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The identification of biomarkers identifying onset of human immunodeficiency virus-associated dementia (HIV-D) is critical for diagnosis and the elucidation of pathophysiologic pathways.To examine the association between platelet decline from baseline and HIV-D.Prospective cohort study within the North-East AIDS Dementia cohort.Four participating referral centers in the United States.A total of 396 subjects with advanced human immunodeficiency virus (HIV) infection recruited between 1998 and 2003 and undergoing serial neurologic assessments. Eligibility criteria required CD4 cell counts less than 200/microL or less than 300/microL with evidence of cognitive impairment. A cohort subset without prevalent HIV-D at baseline and without incident HIV-D at the visit immediately after baseline was analyzed (n = 146). Main Outcome Measure Time to first diagnosis of HIV-D.After a median follow-up of 31.1 months, 40 subjects developed HIV-D. Platelet decline from baseline was associated with the development of HIV-D when examined as a time-dependent variable lagged by 6 to 12 months before outcome (multivariate hazard ratio [HR], 2.39; 95% confidence interval [CI], 1.14-5.02; P = .02). This association was stronger during the first 2 years of follow-up (multivariate HR, 6.76; 95% CI, 2.36-19.41; P.001) than during later years (multivariate HR, 0.94; 95% CI, 0.33-2.67; P = .90).These results suggest that individuals with declining platelet counts are at greater risk for HIV-D and that the dynamics of circulating platelets vary with respect to the temporal progression of HIV-D. This highlights an avenue to be explored in the understanding of HIV-D pathogenesis.

Researchers at Nationwide Children's Memorial Hospital studied the frequency of intracranial hypertension without papilledema in children followed in a multispecialty pediatric intracranial hypertension clinic.

Primary angiitis of the central nervous system (PACNS) is a rare, idiopathic vasculitis diagnosed most frequently in adults. We describe 2 children presenting with hemiplegia from PACNS treated with cyclophosphamide. Diagnosis in one child was based on abnormal angiography. Oral, but not intravenous (IV), cyclophosphamide was effective in preventing progressive weakness. The second child had unremarkable angiography, but brain biopsy revealed vasculitis; IV cyclophosphamide prevented further weakness. Both cases highlight the importance of early diagnosis and treatment.

Various biomarkers have been suggested as associative or predictive of HIV-associated neurocognitive impairment. Plasma levels of monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-alpha), and hematocrit were evaluated for relationships with diffusion tensor imaging measurements of centrum semiovale, caudate, and putamen. MCP-1 levels correlated with tissue status (mean diffusivity) in all examined regions. Plasma markers were also significantly correlated with anisotropy measurements in centrum semiovale (TNF-alpha) and putamen (hematocrit).

Background: HIV infection is associated with a painful distal sensory polyneuropathy (DSP) that can severely limit the quality of life of affected subjects. The pathogenesis of DSP is unknown, although both HIV proteins and products of immune activation triggered by HIV infection have been implicated. Objective: To assess the association between baseline markers of immune activation and HIV RNA levels (viral load) and time to symptomatic DSP (SDSP). Methods: A cohort of 376 subjects, most receiving highly active antiretroviral therapy (HAART), were followed semiannually for up to 48 months. Blood and CSF levels of HIV viral load, monocyte chemotactic protein-1, macrophage colony-stimulating factor (M-CSF), matrix metalloproteinase-2, and tumor necrosis factor-α were measured in addition to CD4 lymphocyte cell count. Results: In subjects without SDSP at baseline (62.5% of the cohort), among the virologic and immunologic markers, only baseline CSF M-CSF levels were associated with time to SDSP (hazard ratio = 2.97, p = 0.05). The Kaplan–Meier estimate of the 1-year incidence of SDSP was 21%, a 15% decrease from that observed in the Dana cohort, a pre-HAART cohort enrolled with the same inclusion/exclusion criteria. Conclusion: Highly active retroviral therapy (HAART) has changed the natural history of HIV-associated symptomatic distal sensory polyneuropathy (SDSP), which may explain, in contrast with studies from the pre-HAART era, the lack of association between SDSP and baseline HIV viral load and CD4 cell count.

Objective: To study whole-brain MR measures derived from diffusion tensor imaging and magnetization transfer imaging (MTI) for the in vivo assessment of cumulative neuropathologic changes in HIV and to evaluate the quantitative imaging strategies with respect to cognitive status measures including the severity of dementia and the degree of impairment in specific cognitive domains including attention, memory, constructional abilities, and motor speed.Methods: Quantitative whole-brain measurements, including fractional anisotropy (FA), apparent diffusion coefficient (ADC), and magnetization transfer ratio (MTR), were derived from histograms and compared in HIV and control participants. Relationships between the MR and cognitive status measures were examined.Results: Whole-brain FA and MTR were reduced in patients with HIV and correlated with dementia severity. Whole-brain MTR and ADC were correlated with psychomotor deficits. Evaluation of relationships between the studied MR measures indicated a correlation between ADC and MTR; FA was not correlated with either ADC or MTR.Conclusions: Findings from this investigation support the use of quantitative whole-brain MR measures for evaluation of disease burden in HIV. Reductions in whole-brain fractional anisotropy and magnetization transfer ratio (MTR) distinguished HIV and control subjects, and these measures were associated with dementia severity. Relationships were identified between whole-brain MTR and apparent diffusion coefficient and psychomotor deficits. Combining these quantitative strategies in neuroimaging examinations may provide more comprehensive information concerning ongoing changes in the brains of HIV patients.

The imminent deadline for the 1991 Persian Gulf War and, subsequently, the 18 missile attacks by Iraq on Israel represented an unusual, short-term, life-threatening stressor for an entire nation. We studied mortality in Israel in January and February 1991 to determine whether excess deaths were precipitated on days of missile attacks.A time-series mortality study.The state of Israel.All Israelis aged 25 years and older.Daily mortality by sex, age, region, underlying cause, and place of death.On January 18, 1991, the day of the first strike on Israeli cities, a 58% increment in total mortality occurred in the Israeli population (95% confidence interval [CI], 34% to 86%; P.0001), a 77% excess (95% CI, 40% to 120%) in women and a 41% excess (95% CI, 10% to 79%) in men. This excess mortality occurred largely in the targeted Tel Aviv-central coastal plain and Haifa regions from cardiovascular causes and mainly out of hospital, significantly more so (P.01) in women than men. Subsequently, on 16 attack days no overall excess was noted, yet a 10% increase in out-of-hospital deaths occurred.Likely explanations for the initial increase in mortality include acute emotional stress coupled with breathing difficulties induced by gas masks and extended stay in sealed rooms with resultant hypoxia in susceptible individuals. Women were more vulnerable than men. The absence of elevated total mortality in the subsequent attacks suggests a rapid adaptation to the circumstances surrounding the war. The policy of an unventilated sealed room may have been detrimental.

In order to detect latent infection in neurons or other cell types in formalin-fixed brain tissue, we performed polymerase chain reaction amplification with incorporation of digoxigenin-conjugated deoxynucleotides, followed by in situ hybridization with biotinylated probes. The use of this two-step technique in brain tissue from a child with severe HIV-1 encephalitis revealed signal in both nuclear and perinuclear regions of cells identified as monocytes and astrocytes, and also in perineuronal satellite cells of glial morphology, but HIV-1 infection of neurons was not detected.

We report four children with idiopathic stroke syndromes who were assayed for human leukocyte antigen (HLA) class I markers and found to have HLA-B51 in common. This finding suggests that there may be a genetic predisposition for "idiopathic" childhood stroke, and host factors, possibly in concert with environmental factors or viruses, may play a major role in the mechanism of unexplained occlusion of the cerebral vasculature in children.

Progressive Multifocal Leukoencephalopathy (PML) is a primary demyelinating disease of the central nervous system occurring almost exclusively in individuals with impaired cell-mediated immunity. The JC polyoma virus has been accepted as the etiologic agent of PML. Using a two-step in-situ polymerase chain reaction procedure to amplify and detect genomic DNA of human herpesvirus-6 (HHV6) in formalin-fixed paraffin-embedded archival brain tissues, a high frequency of infected cells was consistently detected in PML white matter both within and surrounding demyelinative lesions and HHV6 genome was found mainly within oligodendrocytes. Lesser amounts of HHV6 genome were detected in most normal, AIDS, and other neurological disease control tissues. Immunocytochemistry for HHV6 antigens showed actively infected nuclei of swollen oligodendrocytic morphology only within the demyelinative lesions of PML but not in adjacent uninvolved tissue. In addition, no HHV6 antigens were detectable in control tissues including brains of individuals with HIV-1 encephalopathy but without PML. Double immunohistochemical staining for JC virus large T antigen and HHV6 antigens demonstrated co-labeling of many swollen intralesional oligodendrocytes in the PML cases. The evidence suggests that HHV6 activation in conjunction with JC virus infection is associated with the demyelinative lesions of PML.

The capacity of a panel of HIV-1 isolates to infect primary mixed fetal brain cell cultures was estimated and their sensitivity to inhibition by a range of coreceptor ligands assessed. Our results show that (1) HIV-1 strains that predominantly use CCR5 or only CXCR4 are able to infect microglia in primary brain cell cultures, and (2) ligands to these two coreceptors can inhibit brain cell infection. CCR5 ligands (including AOP-RANTES, a potent inhibitor of CCR5-dependent infection), however, blocked infection only weakly, raising the possibility that alternative unidentified coreceptors are also used. Interestingly, vMIP-II, a chemokine encoded by the Kaposi sarcoma-associated herpes virus (KSHV), reduced brain cell infection by all HIV-1 strains tested, including both R5 and X4 viruses. Our results therefore indicate that novel drugs targeted to the major HIV-1 coreceptors will influence HIV replication in the brain, if they cross the blood-brain barrier.

Human immunodeficiency virus (HIV)-l neuropathogenesis can be divided into three important components: (i) virus entry into the nervous system; (ii) the role of viral proteins and/or cellular products in neural tissue damage; and (iii) the mechanisms of neuronal injury/death. Both blood derived macrophages or trafficking HIV-1 infected T-lymphocytes have been implicated in viral entry to the central nervous system (CNS). The major cell type harboring productive HIV-1 infection in the nervous system is the perivascular macrophage/ microglia. The HIV-1 infection of brain astrocytes, restricted to the expression of regulatory gene products, may cause astrocyte dysfunction and contribute to neuronal injury or to disruption of the blood-brain barrier (BBB). Studies of cerebrospinal fluid and postmortem tissues reveal chronic inflammation/immune activation in the nervous system during the later stages of HIV-1 infection associated with disruption of BBB integrity. Blood-brain barrier damage may underlie the white matter pallor described in HIV-1 infection and could result in further entry into the CNS of toxic viral or cellular products, or additional HIV-1 infected cells. The HIV infected and activated macrophages/microglia produce excessive amounts of pro-inflammatory cytokines, including tumor necrosis factor alpha, and platelet activating factor. These products are directly toxic to human neurons in vitro. The HIV-1 envelope glycoprotein, gp 120 may stimulate the release of toxic factors from brain macrophages. Blocking N-methyl-D-aspartate (NMDA; or AMPA) glutamate receptors can antagonize candidate toxins of both viral and cellular origin. It has been postulated that (weak) excitotoxicity leads to oxidative stress in neurons and ultimately to apoptosis. Neuronal apoptosis occurs in the brains of both children and adults with HIV-1 infection. This understanding of HIV neuropathogenesis implies that therapeutic strategies should include: (i) anti-retroviral medications to decrease systemic and CNS virus load, and possibly to prevent perinatal transmission of HIV; (ii) anti-inflammatory compounds to decrease the chronic immune activation in microglia and allow the restoration of BBB integrity; and (iii) neuroprotective compounds to reduce neuronal injury and apoptotic death.

We report a family with band heterotopia in a mother and daughter and lissencephaly in a son (X-linked inheritance pattern). Postmortem examination of the boy revealed classical lissencephaly and, among other findings, simplified and discontinuous inferior olives without inferior olivary heterotopia. The absence of inferior olivary heterotopia may distinguish X-linked lissencephaly from other conditions with classic lissencephaly such as Miller-Dieker syndrome.

The transmissible spongiform encephalopathies are a large group of neurodegenerative disorders that affect both humans and animals. [1] The transmissible agent has been identified as an isoform of a normal brain protein PrPc designated PrP sup sc, or the prion protein. [2] These disorders have common pathologic features, including, as the name implies, spongiform change in the brain associated with astrogliosis, neuronal loss, and the deposition of proteinase-resistant amyloid protein (PrP) in brain plaques, usually with a characteristic distribution. In humans, the most common spongiform encephalopathy, Creutzfeldt-Jakob disease (CJD), occurs sporadically with a frequency of approximately one case per million population per year. [1] In addition, there are a number of genetically determined forms of spongiform encephalopathy caused by mutations in the PrP gene. [1,3] The transmissibility of scrapie between sheep with use of nervous tissue was reported as early as 1936 in France. [4] Pathologic similarities between scrapie in sheep and kuru in humans were noted by Hadlow in 1959. [5] Landmark experiments by Gajdusek and colleagues [6,7] demonstrated the transmissibility of CJD and kuru to a number of nonhuman primate and other mammalian hosts. Human-to-human transmission was described for kuru associated with ritualistic cannibalism in the highlands of New Guinea [6] and a number of iatrogenic transmissions were described in association with corneal and dura mater transplants, inadequately sterilized neurosurgical instruments, and contaminated growth hormone prepared from cadaveric pituitary tissue. [1] The appearance in 1986 of a new spongiform encephalopathy in British cattle, bovine spongiform encephalopathy (BSE), [8] raised the concern of possible transmission of this disorder to the human population by consumption of beef or other tissues from infected cattle. This concern was, in part, balanced by the knowledge that scrapie-infected sheep in large numbers had been consumed for many decades with no documented transmission of …

Clinicians have long suspected an association between migraine and infantile colic.1- 3 Previous studies have linked maternal migraine with infantile colic.4 In this issue of JAMA, a case-control study of 208 children with migraine and 471 age-matched controls by Romanello and colleagues5 answers a long-standing scientific question by demonstrating an association between migraine, with or without aura, and infantile colic in pediatric patients, with an odds ratio of 6.61 (95% CI, 4.38-10.00). The specificity of this finding is bolstered by the absence of any association between tension headaches and infantile colic in a separate group of 120 children.5

HIV-1 infection is a worldwide pandemic, with an estimate of one to two million children infected by the end of the decade. The neurologic manifestations of primary HIV-1 infection in children are a major cause of morbidity and contribute to the fatal outcome in this condition. In the United States, HIV-1 is the most frequent cause of dementia in young adults. Because antiretroviral therapies and treatment for opportunistic infections have lengthened the survival time but not eradicated the virus from the central nervous system, it is likely that the incidence of neurologic dysfunction, including HIV-1 dementia, will increase. Available evidence suggests that the HIV-1 virus does not productively infect neurons but rather induces programmed cell death (apoptosis) in neurons by production of neurotoxic factors, including cytokines, phospholipid mediators, and eicosanoids, and HIV-1 gene products from HIV-1-infected macrophages in the brain. Understanding the mechanisms involved in neuronal cell injury and death may lead to new therapeutic interventions for the neurologic dysfunction associated with HIV-1 infection of the developing central nervous system.

The human immunodeficiency virus (HIV) is neuroinvasive and can be neurovirulent. Indeed, 20-30% of individuals with the acquired immune deficiency syndrome (AIDS) develop cognitive and motor dysfunction (termed the AIDS dementia complex or HIV dementia) coincident with advanced immunosuppression. Despite massive research efforts to discern viral neuropathogenic mechanisms, much remains incompletely understood. Recently, we and others developed animal model systems to elucidate how HIV infection within the brain can lead to impairment of central nervous system function. In this report, we evaluate each of the published animal models for their ability to mirror HIV dementia. Ease of handling and expense were also under consideration. Ultimately, studies in animal systems should permit a better understanding of the nature of HIV-1-induced neurological injury and aid in the development of effective treatments for this dreaded complication of HIV infection.

Tumor necrosis factor alpha (TNF-alpha) is a candidate human immunodeficiency virus type 1-induced neurotoxin that contributes to the pathogenesis of AIDS dementia complex. We report here on the effects of exogenous TNF-alpha on SK-N-MC human neuroblastoma cells differentiated to a neuronal phenotype with retinoic acid, TNF-alpha caused a dose-dependent loss of viability and a corresponding increase in apoptosis in differentiated SK-N-MC cells but not in undifferentiated cultures. Importantly, intracellular signalling via TNF receptors, as measured by activation of the transcription factor NF-kappa B, was unaltered by retinoic acid treatment. Finally, overexpression of bcl-2 or crmA conferred resistance to apoptosis mediated by TNF-alpha, as did the addition of the antioxidant N-acetylcysteine. These results suggest that TNF-alpha induces apoptosis in neuronal cells by a pathway that involves formation of reactive oxygen intermediates and which can be blocked by specific genetic interventions.

Human herpesvirus-6, the etiologic agent of exanthem subitum, is a ubiquitous virus that infects almost all children by the age of 2 years and that has previously been shown to be neuroinvasive. These characteristics suggest that human herpesvirus-6 may be important in the neuropathogenesis of acquired immune deficiency syndrome (AIDS) in children. To address this hypothesis, we evaluated postmortem pediatric brain tissues for the presence of human herpesvirus-6 infection. Using in situ hybridization with a digoxigenin-labeled DNA probe for the large tegument protein gene of human herpesvirus-6, we detected nuclear signals in postmortem brain tissue from 4/5 children with human immunodeficiency virus-1 encephalitis. Human herpesvirus-6 DNA was found in numerous oligodendrocytes of the white matter and less frequently in astrocytes, macrophages, microglia and neurons. The human herpesvirus-6 positive cells detected by in situ hybridization were not immunoreactive either for human herpesvirus-6 early nuclear phosphoproteins or for surface glycoproteins associated with productive infection. Only rare human herpesvirus-6 infected cells were found in age-matched control brain tissues. No human herpesvirus-6 infected cells were found in human fetal brain tissue. These data suggest that human herpesvirus-6 is more extensively disseminated in neural cells in the presence of human immunodeficiency infection and immunodeficiency in pediatric AIDS patients, and it may contribute to the pathogenesis of AIDS encephalopathy.

HIV infection of the nervous system is responsible for the clinical subcortical dementia in adult AIDS patients1 and for the analogous progressive encephalopathy in children with AIDS.2 Neuropathological studies have described inflammatory cell infiltrates composed largely of HIV-infected macrophages and multinucleated giant cells, white matter damage (edema), and neuronal loss or damage to the dendritic processes of neurons in the neocortex.3–7

This discussion of the pathogenesis of infant human immunodeficiency virus (HIV) type 1 infection emphasizes features unique to pediatric disease and provides general insights into HIV illness in all populations. Therapies designed to interrupt transmission of HIV can be most efficiently addressed through studies of maternal-infant transmission. The rapid progression of disease in children constantly emphasizes the urgent need for continued progress in treatment of HIV infection and presents a unique opportunity optimally to assess effects of early intervention.

Summary Human immunodeficiency virus type 1 (HIV-1) infection is highly specific for its human host. In order to study HIV-1 infection of the human nervous system, we have established a small animal model in which second-trimester (11–17.5 weeks) human fetal brain or neural retina is transplanted into the anterior chamber of the eye of immunosuppressed adult rats (Epstein et al., 1992; Cvetkovich et al., 1992), and more recently in immunodeficient (SCID) mice. The human xenografts survive for many months, vascularize and form a blood-brain barrier. Immunohistochemistry with PGP 9.5 identified neuronal cell bodies and neuritic processes. Electron microscopy revealed axonal growth cones and synaptic junctions. Infection of these xenografts with cell-free HIV-1 proved difficult, however co-engraftment with HIV-1-infected human monocytes resulted in characteristic pathological changes, including the formation of syncytial giant cells, neuronal loss, and astroglial proliferation, supporting the hypothesis that these cells can mediate neurotoxicity. In other studies, xenografts of human fetal retinal tissue were readily infected with cell-free human cytomegalovirus (HCMV) strain AD169. These grafts contained cells with intracytoplasmic and intranuclear inclusions typical of HCMV infection. Productive infection within these grafts was demonstrated by the presence of immediate early, and late (capsid) HCMV antigens, by recovery of HCMV on human fibroblast cultures, and by serial passage of virus to additional retinal xenografts (DiLoreto et al., 1994). The aim of these studies is to develop a small animal model to study direct and indirect effects of HIV-1 infection on human neural tissues, and to study interactions between HIV-1 and other opportunistic pathogens such as HCMV. This model should prove useful in evaluating antiviral therapies.

Thirty HIV isolates, obtained from 15 patients before and after receiving single drug therapy with didanosine (ddI), were examined for sensitivity to ddI and zidovudine (ZDV) using a peripheral blood mononuclear leukocyte (PBML)-based assay. Fourteen of the patients had ARC, one had AIDS and 12 had received previous therapy with ZDV. After a median of 1 year of ddI therapy, isolates were significantly less sensitive to ddI than were isolates obtained prior to therapy (P = 0.03). A decrease in ddI sensitivity was observed in ten of the 15 isolate pairs. In contrast to ddI susceptibilities, sensitivity to ZDV increased over the same period of time (P = 0.03). Additional isolates were obtained from four patients who received ddI monotherapy for 2 years. Three of these isolates demonstrated no change in ddI sensitivity compared to baseline. No correlation could be made in this study between development of decreased ddI sensitivity and serum p24 levels, CD4 counts, or clinical outcome. Decreased ddI sensitivity occurs frequently among HIV isolates obtained from long-term recipients of ddI. This decreased sensitivity is modest in degree and is of unknown clinical significance.

Successful xenografting of first trimester human fetal CNS tissue and retina has been reported in the literature. We wished to test the feasibility ofusing the anterior chamber ofthe rat eye to support the development of more mature human fetal xenografts. Here we report on the successful outcome of human brain and retinal transplants. Adult host rats immunosuppressed with cyclosporin A accepted these xenografts and supported their further development. Periodic examination of the host eyes using a direct ophthalmoscope or an ophthalmic slit lamp permitted direct visual monitoring of the health and growth of the transplants. Histologically it was possible to identify neuronal, macroglial, and microglial (macrophage) cell types within the grafts. Mitotic activity and histogenetic differentiation took place. Blood vessels filled with hematic cells were commonly present within the grafts. The walls of these vessels prevented the leakageofhorseradish peroxidase, suggesting the presence of a functional brain-blood barrier in the graft. These results indicate that it is possible to use a small animal model to study normal and pathological phenomena oniate fetal human neural tissues. Our group has already taken advantage of the model to achieve HIV infectivity offetal human brain outside the human body.

An autopsy study was performed on spinal cords from 18 children who died with HIV-1 infection, using standard histopathologic techniques as well as in situ hybridization and immunocytochemistry for HIV-1. Of 16 spinal cords examined by histology, nine had inflammatory cell infiltrates and six had multinucleated cells; both types of lesion are associated with the presence of HIV-1 in central nervous system tissue. HIV-1 type lesions were often present in the spinal cord and brain from the same patient. Pallor of myelin in corticospinal tracts in the cord was present in half of the cases; this change correlated with diffuse myelin pallor in the corresponding brains, but not with the HIV-1 associated changes in the cords. In situ hybridization for HIV-1 nucleic acid sequences gave positive results in seven of 18 spinal cords, with hybridizing signal usually localized to inflammatory cell infiltrates and multinucleated cells. Positive in situ hybridization, on frozen sections, correlated with the presence of HIV-1 associated changes on paraffin sections from the same cases. Immunocytochemistry for p25 core protein of HIV-1, using a monoclonal antibody on frozen sections, was positive in multinucleated cells, macrophages, and microglia. In this series there were two cases of vacuolar myelopathy, one a 30-month-old boy who had concomitant measles virus in the spinal cord grey matter, and the other nine-year-old girl who had severe HIV-1 infection of the cord. Other than the single case of measles virus, there were no opportunistic infections in the cords in this series. HIV-1 frequently involves the spinal cord in children with AIDS, while opportunistic infections are rare. Vacuolar myelopathy occurs in children with HIV-1 infection, although its occurrence is much less frequent than in adults with AIDS.

Several markers of immune activation have been identified as potential prognostic markers for human immunodeficiency virus (HIV)-associated morbidity and mortality, but the results from studies are conflicting.To evaluate whether neurocognitive status and baseline levels of plasma and cerebrospinal fluid tumor necrosis factor alpha (TNF-alpha), macrophage chemoattractant protein 1 (MCP-1), matrix metalloproteinase 2 (MMP-2), or macrophage colony-stimulating factor (M-CSF) are associated with time to death in a cohort with advanced HIV infection.Cohort study.Enrollees in the Northeast AIDS Dementia Study.Three hundred twenty-nine subjects who were positive for HIV-1 and had a CD4 cell count of less than 200/microL (or300/microL but with cognitive impairment at baseline) were assessed for CD4 cell count, neurocognitive status, pertinent demographic and clinical variables, and plasma and cerebrospinal fluid HIV RNA, TNF-alpha, MCP-1, MMP-2, and M-CSF levels.Cox proportional hazards regression models were used to examine the associations between the variables of interest (using time-dependent covariates, where applicable) and time to death, adjusting for possible confounders.There were 50 deaths in the cohort after a median of 25.2 months of follow-up. The cumulative incidences of death were 7% at 1 year and 16% at 2 years. In Cox proportional hazards regression analyses adjusting for demographic, clinical, and immunological variables, HIV-associated dementia (hazard rate, 6.10; P = .001) was significantly associated with time to death; (log) plasma MCP-1 level (hazard rate, 3.38; P = .08) trended toward significance.In patients with advanced HIV infection, HIV-associated dementia is an independent predictor of time to death.

Background Before the introduction of combination antiretroviral therapy (CART), neurological disease correlated with cerebrospinal fluid (CSF) levels of human immunodeficiency virus (HIV) RNA. Objective To investigate the relationships among HIV RNA levels, immune activation markers, and neurological status in patients receiving CART. Design Multicenter cohort study. Setting Academic neurology departments. Patients A total of 371 patients unselected for neurological complaints and with CD4 cell counts less than 200/μL or with cognitive symptoms and CD4 cell counts less than 300/μL were enrolled into the Northeastern AIDS Dementia cohort in 1998-2002. Diagnoses of HIV-associated dementia (HIV-D) and minor cognitive-motor disorder (MCMD) were obtained with a computerized algorithm. Plasma and CSF levels of HIV RNA, monocyte chemotactic protein 1, macrophage colony-stimulating factor, and tumor necrosis factor α were quantified. Results The mean ± SD age was 41.5 ± 7.2 years, and the mean ± SD educational level was 12.3 ± 2.2 years. Seventy percent of the cohort was black, and 30% were women. The mean ± SD CD4 cell count was 136.8 ± 87.9/μL, and CART was used in 71%. Twenty-nine percent of the patients were unimpaired (n = 106), 36% had MCMD (n = 133), and 35% had HIV-D (n = 128). Mean log 10 CSF HIV RNA copies per milliliter was 2.6 ± 0.8, with no differences among the neurological groups, even after adjustments for baseline CD4 cell counts and antiretroviral therapy. Cerebrospinal fluid HIV RNA was undetectable in 47% of unimpaired, 46% of MCMD, and 43% of HIV-D patients ( P = .91). Plasma levels of monocyte chemotactic protein type 1 and tumor necrosis factor α correlated weakly with HIV RNA levels but did not distinguish those with neurological deficits. Conclusions In contrast to observations in individuals not treated with CART, we found no relationshipbetween CSF markers and neurological status in this CART-using cohort with advanced HIV/AIDS. This was not explicable by demographic differences or plasma virological control. CART may substantially attenuate the degree of central nervous system HIV infection and immune activation, and in CART users, CSF HIV RNA and immune activation markers may fail to discriminate milder degrees of HIV-D and MCMD.

This monograph includes the proceedings of the 72nd Annual Meeting of the Association for Research in Nervous and Mental Disease, held in New York, NY, in December 1992. Many of the leading investigators and clinical scientists were assembled for this meeting and contributed manuscripts. Price provides an insightful overview and highlights many of the critical unsolved issues regarding primary human immunodeficiency virus (HIV) infection of the nervous system. The first section of the book is devoted to interactions between the virus and the host immune system. This section includes an excellent review of cytokine circuitry by Benveniste. The important role of astrocyte and microglial activation, particularly in the face of bloodbrain barrier damage, is emphasized, as well as the complex interactions between proinflammatory and immunosuppressive cytokines. This chapter serves as an excellent basis for numerous recent studies that implicate cytokines in HIV-induced neural damage. This is followed by an equally

This is an excellent monograph, edited by Professor Hagberg, a respected international authority on Rett syndrome. At present, no definitive biochemical or genetic basis has been identified for Rett syndrome, and hence, this represents one of the major enigmas of pediatric neurology. Much of this book is aimed at clinicians, and, in particular, chapters 1 through 7 are largely based on Professor Hagberg's extensive experience with his Swedish cohort of 130 girls and women (aged 3 to 50) with Rett syndrome. A detailed account of the major features and the four clinical stages of classic Rett syndrome are presented in lucid form. In addition, many of the less well-known features are described, including the characteristic night laughing and screaming spells. Important clinical insights are recounted, including the observation that some school-aged girls with Rett syndrome either become refractory to anticonvulsant medications or exhibit an exquisite sensitivity to the side effects

Background Antecedents to human immunodeficiency virus–dementia (HIV-D) are poorly understood. Objective To identify risk factors for HIV-D. Methods Subjects who are positive for HIV who have CD4 + counts either below 200/µL or below 300/µL with evidence of cognitive impairment were enrolled in this study. Neurologic, cognitive, functional, and laboratory assessments were done semiannually for up to 30 months. Human immunodeficiency virus–dementia was diagnosed using American Academy of Neurology criteria for probable HIV-1–associated dementia complex. Results One hundred forty-six nondemented patients were enrolled, 45 of whom subsequently met criteria for incident HIV-D. In univariate analyses using the Cox proportional hazards regression model, the following variables were significantly associated with time to develop dementia: cognitive: abnormal scores on Timed Gait, Verbal Fluency, Grooved Pegboard, and Digit Symbol tests; attention-memory, psychomotor, and executive function domain scores; and the diagnosis of minor cognitive/motor disorder; neurologic and medical: increased abnormalities on the neurologic examination, extrapyramidal signs, history of HIV-related medical symptoms; functional: higher reported role or physical function difficulties. Depression was also a strong risk factor, along with sex, hematocrit, hemoglobin, and β 2 -microglobulin levels. In a multivariate model that used cognitive domain scores, covariates with significant hazard ratios included depression, executive dysfunction, and the presence of minor cognitive/motor disorder. Conclusion Cognitive deficits, minor cognitive/motor disorder, and depression may be early manifestations of HIV-D.

Objective: To assess the safety and tolerability of lexipafant in HIV-associated cognitive impairment. Background: Cognitive impairment is the most common neurologic complication of advanced HIV-1 infection. There is evidence that a variety of inflammatory mediators, including platelet-activating factor (PAF), may contribute to neuronal injury. We hypothesized that lexipafant, a PAF antagonist, might improve cognitive dysfunction in HIV-infected people. Methods: We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the safety and tolerability of lexipafant 500 mg/day. The primary outcome measure for tolerability was the ability to complete the study on the originally assigned dosage of medication. Thirty patients with cognitive impairment were enrolled. Results: Lexipafant was safe and well tolerated. Ninety-three percent in the placebo group and 88% in the lexipafant group completed the study at the originally assigned dosage. Trends toward improvement were seen in neuropsychological performance, especially verbal memory, in the lexipafant treatment group. Conclusions: This study shows that lexipafant, the first PAF antagonist used in HIV-associated cognitive impairment, is a safe and well tolerated compound. The observed trends toward improvement in neuropsychological test scores warrant the pursuit of a larger and longer efficacy trial to assess the impact of lexipafant on cognitive performance.

In previous studies, using polymerase chain reaction amplification of HIV-1 genes directly from pathologic tissues of children who died with AIDS encephalopathy, we showed that the reading frame of the HIV-1 regulatory nef gene is open, suggesting that the nef protein was expressed. We now show, using immunocytoehemistry and in situ hybridization with nef-specific probes in postmortem pediatric CNS tissues, that nef mRNA and protein are present in up to 20% of astrocytes in tissue sections selected for extensive histopathology. By contrast, HIV-1 structural proteins such as gag and their coding mRNAs are present in multinucleated giant cells that harbor productive infection and are the hallmark of HIV-1 infection in the CNS. These findings are consistent with the nonproductive infection of glial cells observed in vitro, and imply that HIV-1 infection of astrocytes is restricted to early regulatory gene products, of which nef is the best target as it is expressed at high levels and is membrane-anchored. In developing central nervous tissues of children, restricted and latent HIV-1 infection of astrocytes may be extensive and contribute significantly to HIV-1 neuropathogenesis.

Objective. —To ascertain whether depressive symptoms as determined by the Center for Epidemiologic Studies—Depression scale (CES-D) predict accelerated mortality and worse medical outcomes in patients infected with human immunodeficiency virus (HIV). Design. —Eight-year cohort study with semiannual follow-up. Setting. —Community volunteers. Participants. —A total of 1809 HIV-seropositive homosexual men without the acquired immunodeficiency syndrome (AIDS) who entered the Multicenter AIDS Cohort Study in 1984 or 1985. Eight-year follow-up data were available on 75% of eligible participants. Outcome Measures. —Times to AIDS, death, and prophylactic treatment, and slopes describing the decline in CD4 count for each individual participant. Results. —Using a conventional definition of depression (CES-D ≥16 at the first study visit), 21.3% of participants were classified as depressed. Depressed participants had lower CD4 counts and reported more AIDS-related symptoms. There were no significant differences between depressed and nondepressed participants on any of the outcome measures ( P >.05 in all cases). In contrast, men reporting AIDS-related symptoms had shorter times to AIDS and to death even after adjusting for CD4 counts ( P Conclusions. —We find no evidence that depressive symptoms independently prognosticate worse outcomes in HIV infection. Because of associations of depression with symptom reports, CD4 counts, and indicators of socioeconomic status, future studies of the relationship between depression and HIV outcome should consider these variables as confounders. ( JAMA . 1993;270:2563-2567)

• Human immunodeficiency virus infection is frequently complicated by a syndrome of central nervous system dysfunction known as the acquired immunodeficiency syndrome dementia complex (ADC). The ADC is characterized by abnormalities in cognition, motor performance, and behavior, and it produces serious morbidity in a significant number of patients with acquired immunodeficiency syndrome. The pathogenesis of ADC is unclear, but appears to be caused by the human immunodeficiency virus itself, rather than by a secondary opportunistic process. Herein, we review the data regarding the pathogenesis of ADC and hypothesize a mechanism involving excitotoxicity and dopaminergic dysfunction.N-methyl-D-aspartate receptor antagonists may be of therapeutic benefit, as these agents may both limit glutamate-mediated neuronal dysfunction and improve dopaminergic neuronal function.

Antibodies elicited by HIV-1 strains, and which neutralize such strains in vitro, bind to synthetic peptides of 5-8 amino acids in length. These amino acids, although variable, have a fixed location between two cysteines in the carboxyl terminus of the HIV-1 external envelope. Nine peptides of 9 amino acids corresponding to the gp120 domains of European and American (LAV-1, NY5, CDC4, SF2), Haitian (RF) and African (ELI, MAL, Z3, Z6) HIV-1 strains, were synthesized using LAV-1 and RF neutralization epitopes as models. Serum of chimpanzees infected with LAV-1, HTLV-IIIB or HTLV-IIIRF reacted predominantly with the homologous peptide, although cross-reactivity with heterologous peptides occurred: 8 out of 11 human sera with HTLV-IIIB-neutralizing activity bound the LAV-1/HTLV-IIIB peptide, and 6 out of 7 sera with HTLV-IIIRF-neutralizing activity bound the RF peptide. African sera reacted most frequently with the Z3 peptide (78%) while only 35% (p = 0.0001) of European and 20% (p less than 0.0001) of American sera recognized it. Recognition patterns of children from the USA and Europe were different. Although multiple reactivities were observed, blocking experiments favoured cross-reactivity as the explanation. Based on the antibody profiles of nonapeptide recognition, peptides LAV-1, RF and SF2 were clustered, as were NY5 and CDC4, and so were Z6, MAL and ELI. This antigenic relatedness of HIV-1 strains could not entirely be explained by the physico-chemical characteristics of the nonamers per se. Resemblance was observed with the clustering of HIV-1 strains based on the divergence of the nucleotide sequence of entire HIV-1 envelopes. This implies a role of peripheral envelope residues, in the context of infectious particles or infected cells, in determining the specificity of antibodies reactive to the V3 domain. Therefore, the neutralization domain in this variable region may be considered part of a conformational structure involving several envelope regions which appear distinct from each other in the primary sequence.

This report describes the neurologic manifestations of 36 children with human immunodeficiency virus (HIV) infection. In this cohort, in 16 of 21 children with acquired immunodeficiency syndrome (AIDS), three of 12 children with AIDS-related complex, and one of three asymptomatic seropositive children, a progressive encephalopathy developed. Neurologic signs were often detected early but tended to worsen coincident with progression of the immunodeficiency. The presence of progressive encephalopathy correlated with the absence of serum neutralizing antibodies to HIV and with a poor, usually fatal, outcome. The incubation period from initial HIV infection in the perinatal period to the onset of progressive encephalopathy varied from 2 months to 5 years. Intrablood-brain barrier synthesis of HIV-specific antibodies was demonstrated in eight of 14 children with AIDS and AIDS-related complex, indicating active brain infection with HIV. In three cases this was unassociated with progressive neurologic signs. Unique neuropathologic findings in children who died with HIV infection further suggest that the progressive encephalopathy is the result of primary and persistent infection of the brain with this retrovirus. These findings broaden the spectrum of HIV infection in children and have important implications for the development of antiviral therapy.