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Biomedical subjects

D H Gilden

Publications and source records attributed to D H Gilden.

At least 19 recordsLinked to original sources
PubMed2003

Chronic active VZV infection manifesting as zoster sine herpete, zoster paresis and myelopathy.

After lumbar-distribution zoster, an HTLV-1-seropositive woman developed chronic radicular sacral-distribution pain (zoster sine herpete), cervical-distribution zoster paresis and thoracic-distribution myelopathy. Detection of anti-varicella zoster virus (VZV) IgM and VZV IgG antibody in cerebrospinal fluid (CSF), with reduced serum/CSF ratios of anti-VZV IgG compared to normal serum/CSF ratios for albumin and total IgG, proved that VZV caused the protracted neurological complications. Diagnosis by antibody testing led to aggressive antiviral treatment and a favorable outcome.

Chronic Disease↗
PubMed2001

Antigen discovery in chronic human inflammatory central nervous system disease: panning phage-displayed antigen libraries identifies the targets of central nervous system-derived IgG in subacute sclerosing panencephalitis.

The presence of increased IgG in the brains of humans with infectious and inflammatory CNS diseases of unknown etiology such as multiple sclerosis may be a clue to the cause of disease. For example, the intrathecally synthesized oligoclonal bands in diseases such as subacute sclerosing panencephalitis (SSPE) or cryptococcal meningitis have been shown to represent Ab directed against the causative agents, measles virus (MV), or Cryptococcus neoformans, respectively. Using SSPE as a model system, we developed a strategy to identify the antigenic targets of the intrathecal disease-relevant IgG in chronic human inflammatory and demyelinating diseases of the CNS. Libraries of cDNA Ags were displayed on the surface of T7Select bacteriophage and biopanned on IgG extracted from the brain of an SSPE patient, or on a monospecific recombinant Fab identified from SSPE brain. After three or six rounds of biopanning on either Ab, positive phage-displayed Ags reacting with IgG were enriched to 35-77% of all panned clones. Sequence analysis of the positive clones identified fragments of the nucleocapsid protein of MV, the cause of SSPE. The sensitivity of the system was determined by diluting the positive clones from this SSPE phage-displayed library at a ratio of 10(-6) into another phage-displayed library that did not contain any detectable MV Ags; after six rounds of panning, the positive clones comprised 34% of all phage and were also shown to be MV nucleocapsid specific. This strategy will be useful to identify potentially rare Ags in diseases of unknown cause.

Adult↗
PubMed2001

Acute, chronic, and recurrent varicella zoster virus neuropathy without zoster rash.

The authors report three patients with acute, chronic, and recurrent neuropathy associated with varicella zoster virus (VZV) infection but without zoster rash. CSF of all three patients contained VZV immunoglobulin G antibody, but not herpes simplex virus. In two patients, serum/CSF ratios of VZV immunoglobulin G were reduced compared to normal ratios for immunoglobulin G and albumin, and one patient also had VZV immunoglobulin M in CSF. All three patients received antiviral therapy and improved. The diagnosis of nervous system infection by VZV may be confirmed by the presence of antibody to VZV in CSF even without detectable VZV DNA.

Acute Disease↗
PubMed2001

Anti-DNA antibodies are a major component of the intrathecal B cell response in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of unknown cause that afflicts the central nervous system. MS is typified by a highly clonally restricted antigen-driven antibody response that is confined largely to the central nervous system. The major antigenic targets of this response and the role of antibody in disease pathogenesis remain unclear. To help resolve these issues, we cloned the IgG repertoire directly from active plaque and periplaque regions in MS brain and from B cells recovered from the cerebrospinal fluid of a patient with MS with subacute disease. We found that high-affinity anti-DNA antibodies are a major component of the intrathecal IgG response in the patients with MS that we studied. Furthermore, we show DNA-specific monoclonal antibodies rescued from two subjects with MS as well as a DNA-specific antibody rescued from an individual suffering from systemic lupus erythematosus bound efficiently to the surface of neuronal cells and oligodendrocytes. For two of these antibodies, cell-surface recognition was DNA dependent. Our findings indicate that anti-DNA antibodies may promote important neuropathologic mechanisms in chronic inflammatory disorders, such as MS and systemic lupus erythematosus.

Adult↗
PubMed2001

Simian varicella virus infects ganglia before rash in experimentally infected monkeys.

Monkeys experimentally infected with simian varicella virus (SVV) develop rash 10-14 days later. However, the route and the time of ganglionic infection are unknown. Using PCR, we analyzed DNA extracted from tissues of 13 monkeys 5 to 60 days after either intratracheal or intravenous inoculation with SVV. SVV DNA was detected in ganglia from four of five monkeys sacrificed 6 to 7 days after intratracheal inoculation. Further, analysis of ganglia from monkeys sacrificed at 10 days revealed that intravenous inoculation produced a higher proportion of SVV DNA-positive ganglia (63%) than that after intratracheal inoculation (13%), pointing to the role of hematogenous spread in ganglionic infection. Like other organs, monkey ganglia become infected with SVV before the appearance of rash.

Animals↗
PubMed2001

Molecular immunologic strategies to identify antigens and b-cell responses unique to multiple sclerosis.

Identification of the causative agent of multiple sclerosis (MS) has long eluded investigators and has become the "Holy Grail" of researchers in the field. The immune response in cerebrospinal fluid of patients with MS, indicated by an increased IgG level and the presence of specific oligoclonal bands after electrophoresis, strongly parallels that found in various infectious diseases of the central nervous system. To understand the nature of B-lymphocyte activation in MS, 4 laboratories studied the antigen-binding regions of antibodies found in MS brain demyelinative plaques and cerebrospinal fluid. Each analysis revealed (1) limited germline expression, results not expected for a random bystander response; (2) features consistent with a specific antigen-targeted process; and (3) the clonal expansion of populations of B lymphocytes in MS. The screening of libraries expressing protein products derived from chronic MS plaque messenger RNA with antibodies purified from plaques, cerebrospinal fluid, or serum of patients with MS has thus far not revealed the antigenic target(s) of the MS antibody response. Because putative MS antigens could be in low abundance, the screening of large libraries of random peptides expressed on phage surfaces might offer an alternative approach to identify peptide sequences recognized by MS antibodies. New sophisticated molecular immunologic techniques described herein should enhance our ability to identify putative antigen(s) targets in MS.

Antibodies, Monoclonal↗
PubMed2001

The immunoglobulin G heavy chain repertoire in multiple sclerosis plaques is distinct from the heavy chain repertoire in peripheral blood lymphocytes.

Analyses have shown that the repertoire of Ig heavy chain sequences (VH) expressed in multiple sclerosis (MS) plaques or cerebrospinal fluid is consistent with B cell clonal expansion and affinity maturation. PCR amplification of VH sequences from MS lesions obtained from an acute MS patient at autopsy revealed oligoclonal and extensively mutated VH sequences from plaque-periplaque regions with discrete intraclonal differences indicative of B cell clonal expansion in the groups of overrepresented major sequences. None of the VH sequences expressed in plaque regions were detected in peripheral blood lymphocytes from this patient. These data indicate the presence of a CNS-targeted antigen-driven response in MS plaques.

Amino Acid Sequence↗
PubMed2001

Chlamydia pneumoniae and multiple sclerosis: no significant association.

The cause of multiple sclerosis (MS) is unknown. Despite indications from epidemiological and identical-twin studies that MS is infectious, no virus or other infectious agent has been tightly linked to disease. The isolation of Chlamydia pneumoniae from the cerebrospinal fluid (CSF) of MS patients and the detection of both Chlamydia-specific DNA and antibody in MS CSF have been reported. Other analyses of brain and CSF have shown no significant difference in C. pneumoniae-specific DNA or antibody between MS and control subjects. Recent work has revealed intrathecal production of C. pneumoniae-specific IgG in only 24% of MS patients compared with 5% of control patients. More importantly, the major CSF oligoclonal bands from MS patients did not react to C. pneumoniae.

Adult↗
PubMed2001

Presence of VZV and HSV-1 DNA in human nodose and celiac ganglia.

Polymerase chain reaction (PCR) revealed herpes simplex virus (HSV) and varicella zoster virus (VZV) DNA in human nodose and celiac ganglia. This is the first detection of VZV DNA in ganglia of the human autonomic nervous system. The ability of reactivated VZV to produce serious, sometimes fatal neurological disease in the absence of rash, raises the possibility that VZV reactivation from autonomic ganglia might be involved in visceral disease.

Aged↗
PubMed2001

Varicella-zoster virus: a re-emerging infection.

Varicella-zoster virus (VZV) causes chickenpox (varicella), becomes latent in cranial nerve and dorsal root ganglia, and can reactivate many years later to produce shingles (zoster) and postherpetic neuralgia (PHN). Elderly and immunocompromised individuals are also at risk for complications of VZV reactivation involving the central nervous system (CNS), including myelitis, large-vessel encephalitis/granulomatous arteritis, small-vessel encephalitis, meningoencephalitis, and ventriculitis. Peripheral nervous system (PNS) complications range from zoster and postherpetic neuralgia to postinfectious polyneuritis (Guillain-Barre syndrome, GBS). These complications can occur with or without cutaneous manifestations. An increase in elderly and immunocompromised individuals will likely result in a higher prevalence of these conditions; therefore, VZV can be seen as a "re-emerging" infection of the early twenty-first century. In this review, we summarize our experience and the existing literature on CNS and PNS complications of VZV reactivation. Special attention is paid to reports of complications without rash, as these entities are more difficult to diagnose.

Chickenpox↗
PubMed2001

The expanding spectrum of herpesvirus infections of the nervous system.

Herpesviruses cause various acute, subacute, and chronic disorders of the central (CNS) and peripheral (PNS) nervous systems in adults and children. Both immunocompetent and immunocompromised individuals may be affected. Zoster (shingles), a result of reactivation of varicella zoster virus (VZV), is the most frequent neurologic complication. Other neurological complications include encephalitis produced by type I herpes simplex virus (HSV-1), and less frequently HSV-2, as well as by VZV and cytomegalovirus (CMV). Acute meningitis is seen with VZV and HSV-2, and benign recurrent meningitis with HSV-2. Combinations of meningitis/ encephalitis and myelitis/radiculitis are associated with Epstein Barr Virus (EBV); myelitis with VZV, CMV, EBV, and HSV-2; and ventriculitis/encephalitis with VZV and CMV. Brainstem encephalitis due to HSV and VZV, and polymyeloradiculitis due to CMV are well documented. HHV-6 produces childhood exanthem subitum (roseola) and febrile convulsions. Immunocompetent and immunocompromised hosts manifest different incidences and patterns of herpesvirus infections. For example, stroke due to VZV-mediated large vessel disease (herpes zoster ophthalmicus) occurs predominantly in immunocompetent hosts, while small vessel disease (leukoencephalitis) and ventriculitis develop almost exclusively in immunocompromised patients. EBV-associated primary CNS lymphomas also are restricted to immunosuppressed individuals. Recent large CSF PCR studies have shown that VZV, EBV, and CMV more frequently produce meningitis, encephalitis, or encephalopathy in immunocompetent hosts than was formerly realized. We review herpesvirus infections of the nervous system and illustrate the expanding spectrum of disease by including examples of a 75-year-old male on steroid treatment for chronic lung disease with fatal HSV-2 meningitis and an 81-year-old male with myasthenia gravis, long-term azathioprine use, and an EBV-associated primary CNS lymphoma.

Adolescent↗
PubMed2001

Human herpesvirus latency.

Herpesviruses are among the most successful human pathogens. In healthy individuals, primary infection is most often inapparent. After primary infection, the virus becomes latent in ganglia or blood mononuclear cells. Three major subfamilies of herpesviruses have been identified based on similar growth characteristics, genomic structure, and tissue predilection. Each herpesvirus has evolved its own unique ecological niche within the host that allows the maintenance of latency over the life of the individual (e.g. the adaptation to specific cell types in establishing latent infection and the mechanisms, including expression of different sets of genes, by which the virus remains latent). Neurotropic alphaherpesviruses become latent in dorsal root ganglia and reactivate to produce epidermal ulceration, either localized (herpes simplex types 1 and 2) or spread over several dermatomes (varicalla-zoster virus). Human cytomegalovirus, the prototype betaherpesvirus, establishes latency in bone marrow-derived myeloid progenitor cells. Reactivation of latent virus is especially serious in transplant recipients and AIDS patients. Lymphotropic gammaherpesviruses (Epstein-Barr virus) reside latent in resting B cells and reactivate to produce various neurologic complications. This review highlights the alphaherpesvirus, specifically herpes simplex virus type 1 and varicella-zoster virus, and describes the characteristics of latent infection.

Alphaherpesvirinae↗
PubMed2001

An animal model of varicella virus infection.

Varicella-zoster virus (VZV) causes chickenpox in children; establishes latency in cranial nerve, dorsal root, and autonomic ganglia; and reactivates decades later to produce zoster. VZV produces disease only in humans. Although attempts to produce disease and study VZV latency in experimentally infected animals have resulted in virus in trigeminal or dorsal root ganglia, no clinical signs of infection or reactivation developed. In contrast, simian varicella virus (SVV) produces a naturally occurring exanthematous disease in non-human primates that mimics human varicella. Experimental inoculation of non-human primates causes similar, if not identical, clinical and pathological changes observed in monkeys naturally infected with SVV. Like VZV, SVV becomes latent in ganglia and reactivates, often with entire body rash. SVV and VZV encode antigenically related polypeptides. Both virus genomes have been sequenced and shown to be colinear, sharing up to 75% DNA homology. During latency, an SVV homolog of one of the five VZV genes transcribed in latently infected human ganglia has been detected in monkey ganglia. Preliminary studies in which monkeys were inoculated intratracheally with SVV revealed the presence of viral DNA and RNA in multiple tissues, including blood mononuclear cells, months after experimental infection. These findings differed from the expected restricted localization of the virus DNA to ganglia only and the expected limited viral gene expression, and probably reflect the high virus load delivered intratracheally compared to natural SVV infection in monkeys. Nevertheless, clinical, pathological, and molecular similarities between SVV and VZV indicate that SVV infection in non-human primates has considerable potential as an animal model for human varicella.

Animals↗
PubMed2001

Ramsay Hunt syndrome.

The strict definition of the Ramsay Hunt syndrome is peripheral facial nerve palsy accompanied by an erythematous vesicular rash on the ear (zoster oticus) or in the mouth. J Ramsay Hunt, who described various clinical presentations of facial paralysis and rash, also recognised other frequent symptoms and signs such as tinnitus, hearing loss, nausea, vomiting, vertigo, and nystagmus. He explained these eighth nerve features by the close proximity of the geniculate ganglion to the vestibulocochlear nerve within the bony facial canal. Hunt's analysis of clinical variations of the syndrome now bearing his name led to his recognition of the general somatic sensory function of the facial nerve and his defining of the geniculate zone of the ear. It is now known that varicella zoster virus (VZV) causes Ramsay Hunt syndrome. Compared with Bell's palsy (facial paralysis without rash), patients with Ramsay Hunt syndrome often have more severe paralysis at onset and are less likely to recover completely. Studies suggest that treatment with prednisone and acyclovir may improve outcome, although a prospective randomised treatment trial remains to be undertaken. In the only prospective study of patients with Ramsay Hunt syndrome, 14% developed vesicles after the onset of facial weakness. Thus, Ramsay Hunt syndrome may initially be indistinguishable from Bell's palsy. Further, Bell's palsy is significantly associated with herpes simplex virus (HSV) infection. In the light of the known safety and effectiveness of antiviral drugs against VZV or HSV, consideration should be given to early treatment of all patients with Ramsay Hunt syndrome or Bell's palsy with a 7-10 day course of famciclovir (500 mg, three times daily) or acyclovir (800 mg, five times daily), as well as oral prednisone (60 mg daily for 3-5 days). Finally, some patients develop peripheral facial paralysis without ear or mouth rash, associated with either a fourfold rise in antibody to VZV or the presence of VZV DNA in auricular skin, blood mononuclear cells, middle ear fluid, or saliva. This indicates that a proportion of patients with "Bell's palsy" have Ramsay Hunt syndrome zoster sine herpete. Treatment of these patients with acyclovir and prednisone within 7 days of onset has been shown to improve the outcome of recovery from facial palsy.

Bell Palsy↗
PubMed2001

Varicella-Zoster virus infections of the nervous system: clinical and pathologic correlates.

BACKGROUND: Diseases that present with protean manifestations are the diseases most likely to pose diagnostic challenges for both clinicians and pathologists. Among the most diverse disorders caused by a single known toxic, metabolic, neoplastic, or infectious agent are the central and peripheral nervous system complications of varicella-zoster virus (VZV). METHODS: The pathologic correlates of the neurologic complications of VZV infection, as well as current methods for detecting viral infections, are discussed and presented in pictorial format for the practicing pathologist. RESULTS: Varicella-zoster virus causes chickenpox (varicella), usually in childhood; most children manifest only mild neurologic sequelae. After chickenpox resolves, the virus becomes latent in neurons of cranial and spinal ganglia of nearly all individuals. In elderly and immunocompromised individuals, the virus may reactivate to produce shingles (zoster). After zoster resolves, many elderly patients experience postherpetic neuralgia. Uncommonly, VZV can spread to large cerebral arteries to cause a spectrum of large-vessel vascular damage, ranging from vasculopathy to vasculitis, with stroke. In immunocompromised individuals, especially those with cancer or acquired immunodeficiency syndrome, deeper tissue penetration of the virus may occur (as compared with immunocompetent individuals), with resultant myelitis, small-vessel vasculopathy, ventriculitis, and meningoencephalitis. Detection of the virus in neurons, oligodendrocytes, meningeal cells, ependymal cells, or the blood vessel wall often requires a combination of morphologic, immunohistochemical, in situ hybridization, and polymerase chain reaction (PCR) methods. The PCR analysis of cerebrospinal fluid remains the mainstay for diagnosing the neurologic complications of VZV during life. CONCLUSIONS: Varicella-zoster virus infects a wide variety of cell types in the central and peripheral nervous system, explaining the diversity of clinical disorders associated with the virus.

Adult↗
PubMed2000

Sequence analysis of the leftward end of simian varicella virus (EcoRI-I fragment) reveals the presence of an 8-bp repeat flanking the unique long segment and an 881-bp open-reading frame that is absent in the varicella zoster virus genome.

Simian varicella virus (SVV) causes varicella (chickenpox) in nonhuman primates, becomes latent in cranial and dorsal root ganglia, and reactivates to produce zoster (shingles). Because the clinical and molecular features of SVV closely resemble those of varicella zoster virus (VZV) infection of humans, SVV infection of primates has served as an experimental model of VZV pathogenesis and latency. The SVV genome has been completely mapped, but attempts to clone the 3600-bp EcoRI fragment located at the leftward end of the virus genome have hitherto been unsuccessful. Herein, we report the cloning and the complete nucleotide sequence of this region. Comparison of the SVV and VZV sequences in this region revealed an 8-bp inverted repeat sequence flanking the unique long segment of the SVV genome; an 879-bp open-reading frame (ORF) A in SVV that is absent in VZV but has 42% amino acid identity to SVV ORF 4 and 49% to VZV ORF 4; a 342-bp ORF B in SVV with 35% amino acid identity to a 387-bp ORF located to the left of ORF 1 on the VZV genome; and a 303-bp ORF in SVV with 27% amino acid identity to VZV ORF 1. No homologue of VZV ORF 2 was detected. Transcripts specific for ORFs A and B were present in SVV-infected cells in culture and in acutely infected monkey ganglia. Overall, there are more than 2000 bp of DNA in the SVV genome that are absent in the VZV genome.

Amino Acid Sequence↗