Herpes simplex and lymphocytic choriomeningitis viruses in infections of the central nervous system--clinical and cerebrospinal fluid characteristics

INTRODUCTION: A great number of various viruses are stated as the cause of acute infections and damages of the central nervous system. In most cases these are minor damages which exhibit as meningeal syndrome and a specific finding in the cerebrospinal fluid. According to the dominant location, central nervous system infections can take a form of meningitis, encephalitis or myelitis. Since the inflammatory process of the meninges can not be separated from the inflammatory process of the brain, we usually speak of meningoencephalitis. The etiological diagnosis of meningitis and encephalitis is established by isolating the virus from the cerebrospinal fluid and by finding the presence of the specific antibodies in the blood and in the cerebrospinal fluid. The most common causes of the viral meningitis are Enteroviruses, the Mumps virus, Arthropode borne viruses, the Herpes viruses, Adeno viruses and the Lymphocytic choriomeningitis virus. The aim of our study was to establish the correlation between the clinical features and immunological and cerebrospinal fluid changes and the degree of the damage to the blood-brain barrier during the infections of the central nervous system, caused by the Herpes Simplex virus and the Lymphocytic choriomeningitis virus. MATERIAL AND METHODS: From a group of 103 patients, who had been treated for viral meningitis and meningoencephalitis, a group of 27 patients with established specific viral etiology--Herpes Simplex virus and Lymphocytic choriomeningitis virus, had been taken into the account. Herpes Simplex infection had been proven by the complement binding reaction and the neutralisation test of the even samples of serum. The diagnosis of Lymphocytic choriomeningitis was confirmed by the immunofluorescence test of the pharynx swabs and cerebrospinal fluid. The clinical features, such as body temperature, encephalitic signs, and electroencephalographic findings had been followed and compared. RESULTS: Herpes Simplex infection had been found in 20 patients, Lymphocytic choriomeningitis had been proven in 7 patients. All the patients had increased body temperature. Only four of the patients exhibited encephalitic signs, all infected by the Herpes Simplex virus. Patients from the Herpes Simplex group showed various degrees of consciousness disturbances, ranging from somnolence to coma, while the Lymphocytic choriomeningitis patients exhibited none. Higher pleocytosis and protein level had been found in the Lymphocytic choriomeningitis group. DISCUSSION: Viral diseases of the central nervous system are the result of the direct damage of the brain and meninges by the virus and immunological processes. Herpes Simplex meningitis usually has a good prognosis. Lymphocytic choriomeningitis has longer course of the disease and exhibits more severe clinical features. CONCLUSION: In cases of the central nervous system infections, caused by Herpes Simplex virus or Lymphocytic choriomeningitis virus, the correlation between the severeness of clinical features and the degree of damage of the blood-brain barrier, the level of pleocytosis and the increase of the cerebrospinal fluid proteins had been established.     

Recurrent Mollaret's meningitis of herpetic origin

BACKGROUND: Benign recurrent meningitis, or Mollaret's meningitis, is an uncommon disease whose viral origin was long unidentified. Since 1991, about twenty cases have been reported in patients with herpes infection. CASE REPORT: A female patient had experienced repeated episodes of spontaneous meningitis since 1983. The episodes resolved spontaneously and no etiology had been identified. A spinal tap was performed when the patient was again hospitalized a new episode of meningitis and PCR amplification of the herpes simplex virus type 2 (HSV 2) was positive. The patient was given long term acyclovir per os. A new spinal tap after resolution of the meningitis episode was PCR HSV2 negative. DISCUSSION: HSV2 infection is one of the known causes of Mollaret's meningitis. Long-term antiviral therapy appears to prevent recurrence as was observed in our patient.     

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.     

Acute encephalitis and bacterial meningitis in children in Aichi Prefecture (1984-1993)

A survey was performed of acute encephalitis and bacterial meningitis in infancy and childhood from 1984 to 1993 using a questionnaire directed to departments of pediatrics in large hospitals in Aichi prefecture. The case records for 391 patients with acute encephalitis including related diseases and 328 patients with bacterial meningitis were obtained from 63 hospitals. Of 391 patients with acute encephalitis, 224 were male and 167 were female. Of 328 patients with bacterial meningitis, 200 were male and 128 were female. Sex ratio were 1.3, 1.6 respectively. Of the patients, 52.4% of encephalitis and 84.8% of meningitis were under 4 years of age and 0 year olds made up 53.7% of the latter. The causes of these diseases were confirmed in 38.7% and 82.9% of the encephalitis and meningitis patients, respectively, etiologically. In encephalitis, rubella virus was the most frequent with 29 cases, followed by measles virus (27 cases), herpes simplex virus (24) and varicella-zostervirus (19). In meningitis H. influenzae (95 cases), S. pneumoniae (56), Group B streptococcus (41) and E. coli (27) were frequently diagnosed. These diseases showed respective patterns of age distribution and clinical course, and moreover, the increases in their onset were clearly related to the prevalence of causal infections. Therefore, the results of this study should be utilized in the development of administrative measures for prevention of these diseases.     

Immunomodulatory activity of thunberginol A and related compounds isolated from Hydrangeae Dulcis Folium on splenocyte proliferation activated by mitogens

We have prospectively studied 27 adult patients attending the Department of Infectious Diseases, G?teborg, Sweden, between October 1992 and October 1996 with a diagnosis of acute viral encephalitis. In addition to cerebrospinal fluid (CSF) virus isolations and antibody analyses against herpes simplex virus, cytomegalovirus, varicella zoster virus, Epstein-Barr virus (EBV), enterovirus, adenovirus, tick-borne encephalitis virus, and mycoplasma, polymerase chain reaction test (PCR) to 5 viruses from the family of human herpes viridae, and to adenovirus as well as to enterovirus were analysed in CSF. 10 patients had herpes simplex virus type-1 (HSV-1), 1 had varicella zoster virus, 1 had tick-borne encephalitis, and 2 had Influenza A infections. In 13 patients the aetiology remained unclear. Eight patients with HSV-1 encephalitis and clinical symptoms for 2-11 d before admission were PCR-positive, while 2 patients with a < or = 2 d history of disease were negative for HSV-1 DNA on admission. These 2 patients became positive for HSV-1 DNA in CSF samples taken 4 d later in 1 case and 7 d later in the other. In 4 patients with HSV-1 encephalitis, in 1 patient with Influenza A complicated by encephalitis, and in 1 patient with encephalitis of unknown origin EBV DNA was found in CSF samples during the study. The clinical significance of these findings is unclear. The study shows that HSV-1 was the most common etiological agent in patients with viral encephalitis in the G?teborg area. In spite of improved diagnostic procedures, a large proportion of patients with symptoms and laboratory findings compatible with viral encephalitis still have an unclear aetiology.     

Viral encephalitis in children: detection with technetium-99m HMPAO brain single-photon emission CT and its value in prediction of outcome

PURPOSE: To assess the role of regional cerebral blood flow measured by technetium-99m hexamethyl propyleneamine oxime (HMPAO) brain single-photon emission CT (SPECT) in viral encephalitis of children. METHODS: Eighteen children diagnosed as having viral encephalitis (12 Epstein-Barr virus, 4 herpes simplex virus, and 2 Japanese B virus) underwent Tc-99m HMPAO brain SPECT and brain MR and/or CT. RESULTS: During the acute episode, 4 (22%) of the 18 patients had localized abnormality on brain MR and/or CT. Tc-99m HMPAO brain SPECT in the acute phase showed that 17 (94%) of the 18 patients had increased regional cerebral blood flow and 1 (6%) of the 18 children had a normal brain SPECT. Follow-up brain SPECT was performed at least 15 days after the acute episode. In 17 patients with abnormal first brain SPECT, 12 (71%) had normal second brain SPECT and 5 (29%) had decreased regional cerebral blood flow. The group of patients with normal regional cerebral blood flow on the follow-up brain SPECT had a better outcome than the group of patients with decreased regional cerebral blood flow. CONCLUSIONS: (a) The Tc-99m HMPAO brain SPECT was abnormal more often than CT or MR in children with acute viral encephalitis and provided better location. (b) In acute episodes of encephalitis, most patients showed locally increased regional cerebral blood flow. (c) After acute episodes, the regional cerebral blood flow returned to normal in most cases. (d) A normal Tc-99m HMPAO brain SPECT in the subacute phase usually indicates a good clinical outcome (no neurologic defect) 1 year after the acute illness in children with viral encephalitis.     

Varicella-zoster virus is strongly associated with atypical necrotizing herpetic retinopathies

Aqueous humor samples from nine patients with atypical necrotizing retinopathies of suspected viral origin, six with acute retinal necrosis syndrome (ARN), and 17 with active cytomegalovirus (CMV) retinitis underwent amplification for viral DNA of herpes simplex virus type 1 (HSV-1), varicella-zoster virus (VZV), and human CMV. VZV DNA was detected in seven of the nine aqueous humor samples from patients with atypical necrotizing retinopathies of suspected viral origin and in four of the six samples from individuals with ARN; of the two other samples from patients with ARNS, no viral DNA was found in one, and both CMV DNA and HSV-1 DNA, but not VZV DNA, were detected in one (this patient presented with bilateral ARNS 2 months after being successfully treated for CMV retinitis). Thus, VZV is likely to be the main pathogen of atypical necrotizing herpetic retinopathies. DNA amplification may be used to establish an early, sensitive, and reliable diagnosis of any form of necrotizing retinopathy in 80% of cases, irrespective of viral etiology.     

Hypouricemia in patients with meningitis

Serum urate and sodium concentrations were measured in 23 patients with acute viral and bacterial meningitis. Serum urate level was 3.0 +/- 0.2 mg/dl (mean +/- S.D.) (3.6 +/- 1.2 mg/dl in male and 2.5 +/- 0.9 mg /dl in female) on admission, but gradually elevated with improvements of meningitis. It turned to 4.8 +/- 0.2 mg/dl after recovery, and the value on admission was significantly lower than that after recovery (p < 0.0001). Serum sodium level was 137.6 +/- 2.9 mEq/l on admission and 139.7 +/- 2.7 mEq/l after recovery; also lower in the former (p < 0.01). These results show that patients develop transient hypouricemia, which may be explained by SIADH (syndrome of inappropriate secretion of ADH), although SIADH is subclinical in most cases of meningitis.     

Hydrocephalus in mice infected with a Theiler's murine encephalomyelitis virus variant

The etiology of hydrocephalus is never established in the majority of clinical cases, while various agents, nutritional deficiencies, and genetic factors have been shown to play a role. Viral infection has been recognized as one of the causative factors in the development of hydrocephalus. The wild-type DA strain of Theiler's murine encephalomyelitis virus (TMEV), which belongs to the family Picornaviridae, causes a chronic demyelinating disease in mice with viral persistence that resembles multiple sclerosis. We found that a DA virus variant, hydrocephalus 101 virus (H101 virus), caused hydrocephalus in mice, a condition previously never described for TMEV. To clarify the relationship between DA virus infection and hydrocephalus, we compared H101 virus and wild-type DA virus infection in mice. Using immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL), we found that during the acute phase of infection, H101 virus caused macrocephaly and meningitis with the presence of apoptosis, while parenchymal involvement was not evident. In contrast, wild-type DA virus caused an acute polioencephalomyelitis with parenchymal infection and apoptosis. During the chronic phase, H101 virus infection caused communicating hydrocephalus without viral persistence. No demyelination and little or no anti-TMEV antibodies were observed in H101 virus-infected mice. Sequence analysis revealed that H101 virus had mutations in the 5'UTR and capsid protein coding region. Characterization of this new hydrocephalus model gives insight into the possible viral involvement in human hydrocephalus cases of obscure etiology.     

Acyclovir given as prophylaxis against oral ulcers in acute myeloid leukaemia: randomised, double blind, placebo controlled trial

OBJECTIVES: To evaluate (a) the prophylactic effect of the antiherpetic drug acyclovir on oral ulcers in patients with acute myeloid leukaemia receiving remission induction chemotherapy and thus (b), indirectly, the role of herpes simplex virus in the aetiology of these ulcers. DESIGN: Randomised, double blind, placebo controlled trial. SUBJECTS: 74 herpes simplex virus seropositive patients aged 18-84. Thirty seven patients received acyclovir (800 mg by mouth daily) and 37 placebo. The patients were examined daily for 28 days. MAIN OUTCOME MEASURES: Occurrence of herpes labialis, intraoral ulcers, and acute necrotising ulcerative gingivitis. RESULTS: The two populations were comparable in age, sex, type of antineoplastic treatment, and history of herpes labialis. Acute oral infections occurred in 25 of the acyclovir treated patients and 36 of the placebo treated patients (relative risk 0.69 (95% confidence interval 0.55 to 0.87)). This difference was due to a reduction in the incidence of herpes labialis (one case versus eight cases; relative risk 0.13 (0.02 to 0.95)), intraoral ulcers excluding the soft palate (one case versus 13 cases; relative risk 0.08 (0.01 to 0.56)), and acute necrotising ulcerative gingivitis (one case versus eight cases; relative risk 0.13 (0.02 to 0.95)). However, ulcers on the soft palate were diagnosed with similar frequency in the two groups. Isolation of herpes simplex virus type 1 in saliva was reduced from 15 cases in the placebo group to one case in the acyclovir group (relative risk 0.07 (0.01 to 0.48)). CONCLUSION: Intraoral ulcers excluding the soft palate are most often due to infection with herpes simplex virus, whereas ulcers on the soft palate have a non-herpetic aetiology. The findings suggest that acute necrotising ulcerative gingivitis may also be due to herpes simplex virus. Prophylaxis with acyclovir should be considered for patients with acute myeloid leukaemia during remission induction therapy.     

Pathogenesis of nervous system lesions in epidemic parotitis in children

The authors studied antibodies to the nervous tissue in the blood (pair serum with an interval of 10 days) and in the CSF in 155 patients with epidemic parotitis and signs of neurotoxicosis, parotit meningitis and meningoencephalitis. Depending upon the intensivity of antibody elaboration 3 groups were distinguished. The first group (40 cases), with a high content of antibodies to the nervous tissue, was characterized by a prevalence of encephalitic forms (in 30 of the 40 cases). In the second group (32 cases) with a less antibody content there was a prevalence of meningitis, while meningoencephalitis was seen only in 3 cases. The third group (83 cases) with a low concentration or absence of antibodies was characterized by a mild course of the disease. This group included as well patients with neurotoxicosis. These data may indicate involvement of allergic mechanisms of a retarded type in the pathogenesis of remote lesions of the nervous system in epidemic parotitis.     

Advances in the treatment of herpesvirus infection: the role of famciclovir

Shingles (herpes zoster) is the result of reactivation of varicella-zoster virus after years of latency. The acute phase is self-limiting but is often associated with moderate-to-severe pain; postherpetic neuralgia is the most frequent and debilitating complication of shingles, occurring in 3.4 per 1000 individuals per year. In the case of genital herpes, herpes simplex virus can reactivate to cause recurrent episodes as often as several times a year, sometimes for the remainder of a person's life. Antiviral agents such as famciclovir, valacyclovir, and acyclovir can be used to shorten the course and decrease the severity of these diseases and may suppress the virus itself, thereby preventing future outbreaks of genital herpes. This article presents a brief synopsis of the etiology of herpes zoster and genital herpes and reviews 12 key studies that demonstrate the efficacy of famciclovir in the management of these two conditions.     

Cerebrospinal fluid leukocyte aggregation in meningitis

OBJECTIVE: To evaluate whether the difference in aggregation of cerebrospinal fluid cells from patients with bacterial, viral, aseptic and partially treated meningitis can be used for diagnostic purposes. METHODS: Cerebrospinal fluid samples of 100 patients with meningitis (15 bacterial, 13 partially treated, 10 viral and 62 aseptic) were compared on the basis of the predefined leukocyte aggregation score (LAS). RESULTS: Mean LAS was 56% in the bacterial meningitis group (range, 15 to 90%), 5.8% in the partially treated meningitis group (range, 0 to 27%), 2% in the proven viral meningitis group (range, 0 to 5%) and 2% in the aseptic meningitis group (range, 0 to 15%). All patients with bacterial meningitis had a LAS of > 15%, whereas all those with viral or aseptic meningitis had a score of < 15%. Although most patients with partially treated meningitis had a low LAS, several had higher scores, which may indicate bacterial infection. There was no statistical correlation between number of cells, type of cells (mononuclear or polymorphonuclear) or cerebrospinal fluid protein and glucose concentration and degree of leukocyte aggregation for the different groups. CONCLUSION: Measurement of the LAS may contribute to the immediate differential diagnosis of bacterial or viral meningitis, especially in patients with very high pleocytosis, as sometimes seen in enteroviral meningitis. It may also serve as a guide for the likelihood of bacterial infection in cases of partially treated meningitis. Additional studies are needed to confirm these observations.     

Comparative study of transfer factor and acyclovir in the treatment of herpes zoster

Reactivation of varicella herpes virus (VHV), latent in individuals who have previously suffered varicella, gives rise to herpes zoster and in some cases leads to a sequela of post herpetic neuritis with severe pain which is refractory to analgesics. Many different antiviral agents have been tried without achieving satisfactory results. Of all the antiviral agents employed, acyclovir has been the most successful in reducing post herpetic pain. However acyclovir has not been as reliable as interferon alpha (IFN-alpha). We have previously looked into the use of transfer factor (TF) as a modulator of the immune system, specifically with respect to its effectiveness in the treatment of herpes zoster. In this work findings from a comparative clinical evaluation are presented. A double blind clinical trial of TF vs acyclovir was carried out in which 28 patients, presenting acute stage herpes zoster, were randomly assigned to either treatment group. Treatment was administered for seven days and the patients were subsequently submitted to daily clinical observation for an additional 14 days. An analogue visual scale was implemented in order to record pain and thereby served as the clinical parameter for scoring results. The group treated with TF was found to have a more favorable clinical course, P < or = 0.015. Laboratory tests to assess the immune profile of the patients were performed two days prior and 14 days after initial treatment. The results of these tests showed an increase in IFN-gamma levels, augmentation in the CD4+ cell population but not the percentage of T rosettes in the TF treated group. These parameters were however insignificantly modified in patients receiving acyclovir. Although TF treated patients showed an increase in CD4+ counts these cells remained below the levels for healthy individuals. The fact that IFN-gamma levels as well as the counts for CD4+ cells rose in the TF treated group and not in the acyclovir one is very significant and confirms the immunomodulating properties of TF.     

Measuring health outcomes--putting gains into perspective

Human herpesvirus-6 (HHV-6) is the etiologic agent of roseola infantum, and has been implicated as a possible cause of encephalitis in pediatric and adult patients. A case of meningoencephalitis in an otherwise healthy, immunocompetent 59-year-old woman is described. The diagnosis of HHV-6 meningoencephalitis was confirmed by detecting viral DNA in cerebrospinal fluid collected in the acute stage of the disease by polymerase chain reaction. The patient was treated with acyclovir and recovered without any sequelae. The current knowledge of the pathophysiology, clinical course and outcome of HHV-6 meningoencephalitis in immunocompetent adult patients is also reviewed.     

Herpes simplex meningoencephalitis in an infant observed during an epidemic of enteroviral infections of the nervous system

An infant with Herpes simplex meningoencephalitis which occurred during an epidemic of enteroviral neuroinfections is described. Clinical and laboratory signs of meningitis as well as preceding aphtous oropharyngeal inflammation, initially suggested an enteroviral etiology. The appearance of signs of encephalitis with focal neurologic disturbances and the results of brain imaging by computed tomography, primarily the detection of temporoparietal areas of hypodensity, raised the possibility of HSV infection. Thanks to early specific treatment with acyclovir, the infant recovered from meningoencephalitis and 4 months later presented only minor neurological sequelae (slight left hemiparesis). The diagnosis of Herpes simples meningoencephalitis was confirmed by detecting IgM and IgG anti-HSV antibodies in the serum and cerebrospinal fluid both at the beginning and after 10 days of treatment and also by a eightfold rise of the anti-HSV-1 antibody level in serum. The authors emphasize the role of brain imaging (computed tomography and magnetic resonance) in the differential diagnosis of viral nervous system infections and suggest early treatment with acyclovir in case of suspicion of HSV-encephalitis.     

Polymerase chain reaction-based assays of vitreous samples for the diagnosis of viral retinitis. Use in diagnostic dilemmas

OBJECTIVE: This study aimed to review the authors' results using polymerase chain reaction (PCR)-based assays for the diagnosis of viral retinitis. DESIGN: The study design was a retrospective case series. PARTICIPANTS: Thirty-seven patients (38 eyes) with active retinitis from whom vitreous biopsy specimens were received in the authors' laboratory for diagnostic evaluation. INTERVENTION: Vitreous biopsy specimens were evaluated with previously described PCR-based assays for cytomegalovirus (CMV), varicella zoster virus (VZV), and herpes simplex virus (HSV) DNA; clinical histories were reviewed. MAIN OUTCOME MEASURES: Laboratory findings and clinical course were measured. RESULTS: The results of the authors' assays were consistent with the long-term clinical course of each patient. Cytomegalovirus, VZV, or HSV DNA was detected in the vitreous from 24 patients. Cytomegalovirus DNA was detected in vitreous biopsy specimens from 10 patients (11 eyes). Nine patients (ten eyes) with acquired immune deficiency syndrome ultimately were diagnosed with CMV retinitis as they were followed clinically over time. Varicella zoster virus DNA was detected in vitreous biopsy specimens from eight patients; seven adult patients were ultimately diagnosed with acute retinal necrosis or progressive outer retinal necrosis. Herpes simplex virus DNA was detected in vitreous biopsy specimens from six patients; five patients had previous or subsequent herpes encephalitis. No viral DNA was detected in the vitreous from 13 patients; all were ultimately diagnosed with toxoplasmosis, syphilis, Behcet disease, fungal endophthalmitis, or idiopathic inflammation. CONCLUSIONS: These data further support the use of PCR-based assays of vitreous specimens in the diagnostic evaluation of patients with infectious retinitis.     

Imaging fistula-in-ano

Intrauterine viral infection commonly presents as nonimmune hydrops fetalis or intrauterine growth restriction. Cytomegalovirus (CMV) and parvovirus are commonly recognized causes of fetal infection using serology and cultures. We used the polymerase chain reaction (PCR) to evaluate the frequency of fetal viral infection and the associated clinical course and outcome. Specimens (amniotic fluid, fetal blood, pleural fluid, tissue) from 303 abnormal pregnancies at risk for viral infection and 154 controls were analyzed using primers for CMV, herpes simplex virus, parvovirus B19, adenovirus, enterovirus, Epstein-Barr virus, and respiratory syncytial virus. Viral genome was detected in 144/371 samples (39%) or 124/303 patients (41%), with adenovirus (n = 74 patients; 24%), CMV (n = 30 patients; 10%), and enterovirus (n = 22 patients; 7%) most common. Only 4/154 (2.6%), unaffected control patients' samples were PCR positive. We conclude that diagnosis of fetal viral infection by PCR is common in abnormal pregnancies. Adenovirus and enterovirus may cause fetal infection that have been previously unrecognized.