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

OBJECTIVES: To 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. METHODS: A 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. Fifty nine batched, paired CSF and serum samples from the eight HSE patients were analysed for soluble activity markers, predominantly cytokines and mediators (interferon-gamma, soluble CD8, tumour necrosis factor-alpha, and interleukin-10), amount of HSV-DNA and markers of glial and neuronal destruction (neurofilament protein, glial fibrillary acidic protein, S-100-beta, and neuron specific enolase). RESULTS: Relapse 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. CONCLUSION: The 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.

Regional cerebral blood flow scintigraphy in tick-borne encephalitis and other aseptic meningoencephalitis.

UNLABELLED: In a prospective study, regional cerebral blood flow (rCBF) was studied in patients with aseptic meningoencephalitis at 6 wk and 1 yr after onset of disease. METHODS: Patients with tick-borne encephalitis ([TBE] n = 73) and meningoencephalitis of other etiology ([non-TBE] n = 56) were investigated with rCBF-scintigraphy (SPECT). SPECT images in the acute phase of disease and at long-term follow-up were analyzed for blood-flow disturbances and their localization in the central nervous system and were correlated to clinical course and outcome. RESULTS: Decreased rCBF was seen in 50% of patients after 6 wk (TBE 49%, non-TBE 50%) and in 46% (TBE 47%, non-TBE 46%) after 1 yr. The decrease in rCBF was moderate in 18% and 11% at 6 wk and in 8% and 9% at the 1-yr follow-up of TBE and non-TBE patients, respectively. Reduced rCBF was significantly more common among patients with encephalitis than among those with meningitis, and more common in males. The distribution of cerebral flow changes was predominantly patchy or multifocal. At long-term follow-up, improvement in rCBF was seen in 28 of 109 patients (26%), but worsening of decreased rCBF was demonstrated in 19 of 109 (17%). In TBE patients, remaining neurological symptoms at 6 wk of disease were associated with worsening of decreased rCBF at the 1-yr follow-up. CONCLUSION: With SPECT, rCBF changes, mostly slight and patchy or multifocal, were detected in patients with aseptic meningoencephalitis. Decreased rCBF was more frequent in patients with moderate-to-severe encephalitis, although the clinical use in predicting long-term outcomes in aseptic meningoencephalitis (e.g., TBE) seems limited.

Intrathecal IgM, IgA and IgG antibody response in tick-borne encephalitis. Long-term follow-up related to clinical course and outcome.

BACKGROUND: Tick-borne encephalitis (TBE) of western subtype causes long-term morbidity and is considered a health problem in Scandinavia, eastern and central parts of Europe and Russia. The pathophysiology is not fully elucidated. As TBE RNA is rarely demonstrable in cerebrospinal fluid (CSF) the kinetics of the CSF antibody response to the disease has attracted attention. OBJECTIVES: To investigate the intrathecal TBE-specific antibody response and to correlate its intensity and persistence to the clinical course. To compare indirect, commercially-based ELISA methods indexed against albumin ratio or IgG ratio with the capture ELISA method for the establishment of CSF response. STUDY DESIGN: The specific IgM, IgG and IgA antibody responses in serum and CSF were analysed in 69 Swedish patients included in a prospective study of TBE from the acute phase up to 11-13 months after onset. RESULTS: Antibody response by all three classes was demonstrable in serum and CSF. All methods were useful, but capture technique was the most sensitive and results were easiest to interpret. Peak IgM activity was seen early during the disease and persisted after 6 weeks. Maximum IgG levels were encountered in late convalescent samples (median 6 weeks). Intrathecal antibody production was demonstrable in nearly all patients: in 41% days 0-6, in 97% days 7-19, in 98% days 21-61 and-at lower levels-in 84% of the patients after 1 year (50/52 of CSF-serum sampled in the interval 11-61 days). Day 9 after onset, patients with dominating encephalitic symptoms showed significantly lower intrathecal IgM activity. The persistence of serum and CSF antibodies did not correlate to severity of disease. CONCLUSIONS: Capture IgM and IgG assays were superior to indirect ELISA. Low early CSF IgM response correlated to encephalitic symptoms, otherwise the intensity and duration of intrathecal antibody response were of limited value for the prediction of clinical course and long-term outcome.

Tick-bone encephalitis in Sweden in relation to aseptic meningo-encephalitis of other etiology: a prospective study of clinical course and outcome.

A total of 149 patients with clinical symptoms of acute viral meningo-encephalitis were enrolled in this study from June 1991 to December 1993. Tick-borne encephalitis (TBE) was diagnosed in 85 of the 149 patients (males 54%, median age 42 years (range 15-78)). The initial clinical appearance of TBE was classified as mild (mainly meningeal; (n = 47), moderate (n = 31) or severe (n = 7), more or less encephalitic. The most common acute symptoms of encephalitis were ataxia (26%), altered consciousness (20%), decreased concentration or memory (9%), irritable response to light and sound (28%), tremor (9%) and dysphasia (9%). Spinal nerve paralysis (11%) occurred in all three clinical stages and did not correlate with the severity or duration of encephalitis. The duration of hospitalisation, the time on the sick-list and the time to recovery were significantly longer in TBE patients. All patients survived, but many patients with TBE suffered an extended period of neurological dysfunction. Of patients with TBE 80% (68/85) showed persisting symptoms of CNS dysfunction on follow-up at week 6, compared with 55% (35/64) of the patients with aseptic meningitis of other aetiology. The corresponding figures after 1 year were 40% (33/83) and 20% (13/64). One year after TBE 13 (28%) patients with initially mild, meningeal symptoms had decreased memory and decreased concentration capacity, dysphasia or ataxia. Spinal nerve paralysis persisted after 1 year in 5 of 9 patients with TBE. In conclusion, TBE in Sweden is associated with a significant morbidity and a post-TBE syndrome existed after 1 year in more than one third of the patients.

Intrathecal production of neopterin and beta 2 microglobulin in tick-borne encephalitis (TBE) compared to meningoencephalitis of other etiology.

To study the pathophysiology of tick-borne encephalitis (TBE), the kinetics of neopterin and beta 2 microglobulin (beta 2M) production were measured in sequential, cerebrospinal fluid (CSF) and serum samples in 133 patients with aseptic meningoencephalitis (TBE, n = 72; non-TBE, n = 61). Intrathecal production of neopterin was demonstrable in all patients. Neopterin levels in CSF were elevated already at day 2: geometric mean value in TBE 36 nmol/l (range 1-253), in the non-TBE group 29 nmol/l (0.2-96). At day 9 and week 6 the neopterin level was significantly higher in TBE (86 (19-725) and 17 (4-122) nmol/l) than in non-TBE (28 (5-109) and 3 (0.2-58) nmol/l) (p < 0.001). After 1 year CSF levels were within the normal range. The beta 2M response in CSF followed the pattern of neopterin. The intensity and duration of neopterin and beta 2M was not correlated to the clinical course. Neopterin seems to be a more sensitive indicator of intrathecal T-cell response and inflammatory reaction than beta 2M. The results indicate that a long-lasting strong inflammatory reaction is of pathophysiological significance in TBE.

Herpes simplex encephalitis.

Herpes simplex encephalitis (HSE) is a life-threatening condition with high mortality as well as significant morbidity in survivors. In most cases herpes simplex virus type 1 (HSV-1) is responsible for the diseases, however, the type 2 virus (HSV-2) is involved in 4-6% of cases. Primary HSV infection is identified in only one-third of patients with HSE. The majority of cases are recorded in adults with recurrent HSV infection who are already seropositive for HSV at the onset of symptoms, but only 6-10% of these patients have a history of labial herpes. Acute focal, necrotizing encephalitis with inflammation and swelling of the brain tissue are consistent features of the pathology of HSE. HSV-induced cytolysis certainly damages neurones, oligodendrocytes and astrocytes, but the role of cellular and humoral immunopathology is important. A complex network of cytokines seems to be active in regulating the local immune response and inflammation during and after HSE. Brain biopsy, serological analysis of intrathecal HSV antibodies and detection of HSV-DNA in the cerebrospinal fluid (CSF) are all useful techniques to confirm the aetiology of HSE. Neurodiagnostic tests which support a presumptive diagnosis of HSE include: CSF analysis, electroencephalography, computer-assisted tomography and magnetic resonance imaging. Although aciclovir is the treatment of choice in HSE, mortality and morbidity still remain problematic. Long-term follow-up indicates that intrathecal cellular and humoral activation persist in HSE.

Cytokines and other markers of intrathecal immune response in patients with herpes simplex encephalitis.

Sequential samples of serum and cerebrospinal fluid (CSF), from 9 patients with herpes simplex encephalitis (HSE), were analyzed for cytokines and soluble cytokine receptors. The response to herpes simplex virus was characterized by a vigorous compartmentalized immune response. The intrathecal response comprised three different phases: an acute stage (first week of illness), characterized by elevated CSF levels of interleukin (IL)-6 and interferon-gamma; an early convalescence stage (weeks 2-6 after onset of disease), associated with peaking levels of tumor necrosis factor-alpha and late markers of the specific T cell-mediated immune response, soluble IL-2 receptor, and soluble CD8 antigen (sCD8); and finally, a late convalescence stage, lasting months to years and associated with persistently increased levels of sCD8 in particular. These findings show the compartmentalization and kinetics of the inflammatory response in HSE and demonstrate persistence of the intrathecal inflammatory process, which may have implications for antiviral and antiinflammatory therapy.

Persistent intrathecal immune activation in patients with herpes simplex encephalitis.

Neopterin and beta 2-microglobulin (beta 2M) levels were analyzed in sequential cerebrospinal fluid (CSF) and serum samples from 20 patients with herpes simplex encephalitis (HSE) and 30 patients with acute febrile encephalopathy of other cause (non-HSE). Markedly elevated acute phase CSF levels of neopterin and beta 2M were found in 19 HSE patients, but the levels were only moderately increased in most of those with non-HSE. Neopterin levels were analyzed in an additional 15 HSE patients who died within a month of the onset of neurologic symptoms and correlated with the clinical severity of the HSE. After HSE, but not after non-HSE, increased levels of neopterin and beta 2M persisted for a long time (> or = 13 years). Specific intrathecal IgG activity persisted in all but 2 HSE patients. These findings indicate that there is a vigorous acute inflammatory response and a long-term persistence of intrathecal cellular and humoral immune activity in HSE.

Encephalitis in immunocompetent patients due to herpes simplex virus type 1 or 2 as determined by type-specific polymerase chain reaction and antibody assays of cerebrospinal fluid.

A herpes simplex virus type 2 (HSV 2) etiology was sought in 93 consecutive cases of herpes simplex encephalitis (HSE) in immunocompetent post neonate patients. Antibodies to HSV 2 glycoprotein G antigen were determined by an enzyme-linked immunosorbent assay (ELISA) and HSV 2 DNA in cerebrospinal fluid (CSF) by a nested polymerase chain reaction (PCR) assay with primer pairs in the glycoprotein G gene. Evidence of HSV 2 infection was found in 6 patients; HSV 2 DNA was demonstrated in CSF and the intrathecal HSV 2 antibody response confirmed the findings. Five of the 6 patients with HSV 2 encephalitis presented a clinical picture, CSF, EEG, and CT findings characteristic of severe HSE. An atypically mild clinical course was seen in one patient. HSV 2 should be considered as an etiological agent in the viral diagnosis of HSE. With a combination of nested PCR assays for HSV 1 (primer pairs in the glycoprotein D gene) and HSV 2 in 10 microliters of CSF with no other preparation than freeze-thawing, HSV 1 or HSV 2 DNA was detected in 88 out of 93 (95%) of the first CSF specimens collected after the onset of neurological HSV disease. These findings extend and confirm previous results with PCR as a rapid and sensitive tool for early diagnosis of HSE.

Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid.

With the aim of improving early diagnosis of herpes simplex encephalitis a polymerase chain reaction (PCR) assay with two "nested" primer pairs was developed for the amplification of herpes simplex virus DNA in cerebrospinal fluid (CSF). Southern blotting was used to confirm the specificity of the amplification. The assay was applied to 151 CSF samples from 43 consecutive patients with herpes simplex encephalitis verified by the finding of herpes simplex virus/viral antigen in a brain biopsy sample or at necropsy (13) and/or intrathecal production of IgG antibody to the virus (40). As controls, 87 CSF samples from 60 patients with acute febrile focal encephalopathy (initially suspected to be herpes simplex encephalitis but excluded by the absence of intrathecal antibody synthesis) were tested. PCR detected herpes simplex virus DNA in 42 of the 43 patients with proven herpes simplex encephalitis; all but 1 were positive in the first CSF sample taken. The 1 PCR-negative patient had been treated with acyclovir from 20 h after the onset of symptoms. All the control subjects were PCR negative, as were 270 internal contamination controls. The PCR result remained positive in samples drawn up to 27 days after the onset of neurological symptoms. This method is a rapid and non-invasive means to diagnose herpes simplex encephalitis; it is highly sensitive and specific.

Herpes simplex encephalitis.

Diagnostic and therapeutic advances in the management of herpes simplex encephalitis (HSE) have been significant over the last decade. Serological analysis of simultaneously drawn CSF and serum samples allows reliable diagnostics of HSE, but not until after 3-10 days following the onset of neurological symptoms. Polymerase chain reaction (PCR) assay with two nested primer pairs, being developed for the amplication of HSV DNA in CSF, was applied to 151 CSF samples from 43 consecutive patients with HSE. As controls, 87 CSF samples from 60 patients with acute febrile focal encephalopathy (initially suspected to be HSE but excluded by the absence of intrathecal HSV antibody synthesis) were tested. PCR detected HSV DNA in 42/43 patients and remained positive up to 27 days after the onset of neurological symptoms. By a combination of PCR and serological analysis of intrathecal HSV antibody synthesis, aetiological diagnosis of HSE can be made by one or both methods from early disease and up to 15 years after the onset of HSE. In one Swedish and one American trial of acyclovir versus vidarabine in HSE, acyclovir 10 mg/kg 8-hourly for 10 days significantly decreased mortality as well as morbidity in the survivors. Early start of acyclovir treatment is necessary in HSE; the prognosis is correlated to age and stage of consciousness and neurological involvement at start of the therapy. Data has shown the need of neuropsychological assessment in final determination of the level of disability after HSE. The profiles and dynamics of the inflammatory cascade of cytokines from lymphocytes and other brain cells, provoked by the intracerebral HSV infection, needs to be characterized to enable understanding of the pathogenic process in HSE and hence its adequate antiinflammatory treatment.

Neurovirulence of herpes simplex virus types 1 and 2 isolates in diseases of the central nervous system.

Herpes simplex virus (HSV) isolates derived from the central nervous system of ten patients with HSV-1-induced encephalitis, one patient with multiple sclerosis, and 14 patients with HSV-2-induced meningitis were investigated for neurovirulence by assaying the LD50 after nose and intracerebral (i.c.) inoculation of mice. HSV-1 encephalitis strains were significantly more virulent after nose inoculation (i.e. neuroinvasive) when compared with HSV-1 isolates from patients with oral lesions only, whereas HSV-2 meningitis strains were significantly more virulent after i.c. inoculation when compared with HSV-2 isolates from patients with genital lesions only. No correlation between high neurovirulence (defined as low LD50 for both routes of infection) and replication in cell cultures of neuronal and non-neuronal cell lines was found, but the weakly neurovirulent HSV-1 strain isolated from a patient with multiple sclerosis gave low replication yields. After nose inoculation, a highly neuroinvasive HSV-1 laboratory reference strain replicated to high titers in nose tissue, the trigeminal ganglia and brainstem, while a strain with low neuroinvasiveness but high i.c. virulence replicated less well in the brainstem. Neuroinvasiveness of the virus strain might be one factor of relevance in the pathogenesis of HSV-1 encephalitis in man.

HIV isolation from cerebrospinal fluid in relation to immunological deficiency and neurological symptoms.

Human immunodeficiency virus (HIV) could be isolated from the cerebrospinal fluid (CSF) of the majority (62%) of 72 patients in various stages of HIV infection. This high rate of successful virus isolation was achieved only when the time from lumbar puncture to initiation of the cell cultures was short, i.e. not exceeding 5 h. The HIV isolation rates were equally high in patients with persistent generalized lymphadenopathy (PGL), AIDS-related complex (ARC) and AIDS. Although the HIV recovery rate was low in patients with normal immunological parameters it was not correlated with the degree of severity of the immunodeficiency in the other patients. Furthermore, the recovery rates were not significantly correlated to the duration of the infection. HIV was recovered as often from patients with neurological symptoms as from patients without such symptoms. These findings suggest that in the majority of patients there is central nervous system (CNS) involvement early in the course of HIV infection and that HIV replication in the CNS may occur in the absence of a pronounced systemic cellular immunodeficiency and frequently without causing overt neurological symptoms.

Treatment of Lyme borreliosis with emphasis on neurological disease.

We have studied 113 patients with neurologic Lyme borreliosis and meningitis who were treated with intravenous high-dose antibiotics (penicillin G, 12 g, mostly for 14 days in 47 patients; penicillin G, 9 g, mostly for 10 days in 58 patients; doxycycline, 200 mg, in 5 patients; and cefuroxime, 4.5-9 g, in 3 patients). Seventy percent of the patients had peripheral nerve symptoms and 13% had central nervous symptoms. Almost half of the patients were treated more than 4 weeks after the onset of symptoms and 15% of the patients had persisting or progressive symptoms between 4 and 11 months. There seemed to be clinical benefit as well as a decrease of spinal fluid pleocytosis and spinal proteins. No significant symptoms of Herxheimer reaction were demonstrated.

Clinical manifestations and diagnosis of neuroborreliosis.

Lyme borreliosis has in a few years turned out to be a health problem not only in the United States, but also in many European countries. When it affects the nervous system, Lyme borreliosis acts as the great disease imitator. Because of this characteristic it is often difficult to diagnose on clinical grounds. Patients with neuroborreliosis might appear within all medical disciplines. Clinical markers, such as preceding tick bite and/or ECM, are important clues to the diagnosis. Mononuclear pleocytosis and elevated CSF protein are present in most patients with neuroborreliosis. Final evidence for the diagnosis is the demonstration of specific antibodies in serum and/or CSF. Measurement of antibody titers should be carried out in both serum and CSF, since these methods are complementary when trying to obtain a serological diagnosis of neuroborreliosis.