Potential role of the Virchow Robin space in the pathogenesis of bacterial meningitis.

Meningitis is an infectious disease commonly arising from a bacterial etiology. The rapid progression of morbidity and mortality due to bacterial meningitis requires critical and imminent time-dependent clinical intervention. Although it is unambiguously clear that bacteria must infiltrate the cerebrospinal fluid, the sequence of events in the pathogenesis of bacterial meningitis has not been fully elucidated. Most reviews of the pathogenesis of bacterial meningitis do not specify the anatomical location of bacteria following BBB traversal. We propose an additional hypothesis focusing on the Virchow-Robin space (VRS). The VRS consists of a small, but identifiable perivascular space formed by a sheath of cells derived from the pia mater. The VRS has been described as an immunological space and possibly having a role in several neuropathological diseases. Solute exchange between cerebrospinal fluid and extracellular fluid occurs at the VRS, with subsequent drainage into the subarachnoid space. Because the VRS is continuous with the subpial space, a more direct route to the meninges is facilitated. The involvement of the VRS may have profound implications on the pathogenesis and therapeutic strategies: (1) nasopharyngeal colonization; (2) penetration into the blood stream after crossing the mucosal and epithelial membranes; (3) proliferation in the bloodstream; (4) extravasations through the endothelium of the post-capillary venules to the perivascular VRS; (5) migration from VRS to subpial space; (6) traversal through pia mater, entering the CSF in the subarachnoid space; (7) invasion of the meninges. The implication of the VRS in the pathogenesis of bacterial meningitis would be twofold. First, the VRS could provide an additional route of entry of bacteria into the brain. Second, the VRS could provide an area for bacterial proliferation, and thereby serve as a bacterial reservoir in relatively close proximity to the meninges. The clinical consequences of this hypothesis are: 1) clinical interpretation of laboratory findings, and 2) effective antibiotic delivery into the VRS. If the role of the VRS is established as part of bacterial meningitis pathogenesis, antibiotic pharmacokinetics and pharmacodynamics in the VRS need to be determined. This may result in developing novel antibiotic delivery and clinical strategies to improve morbidity and mortality.

Bacterial meningitis: current therapy and possible future treatment options.

Despite targeted therapy, case-fatality rates and neurologic sequelae of bacterial meningitis remain unacceptably high. The poor outcome is mainly due to secondary systemic and intracranial complications. These complications seem to be both a consequence of the inflammatory response to the invading pathogen and release of bacterial components by the pathogen itself. Therefore, within the last decades, research has focused on the mechanism underlying immune regulation and the inhibition of bacterial lysis in order to identify new targets for adjuvant therapy. The scope of this article is to give an overview on current treatment strategies of bacterial meningitis, to summarize new insights on the pathophysiology of bacterial meningitis, and to give an outlook on new treatment strategies derived from experimental models.

Bacterial toxins and Multiple Sclerosis.

The primary pathogenetic mechanism responsible for the distinctive demyelinating lesions in the Central Nervous System (CNS) in Multiple Sclerosis (MS), first described in remarkable detail by Charcot more than 170 years ago, remains one of the most baffling conundrums in medicine. A possible role for bacterial cell molecules and transportable proteins in the pathogenesis of MS is reviewed. The ability of bacterial toxins to distort immunity and to cause distinctive toxic damage in the nervous system is discussed in the light of largely forgotten data linking bacterial nasopharyngeal infections with optic neuritis, optochiasmatic arachnoiditis and MS. While the blood-brain barrier substantially protects the CNS from hematogenous toxins, there is a route by which the barrier may be by-passed. Data is reviewed which shows that the CSF and extra-cellular fluid circulation is bi-directionally linked to the lymphatic drainage channels of the nasopharyngeal mucosa. While this provides a facility by which the CNS may mount immunological responses to antigenic challenges from within, it is also a route by which products of nasopharyngeal infection may drain into the CNS and be processed by the immune cells of the meninges and Virchow-Robin perivascular spaces. If potentially toxic bacterial products are identified in early MS tissues at these sites, this would provide an entirely new insight into the pathogenetic mechanisms of this frustratingly enigmatic disease.

Petrous apex aspergillosis as a long-term complication of cholesterol granuloma.

Aspergillus infection of the petrous apex is a rare and devastating condition. To date, only two such cases have been reported, which resulted from direct extension of chronic Aspergillus otitis media. We present a case of petrous apex aspergillosis occurring years after surgical drainage of a petrous apex granuloma cyst. Because of the potential lethal nature of this condition, aggressive surgical therapy should be considered early in this illness and may provide the best chance for survival.

Late bacterial granuloma at an intrathecal drug delivery catheter.

In the case reported, neurological complaints were pain and dysaesthesiae in the lower back and thigh, as well as paresis of the ileopsoas muscle. MRI of the lumbar spine showed an intradural-extramedullary mass at the level of L1 homogeneously enhancing with gadolinium. This mass was situated at the tip of an intrathecal catheter implanted 11 years before for a morphine trial infusion as therapy for phantom pain after amputation of the right arm. Now, removal of the catheter was performed. Cultures of lumbar CSF and the catheter tip demonstrated coagulase negative staphylococcus. Antibiotic medication with cephalosporines was given for 6 weeks. After removal of the catheter, the patient was free of pain and he progressively regained full neurological function. Although most catheter-associated granulomas reported so far were sterile in nature, bacterial infection should still be considered even years after catheter placement.

Meningitis tras anestesia intradural y asepsia: ¿dos cuestiones irreconciliables? / Meningitis following spinal anaesthesia and asepsis: two irreconcilable issues?]

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Method for inducing experimental pneumococcal meningitis in outbred mice.

BACKGROUND: Streptococcus pneumoniae is the leading cause of bacterial meningitis. Pneumococcal meningitis is associated with the highest mortality among bacterial meningitis and it may also lead to neurological sequelae despite the use of antibiotic therapy. Experimental animal models of pneumococcal meningitis are important to study the pathogenesis of meningitis, the host immune response induced after infection, and the efficacy of novel drugs and vaccines. RESULTS: In the present work, we describe in detail a simple, reproducible and efficient method to induce pneumococcal meningitis in outbred mice by using the intracranial subarachnoidal route of infection. Bacteria were injected into the subarachnoid space through a soft point located 3.5 mm rostral from the bregma. The model was tested with several doses of pneumococci of three capsular serotypes (2, 3 and 4), and mice survival was recorded. Lethal doses killing 50 % of animals infected with type 2, 3 and 4 S. pneumoniae were 3.2 x 10, 2.9 x 10 and 1.9 x 10(2) colony forming units, respectively. Characterisation of the disease caused by the type 4 strain showed that in moribund mice systemic dissemination of pneumococci to blood and spleen occurred. Histological analysis of the brain of animals infected with type 4 S. pneumoniae proved the induction of meningitis closely resembling the disease in humans. CONCLUSIONS: The proposed method for inducing pneumococcal meningitis in outbred mice is easy-to-perform, fast, cost-effective, and reproducible, irrespective of the serotype of pneumococci used.

[Purulent meningitis]. / Méningites purulentes.

Purulent meningitis is a bacterial infection of the subarachnoid space. It constitutes a diagnostic and therapeutic emergency. The vital and functional prognosis is always engaged and depends on the rapidity and the adequacy of management. Treatment is based on a bactericidal antibiotic treatment which is at first empirically prescribed, on the basis of the underlying condition, the clinical examination and the epidemiological context, and then adjusted according to the micro-organism isolated from the cerebrospinal fluid. The recent emergence and increase of penicillin-resistant Streptococcus pneumoniae has led to a modification of antibiotic guidelines.

Models of experimental bacterial meningitis. Role and limitations.

The seriousness of bacterial meningitis has encouraged the development of animal models that characterize complex pathogenetic and pathophysiologic mechanisms, provide evaluation of pharmacokinetic and antimicrobial effects of antibiotics (especially since the worldwide emergence of multiresistant bacteria), and establish new adjuvant treatment strategies (e.g., use of anti-inflammatory agents). The information obtained from an animal model depends on the site of inoculation. For example, using intranasal, intravenous, subcutaneous, or intraperitoneal inoculation, it is the bacterial and host factors that determine the development of bacteremia and the potential for a pathogen to invade the central nervous system that primarily are studied. In contrast, experimental models using direct inoculation into the cerebrospinal fluid can reliably produce lethal infections over a predictable time course. Furthermore, because adult animals will not reliably develop meningitis after intranasal or intraperitoneal challenge, infant animals are used. Because these models bypass the natural dissemination of bacteria from the intravascular compartment to the central nervous system, the pathogenesis is artificial. These models, however, are extremely useful for the study of pathogen and host factors leading to meningeal inflammation and resulting complications, and for evaluating potentially useful agents for treatment therapy. During the past decade, the design of clinical studies has been stimulated by findings obtained from these animal models.

Pathogenesis of bacterial meningitis.

Bacterial meningitis is fatal in 5% to 40% of patients and causes neurologic sequelae in up to 30% of survivors. Much has been learned recently about the mechanisms that lead to brain injury during meningitis. Once bacteria have gained access to the central nervous system, their multiplication triggers a complex host response consisting of humoral and cellular immune mediators, reactive oxygen intermediates, matrix-metalloproteinases, and other host-derived factors. Alterations of the cerebral vasculature, with disruption of the blood brain barrier and global and focal ischemia, ultimately lead to functional and structural brain damage. This article reviews current concepts of the pathophysiology of bacterial meningitis and emphasizes possible therapeutic strategies to prevent its harmful consequences.

Quinupristin/dalfopristin attenuates the inflammatory response and reduces the concentration of neuron-specific enolase in the cerebrospinal fluid of rabbits with experimental Streptococcus pneumoniae meningitis.

The inflammatory response following initiation of antibiotic therapy and parameters of neuronal damage were compared during intravenous treatment with quinupristin/dalfopristin (100 mg/kg as either a short or a continuous infusion) and ceftriaxone (10 mg/kg/h) in a rabbit model of Streptococcus pneumoniae meningitis. With both modes of administration, quinupristin/dalfopristin was less bactericidal than ceftriaxone. However, the concentration of proinflammatory cell wall components (lipoteichoic acid (LTA) and teichoic acid (TA)) and the activity of tumour necrosis factor (TNF) in cerebrospinal fluid (CSF) were significantly lower in the two quinupristin/dalfopristin groups than in ceftriaxone-treated rabbits. The median LTA/TA concentrations (25th/75th percentiles) were as follows: (i) 14 h after infection: 133 (72/155) ng/mL for continuous infusion of quinupristin/dalfopristin and 193 (91/308) ng/mL for short duration infusion, compared with 455 (274/2042) ng/mL for ceftriaxone (P = 0.002 and 0.02 respectively); (ii) 17 h after infection: 116 (60/368) ng/mL for continuous infusion of quinupristin/dalfopristin and 117 (41/247) ng/mL for short duration infusion, compared with 694 (156/2173) ng/mL for ceftriaxone (P = 0.04 and 0.03 respectively). Fourteen hours after infection the median TNF activity (25th/75th percentiles) was 0.2 (0.1/1.9) U/mL for continuous infusion of quinupristin/dalfopristin and 0.1 (0.01/3.5) U/mL for short duration infusion, compared with 30 (4.6/180) U/mL for ceftriaxone (P = 0.02 for each comparison); 17 h after infection the TNF activity was 2.8 (0.2/11) U/mL (continuous infusion of quinupristin/dalfopristin) and 0.1 (0.04/6.1) U/mL (short duration infusion), compared with 48.6 (18/169) U/mL for ceftriaxone (P = 0.002 and 0.001). The concentration of neuron-specific enolase (NSE) 24 h after infection was significantly lower in animals treated with quinupristin/dalfopristin: 4.6 (3.3/5.7) microg/L (continuous infusion) and 3.6 (2.9/4.7) microg/L (short duration infusion) than in those treated with ceftriaxone (17.7 (8.8/78.2) microg/L) (P = 0.03 and 0.009 respectively). In conclusion, antibiotic treatment with quinupristin/dalfopristin attenuated the inflammatory response within the subarachnoid space after initiation of antibiotic therapy. The concentration of NSE in the CSF, taken as a measure of neuronal damage, was lower in quinupristin/dalfopristin-treated rabbits than in ceftriaxone-treated rabbits.

A case of acute monocytic ehrlichiosis with prominent neurologic signs.

Human monocytic ehrlichiosis is a recently described tick-borne infection with the rickettsial organism Ehrlichia chaffeensis. We describe a patient with documented E chaffeensis infection and multiple organ system involvement. Prominent neurologic symptoms and signs included severe headache, meningismus, and altered mental status. Additional neurologic findings included unilateral arm weakness and a Bell's palsy. Biopsy of brain and meninges demonstrated an infiltrate of atypical lymphoid cells in the leptomeninges with involvement of blood vessel walls and extension into the Virchow-Robin spaces. Bone marrow biopsy revealed fibrin-ringed granulomas. The patient also developed a nonspecific increase in immunoglobulin production. Host immune response may play a critical role in the pathophysiology of ehrlichiosis.

Fulminant Streptococcus pneumoniae meningitis in a lion-tailed macaque (Macaca silenus) without detected signs.

A 3-month-old lion-tailed macaque (Macaca silenus) infant that died on 2 February 1985 in the Baltimore Zoo (Baltimore, Maryland, USA) due to fulminating Streptococcus pneumoniae meningitis had congested, edematous lungs, and thickened and congested brain leptomeninges with a grayish-yellow fluid within the subarachnoid brain space. From bacterial cultures made postmortem of the subarachnoid brain space fluid, cerebrospinal fluid, throat secretions, nasal secretions, and lung fluid, we isolated pure cultures of group B streptococci, alpha hemolytic S. pneumoniae, type 19F (capsular). We also isolated Staphylococcus aureus and S. hemolytica from antemortem nasal and throat bacterial cultures from all 13 animals of the M. silenus colony. Streptococcus pneumoniae meningitis in M. silenus has not been previously reported.

Targeted gene replacement demonstrates that myristoyl-CoA: protein N-myristoyltransferase is essential for viability of Cryptococcus neoformans.

Cryptococcus neoformans is a major cause of systemic fungal infection in immunocompromised patients. Myristoyl-CoA:protein N-myristoyltransferase (Nmt) catalyzes the transfer of myristate (C14:0) from myristoyl-CoA to the N-terminal glycine of a subset of cellular proteins produced during vegetative growth of C. neoformans. A Gly487-->Asp mutation was introduced into C. neoformans NMT by targeted gene replacement. The resulting strains are temperature-sensitive myristic acid auxotrophs. They are killed at 37 degrees C when placed in medium lacking myristate and, in an immunosuppressed animal model of cryptococcal meningitis, are completely eliminated from the subarachnoid space within 12 days of initial infection. C. neoformans and human Nmts exhibit differences in their peptide substrate specificities. These differences can be exploited to develop a new class of fungicidal drugs.

Pathogenesis and pathophysiology of bacterial meningitis.

Bacterial meningitis remains a disease with associated unacceptable morbidity and mortality rates despite the availability of effective bactericidal antimicrobial therapy. Through the use of experimental animal models of infection, a great deal of information has been gleaned concerning the pathogenic and pathophysiologic mechanisms operable in bacterial meningitis. Most cases of bacterial meningitis begin with host acquisition of a new organism by nasopharyngeal colonization followed by systemic invasion and development of a high-grade bacteremia. Bacterial encapsulation contributes to this bacteremia by inhibiting neutrophil phagocytosis and resisting classic complement-mediated bactericidal activity. Central nervous system invasion then occurs, although the exact site of bacterial traversal into the central nervous system is unknown. By production and/or release of virulence factors into and stimulation of formation of inflammatory cytokines within the central nervous system, meningeal pathogens increase permeability of the blood-brain barrier, thus allowing protein and neutrophils to move into the subarachnoid space. There is then an intense subarachnoid space inflammatory response, which leads to many of the pathophysiologic consequences of bacterial meningitis, including cerebral edema and increased intracranial pressure. Attenuation of this inflammatory response with adjunctive dexamethasone therapy is associated with reduced concentrations of tumor necrosis factor in the cerebrospinal fluid, with diminished cerebrospinal fluid leukocytosis, and perhaps with improvement of morbidity, as demonstrated in recent clinical trials. Further information on the pathogenesis and pathophysiology of bacterial meningitis should lead to the development of more innovative treatment and/or preventive strategies for this disorder.

Spread of herpes simplex virus to the cerebrospinal fluid and the meninges in experimental mouse encephalitis.

The development of the inflammatory response within the brain, meninges and cerebrospinal fluid (CSF) compartment has been studied for the first time simultaneously in experimental herpes simplex virus (HSV) encephalitis after inoculation via the cornea. Two major viral pathways were found from the eye to the brain: one through the trigeminal nerve to the brain stem and one through the nasolacrimal duct to the olfactory system. Viral antigen was found to be present in the CNS before there were clinical signs or cellular infiltration of brain tissue. Subsequently, the virus spread to all parts of the trigeminal brain stem complex. This phenomenon was accompanied by severe inflammation of the meninges covering the trigeminal root near its entry into the brain stem. The meninges near the entry of the olfactory fila also contained antigen. However, HSV-1 did not spread along meningeal rami of the trigeminal nerve and, consequently, is--at least in this experimental model--not a route to reach the inferior frontal and temporal lobes. The development of CSF changes followed the histopathological development of meningitis and encephalitis closely. HSV-DNA could be detected in the CSF from day 4 post inoculation (p.i.) and HSV-1-specific immunofluorescence in CSF cells was convincingly present on day 5 p.i.; on the same days (4 and 5 p.i.) inflammatory cells were found in apposition to infected cells in the brain. We postulate that HSV is carried to the CSF by infected leukocytes rather than a direct spread to the CSF by simple extension of the encephalitic process to the meningeal surface.(ABSTRACT TRUNCATED AT 250 WORDS)