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Brain Research Urged in Paper in AIDS: "HIV-1 infection and cognitive impairment in the cART-era: a review" - "studies....report abnormal scores on neuropsychological assessments in 15 - 50% of patients.....clinical course should be followed closely in large cohorts of patients.....promising therapies should be studied" - published pdf attached
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Download the PDF here
AIDS: POST ACCEPTANCE, 14 December 2010
Judith Schoutena,c, Paola Cinquee, Magnus Gisslenf, Peter Reissb,c and Peter Portegiesa,d
aDepartment of Neurology, bInternal Medicine, Division of Infectious Diseases, Tropical Medicine & Aids, Academic Medical Center, Amsterdam, The Netherlands, cCenter for Poverty-related Communicable Diseases, Academic Medical Center and Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands, dDepartment of Neurology, OLVG Hospital, Amsterdam, The Netherlands, eDepartment of Infectious Diseases, San Rafaele Scientific Institute, Milan, Italy, and fDepartment of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden.
Correspondence to Judith Schouten, Center for Poverty-related Communicable Diseases and Amsterdam Institute for Global Health and Development, Academic Medical Center, Trinity building C, room 3.09, P.O.Box 22700, 1100 DE Amsterdam, The Netherlands.
E-mail: j.schouten@amc.uva.nl
"Within years after the start of the epidemic it became clear that many HIV-1-infected patients developed severe progressive cognitive and motor impairment in the final months of their illness......With the introduction of combination antiretroviral therapy (cART), ADC or HIV-associated dementia (HAD), as it was termed later, largely disappeared in clinical practice.....However, in the past few years, patients, long-term infected and treated, including those with systemically well-controlled infection, started to complain about milder memory problems and slowness, difficulties in concentration, planning, and multitasking......studies from different parts of the world, including large cohorts, report abnormal scores on neuropsychological assessments in 15 - 50% of patients......clinical course of these impairments should be followed closely in large cohorts of patients. Risk factors and conditions other than HIV that could lead to neurocognitive dysfunction need to be defined more accurately.....Promising adjunctive treatments should also selectively be studied. These efforts are essential to understand what is going on in the brain in longstanding HIV-1-infection and to prevent dysfunction and provide optimal management and cure."
"in the past few years, patients, long-term infected and treated, including those with systemically well-controlled infection, started to complain about milder memory problems and slowness, difficulties in concentration, planning, and multitasking.....Among HIV-1-infected patients cognitive impairment was and is one of the most feared complications of HIV-1- infection. In addition, neurocognitive impairment may affect adherence to treatment and ultimately result in increased morbidity for systemic disease [6]. So what may be going on in the CNS after so many years of apparently controlled HIV-1-infection is an urgent and important challenge in the field of HIV-medicine.....We try to integrate data on pathogenesis and finally discuss possible therapeutic interventions. In doing so it will become clear that there remains a broad research agenda in this field for the years ahead......studies from different parts of the world, including large cohorts, report abnormal scores on neuropsychological assessments in 15 - 50% of patients......the core abnormality is slowness; patients do poor on all tests with a time-factor in it. The longer-term course of these cognitive impairments however is not known yet.....What is going on in the brain? Chronic immune-activation, HIV-driven or caused by other conditions such as aging (or a combination), might be the mechanism behind the cognitive problems we see today. But many uncertainties remain. The clinical course of the cognitive impairment is unknown; it might be the result of a process that has been going on for years or there could be a subacute deterioration in which viral control in the CNS is suddenly lost. We do not know whether this will in the end happen in all HIV-infected individuals or in a subset of patients at risk. We may have missed an ongoing CNS replication in systemically well-controlled patients. We still do not know how to manage patients with low-level detectable HIV-1-RNA in the CSF. CSF, MRI and neuropathological studies have provided information about the localization, the character and the magnitude of the pathology that is present in cognitive impairment though this information is fragmented and so far unable to elucidate and interconnect all aspects related to cognitive impairment."
Abstract:
With the introduction of combination antiretroviral therapy (cART) AIDS dementia complex (ADC) or HIV-associated dementia (HAD), as it was termed later, largely disappeared in clinical practice. However, in the past few years, patients, long-term infected and treated, including those with systemically well-controlled infection, started to complain about milder memory problems and slowness, difficulties in concentration, planning, and multitasking.
Neuropsychological studies have confirmed that cognitive impairment occurs in a substantial (15-50%) proportion of patients.
Among HIV-1-infected patients cognitive impairment was and is one of the most feared complications of HIV-1-infection. In addition, neurocognitive impairment may affect adherence to treatment and ultimately result in increased morbidity for systemic disease.
So what may be going on in the CNS after so many years of apparently controlled HIV-1-infection is an urgent and important challenge in the field of HIV-medicine.
In this review we summarize the key currently available data. We describe the clinical neurological and neuropsychological findings, the preferred diagnostic approach with new imaging techniques and CSF-analysis. We try to integrate data on pathogenesis and finally discuss possible therapeutic interventions.
INTRODUCTION
Within years after the start of the epidemic it became clear that many HIV-1-infected patients developed severe progressive cognitive and motor impairment in the final months of their illness. This clinical syndrome was characterized clinically and neuropathologically by Price and Navia in 1986 and termed AIDS dementia complex (ADC) [1,2]. ADC causes symptoms in three areas: cognition, motor function and behavior. Cognitive impairment predominantly consists of mental slowing and attention/memory deficits. Motor symptoms comprise slowness and loss of balance; behavioural changes are characterized by apathy, social withdrawal and mood disturbances.
Many studies confirmed the hypothesis that HIV-1 itself was causing dysfunction and damage in the central nervous system (CNS). Shortly after the primary infection HIV-1 enters the brain in mononuclear cells, and settles in perivascular macrophages and microglial cells. Replication of HIV-1 in these cells leads to immune-activation and the production of viral and inflammatory proteins that eventually leads to cognitive decline and motor dysfunction in a subset of patients.
With the introduction of combination antiretroviral therapy (cART), ADC or HIV-associated dementia (HAD), as it was termed later, largely disappeared in clinical practice. Many clinical, pathological, and cerebrospinal fluid (CSF) studies showed that antiretroviral drugs inhibit local virus-replication in the brain and in doing so limit local damage. Even severely impaired patients could improve after the initiation of treatment. Some drugs likely did better than others, but in general most combinations prevented the development of HAD. HAD became a rare complication, occurring occasionally in late-presenting as yet untreated patients, in patients on treatment but with poor adherence, or in patients in whom systemic and CNS-infection had an unparalleled course.
However, in the past few years, patients, long-term infected and treated, including those with systemically well-controlled infection, started to complain about milder memory problems and slowness, difficulties in concentration, planning, and multitasking.
In recent years a new terminology has been developed to classify a broadening clinical spectrum of neurocognitive impairment, including milder abnormalities (Table 1) [3]. Neuropsychological studies have confirmed that cognitive impairment occurs in a substantial (15-50%) proportion of patients [4,5]. It has, however, to be noted that there is a current discussion about the prevalence of neurocognitive dysfunction, which might be overestimated because of very sensitive criteria when applying the new terminology. In addition, compared to the first decade of the epidemic, a shift has occurred in certain demographic variables and risk factors, e.g. increased age, lower transmission among drug users, which might affect the proportion of patients with cognitive impairment.
Among HIV-1-infected patients cognitive impairment was and is one of the most feared complications of HIV-1- infection. In addition, neurocognitive impairment may affect adherence to treatment and ultimately result in increased morbidity for systemic disease [6]. So what may be going on in the CNS after so many years of apparently controlled HIV-1-infection is an urgent and important challenge in the field of HIV-medicine.
In this review we summarize the key currently available data. We describe the clinical neurological and neuropsychological findings, the preferred diagnostic approach with new imaging techniques and CSF-analysis. We try to integrate data on pathogenesis and finally discuss possible therapeutic interventions. In doing so it will become clear that there remains a broad research agenda in this field for the years ahead.
Discussion
Do we see new cognitive problems in HIV-1- infected individuals?
Yes, studies from different parts of the world, including large cohorts, report abnormal scores on neuropsychological assessments in 15 - 50% of patients. Neuropsychological test batteries differ between studies and there is discussion on what is an abnormal test result. Patients with cognitive complaints show worse test results than those without.
What is the character of the abnormalities found?
The abnormalities found on neuropsychological assessments are milder than in full-blown HAD. In essence the core abnormality is slowness; patients do poor on all tests with a time-factor in it. The longer-term course of these cognitive impairments however is not known yet.
Which diagnostic tests are useful in the clinical setting?
Neuropsychological assessment, CSF-examination and MRI of the brain are important tools and accessible in many clinical settings. Neuropsychological examination will more reliably reveal the presence and character of neurocognitive disturbances. Virological, host response and CNS tissue damage CSF-markers may be helpful to diagnose CNS immune-activation and HIV-RNA load in particular reflects more directly to what extent the process is HIV-driven. DTI, providing detailed infor- mation of the integrity of the white matter, may become an important marker in the future.
What is going on in the brain?
Chronic immune-activation, HIV-driven or caused by other conditions such as aging (or a combination), might be the mechanism behind the cognitive problems we see today. But many uncertainties remain. The clinical course of the cognitive impairment is unknown; it might be the result of a process that has been going on for years or there could be a subacute deterioration in which viral control in the CNS is suddenly lost. We do not know whether this will in the end happen in all HIV-infected individuals or in a subset of patients at risk. We may have missed an ongoing CNS replication in systemically well-controlled patients. We still do not know how to manage patients with low-level detectable HIV-1-RNA in the CSF. CSF, MRI and neuropathological studies have provided information about the localization, the character and the magnitude of the pathology that is present in cognitive impairment though this information is frag- mented and so far unable to elucidate and interconnect all aspects related to cognitive impairment.
The HIV-neurology research agenda
In the coming years the clinical course of these impairments should be followed closely in large cohorts of patients. Risk factors and conditions other than HIV that could lead to neurocognitive dysfunction need to be defined more accurately. More CSF-parameters need to be assessed and new MRI- techniques will hopefully provide us with more information on the white matter pathology, blood flow and vascular changes. For all antiretroviral drugs, CNS/ CSF-penetration studies should be performed, as well as clinical trials comparing different antiretroviral regimens. Promising adjunctive treatments should also selectively be studied. These efforts are essential to understand what is going on in the brain in longstanding HIV-1-infection and to prevent dysfunction and provide optimal management and cure.
Table 4. Risk factors and conditions/comorbidities associated with neurocognitive impairment in HIV-1-infection.
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