HIV Encephalitis

Etiology

The exact mechanism by which HIV infection leads to HIV encephalitis is not entirely clear.[1] A genetic basis for HIV encephalitis has also been studied, with the presence of an E4 allele for apoE being associated with an increased risk of neurocognitive damage.[2] However, some studies have demonstrated no proven association between the presence or absence of genetic polymorphisms and the prevalence of HIV encephalitis.[3] A low CD4 count and high plasma viral load are the key factors determining the development of HIV encephalitis. The patient's age at seroconversion is another important determinant, with patients of older age groups having an increased prevalence of cognitive deficits compared to younger populations. The presence of various comorbidities in older age groups, such as insulin resistance and obesity, also contributes to an extent.

Epidemiology

The neurological disease spectrum in patients with HIV infection can be attributed to various causes, such as opportunistic infections of the central nervous system (CNS), polyneuropathies, spinal cord pathologies, and HIV encephalitis. In the United States, where antiretroviral therapy is widely accessible, the neurologic symptoms in patients with HIV disease are often due to HIV encephalitis. On the other hand, in developing countries where access to HIV treatment still demands improvement, neurologic deterioration is often implicated in opportunistic CNS infections such as toxoplasmosis and cryptococcosis, to name a few. No gender preponderance has been observed relative to HIV encephalitis.

There has been a significant decrease in the severity of HIV encephalitis over the years, owing to the advent and widespread usage of antiretroviral therapy (ART).[4] But, even in the setting of ART, almost half of HIV-infected patients have been shown to suffer from mild to moderate neurocognitive dysfunction during their illness.[5][6] However, the presence of other comorbidities such as substance abuse, diabetes, hypertension, and the effects of aging prevents us from getting a clearer estimate of the degree of cognitive deficits that can be exclusively attributed to HIV encephalitis.

Pathophysiology

Direct damage of central nervous system tissue due to HIV combined with activated immune responses to infection has been implicated in causing the neurocognitive decline associated with HIV encephalitis. HIV infection results in rapid virus seeding in various body premises, including CNS tissues, which are usually asymptomatic. Following infection with HIV, monocytes circulating in the blood migrate to the brain after traversing the blood-brain barrier, thus enabling HIV to gain access to the central nervous system. The entry of HIV into brain tissue through brain endothelium is believed to be aided by the induction of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin. Though the direct impact of HIV on neurocognitive dysfunction after further development of distinct genetic sequences has been studied, the more significant impact has been attributed to the indirect immune pathways triggered after viral entry into brain tissue.[7]

The release of monocyte-derived cytokines such as interleukin-1, tumor necrosis factor-α, and transforming growth factor-β, which trigger neurotoxic changes, is believed to be the more damaging entity in the pathophysiology of HIV encephalopathy.[8] Increased levels of monocytic chemotactic protein-1 in cerebrospinal fluid (CSF) have been shown to correlate with the severity of HIV encephalopathy.

The compartmentalization of HIV infection in the CNS also plays a particularly important role in developing HIV encephalitis. After the virus's initial development from the circulating CD4 cells, in later stages of infection, CSF viral replication occurs independently of plasma viral replication. A change in the tropism of the CNS viruses in the later stages of the infection also worsens the severity of the illness. 

Several factors determine the neurological deterioration in HIV encephalitis. The production of neurotoxic HIV proteins, uncontrolled viral replication in brain tissue, and immune activation are underlying factors controlling the rate of neurological decline.[9]

Histopathology

Although HIV encephalitis can involve any part of the brain, pathologic changes such as pallor and gliosis are most often noted in the basal ganglia and nigrostriatal areas in the initial stages of the illness. These changes can be identified as early as within 1 year of the development of HIV encephalitis.[10] Later stages involve diffuse cerebral involvement, particularly in the temporal and frontal regions. In these areas, microglial cells are stimulated by the virus to fuse and form multinucleated microglial cells. Perivascular infiltrates are often seen. This resultant subcortical microglial nodule encephalitis is pathognomic for HIV encephalitis.

The effect of HIV on astrocytes and oligodendrocytes has also been identified, but the pathologic significance of this cellular affliction has not been clearly demonstrated.[11]

History and Physical

History

The classical presentation of HIV encephalitis presents in a waxing and waning pattern rather than a progressive deterioration, as noted in conditions such as Alzheimer disease. Though HIV encephalitis is usually considered a late manifestation of HIV disease, it has also been known to occur in patients with CD4 counts of more than 350 cells/μL. The elucidation of symptoms that show a cognitive decline from the previous level indicates the presence of HIV encephalitis. Subcortical deficits such as psychomotor retardation, decreased concentration, and decreased attention are often the hallmark of the presentation of this disease. An increase in forgetfulness and difficulty in performing complex tasks may also be noted often. Later stages of the disease may present with bowel and/or bladder complaints.

Physical Examination

Motor abnormalities such as tremors, gait, and balance disturbances are often demonstrated along with increased deep tendon reflexes and muscle tone. Mini-Mental Status Examination (MMSE) is done to objectively establish the cognitive function of individuals and compare it to earlier scores to check for deterioration.[12] The absence of cortical dysfunction signs such as agnosia, apraxia, and aphasia points away from the diagnosis of cortical dementia, such as Alzheimer disease, and substantiates the diagnosis of HIV encephalitis.

Clinical staging of HIV encephalitis is based mainly on the combined neurocognitive and functional status of the patient. The 3 main stages are namely, asymptomatic (neurocognitive status of 1 SD below mean in 2 cognitive domains with no impairments in activities of daily living), mild (neurocognitive status of 1 SD below mean in 2 cognitive domains with impairments in activities of daily living) and HIV-associated dementia (neurocognitive status of 2 SD below mean in 2 cognitive domains with notable impairments in activities of daily living).

Evaluation

Lab Studies

Cerebrospinal fluid (CSF) analysis by lumbar puncture plays an important role in evaluation. An increase in CSF protein, cell count, and the identification of HIV RNA in CSF are all noted but are often non-specific findings related to HIV encephalopathy. In patients with HIV infection presenting with neurologic problems, CSF analysis helps rule out other opportunistic infections. The role of HIV culture in cerebral tissue samples of patients with HIV encephalitis has been extensively studied, with HIV cultures obtained from nerve, CSF, and brain tissues yielding positive results. However, this culture positivity has been noted in all the stages of HIV infection and does not correlate with the presence or absence of neurological symptoms or signs. Testing for CSF HIV viral levels and drug resistance is not routinely performed. An extensive metabolic panel needs to be undertaken in these patients to rule out conditions related to thyroid disease, folate, B12, syphilis, and hepatic disorders, which can present with a similar neurologic presentation. 

Radiology

Neuroimaging studies in patients suffering from HIV encephalopathy usually show cerebral atrophy on CT or MRI. In advanced stages of the disease, on T2-weighted sequences, multiple symmetric foci of hyperintense, non-enhancing lesions are seen predominantly in a subcortical distribution.[13]

Treatment / Management

The only proven option in managing HIV encephalitis, HART has proved to be of benefit in patients with HIV encephalitis, with significant improvements demonstrated in neuropsychiatric and cognitive test scores. The treatment has been shown to decrease and effectively reverse the pathologic damage caused by HIV clinically and radiographically. ART also helps to delay or prevent the onset of neurocognitive impairment in patients with HIV disease.[14] The effectiveness of ART in these patients has led to a decrease in the prevalence of severity of HIV encephalopathy, with a notable decrease in the number of cases of AIDS-dementia complex and an increased prevalence in the milder presentation of this disease.[15] ART has shown to be of clear benefit in patients presenting with HIV-associated dementia, whereas patients with milder cognitive impairment have not shown any significant improvement.[16]

Drug regimens that have higher CNS penetrance have been proven to be of better effect in managing patients with HIV encephalitis.[17] Tailoring treatment after considering both the CNS penetrance effect and the individual patient profile can provide optimum patient benefit. Efavirenz is usually not preferred in neurocognitive disorders owing to its many neuropsychiatric adverse effects.(A1)

In patients diagnosed with HIV-associated dementia in whom initiation of ART is planned, the preferred regimen is tenofovir, dolutegravir plus emtricitabine, or a combination of lamivudine, abacavir plus dolutegravir. 

Drugs such as lithium, memantine, and minocycline have not proven beneficial in patients with HIV encephalitis.[18][19][20](A1)

Differential Diagnosis

The differential diagnoses for HIV encephalitis include the following:

• Primary CNS lymphoma: This can also present with cognitive decline, memory loss, and motor symptoms such as hemiparesis. However, there are usually constitutional symptoms such as night sweats and fever. Imaging helps in differentiating between the 2 entities. Primary CNS lymphoma presents as mass lesions predominantly in the periventricular regions.
• Progressive multifocal leukoencephalopathy (PML): This is a rapidly progressive demyelinating disorder seen in immunosuppressed patients. Caused by the JC virus, it can present with hemiparesis, ataxia, and memory loss. MRI shows bilateral, asymmetric foci of demyelination without mass effect in the periventricular and subcortical regions.
• Opportunistic infections: These include cryptococcosis and toxoplasmosis, which can be differentiated from HIV encephalitis by the associated clinical features, such as seizures. On imaging, both cryptococcus and toxoplasmosis show focal enhancing lesions with a mass effect. Cryptococcus can also present as meningitis, and toxoplasmosis leads to brain abscess.
• Nutritional deficiencies: Vitamin B12 and folate deficiency disorders must be ruled out.

Prognosis

Without the administration of ART, the AIDS-dementia complex can be fatal within 1 year. ART helps slow the disease's progression and leads to increased life expectancy in patients. Older patient age and poor adherence to ART are the factors that are usually responsible for poorer outcomes in these patients.[21] The type of ART administration also determines the mode and severity of neuropsychiatric symptom patterns. Some studies have demonstrated that the use of combination ART compared to a single drug ART has shown improvements in visuospatial orientation and attention but a regression in learning efficiency.[22]

The presence of even asymptomatic or mild neurocognitive impairment at baseline is an indicator of future neurologic decline. Some studies have demonstrated that even in this era of ART, the presence of neurocognitive deficits in a patient with HIV infection is a marker for increased mortality.[23]

Complications

The implementation of ART usage primarily determines the course of illness and complications in patients with HIV encephalitis. A rare condition termed CNS viral escape syndrome has been demonstrated in ART-treated patients. This condition presents with new-onset neurocognitive defects, and lab studies demonstrate high CSF viral replication despite low plasma viral levels.[24]