Acute toxoplasmic encephalitis in a normal adult

Acute encephalitis associated with an impressive skin rash developed in an otherwise healthy man. Brain biopsy findings were not diagnostic, but serologic data confirmed the diagnosis of acute toxoplasmosis. The patient improved after antimicrobial therapy with pyrimethamine and sulfadiazine, but he was left with neurologic deficits.     

Unusual cause of dementia in an immunocompetent host: toxoplasmic encephalitis

A 69-year-old male was presented with a 2-month history of cognitive decline. The most profound deficit was observed in short-term verbal and visual memory and recognition. He was otherwise healthy, apart from atrial fibrillation diagnosed 5 months before. Brain MRI revealed T2 hyperintensities in the left thalamus, right pulvinar thalami, both putamina and right head of caudate nucleus without diffusion restriction on DWI sequences. CSF examination revealed elevated proteins. He was HIV negative. The course of the disease was complicated with gram negative sepsis and the patient died 14 days later. Autopsy revealed the brain lesions to have been caused by toxoplasmic encephalitis. Toxoplasmic encephalitis is an extremely rare cause of rapidly progressive dementia in immunocompetent patients. In patients with multiple lesions, hyperintense on T2 and hypointense on T1 weighted sequences, without diffusion restriction and some expansive effect, infectious causes should be considered, even in the absence of classical signs of infectious diseases and CSF pleocythosis.     

Central origin of IL-1beta produced during peripheral inflammation: role of meninges

Brain expression of Interleukin-1beta (IL-1beta) and its modulation have been extensively documented in different animal models. The majority of the studies were based on techniques such as RT-PCR, RIA and ELISA using global extracts. Meningeal tissue or choroid plexus both belong to the peripheral compartment. Thus, their presence in nervous tissue extracts may lead to erroneous interpretations. We measured IL-1beta mRNA in the cerebellum, hippocampus and cerebral cortex collected with meninges and in the same structures collected without meninges after a peripheral lipopolysaccharide (LPS) stimulation (0.5 microgram/g body weight), using RT-PCR. The presence of meninges in the extracts dramatically increased IL-1beta mRNA levels after LPS treatment while basal levels (before LPS injection) were not affected. Indeed, two-thirds of the response originated from the meningeal tissue and choroid plexus. Immunohistochemical studies showed that IL-1beta labelled cells, identified as macrophages, were exclusively localized in the ventricular and meningeal spaces, in our LPS condition treatment. These results point out the need of integrated analyses of data obtained with different techniques to demonstrate the presence in the nervous tissue of a molecule which is also widely expressed in the peripheral compartment.     

Damage of maturing brain in the course of toxoplasmic encephalitis.

The aim of the study is to present the damaging influence of toxoplasmic encephalitis on newborn brains. The material consisted of six cases of toxoplasmosis who died during the first months of life. The neuropathological picture indicated indirectly the mechanism of spread of the inflammatory-necrotic process. In the first stage of pathologic process intensive inflammatory infiltrations in the periventricular white matter were seen. In the next stage the necrotic changes involved the majority of the hemispheric white matter. Further development of the disease transformed the brain hemispheres into thin-walled sacs composed of meninges and remnants of the nervous system. Finally, the inflammatory process resulted in hydranencephaly. Proliferation of subependymal glia evident in all cases and blocking the pathways of the cerebro-spinal fluid circulation, may have played a role in this process.     

细胞因子IL-2、IL-10、TNF-α在小鼠单纯疱疹病毒性脑炎中的表达

目的检测细胞因子IL-2、IL-10、TNF-α在单纯疱疹病毒性脑炎(HSE)中的表达和变化,探讨细胞因子IL-2、IL-10、TNF-α在HSVE发病机制中的作用.方法使用逆转录-聚合酶链反应(RT-PCR)检测颅内感染单纯疱疹病毒1型(HSV1)的小鼠在感染后及使用无环鸟苷(ACV)治疗后细胞因子IL-2、IL-10、TNF-α变化及病理变化.结果HSV1感染后出现脑内出血坏死性的病理改变,IL-2、IL-10、TNF-α均明显上升;无环鸟苷治疗好转后脑内病理变化改善,IL-2保持稳定,IL-10继续上升,TNF-α显著下降.结论在小鼠HSVF急性期TH1型及TH2型反应同时被激活,发挥抗病毒作用,并以TH1型反应为主;在HSVE恢复期以TH2型反应为主,并抑制体内免疫反应的扩大;3种细胞因子的动态变化反映出机体免疫调节的动态平衡,并可反映HSVE的预后,早期应用ACV治疗HSVE确有极其明显的抗病毒治疗作用.     

Limited value of cerebrospinal fluid for direct detection ofToxoplasma gondii in toxoplasmic encephalitis associated with AIDS

The diagnosis of acquired immunodeficiency syndrome-associated toxoplasmic encephalitis (TE), a typically focal disease resulting from reactivation of tissue cysts, relies mainly on indirect diagnostic methods. In a prospective study, we investigated the value of detection ofToxoplasma gondii in cerebrospinal fluid (CSF) by using the polymerase chain reaction and the mouse inoculation test. Twenty-four patients with 26 episodes of TE, 2 HIV-infected patients with primary acuteToxoplasma infection, and 38 HIV-infected control patients with latentToxoplasma infection were investigated. Detection ofT. gondii in CSF by both methods was possible in only 3 of the TE patients (11.5%), the remaining patients being negative with either of the methods. In contrast,T. gondii DNA was detected in both of the acutely infected patients, indicating that in primary acute toxoplasmosis parasites may easily be found in the CSF, whereas in the majority of TE cases in immunocompromised patients,T. gondii parasites do not gain access to the CSF drawn by lumbar puncture.     

A critical role for beta-endorphin in cocaine-seeking behavior

Endogenous beta-endorphin levels in the brain are elevated in response to cocaine and are downstream of the mesolimbic dopaminergic system. However, beta-endorphin's direct involvement in cocaine reinforcement has not been demonstrated. In the present study, a single bilateral microinjection of anti-beta-endorphin antibodies (4 microg) to the nucleus accumbens during the maintenance phase of cocaine self-administration (1 mg/kg/infusion) significantly increased the number of active and inactive lever responses. The increase in lever responses is reminiscent of rat behavior during extinction of cocaine self-administration. Further, a cocaine dose-response demonstrates that the increased lever presses in anti-beta-endorphin antibody-injected rats was still present after substitution with a lower dose of cocaine. These findings support a critical role for beta-endorphin in the cocaine brain reward system.     

Leptomeningeal cells activate microglia and astrocytes to induce IL-10 production by releasing pro-inflammatory cytokines during systemic inflammation

The leptomeninges covering the surface of the brain parenchyma play the physical role at the cerebrospinal fluid-blood barrier. We report here that leptomeningeal cells may transduce peripheral proinflammatory signals to the central anti-inflammatory response through the activation of glial cells in the brain parenchyma. After adjuvant injection, both microglia and astrocytes in the cerebral cortex localized in the proximity of the leptomeninges were activated. The protein levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) in the cortical extracts were significantly increased at different time after adjuvant injection. The TNF-alpha immunoreactivity was most prominent in the leptomeninges covering astrocytes. On the other hand, the IL-10 immunoreactivity was observed in both activated microglia and astrocytes localized along the leptomeninges. Cultured leptomeningeal cells covering the cerebral cortex released TNF-alpha which was significantly increased by lipopolysaccharide (LPS). Upon stimulation with LPS, cultured leptomeningeal cells also secreted interleukin-1beta and interleukin-6 with differential time-courses. When primary cultured rat astrocytes and microglia were treated with the conditioned medium of LPS-activated cultured leptomeningeal cells, the immunoreactivity of IL-10 was markedly increased. These observations strongly suggest that leptomeningeal cells release pro-inflammatory cytokines to activate both microglia and astrocytes during systemic inflammation. The activated astrocytes and microglia may in turn regulate anti-inflammatory response in the brain by providing IL-10.     

A study on viral CNS inflammation beyond herpes encephalitis

The early diagnosis of herpes simplex virus encephalitis (HSVE) enables induction of antiviral therapy in this potentially life-threatening disease. The study aimed to determine clinical findings including cerebrospinal fluid (CSF) data and MRI imaging in HSVE patients and to identify features distinguishing HSVE from encephalitis of other viral etiologies. We retrospectively reviewed consecutive patients who were diagnosed with viral encephalitis between 2000 and 2014 at the University Hospital Halle. Forty-nine patients with viral encephalitis were identified. A viral etiology could be confirmed by PCR or antibody testing in 22/49 (44.9 %) of patients (15 (30.6 %) HSV, 5 (10.2 %) VZV, 2 (4.1 %) EBV). In HSVE, typical findings were focal slowing in electroencephalophy (EEG) (80 %, p?=?0.021) and presence of cortical (86.7 %, p?=?0.030) lesions in MRI. Restricted diffusion was particularly helpful in detection of early signal abnormalities in HSVE (p?=?0.014). In 27/49 (55.1 %) of patients, no causative agent could be elucidated. In these patients, 15/27 (55.6 %) experienced a rather “benign” disease course with no MRI pathology despite initially HSVE mimicking clinical picture. However, CSF was significantly different showing a higher amount of granulocytes and activated lymphocytes. The remaining 12/27 (44.4 %) patients developed MRI changes consistent with encephalitis, in 4 of these patients, disease course was fatal. Beside PCR-based serology as standard procedure, MRI including diffusion-weighted images and EEG represent additional tools in early HSVE diagnosis. CSF cytology might be particularly supportive in differentiating likely benign forms of encephalitis.     

Absence of seizures in Rasmussen encephalitis with active inflammation

Severe focal motor epilepsy is considered a clinical hallmark of Rasmussen encephalitis (RE). The authors report a 6-year-old girl with progressive right sided hemiparesis, loss of language skills, left sided hemispheric atrophy, and brain pathologic features characteristic for RE. The patient did not experience seizures over a 2 year period after symptom onset and for several months during follow-up. This report expands the clinical spectrum of RE and suggests that seizures are not a universal symptom of RE. Our patient’s quite remarkable neurologic deficits along with active inflammation in the absence of epilepsy supports that, at least in some individuals, unilateral hemispheric progressive inflammation can occur without active seizure activity.     

Risk mitigation for children exposed to drugs during gestation: A critical role for animal preclinical behavioral testing

Many drugs with unknown safety profiles are administered to pregnant women, placing their offspring at risk. I assessed whether behavioral outcomes for children exposed during gestation to antidepressants, anxiolytics, anti-seizure, analgesic, anti-nausea and sedative medications can be predicted by more extensive animal studies than are part of the FDA approval process. Human plus rodent data were available for only 8 of 33 CNS-active drugs examined. Similar behavioral and cognitive deficits, including autism and ADHD emerged in human offspring and in animal models of these disorders after exposure to fluoxetine, valproic acid, carbamazepine, phenytoin, phenobarbital and acetaminophen. Rodent data helpful in identifying and predicting adverse effects of prenatal drug exposure in children were first generated many years after drugs were FDA-approved and administered to pregnant women. I recommend that enhanced behavioral testing of rodent offspring exposed to drugs prenatally should begin during preclinical drug evaluation and continue during Phase I clinical trials, with findings communicated to physicians and patients in drug labels.     

The relationship between encephalitis lethargica and influenza: A critical analysis

Since encephalitis lethargica's (EL) prevalence in the 1920s, epidemiologic and clinical debate has persisted over whether EL was caused by, potentiated by, or merely coincident with the Spanish influenza pandemic. Epidemiologic analyses generally suggest that the disorders were coincidental. Beginning in the 1970s, modern experiments on archival brain samples mainly failed to confirm a direct relationship between influenza and EL. These experimental studies have technical limitations, e.g., the appropriateness of antibodies, polymerase chain reaction (PCR) primers and controls, and the extreme paucity and age of available material. These factors render the case against influenza less decisive than currently perceived. Nevertheless, there is little direct evidence supporting influenza in the etiology of EL. Almost 100 years after the EL epidemic, its etiology remains enigmatic, raising the possibility of a recurrence of EL in a future influenza pandemic.     

Substance P does not play a critical role in neurogenic inflammation in the rat masseter muscle

Apolipoprotein E (apo E), a plasma protein involved both in the metabolism of cholesterol and triglycerides, particularly in nervous tissue, has been associated with a higher risk of Alzheimer's disease. It has been shown that apo E increased the production of nitric oxide (NO) from human monocyte-derived macrophages (MDM); this effect could represent an important link between tissue redox balance and inflammation, since inflammation and oxidative stress are involved in chronic neurodegenerative disorders. Moreover, it has been evidenced that an overproduction of NO in the central nervous system (CNS) may play a key role in aging and that the glial cells (microglials cells and probably astrocytes) are able to form consistent amounts of NO through the induction of a nitric oxide synthase (iNOS) isoform so-called inducible or inflammatory. This report was performed in order to elucidate the effects produced by lipoproteins from control subjects, AD patients and first degree relatives (offspring) on human astrocyte cells after a short incubation. Peroxynitrite and NO production and NOS expression in cultured astrocytes were measured. We observed a decreased NO production after incubation with both LDL and HDL and an increased peroxynitrite production. As it concerns NOS expression, densitometric analysis of bands indicated that iNOS protein levels were significantly higher in the cells incubated with both AD lipoproteins and offspring lipoproteins compared to cells incubated with control lipoproteins. These findings suggest the possibility to identify in NO pathway a precocious marker of AD.     

Immune system's role in viral encephalitis

Viral infections can be a major thread for the central nervous system (CNS), therefore, the immune system must be able to mount a highly proportionate immune response, not too weak, which would allow the virus to proliferate, but not too strong either, to avoid collateral damages. Here, we aim at reviewing the immunological mechanisms involved in the host defense in viral CNS infections. First, we review the specificities of the innate as well as the adaptive immune responses in the CNS, using several examples of various viral encephalitis. Then, we focus on three different modes of interactions between viruses and immune responses, namely human Herpes virus-1 encephalitis with the defect in innate immune response which favors this disease; JC virus-caused progressive multifocal leukoencephalopathy and the crucial role of adaptive immune response in this example; and finally, HIV infection with the accompanying low grade chronic inflammation in the CNS in some patients, which may be an explanation for the presence of cognitive disorders, even in some well-treated HIV-infected patients. We also emphasize that, although the immune response is generally associated with viral replication control and limited cellular death, an exaggerated inflammatory reaction can lead to tissue damage and can be detrimental for the host, a feature of the immune reconstitution inflammatory syndrome (IRIS). We will briefly address the indication of steroids in this situation.     

Soluble IL-2 receptors in acute and subacute encephalitis

Elevated levels of soluble interleukin-2 receptors were present in the serum from patients with acute primary and postinfectious encephalitis and subacute sclerosing panencephalitis. In addition, soluble interleukin-2 receptors were detected in the cerebrospinal fluid from patients with acute primary encephalitis. Their presence in the cerebrospinal fluid was not explained by damage to the blood-brain barrier and our data attest to their local origin. This suggests that it may be possible in certain neurological diseases to detect cerebral T-lymphocyte activation through a specific marker in the cerebrospinal fluid.