DESORDENES NEUROCOGITIVOS ASOCIADOS A INFECCION POR VIRUS DE INMUNODEFICIENCIA HUMANA
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Presentado en Buenos Aires el 16 de mayo 5to Encuentro Latinoamericano sobre Deterioro Cognitivo
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DESORDENES NEUROCOGITIVOS ASOCIADOS A INFECCION POR VIRUS DE INMUNODEFICIENCIA HUMANA
- 1. Desordenes neurocognitivos asociados aDesordenes neurocognitivos asociados a infección por Virus de inmunodeficienciainfección por Virus de inmunodeficiencia humana (DNcAVih)humana (DNcAVih) Nilton CustodioNilton Custodio
- 2. Agenda DNcAVih • Muchos términos, escasos cambios en la prevalencia. • VIH induce neuro-degeneración. • Cuadro clínico típicamente subcortical. • Cribado y criterios diagnósticos. • Ensayos clínicos y opciones de tratamiento.
- 3. Agenda DNcAVih • Muchos términos, escasos cambios en la prevalenciaMuchos términos, escasos cambios en la prevalencia. • VIH induce neuro-degeneración. • Cuadro clínico típicamente subcortical. • Cribado y criterios diagnósticos. • Ensayos clínicos y opciones de tratamiento.
- 4. Revisión crítica y evolución de los criterios de definición – Encefalitis subaguda – Encefalitis a células gigantes multinucleadas – Encefalopatía por VIH – Desorden cognitivo/motor asociado a infección por VIH – Complejo Demencia/SIDA – Demencia/SIDA – Demencia asociada a infección por VIH (DVIH) – Desordenes neurocognitivos asociados a VIH (DNcAVih) 1983 AAN 2007 AAN 1991
- 5. Deterioro neuropsicológico de pacientes con infección VIH después de TARGA Infección VIH sin deterioro cognitivo Deterioro Neurocognitivo Asintomático Deterioro Neurocognitivo Menor Demencia asociada a VIH Antinori A, et al. Neurology 2007;69:1789-1799Antinori A, et al. Neurology 2007;69:1789-1799
- 6. Prevalencia de DNcAVih según estadio de la enfermedad%conDesordenNeuro-Cognitivo Antinori A, et al. Neurology 2007;69:1789-1799Antinori A, et al. Neurology 2007;69:1789-1799
- 7. No hay variación en la proporción de pacientes con DNcAVih después de TARGA según estadio PacientesconDesordenNeuro-Cognitivo Ances BM & Ellis RJ. Semin Neurol 2007;27:86-92Ances BM & Ellis RJ. Semin Neurol 2007;27:86-92
- 8. En la era TARGA, los casos severos han disminuido; pero las tasas de asintomáticos y deterioros menores, aun persiste Heaton RK, et al. Neurology 2010;75:2087-2096Heaton RK, et al. Neurology 2010;75:2087-2096 53 33 12 2 Estimadosdeprevalencia(%) 47 %
- 9. DNcAVih también es frecuente en población VIH con viremia suprimida ProporcióndepacientesconDNcAVih 84 % 64 % 69 % Estimado en población avirémica Simioni S, et al. AIDS 2010;24:1243-1250Simioni S, et al. AIDS 2010;24:1243-1250 Quejas cognitivas espontáneas SI NO
- 10. Ciertos factores de riesgo para DNcAVih pueden ser usados para incrementar la sospecha clínica Factores huéspedFactores huésped Factores VIHFactores VIH ComorbilidadesComorbilidades CD4/SIDACD4/SIDAPredisposición GenéticaPredisposición Genética AnemiaAnemia TrombocitopeniaTrombocitopenia MalnutriciónMalnutrición Desórdenes MetabólicosDesórdenes Metabólicos EdadEdad Uso estimulantesUso estimulantes Hepatitis CHepatitis C DepresiónDepresión Neuro-adaptaciónNeuro-adaptación Subtipo VIHSubtipo VIH Resistencia a drogasResistencia a drogas Activación inmuneActivación inmune
- 11. Ciertos factores de riesgo para DNcAVih pueden ser usados para incrementar la sospecha clínica Factores huéspedFactores huésped Factores VIHFactores VIH ComorbilidadesComorbilidades CD4/SIDACD4/SIDAPredisposición GenéticaPredisposición Genética AnemiaAnemia TrombocitopeniaTrombocitopenia MalnutriciónMalnutrición Desórdenes MetabólicosDesórdenes Metabólicos EdadEdad Uso estimulantesUso estimulantes Hepatitis CHepatitis C DepresiónDepresión Neuro-adaptaciónNeuro-adaptación Subtipo VIHSubtipo VIH Resistencia a drogasResistencia a drogas Activación inmuneActivación inmune
- 12. Adultos mayores tienen mayor riesgo de desarrollar DNcAVih Cherner M, et al. AIDS 2004;18 (suppl 1):S27-34Cherner M, et al. AIDS 2004;18 (suppl 1):S27-34
- 13. Los factores de riesgo cardiovascular se asocian con bajo rendimiento cognitivo basal Wright RJ, et al. Neurology 2010;75:864-873Wright RJ, et al. Neurology 2010;75:864-873
- 14. DNcAVih predice el aumento en riesgo de muerte Vivithanaporn P, et al. Neurology 2010;75:1150-1158Vivithanaporn P, et al. Neurology 2010;75:1150-1158
- 15. Agenda DNcAVih • Muchos términos, escasos cambios en la prevalencia. • VIH induce neuro-degeneración.VIH induce neuro-degeneración. • Cuadro clínico típicamente subcortical. • Cribado y criterios diagnósticos. • Ensayos clínicos y opciones de tratamiento.
- 16. Neuroinvasión: La hipótesis de “caballo de Troya”
- 17. Kaul M. Nature 2001;410:988-994Kaul M. Nature 2001;410:988-994 Injuria Neuronal por VIH-1 Infección VIH-1 M/m Infectado VIH 1 M/m No Infectado Neurotoxinas y Proteínas Virales gp 120 Neurotoxinas Citocinas: TNF-a Neuronas Ingreso Glutamato Glutamato Astrocito ON
- 18. Kaul M. Nature 2001;410:988-994Kaul M. Nature 2001;410:988-994 Infección VIH-1 M/m Infectado VIH 1 M/m No Infectado Neurotoxinas y Proteínas Virales gp 120 Neurotoxinas Citocinas: TNF-a Neuronas Ingreso Glutamato Glutamato Astrocito ON Injuria Neuronal por VIH-1: Activación de TNF-α y Neurotoxinas
- 19. Kaul M. Nature 2001;410:988-994Kaul M. Nature 2001;410:988-994 Injuria Neuronal por VIH-1: Activación de TNF-α y Neurotoxinas
- 20. Kaul M. Nature 2001;410:988-994Kaul M. Nature 2001;410:988-994 Infección VIH-1 M/m Infectado VIH 1 M/m No Infectado Neurotoxinas y Proteínas Virales gp 120 Neurotoxinas Citocinas: TNF-a Neuronas Ingreso Glutamato Glutamato Astrocito ON Injuria Neuronal por VIH-1: Activación de Astrocitos
- 21. Kaul M. Nature 2001;410:988-994Kaul M. Nature 2001;410:988-994 Injuria Neuronal por VIH-1: Activación de Astrocitos
- 22. Kaul M. Nature 2001;410:988-994Kaul M. Nature 2001;410:988-994 Infección VIH-1 M/m Infectado VIH 1 M/m No Infectado Neurotoxinas y Proteínas Virales gp 120 Neurotoxinas Citocinas: TNF-a Neuronas Ingreso Glutamato Glutamato Astrocito ON Injuria Neuronal por VIH-1: Apoptosis Neuronal
- 23. Kaul M. Nature 2001;410:988-994Kaul M. Nature 2001;410:988-994 Injuria Neuronal por VIH-1: Apoptosis Neuronal
- 24. Stress Neuronal Muerte Neuronal Gliosis Sangre SNC M/m infectado M/m Virus M/m infectado gp 120, TatVirus M/m Astrocitos Neuronas Inhibición Producción Factor de Crecimiento Inhibición entrada Glutamato Virus, Tat, gp 120 M/m M/m ON FNT a IL-1B MCP-1 Reclutamiento Activación InflamatoriaNo Inflamatoria Avison MJ. TNS 2002;25:468-4473Avison MJ. TNS 2002;25:468-4473
- 25. Agenda DNcAVih • Muchos términos, escasos cambios en la prevalencia. • VIH induce neuro-degeneración. • Cuadro clínico típicamente subcortical.Cuadro clínico típicamente subcortical. • Cribado y criterios diagnósticos. • Ensayos clínicos y opciones de tratamiento.
- 26. Múltiples factores intervienen en neurodegeneración Factores relacionados a edad Enfermedad neurodegenerativ a concurrente Comorbilidad cerebrovascular acumulativa Activación crónica inmune Exposición a ARVs por largos plazos Otros factores Bajo nivel educativo Factores específicos del VIH APO E4 Carga de VIH plasma y/o LCR Daño cerebral acumulativo multifactorial Presentación clínica de desorden motor/cognitivo/conductual
- 27. Rendimiento neuropsicológico similar entre jóvenes con SIDA y adultos mayores normales Hinkin CH, et al. Canadian Journal on Aging 1990;9:104-119Hinkin CH, et al. Canadian Journal on Aging 1990;9:104-119
- 28. Dominios cognitivos afectados antes de TARGA Heaton RK, et al. J Int Neuropsychol Soc 1995;1(3):231-251Heaton RK, et al. J Int Neuropsychol Soc 1995;1(3):231-251
- 29. Consecuencias funcionales del DNcAVih Heaton RK, et al. J Int Neuropsychol Soc 2004;10(3):17-31Heaton RK, et al. J Int Neuropsychol Soc 2004;10(3):17-31
- 30. Cuadro clínico en DNcAVih CogniciónCognición Velocidad del procesamiento de informacion Atención / Memoria de trabajo Funciones ejecutivas Aprendizaje Memoria Fluencia verbal Velocidad y destreza motora ConductualConductual Apatía Depresión Agitación Manía MotorMotor Inestabilidad Marcha Pobre coordinación Temblor
- 31. DNcAVih tiene características subcorticales • Los síntomas predominantes al inicio están relacionados con enlentecimiento motor y compromiso de las habilidades de atención y ejecutivas. • Luego, puede afectar diversas áreas del lenguaje. • Recién, en estadios avanzados se afectan tanto áreas corticales, como subcorticales y puede afectar las áreas de memoria.
- 32. La batería neuropsicológica debe incluir, como mínimo: • Velocidad procesamiento de informacion: – WAIS-R: símbolos y dígitos – TMT-A • Atención / Memoria de trabajo: – WAIS-R: Span de dígitos • Funciones ejecutivas: – TMT-B • Aprendizaje • Memoria • Fluencia verbal: – Test de denominación de Boston – Fluencia categorical (animales) • Velocidad y destreza motora: – Grooved Pegboard – Finger Taping
- 33. Agenda DNcAVih • Muchos términos, escasos cambios en la prevalencia. • VIH induce neuro-degeneración. • Cuadro clínico típicamente subcortical. • Cribado y criterios diagnósticos.Cribado y criterios diagnósticos. • Ensayos clínicos y opciones de tratamiento.
- 34. El diagnostico en la practica clínica MOS-HIV PAOFI Cuestionario de Síntomas Cuestionario de Síntomas HIV Dementia Scale International HIV Dementia Scale Pruebas Neurocognitivas breves Grooved Pegboard Fluencia de acción Tests computarizados Por lo menos 5 dominios cognitivos Por lo menos 2 tests cognitivos por cada dominio Pruebas de Cribado Pruebas de Cribado Pruebas NP breves Pruebas NP breves Pruebas NP estandares Pruebas NP estandares
- 35. Internacional HIV Dementia Scale • MEMORIA: Registro • Cuatro Palabras: Perro, Abrigo, Frejol, Rojo. • RAPIDEZ MOTORA • Primer y segundo dedos de mano no dominante, a manera de “pinza”, tan amplio y rápido como sea posible. • RAPIDEZ PSICOMOTORA • Movimiento sucesivo y secuenciales de mano no dominante tan rápido como sea posible: 1) Mano extendida, palma hacia arriba sobre superficie plana. 2) Mano extendida, palma hacia abajo sobre superficie plana. 3) Mano extendida, perpendicular a superficie plana, con base en el V dedo. • MEMORIA: Recuerdo • Recuerdo de cuatro palabras. • Ayuda con claves semánticas. Sacktor NC et al. AIDS 2005;19:1367-1374Sacktor NC et al. AIDS 2005;19:1367-1374
- 36. • RAPIDEZ MOTORA 4 • 4 = 15 en 5 segundos • 3 = 11-14 en 5 segundos • 2 = 7-10 en 5 segundos • 1 = 3-6 en 5 segundos • 0 = 0-2 en 5 segundos • RAPIDEZ PSICOMOTORA 44 • 4 = 4 secuencias en 10 segundos • 3 = 3 secuencias en 10 segundos • 2 = 2 secuencias en 10 segundos • 1 = 1 secuencia en 10 segundos • 0 = no puede realizar la prueba • MEMORIA: Recuerdo 44 • Un punto por cada palabra respondida espontáneamente. • Medio punto por cada palabra, si requirió ayuda. Sacktor NC et al. AIDS 2005;19:1367-1374Sacktor NC et al. AIDS 2005;19:1367-1374 Internacional HIV Dementia Scale
- 37. Exclusión de diagnostico alternativo Anamnesis Examen físico Anamnesis Examen físico Pruebas sanguíneas Pruebas sanguíneas Punción Lumbar Punción Lumbar IRM Estructural IRM Estructural Neuroimagen Especializada Cuestionario de Síntomas Cuestionario de Síntomas Pruebas de Cribado Pruebas de Cribado Pruebas NP breves Pruebas NP breves Pruebas NP estandares Pruebas NP estandares
- 38. Neuroimágenes en DNcAVih Femenino, 15 Infección VIH Femenino, 16 Normal
- 41. Neuroimágenes en DNcAVih Basal 9 meses 22 meses
- 42. Neuroimágenes en DNcAVih Basal 6 semanas 7 meses
- 44. La clave radica en evaluar “funcionalidad” Demencia asociada a VIH No compromiso funcional Compromiso funcional leve Compromiso funcional moderado a severo 1 DE 2 Dominios 2 DE 2 Dominios 1 DE 2 Dominios Deterioro Neurocognitivo Asintomático Deterioro Neurocognitivo Menor
- 45. Algoritmo general para clasificación de DNcAVih Dentro de límites normales Deterioro Neurocognitivo Menor HIV- Associated Dementia Deterioro Neurocognitivo Asintomatico Clasificar deterioro cognitivo Clasificar AVDs Normal Yes Clasificar AVDs Normal a Leve Leve a Severo Severo Normal Leve Severo *Clasificación requiere exclusión de otros diagnósticos potenciales.
- 46. Agenda DNcAVih • Muchos términos, escasos cambios en la prevalencia. • VIH induce neuro-degeneración. • Cuadro clínico típicamente subcortical. • Cribado y criterios diagnósticos. • Ensayos clínicos y opciones de tratamiento.Ensayos clínicos y opciones de tratamiento.
- 47. Opciones de tratamiento en DNcAVih • Tratamiento sintomático: – Modafinilo – Metilfenidato – Inhibidores de colinesterasa • Tratamiento modificador de la enfermedad: – Antiretrovirales – Neuroprotectores: • Minociclina • Memantina • Selegilina
- 48. Rivastigmina parece mejorar la velocidad psicomotora, pero ineficaz para variar ADAScog Simioni S, et al. Neurology 2013;80:553-560Simioni S, et al. Neurology 2013;80:553-560
- 49. Los antiretrovirales podrían mejorar modestamente algunas áreas cognitivas Al-Khindi T, et al. J Int Neuropsychol Soc 2011;17:956-969Al-Khindi T, et al. J Int Neuropsychol Soc 2011;17:956-969
- 50. BHE Luz capilar (5) Alteración de la integridad de la BHE facilitan transmigración de macrofagos/monocitos infectados (3) Impacto sobre celulas cerebrales conduce a disfunción cognitiva (2) Transferencia de VIH hacia el cerebro - infección establecida en macrofagos perivasculares (1) Monocitos VIH-infectados, algunos activados VIH (4) Disfunción y muerte neuronal Patología muestra células multinucleadas infectadas (monocitos perivasculares), escasa infección neuronal, pero disfuncionales con arborización disminuida y función sináptica dañada. TARGA
- 51. Minociclina, como memantina y seligilina, tampoco mejora los síntomas cognitivos Nakasujja N, et al. Neurology 2013;80:196-202Nakasujja N, et al. Neurology 2013;80:196-202
Notes de l'éditeur
- Teniendo en cuenta que el hallmark de la infeccion del cerebro por VIH son la celulas gigantes multinucleadas (CGM)-las cuales resultan de la fusion inducida por los virus de los macrofagos infectados -REFLEJAN TANTO INFECCION PRODUCTIVA COMO EL ROL PATOGENICO DEL VIRUS , las primeras denominaciones del compromiso cognitivo por el VIH, estan relacionadas con sus cambios patologicos. Se ha demostrado que CGM y microglia contienen proteina VIH. Se han observado 3 tipos de cambios en el cerebro de pacientes con VIH: ENCEFALITIS VIH LEUCOENCEFALOPATIA VIH LEVE COMPROMISO DE LA SUSTANCIA GRIS: En su forma mas extrema se denomina POLIDISTROFIA DIFUSA Recien a partir de 1991 la AAN decide formar un grupo de trabajo para definir las manifestaciones neurologicas del individuo con infeccion VIH: Janssen RS, Cornblath DR, Epstein LG, et al. Nomenclature and research case definitions for neurological manifestations of human immunodeficiency virus type-1 (HIV-1) infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force. Neurology 1991;41:778–785. Y luego en 2007, se replantea la denominación del compromiso cognitivo de individuos con VIH: Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007;69:1789 –1799.
- Although CART has had a major impact on the course and long-term prognosis of HIV infection, all but the most severe CNS manifestations of infection remain very common. One important finding is that profound neurocognitive impairment—HAD—has become rare. Whereas estimates of HAD prevalence in the pre-CART era ranged from about 10% to 15%, only 2% of the large CHARTER cohort met both NP and functional criteria for dementia. By contrast, 44% of CHARTER participants without severe comorbidities met criteria for milder forms of HAND, and this is consistent with pre-CART reports. Objectives: This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals in the era of combination antiretroviral therapy (CART). Methods: A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment). Results: Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n =843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 200 cells/mm3 (30% vs 47% in remaining subgroups). Conclusions: The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.
- Objective: To determine the prevalence of cognitive complaints and HIV-associated neurocognitive disorders (HANDs) in a cohort of aviremic HIV-positive patients. To evaluate the relevance of the HIV dementia scale to detect HANDs. Design: Assessment of HANDs with neuropsychological tests. Methods: Two hundred HIV-infected patients with undetectable HIV-1 RNA concentrations in the plasma, no history of major opportunistic infection of the central nervous system in the past 3 years, no current use of intravenous drugs, and no major depression answered a questionnaire designed to elicit cognitive complaints. Cognitive functions of 50 complaining and 50 non complaining HIV-positive patients were assessed. Results: Patients had undetectable HIV-1 RNA concentrations for a median time of 48 months (range 3.2–136.6). The prevalence of cognitive complaints was 27%. The prevalence of HANDs was 84% among patients with cognitive complaints (asymptomatic neurocognitive impairment 24%, mild neurocognitive disorders 52%, and HIV associated dementia 8%) and 64% among non complainers (asymptomatic neurocognitive impairment 60%, mild neurocognitive disorders 4%, and HIV-associated dementia 0%; P<0.001). A score of 14 points or less on the HIV dementia scale yielded a positive predictive value of HANDs of 92% in complainers and 82% in non complainers. Conclusion: The prevalence of HANDs is high even in long-standing aviremic HIV positive patients. However, HANDs without functional repercussion in daily life (asymptomatic neurocognitive impairment) is the most frequent subtype observed. In this population, the HIV dementia scale with a cutoff of 14 points or less seems to provide a useful tool to screen for the presence of HANDs.
- OBJECTIVE: The effects of aging on the presentation of HIV-associated neurocognitive disorders are largely unknown. In a cross-sectional observational study, we compared the neuropsychological profiles of 67 HIV-positive patients aged at least 50 years with those of 52 participants aged 35 years or less. METHODS: Participants received neuropsychological, psychiatric and neuromedical evaluations. Raw neuropsychological test scores were converted to demographically corrected T-scores; all were corrected for the effects of normal aging. Clinical ratings of impairment were assigned to the neuropsychological results. RESULTS: The two groups did not differ statistically with respect to demographic variables, percentage with AIDS, or CD4 cell counts. The 'younger' group had higher viral burdens in plasma and cerebrospinal fluid (CSF), and fewer were receiving antiretroviral treatment. The proportion of neuropsychologically impaired subjects in the 'older' group was slightly greater than in the younger group, and the older group tended to have higher rates of impairment across most ability domains. When group differences in CSF viral load were modeled statistically, both viral burden and age were significant predictors of neuropsychological impairment, together with a significant interaction between viral burden and age. Older individuals with detectable virus in CSF had twice the prevalence of neuropsychological impairment of those with undetectable levels. Among younger individuals, this proportion was not affected by viral load. Lifetime major depression, substance use disorder, and current depression symptoms were not associated with neuropsychological impairment. CONCLUSION: Although further studies with larger and older samples are needed, this investigation suggests that older adults may be at greater risk of HIV-related neurocognitive dysfunction
- Objective: To determine factors associated with baseline neurocognitive performance in HIV infected participants enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) neurology sub study. Methods: Participants from Australia, North America, Brazil, and Thailand were administered a 5-test neurocognitive battery. Z scores and the neurocognitive performance outcome measure, the quantitative neurocognitive performance z score (QNPZ-5), were calculated using US norms. Neurocognitive impairment was defined as z scores ˂ - 2 in two or more cognitive domains. Associations of test scores, the QNPZ-5, and impairment with baseline factors including demographics and risk factors for HIV-associated dementia (HAD) and cardiovascular disease (CVD) were determined in multiple regression. Results: The 292 participants had a median CD4 cell count of 536 cells/mm3, 88% had an HIV viral load ≤ 400 copies/mL, and 92% were taking antiretrovirals. Demographics, HIV, and clinical factors differed between locations. The mean QNPZ-5 score was 0.72; 14% of participants had neurocognitive impairment. For most tests, scores and z scores differed significantly between locations, with and without adjustment for age, sex, education, and race. Prior CVD was associated with neurocognitive impairment. Prior CVD, hypercholesterolemia, and hypertension were associated with poorer neurocognitive performance but conventional HAD risk factors and the CNS penetration effectiveness rank of antiretroviral regimens were not. Conclusions: In this HIV-positive population with high CD4 cell counts, neurocognitive impairment was associated with prior CVD. Lower neurocognitive performance was associated with prior CVD, hypertension, and hypercholesterolemia, but not conventional HAD risk factors. The contribution of CVD and cardiovascular risk factors to the neurocognition of HIV-positive populations warrants further investigation
- Background: Combination antiretroviral therapy (cART) has improved the survival of patients with HIV/AIDS but its impact remains uncertain on the changing prevalence and incidence of neurologic disorders with ensuing effects on mortality. Methods: The prevalence and incidence of neurologic disorders were examined in patients receiving active care in a regional HIV care program from 1998 to 2008. The mortality hazard ratio (HR) was calculated by Cox proportional hazard models with adjustment for demographic and clinical variables. Results: Of 1,651 HIV-infected patients assessed, 404 (24.5%) were identified as having one or more neurologic disorders, while 41% of AIDS-affected persons exhibited neurologic disease. Symptomatic distal sensory polyneuropathy (DSP, 10.0%) and HIV-associated neurocognitive disorder (HAND, 6.2%) represented the most prevalent disorders among 53 recognized neurologic disorders. Patients with at least one neurologic disorder exhibited higher mortality rates (17.6% vs 8.0%, p < 0.0001), particularly AIDS-related deaths (9.7% vs 3.2%, p < 0.0001), compared with those without neurologic disorders. The highest mortality HR was associated with opportunistic infections of CNS (HR 5.3, 95% confidence interval [CI] 2.5–11.2), followed by HAND (HR 3.1, 95% CI 1.8–5.3) and the presence of any neurologic disorder (HR 2.0, 95% CI 1.2–3.2). The risk of AIDS-related death with a neurologic disorder was increased by 13.3% per 100 cells/mm 3 decrement in blood CD4+ T-cell levels or by 39% per 10-fold increment in plasma viral load. Conclusions: The burden and type of HIV-related neurologic disease have evolved over the past decade and despite the availability of cART, neurologic disorders occur frequently and predict an increased risk of death.
- 1) According to the "Trojan Horse hypothesis" entry of HIV-1 into the brain takes place by the migration of infected monocytes which differentiate into perivascular macrophage. 2) The passage of infected CD4+ T cells can be another source of infection in the brain. Other probable causes of CNS infection might be: 3) the direct entrance of the virus or 4) entrance of HIV-1 by transcytosis of brain microvascular endothelial cells. Once the virus is in the brain it infects productively macrophages and microglia. Astrocyte infection is known to be restricted. The infection of oligodendrocytes and specially neurons is questionable.
- La principal vía de ingreso del VIH-1 al cerebro ocurre por medio de macrófagos infectados. Los M/m infectados producen: Proteínas de envoltura: gp120, y sus respectivos receptores(CD4) y co-receptores(CXCR4 y CCR5), que se van a expresar tanto en M/m no infectadas, astrocitos y neuronas. citocinas (TNF-a ) y cimocinas, las cuales a su vez activan macrófagos y microglia no infectadas. Liberación de sustancias neurotóxicas :ácido quinolinico, AAEs como glutamato y l-cisteina, ácido araquidonico, PAF(Factor de Agregación Plaquetaria), radicales libres y FNTa, las cuales inducen injuria neuronal, daño dendritico y sinaptico, y apoptosis de neuronas por mecanismos de excitotoxicidad, que involucran mayor ingreso de calcio, por sobreactividad de NMDA. Pero, un proceso crucial, por ser reverberante y recíproco, es la estimulación y activación de astrocitos por M/m infectados, y viceversa, por citocinas inflamatorias como FNTa e IL1B. Las cuales generan: 1) Astrocitosis Reactiva, y con ello, generación de radicales libres, pero sobre todo ON. 2) Compromiso en el ingreso de glutamato, por lo que habrá más glutamato extracelular y así contribuye a la excitotoxicidad de células de la vecindad, pero sobre todo de las neuronas. A estas alturas ustedes, pueden ir sospechando el rol de los antagonistas de NMDA, de barredores de radicales libres y bloqueadores de canales de calcio.
- gp 120 de VIH interactua con receptores de cimocinas CXCR4 o CCR5 en conjunto con CD4 para estimular o infectar M/m (si el virus completo está presente). Los ligandos Naturales de CXCR4 y CCR5, la cimocina SDF-1, y la cimocina MIP-1 y RANTES, respectivamente, interfieren con la unión y señal de gp120. Este gp120 desencadena una serie de señales que involucran a p38 MAPK, un factor pivot en la estimulación inmune de macrofagos que activan el factor de transcripcion MEF2C, induciendo: La liberación de neurotoxinas, como AAEs, ácido araquidonico y moléculas relacionadas como PAF, que generan liberación de glutamato neuronal; Liberación de citocinas inflammatorias, como FNT a, las cuales pueden can activar M/m y astrocitos adyacentes, y así contribuir indirectamente a la injuria cerebral.
- A pesar que los astrocitos expresan los co-receptors de VIH, CXCR4 y CCR5, además de otros receptores de cimocinas, pero en ausencia de CD4, ellos pueden ser activados por efectos independientes de CD4, como FNTa , IL-1B e IFN g, los cuales generan tres hechos importantes: Compromiso en el reingreso de glutamato, que es exacerbado por la exposición a ácido araquidónico, liberado por la activación de macrofagos, lo cual resulta en incremento en la liberación de glutamato. Inducción de SONi, conduciendo liberación oxido nítrico, potencialmente neurotóxico. El FNTa también promueve expresión del receptor de fractalina (Fkn) astrocitarias, CX3CR1, cuya estimulación induce liberación de un factor soluble que desencadena proliferación microglial.
- Apoptosis es desencadenada por activación excesiva de NMDA y receptores de cimocinas. La sobre-estimulación de NMDA es desencadenada por las neurotoxinas liberadas de M/m infectados por VIH, o por la estimulación inmune; y por el compromiso en el reingreso de glutamato originado en los astrocitos activados. Consecuentemente, el influjo excesivo de Ca 2+ hacia las neuronas desencadena activación de p38 MAPK, sobrecarga mitochondrial de Ca 2+ y liberación de citocrom c (Cyt c ), generación de radicales libres (ON y ROS), activación de caspase, y apoptosis. La activación de p38 MAPK, mediada por mecanismos relacionados al Ca 2+, también puede ser estimulada por CXCR4, y puede conducir a fosforilación/activación de factores de transcripción, comprometidos en apoptosis. Por el contrario, la activación de los receptores de cimocina, CCR5 pareciera tener un efecto neuroprotector que interfiere con la toxicidad desencadenada por HIV/gp120 o NMDAR. La cimocina fractalina (Fkn) es liberada de las neuronas subsecuentemente a la excitotoxicidad y puede representar un feedback de señalización hacia las células no neuronales. Evidencia de apoptosis neuronal, en células TUNEL Positiva ( es una tinción para determinar apoptosis; son las siglas de terminal deoxy nucleotidyltransferase-mediated dUTP end labeling) a nivel de ganglios basales
- As can be seen in this figure, the Trail Making Test Part B (a test of processing speed and attention) showed the largest deficit in the AIDS group and in the older adults. Lending quantitative and statistical support to the finding of a similar pattern of performance, a discriminant function analysis classified all 14 of the older adults into the same group as the HIV-positive patients in comparison to the younger control group. With no older HIV-positive group, the potential interactive effects of aging with HIV were not directly examined here. However, the results from these studies do suggest that because of the similarity in cognitive sequelae (in severity and pattern) between adults with HIV and normal older adults, HIV infection in older adults will result in a compounding or exacerbation of cognitive symptoms.
- The characteristics of HAND, mainly due to its diffuse nature, present significant challenges translating specific neurobiological mechanisms of HIV into cognitive neuropsychology quantification. Due to the aforementioned diffuse nature of the disorder, HIV infection offers a limited conceptual model for the development of hypotheses on the role of specific cerebral systems in cognition: something which would be better evidenced in focal or restricted lesions2. Although these constraints make the clinical diagnosis, the specific therapeutic approach and the investigation of the different cognitive domains involved difficult, the authors have succeeded in describing, discriminating and individualizing some patterns of impact and damage. In a classic study from 19954 – which was carried out previously to HAART and which therefore offered “cleaner” results – there were eight main domains affected by HIV in seropositive individuals (Figure 2). More recently, the HIV Neurobehavioral Research Center (HNRC) of the University of California established seven nuclear neurocognitive domains in their evaluation of patients, exposing the subcortical predominance of HIV impact on the CNS: speed of information processing; attention/working memory; executive function; learning; memory; verbal fluency and motor speed and dexterity
- HIV-1 infection can be associated with neuropsychological (NP) deficits ranging from subtle to severe. The purpose of this study was to evaluate the functional, or "real-world" impact of HIV-associated NP impairment in a group of 267 HIV-infected participants. All participants received comprehensive NP, neuromedical, and standardized functional evaluations that included laboratory measures of shopping, cooking, financial management, medication management and vocational abilities. Compared to NP-normal participants, those with NP impairment performed significantly worse on all laboratory measures of everyday functioning. Multivariate analyses revealed that the NP ability domains of Abstraction/Executive Function, Learning, Attention/Working Memory and Verbal abilities most strongly and consistently predicted failures on the functional battery. Both NP impairment and impairment on the functional battery were significantly associated with subjective experiences of cognitive difficulties, as well as unemployment and increased dependence in activities of daily living; multivariate prediction models that also considered depressed mood and biological measures of disease progression revealed that impairment on the functional battery and depression were the only unique predictors of all three indicators of "real-world" functioning. The current results add to growing evidence concerning the clinical significance of HIV-associated NP impairment. Objective, laboratory based functional measures, such as those used here, may compliment NP testing in future studies directed at understanding the impact on life quality of central nervous system disorders and their treatments. Finally, there is a need for additional research investigating the apparently independent effect of depression on level of everyday functioning in HIV infected persons.
- A patient with a score of 10 should be evaluated further for possible dementia .
- LCR: exclusión de neurosífilis y criptococosis. Ausencia de deterioro cognitivo degenerativo. Ausencia de desorden psiquiátrico o intoxicación Ausencia de trastorno metabólico, o infeccioso. Ausencia de procesos oportunista activos del SNC
- Magnetic resonance imaging of the patient, age 15 (top row) and of a normal 16-year-old girl for comparison (bottom row). Near-midline sagittal T1-weighted images are on the left. Axial fluid-attenuated inversion recovery images through the basal ganglia are on the right. All four ventricles in the patient are prominent. Her sulci are prominent throughout the brain, involving all lobes of the cerebrum and also the cerebellum. There is thinning of the corpus callosum. The magnetic resonance imaging findings are consistent with diffuse atrophy.
- En TC se evidencia atrofia difusa y dilatación ventricular, así como atenuación de sustancia blanca periventricular. En la IRM, EN T2 se observa dilatación ventricular y grandes área de hiperseñal en la sustancia blanca subcortical de ambos lóbulos frontales.
- En T1 y FLAIR se observa hiperseñal de sustancia blanca bilateral.
- MR findings in a 56-year-old man (patient 1) with HIV-leukoencephalopathy being treated with a combination therapy of nonnucleoside analogues and protease inhibitors. He presented with impairment in concentration and memory and depressive symptoms. Neuropsychological testing was consistent with subcortical dementia. A–C, TSE-FLAIR (7374/130, TI = 2100) images show symmetric regions of abnormally increased signal intensity ( arrows, B and C ) without mass effect in the periventricular white matter bilaterally. Additionally, high signal intensity was observed in the midbrain ( arrow, A ) and left cerebral peduncle. D–F, Nine months after the initiation of therapy, follow-up TSE-FLAIR (7374/130, TI = 2100) images show interval increase in the hyperintense signal abnormalities ( asterisks, E and F ) in the periventricular white matter and progression of the cerebral atrophy, as well as almost complete resolution of the signal abnormality in the midbrain ( arrow, D ). Neuropsychological testing revealed an improvement in mental status. G–I, Subsequent TSE-FLAIR (9000/105, TI = 2370) images of the brain 22 months after start of treatment show no interval change in distribution or severity of the white matter abnormalities, and complete resolution of the signal abnormality in the midbrain ( arrow, G ).
- MR findings in a 31-year-old woman (patient 3) with AIDS who presented initially with headache, slowing of thoughts, aphasia, and impairment in memory. HIV-1 RNA assay revealed high viral load in serum and CSF. Imaging findings were consistent with HIV encephalitis. HAART, including one protease inhibitor, was started. A and B, Pretreatment axial FSE-FLAIR images (10000/150, TI = 2600) show areas of increased signal intensity at the anterior portions of the external capsules bilaterally, in the right caudate nucleus ( curved arrow, A ), and periventricular white matter in the frontal, parietooccipital, and central areas bilaterally ( straight arrows ). Additional lesions are present in both thalami ( open arrows, A ). C and D, Six weeks after the initiation of HAART, including protease inhibitors, corresponding axial FSE-FLAIR images (7374/130, TI = 2100) show resolution of the signal intensity abnormalities in the basal ganglia and thalami ( C ) but progression of the white matter abnormalities ( arrows ). The patient had improved clinically at that time. E and F, Seven months after the start of a potent antiretroviral therapy regimen, axial FSE-FLAIR images (7385/130, TI = 2100) at the same level show an interval decrease in the high signal abnormalities within the occipital, parietal ( arrows, F ), and frontal ( arrows, E ) white matter.
- SECTION 1: REVIEW OF DEFINITIONAL CRITERIA A: Current AAN definitional criteria. The 1991 AAN criteria defined two levels of neurologic manifestations of HIV infection: HIV associated dementia (HAD) and minor cognitive motor disorder (MCMD) . Briefly, the AAN criteria for HAD were 1) an acquired abnormality in at least two cognitive (non motor) areas causing impairment in work or activities of daily living (ADLs), and 2) either an abnormality of motor function or specified neuropsychiatric or psychosocial functions (e.g., motivation, emotional control, social behavior). Moreover, the patient had to have sufficient consciousness for cognitive abilities to be assessed, and could not have other etiologies that might explain the disorder. The AAN diagnostic scheme defined three subtypes of HAD: 1) HAD with motor symptoms (criterion 1 met fully, but only motor symptoms meeting criterion 2) 2) HAD with behavioral or psychosocial symptoms (criterion 1 met fully, but only behavioral symptoms meeting criterion 2) 3) HAD with both motor and behavioral/psychosocial symptoms (criteria 1 and 2 met fully). The AAN criteria also defined a less severe condition called MCMD. The essential features of MCMD according to the AAN criteria were a history of impaired cognitive/behavioral function in two areas (e.g., impaired attention-concentration, mental slowing, abnormal memory or other cognitive functions, slowed movements, incoordination, personality change, irritability, lability), and these abnormalities cause mild impairment in work or ADLs, do not meet criteria for HAD or HIVassociated myelopathy, and cannot be attributed to other etiologies. In our review, we identified issues that may restrict the applicability of the 1991 AAN criteria. One issue is that the number of domains of impairment that should be examined for diagnosis was not clearly defined. Moreover, the degree of neurocognitive impairment was not fully specified, permitting variability in the clinical estimation of severity. Third, there appeared to be some overlap between the criteria for HAD with mild functional decline and MCMD . Finally, the schema did not admit mild forms of reliably identified cognitive difficulties which had not developed to the point of interfering substantially with everyday functioning. There is increasing recognition of the frequency of confounding conditions that are potentially acting as compounding factors (deficits with mixed etiologies), and these were not adequately considered in the 1991 schema other than the simple exclusionary stipulation. B: Proposed research criteria developed by HIV Neurobehavioral Research Center at UCSD. To address some of these concerns, the HIV Neurobehavioral Research Center (HNRC) at UCSD established working research criteria for HIV related neurocognitive complications which were intended to represent a refinement of the AAN criteria. These criteria recognize the following three conditions: asymptomatic neurocognitive impairment (ANI), HIV-associated mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). These modified criteria were developed by starting with the existing AAN criteria, and introduced changes based on research and observations made at HNRC, and other published sources. The most notable change is addition of the category of ANI based on the observation that some individuals have demonstrable (and usually mild) cognitive impairment demonstrated by formal neuropsychological tests without any observed abnormality in everyday functioning. The caveat to this statement is that the assessment of functional capacity is difficult and frequently requires third-party report, or prolonged observation. Furthermore, the HNRC criteria are more fully specified in terms of types and severities of cognitive difficulties.
- Asymptomatic Neurocognitive Impairment (ANI) is defined by performance at least 1 SD below the mean of demographically adjusted normative scores in at least two cognitive areas (attention-information processing, language, abstraction-executive, complex perceptual motor skills, memory, including learning and recall, simple motor skills or sensory perceptual abilities); these criteria specify that at least five cognitive domains be examined or observed. Finally, the impairment does not occur solely as part of a delirium (i.e., a confusional state secondary to opportunistic CNS disease, vascular insult, metabolic derangement, drug effects, or other systemicdisorders) and, as in all AAN criteria, the diagnosis is possible only if the cognitive impairment cannot be explained by other comorbidities. There does appear to be empirical support to adding this third category of HIV-related neurocognitive disorder, because it appears to have a priori prognostic value. HIV-associated mild neurocognitive disorder (MND): The MND defined by HNRC is similar to the MCMD previously defined by AAN but, in addition to criteria for asymptomatic neurocognitive abnormality, MND requires that there also be impairment in everyday functioning. Specifically, MND is defined by the following features: 1) an acquired mild-to-moderate impairment in cognitive function documented by a score of at least 1 SD below demographically corrected norms on tests of at least two different cognitive domains, 2) the cognitive impairment interferes, at least mildly, with activities of daily living, 3) the impairment does not meet criteria for delirium or dementia, and 4) the impairment is not fully explained by comorbid conditions. Finally, diagnosis of HIV-associated dementia ( HAD) according to these suggested criteria requires 1) acquired moderate to-severe cognitive impairment, documented by a score at least 2 SD below demographically corrected normative means in at least two different cognitive areas, 2) marked difficulty in ADLs due to the cognitive impairment, 3) the impairment does not meet criteria for delirium, and 4) the impairment is not adequately explained by comorbid conditions. CONCLUSIONS: The existing AAN criteria have served researchers and clinicians well for 15 years. They offer reasonable sensitivity and specificity for predicting future neuropathologic diagnoses of HIV encephalitis, although the positive predictive power can be enhanced by considering asymptomatic neurocognitive abnormality. A limitation of the existing AAN criteria is that they do not recognize a subgroup of HIV-infected patients (15%) who actually have neurocognitive impairment despite the absence of overt functional decline in ADLs. We recognize that further work needs to be conducted on the real-life impact of ANI, but at this stage recommend adding this condition to the criteria for HAND. We recommend that the presence and degree of neurocognitive impairment constitute the fundamental criteria for establishing a diagnosis, while other criteria, e.g., motor disorders and emotional or personality changes, be considered ancillary or corroborative information, possibly for defining disorder subtypes. Finally, determination of neurocognitive impairment should be based on appropriately normed tests (see the Neurology ® Web site), and should consider the presence of confounding factors. It is timely to work toward a revision of the diagnostic criteria along the lines displayed in the table, and we strongly recommend that revised criteria be field tested and further refined through research.
- Mild functional decline requires at least two of the following that are not readily attributable to comorbid conditions in the judgment of the examiner: 1) Self report or other report of some increased assistance with at least two IADLs such as medication management, financial management, shopping, meal preparation, light housekeeping, laundry, driving, use of public transportation, maintaining personal schedules, understanding media events, and child care. (More IADLs could be considered as appropriate to the individual.) 2) Patient is unable to perform some aspects of a previous job. This is not due to medical symptoms. 3) Although patient may maintain employment and/or full IADL independence, he or she reports less efficiency, reduced productivity, more errors in performing tasks, more difficulty meeting expectations, or greater effort expended performing the same activities. 4) In the absence of significant depression (e.g., Beck Depression Inventory ≥ 17), which may bias reporting of symptoms, patient reports that he or she is experiencing increased difficulty with 2 aspects of cognition in daily life. These may include difficulties with memory for recent events (people, conversations, names, commitments, where things are placed), understanding conversations or reading materials, word finding, planning activities, problem solving, concentrating, thinking clearly or logically, finding his or her way about, calculating, or following directions or instructions. Reports of these difficulties also may be obtained from a knowledgeable informant. (Instruments to assess depression that allow one to separate out items concerning somatic symptoms from those describing depressed mood are preferred for this purpose, as somatic symptoms associated with depression may also be caused by HIV itself.) 5) If performance-based, standardized functional tests are administered, patient scores 1 SD below an appropriate normative mean on at least one such task. Major functional decline requires two or more of the following that are not readily attributable to medical or other comorbid conditions in the judgment of the examiner: 1) Patient is unable to maintain former employment and this is not due to systemic illness or other factors not related to cognitive impairment (e.g., healthcare coverage being dependent upon disability status). 2) Patient requires substantially greater assistance (or is dependent) with more than two IADLs, as listed above. 3) Patient or a knowledgeable informant reports that he or she experiences/shows significantly greater difficulty with 4 aspects of cognition, as listed above. However, self report is not sufficient (would need confirmation by another informant) if patient is significantly depressed (e.g., BDI 17). 4) If performance-based, standardized functional tasks are administered, patient scores 2 SD below an appropriate normative mean on at least one such task, or 1 SD below the mean on at least two tasks. Questionnaires and performance-based tests for measuring functional decline have been standardized in Western countries, and many have been used in published studies of HIV-infected groups. As is the case with NP testing, measures of everyday functioning (and available normative standards for them) cannot be assumed to be valid across populations having substantially different linguistic, cultural, and educational backgrounds. ADLs themselves may be different in different cultures (e.g., reflecting differences in common modes of transportation, shopping, and financial transactions). Thus, compared to NP testing, which is intended to measure more fundamental human abilities, measures of functional decline may require even more adaptation for cross cultural use. Before they are selected for use in a new (different) population, IADL tests and questionnaires should be carefully screened for relevance to the everyday lives of the people involved.
- Modafinilo (Rabkin JG, et al. J Clin Psychiatry 2004;65(12):1688’1695) : Ensayo abierto de 4 semanas, 30 pacientes completaron las 4 semanas de tratamiento. 24/30 (80%) mejoraron en los patrones de fatiga, síntomas depresivos y funciones ejecutivas. Efectos adversos: cefalea irritabilidad. Precaucion para la interpretación, sus efectos podrían reflejar beneficio sobre la cognición vs afecto/energía.
- Objective: To assess the efficacy and safety of rivastigmine for the treatment of HIV-associated neurocognitive disorders (HAND) in a cohort of long-lasting aviremic HIV1 patients. Methods: Seventeen aviremic HIV1 patients with HAND were enrolled in a randomized, double-blind, placebo-controlled, crossover study to receive either oral rivastigmine (up to 12 mg/day for 20 weeks) followed by placebo (20 weeks) or placebo followed by rivastigmine. Efficacy endpoints were improvement on rivastigmine in the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-Cog) and individual neuropsychological scores of information processing speed, attention/working memory, executive functioning, and motor skills. Measures of safety included frequency and nature of adverse events and abnormalities on laboratory tests and on plasma concentrations of antiretroviral drugs. Analyses of variance with repeated measures were computed to look for treatment effects. Results: There was no change on the primary outcome ADAS-Cog on drug. For secondary outcomes, processing speed improved on rivastigmine (Trail Making Test A: F1,13 5 5.57, p 5 0.03). One measure of executive functioning just failed to reach significance (CANTAB Spatial Working Memory [strategy]: F1,13 5 3.94, p 5 0.069). No other change was observed. Adverse events were frequent, but not different from those observed in other populations treated with rivastigmine. No safety issues were recorded. Conclusions: Rivastigmine in aviremic HIV1 patients with HAND seemed to improve psychomotor speed. A larger trial with the better tolerated transdermal form of rivastigmine is warranted. Classification of evidence: This study provides Class III evidence that rivastigmine is ineffective for improving ADAS-Cog scores, but is effective in improving some secondary outcomemeasures in aviremic HIV1 patients with HAND
- The development of antiretroviral therapy (ART) has dramatically improved survival for those living with human immunodeficiency virus (HIV), but whether ART improves cognitive functioning remains unclear. The aim of the present review was to examine systematically the extent to which ART improves cognition among individuals with HIV using meta-analytic methods. Twenty-three studies were included in the quantitative review. ART was associated with modest improvements in attention (mean d5.17; p,.001; 95% confidence interval [CI], .09/.25), executive function (mean d5.18; p,.001; 95% CI, .10/.26), and motor function (mean d5.24; p,.001; 95% CI, .16/.32). ART did not improve language, verbal memory, visual memory or visuospatial function. The extent to which cognition improved was correlated with the change in CD4 cell count following ART, suggesting a link between cognitive outcome and immune system integrity. Together, the present findings indicate that the neuropsychological test performance of most HIV patients taking ART is comparable to those not taking ART. Development of pharmaceutical treatments and rehabilitation strategies that target the cognitive effects of HIV infection is needed. The present findings indicate that the efficacy of ART in alleviating HIV-associated cognitive dysfunction is modest. Results from our quantitative review indicate that 85% to 92% of HIV patients taking ART performed at levels comparable to HIV patients not taking ART. The modest benefits of ART may explain why the prevalence of HIV-associated cognitive impairment has remained high despite the advent of HAART (Robertson et al., 2007; Sacktor, 2002). Individual patients may exhibit dramatic improvement in cognitive functioning after taking ART, but the present data suggest that these patients are the exception rather than the rule. Additionally, the benefits of ART are restricted to particular cognitive domains. Robust improvements were observed only in attention, motor function, and executive function. Enhanced performance in these domains was expected; a meta-analysis by Reger and colleagues (2002) found that attention, motor function, and executive function were particularly compromised among individuals with HIV. The observed improvement in motor function is consistent with recent data from the national CHARTER study showing a reduction in the prevalence of motor impairments since the advent of HAART (Heaton et al., 2011). Of interest, patients taking ART showed poorer immediate visual memory than patients not taking ART, suggesting that ART may have detrimental effects on certain aspects of cognition. This finding is consistent with prior studies showing persistent inflammation in the hippocampus, a brain region involved in memory (Squire, Stark, & Clark, 2004), among HIV patients taking HAART (Anthony, Ramage, Carnie, Simmonds, & Bell, 2005). Mechanistically, ART may exert its detrimental effects by facilitating central nervous system hyperstimulation (Marzolini et al., 2001). The finding that HIV patients show poorer immediate visual memory after ART, however, must be interpreted with caution. The result was only based on three studies and the low fail-safe N value suggests that the finding is not robust and may be an artifact of publication bias. There were no observed benefits of ART on delayed visual memory or visuospatial function, two other domains commonly impaired in HIV patients (Reger et al., 2002). Despite the importance of these two domains, only four and seven studies examined the effects of ART on delayed visual memory and visuospatial function, respectively. The paucity of research on visual memory and visuospatial function after ART is surprising given that atrophy of the visual cortex is commonly observed among patients with HIV (Thompson et al., 2005). Additional studies are needed to further explore the integrity of visual memory and visuospatial function after ART. Despite no statistical differences in effect size between studies using HAART and those using monotherapy, a qualitative examination of the data indicates that, across cognitive domains, the mean effect size for HAART is greater than the mean effect size for monotherapy (Figure 2). The failure to find statistical differences between monotherapy and HAART may be attributed to the small number of studies using monotherapy. The superior benefits of HAART may be partially attributed to its ability to normalize CD4 cell count (Hammer et al., 1997; Mocroft et al., 2007). Indeed, univariate and multivariate analyses revealed that, in the case of attention, executive function, motor function, and visuospatial function, the extent to which ART improved cognitive outcome was correlated with its ability to enhance CD4 cell count. The integrity of the immune system thus appears to be linked to cognitive outcome among individuals with HIV. This finding supplements recent data from the national CHARTER study in which nadir CD4 cell count was found to correlate with neurocognitive functioning (Heaton et al., 2011). Since only 3 of the 23 included studies reported nadir CD4 cell count, the predictive strength of this variable could not be assessed in the current meta-analysis. The observed relationship between CD4 cell count and cognitive functioning stands in stark contrast to several studies observing no correlation between CD4 cell count and neuropsychological test performance (Ferrando et al., 1998; Sun et al., 2010). By virtue of their small sample size, these individual studies may have had insufficient statistical power to detect correlations between CD4 cell count and cognitive functioning. By contrast, meta-analytic techniques, by synthesizing data across multiple studies, may possess sufficient power to detect such correlations (Borenstein et al., 2009). As well as CD4 cell count, patient characteristics also mediate the ability of ART to improve cognitive functioning. Older patients showed smaller improvements in attention, visuospatial function, immediate verbal memory, and delayed verbal memory after taking ART. Why older individuals experienced smaller improvements in cognitive functioning after ART is unknown. Older individuals may have been infected with HIV for a longer time period. As a result, brain injury in older patients may have progressed to a stage where ART could no longer improve cognitive functioning. Prior studies suggest that time since AIDS diagnosis and stage of HIV illness are important determinants of the extent of cognitive impairment (Cysique & Brew, 2009; Heaton et al., 2011; Reger et al., 2002). Unfortunately, only 3 studies reported the time since AIDS diagnosis and the stage of HIV illness, so analyzing the contributions of these variables was not possible. Future studies should investigate how the efficacy of ART changes depending on the duration and stage of HIV illness. The development of antiretroviral medications has transformed HIV infection from an inevitably fatal disease into a treatable condition. Despite the positive effects of ART on survival and immunological functioning (Fischl et al., 1987), the present results indicate that ART has only modest benefits in reducing HIV-associated cognitive impairment. Our findings may, therefore, be of interest to the practicing clinical neuropsychologist when interpreting change scores in the context of serial neuropsychological examinations of patients with HIV/AIDS before and after ART. Development of novel pharmaceutical treatments and rehabilitation strategies is needed to address the pressing issue of HIV-associated cognitive dysfunction.
- Objective: To evaluate the efficacy and safety of minocycline in the management of HIV-associated cognitive impairment. Methods: We enrolled HIV-positive participants with a CD4 count of 250 to 500 cells/mL in a randomized, double-blind, placebo-controlled study. They received 100 mg of minocycline or matching placebo orally every 12 hours for 24 weeks. Cognitive function was measured using the Uganda Neuropsychological Test Battery Summary Measure (U NP Sum) and the Memorial Sloan-Kettering (MSK) scale. The primary efficacy measure was the 24-week change in an average of 9 standardized U NP Sum z scores. Results: Seventy-three participants were enrolled. Of these, 90% were female, 49% were between the ages 30 and 39 years, and 74% had 6 or more years of education. One participant had MSK score of stage 1 (i.e., mild HIV dementia), and 72 participants had MSK stage 0.5 (i.e., equivocal or subclinical dementia) at the baseline evaluation. The minocycline effect on the 24-week change of the U NP Sum compared with placebo was 0.03 (95% confidence interval 20.51, 0.46; p 5 0.37). Conclusion: Minocycline was safe and well tolerated in HIV-positive individuals. However, it did not improve HIV-associated cognitive impairment. Classification of evidence: This study provides Class II evidence that 100 mg of minocycline given orally every 12 hours for 24 weeks had no significant effect compared with placebo in the improvement of cognitive function in antiretroviral therapy–naive, HIV-positive patients