Etiology

Causes of altered mental status in HIV infection include acutely presenting conditions (which often represent HIV-related opportunistic infection or associated systemic illness) and more progressive (and often previously documented) neurocognitive disease or psychological comorbidity. The prevalence of specific HIV-related conditions is dependent upon the degree of immunosuppression (as assessed by CD4 count) and whether the underlying HIV infection is being actively treated with combination antiretroviral therapy (ART).

HIV-associated conditions

HIV-associated neurocognitive disorder (HAND)

Represent a spectrum of progressive neurocognitive impairment:[6]

  • Asymptomatic neurocognitive impairment (ANI): acquired impairment in cognitive functioning involving at least 2 ability domains, documented by performance of at least 1 standard deviation (SD) below demographically corrected means for age-education-appropriate norms, but with no impairment in the ability to perform everyday activities.

  • Mild neurocognitive disorder: similar neurocognitive performance on neuropsychological tests as in ANI with mild interference in daily functioning at work or home, or in social functioning.

  • HIV-associated dementia: marked acquired impairment in cognitive functioning involving at least 2 ability domains, documented by performance of at least 2 SD below demographically corrected means and associated with a marked impairment in performing daily activities.

Effects of HIV therapy

Antiretroviral agents may induce cognitive and psychiatric problems directly as an adverse effect or indirectly through their effect on the immune system. The nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is associated with the development of neuropsychiatric adverse effects, especially in the first weeks of treatment.[17][18][19][20][21] Rates of similar neuropsychiatric adverse effects are significantly lower with other NNRTI agents such as nevirapine, etravirine, and rilpivirine.[22][23] The integrase inhibitor raltegravir has been associated with infrequent neuropsychiatric adverse effects, and dolutegravir may be associated with insomnia and other central nervous system (CNS) effects.[24][25][26][27][28][29]

Patients receiving antiretroviral therapy may also develop immune reconstitution inflammatory syndrome (IRIS), a paradoxical deterioration in clinical status associated with rapid improvement in CD4 counts and a decrease in viral loads within the first few months after ART initiation. IRIS develops as a consequence of the reaction of the restored immune system to infectious agents, most commonly Mycobacterium tuberculosis or M avium complex, although a variety of other causes (e.g., herpes simplex virus [HSV], varicella zoster virus [VZV], progressive multifocal leukoencephalopathy [PML], and Toxoplasmosis gondii) are also recognized triggers.[30] IRIS arising from underlying cryptococcal infection has also been described.[31]

CNS opportunistic infections and tumors

HIV-related opportunistic infections (OIs) arise as a consequence of impaired immunity in advanced stages of HIV infection. These illnesses tend to occur most often in patients who have untreated HIV infection or who have poor adherence to ART. The risk of OIs in HIV-infected people increases as the CD4 count declines, and neurologic involvement typically occurs in those with CD4 cell count <100 cells/mm³.

Common manifestations include:

  • Encephalitis due to infection with Toxoplasma gondii, HSV, or, rarely, VZV or cytomegalovirus

  • Meningitis due to infection with Cryptococcus neoformans or M tuberculosis

  • PML due to infection with John Cunningham virus

  • Primary CNS lymphoma associated with Epstein-Barr virus.

In addition, non-opportunistic infections such as bacterial causes of meningitis (including neurosyphilis), must be considered in patients presenting with acute neurologic deterioration and infectious signs or symptoms.

Non-HIV-associated conditions

Systemic comorbidity

Concomitant nutritional deficiency (e.g., folate, vitamin B12, vitamin D) may cause cognitive impairment.[32] Patients with advanced HIV infection are at an increased risk of ischemic stroke.[33] The underlying pathogenesis varies and includes cerebral emboli secondary to cardiac disease, as well as cerebral vasculitis as a consequence of syphilis or amphetamine/cocaine use.

HIV-infected patients with concomitant hepatitis C infection have higher rates of cognitive impairment.[32][34] Thyroid disease and hypogonadism are more common in patients with HIV, and can represent an underlying cause of altered mental status in HIV-infected people.[32][35][36][37]

Psychiatric comorbidity

Psychiatric comorbidity is highly prevalent in HIV-infected people and can contribute to cognitive difficulties.[32] These include:

  • Depression

  • Alcohol and substance use disorders

  • Cognitive impact of many prescription drugs, in particular those with anticholinergic properties and psychotropic medications.[32]

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