Gist recall in multiple sclerosis.

This study examined gist recall (memory for important story ideas) in patients with multiple sclerosis. Twelve patients with clinically probable or definite multiple sclerosis and 10 neurologically intact control subjects were read prose passages from the Wechsler Memory Scale-Revised Logical Memory subtest. The idea units from these passages contained low, medium, and high information content to the stories. In comparison with the control subjects, the patients recalled fewer total elements over immediate and delayed conditions. However, similar to controls, they recalled more ideas that were of high rather than low or medium importance. These results suggest that semantic sensitivity to important ideas of narratives is a relatively preserved feature in multiple sclerosis.

Cerebrospinal fluid immunoglobulin abnormalities in neurosarcoidosis.

A retrospective chart review of neurosarcoidosis at the University of Texas Medical Branch (Galveston) between 1982 and 1987 revealed 99 patients with sarcoidosis. Six patients were diagnosed with neurosarcoidosis and had electrophoresis of serum and cerebrospinal fluid performed (one patient with a ventriculoperitoneal shunt was later excluded). Cerebrospinal fluid immunoglobulins and albumin levels were determined followed by calculation of an IgG index and synthesis rate for each patient. Four (80%) of five patients had elevated IgG indexes and synthesis rates indicative of intrathecal immunoglobulin production. No patient had immunoglobulin oligoclonal bands detected. To date, results of electrophoresis of cerebrospinal fluid in neurosarcoidosis have been reported in 37 patients among four series. Of these, only nine patients (24%) have had either an elevated IgG index or synthesis rate. Our series suggests that intrathecal immunoglobulin production in neurosarcoidosis occurs more frequently than previously described. Furthermore, the elevated indexes and synthesis rates without associated oligoclonal bands suggests a polyclonal immunoglobulin response.

Cytomegalovirus meningoencephalitis in a homosexual man with Kaposi's sarcoma: isolation of CMV from CSF cells.

A 36-year-old homosexual man developed a lymphocytic meningoencephalitis, lymphadenopathy, decreased helper/suppressor ratio in peripheral blood, and Kaposi's sarcoma. After repetitive evaluations for bacterial and fungal agents were negative, viral cultures were positive for cytomegalovirus. Virus was isolated only from CSF cells obtained from a large volume of fresh CSF. We present this case to document the association of CMV meningoencephalitis and acquired immunodeficiency syndrome (AIDS), and to emphasize that aggressive attempts to isolate CMV from CSF cells may be warranted in undiagnosed meningoencephalitis in patients at risk for AIDS.

HTLV-I-associated myelopathy endemic in Texas-born residents and isolation of virus from CSF cells.

We report three Texas-born patients with spastic paraparesis and well-documented infection with HTLV-I. CSF examination showed moderate pleocytosis, protein elevation, and elevated IgG index. Oligoclonal bands were present in two patients. On MRI, one patient had frontal lobe lesions that were low intensity on T1- and high intensity on T2-weighted images. HTLV-I immunoblot studies of serum and CSF revealed reactivity to p19, p24, p53, gp46, or gp68 from all three patients. Titration studies of serum and CSF antibodies on ELISA and immunoblot assays indicated an intrathecal virus-specific response. HTLV-I-specific p19 antigen capture assay and polymerase chain reaction (PCR) demonstrated HTLV-I in lymphocyte cultures derived from each patient's peripheral blood mononuclear cells (PBMC) or CSF cells. Using HTLV-I- and HTLV-II-specific pol and gag primers, PCR studies of PBMC cells obtained directly from the patients demonstrated that the patients were infected with HTLV-I and not HTLV-II. These three cases are to our knowledge the only US cases in whom virus isolation from the CSF has been accomplished. Importantly, two patients may be the first US cases of myelopathy arising from endemic infection.

HTLV-I-associated myelopathy/tropical spastic paraparesis in the United States.

HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is endemic in the Caribbean basin and Japan. Because of the close proximity of the United States to the Caribbean and the presence of HTLV-I-seropositive persons in the United States, we sought reports of patients who were HTLV-I seropositive and had a slowly progressive myelopathy. Over a 2-year period, there were 25 patients reported, 19 of whom were black and 12 of whom had been born in the United States. All patients except two had become symptomatic while living in the United States. Six patients had no apparent risk factor for acquiring HTLV-I. These data demonstrate that HAM/TSP is occurring in the United States and that the diagnosis of HAM/TSP should be considered in patients with a slowly progressive myelopathy regardless of risk factors for acquiring HTLV-I.

Microtiter radioimmunoprecipitation assay of HSV-1 polypeptides with recovery and SDS-PAGE analysis of precipitated proteins: usefulness as screening test for large numbers of specimens including hybridoma supernates.

Immunoprecipitation of radiolabeled polypeptides from complex mixtures of proteins was performed in polystyrene microtiter plates using staphylococcus protein A and various antibody preparations. The method is (1) rapid, (2) uses multichannel micropipettor technology, (3) handles large numbers of specimens easily, (4) requires very small volumes of antigen and antibody (5-50 microliters), (5) provides replicates for statistical analysis and (6) allows recovery of precipitated proteins for direct SDS-PAGE analysis of precipitated proteins. We have shown it is useful as a test to screen large numbers of sera or to characterize monoclonal antibody-containing samples.

Lymphoid cell infection by measles virus in newborn hamsters. Role for monocytes in virus spread to distant sites.

Following intraperitoneal inoculation of measles (HBS) virus into newborn hamsters widespread but variable productive lymphoid tissue infection was detected by a sensitive viral isolation technique. Peritoneal wash cells and spleen were the most common sites of infection. Virus was frequently isolated from the bone marrow and was commonly found in multiple lymph nodes. Thymic infection was only rarely demonstrated. A mononuclear cell associated viremia was demonstrated by Ficollhypaque fractionation of peripheral blood from animals receiving both high- and low-dose virus. Infection was present in both plastic adherent and non-adherent fractions of the blood mononuclear cells. The infected cell population in the spleen had both nylon wool and plastic adherent characteristics and infection was therefore thought to be macrophage-associated. The possible relevance of such macrophage associated infection is discussed with regard to the pathogenesis of natural measles infection and the immunosuppression observed in measles-infected hosts.

The polyspecific immunoglobulin response to HSV-1 viral proteins: determination of immunogenic proteins and relative antibody titres to individual polypeptides by immunoblotting.

We developed an immunoblotting procedure to characterise the polyspecific immunoglobulin response to the proteins of herpes simplex virus (HSV)-1. We found that 8-20% gradient polyacrylamide gels provided no advantage over fixed 8.5% gels for preparing Western blots for use in immunoblotting. The amount of protein loaded on the gels markedly influenced which proteins were detected by immune serum. The presence of Triton-X-100 0.5% in washes and buffers improved band clarity on immunoblots. In optimal conditions, immune mouse serum reacted with up to 33 HSV-1 lysate proteins. Six bands or regions appeared to be of major immunogenic reactivity, including the (122-130) x 10(3)-mol. wt region, a 75 x 10(3)-mol. wt protein, the gD region of approximately (56-64) x 10(3)-mol. wt and two non-glycosylated bands at mol. wts(10(3)) 42 and 44. Minor proteins, more weakly reactive, were detected at 27 other areas. The relative antibody titres in immune mouse serum to the different major regions showed antibody titre to gD greater than gB/gC greater than (42/44) x 10(3) much greater than P75 much greater than VP154. Most human sera reacted with all of the major and many of the minor immunogenic proteins but individual sera varied markedly in the proteins recognised. We conclude that immunoblotting is valuable for evaluating immunoglobulin responses to major and minor immunogenic proteins of HSV-1.

The immunoglobulin response to individual HSV-1 viral polypeptides: kinetics of the response during primary and secondary experimental infection with herpes simplex virus.

We studied the immunoglobulin response to individual viral polypeptides in experimental primary and secondary infection with herpes simplex virus (HSV)-1 in mice. After a single footpad inoculation with 10(5.6) pfu of HSV-1, immunoglobulin to proteins mol. wts (10(3)) 44 and 75 appeared on day 7. Antibodies to gB, gC, gD, 42 x 10(3)- and (48-52) x 10(3)-mol. wt proteins appeared on day 11 and antibody to the major capsid protein, VP154, appeared on day 15 after infection. The secondary immune response was characterised by early production of antibody to gD on day 3 followed by antibodies against the 42 x 10(3)- and 44 x 10(3)-mol. wt proteins on days 4 and 5 respectively. Antibodies to glycoprotein gC and gB were delayed until day 7 of the secondary immune response. In both primary and secondary immune responses the responses against proteins of mol. wts (10(3)) 42 and 44 were particularly intense and of high titre. We conclude that the kinetics of anti-polypeptide antibody appearance is markedly asynchronous; and that the anti-glycoprotein responses occur too late in primary infection to contribute to viral clearance.

Plasma exchange: a treatment for neuropathy associated with IgG-kappa gammopathy.

A patient with a peripheral neuropathy associated with an IgG-kappa gammopathy is reported who was treated with plasma exchange as the only therapeutic modality and showed dramatic clinical improvement, which fluctuated based on the frequency of plasma exchange. Therapeutic plasma exchange is recommended as one form of possible treatment for neuropathies resulting from IgG gammopathies. The literature is reviewed.

Possible neural basis for age-dependent resistance to neurologic disease from herpes simplex virus.

Twenty-week-old mice are known to be resistant to HSV induced neurologic disease, while 5-week-old mice are susceptible. Although age-dependent resistance to disease has been attributed to immunologic maturation, most immunologic development is complete by about 3 weeks of age. We, therefore, postulated that differences in neural spread were involved and we compared the pathogenesis of viral spread in 5-week- and 20-week-old mice. Following footpad infection with 10(5.3) PFU HSV-1, virus was detected in homogenates of sciatic nerve and spinal cord 3-4 days sooner in 5-week-old versus 20-week-old mice. Virus titers in footpad homogenates were 10(5.2) to 10(6.0) in both groups, thus differences in virus replication or immunologic restriction at the initial site of infection could not account for the difference in neural spread. The rate of virus spread to the dorsal root ganglia (DRG) was assessed by ganglia explant/co-cultivation to detect virus presence at various times after footpad infection and by measuring sciatic nerve length. In 5- and 20-week-old mice the rate of virus spread to DRG was 28 mm/day and 4-12 mm/day respectively. We conclude that neural uptake and/or transport of virus may contribute to the difference in susceptibility to neurologic disease.

Pharmacology of antiviral chemotherapeutic agents useful in human viral infections of the nervous system.

Several drugs that have antiviral activity and acceptably low toxicity for systemic use in humans have been discussed in this paper. For ara-A, acycloguanosine, and interferon, there is convincing evidence of effectiveness in limiting certain viral diseases of the nervous system. At this moment use of these drugs cannot be justified for benign, self-limiting, and uncomplicated viral diseases (e.g., localized herpes labialis). However, data from large controlled clinical trials are just beginning to be available and therefore the indications for use of these drugs may change rapidly. It is anticipated that these drugs will have a definite and welcome role in medical therapeutics.

IgG-mediated viral clearance in experimental infection with herpes simplex virus type 1: role for neutralization and Fc-dependent functions but not C' cytolysis and C5 chemotaxis.

For determination of whether the Fc moiety is required for antibody effectiveness in models of herpes simplex virus type 1 (HSV-1) infection, the effects of immune IgG and F(ab')2 fragments were compared by using a passive transfer model of footpad infection. In the IgG- and the F(ab')2-treated groups illness developed in 2 (10%) of 20 and 6 (25%) of 24 mice, respectively, compared with 10 (63%) of 16 controls. IgG treatment markedly, and F(ab')2 treatment moderately, reduced footpad viral titer and viral spread to sciatic nerve and spinal cord. The marked viral clearance by IgG was not attributable to C'-dependent lysis because rapid viral clearance was observed in C5-deficient B10.D2/oSn mice. Viral latency as a consequence of acute infection occurred in 38 (63%) of 60 lumbosacral dorsal root ganglia in the control group, 5 (8%; P less than .001) of 60 in the IgG-treated group, and 26 (33%; P less than .01) of 78 in the F(ab')2-treated group.

Restricted antibody diversity to major viral proteins of herpes simplex virus in individual syngeneic mice.

The antibody response to HSV-1 proteins in individual inbred mice during natural primary and secondary infection has been observed to be markedly restricted in its clonality. Despite the presence of an adequate and large potential repertoire, the resultant antipolypeptide response is directed against just a few viral peptides. With repetitive exposure to virus, the apparent expressed repertoire is enlarged to include antibody to more and more viral proteins. The subsequent antibody responses appear randomly to different proteins. gB, gC, gE, and 155-kDa proteins vary the most as inducers of antibody responses. Somatic events including variation in precursor cell frequency and immunoregulatory influences are thought to explain the observation that different individual mice respond to different viral proteins and also that each mouse will respond to different proteins upon reexposure to virus at later times.

Delayed IgG-mediated clearance of herpes simplex virus type 1 from the CNS but not footpad during the early stages of infection: possible result of relative integrity of the blood-brain barrier.

Following footpad inoculation in mice, herpes simplex virus type 1 spreads along nerves to the spinal cord where a myelitis causes hind limb paralysis beginning on day 6. Neutralizing antibody effectively prevents this illness only if given within 72 h. We therefore studied the timing of blood-brain barrier (BBB) disruption relative to the appearance of virus and inflammatory cell infiltrates in the spinal cord. Virus was detectable in dorsal root ganglion and spinal cord explants by 48 h. By 72 h, mononuclear cell infiltrates were evident in the spinal cord. By day 4, high titres of virus were demonstrable in the spinal cord. On day 6 125I-labelled IgG tracers penetrated the spinal cord BBB. In addition, using a passive transfer model, mice given neutralizing IgG completely cleared footpad virus within 72 h while brain virus titres were unaffected by IgG treatment up to day 7. These observations indicate that the BBB may prevent IgG-mediated virus clearance during the early stages of infection.

Comparative neurovirulence and latency of HSV1 and HSV2 following footpad inoculation in mice.

The effect of virus dose and animal age on the appearance of acute and latent neurologic infection by HSV1 and HSV2 was studied in Balb/c and ICR mice inoculated in the footpad. At low viral doses HSV2 was found to be 1,500 times more neurovirulent than HSV1. At high doses there was no difference in neurovirulence. Age-acquired resistance to disease was shown to be less complete with HSV2 than with HSV1. Neurovirulence was shown to be associated with spread of infection to the spinal ganglia. The data indicate that the factor(s) responsible for the differential neurovirulence of these two viruses is related to events at the level of the footpad and/or sciatic nerve.

Efficacy of herpes simplex virus type 1 immunization in protecting against acute and latent infection by herpes simplex virus type 2 in mice.

ICR mice were immunized with herpes simplex virus type 1 (HSV-1) and later challenged with HSV-2 by footpad inoculation. Both immunized animals and age-matched, nonimmunized controls were observed for ascending neurological disease and latent infection of spinal ganglia resulting from the HSV-2 challenge. Control animals had a 78% incidence of acute and latent infection compared with a 1.7% incidence in immunized mice. The data show immunity to HSV-1 is protective against both acute and latent infection by HSV-2.

Antibody activity to herpes simplex virus in mouse Ig classes and IgG subclasses.

Recent studies indicate that Ig class and IgG subclass induction varies for different proteins and further that some Ig subclasses, like IgG2a, are more efficient in important biologic processes such as antibody-dependant cell-mediated cytotoxicity (ADCC). Many proteins of herpes simplex virus type 1 (HSV-1) are immunogenic and induce immunoglobulin responses. To determine the distribution of immunoglobulins induced by HSV-1 proteins, we studied immune mouse serum using an Ig isotype specific Elisa assay for antiviral activity. We found by endpoint analysis that the antiviral titer was 1:12,903 for IgG1, 1:5141 for IgG2a, 1:2140 for IgG2b and 1:229 for IgG3. To identify which isotypes were induced by individual glycoproteins and other viral proteins, Western blots containing HSV-1 proteins were probed with immune serum and isotype specific second antibodies. gB, gC, gD and the 42/44KDa nucleocapsid complex induced strong IgG1, IgG2a, IgG2b responses. IgG3 reactivity with viral proteins appeared weaker. Among the IgG3 reactivities detected on immunoblots, gB and gC were the most intense. Other proteins which elicited IgG1, IgG2a and IgG2b responses were 170KDa, 154KDa and gE. IgA responses were induced by 154KDa, gC, gB, gE and gD. Prominent IgM responses included gB, gC, gD and the 42KDa protein. These results indicate that HSV-1 glycoproteins induce prominent responses in all IgG isotypes except IgG3. The biologic implications of the data are discussed.

Murine IgG subclass responses to herpes simplex virus type 1 and polypeptides.

The antibody response to herpes simplex virus (HSV) is complex and involves antibody to at least 33 virus-induced polypeptides. Serum IgG contains four isotypes in mice and it is known that the isotypes differ in their biological functions and that individual antigenic proteins may preferentially elicit restricted isotype responses. We therefore examined the anti-polypeptide isotypes induced in immune mouse serum. By ELISA, we found that the total serum virus-specific antibody activity was 51% IgG1, 39% IgG2a, 11% IgG2b and 1% IgG3 in immune ICR strain mice and 51%, 45%, 4% and 0.4% respectively in strain BALB/c mouse immune serum. These proportions are significantly different from those reported for other virus infections. Sepharose-Protein A affinity-purified isotypes were also studied and showed IgG1 greater than IgG2a greater than or equal to IgG2b much greater than IgG3 activity per microgram of isotype, indicating that competition between isotypes present in high concentrations did not significantly alter the results. Immunoblotting studies of the purified isotypes showed that the major immunogenic HSV-1 proteins (VP155, gC, gB, pgB, gD and nucleocapsid proteins 42K and 44K) induced all isotypes. However, the isotype responses were not uniform among the glycoproteins and some other proteins. In addition neutralization assays of the purified isotypes indicated that IgG2a and IgG2b had significantly greater neutralizing capacity than IgG1, suggesting that less of the IgG1 was directed against neutralizing virion epitopes. These data are discussed with respect to the biological implications in host defence.