Involvement from HIV infection itself: HIV encephalopathy-AIDS dementia complex.

HIV encephalopathy is the most common complication in HIV-infected patients from countries where antiretroviral therapy is available. It consist of a spectrum of neurological disorders from asymptomatic to significant impairment if activities of daily living.  It is included in HIV-associated  neurocognitive disorders (HAND), that encompasses asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD).

Symptoms may be early dementia, loss of attention and concentration, marked motor slowing and variable behavioral components and it occurs prior to opportunistic infections.  It predominantly affects the white matter by producing demyelination and gliosis.

Imaging features (Fig. 1):

Generalized and symmetric cerebral atrophy in out of proportion for the patient´s age.

Symmetric abnormal low attenuation in the periventricular and deep white matter on CT (patchy or confluent areas of T2 hyperintensity on MRI).

There is not contrast enhancement and no mass effect. If those are present, we must consider another diagnosis.

Frontal predominance that may include involvement of the genu of the corpus callosum.

MR spectroscopy: decreased N-acetylaspartate (NAA) and elevated peaks of choline and myoinositol.

Opportunistic infections.

The opportunistic infections are still the mayor cause of neurologyc complications in patients from countries that do not commonly use HAART.  They are varied, and include PML, Cytomegalovirus (CMV) infection, CNS tuberculosis and fungal infections.

Development of neurologic manifestations depends on multiple factors, including HAART and the patient´s degree of immunosupression. A decrease in the CD4 lymphocytes is the best predictor of potential development of opportunistic infections, especially when CD4 counts falls below 200 cell/μL.

PML

PML is a progressive demyelinating disorder that results from infection of the oligodendrocytes by John Cunningham (JC) virus in patients with compromised immune function. The virus remains latent in the CNS after the infection (usually in childhood or early adolescence) and it´s reactivated in the setting of immunodeficiency. PML not only occurs in HIV infection, but also in other immunocompromising diseases and treatments. It usually occurs with CD4 counts < 100 cell/μL and occasionally with CD4 < 200 cell/μL, even in those with normal CD4 counts.

The symptoms may be several neurological deficits including blindness, dysphasia, hemiparesis, ataxia, dysmetria, dementia, altered mental status, personality changes and seizures. Without treatment there is a progressive course with death within 1 year of diagnosis in 90% of patients.

Imaging features (Fig. 2):  

Bilateral asymmetrical T2 hyperintensity (or low attenuation in CT) involving subcortical U fibers extending into the deep white matter.

May be solitary, multifocal or confluent. Commonly bilateral and multiple lesions,  located in frontal lobe, parieto-occipital lobe, basal ganglia and thalamus.

We can observe a leading edge of high signal intensity on diffusion-weighted images.

There is no mass effect or contrast enhancement.

Differential diagnosis HIV encephalopathy vs PML (Fig 3).

In PML there is involvement of the subcortical U fibers, and it has a bilateral asymmetric distribution, while in HIV encephalopathy there is a bilateral symmetric involvement and the subcortical U fibers are respected with a predominance of periventricular white matter involvement.

Toxoplasmosis

Toxoplasmosis is the most common opportunistic infection in the CNS and the most common cause of intracranial mass lesion in AIDS. It´s caused by Toxoplasma gondii, an obligate intracellular protozoon. Latent infection is reactivated during immunosuppression, usually with CD4 counts < 100 cells/μL. Symptoms may be fever, headache, malaise, confusion, cranial nerve palsies and seizures. Clinical and radiologic features may be indistinguishable from PCNSL.

Imaging features (Fig 4, Fig 5):

Lesions are multiple, rounded, T2 hypo-isointense lesions, with surrounding vasogenic edema.

Commonly in the basal ganglia, corticomedullary junction, thalamus or cerebellum.

Nodular or peripheral ring- enhancement. May be a central enhancing nodule (“target sign”). This finding is highly suggestive of toxoplasmosis.

Hemorrhage may be seen occasionally, a finding that can help differentiate toxoplasmosis from lymphoma, where typically there isn´t hemorrhage before treatment.

CNS Tuberculosis

Infection of the CNS is the most severe extrapulmonary manifestation of tuberculosis (TB), with a high mortality rate and residual neurologic sequelae, even with adequate treatment.  It´s caused by Mycobacterium tuberculosis and usually is a complication of hematogenous spread from pulmonary tuberculosis.  HIV-infected patients with TB are 5 times more likely to have CNS involvement.

The most common manifestations are tuberculous meningitis and intracerebral tuberculomas (granulomas). The risk of meningitis is higher in patients with CD4 counts < 100 cells/μL.

Symptoms may be raised intracranial pressure, fever, headache, confusion, seizures, cranial nerve dysfunction and focal neurologic deficits.

Imaging features:

Tuberculous meningitis (Fig. 6, Fig. 7): thick or nodular meningeal enhancement in the basal cisterns, especially around the circle of Willis. Hydrocephalus may occur as result from obstruction of the basal cistern by inflammatory exudate. Intracranial vasculopathy is also frequent, and cerebral infarction can occur as a complication of vasospasm, thrombosis or vasculitis.

Tuberculoma (Fig. 8):  usually in supratentorial location. Lesions may be solitary or multiple (most often), are usually hypointense on T2-wheighted images and with surrounding edema and ring or nodular enhancement

CMV infection:

CMV becomes reactivated in the setting of severe immune suppression (CD4 counts < 50 cell/μL). T2-weighted MR images show focal or difuse increased signal intensity in white matter, as well as in ependymal, subependymal and periventricular location, usually without enhancement.

Fungal infections:  the most common in this population are Candida, Cryptococcus and Aspergillus.

Cryptococcus.

Cryptococcosis is caused by Cryptococcus neoformans. CNS infection is a consequence of hematogeneous dissemination from a pulmonary infection acquired by inhaling fungal spores.

Imaging features: meningoencephalitis, intraventricular or intraparenchymal cryptococcomas, dilated perivascular spaces and gelatinous pseudocysts . Variable enhancement.

Aspergillus.

Apergillosis  is usually caused by Aspergillus fumigatus. CNS infection also results from hematogenous spread from a pulmonary focus. It´s typical the presence of intraparenchymal hemorrhage.

Neoplasms:  PCNSL.

PCNSL is the most common CNS neoplasm in HIV patients. It´s a non-Hodgkin B-cell lymphoma that arises from malignant transformation of lymphocytes chronically activated by the Ebstein-Barr virus (EBV).  PCNSL is much more common in HIV patients compared to the general population.  CD4 counts < 50 cell/μL is associated with an increased risk of PCNSL. Symptoms may be fever, headache and confusion, personality changes, focal neurological deficits and seizures.

Imaging features (Fig. 9):

Single or multiple enhancing lesions in periventricular location and basal ganglia, often involving corpus callosum, with mass effect and variable surrounding edema.

Enhancement may be solid or peripheral (in immunocompromised status).

Typically hyperdensity on CT. Hyperintense on diffusion-weighted images.

Differential diagnosis toxoplasmosis vs PCNSL (Fig.10).

Differentiating lymphoma from toxoplasmosis may be difficult, because both may produce focal, enhancing mass lesions and both are common in AIDS patients, and clinical and radiologic features may be indistinguishable.

In general, multiple lesions are likely due to toxoplasmosis, while a single lesion suggests PCNSL, but this is not invariable. Toxoplasmosis´ lesions usually are smaller and more numerous.

Hemorrhage may be seen occasionally in toxoplasmosis, but in lymphoma typically there isn´t hemorrhage before treatment.

If “typical” imaging findings of toxoplasmosis don´t improve considerably after treatment, we have to reevaluate the diagnosis. We have other imaging modalities:

Thallium-201 brain single photon emission computed tomography (SPECT): positive in lymphoma (highly specific, not highly sensitive) and negative in toxoplasmosis.

Fluorodeoxyglucosa positron emission tomography (FDG-PET): positive in lymphoma, negative in toxoplasmosis.

MR spectroscopy:

                                Lymphoma: elevated peak of cholina.

                                Toxoplasmosis: elevated peaks of lipid and lactate (also in lymphoma if there is necrosis), decreased peaks of NAA and cholina.

MR perfusion: lymphoma shows and elevated relative cerebral blood volume (rCBV), not in toxoplasmosis.

Diffusion-weighted imaging: lymphoma typically has reduced diffusion. Toxoplasmosis has a variable diffusion.

Result of HAART: immune reconstitution inflammatory syndrome (IRIS).

It´s an abnormal inflamatory reaction after initiation of HAART. It occurs in some patients in the weeks, months or, less frequently, years after the institution of HAART, and causes a paradoxical worsening  of preexisting disease, with  increased or development of new signs, symptoms or radiologic manifestations of opportunistic infections.

 IRIS is associated with the recovery of CD4 counts in HIV-infected patients receiving HAART. Occasionally, it may be associated with a fatal outcome.

It can occur with any opportunistic infection, but most commonly with PML and cryptococcal infection, and usually with CD4 counts < 50 cell/μL.

Imaging features (Fig. 11):

It depends on the underlying pathologic condition, but usually shows worsening of imaging appearance, with increase edema and increased or development of enhancement.

Several radiologic signs on MR have been suggested, including the presence of intrinsic gray matter T1 signal hyperintensity, marginal reduced diffusion, marginal contrast enhancement and perivascular enhancement.

In PML with appearance of enhancement or mass effects after the onset or HAART, we should think about IRIS.