HIV-1 Encephalopathy And Aids Dementia Complex


Article Author:
Michael Kopstein


Article Editor:
David Mohlman


Editors In Chief:
Rodrigo Kuljis
Oleg Chernyshev
Aninda Acharya


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/4/2019 5:15:57 PM

Introduction

Neurocognitive deficits are the presenting complaint in 4% to 15% of patients diagnosed with HIV. Patients may present with nonspecific complaints such as deficits in memory, concentration, attention, and motor skills. These symptoms are common in many disorders, and accurate diagnosis is critical for appropriate treatment. The AIDS dementia complex (ADC) was first defined in 1986 and was a frequent feature of HIV disease before antiretroviral therapy (ART) and highly active antiretroviral therapy (HAART) came into common use in the mid-1990s. In addition to medical comorbidities, patients also frequently suffer from various mental or psychosocial issues that can affect cognitive function, including mood disorders, post-traumatic stress disorder (PTSD), and substance abuse or dependence. Increased risk of opportunistic infections, tumors, and a side effects of antiretroviral drugs may also contribute to neurologic effects. Patients can experience delirium as part of the acute HIV syndrome or develop dementia during the later stages of their disease.[1][2]

The spectrum of progressively more severe neurologic and cognitive symptoms (previously known as ADC) are now referred to as HIV-associated neurocognitive disorders (HAND) and were categorized in 2007 by the United States National Institutes of Health to include three classifications. These range in severity from asymptomatic neurocognitive impairment (ANI) to minor neurocognitive disorder (MND), and HIV-associated dementia (HAD). The distinction between these levels is made by use of neuropsychological testing in addition to observation of symptomatic functional impairment. The observed impairment must not be explained by any other condition, including infection, cerebrovascular disease, or toxic encephalopathy. In practice, making a distinction between the less severe categories of disease in the acute care setting is difficult due to the necessity of neuropsychological testing. Due to the profound symptomology and functional deficits associated with HAD this diagnosis may be presumed, especially in patients with untreated or advanced stages of AIDS disease.[3]

Etiology

The relationship between HIV infection and observed neurocognitive deficits is not clearly understood but thought to be due to several factors. Proteins expressed from viral genes in infected cells can directly damage neurons. Cytokines produced by activation of 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 the cerebrospinal fluid (CSF) of patients 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 suggests an incidence of HAD of 0.66 per 1000 person-years which is 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. Prevalence of HAND among white and non-white 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 a reduction in the 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. 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. Deficits in verbal fluency, decision-making, executive functioning and memory 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. EEG will show generalized slowing in advanced disease.

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 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 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

  • Central nervous system (CNS) infection, especially in those with a low CD4 count who are not on antibiotic prophylaxis. Consider herpes simplex virus, varicella-zoster virus, CMV, EBV, JC virus, toxoplasmosis, syphilis, 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 increased risk of dementia syndromes due to increase in 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; this 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. 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]

Consultations

Consultation with an infectious disease specialist or practitioner experienced in caring for HIV-infected patients is recommended for management of HAART regimen. Psychiatric consultation may also be indicated as HIV-infected patients with HAD commonly have comorbidities including generalized anxiety disorder, major depressive disorder and agitation and may present with psychosis. A neurologic evaluation may be necessary to fully complete workup for alternative causes of cognitive deficits.

Pearls and Other Issues

  • Alteration in mental status is common in HIV-infected patients and etiology may be unclear.
  • The common use of HAART in developed countries has greatly decreased the risk of developing HAND; however, disorders on this spectrum are common in patients from developing countries or in patients whose advanced disease have gone untreated.
  • Cognitive deficits associated with HAD include impaired executive function, decision making and language; these are generally slow and progressive in onset.
  • Patients with nonspecific cognitive symptoms, low CD4 count or risk factors for HAD should be screened using neuropsychologic testing.
  • Workup should focus on excluding other causes of cognitive impairment in immunocompromised individuals.
  • Treatment for HIV-infected patients with neurocognitive impairment is the initiation of or adherence to HAART therapy.
  • Rapid neurologic or cognitive decline, especially in an appropriately treated patient with high CD4 count and low viral load, should prompt investigation into alternative causes including CNS infection, tumor, neurodegenerative diseases or toxic encephalopathy.

Enhancing Healthcare Team Outcomes

Consultation with an infectious disease specialist or nurse practitioner experienced in caring for HIV-infected patients is recommended for the management of HAART regimen. Psychiatric consultation may also be indicated as HIV-infected patients with HAD commonly have comorbidities including generalized anxiety disorder, major depressive disorder, and agitation and may present with psychosis. A neurologic evaluation may be necessary to fully complete workup for alternative causes of cognitive deficits.

To improve outcomes in HIV patients, the key is to encourage compliance with HAART. 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. Continual monitoring of neurophysiological function is recommended to ensure that the patient is not deteriorating.


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

HIV-1 Encephalopathy And Aids Dementia Complex - Questions

Take a quiz of the questions on this article.

Take Quiz
Which of the following is not a potential central nervous system manifestation of AIDS?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
An HIV positive male presents with confusion and general malaise. Blood work reveals that he is anemic and brain CT shows generalized brain atrophy. What is the most common HIV disorder of the brain?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What will the brain biopsy of an AIDS patient who developed encephalopathy generally show?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What will most likely show in the biopsy of a brain in patients with AIDS who develop encephalopathy?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is NOT an identified disorder caused by the human immunodeficiency virus?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the etiology of acquired immunodeficiency syndrome (AIDS) dementia complex?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which one of the following symptoms is not part of the AIDS dementia complex?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A patient with AIDS develops symptoms of dementia, cognitive dysfunction and impairment in executive function. Which of the following findings is unlikely to be seen on brain histolopathology?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is true about neurocognitive disease in patients with HIV?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
50-year-old male has a history IV drug abuse and has had progressive memory problems. The patient has difficulty with short and long term memory, word finding problems, labile affect, and mild dysarthria. There is a left Babinski reflex and the right biceps reflex is hyperactive and shows transient clonus. MRI is normal. What is the most likely diagnosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
An HIV+ patient is brought in by his partner who reports the patient is forgetful and confused. He is intermittently compliant with antiviral medication. Which of the following are true?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 25-year-old female presents with a persistent cough, fever, and a 15 pound weight loss over the past month. She also has been having mental status changes as well, which include getting lost while driving and making many more mistakes at work. She looks very ill in appearance on exam. Which of the following diagnostic tests will be most helpful?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 55-year-old male with a past medical history of intravenous drug use and recent HIV diagnosis presents for health maintenance. He denies any complaints. Neuropsychological testing reveals mild memory impairment. Laboratory studies show a CD4+ cell count of 600 and are otherwise unremarkable. Which of the following steps should be taken to avoid decline of his neurocognitive status?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 65-year-old male with past medical history of HIV infection and dementia is seen for acute mental status decline. His son reports that in the last week, he has frequently been falling and has become confused and been found wandering around the neighborhood. He was diagnosed with HIV-associated dementia approximately 10 years ago and had been fairly stable until 1 week ago. He is currently being treated with highly active antiretroviral therapy (HAART). What should be done next in the evaluation of this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

HIV-1 Encephalopathy And Aids Dementia Complex - References

References

Singh H,Nain S,Krishnaraj A,Lata S,Dhole TN, Genetic variation of matrix metalloproteinase enzyme in HIV-associated neurocognitive disorder. Gene. 2019 May 25;     [PubMed]
Kumar S,Maurya VK,Dandu HR,Bhatt ML,Saxena SK, Global Perspective of Novel Therapeutic Strategies for the Management of NeuroAIDS. Biomolecular concepts. 2018 May 8;     [PubMed]
Zipeto D,Serena M,Mutascio S,Parolini F,Diani E,Guizzardi E,Muraro V,Lattuada E,Rizzardo S,Malena M,Lanzafame M,Malerba G,Romanelli MG,Tamburin S,Gibellini D, HIV-1-Associated Neurocognitive Disorders: Is HLA-C Binding Stability to β{sub}2{/sub}-Microglobulin a Missing Piece of the Pathogenetic Puzzle? Frontiers in neurology. 2018;     [PubMed]
Guha D,Wagner MCE,Ayyavoo V, Human immunodeficiency virus type 1 (HIV-1)-mediated neuroinflammation dysregulates neurogranin and induces synaptodendritic injury. Journal of neuroinflammation. 2018 Apr 27;     [PubMed]
Wilmshurst JM,Hammond CK,Donald K,Hoare J,Cohen K,Eley B, NeuroAIDS in children. Handbook of clinical neurology. 2018;     [PubMed]
Sillman B,Woldstad C,Mcmillan J,Gendelman HE, Neuropathogenesis of human immunodeficiency virus infection. Handbook of clinical neurology. 2018;     [PubMed]
Hu G,Yelamanchili S,Kashanchi F,Haughey N,Bond VC,Witwer KW,Pulliam L,Buch S, Proceedings of the 2017 ISEV symposium on     [PubMed]
Jayant RD,Atluri VSR,Tiwari S,Pilakka-Kanthikeel S,Kaushik A,Yndart A,Nair M, Novel nanoformulation to mitigate co-effects of drugs of abuse and HIV-1 infection: towards the treatment of NeuroAIDS. Journal of neurovirology. 2017 Aug;     [PubMed]
Tan IL,McArthur JC, HIV-associated neurological disorders: a guide to pharmacotherapy. CNS drugs. 2012 Feb 1;     [PubMed]
Eggers Ch, HIV-1 associated encephalopathy and myelopathy. Journal of neurology. 2002 Aug;     [PubMed]
Narayanan K,Gupta A,Manoj S,Seshadri K, HIV Infection Presenting with Dementia. The Journal of the Association of Physicians of India. 2015 Aug;     [PubMed]
Chan P,Hellmuth J,Spudich S,Valcour V, Cognitive Impairment and Persistent CNS Injury in Treated HIV. Current HIV/AIDS reports. 2016 Aug;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Neurology. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Neurology, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Neurology, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Neurology. When it is time for the Neurology board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Neurology.