SEMINARS I N NEUROLOGY-VOL.UME
12, NO. 1 MARCH 1992
Brain Imaging in Human Immunodeficiency Virus Infection
Imaging of the central nervous system (CNS) tained from a full set of unenhanced images to be has assumed an increasingly important role in the s~fficient.'~"~Wadolinium has been shown to imneurologic evaluation of the patient infected with prove the sensitivity of MR in several conditions,l"'"ncluding AIDS in cases we have reported.16 human immunodeficiency virus (HIV).l-"ecause of the nonspecific symptoms associated with many Thus, where it is appropriate, we will give the MR of the opportunistic processes and the widely dif- enhancement characteristics of selected lesions in ferent treatments that are used, imaging is often this article. important in narrowing the differential diagnosis. T h e most important reasons to obtain an imaging study of the HIV-infected patient are to IMAGING TECHNIQUE identify and localize potentially treatable lesions and to follow the effect of treatment.',, In general, C T brain imaging protocols are fairly uniform this means differentiating toxoplasmosis from lym- among different institutions, typically requiring 5 phoma, which is more difficult to treat, although mm posterior fossa cuts and 10 mm sections other treatable infections are increasingly being through the remainder of the brain. T h e scans are characterized by computed tomography (CT) and usually done without and with contrast enhancemagnetic resonance (MR) Another role ment, with evidence that a double-dose delayed of neuroimaging is to identify possible complica- technique can further increase the C T sensitivity.17 tions of infections or mass lesions, such as hydroThe MR protocol for HIV-infected patients is cephalus or hemorrhage. In addition, imaging is not as well standardized, although most authors important in guiding the stereotactic biopsy of agree that T, weighted axial images are needed for small lesions.8," every patient. On our 1.5 tesla scanner, our-imagThe debate regarding which is better, C T or ing protocol includes TI weighted sagittal (TR = MR, has subsided somewhat, with evidence that 600, TE = 20), as well as proton density and T, MRI is more sensitive for identifying CNS abnor- weighted axial (TR = 2000, T E = 30, 90) images. malities.2.:+.~o. 1 1 CT still has many uses, because of We believe that the proton density images are vital its lower cost and easier availability. C T may also for detecting increased signal in the periventricube used on an emergency basis to rule out a mass lar and fornix-subcallosal regions, which may be lesion prior to a lumbar puncture. We will there- missed on the T, weighted images because of the fore include C T along with MR images in the high signal CSF. In addition, we usually also obtain article. a set of short flip angle coronal images. T h e numIntravenous contrast enhancement is often ber of excitations and the matrix size are chosen to used to help characterize lesions on CT. T h e value give good resolution with reasonable scan times. of contrast in the MR evaluation of acquired imT h e need for gadolinium contrast should be munodeficiency syndrome (AIDS) patients has judged on a case by case basis. Gadolinium has not been widely explored. Although contrast agents proved useful in patients who have symptoms can enhance parenchymal masses and the menin- suggestive of meningeal involvement or focal brain ges, many authors consider the information ob- lesions, or when the noncontrast MRI does not ex-
Department of Radiology, University of Rochester Medical Center, Rochester, New York Reprint requests: Dr. Ketonen, PO Box 648, Department of Radiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, N Y 14642 Copyright O 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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Leena Ketonen, M.D., Ph.D. and Michael J. Tuite, M.D.
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plain the symptom^.'^-^^ In addition, contrast enhancement is recommended if a lesion on the noncontrast study needs further characterization, or if surgery or biopsy is planned.Vhe use of contrast may also verify the presence of multiple lesions, a finding favoring an infectious etiology.Vhis may alleviate the need for biopsy, since most reports now recommend a trial of antitoxoplasmosis therapy in these cases.''
HUMAN IMMUNODEFICIENCY VIRUS
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The most common CNS complication in the HIV-infected patient is the HIV-associated cognitivelmotor complex, or AIDS dementia complex (ADC)."','8 These patients present with progressive cognitive and motor impairment, often being referred to the physician when they cannot carry out normal daily activities. The exact mechanism of this syndrome, first described by Price and colleagues18and unique to AIDS patients, is poorly understood.'"t postmortem examination, however, the primary changes of HIV encephalitis are known to be scattered microglial nodules and HIVinfected multinucleated giant cells located primarily in the white matter." Other abnormalities includecentral white matter pallor and rarefaction.18 Neither C'T nor M R is sensitive enough to detect the microglial nodules induced by HIV,"' and, for this reason, the neuroimaging appearance early in the disease is usually normal. As the disease worsens, the diffuse white matter changes seen especially with MR most often reflect secondary demyelination and gliosis rather than microglial nodule^."',^' Therefore, with progression of the disease, the clinical triad of motor, cognitive, and behavioral dysfunction manifests itself as a radiologic triad: (1) atrophy; (2) white matter changes; (3) fornix-subcallosal high signal. These three imaging abnormalities may be present either alone or in combination. The atrophy is nonfocal, involving both deep 'The and superficial cerebral structures (Fig. C T and MR findings therefore consist of dilated ventricles and subarachnoid spaces with prominent cortical sulci. The white matter changes have been reported to be greater in the deep frontal white matter tracts," but often the entire centrum semiovale and periventricular regions are in~olved."~" Although some low attenuation may be seen on CT, the T, weighted or proton density MR image is much more sensitive for detecting these changes (Fig. 2).2.24These sequences are also very sensitive
Figure 1. T, weighted axial image (TRITE = 2000190) from a 28-year-old man demonstrating marked enlargement of sulci, temporal horns, and subarachnoid spaces at the base of the brain.
when secondary demyelination occurs in unusual locations (Fig. 3). Abnormalities seen on MK or C'I' correlate well with the pathologic findings; however, many lesions seen in pathologic examination were not detectable by M R or CT." In addition, it is well accepted that diffuse white matter changes are not a good indicator of early neurologic dysfunction."^'" In a study by Olsen et al" only 70% of patients with ADC were shown to have white matter changes. In one autopsy series of patients with severe HIV encephalitis, many had no atrophy on their most recent imaging study.''~'~uantitativemeasurement of atrophy and white matter changes by MR is an active area of research. In some patients, the cognitive impairment occurs early in the course of the disease, when atrophy and white matter changes are not present.'"n one study, 88% of patients with early cognitive impairment due to HIV had high signal in the fbrnixsubcallosal area in the proton density images (Fig. 4).'Vhis finding could be present without associated white matter changes or atrophy. No contrast enhancement was seen in this abnormal area. The fornix-subcallosal high signal was not seen in patients with cognitive impairment caused by drugs, intoxication, or depression.
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ACQUIRED IMMUNODEFICIENCY SYNDROME DEMENTIA COMPLEX
Figure 2. A: Axial T, weighted image (TRITE = 2000190) from the same patient as in Figure 1, demonstrating bilateral, symmetrical, diffuse high signal white matter at the level of the lateral ventricles consistent with HIV encephalopathy. There is no mass effect, as is evident from the enlarged ventricles and sulci. B: On a more caudal image, involvement of the corpus callosum is seen (arrows).
Figure 3. Axial T, weighted images (TR/TE = 2000/90) through the pons in a 36-year-old man. A: The MR demonstrates brain and cerebellar atrophy. There are only minimal changes in the brainstem. B: One month later the brainstem demonstrates extensive demyelination. Brain and cerebellar atrophy had also progressed.
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MARCH 1992
Figure 4. A: A proton density (TRITE = 2000130) MR image through the fornix-subcallosal area in a 42-year-old woman with AIDS without cognitive decline. The normal-appearingfornix is marked with arrows. B: Proton density (TRI TE = 2000130) MR in a 30-year-old man with cognitive decline and abnormal high signal in the fornix-subcallosal area (arrows).
Figure 5. Precontrast (A) and postcontrast (B) axial T, weighted images (TRITE eral dural enhancement (arrows).
=
600120) demonstrate thick bilat-
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BRAIN I M A G I N G K E T o N E NTUITE ,
Figure 6. Proton density (TRITE = 2000130) (A) and T, weighted (TRTTE = 600120) (B) gadolinium enhanced MR in a 30-year-old man demonstrating a ring-enhancing lesion with significant edema and mass effect in the left basal ganglia. C: Another, hemorrhagic lesion is present in the CT scan (arrows), which also demonstrates atrophy. The multiple lesions regressed with empirical treatment for toxoplamosis.
VOLUME 12, NUMBER 1 MARCH 1992
Figure 7. A: AT, weighted (TRITE = 2000190) MR image through the centrum semiovale showing a small area of high signal (arrow) without mass effect. B: Contrast enhanced, T, weighted image (TRITE = 600120) through the area shows a nodular area of enhancement. The lesion disappeared following toxoplasmosis treatment.
MENINGITIS
HIV can cause an aseptic meningitis, which is assoc~atedwith meningeal enhancement on contrast-enhanced scans (Fig. 5)." There has been some association between enhancing meninges and mania."
MASS LESIONS TOXOPLASMOSIS AND LYMPHOMA
Probably the most important reason to obtain a brain imaging study is to rule out a mass lesion, which in one series was found in 22% of AIDS patients presenting with neurologic symptoms.* T h e most common masses are toxoplasmosis, which affects 2 to 13% of all AIDS patients, and lymphoma, seen in 1 to 2% of all AIDS patients.'.1° These two mass lesions are very difficult to differentiate by neuroimaging alone. We will give the characteristics of both lesions and describe the few imaging features that may help the examiner to tell the two apart. At this time, however, lymphoma is diagwith and, the clinical diagnosis of toxoplasmosis is suggested by a rising toxoplasma titer, diagnostic proof of the
Figure 8. Contrast-enhanced CT scan of a 36-year-old man with left hemiparesis. There is a solitary ring-enhancing lesion with edema and mass effect, centered in the right basal ganglia. Biopsy of the lesion revealed lymphoma.
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Figure 9. A: T, weighted (TRITE = 600120) axial MR through the centrum semiovale following intravenous gadolinium reveals a solitary ring-enhancing, relatively smooth-walled lesion in the left parietal region. B: A proton density (TRITE = 2000130) MR image through the same area reveals the mass with significant edema not seen on the T, weighted image. Autopsy revealed toxoplasmosis.
disease requires either a response to therapy or a positive biopsy. On CT, both masses tend to be isodense, with occasional surrounding low-density edema. Hyperdense lesions are less common, and in the absence of hemorrhage are more typical of lymphoma.Wn MR, the lesions are typically isointense to low signal on T, weighted images and isointense to high signal, with surrounding edema, on T, weighted images (Fig. 6). Either lesion may show uniform enhancement when small (Fig. 7), or ring enhancement with a central necrotic region when larger (Figs. 8,9).4." Lymphoma in AIDS patients differs from the classic appearance of primary CNS lymphoma in immunocompetent patients. In non-AIDS patients, it is almost invariably a solitary hyperdense mass with homogeneous contrast enhancement.ll Location of the lesion may help in distinguishing toxoplasmosis from lymphoma. Lymphoma is more common in the corpus callosum and periventricular region with occasional subependymal s~read.~>"his subependymal spread may cause ventricular encasement, leading to constriction of the ventriCles.'8 Toxop~asmosis, on the other hand, is seen more in the ganglia Or at the corticomedullary junction (Fig. lo)." The number of lesions may also be helpful in
Figure lo. density (TRITE = 2000130) MR image of a patient with autopsy-proven basal ganglia toxoplasmosis (arrow). The patient also had cognitive decline and abnormal hiah " sianal ., in the fornix-subcallosal reaion ., (arrowheads).
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differentiating the two, with some authors finding that lymphoma is more likely if only a single lesion is present."Wther authors report an equal incidence of solitary and multiple lesions in both entiTherefore, the fact that MR can disclose additional lesions not seen on C T may or may not help to differentiate the two diseases, unless the location of the additional lesions is characteristic. Given the overlap in the appearance of these two entities, a brain biopsy is often required for definitive diagnosis.
OTHER INFECTIONS
Cryptococcus is the fungus that most commonly infects the CNS of AIDS patient^.'.^ T h e infection may present as an abscess, called a cryptococcoma, although this is unusual (Fig. 11). It can also appear on T, weighted MR images as multiple high signal foci, which represent dilated VirchowRobin spaces, or as enhancing leptomeningeal nodule^.^ In 67% of cases, however, Cryptococcus presents as a meningitis, which may be by C T or MR."' Other fungi such as Candida (Fig. 12) and Aspergillus can also infect the CNS of AIDS patients, with varied findings6
Figure 12. Axial T2 weighted image (TRITE = 2000/90) of a 26-year-old woman with cortical blindness. There is abnormal high signal in both occipital lobes, more extensive on the right than the left, consistent with infarctions. At autopsy, the patient was found to have bilateral occipital infarcts, caused by vascular involvement by Candida albicans.
BACTERIAL INFECTION
Figure 11. Contrast-enhanced CT demonstrates bioccipital and parietal enhancing mass lesions with significant surrounding edema. Autopsy confirmed the lesions to be cryptococcomas.
Pyogenic infections are uncommon in HIV-infected persons, except for intravenous drug abusers who use unsterile needle^.^ Brain abscesses, which look like those in immunocompetent patients, are usually multiple, enhancing masses with surrounding edema. Reported organisms include Escherichia coli and Nocardia asteroides." Syphilis is more common in several of the groups at increased risk for HIV, and therefore CNS syphilis is seen increasingly in this populati~n."~~Qecause these patients often have an atypical natural history and clinical presentation, as well as other possible causes for their neurologic symptoms, MR may become important in making the d i a g n o ~ i s . ~ ~ Neurosyphilis is most commonly meningovascular;" this form produces a combination of meningeal enhancement (best demonstrated with gadolinium-enhanced MR) and areas of ischemia or infarct (Fig. 13). In addition, parenchymal syphilitic lesions can also be seen, with enhancement on CT and MR, and surrouding edema on T, weighted Because the CSF VDRL has a sensitivity of
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FUNGAL INFECTION
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BRAIN I MAGINC-KETONEN,TUITE
Figure 13. Gadolinium-enhancedT, weighted (TRITE = 600120) axial image (A) from a patient with a history of syphilis and new seizures and confusion. Multiple enhancing parenchymal lesions (arrows), as well as meningeal enhancement (arrowheads), are seen. B: A T, weighted image (TRITE = 2000190) at the same level reveals no significant edema around the parenchymal lesions, but a region of high signal is noted in the right temporal lobe. The patient was treated with penicillin for presumed neurosyphilis, and on a follow-up MR the parenchymal lesions and meningeal enhancement had resolved. The region of abnormal signal in the right temporal lobe went on to become a site of infarction.
only 22 to 27%, and the CSF fluorescent treponema1 antibody-absorbed test (FTA-ABS), a specificity of 39%, MK may be helpful in establishing the diagnosis of neurosyphilis in patients with a con. ~ ~is~ fusing clinical and laboratory p i c t ~ r e This especially true of AIDS patients, in whom the falsenegative rates for these tests are higher than in the normal population. Mycobacterium tuberculosis has also been described in this patient population. It can present either as an abscess with ring enhancement and surrounding edema or as a meningitis with men~ mycobacingeal or dural e n h a n ~ e m e n t .Other teria, such as M. avium intracellulare, are uncommon in the CNS.
OTHER VIRUSES
Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by a papovavirus; it occurs in about 4% of all AIDS patients."' T h e viral attack on myelin-producing oligodendrocytes leads to intranuclear inclusions and .~ usually preadjacent myelin b r e a k d ~ w n Patients sent with weakness, but various other symptoms
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such as headache, aphasia, and cognitive decline are also ~ e e n . ~ v l ~ PML is characterized by a triad of features: (1) white matter involvement, usually with sparing of ~ the ~ cortical gray matter; (2) multiple focal lesions; (3) progressive course. On CT, the lesion of PML is of low density, often oval and shows no enhancement, mass effect, or edema. On MR, the lesions are hyperintense on T2 weighted sequences, and on T, weighted sequences are low-intensity to isointense (Fig. 14). T h e lesions are found first in the subcortical white matter and progress to involve deeper white matter tracts6 T h e most common location is the posterior centrum semiovale in the parietal and occipital r e g i o n s . ~ p p r o x i m a t e l y 10% of lesions, however, are solely infratentorial, affecting the brainstem and ~ e r e b e l l u mThe . ~ ~ lesions usually spare the gray matter and, except when the changes are extensive, the basal ganglia and t h a l a m u ~ . ~ . ~ ~ The lesions of PML may be difficult to differentiate from white matter disease accompanying HIV encephalitis, although the latter is usually symmetrical and nonfocal, and tends to involve the periventricular white matter as well as the entire centrum semiovale. A subacute infarct can also appear similar to PML, and a biopsy may be required to make a definitive diagnosis.
Figure 14. A: Axial T, weighted (TRITE = 2000I90) image at the level of the lateral ventricles demonstrates bilateral focal high signal white matter lesions (arrows). B: The cortical gray matter is involved in the left parieto-occipital lesion. Biopsy of this lesion revealed progressive multifocal leukoencephalopathy.
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BRAIN IMAGING-KETONEN, TUITE
Cytomegalovirus (CMV) infection is common in the HIV population, but may be asymptomatic . ~ . ' ~ findings and detected only at a ~ t o p s ~ Specific are uncommon on CT, although ependymal enhancement is occasionally seen (Fig. 15).' Necrotic foci with mass effect from acute encephalitis may also appear, although this is usually a near-terminal event.' On MR, periventricular high signal on the T, weighted images is sometimes present (Fig. 16), and ependymal enhancement can occur with gadolinium on T, weighted sequences6
Herpesvirus Herpes is an uncommon cause of neurologic symptoms in the HIV-infected population, and appears to produce a more diffuse encephalitis than . ~addition, in the immunocompetent p ~ p u l a t i o nIn although herpes encephalitis in adults is usually caused by herpes simplex virus (HSV-l), in AIDS patients it may be caused by HSV-II.3%s in other patients, however, bilateral temporal lobe lesions are almost pathognomonic for HSV encephalitis when seen in the AIDS ~ a t i e n t . ~ ~
Figure 15. Contrast-enhanced axial CT demonstrates diffuse periventricular enhancement (arrows) consistent with cytomegalovirus ependymitis.
OTHER NEOPLASMS Kaposi's sarcoma in the CNS is rare, although involvement of the scalp is seem6 When the sarcoma is metastatic to brain, C T demonstrates a high density, contrast-enhancing l e s i ~ n . ~ Systemic lymphoma involves the CNS, usually by invading the meninges, in 20% of AIDS patients Although primary CNS lymphoma who have it.32334 usually involves the brain parenchyma, systemic lymphoma most commonly affects the meninges, producing meningitis or cranial n e ~ r o p a t h i e s . ~ ~ T h e meningitis may appear as thickened, enhancing meninges on MR, with the C T usually being normal."' Meningeal spread of lymphoma may lead to hydrocephalus, which can be diagnosed with CT.
CEREBROVASCULAR COMPLICATIONS Infarction, which is common in HIV-infected patients, appears in up to 20% of AIDS patients at a u t o p ~ ~ . "There ~ - ~ ' are several etiologies, with HIV vasculopathy probably the most common. We have already presented cases of meningovascular syphilis and candidiasis resulting in infarction, and other opportunistic processes such as lymphoma
Figure 16. Axial proton density (TRITE = 2000130) image from a 41-year-old man depicts a rim of high signal intensity surrounding the lateral ventricles, without mass effect. Ependymal involvement by cytomegalovirus was proven at autopsy.
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Cytomegalovirus
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Figure 17. CT-guided biopsy of a mass near the right basal ganglia, 4.8 cm from the skin surface (same patient as in Figure 8). By measuring the location of the 9 position markers around the patient's head, the exact axial location of the mass can be determined in the operating room. Artifact from the halo device is seen in the left frontal region.
and fungal infection are potential causes. The neuroimaging findings are nonspecific, with the infarct- giving the typical low attenuation region on CT, which is high signal on T, weighted MR images.
BRAIN BIOPSY Another, increasingly important role for neuroimaging is in stereotactic biopsy of brain lesions (Fig. 17)."9 Imaging is often required to guide needle placement for small, deep lesions, and sometimes is the only way to make the definitive diagnosis of CNS toxoplasmosis or lymphoma. Contrast is helpful when defining a lesion for biopsy, since it delineates the region of blood-brain barrier breakdown, separating it from necrotic areas where a successful biopsy result is less l i k e l ~ . With ~ , ~ the availability of the new nonferromagnetic biopsy apparatus and halo devices, biopsy can be performed with MR localization as well as CT.
CONCLUSION Neuroimaging is an important part of the workup of neurologic symptoms in the HIV-infected population. Treatable lesions can be discovered and localized, and imaging characteristics often help to narrow the differential diagnosis. Imaging is also important in following the effects of treatment. MR is clearly more sensitive than C T and, if available, is recommended in the CNS evaluation of the AIDS patient. T h e optimal imaging technique includes T, and axial T, weighted images. In addition, we believe that proton density images are vital in the evaluation of AIDS patients with suspected ADC. T h e administration of gadolinium is probably not necessary for all HIV-infected patients and should be considered on a case-by-case basis. Although not as helpful in patients with a normal precontrast MR, we found contrast useful when pathologic changes in the meninges or a mass lesion was suspected. We have attempted to give the most likely imaging presentation of the more common lesions seen in the AIDS population. Because of the high frequency of coexistent infections and neoplasms, however, the nonspecific imaging findings are often difficult to analyze, and biopsy may be required.
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Positron emission tomography (PET) and single photon emission computed tomography (SPECT) have been used to study patients with
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ADC. PET scans have shown abnormalities in glucose metabolism in AIDS patient^.:'^ SPECT scans using both perfusion agents and a mixed perfusion-receptor agent have demonstrated multiple scattered defects in patients with ADC who have future role of nonfocal C T and MR images.""he nuclear medicine brain imaging in AIDS is still somewhat unclear. Echo planar imaging (EPI) is a recent MR software adaptation that uses a time varying read gradient. It allows the MR scanner to obtain improved tissue discrimination, including information on molecular diffusion and cerebral perfusion. EPI may show promise in the future for AIDS patients, especially in centers that d o riot have a PET scanner. It not only gives information analogous to PET, but is less expensive and has better spatial resolution."'
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Brain Imaging in Human Immunodeficiency Virus Infection
Imaging of the central nervous system (CNS) tained from a full set of unenhanced images to be has assumed an increasingly important role in the s~fficient.'~"~Wadolinium has been shown to imneurologic evaluation of the patient infected with prove the sensitivity of MR in several conditions,l"'"ncluding AIDS in cases we have reported.16 human immunodeficiency virus (HIV).l-"ecause of the nonspecific symptoms associated with many Thus, where it is appropriate, we will give the MR of the opportunistic processes and the widely dif- enhancement characteristics of selected lesions in ferent treatments that are used, imaging is often this article. important in narrowing the differential diagnosis. T h e most important reasons to obtain an imaging study of the HIV-infected patient are to IMAGING TECHNIQUE identify and localize potentially treatable lesions and to follow the effect of treatment.',, In general, C T brain imaging protocols are fairly uniform this means differentiating toxoplasmosis from lym- among different institutions, typically requiring 5 phoma, which is more difficult to treat, although mm posterior fossa cuts and 10 mm sections other treatable infections are increasingly being through the remainder of the brain. T h e scans are characterized by computed tomography (CT) and usually done without and with contrast enhancemagnetic resonance (MR) Another role ment, with evidence that a double-dose delayed of neuroimaging is to identify possible complica- technique can further increase the C T sensitivity.17 tions of infections or mass lesions, such as hydroThe MR protocol for HIV-infected patients is cephalus or hemorrhage. In addition, imaging is not as well standardized, although most authors important in guiding the stereotactic biopsy of agree that T, weighted axial images are needed for small lesions.8," every patient. On our 1.5 tesla scanner, our-imagThe debate regarding which is better, C T or ing protocol includes TI weighted sagittal (TR = MR, has subsided somewhat, with evidence that 600, TE = 20), as well as proton density and T, MRI is more sensitive for identifying CNS abnor- weighted axial (TR = 2000, T E = 30, 90) images. malities.2.:+.~o. 1 1 CT still has many uses, because of We believe that the proton density images are vital its lower cost and easier availability. C T may also for detecting increased signal in the periventricube used on an emergency basis to rule out a mass lar and fornix-subcallosal regions, which may be lesion prior to a lumbar puncture. We will there- missed on the T, weighted images because of the fore include C T along with MR images in the high signal CSF. In addition, we usually also obtain article. a set of short flip angle coronal images. T h e numIntravenous contrast enhancement is often ber of excitations and the matrix size are chosen to used to help characterize lesions on CT. T h e value give good resolution with reasonable scan times. of contrast in the MR evaluation of acquired imT h e need for gadolinium contrast should be munodeficiency syndrome (AIDS) patients has judged on a case by case basis. Gadolinium has not been widely explored. Although contrast agents proved useful in patients who have symptoms can enhance parenchymal masses and the menin- suggestive of meningeal involvement or focal brain ges, many authors consider the information ob- lesions, or when the noncontrast MRI does not ex-
Department of Radiology, University of Rochester Medical Center, Rochester, New York Reprint requests: Dr. Ketonen, PO Box 648, Department of Radiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, N Y 14642 Copyright O 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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Leena Ketonen, M.D., Ph.D. and Michael J. Tuite, M.D.
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plain the symptom^.'^-^^ In addition, contrast enhancement is recommended if a lesion on the noncontrast study needs further characterization, or if surgery or biopsy is planned.Vhe use of contrast may also verify the presence of multiple lesions, a finding favoring an infectious etiology.Vhis may alleviate the need for biopsy, since most reports now recommend a trial of antitoxoplasmosis therapy in these cases.''
HUMAN IMMUNODEFICIENCY VIRUS
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The most common CNS complication in the HIV-infected patient is the HIV-associated cognitivelmotor complex, or AIDS dementia complex (ADC)."','8 These patients present with progressive cognitive and motor impairment, often being referred to the physician when they cannot carry out normal daily activities. The exact mechanism of this syndrome, first described by Price and colleagues18and unique to AIDS patients, is poorly understood.'"t postmortem examination, however, the primary changes of HIV encephalitis are known to be scattered microglial nodules and HIVinfected multinucleated giant cells located primarily in the white matter." Other abnormalities includecentral white matter pallor and rarefaction.18 Neither C'T nor M R is sensitive enough to detect the microglial nodules induced by HIV,"' and, for this reason, the neuroimaging appearance early in the disease is usually normal. As the disease worsens, the diffuse white matter changes seen especially with MR most often reflect secondary demyelination and gliosis rather than microglial nodule^."',^' Therefore, with progression of the disease, the clinical triad of motor, cognitive, and behavioral dysfunction manifests itself as a radiologic triad: (1) atrophy; (2) white matter changes; (3) fornix-subcallosal high signal. These three imaging abnormalities may be present either alone or in combination. The atrophy is nonfocal, involving both deep 'The and superficial cerebral structures (Fig. C T and MR findings therefore consist of dilated ventricles and subarachnoid spaces with prominent cortical sulci. The white matter changes have been reported to be greater in the deep frontal white matter tracts," but often the entire centrum semiovale and periventricular regions are in~olved."~" Although some low attenuation may be seen on CT, the T, weighted or proton density MR image is much more sensitive for detecting these changes (Fig. 2).2.24These sequences are also very sensitive
Figure 1. T, weighted axial image (TRITE = 2000190) from a 28-year-old man demonstrating marked enlargement of sulci, temporal horns, and subarachnoid spaces at the base of the brain.
when secondary demyelination occurs in unusual locations (Fig. 3). Abnormalities seen on MK or C'I' correlate well with the pathologic findings; however, many lesions seen in pathologic examination were not detectable by M R or CT." In addition, it is well accepted that diffuse white matter changes are not a good indicator of early neurologic dysfunction."^'" In a study by Olsen et al" only 70% of patients with ADC were shown to have white matter changes. In one autopsy series of patients with severe HIV encephalitis, many had no atrophy on their most recent imaging study.''~'~uantitativemeasurement of atrophy and white matter changes by MR is an active area of research. In some patients, the cognitive impairment occurs early in the course of the disease, when atrophy and white matter changes are not present.'"n one study, 88% of patients with early cognitive impairment due to HIV had high signal in the fbrnixsubcallosal area in the proton density images (Fig. 4).'Vhis finding could be present without associated white matter changes or atrophy. No contrast enhancement was seen in this abnormal area. The fornix-subcallosal high signal was not seen in patients with cognitive impairment caused by drugs, intoxication, or depression.
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ACQUIRED IMMUNODEFICIENCY SYNDROME DEMENTIA COMPLEX
Figure 2. A: Axial T, weighted image (TRITE = 2000190) from the same patient as in Figure 1, demonstrating bilateral, symmetrical, diffuse high signal white matter at the level of the lateral ventricles consistent with HIV encephalopathy. There is no mass effect, as is evident from the enlarged ventricles and sulci. B: On a more caudal image, involvement of the corpus callosum is seen (arrows).
Figure 3. Axial T, weighted images (TR/TE = 2000/90) through the pons in a 36-year-old man. A: The MR demonstrates brain and cerebellar atrophy. There are only minimal changes in the brainstem. B: One month later the brainstem demonstrates extensive demyelination. Brain and cerebellar atrophy had also progressed.
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MARCH 1992
Figure 4. A: A proton density (TRITE = 2000130) MR image through the fornix-subcallosal area in a 42-year-old woman with AIDS without cognitive decline. The normal-appearingfornix is marked with arrows. B: Proton density (TRI TE = 2000130) MR in a 30-year-old man with cognitive decline and abnormal high signal in the fornix-subcallosal area (arrows).
Figure 5. Precontrast (A) and postcontrast (B) axial T, weighted images (TRITE eral dural enhancement (arrows).
=
600120) demonstrate thick bilat-
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BRAIN I M A G I N G K E T o N E NTUITE ,
Figure 6. Proton density (TRITE = 2000130) (A) and T, weighted (TRTTE = 600120) (B) gadolinium enhanced MR in a 30-year-old man demonstrating a ring-enhancing lesion with significant edema and mass effect in the left basal ganglia. C: Another, hemorrhagic lesion is present in the CT scan (arrows), which also demonstrates atrophy. The multiple lesions regressed with empirical treatment for toxoplamosis.
VOLUME 12, NUMBER 1 MARCH 1992
Figure 7. A: AT, weighted (TRITE = 2000190) MR image through the centrum semiovale showing a small area of high signal (arrow) without mass effect. B: Contrast enhanced, T, weighted image (TRITE = 600120) through the area shows a nodular area of enhancement. The lesion disappeared following toxoplasmosis treatment.
MENINGITIS
HIV can cause an aseptic meningitis, which is assoc~atedwith meningeal enhancement on contrast-enhanced scans (Fig. 5)." There has been some association between enhancing meninges and mania."
MASS LESIONS TOXOPLASMOSIS AND LYMPHOMA
Probably the most important reason to obtain a brain imaging study is to rule out a mass lesion, which in one series was found in 22% of AIDS patients presenting with neurologic symptoms.* T h e most common masses are toxoplasmosis, which affects 2 to 13% of all AIDS patients, and lymphoma, seen in 1 to 2% of all AIDS patients.'.1° These two mass lesions are very difficult to differentiate by neuroimaging alone. We will give the characteristics of both lesions and describe the few imaging features that may help the examiner to tell the two apart. At this time, however, lymphoma is diagwith and, the clinical diagnosis of toxoplasmosis is suggested by a rising toxoplasma titer, diagnostic proof of the
Figure 8. Contrast-enhanced CT scan of a 36-year-old man with left hemiparesis. There is a solitary ring-enhancing lesion with edema and mass effect, centered in the right basal ganglia. Biopsy of the lesion revealed lymphoma.
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Figure 9. A: T, weighted (TRITE = 600120) axial MR through the centrum semiovale following intravenous gadolinium reveals a solitary ring-enhancing, relatively smooth-walled lesion in the left parietal region. B: A proton density (TRITE = 2000130) MR image through the same area reveals the mass with significant edema not seen on the T, weighted image. Autopsy revealed toxoplasmosis.
disease requires either a response to therapy or a positive biopsy. On CT, both masses tend to be isodense, with occasional surrounding low-density edema. Hyperdense lesions are less common, and in the absence of hemorrhage are more typical of lymphoma.Wn MR, the lesions are typically isointense to low signal on T, weighted images and isointense to high signal, with surrounding edema, on T, weighted images (Fig. 6). Either lesion may show uniform enhancement when small (Fig. 7), or ring enhancement with a central necrotic region when larger (Figs. 8,9).4." Lymphoma in AIDS patients differs from the classic appearance of primary CNS lymphoma in immunocompetent patients. In non-AIDS patients, it is almost invariably a solitary hyperdense mass with homogeneous contrast enhancement.ll Location of the lesion may help in distinguishing toxoplasmosis from lymphoma. Lymphoma is more common in the corpus callosum and periventricular region with occasional subependymal s~read.~>"his subependymal spread may cause ventricular encasement, leading to constriction of the ventriCles.'8 Toxop~asmosis, on the other hand, is seen more in the ganglia Or at the corticomedullary junction (Fig. lo)." The number of lesions may also be helpful in
Figure lo. density (TRITE = 2000130) MR image of a patient with autopsy-proven basal ganglia toxoplasmosis (arrow). The patient also had cognitive decline and abnormal hiah " sianal ., in the fornix-subcallosal reaion ., (arrowheads).
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differentiating the two, with some authors finding that lymphoma is more likely if only a single lesion is present."Wther authors report an equal incidence of solitary and multiple lesions in both entiTherefore, the fact that MR can disclose additional lesions not seen on C T may or may not help to differentiate the two diseases, unless the location of the additional lesions is characteristic. Given the overlap in the appearance of these two entities, a brain biopsy is often required for definitive diagnosis.
OTHER INFECTIONS
Cryptococcus is the fungus that most commonly infects the CNS of AIDS patient^.'.^ T h e infection may present as an abscess, called a cryptococcoma, although this is unusual (Fig. 11). It can also appear on T, weighted MR images as multiple high signal foci, which represent dilated VirchowRobin spaces, or as enhancing leptomeningeal nodule^.^ In 67% of cases, however, Cryptococcus presents as a meningitis, which may be by C T or MR."' Other fungi such as Candida (Fig. 12) and Aspergillus can also infect the CNS of AIDS patients, with varied findings6
Figure 12. Axial T2 weighted image (TRITE = 2000/90) of a 26-year-old woman with cortical blindness. There is abnormal high signal in both occipital lobes, more extensive on the right than the left, consistent with infarctions. At autopsy, the patient was found to have bilateral occipital infarcts, caused by vascular involvement by Candida albicans.
BACTERIAL INFECTION
Figure 11. Contrast-enhanced CT demonstrates bioccipital and parietal enhancing mass lesions with significant surrounding edema. Autopsy confirmed the lesions to be cryptococcomas.
Pyogenic infections are uncommon in HIV-infected persons, except for intravenous drug abusers who use unsterile needle^.^ Brain abscesses, which look like those in immunocompetent patients, are usually multiple, enhancing masses with surrounding edema. Reported organisms include Escherichia coli and Nocardia asteroides." Syphilis is more common in several of the groups at increased risk for HIV, and therefore CNS syphilis is seen increasingly in this populati~n."~~Qecause these patients often have an atypical natural history and clinical presentation, as well as other possible causes for their neurologic symptoms, MR may become important in making the d i a g n o ~ i s . ~ ~ Neurosyphilis is most commonly meningovascular;" this form produces a combination of meningeal enhancement (best demonstrated with gadolinium-enhanced MR) and areas of ischemia or infarct (Fig. 13). In addition, parenchymal syphilitic lesions can also be seen, with enhancement on CT and MR, and surrouding edema on T, weighted Because the CSF VDRL has a sensitivity of
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FUNGAL INFECTION
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BRAIN I MAGINC-KETONEN,TUITE
Figure 13. Gadolinium-enhancedT, weighted (TRITE = 600120) axial image (A) from a patient with a history of syphilis and new seizures and confusion. Multiple enhancing parenchymal lesions (arrows), as well as meningeal enhancement (arrowheads), are seen. B: A T, weighted image (TRITE = 2000190) at the same level reveals no significant edema around the parenchymal lesions, but a region of high signal is noted in the right temporal lobe. The patient was treated with penicillin for presumed neurosyphilis, and on a follow-up MR the parenchymal lesions and meningeal enhancement had resolved. The region of abnormal signal in the right temporal lobe went on to become a site of infarction.
only 22 to 27%, and the CSF fluorescent treponema1 antibody-absorbed test (FTA-ABS), a specificity of 39%, MK may be helpful in establishing the diagnosis of neurosyphilis in patients with a con. ~ ~is~ fusing clinical and laboratory p i c t ~ r e This especially true of AIDS patients, in whom the falsenegative rates for these tests are higher than in the normal population. Mycobacterium tuberculosis has also been described in this patient population. It can present either as an abscess with ring enhancement and surrounding edema or as a meningitis with men~ mycobacingeal or dural e n h a n ~ e m e n t .Other teria, such as M. avium intracellulare, are uncommon in the CNS.
OTHER VIRUSES
Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by a papovavirus; it occurs in about 4% of all AIDS patients."' T h e viral attack on myelin-producing oligodendrocytes leads to intranuclear inclusions and .~ usually preadjacent myelin b r e a k d ~ w n Patients sent with weakness, but various other symptoms
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such as headache, aphasia, and cognitive decline are also ~ e e n . ~ v l ~ PML is characterized by a triad of features: (1) white matter involvement, usually with sparing of ~ the ~ cortical gray matter; (2) multiple focal lesions; (3) progressive course. On CT, the lesion of PML is of low density, often oval and shows no enhancement, mass effect, or edema. On MR, the lesions are hyperintense on T2 weighted sequences, and on T, weighted sequences are low-intensity to isointense (Fig. 14). T h e lesions are found first in the subcortical white matter and progress to involve deeper white matter tracts6 T h e most common location is the posterior centrum semiovale in the parietal and occipital r e g i o n s . ~ p p r o x i m a t e l y 10% of lesions, however, are solely infratentorial, affecting the brainstem and ~ e r e b e l l u mThe . ~ ~ lesions usually spare the gray matter and, except when the changes are extensive, the basal ganglia and t h a l a m u ~ . ~ . ~ ~ The lesions of PML may be difficult to differentiate from white matter disease accompanying HIV encephalitis, although the latter is usually symmetrical and nonfocal, and tends to involve the periventricular white matter as well as the entire centrum semiovale. A subacute infarct can also appear similar to PML, and a biopsy may be required to make a definitive diagnosis.
Figure 14. A: Axial T, weighted (TRITE = 2000I90) image at the level of the lateral ventricles demonstrates bilateral focal high signal white matter lesions (arrows). B: The cortical gray matter is involved in the left parieto-occipital lesion. Biopsy of this lesion revealed progressive multifocal leukoencephalopathy.
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BRAIN IMAGING-KETONEN, TUITE
Cytomegalovirus (CMV) infection is common in the HIV population, but may be asymptomatic . ~ . ' ~ findings and detected only at a ~ t o p s ~ Specific are uncommon on CT, although ependymal enhancement is occasionally seen (Fig. 15).' Necrotic foci with mass effect from acute encephalitis may also appear, although this is usually a near-terminal event.' On MR, periventricular high signal on the T, weighted images is sometimes present (Fig. 16), and ependymal enhancement can occur with gadolinium on T, weighted sequences6
Herpesvirus Herpes is an uncommon cause of neurologic symptoms in the HIV-infected population, and appears to produce a more diffuse encephalitis than . ~addition, in the immunocompetent p ~ p u l a t i o nIn although herpes encephalitis in adults is usually caused by herpes simplex virus (HSV-l), in AIDS patients it may be caused by HSV-II.3%s in other patients, however, bilateral temporal lobe lesions are almost pathognomonic for HSV encephalitis when seen in the AIDS ~ a t i e n t . ~ ~
Figure 15. Contrast-enhanced axial CT demonstrates diffuse periventricular enhancement (arrows) consistent with cytomegalovirus ependymitis.
OTHER NEOPLASMS Kaposi's sarcoma in the CNS is rare, although involvement of the scalp is seem6 When the sarcoma is metastatic to brain, C T demonstrates a high density, contrast-enhancing l e s i ~ n . ~ Systemic lymphoma involves the CNS, usually by invading the meninges, in 20% of AIDS patients Although primary CNS lymphoma who have it.32334 usually involves the brain parenchyma, systemic lymphoma most commonly affects the meninges, producing meningitis or cranial n e ~ r o p a t h i e s . ~ ~ T h e meningitis may appear as thickened, enhancing meninges on MR, with the C T usually being normal."' Meningeal spread of lymphoma may lead to hydrocephalus, which can be diagnosed with CT.
CEREBROVASCULAR COMPLICATIONS Infarction, which is common in HIV-infected patients, appears in up to 20% of AIDS patients at a u t o p ~ ~ . "There ~ - ~ ' are several etiologies, with HIV vasculopathy probably the most common. We have already presented cases of meningovascular syphilis and candidiasis resulting in infarction, and other opportunistic processes such as lymphoma
Figure 16. Axial proton density (TRITE = 2000130) image from a 41-year-old man depicts a rim of high signal intensity surrounding the lateral ventricles, without mass effect. Ependymal involvement by cytomegalovirus was proven at autopsy.
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Figure 17. CT-guided biopsy of a mass near the right basal ganglia, 4.8 cm from the skin surface (same patient as in Figure 8). By measuring the location of the 9 position markers around the patient's head, the exact axial location of the mass can be determined in the operating room. Artifact from the halo device is seen in the left frontal region.
and fungal infection are potential causes. The neuroimaging findings are nonspecific, with the infarct- giving the typical low attenuation region on CT, which is high signal on T, weighted MR images.
BRAIN BIOPSY Another, increasingly important role for neuroimaging is in stereotactic biopsy of brain lesions (Fig. 17)."9 Imaging is often required to guide needle placement for small, deep lesions, and sometimes is the only way to make the definitive diagnosis of CNS toxoplasmosis or lymphoma. Contrast is helpful when defining a lesion for biopsy, since it delineates the region of blood-brain barrier breakdown, separating it from necrotic areas where a successful biopsy result is less l i k e l ~ . With ~ , ~ the availability of the new nonferromagnetic biopsy apparatus and halo devices, biopsy can be performed with MR localization as well as CT.
CONCLUSION Neuroimaging is an important part of the workup of neurologic symptoms in the HIV-infected population. Treatable lesions can be discovered and localized, and imaging characteristics often help to narrow the differential diagnosis. Imaging is also important in following the effects of treatment. MR is clearly more sensitive than C T and, if available, is recommended in the CNS evaluation of the AIDS patient. T h e optimal imaging technique includes T, and axial T, weighted images. In addition, we believe that proton density images are vital in the evaluation of AIDS patients with suspected ADC. T h e administration of gadolinium is probably not necessary for all HIV-infected patients and should be considered on a case-by-case basis. Although not as helpful in patients with a normal precontrast MR, we found contrast useful when pathologic changes in the meninges or a mass lesion was suspected. We have attempted to give the most likely imaging presentation of the more common lesions seen in the AIDS population. Because of the high frequency of coexistent infections and neoplasms, however, the nonspecific imaging findings are often difficult to analyze, and biopsy may be required.
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Positron emission tomography (PET) and single photon emission computed tomography (SPECT) have been used to study patients with
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