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HIV Encephalitis


HIV Encephalitis

Article Author:
Vasudev Malik Daliparty
Article Editor:
Rashmi Balasubramanya
Updated:
4/12/2020 10:38:44 PM
For CME on this topic:
HIV Encephalitis CME
PubMed Link:
HIV Encephalitis

Introduction

HIV encephalitis, also referred to as HIV-associated neurological disorder (HAND), includes a range of neurocognitive defects of varying severity following HIV infection. The clinical presentation of this condition varies from asymptomatic or minor neurocognitive impairment to severe dementia. HIV encephalopathy, also known as AIDS-dementia complex, lies at the most severe end of this spectrum. The diagnosis is based on a combination of clinical neuropsychiatric evaluation and radiological studies. Prompt and effective administration of antiretroviral therapy (ART) is the most effective therapy in managing 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 that there is 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 age of the patient 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 at 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 a variety of 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 upon opportunistic CNS infections such as toxoplasmosis and cryptococcosis, to name a few. No gender preponderance has been observed in relation 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 the 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 seeding of the virus in various body premises, including CNS tissues, which is usually asymptomatic. Following infection with HIV, monocytes in circulating 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 that are triggered after viral entry into brain tissue.[7]

The release of monocyte-derived cytokines such as IL-1, TNF-a, TGF-B, which triggers 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) has 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 the development of HIV encephalitis. After the initial development of the virus 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 results in the worsening severity of the illness. 

A number of factors determine the neurological deterioration in HIV encephalitis. The production of neurotoxic HIV proteins, uncontrolled viral replication in brain tissue, and immune activation are some of the 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 one year of 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 that is noted in conditions such as Alzheimer disease.  Though HIV encephalitis is usually considered to be a late manifestation of HIV disease, it has also been known to occur in patients with CD4 counts of more than 350 cells/microL. 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, decreased attention is often the hallmark of 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 tremor, 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 compared 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's 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 three 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 identification of HIV RNA in CSF are all noted but are often non-specific findings in relation to HIV encephalopathy. In patients with HIV infection presenting with neurologic problems, CSF analysis helps to 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 the management of 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 also effectively reverse the pathologic damage caused by HIV clinically and radiographically as well. 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 the management of patients with HIV encephalitis.[17] Tailoring of treatment after consideration of both the CNS penetrance effect as well as the individual patient profile can provide optimum benefit to patients. Efavirenz is usually not preferred in neurocognitive disorders owing to its many neuropsychiatric adverse effects.

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 proved to be of benefit in patients with HIV encephalitis.[18][19][20]

Differential Diagnosis

Neoplasms- 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 two 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- Cryptococcosis, Toxoplasmosis. These can be differentiated from HIV encephalitis from the associated clinical features such as seizures. On imaging, both cryptococcus and toxoplasmosis show focal enhancing lesions with mass effect. Cryptococcus can also present as meningitis. Toxoplasmosis leads to brain abscess.

Nutritional deficiencies- Vitamin B12 and folate deficiency disorders need to be ruled out.

Prognosis

Without the administration of ART, the AIDS-dementia complex can be fatal within 1 year. ART helps to slow the progression of the disease 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 as 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]

Deterrence and Patient Education

ART administration should be considered promptly after the diagnosis of HIV disease owing to its beneficial effect. Emphasis should be placed on the importance of adherence to ART, which can lead to significantly better patient outcomes.

Pearls and Other Issues

The initial stages of HIV encephalopathy are often similar in presentation to depression, fatigue or Alzheimer’s disease and should be carefully differentiated.

A baseline MMSE should be established for all patients in whom HIV infection has been diagnosed.

CSF analysis following lumbar puncture plays a crucial role in ruling out the diagnoses of opportunistic infections.

Patients with HIV encephalopathy demonstrate increased sensitivity to neuroleptic drugs. Therefore, patients with HIV encephalopathy who receive these drugs should be monitored carefully, as they have an increased risk of developing extrapyramidal side effects.

Enhancing Healthcare Team Outcomes

A consultation with an infectious disease specialist for prompt and efficient ART administration and a neurological consultation for careful evaluation and monitoring of neurocognitive functioning provide the most benefit in the management of patients with HIV encephalitis. ART administration is the most important factor determining outcomes in patients suffering from HIV encephalitis.[25]


References

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