Histoplasmosis of the nervous system
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This article includes discussion of neonatal herpes encephalitis, disseminated herpes infection with encephalitis, localized CNS neonatal herpes infections, and congenital herpes encephalitis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Herpes simplex virus encephalitis is a catastrophic disease of newborns. Without specific therapy, 40% to 50% of neonates with this infection will die, and survivors have a high rate of neurologic sequelae. Herpes simplex virus cultures and polymerase chain reaction can reliably demonstrate herpes simplex virus infection in many neonates with herpes simplex encephalitis. However, antiviral treatment should be started immediately in all cases of suspected neonatal herpes simplex virus encephalitis because delay of treatment can substantially worsen outcome. In this update, the authors present a vignette of herpes simplex encephalitis with typical symptoms, radiographic findings, laboratory results, and outcome. In addition, the authors discuss effective measures to prevent, diagnose, and treat this devastating infection.
• In most cases of neonatal herpes encephalitis, the infection is acquired during the birthing process.
• The application of polymerase chain reaction to CSF samples has revolutionized the diagnosis of central nervous system disease in neonates, as this method allows rapid and reliable detection of the viral infection.
• Prompt institution of antiviral therapy is critical to minimize mortality and morbidity.
• As CNS disease has significant morbidity, strategies to prevent vertical transmission are of fundamental importance.
• Oral acyclovir suppression following acute treatment of neonatal herpes encephalitis improves neurodevelopmental outcome at 1 year.
"Herpes," from the Greek meaning "creeping or crawling," has been used historically as a descriptor for a variety of febrile illnesses associated with vesicular exanthems or enanthems. Many of these infectious illnesses, such as herpangina, are recognized today, however, as being caused by infective agents other than the herpes viruses. More than 50 viruses are classified in the family of herpesviruses, but the most important with regard to human illness are herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8). Although all of these viruses can cause intrauterine and neonatal CNS infections, herpes simplex virus is the most common cause of acute, life-threatening neonatal encephalitis.
The clinical manifestations of herpes simplex virus infections in older children and adults have been known for centuries. However, it was not until the 1930s that clinical reports began to appear that distinguished neonatal herpes infection as a distinct clinical entity (19; 51).
In the early and mid-1960s, viral culture and immunologic techniques were developed that made it possible to distinguish herpes simplex virus-1 from herpes simplex virus-2 (36). Using these laboratory techniques, investigators have defined more clearly the epidemiology and pathogenesis of infections with these 2 types of herpes simplex virus (37; 38; 39). Herpes simplex virus-1 infects primarily the mouth, lips, eyes, and skin of the upper body and is the major cause of herpes encephalitis seen after the neonatal period. Herpes simplex virus-2 infects primarily the genital tract and skin of the lower body and causes most of cases of neonatal herpes simplex virus encephalitis. With further advances in virology and immunology during the 1970s and 1980s, knowledge regarding herpes simplex virus transmission, replication, latency, and reactivation expanded markedly. Based on the better understanding of the epidemiology, pathogenesis, and biology of herpes simplex virus infections that has been achieved during the past 15 to 20 years, major advances have occurred in prevention of neonatal herpes simplex virus infection and in the development of effective, safe, and specific anti-herpes simplex virus drugs.
The clinical illnesses caused by herpes simplex virus in neonates can be classified into 4 principal categories: (1) intrauterine, congenital infection, (2) natally or postnatally acquired localized eye, mouth, and skin infection, (3) natally or postnatally acquired disseminated infection, and (4) natally or postnatally acquired localized CNS infection (56).
Intrauterine congenital infections, which can be due to herpes simplex virus-1 or herpes simplex virus-2, result from transplacental transmission of virus from mother to fetus, possibly by infected leukocytes, during the third trimester. Only a small portion of neonatal herpes infections are acquired transplacentally. The great majority are acquired natally or postnatally. Once within the fetal circulation, the virus may become widely disseminated and infect multiple organs. The virus has strong affinity for neural tissue and can cause large regions of cystic necrosis, cavitation, and calcifications. Intrauterine herpes simplex virus infections often impair fetal head growth and general somatic growth; produce cataracts, retinal scars, and blindness; and cause hepatosplenomegaly (45; 15; 34). Symptoms and signs of intrauterine herpes infection are present at birth. If active infection of the infant is still present at the time of delivery, progression of CNS symptoms may occur in association with multiorgan, systemic disease. When the virus is transmitted to the fetus in utero several hours or days before delivery, presumably through tears in the amniotic membranes, signs of illness appear 24 to 48 hours after delivery. Disseminated infection or encephalitis develops and progresses.
When the infant is exposed to virus during delivery (most often HSV-2), the onset of clinical manifestations of infection is delayed for 1 to 3 weeks. These infections can be localized, disseminated, or localized to the CNS. Approximately 30% of natally or postnatally infected neonates develop localized vesicular skin or mouth lesions or conjunctivitis. If left untreated, 70% of these localized infections will become disseminated.
Disseminated herpes simplex virus infection accounts for approximately 40% of natally or postnatally acquired herpes simplex virus encephalitis and is characterized by generalized systemic signs and symptoms that begin 9 to 11 days after delivery. Ninety percent of patients have skin, eye, or mouth lesions. Primary target organs include the liver, skin, and adrenal gland. The CNS is involved in 50%. Early symptoms include fever, temperature instability, lethargy, decreased feeding, vomiting, respiratory distress, pneumonitis, and jaundice. Disseminated coagulopathy and shock may develop. CNS symptoms include tense fontanelle, seizures, posturing, and coma. Without early antiviral and supportive therapy, the mortality is 70% to 80%.
Localized CNS infection accounts for 30% of cases of neonatal herpes simplex virus-2 infections. Onset of neurologic disease typically occurs 11 to 17 days after delivery. Fever, temperature instability, and tense fontanelle may be noted as initial features followed by the rapid appearance of seizures, posturing, and coma. If no skin lesions are present, there is nothing specific about the neurologic presentation of herpes simplex virus encephalitis that allows it to be distinguished immediately from other catastrophic neonatal neurologic infections and diseases. Without specific antiviral and supportive therapy, 40% to 50% of infected neonates die. Survivors experience a high rate of neurologic sequelae including developmental delay, epilepsy, impaired growth, retinopathy, and cystic encephalomalacia.
Without antiviral therapy, the mortality for neonatal herpes simplex virus infections is high. For disseminated infections the mortality is 70% to 80%, for encephalitis, 40% to 50%, and for localized skin, mouth, and eye infections, 10%. However, it is important to emphasize that, if localized infections are not treated, more than 50% will disseminate, with subsequently high mortality. Specific antiviral therapy markedly reduces mortality in all clinical forms of infection. For disseminated and CNS disease, antiviral treatment reduces mortality to about one half to one third the rate that occurs when no therapy is given. Mortality almost never occurs when localized infections are treated with anti-herpes simplex virus therapy.
Although the rate of sequelae is reduced by antiviral therapy, it remains high in cases of disseminated infection and encephalitis. Even with vigorous, early antiviral therapy, permanent neurologic sequelae occur in up to 70% of survivors (25). The sequelae and complications of neonatal herpes infections lead to frequent emergency department visits and hospital readmissions. A study found that the median cost of neonatal herpes infection was in excess of $87,000 per case for the first 6 months (30).
Complications encountered during acute infection include fluid and electrolyte disturbances, disseminated intravascular coagulopathy, pneumonitis, respiratory distress, hepatitis, adrenal necrosis, seizures, and coma. Chronic sequelae include cognitive impairment, cystic brain destruction with secondary blindness and deafness, seizures, spastic quadriparesis, microcephaly, chorioretinopathy, microphthalmia, and impaired somatic growth.
Acyclovir is most commonly used to treat neonatal herpes simplex virus infection. A common complication of high-dose acyclovir treatment is neutropenia. Twenty percent of infants treated with high-dose acyclovir will develop this complication. However, the neutropenia resolves spontaneously in most cases, even without cessation of the medication, and clinically significant adverse outcomes from this neutropenia are rare (26; 18). A second major complication of acyclovir treatment in neonates is nephrotoxicity, which occurs in 17% to 35% of patients. The nephrotoxicity may be due to tubular obstruction secondary to drug crystallization or to a direct tubular toxicity from acyclovir metabolites. Risk of acyclovir-induced nephrotoxicity in neonates can be minimized by keeping patients well-hydrated and by diligently monitoring kidney function throughout treatment (17).
Persistence of herpes simplex virus DNA by PCR in CSF after a standard course of high-dose acyclovir therapy for herpes simplex virus encephalitis may predict worse outcome (32). Recurrence of herpes simplex virus encephalitis in infants treated with acyclovir in the neonatal period has been reported (31). In some cases, the persistence of herpes PCR positivity in CSF following a 21-day course of acyclovir is due to an acyclovir-resistant herpes simplex virus strain. Acyclovir-resistant herpes strains are most commonly seen in immunocompromised patients who have been receiving acyclovir over a prolonged period. However, acyclovir-resistant herpes has been reported in neonates as well (20). Acyclovir-resistant herpes may be treated with an alternative antiviral agent, such as ganciclovir or foscarnet. However, the safety and efficacy of these agents for neonates is not fully known (50).
Following herpes simplex virus encephalitis, some patients develop a secondary encephalitis that is noninfectious and is autoimmune in its etiology. This occurs in 27% of patients with herpes simplex encephalitis and is associated with development of antineuronal antibodies. It usually presents within 2 months of the herpes encephalitis (01). Anti-NMDA receptor encephalitis is the most common among these. These autoimmune encephalitides, whose symptoms include psychosis, movement disorders, seizures, autonomic instability, and coma, do not respond to antiviral medications. Instead, they respond to anti-inflammatory measures, including steroids, IVIG, and plasma exchange. Although most cases of postherpes autoimmune encephalitis have been described in juveniles and adults, cases have also occurred in neonates (10). Thus, in neonates with continued signs of encephalitis or relapse of encephalitis following an adequate course of acyclovir, autoimmune encephalitis should be suspected. Suspicion should be especially high in those patients in whom the follow-up PCR for herpes is negative (43).
The patient was a 17-day-old boy who had been in his usual state of good health until the day prior to admission, when he seemed more sleepy than usual. He was seen in the pediatrician’s office, where he was sleepy but arousable and willing to feed. He was afebrile, had a normal CBC, and was sent home with instructions for the parents to call if he developed a fever or any other signs of infection.
On the day of admission, he was lethargic and had a fever to 100.2° F. He returned to his pediatrician’s office, where he had a seizure, consisting of clonic movements of the right upper extremity.
He was transported by ambulance to the emergency room, where he continued to have right-sided clonic seizures, which were stopped with intravenous lorazepam.
On examination, he was febrile with a temperature of 101.2° F. Other vital signs were normal with blood pressure 100/53, heart rate 136, and respiratory rate 26. He had no respiratory distress. His head was normocephalic and atraumatic. The anterior fontanelle was soft and flat. His heart had a regular rate and rhythm with no murmur. His abdomen was soft and flat. His skin was notable for eczema on the arms and face but otherwise had no rash or lesions. On neurologic examination, he was lethargic but would arouse to tactile stimulation. His movements were asymmetric, as he moved his left arm and leg to a greater extent than the right. His deep tendon reflexes were more pronounced in the right extremities than in the left. He had a positive Babinski sign on the right and negative on the left.
Laboratory studies included a basic metabolic panel, complete blood count, and liver enzyme levels, all of which were normal. CSF examination showed 200 white blood cells per microliter (35% neutrophils, 65% lymphocytes), 17 red blood cells per microliter, protein 74 mg/dL, and glucose 35 mg/dL (peripheral blood glucose was 110 mg/dL).
Head CT scan and chest x-ray on the day of admission were normal. However, MRI scan of the brain on the third hospital day was markedly abnormal, as it revealed (1) multiple foci of pial enhancement, (2) increased signal in the T2 and FLAIR sequences in the gyri deep to the regions of pial enhancement, (3) decreased signal in those same regions in the T1 sequences, and (4) multiple foci of diffusion restriction, especially in the left temporal lobe and left parietal lobe.
While still in the emergency department, the infant developed recurrent focal seizures involving the right upper and lower extremities. The seizures were stopped with several doses of lorazepam and a loading dose (20 mg/kg) of phenobarbital. Shortly thereafter, he developed respiratory failure and required intubation.
Diagnosed with meningitis or encephalitis, he was admitted to the Pediatric Intensive Care Unit, where he was treated empirically with antibiotics (ceftriaxone and vancomycin) and acyclovir. PCR for herpes simplex virus-2 was positive in CSF and blood. CSF and blood cultures were otherwise negative. He was treated with intravenous acyclovir at a dose of 60 mg/kg/day, divided into 3 times per day dosing, for 21 days. A repeat lumbar puncture on hospital day 18 revealed normal CSF components, and PCR for HSV-2 was negative.
His hospital course was complicated by recurrent focal and generalized seizures. Continuous EEG early in the hospitalization revealed frequent subclinical seizures from the left hemisphere. Some of these were associated with desaturation spells. Control of these seizures was eventually gained on the combination of phenobarbital and levetiracetam.
He remained lethargic during the first week of the hospitalization but gradually became more awake and alert. By the time of discharge on hospital day 22, he had regained a full level of consciousness and had no evident neurologic deficits. He was discharged on levetiracetam and a 6-month course of oral acyclovir.
His post-hospitalization course has been marked by recurrent seizures and global developmental delay. The seizures are focal in onset and consist of right-sided clonic activity of the upper extremity. The seizures, which sometimes secondarily generalize, are moderately well controlled on levetiracetam.
A follow-up MRI scan, obtained at age 8 months, revealed large areas of encephalomalacia in the left hemisphere, corresponding to the regions of abnormal signal on the original MRI scan during the acute phase of the illness.
At a follow-up appointment, at the age of 18 months, he was moderately, but globally, developmentally delayed. He had learned to acquire a seated position and was beginning to crawl. He babbled, but uttered no intelligible words.
At the latest follow-up appointment at age 5 years, he remained globally developmentally delayed. He understood some language and could follow simple commands but he spoke only single words. He had right-sided hemiparesis involving the upper and lower extremities. He could walk but not run. He continued to have epilepsy that was reasonably well controlled on levetiracetam but still suffered from occasional break-through seizures.
Herpes simplex virus-1 and herpes simplex virus-2 are antigenically distinct strains of herpes simplex virus. All herpesviruses are enveloped, double-stranded DNA viruses that replicate within host cell nuclei. In the mid-1960s, laboratory techniques to distinguish herpes simplex virus-1 from herpes simplex virus-2 were developed (36). Results of studies using these techniques showed that 75% of neonatal encephalitis is caused by herpes simplex virus-2 and the remainder by herpes simplex virus-1. Neonatal herpes simplex virus-2 encephalitis is usually a more severe disease than neonatal herpes simplex virus-1 encephalitis, with higher mortality and sequelae rates (08).
Herpes simplex virus infection acquired in utero represents only about 4% of all neonatal herpes simplex virus infections. Virus may be transmitted transplacentally, possibly by infected maternal leukocytes, or through tears in the amniotic membrane to the fetus.
In 86% of cases, infants acquire the virus during delivery from exposure to an infected, maternal genital tract. Approximately 10% of cases occur as a result of postnatal exposure. In most instances virus is probably aspirated into the infant's lung, although scalp and skin lesions provide alternative portals of entry. Initial local replication and uptake of the virus by susceptible leukocytes is followed by cell-associated viremia with secondary infection of and replication within primary target organs such as liver, adrenal gland, skin, mucous membranes, conjunctiva, and brain.
Once herpes simplex virus reaches susceptible target organs, the virus attaches to cell surfaces by specific receptor site binding. The virus is then taken inside the cell where it is uncoated and becomes inserted into host cell nuclear DNA. Once viral replication begins, normal host cell protein and DNA synthesis are markedly impaired, and cell death ensues.
In disseminated infections, the virus spreads to CNS mostly hematogenously. In contrast, in cases of localized CNS infections, the virus reaches the CNS principally through retrograde axonal transport of virus from peripheral sites.
Hemorrhagic necrosis, intranuclear eosinophilic inclusions, giant cell formation, and lymphocytic infiltrates are characteristic histopathologic features of herpes simplex virus-infected tissue.
Because herpes is a prevalent pathogen, many pregnant women have been exposed to both herpes simplex virus-1 and herpes simplex virus-2 prior to pregnancy. One study demonstrated that among pregnant women, herpes simplex virus-1 seroprevalence was 59.3% whereas herpes simplex virus-2 seroprevalence was 21.1%. Among pregnant women who have had 3 sex partners or fewer (which is approximately 40% of all pregnant women), seronegativity for both herpes simplex virus-1 and herpes simplex virus-2 is approximately 51%. Because primary infection during pregnancy confers the greatest risk of transmitting herpes simplex virus to the neonates, it is the offspring of these seronegative women who are most vulnerable to a serious neonatal herpes infection (41).
Estimates of the incidence of neonatal herpes simplex virus encephalitis in the United States range from 0.1 to 0.3 per 1000 live births per year (47; 40; 14). Approximately 350 to 1100 cases are reported annually. Over the course of the past decade, the incidence of neonatal herpes infections has risen. This rise is thought to be due to changes in the epidemiology of herpes simplex virus-1 infection and sexual practices. More adolescents are susceptible to herpes simplex virus-1 infection. Furthermore, oral sex practices among adolescents and young adults have increased, which increases the risk of herpes simplex virus-1 genital infection (30).
Neonatal infections are more likely to occur when the maternal genital infection is primary. The risk of neonatal infection is about 50% if the maternal genital lesions are primary, but only 4% to 5% if the lesions are recurrent. Recurrent lesions are more likely to be associated with the presence of maternal antibody, which may play a role in limiting viral exposure to the fetus. In addition, anti-herpes simplex virus maternal IgG passively acquired by the fetus from mothers with recurrent herpes may provide partial protection against infection. If asymptomatic shedding occurs during primary infection the risk of neonatal infection is about 30%, but if shedding occurs during recurrent infection the risk drops to 0 to 3% (42). It is important to emphasize that more than 60% of herpes simplex virus-infected neonates acquired their infection from asymptomatically infected mothers.
Prematurity also plays a role in the susceptibility to infection (51). Approximately 40% to 50% of reported neonatal herpes simplex virus infections occur in premature infants, whereas only about 6% to 7% of infants are born prematurely. This increased risk imposed by prematurity may result in part from associated events that enhance viral entry such as premature rupture of membranes, placental abnormalities that allow transmission of virus to fetus more easily, trauma to the infant, and invasive mechanical manipulations of the infant (eg, intubation).
Identifying women with active herpes lesions or herpes shedding and limiting exposure of the infant to infected secretions during delivery is the principal preventive strategy. The American College of Obstetricians and Gynecologists recommends institution of acyclovir prophylaxis in women at 36 weeks’ gestation who have active recurrent genital herpes to decrease the risk of vertical transmission. In addition, the American Academy of Pediatrics has published guidelines for management of asymptomatic infants born to women with active genital HSV lesions (23). Unfortunately, because more than 50% of infected infants are born to asymptomatic women with no observable lesions, this strategy has obvious limitations.
For women with active herpetic lesions in the genital region, cesarean-section markedly reduces the risk of neonatal herpes infection (04); however, disseminated HSV can occur in infants delivered by caesarian section even in the absence of prolonged rupture of membranes (28). Many experts believe that if maternal herpes infection occurred in the first trimester, vaginal birth can proceed safely, even in the presence of active lesions (29).
Factors associated with increased risk for the neonate developing herpes simplex virus infection include prematurity, premature rupture of membranes, vaginal delivery, and intubations and other invasive procedures. Maternal risk factors include active genital herpetic lesions, active shedding of virus, primary herpes simplex virus infection, history of genital herpes lesions, history of other sexually transmitted diseases, sexual partner with genital herpes, multiple sexual partners, and maternal age less than 21 years (05).
Prophylactic antiviral therapy is recommended for infants at high risk such as premature neonates, even if asymptomatic, born to mothers shedding virus as a primary infection. If mothers have recurrent lesions or are shedding virus during reactivation, specimens from infants are tested for herpes by culture, polymerase chain reaction, or direct immunofluorescence assays, and the infants are observed for any evidence of clinical disease. If the testing results are positive or if clinical signs develop, antiviral therapy is begun.
The symptoms and signs associated with neonatal herpes simplex virus encephalitis are nonspecific and similar to those produced by other neonatal infections, systemic illnesses, and CNS diseases. Bacterial sepsis and meningitis, most frequently from group B streptococci, staphylococci, and gram-negative bacteria, are the main conditions requiring differentiation because they require a specific alternative form of therapy.
Neonatal enteroviral infections are similar to herpes simplex virus infections in that they are severe and life threatening. Viral cultures and serologic testing are required to make the correct diagnosis. Occasionally, herpes simplex virus must be differentiated from congenital or neonatal cytomegalovirus, lymphocytic choriomeningitis virus, and rubella infections. Noninfectious conditions such as hyaline membrane disease, intraventricular hemorrhage, and hypoxic-ischemic encephalopathy should also be considered.
Before laboratory test results are available, the most helpful information for suspecting herpes simplex virus encephalitis is the mother's history of genital herpes lesions and the presence of vesicular skin, eye, or mouth lesions on the infant.
The possibility of herpes simplex virus infection needs to be considered in any neonate with a sepsis-like presentation.
Results of general laboratory tests of blood and urine may be abnormal, but these results are nondiagnostic. Elevated peripheral white blood cell counts, elevated sedimentation rates, hypernatremia and hyponatremia, hypoglycemia, increased serum concentrations of hepatocellular enzymes, and abnormal coagulation test results all attest to the multisystemic nature of the infection and its complications.
CSF obtained from neonates with CNS herpes simplex virus infection contains dozens to hundreds of white cells, both polymorphonuclear leukocytes and lymphocytes, and often hundreds to thousands of red cells. The concentration of protein in CSF may exceed 500 mg/dl, and the glucose concentration may be markedly depressed. Virus can occasionally be cultured from CSF (46; 51).
Cranial computerized axial tomographic and magnetic resonance scans demonstrate patchy, multifocal areas consistent with necrosis, edema, or both, and these areas often appear hemorrhagic during acute illness (09; 12). Later, widespread cystic encephalomalacia may be seen (07; 11).
In children beyond the neonatal age and in adults, neuroimaging in herpes simplex encephalitis typically reveals lesions in the inferior frontal and mesial temporal cortex. This characteristic distribution often aids in the diagnosis. In contrast, for neonates with herpes simplex encephalitis, the distribution of brain lesions varies and can involve the cortex, thalamus, basal ganglia, white matter, cerebellum, and brainstem. This varied and nonspecific distribution of lesions can further delay the diagnosis in neonates. However, a study suggests that the distribution of lesions may not be as varied as previously assumed. In particular, lesions in neonatal herpes encephalitis most commonly involved 3 regions: (1) the inferior frontal and polar temporal area, (2) borderzone regions between the anterior, middle, and posterior cerebral arteries, and (3) the corticospinal tract area. Whether these patterns of involvement can aid in diagnosis or have different clinical outcomes remains unknown (21).
EEGs are almost always abnormal in neonates with herpes simplex virus encephalitis (33). Rhythmic, periodic slowing and multifocal periodic sharp-wave activity are highly characteristic of herpes simplex virus. However, these patterns are not pathognomonic and may be seen with other CNS infections and severe noninfectious encephalopathies.
Serologic tests are of little help diagnostically. Most serologic tests cannot differentiate between herpes simplex virus-1 and herpes simplex virus-2, cannot distinguish maternal from infant antibody, and require up to 2 weeks to confirm infection. Rapid serologic tests that detect IgM-specific anti-herpes simplex virus antibodies may help with early decisions regarding therapy of asymptomatic, high-risk neonates, but they do not eliminate the need to confirm infection (Wang and Huang 1993).
The laboratory diagnosis of neonatal herpes infection can be established in any of 3 ways: (1) virologically by isolating the virus in traditional viral culture; (2) molecularly by detecting viral DNA using polymerase chain reaction assays; or (3) immunologically by detecting viral antigens using rapid direct immunofluorescence assays (02). For infants at risk for herpes simplex virus infection, cultures should be obtained from swabs of oropharynx and conjunctiva, fluid from skin vesicles, CSF, blood buffy coat, and urine (51). Viral culture from CSF has a poor yield, likely due to neutralization by anti-HSV IgG antibodies (13). Brain biopsies are rarely required to diagnose neonatal herpes simplex virus encephalitis, but the virus can be recovered from fresh brain tissue obtained by biopsy or from autopsy.
Any visible lesion should be scraped and the cells obtained stained for inclusion bodies. Unfortunately, histologic and immunocytochemical stains have a false-negative rate of about 30% and, therefore, cannot be relied on exclusively for confirmation of infection.
For patients with suspected CNS infection with herpes, molecular technique (polymerase chain reaction) to detect the viral nucleic acids within CSF has become the diagnostic test of choice. Polymerase chain reaction of CSF samples for herpes simplex virus 1 and 2 is a reliable test with a high sensitivity and specificity (02). In addition, the polymerase chain reaction technique can be performed rapidly – within 1 to 2 hours – as compared to viral culture and antigen detection tests, which take longer and may take days (35). There are some important limitations to the use and interpretation of polymerase chain reaction for herpes, however. Most importantly, although the polymerase chain reaction test is quite sensitive, a negative result does not exclude neonatal herpes. This may be due to sole localization of virus within brain parenchyma or to early sample collection time in the course of the disease, before virus reaches lumbar CSF. For this reason, if there is a high suspicion of CNS herpes, then collection of multiple CSF samples is necessary (35).
The possibility of herpes simplex virus infection must be considered in any neonate with signs or symptoms of sepsis. Specific anti-herpes simplex virus drug therapy instituted as early as possible is essential to prevent death and to minimize sequelae. The first drug proven to be effective for neonatal herpes simplex virus infections was vidarabine (adenine arabinoside [ARA-A]) (06; 55; 52). Vidarabine is given at a dose of 15 mg/kg per day as a 12-hour intravenous infusion.
Subsequent studies have shown acyclovir to be equally effective at lowering mortality and improving outcome of survivors (54; 03). Acyclovir is now the drug of choice for herpes simplex virus encephalitis because it is more convenient to administer and more soluble in intravenous fluids and requires smaller volumes of fluid to administer than vidarabine. Acyclovir should be started empirically in infants with suspected infection as delayed treatment of neonates with herpes virus infection is associated with increased risk of death (44). Acyclovir is given intravenously at a dose of 20 mg/kg every 8 hours (60 mg/kg per day), and treatment is continued for at least 21 days for neonatal herpes simplex virus encephalitis and disseminated herpes simplex virus disease (24). Patients’ white blood cell counts should be monitored throughout treatment as acyclovir can cause significant neutropenia. Repeat CSF polymerase chain reaction for herpes simplex virus should be performed at the end of treatment, and antiviral therapy should be continued if still positive (22). Evaluating CSF for signs of inflammation at 1 to 2 and 4 to 6 weeks post-treatment has also been recommended as a method to detect subclinical recurrence of herpes simplex virus encephalitis (16).
Trifluridine ophthalmic ointment is used to treat herpes simplex keratoconjunctivitis with vidarabine ophthalmic ointment as an alternative treatment (53).
Because many patients have multiorgan systemic illness, aggressive supportive treatment of shock, coagulation disorders, and respiratory distress is of paramount importance. Secondary bacterial infections require parenteral antibiotic therapy. Antiepileptic medication for acute seizures, as well as postencephalitic epilepsy, may be required.
Following completion of high-dose intravenous acyclovir, infants should receive oral acyclovir (300 mg/meter square per dose) 3 times daily for 6 months. The dose should be adjusted each month to account for growth. This “suppressive” acyclovir therapy has been shown to improve neurodevelopmental outcome and reduce cutaneous recurrences (48; 26).
Infected infants should be isolated from other infants in the nursery, and caregivers must observe strict handwashing precautions to prevent spread of herpes simplex virus to other susceptible infants.
Women who acquire primary herpes simplex virus infections during the third trimester of pregnancy are at highest risk of transmitting herpes simplex virus to their infants. Although most maternal herpes simplex virus infections that cause neonatal infections are genital, mothers with primary herpes simplex virus skin, mouth, eye, or visceral infections can also transmit the virus to their infant. Neonatal encephalitis is most frequently caused by herpes simplex virus-2, but herpes simplex virus-1 can also be transmitted from mothers to neonates, especially during primary infections. When women develop herpes simplex virus encephalitis during pregnancy, the outcome is usually fatal for both mother and fetus, but favorable outcomes for both mother and fetus have been reported (27).
Christina M Marra MD
Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.See Profile
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