Quality Enhancement Research Initiative in stroke: prevention, treatment, and rehabilitation.

Stroke is the third leading cause of death and a leading cause of adult disability in the United States. Both within and outside of the Veterans Health Administration (VHA), the lack of a systematic approach to stroke prevention and treatment may have contributed to reduced rates of compliance with recommended practices and increased rates of stroke. Gaps in the knowledge base inhibit a systematic approach to high-quality care within the veteran population. Initial recommendations for closing those gaps are proposed. In some cases (eg, systematic anticoagulation management), the VHA is perceived as a leader in applied research; therefore, a systematic national policy for implementing these clinics may significantly reduce stroke rates. In other areas (eg, carotid endarterectomy), databases exist that would help advance quality and outcomes, but short-term studies are necessary to establish their utility. To promote strategic improvement in prevention, treatment, and rehabilitation for veterans who may be at risk or have had a stroke, specific objectives are proposed to (1) identify best practices for the effective delivery of long-term anticoagulation and enhance veterans' access to these services, (2) develop risk-adjusted models for the surgical preventive procedure carotid endarterectomy to understand facility variation in outcomes so practices can be improved, (3) define a systematic acute stroke management system so that high-quality stroke-related care can be generalizable to a variety of VHA settings, and (4) assess the impact of poststroke rehabilitation on risk adjustment and the location of outcomes so as to facilitate the implementation of best rehabilitation practices.

Chronic-treated HIV: a neurologic disease.

The concept of slow virus diseases was developed by Sigurdsson in the 1950s in studies of infections of Icelandic sheep, including Visna, a slow (lenti) viral infection of the central nervous system. Human immunodeficiency virus (HIV) belongs to the same lentivirus subfamily of retroviruses and causes significant dysfunction of all levels of the nervous system. Highly active antiretroviral therapy should allow host control of opportunistic infections, producing a clinical state of chronic-treated HIV. However, viral persistence may occur in the sanctuary of the central nervous system. As a consequence, major disabilities in the chronic-treated phase of the HIV epidemic may include cognitive impairment, gait disorders, and various pain syndromes. Policy planning will need to take into account the long-term residential, social, and health care needs of this population.

Progressive multifocal leukoencephalopathy in AIDS: are there any MR findings useful to patient management and predictive of patient survival? AIDS Clinical Trials Group, 243 Team.

BACKGROUND AND PURPOSE: While MR findings in progressive multifocal leukoencephalopathy (PML) have been described previously, usually in retrospective studies with limited sample size, what has not been well addressed is whether any are predictive of longer survival. Our participation in a large prospective clinical trial of AIDS patients with biopsy-proved PML and MR correlation allowed us to test our hypothesis that certain MR features could be found favorable to patient survival. METHODS: The patient cohort derived from a randomized multicenter clinical trial of cytosine arabinoside for PML. Pretreatment T1- and T2-weighted noncontrast images (n = 48) and T1-weighted contrast-enhanced images (n = 45) of 48 HIV-positive patients with a PML tissue diagnosis as well as the follow-up images in 15 patients were reviewed to determine signal abnormalities, lesion location and size, and the presence or absence of mass effect, contrast enhancement, and atrophy, and to ascertain the frequency of these findings. A statistical analysis was performed to determine if any MR abnormalities, either at baseline or at follow-up, were predictive of patient survival. RESULTS: No MR abnormalities either on univariate or multivariate analysis significantly correlated with patient survival, with the exception of mass effect, which was significantly associated with shorter survival. The mass effect, however, always minimal, was infrequent (five of 48). More severe degrees of cortical atrophy and ventricular dilatation, lesion location and size, and other MR variables were not predictive of outcome. CONCLUSION: Except for mass effect, we found no MR findings predictive of the risk of death in patients with PML. The mass effect, however, was so infrequent and minimal that it was not a useful MR prognostic sign.

Prevention of a first stroke: a review of guidelines and a multidisciplinary consensus statement from the National Stroke Association.

OBJECTIVE: To establish, in a single resource, up-to-date recommendations for primary care physicians regarding prevention strategies for a first stroke. PARTICIPANTS: Members of the National Stroke Association's (NSA's) Stroke Prevention Advisory Board and Cedars-Sinai Health System Department of Health Services Research convened on April 9, 1998, in an open meeting. The conference attendees, selected to participate by the NSA, were recognized experts in neurology (9), cardiology (2), family practice (1), nursing (1), physician assistant practices (1), and health services research (2). EVIDENCE: A literature review was carried out by the Department of Health Services Research, Cedars-Sinai Health System, Los Angeles, Calif, using the MEDLINE database search for 1990 through April 1998 and updated in November 1998. English-language guidelines, statements, meta-analyses, and overviews on prevention of a first stroke were reviewed. CONSENSUS PROCESS: At the meeting, members of the advisory board identified 6 important stroke risk factors (hypertension, myocardial infarction [MI], atrial fibrillation, diabetes mellitus, blood lipids, asymptomatic carotid artery stenosis), and 4 lifestyle factors (cigarette smoking, alcohol use, physical activity, diet). CONCLUSIONS: Several interventions that modify well-documented and treatable cardiovascular and cerebrovascular risk factors can reduce the risk of a first stroke. Good evidence for direct stroke reduction exists for hypertension treatment; using warfarin for patients after MI who have atrial fibrillation, decreased left ventricular ejection fraction, or left ventricular thrombus; using 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors for patients after MI; using warfarin for patients with atrial fibrillation and specific risk factors; and performing carotid endarterectomy for patients with stenosis of at least 60%. Observational studies support the role of modifying lifestyle-related risk factors (eg, smoking, alcohol use, physical activity, diet) in stroke prevention. Measures to help patients improve adherence are an important component of a stroke prevention plan.

Change in the Department of Veterans Affairs: what should be done?

Health care in the Department of Veterans Affairs is undergoing the most dramatic change since the era following World War II. The Congress has supported the Undersecretary for Health in his guidance of this change. Traditional hospital-based, specialty-focused care has given way to outpatient and primary care focused health care. Administrative authority has been shifted to 22 Veterans Integrated Service Networks (VISNs). Research goals are being reoriented, and neurology resident allocation is being reduced. VA neurologists and neurology chairs must organize strong service lines in their own VA facilities and in their networks to provide care for veterans with neurologic diseases. VA neurologists must also emphasize their role in principal care and increase their involvement in outcomes research.

Neurologic infections of the fetus and newborn.

This article concentrates primarily on infections of viral origin, although numerous microorganisms can infect the fetal and newborn brain (see Tables 1 and 2). Intrauterine infections occur most often for HIV, CMV and rubella, whereas HSV is preferentially transmitted intrapartum. In the last decade, changes in the epidemiology of some of the neonatal infections have occurred largely because of the AIDS epidemic. Indeed, pediatric HIV is now the second most frequent viral infection of the newborn (see Table 1) and congenital syphilis has reemerged. Surprisingly, the AIDS epidemic appears to have had minimum impact on infections with other organisms such as Toxoplasma and CMV that commonly infect the brain of adults with AIDS. The recent availability of improved viral diagnostic methods and anti-viral drugs has aided in the identification and treatment of infected newborns.

Human immunodeficiency virus-associated motor axonal polyradiculoneuropathy.

OBJECTIVE: To report two cases of an axonal motor polyradiculoneuropathy associated with human immunodeficiency virus infection in otherwise asymptomatic subjects. DESIGN: Case series. SETTING: Tertiary care hospital neurology inpatient service. RESULTS: Electrophysiologic testing showed acute denervation with almost normal sensory potentials and no evidence of demyelination. CONCLUSIONS: These cases present an example of an acute axonal polyradiculoneuropathy in persons infected with human immunodeficiency virus without acquired immunodeficiency syndrome.

Localization of TNF alpha and IL-1 alpha immunoreactivities in striatal neurons after surgical injury to the hippocampus.

Since the inflammatory process develops after transplantation to the brain, we sought to determine the presence of cytokines following a surgical trauma to the brain of an adult mouse. We report the early and marked presence of tumor necrosis factor-alpha and interleukin-1 alpha in neuronal somata of the striatum following a surgical injury to the hippocampus. The expression of cytokines later extends to neuronal cells of the hippocampus, thalamus, cerebral cortex, brain stem, and cerebellum and to glial cells of the corpus callosum. By contrast, these cytokines are not expressed by neuronal cells following injury to other regions, such as the striatum, cerebellum, and cortex. This study suggests a possible role for certain neurons in the brain's early reaction to a penetrating injury.

Host response during successful engraftment of fetal xenogenic astrocytes: predominance of microglia and macrophages.

Grafting of fetal rabbit brain fragments into the brains of newborn mice results in the successful establishment and migration of xenogenic astrocytes in the majority of recipients. This can be demonstrated by the use of Tp-GFAP1 monoclonal antibody which binds with rabbit, but not with murine glial fibrillary acidic protein. In the first phase, donor astrocytes are found in more than 80% of recipients 3 and 4 weeks after grafting. In the second phase, there is a decline and disappearance of donor astrocytes by the tenth week. We have recently demonstrated that the decline and disappearance of donor astrocytes was co-incident with infiltration of T cells into the brain, compatible with T-cell-mediated graft rejection. In the present studies, we wished to characterize the types of host cells responding during the period of graft success, in the first 4 weeks after transplantation. It was found that responses by microglia, macrophages, and astrocytes occurred promptly and were sustained throughout this period. Host responses occurred at the graft site and at sites of migration. Examination of sham transplanted control mice revealed responses by the same types of cells. No expression of donor Ia antigen was observed, and the expression of Ia antigen by the host was variable and of low magnitude. T cells were rarely present in transplanted brains during this period. Taken together with previous findings, the present studies demonstrate a clear difference in the host response in the brain at the time when xenogenic astrocytes migrate and survive compared to the period when they disappear.(ABSTRACT TRUNCATED AT 250 WORDS)

Disappearance of xenogenic astrocytes transplanted into newborn mice is associated with a T-cell response.

Following transplantation of fragments of embryonic rabbit brain into the brains of newborn mice, the proportion of mice bearing detectable xenogenic astrocytes increases to over 80% in the first 3-4 weeks. Recent studies have demonstrated that the host response at this time was dominated by non-specific elements of host defense: macrophages, microglia and astrocytes. In the second phase, the proportion of mice bearing xenogenic astrocytes declines rapidly after 4 weeks and reaches zero by 10 weeks. In the present experiments, designed to characterize the host defense during this period, a dramatic increase in the proportion of mice displaying T-cells in the brain in the fourth and fifth weeks after transplantation was found. This corresponded with a marked decline of xenogenic astrocytes. Both subsets of T-cell, helper-inducer (L3T4) and cytotoxic-suppressor (Lyt2), were found, with L3T4 more numerous in many samples. T-cells were found at the site of transplantation and at sites of migration. The division of the host-defense response in this model into a phase of antigen non-specific cells followed by a period when T-cells appear and transplanted astrocytes disappear, should facilitate kinetic studies into the mechanisms of brain-graft rejection.

Migration of xenogenic astrocytes in myelinated tracts: a novel probe for immune responses in white matter.

Experimental brain transplantation allows the study of the development of the immune response against brain antigens within the brain itself. This laboratory has developed a transplantation model in which rabbit embryo brain fragments are placed in the brains of newborn mice. The migration of xenogenic astrocytes is traced by a monoclonal antibody which combines with donor but not host glial fibrillary acidic protein. In the first 4 weeks after transplantation, the donor astrocytes successfully migrate, often within myelinated tracts. Following this period, T cells make their appearance and xenogenic astrocytes disappear by 10 weeks. The propensity for clearly identified foreign astrocytes to migrate in myelinated tracts coupled with a well-defined time course of host-vs-graft interaction suggested that the model could be used to study the immune response in white matter. The studies reported here provide sequential examples of the relationship between migration by foreign astrocytes in myelinated tracts and the development of the host immune response. Extensive migration in white matter tracts was first observed in the absence of any T cell response. Subsequently T cells were found at the transplantation site. Finally Ia was found to be expressed on blood vessels and microglia were strongly reactive in white matter that contained T cells but no foreign astrocytes. These observations support the suggestion that the model can be used to more precisely define cellular immune events that occur within white matter.

Mechanisms of injury to the central nervous system following experimental cytomegalovirus infection.

A guinea pig model was used to determine the mechanisms of injury to the central nervous system by cytomegalovirus. Focal, well-contained, histopathologic responses included the microglial nodule without residua, and the ependymitis with focal residual glial scarring. Higher virus dose infection in the brain resulted in inflammatory necrosis with an astrocytic response to injury. However, monocytes and microglia were the predominant responding cells of host defense. A vasogenic pathogenesis was suggested by the involvement of the vascular endothelium, and separately by central nervous system vasculitis, demonstrated here for the first time in this model. Hence, our studies suggest four potential mechanisms of injury to the central nervous system by cytomegalovirus: viral cytopathology, inflammatory mediators from cells of the monocyte series, two separate types of vascular impairment, and astroglial scarring.

Viremia and glial nodule encephalitis after experimental systemic cytomegalovirus infection.

Despite the importance of cytomegalovirus (CMV) infection of the central nervous system in acquired immune deficiency syndrome, a well characterized laboratory model of glial nodule encephalitis after systemic CMV infection is not available. We now report that after intraperitoneal infection of young guinea pigs with CMV, infection of the brain was routinely found in the 2nd week. Recovery of virus from the brain was achieved at the time of viremia. Histopathologic changes in the brain followed the recovery of virus and continued beyond the point that virus was cleared from the brain. Microglial nodules, which were sometimes observed in association with intranuclear inclusion bearing cells, were the predominant feature. Other histopathology included perivascular infiltrates, vascular endothelial swelling, subependymal infiltrates, and sporadic focal leptomeningitis. In comparison to our previous studies after intracerebral inoculation, parenchymal changes dominated and leptomeningitis was found infrequently. The present studies suggest that focal central nervous system infection by CMV may be relatively common, though clinically silent, in the course of systemic infection. Relevant to acquired immune deficiency syndrome, the model should facilitate studies of the mechanism of brain infection, local central nervous system host defense, and mechanisms of injury to the brain.

Cytomegalovirus encephalitis: neuropathological comparison of the guinea pig model with the opportunistic infection in AIDS.

The AIDS epidemic has transformed the importance of cytomegalovirus (CMV) as a pathogen for the adult human central nervous system (CNS). At autopsy, about 25 percent of AIDS cases have cytopathologic evidence of CNS infection by CMV. Since almost nothing is known of the host CNS-viral interactions, we have developed a laboratory model of CMV infection of the brain in the guinea pig. In the present paper, we review the syndromes of CMV infection of the human CNS and compare the neuropathological findings of the opportunistic CMV brain infection in AIDS with the model. Destructive meningoencephalitis, perivascular infiltrates, and subependymal inflammation are found in both, but the glial nodule is the most characteristic feature of each. Thus, we demonstrate that the model faithfully reflects the histopathology of the human disease. Furthermore, since we have found that CNS infection is achieved following systemic infection in the guinea pig, the model recapitulates the sequence of infection in humans.

Varicella zoster-associated neurologic disease without skin lesions.

We have investigated a group of cases with inflammatory neurologic disease and serologic evidence of varicella zoster virus activity without cutaneous vesicles. In agreement with experience, a case of cranial polyneuropathy with facial palsy and cases of aseptic meningitis were found. However, cases of acute polyneuropathy, myelitis, and encephalitis were also identified. Thus, it seems that the spectrum of neurologic disease associated with varicella zoster virus in the absence of skin lesions is considerably broader than previously recognized.

Host defense response to cytomegalovirus in the central nervous system. Predominance of the monocyte.

Cytomegalovirus (CMV) infection of the brain is common in AIDS; however, little is known of the host defense response to CMV in the central nervous system (CNS). A guinea pig model was developed to study this problem. In the present studies the percentages of T cells and monocytes invading the leptomeninges during the course of acute CMV infection were compared. In addition, qualitative observations on parenchymal infiltrates were made. Such studies have not been performed previously in CMV infection of the CNS. Monocytes, defined cytochemically, predominated in the leptomeninges and in parenchymal foci. In contrast, T cells, defined immunohistologically, were found in a low percentage in the leptomeningeal reaction and only rarely in the parenchyma. These novel results differ significantly from other viral infections in which the T cell predominates in the leptomeningeal response and plays a major role in the parenchyma.

Idiopathic CSF pleocytosis in relapsing polychondritis.

The association of relapsing polychondritis with CSF pleocytosis is reported for the first time. Three cases are described in which infectious etiologies of the pleocytosis were excluded by appropriate cultures and serologic studies. We suggest that the finding of CSF pleocytosis in relapsing polychondritis does not merit empiric antimicrobial therapy in the absence of demonstrated infection.

Glial nodule encephalitis in the guinea pig: serial observations following cytomegalovirus infection.

Cytomegalovirus (CMV) encephalitis, characterized by microglial nodules, is a major neurological complication in AIDS. There is a clear need for a well-characterized laboratory model of CMV encephalitis. We report here the sequential virological, histopathological, and antibody responses of young guinea pigs inoculated intracerebrally with guinea pig CMV. Virus was found to peak in the brain in the 1st week, to peak in the spleen in the 2nd week, and to be cleared from the brain with the development of serum neutralizing antibody 3 to 4 weeks post infection. Leptomeningitis peaked at the end of the 1st week, independent of the changes found in the parenchyma. Diffuse and focal infiltration of systemic cells was found in the cortex. Microglial nodules consisting of swirled and elongated cells, sometimes in association with intranuclear inclusion bearing cells, were prominent. The parenchymal changes, including scattered foci of ependymitis and ventriculitis, were most prominent in the 2nd week post infection. This model should facilitate studies of the host defense response in the brain and of the role of antiviral therapy in CMV encephalitis.