Patients with Human immunodeficiency virus infection (HIV infection) have been noted to have various forms of neuropsychiatric illnesses. Notably, neuropsychiatric illnesses include symptoms of both cognitive disorders as well as mood and anxiety symptoms, which will be further discussed in the body of the article. In the past, before the advent of antiretroviral treatment, several neuropsychiatric disorders remained untreated, resulting in a large mortality rate. Most of these disorders stemmed from untreated infectious diseases secondary to AIDS (acquired immunodeficiency syndrome) like toxoplasmosis and encephalitis. The decline in neurocognitive disorders notably came hand in hand with the advent of HAART (highly active antiretroviral therapy). Combination treatment for HIV was developed around the year 1996, and since then, HIV related neuropsychiatric disorders started to show a decline.
The human immunodeficiency virus (HIV) directly crosses the blood-brain barrier during the acute phase of infection. However, it is during the chronic inflammation phase that cognitive changes are seen. Monocytes, macrophages, and white matter are all affected in the brain. HIV reproduces in the microglia, which are known as the brain's "immune cells." These changes are associated with clinical signs and symptoms of neurocognitive disorder seen with HIV disease.
The epidemiological study of HIV-associated dementia had started after the advent of antiretroviral (ARV) treatment after noticing that the virus causes cognitive impairments. This was a common occurrence and seen in about 40% of people dying with AIDS. Of note, the initial description was of a feature of ongoing neurocognitive impairment along with Parkinson like features. However, with the advent of cART (combination antiretroviral therapy) and increased longevity of persons infected with HIV, the ongoing cognitive impairments continued to be present for a long period of illness.
However, neurocognitive disorders have undergone a significant change, initially, in the late 1980s, the large body of neurocognitive disorders collectively was known as AIDS dementia complex given the degree of neurocognitive impairment seen.
The AIDS task force of the American Association of Neurology included minor cognitive-motor disease and HIV associated dementia, a term that came in the early 1990s. The variability of cognitive impairment was notable; hence an initial idea had been two categories.
A newer classification includes the Frascati Panel of 2006 for HIV-associated neurocognitive disorder, which includes asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). Some of the neurocognitive deficits include lack in processing, attention, concentration, memory, and abstraction. There were notably three categories that are now universally accepted as the classification of HIV associated dementia. These three categories are :
I. Asymptomatic neurocognitive impairment (ANI), which includes impairment in at least two cognitive domains, at least one standard deviation below the mean in testing and no impairment with daily functioning.
II. Mild neurocognitive disorder (MND) in which neuropsychological testing results as above with at least mild interference with daily functioning.
III. HIV-associated dementia (HAD), which is impairment in two cognitive domains(the five cognitive domains include attention/speed of information, working memory, verbal skills, executive functioning, and motor skills) and two standard deviations below in neuropsychological testing.
The above definitions apply to primary HIV-associated neurocognitive disorder (HAND), however secondary cognitive limitations due to ongoing infections, encephalitis, etc. may be seen.
In the United States, approximately 50% of persons with ongoing HIV infection were noted to have a cognitive impairment when studies were first conducted around multiple sites in the country. Again with the advent of antiretroviral therapy, the prevalence of HAND has shown a decline, especially in people who are on treatment consistently. HIV-associated dementia is currently seen in people that are seropositive and have CD4 counts that are below 200/mm3.
HIV crosses the blood-brain barrier and infiltrates the macrophages in the central nervous system. A virus-induced fusion of macrophages leads to the formation of giant cells and astrocytes activation and damage ( astrocytes are cells that provide metabolic support and detoxify neurons), which ultimately leads to neuronal damage in many parts of the brain. The damage is caused by verotoxins, including HIV proteins gp41, gp120, Tat, Vpr, Nef, and Rev. The subcortical structures are most affected like the limbic structures and basal ganglia. HIV infection also causes a breakdown of white matter and axonal damage. Ultimately, this leads to a decline in cognition and notably a decreased volume of the brain structures like basal ganglia and caudate nucleus, causing atrophy of the brain volume.
In the pre HAART era, when the incidence of HIV-associated dementia was considerably high, brain autopsies showed meningitis with low counts of lymphocytes and perivascular lymphocytic cuffing. The cells that are seen are generally CD 8 T- lymphocytes and CD 4 lymphocytes.
HIV enters the brain via HIV-infected lymphocytes and macrophages. In addition to the passage of cell-free virus into the brain and release of the virus from the infected endothelial cells. The virus replicates in these cells and infects the microglia, astrocytes, oligodendrocytes, and neurons. HIV infection in the CNS can be detected and monitored by cerebrospinal fluid (CSF) viral load measurements. Another pathological feature in HIV associated encephalitis is the presence of multinucleated giant cells, which was very prominent before the advent of antiretroviral drugs. Multiple studies established a positive correlation between CSF viral load and the extent of cognitive dysfunction.
While obtaining a history from patients with HIV infection, some risk factors need to be noted as well. These include having a low CD4 count and the amount of virus in the blood. HIV is a disease that causes overall immunodeficiency and puts individuals at risk for opportunistic infections. Often patients may carry comorbid Hepatitis B or Hepatitis C infection. Studies have shown that patients infected with Hepatitis C have a higher risk of developing cognitive impairment. Another risk factor includes concurrent substance use disorders. One particular drug that has been associated with neurocognitive impairment is methamphetamine use. The use of intravenous drugs in patients with HIV infection leads to further cognitive impairment. Data in the past showed that HIV infection and drug abuse, especially intravenous drug abuse, lead to overexpression of CD68 inflammatory markers and major histocompatibility complexes, which lead to further cognitive impairment.
Another important aspect while taking history in HIV patients is to recognize the clinical features of HIV-associated neurocognitive disorder, which is characterized by insidious onset and slow progression. If the onset is less than 4 weeks, consider alternative causes. At the time of clinical evaluation and testing, the patient must not be febrile, excessively tired, or sedated. Delay in diagnosis of HIV, initiation of HAART, and longer periods of low CD4 count are associated with a higher risk of cognitive impairment.
The earliest symptoms and signs are impairment in concentration, memory, and executive functioning. As the disease progresses, psychomotor retardation, depressive symptoms, irritability, and at times subclinical motor signs are observed. These motor signs include tremors, hyperreflexia, etc. Later on, clinical features evolve to overall global dementia, myelopathy, neuropathy, and even Parkinson like features.
The main tool for evaluation is neuropsychological testing. Some domains of neuropsychological testing that have shown impairment include episodic memory (learning and recall), executive functions, attention/working memory, information processing, verbal fluency, and fine motor skills. Some other aspects of neurocognitive testing include trail making test (to test executive functioning), use of a grooved keyboard (to test for psychomotor skills), digit span test (to determine for psychomotor speed, abstraction, memory, and attention) and also use of the Stroop test (test attention and processing speed).
Another form of evaluation is the use of imaging. In the pre-HIV era, imaging was significant for global brain atrophy. HIV related encephalitis can be evaluated with FLAIR imaging, which will show focal atrophy in the basal ganglia, thalamus, corpus callosum, and frontal lobes. Recently, 3D imaging has studied the patterns of brain atrophy to correlate with ongoing cognitive impairment. Specific areas included sensorimotor areas, parts of the corpus callosum, and parts of the frontal lobes. Many of the new imaging studies have compared infected individuals to normal same age controls. Hence, the correlation of cognitive decline in infected individuals and relevant brain areas is now well established.
A good screening tool is the International HIV Dementia Scale, which tests memory, motor speed, and psychomotor speed. The test includes:
1. Memory-registration is tested by giving a patient four words and asking them to repeat. Then the patient is requested to retain the words.
2. Motor speed is tested by having the patient tap the first two fingers of their non-dominant hand as quickly as possible. The number of taps in five seconds is counted.
3. The psychomotor speed is measured by having the patient use their non-dominant hand to do a series of tasks, for example, having the patient clench their fist, place the palm face down and then place it perpendicularly on the table. The speed and sequence are measured.
4. The patient is asked to recall the four words practiced earlier.
Another screening tool is the modified HIV scale, which tests immediate memory and delayed recall. Immediate and delayed memory is tested by asking patients to register four words and then asking them to repeat the words a few minutes later. Executive functioning is tested by copying a cube. Psychomotor speed is tested by asking the patient to write the alphabet in capital letters.
One study showed that clinically three simple questions might be a good screening tool for HIV associated Neurocognitive Disorder, these include asking whether a patient experiences memory loss, have difficulty paying attention, and if they feel slower while reasoning or doing complicated tasks. However, the mainstay for evaluation is still getting a good clinical history and collaborative information around the start of cognitive decline. It is highly recommended by the Mind Exchange Program, which is established by expert clinicians around the world.
Treatment with antiretroviral drugs (HAART) has shown improvement in cognitive function, including all cognitive domains. Also, the increase in CD4 count and the decrease in viral load are correlated with cognitive improvement. The other indicator of treatment success includes the CNS penetration abilities of antiretroviral drugs. The ability of the drug to cross the blood-brain barrier and achieve a high concentration in the cerebrovascular fluid is extremely important to lower the amount of viral load. Letendre S et al. studied the CNS penetrability of ARV drugs. Individual ARV drugs were assigned a penetration rank of 0 (low), 0.5 (intermediate), or 1 (high). This ranking system was based on drug concentration in CSF, chemical properties, and effectiveness in CNS in clinical studies. The CNS penetration-effectiveness (CPE) Rank was calculated by summing the individual penetration ranks for each ARV in the regimen. For example, combinations of efavirenz, lamivudine, and zidovudine have high CPE. Drugs like abacavir have a lower CPE score. Lower CPE ranks correlated with higher CSF viral load. A small study that included 37 people showed greater cognitive improvement with greater penetrability of the drug. Another study looked at both HIV patients with cognitive impairment and patients with cognitive impairment without HIV, and it showed a worsening of cognitive scores. The theory is that ARV drugs with high penetrability can be neurotoxic too. So, it is suggested to suspect ARV drugs neurotoxicity when cognitive improvement is not seen with antiretroviral treatment.
Most research articles emphasize the use of psychiatric medications as needed for mood disorders like depression. Many subtypes of antidepressants have been studied, including selective serotonin reuptake inhibitors, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors. All of these showed a moderate symptomatic relief. Psychostimulants may also be used for fatigue and apathy. Psychotic and manic symptoms are less studied in HIV positive patients; however, research was done on a small sample with psychosis and has shown a greater incidence of extrapyramidal symptoms. Some of the mood stabilizers like lithium have concurrent neurotoxic effects, and some medications like carbamazepine can induce the same CYP enzyme system as many of the antiretroviral drugs causing drug interactions. In theory, several drugs are considered to be neuroprotective such as memantine, pentoxifylline, selegiline, nimodipine, and peptide T. However, only selegiline has shown efficacy.
Differential diagnoses include primary neurocognitive disorder and its subtypes. Given that persons with HIV have increased longevity, the primary neurocognitive disorder may also set in. It often becomes progressively more difficult to differentiate between neurocognitive disorder secondary to HIV and primary neurocognitive disorder. Another differential diagnosis is major depressive disorder, which can present with signs and symptoms of pseudodementia. Some common features also include psychomotor retardation and lack of concentration. The prevalence of Major depressive Disorder is higher in persons with HIV. Some symptoms remain in common, including apathy rather than the lack of interest in other activities. There is an increased incidence of dysphoria in both entities.
Other differentials include substance intoxication and withdrawal, metabolic disorders, opportunistic infections (CNS toxoplasmosis, cryptococcal meningitis), brain tumors, traumatic brain injury, and even adverse effects of antiretroviral medications like efavirenz.
The following conditions are important to remember in the differential diagnosis when considering possible HIV-associated dementia :
Central Nervous System Disease
Substance Withdrawal or Intoxication
Metabolic and Endocrine Disease
The longitudinal CHARTER study is one of the most prominent clinical research studies that focus on neurocognitive deficits in persons with HIV. It investigated the incidence and predictors of neurocognitive change over 16-72 (mean 35) months in 436 HIV-infected participants in the CNS HIV Anti-Retroviral Therapy Effects Research cohort. The conclusion was that neurocognitive changes were complex and depended on several factors, including HIV treatment and the extent of HIV infection and comorbid infections.
In a study of Use of Nonantiretroviral Medications That May Impact Neurocognition, Three thousand three hundred women (71% with HIV) and data from almost 42,000 visits were studied. HIV infection was associated with neurocognitive adverse effects (NC-AE) medication use, which may influence the determinations of HIV-associated neurocognitive impairment. So it is advised that physicians should consider the impact of NC-AE medications when evaluating patients with HIV and concurrent neurocognitive symptoms.
The mind exchange working group consists of sixty-six experts from thirty countries who have published their guidelines of assessment, diagnosis, and treatment of HIV associated neurocognitive disorder.
Per the MIND exchange working group there have been no studies that discuss the prognosis of HIV-associated neurocognitive disorder (HAND), however markers of HIV disease (low CD4 count and high viral load), ongoing poor scores on neuropsychological testing, and concurrent mood disorder all point toward a poor prognosis.
Complications of HIV dementia, as mentioned above, can also include comorbid mood and anxiety disorders. Research has shown that chronic stress can lead to a weakened immune system and increase the risk of other diseases. Also, given the longevity of persons living with HIV now, other forms of dementia, including primary neurocognitive illness, have become a comorbid complication.
Patient education is primarily around early diagnosis and treatment of the disease. Treatment with HAART can delay and even deter the onset of dementia secondary to HIV disease. High viral loads and low CD4 cell counts are associated with a higher incidence of HIV-associated dementia.
The mainstay of treatment lies in early detection. All providers who encounter patients with HIV disease should be encouraged to start their patients on HAART. Patients must be educated about the onset of HIV-associated dementia, especially early signs of asymptomatic neurocognitive impairment, which may simply show a decrease in functioning. All providers must also be educated about the stages of dementia, especially when patients speak about the gradual loss of functioning in daily activities.
Infectious disease specialists treating these patients are encouraged to perform simple screening tests like the Mini-Mental State Exam or the Montreal Cognitive Assessments to look for neurocognitive impairment. They are also encouraged to simultaneously screen for symptoms of depression, including anhedonia, apathy, and lack of concentration. If there is any deficit seen in the screening tests, providers are highly encouraged to refer the patients for neuropsychological testing to determine areas of dysfunction.
Given that mood symptoms are prevalent in patients with HIV disease, a careful history must be obtained about the onset of mood symptoms, and screeners such as the PHQ-9 may be used. If a patient scores in the range of moderate to severe depression, then a referral to a mental health provider should be made. Evidence has shown that treatment of concurrent mood and even psychotic symptoms have played a role in the overall treatment of HIV associated neurocognitive disorder.
Providers are encouraged to conduct a cognitive screen every year for patients and are encouraged to monitor scores to recognize any sharp decline and make appropriate referrals to neurologists.
Providers and their staff are encouraged to educate patients regarding the importance of compliance with HAART, and if there are signs of cognitive impairment, providers are encouraged to use less neurotoxic regimen. Providers are also encouraged to check drug-drug interaction of HAART and particularly psychotropic medications as they are all metabolized through the CYP enzyme system.
In case patients with HIV disease are hospitalized and show signs of cognitive dysfunction, a careful distinction must be made between delirium and cognitive decline. Longitudinal cognitive assessments and neurological exams must be made during the hospitalization.
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