INTRODUCTION — Changes in memory, concentration, attention, and motor skills are common in patients with HIV and present a diagnostic challenge to the clinician . Since these symptoms can be caused by a variety of disorders, accurate diagnosis is critical for patient treatment . When not clearly attributable to an alternate cause other than HIV infection, such impairments have been collectively classified as HIV-associated neurocognitive disorders (HAND).
The epidemiology, clinical manifestations, and diagnosis of HIV-associated neurocognitive disorders will be discussed here. Management of HIV-associated neurocognitive disorders are discussed elsewhere. (See "HIV-associated neurocognitive disorders: Management".)
An overview of the range of neuropsychiatric conditions associated with HIV infection and more detailed reviews of other specific conditions are discussed separately. (See "Overview of the neuropsychiatric aspects of HIV infection and AIDS" and "Depression, mania, and schizophrenia in HIV-infected patients" and "Substance abuse and addiction in HIV-infected patients".)
TERMINOLOGY — The presence of neurocognitive deficits in certain individuals with HIV, without alternative explanation other than HIV infection, has long been recognized. However, the terminology to refer to this phenomenon has undergone substantial evolution since its initial characterization. In order to assist in diagnosis and categorization for research and clinical purposes, a working group supported by the United States National Institutes of Health published a classification scheme in 2007 that was initially proposed by the HIV Neurobehavioral Research Center at the University of California, San Diego . This classification, often referred to as the "Frascati criteria," has been widely, but not universally, adopted [4,5]. It includes three levels of impaired neuropsychological test performance and functional impairment within an umbrella term, HIV-associated neurocognitive disorders (HAND):
●Asymptomatic neurocognitive impairment (ANI) – defined by a score of one standard deviation or more below the mean in at least two cognitive domains on standardized neuropsychological testing without a symptomatic or observable functional impairment.
●Mild neurocognitive disorder (MND) – defined by a score of one standard deviation or more below the mean in at least two cognitive domains on standardized neuropsychological testing with at least mild symptomatic or functional impairment.
●HIV-associated dementia (HAD) – defined by a score of two standard deviations or more below the mean in at least two cognitive domains on standardized neuropsychological testing with concomitant impairment in activities of daily living.
The definitions are applied only when the observed impairment cannot be explained by other conditions, either alternative neurological diagnoses (such as opportunistic infection, stroke, or metabolic or toxic encephalopathy) or underlying "confounding" comorbidities that might alter neuropsychological test performance (such as severe substance abuse, prior head trauma, or severe psychiatric disease).
These diagnostic categories were developed to apply a common set of criteria for research studies and, in the strict sense, they should not be used in the clinical setting without formal neuropsychological testing. However, because of the functional impairment associated with HAD, it is usually possible to apply this term to the severe form. The two milder forms of HAND require this testing for characterization, and, in particular, ANI cannot be diagnosed without formal testing.
HAD has also been previously referred to as AIDS dementia complex, HIV encephalitis, or HIV encephalopathy, all terms that referred to a circumscribed, often subacute syndrome of progressive cognitive and motor dysfunction. (See 'HIV-associated dementia' below.)
PATHOPHYSIOLOGY — HIV disseminates to the central nervous system (CNS) during the initial days of systemic infection and can be detected in the cerebrospinal fluid (CSF) of most untreated patients thereafter [6-11]. However, the character of CSF infection changes over the course of infection and disease evolution. Initially, CSF viruses are genetically identical to those in blood and likely originate from trafficking CD4 cells. Later, CNS infection can become "compartmentalized," with the virus evolving independently from the virus found in blood. Additionally, the cell tropism of the CNS virus may change to become largely macrophage-tropic (M-tropic), in contrast to blood virus which characteristically maintains tropism for T-lymphocytes.
Whether viruses with M-tropism originate within the CNS or are introduced by infected monocytes is uncertain. However, macrophages and microglia are clearly critical to the switch from seemingly benign meningeal infection involving mainly T-lymphocytes to a more invasive encephalitis. Perivascular macrophages and related cells sustain compartmentalized brain infection and, whether infected or not, serve as important sources of the toxic signaling pathways involved in brain dysfunction that underlie HIV-associated dementia (HAD) and perhaps milder forms of HIV-neurocognitive disorders .
While HIV also appears to infect astrocytes [13-15], this is usually nonproductive (ie, does not propagate infection), and its pathogenic significance remains uncertain. There is little evidence that HIV infects neurons or oligodendrocytes. Thus, alteration of the metabolism or death of such cells occurs by "indirect" mechanisms, through the aforementioned toxic signaling pathways, which likely involve both viral and cellular molecules .
Autopsy studies of AIDS patients with HAD show characteristic white matter pallor, microglial nodules, multinucleated giant cells, and perivascular infiltrates [17-19]. Basal ganglia and nigrostriatal structures can be affected early in the course of the dementia, with subsequent diffuse neuronal loss resulting in up to 40 percent reduction in frontal and temporal neurons. More subtle structural brain changes (eg, decreased cortical grey matter volume) may be detected even within the first year of HIV infection in the absence of overt encephalitis more clearly associated with HAD . However, there are no specific pathologic findings associated with milder forms of HAND (ie, minor neurocognitive disorder [MND] and asymptomatic neurocognitive impairment [ANI]).
Although antiretroviral therapy (ART) reduces HIV RNA in CSF, a substantial proportion of patients continue to show biomarker evidence of mild immune activation within the CNS even after years of durable viral suppression . The pathophysiologic mechanisms that drive this persistent inflammatory response are unknown, although persistent CNS infection below levels detected in CSF is one possible explanation [22-27].
Other comorbidities that are common in patients with HIV may also play a pathogenic role in the development of neurocognitive impairment. (See 'Comorbidities' below.)
Prevalence in the ART era — The widespread use of suppressive combination antiretroviral therapy (ART) has been associated with a marked decrease in the incidence of more severe neurocognitive deficits (ie, HIV-associated dementia [HAD]) . Data from 15,380 patients with HIV followed in the CASCADE cohort (Concerted Action on Seroconversion to AIDS and Death in Europe) demonstrated a decrease in the incidence of HAD from 6.49 per 1000 person-years in the pre-ART era to 0.66 per 1000 person-years by 2003 to 2006 . Similarly, a Danish population study reported that the incidence of severe neurological deficits in those with HIV infection was approaching that of the uninfected population .
In contrast to the major impact of ART on the incidence of HAD, a number of reports document a continued, substantial prevalence of milder impairment on testing in the setting of HIV infection (ranging from 20 to 69 percent in various series), even among patients with viral suppression [31-38]. In a study of 1521 patients with HIV from the eras before and after combination ART, neurocognitive impairment of any type was seen slightly more frequently in the post-ART compared with pre-ART cohorts (40 versus 33 percent, respectively) . In a separate analysis of the same post-ART cohort, the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, asymptomatic neurocognitive impairment (ANI) was most common, occurring in 33 percent, with mild neurocognitive disorder in 12 percent and HAD in only 2 percent of 1316 patients with HIV (the majority were on ART) .
The pattern of neuropsychological impairment seen in patients with HIV may also be affected by the use of ART. Whereas early reports of HAD emphasized the "subcortical" character of the dementia associated with HIV, with prominent slowing of processing and difficulty with attention and concentration, more recent observations have suggested a more "cortical" pattern of deficits .
A critical issue is whether milder cognitive impairment in virally suppressed patients is a residual effect of earlier, possibly subclinical brain injury that developed before treatment was started or whether brain injury can continue despite effective viral suppression. This issue is not yet fully resolved. Additionally, the frequency or degree to which the cognitive impairments in treated patients can be attributed to HIV infection itself is unclear  (see 'Comorbidities' below). Finally, there is concern that ART itself may have chronic toxic effects on the brain and contribute to the impairments in test performance . A study that followed a subset of patients from the CHARTER cohort with repeated neuropsychological testing over a mean of three years noted a stable neurocognitive status in 61 percent, improvement in 17 percent, and worsening in 23 percent . The factors associated with neurocognitive deterioration were complex and related to HIV disease and treatment status, but also involved other comorbid conditions.
Compared with individuals without HIV — Neurocognitive deficits are reported to be more common in individuals with HIV, including those using or not using ART, than in those without HIV in many [39,43,44], but not all [31,45], studies. One large study compared the prevalence of neurocognitive impairment as measured by comprehensive neuropsychological testing among several cohorts of patients with HIV (n = 1521) and patients without HIV (n = 273) from the eras before and after the introduction of combination ART (1988 to 1995 and 1999 to 2004, respectively) . The prevalence of any impairment was 16 to 19 percent among patients without HIV, but ranged from 25 to 52 percent among individuals with HIV, depending on the era (pre- or post-ART) and disease state. By contrast, in a subsequent study of 200 patients with HIV, among whom the median CD4 cell count was 546 cells/microL and HIV viral suppression was achieved in 55 percent, the rate of cognitive impairment was comparable to that observed in 50 controls without HIV . Similarly, in a study of over 1000 women, the effect of HIV status on cognition was less than that of years of education, age, race, income, and reading level .
Risk factors — Risk factors for the development of HIV-associated neurocognitive disorders (HAND) include HIV disease factors, other comorbidities, and possibly host genetic factors.
HIV disease factors — In several studies, lower nadir CD4 cell count has been associated with an increased risk of neurocognitive impairment among patients with HIV on ART [33,35,47]. In the CASCADE cohort of 15,380 patients with HIV followed longitudinally, risk factors for the development of HAD specifically included lower CD4 cell counts, older age at seroconversion, duration of HIV infection, and the presence of a prior AIDS-defining diagnosis . A period of severe immunosuppression appears to confer a long-lasting impact on neuropsychiatric performance regardless of subsequent viral suppression and immune reconstitution.
The underlying reasons for this are not known. There is possibly a higher incidence of HIV-associated brain injury in those with more advanced immunosuppression, which leaves residual impairment and a legacy of diminished "brain reserve" . Alternatively, advanced infection and immune injury may initiate a neuropathic process that continues even after treatment and CD4 cell restoration, regardless of ongoing viral replication or gene expression within the CNS. Evolution of compartmentalized infection with macrophage tropism, which is more common in advanced infection, may predispose to persistent CNS infection .
Comorbidities — Adults older than 50 years of age with HIV have an increased prevalence of neurocognitive deficits and dementia compared with patients younger than 40 years [49-51]. However, whether increased age affects cognitive function in patients with HIV to a greater extent than in patients without HIV is unclear. A 12-year longitudinal study of 402 patients with HIV found that comorbidities such as diabetes, hypertension, chronic pulmonary disease, frailty, neuropathic pain, depression, and lifetime history of cannabis use disorder contributed to declining cognitive status while the effects of aging and HIV status failed to predict decline . In another study, age greater than 50 years was associated with similarly decreased performance on neuropsychological testing among 115 individuals with HIV and 30 without . (See "HIV infection in older adults".)
In an aging HIV population, Alzheimer disease, the most common age-associated degenerative brain disease, is increasingly reported. Emerging therapeutics specific to Alzheimer disease make it critical that this diagnosis be considered regardless of HIV status. Indeed, since HAND is most often relatively static, a subacutely progressive cognitive decline is more likely to be a comorbid condition like Alzheimer disease and, thus, deserves appropriate evaluation and treatment (see "Clinical features and diagnosis of Alzheimer disease", section on 'Evaluation'). Patients with HIV have not been shown to have a higher incidence of Alzheimer disease, and the cerebrospinal fluid (CSF) and imaging findings characteristic of Alzheimer disease are not found in HAD patients [53-55].
Other general comorbidities that have been associated with HAND include anemia, vascular disease, and metabolic abnormalities (including increased waist circumference and insulin resistance), particularly in older adults [56-62]. Traditional cardiovascular risk factors are associated with a higher risk for dementia in the general population and in patients with HIV and are more strongly associated with neurocognitive impairments than are HIV risk factors, such as CD4 cell count or viral load .
Coinfection with hepatitis C virus (HCV) has also been identified as a possible, but not universally identified , risk factor for greater neurocognitive deficits in the setting of HIV infection [65-67]. It has been hypothesized that HCV could have direct neurotoxic effects. As an example, HCV RNA as well as nonstructural and core proteins have been detected in CSF and brain tissue; HCV may traffic into the CNS via macrophages and infect microglia and astrocytes, and HCV core protein may cause neuronal damage through the production of proinflammatory cytokines [68-73].
Prior infection with Toxoplasma has also been associated with neurocognitive deficits .
Host genetic factors — Whether there are associations between specific genetic factors and HAND is uncertain, and data are mixed. Polymorphisms in several genes, including those encoding apolipoprotein E4, the chemokine receptor CCR2, and monocyte chemoattractant protein-1, have been associated with the presence or development of HAD [75-77]. However, a genome-wide association study that involved 1287 patients from the Multicenter AIDS Cohort Study did not detect an association between those or any other polymorphisms and HAND or HAD . Other studies evaluating apolipoprotein E4 genotype specifically have also not found an association with HAND [79,80].
Spectrum of findings by ART status — Antiretroviral treatment (ART) status impacts the presentation of HIV-associated neurocognitive disorders (HAND). The most severe form, HIV-associated dementia (HAD), typically occurs in patients with advanced, untreated HIV infection, with CD4 cell counts <200 cells/microL and high plasma viral levels. This is much less likely to occur in patients on ART, among whom it is more common to find milder deficits that are residual or develop more indolently. Rarely, successfully treated patients can present with a "CNS escape syndrome," in which deficits as severe and subacutely progressive as those seen in HAD develop with detectable HIV in the CSF despite plasma viral suppression on antiretroviral therapy (ART).
The following sections discuss the clinical findings of these syndromes in more detail.
HIV-associated dementia — HIV-associated dementia (HAD), in its classic form, is primarily characterized by subcortical dysfunction, with attention-concentration impairment, depressive symptoms, and impaired psychomotor speed and precision; this is consistent with pathology suggesting that HIV affects predominantly subcortical and deep grey matter structures [81,82]. It occurs predominantly in untreated patients with advanced HIV infection. The onset of the impairments is typically subacute. Some emphasize that the deficits associated with HAD may wax and wane over time , unlike the progressive neurological decline seen in other neurodegenerative diseases, such as Alzheimer disease.
Cognitive deficits — Prominent features of HAD include substantial memory deficits, impaired executive functioning, poor attention and concentration, mental slowing, and apathy [84,85]. Typically, cognitive deficits are evident and clearly impair functional status. Patients with HAD are often too slow and forgetful to work or prepare meals and can get lost while walking or driving . Judgement, however, frequently remains relatively intact.
The absence of higher cortical dysfunction including aphasia, agnosia, and apraxia help distinguish HAD from classical "cortical" dementia, such as Alzheimer disease. However, the distinction between cortical and subcortical dementias can be blurred as a patient with late and severe HAD may have dysfunction in both language and praxis.
Behavioral and mood changes — Behavioral changes in HAD are commonly characterized by apathy and lack of motivation (abulia) . Patients with HAD may also display irritable mood, sleeplessness, weight loss, restlessness, and anxiety. Although these changes may be attributed to depression, patients with HAD are not typically dysphoric, and lack crying spells or reported sadness.
However, mood-changes associated with HAD may progress to psychosis with paranoid ideas and hallucinations. Furthermore, a small proportion of patients with HAD may develop mania. (See "Depression, mania, and schizophrenia in HIV-infected patients".)
Motor symptoms and signs — Most patients with frank HAD exhibit slowness of movement (tested by rapid finger opposition or toe tapping) and gait (assessed by a timed gait test). In addition, patients can experience impaired saccadic eye movements, marked difficulty with smooth limb movement (especially in the lower extremities), dysdiadochokinesia, hyperreflexia, and frontal release signs such as grasp, root, snout, and glabellar reflexes.
Imaging findings — In patients with HAD, cerebral atrophy is typically evident on brain imaging [87,88]. It affects mainly the basal ganglia (particularly the caudate) and white matter, but also cortical regions. On magnetic resonance imaging (MRI), T2-weighted images also demonstrate diffuse or patchy white matter hyperintensity (image 1), which may correlate neuropathologically with high levels of HIV in those regions of the brain . Some of these findings are common in older patients with and without cognitive impairment. (See "Evaluation of cognitive impairment and dementia", section on 'Findings'.)
More advanced neuroimaging techniques, such as magnetic resonance spectroscopy, functional MRI, and positron emission tomography (PET), also demonstrate abnormalities in the subcortical regions, in some cases even in patients with more mild neurocognitive deficits [53,87,90-93].
CSF findings — In observational studies, patients with HAD who are not on ART often have elevated cerebrospinal fluid (CSF) protein and elevated HIV levels in the CSF. Lymphocytic pleocytosis in the CSF is variable. However, these findings are not specific to patients with HAD and are observed in many untreated patients with HIV without neurocognitive impairment. As an example, in a cross-sectional study that included 46 untreated patients with HIV, the mean CSF viral level in this population was 3.6 log copies/mL, and the CSF white blood cell count ranged from 0 to 11 cells/microL . There was no association between the presence of neurologic deficits and the CSF HIV level. However, in our experience and some observational studies, a CSF viral load that is equal to or greater than the plasma viral load is associated with HAD [95,96].
Additionally, in untreated patients with HAD, the drug resistance profile of the CSF virus may differ from that of the plasma virus, although there has been no direct evidence that such differences are clinically important .
Of note, testing of HIV viral levels and genotype in the CSF is not widely available, is not diagnostically informative in most cases of HAD, and is not routinely performed. (See 'Severe deficits, not on ART' below.)
Milder neurocognitive deficits — In the full spectrum of HAND, the cognitive deficits reported are more diverse and variable than those initially reported in HAD . Successfully treated patients typically present with milder cognitive impairments.
The main cognitive deficits reported in milder presentations of HAND include difficulty with attention and working memory, executive functioning (eg, complex problem solving), and speed of informational processing [3,87]. The majority of patients with HIV who have evidence of such neurocognitive defects on testing actually have no evident symptoms or impairment in functioning (ie, asymptomatic neurocognitive impairment [ANI]). For those with mild symptomatic disease (ie, mild neurocognitive disorder [MND]), these deficits may manifest as difficulty with reading, performing complex tasks, or maintaining concentration in conversations or activities. Such symptoms may be subtle and overlooked or attributed to fatigue or other illness. Early language deficits are uncommon .
The onset and time course of cognitive deficits in milder forms of HAND is generally more indolent than the typically subacute presentation of HAD, and deficits may remain stable or seemingly unchanged for years .
Motor problems are not common in milder cases of HAND. Early motor symptoms can include unsteady gait, slowed or clumsy fine hand coordination (eg, a change in handwriting), or tremor . Individuals may notice difficulties in performing activities that depend on fine coordination or rapid movements. On exam, rapid movement and gait may be slowed.
Affective disturbance is frequently associated with HAND . Early manifestations may include apathy, lethargy, loss of sexual drive, and diminished emotional responsiveness.
Patients with mild neurocognitive deficits typically have normal brain imaging; findings similar to those of HAD, with cerebral atrophy or white matter abnormalities, can rarely be seen. Thus, imaging findings cannot distinguish these patients. Likewise, routine CSF studies do not distinguish them from patients with HIV without neurocognitive impairment. (See 'Imaging findings' above and 'CSF findings' above.)
CNS viral escape syndrome — Several studies have described an uncommon condition in ART-treated patients who present with severe new-onset neurological deficits and exhibit "CNS viral escape," in which there is evidence of CNS HIV replication in the CSF despite low viral levels or viral suppression in the plasma [101-104]. In most, there is also documented drug resistance in the CSF virus.
As examples, two retrospective studies described 10 and 11 patients, respectively, who developed new neurocognitive symptoms without alternate diagnosis and had detectable CSF HIV RNA (range 558 to 12885 and 134 to 9056 copies/mL) despite stable ART and virologic control in the plasma (at least <500 copies/mL, most had <50 copies/mL) [101,103]. The clinical presentations were heterogeneous, with some having a HAD-like presentation and others with more focal neurological manifestations accompanied by multifocal MRI lesions. CSF pleocytosis was present in most. A predominance of CD8 pleocytosis has also been described in a few patients with potential CNS escape syndrome . Viral drug resistance mutations were identified in the majority of cases in which genotyping of the CSF virus was performed, suggesting "compartmentalization" of resistant virus within the CSF. In this isolated clinical setting, evaluating the CSF for HIV RNA level and genotype can be valuable to diagnose CNS viral escape and guide antiretroviral regimen changes. (See 'Severe deficits, on ART' below.)
This syndrome of symptomatic CNS escape in a previously asymptomatic or minimally symptomatic patient, as described in these cases, is rare. It should be clearly distinguished from asymptomatic, minor elevations of CSF HIV RNA levels despite plasma viral suppression that have been reported in several studies [105,106]. As an example, in a study of 1264 patients with viral suppression on ART who were followed for a median of 30 months and underwent lumbar puncture testing, detectable CSF HIV RNA was observed in 55 patients (7.1 percent) . However, there was no association with detectable CSF HIV RNA and neurocognitive performance. Previous smaller retrospective series, generally consisting of fewer than 100 patients with plasma virologic suppression, described detectable CNS HIV RNA >50 copies/mL in 5 to 23 percent [102,103,107]. There were no clear associations with detectable CSF HIV and neurocognitive function in those studies either, although there was an association with mild elevations of CSF neopterin, a marker of macrophage activation.
Immune reconstitution inflammatory syndrome — Very rarely, new-onset severe neurological symptoms may represent immune reconstitution inflammatory syndrome (IRIS) related to HIV CNS infection itself. This can present with severe CD8 cell encephalitis, with diffuse white and gray matter abnormalities on MRI and CD8 cell pleocytosis in the CSF [104,108].
SCREENING FOR DEFICITS — For patients who do not report or have evident neurocognitive deficits, screening may be able to identify mild deficits. However, the value of broadly screening patients with HIV for neurocognitive impairment is controversial. Arguments in its favor include the potential value of identifying deficits that might affect medication adherence. However, the speculation that patients identified by neurocognitive impairment screening might benefit from use of antiretroviral regimens that optimally penetrate the central nervous system has not been supported by clinical trial evidence . Other arguments against the practice include its consumption of precious resources in the busy clinical setting. Given limited resources and the absence of clear evidence to support changing management on the basis of mild deficits, we do not routinely screen for such deficits. However, when resources allow, screening is reasonable to establish a baseline assessment of a patient’s neurocognitive function in case there is subsequent deterioration.
Screening for deficits can be done by inquiring about symptoms and/or performing brief neurocognitive tests in the clinic. Some experts have suggested the following series of questions [32,110]:
●Do you experience frequent memory loss (eg, do you forget the occurrence of special events, even the more recent ones, appointments, etc.)?
●Do you feel that you are slower when reasoning, planning activities, or solving problems?
●Do you have difficulties paying attention (eg, to a conversation, a book, or a movie)?
For each question, patients can answer "never," "hardly ever," or "yes, definitely." A "yes, definitely" answer to any of the three questions can prompt further evaluation. While a symptom-based approach would overlook the subset of patients with asymptomatic neurocognitive impairment (ANI), it may be the easiest for clinicians to implement.
Additional screening tools for neurocognitive function have been evaluated in patients with HIV. The Montreal Cognitive Assessment (MoCA) can be performed in the office in less than 10 minutes and may be the most practical bedside test for periodic assessment [111-115]. The CogState-based assessment has reasonably good performance but is not publicly available [116-119]. The HIV Dementia Scale and the International Dementia Scale may not be highly sensitive for mild cognitive impairments [120-122]. Additionally, the mini-mental status examination does not thoroughly test executive function and is an insensitive tool for detection of HAND [120,123].
Some experts have recommended a screening interval of 6 to 24 months, depending on the presence of risk factors for HAND (see 'Risk factors' above) [124,125]. As an alternative, an approach that involves regularly screening every patient presenting for HIV care (such as having them complete a self-report screen in the waiting room), if feasible, allows the clinician to focus on determining next steps for those who screen positive instead of trying to decide whom and how often to screen.
EVALUATION — The possibility of an HIV-associated neurocognitive disorder (HAND) is suspected in patients with HIV who present with symptomatic cognitive deficits or are found to have deficits on screening tests. The diagnosis requires evaluation for pre-existing or alternative disorders that could account for the observed cognitive impairment, including other neurologic or neurodegenerative disorders, primary psychiatric disorders (eg, major depression, schizophrenia), severe substance use disorders, and complications of polypharmacy. Depending on the presentation, excluding alternate conditions may involve a number of laboratory tests and potentially neuroimaging (MRI) followed by cerebrospinal fluid (CSF) analysis.
Because of the frequency with which comorbid conditions exist in those with HAND, the assessment for persistent cognitive deficits should be made when pre-existing conditions are under optimal control. The differential diagnosis of cognitive impairment in patients with HIV is discussed in further detail below. (See 'Differential diagnosis' below.)
Initial assessment — The goal of the initial assessment is to characterize the degree, time course, and functional impact of any cognitive deficits, establish the stage of HIV disease and treatment status, and start to evaluate for other potential causes of cognitive symptoms.
Characterization of the cognitive impairment — Characterizing cognitive deficits begins with a history from the patient and, if possible, family members or someone who knows the patient well. History should assess the domains affected by the cognitive impairment (eg, learning and memory, language, executive function), any accompanying behavioral or personality changes, the time course of symptoms, and particularly, the degree that any of these difficulties lead to functional impairment in common activities and in work. (See 'Cognitive deficits' above and 'Milder neurocognitive deficits' above.)
For patients who present with subacute or progressive symptoms typical of HIV-associated dementia (HAD), cognitive impairment that leads to functional deterioration is usually evident on such history and confirmed on bedside cognitive testing (see "Evaluation of cognitive impairment and dementia", section on 'Cognitive testing'). In such cases, formal neuropsychological testing is superfluous.
When the history is less clear and suggests a more static impairment or if impairments are only detected on screening tests, formal neuropsychological testing can be useful for establishing both the magnitude and profile of impairment. If performed, neuropsychological testing usually evaluates at least five of the following cognitive abilities :
●Speed of informational processing
Additional history and physical exam — In addition to elucidating the extent and impact of cognitive impairment, history should evaluate for other potential causes of neurological impairment, including prior neurologic insults (eg, traumatic brain injury, vascular insults, other CNS infections) and major depressive, anxiety, and substance use disorders. A prevalent but often unappreciated issue is polypharmacy, which can result in cognitive impairment (table 1); often, simplification of prescribed therapies, particularly sedating agents, antidepressants, and anticholinergic drugs, is helpful for cognition [126,127]. (See "Evaluation of cognitive impairment and dementia", section on 'History'.)
Both a general physical exam to evaluate for signs of alternate causes of cognitive impairment (eg, physical findings suggestive of thyroid or liver disease) and a dedicated neurologic exam should be performed. Findings of psychomotor slowness and hyperreflexia are suggestive of HAD. Other neurological findings could be suggestive of other causes of cognitive decline, such as rigidity and tremors in Parkinson's disease and a focal deficit in stroke or other focal brain lesions. Patients with HAND are characteristically alert; altered consciousness would be suggestive of alternative conditions. (See 'Cognitive deficits' above and 'Behavioral and mood changes' above and 'Motor symptoms and signs' above.)
Laboratory testing — Assessment of the stage of HIV infection (ie, with CD4 cell count and plasma viral load) is an important element in the evaluation of HAND. The CD4 cell count informs the likelihood that progressive cognitive impairment is due to HAD, which occurs predominantly (though not exclusively) at counts <200 cells/microL in untreated patients. It also informs the differential diagnosis, as opportunistic infections that could cause cognitive impairment are more likely at lower CD4 cell counts. (See 'Differential diagnosis' below.)
Other laboratory testing that should be performed to evaluate for other causes of cognitive declines include a complete metabolic panel that includes liver function tests and glucose, vitamin B12 level, folate level, thyroid stimulating hormone, and serologic testing for syphilis and hepatitis C virus. (See "Evaluation of cognitive impairment and dementia", section on 'Laboratory testing' and "Neurosyphilis", section on 'Diagnosis' and "Screening and diagnosis of chronic hepatitis C virus infection", section on 'Diagnosis'.)
Further evaluation — The focus of further diagnostic evaluation depends on the severity of the presentation and whether the patient is on ART, as outlined below.
Severe deficits, not on ART — HAD develops almost exclusively in untreated patients with HIV, particularly when the CD4 cell count is <200 cells/microL. Thus, additional diagnostic evaluation usually focuses on ruling out other opportunistic processes that such patients are at risk for and that can present with neurocognitive decline.
Neuroimaging with magnetic resonance imaging (MRI) is typically performed first to evaluate for other neurological disorders (infection, neoplasm, infarction, leukoencephalopathy) that can occur in untreated patients with HIV. Although these disorders are often suspected on the basis of history or exam, these disorders may sometimes present with predominantly cognitive impairment and no other localizing findings (see "Approach to the patient with HIV and central nervous system lesions"). Diffuse cerebral atrophy and subcortical or periventricular white-matter changes (hypodense on computed tomography and bright on T2-weighted MRI) are consistent with HAD, but are neither sensitive nor specific. (See 'Imaging findings' above.)
Similarly, performance of other tests, including lumbar puncture for CSF evaluation, is done mainly to assess for other possible diagnoses. Such testing is guided by the clinical presentation and imaging findings:
●In patients with focal clinical or imaging features, toxoplasma blood serology (to assess susceptibility), CSF JC virus PCR (for diagnosis of progressive multifocal leukoencephalopathy), CSF EBV PCR (for primary CNS lymphoma), and CSF CMV PCR may be useful. (See "Approach to the patient with HIV and central nervous system lesions", section on 'Lumbar puncture'.)
●In patients with a nonfocal presentation, CSF syphilis tests, CSF cryptococcal antigen, and CSF CMV PCR are usually assessed.
CSF findings in HAD can include elevated CSF protein and elevated ratio of CSF to blood albumin, but these routine assessments do not distinguish these patients from those without HAD. CSF HIV RNA levels in HAD also do not distinguish HAD patients; however, a CSF HIV RNA level that is equal to or greater than the plasma level is suggestive of HAD. (See 'CSF findings' above.)
Severe deficits, on ART — In patients who are on ART, particularly if viremia is suppressed and the CD4 cell count has rebounded, neurological signs and symptoms are more likely due to non-HIV-related processes, such as cerebrovascular or neurodegenerative disease. Thus, the evaluation of such patients focuses on other non-HIV-related causes of neurocognitive decline, as would be done for uninfected individuals with cognitive decline. MRI and lumbar puncture are typically included in the evaluation. This is discussed in detail elsewhere. (See "Early-onset dementia in adults", section on 'Initial evaluation' and "Early-onset dementia in adults", section on 'Additional testing'.).
If no other causes are identified, there is the rare possibility that CNS escape syndrome underlies the cognitive decline. If this is suspected, CSF HIV RNA should also be evaluated, as CNS escape is characterized by detectable CSF HIV RNA despite plasma viral suppression. CSF pleocytosis in this setting may also be suggestive of CSF escape, since a normal CSF cell count is typically seen in patients on ART. Additionally, genotypic testing of the CSF virus can potentially help guide management in this limited setting. CSF HIV viral load testing is not readily available to all clinicians since it is not a generally approved laboratory test. If the clinical laboratory will not perform HIV viral load or genotypic testing on CSF, CSF can be frozen and sent to a research or commercial laboratory that does perform those assays. (See "HIV-associated neurocognitive disorders: Management", section on 'Evaluating CSF for HIV'.)
Even more rarely, new-onset severe neurological symptoms in patients on ART can represent immune reconstitution inflammatory syndrome. This is suggested by diffuse white and gray matter abnormalities on MRI and, if performed, CD8 cell pleocytosis in the CSF. (See 'Immune reconstitution inflammatory syndrome' above.)
Mild deficits — Whether additional neurological evaluation is warranted for patients with mild deficits depends on the severity of symptoms and signs, the presence of alternate explanations, and whether the impairment is of recent onset or longstanding. In general, for patients with very mild symptoms, without functional impairment in work or daily life, and without recent onset or progression, it is reasonable to follow symptoms and signs without further dedicated neurological evaluation. In those with more prominent symptoms, functional impairment, or recent onset of deficits, additional evaluation is similar to that for patients with more severe deficits, with MRI and, in some instances, lumbar puncture for CSF evaluation. (See 'Severe deficits, not on ART' above and 'Severe deficits, on ART' above.)
DIAGNOSIS — The diagnosis of an HIV-associated neurocognitive disorder (HAND) is made in a patient with HIV who has neurocognitive impairment (particularly if it is new onset or there is suggestion of progression) by history and exam or by detection of cognitive impairment through neuropsychological testing, and whose deficits cannot be fully explained by alternate conditions or pre-existing causes after thorough evaluation. (See 'Evaluation' above.)
Strictly speaking, classification of deficits as HIV-associated dementia (HAD), minor neurocognitive disorder (MND), or asymptomatic neurocognitive impairment (ANI) requires formal neuropsychological testing. However, comprehensive neuropsychological testing is costly, requires highly skilled professionals for administration and interpretation, and may not be readily accessible. From a practical standpoint, HAD can often be diagnosed in the absence of formal neuropsychological testing on the basis of more severe cognitive and motor dysfunction that substantially impairs functioning, and MND on the basis of symptoms or signs of milder cognitive decline that impair functioning. ANI, by definition, can only be diagnosed by formal testing. (See 'Terminology' above.)
The rare CNS viral escape syndrome can be diagnosed in patients who have virologic suppression on antiretroviral therapy (ART) and yet develop subacute progressive cognitive deficits that are unexplained by other conditions and accompanied by detectable CSF HIV RNA levels.
DIFFERENTIAL DIAGNOSIS — Cognitive impairment in patients with HIV may be a presenting symptom of numerous other disease processes. The differential diagnosis depends on the degree of immunosuppression and whether the patient is off or on antiretroviral agents. Among these are the following:
●Central nervous system (CNS) infections – In patients with CD4 cell counts <200 cells/microL, other CNS infections that can cause cognitive deficits are toxoplasmosis and progressive multifocal leukoencephalopathy (PML, caused by JC virus infection), both of which usually present with focal deficits and can be detected by magnetic resonance imaging (MRI). Cryptococcal meningitis is also relatively common in this setting, is usually nonfocal with headache and altered mentation, and is diagnosed by cryptococcal antigen or growth in the CSF. CMV encephalitis also can occur in these patients and may be nonfocal or occasionally include focal features; it is diagnosed by CSF CMV PCR testing. In patients with any CD4 cell count, neurosyphilis is an important consideration and can be differentiated by CSF testing for syphilis. (See "Toxoplasmosis in patients with HIV" and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Syphilis in patients with HIV", section on 'Who should be evaluated for neurosyphilis'.)
●CNS malignancies (eg, primary CNS lymphoma) – Primary CNS lymphoma associated with EBV infection presents much like toxoplasmosis and PML with focal manifestation and a mass lesion on imaging, although depending on the location of the mass, it may present only with changes in cognition and behavior. Imaging findings usually distinguish it from HIV-associated dementia (HAD). (See "HIV-related lymphomas: Primary central nervous system lymphoma".)
●Other dementia syndromes – With longer survival, patients with well-controlled HIV infection on antiretroviral treatment may develop other dementing illnesses. Alzheimer disease is usually distinguished by early and relatively isolated memory loss followed by other "cortical" abnormalities, such as aphasia and apraxia. CSF biomarkers of Alzheimer disease (t- and p-tau and amyloid beta 1-42) or amyloid positron emission tomographic (PET) scanning can be used to establish the Alzheimer diagnosis. Early recognition of these biomarkers can enhance the diagnosis and should be checked in patients with HIV and severe cognitive decline . Given emerging options for treatment of Alzheimer disease, consideration of this diagnosis is of increasing importance [129,130]. Vascular dementia can present much like HAD with subcortical features but is usually distinguished by a background of hypertension, episodes of lacunar stroke, and distinct MRI findings. (See "Evaluation of cognitive impairment and dementia", section on 'Dementia syndromes'.)
●Nutritional deficiencies (eg, vitamin B12 deficiency) – Cognitive impairment secondary to vitamin B12 deficiency can be accompanied by other neurologic symptoms, including paresthesias and sensory deficits. Vitamin B12 deficiency is not uncommon in the setting of HIV infection and can be easily identified through laboratory testing. (See "Treatment of vitamin B12 and folate deficiencies".)
●Endocrine disorders (eg, thyroid dysfunction and adrenal insufficiency) – Hormonal aberrations are also frequent findings in HIV infection and can lead to confusion and other cognitive deficits. These can also be easily identified through laboratory testing. While gonadal insufficiency is a common finding in the aging HIV population, the impact of that on cognition is not well established. (See "Clinical manifestations of hypothyroidism" and "Clinical manifestations of adrenal insufficiency in adults" and "Hypogonadism in males with HIV".)
●Severe substance use or psychiatric disorder – These are frequent comorbidities and confounders in the diagnosis of HAND and are often evident on detailed history. (See "Substance abuse and addiction in HIV-infected patients" and "Depression, mania, and schizophrenia in HIV-infected patients".)
●Delirium – Patients with delirium have a reduced ability to sustain, focus, or shift attention, which occurs over a short period of time. The presence of a disturbance in consciousness is a key factor in distinguishing delirium from HAND, in which the patient has a clear level of consciousness. (See "Overview of the neuropsychiatric aspects of HIV infection and AIDS", section on 'Delirium'.)
●Polypharmacy – Various drugs, in particular anticholinergic agents, opioids, and anxiolytics, can negatively impact cognition (table 1) [126,127]. Discontinuing some of these medications can potentially improve associated cognitive impairment.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary care of adults with HIV".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: HIV-associated neurocognitive disorders (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Terminology – Changes in memory, concentration, attention, and motor skills are common in patients with HIV. When these occur without an evident cause other than HIV infection, such impairments have been collectively classified as HIV-associated neurocognitive disorders (HAND). Depending on the severity and impact on daily functioning, cognitive deficits can be classified into three conditions: asymptomatic neurocognitive impairment (ANI), HIV-associated mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). (See 'Introduction' above and 'Terminology' above.)
●Epidemiology – The widespread use of combination antiretroviral therapy (ART) has been associated with a decrease in the prevalence of more severe neurocognitive deficits (ie, HAD), but milder cognitive deficits without alternative explanation remain common in the setting of HIV infection, even among patients with viral suppression. Risk factors for HAND include low nadir CD4 cell count, age, and other comorbidities, such as cardiovascular and metabolic disease. (See 'Epidemiology' above.)
•HIV-associated dementia – HAD occurs predominantly in untreated patients with advanced HIV infection. In its classic form, it is primarily characterized by subcortical dysfunction, with attention-concentration impairment, depressive symptoms, and impaired psychomotor speed and precision. The onset of the impairments is typically subacute. Cerebral atrophy is typically evident on brain imaging, which can also demonstrate diffuse or patchy white matter hyperintensity. (See 'HIV-associated dementia' above.)
•Milder neurocognitive deficits – The main cognitive deficits reported in milder presentations of HAND include difficulty with attention and working memory, executive functioning, and speed of informational processing. The onset and time course is generally more indolent than the typically subacute presentation of HAD, and deficits may remain stable or seemingly unchanged for years. There are no specific imaging findings. (See 'Milder neurocognitive deficits' above.)
●Screening for deficits – The value of broadly screening patients with HIV for neurocognitive impairment is controversial. Given limited resources and the absence of clear evidence to support changing management on the basis of mild deficits, we do not routinely screen for such deficits. However, when resources allow, screening is reasonable to establish a baseline assessment of a patient’s neurocognitive function in case there is subsequent deterioration. (See 'Screening for deficits' above.)
•Initial assessment – The possibility of HAND is suspected in patients with HIV who present with symptomatic cognitive deficits or are found to have deficits on screening tests. The goal of the initial assessment is to characterize the degree, time course, and functional impact of any cognitive deficits, establish the stage of HIV disease and treatment status, and start to evaluate for other potential causes of cognitive symptoms, such as other neurologic or neurodegenerative disorders, primary psychiatric disorders, severe substance use disorders, and polypharmacy. (See 'Initial assessment' above and 'Differential diagnosis' above.)
•Further evaluation – The focus of further diagnostic evaluation depends on the severity of the presentation and whether the patient is on ART. For patients with very mild symptoms, without functional impairment in work or daily life, and without recent onset or progression, it is reasonable to follow symptoms and signs without further dedicated neurological evaluation. For patients with severe deficits, magnetic resonance imaging (MRI) and lumbar puncture for cerebrospinal fluid evaluation are generally performed to evaluated for other potential etiologies. (See 'Further evaluation' above and 'Differential diagnosis' above.)
●Diagnosis – The diagnosis of HAND is made in a patient with HIV who has neurocognitive impairment (particularly if it is new onset or there is suggestion of progression) by history and exam or by detection of cognitive impairment through neuropsychological testing, and whose deficits cannot be fully explained by alternate conditions or pre-existing causes after thorough evaluation. (See 'Diagnosis' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Richard Price, MD, Alexander Thompson, MD, MBA, MPH, Andrew Pieper, MD, PhD, and Glenn Treisman, MD, PhD, who contributed to an earlier version of this topic review.
UpToDate also gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.
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