Hospital Medicine

Complications of human immunodeficiency virus: Neurologic complications of HIV

Complications of human immunodeficiency virus

I. Problem/Condition.

Complications of human immunodeficiency virus (HIV) infection include a wide array of clinical problems that can affect virtually every organ system. Prior to the advent of highly active antiretroviral therapy (HAART), the bulk of the complications were comprised of opportunistic illnesses (OIs), which included infections and malignancies. In current times, the spectrum of disease encompasses more non-acquired immune deficiency syndrome (AIDS) defining cancers, complications of concomitant illnesses and side effects of HAART.

Important points to remember are: 1) the level of immunocompromise dictates the differential diagnosis and what testing need to be ordered, and 2) regardless of degree of immunocompromise, individuals with HIV often suffer from common illnesses unrelated to their immunodeficiency.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

Neurologic complications

Patients with HIV presenting with acute to subacute meningoencephalitis may be presenting with primary HIV infection, cytomegalovirus (CMV) infection (CD4<50), cryptococcal meningitis (CD4<50), toxoplasma encephalitis (TE) (CD4<100), TB meningitis, or coccidiomycosis meningitis.

All the above infections can cause focal neurological symptoms such a seizure or hemiplegia. The rates of TE have decreased, as trimethoprim/sulfamethoxazole (TMP/SMX), also known as (Bactrim), prophylaxis against pneumocystis is also active against this infection. Herpes simplex virus (HSV) can cause either meningitis or encephalitis.

Progressive multifocal leukoencephalopathy (PML) is a central nervous system demyelinating neuropathy which presents with subacute changes in mental status, hemiparesis or ataxia when CD4 is less than 100. HIV is also associated with multiple peripheral neuropathies and myelopathies.

Primary CNS lymphoma is associated with severe immunosuppression and can present as lethargy, confusion and focal signs secondary to elevated intracranial pressure.

AIDS dementia (now called HIV-associated neurocognitive disorder) is characterized by chronic progressive motor, cognitive and behavioral abnormalities. In the pre-HAART era, the cognitive impairments seen were severe, but now mild forms are being recognized.

B. Describe a diagnostic approach/method to the patient with this problem

The diagnostic approach will depend on a careful history and physical examination, in addition to understanding the patient's HIV treatment history. A recent CD4 count (and preferably a recent trend) is the single most helpful element in formulating a differential diagnosis.

All HIV-infected individuals, regardless of CD4 count, are at increased risk of the following neurological complications:

  • TB (those with CD4 <200 are more likely to have extrapulmonary disease)

  • Syphilis

  • HSV

  • Varicella zoster virus (VZV)

  • Histoplasmosis (pulmonary at any count, CD4 <150 for disseminated infection)

HIV-infected individuals with CD4 less than 200 are at risk for all of the above, and the following:

  • Toxoplasmosis

  • Coccidioidomycosis (may have CD4 counts up to 250)

HIV-infected individuals with CD4 less than 100 are at risk for all of the above, and the following:

  • Microsporidium

  • Cryptosporidium

  • PML

HIV-infected individuals with CD4 less than 50 are at risk for all of the above, and the following:

  • Cryptococcosis (meningitis)

  • Aspergillosis (meningitis or pulmonary disease)

  • CMV (retinitis, esophagitis, colitis, CNS disease)

  • CNS lymphoma

1. Historical information important in the diagnosis of this problem.

Important questions to ask include the following:

  • Careful history and timing of chief complaint.

  • Associated symptoms - there may be more than one diagnosis.

  • History of HAART and adherence - presentation may be related to drug side effects.

  • Any bacterial prophylaxis and adherence - if on TMP/SMX prophylaxis, less likely to have bacterial pneumonia, pneumocystis or toxoplasmosis. If taking azithromycin, less likely to acquire MAC.

  • CD4 count and history - previous AIDS-defining illness or CD4 count less than 200 predisposes to more serious infection even if counts are currently above 200.

  • Travel history - Mississippi River valley for histoplasmosis, Southwest US for coccidioidomycosis, foreign TB endemic area.

  • Careful sexual history for epidemiology - secondary syphilis can cause high fevers, rash, and mental status changes.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

In the scope of focusing on a HIV-infected individual presenting to a hospital setting, it is of utmost importance to perform a thorough physical examination, including skin, oropharynx, and abdominal exam regardless of the chief complaint. Skin findings such as Kaposi's or bacillary lesions can suggest level of immunocompromise and point at the causative process. Organomegaly and lymphadenopathy can suggest the presence of a systemic process.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

The approach to the patient with HIV infection and neurologic symptoms begins with a CT scan of the head. Contrast-enhanced cranial CT and/or magnetic resonance imaging (MRI) will identify mass lesions, and enhancement can give a clue to the diagnosis. If multiple mass lesions are present and are also ring-enhancing, TE is the likely diagnosis. MRI head is more sensitive in ensuring solitary masses are truly solitary.

CNS lymphoma lesions are often supratentorial and multicentric, enhance uniformly and have surrounding edema. However, the two lesions can present very similarly and can be hard to distinguish radiographically.

Stereotactic brain biopsy is the gold standard in diagnosing mass lesions in the CNS in HIV-infected individuals. This is an invasive procedure, and though mortality rates are generally low, they have been reported as high as 9%. Several strategies are used in order to attempt to avoid biopsy.

If the radiographic appearance is consistent with TE and serum antigen for toxoplasma is positive, patients often get empirically treated for TE and response to therapy guides the diagnosis. Also, there are some promising results with using single positron emission CT (SPECT) to differentiate between malignancy and infection, but this test is expensive and not uniformly available.

Non-mass lesions of the CNS are better characterized with MRI which can show typical appearance PML, cryptococcal pseudocysts if present, HIV, and CMV encephalitis.

Lumbar puncture (LP) is often obtained after a CT scan of the head and can aid in diagnosing non-mass-occupying lesions. However, LP is contraindicated in lesions with mass effect.

Cerebrospinal fluid (CSF) JCV polymerase chain reaction (PCR) has 95% specificity for PML. CSF CMV PCR specificity for CMV encephalitis exceeds 90%. Cryptococcal antigen in the CSF is highly specific for cryptococcal meningitis and usually found in high titer in the CSF. If there is evidence of increased opening pressure, these patients will need serial LPs in addition to antifungal therapy.

Tuberculous meningitis at times has focal imaging presentations but should be suspected in subacute to chronic meningitis in a patient with high risk or previous exposure to TB; it is not ruled out by negative CSF AF smear or culture.

The diagnosis of AIDS cognitive disorder is based on a history of cognitive decline and neuropsychiatric testing.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Please see disease-specific chapters for exact diagnostic criteria.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

This is a population of patients, especially the ones with severe immunocompromise, in which it is worthwhile to cast a wide net for diagnostic purposes. HIV-infected patients often have extended hospital stays, and undergo multiple costly tests and procedures. This is hard to avoid because of the high morbidity and mortality associated with complications of this disease.

The utility of obtaining a CD4 count in the setting of acute illness is questionable. There is a body of literature showing that patients with acute illness in the intensive care unit (ICU) have falsely depressed CD4 counts even if they do not have HIV infection. This likely applies to HIV patients with acute illness; the CD4 count obtained will be falsely low leading to unnecessary investigations. Thus, if a patient has a recent CD4 count from an outpatient clinic, it is appropriate to assume those are accurate and forego obtaining a new confounding lab in the hospital.

That said, patients with a new diagnosis and no previous CD4 count should have one obtained on presentation.

Also, viral loads obtained in the hospital are often seen, but there are usually no therapeutic decisions that depend on them.

III. Management while the Diagnostic Process is Proceeding

A. Management of complications of human immunodeficiency virus.

The severity of presenting illness will dictate the amount of resuscitative effort. After stabilization, a focused investigation should be expedited based on presenting symptoms and likelihood of particular diseases based on level of immunocompromise. If the patient does not have a previous CD4 count, one should be obtained.

In general, presentations of acute and subacute meningitis or meningoencephalitis can often be fatal if not treated rapidly; thus, a timely investigation should be performed to isolate the causative organism. As stated previously, CNS lymphoma and TE may often be hard to distinguish from each other radiographically. If such a case arose clinically, it would be reasonable to treat for TE while undergoing further evaluation, especially if toxoplasma serum antigen is positive.

Do not forget to consider TB in patients who have risk factors. HIV infection greatly increases the risk of reactivation of TB. Isolate these patients in negative pressure if pulmonary TB is suspected.

For management of specific complications once diagnosed, please see disease-specific chapters.

It is ideal in these cases to have the help of a specialist who has experience in HIV, not only to aid with the diagnosis, but also to make decisions about whether to stop or continue HAART as it relates to the acute illness, and when to start HAART if the patient is not currently on antiretrovirals. The guidelines for these decisions are changing and the decision process is complex and disease-dependent.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

Generally, both HAART and specific treatments for the conditions above have significant toxicities. Please see disease-specific chapters for a discussion on those and specific treatment regimens.

IV. What's the Evidence?Infectious Diseases Society of America: IDSA guidelines. www.idsasociety.org/IDSA_Practice_Guidelines/SingerEJ et al.: Neurologic Presentations of AIDS. Neurol Clin28(1): 253-75, 2010SkiestDJ: Focal neurological disease in patients with acquired immunodeficiency syndrome. Clin Infect Dis34(1): 103-15, 2002UtsukiS et al.: Primary central nervous system lymphoma in acquired immune deficiency syndrome mimicking toxoplasmosis. Brain Tumor Pathol28(1): 83-7, 2011
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