Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults
ABSTRACT 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.
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).
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.
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.
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ABSTRACT: Introduction. Relapse after Herpes simplex encephalitis (HSE) occurs in 12-26%, it is related to antiviral treatment in dose low and less than 14 days' duration. A case of relapse after optimal antiviral treatment is reported. Description. a three years old female presented with seven days fever, vomiting, behavioral changes and focal seizures, la- ter generalized and recurrent. She had to be admitted into the Intensive Care Unit (ICU). The CSF study showed mononuclear pleocytosis of 197 WBCS/μL; proteins in 38 mg/dL and glucose of 38 mg/dL, the CSF culture and latex agglutination test were negative. PCR test was positive for VHS in CSF and IgM antibodies (+) in serum. The MRI and EEG showed localized right temporal abnormalities. Acyclovir was initiated to 60 mg/kg per day IV for 21 days and she was discharged. Thirty days later she presented again behavioral changes without fever. The CSF had 10 WBCS/μL, positive IgG-VHS antibodies but negative VHS-PCR; both serum IgG and IgM antibodies were positive to VHS. In the MRI, an increased enhancement was observed in whole right brain hemisphere and white matter of left frontal lobe with right brain atrophy. The EEG showed an increased focal abnormality, asymmetric and delta activity. Immunoglobulin serum levels were normal. Acyclovir was restarted to 60 mg/kg per day, prednisone 2 mg/kg per day for 14 days and IGIV 400mg/kg per day for 5 days. After treatment the high signal intensity observed in MRI disappeared. Discussion. at least two different mechanisms have been related with relapse after HSE: 1) viral replication restarting; or 2) a post-infectious immuno-inflammatory process. Due to the difficulty to identify in some cases, like this one, the implied mecha- nism, we decided to offer a treatment for the two options with the purpose of improving the prognosis of the patient. Fecha de aceptación: diciembre 2007
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ABSTRACT: Domino logic is one of the most popular dynamic circuit configurations for implementing high- performance logic designs. Since domino logic is inherently non-inverting, it presents a fundamental constraint of implementing logic functions without any intermediate inversions. Removal of intermediate inverters requires logic duplication for generating both the negative and positive signal phases, which results in significant area overhead. This area overhead can be substantially reduced by selecting an optimal output phase assignment, which results in a minimum logic duplication penalty for obtaining inverter-free logic. In this paper, we present this previously unaddressed problem of output phase assignment for minimum area duplication in dynamic logic synthesis. We give both optimal and heuristic algorithms for minimizing logic duplication.Computer-Aided Design, 1996. ICCAD-96. Digest of Technical Papers., 1996 IEEE/ACM International Conference on; 01/1996
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ABSTRACT: Herpes simplex encephalitis (HSE) is the most common cause of non-epidemic, acute and fatal viral encephalitis. A pronounced mortality and morbidity remains in HSE despite antiviral treatment. There is evidence of a vigorous intrathecal immune activity in acute phases of HSE and of persistently increased activity at follow-ups after years. The role of apoptosis of neuronal cells in HSE patients as a mechanism of damage has been brought up lately. We hypothesize that the severity and the progression of the cerebral injury resulting from HSE can be evaluated by quantitative measurement of a compartment of immune activation molecules i.e. soluble Fas (sFas) involved in apoptosis through the Fas/Fas Ligand pathway. Consecutive cerebrospinal fluid (CSF) samples from a prospectively followed cohort, included in an antiviral treatment trial in HSE, were enrolled for quantitative measurement of sFas using commercial capture ELISA. In total, CSF samples from 49 patients with HSE, 63 patients with non-HSE encephalitis and 18 healthy individuals were studied. High levels of sFas were expressed in CSF samples collected between days 0-45 after neurological onset in 41/49 (84%) HSE patients, whereas only 21/63 (33%) of non-HSE patients and none of 18 healthy controls demonstrated measurable levels of sFas. Following the consecutive CSF sFas levels over the time and considering the clinical state of patients at admission, their neurological or lethal outcome at 12 months, and antiviral treatment, we observed that HSE patients with severe neurological sequels revealed an increase in changes of CSF sFas as compared to patients with mild or moderate neurological outcome (57.6+/-55.6 pg/ml, n=10 versus 26.3+/-97.5 pg/ml, n=14; P=0.008). Also HSE patients undergoing vidarabine treatment expressed significantly higher levels of changes of CSF sFas when compared to acyclovir-treated patients (63.7+/-52.8 pg/ml, n=9 versus 26.1+/-98.4 pg/ml, n=14; P=0.003). Interestingly, regardless of the clinical state at admission, and subsequent disease progression of the HSE patients, we could not observe any significant differences in the CSF sFas levels during the first 7 days of neurological symptoms. These observations underline the role of immunological response throughout the course of HSV infection in the brain and the role of the Fas/FasL pathway in particular in disease progression of HSE. The findings further enforce the need of expanding the knowledge of the pathogenesis of HSE to direct to more effective, in particular not only antiviral but also anti-apoptotic or anti-inflammatory treatment.Journal of Neuroimmunology 03/2006; 171(1-2):171-6. DOI:10.1016/j.jneuroim.2005.10.003 · 2.79 Impact Factor