Severe Central Nervous System Disease Research Articles

Accumulation of T-Cells with Selected T-Cell Receptors in the Brains of Japanese Encephalitis Virus-Infected Mice

Japanese encephalitis is a severe central nervous system (CNS) disease with a high case fatality rate in humans. We characterized T-cells infiltrating the brain after infection with Japanese encephalitis virus (JEV) in a mouse model and determined the clonality of the infiltrating T-cells by analyzing the sequences of complementary determining region 3 (CDR3) of the T-cell receptor. C3H/He mice died after intraperitoneal infection with the JaTH160 strain of JEV, demonstrating CNS degeneration and prominent T-cell infiltration. The percentages of T-cells bearing the VA5-1, VA17-1, VA19-1, VB2-1, VB8-3 and VB13-1 subfamilies were significantly increased following infiltration of the brains in infected mice. Additionally, CDR3 size spectratyping revealed the oligoclonality in T-cells bearing VA11-1 and VA18-1. CDR3 amino acid sequences were then determined for the VA5-1, VA11-1, VA18-1, VB8-3 and VB13-1 subfamilies. There were high levels of identity and similarity in amino acid sequences of CDR3 in these T-cells. Quantitative real-time PCR analysis also revealed that CD8, interferon-gamma and tumor necrosis factor-alpha were highly expressed in the infected mouse brain. These results indicate that T-cells with high clonality and similarity infiltrate the JEV-infected mouse brain, and that these T-cells are mainly CD8-positive and have the Th1/Tc1 phenotype.

Juvenile systemic lupus erythematosus in multicase families from Saudi Arabia: comparison of clinical and laboratory variables with sporadic cases

The object of this study was to compare patients with familial versus sporadic systemic lupus erythematosus (SLE) with respect to clinical, laboratory variables and outcome. The familial SLE group comprised 12 patients while the comparative group comprised 24 patients selected by systemic sampling from our pediatric rheumatology clinic database. Those patients are listed according to the date of referral, which represents a sampling frame. The first patient was chosen randomly and subsequent patients were chosen at intervals of three. The two groups were compared with respect to: demographic information, age of onset of SLE, disease and follow up duration, clinical and laboratory variables and outcome. The patients from the familial group were younger and had an earlier age of onset of disease (P = 0.03, 0.001 respectively). Seven patients with familial SLE were from the eastern region of Saudi Arabia (P = 0.006). The two groups were comparable with respect to gender, disease duration and follow-up. At diagnosis, the discoid rash was more frequent in the familial group (P = 0.03) while other clinical and laboratory variables including disease activity as measured by SLEDAI did not show significant differences. The mean dose of steroid and use of other immunosuppressive therapy were similar in both groups. Three patients from the familial group died; two of them had unusual complications (one patient had transverse myelitis and pancreatic pseudocyst and the other one had extensive pyoderma gangrenosum). All patients from the sporadic group are alive in stable condition but one patient had severe central nervous system disease. Familial SLE patients tend to be younger and more likely to have discoid rash, in addition a marked difference in the origin of patients was noted. These differences may be helpful in identifying SLE patients with a stronger genetic predisposition. The mortality among familial SLE patients is more frequent which may reflect the disease severity.

Differences in SLE disease activity between patients of Caucasian and South‐East Asian/Chinese background in an Australian hospital

AbstractAim: We performed a semiprospective and retrospective review of all admissions to a single institution of systemic lupus erythematosus (SLE) patients, admitted due to active disease. The aim was to describe differences in disease activity as a cause of hospital admissions between patients originating from South‐East Asia/China (SAC) and Caucasians.Method: There were 210 patients admitted for active disease, with a total of 567 admissions for active SLE over a 16‐year period. Allowing for patients who had left our database, there was a total of 3415 patient years of observation.Results: Patients from SAC with a flare requiring admission presented earlier in their disease course and with more active disease than did Caucasians (median SLE Disease Activity Index 13 vs. 8, P= 0.002). They had longer inpatient stays (7 vs. 5 days P = 0.03). There was a trend to higher rates of re‐presentation to hospital for flare (59% in SAC patients vs. 41% in Caucasians, P = 0.09) with more subsequent admissions (3 vs. 2 P = 0.06) despite a shorter period of observation.Conclusions: South‐East Asian/Chinese were more likely to be diagnosed with class III/IV glomerulonephritis and require cyclophosphamide both at presentation and subsequent admissions. More patients from SAC were readmitted to hospital for severe central nervous system disease after their first hospital admission. In this population, lupus patients had more severe flares and more frequently required admission for these than Caucasians.

Characterization of neuronopathic Gaucher disease among ethnic Poles

Purpose: Gaucher disease is a common lysosomal storage disease that results from inherited mutations in the gene (GBA) encoding acid β-glucosidase (GCase). Here, the clinical and molecular findings of the subacute neuronopathic variant are delineated among ethnic Poles.Methods: Longitudinal studies of visceral, bony, and central nervous system involvement are delineated clinically. Complete gene GBA sequencing was used to characterize the mutations and haplotypes in this population.Results: A greater frequency of subacute neuronopathic Gaucher disease (type 3) is present among ethnic Poles compared with other European countries. Two type 3 phenotypes were found: The first was an early-onset variant with massive visceral disease, progressive kyphoscoliosis, mild cognitive deficits, and survival for three or more decades. This variant resembles the “Norrbottnian” Swedish phenotype. The other variant had more severe progressive central nervous system disease, milder visceral involvement, and absence of kyphoscoliosis. Myoclonus was present in some patients. Neither variant had bone crises and/or pain as major components. The L444P/L444P genotype was most common, but on several different haplotype backgrounds. Other alleles encoded D409H, V305L, and E326K/A446P on various haplotypes.Conclusions: These studies provide additional expansion of the type 3 genotypes with some commonalities with and differences from other reported variants. Also, such phenotypic expansion should be expected in the other variants of Gaucher disease as the spectrum of ethnic variation becomes more fully delineated.

Histologic and Molecular Correlates of Fatal Measles Infection in Children

The purpose of this study is to document three cases of fatal measles infection in children who ranged in age from 1 to 6 years old. In each case, there was a rapidly progressive illness marked by severe respiratory and central nervous system disease; in two cases, tonsillar herniation occurred. The lung tissues showed marked interstitial pneumonitis with diffuse endothelial cell and pneumocyte degeneration; occasional multinucleated giant cells were observed. Brain sections showed a paucicellular inflammatory infiltrate with diffuse neuronal damage. Measles nucleoprotein and measles RNA were detected in each case by immunohistochemistry and reverse transcriptase (RT) in situ PCR, respectively. In the lung tissues, the viral protein and RNA localized primarily to pneumocytes and macrophages; infected endothelial cells were also evident. In the brain sections, the virus-infected cells cytologically had the appearance of neurons and microglial cells. The viral load, defined by the percentage of cells infected in a given field, was very high in the lung, spleen, and brain. Viral infection was associated with a marked increase in the number of cells expressing tumor necrosis factor alpha and concomitant reduction in the cells expressing suppressors of cytokine signaling (SOCS). It is concluded that measles infection should be in the differential diagnosis of a rapidly progressive illness in young children in the United States and that the pathogenesis is based, in part, on massive viral infection with up-regulation of cytokine expression that likely reflects, in part, down-regulation of inhibitors of cytokine mRNA receptor synthesis.

Severe and fatal central nervous system disease in humans caused by Baylisascaris procyonis, the common roundworm of raccoons: a review of current literature

Baylisascaris procyonis, a parasitic infection of raccoons, causes severe neurologic disease in humans when infective eggs from raccoon feces are ingested. Definitive diagnosis is challenging, but can be made by isolation of larvae in brain biopsy or exclusion of other potential causes of eosinophilic meningoencephalitis. Prevention efforts are critical due to the lack of effective treatment.

Enteroviruses as agents of emerging infectious diseases

Although the enteroviruses as a group are ubiquitous and not normally considered as "emerging pathogens," the many different serotypes circulate at different frequencies in any given year and the prevalence of a given serotype may fluctuate wildly from year to year. As a result, several enterovirus serotypes have been associated with the emergence of specific diseases (for example, pandemic acute hemorrhagic conjunctivitis) and specific serotypes have emerged to cause outbreaks of major public health concern. Enterovirus 71 is a recognized cause of epidemic severe central nervous system disease in Southeast Asia. Acute hemorrhagic conjunctivitis was a newly described disease in the 1970s associated with emergence of enterovirus 70 and coxsackievirus A24 variant. In addition, the impending eradication of poliovirus and some of the challenges currently faced by the eradication program present the possibility that poliomyelitis could emerge in the posteradication era. These links between enterovirus infections and emerging diseases are reviewed.

Reviews in NeuroVirology: An introduction

This issue highlights the intersection of neurovirology and emerging infectious diseases. The enclosed reviews illustrate several points: first, that many emerging infections, even thosewhere the respiratory system is the primary site for clinical manifestations, e.g., SARS (seeYuen) orNipah (seeBellini), can cause severe central and peripheral nervous system disease. Second, infections of wildlife and domestic animals pose threats to global human health. More than 75%of emerging infectious diseases, includingAIDS, Nipah (Bellini), West Nile encephalitis (see Bernard and Briese), new variant Creutzfeldt Jakob disease (see Chesebro), influenza, and SARS are zoonoses (diseases caused by microbes that jump from animals to humans). The number of zoonotic microbes that jump to human hosts is increasing with close contact between wildlife, domestic animal and human populations due to political instability, deforestation, urbanization, international travel and trade (see Mackenzie). We have only defined a small portion of the microbial world and know little about the microbial flora of domestic animals let alone those in

ENT Wegener’s granulomatosis can hide severe central nervous system involvement

The clinical manifestations of localised or early systemic forms of Wegener's granulomatosis (WG) do not require immediate treatment to save the patient's life and/or the function of a vital organ. The organs mainly involved are the ear, nose, throat (ENT) and lung, and the results of antineutrophil cytoplasmic antibody (ANCA) assays are frequently negative. We here describe three cases of the ANCA-negative early systemic form of WG with prevalent ENT involvement complicated by severe central nervous system (CNS) disease; in two cases, the only symptom was a mild headache. We conclude that, although apparently mild, the localised and early systemic forms of WG can hide CNS involvement and may require immediate treatment. This complication should be suspected and investigated in the case of patients with localised or early systemic disease especially in the presence of ENT involvement and negative ANCA assays.

Retrospective Analysis of 23 Cases with Human Herpesvirus-6 Associated Encephalitis after Allogeneic Hematopoietic Cell Transplantation.

<Background> Cases of human herpesvirus-6 (HHV-6) associated central nervous system (CNS) dysfunction such as encephalitis after hamatopoietic cell transplantation (HCT) have been increasingly reported. However, clinical features, appropriate diagnostic methods, treatments and outcomes of HHV-6 encephalitis are not fully understood.<Methods> A questionnaire was sent to transplant centers in Japan, and adult allogeneic HCT recipients with CNS dysfunction who had HHV-6 DNA detected by polymerase chain reaction (PCR) in cerebrospinal fluid (CSF) were retrospectively analyzed.<Results> We describe 23 cases with HHV-6 associated encephalitis. Median age was 38 (range; 18–63) years. Underlying diagnosis included acute leukemia (AML, N=8; ALL, N=6), lymphoma (N=5), and others (N=4); 12 of whom had refractory or relapsed disease before HCT. Patients received bone marrow or peripheral blood stem cell from HLA-matched (N=2) or mismatched (N=9) related donors, unrelated donors (N=7), or umbilical cord blood (N=5). Conditioning included high-dose TBI-containing myeloablative regimens (N=16) and reduced-intensity regimens (N=7). In majority of cases, GVHD prophylaxis contained tacrolimus and methotrexate. Median onset of CNS dysfunction was day 22 (range; days 12–614) after HCT; 17 of whom had CNS symptoms within 7 days of neutrophil engraftment. Symptoms included coma/impaired consciousness (N=21; 91%), amnesia/loss of short-term memory (N=17; 73%), seizure (N=16; 70%), and fever (N=14; 61%). All patients had HHV-6 DNA in the CSF identified by qualitative (N=9) or quantifiable (N=14) PCR. Median HHV-6 DNA levels in the CSF was 3.3 (range; 0.8–500) x 103 copies/ml. HHV-6 typing study revealed subtype B virus in all 8 cases examined. No other causative agents were detected. Analysis of the CSF samples revealed increased WBCs in 10 of 22 patients (45%). Brain MRI scans showed abnormal findings within the temporal lobe in 17 patients (73%). Treatment for HHV-6 encephalitis included ganciclovir (N=17), foscarnet (N=11), intraveneous immunoglobulin (N=13), acyclovir (N=4), vidarabine (N=1), and donor lymphocyte infusion (N=1), and 5 were switched from ganciclovir to foscarnet due to ineffectiveness or toxicities. Although the clinical status appeared to improve after treatment in 21 of 23 patients (91%), 10 had a sequela such as memory problem.<Summary> These data suggest that HHV-6 may cause severe CNS disease after HCT, and detection of viral DNA in the CSF appeared to be useful for the rapid diagnosis and early anti-viral treatment. The presence of amnesia and abnormal findings within the temporal lobe may be a useful diagnostic indicator of HHV-6 associated encephalitis after HCT. In this analysis, majority of HHV-6 encephalitis cases were those who received cord blood transplant or grafts from unrelated or HLA-mismatched donors. Prospective studies are warranted to determine accurate diagnostic methods and appropriate treatment for HHV-6 encephalitis in high-risk patients.

Henoch-Schönlein purpura.

Henoch-Schönlein purpura (HSP) is a multisystem immunoglobulin A-mediated vasculitis with a self-limited course affecting the skin, joints, gastrointestinal tract, and kidneys. HSP occurs most often in children between the ages of 3 and 10 years, and presents classically with a unique distribution of the rash to the lower extremities and the buttocks area. For this reason, a skin biopsy in children is rarely necessary for diagnosis. However, in the very young age children and adults, the rash is not classically distributed, and therefore a skin biopsy is often needed. Although there are currently no prospective controlled studies on the treatment of the different manifestations of HSP, there are several retrospectively designed studies and other physicians' personal experiences supporting the use of steroids in patients with severe gastrointestinal, severe renal, central nervous system, and testicular involvements. Severe renal and central nervous system disease may lead to life-threatening conditions, and immunosuppressive agents and plasmapheresis may be needed. The overall prognosis in HSP is excellent, but the long-term morbidity depends on the renal and neurologic involvement. One third to one half of these patients will have one or more recurrences of symptoms, usually within 6 weeks, but may occur as late as 3 to 7 years later.

Infección por Myoplasma Pneumoniae: tres casos con complicaciones neurológicas

Summery. Introduction. Mycoplasma pneumoniae infection has been associated with severe central nervous system diseases. The pathogenesis of these disorders is unknown and the treatment uncertain. Case reports. The authorspresent three cases of central nervous system diseases: acute transverse myelitis, cerebellitis and encephalomyelitis associated with M. pneumoniae infection. Conclusions. M. pneumoniae infection should be considered in all cases of severe acute central nervous system symptomatology.

High-dose Borna disease virus infection induces a nucleoprotein-specific cytotoxic T-lymphocyte response and prevention of immunopathology.

Experimental Borna disease virus (BDV) infection of rats and natural infection of horses and sheep leads to severe central nervous system disease based on immunopathological pathways. The virus replicates slowly, and the cellular immune response results in immunopathology. CD8(+) T cells exert effector cell functions, and their activity results in the destruction of virus-infected cells. Previously, Oldach and colleagues (D. Oldach, M. C. Zink, J. M. Pyper, S. Herzog, R. Rott, O. Narayan, and J. E. Clements, Virology 206:426-434, 1995) have reported protection against Borna disease after inoculation of high-dose cell-adapted BDV. Here we show that the outcome of the infection, i.e., immunopathology versus protection, is simply dependent on the amount of virus used for infection. High-dose BDV (10(6) FFU) triggers an early virus-specific reaction of the immune system, as demonstrated by strong cellular and humoral responses. In particular, the early presence and function of nucleoprotein-specific CD8(+) T cells could be demonstrated in the brain. We present evidence that in a noncytolytic and usually persistent virus infection, high-dose input virus mediates early control of the pathogen due to an efficient induction of an antiviral immune mechanism. From these data, we conclude that immune reactivity, in particular the cytotoxic T-cell response, determines whether the virus is controlled with prevention of the ensuing immunopathological disease or whether a persistent infection is established.

FORAGING AMONG FECES: FOOD AVAILABILITY AFFECTS PARASITISM OF PEROMYSCUS LEUCOPUS BY BAYLISASCARIS PROCYONIS

Baylisascaris procyonis is a parasitic nematode of raccoons (Procyon lotor) capable of infecting many species of small vertebrates as intermediate hosts. In these hosts, migrating larvae often cause fatal or severe central nervous system (CNS) disease. Previous research suggested that intermediate hosts become infected with B. procyonis while visiting raccoon latrines. We tested effects of ambient availability of food and duration of exposure on dynamics of transmission of B. procyonis to white-footed mice (Peromyscus leucopus )i n a factorial design within enclosures containing artificially constructed raccoon latrines. Fifty percent of experimental mice acquired B. procyonis infections and 43% of infected mice developed CNS disease. Visitation to latrines was marginally greater (P 5 0.095) for mice subjected to low availability of ambient food. The mean number of larvae per mouse was greater (P 5 0.001) in low food group after exposures of 14‐28 days. Probability of infection varied predictably as a function of duration of exposure ( P 5 0.005), and probability of CNS disease varied predictably as a function of level of ambient food available (P 5 0.023). We conclude that transmission of B. procyonis occurs at raccoon latrines and that increased visitation to latrines and duration of residence in close proximity to a latrine, both increase probability of mortality due to CNS disease, especially when individuals are stressed by reduced resources or poor habitat.

Neurologic involvement in an outbreak of enterovirus 71 infection: a hospital-based study.

Enterovirus (EV) can cause varied clinical manifestations. Involvement of the central nervous system (CNS) with the nonpolio EVs are common and important causes of morbidity in children. To investigate the manifestations of nonpolio enteroviral infections with CNS involvement during the EV outbreak, from February 1998 to January 1999, we collected 153 hospitalized patients in our pediatric ward caused by nonpolio EV infections which were diagnosed by history, clinical features, or detected from viral cultures. Fourteen patients (9.2%) had CNS presentations, 13 males and one female. The ages ranged from one month to 10.3 years. The spectrum of CNS presentations included aseptic meningitis (4 cases, 28.6%), encephalitis (5 case, 35.7%), encephalomyelitis (3 cases, 21.4%), and poliomyelitis-like syndrome (2 cases, 14.3%). Among these patients, 8 cases (57.1%) were isolated with EV71 from at least one site of rectal or throat swab sampling. Two fatal cases were presented as encephalitis and complicated with pulmonary edema. Generally, enteroviral infections are considered as a benign infectious disease in children. However, pediatricians should keep in mind that EV71 has caused several endemic outbreaks and continues to be an occasional cause of severe CNS disease. Early evaluation and appropriate treatment of CNS enteroviral infections may minimize the neurologic sequelae.

Primary Sjögren's syndrome with severe central nervous system disease

Objective: Central nervous system (CNS) involvement in primary Sjögren's syndrome (pSS) is controversial with regard to frequency, significance, and etiology. Methods: We describe a young woman with pSS and severe CNS disease and review the literature on the pathophysiology, clinical significance, symptoms, diagnostic examinations, and treatment of CNS disease with concomitant pSS (CNS-SS). Results: Our patient with pSS had a 5-month history of benign lymphadenopathyand myositis, after which she developed severe CNS disease, vasculitic lesions on her hands, and a neurogenic bladder attributable to spinal cord involvement. The diagnosis was based on the clinical picture and the results of a brain magnetic resonance imaging (MRI) scan, electroencephalography (EEG), and cerebrospinal fluid (CSF) analysis. The disease did not respond to corticosteroids, but the administration of cyclophosphamide resulted in recovery. In the literature, the incidence of CNS-SS varies widely, from rare to incidence rates of 20% to 25%. The clinical picture is diverse, ranging from mild cognitive symptoms to fatal cerebrovascular accidents. The pathophysiology of CNS-SS is unclear, specific diagnostic methods are not available, and diagnosis is based on the clinical picture and a combination of examinations. MRI is the most sensitive test and cerebral angiography the most specific. CSF reflects involvement of the leptomeninges, and EEG is nonspecific. There are no controlled studies of the treatment of CNS-SS. Regimens for vasculitis are commonly used. Conclusions: CNS-SS is uncommonly recognized and difficult to diagnose.Increasingly accurate and available diagnostic examinations will yield more information about the association of CNS disease with pSS.

CD28 Costimulation Is Crucial for the Development of Spontaneous Autoimmune Encephalomyelitis

Multiple sclerosis (MS) is a severe central nervous system disease. Experimental autoimmune encephalomyelitis (EAE) mimics MS in mice. We report that spontaneous development of EAE in RAG-1-deficient mice transgenic for a myelin basic protein (MBP)-specific TCR (TgMBP+/RAG-1-/-) requires expression of the T cell costimulatory molecule CD28. Surprisingly, T cells from CD28-/-TgMBP+/RAG-1-/- mice proliferate and produce IL-2 in response to MBP1-17 peptide in vitro, excluding clonal anergy as the mechanism of CD28-regulated pathogenesis. Proliferation of autoaggressive T cells was dependent on the concentration of the MBP peptide, as was the development of MBP-induced EAE in CD28-deficient PL/J mice. These results provide the first genetic evidence that CD28 costimulation is crucial for MBP-specific T cell activation in vivo and the initiation of spontaneous EAE.

Enterovirus 71 from Fatal and Nonfatal Cases of Hand, Foot and Mouth Disease Epidemics in Malaysia, Japan and Taiwan in 1997-1998

Enterovirus 71 (EV71), one of the major causative agents for hand, foot and mouth disease (HFMD), is sometimes associated with severe central nervous system diseases. In 1997, in Malaysia and Japan, and in 1998 in Taiwan, there were HFMD epidemics involving sudden deaths among young children, and EV71 was isolated from the HFMD patients, including the fatal cases. The nucleotide sequences of each EV71 isolate were determined and compared by phylogenetical analysis. EV71 strains from previously reported epidemics belonged to genotype A-1, while those from recent epidemics could be divided into two genotypes, A-2 and B. In Malaysia, genotype A-2 was more prevalent, while in Japan and Taiwan, B genotype was more prevalent. Two isolates from fatal cases in Malaysia and one isolate from a fatal case in Japan were genotype A-2. However, all isolates from three fatal cases in Taiwan belonged to genotype B. The severity of the HFMD did not link directly to certain genotypes of EV71.

Méningoencéphalite à Mycoplasma pneumoniae

Severe central nervous system diseases, such as encephalitis, have been reported in association with Mycoplasma pneumoniae infections. After an ENT infection, a 9-year-old boy with Down's syndrome developed encephalitis revealed by an acute alteration in consciousness. Head computed tomography showed, after 2 weeks, an infiltration in the basal ganglia region. The diagnosis of Mycoplasma pneumoniae encephalitis was made; recovery was complete in a few weeks. Mycoplasma pneumoniae infection should be considered in all cases of acute encephalopathy; yet the pathogenesis of the disorder is unknown and the treatment uncertain.

1990-1996: experiencia del Grupo de Trasplante Pulmonar La Fe (Valencia)

Objective to review the experience of the lung transplantation unit at Hospital La Fe (Valencia). Between February 1990 and March 1996 we performed 40 lung transplants. The following causes were most common: cystic fibrosis (9 cases), emphysema (8), pulmonary fibrosis (8) and bronchiectasis (7). Types of intervention were 27 double lung transplants (25 sequential and 9 blocked), 9 single lung transplants, and 4 heart-lung transplants. We then reviewed the 36 single and double lung transplants. The main exclusion criteria were age over 65 years, malignant disease, kidney or liver disease, severe or non reversible central nervous system disease, and drug addiction. Prior surgery, mechanical ventilation and the presence of Aspergillus were considered lower-order contraindications. Mean patient age was 37.7 years (14-59). Six patients were colonized by Aspergillus before transplantation. Five had undergone earlier surgery and two were mechanically ventilated before the transplant. The most common complication was respiratory infection, which was present in 6 of the 7 patients who died. Other complications in order of frequency were dehiscence and/or bronchial stenosis, corticoid myopathy and postoperative bleeding. The actuarial survival rate of single and double lung transplants was 67.85 after 3 years, and 87.5% in patients with cystic fibrosis. Lung transplantation is a well-established procedure that is gradually being extended to treat more conditions. The main obstacle is the scarcity of donors. The main challenge at present is bronchiolitis obliterans.