIV-1 infection of the CNS or peripheral nervous system are aseptic meningitis, meningoencephalitis, myopathy, and Guillain–Barré syndrome-like conditions [Srugo et al., 1992]. HIV/AIDS can lead to numerous secondary CNS complications, including stroke [Park et al., 1990], primary CNS lymphoma, and CNS infections with T. gondii, cytomegalovirus [Griffiths, 2006], varicella zoster virus, Mycobacterium tuberculosis, fungi, and JC virus, the cause of progressive multifocal leukoencephalopathy [Wrzolek et al., 1995]. The last-mentioned condition occurs in approximately 4 percent of adults with AIDS and some children, and causes weakness, visual loss, cognitive decline, gait abnormalities, and sensory disturbances [Berger et al., 1992]. PCR can be used to detect JC virus in clinical samples [McGuire et al., 1995].

Diagnosis

Passive transfer of maternal antibody complicates detection of HIV-1 infection during the first 18 months of life, and 30 percent or more of exposed infants serorevert [American Academy of Pediatrics, 2009; Read, 2007]. Consequently, detection of HIV-1 nucleic acids (DNA or RNA) by the PCR is necessary to diagnose HIV-1 infection in young infants [American Academy of Pediatrics, 2009; Belman, 2002; Bremer et al., 1996; Read, 2007]. HIV-1 infection in exposed infants (i.e., infants with positive antibody tests shortly after birth or infants born to HIV-1-seropositive mothers) can be confirmed by serial serum PCR assays, with the first test in the immediate newborn period, a second test during the first or second month of life, and a third test at 3–6 months of age. If two samples are positive for HIV-1, the infant is considered infected; two successive negative tests indicate that infection is unlikely [American Academy of Pediatrics, 2009; Read, 2007]. In children and adolescents, serologic studies using enzyme-linked immunosorbent assay and Western blotting can identify HIV-1 infection. Reverse transcriptase PCR monitoring of virus loads guides the treatment of HIV-1-infected infants, children, and adolescents [American Academy of Pediatrics, 2009].

The CSF is usually normal in HIV-1-associated progressive encephalopathy, whereas the EEG may exhibit diffuse slowing. Neuroimaging studies reveal cortical atrophy in vertically or horizontally acquired infections (Figure 81-17). Calcifications of the basal ganglia or frontal white matter – best detected by CT – and nonspecific abnormalities of white or gray matter – most evident by MRI – occur in vertically acquired HIV infections [DeCarli et al., 1993; Belman et al., 1986]. CT, MRI, and studies of CSF or blood can identify secondary infectious and neoplastic complications in HIV-1-infected children. Combination antiretroviral therapy has improved the prognosis for many of the opportunistic infections in persons with HIV/AIDS [American Academy of Pediatrics, 2009; Belman, 2002; Clifford et al., 1999].

Fig. 81-17 Unenhanced computed tomography scan of a male with hemophilia and progressive encephalopathy resulting from human immunodeficiency virus infection.

The scan reveals diffuse cortical atrophy.

(From Bale JF. Encephalitis and other virus induced disorders of the nervous system. In: Joynt RJ, Griggs RC, eds. Clinical neurology. New York: Lippincott–Raven, 1996.)

Treatment and outcome

Combination antiretroviral therapy and refined treatments for the infectious or neoplastic complications of AIDS have enhanced the survival of HIV-1-infected persons greatly [American Academy of Pediatrics, 2009; Belman, 2002; Melvin, 1997; van Rossum et al., 2002; Patel et al., 2009]. The mean survival time for treated children with HIV/AIDS exceeds 10 years, which is substantially greater than that of HIV-1 infected children who were treated in the early 1990s; the risk of death has thus declined considerably [Palumbo, 2000; Patel et al., 2009; Pizzo et al., 1988]. Although children comprise a very small proportion of AIDS deaths in the United States, achieving similar outcomes remains challenging in resource-poor countries. Worldwide, a child dies with HIV/AIDS approximately every minute, and of the more than 2 million children living with HIV/AIDS worldwide, only 10 percent were receiving antiretroviral therapy in 2007 [WHO, 2008].

Several infectious disorders, including cytomegalovirus retinitis, cerebral toxoplasmosis, P. jiroveci, herpes zoster, and CNS or systemic fungal infections, respond favorably to current antiviral, antiparasitic, and antifungal therapies [American Academy of Pediarics, 2009]. Intravenous immunoglobulin also benefits selected children with hypogammaglobulinemia or recurrent, serious bacterial infections [Spector et al., 1994]. Certain complications, such as progressive multifocal leukoencephalopathy or primary CNS lymphoma, respond poorly to the available therapies; the prolonged survival of HIV-1-infected patients appears to increase their lifetime risk of developing progressive multifocal leukoencephalopathy or CNS lymphoma.

Current strategies uses combinations of at least three different antiretroviral drugs from the classes of nucleoside/nucleotide reverse transcriptase inhibitors, protease inhibitors, and non-nucleoside reverse transcriptase inhibitors. The goal of the therapeutic strategies is to reduce the HIV-1 viral load to undetectable levels and to restore immune function. Combination therapy produces immunologic and neurocognitive improvement, even in advanced HIV-1 infection [American Academy of Pediatrics, 2009; Department of Health and Human Services, 2008; Essajee et al., 1999; Patel et al., 2009]. Assessments at the start of antiretroviral therapy should include testing for CD4 T-cell count, plasma HIV-1 RNA, complete blood cell count, serum chemistry profile (especially tests of renal and liver function), and opportunistic infections, including T. gondii, hepatitis viruses, and tuberculosis. Frequent measurements of CD4 T-cell counts and HIV-1 RNA load by quantitative reverse transcriptase PCR, as well as routine laboratory studies (complete cell count, urinalysis, and serum chemistry profiles), have essential roles in monitoring HIV-1-infected children while they are undergoing antiretroviral therapy [Department of Health and Human Services, 2008].

The development of drug resistance remains a serious potential threat for HIV-1-infected patients and necessitates testing upon entry into treatment and when response to treatment is suboptimal [Boden et al., 1999; Department of Health and Human Services, 2008; Hirsch et al., 2008]. As many as 15 percent of HIV-1-infected adults display HIV-1 drug resistance prior to antiretroviral therapy [Department of Health and Human Services, 2008]. Therapy-associated immune reconstitution in patients with AIDS can lead to immune restoration disease, a condition characterized by paradoxical exacerbation of secondary infections during the initial 6 months of treatment [French et al., 2004; Stoll and Schmidt, 2003]. Immune restoration disease may occur in 30 percent of AIDS patients with low CD4+ cell counts who begin combination antiretroviral therapy. Children who undergo combination antiretroviral therapy can experience lipodystrophy, insulin resistance, osteopenia, and growth failure [Leonard and McComsey, 2003]. Secondary infectious complications of AIDS, such as cytomegalovirus retinitis, T. gondii encephalitis, and cryptococcal or tuberculous meningitis, require therapy with appropriate antimicrobial agents. Treatment of primary CNS lymphoma in persons with AIDS remains problematic [Belman, 2002].

Because treatment of HIV/AIDS continues to evolve, individuals and centers experienced in HIV/AIDS treatment should be consulted regarding current therapeutic approaches [Kitahata et al., 1996]. For updated, downloadable information regarding the available antiretroviral therapies and current evaluation and treatment guidelines for infants, children, and adolescents, see www.aidsinfo.nih.gov (accessed November 15, 2009). Despite the remarkable success of combined antiretroviral therapy, current drugs do not eradicate HIV-1 from infected persons [Lambotte et al., 2003]. Persons who reach end-stage AIDS, despite therapy, frequently experience AIDS-defining conditions, such as dementia/encephalopathy, progressive multifocal leukoencephalopathy, lymphoma, or invasive cytomegalovirus infections, during the 12 months before death [Welch and Morse, 2002]. Vaccines to prevent HIV/AIDS, although the focus of considerable research, are not yet available.