Trigeminal ganglion infection by thymidine kinase-negative mutants of herpes simplex virus.

The incidence of trigeminal ganglion infection after corneal inoculation of guinea pigs with thymidine kinase-negative mutants of herpes simplex virus was markedly reduced compared to infection after inoculation of thymidine kinase-positive virus. Thymidine kinase-negative herpes simplex virus replicated well in ocular tissues in which dividing or potentially dividing cells were present, but not in trigeminal ganglion infection of nondividing neurons. Thymidine kinase-positive virus, however, replicated well in ocular tissues as well as in trigeminal ganglion. These results suggest that thymidine kinase expression of herpes simplex virus may be important in infections of sensory ganglia.

Myokymia and facial contraction in multiple sclerosis.

Continuous unilateral facial myokymia and facial contraction occurred in a patient with multiple sclerosis and there was subsequent resolution of these abnormalities. I compare abnormal facial movements of this type with those caused by other neurological diseases and discuss the possible mechanism of myokymia in diseases of the central and peripheral nervous systems.

Oncornavirus particles in neurons of guinea pig trigeminal ganglion.

Virus-like particles morphologically similar to oncornaviruses were observed in trigeminal ganglion neurons of two normal, random-bred, adult Hartley guinea pigs. Only a few neurons showed virus particles, but the particles were numerous in the cells in which they were present. Extracellular virus particles were not observed. Similar oncornavirus particles were observed in trigeminal ganglion explant cultures derived from normal guinea pigs after treatment with bromodeoxyuridine. Both intracellular and extracellular particles were frequently observed in and around supporting cells. Intracytoplasmic oncornavirus-like particles were occasionally observed within neurons. These results support consideration that trigeminal ganglion and other sensory ganglion neurons may be primary sites for latent oncornavirus infection of the nervous system.

Immunoglobulin G immunosuppression of multiple sclerosis. Suppression of all three major lymphocyte subsets.

Six patients with relapsing chronic progressive multiple sclerosis were treated on 2 consecutive days with large amounts of IgG to induce immunosuppression. Peripheral blood lymphocyte subsets were monitored for 5 weeks after IgG treatment to determine immunosuppression. Decreased numbers of B, T, and natural killer lymphocytes were detected after treatment. Lymphocyte numbers were at a nadir 1 week after treatment, but an immunosuppressive effect continued to be present after 5 weeks. Although clinical efficacy was not evident in this brief open trial, the decrease of peripheral lymphocyte numbers and the apparent safety of the procedure warrant further study.

Trigeminal neuralgia: mechanisms of treatment.

BACKGROUND: Mechanisms of the surgical treatment of trigeminal neuralgia are considered. RESULTS: Trigeminal neuralgia is effectively treated by microvascular decompression (MVD) and other surgical procedures. These procedures often cause reactivation of herpes simplex virus (HSV), which is latent in trigeminal ganglion neurons. CONCLUSION: MVD and other surgical procedures alter ganglion neuron transcription, as indicated by HSV reactivation. Controlled injury of the trigeminal root-ganglion probably occurs with the disparate surgical procedures, and this is likely the means of their effectiveness.

Clinical significance of types of cerebellar amyloid plaques in human spongiform encephalopathies.

We report three patients with both spongiform encephalopathy and cerebellar amyloid plaques; one showed kuru-like plaques and was diagnosed as having Creutzfeldt-Jakob disease (CJD), and two had multicentric plaques and were diagnosed as having Gerstmann-Sträussler-Scheinker disease (GSSD). Evaluation of these cases and review of others previously reported suggests a clinicopathologic correlation between type of cerebellar plaque and neurologic clinical course. CJD patients who showed kuru-like plaques generally had disease with early onset (average age, 49.1 years) and long duration (average, 34 months), as compared with CJD patients without kuru-like plaques. GSSD patients usually had multicentric cerebellar plaques, and cases were usually familial, had early age of onset (average, 42.7 years), and were of long duration (average, 73 months). Myoclonus was infrequent in GSSD patients and pathologically spongiform change was minimal; spinal tract degeneration was common.

The role of herpes simplex thymidine kinase expression in neurovirulence and latency in newborn vs. adult mice.

Infection by standard thymidine kinase-positive (TK+) and TK- mutant herpes simplex virus (HSV) was performed in order to evaluate the role of HSV TK expression in neurovirulence and in HSV latency. In newborn mice, mortality and trigeminal ganglion (TG) HSV titer correlated (both were high) for TK+ and TK- HSV. In adult mice after TK- HSV infection they also correlated (both were low). After TK+ infection of adult mice, correlation was not present; mortality was low while HSV titer was moderately high. During the period of HSV latent infection (> 28 days after HSV infection), the number of neurons expressing HSV latency-associated transcript (LAT) was much greater for TK- HSV newborn-inoculated mice (average of 943/ganglion) than adult-inoculated mice (average of 138/ganglion). In addition, total amount of TG LAT was greater in the former than the latter. Reactivation from latency was restricted, however, for both groups. This result supported the important role of HSV TK expression in HSV reactivation, even when the number of LAT-positive neurons was greatly increased. The following conclusions were drawn from the study of TK- HSV in newborn mice: (i) HSV TK expression was of limited importance for neurovirulence and in vivo HSV TG infection (but was of importance in adult mice); (ii) increased in vivo HSV TG infection correlated with increased number of LAT-positive neurons, so that HSV replication and establishment of latency were not completely separable; and (iii) even with greatly increased numbers of latently infected neurons, HSV TK expression was important for reactivation from latency. Results in newborn mice suggested that the role of HSV TK expression in reactivation from latency and in neurovirulence were separable. To further investigate HSV replication in newborn and adult mice, ganglia were infected with HSV in vitro and either maintained in vitro or transplanted beneath the renal capsule of adult recipients. In both of these studies, HSV titers in ganglia were much higher in newborn than adult ganglia. This suggested that in addition to the well-know role of the immune system in HSV neurovirulence in newborn mice, it is likely that HSV replication per se in neural tissue is greater in newborn than adult mice. This may be related to the high level of HSV neurovirulence in newborn mice.

Sequential changes of sensory neuron (fluoride-resistant) acid phosphatase in dorsal root ganglion neurons following neurectomy and rhizotomy.

Five to seven days after sciatic nerve section in rats, fluoride-resistant acid phosphatase (FRAP) expression in dorsal root ganglion (drg) neurons was markedly decreased. The decrease was in contrast to increased acid phosphatase which has been reported to occur in other neurons after nerve section. FRAP expression in ganglion neurons subsequently increased 14-21 days after nerve section; this preceded the restitution of enzyme expression in the spinal cord substantia gelatinosa. FRAP expression in drg neurons was not decreased after dorsal root section.

Reversible decrease of fluoride resistant acid phosphatase-positive neurons after herpes simplex virus infection.

Herpes simplex virus (HSV) frequently infects human sensory ganglion neurons, and similar infections have been reported in experimental animals. Reported here is an investigation of in vivo neuronal function after HSV infection. It was observed that the proportion of fluoride resistant acid phosphatase (FRAP)-positive trigeminal ganglion neurons was decreased for several months after experimental infection of mice, and it is suggested that other neuronal functions may also be altered by HSV.

Isolation of JC virus capsomer-like structures from progressive multifocal leukoencephalopathy brain.

Brain tissue from a patient with progressive multifocal leukoencephalopathy (PML) was analyzed by molecular biological and electron-microscopic techniques. Viral DNA was isolated directly from brain tissue, cloned into a plasmid vector, and subjected to restriction endonuclease analysis. The pattern of restriction fragments identified by gel electrophoresis was almost indistinguishable from that of prototype JC virus. By this procedure the etiologic agent of PML in this patient was identified without the isolation of infectious virus. After centrifugal clarification of brain homogenates, high speed centrifugal pellets were studied by electron microscopy. Large numbers of 9-nm polygonal particles, sometimes in paracrystalline arrays, were observed. It was thought likely that these particles were capsomer subunits of 41-43 nm JC virus virions. That the particles were capsomers was supported by negative stain electron microscopy, including reconstruction studies with simian virus 40.

Herpes simplex and herpes zoster. Nervous system involvement.

Mainly discussed are neurologic complications of two neurotropic herpesviruses: herpes simplex viruses types 1 and 2 and varicella-zoster virus. Briefly discussed are cytomegalovirus and Epstein-Barr virus. Treatment of immunosuppressed and nonimmunosuppressed patients is reviewed.

Herpes zoster infection and postherpetic neuralgia.

Varicella-zoster virus (VZV), the cause of chicken pox, establishes latent infection in sensory ganglia. Reactivation results in zoster (shingles), sometimes complicated by encephalitis (myelitis). Postherpetic neuralgia (PHN) is the major morbidity of zoster. PHN typically increases in frequency with age. The VZV vaccine, which was developed for children, may be effective in enhancing VZV immune reactivity and decreasing zoster in adults. Early antiviral treatment may be effective in decreasing PHN onset. Several other medications may be useful in treating established PHN. A recent report discussed intrathecal steroid use.

Role of herpes simplex virus thymidine kinase expression in viral pathogenesis and latency.

Herpes simplex virus (HSV) thymidine kinase (TK) expression and the HSV TK gene have been evaluated in studies of gene control, as well as in animal and human studies of viral pathogenesis, including HSV latency. In investigations of the biological role of HSV TK, enzyme expression was noted to be important for HSV infection of nonreplicating cells in culture; and, in experimental animal studies, HSV TK was shown to be important for in vivo latent infection of sensory ganglion neurons. Latency in these studies was determined by the ability of HSV to reactivate from sensory ganglion explants. In recent studies, investigators sought to determine whether the role HSV TK expression plays in latency is primarily in the establishment and maintenance of latency or in the reactivation process. Following infection of experimental animals with HSV TK-deficient mutants, the presence of HSV in ganglia was detected in complementation, rescue, and molecular biological studies. Results suggest that HSV TK expression may be important for HSV reactivation from latency. This was supported by in situ hybridization investigations. In the latter studies, HSV latency associated transcript (LAT) was present in ganglion neurons, although reactivation of HSV from such ganglia was defective. LAT-expressing, reactivation-defective infections established by TK mutants of HSV are considered examples of incomplete latency. From the present review, it appears that HSV TK expression, particularly TK expression of HSV-1, is important for the reactivation of latent HSV infection of sensory ganglion neurons, probably because of limited neuronal TK expression and absent replication capacity of these cells.

Ultracentrifugal inoculation of herpes simplex virus.

By ultracentrifugation of 30 ml of highly dilute suspensions of herpes simplex virus (HSV) directly onto monolayer cultures grown in centrifuge tubes, infectivity was significantly greater than without centrifugation. Ultracentrifugation at 20,000 to 25,000 rpm (28,000 to 45,000 X g) for 1.5 to 2.3 h was utilized with good preservation of cultures. With low-speed centrifugation at 3,000 rpm (1,100 X g), infectivity was almost 10-fold greater than without centrifugation. With ultracentrifugal inoculation, infectivity was about 100-fold greater than without centrifugation. Ultracentrifugal inoculation permitted the detection of HSV at concentrations as low as 0.05 plaque-forming units per ml. Similarly, ultracentrifugal inoculation of cultures was almost 100-fold more sensitive a method of detecting infectious HSV than was pelleting HSV from dilute suspensions followed by resuspension and inoculation of cultures. Ultracentrifugal inoculation of cultures may permit the isolation of HSV in situations where virus cannot be detected by ordinary means and may prove applicable to the study of other viruses.