Acute Central Nervous System Disease Research Articles

Seroepidemiology of California and Bunyamwera serogroup bunyavirus infections in humans in California.

Several human populations in California were surveyed cross-sectionally and longitudinally for neutralizing antibodies to selected arthropod-borne bunyaviruses in the California and Bunyamwera serogroups. Overall, the prevalence of antibodies to California serogroup viruses was 6.4% in 702 individuals sampled during 1963-1988. Comparative antibody titers in individual sera indicated that 4.1% and 1.6% of these infections were caused by viruses similar or identical to Jamestown Canyon and California encephalitis, respectively. Evidence of prior infection with the Jamestown Canyon serotype was found in 10% of 118 humans employed outdoors in high elevation areas and sampled in 1988, including 5 of 16 persons (31%) employed as rangers patrolling in remote forests and meadows. This probably reflects increased exposure to bites of boreal mosquitoes that breed in pools of melted snow. Antibodies to Bunyamwera serogroup viruses, including the Northway serotype, which was recently shown to be enzootic in California, were found in only 2 of 702 humans studied. No seroconversions were detected to selected California or Bunyamwera serogroup viruses in paired samples from 392 humans, including 349 patients with acute central nervous system disease or undifferentiated febrile illnesses who were sampled during 1963-1988, and thus these viruses are currently unconfirmed as human pathogens in California.

Role of the virology laboratory in diagnosis and management of patients with central nervous system disease.

A number of viruses cause acute central nervous system disease. The two major clinical presentations are aseptic meningitis and the less common meningoencephalitis. Clinical virology laboratories are now more widely available than a decade ago; they can be operated on a modest scale and can be tailored to the needs of the patients they serve. Most laboratories can provide diagnostic information on diseases caused by enteroviruses, herpesviruses, and human immunodeficiency virus. Antiviral therapy for herpes simplex virus is now available. By providing a rapid diagnostic test or isolation of the virus or both, the virology laboratory plays a direct role in guiding antiviral therapy for patients with herpes simplex encephalitis. Although there is no specific drug available for enteroviruses, attention needs to be paid to these viruses since they are the most common cause of nonbacterial meningitis and the most common pathogens causing hospitalization for suspected sepsis in young infants in the United States during the warm months of the year. When the virology laboratory maximizes the speed of viral detection or isolation, it can make a significant impact on management of these patients. Early viral diagnosis benefits patients with enteroviral meningitis, most of whom are hospitalized and treated for bacterial sepsis or meningitis or both; these patients have the advantage of early withdrawal of antibiotics and intravenous therapy, early hospital discharge, and avoidance of the risks and costs of unnecessary tests and treatment. Enteroviral infection in young infants also is a risk factor for possible long-term sequelae. For compromised patients, the diagnostic information helps in selecting specific immunoglobulin therapy. Good communication between the physician and the laboratory will result in the most benefit to patients with central nervous system viral infection.

Increased levels of plasma anaphylatoxins in systemic lupus erythematosus predict flares of the disease and may elicit vascular injury in lupus cerebritis.

We measured levels of complement anaphylatoxin split products, C3a and C5a, in the circulation of patients with systemic lupus erythematosus (SLE). In 23 SLE patients who were followed serially, the mean C3a value was 179 ng/ml during stable disease and 550 ng/ml during a disease flare. In 10 patients, C3a levels predicted disease activity, with the C3a value rising from a mean of 183 ng/ml at a time of stable disease to a mean of 242 ng/ml 1-2 months prior to a clinical exacerbation of disease. The mean C3a level in 5 patients with acute dysfunction of the central nervous system (CNS) was 1,297 ng/ml, which is significantly higher than that observed in patients with active disease but without CNS involvement (P less than 0.01). C5a levels were also significantly elevated in 4 patients with acute CNS disease. Pathologic specimens from 2 patients who died during an acute lupus flare revealed neutrophils occluding the cerebral and intestinal vessels. Fluorescein angiography in a patient with CNS lupus revealed vasoocclusive retinopathy. In 5 of 7 SLE patients who were pregnant, C3a levels were elevated, with a group mean value of 310 ng/ml. There was a negative correlation (r = -0.59) between C3a and C3 levels in pregnant patients with SLE, and this finding is consistent with complement activation as the cause of decreasing C3 levels. We suggest that serial measurements of C3a can predict flares of disease in lupus patients and can demonstrate complement activation during pregnancy in women with SLE. In addition, release of C3a and C5a (mediators of inflammation) into the circulation may elicit vascular injury, particularly in patients with lupus cerebritis.

Emergency department lumbar puncture: Clinical application and utility of laboratory testing

Lumbar puncture is an emergency department procedure for evaluating patients with suspected central nervous system infection or hemorrhage. To determine whether extensive testing of cerebrospinal fluid (CSF) obtained from emergency department patients was useful, charts of 104 adult patients who underwent lumbar puncture in a university hospital emergency deparment were revlewed. Examination of the CSF disclosed pleocytosis in 25 (24%) of the patients; the presence of red blood cells was considered to be clinically significant in two patients. An abnormal level of CSF protein was present in 62% of patients, and abnormal levels of glucose in 32%. Fungal element testing was negative each of the 72 times it was performed; Gram stain disclosed a bacterial pathogen in one patient. Cultures for fungus and tuberculosis were uniformly negative, as were all immunologic tests. Bacterial cultures grew a pathogen in one patient. No patient with a normal neurologic examination and normal initial CSF analysis was diagnosed subsequently as having acute central nervous system disease. The preponderance of negative or normal results of testing of CSF suggests that extensive testing may not be necessary for all patients. Limitation of sophisticated testing to only those samples with abnormal cell counts or chemistries or from patients at high risk should result in substantial cost saving without compromising patient care.

Meningeal macrophages reflect lymphocytic choriomeningitis virus pathogenic phenotypes.

Intracerebral (i.c.) infection of adult mice with lymphocytic choriomeningitis (LCM) virus can result in acute lethal central nervous system (CNS) disease which is the result of the host's thymus-derived lymphocyte (T cell) response against the virus. Whether the specific effector function of the T cell is that of a cytotoxic cell (Tc) or a delayed-type hypersensitivity cell (Td) is still under debate. We assumed that if Td cells were important in pathogenesis then accessory cells in the brain (specifically, glass-adherent macrophages) might vary with the outcome of i.c. infection. We found that accumulation of macrophages in the brain (washed from meninges and skull cap) appeared to be independent of the severity of the infection (controlled by the mouse strain as well as the strain and dose of virus used). However, differentiation of macrophages was clearly linked to whether or not the infection caused rapid death. In mice that were destined to survive, macrophages became large, extensively vacuolated, and phagocytically active. In lethally-infected mice macrophages were small and had poor phagocytic abilities. At present this dichotomy could be viewed as either a cause or a consequence of disease outcome. However, the data are not inconsistent with the hypothesis that Td lymphocytes may be of primary importance in pathogenesis.

Production and characterization of T cell clones specific for mouse hepatitis virus, strain JHM: in vivo and in vitro analysis.

Mouse hepatitis virus, strain JHM, is a coronavirus capable of inducing both acute and chronic central nervous system disease. To characterize the cell-mediated immune response directed toward JHMV antigens, we have generated and analyzed the properties of four T cell clones reactive to JHMV antigens. All four clones are of the Ly-1+2- phenotype and show an antigen-specific, I-Ab-restricted proliferative response that is dependent on antigen-presenting cells (APC). The fine specificity of I-A restriction was revealed by their differential recognition of JHMV antigen in the context of mutant I-A molecules present on B6.C-H-2bm12 APC. Two clones were unable to recognize JHMV antigen presented on bm12 APC, whereas a third clone showed an equivalent response with both bm12 and wild type B6 APC. In the analysis of the viral specificity, three of the clones showed distinct cross-reactions with MHV-2 and very little if any cross-reaction with MHV-A59. In addition, three of three clones tested responded well to sucrose gradient-purified, UV-inactivated JHMV, indicating that their specificity is directed toward virus structural rather than nonstructural proteins. Finally, two of the clones were analyzed for their ability to induce a DTH reaction when injected together with antigen into the footpads of various mouse strains. Consistent with the in vitro data, both clones produced a marked DTH response only in those strains carrying the I-Ab genotype. These data demonstrate, both in vivo and in vitro, that at least one component of the cell-mediated immune response to JHMV is characterized by an Ly-1+2-, I-A-restricted T cell specific for JHMV structural proteins.

CSF lysosomal enzyme activities in children treated for acute leukaemia

Activities of the lysosomal enzymes, β-hexosaminidase, α-Mannosidase, acid phosphatase, α-fucosidase and β-glucuronidase in cerebrospinal fluid (CSF) were studied in controls, patients with central nervous system (CNS) damage, and patients with leukaemia. Activities were markedly increased in patients with acute CNS disease. Activity levels in patients with leukaemia were in the normal range whether during induction with intrathecal chemotherapy or cranial irradiation or off treatment. These results suggest that lysosomal enzyme activities in CSF may not provide a sensitive enough marker of CNS damage following induction therapy in leukaemia. Acute leukaemia, cerebrospinal fluid, lysosomal enzymes.

Lymphocytic choriomeningitis virus killer T cells are lethal only in weakly disseminated murine infections.

Two types of lymphocytic choriomeningitis (LCM) viruses were studied which, upon intracerebral injection into adult C3H mice, provoked either (a) acute fatal central nervous system (CNS) disease or (b) life-long persistent infection. Both virus types, (a) aggressive and (b) docile, had been found to induce LCM-specific lymphocytes with comparable in vitro lytic activity (11). Because the requirement for T cells in the development of adult LCM disease has been extensively documented, we sought other reasons for the lack of acute disease in mice infected with docile virus. A striking correlation was found between the outcome of the infection and spread of virus to visceral organs. Adoptive transfer experiments showed that a 300-plaque forming unit inoculum of docile virus induced a population of T cells in donor mice fully capable of causing CNS disease in identically infected recipients. This disease causing ability was lost if the interaction was delayed beyond 3 d after infection of the recipients, but could be preserved by lowering the size of the viral inoculum in the recipients. Furthermore, without adoptive transfer, very low intracerebral doses of docile virus (which mimicked the normally slow spread of aggressive virus) were lethal. On the other hand, very high doses of aggressive virus, which mimicked the normally rapid spread of docile virus, did not induce fatal CNS disease. The results suggest that rapid dissemination of the LCM infection creates multiple target organs which divert the focused lethal T cell attack on the brain.

Viruses versus other causes of acute central nervous system (CNS) disease

Viruses versus other causes of acute central nervous system (CNS) disease

Resistance to fatal central nervous system disease by mouse hepatitis virus, strain JHM. II. Adherent cell-mediated protection.

Resistance of SJL/J mice to intracranial inoculation with the JHM strain of mouse hepatitis, a coronavirus, is dependent upon the age of the animals at inoculation. Animals 12 weeks of age or older are resistant, whereas those 6 weeks or younger are uniformly susceptible to viral infection. Spleen cells or thioglycolate elicited peritoneal exudate cells can transfer resistance from 12-week-old to 6-week-old recipients. Removal of the adherent cells from either spleen or peritoneal cells ablated protection. Adherent cells from 12-week-old mice were protective even after depletion of Ia- and Thy-1-bearing cells. Antiviral antibody, thioglycolate injection into 6-week-old animals, and nylon wool-purified T cells were ineffective in mediating resistance. Adherent cells transferred 4 days before virus challenge, but not after challenge, were protective. Thus, there is an age-related change in SJL mice that protects from acute central nervous system disease, which may be due to maturation of a specialized adherent cell population.

Lack of B-cell participation in acute lymphocyte choriomeningitis disease of the central nervous system

The pattern of acute lymphocytic choriomeningitis (LCM) virus-induced central nervous system (CNS) disease was studied in BALB/c mice rendered deficient in B cells and incapable of producing a humoral immune response. The CNS disease in mice treated from birth with goat anti-mouse μ-chain globulin (μ-suppressed mice) was clinically and histopathologically indistinguishable from that of controls. This result demonstrates that neither B cells nor antibody participate in the pathogenesis of acute LCM of the CNS. These observations support the view that the host cell-mediated response to viral antigens is solely responsible for acute CNS disease induced by the intracerebral inoculation of LCM virus.

Cardiac arrhythmias in acute central nervous system disease. Successful management with stellate ganglion block

Cardiac arrhythmias in acute central nervous system disease. Successful management with stellate ganglion block

Functional heterogeneity of lymphocytic choriomeningitis virus-specfic T lymphocytes. I. Identification of effector amd memory subsets.

At varying intervals after immunizing infections of adult BALB/c mice with lymphocytic choriomeningitis (LCM) virus, splenic lymphocytes were tested for their ability to either elicit acute LCM or protect against lethal intracerebral LCM virus challenge when transferred to syngeneic recipients that were, respectively, virus carriers induced by cyclophosphamide-induced immunosuppression and normal susceptible mice. These lymphocytes were also assayed for their capacity to lyse, in vitro, LCM virus-infected BALB 3T3 cells labeled with 51Cr. Only lymphocytes obtained from donor mice between 6 and 8 days postimmunization significantly protected normal recipients from the development of lethal central nervous system (CNS) disease when transferred 18-24 h before virus challenge. At 10 days they were not protective even though their cytolytic activity in vitro either exceeded or approximated that of protective lymphocytes. The capacity to protect more closely corresponded with a period of virus-induced DNA synthesis in donor spleens as measured by the incorporation of [5--125I]-2'-DEOXYURIDINe. However, none of these cytolytically active lymphocyte populations were effective in mediating acute CNS disease when transferred to virus-carrier mice. In contrast, lymphocytes obtained 18 days or later after primary immunization, although having no protective capacity and exhibiting minimal cytolytic activity in vitro, were able to regularly produce acute disease in virus-carrier mice. The ablation by anti-theta-serum treatment of these in vivo and in vitro virus-specific immune functions established that the relevant lymphoid cells were T lymphocytes. Similarly, reconstitution of C3H times C57BL F1 adult mice, depleted of lymphocytes by thymectomy and lethal irradiation, with syngeneic day 8 immune donor lymphocytes rendered them resistant to the development of the carrier state after intracerebral virus challenge; reconstitution of such animals with nonimmune lymphocytes restored their ability to develop typical LCM. Collectively, these data indicate that immunogenic stimulation with LCM virus leads to the development of at least two different virus-specific T-lymphocyte subsets: (a) an early appearing transient effector population of cells and, perhaps, their immediate precursors whose generation requires the presence of virus, and (b) a stable memory population that appears well after virus clearance and which has little or not no cytolytic activity. The possible mechanism by which these functionally different subsets can influence the outcome of acute or chronic LCM virus infections is discussed.

MENINGOENCEPHALITIS AND LABORATORY EVIDENCE OF TRIPLE INFECTION WITH CALIFORNIA ENCEPHALITIS VIRUS, ECHOVIRUS II, AND MUMPS

This report emphasizes that in acute central nervous system disease, multiple viral agents may be implicated in the same patient. A 6-year-old girl with meningoencephalitis had laboratory evidence for simultaneous or closely spaced infections with California encephalitis virus, echovirus type 11, and mumps. Documentation of the finding of triple viral infection was based on at least two laboratory findings for each agent. The patient lived in an area where California encephalitis was prevalent.

Immunopathogenesis of acute central nervous system disease produced by lymphocytic choriomeningitis virus. I. Cyclophosphamide-mediated induction by the virus-carrier state in adult mice.

A single dose of 150 mg/g of cyclophosphamide (CY), given 3 days after intracerebral (i.c.) inoculation of lymphocytic choriomeningitis (LCM) virus, protected over 90% of adult BALB/c mice against acutely fatal choriomeningitis. Surviving mice became persistently infected carriers, with high virus titers in blood and brain. Immunofluorescent examination of the brain showed that in CY-induced carriers infection was initially confined to the choroid plexus, ependyma, and leptomeninges, but over the next 30 days gradually spread to the neural parenchyma, most notably to the molecular layer of the cerebellum. By contrast, LCM virus-carrier mice produced by neonatal virus injection and examined as adults, showed a much less marked infection of choroid plexus and much more widespread infection of parenchyma, with a different distribution among brain nuclei, including heavy infection of the Purkinje cells of the cerebellum.

Immunopathogenesis of acute central nervous system disease produced by lymphocytic choriomeningitis virus. II. Adoptive immunization of virus carriers.

Lymphocytic choriomeningitis (LCM) virus carriers were established by intracerebral inoculation of adult BALB/c mice followed by a single dose of cyclophosphamide (CY) (150 mg/kg) 3 days after infection, and by intracerebral injection within 24 hr of birth. These carriers were then adoptively immunized with spleen cells or serum from immune or normal BALB/c donors. Transfer of immune spleen cells into drug-induced carriers consistently resulted in acutely fatal choriomeningitis, histologically strikingly similar to classical LCM. Normal spleen cells or immune serum failed to produce either central nervous system (CNS) pathology or illness with any regularity. In addition, focal necrosis of the cerebellum was seen after adoptive immunization of drug-induced carriers but only when mice received cells at least 3 wk after inoculation, which is probably explained by the gradual spread of infection from membranes to the neural parenchyma during the first month after establishment of the carrier state in adult mice. Immune spleen cells, when transferred to neonatal carriers, led to a decrease in virus titers in blood and brains and to development of antibody without acute CNS disease. It appears that the production of fatal choriomeningitis after LCM infection is determined in part by the distribution of viral antigen, and this is markedly different in neonatal and drug-induced carriers at the time of cell transfer. Another factor of potential importance is the much higher level of circulating viral antigen in the plasma of neonatal than in that of drug-induced LCM carriers. Classical LCM disease can only be transferred by immune lymphoid cells and not by antiserum. Furthermore, little or no complement-fixing (CF) antibody was found in the plasma of mice dying of acute choroiditis. These observations strongly suggest that acute choroiditis is dependent upon the cell-mediated immune response.

Dual virus infections. Simultaneous enteroviral disease and St. Louis encephalitis.

During the summer of 1964, Houston recorded its first epidemic of St. Louis encephalitis; a significant number of enteroviral infections also occurred, mostly in children. A total of 31 enteroviruses were identified. At a charity hospital, specimens from 15 of 50 children (30%) with acute febrile central nervous system (CNS) disease yielded enteroviruses. Seven of these 15 also had laboratory confirmed St. Louis encephalitis infections. No enteroviruses were found in specimens from 51 adults in the same hospital with acute CNS disease. In other (private) hospitals, specimens from 11 of 23 children (48%) and 5 of 28 adults (18%) yielded enteroviruses. During the summer months, enteroviruses and other neurotropic viruses such as arboviruses must be considered in the differential diagnosis of any acute febrile CNS disease. Although the clinical picture may suggest arboviral, enteroviral, or dual infection, final determination of etiology rests with the laboratory.

Coxsackie viruses and “virus-like” diseases of the adult: A three-year study in a contagious disease hospital

1. 1. Coxsackie viruses were not recovered from adult patients hospitalized for either “viruslike” or etiologically defined febrile diseases during a three-year study in Louisiana. 2. 2. Group A Coxsackie viruses were recovered from four instances of acute central nervous system disease, including a patient with a postexanthem encephalitis. The possible etiologic role of these viruses in the genesis of central nervous system infections is discussed. 3. 3. A Group B, type 3 Coxsackie virus was recovered from a sporadic case of pleurodynia. 4. 4. It is concluded that Coxsackie viruses are not important incitants of interepidemic “viruslike” disease in adults. Viruses of Group A may have a hitherto unappreciated role in disease manifested by central nervous system symptomatology.