Human CMV is highly species-specific, and humans are believed to be its only reservoirs1. Seroepidemiologic surveys have found CMV infection in every population that has been tested including remote Indian tribes in the Amazon basin who lacked evidence of past measles or influenza infections2,3. CMV infection is endemic and without seasonal variation. Climate does not affect the prevalence of the infection, and there are no known vectors in the natural transmission cycle. The prevalence of CMV infection increases with age, but according to geographic, ethnic, and socioeconomic factors. The pattern of acquisition of this infection varies widely among populations4. CMV is acquired earlier in life in developing countries and among the lower socioeconomic segments in developed countries. Differences between populations can be particularly striking during childhood, with rates of seropositivity in four to six year old children varying from less than 10 percent in Great Britain and certain populations in the United States, to nearly 100 percent in Africa and the South Pacific4. Presumably, these significant differences are the reflection of factors that account for increased exposure to CMV such as crowding, breastfeeding, sexual practices, and certain child rearing practices. Transmission occurs by direct or indirect person to person contact. Sources of virus include urine, oropharygeal secretions, cervical and vaginal secretions, semen, milk, tears, and blood5,6. CMV is not very contagious; the spread of infection requires close or intimate contact with infected secretions.

Using the decision analysis technique and multivariate regression methods, a statistical model was established to define the utility of brain biopsy for diagnostic evaluation of patients with suspected herpes simplex encephalitis (HSE). Two strategies were compared: strategy I, brain biopsy with acyclovir (ACV) treatment for 10 days in biopsy-positive patients, and strategy II, ACV therapy without brain biopsy. Strategy I resulted in a greater 6-month survival rate when the likelihood of patients having HSE was less than 70%. Based on the current estimated prevalence of HSE (for patients with suspected HSE) of 35%, strategy I showed a slight advantage of a 3.2% increase in 6-month survival rate. An individual patient's chance of a positive brain biopsy can be predicted using a mathematical equation based on several important clinical assessments. This equation in conjunction with the decision analysis is a useful guide for the clinical management of patients with regard to brain biopsy.

A total of 432 patients underwent brain biopsy for presumptive herpes simplex encephalitis. Three patient groups were identified. The first group, 195 patients (45%), had herpes simplex encephalitis confirmed by the isolation of herpes simplex virus from brain tissue at biopsy (193 patients) or autopsy (2 patients). The second group, 95 patients (22%), had diseases that were identified but that were not caused by herpes simplex virus. Three subgroups were recognized: (1) 38 patients (9%) with treatable disease, (2) 40 patients (9%) with nontreatable but diagnosed viral infection, and (3) 17 patients (4%) with identified diseases neither of viral etiology nor treatable. The third group, 142 patients (33%), remained without a diagnosis. Clinical presentation of patients in the second group was similar to that of those with herpes simplex encephalitis and those without a diagnosis. Patients in the subgroup with nontreatable but diagnosed viral infections had the greatest likelihood of returning to normal.

An open study of vidarabine (adenine arabinoside) therapy was performed to verify the mortality from neonatal herpes simplex virus infection and to define further long-term morbidity. A total of 39 babies not previously reported were treated with either 15 mg/kg/d (16 newborns) or 30 mg/kg/d (23 newborns) of vidarabine administered intravenously for ten to 14 days. Outcome was compared with that from 56 newborns evaluated in a prior trial. Irrespective of the dose of medication, therapy decreased the mortality in babies with disseminated and CNS disease to 40%. The extent of organ involvement and, in particular, pulmonary herpes simplex infection were predictive of mortality (P = .001, for both). For these babies, 32% achieved normal developmental milestones 2 years after therapy. Disease localized to the skin, eye, and/or mouth was not associated with death. However, neurologic impairment occurred in 12% of this treated group of newborns. These findings underscore the value of vidarabine therapy of neonatal herpes simplex virus infection. However, an increase in dosage did not appear to result in significant improvement in either mortality or morbidity. Further improvement in the mode of therapy and the utilization of more potent antiviral drugs are currently being tested.

Stagno, Sergio MD; Pass, Robert F. MD; Dworsky, Meyer E. MD; Alford, Charles A. Jr., MD Author Information

Continuing evaluations of antiviral agents for treatment of herpes simplex encephalitis (HSE) provided an opportunity to collect clinical data from 113 patients in whom the diagnosis was proved by viral isolation. Occurrence of HSE was in all ages and in both sexes and was nonseasonal. Characteristically, patients had behavioral changes, fever, confusion, speech disturbances, and, less frequently, seizures. The EEG was the most useful neurodiagnostic aid followed by technetium and computed axial tomographic scans. Employing a logistic regression model for variable selection, the diagnosis could be predicted by clinical findings and neurodiagnostic tests in 83% of the proved cases, but the evidence in 25% was falsely positive. There was evidence of localization by either clinical or neurodiagnostic assessment in all patients with proved disease. Among patients with negative findings for HSE, similar focal findings predominated in all but a few. The CSF and brain scans were normal in many patients with proved HSE. This extensive clinical experience in patients with diagnosis proved by viral isolation shows that diagnosis can be confirmed only by brain biopsy. (JAMA1982;247:317-320)

To learn more about the treatment of herpes simplex encephalitis with vidarabine, we conducted an uncontrolled study of 132 patients referred to 22 hospitals because of suspected disease. All had a brain biopsy and were started on vidarabine, but only 75 were diagnosed by isolation of virus from a brain-biopsy specimen. Cumulative mortality in the latter group was 39 per cent at one year. Other than therapy, levels of consciousness and age were the major variables that influenced outcome. Of 23 patients under 30 years of age who were lethargic at the initiation of therapy, two died and 16 returned to normal. Of 26 patients over 30 years of age who were lethargic at the outset, nine died and 10 returned to normal. Semicoma and coma were associated with worse outcomes, especially in older patients. Our data suggest that outcome is improved with treatment; they provide more support for the use of brain biopsy to diagnose the infection and indicate a need for better therapy.

Epidemiological data presented here indicate that cytomegaloviral (CMV) infection is one of the most common perinatal infections found in human beings. Transmission to the offspring occurs in utero at birth and postnatally. Intrauterine infection results from primary or recurrent maternal involvement, the latter being more common in populations where infection is initially acquired during childhood or adolescence, such as in low socioeconomic settings. Congenital infection is usually subclinical with either type of maternal involvement but primary infection has a greater tendency to produce disease in the fetus. About 20% of the offspring infected in utero are damaged, infrequently with generalized disease, but more often with auditory involvement. The latter can develop in utero or postnatally and can be progressive. The major cause of recurrent maternal infection according to restriction enzyme analysis is reactivation of latent virus, which occurs in the face of substantial maternal humoral immunity, even with intrauterine transmission of virus. Reinfection by exogenous virus remains a lesser possibility for maternal recurrences. Even more commonly, CMV can be transmitted at birth from the infected maternal genital tract and postnatally through infected breast milk, especially in highly immune populations. With the possible exception of early pneumonia, these infections appear to be innocuous.

The kinetics of the response to passively transferred maternal neutralizing antibody were studied for determination of whether this antibody offered protection against primary cytomegalovirus (CMV) infection in the offspring. Antibody response was determined in 17 infants infected in the immediate perinatal period and in 18 appropriate control subjects. Levels of neutralizing antibody in serum obtained at birth and at one month of age were similar in infected and in exposed, uninfected neonates. In addition, the quantity of neutralizing antibody did not influence the time of onset of viruria. Clearly, passive humoral immunity failed to prevent naturally acquired primary CMV infection in a significant number of young infants exposed to virus during and shortly after delivery.

Pretreatment (12-48 h) of human fibroblasts with crude, human chorionic gonadotropin (HCG) was found to suppress cytomegalovirus infection and enhance productive herpes simplex type 1 (HSV) infection in vitro. Maximal effect on virus replication occurred at the time of maximal infectivity of control cultures (48 h and 6 days after viral innoculation for HSV and cytomegalovirus, respectively). The alteration in viral growth was not due to the HCG itself, but rather to epidermal growth factor, a contaminant of crude HCG. The effect of epidermal growth factor on viral infectivity was shown to be a cell-mediated event requiring protein synthesis.

C-CMV is exceedingly common in our low socioeconomic population (2.3% of all live births). Over 90% of the cases however, are asymptomatic at birth. Nevertheless, the chronic nature of this infection may lead in time to low grade morbidity in particular SNHL. To define the incidence and significance of this process, the hearing acuity of 59 patients (mean age 54 months, range 2-102) born with C-CMV and of 41 uninfected controls (mean age 46 months, range 7-124) was tested by pure tone audiometry in a sound field (<2 years of age) and/or under earphones. Significant SNHL (50 decibel or over) occurred in 10 infected patients (17%) and had a progressive course in 2 of them. In contrast only 1 uninfected subject had SNHL of borderline significance at 12 months of age. To better define the CMV-SNHL etiologic relationship we performed histopathologic studies of the inner ear of 3 patients who died with symptomatic C-CMV. Typical inclusion bodies were found in the stria vascularls and the Reissner's membranes. By means of an anticomplementary immunofluorescent assay, CMV antigens were in addition detected in the cells of the organ of Corti and the neurones of the spiral ganglia. These findings clearly suggest that CMV has the potential to infect cells of the most vital structures of the inner ear and thus give further credence to the pathogenic role of this virus in SNHL.