INTRODUCTION — The evaluation and management of the patient with human immunodeficiency virus (HIV) who presents with central nervous system (CNS) lesions is a challenging problem. Occasionally, the lesion(s) may represent life-threatening emergencies depending upon their size and location. The most important factor in determining the differential diagnosis is the degree of immunosuppression in the host and whether they are taking antiretroviral therapy.
This topic will address the differential diagnosis and initial clinical and diagnostic evaluation of central nervous system lesions in patients with HIV, particularly those with CD4 counts <200 cells/microL. Occasionally, patients with HIV and CD4 counts between 200 and 500 can also present with opportunistic infections. Patients with HIV who have CD4 counts >500 cells/microL are less likely to present with acquired immunodeficiency syndrome (AIDS)-defining illnesses and thus the approach is similar to patients without HIV.
Neurocognitive and neuropsychiatric disorders in patients with HIV are discussed elsewhere. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis" and "HIV-associated neurocognitive disorders: Management" and "Overview of the neuropsychiatric aspects of HIV infection and AIDS" and "HIV infection in older adults", section on 'Neurologic complications'.)
HISTORY AND PHYSICAL EXAMINATION
Assessing for impending herniation — Lesions inducing a mass effect on the surrounding brain parenchyma can lead to cerebral herniation if intraparenchymal pressure reaches a certain threshold. Clinical signs of increased intracranial pressure (eg, papilledema, Cushing triad [hypertension, bradycardia, and irregular breathing], and impaired consciousness) as well as concerning signs on imaging (eg, midline shift) should prompt urgent evaluation for possible impending herniation. These patients should not undergo a lumbar puncture and instead require medical and surgical treatment to reduce the intracranial pressure. (See "Evaluation and management of elevated intracranial pressure in adults".)
Urgent medical and surgical interventions are necessary to reduce intracranial pressure. Medical interventions include hypertonic saline or mannitol, corticosteroids, and hyperventilation. If surgical decompression is necessary, brain biopsy should be performed at the time of surgery to facilitate diagnosis. (See 'Brain biopsy' below and "Evaluation and management of elevated intracranial pressure in adults", section on 'General management'.)
Other clinical features — Although clinical features cannot reliably distinguish between the various etiologies, presence or absence of certain signs and symptoms can increase or decrease the likelihood of certain disease entities.
●History – History should assess the presence of constitutional symptoms, such as fevers, night sweats, and weight loss. Presence of all three suggests primary CNS lymphoma (PCNSL) or disseminated tuberculosis, although fever can also be seen in toxoplasmic encephalitis (TE) and other brain abscesses. Patients with progressive multifocal leukoencephalopathy (PML), HIV encephalopathy (HIVE), cytomegalovirus (CMV) encephalitis, or neurocysticercosis rarely present with fevers.
Presence of progressive subacute or chronic dementia should prompt suspicion for HIV encephalopathy; occasionally PML can also present similarly.
Seizures are common in space-occupying lesions (eg, TE, PCNSL, abscesses) as well as in PML. CNS viral infections (eg, CMV encephalitis) may also occasionally present with seizures. Patients with HIVE usually do not present with seizures.
Patients should be asked about prior history of tuberculosis, known or possible exposure to tuberculosis (eg, prison, homeless shelters, certain health care settings), and past/present travel or residence in an endemic area for tuberculosis or neurocysticercosis.
We evaluate the patient’s medication list and their adherence to the medications. Opportunistic infections, in general, are unlikely in patients taking a stable antiretroviral therapy regimen, even if CD4 count is <200 cells/microL. Toxoplasmic encephalitis is unlikely in a patient who has been consistently taking a prophylactic regimen against toxoplasmosis (eg, trimethoprim-sulfamethoxazole, atovaquone).
●Physical examination – Physical exam should include a thorough mental status and neurologic exam to evaluate the extent of mental status changes and/or focal neurologic deficits. In certain patients, the signs may be subtle. Clinical presentations of patients with CNS lesions vary widely as neurologic deficits are determined by the location of the CNS lesion.
Exam should also evaluate for any other abnormalities (eg, dysphagia, oral thrush, skin lesions) that may indicate the presence of opportunistic infection(s). This can be especially useful in situations where the immune status is not yet established and presence of certain AIDS-defining conditions (eg, oral candidiasis) may modify the differential diagnosis.
LABORATORY TESTING — Although laboratory testing cannot be used to establish a diagnosis, it may be helpful in modifying the likelihood of certain conditions. We typically send:
●CD4 cell count and HIV viral load
●Syphilis testing (eg, syphilis immunoglobulin [Ig]G, rapid plasma reagin)
●Serum cryptococcal antigen
●Toxoplasma IgG serology (if recent result not available) − Toxoplasma IgG serology should be sent if recent results are not available; negative IgG serology greatly reduces the likelihood of toxoplasmosis encephalitis (TE), although it does not rule it out completely [1,2]. If a patient is seropositive, then TE becomes more likely, although the likelihood decreases significantly if the seropositive patient has been consistently taking antiretroviral therapy or prophylaxis active against toxoplasmosis (eg, trimethoprim-sulfamethoxazole, atovaquone) [3]. (See "Toxoplasmosis in patients with HIV", section on 'Diagnosis'.)
●Bacterial and fungal blood cultures - If a bacterial or fungal brain abscess is suspected, routine and fungal blood cultures should be sent. If the patient has risk factors for tuberculosis, mycobacterial blood cultures may be sent although sensitivity is low. (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess", section on 'Laboratory studies' and "Central nervous system tuberculosis: An overview", section on 'Diagnosis'.)
Routine blood work (eg, complete blood count, chemistry panel) is not helpful in the evaluation of patients with CNS lesions, as the results are often normal.
Interferon gamma release assays, serum JC virus polymerase chain reaction (PCR), and serum cytomegalovirus (CMV) PCR are not helpful in the diagnosis of tuberculoma, progressive multifocal leukoencephalopathy, and CMV encephalitis, respectively. (See "Central nervous system tuberculosis: An overview", section on 'Diagnosis' and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis' and "AIDS-related cytomegalovirus neurologic disease", section on 'Encephalitis'.)
IMAGING — The discovery of a CNS lesion is typically made by head computed tomography (CT) or magnetic resonance imaging (MRI). Imaging characteristics such as contrast enhancement, number of lesions, size, and location can help differentiate certain conditions. However, clinical and MRI/CT criteria alone are usually insufficient to establish a diagnosis or to direct appropriate treatment in patients with HIV and CNS lesions.
MRI preferred over CT — We favor imaging with MRI with contrast to fully assess the characteristics of CNS lesion(s), when possible. MRI has many advantages compared with CT scan. It is much more sensitive than CT scan in determining if a lesion is truly solitary, it has greater sensitivity for white matter disease or lesions in the posterior fossa [2], and, if a biopsy is being considered, it may identify a peripheral lesion that is more accessible for histologic sampling [4] (image 1).
Both head CT and MRI must be performed before and after injection of contrast material to determine whether a lesion enhances on neuroimaging. CT head without contrast (and sometimes with contrast) may not capture certain nonenhancing CNS lesions and cannot reliably confirm absence of lesions. For patients with renal insufficiency (eg, chronic kidney disease, acute kidney injury), brain imaging should not be delayed due to concern for nephrogenic systemic fibrosis (NSF) given the low risk of NSF with the newer gadolinium-containing contrast agents [5].
Other imaging modalities — The role of thallium single-photon emission computerized tomography (SPECT) scans, perfusion MRI, magnetic resonance spectroscopy, and positron emission tomography (PET) in facilitating the diagnosis of a CNS lesion is unclear. Most studies have evaluated these modalities in the differentiation of TE from primary CNS lymphoma (PCNSL) [6-15]. For example, since thallium is more avidly taken up by tumor cells, thallium 201 SPECT scan was studied in 37 patients with AIDS and intracranial mass lesions and found that all 12 patients with increased isotope uptake had biopsy proven PCNSL, while 24 of 25 without uptake had toxoplasmosis encephalitis (TE) [7]. Further discussion on the role of these imaging modalities in the diagnosis of PCNSL are discussed elsewhere. (See "HIV-related lymphomas: Primary central nervous system lymphoma", section on 'Neuroimaging features'.)
Lesion features — While certain lesion features (eg, size, location, degree of enhancement) may help support a diagnosis, none of the following features are specific enough to be sufficient to establish a diagnosis. Many of these characteristics are not pathognomonic and can be seen in other conditions. However, there are a few characteristic presentations that can help guide a clinician towards one etiology over the others.
Space-occupying versus nonspace-occupying lesions
●Space-occupying lesions – A space-occupying lesion is an abnormality that occupies excess space and volume within the brain parenchyma. CNS space-occupying lesions are characterized by the presence of swelling and edema and often can exert mass effect on surrounding structures. In some cases, especially for lesions located in the posterior fossa, cerebral herniation can occur (see 'Assessing for impending herniation' above). Space-occupying lesions usually enhance after the injection of contrast material, indicating local inflammation and breakdown of the blood-brain barrier. Common causes of space-occupying lesions in the brain include TE, PCNSL, and bacterial/fungal brain abscesses. In patients with specific epidemiologic risk factors, tuberculomas are also common. Rare causes of space-occupying lesions include cryptococcomas [16,17], syphilitic gummas [18], and neurocysticercosis. Occasionally, progressive multifocal leukoencephalopathy (PML) can present as a space-occupying lesion, especially in the setting of immune reconstitution inflammatory syndrome (IRIS) that occurs with the rise in CD4 count or the fall in plasma HIV viral load after initiation of antiretroviral therapy (ART). (See 'Space-occupying lesions' below.)
●Nonspace-occupying lesions − Nonspace-occupying lesions do not occupy volume but rather reflect inflammation or destruction of the brain parenchyma. Nonspace-occupying lesions usually do not enhance after the injection of contrast material and are not associated with a risk of herniation. Most lesions are due to PML or HIV-associated encephalopathy (HIVE), although the incidence has been declining since the introduction of effective combination ART [19,20]. Cytomegalovirus (CMV) encephalitis is rare in the ART era. (See 'Nonspace-occupying lesions' below.)
Contrast enhancement
●Presence of contrast enhancement − Enhancement usually signifies the presence of inflammation. Contrast enhancement is typically more common in space-occupying lesions, such as TE, PCNSL, or brain abscess. Periventricular enhancement and increased periventricular signal on T2-weighted MRI images is suggestive of CMV ventriculoencephalitis [21]. Rarely, CMV can cause focal ring-enhancing lesions with edema and mass effect [22]. Diffuse ring enhancement with surrounding edema and mass effect is typical for TE and is present in approximately 90 percent of TE cases (image 2). Uncommonly, TE can present as a diffuse encephalitis, which is not associated with focal abscess formation [23]. In contrast, lesions with irregular or patchy enhancement is suggestive of PCNSL (image 3). However, diffuse ring enhancement, identical to that commonly seen in TE, can occur.
●Absence of contrast enhancement – Nonspace-occupying lesions tend to be contrast nonenhancing. Presence of nonenhancing, nonspace-occupying lesions suggests PML or HIVE as the cause.
PML is characterized by noncontrast-enhancing lesions that are not surrounded by edema; as a result, substantial mass effect on surrounding structures is absent. However, PML may occur in the setting of an IRIS associated with increase of CD4 cell count and drop of HIV plasma viral load on ART. In this context, PML/IRIS can present with contrast enhancement on MRI, as well as focal edema and mass effect [24].
HIVE is characterized by multiple hyperintense signals on MRI T2-weighted images, which are generally nonenhancing and localized bilaterally in the subcortical white matter (image 4).
Clinicians need to be aware that steroid therapy, which reduces inflammatory responses, can convert enhancing lesions into nonenhancing lesions. (See 'Avoid corticosteroids except in select circumstances' below.)
Solitary versus multiple lesions — The number of lesions can be helpful when determining the likelihood of a specific diagnosis. A solitary lesion seen on CT should be followed up with an MRI to determine whether the lesion is truly solitary. A solitary lesion (especially >4 cm in size) is particularly concerning for PCNSL [3]. In contrast, TE presents with multiple ring-enhancing lesions, although rarely, single lesions can also be seen [25].
Many conditions commonly present with either solitary or multiple contrast-enhancing lesions, including PCNSL, brain abscesses, tuberculomas, and neurocysticercosis [26-28]. Nonenhancing lesions due to PML or HIVE are unlikely to present as solitary lesions.
Location — Location of the lesions can be helpful in establishing the diagnosis. Lesions within the cortex are typically caused by toxoplasmosis, abscesses, CMV, and neurocysticercosis [25]. In contrast, lesions found in the periventricular area are typically caused by PCNSL or PML but can be caused by CMV as well [24]. Involvement of the subcortical white matter suggests PML or HIVE. Presence of asymmetric nonspace-occupying lesions that primarily involve white matter is very suggestive for PML. PCNSL often affects the corpus callosum and periependymal areas [3]. Tuberculomas, as well as toxoplasmosis and CMV, are known to preferentially affect the basal ganglia [25].
Symmetry — Almost all the conditions discussed above present asymmetrically when multiple lesions are present. The one exception is HIVE, which typically presents with multiple, poorly demarcated, bilateral symmetric lesions.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis is determined by the degree of immunosuppression (eg, CD4 count), whether the patient is on a stable antiretroviral therapy (ART) regimen, exposure history (eg, known tuberculosis exposure), and whether the lesion occupies space and volume within the brain parenchyma. Occasionally, multiple etiologies can coexist in an immunosuppressed individual [29-31]. As an example, in one study of patients with AIDS undergoing brain biopsy for the diagnosis of focal CNS lesions, 6 percent had more than one etiology established from histologic sampling of a single lesion [30].
Role of CD4 count and ART — The CD4 count and degree of immunocompromise, as well as whether the patient is taking ART, both play a large role in the differential diagnosis of CNS lesions in a patient with HIV.
CD4 count >500 cells/microL — In patients with CD4 counts >500 cells/microL, the differential diagnosis of CNS lesions is the same as in immunocompetent adults. These include benign and malignant brain tumors, brain metastases, and brain abscesses. Opportunistic infections and AIDS-related malignancies are less likely, although the risk for tuberculosis (and tuberculomas) remains even in patients with a recovered immune system. (See "Risk factors for brain tumors" and "Overview of the clinical features and diagnosis of brain tumors in adults".)
CD4 count 200 to 500 cells/microL — Although patients with CD4 counts from 200 to 500 cells/microL are moderately immunosuppressed, they do not usually present with focal lesions from AIDS-defining illnesses, especially if they are also taking a stable ART regimen. CNS lesions are most commonly the same as are found in immunocompetent patients. However, the disease entities discussed in this topic should be considered in the following individuals:
●In whom percentage of CD4 cells ≤14 percent
●Not taking ART
●Recently initiated ART and are at risk for immune reconstitution inflammatory syndrome (IRIS)
●Have existing or prior opportunistic infections
CD4 count <200 cells/microL — The etiologies of CNS lesions discussed in this topic are most common in severely immunosuppressed patients with CD4 counts <200 cells/microL and not on ART. The most likely diagnostic considerations include opportunistic infections and AIDS-associated tumors, with toxoplasmic encephalitis (TE), primary CNS lymphoma (PCNSL), and progressive multifocal leukoencephalopathy (PML) being the most common diagnoses [32]. Tuberculomas are also very common in tuberculosis-endemic areas. Although widespread use of ART has significantly decreased the incidence of the following disease entities, these conditions remain a cause of morbidity and mortality in patients with uncontrolled HIV.
Patients who are on a stable ART regimen with CD4 counts persistently below 200 cells/microL are unlikely to present with opportunistic infections.
Space-occupying lesions — A space-occupying lesion occupies excess space and volume within the brain parenchyma and is characterized by the presence of swelling, edema; it can exert mass effect on surrounding structures. (See 'Space-occupying versus nonspace-occupying lesions' above.).
Etiologies that cause space-occupying lesions are discussed below.
Toxoplasmic encephalitis — TE represents reactivation of disease from prior infection and is typically seen in patients with CD4 counts <100 cells/microL and positive Toxoplasma gondii serology who are not taking ART. Affected patients present with fever, headache, altered mental status, and focal neurologic complaints or seizures. (See "Toxoplasmosis in patients with HIV", section on 'Toxoplasmic encephalitis'.)
Primary central nervous system lymphoma — PCNSL is generally seen in patients with CD4 counts <50 cells/microL who are not on ART. Patients present with headache, confusion, lethargy, memory loss, hemiparesis, aphasia, and/or seizures. In addition, constitutional symptoms, such as fever, night sweats, and weight loss, occur in over 80 percent of patients. (See "HIV-related lymphomas: Primary central nervous system lymphoma".)
Bacterial/fungal brain abscess — Brain abscesses secondary to Staphylococcus spp, Streptococcus spp, Salmonella spp, Aspergillus spp, Nocardia spp, Rhodococcus spp, and Listeria spp have been reported in patients with advanced HIV [33]. Although abscesses can present either with or without mass effect, contrast-enhancing mass lesions are characteristic and they can lead to herniation in severe cases. Patients present with headache, confusion, seizures, and focal neurologic deficits. Fever is also commonly seen. (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess".)
Tuberculoma — Tuberculoma is a granulomatous accumulation of coalescing tubercles that occurs due to disseminated tuberculosis. Tuberculoma should be suspected in any patient with history of prior tuberculosis infection or disease, known or possible tuberculosis exposure, and/or past or present residence in or travel to an area where tuberculosis is endemic. Tuberculomas can present as a focal lesion without evidence of systemic illness or meningeal infection. In countries with a high incidence of tuberculosis, tuberculomas are a leading diagnostic consideration [28]. Patients present with headache, seizures, progressive hemiplegia, and elevated intracranial pressure. Tuberculomas can also occur during immune reconstitution after a patient has initiated ART. (See "Central nervous system tuberculosis: An overview", section on 'Tuberculoma'.)
Neurocysticercosis — Neurocysticercosis is caused by the larval stage of the pork tapeworm Taenia solium. The appearance of neurocysticercosis depends upon the stage of the infection and the host immune response. Neurocysticercosis should be suspected in patients with risk factors for the ingestion of T. solium eggs shed in the stool of a tapeworm carrier. This typically occurs in patients with past/present residence in or travel to an area where T. solium is endemic or who are in close contact or live with an asymptomatic carrier. (See "Cysticercosis: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)
Nonspace-occupying lesions — Nonspace-occupying lesions do not occupy volume but rather reflect inflammation or destruction of the brain parenchyma. (See 'Space-occupying versus nonspace-occupying lesions' above.)
Etiologies that cause non space-occupying lesions are discussed below.
Progressive multifocal leukoencephalopathy — PML is a demyelinating disease caused by the reactivation of the JC virus in the setting of severe immunosuppression (eg, CD4 counts <200 cells/microL). PML can also occur in the setting of immune reconstitution as HIV viral load drops and CD4 cell counts rise. Although PML typically presents as a space-destroying CNS lesion and does not exert mass effect, PML associated with IRIS can present as a contrast-enhancing space-occupying lesion. Patients with PML characteristically present with rapidly progressive focal neurologic deficits including hemiparesis, visual field deficits, ataxia, aphasia, and cognitive impairment. Seizures are also commonly seen. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)
HIV-associated encephalopathy — HIV encephalopathy can present as a severe, demyelinating leukoencephalopathy with prominent white matter lesions in highly immunocompromised patients with HIV (eg, CD4 counts <200 cells/microL) who are not taking ART [34]. It generally presents with the classic triad of symptoms of subcortical dementia: memory and psychomotor speed impairment, depressive symptoms, and movement disorders. Although this entity is not usually included in the category of CNS lesions, it can masquerade as PML. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis".)
Cytomegalovirus encephalitis — Encephalitis due to cytomegalovirus (CMV) results from reactivation in patients with CD4 counts <50 cells/microL who are not taking ART. CMV can present as a diffuse micronodular encephalitis or ventriculoencephalitis [35]. These patients present with delirium, confusion, and focal neurologic abnormalities. CMV ventriculoencephalitis may also cause cranial nerve defects. Patients with CMV encephalitis typically have retinal or gastrointestinal involvement as well. (See "AIDS-related cytomegalovirus neurologic disease".)
DIAGNOSTIC EVALUATION — Establishing a diagnosis requires taking into account serology, cerebrospinal fluid (CSF), and histopathology (if done) results, as well as the patient’s degree of immunocompromise, clinical symptoms and signs, neuroimaging findings, and use of concomitant medications (eg, trimethoprim-sulfamethoxazole, antiretroviral therapy [ART]) that could alter the likelihood of a diagnosis. The diagnostic approach that we usually follow is summarized in the algorithm (algorithm 1).
Lumbar puncture — Lumbar puncture (LP) should be performed in all patients presenting with CNS lesions unless it is contraindicated (eg, increased intracranial pressure, severe thrombocytopenia) (see 'Contraindications to lumbar puncture' below). Although the utility of lumbar puncture in establishing a diagnosis is limited, we recommend performing an LP as it may alleviate the need for a brain biopsy in some patients. If LP cannot be performed in a timely manner, empiric treatment should be considered if toxoplasmic encephalitis is strongly suspected (see 'Empiric treatment against toxoplasmic encephalitis in select toxoplasma-seropositive patients' below). If diagnosis cannot be established based on LP results, brain biopsy should be pursued. (See 'Brain biopsy' below.)
Contraindications to lumbar puncture — Impending herniation is an absolute contraindication to lumbar puncture. LP is also contraindicated in patients with focal signs or with lesions producing mass effect, especially in the posterior fossa, due to the risk of transtentorial herniation, and in patients with an increased risk of bleeding (eg, severe thrombocytopenia, presence of a coagulopathy). (See "Lumbar puncture: Technique, indications, contraindications, and complications in adults", section on 'Contraindications'.)
Routine CSF testing — CSF testing should include the routine cell count with differential, glucose, protein, bacterial Gram stain and culture, and fungal stain and culture. However, since most patients with HIV present with mild pleocytosis with or without an elevated protein concentration, routine testing is generally not useful in differentiating the cause of the CNS lesion. Even in patients with a bacterial CNS abscess, CSF findings usually reflect a parameningeal pattern with <500 leukocytes/microL (predominantly lymphocytes), a normal glucose concentration, and a normal to mildly elevated protein concentration. CSF cultures in the setting of an isolated bacterial brain abscess are often negative.
In addition to the general CSF testing, we also send the following tests as part of our evaluation of patients with HIV and CNS lesions:
●Cytology and flow cytometry − CSF cytology can help in the diagnosis of lymphoma if it is positive, but this occurs in only 15 percent of cases with meningeal seeding. Patients with high suspicion of primary CNS lymphoma (PCNSL) and a negative cytology and flow cytometry should undergo further diagnostic evaluation for PCNSL with Epstein-Barr virus (EBV) polymerase chain reaction (PCR) and if necessary, brain biopsy. (See 'Brain biopsy' below and "HIV-related lymphomas: Primary central nervous system lymphoma", section on 'Cytology and flow cytometry'.)
●Cryptococcal antigen − Cryptococcal antigen is a highly sensitive and specific test with a fast turnaround time that can help diagnose cryptococcal meningitis and cryptococcomas. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV", section on 'Spinal fluid' and "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'Cryptococcal antigen'.)
●T. gondii PCR − PCR detection of T. gondii in CSF can be helpful in diagnosing toxoplasmosis when the result is positive, since the specificity ranges from 96 to 100 percent; however, the sensitivity of this test is only 50 percent, so a negative test is not sufficient to rule out the diagnosis [2,3,36,37]. (See "Toxoplasmosis in patients with HIV", section on 'Polymerase chain reaction'.)
●JC virus PCR − PCR detection of JC virus deoxyribonucleic acid (DNA) in progressive multifocal leukoencephalopathy (PML) had a sensitivity of 74 to 93 percent and a specificity of 92 to 100 percent before the widespread use of combination ART [3,36,38-45]. Since then, the sensitivity of this test has dropped to 58 percent [46,47]. This is likely explained by ART-induced immune recovery, which may lower JC virus replication below the level of assay detection. Accordingly, a patient with a positive PCR result who has a compatible radiologic picture can be presumed to have PML [2]. Conversely, patients who present with clinical and radiologic findings consistent with PML but have a negative CSF JC virus PCR should still be considered as having possible PML if other diagnoses have been ruled out [48]. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Lumbar puncture and PCR'.)
●EBV PCR − We send EBV PCR in most patients to facilitate the diagnosis of PCNSL and potentially avoid a brain biopsy. The utility of using PCR for EBV DNA is unclear however, as the sensitivity and specificity have varied widely depending upon whether the assay is performed in a research setting or a clinical laboratory [3,37,49], as well as the pretest probability of PCNSL. Although a positive EBV DNA PCR in an immunosuppressed patient with findings consistent with PCNSL is supportive of the diagnosis, it does not exclude other causes of CNS disease. (See "HIV-related lymphomas: Primary central nervous system lymphoma", section on 'EBV PCR'.)
Additional CSF testing in select patients — We send the following tests in patients in whom the initial CSF testing was nondiagnostic or when there is a strong suspicion of a certain etiology based on clinical and imaging features (see 'Other clinical features' above and 'Lesion features' above). Which of the following tests to order depends upon the clinical presentation.
●In patients with risk factors for tuberculosis exposure, we send acid-fast bacilli (AFB) stain and culture as well as a tuberculosis nucleic acid amplification test. The sensitivity of these tests (especially AFB stain and culture) is quite low though and brain biopsy is often necessary for diagnosis unless tuberculosis is identified elsewhere in the body. (See "Central nervous system tuberculosis: An overview", section on 'Diagnosis'.)
●In patients with a high suspicion of cytomegalovirus (CMV) encephalitis, we send CMV PCR which has a reported sensitivity exceeding 80 percent and a specificity of 90 percent [2,50]. (See "AIDS-related cytomegalovirus neurologic disease", section on 'Encephalitis'.)
●In patients in whom other non-HIV causes seem unlikely, we send HIV viral load in the CSF to evaluate for CSF viral escape phenomenon. A detectable HIV viral load in the CSF that is higher than the plasma HIV viral load is suggestive of CSF viral escape phenomenon, which increases the risk for HIV-associated neurocognitive disorders such as HIV encephalopathy. If CSF HIV viral load is detectable, we send CSF for HIV genotype to evaluate for any discordance in HIV mutations that may alter management [51]. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis", section on 'CNS viral escape syndrome' and "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis", section on 'Further evaluation'.)
Approach to those with contraindications to lumbar puncture — Patients who cannot undergo an LP or for whom a LP was nondiagnostic should undergo either a trial of empiric therapy for TE, if certain criteria are met, or proceed to a brain biopsy. (See 'Empiric treatment against toxoplasmic encephalitis in select toxoplasma-seropositive patients' below and 'Brain biopsy' below.)
Empiric treatment against toxoplasmic encephalitis in select toxoplasma-seropositive patients — A trial of empiric therapy for possible TE may be considered as an alternative to brain biopsy in patients with characteristic radiographic findings who are not candidates for LP or in whom the LP was nondiagnostic.
A trial of empiric toxoplasmosis therapy should be initiated if all the following are present:
●CD4 count <200 cells/microL
●Radiographic findings consistent with TE (eg, multiple diffuse ring-enhancing lesions)
●Patient has not received consistent prophylaxis against toxoplasmosis for 12 weeks preceding the onset of symptoms (eg, trimethoprim-sulfamethoxazole, atovaquone)
This option may be particularly attractive in patients with rapid clinical deterioration.
It is critical to closely monitor the patient's neurologic examination during a trial of empiric therapy. Clinical improvement is expected within one to two weeks and imaging should be repeated within this time frame to assess radiographic changes [52]. The diagnosis of TE is established if the patient clinically improves and there is a reduction in lesion size within two weeks. A brain biopsy should be pursued in patients who do not have clinical and radiologic improvement.
Occasionally, empiric toxoplasmosis therapy can also be initiated in patients with solitary ring-enhancing lesions if PCNSL is unlikely, such as in a patient with a CD4 count between 50 to 200 cells/microL. In these situations, an imaging study should be repeated in approximately one week with plans for early biopsy if no improvement is seen.
For patients who do not meet the criteria for empiric toxoplasmosis treatment, brain biopsy should be pursued rapidly to make a diagnosis. (See 'Brain biopsy' below.)
A more detailed discussion of empiric and definitive therapy for toxoplasmosis is presented in a separate topic review. (See "Toxoplasmosis in patients with HIV".)
Brain biopsy — Brain biopsy can be performed in patients who are already undergoing surgical decompression for elevated intracranial pressure. In these situations, biopsy specimens should be collected at the time of surgery and sent for histopathology and culture to facilitate diagnosis. If corticosteroids are administered to reduce the intracranial pressure, specimens should be collected as soon as possible; corticosteroids can interfere with the ability to detect lymphoma on specimen tissue. (See 'Avoid corticosteroids except in select circumstances' below.)
Brain biopsy is also indicated in patients in whom diagnosis remains inconclusive after LP results. Brain biopsy is the gold standard for the diagnosis of focal CNS lesions in AIDS [2,30] since several studies have demonstrated the inadequacy of clinical acumen alone [30,53]. A definitive diagnosis is reached in as many as 93 to 96 percent patients [3,54]. However, biopsy may not be possible with lesions in certain locations.
Brain tissue specimens should be sent to pathology and to microbiology for bacterial and fungal stains and culture. AFB stain and culture should also be sent if tuberculosis is suspected.
Although brain biopsy is effective in establishing the diagnosis in most patients, it is associated with significant risk. The overall reported complication rate has ranged from 0 to 3.1 percent mortality, 0.5 to 9 percent major morbidity, and 2 to 4 percent minor morbidity [3,54-56]. The outcomes are better in centers with technical expertise.
AVOID CORTICOSTEROIDS EXCEPT IN SELECT CIRCUMSTANCES — Corticosteroids should generally be avoided while undergoing evaluation for CNS lesions, as corticosteroids can convert enhancing lesions into non-enhancing ones on imaging (thereby modifying the differential diagnosis) and cause false negative results on brain biopsy in patients with primary CNS lymphoma (PCNSL).
However, corticosteroid therapy may be considered when:
●Substantial mass effect can be demonstrated on imaging and the mental status is significantly depressed. Such patients are at risk for cerebral herniation. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Glucocorticoids' and "Management of vasogenic edema in patients with primary and metastatic brain tumors", section on 'Symptomatic treatment'.)
OR
●The diagnosis of PCNSL has already been established and glucocorticoids are considered as part of treatment. (See "Primary central nervous system lymphoma: Clinical features, diagnosis, and extent of disease evaluation", section on 'Avoidance of glucocorticoids'.)
Corticosteroids will decrease brain swelling whether or not the mass is due to infection. As a result, a clear response to therapy is of no value in diagnosis.
SUMMARY AND RECOMMENDATIONS
●History and physical examination
•Assessing for impending herniation − Clinical signs suggestive of impending herniation include papilledema, Cushing triad (hypertension, bradycardia, and irregular breathing), and impaired consciousness. These patients should not undergo a lumbar puncture (LP) and instead require urgent medical and surgical treatment to reduce the intracranial pressure. (See 'Assessing for impending herniation' above and "Evaluation and management of elevated intracranial pressure in adults".)
•Assessing other clinical features – When taking a history, we ask about symptom characteristics, the presence of seizures, and any exposure to tuberculosis and neurocysticercosis. We also review the patient’s medications and their adherence to them. Physical examination should include a detailed neurologic exam as well as an evaluation for the presence of opportunistic infections (eg, oral candidiasis). (See 'Other clinical features' above.)
●Laboratory testing – We typically send CD4 cell count and HIV viral load, toxoplasma IgG serology (if recent result not available), syphilis testing, bacterial and fungal blood cultures, and serum cryptococcal antigen; if tuberculosis is suspected, we send off mycobacterial blood cultures as well. Interferon gamma release assays, serum JC virus polymerase chain reaction (PCR), and serum cytomegalovirus (CMV) PCR are not helpful in the diagnosis of tuberculoma, progressive multifocal leukoencephalopathy (PML), and CMV encephalitis, respectively (algorithm 1). (See 'Laboratory testing' above.)
●Imaging
•MRI preferred over CT − We prefer magnetic resonance imaging (MRI) over computed tomography (CT) for the evaluation of central nervous system (CNS) lesions because of MRIs higher sensitivity in detecting CNS lesions. Imaging must be performed before and after injection of contrast material to determine whether a lesion enhances on neuroimaging. (See 'MRI preferred over CT' above.)
•Lesion features − Certain lesion features (eg, size, location, degree of enhancement) may help inform the differential diagnosis. (See 'Lesion features' above.)
●Differential diagnosis
•Role of the CD4 count and ART − The most important factor in determining the differential diagnosis in a patient with HIV and suspected CNS lesions is the degree of immunosuppression in the host. Infections and AIDS-related malignancies are most common in severely immunosuppressed patients with CD4 cell counts ≤200/microL who are not on antiretroviral therapy (ART). (See 'Role of CD4 count and ART' above.)
•Space-occupying lesions − Space-occupying lesions are characterized by the presence of swelling, edema, and mass effect on surrounding structures. The two leading diagnoses associated with mass effect in developed countries are toxoplasmic encephalitis and primary CNS lymphoma (PCNSL). Tuberculomas are also common in tuberculosis-endemic settings. (See 'Space-occupying lesions' above.)
•Nonspace-occupying lesions − Nonspace-occupying lesions usually do not enhance after the injection of contrast material and are not associated with a risk of herniation; most lesions are due to PML or HIV-associated encephalopathy. (See 'Nonspace-occupying lesions' above.)
●Diagnostic evaluation and initial management − Diagnostic evaluation consists of an LP and/or a brain biopsy if LP is contraindicated or nondiagnostic (algorithm 1). (See 'Diagnostic evaluation' above.)
•Lumbar puncture
-All patients should have cerebrospinal fluid sent for cell count, glucose, protein, and bacterial and fungal culture. We also send cryptococcal antigen, cytology and flow cytometry, Toxoplasma gondii PCR, JC virus PCR, and Epstein-Barr virus PCR for all patients with HIV and CNS lesions. (See 'Routine CSF testing' above.)
-Additional testing based on clinical presentation and differential diagnosis includes tuberculosis testing, CMV PCR, and HIV viral load and genotype. (See 'Additional CSF testing in select patients' above.)
•Contraindications to lumbar puncture − LP is contraindicated in patients with focal signs or with lesions producing mass effect and in those with increased risk of bleeding (eg, severe thrombocytopenia). (See 'Contraindications to lumbar puncture' above.)
-In patients with characteristic radiographic findings who are not candidates for LP or in whom LP was nondiagnostic, a trial of empiric therapy for possible toxoplasmic encephalitis may be considered as an alternative to brain biopsy. (See 'Empiric treatment against toxoplasmic encephalitis in select toxoplasma-seropositive patients' above.)
-Open or stereotactic brain biopsy can be helpful in establishing the diagnosis in cases where LP is inconclusive or contraindicated. (See 'Brain biopsy' above.)
•Avoid corticosteroids except in certain circumstances − Corticosteroids should be avoided because they can convert enhancing lesions into nonenhancing ones on imaging (thereby modifying the differential diagnosis) and cause false-negative results on brain biopsy in patients with PCNSL. Corticosteroid therapy should only be considered in patients at increased risk of herniation. (See 'Avoid corticosteroids except in select circumstances' above.)
ACKNOWLEDGMENT — We are saddened by the death of John G Bartlett, MD, who passed away in January 2021. UpToDate gratefully acknowledges Dr. Bartlett's role as section editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Infectious Diseases, and his dedicated and longstanding involvement with the UpToDate program.
