HIV-1 Encephalopathy and Aids Dementia Complex

Etiology

The relationship between HIV infection and observed neurocognitive deficits is not clearly understood but is thought to be due to several factors. Proteins expressed from viral genes in infected cells can directly damage neurons. Cytokines produced by activating 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 patients' cerebrospinal fluid (CSF) following treatment and may explain the progression of symptoms in patients with low viral counts.[4][5][6]

Epidemiology

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 suggest an incidence of HAD of 0.66 per 1000 person-years, 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. The prevalence of HAND among white and nonwhite patients, as well as between men and women, appears to mimic that of HIV infection and increases with age.[7]

Pathophysiology

Initial pathological changes include reduced 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.

Histopathology

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. The 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.[8]

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. Verbal fluency, decision-making, executive functioning, and memory deficits 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.

Evaluation

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.[9][10]

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. In advanced disease, an electroencephalogram shows generalized slowing.

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 of 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 the 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

The differential diagnoses for HIV-1 encephalopathy and aids dementia complex include the following

• CNS infection, especially in those with a low CD4 count who are not on antibiotic prophylaxis
  • Consider herpes simplex, varicella-zoster, CMV, EBV, JC, toxoplasmosis, syphilis, and 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 the increased risk of dementia syndromes due to the increase in the 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, may be associated with paresthesia and sensory problems.
• Acute intoxication
• Drug effects

Prognosis

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. A 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.[11][12]