EBV Serology: Igg +Ve, Igm Ve

2002 FRACP ID Q3

HIV +ve man with CD4 count =10 and 250,000 copies of RNA developes focal neurological deficits. Given the following results: EBV serology: IgG +ve, IgM –ve Toxo serology : IgG –ve, IgM –ve CMV serology : IgG +ve, IgM –ve CSF : 20 lymphocytes/hpf. Biochem normal, Cryptococcal Ag –ve CSF PCR: JC virus –ve, EBV +ve

Head CT( coronal- top half of head, no ventricles shown): 2 ring enhancing lesions in each hemisphere. Likely diagnosis:

a) Toxoplasmosis b) Cerebral lymphoma c) Cerebral abscess d) Multifocal leucoencephalopathy e) Cryptococal meningitis

Answer: b)

HIV-infected patients presenting with a change in mental status or an abnormal neurologic examination often have lesions on brain imaging, either computed tomography (CT) scan or magnetic resonance imaging (MRI).

The most important factor in the differential diagnosis is the degree of immunosuppression in the host.

• In patients with CD4 cell counts >500/µL, benign and malignant brain tumors and metastases predominate in the differential diagnosis of CNS lesions, just like in immunocompetent hosts. These lesions are most likely unrelated to HIV infection.

• In those moderately immunosuppressed with CD4 counts from 200 to 500/µL, HIV-associated cognitive and motor disorder are common, but they usually do not present with CNS mass lesions.

• Mass lesions are most common in severely immunosuppressed patients with CD4 cell counts <200/µL, and these are the patients in whom opportunistic infections (OIs) and acquired immunodeficiency syndrome (AIDS)-associated tumors are the most probable consideration.

RADIOLOGIC APPEARANCE OF CNS MASS LESIONS – The discovery of a CNS mass lesion is made by a head CT or a MRI. These examinations must be performed before and after injection of contrast material, which is crucial to determine the inflammatory component of a lesion. The MRI is much more sensitive than the CT scan and should be preferred whenever it is available [1]. CNS mass lesions can be classified in two categories, according to the presence or absence of mass effect.

A) CNS lesions with mass effect – These lesions are characterized by the presence of swelling, edema, and mass effect on the surrounding structures. In some cases, especially for lesions located in the posterior fossa, cerebral herniation can occur. These lesions usually enhance after the injection of contrast material, indicating local inflammation and breakdown of the blood-brain barrier.

Toxoplasma encephalitis (TE) – Toxoplasma encephalitis (TE) is the most common cerebral mass lesion in patients with AIDS. Head CT and MRI will demonstrate CNS lesions in almost all cases, with exception of the rare diffuse form of toxoplasmosis. Lesions are multiple in two-thirds of cases and display ring enhancement in approximately 90 percent . The MRI has been shown to be more sensitive than the CT to detect multiple lesions. Other common findings are fever, focal neurologic findings, and positive T. gondii IgG serology.

These lesions are generally localized at the cortico-medullar junction, in the white matter or the basal ganglia, and are surrounded by edema with frequent mass effect on surrounding structures. Unfortunately, the neuroradiologic characteristics of TE are not pathognomonic and may be observed in other conditions, particularly lymphoma.

Primary central nervous system lymphoma (PCNSL) – The head CT or MRI in most cases of primary central nervous system lymphoma (PCNSL) will show findings consistent with CNS tumor. Solitary mass lesions and multiple lesions occur with approximately equal frequency [2].

The majority of these lesions display some degree of enhancement, most commonly nodular or patchy . However, ring enhancement, identical to that commonly seen in TE, can occur. These correlate with central tumor necrosis. Subependymal enhancement seems more specific to PCNSL. PCNSL in non-AIDS patients usually has a periventricular location. However, this localization does not apply in AIDS patients in whom most PCNSL lesions are localized to the cortex or deep structures.

Lesions can be surrounded by edema and produce variable mass effect on neighboring structures. MRI is more sensitive than CT in revealing multiple lesions, which can be useful if a biopsy is considered.

Others – Other OIs can be associated with mass effect. These include cryptococcomas, fungal infections, tuberculosis, and CMV encephalitis. However, all of these entities are much less common and often associated with a disseminated infection.

B) CNS lesions without mass effect – These lesions are devoid of mass effect and do not enhance after the injection of contrast material. They are not associated with a risk of herniation.

Progressive multifocal leukoencephalopathy (PML) – The hallmark of progressive multifocal leukoencephalopathy (PML) is patchy or confluent areas of low attenuation on CT or hyperintensity of T2-weighted images on MRI. The MRI is twice as sensitive as CT in distinguishing multiple lesions [1].

These lesions are generally not contrast-enhancing and are not surrounded by edema; hence, substantial mass effect on surrounding structures is absent. However, 8 percent of lesions can show faint, peripheral, and irregular enhancement.

Lesions are usually bilateral, asymmetric, and localized preferentially to the periventricular areas and the subcortical white matter [1]. Involvement of the deep gray structures, including basal ganglia and thalamus, can nevertheless be found in up to 17 percent of cases. A normal CT or MRI does not rule out PML since microscopic lesions may be smaller than the power of resolution of these tests. One such case showed multiple, small foci of demyelination disseminated among the cortical U fibers at autopsy [3].

HIV encephalopathy (HIVE) – HIVE has a variable presentation on CT scan and MRI. A subcortical and cortical atrophy is often associated with multiple hyperintense signals in T2-weighted images on MRI; these are generally non enhancing and localized bilaterally in the subcortical white matter. Although this entity is not usually included in the category of CNS mass lesions, it can masquerade as PML. However, HIVE lesions are usually symmetrical, less demarcated than lesions of PML, and may be associated with symptoms of AIDS dementia but not with focal motor and sensory deficits.

CSF examination – A cerebrospinal fluid (CSF) examination is the next step in the diagnosis of CNS mass lesions in HIV-infected patients. In patients with lesions producing mass effect, especially in the posterior fossa, a lumbar puncture (LP) may not be possible because of the risk of provoking a transtentorial herniation. In addition, none of the organisms most frequently responsible for CNS mass lesions in HIV infection can be readily identified by culture. 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. Lymphomatous meningitis can also be present in patients with systemic lymphomas, who do not have CNS involvement.

CSF polymerase chain reaction – While most of the organisms of interest cannot be recovered from CSF, polymerase chain reaction (PCR) has been very useful for the detection of Epstein-Barr virus (EBV) DNA, which is found in association with almost 100 percent of CNS lymphomas in AIDS. This technique has a sensitivity of 83 to 100 percent and a specificity of 93 to 100 percent, which is comparable to a brain biopsy [10-12]. PCR detection of JC virus (JCV) DNA in PML has also a sensitivity of 74 to 93 percent and a specificity of 92 to 100 percent [10,13-20]. Thus, PCR has now become an established way to ascertain the diagnosis of PML. For unclear reasons, PCR has not been as helpful for the detection of Toxoplasma gondii in the CSF, with a sensitivity of only 44 to 65 percent, and a specificity of 100 percent [12,21].

The Immunocompromised Host

As discussed above, in patients with AIDS, the presence of IgG and radiologic findings consistent with toxoplasmosis are grounds for a presumptive diagnosis. Attempts to evaluate rising IgG titers or to determine whether IgM is present are not productive. Serologic evidence of infection virtually always precedes the development of Toxoplasma encephalitis. It is therefore important to determine the Toxoplasma antibody status of all patients infected with HIV. Antibody titers may range from negative to 1:1024 in patients with AIDS and Toxoplasma encephalitis. Fewer than 3% of patients have no demonstrable antibody to Toxoplasma at the time of diagnosis. Determination of the intrathecal antibody titer may be useful in identifying prior infection. PCR amplification of genetic material of the parasite found in the CSF may prove diagnostically beneficial in the future.

Patients with toxoplasmic encephalitis have focal or multifocal abnormalities demonstrable by CT or MRI. These findings are not pathognomonic of Toxoplasma infection since 40% of CNS lymphomas are multifocal and 50% are ring-enhancing. Lesions on MRI scan are multiple and are located in both hemispheres, with the basal ganglia and corticomedullary junction most commonly involved. For both MRI and CT scans, the rate of false-negative results is approximately 10%. The finding of a single lesion on an MRI scan increases the suspicion of primary lymphoma and strengthens the argument for the performance of a brain biopsy.

If the patient is seronegative for T. gondii, the likelihood that a mass lesion is due to toxoplasmosis is <10%.

Primary CNS lymphoma accounts for approximately 20% of the cases of lymphoma in patients with HIV infection. In contrast to HIV-associated Burkitt's lymphoma, primary CNS lymphomas are usually positive for EBV. In one study, the incidence of Epstein-Barr positivity was 100%. This malignancy does not have a predilection for any particular age group. The median CD4+ T cell count at the time of diagnosis is approximately 50/ L. Thus, CNS lymphoma generally presents at a later stage of HIV infection than systemic lymphoma. This fact may at least in part explain the poorer prognosis for this subset of patients.

The clinical presentation of lymphoma in patients with HIV infection is quite varied, ranging from focal seizures to rapidly growing mass lesions in the oral mucosa (Fig. 309-36) to persistent unexplained fever. At least 80% of patients present with extranodal disease, and a similar percentage have B-type symptoms of fever, night sweats, or weight loss. Virtually any site in the body may be involved. The most common extranodal site is the CNS, which is involved in approximately one-third of all patients with lymphoma. Approximately 60% of these cases are primary CNS lymphoma. Primary CNS lymphoma generally presents with focal neurologic deficits, including cranial nerve findings, headaches, and/or seizures. MRI or CT generally reveals a limited number (one to three) of 3- to 5-cm lesions (Fig. 309-37). The lesions often show ring enhancement on contrast administration and may occur in any location. Locations that are most commonly involved with CNS lymphoma are deep in the white matter. Contrast enhancement is usually less pronounced than that seen with toxoplasmosis. The main diseases in the differential diagnosis are cerebral toxoplasmosis and cerebral Chagas' disease. In addition to the 20% of lymphomas in HIV-infected individuals that are primary CNS lymphomas, CNS disease is also seen in HIV-infected patients with systemic lymphoma. Approximately 20% of patients with systemic lymphoma have CNS disease in the form of leptomeningeal involvement. This fact underscores the importance of lumbar puncture in the staging evaluation of patients with systemic lymphoma.