Updated research nosology for HIV-associated neurocognitive disorders.

In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclature and research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infection. Now, 16 years later, the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke have charged a working group to critically review the adequacy and utility of these definitional criteria and to identify aspects that require updating. This report represents a majority view, and unanimity was not reached on all points. It reviews our collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to categorize individuals with subclinical impairment. An algorithm is proposed to assist in standardized diagnostic classification of HAND.

Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy.

OBJECTIVE: To demonstrate the relationship between epidermal nerve fiber density (ENFD) in the leg and the phenotype of HIV-associated distal sensory polyneuropathy (HIV-DSP) in a multicenter prospective study (ACTG A5117). METHODS: A total of 101 HIV-infected adults, with CD4 cell count <300 cells/mm(3) and who had received antiretroviral therapy (ART) for at least 15 consecutive weeks, underwent standardized clinical and electrophysiologic assessment. All 101 subjects were biopsied at the distal leg (DL) and 99 at the proximal thigh (PT) at baseline. ENFD was assessed by skin biopsy using PGP9.5 immunostaining. Associations of ENFD with demographics, ART treatment, Total Neuropathy Score (TNS), sural sensory nerve action potential (SNAP) amplitude and conduction velocity, quantitative sensory testing (QST) measures, and neuropathic pain were explored. RESULTS: ENFD at the DL site correlated with neuropathy severity as gauged by TNS (p < 0.01), the level of neuropathic pain quantified by the Gracely Pain Scale (GPS) (p = 0.01) and Visual Analogue Scale (VAS) (p = 0.01), sural SNAP amplitude (p < 0.01), and toe cooling (p < 0.01) and vibration (p = 0.02) detection thresholds. ENFD did not correlate with neurotoxic ART exposure, CD4 cell count, or plasma HIV-1 viral load. CONCLUSIONS: In subjects with advanced HIV-1 infection, epidermal nerve fiber density (ENFD) assessment correlates with the clinical and electrophysiologic severity of distal sensory polyneuropathy (DSP). ENFD did not correlate with previously established risk factors for HIV-DSP, including CD4 cell count, plasma HIV-1 viral load, and neurotoxic antiretroviral therapy exposure.

Biochip array-based analysis of plasma cytokines in HIV patients with immunological and virological discordance.

Assessment of cytokines in body fluids or cells provides important information in understanding the disease process and designing treatment strategies. Recent introduction of antibody-based protein arrays have provided investigators simultaneous and specific detection of multiple analytes in a single sample using minimum volumes. In this study, we used a biochip array system capable of measuring 12 cytokines and growth factors (IL-2, IL-4, IL-6, IL-8, IL-10, IL-1alpha, IL-1beta, IFN-gamma, TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF)) in HIV patients with immunological and virological discordance (discordant) to find out differences if any, in their plasma cytokine profiles when compared with concordant HIV-infected individuals. A sandwich chemiluminescent assay was performed with plasma specimens of 110 HIV patients (55 discordant, 55 concordant) and 22 normal healthy individuals followed by enzyme-linked immunosorbent assay (ELISA) to the confirm levels of cytokines and growth factors that showed significant differences in the two groups. The discordant HIV patients showed significantly higher levels of plasma VEGF (P = 0.001) and EGF (P = 0.034) levels when compared with concordant patients. Overall, the patients showed significantly higher levels of TNF-alpha, MCP-1 and VEGF when compared with the normal healthy controls (P < 0.05). ELISA for VEGF (P < 0.001) and EGF (P = 0.004) confirmed the comparison obtained with biochip array, between the discordant and concordant patients. The results of cytokine quantitation by biochip array and ELISA confirmed that this technology is not only comparable but also has a good potential in the future applications involving measurement of multiple cytokines with limiting specimens.

HIV neuropathy natural history cohort study: assessment measures and risk factors.

BACKGROUND: Distal sensory polyneuropathy (DSP) is the most common neurologic complication of human immunodeficiency virus (HIV) infection. Risk factors for DSP have not been adequately defined in the era of highly active antiretroviral therapy. METHODS: The authors evaluated 101 subjects with advanced HIV infection over 48 weeks. Assessments included a brief peripheral neuropathy (PN) screen (BPNS), neurologic examination, nerve conduction studies, quantitative sensory testing (QST), and skin biopsies with quantitation of epidermal nerve fiber density. Data were summed into a Total Neuropathy Score (TNS). The presence, severity, and progression of DSP were related to clinical and laboratory results. RESULTS: The mean TNS (range 0 to 36) was 8.9, with 38% of subjects classified as PN-free, 10% classified as having asymptomatic DSP, and 52% classified as having symptomatic DSP. Progression in TNS from baseline to week 48 occurred only in the PN-free group at baseline (mean TNS change = 1.16 +/- 2.76, p = 0.03). Factors associated with progression in TNS were lower current TNS, distal epidermal denervation, and white race. As compared with the TNS diagnosis of PN at baseline, the BPNS had a sensitivity of 34.9% and a specificity of 89.5%. CONCLUSIONS: In this cohort of advanced human immunodeficiency virus (HIV)-infected subjects, distal sensory polyneuropathy was common and relatively stable over 48 weeks. Previously established risk factors, including CD4 cell count, plasma HIV RNA, and use of dideoxynucleoside antiretrovirals were not predictive of the progression of distal sensory polyneuropathy (DSP). Distal epidermal denervation was associated with worsening of DSP. As compared with the Total Neuropathy Score, the brief peripheral neuropathy screen had relatively low sensitivity and high specificity for the diagnosis of DSP.

Psychosocial factors and the course of cervical intra-epithelial neoplasia: a prospective study.

OBJECTIVE: To investigate the influence of psychosocial factors on the course of cervical intra-epithelial neoplasia (CIN). METHODS: A group of 93 patients with CIN 1 or 2 was followed for 2.25 years by half-yearly colposcopy and cytology. Negatively-rated life events, social support, and coping style were studied in relation to distress during follow-up and in relation to time till progression and regression of CIN. Human papillomavirus (HPV) infection was controlled for as well as sick role bias caused by suspicion of having cervical cancer and distress due to the abnormal cervical smear. RESULTS: During follow-up, progression was found in 20 patients (22%), stable disease in 22 patients (24%), and regression in 51 patients (55%). Negatively-rated life events and lack of social support predicted distress longitudinally. No association was found between progression or regression of CIN and negatively-rated life events, lack of social support, coping style, and distress. CONCLUSION: We found no evidence that psychosocial factors influence the course of CIN.

Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) affects about 1 in 20 individuals with the acquired immunodeficiency syndrome (AIDS) and has been associated with poor survival. This report describes the results of a phase II clinical trial using the drug topotecan, a semisynthetic analogue of camptothecan, administered to a cohort of subjects with AIDS-related PML. Data were evaluated on 11 of 12 subjects enrolled in the study. Three responded to therapy. Additionally, one patient was treated off-protocol and showed a response to treatment. Progression occurred after the first course; however, a partial response was noted after five courses. One study patient died from accidental overdose of topotecan. Overall, responders had higher pretreatment Karnofsky and lower Kurtzke expanded disability status scale scores than nonresponders. The most frequent toxicities were hematologic (anemia, neutropenia, and thrombocytopenia). Five patients had dose delays; all delays were due to hematologic adverse events. This study demonstrates that topotecan treatment may be associated with decreased lesion size and prolonged survival from the infection. Because of the small number of subjects in the study, further studies are required to evaluate the efficacy of topotecan in treating this disease.

[HUMANS: a neuropsychological battery for evaluating HIV 1 infected patients]. / HUMANS: una batería neuropsicológica para la evaluación de pacientes infectados con VIH-1.

OBJECTIVE: To develop a neuropsychological test battery in Spanish for the cognitive evaluation of HIV 1 infected patients. DEVELOPMENT: Departing from the suggestions presented by the work group of the National Institute of Mental Health (USA), a neuropsychological assessment battery was developed. It was named HUMANS (HIV/University of Miami Annotated Neuropsychological test battery in Spanish). This battery includes the following domains: 1) attention and speed of processing information, 2) memory, 3) executive function, 4) language, 5) visuospacial/visuoconstructive abilities, and 6) motor abilities. Administration takes about 3 4 hours. The English parallel version of this battery has been successfully used in English for over a decade with HIV 1 infected patients. In the paper the development and adaptation to Spanish language of the HUMANS neuropsychology section is presented. CONCLUSIONS: HUMANS neuropsychological test battery fulfill the recommendations presented by the work group of the National Institute of Mental Health for evaluating HIV 1 infected patients. Studies regarding validity and reliability are still required.

HUMANS: una batería neuropsicológica para la evaluación de pacientes infectados con VIH-1 / HUMANS: a neuropsychological battery for evaluating HIV-1 infected patients

Objetivo. Desarrollar una batería de diagnóstico neuropsicológico en español para la evaluación cognitiva de pacientes infectados con VIH-1.Desarrollo. Se parte de las sugerencias presentadas por el grupo de trabajo del Instituto Nacional de Salud Mental de EE.UU. y se desarrolla una batería de diagnóstico neuropsicológico, denominada HUMANS (delinglés, HIV/ University of Miami Annotated Neuropsychological test battery in Spanish). Esta batería incluye las siguientes áreas: 1) atención y velocidad de procesamiento de la información, 2) memoria, 3) función ejecutiva, 4) lenguaje, 5) habilidades visuoespaciales /visuoconstruccionales, y 6) habilidades motoras. Su realización requiere aproximadamente 3-4 horas. La versión paralela en inglés de esta batería se ha utilizado con éxito durante más de una década con pacientes VIH-1 positivos. En este artículo se presenta la sección neuropsicológica de la batería HUMANS y se explica el proceso de desarrollo y su adaptación al español. Conclusiones. La batería HUMANS cumple con las recomendaciones hechas por el grupo de trabajo del Instituto Nacional de Salud Mental de los EE.UU. para la evaluación de los cambios cognitivos en pacientes infectados con VIH-1. Sin embargo, todavía se requieren estudios relativos a su validez y confiabilidad (AU)

Objective. To develop a neuropsychological test battery in Spanish for the cognitive evaluation of HIV-1 infected patients. Development. Departing from the suggestions presented by the work group of the National Institute of Mental Health (USA), a neuropsychological assessment battery was developed. It was named HUMANS (HIV/University of Miami Annotated Neuropsychological test battery in Spanish). This battery includes the following domains: 1) attention and speed of processing information, 2) memory, 3) executive function, 4) language, 5) visuospacial/visuoconstructive abilities, and 6) motor abilities. Administration takes about 3-4 hours. The English parallel version of this battery has been successfully used in English for over a decade with HIV-1 infected patients. In the paper the development and adaptation to Spanish language of the HUMANS neuropsychology section is presented. Conclusions. HUMANS neuropsychological test battery fulfill the recommendations presented by the work group of the National Institute of Mental Health for evaluating HIV-1 infected patients. Studies regarding validity and reliability are still required (AU)

Psychological symptoms among persons 50 years of age and older living with HIV disease.

Although persons 50 years of age and older account for 10% of all US AIDS cases, the mental health needs of this growing group remain largely overlooked. The current study delineated patterns and predictors of psychological symptoms amongst late middle-aged and older adults living with HIV/AIDS in two large US cities. In late 1998, 83 HIV-infected individuals 50-plus years of age (M = 55.2, Range = 50-69) completed self-report surveys eliciting data on psychological symptomatology, HIV-related life-stressor burden, social support, barriers to health care and social services, and sociodemographic characteristics. Based on the Beck Depression Inventory, 25% of participants reported 'moderate' or 'severe' levels of depression. HIV-infected older adults also evidenced an elevated number of symptoms characteristic of somatization. A hierarchical multiple regression analysis revealed that HIV-infected older adults who endorsed more psychological symptoms also reported more HIV-related life-stressor burden, less support from friends, and reduced access to health care and social services due to AIDS-related stigma. As the impact of HIV on older communities continues to increase, geropractitioners must be prepared to provide care to greater numbers of HIV-infected older adults, a substantial minority of whom will present with complex comorbid physical and mental health conditions.

Aging and neuro-AIDS conditions and the changing spectrum of HIV-1-associated morbidity and mortality.

Older individuals (>50 years of age) now comprise over 11% of patients with AIDS in the United States. This percentage is expected to continue to grow, due both to the improved longevity of patients prescribed highly active antiretroviral therapy (HAART) and to new infections among older individuals. This review focuses on the neuropsychiatric and neurological conditions that are most likely to be affected by advancing age-HIV-1-associated cognitive-motor disorder, peripheral neuropathy, progressive multifocal leukoencephalopathy, primary CNS lymphoma, and risk for cerebrovascular accident. Age associations with incidence of these disorders and with treatment foci are specified. Implications for future changes in management are discussed.

Neuropsychiatric aspects of HIV infection among older adults.

Treatment advances such as the advent of highly active antiretroviral therapy (HAART) have translated into greater life expectancy for HIV-infected individuals, which will ultimately result in a "graying" of the HIV/AIDS epidemic. In addition, older individuals are engaging in a higher rate of high risk behaviors than had been previously expected. As such, study of older HIV-infected patients, including study of the psychiatric and neurocognitive aspects of the disease, appears highly indicated. Epidemiological studies have demonstrated that HIV infection is associated with higher rates of several psychological/psychiatric disorders when compared to general population base rates. There is also a rich literature that has documented the adverse neurocognitive effects of HIV infection, ranging from subtle cognitive complaints to frank dementia, among younger adults. Although it has been hypothesized that older age may potentiate the deleterious effects of HIV infection, little is actually known, however, regarding the incidence, prevalence, course, and clinical features of HIV-associated psychiatric and cognitive dysfunction among older adults. This article provides an overview of the epidemiology and clinical manifestations of HIV-associated cognitive and psychiatric disorder across the age spectrum, with particular focus on what is known regarding the interaction of advancing age and HIV infection. Future directions for research are suggested, including basic epidemiologic study of incidence and prevalence rates of neurodisease among older HIV-infected adults as well as investigations designed to determine whether the nature, severity, course, or treatment of such disorders differs among older versus younger patients.

Cerebrospinal fluid 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in HIV-1 infection.

Reduced level of serotonin (5-hydroxytryptamine, 5-HT) in humans has been associated with a number of mental health and behavioral problems including depression, aggression, violence, sexual dysfunctions, sleep and eating disorders. Even though among HIV-1-infected individuals, prevalence of mental health and behavioral problems are common, their relationship with central nervous system serotonin functions is not clearly understood. This investigation was carried out to study the status of CSF 5-HT in HIV-1+ subjects (n = 21), in the early stage of infection, and HIV-1- control subjects (n = 24). Samples of CSF were obtained by lumbar puncture and were analyzed for 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), using high-performance liquid chromatography equipped with electrochemical detector. Levels of CSF 5-HT were significantly lower in the HIV-1+ group compared to the HIV-1- group. There was no significant difference in the CSF 5-HIAA levels between the two groups. In both groups, however, there was a significant correlation between CSF 5-HT and 5-HIAA. In the HIV-1 + group, although CSF 5-HT level was significantly negatively correlated with serostatus, there was no correlation between either CSF 5-HT or 5-HIAA levels and CD4 cell number or any behavioral measures evaluated in this study, including Beck's Depression Inventory and state/trait anxiety scores. These data suggest that HIV-1 infection affects the CNS 5-HT status with no significant association with measures of depression and anxiety, at least in the early stage of infection.

A bereavement support group intervention affects plasma burden of human immunodeficiency virus type 1. Report of a randomized controlled trial.

OBJECTIVES: This study investigates the potential impact of a bereavement support group on plasma viral load. METHODS: A randomly selected subsample of human immunodeficiency virus type 1 (HIV-1)-positive homosexual men participating in a controlled clinical trial of a bereavement support group intervention was studied. The intervention consisted of one 90-minute group session per week for 10 weeks. The plasma HIV-1 RNA copy number was measured at baseline and after intervention (10 weeks) by the Roche AMPLICOR assay. RESULTS: There was a significant effect of the intervention on the change on the plasma HIV-1 RNA copy number (limited control model, beta = -0.49, p = 0.02; extended control model, beta = -0.37, p = 0.01), independent of antiretroviral therapies; prophylactic therapies against potentially lethal HIV-1 associated conditions; CD4 cell count; viral load; and Centers for Disease Control and Prevention clinical disease stage at baseline. CONCLUSIONS: Bereavement support group interventions may prove to be not only a primary therapy for psychologic distress after bereavement but also an adjunctive therapy for sustained control of plasma viral load in conjunction with highly active antiretroviral therapy in this population.

Late middle-aged and older men living with HIV/AIDS: race differences in coping, social support, and psychological distress.

Although AIDS mental health research has recently devoted more attention to the psychosocial needs of older adults living with human immunodeficiency virus (HIV) disease, studies of this population have typically combined older African-American and white participants into one large sample, thereby neglecting potential race differences. The current study examined race differences in stressor burden, ways of coping, social support, and psychological distress among late middle-aged and older men living with HIV/AIDS. Self-administered surveys were completed by 72 men living with HIV/AIDS in New York City and Milwaukee, WI (mean age = 53.4 years). Older African-American and white men experienced comparable levels of stress associated with AIDS-related discrimination, AIDS-related bereavement, financial dilemmas, lack of information and support, relationship difficulties, and domestic problems. However, in responses to these stressors, older African-American men more frequently engaged in adaptive coping strategies, such as greater positive reappraisal and a stronger resolve that their future would be better. Compared to their African-American counterparts, HIV-infected older white men reported elevated levels of depression, anxiety, interpersonal hostility, and somatization. African-American men also received more support from family members and were less likely to disclose their HIV serostatus to close friends. As AIDS becomes more common among older adults, mental health-interventions will increasingly be needed for this group. The development of intervention programs for this group should pay close attention to race-related differences in sociodemographic, psychosocial, and behavioral characteristics.

Cobalamin level is related to self-reported and clinically rated mood and to syndromal depression in bereaved HIV-1(+) and HIV-1(-) homosexual men.

OBJECTIVE: An examination of the relationship of plasma cobalamin (vitamin B(12)) level to overall psychological distress, specific mood states, and major depressive disorder was conducted in 159 bereaved men (90 HIV-1(+) and 69 HIV-1(-)). METHODS: The relationship of a continuous measure of cobalamin level to psychological distress was examined, while controlling for HIV-1 serostatus, life stressors, social support, and coping styles. RESULTS: Of this sample, 23.9% were either overtly or marginally cobalamin deficient; however, the deficiency rate was not significantly different by HIV-1 serostatus. Cobalamin level was inversely related to self-reported overall distress level and specifically to depression, anxiety, and confusion subscale scores, as well as to clinically rated depressed and anxious mood. Lower plasma cobalamin levels also were associated with the presence of symptoms consistent with major depressive disorder. CONCLUSION: These findings suggest that cobalamin level may be physiologically related to depressed and anxious mood level, as well as to syndromal depression.

HIV-1-Associated Cognitive-Motor Disorders: A Research-Based Approach to Diagnosis and Treatment.

The diagnosis of human immunodeficiency virus type 1 (HIV-1)-associated cognitive-motor disorder--either minor cognitive-motor disorder (MCMD) or HIV-1-associated dementia (HAD)--is fraught with potential pitfalls for the clinician. Before making such a diagnosis, clinicians should exclude other etiologies by using neuroimaging, lumbar puncture, and serum chemistries to screen for opportunistic and non-opportunistic infections of the brain and meninges. Clinicians should also consider psychoneurotoxicity (caused from the use of psychoactive substances and prescribed medications) and psychopathology, such as mood, anxiety, and other disorders. In addition, a thorough medical history and physical examination, including a complete neurologic and neuropsychiatric mental status examination, are necessary for an accurate diagnosis. There is also a need for standardized neuropsychological and functional status tests, since the diagnostic criteria for these disorders are partly based on these criteria. Treatment targets should include subclinical cognitive-motor impairment and neuroprotection, as well as MCMD and HAD. Currently, zidovudine remains the best proven treatment for these disorders, but other nucleoside reverse transcriptase inhibitors, as well as nonnucleoside reverse transcriptase inhibitors and protease inhibitors, show promise, and selected agents from these classes are being tested in clinical trials. Other areas that should be investigated are the modulation of inflammatory mediators (such as tumor necrosis factor alpha), neurotransmitter manipulation (especially of dopamine), and nutritional interventions.

Theory-Driven Interventions in Psychoneuroimmunology and HIV-1 Infection.

Psychoneuroimmunology (PNI) is a rapidly evolving multidisciplinary field founded on the premise that psychosocial factors, the central nervous system, and the immune system are intimately linked. Following publication of scientific evidence supporting this link, a number of animal and human studies have been published, both inside and outside the area of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome. These studies support the existence of bidirectional feedback mechanisms operating between the brain and the immune system. To date, however, there is no all-encompassing model that predicts individual differences in the relationship among psychosocial factors, immunologic measures, and clinical disease progression in HIV type 1 (HIV-1) infection. This variability in human response has been explained by a number of cofactors (host as well as environmental) that appear to accelerate the course of the disease. Since psychosocial factors are highly amenable to behavioral interventions, several models for intervention research have been proposed to evaluate whether such interventions can enhance immune functioning, thereby curtailing disease progression. Examination of these interventions in the context of PNI and HIV-1 infection, however, is rather limited. Therefore, researchers and clinicians must not only consider conceptualizations and paradigms in this area of research, but also focus on empirically testable, theory-driven models that allow for the unique characteristics of individual patients.

Cognitive Effects of HIV-1 Infection.

The major neurological complication of human immunodeficiency virus type 1 (HIV-1) infection is cognitive impairment, which can range in severity from a mild subclinical cognitive inefficiency to a severe dementing illness. Mild to moderate cognitive impairment is identified primarily by neuropsychological tests. The prevalence and severity of cognitive impairment associated with HIV-1 infection increases as the disease progresses. Deficits in attention, information processing speed, memory, and motor abilities can occur early in the course of HIV-1 infection, with deficits in abstraction and executive functions observed in later stages of infection. The nature of the cognitive impairment observed is thought to reflect the effects of HIV-1 infection on the integrity of subcortical or frontostriatal brain systems. Issues related to the detection of subclinical to severe cognitive impairment are discussed, along with the clinical significance of mild cognitive impairment as a significant risk factor for mortality in HIV-1 infection. The need to control for possible confounding factors that can influence test performance is also reviewed.