Herpes simplex virus

CNS infections caused by human herpesvirus 1 and human herpesvirus 2-herpes simplex virus type 1 and herpes simplex virus type 2--are reviewed. The major diseases associated with these viruses are meningitis and encephalitis. Two forms of encephalitis are known, neonatal encephalitis and encephalitis occurring after the neonatal period. Both diseases are associated with high mortality and morbidity and require prompt diagnosis and aggressive antiviral chemotherapy. Methods for the specific diagnosis of these infections are reviewed and the value of intrathecal antibody assay and nucleic acid amplification techniques are emphasised.     

In vitro activation of human herpesviruses 6 and 7 from latency

Human herpesviruses 6 and 7 (HHV-6 and HHV-7) are prevalent lymphotropic viruses that infect more than 80% of children at infancy or during early childhood. Infection ranges from asymptomatic to severe disease. HHV-6B causes exanthem subitum. The virus can be recovered from peripheral blood mononuclear cells during the acute phase of exanthem subitum, but the host remains latently infected throughout life. In immunocompromised patients undergoing kidney, liver, or bone marrow transplantation latent HHV-6B is reactivated, at times causing severe or fatal disease. Here, we describe the establishment of an in vitro system for reactivation of HHV-6B and HHV-7 from latency. HHV-7 is reactivated from latently infected peripheral blood mononuclear cells by T-cell activation. HHV-6B could not be reactivated under similar conditions; however, the latent HHV-6B could be recovered after the cells were infected with HHV-7. Once reactivated, the HHV-6B genomes became prominent and the HHV-7 disappeared. We conclude that HHV-7 can provide a transacting function(s) mediating HHV-6 reactivating from latency. Understanding the activation process is critical for the development of treatments to control the activation of latent viruses so as to avoid these sometimes life threatening infections in transplant recipients.     

Restriction endonuclease mapping and molecular cloning of the human herpesvirus 6 variant B strain Z29 genome

Human herpesvirus 6(HHV-6) variants A and B differ in cell tropism, reactivity with monoclonal antibodies, restriction endonuclease profiles, and epidemiology. Nonetheless, comparative nucleotide and amino acid sequences from several genes indicate that the viruses are very highly conserved genetically, The B variant is the major etiologic agent of exanthem subitum and is frequently isolated from children with febrile illness; no disease has been etiologically associated with HHV-6A. One HHV-6A strain has been cloned and sequenced, but similar information and reagents are not available for HHV-6B. We report here the determination of maps of the restriction endonuclease cleavage sites for BamHI, C1aI, HindIII, KpnI, and Sa1I, and the cloning in plasmids and bacteriophages of fragments representing over 95% of the HHV-6B strain Z29 [HHV-6B(Z29)] genome. Hybridization experiments and orientation of several blocks of nucleotide sequence information onto the genomic map indicate that HHV-6A and HHV-6B genomes are colinear.     

Factors affecting outcome in hypoxic-ischemic encephalopathy in term infants

Forty-nine term infants were prospectively shown to have hypoxic-ischemic encephalopathy (HIE). All infants survived the neonatal period, and all but two infants (seen at 12 months) were followed up to at least 27 months of age. Factors that significantly correlated with outcome included the Sarnat encephalopathy stage and the occurrence of intractable seizures not controlled by phenobarbital sodium alone. There was no association between the one- or five-minute Apgar score, the need for early ventilation, the EEG, the occurrence of seizures, and the subsequent outcome. There was no significant difference in outcome for those infants who received dexamethasone sodium phosphate (n = 29) v those who did not receive the drug (n = 20). A review of 97 term infants with HIE from a regional perinatal program during a one-year period (1979), including 35 of the 49 infants in the present study, did show a significant increase in morbidity and mortality for transported infants.     

Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated opportunistic diseases of the central nervous system in HIV-infected patients

OBJECTIVE: To assess the diagnostic reliability of polymerase chain reaction (PCR) on cerebrospinal fluid (CSF) for virus-associated opportunistic diseases of the central nervous system (CNS) in HIV-infected patients. DESIGN: CSF samples from 500 patients with HIV infection and CNS symptoms were examined by PCR. In 219 patients the PCR results were compared with CNS histological findings. METHODS: Nested PCR for detection of herpes simplex virus (HSV) type 1 or 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and JC virus (JCV) DNA. Histopathological examination of CNS tissue obtained at autopsy or on brain biopsy. RESULTS: DNA of one or more viruses was found in CSF in 181 out of 500 patients (36%; HSV-1 2%, HSV-2 1%, VZV 3%, CMV 16%, EBV 12%, HHV-6 2%, and JCV 9%). Among the 219 patients with histological CNS examination, HSV-1 or 2 was detected in CSF in all six patients (100%) with HSV infection of the CNS, CMV in 37 out of 45 (82%) with CMV infection of the CNS, EBV in 35 out of 36 (97%) with primary CNS lymphoma, JCV in 28 out of 39 (72%) with progressive multifocal leukoencephalopathy. Furthermore, HSV-1 was found in one, VZV in four, CMV in three, EBV in three, HHV-6 in seven, and JCV in one patient without histological evidence of the corresponding CNS disease. CONCLUSIONS: CSF PCR has great relevance for diagnosis of virus-related opportunistic CNS diseases in HIV-infected patients as demonstrated by its high sensitivity, specificity, and the frequency of positive findings.     

Cytomegalovirus encephalitis

PURPOSE: To review the pathologic and clinical features of and establish the frequency of cytomegalovirus encephalitis in adults and to review the methods available for diagnosis and treatment. DATA SOURCE: MEDLINE search of all English-language articles from January 1965 to August 1995. STUDY SELECTION: Articles dealing with cytomegalovirus infection of the brain in adults. We also reviewed all unselected autopsies of these populations to establish the frequency of cytomegalovirus encephalitis in recipients of organ transplants and in patients infected with the human immunodeficiency virus (HIV). DATA EXTRACTION: Epidemiologic and pathologic characteristics, clinical manifestations, diagnostic methods, pathogenetic mechanisms, and use of anticytomegalovirus treatments. DATA SYNTHESIS: Of 676 patients receiving a diagnosis of cytomegalovirus encephalitis, 574 (85%) were infected with HIV, 81 (12%) had other causes of immunosuppression, and 21 (3%) were otherwise healthy. Cytomegalovirus encephalitis was confirmed during autopsy in 12% of HIV-infected patients and 2% of transplant recipients. The most common lesion was microglial nodule encephalitis, but the clinical findings corresponding to this pathologic entity are not well defined. In contrast, the pathologic entity of cytomegalovirus ventriculoencephalitis, found almost exclusively in patients with advanced HIV infection, has distinct clinical features that allow recognition even in patients with HIV encephalopathy. Polymerase chain reaction has been shown to be useful for diagnosis of cytomegalovirus encephalitis. CONCLUSIONS: Cytomegalovirus encephalitis is an important opportunistic infection in HIV-infected patients but is rarely recognized in other groups. Cytomegalovirus ventriculoencephalitis has emerged as a unique entity in patients with advanced HIV infection. Recent developments in diagnostic techniques allow early recognition and may make more aggressive approaches to therapy possible.     

Human herpesvirus-6 antibodies in idiopathic facial nerve palsy and sudden deafness

Human herpesvirus-6 (HHV-6) is the causative agent for exanthem subitum. This study investigated the relationship between idiopathic facial nerve palsy (Bell's palsy), sudden deafness and HHV-6 infection. Both Bell's palsy and sudden deafness are syndromes which causes are unknown. Both of them are suspected viral infection as causative agents. Paired sera from 22 patients of Bell's palsy and 39 patients of sudden deafness were examined for reactivity to HHV-6 by the indirect immunofluorescence test. On a case of Bell's palsy and two cases of sudden deafness each of the HHV-6 antibody titers was increased.     

Obesity, salt intake, and renal perfusion in healthy humans

OBJECTIVE: To evaluate the pathogenicity of a recently discovered arthropod-transmitted bunyavirus (Toscana virus) on the CNS in children and to provide information on the epidemiologic and clinical aspects of Toscana virus infection. STUDY DESIGN: Case-series analysis of children hospitalized with clinical and cerebrospinal fluid examination compatible with a CNS disease of viral origin. METHODS: Cerebrospinal fluid, acute, and convalescent sera were investigated for conventional neurotropic viruses and for Toscana and tickborne encephalitis viruses. A clinical-epidemiologic analysis was carried out on confirmed Toscana virus cases to clarify the profile of Toscana virus infection in children. RESULTS: The study indicates that (1) Toscana virus has been endemic in the Siena province for at least 15 years; (2) the virus is responsible for at least 80% of acute viral infections of the CNS in children throughout the summertime; (3) the clinical signs and symptoms range from aseptic meningitis to meningoencephalitis; (4) infected children resided habitually or temporarily in rural or suburban areas of the Siena province, where ecological characteristics allow arthropods to be peridomestic in human settlements. CONCLUSIONS: Toscana virus is the most common viral agent involved in acute infections of CNS in children in central Italy.     

Improved algorithm for statistical batch-by-batch analysis of corneal topographic data

Congenital parvovirus infection was diagnosed in two liveborn premature infants born at 24 and 35 weeks of gestational age. The illnesses were associated with placentomegaly, petechial rash, edema, hepatomegaly, anemia and thrombocytopenia, respiratory insufficiency, and death at 5 and 6 days of age. The syndromes exhibited by these cases shared common but nonspecific features with other life-threatening congenital infections. Serological studies in one case supported the diagnosis of parvoviral infection. Postmortem examination of both revealed nuclear inclusions in erythroid precursor cells characteristic of parvovirus infection. Use of the polymerase chain reaction confirmed the presence of parvovirus DNA in one of the cases. Intrauterine parvovirus B19 infection is most commonly associated with hydrops fetalis, "transient" hydrops, or a favorable outcome in infants found to be viremic after birth. These and previously reported examples of congenital B19 disease exemplify an exceptional form of human parvovirus infection.     

Single-voxel proton MR spectroscopy of nonneoplastic brain lesions suggestive of a neoplasm

BACKGROUND AND PURPOSE: MR spectroscopy is used to characterize biochemical components of normal and abnormal brain tissue. We sought to evaluate common histologic findings in a diverse group of nonneoplastic diseases in patients with in vivo MR spectroscopic profiles suggestive of a CNS neoplasm. METHODS: During a 2-year period, 241 patients with suspected neoplastic CNS lesions detected on MR images were studied with MR spectroscopy. Of these, five patients with a nonneoplastic diagnosis were identified retrospectively; a sixth patient without tissue diagnosis was added. MR spectroscopic findings consistent with a neoplasm included elevated choline and decreased N-acetylaspartate and creatine, with or without detectable mobile lipid and lactate peaks. RESULTS: The histologic specimens in all five patients for whom tissue diagnoses were available showed significant WBC infiltrates, with both interstitial and perivascular accumulations of lymphocytes, macrophages, histiocytes, and (in one case) plasma cells. Reactive astrogliosis was also prominent in most tissue samples. This cellular immune response was an integral component of the underlying disorder in these patients, including fulminant demyelination in two patients, human herpesvirus 6 encephalitis in one patient, organizing hematoma from a small arteriovenous malformation in one patient, and inflammatory pseudotumor in one patient. Although no histologic data were available in the sixth patient, neoplasm was considered unlikely on the basis of ongoing clinical and neuroradiologic improvement without specific therapy. CONCLUSION: Nonneoplastic disease processes in the CNS may elicit a reactive proliferation of cellular elements of the immune system and of glial tissue that is associated with MR spectroscopic profiles indistinguishable from CNS neoplasms with current in vivo MR spectroscopic techniques. Such false-positive findings substantiate the need for histologic examination of tissue as the standard of reference for the diagnosis of intracranial mass lesions.     

Hypoxic-ischaemic encephalopathy: early and late magnetic resonance imaging findings in relation to outcome

Sixteen infants with hypoxic-ischaemic encephalopathy (HIE) were studied using serial magnetic resonance imaging (MRI) up to the age of 2 years. The infants had regular neurological and developmental assessments. An nuclear magnetic resonance (NMR) score was devised to quantify the early and late MRI findings and a neurological optimality score was used to quantify abnormal neurological signs at the time of the final examination. The follow up MRI score was compared with the neonatal MRI score and the outcome of the child. There was a strong positive correlation between the neonatal and follow up MRI scores and between MRI scores and optimality score. All infants with a normal outcome had patchy white matter abnormalities. All infants with an abnormal outcome had extensive white matter abnormalities. The outcome was most severe in those infants with additional basal ganglia atrophy with or without cyst formation. Infants with mild HIE who are developmentally normal at the age of 2 years do not have normal MRI scans and may be at risk of minor neurological problems by school age. Bilateral basal ganglia abnormalities are associated with severe developmental delay, but infants with mainly white matter and cortical abnormalities have less severe problems despite extensive tissue loss.     

Human herpesvirus-6: neurologic implications of a newly-described viral pathogen

Discovered only 12 years ago, human herpesvirus-6 (HHV-6) has been associated with central nervous system (CNS) findings such as febrile seizures, encephalitis, meningitis, and possibly multiple sclerosis. These manifestations have been reported in both immunocompetent and immunocompromised individuals. The applications of such sophisticated laboratory tools as polymerase chain reaction, in situ hybridization, immunohistochemical staining, and representational difference analysis have expanded knowledge of the spectrum of CNS disease attributable to HHV-6 while delineating pathogenic mechanisms of both primary HHV-6 infection and reactivation from latency. This article reviews existing knowledge of the CNS manifestations of HHV-6, focusing on both clinical aspects of HHV-6 infection and its pathogenesis on neurologic diseases.     

Laboratory diagnosis of subacute and acute encephalitis probably of viral origin: seven years of experience

The results obtained in the laboratory diagnosis of 609 cases of acute or subacute encephalitis, studied during a period of time of even years, is briefly presented. Diagnostic methods included virus isolation from stools and cerebrospinal fluid (CSF); specific serology in serum; detection of intrathecal production of IgG antibody; and, in the last two years, detection of viral genome sequences in CSF by the polymerase chain reaction. Significant results were obtained in 196 cases (32.2%) and the alfa-herpesviruses were responsible for a major part of them (77.5%). Furthermore, 18 cases were likely to respond to dual infection by both herpes simplex and varicella-zoster viruses. Epstein-Barr virus and Human herpesvirus 6 were found in CSF from three immunocompetent patients. Besides the current vaccination program, measles virus is still responsible for an important part (22/196, 11.2%) of cases of viral encephalitis.     

Synaptic and dendritic pathology in murine retroviral encephalitis

Central nervous system (CNS) damage occurs during retroviral infection in both man and animals. As a model of human disease, we studied the distribution and extent of CNS damage during retroviral infection with two molecularly cloned, neurotropic murine leukemia viruses. Both viruses mediate a spongiform encephalopathy involving predominantly the brainstem and spinal cord. During the course of disease, immune reactivity for synaptophysin (SYN) (to identify presynaptic elements) and microtubule-associated protein-2 (MAP-2) (to identify postsynaptic elements) were quantified using confocal laser microscopy. Immunostaining of SYN in the cerebral cortex (an area not exhibiting spongiform lesions) was similar in viral infected and age-matched control mice. However, compared to age matched controls, SYN staining in the brainstem (an area exhibiting spongiform lesions) of viral infected mice progressively declined during the course of disease. Quantitative analysis showed greater reduction of MAP-2 immunostaining in viral-infected mice compared to age-matched controls. In infected mice, both regions with and without spongiform lesions showed diminished MAP-2 staining. Widely distributed microscopic vacuolation of dendritic processes was observed in confocal preparations. These findings suggest primary dendritic damage in murine retroviral infection of the CNS similar to what has been described in human immunodeficiency virus-1 encephalitis.     

Mouse adenovirus type-1 replication is restricted to vascular endothelium in the CNS of susceptible strains of mice

Previous studies have shown that mouse adenovirus type-1 (MAV-1) caused a fatal hemorrhagic encephalitis in certain strains of mice. C57BI/6 mice exhibited 100% mortality when given as little 10(3) plaque-forming units (PFU) of MAV, in contrast to BALB/c mice which were resistant to as many as 10(6) PFU. Susceptible animals died with a flaccid paralysis on the 3rd or 4th day after inoculation. The brains and spinal cords of these animals displayed numerous petechial hemorrhages that were found in virtually all areas of the brain, but were more numerous in white matter. In this paper, immunohistochemistry and electron microscopy were used to identify the viral target of replication within the CNS of susceptible mice. These studies showed that the CNS vascular endothelial cell was the primary site of viral replication within the CNS of mice infected with MAV-1. Characterization of cytokine mRNA levels and disease course in immunodeficient mice revealed that the host immune response played little, if any, role in the pathogenesis of MAV-1 disease in susceptible mice and was not responsible for the resistance of BALB/c mice. These results support the conclusion that disease course and outcome in susceptible and resistant strains of mice were determined primarily by the ability of the virus to replicate within the CNS vascular endothelium.     

Absence of human herpesvirus 8 and Epstein-Barr virus genome sequences in cutaneous epithelial neoplasms arising in immunosuppressed organ-transplant patients

Recent studies have implicated herpesvirus 8 and Epstein-Barr virus in the development of cutaneous malignancies in immunosuppressed patients. In order to examine the strength of this association, we examined 37 malignant, pre-malignant and benign cutaneous epithelial neoplasms removed from immunosuppressed organ recipients for the presence of human herpesvirus 8 and Epstein-Barr viral genome sequences using polymerase chain reaction (PCR) and in situ hybridization. We examined 2 actinic keratoses, 1 benign keratosis, 11 invasive squamous cell carcinomas, 17 squamous cell carcinomas in situ and 6 basal cell carcinomas. We also examined 4 basal cell carcinomas, 1 invasive squamous cell carcinoma and 3 squamous cell carcinomas in immunocompetent hosts. In contrast to findings reported by other investigators, we were unable to detect viral genome sequences in any of the biopsies examined. Our findings suggest that human herpesvirus 8 and Epstein-Barr virus likely do not play an etiologic role in cutaneous epithelial oncogenesis in immunocompromised patients.     

Comparison of genotype and intellectual phenotype in untreated phenylketonuric children

Plasmocytic variants of Castleman's disease are uncommon. We report a new case of abdominal location with a rapidly fatal outcome. Another particularity of that case was the negativity of Kaposi's sarcoma associated herpesvirus, a virus recently implicated in human immunodeficiency virus associated Castleman's disease.     

Measles inclusion-body encephalitis in a child with treated acute lymphoblastic leukaemia

A child with acute lymphoblastic leukaemia, being treated in the UKALL II Trial, had while in remission an attack of measles and made a normal recovery. Four months later she developed an acute encephalopathy and died within two weeks. The brain showed mild inflammatory features and widespread inclusion bodies in neurones and glial cells. Immunofluorescence proved an infection with measles virus. Similar cases have been called SSPE; reasons are given for preferring the term "measles inclusion-body encephalitis".     

Human cytomegalovirus (HCMV) encephalitis in an immunocompetent young person and diagnostic reliability of HCMV DNA PCR using cerebrospinal fluid of nonimmunosuppressed patients

Human cytomegalovirus (HCMV) encephalitis in adult nonimmunosuppressed patients has rarely been reported. We have diagnosed HCMV encephalitis in an anti-HCMV immunoglobulin G-negative, nonimmunosuppressed young woman by HCMV DNA PCR and virus isolation from cerebrospinal fluid (CSF). At the same time, HCMV antigen and HCMV DNA could be demonstrated in peripheral blood leukocytes, and the virus was isolated in fibroblast cultures. After 22 days of acute illness, the virus disappeared from the CSF. Remarkably, the patient did not generate detectable anti-HCMV antibodies within 5 months after the beginning of illness. To investigate the significance of HCMV DNA detection in CSF, samples of CSF, blood cells, and serum from 35 nonimmunosuppressed patients with various neurological disorders (but no herpes simplex virus central nervous system [CNS] disease) were tested for HCMV DNA, antigen, and antibodies. Eleven of these patients were found to be positive for virus DNA and/or antigen in peripheral blood leukocytes. Additionally, HCMV DNA was detected in the CSF of two patients with noninflammatory CNS diseases. A causative role of HCMV in the CNS diseases of these two patients was not evident. In summary, HCMV DNA amplification from CSF samples is a very suitable method to verify HCMV-associated encephalitis, but it should be taken into consideration that there are few cases of positive PCR with DNA from CSF without any known clinical correlative.