HIV-1 Encephalopathy And Aids Dementia Complex

Article Author:
Michael Kopstein
Article Editor:
David Mohlman
1/19/2019 12:51:01 PM
PubMed Link:
HIV-1 Encephalopathy And Aids Dementia Complex


Neurocognitive deficits are the presenting complaint in 4% to 15% of patients diagnosed with HIV. Patients may present with nonspecific complaints such as deficits in memory, concentration, attention, and motor skills. These symptoms are common in many disorders, and accurate diagnosis is critical for appropriate treatment. The AIDS dementia complex (ADC) was first defined in 1986 and was a frequent feature of HIV disease before antiretroviral therapy (ART) and highly active antiretroviral therapy (HAART) came into common use in the mid-1990s. In addition to medical comorbidities, patients also frequently suffer from various mental or psychosocial issues that can affect cognitive function, including mood disorders, post-traumatic stress disorder (PTSD), and substance abuse or dependence. Increased risk of opportunistic infections, tumors, and a side effects of antiretroviral drugs may also contribute to neurologic effects. Patients can experience delirium as part of the acute HIV syndrome or develop dementia during the later stages of their disease.

The spectrum of progressively more severe neurologic and cognitive symptoms (previously known as ADC) are now referred to as HIV-associated neurocognitive disorders (HAND) and were categorized in 2007 by the United States National Institutes of Health to include three classifications. These range in severity from asymptomatic neurocognitive impairment (ANI) to minor neurocognitive disorder (MND), and HIV-associated dementia (HAD). The distinction between these levels is made by use of neuropsychological testing in addition to observation of symptomatic functional impairment. The observed impairment must not be explained by any other condition, including infection, cerebrovascular disease, or toxic encephalopathy. In practice, making a distinction between the less severe categories of disease in the acute care setting is difficult due to the necessity of neuropsychological testing. Due to the profound symptomology and functional deficits associated with HAD this diagnosis may be presumed, especially in patients with untreated or advanced stages of AIDS disease.


The relationship between HIV infection and observed neurocognitive deficits is not clearly understood but thought to be due to several factors. Proteins expressed from viral genes in infected cells can directly damage neurons. Cytokines produced by activation of the immune response in surrounding healthy glial cells may also contribute to neuronal damage. Additionally, autoimmune antibodies against brain tissue have been isolated in HIV-infected patients suffering from HAD which appear to be present less frequently in those who do not develop dementia. Autoantibodies continue to be present in the cerebrospinal fluid (CSF) of patients following treatment and may explain the progression of symptoms in patients with low viral counts.


Neuropsychological testing may reveal subtle cognitive deficits (ANI or MND) in as many as 40% of HIV-infected patients treated with antiretrovirals.  A nationwide Danish study estimated that 1 of 1000 patients not treated with HAART and with low CD4 counts would progress to HAD. Data from the European CASCADE study suggests an incidence of HAD of 0.66 per 1000 person-years which is a decrease of almost tenfold from the pre-ART era. In the United States, the CHARTER study estimated an incidence of HAD of 10.5 cases per 1000 patient-years; this is down from 21 cases per 1000 patient years before the advent of ART therapy. Prevalence of HAND among white and non-white patients as well as between men and women appears to mimic that of HIV infection and increases with age.


Initial pathological changes include a reduction in the cortical gray matter and brain atrophy. Autopsy examination of affected patients' brain tissue may show perivascular macrophage and lymphocyte infiltration, multinucleated giant cells, myelin loss, and white matter astrogliosis. The basal ganglia are most commonly affected.


Microscopic analysis is also likely to show evidence of encephalitis due to common complications of HIV including progressive multifocal leukoencephalopathy (PML), non-Hodgkin lymphoma (NHL), or infection such as from cytomegalovirus, toxoplasmosis, varicella-zoster, herpes simplex, or BK virus.

History and Physical

A complete history and physical examination should be obtained to identify risk factors for HAND/HAD as well as to rule out other causes of dementia. Risk factors identified by the CASCADE study include low CD4 count, advanced age at seroconversion, duration of HIV infection, and prior AIDS-defining diagnosis. Particular attention should be given to adherence to the medication regimen and medical follow up as well as the timing of HIV diagnosis, stage of disease and current treatment. Time course of symptoms and degree of functional impairment should be elicited. Other conditions potentially contributing to cognitive impairment should be identified including any history of head trauma, substance abuse or psychiatric disorders.  The onset of complaints is generally indolent. Patients and their families or caregivers may report mood changes, memory impairment, insomnia, weight loss or apathy. 

Patients experiencing mild neurocognitive deficits are unlikely to have specific complaints. As a result, neuropsychological testing should be administered routinely with HAD risk factors or low CD4 counts. Patients may exhibit flattened affect and lack of emotional lability which may distinguish them from those with a major depressive disorder. Deficits in verbal fluency, decision-making, executive functioning and memory are common. Higher cortical dysfunctions such as aphasia, agnosia and apraxia are generally absent but may develop in the later stages of progression. Patients with advanced disease may develop frontal release signs, hyperreflexia and difficulty with rapid alternating movements. A neurologic exam should assess the level of alertness (HAD generally does not cause an alteration in the level of consciousness) and findings suggestive of an alternative neurologic disorder such as Parkinson disease, stroke, tumor or progressive multifocal leukoencephalopathy.


Diagnostic studies should focus on excluding the presence of other conditions producing the patient's cognitive impairment. This may include infectious, neurological, or psychiatric disorders in addition to toxic encephalopathies. Liver function, blood glucose, vitamin B12, thyroid hormone, syphilis and hepatitis serologies may be useful depending on the patient's presentation.  The stage of HIV infection may be assessed with CD4 count and viral load.

Neuroimaging such as MRI should be ordered to evaluate for neurologic disorders or cerebrovascular disease. Diffuse cerebral atrophy is usually present and can affect the basal ganglia, white matter and cortical regions. EEG will show generalized slowing in advanced disease.

CSF studies may show elevated viral load, lymphocytic pleocytosis and increased total protein levels however these findings are nonspecific. If drawn, CSF serologies should include toxoplasmosis, cryptococcal antigen, syphilis and viral polymerase chain reaction studies including John Cunningham (JC) virus, Epstein-Barr virus (EBV) and cytomegalovirus (CMV).

Treatment / Management

The mainstay of prevention and treatment of HAND spectrum disorders is adherence to ART. Appropriate treatment of HIV infection shows improvement in cognitive function in patients diagnosed with severe deficits. The incidence of HAD has also decreased over time with the widespread use of ART in observational studies. ART should be initiated for any untreated patient with HIV infection who is beginning to experience cognitive decline. The selection of a specific ART regimen should follow standard protocols based on viral ribonucleic acid (RNA) load, genotype, drug interactions and presence of comorbidities.

The effectiveness of ART to prevent the milder forms MND and ANI is less clear as these conditions are subtle and likely underdiagnosed. It is unclear if specific ART regimens are more effective at preventing progression of cognitive decline. The antiretroviral efavirenz should be avoided in patients undergoing evaluation for HAD due to its adverse effect profile that may interfere with neuropsychological testing. In patients on appropriate therapy with low viral counts and high CD4 levels, progressive neurocognitive deficits are more likely to be due to another etiology. Appropriate evaluation should be done to rule out these conditions.

Psychiatric comorbidities may be present and treatment should be initiated following a psychiatric evaluation.

Differential Diagnosis

  • Central nervous system (CNS) infection, especially in those with a low CD4 count who are not on antibiotic prophylaxis. Consider herpes simplex virus, varicella-zoster virus, CMV, EBV, JC virus, toxoplasmosis, syphilis, Cryptococcus.
  • Malignancy, including CNS lymphoma and metastatic disease. Usually identified on neuroimaging.
  • Dementia, including Parkinson, Alzheimer, Lewy Body and frontal and temporal lobe dementias. Be aware of increased risk of dementia syndromes due to increase in long-term survival of the HIV-infected population in general.
  • Endocrine disorders such as adrenal insufficiency or hypothyroidism.
  • Substance use or acute intoxication
  • Delirium
  • Nutritional deficiencies, particularly cognitive impairment secondary to B12 deficiency; this may be associated with paresthesia and sensory problems.
  • Acute intoxication
  • Drug effects


Mean survival in HAD without ART is 3 to 6 months. This increased to 38.5 months with the initiation of ART therapy in the 1990s and it is thought that with adherence to HAART, mean survival should approach that of the general HIV-affected population. Worse prognosis is associated with the following factors: lower educational level, increasing age, lower CD4 count, higher viral load, decreasing hemoglobin, decreasing platelets, lower body mass index, hepatitis C coinfection, intravenous drug use and poor medication adherence. In addition, the presence of HAD is an independent predictor of risk of death in HIV-infected patients.


Consultation with an infectious disease specialist or practitioner experienced in caring for HIV-infected patients is recommended for management of HAART regimen. Psychiatric consultation may also be indicated as HIV-infected patients with HAD commonly have comorbidities including generalized anxiety disorder, major depressive disorder and agitation and may present with psychosis. A neurologic evaluation may be necessary to fully complete workup for alternative causes of cognitive deficits.

Pearls and Other Issues

  • Alteration in mental status is common in HIV-infected patients and etiology may be unclear.
  • The common use of HAART in developed countries has greatly decreased the risk of developing HAND; however, disorders on this spectrum are common in patients from developing countries or in patients whose advanced disease have gone untreated.
  • Cognitive deficits associated with HAD include impaired executive function, decision making and language; these are generally slow and progressive in onset.
  • Patients with nonspecific cognitive symptoms, low CD4 count or risk factors for HAD should be screened using neuropsychologic testing.
  • Workup should focus on excluding other causes of cognitive impairment in immunocompromised individuals.
  • Treatment for HIV-infected patients with neurocognitive impairment is the initiation of or adherence to HAART therapy.
  • Rapid neurologic or cognitive decline, especially in an appropriately treated patient with high CD4 count and low viral load, should prompt investigation into alternative causes including CNS infection, tumor, neurodegenerative diseases or toxic encephalopathy.


Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance., Marra CM,Zhao Y,Clifford DB,Letendre S,Evans S,Henry K,Ellis RJ,Rodriguez B,Coombs RW,Schifitto G,McArthur JC,Robertson K,, AIDS (London, England), 2009 Jul 17     [PubMed PMID: 19424052]
Zidovudine treatment of the AIDS dementia complex: results of a placebo-controlled trial. AIDS Clinical Trials Group., Sidtis JJ,Gatsonis C,Price RW,Singer EJ,Collier AC,Richman DD,Hirsch MS,Schaerf FW,Fischl MA,Kieburtz K,, Annals of neurology, 1993 Apr     [PubMed PMID: 8489204]
Adjunctive therapies for AIDS dementia complex., Uthman OA,Abdulmalik JO,, The Cochrane database of systematic reviews, 2008 Jul 16     [PubMed PMID: 18646159]
Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy., Bhaskaran K,Mussini C,Antinori A,Walker AS,Dorrucci M,Sabin C,Phillips A,Porter K,, Annals of neurology, 2008 Feb     [PubMed PMID: 17894380]
Human immunodeficiency virus and depression in primary care: a clinical review., Colibazzi T,Hsu TT,Gilmer WS,, Primary care companion to the Journal of clinical psychiatry, 2006     [PubMed PMID: 16964315]
HIV-1-related central nervous system disease: current issues in pathogenesis, diagnosis, and treatment., Spudich S,González-Scarano F,, Cold Spring Harbor perspectives in medicine, 2012 Jun     [PubMed PMID: 22675662]
The neuropathogenesis of AIDS., González-Scarano F,Martín-García J,, Nature reviews. Immunology, 2005 Jan     [PubMed PMID: 15630430]
The changing pattern of HIV neuropathology in the HAART era., Gray F,Chrétien F,Vallat-Decouvelaere AV,Scaravilli F,, Journal of neuropathology and experimental neurology, 2003 May     [PubMed PMID: 12769183]
HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study., Heaton RK,Clifford DB,Franklin DR Jr,Woods SP,Ake C,Vaida F,Ellis RJ,Letendre SL,Marcotte TD,Atkinson JH,Rivera-Mindt M,Vigil OR,Taylor MJ,Collier AC,Marra CM,Gelman BB,McArthur JC,Morgello S,Simpson DM,McCutchan JA,Abramson I,Gamst A,Fennema-Notestine C,Jernigan TL,Wong J,Grant I,, Neurology, 2010 Dec 7     [PubMed PMID: 21135382]
Changing patterns in the neuropathogenesis of HIV during the HAART era., Langford TD,Letendre SL,Larrea GJ,Masliah E,, Brain pathology (Zurich, Switzerland), 2003 Apr     [PubMed PMID: 12744473]
HIV dementia: an evolving disease., McArthur JC,, Journal of neuroimmunology, 2004 Dec     [PubMed PMID: 15579274]
The AIDS dementia complex: I. Clinical features., Navia BA,Jordan BD,Price RW,, Annals of neurology, 1986 Jun     [PubMed PMID: 3729308]
Evolving character of chronic central nervous system HIV infection., Price RW,Spudich SS,Peterson J,Joseph S,Fuchs D,Zetterberg H,Gisslén M,Swanstrom R,, Seminars in neurology, 2014 Feb     [PubMed PMID: 24715483]
HIV-associated neurologic disease incidence changes:: Multicenter AIDS Cohort Study, 1990-1998., Sacktor N,Lyles RH,Skolasky R,Kleeberger C,Selnes OA,Miller EN,Becker JT,Cohen B,McArthur JC,, Neurology, 2001 Jan 23     [PubMed PMID: 11160967]
HIV-1 infection and cognitive impairment in the cART era: a review., Schouten J,Cinque P,Gisslen M,Reiss P,Portegies P,, AIDS (London, England), 2011 Mar 13     [PubMed PMID: 21160410]
An evaluation of neurocognitive status and markers of immune activation as predictors of time to death in advanced HIV infection., Sevigny JJ,Albert SM,McDermott MP,Schifitto G,McArthur JC,Sacktor N,Conant K,Selnes OA,Stern Y,McClernon DR,Palumbo D,Kieburtz K,Riggs G,Cohen B,Marder K,Epstein LG,, Archives of neurology, 2007 Jan     [PubMed PMID: 17210815]
Neurologic disease burden in treated HIV/AIDS predicts survival: a population-based study., Vivithanaporn P,Heo G,Gamble J,Krentz HB,Hoke A,Gill MJ,Power C,, Neurology, 2010 Sep 28     [PubMed PMID: 20739646]
Antibodies to myelin oligodendrocyte glycoprotein in HIV-1 associated neurocognitive disorder: a cross-sectional cohort study., Lackner P,Kuenz B,Reindl M,Morandell M,Berger T,Schmutzhard E,Eggers C,, Journal of neuroinflammation, 2010 Nov 17     [PubMed PMID: 21083890]
Autoimmune markers in HIV-associated dementia., Schutzer SE,Brunner M,Fillit HM,Berger JR,, Journal of neuroimmunology, 2003 May     [PubMed PMID: 12742665]