Elisabeth Aurelius

Rapid development of isolate-specific neutralizing antibodies after primary HIV-1 infection and consequent emergence of virus variants which resist neutralization by autologous sera.

The kinetics of appearance and specificity of HIV-1 neutralizing antibodies was studied in four individuals. HIV-1 was isolated during symptomatic primary HIV-1 infection and repeatedly thereafter, and tested against autologous sera collected in parallel. Our patients developed isolate-specific low-titer neutralizing antibodies within 2-4 weeks, and the titers to the first isolates increased with time. We documented the emergence of virus variants with reduced sensitivity to neutralization by autologous, but not heterologous, sera in three patients. These virus variants were not, however, resistant to neutralization per se, since they were readily neutralized by the positive control serum. Our patients did not develop antibodies capable of neutralizing the new virus variants during the observation period. This suggests either a failure of the immune system to respond to the new virus variants or a mechanism by which the virus evades detection by the immune system. The emergence of neutralization-resistant virus variants was not directly correlated with disease progression since two patients have remained asymptomatic after the emergence of such virus variants. It is, however, likely that the emergence of virus variants which the patient fails to neutralize in the long run contributes to disease progression.

Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults

ObjectivesTo study the occurrence of relapse of herpes simplex encephalitis (HSE) and to find out whether soluble activity markers in cerebrospinal fluid (CSF) indicate direct viral or immune– mediated events.MethodsA consecutive series of 32 adult survivors of HSE were followed to determine the incidence of clinical relapse of HSE. Four patients had neurological deterioration interpreted as relapsing HSE. Four non–relapsing HSE cases were selected as matched controls. Fiftynine batched, paired CSF and serum samples from the eight HSE patients were analysed for soluble activity markers, predominantly cytokines and mediators (interferon– γ, soluble CD8, tumour necrosis factor–α, and interleukin–10), amount of HSV–DNA and markers of glial and neuronal destruction (neurofilament protein, glial fibrillary acidic protein, S–100–β, and neuron specific enolase).ResultsRelapse of HSE was diagnosed in 3 of 26 (12 %) acyclovir–treated patients (5 episodes during 6.1 years of followup) and in 1 of 6 vidarabine–recipients. All relapses occurred from 1 to 4 months after acute HSE, except for a second relapse after 3.3 years in one patient. Computer tomography at relapses revealed few abnormalities apart from those found during the primary disease. Intravenous acyclovir and corticosteroids were given for 7–21 days in all the relapse patients. All relapse patients seemed to recover to the pre–relapse condition. HSV–DNA was demonstrated in CSF in all patients during the acute stage but not in any of 13 CSF samples taken during relapse phases. The HSV viral load during the acute stage of HSE was not higher or of longer duration in the relapsing patients than in the non–relapsing HSE controls. The levels of sCD8 were increased in nearly all CSF samples tested with peaks of sCD8 at one month of acute HSE. In all episodes of relapse, sCD8 peaks were detected during the first week at high levels. CSF levels of neuron–specific enolase, S–100 and glial fibrillary acidic protein were markedly lower at relapse than at the acute stage of HSV–1 encephalitis.ConclusionThe lack of demonstrable HSV DNA in CSF, the lack of acute CSF signs and the lack of signs of neural and glia cells destruction indicate that a direct viral cytotoxicity is not the major pathogenic mechanism in relapse. Instead, the pronounced CSF proinflammatory immunological response and the relative lack of CSF anti–inflammatory cytokine IL–10 response suggest immunologically–mediated pathogenicity.

Serum C-reactive protein in the differential diagnosis of acute meningitis

The ability of serum C-reactive protein (S-CRP) to differentiate between acute bacterial and viral meningitis was evaluated in 235 patients, both children and adults. The patients underwent lumbar puncture due to suspected central nervous system (CNS) infection. In patients with bacterial meningitis, 7/60 (12%) had S-CRP concentrations below 50 mg/l. Of these patients, 4 were children below 6 years of age, all with symptoms of meningitis for less than 12 h before admission and 3 adults of whom 1 had symptoms of meningitis for less than 12 h. In patients with viral meningitis, 15/146 (10%) had S-CRP concentrations above 50 mg/l. Only 3 children below 6 years of age with viral meningitis had S-CRP concentration above 20 mg/l, but none exceeded 50 mg/l. An S-CRP value above 50 mg/l in patients with CSF pleocytosis usually indicates bacterial etiology. However, S-CRP values above 50 mg/l may occasionally be seen in viral meningitis. In children younger than 6 years of age a discriminatory level for S-CRP of 20 mg/l can be used to distinguish between bacterial and viral meningitis, but for older patients a discriminatory level of 50 mg/l is more appropriate. If the duration of the illness is less than 12 h, S-CRP concentrations below the discriminatory levels are of limited diagnostic value.

Neurologic Morbidity after Herpes Simplex Virus Type 2 Meningitis: A Retrospective Study of 40 Patients

In order to study the long-term course after herpes simplex virus type 2 (HSV-2) meningitis and/or myeloradiculitis the records of 40 consecutive patients were studied. During the year following the acute phase, verified or suspected neurologic recurrences were noted in nearly half of the patients: 1 or more episodes of recurring meningitis were noted in 8 patients; new episodes of myelitis or radiculitis in 3; distinct attacks of headache in 4; and diffuse neurologic complaints impairing daily life in 3. Recurring mucocutaneous symptoms were observed in 16 patients. Eleven patients experienced concurrent or separate episodes of recurring mucocutaneous and neurologic symptoms, 7 had neurologic recurrences only and 5 had only mucocutaneous recurrences. As considerable morbidity may result, patients with HSV-2 meningitis and/or myeloradiculitis should be identified by means of thorough history-taking, careful examination and a specific viral diagnosis in order to enable adequate advice and counseling to be provided and to aid decision-making regarding antiviral therapy.

Detection of Herpes Simplex and Varicella-Zoster Viruses in Patients with Bell's Palsy by the Polymerase Chain Reaction Technique

Objectives: Infectious causes of peripheral facial paralysis are well known. Bells palsy, however, is an idiopathic facial paralysis, and the genesis is still unknown. Herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) have been suggested as etiologic agents. Methods: Twenty consecutive adult patients with Bells palsy were included in the study. Ten adult patients operated on for chronic otitis served as controls. A biopsy specimen from the posterior auricular muscle was resected within 72 hours after the onset of Bells palsy and was analyzed together with cerebrospinal fluid (CSF) by nested polymerase chain reaction for HSV-1 and VZV DNA. Serum samples were analyzed for antibodies to HSV-1 and VZV. Results: HSV-1 DNA was found in the muscle biopsy specimen from 1 of the 20 patients, but was not found in any of the CSF samples. VZV DNA was detected in the muscle biopsy as well as the CSF from 1 other patient. All controls were negative. Seventeen of 19 patients had stationary serum antibody concentrations to HSV-1, and none displayed an antibody titer rise. A significant antibody titer rise to VZV was found in 1 of 19 patients, whereas 17 of 19 had stationary antibody levels. Conclusions: HSV-1 or VZV DNA was detected in 10% of patients with Bells palsy in the present study. Viral replication might already have declined in many cases at the onset of the palsy. Use of an HSV-1/VZV polymerase chain reaction on a muscle biopsy specimen or CSF does not seem to be the method of choice for rapid etiologic diagnosis in the acute phase of Bells palsy.

Acute Viral Infections of the Central Nervous System in Immunocompetent Adults: Diagnosis and Management

Patients with viral infections of the central nervous system (CNS) may present with a variety of neurological symptoms, most commonly dominated by either encephalitis or meningitis. The aetiological panorama varies in different parts of the world as well as over time. Thus, virological first-line diagnostics must be adapted to the current epidemiological situation and to the individual patient history, including recent travels. This review focuses on the diagnostics and treatment of viral CNS infections in the immunocompetent host from a Northern European perspective. Effective vaccines are available for viruses such as poliovirus and tick-borne encephalitis virus (TBEV) and for the childhood diseases morbilli (measles), rubella (German measles), parotitis (mumps) and varicella (chickenpox). However, cases do appear due to suboptimal immunization rates. In viral CNS infections, epidemiological surveillance is essential for establishing preventive strategies and for detecting emerging viruses. Knowledge of the possibilities and limitations of diagnostic methods for specific viral CNS infections is vital. A positive cerebral spinal fluid (CSF) polymerase chain reaction (PCR) finding is usually reliable for aetiological diagnosis. The demonstration of intrathecal antibody synthesis is useful for confirming the aetiology in a later stage of disease, hitherto sufficiently evaluated in herpes simplex encephalitis (HSE) and tick-borne encephalitis (TBE). Despite improved virological and differential diagnostic methods, aetiology remains unknown in about half of the cases with suspected viral encephalitis. Antiviral treatment is available chiefly for infections caused by herpesviruses, and acyclovir (aciclovir) is the drug of choice for empirical therapy in suspected viral encephalitis. However, randomized, controlled antiviral trials have only been conducted for HSE, while such studies are lacking in other viral CNS infections. Viral cytolysis and immune-mediated mechanisms may contribute to varying extents to neurological damage. Although the brain damage is believed to depend, to a varying degree, on the intrathecal host immune response, the use of corticosteroids in viral CNS infections is scarcely studied, as is specific treatment for neuroinflammation. Improved antiviral and immunomodulating treatment is desirable. Since neurological sequelae are still abundant, follow-up after severe viral CNS disease must include a neuropsychological assessment and an individually adapted rehabilitation plan.

Monitoring of Herpes Simplex Virus DNA Types 1 and 2 Viral Load in Cerebrospinal Fluid by Real-Time PCR in Patients With Herpes Simplex Encephalitis

A quantitative polymerase chain reaction (PCR) assay was evaluated retrospectively on 92 cerebrospinal fluid (CSF) samples from 29 patients with herpes simplex virus (HSV) encephalitis with the aim to study if the concentration of HSV genomes can be used as a prognostic marker and for monitoring of antiviral therapy. The results were compared to those obtained previously by nested PCR, and the numbers of HSV genomes/ml were evaluated in correlation to patient outcome and treatment. The aims were to compare the sensitivity of a conventional nested PCR to a quantitative PCR, to investigate the range of HSV genome concentration in initial samples and to evaluate possible relationships between the HSV DNA concentrations in CSF, neopterin levels, and outcome of disease. The 29 initial samples contained between 2 × 102 and 42 × 106 HSV genomes/ml. There was no apparent correlation between the amount of HSV DNA in the initial samples and income status, initial neopterin levels, or prognosis. The number of HSV genomes/ml declined after treatment in all patients, but HSV DNA was still detectable after day 20 in 3 out of 16 patients. A long duration of genome detectability was found to correlate with poor outcome. There was no difference in sensitivity between the nested PCR and the quantitative PCR. While the quantitative PCR is more rational than a nested PCR, the quantitation of HSV genomes does not seem very useful as a prognostic marker in HSV encephalitis. J. Med. Virol. 81:1432–1437, 2009.

Increased Detection Rate in Diagnosis of Herpes Simplex Virus Type 2 Meningitis by Real-Time PCR Using Cerebrospinal Fluid Samples

ABSTRACT Efficient and sensitive diagnostic methods are needed in the management of virus infections in the central nervous system. There is a demand for an evaluation of the sensitivity of PCR methods for early diagnosis of meningitis due to herpes simplex type 2 (HSV-2) and varicella-zoster virus (VZV). The objective of this study was to evaluate real-time PCR in the detection of HSV-2 and VZV DNA from cerebrospinal fluid (CSF) for etiological diagnoses in clinically well-characterized cases of primary and recurrent aseptic meningitis. Samples from 110 patients, 65 of whom were diagnosed with or were strongly suspected of having HSV-2 meningitis and 45 with acute aseptic meningitis of unknown causes, were analyzed. Results were compared with the outcome of nested PCR for HSV-2 infection. Clinical parameters were analyzed in relation to CSF viral load. With real-time PCR, HSV-2 DNA was found in CSF from 80% (52/65) of patients with clinical HSV-2 meningitis compared to 72% (47/65) found by nested PCR. The sensitivity of real-time HSV-2 PCR was found to be 87% (33/38) in primary and 70% (19/27) in recurrent meningitis. The HSV-2 viral load was significantly higher in primary than in recurrent meningitis and correlated with the degree of inflammation. VZV DNA was detected in 2 of 45 samples (4.4%). Real-time PCR for the diagnosis of HSV-2 meningitis was evaluated in a large, clinically well-characterized sample of material and found to identify more cases than nested PCR in the group of patients with recurrent meningitis. Quantification of DNA enables further research of disease prognosis and treatment.

High diagnostic yield by CSF-PCR for entero- and herpes simplex viruses and TBEV serology in adults with acute aseptic meningitis in Stockholm

Acute aseptic meningitis (AAM) affects 10–20/100,000 inhabitants per years in Sweden. Up to the beginning of the 1980s the diagnoses were made by virus isolation and/or determination of viral antibodies in serum. The development of PCR for detection of viruses in CSF samples has increased the sensitivity and diagnostic efficiency considerably. We investigated the aetiology of AAM and the diagnostic efficiency in an adult population in Stockholm, using a limited first-line combination of microbiological assays. CSF and serum samples, consecutively collected in 419 patients with clinical symptoms of AAM in northern Stockholm during 1999–2004, were included. PCR assays for herpes simplex virus (HSV) DNA and enterovirus (EV) RNA in the CSF as well as ELISA for IgM in serum to tick-borne encephalitis virus (TBEV) were performed routinely. A viral diagnosis was obtained in 255 of the 419 cases (62%) with these routinely performed assays. Clinical findings in combination with additional diagnostic tests resulted in an overall aetiological yield of 72%. EV was the major causative agent (27%) followed by TBEV (21%) and HSV-2 (19%). We conclude that consistent use of CSF-PCR for EV and HSV and TBEV serology established a diagnosis in the majority of AAM patients.

Recurrent Encephalitis due to Trimethoprim Intake

We wish to report a 76-year-old woman with 2 episodes of meningitis related to the intake of trimethoprim. On both occasions the patient demonstrated encephalitic symptoms and a pathological electroencephalogram with cerebral function disturbances. A similar case with encephalitic symptoms due to trimethoprim has not been reported earlier.