Molecular diagnosis of the central nervous system (CNS) infections

Central nervous system (CNS) infections such as meningitis and encephalitis are medical emergencies that require rapid diagnosis of the causative pathogen to guide early and adequate treatment since a delay in implementing an adequate antimicrobial therapy can lead to death. The current microbiological diagnostic methods based on culture or antigen detection have important limitations in their capacity to accurately identify the different potential pathogens causing CNS and, in the time, to obtaining results. Rapid syndromic molecular arrays have been developed. The main advantage of using a meningoencephalitis panel based in a multiplex test is that includes bacteria, viruses and fungi, covering the most prevalent microorganisms causing meningitis and encephalitis and the turn-around time is circa 1 h. The use of these multiplex-PCR based tools is reviewed and the advantages and disadvantages of this technique are discussed.     

Primary central nervous system (CNS) lymphoma in immunocompetent patients

Primary CNS lymphoma (PCNSL) has been increasing in incidence among both immunocompetent and immunocompromised patients. Today there is no uniform approach to the treatment of this disease. Whole brain irradiation (WBI) has been standard treatment, resulting in complete remission in the majority of patients, but with most patients relapsing and dying of their disease within 2 years after treatment. The addition of chemotherapy to WBI appears to prolong survival for patients younger than 60 years with median survival reaching a plateau at approximately 40 months. The issue of the best treatment for older patients remains controversial. Prospective studies will be needed, as it is impossible to draw conclusions from the nonrandomized small series published so far. This is because the prognostic variables of age and performance status to date have affected outcome more than therapy. In this review, some of the questions regarding the management of PCNSL are addressed. Since the role of radiotherapy remains unclear, we designed a new randomized multicenter study (G-PCNSL-SG-1 trial) to investigate the optimal timing of WBI after high-dose methotrexate (HD-MTX) chemotherapy.     

Lyme borreliosis of central nervous system (CNS) in children: A diagnostic challenge

Summary Within 24 months in a consecutive series of 84 children with neurological symptoms indicative of Lyme borreliosis of the central nervous system (CNS) 45 seronegative children (group III), 17 seropositive (group II), and 22 children with specificBorrelia burgdorferi results in cerebrospinal fluid (CSF) — i.e.B. burgdorferi antibodies and/or intrathecally producedB. burgdorferi antibodies and/or positiveB. burgdorferi culture in CSF were observed. The results show that intrathecally producedB. burgdorferi antibodies are the most important marker for the diagnosis of neuroborreliosis (with 71.4% positives) andB. burgdorferi cultivation directly from CSF may be successful in the earliest phase of the disease. Since each of the specific CSF parameters may be false negative in some cases, a careful synopsis of laboratory parameters was done. It shows that CSF protein and CSF cell values are higher in group I than in II or III. Neither can seronegativity exclude nor can seropositivity confirm the diagnosis of neuroborreliosis as in only 71% of group I serumB. burgdorferi antibodies were detected. In view of these aspects clinical and laboratory results are discussed.

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Neuroborreliose im Kindesalter: eine diagnostische Herausforderung

Zusammenfassung Bei 84 Kindern mit Verdacht auf Neuroborreliose wurde der klinische Verlauf und eine Palette spezifischer und unspezifischer Laborparameter aus Liquor und Serum untersucht. Als spezifische, für eine Neuroborreliose beweisende Parameter wurdenB. burgdorferi-Antikörper im Liquor und/oder intrathekal produzierteB. burgdorferi-Antikörper und/oder eine positiveB. burgdorferi-Kultur im Liquor gewertet. Diesen Kindern mit definitiver Neuroborreliose (Gruppe I, n=22) wurden 17 nur im SerumB. burgdorferi-positive (Gruppe II) und 45B. burgdorferi seronegative Kinder (Gruppe III) gegenübergestellt und die unspezifischen Parameter im Gruppenvergleich auf ihre Borrelienrelevanz hin überprüft. Aus klinischer Sicht zeigt sich, daß die neurologische Erkrankung oftmals die Erstmanifestation der Lyme Borreliose im Kindesalter ist (seröse Meningitis und/oder Hirnnervenparese), die nach adäquater antibiotischer Therapie in der Regel auscheilt. Aus den serologischen Ergebnissen ist abzuleiten, daß (1) zur Diagnose einer Neuroborreliose die Bestimmung von intrathekalen Antikörpern die höchste diagnostische Trefferquote aufweist (71,4%), (2) die Liquor-Kultur in frühen Krankheitsstadien aussichtsreich erscheint, (3) in Einzelfällen jeder der drei spezifischen Liquor-Parameter falschnegativ sein kann, (4) daß ein erhöhtes Liquor-Protein bei gesicherter Neuroborreliose deutlich häufiger als in den Vergleichsgruppen (II, III) anzutreffen ist und (5) daß ein positiverB. burgdorferi-Titer im Serum ebensowenig ein deutlicher Hinweis auf eine Neuroborreliose sein kann wie ein negativer eine solche ausschließt (71% seropositive in Gruppe I).

     

Dengue virus infection of the central nervous system (CNS): a case report from Brazil

Dengue infection that is accompanied by unusual complications has been described in Brazil. We report on the presence of dengue virus in the central nervous system (CNS) of a patient who died in 1998 in Rio Grande do Norte, northeast Brazil. DEN-2 viruses were isolated from the brain liver, and lymphnode tissue of a 67-year-old man whose signs and symptoms were those of dengue infection and a secondary immune response. A postmortem revealed nose bleeds a liver that was brownish with yellow areas, and pulmonary and cerebrae congestion. Immunoperoxidase staining showed a dengue antigen-specific positive reaction in the gray matter cells of the cerebrall cortex; a granular citoplasmatic reaction was seen in the neurons. Dengue infection should always be considered as a cause encephalitis in tropical countries, especially in those where the disease is endemic.     

Axonal transport of neuronal antigens characteristic of subpopulations of central nervous system (CNS) neurons

Monoclonal antibodies (MAbs) are useful for the identification of nervous system antigens localized to neuronal subpopulations. We have examined the transport of the corresponding antigens of four such MAbs in guinea pig retinal ganglion-cell axons. Determination of the axonal transport rate of radiolabeled antigens allowed their assignment to one of the three major anterograde axonal transport rate components, each of which is through to convey a subcellular structural system in the axon. Antigens identified by three of the MAbs were found to be transported in slow component b of axonal transport, the component thought to convey the cytoplasmic matrix, and an antigen identified by the fourth MAb was found in slow component a, similarly thought to contain the linear cytoskeletal elements. Assignment of these antigens to the different rate components suggests that they may be associated with a particular structural system in neurons. Additionally, in cases where more than one nervous system cell type may express a particular antigen, the identity of the neuronal form of the antigen has been confirmed by its axonal transport. The roles that these antigens may play in the nervous system during normal axonal function and during neuropathogenesis can now be further examined.     

A dynorphin-like opioid in the central nervous system of an amphibian.

We have provided evidence for the existence of a biologically active opioid in toad (Bufo marinus) brain that is immunoreactive with antiserum raised against dynorphin (1-13). Compared with porcine dynorphin, this opioid is similar in apparent molecular weight on the basis of gel permeation chromatography and is more hydrophobic on the basis of high-performance liquid chromatography. After purification, its opioid biological activity was demonstrated on the guinea pig ileum myenteric plexus-longitudinal muscle preparation. It was found to be less potent, and to have a similar sensitivity to antagonism by naloxone, in comparison with porcine dynorphin. Because it is immunoreactive with antiserum specific for porcine dynorphin, it probably has considerable sequence homology. Generally, the tissue distribution of immunoreactive dynorphin in the toad is similar to that in the rat, with highest concentrations in the neurointermediate lobe of the pituitary. However, the anterior lobe of the toad pituitary contains considerably lower concentrations than are found in the rat anterior lobe. There appear to be three size classes of immunoreactive dynorphin in toad neural tissue, each with apparent molecular weight below 12,000, similar to the size classes of immunoreactive dynorphin found in pig and rat. However, in toad spinal cord (and possibly in brain) there is immunoreactive dynorphin of greater apparent molecular weight, which has not been reported in mammalian tissue. The contribution of each molecular size to the total immunoreactivity varies from tissue to tissue and is different from that observed in the rat.     

Somatostatin analog: plasma catecholamine suppression mediated by the central nervous system

The somatostatin analog, des-AA1,2,4,5,12,13-[D-Trp8]somatostatin (ODT8-SS), acts within the central nervous system to suppress the rise in plasma catecholamines associated with a variety of neural stimuli. Insulin-induced hypoglycemia or stress caused significant elevations in plasma catecholamines that were abolished by intracerebroventricular (icv) administration of ODT8-SS. Bombesin, carbachol, or 2-deoxyglucose, injected icv, evoked marked elevations in plasma epinephrine and norepineprine. These effects were also prevented by ODT8-SS given icv. In all experiments, ODT8-SS appeared to be more effective in lowering plasma epinephrine than in lowering plasma norepinephrine. Systemic administration of ODT8-SS was ineffective in lowering plasma catecholamine levels. Native somatostatin given icv produced inconsistent effects on plasma catecholamine levels. These data suggest that the somatostatin analog, ODT8-SS, acts within the central nervous system to modulate sympathetic nervous system activity. It is suggested, but not established, that this analog acts through the same receptor as native somatostatin.     

Ca2+ -mediated degradation of central nervous system (CNS) proteins: Topographic and species variation

Incubation of homogenates of rat, rabbit, and bovine spinal cord and of bovine brain white and gray matter in the presence of calcium (5 mM) produced an extensive degradation of the neurofilament triplet proteins (NFP; 200 K, 150K, and 69K). The breakdown products of the NFPs were identified by immunoblot. The glial fibrillary acidic protein (GFAP), microtubular proteins (MTP), and myelin proteins were also degraded. The 150 K NFP was more susceptible than the other NFPs. The extent of calcium-mediated degradation was slightly greater with rat spinal cord than the others. Bovine brain white matter had more activity than gray, which had no appreciable degradative activity. The breakdown was prevented by both EGTA and leupeptin but a similar concentration of MgCl₂ (5 mM) had no effect. These results suggest that NFPs are degraded by a Ca²⁺ -activated neutral proteinase in the central nervous system (CNS) of several species. The lesser activity in gray matter suggests that the enzyme is enriched in axons, myelin, and/or oligodendroglial cells.     

Alterations in catecholamine release in the central nervous system of spontaneously hypertensive rats.

The aim of the present study was to investigate alterations in catecholamine release in the central nervous system of spontaneously hypertensive rats. Slices of hypothalamus, medulla oblongata and striatum were prepared from spontaneously hypertensive rats (SHR: 9-10 weeks old) and age-matched Wistar Kyoto rats (WKY). The slices were incubated with (3H)norepinephrine (NE) or (3H)dopamine (DA), superfused with Krebs-solution in vitro, and the release of the catecholamines was compared between the two strains. The basal release of hypothalamic (3H)NE did not differ between SHR and WKY slices. However, stimulation (1 Hz)-evoked (3H)NE release was significantly greater in SHR than in WKY (percent fractional release of total tissue NE: WKY 0.494 +/- 0.019%, n = 6, SHR 0.730 +/- 0.053%, n = 6, p less than 0.05). The stimulation-evoked (3H)NE release from the medulla oblongata did not differ significantly between SHR and WKY slices. Finally stimulation-evoked release of striatal (3H)DA was significantly depressed in SHR (percent fractional release of total tissue DA: WKY 2.048 +/- 0.24%, n = 6, SHR 1.460 +/- 0.068%, n = 6, p less than 0.05). These results indicate that the release of hypothalamic NE and striatal DA are altered in SHR. It is suggested that enhanced hypothalamic noradrenergic activity and reduced striatal dopaminergic activity can increase sympathetic outflow to the periphery, which may play a role in the pathogenesis of this form of hypertension.     

Non Hodgkin's lymphoma involving the adrenal glands and the central nervous system (CNS): a particular evolution after chemotherapy

Adrenal lymphoma is extremely rare. The prognostic depends on involvement of other organs (such as the central nervous system) responsible for lower median survival. We report the case of a 51-year-old man with non Hodgkin's Diffuse Large B Cell Lymphoma (DLBCL) involving the central nervous system (CNS) and the adrenal glands simultaneously. The endocrine exploration revealed a partial adrenal insufficiency and ruled out a pheochromocytoma. Computerized tomographic (CT) scan directed needle biopsy of the adrenal gland allowed the diagnostic of non-Hodgkin lymphoma (NHL). CNS biopsies showed similar histopathologic lesions. After aggressive polychemotherapy and methotrexate intrathecal injection, a dissociated therapeutic response was observed with a decrease of the cerebral lesion and an increase of the adrenal mass. This result may be explained by the efficacy of corticosteroid therapy on cerebral edema. The prognosis was poor with tumor infiltration of the leptomeninges and death 16 months after diagnosis.     

High opioid doses,naloxone, and central nervous system active medications received by Medicare-enrolled adults

Background

A limited number of studies have analyzed prescribing among Medicare-enrolled adults at risk for opioid overdoses. The objectives of this study were to evaluate prescribing for naloxone and central nervous system (CNS) active medications and to determine the relationships of patient characteristics with exposure to these medications.

Methods

This was a retrospective cross-sectional analysis of a Medicare-enrolled medication therapy management eligible cohort. Patients were stratified into two cohorts, individuals with a mean daily morphine milligram equivalent (MME) dose <50 and individuals with MME ≥50. Medications assessed included benzodiazepines, skeletal muscle relaxants (SMR), hypnotics, gabapentanoids, selective-serotonin reuptake inhibitors (SSRI), serotonin–norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), antipsychotics, barbiturates, other antiepileptics, hydroxyzine, and naloxone. Chi-square with odds ratios and logistic regressions determined the relationships of medications and patient characteristics with mean daily MME ≥50. Relationship between medications and opioid dose was adjusted for age and sex.

Results

There were 3452 patients with a daily MME <50 and 1116 with a daily MME ≥50. After adjusting for age and sex, patients with a daily MME ≥50 were more likely to be prescribed hypnotics (OR: 1.41, 95% CI 1.17–1.70), SNRIs (OR: 1.39, 95% CI 1.17–1.64), and naloxone (OR: 3.21, 95% CI 2.49–4.12) (p < 0.001). Nine percent of eligible patients received naloxone. Age groups of persons <85 years of age had 1.58–4.04 (p ≤ 0.004) times the odds of being prescribed a mean daily MME ≥50.

Conclusion

Nearly one-fourth of patients were prescribed a mean daily opioid therapy of MME ≥50. These patients were more likely to be prescribed hypnotics, SNRIs, and naloxone. Patients receiving chronic high-dose opioid therapy were more likely to be in age groups of persons <85 years. Naloxone may be underprescribed among eligible adults. Targeted medication services may ensure optimal prescribing among Medicare patients with chronic opioid therapies.     

Secondary central nervous system (CNS) involvement in patients with diffuse large B-cell lymphoma: a therapeutic dilemma

Secondary central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL) includes an isolated CNS relapse or CNS involvement with systemic disease progression. This rare but fatal clinical problem still remains a therapeutic dilemma in the management of DLBCL. However, there are limited data about its treatment outcome. In this study, we gathered 73 cases with secondary CNS involvement of DLBCL from 11 hospitals in Korea. The data were retrospectively compared according to the status of systemic disease (isolated vs. combined CNS involvement) and the use of high-dose methotrexate treatment (HD MTX). Twenty-nine patients showed isolated CNS involvement while 44 had combined CNS involvement with systemic relapse or progression. Thirty-three cases (45.2%) occurred within 6?months from the initial diagnosis, and the majority of these were associated with systemic disease relapse or progression (n?=?27). In isolated CNS involvement, HD MTX resulted in fewer treatment failures (3/11) than the other treatments such as other salvage chemotherapy and/or radiotherapy/intraventricular chemotherapy (14/15). However, neither HD MTX nor other treatments were effective at reducing the treatment failure rate in combined CNS involvement (8/10 and 23/30, respectively). Thus, isolated CNS involvement had a better survival than combined involvement (P?=?0.008), but systemic disease progression was the main cause of death in combined as well as isolated CNS involvement. In conclusion, the prognosis of secondary CNS involvement was dismal even after intensive chemotherapy using HD MTX. Further research focusing on the development of an optimal treatment strategy is warranted.     

Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma

Patients with malignant central nervous system (CNS) involvement of lymphoma have a poor prognosis with intrathecal chemotherapy and radiation. In this paper, we report the results we obtained in such patients by intravenous chemotherapy with high-dose methotrexate and ifosfamide (HDMTX/IFO). The study involved a review of all patients who received HDMTX/IFO for CNS involvement of malignant lymphoma at our hospital. Therapy consisted of 4 g/m² of MTX (4 h infusion on day 1) and 1.5–2 g/m²/day of IFO (3 h infusion on days 3–5). The study included 20 patients with a median age of 65 years (range, 30–83) and CNS relapse of a malignant lymphoma. Seventeen patients had been pretreated with up to two chemotherapy regimens. The objective response rate was 90% with 12 complete or unconfirmed complete (CR and CRu) and six partial remissions. All patients had at least stabilization of their neurological symptoms. Myelosuppression was the most common toxicity. The median follow-up time was 14.9 months. The median time to neurological progression was 8.9 months. Twelve patients received subsequent therapy, including high-dose chemotherapy with autologous stem cell transplantation in five cases. The median overall survival was not reached. Systemic chemotherapy with HDMTX/IFO is a feasible and promising treatment modality for CNS relapse of a malignant lymphoma.     

CNS vasculopathies: Challenging mimickers of primary angiitis of the central nervous system

Primary angiitis of the central nervous system (CNS) is an inflammatory vasculopathy affecting the brain and spinal cord. It is a difficult diagnosis to make because of its insidious nonspecific course and its multiple mimics. This review identifies and discusses some noninfectious mimickers of primary CNS angiitis, including: reversible cerebral vasoconstriction syndrome, Sneddon's Syndrome, amyloid-beta-related angiopathy, Susac Syndrome, and neurosarcoidosis. Each condition will be reviewed in terms of epidemiology, pathology, clinical presentation, diagnostic approach, and treatment. Distinguishing these mimics from the primary angiitis of the CNS is important for proper treatment and prognosis.     

Fuel sensing and the central nervous system (CNS): implications for the regulation of energy balance and the treatment for obesity

This review describes the product of the 3-day International Association for the Study of Obesity (IASO) Stock Conference held in March 2004 and sponsored by Abbott Laboratories. The conference was focused on how the mechanisms by which individual cells sense their own fuel status might influence the energy balance of the entire organism. Whether you are a single-celled organism or a sophisticated mammal with a large cerebral cortex, it is critical that cellular activity be matched to the available fuel necessary for that activity. Rapid progress has been made in the last decade in our understanding of the critical metabolic events that cells monitor to accomplish this critical task. More recent developments have begun to apply this understanding to how critical populations of neurones may monitor similar events to control both food intake and energy expenditure. The picture that emerges is that numerous peripheral fuel sensors communicate to the central nervous system (CNS) via neural and humoral routes. Moreover, it has been known for decades that specific populations of neurones sense changes in ambient glucose levels and adjust their firing rate in response and changes in neuronal glucose metabolism can influence energy balance. The CNS, however, does not just sense glucose but rather appears to be sensitive to a wide range of metabolic perturbations associated with fuel availability. This information is used to adjust both caloric intake and the disposition of fuels in the periphery. Increased understanding of these CNS fuel-sensing mechanisms may lead to novel therapeutic targets for obesity.     

Central nervous system (CNS) tuberculosis following allogeneic stem cell transplantation

Tuberculosis is an uncommon infectious complication after stem cell transplantation. We report a patient who presented with a brain mass, 3 months after pulmonary tuberculosis had been diagnosed and while he was receiving triple antituberculous therapy. He had extensive chronic GVHD. The diagnosis was made after biopsy of the lesion. The cerebral mass was excised, antituberculous treatment was maintained and the patient made a complete neurologic recovery. Six months later, he died of gram-negative septic shock. Mycobacterial infections should be considered in allograft recipients with chronic GVHD and solid lesions in the brain. Bone Marrow Transplantation (2000) 25, 567-569.     

Serotonin and substance P coexist in neurons of the rat''s central nervous system

5-Hydroxytryptamine (serotonin)-containing neurons in the rat's medullary raphe and interfascicularis hypoglossi cell groups were identified by means of autoradiography following prolonged intraventricular administration of 5-hydroxy[(3)H]tryptamine, fluorescence histochemistry for the demonstration of endogenous 5-hydroxytryptamine, and microspectrofluorimetric analysis of excitation and emission spectra. Immunocytochemical methods (the unlabeled primary antibody-peroxidase antiperoxidase and indirect immunofluorescence methods) were applied with antisera to substance P in order to localize immunoreactivity in these medullary neurons. It was demonstrated that the raphe nuclei and the interfascicularis hypoglossi nucleus are heterogeneous cell groups that contain: (i) Neurons that display both an uptake-storage capacity for 5-hydroxy[(3)H]tryptamine and a formaldehyde-induced fluorescence with spectral characteristics identical to those of the 5-hydroxytryptamine fluorophor. These cells exhibit high to low fluorescence intensities without detectable substance P-like immunoreactivity. (ii) Neurons with various 5-hydroxytryptamine fluorescence intensities and intense to low degrees of substance P-like immunoreactivity. (iii) Neurons with various degrees of substance P-like immunoreactivity without detectable 5-hydroxytryptamine fluorescence or 5-hydroxy[(3)H]tryptamine uptake and storage capacity. These results indicate that some neurons contain high or low levels of only 5-hydroxytryptamine or substance P, whereas other neurons contain both 5-hydroxytryptamine and substance P in various proportions. The present findings demonstrate the presence of two putative transmitters, a biogenic amine and a polypeptide, within the same neuron in the mammalian central nervous system.     

Lipofuscin pigment accumulation in the central nervous system of the mouse during aging

Histopathological and autofluorescence investigations were carried out to study lipofuscin pigment accumulation in various age groups of mice. Qualitative studies revealed an increase of lipofuscin pigment accumulation in old animals. Quantitative studies showed a significant increase in the percentage of pigmented nerve cells and the percentage of cytoplasmic areas occupied by lipofuscin pigment granules with advancing age.