Intracranial Infections: Clinical and Imaging Characteristics

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1 Acta Radiologica ISSN: (Print) (Online) Journal homepage: Intracranial Infections: Clinical and Imaging Characteristics B. R. Foerster, M. M. Thurnher, P. N. Malani, M. Petrou, F. Carets-Zumelzu & P. C. Sundgren To cite this article: B. R. Foerster, M. M. Thurnher, P. N. Malani, M. Petrou, F. Carets-Zumelzu & P. C. Sundgren (2007) Intracranial Infections: Clinical and Imaging Characteristics, Acta Radiologica, 48:8, To link to this article: Published online: 04 Aug Submit your article to this journal Article views: 774 View related articles Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at

2 REVIEW ARTICLE ACTA RADIOLOGICA Intracranial Infections: Clinical and Imaging Characteristics B. R. FOERSTER, M.M.THURNHER, P.N.MALANI, M.PETROU, F.CARETS-ZUMELZU &P.C.SUNDGREN Department of Radiology, and Divisions of Infectious Diseases and Geriatric Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA; Department of Radiology, Neuroradiology, Medical University Vienna, Austria; Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA; Geriatric Research Education and Clinical Center (GRECC), Ann Arbor, Michigan, USA Foerster BR, Thurnher MM, Malani PN, Petrou M, Carets-Zumelzu F, Sundgren PC. Intracranial infections: clinical and imaging characteristics. Acta Radiol 2007;48: The radiologist plays a crucial role in identifying and narrowing the differential diagnosis of intracranial infections. A thorough understanding of the intracranial compartment anatomy and characteristic imaging findings of specific pathogens, as well incorporation of the clinical information, is essential to establish correct diagnosis. Specific types of infections have certain propensities for different anatomical regions within the brain. In addition, the imaging findings must be placed in the context of the clinical setting, particularly in immunocompromised and human immunodeficiency virus (HIV)-positive patients. This paper describes and depicts infections within the different compartments of the brain. Pathology-proven infectious cases are presented in both immunocompetent and immunocompromised patients, with a discussion of the characteristic findings of each pathogen. Magnetic resonance spectroscopy (MRS) characteristics for several infections are also discussed. Key words: Infection; intracranial infection; meningitis; MR spectroscopy; neuroradiology Pia C. Sundgren, Department of Radiology, Division of Neuroradiology, University of Michigan, Room B2A209D, 1500 E Medical Center Drive, Ann Arbor, MI , USA (tel , fax , . sundgren@umich.edu) Accepted for publication April 21, 2007 Intracranial infections include a wide range of different processes, each with unique clinical characteristics. Many intracranial infections progress rapidly and result in significant morbidity and mortality if appropriate therapies are not initiated promptly. Clinical presentations of intracranial infection vary significantly. Common manifestations include altered mental status, seizures, as well as more subtle focal deficits, such as cranial nerve palsies (10). In each case, the radiologist plays a vital role in the diagnostic workup of these infections. By interfacing with the clinicians who care for these patients, the radiologist can help direct appropriate testing and treatment, ultimately decreasing the morbidity associated with these infections. In this review, we will discuss several important intracranial infections. We will briefly describe the salient clinical features of specific infections and offer guidance related to the utility of imaging modalities in particular settings. Imaging modalities Computed tomography (CT) and magnetic resonance imaging (MRI) are the two primary imaging modalities used in the setting of suspected central nervous system infection. While CT is widely available and very useful for rapid assessment of hydrocephalus, mass lesions, hemorrhage, or acute brain edema prior to lumbar puncture, MRI is often required to detect more subtle findings. MRI is more sensitive, especially for cerebral spinal fluid (CSF) involvement, leptomeningitis, empyema, ventriculitis, vasculitis, and infarctions (58, 61). However, MRI is not as widely available and can be logistically challenging to obtain in the acutely ill patient. Computed tomography (CT) The standard pre- and post-contrast-enhanced CT protocol of the head includes 5-mm-slice axial DOI / # 2007 Taylor & Francis

3 876 B. R. Foerster et al. images though the entire brain, including brain, soft tissue, and bone windows. While contrast can aid in the detection of small lesions and leptomeningeal enhancement, it is not required to exclude findings that may preclude lumbar puncture, such as a focal mass. In many types of infection, CT findings can be nonspecific or even normal, especially in early stages (21). Magnetic resonance imaging (MRI) Conventional gadolinium-enhanced MRI of the brain should include: 1) axial and sagittal pre- and post-contrast T1-weighted images; 2) coronal postcontrast T1-weighted images; 3) axial T2-weighted and fluid-attenuated inversion recovery (FLAIR)- weighted images; and 4) diffusion-weighted imaging (DWI). MR spectroscopy (MRS) has also been shown to be useful in the evaluation of infection, since brain abscesses and certain pathogens are characterized by specific resonances that are not present in uninfected tissue. Table 1 summarizes MR spectroscopy findings found in several pathogens. Anatomic compartments Bacterial meningitis Meningitis, or inflammation of the meninges, is among the most serious and morbid of all infections. A high index of suspicion, followed by rapid diagnosis and treatment are essential to prevent severe sequelae and death. Diagnosis requires an abnormal number of white blood cells (WBC) in the CSF. Classic clinical characteristics include headache and neck stiffness, followed by mental status changes. Microbiologic culture results from blood or CSF remain the gold standard for diagnosis, although this requires several days to complete. In terms of basic pathophysiology, bacteria lodge in the venous sinuses, creating inflammatory changes that interfere with CSF drainage and potentially causing hydrocephalus. Early in infection, the pia and arachnoid matter become congested and hyperemic. Later, the leptomeninges become thickened, and an inflammatory exudate can cover the brain, particularly in the dependent regions, such as the basal cisterns. CT imaging is generally obtained prior to lumbar puncture to exclude a mass lesion or other signs of elevated intracranial pressure. In addition to helping exclude other diagnoses, such a subarachnoid hemorrhage, CT can also identify complications from meningitis, as discussed below (58). Noncontrast CT and MR imaging can be normal in early cases of meningitis (14). Administration of contrast may be helpful to detect diffuse meningeal enhancement, with MRI being more sensitive than CT (66); meningeal enhancement is not, however, specific to the diagnosis of infectious meningitis and can be seen in other diagnoses, such as leptomeningeal carcinomatosis (58). FLAIR MR imaging can demonstrate high signal in the subarachnoid spaces, which reflects high protein content in the CSF (14, 30, 56). High signal in the subarachnoid space is also nonspecific and can be seen with leptomeningeal carcinomatosis and subarachnoid hemorrhage. Fig. 1 demonstrates the CT and MRI meningeal and subarachnoid findings that can be seen in bacterial meningitis. After excluding a mass lesion, the most important role of neuroimaging is to identify potential complications of meningitis, such as infarction, hydrocephalus, ventriculitis, brain empyema, and venous sinus thrombosis. Communicating hydrocephalus is a common complication, with the inflammatory debris obstructing the flow and reabsorption of CSF (58). Pyogenic ventriculitis is a very severe complication of meningitis. Imaging findings in this setting include periventricular high FLAIR signal, ependymal enhancement, ventricular debris, and fluid fluid levels in the ventricles (11, 22). MRI is the method of choice for the detection of venous thrombosis secondary to meningitis, with a high signal intensity seen on spin-echo sequences in the venous sinuses, reflecting thrombus formation. The subsequent venous thrombosis can lead to infarctions that do not conform to well-defined arterial territories and have accompanying hemorrhage (39). Table 1. Infectious MR spectroscopy findings Infection HSV TB granuloma HIV Toxoplasmosis Mucormycosis Bacterial abscess Findings Reduced N-acetyl aspartate, elevated choline, sometimes elevated lactate Elevated lipid Decreased N-acetyl aspartate, increased choline and myo-inositol Elevated lactate and lipid Elevated lactate, decreased N-acetyl aspartate Succinate, acetate, alanine, amino acids, and lactate peaks

4 Imaging of Intracranial Infections 877 Fig. 1. Bacterial meningitis. A. Pre-contrast CT is unremarkable. B. Post-contrast CT shows meningeal enhancement (black arrows). C. Axial FLAIR MR imaging with high signal in the subarachnoid space (black arrows). D. Axial post-contrast T1-weighted MR image shows extensive meningeal enhancement (black arrows). Viral encephalitis Encephalitis is distinguished from meningitis based on the presence of abnormal brain function. Nuchal rigidity is usually absent in encephalitis in contradistinction from meningitis. Patients can present with focal neurologic deficits and seizures. Viral encephalitis can be either primary or postinfectious. In postinfectious encephalitis, an active virus cannot be isolated and is secondary to an immune-mediated process. MR is more sensitive than CT for the detection of intracranial findings. The predominant MR imaging characteristic of viral encephalitis is parenchymal signal abnormality on T2-weighted imaging. Brain subdural empyema Brain subdural empyemas are infected CSF collections in the potential space between the cranial dura and arachnoid membranes that generally occur in the setting of sinusitis or otitis media (3, 13). In addition to fever, vomiting, and meningismus, patients typically present with focal neurologic signs, including hemiparesis. Since many of the typical presenting symptoms overlap with those of meningitis, the radiologist must diligently search for extra-axial fluid collections, particularly in the setting of paranasal sinus disease. The pathogenesis includes phlebitic bridging veins (from meningitis), hematogenous spread, and direct extension of infection from adjacent structures. Venous thrombosis or brain abscess develops in more than 10% of patients. Delays in appropriate antimicrobial therapy and surgical drainage result in high mortality rates, as well as serious neurologic sequelae in those who do survive. In the early stages of the disease, small subdural empyemas can be very subtle, particularly on

5 878 B. R. Foerster et al. non-contrast CT (74). Subdural empyemas do not cross the midline, distinguishing them from epidural abscesses. Subdural empyemas, like subdural hematomas, also tend to have crescent-like configurations rather than lentiform configurations. On CT, subdural empyemas appear as isoattenuation to low-attenuation extra-axial collections compared to brain parenchyma with rim enhancement (65, 68). MRI is the study of choice for detection of subdural empyema, as MRI has a higher sensitivity for detection of small subdural fluid collections. On MRI, subdural empyemas have iso-intense signal on T1-weighted imaging (T1WI), likely secondary to increased protein content and high signal on T2WI (33, 39, 47). MRI can also help to differentiate subdural empyemas from other extra-axial fluid collections, such as sterile effusions (usually low signal on T1WI) and chronic subdural hematomas (usually high signal on T1WI). A thin rim of enhancement may be seen, which is usually more prominent along the inner table of the skull. Fig. 2 illustrates some of these MRI findings in a patient with a subdural empyema. DWI can be useful in distinguishing between empyemas that are bright with low apparent diffusion coefficient (ADC) values and subdural effusions, which have low signal and ADC values similar to CSF (75). Brain epidural abscess Brain epidural abscesses are usually caused by the contiguous spread of infection from adjacent structures, such as the mastoids or paranasal sinuses, into the epidural space located between the dura and the overlying bone. Compared to subdural empyema, epidural abscess presents in a Fig. 2. Subdural empyema. A. Coronal T2-weighted MR image shows hyperintense crescent-shaped subdural collection. B. On axial FLAIR imaging, the subdural collection has CSF intensity in the anterior portion and iso-intensity in the posterior portion. In addition, high signal is present in the subarachnoid spaces (black arrowheads). Pre-contrast (C) and post-contrast (D) T1-weighted MR images show peripheral enhancement (white arrows), as well as meningeal enhancement (black arrowheads).

6 Imaging of Intracranial Infections 879 more subtle fashion, usually with several days of fever along with mental status changes and neck pain. Epidural abscesses can cross the midline, helping to distinguish them from subdural empyema. In addition, the adjacent brain parenchyma tends to appear normal, whereas abnormal signal in bordering brain tissue can be seen in subdural empyema. On CT, epidural abscess typically appears as a lowattenuation extra-axial mass. On MRI, epidural abscesses have iso-signal on T1WI and high signal on T2WI, with enhancement of the thickened dural surface (14). Two epidural abscesses with lentiform configuration are shown in Fig. 3. Brain abscess Brain abscesses are a focal, intracerebral infection that begin with a localized region of cerebritis, evolving into a discrete collection of pus surrounded by a well-vascularized capsule. Such infections result from either hematogenous dissemination or local extension from an odontogenic, sinus, or otic source. The most common organisms involved in brain abscesses include Staphylococcus and Streptococcus species. Imaging features of a brain abscess depend on the stage at the time of imaging, as well as the etiology of infection (10). Brain abscess development can be divided into four stages: 1) early cerebritis (1 to 4 days); 2) late cerebritis (4 to 10 days); 3) early capsule formation (11 to 14 days); and 4) late capsule formation (w14 days) (26). The majority of abscesses demonstrate considerable surrounding edema, which generally presents during the late cerebritis or early capsule formation stage, secondary to mass effect. Hematogenous abscesses, which can be seen in the setting of endocarditis, cardiac shunts, or pulmonary vascular malformations, are usually multiple, identified at the gray white junction, and located in the middle cerebral artery territory. In the earlier phases, a non-contrast head CT may show only low-attenuation abnormalities with mass effect. In later phases, a complete peripheral ring may be seen. On contrast CT, uniform ring enhancement is virtually always present in later phases. MRI findings also depend on the stage of the infection. In the early phase, MRI can have low T1WI signal and high T2WI signal with patchy enhancement. In later phases, the low T1WI signal becomes better demarcated, with high T2WI signal both in the cavity and surrounding parenchyma. The abscess cavity shows a hyperintense rim on noncontrast T1-weighted images and a hypointense rim on T2-weighted images (26). As on CT, MRI usually demonstrates a ring of enhancement surrounding the abscess (58). Fig. 4 demonstrates an abscess centered in the right occipital lobe. Abscesses tend to grow toward the white matter, away from the better-vascularized grey matter, with thinning of the medial wall (29). However, the enhancing-ring sign is nonspecific and must be evaluated in the context of the clinical history. Thickness, irregularity, and nodularity of the enhancing ring are suggestive of tumor (majority of cases) or, possibly, fungal infection (26). As seen in Fig. 5, DWI may show restricted diffusion (bright signal) that helps to differentiate abscesses from Fig. 3. Epidural abscess. A. Coronal post-contrast T1-weighted MR imaging shows a lentiform, peripherally enhancing, extra-axial fluid collection adjacent to the inferior right frontal lobe (white arrow). B. Axial post-contrast T1-weighted MR imaging depicts a lentiform, peripherally enhancing, extra-axial fluid collection adjacent to the left frontal lobe (white arrow). Additional intraparenchymal abscesses are also shown (black arrows).

7 880 B. R. Foerster et al. Fig. 4. Intraparenchymal abscess. A. Axial FLAIR MR imaging shows a high-signal lesion (black arrow) with surrounding edema and mass effect. Axial pre-contrast (B) and post-contrast (C) T1-weighted MR images display a low-signal intraparenchymal lesion with peripheral post-contrast enhancement. necrotic neoplasms, which are not usually restricted (18, 25), although not all abscesses follow this rule. Fungal and tuberculous abscesses may have elevated diffusivity and low signal on DWI (40). Several studies demonstrate the utility of DWI to differentiate between necrotic or cystic lesions and brain abscesses (18, 25). The latter demonstrates increased signal on the trace images and reduced ADC, while necrotic neoplasms demonstrate decreased signal on the trace image and high ADC values. Initially, DWI was thought to be helpful in differentiation of toxoplasmosis from lymphoma. One study proposed an ADC threshold of 0.8, where ADC ratios less than 0.8 would favor lymphoma over toxoplasmosis; however, the study showed a significant overlap in ADC values in toxoplasmosis and lymphoma (50). The authors concluded that, in the majority of patients, ADC ratios are not definitive in making the distinction between toxoplasmosis and lymphoma. DWI has a high sensitivity to detect early acute ischemic changes in cortical and deep white matter that can occur in the setting of infectious vasculitis. Intracerebral abscesses are characterized by specific resonances on MRS that are not detected in normal or sterile pathologic human tissue. MRS has been shown to be specifically beneficial in differentiating between brain abscesses and other cystic lesions (9), which can be used to expedite implementation of the appropriate antimicrobial therapy. Fig. 5. Intraparenchymal abscess with restricted diffusion. A. Coronal post-contrast T1-weighted MR image shows a peripherally enhancing, low-signal lesion (black arrow) in the left cerebellum. B. Diffusion-weighted imaging shows the abscess has restricted diffusion with bright signal (black arrow).

8 Imaging of Intracranial Infections 881 Metabolic substances, such as succinate (2.4 ppm), acetate (1.9 ppm), alanine (1.5 ppm), amino acids (0.9 ppm), and lactate (1.3 ppm), can all be present in untreated bacterial abscesses or soon after the initiation of treatment (32). Specific pathogens After localizing the infectious process to a specific compartment, there may be certain distinguishing characteristics that may help suggest a specific pathogen. Of course, lumbar puncture, in most cases, clinches the diagnosis, but certain infections, in particular, require specific laboratory testing, for example, the polymerase chain reaction (PCR) test for herpes simplex virus. In addition, the immune status of the patient must be considered, which affects the differential diagnosis. Table 2 summarizes some of the typical findings for different infections, with a discussion of the clinical and imaging features. Herpes simplex virus encephalitis Herpes simplex virus (HSV) is a common cause of encephalitis. Both type 1 and type 2 HSV produce encephalitis, with varying epidemiology, depending primarily on patient age. The virus most often invades the brain after reactivation of latent virus that resides in the trigeminal ganglion. Clinical features that distinguish HSV disease from other intracranial infections include the findings of red blood cells in the CSF. The gold standard for diagnosis is either PCR or viral culture that demonstrates HSV in the CSF. Treatment with antiviral therapy is generally initiated any time there is a suggestion of possible viral meningitis and/or encephalitis. Many radiological findings offer support for a presumptive diagnosis. CT findings are usually subtle, with lowerattenuation areas in the temporal lobe and insular cortex (51). Mass effect on the lateral ventricle can sometimes be present (63). Petechial hemorrhage is possible and may be more easily detected on MRI than CT. On MRI, there is high signal on T2WI, with a predilection for the limbic system (temporal lobes, cingulate gyri, inferior frontal lobes). Enhancement varies, and mass effect may persist (58). Fig. 6 shows the typical asymmetric involvement of the frontal and temporal lobes. HSV type 2 infection, more commonly seen in neonates rather than adults, can demonstrate subtle regions of low attenuation on CT in various regions of the brain, with subsequent enlargement and meningeal and gyriform enhancement. Thalamic hemorrhage is possible, and calcification can be seen several weeks after disease onset (63). Metabolic alterations have been demonstrated in HSV using MR spectroscopy, and are characterized by reduced N-acetyl aspartate (NAA), elevated choline compounds (Cho), and, sometimes, elevation of lactate (Lac) with normalization over time. These findings correspond to histopathological findings and are thought to reflect neuronal or axonal injury (NAA), demyelination (Cho, Lip), and anaerobic metabolism, or the presence of macrophages (Lac) (36, 48, 62). In general, the usual microbiologic diagnostic tests offer reasonable sensitivity and specificity; thus, the routine use of MR spectroscopy is limited. West Nile virus encephalitis West Nile virus (WNV) encephalitis is a potentially fatal viral intracranial infection acquired from Table 2. Typical imaging findings of specific pathogens Infection Anatomic predilection CT MRI HSV Temporal/inferior frontal lobes Subtle low density High T2WI signal, variable enhancement West Nile virus Parenchyma Negative Restricted diffusion, high T2WI signal TB Basal cisterns Poor visualization High FLAIR signal, enhancement Cystercercosis Parenchyma, occasionally ventricles Off-center, spherical calcifications Enhancing cysts with variable signal characteristics Coccidioidomycosis Meninges and parenchyma Negative Dilated VR spaces, poorly visualized cisterns HIV White matter frontal and parietal Negative High T2WI signal PML White matter asymmetric occipital Negative High T2WI signal and parietal Toxoplasmosis Basal ganglia, corticomedullary junction Low- to iso-attenuation nodules High T2WI signal, edema, and ring enhancement Cryptococcus Subarachnoid spaces infiltrating basal ganglia Normal Dilated VR spaces, non-enhancing cystic lesions Aspergillus Basal ganglia and thalami Varying attenuation Low T2WI signal, variable enhancement Mucormycosis Invades along cavernous sinus Paranasal disease High T2WI signal in frontal/temporal lobes VR spaces: Virchow-Robin spaces.

9 882 B. R. Foerster et al. Fig. 6. Herpes simplex virus encephalitis. A. Axial T2-weighted MR imaging depicts asymmetric increased signal (leftwright) in the frontotemporal lobes (white arrows). B. Axial post-contrast T1-weighted MR imaging shows low T1 signal in the same regions and meningeal enhancement (white arrows). infected mosquitoes. This infection has been the source of several epidemics across the United States during the past several years, beginning in 1999 in New York City. The incubation time period of WNV is estimated to range from 3 to 14 days. One in 150 people infected with WNV will develop meningoencephalitis, with the immunocompromised, elderly, and very young at highest risk. Symptoms include fever, headache, neck stiffness, mental status changes, muscle weakness, and flaccid paralysis. Death can occasionally result (7, 42). Imaging findings with WNV infection have generally been unremarkable. MR imaging findings can be normal. Increased T2WI signal has been reported in the lobar gray and white matter, as well as the cerebellum, basal ganglia, thalamus, and brainstem. Isolated restricted diffusion can also be seen (Fig. 7); these patients have a better prognosis than patients with T2WI signal abnormalities. T1WI signal abnormalities and enhancement are rarely present (1, 45). Lyme disease Lyme disease, or neuroborrelia, is a multisystemic disorder caused by the tick-borne spirochete Borrelia burgdorferi. The disease is seen worldwide, and is common in Europe. The underlying pathogenesis is Fig. 7. West Nile virus. A. Diffusion-weighted imaging with increased signal (black arrows) in the bilateral thalami in a patient with proven West Nile virus. B. Corresponding ADC map confirms restricted diffusion in the bilateral thalami (white arrows). (Images courtesy of Nafi Aygun, MD)

10 Imaging of Intracranial Infections 883 poorly understood, and different etiologies such as vasculitis, immune complex mechanisms, and postviral demyelination have been suggested. About 10 to 15% of patients with Lyme disease develop neurologic complications with cranial nerve palsies and peripheral neuropathies being common. MRI findings may vary from being normal to the presence of extensive superficial and/or deep white matter lesions that can be more discrete or confluent in appearance. Some lesions may enhance after contrast administration (2, 59). The lesions are not characteristic and cannot be differentiated from those seen in acute disseminated encephalomyelitis (ADEM) or multiple sclerosis. Diagnosis is based on clinical findings, CSF laboratory testing, and response to antibiotics. Tuberculosis Tuberculosis (TB) remains one of the most common and important infections around the world, with millions infected annually and thousands dying directly of complications related to TB. HIV infection and issues of drug resistance add to the importance of TB infection. Central nervous system (CNS) involvement is a serious manifestation of chronic infection and includes meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis. The mortality rate of those cases remains high for these complications despite effective treatment. For CNS TB, simple microbiology remains the method of choice for diagnosis, since the areas of greatest prevalence generally lack resources for widespread imaging, especially MRI. Tubercles (scattered tuberculosis foci) develop in the CNS or adjacent bony structures during the bacillemia that follows primary TB infection or late reactivation of TB elsewhere in the body. Meningitis most commonly occurs after primary infection in infants and young children. Among adults with intracranial infection, this develops from chronic reactivation, almost always in the setting of some type of immune deficiency (aging, malnutrition, HIV, medications, alcoholism). Tuberculomas are intracranial lesions that develop from deep-seated tubercles acquired during bacillemia. This complication of TB shows a variable clinical course ranging from complete resolution to rupture with associated meningoencephalitis. Patients typically present with confusion, fevers, headache, lethargy, and meningismus. Symptoms can progress to stupor, coma, decerebrate rigidity, cranial nerve palsy, and stroke. On CT, the basal and sylvian cisterns can be poorly visualized without contrast secondary to dense exudates, which can subsequently enhance with contrast (13). On MRI, the basal cisterns can have high FLAIR signal and meningeal enhancement secondary to proteinaceous exudate. The cisterns can enhance, with enhancement extending over cortical surfaces. Hydrocephalus, either communicating or obstructive, is a common finding in tuberculous meningitis. Fig. 8 demonstrates some of the CT and MRI findings seen in tuberculous meningitis. Infarction secondary to panarteritis can also be seen in CNS tuberculosis. Tuberculomas can appear as low- or highattenuation nodules on CT (4). On CT, tuberculomas can also present with a target sign: central calcification or a central region of enhancement, as well as a peripheral ring of enhancement (67). Tuberculomas have a varied clinical course, ranging from complete resolution to rupture with meningoencephalitis. Noncaseating tuberculomas have high signal on T2WI, with peripheral nodular enhancement. The patient s immune response then creates a granulomatous reaction, with central caseation and a solid center, and eventually, progression to a liquid center (52). Caseating tuberculomas with a solid center have low to intermediate signal on T1WI and central low signal on T2WI, with ring-like enhancement (6, 49, 58). Caseating granulomas with a liquid center have low signal on T1WI and high signal on T2WI, and can be indistinguishable from true tuberculous abscesses (seen in immunocompromised patients) or pyogenic abscesses (6). Fig. 9 shows a patient with multiple caseating tuberculomas. MRS typically shows an elevated lipid peak in tuberculosis granulomas. This can be helpful in the differential diagnosis from neurocysticercosis (27). Cysticercosis Cysticercosis results from infection by Taenia solium, the pork tapeworm. This parasite is endemic in Mexico, South America, Asia, Africa, and Eastern Europe, and is generally acquired by ingestion of undercooked pork. The larvae develop into the tapeworm in the gastrointestinal tract and then enter the blood stream to spread to other regions, including the CNS. Patients are typically asymptomatic until the larvae die, which incites an acute inflammatory reaction. The larvae progress through different stages, with varying degrees of edema and enhancement. While most cases of neurocysticercosis are asymptomatic, seizures, other focal neurologic signs, and increased intracranial pressure can result.

11 884 B. R. Foerster et al. Fig. 8. Tuberculosis meningitis. A, B. Non-contrast CT shows dilated lateral ventricles with transependymal migration of CSF. The basilar cisterns are not seen, and the fourth ventricle is patent (white arrow), indicating communicating hydrocephalus. C. Axial FLAIR MR imaging shows increased subarachnoid signal (black arrows) seen with proteinaceous material. D. Sagittal post-contrast T1-weighted MR imaging with enhancement of the basilar meninges (white arrow), as well as a ring-enhancing lesion. The presence of calcifications, as well as nonenhancing cysts and enhancing ring lesions (Fig. 10), are typical findings in a patient with appropriate exposure, and should suggest this diagnosis (33). Characteristic calcifications are well demonstrated on CT, and are slightly off-center and spherical in shape. MRI can show multiple cysts, with changing signal characteristics as the larvae progress through different stages. In the early vesicular stage, small non-enhancing cysts can be seen, which are iso-intense to CSF on T1WI and T2WI, with a mural nodule seen on T1WI. As the larvae mature, a cyst wall becomes visible with increasing T1WI signal within the cyst, relative to CSF. Edema and ring-like enhancement can then be visualized as the larvae die and incite an inflammatory response. Eventually, the cysts decrease in size and become calcified, and are best detected on CT. Intraventricular cysticercal cysts occasionally require surgical intervention if obstructive hydrocephalus occurs (31, 60, 73). Coccidioidomycosis Coccidioidomycosis results from infection by the dimorphic fungi of the genus Coccidioides (C. immitis and C. posadasii). These are endemic fungi present in the southwestern United States as well as in Central and South America. The spore is inhaled, setting up a primary pulmonary infection that can then be hematogenously spread. While the clinical manifestations are protean, meningitis is an important complication that must be recognized and treated aggressively. Without appropriate therapy with systemic antifungals, the clinical course of coccidioidal meningitis is fatal. The initial head CT can be negative. Imaging findings include dilated Virchow-Robin spaces, poor visualization of basal and sylvian cisterns secondary to dense exudates, and, occasionally, hydrocephalus (20, 71). As seen in Fig. 11, enhancing nodules that are nonspecific can also be seen. Infarction can also be a common finding, which may be secondary to direct invasion or vasospasm.

12 Imaging of Intracranial Infections 885 Fig. 9. Tuberculoma. A. Axial FLAIR MR image shows multiple central low-signal lesions with mild associated edema in the cerebellum. B. Axial post-contrast T1-weighted MR image shows multiple ring-enhancing lesions with central low T1 signal. Immunocompromised hosts Intracranial infections are important manifestations of disease in immunocompromised hosts, especially in patients with HIV infection and those with neutropenia related to hematologic malignancies and/or bone marrow transplantation. Patients with solid-organ transplantation are another group where serious CNS infection is seen fairly often. Using imaging to help narrow the differential diagnosis is critical, as treatments differ for different infections. In addition, therapies for many infections carry significant toxicity, as well as drug interactions, making prolonged empiric therapy impractical. Human immunodeficiency virus (HIV) Many HIV/AIDS-related intracranial manifestations seen frequently in the pre-retroviral era are now rarely seen in areas of the world where patients have access to highly active antiretroviral therapy (HAART). Over time, HIV infection results in subacute encephalitis and a syndrome of progressive dementia, with cognitive, motor, and behavioral abnormalities. Pathology shows microglial nodules and multinucleated cells in the white matter. CT imaging may show brain atrophy, but is typically unremarkable. MRI findings include bilateral patchy and confluent, moderately high T2WI signal changes (Fig. 12) in the white matter, predominantly affecting the frontal and parietal lobes without contrast enhancement (8, 12, 70, 43). Proton MR spectroscopy demonstrates metabolic changes in HIV-infected brains. NAA reduction and a low NAA/Cr can be seen in patients with early disease, even before conventional MRI shows any changes. Increases in Cho and myo-inositol (MI) are Fig. 10. Cysticercosis. A. Non-contrast CT images show calcified lesions (white arrows), as well as fluid attenuation lesions, one with a central calcification (black arrows). B. Contrast-enhanced CT shows no significant enhancement of the fluid attenuation lesions (black arrows). (Images courtesy of Nafi Aygun, MD)

13 886 B. R. Foerster et al. Fig. 11. Coccidioidomycosis. A. Contrast-enhanced CT shows nodular meningeal enhancement in the right suprasellar region and adjacent to the left sylvian fissure (white arrows) in a patient who had recently traveled to the southwestern United States. B. Coronal post-contrast T1-weighted MR image shows nodular meningeal enhancement in the region of the left ambient cistern/choroid fissure (white arrow). seen in virtually all cases of HIV infection in the early stages, and a decrease in NAA occurs in HIV encephalopathy (37, 38). HIV patients can develop progressive multifocal leukoencephalopathy (PML) caused by the JC virus. The JC virus is a type of human polyomavirus that primarily infects oligodendrocytes, resulting in a demyelinating process. Unlike HIV encephalitis, dementia is not the main feature in PML; rather, patients characteristically present with rapidly progressive focal neurologic deficits without signs of increased intracranial pressure. Specific deficits can include visual field deficits, ataxia, weakness, and hemiparesis, as well as cognitive deficits. Imaging findings include high T2WI signal in the white matter that is typically asymmetric and commonly affects the occipital and parietal lobes, as depicted in Fig. 13. PML does not exhibit mass effect and does not tend to show contrast enhancement (12, 23, 28). Toxoplasmosis results from Toxoplasma gondii, an intracellular protozoan parasite. Reactivation of latent infection is seen in advanced HIV, usually when CD4 counts fall below 100 cells/ml. Typical imaging findings include multiple abscess formation with a propensity for the basal ganglia, corticomedullary junction, white matter, and periventricular regions. CT can demonstrate areas of Fig. 12. HIV encephalopathy. A, B. A 46-year-old, HIV-positive patient with clinical signs of dementia. Axial FLAIR MR imaging shows severe atrophy and diffuse, increased signal abnormalities in the white matter without mass effect.

14 Imaging of Intracranial Infections 887 low-attenuation or iso-attenuation nodules, both of which can show varying degrees of enhancement (24, 44). MRI features include multiple, high T2WI signal lesions with vasogenic edema and ring or nodular enhancement (19). Fig. 14 shows some of the imaging findings seen in toxoplasmosis. Clinically, toxoplasmosis and intracranial lymphoma are often indistinguishable. Newer imaging techniques are sometimes useful in differentiating between these processes. High-attenuation masses on non-contrast CT, and periventricular lesions with subependymal spread, suggest lymphoma. Thallium- 201 single photon emission computed tomography (SPECT) has been shown to have increased uptake in lymphoma, but not in toxoplasmosis; there is, however, significant overlap, resulting in false positives and false negatives (57). Fluorodeoxyglucose positron emission tomography ( 18 FDG-PET) can also be used to discriminate between toxoplasmosis and lymphoma, as lymphoma exhibits increased 18 FDG uptake (35). Some studies suggest that MRS may help differentiate between toxoplasmosis and lymphoma, whereas other studies have suggested that MRS is less able to discriminate between these two entities (15, 16, 54). A previous report showed that lymphomas were characterized by lower NAA/Cr and NAA/Cho ratios, and by more frequent lipid signals, compared to toxoplasmosis (55). Other studies have demonstrated the presence of a lactate/lipid peak and the absence of the other metabolites in toxoplasmosis, while lymphoma shows increased choline levels similar to those present in malignant tumors (15). Cryptococcus neoformans is an endemic fungus that results in meningoencephalitis among patients with AIDS. The diagnosis is made by staining the organism from the CSF with India ink, detecting cryptococcal antigen in the CSF or blood, or growing the organism in culture. Clinically, the patients present with elevated intracranial pressure and often need repeat lumbar puncture in order to improve clinical symptoms, such as pain and mental status changes. Because the infection results in relatively mild inflammatory changes, many patients have normal contrast-enhanced CT scan (12). MRI can also be normal. Cryptococcomas can present as focal parenchymal masses most commonly located in the basal ganglia, thalamus, and midbrain. Leptomeningeal nodules, with involvement of the choroid plexus and spinal cord, can also be seen, although less frequently (64). Some patients demonstrate mixed findings, including dilated Virchow-Robin spaces, focal masses, and leptomeningeal nodules (69). Cryptococcosis can also present with basal ganglia lesions (Fig. 15), with the differential diagnosis including toxoplasmosis and lymphoma, which more typically show enhancement relative to cryptococcal infection (28). Other immunocompromised hosts Immunocompromised hosts, including those with solid-organ transplants or neutropenia related to hematologic malignancy and/or bone marrow transplantation, can develop serious fungal Fig. 13. Progressive multifocal leukoencephalopathy. Axial T2-weighted (A) and FLAIR MR (B) imaging shows asymmetric increased signal in the bilateral occipital lobes without mass effect. C. Axial post-contrast T1-weighted MR image shows no associated pathologic contrast enhancement.

15 888 B. R. Foerster et al. Fig. 14. Toxoplasmosis. A. Non-contrast CT shows a low-attenuation lesion with a subtle peripheral ring in the left basal ganglia/thalamus (black arrow). B. Axial FLAIR MR imaging re-demonstrates the lesion (black arrow) with surrounding edema. Axial pre-contrast (C) and post-contrast (D) T1-weighted MR imaging demonstrates a low-attenuation lesion (black arrow) with peripheral enhancement. infections of the CNS. Generally, these infections begin in the respiratory tract or sinuses. Intracranial involvement in this setting usually portends a poor prognosis. While biopsy, along with culture, is needed to definitively identify most infecting organisms, imaging modalities offer a means to define the extent of involvement and to track progression. Imaging, along with clinical variables, helps suggest the overall prognosis and is essential for medical decision-making. The Aspergillus species is an important pathogen that can produce meningitis and meningoencephalitis among highly compromised hosts. Fungal organisms gain entry to the CNS, either via direct extension from the sinuses or, less commonly, hematogenously. Patients may present with confusion, fevers, headache, lethargy, and meningismus, progressing to stupor, coma, decerebrate rigidity, cranial nerve palsy, and stroke. Aspergillus invades the vasculature walls, which can result in vascular thrombosis, hemorrhage, infarctions, and propagation of the infection in the infarcted tissue. Aspergillus has a predilection for the basal ganglia, thalami, and corpus callosum (17). On CT, the abnormalities are usually subtle, with varying densities and minimal mass effect, poor contrast enhancement, and no ring formation (41). On MRI, the signs are nonspecific and include high-signal lesions on T2WI and, at times, on T1WI, with variable enhancement (5). However, involvement of the basal ganglia, thalami, corpus callosum, and other perforator artery territories are suggestive of aspergillus infection in the immunocompromised patient. Enhancing soft tissue in the sinuses can

16 Imaging of Intracranial Infections 889 Fig. 15. Cryptococcus. Axial T2-weighted MR image shows patchy and more focal high T2 signal abnormality present in the bilateral basal ganglia. offer further support for the presence of an intracranial aspergillus infection. MRI findings from a patient with aspergillosis are shown in Fig. 16. Mucormycosis Rhinocerebral mucormycosis is a devastating infection that results from zygomycetes. Such infection carries a very grim prognosis and results invariably in patients with altered cellular immunity, including those with diabetes mellitus and hematologic malignancies. Mucormycosis spreads from the paranasal sinuses to the skull base or cribiform plate into the orbits, frontal lobes, and basal ganglia. Infection progresses rapidly, spreading along vascular structures and often involving the cavernous sinus. Infarction is seen frequently in advanced disease. Clinical symptoms associated with mucormycosis include facial pain, bloody nasal discharge, chemosis, exophthalmos, and cranial nerve palsy, progressing rapidly to stroke, encephalitis, and death. Orbital extension from the ethmoid sinuses produces proptosis, chemosis, superior ophthalmic vein thrombosis with extension, and subsequent thrombosis of the cavernous sinus. The diagnosis of mucormycosis must be made clinically. The progression of infection is often so rapid that imaging does not offer much beyond demonstrating the extent of involvement. Intracranial involvement is almost invariably fatal in this infection. CT imaging can demonstrate a rim of soft tissue along the walls of the paranasal sinuses. On MRI, low intensity of the sinuses may be present on T1WI and T2WI. Intracranially, MRI findings can include high T2WI signal in the basal portions of the frontal and temporal lobes with mild mass effect; this likely represents a combination of inflammation and infarction secondary to vascular invasion (34, 46, 72). Fig. 17 shows a patient with intracranial extension of paranasal sinus mucor. Spectroscopy has also been studied for the evaluation of mucor. In a previously published case report, proton MRS showed markedly elevated lactate, depleted NAA, and metabolite resonances attributable to succinate and acetate. The spectroscopy profile is essentially similar to that of bacterial

17 890 B. R. Foerster et al. Fig. 16. Aspergillosis. A. Axial FLAIR MR imaging shows high-signal lesions in the bilateral white matter (black arrows). Axial pre-contrast (B) and post-contrast (C) T1-weighted MR imaging demonstrates several low-attenuation lesions with peripheral enhancement (black arrows). Fig. 17. Mucormycosis. A. Coronal non-contrast sinus CT shows extensive opacification of the right paranasal sinuses, with destruction of the nasal septum and cribiform plate (white arrows). B. Coronal post-contrast T1-weighted MR image shows enhancing, infiltrating lesion in the right cavernous sinus (white arrowhead). C. Diffusion-weighted image shows restricted diffusion of the bilateral frontal lobes and right basal ganglia. D. Magnetic resonance arteriography shows asymmetric decreased caliber of the cavernous portion of the right internal carotid artery compared to the left internal carotid artery (black arrows). (Images courtesy of Stephen Gebarski, MD)

18 Imaging of Intracranial Infections 891 abscess, but without the commonly seen resonances of the amino acids valine, leucine, and isoleucine (53). Conclusion The radiologist plays a central role in the diagnosis and management of patients with intracranial infections. Different imaging modalities offer different advantages in the diagnostic paradigm. CT is helpful in rapidly excluding a focal mass lesion in the acute setting, prior to lumbar puncture. MRI is much more sensitive for defining the extent of infection, and for identifying infection-related complications, such as infected subdural effusions and venous sinus thrombosis. Many investigators have demonstrated the value of MR spectroscopy to aid in the differentiation of abscesses and neoplasms. A thorough understanding of the imaging patterns associated with common intracranial infections allows the radiologist to help narrow the differential diagnosis and facilitate timely implementation of appropriate therapies. 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