HIV-Associated Neurocognitive Disorders

A 17-year-old male presents for medical evaluation of new academic and attention problems at school. He attends a local public high school where he is in the 11th grade, and has previously been an A and B student. Over the course of this academic year, teachers have begun to note worsening attention in class, disinhibited behavior, and a drop in grades. His family and friends also note poor attention and new working memory problems. There are no significant social or financial stressors, no new alcohol or substance abuse, and he does not endorse symptoms of depression.

His past medical history is remarkable for HIV infection, acquired via sexual contact at the age of 14. He has received regular routine HIV-related care and screening since he was diagnosed, although he has thus far chosen not to start antiretroviral therapy (ART). His nadir CD4 count was 100 around the time of diagnosis; his current CD4 count is 360. His current viral load set point is around 100,000. The remainder of his medical history and review of systems is normal.

On neurologic examination, you note difficulties engaging in conversation and attentional deficits with serial 7s (serial subtractions of seven from 100) and spelling backwards and forwards. He also demonstrates non-specific executive dysfunction. The remainder of his neurologic and general medical examination is normal.

You obtain a gadolinium-enhanced MRI of his brain, which is normal. You subsequently refer him to CHOP Neuropsychology for formal neurocognitive evaluation. There, he demonstrates deficits in attention and executive function domains of more than 1 SD for age and demographically matched normal values, and functional surveys demonstrate his daily life is affected by these deficits.

Discussion: The diagnosis is mild neurocognitive disorder (MND), a subset of HIV-associated neurocognitive disorder (HAND). HAND is a common and devastating complication of HIV infection, affecting up to 52% of HIV-infected adults in the combined ART era. Clinical risk factors include low CD4 nadir count and high viral load. The prevalence in adolescents with behaviorally acquired disease is less well described, but may be as high as 65%. The diagnosis of HAND is difficult to make in the clinical setting because it is based on lengthy and costly batteries of neurocognitive testing. However, efficient identification of affected individuals is imperative: In addition to worsening medication adherence, HAND independently predicts non-central nervous system (CNS) morbidity and overall mortality.

Diagnostic Classification of HIV-Associated Neurocognitive Disorders

ANI

Asymptomatic Neurocognitive Impairment (70% of HAND)

Neuropsychological performance at least 1 SD below demographically matched normative scores in at least 2 cognitive domains*. Cognitive impairment does not interfere with everyday functioning.

MND

Mild Neurocognitive Disorder (25% of HAND)

Neuropsychological performance at least 1 SD below demographically matched normative scores in at least 2 cognitive domains*. Cognitive impairment results in mild interference in daily functioning.

HAD

HIV-Associated Dementia (5% of HAND)

Neuropsychological performance at least 2 SD below demographically matched normative scores in at least 2 cognitive domains*. Cognitive impairment results in marked interference in daily functioning.

*Impairments must not be explained by comorbid conditions, and individual may not meet criteria for delirium or dementia

Adapted from Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789-1799.

HIV invades the nervous system early in infection via infected monocytes and lymphocytes that migrate across the blood-brain barrier (BBB). Infected monocytes then differentiate into macrophages that support low-level viral replication, infect neighboring astrocytes and microglia, and release soluble cytokines/chemokines. These soluble mediators cause a diffuse immune dysregulation, increased BBB permeability, and elevated parenchymal concentrations of excitatory neurotransmitters and neurotoxins, which ultimately result in neuronal and white matter damage. Congenital HIV infection has a different pathophysiology and clinical course compared to classical HAND and is not discussed here.

Blood testing for HAND is not currently available. Instead, the diagnosis rests on clinical neurocognitive testing and exclusion of other known causes of cognitive impairment. Neuroimaging is an important component of diagnosis to exclude CNS opportunistic processes. MRI may also demonstrate cortical and subcortical atrophy and confluent signal abnormalities in the deep white matter.

Research is currently underway to identify plasma, CSF, and neuroimaging biomarkers of HAND to help recognize affected and at-risk youth. Starting ART in affected individuals improves cognition in those most severely affected, but milder forms of HAND are persistent despite adequate therapy. Trials for adjunctive pharmacologic therapies and cognitive rehabilitation are underway.

References and Suggested Readings

McArthur JC, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol. 2010;67(6):699-714.

Lindl KA, Marks DR, Kolson DL, Jordan-Sciutto KL. HIV-associated neurocognitive disorder: pathogenesis and therapeutic opportunities. J Neuroimmune Pharm. 2010;5(3):294-309.

Nichols S, Bethel J, Garvie B, Patton D, Thornton S, Kapogiannis B, Ren W, Li T. Neurocognitive functioning in antiretroviral therapy-naïve youth with behaviorally acquired HIV. Conference on Retroviruses and Opportunistic Infections (CROI), Atlanta, GA. March 2013.

Referral Information

To refer a patient to the Division of Neurology or one of its specialty programs, call 215-590-1719.