Herpes Simplex Encephalitis Patients Research Articles

Perirhinal Contributions to Human Visual Perception

SummaryMedial temporal lobe (MTL) structures including the hippocampus, entorhinal cortex, and perirhinal cortex are thought to be part of a unitary system dedicated to memory [1, 2], although recent studies suggest that at least one component—perirhinal cortex—might also contribute to perceptual processing [3–6]. To date, the strongest evidence for this comes from animal lesion studies [7–14]. In contrast, the findings from human patients with naturally occurring MTL lesions are less clear and suggest a possible functional difference between species [15–20]. Here, both these issues were addressed with functional neuroimaging in healthy volunteers performing a perceptual discrimination task originally developed for monkeys [7]. This revealed perirhinal activation when the task required the integration of visual features into a view-invariant representation but not when it could be accomplished on the basis of simple features (e.g., color and shape). This activation pattern matched lateral inferotemporal regions classically associated with visual processing but differed from entorhinal cortex associated with memory encoding. The results demonstrate a specific role for the perirhinal cortex in visual perception and establish a functional homology for perirhinal cortex between species, although we propose that in humans, the region contributes to a wider behavioral repertoire including mnemonic, perceptual, and linguistic processes.

Temporal lobe lesions and semantic impairment: a comparison of herpes simplex virus encephalitis and semantic dementia

Both herpes simplex virus encephalitis (HSVE) and semantic dementia (SD) typically affect anterior temporal lobe structures. Using voxel-based morphometry (VBM), this study compared the structural damage in four HSVE patients having a semantic deficit particularly affecting knowledge of living things and six SD patients with semantic impairment across all categories tested. Each patient was assessed relative to a group of control subjects. In both patient groups, left anterior temporal damage extended into the amygdala. In patients with HSVE, extensive grey matter loss was observed predominantly in the medial parts of the anterior temporal cortices bilaterally in SD patients the abnormalities extended more laterally and posteriorly in either the left, right or both temporal lobes. Based on a lesion deficit rationale and converging results from several other sources of evidence, we suggest that (i) antero-medial temporal cortex may be important for processing and differentiating between concepts that are 'tightly packed' in semantic space, such as living things, whereas (ii) inferolateral temporal cortex may play a more general role within the semantic system.

Computed tomography perfusion usefulness in early imaging diagnosis of herpes simplex virus encephalitis

An early diagnosis is crucial in herpes simplex virus encephalitis patients in order to institute acyclovir therapy and reduce mortality rates. Magnetic resonance imaging (MRI) is considered the gold standard for evaluation of these patients, but is frequently not available in the emergency setting. We report the first case of a computed tomography (CT) perfusion study that helped to establish a prompt diagnosis revealing abnormal increase of blood flow in the affected temporoparietal cortex at an early stage.

Serial ultrasound assessment of the basal vein of Rosenthal in HSV encephalitis

Herpes simplex virus encephalitis (HSVE) typically affects the baso-temporal brain. The venous blood drainage of this region mainly occurs via the basal vein of Rosenthal (BVR), which can easily be monitored by transcranial color-coded duplex sonography (TCCS), and might be a useful parameter for the activity of the disease. Serial blood flow velocity (BFV) measurements of the BVR and the basal cerebral arteries were performed in five acute HSVE patients by means of transcranial color-coded duplex sonography (TCCS). Remarkable increased BFV of the BVR at the affected side was found in all patients, showing a maximum within the first 8 d of infection followed by a tendency toward normalisation during the next weeks. In comparison, changes of BFV in the basal cerebral arteries were much more heterogeneous. Our findings suggest that TCCS measurements of the BVR might be used as an additional diagnostic bed-side tool to evaluate patients with HSVE during the acute stage. (E-mail: florian.doepp@charite.de)

Modulation of sFas indicates apoptosis in human herpes simplex encephalitis

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.

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

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.

Herpes simplex encephalitis in a post-operative patient with a negative PCR

We describe a case in which an immunosuppressed post operative patient had a sudden neurological deterioration due to Herpes Simplex Virus encephalitis (HSV). Of particular interest was the presence of a negative Polymerase chain reaction (PCR) to Herpes simplex virus (HSV). Potential hazards in the management of HSV encephalitis patients in the intensive care department are discussed.

Dissociations in processing past tense morphology: neuropathology and behavioral studies.

Neuropsychological research showing that the regular ("jump-jumped") and irregular ("drive/drove") past tense inflectional morphology can dissociate following brain damage has been important in testing claims about the cognitive and neural status of linguistic rules. These dissociations have been interpreted as evidence for two different computational systems-a rule-based system underlying the processing of regulars and the irregulars being individually listed in the mental lexicon. In contrast, connectionist accounts claim that these dissociations can be modeled within a single system. Combining behavioral data from patients with detailed information about their neuropathology can, in principle, provide strong constraints on accounts of the past tense. In this study, we tested five nonfluent aphasic patients, all of whom had extensive left hemisphere (LH) damage involving the left inferior frontal gyrus and underlying structures, and four patients with semantic deficits following herpes simplex encephalitis (HSE) who had extensive damage to the inferior temporal cortex. These patients were tested in experiments probing past tense processing. In a large priming study, the nonfluent patients showed no priming for the regular past tense but significant priming for the irregulars (whereas controls show priming for both). In contrast, the HSE patients showed significantly impaired performance for the irregulars in an elicitation task. These patterns of behavioral data and neuropathology suggest that two separable but interdependent systems underlie processing of the regular and irregular past tense.

Polymerase chain reaction-proved herpes simplex encephalitis in children.

To investigate the clinical features in PCR-proved herpes simplex encephalitis (HSE) in children, excluding neonates. We studied the clinical manifestations and laboratory findings of 24 children in whom the diagnosis of herpes infection was confirmed by the PCR assay and compared them with those of 38 children with central nervous system infections other than HSE. There were no significant differences between groups in the percentage with fever or convulsions, the initial neurologic symptoms or the level of consciousness. Analysis of cerebrospinal fluid showed no significant differences in the cell count or concentration of protein and glucose. Computerized tomography of the brain identified localized abnormalities in 18 (75%) of the 24 HSE patients and in 10 (31%) of the 32 non-HSE patients (P = 0.001). Periodic lateralized epileptiform discharges, abnormal findings on electroencephalography, were detected in 8 (36%) of 22 HSE patients and in none of the non-HSE patients (P = 0.0001). The rates of moderate to severe morbidity and death were significantly higher in the HSE patients than in the non-HSE patients. Of the 9 HSE patients with a Glasgow Coma Scale score > or = 11, all patients recovered completely. HSE patients younger than 3 years of age were more likely to develop severe sequelae or to die of the disorder than older patients (P = 0.02). There were no specific clinical characteristics of HSE patients. The results of electroencephalography and computerized tomography were helpful, but not confirmatory, in diagnosing HSE. The Glasgow Coma Scale score and age significantly influenced the mortality and morbidity in the HSE patients.

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.

Serodignosis of herpes simplex encephalitis by antibody capture enzyme-linked immunosorbent assay

The sensitivity of a herpes simplex virus (HSV) IgG capture enzyme-linked immunosorbent assay was tested in 103 cerebrospinal fluid (CSF) and serum samples from 47 patients with herpes simplex encephalitis (HSE). Significant differences between CSF and serum absorbances were found in all HSE patients; earlier in three out of 30 patients by the capture technique than by the indirect ELISA. In follow-up samples with exceedingly high anti-HSV activity, maximal absorbance values were found in CSF and serum resulting in falsely-negative absorbance differences. Reanalysis with a lower concentration of capture anti-IgG solved the problem. This lower anti-IgG concentration was found suboptimal for analysis of early specimens. The specificity was tested in specimens from 115 patients without intrathecal anti-HSV production as determined by indirect ELISA. Five out of 73 patients with focal encephalitis of non-HSV origin had low level positive capture results. Four of them had varicella zoster (VZ) meningoencephalitis. Severe blood-CSF barrier damage did not interfere in seven patients tested. The IgG-capture was found advantageous to the indirect technique as the results were more sensitive and clearcut. It is less labour intensive and may be completed within five to six hours.

Specific IgG subclass reactivity in herpes simplex encephalitis.

Serum and cerebrospinal fluid (CSF) samples from 19 patients with a previous diagnosis of herpes simplex virus encephalitis (HSVE), from 14 patients with a previous diagnosis of non HSVE encephalitis and from 21 healthy subjects were examined to detect IgG subclasses 1-4 reactive with herpes simplex virus (HSV), cytomegalovirus (CMV) and varicella zoster virus (VZV). Antibodies to HSV were detected in CSF and serum from the 14 HSVE-patients with a reactivated HSV infection and from 3 of the 5 patients with a primary HSV infection. The predominant subclass pattern was an early HSV-specific IgG1 rise, followed by IgG3 and, more seldom, IgG4; HSV IgG2 was rarely seen. In HSVE patients, HSV IgG3 was absent in early samples and usually appeared 10-20 days after onset of disease. In 14 out of 16 seropositive healthy controls, on the other hand, HSV IgG3 was present in the CSF. Rising VZV IgG levels in serum and CSF were found in 11 HSVE patients. Eight of them showed signs of intrathecal VZV IgG1 synthesis. The VZV IgG reactivity was restricted to IgG1 in 7 of these whereas the HSV IgG subclass response also included IgG3 or 4. The appearance of several HSV IgG subclasses appeared to serve as a marker of HSV infection in spite of the serological VZV reaction, usually restricted to VZV IgG1. Intrathecal synthesis of the quantitatively minor HSV IgG3 and 4 subclasses was detected earlier than intrathecal synthesis of total HSV IgG, dominated by IgG1 in 4 patients with HSVE.

Detection of viral antigens in cerebrospinal fluid of patients with herpes simplex virus encephalitis.

Thirty-two cerebrospinal fluid (CSF) samples from eighteen patients with confirmed herpes simplex encephalitis (HSE) were assayed by an indirect enzyme-linked immunosorbent assay (ELISA) for the presence of viral antigens. The results are expressed as an antigen ratio distinguishing between herpes simplex virus (HSV) antigens containing samples and negative samples. Judged by this criterion a positive result was obtained in 33% of the patients. Overall, 25% of the CSF samples from HSE patients were positive. In one out of 33 control patients with other neurological disorders a positive antigen ratio was found. Two or more CSF samples were available from eleven patients. In six of these, the second or later samples showed a decreased antigen ratio when compared to the first CSF sample. An increase of the anti-HSV antibody titer was seen in the CSF of five of these six patients. Five out of six patients with a decreasing antigen ratio had an unfavorable outcome of their encephalitis, while a favorable outcome was seen in four of the five patients with an increasing or steady antigen ratio. A decrease of the antigen ratio in the course of HSE can be explained by the presence of immune complexes in CSF and may indicate a poor prognosis.

Anti-herpes simplex type 1 activity in IgG subclasses produced systemically and intrathecally in patients with herpes encephalitis.

The role of the humoral immune response in herpes simplex encephalitis (HSE) is largely unknown. The finding that herpes simplex virus type 1 (HSV 1) induced IgG Fc receptor binds to all IgG subclasses except IgG 3 prompted an investigation of anti-HSV activity in IgG subclasses from serum and cerebrospinal fluid (CSF) in ten patients with proven or highly probable HSE by means of a monoclonal antibody IgG subclass-specific solid-phase radioimmunoassay (SPRIA). In contrast to serum, CSF contained no or low anti-HSV IgG titres during the first 2 weeks of disease in five of seven patients tested. The IgG titres rose thereafter for at least 4 weeks after the start of illness and remained high in both serum and CSF up to 393 days. The anti-HSV IgG subclass distribution in serum was IgG 1 (ten of ten), IgG 2 (two of ten), IgG 3 (six of ten), and IgG 4 (six of ten). Two patients had a simultaneous anti-HSV IgG 3 and IgG 4 response. With the exception of one patient lacking anti-HSV IgG 4 and two patients lacking anti-HSV IgG 2, the subclass distribution in CSF was the same as in serum. The anti-HSV subclass distribution in sera from ten seropositive patients without evidence of recent herpes infection did not differ from that of the HSE patients, except that five of ten patients had simultaneous anti-HSV IgG 3 and IgG 4 responses. Thus we could not correlate the anti-HSV subclass response in patients with HSE with the subclass preference of the HSV-induced Fc receptor.

Effect of Vidarabine on Chronic Hepatitis B Virus Infection

SERA of patients with hepatitis B virus (HBV) infection contain several viral forms. The development of reproducible assays for these markers facilitates the evaluation of intervention with antiviral agents. Human leukocyte interferon, given systemically to patients with chronic HBV infection, resulted in a decrease in the Dane particle markers core antigen (HB_cAg), DNA polymerase, and the e antigen (HB_eAg) to undetectable levels in the serum.¹The hepatitis B surface antigen (HB_sAg) level also decreased in two interferon-treated patients. Vidarabine (adenine arabinoside), a purine nucleoside that inhibits replication of certain DNA viruses in tissue culture, has been administered to humans in an attempt to alter the course of various herpesvirus infections. Herpes simplex encephalitis patients treated with vidarabine had a significantly reduced mortality in a recent report.²Toxic reactions with this agent have been minimal at the dosage used in the reported studies.

Herpes simplex encephalitis

Herpes simplex encephalitis (HSE) is a severe disease with high mortality and morbidity. As effective antiviral therapy improves the outcome of younger patients, the early diagnosis of the disease has become important, especially in children. The annual incidence of HSE in Japan among children is estimated to be about 100-200 cases, and the mortality is 10-20%. Instead of brain biopsy, we applied the polymerase chain reaction (PCR) assay to the early diagnosis. The DNA of herpes simplex virus was detectable in CSF of all HSE patients in the acute phase. Serial quantitation of viral genome by PCR also revealed that the amount of DNA decreased gradually corresponding to antiviral therapy, and it turned to be negative 3 to 18 days after the onset of neurological signs and symptoms (mean 10.1 days). These results show the PCR assay is a useful diagnostic tool for the early and non-invasive diagnosis of HSE.