Handbook of Clinical Neurology, Vol. 123 (3rd series) Neurovirology A.C. Tselis and J. Booss, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 6

Neuroimaging of viral infections of the central nervous system MAHAN MATHUR, KARL MUCHANTEF, AND GORDON SZE* Department of Radiology, Yale University School of Medicine, New Haven, CT, USA

BASIC PRINCIPLES OF IMAGING Computed tomography (CT) and magnetic resonance imaging (MRI) are the two principal modalities used for imaging of infectious/inflammatory central nervous system (CNS) diseases. Like conventional radiography, CT is an X-ray-based technology. A narrow beam of X-rays is generated on one side of the patient with detectors on the other side that measure X-ray beam transmission. These measurements are then used by a computer algorithm to reconstruct a cross-sectional image of the body. The image generated is an attenuation map. For our purposes, attenuation is essentially equivalent to density. As such, CT images can be viewed as representative of tissue density. The terms hyperdense and hypodense are used frequently to refer to areas which appear brighter or darker, respectively, on CT images. Spatial resolution by CT is excellent, and is on the order of a fraction of a millimeter. The physics of MRI can be very complex and is beyond the scope of this chapter; however, a few salient features should be mentioned here. T1- and T2-weighted pulse sequences continue to be ubiquitous in MRI. T1-weighted images are useful in that they depict CNS anatomic changes such as can be seen with a mass or mass effect. T1-weighted sequences are also used in imaging with gadolinium-based contrast. In the setting of an intact blood–brain barrier, contrast does not enter the brain parenchyma and no enhancement is evident (a few CNS areas are normally lacking a blood–brain barrier, such as the pituitary, choroid, pineal gland, and others; these normally enhance). If the blood– brain barrier is deficient – as can be seen in inflammatory conditions or neoplasms – gadolinum-based contrast can escape the vasculature and enhancement will be seen at MRI. T2-weighted images are able to demonstrate many pathologic conditions due to their sensitivity to the presence

of water. Because many CNS pathologies result in an increase in water content (edema, inflammation, gliosis, demyelination, and others), these are well depicted as bright areas on T2-weighted images. Fluid attenuated inversion recovery (FLAIR) images are similar to T2-weighted images in that they are sensitive to water, but these also include a recovery pulse which suppresses cerebrospinal fluid signal, rendering parenchymal pathology more conspicuous. Diffusion-weighted MRI (DWI) measures the diffusion of water molecules in tissues. Molecular diffusion is related to Brownian motion. In an isotropic medium (such as a glass of water) water molecules are free to move randomly in any direction according to Brownian motion. In the body intracellular molecules are more restricted in their ability to move about than are extracellular molecules (intracellular molecules are constrained by the cell wall that contains them). As such, intracellular molecules have restricted diffusion. The more tightly restricted the motion of molecules, the more brightly these appear on diffusionweighted MR images. In some pathologies, DWI is more useful and more sensitive than conventional MR sequences. For example, DWI is a key sequence in stroke imaging; it can also be useful in certain viral infections. Proton magnetic resonance spectroscopy (MRS) can assess the neurochemical composition of brain tissue and demonstrate abnormal quantities of metabolites. Choline, creatine, myoinositol, N-acetylaspartate (NAA), and lactate are used commonly. Choline is thought to reflect phospholipid membrane synthesis and cellular turnover. Creatine reflects cellular energy and acts as a reference peak. Myoinositol is a putative measure of neurologic cell activation. NAA is a marker of neuronal integrity. Lactate reflects anaerobic metabolism. MR spectra are often abnormal in disease states, with certain identifiable characteristic changes.

*Correspondence to: Gordon Sze, MD, FACR, Professor, Radiology. Chief, Neuroradiology, Department of Radiology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06510, USA. Tel: þ1-203-785-3667, Fax: þ1-203-737-1241, E-mail: gordon. [email protected]

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An understanding of the concept of contrast resolution is important when considering the physics of CT or MRI. Contrast resolution denotes the ability to differentiate different tissues. CT differentiates tissues based upon differences in X-ray beam attenuation. MRI differentiates tissues based upon the differences in the relaxation properties of protons. The attenuation differences between gray matter, white matter, and many CNS pathologies is relatively slight; the differences between the behavior of protons in these same tissues as seen by MR is relatively greater. Thus, MRI and advanced techniques such as MRS are better able to demonstrate gray matter, white matter, and many of the potential pathologic states we encounter in the brain, particularly in the setting of CNS viral infections.

HERPESVIRUSES Herpes simplex virus 1 (HSV-1) Imaging plays a key diagnostic role in the setting of suspected HSV-1 encephalitis (Baringer, 2008). Brain infection is postulated to occur secondary to reactivation of latent HSV-1 virus within the trigeminal and/or olfactory ganglion following an oral childhood infection (Barnett et al., 1994). Neuronal transmission of infection through meningeal branches of the trigeminal nerve results in the typical distribution of disease within the brain parenchyma of the anterior and middle cranial fossa (Davis and Johnson, 1979; Baringer, 2008). Pathologically, HSV-1 results in a necrotizing infection involving the inferomedial aspect of the temporal lobes as well as the inferior frontal lobes (Jordan and Enzman, 1991), which may subsequently spread to the

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cingulate cortex as well as the subfrontal and insular regions (Baringer, 2008). Further progression of disease may result in petechial hemorrhages and eventual cavitation (Baringer, 2008). CT is often normal, although non-specific hypoattenuating lesions in the temporal and/or frontal lobes with or without enhancement and superimposed hemorrhage may be demonstrated in severe illness (Ch’ien et al., 1977). While MRI can be normal in up to 10% of patients with polymerase chain reaction-positive herpes encephalitis, the majority of MR scans will demonstrate abnormalities early on in the course of the disease (Pruitt, 2010). The most characteristic pattern finding is unilateral high T2 signal involving the insula, medial temporal and inferior frontal lobes with or without involvement of the adjacent limbic structures (Fig. 6.1A) (Pruitt, 2010). Enhancement and hemorrhage may be absent in the early stages and become more prominent with disease progression (Fig. 6.1B, C) (Leonard et al., 2000). DWI demonstrates regions of patchy restricted diffusion and may be more sensitive than T2-weighted or FLAIR imaging in depicting regions of encephalitis (Tsuchiya et al., 1999; Teixeira et al., 2001).

Herpes simplex virus 2 (HSV-2) HSV-2 may result in severe neonatal encephalitis, with transmission most commonly occurring through an infected birth canal (Baringer, 2008). Pathologic examination demonstrates diffuse parenchymal and leptomeningeal inflammation which can progress to hemorrhage and necrosis (Whitley and Schlitt, 1991; Baringer, 2008). Imaging findings reflect this diffuse pathologic process, with MR demonstrating loss of

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Fig. 6.1. Herpes encephalitis with subsequent hemorrhage. Axial fluid attenuated inversion recovery image (A) demonstrates a region of increased signal intensity in the right temporal lobe in this immunosuppressed patient (arrow). Axial T1 precontrast images (B, C) performed 3 weeks apart (C is after B) demonstrate curvilinear regions of high T1 signal intensity within the right temporal lobe (arrow, C), compatible with petechial hemorrhage in this patient with herpes encephalitis.

NEUROIMAGING OF VIRAL INFECTIONS OF THE CENTRAL NERVOUS SYSTEM gray–white differentiation and high T2 signal within the periventricular and subcortical white matter, with relative sparing of the central gray matter (basal ganglia, thalami) and posterior fossa (Enzmann et al., 1990). With disease progression, decreased T2 signal intensity within the cortex may develop corresponding to the presence of focal hemorrhagic necrosis and parenchymal calcifications (Enzmann et al., 1990). Severe cerebral sequelae such as cystic encephalomalacia or hydranencephaly may eventually be seen with more advanced disease (Baringer, 2008).

Varizella-zoster virus (VZV) While acute varicella can uncommonly have neurologic sequelae in the immunocompetent patient (such as cerebellar ataxia and transverse myelitis), imaging findings are often unremarkable (Tien et al., 1993). Meningoencephalitis is a rare but serious complication of acute varicella resulting in widespread edema, with MRI demonstrating diffuse, multifocal areas of high T2 signal intensity within the cerebral cortex (Tien et al., 1993). Diffuse encephalitis may occur via retrograde neuronal spread of disease or hematogenous spread (Gray et al., 1994), resulting in non-specific regions of high T2 signal within the white matter. VZV may also spread to the cranial nerves, most often affecting the ophthalmic division of the trigeminal nerve, although the facial nerve and/or vestibulocochlear nerve may also be involved (Tien et al., 1993). Fatsuppressed T1-weighted images with intravenous gadolinium contrast can show abnormal enhancement of the affected nerves, which is thought to be either secondary to hypervascularity of the adjacent perineural

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structures or disruption of the blood–nerve barrier from the underlying inflammatory changes (Tien et al., 1993). VZV involvement of large vessels at the base of the brain may result in a variety of pathologic findings, ranging from necrotizing arteritis to remote vascular occlusion within the small blood vessels of the brain resembling atherosclerotic disease (KleinschmidtDeMasters and Gilden, 2001). The spectrum of arterial involvement results in cerebral infarctions in various locations, including the basal ganglia and at the gray– white-matter interface (Silverstein and Brunberg, 1995). CT imaging demonstrates regions of decreased attenuation while MRI shows high T2 signal and restricted diffusion in the region of the infarctions (Fig. 6.2) (Silverstein and Brunberg, 1995; Nagel et al., 2008). The spread of VZV from blood vessels to the ependymal cells lining the ventricles may result in ventriculitis, resulting in abnormal ependymal enhancement and high T2/FLAIR signal intensity (Fukui et al., 2001; Kleinschmidt-Demasters and Gilden, 2001). Furthermore, spread of VZV to oligodendrocytes can result in a multifocal leukoencephalopathy which manifests as subcortical high T2 signal plaques which may coalesce into larger regions of extentive parenchymal involvment with varying degrees of edema and hemorrhage (Aygun et al., 1998). If active, the plaques may demonstrate enhancement after gadolinium contrast administration (Portegies and Corssmit, 2000). Neurologic sequelae of reactivated VZV are more often seen in the immunocompromised population (Kleinschmidt-DeMasters and Gilden, 2001). VZV can also affect the spinal cord. Spread of latent virus from the dorsal root ganglia to the spinal cord may result in a focal myelitis with pathologic

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Fig. 6.2. Varicella-zoster virus encephalitis with multifocal vasculopathy. Axial fluid attenuated inversion recovery (FLAIR) (A) and T2-weighted image (B) demonstrate high FLAIR signal in the left caudate nucleus and in the posterior limb of the internal capsule as well as hyperintense T2 signal along the right paramedian frontal lobe. Magnetic resonane angiogram (C) demonstrates irregular narrowing in the left proximal middle cerebral and right anterior cerebral artery. (Reproduced from Snook et al., 2003.)

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examination demonstrating varying degrees of spinal cord meningeal inflammation, necrosis, demyelination, and influx of microglial cells (KleinschmidtDeMasters and Gilden, 2001). MRI reflects these inflammatory findings, demonstrating long segments of diffusely increased T2 signal within the spinal cord associated with mild expansion of the cord (Tien et al., 1993).

The pathogenesis is thought to stem from uncontrolled EBV-induced replication of infected B lymphocytes (Portegies and Corssmit, 2000). CT imaging may demonstrate non-specific regions of low attenuation with adjacent mass effect related to edema, while MR may reveal single or multiple homogeneously or ring-enhancing lesions on gadolinium-infused images (Portegies and Corssmit, 2000).

Epstein–Barr virus (EBV)

Cytomegalovirus (CMV)

EBV infection of the nervous system is uncommon but may result in meninigitis, encephalitis, myelitis, and/or cranial nerve palsies (Portegies and Corssmit, 2000). CT findings are often normal and MRI may demonstrate non-specific high signal intensity within the cerbral cortex, at the gray–white junction, and/or within the deep nuclei (basal ganglia, thalamus) on T2-weighted images which may resolve on subsequent imaging (Fig. 6.3A, B) (Cecil et al., 2000; Hagemann et al., 2006). A case of restricted diffusion within the splenium of the corpus callosum which resolved after treatment has also been reported (Hagemann et al., 2006). Most case series suggest that patients recover without neurologic sequelae, as evidenced by Schnell et al. (1966), who followed 8 patients with EBV encephalitis for 14 years without noting any residual neurologic deficitis. Even so, case reports of progression to hemorrhagic encephalitis have been published and should be a consideration with worsening neurologic deficits (Fig. 6.3C) (Francisci et al., 2004; Takeuchi et al., 2010). Neuritis and myelitis may result in high T2 signal abnormality and swelling within the affected nerve and spinal cord respectively (Donovan and Zimmerman, 1996; Hagemann et al., 2006). EBV infection has a high association with primary CNS lymphoma in the setting of acquired immune deficiency syndrome (AIDS) (Portegies and Corssmit, 2000).

CMV infection of the nervous system is most often seen with immunocompromised patients in the setting of AIDS or in those who have undergone a solid or bone marrow transplantation (Vancı´kova´ and Dvora´k, 2001). In addition, CMV is the leading cause of congenital CNS infection, with an incidence of approximately 1–2% of live births (Vancı´kova´ and Dvora´k, 2001). Infection in immunocompetent patients is often subclinical and self-limited, with a resultant paucity of imaging findings (Maschke et al., 2002). The pathophysiology is thought to be related to hematogenous or cerebrospinal fluid dissemination of reactivated virus in the setting of immunosuppression with subsequent virus and cytotoxic-induced necrosis of neural tissue (Reinke et al., 1999; Maschke et al., 2002). Pathology studies have reported intracellular CMV inclusions (resulting in the characteristic “owl’s-eye” appearance) in the cortex, brainstem, basal ganglia, capillary enodothelia, and subependymal astrocytes as well as the presence of widespread well-circumscribed microglial nodules (Petito et al., 1986; Maschke et al., 2002). Dissemination of intracellular CMV inclusions into the meninges, spinal nerves, and retina has also been reported (Post et al., 1986). The resultant imaging findings reflect the distribution of disease: meningitis, encephalitis, ventriculoencephalitis,

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Fig. 6.3. Epstein–Barr virus. Axial fluid attenuated inversion recovery (A) imaging demonstrates abnormal increased signal in the right temporal lobe. Axial T2-weighted image (B) performed 3 days later demonstrates progression of abnormal signal in the right temporal lobe. A non-contrast CT scan (C) performed the same day demonstrates partial hemorrhagic conversion of the lesion with adjacent swelling and right-to-left midline shift. (Reproduced from Takeuchi et al., 2010.)

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Fig. 6.4. (A, B) In utero cytomegalovirus (CMV) infection. Coronal true inversion recovery image demonstrates thickened and disordered cortex in the right frontal and temporal lobes (arrows) compatible with pachygyria in this infant with in utero CMV infection.

myelitis, and retinitis (Maschke et al., 2002). CT imaging is less sensitive than MRI and may demonstrate non-specific cortical atrophy and/or decreased attenuation within the white matter (Ball, 1984). With contrast-enhanced imaging, periventricular enhancment may be present, indicative of underlying ventriculoencephalitis (Maschke et al., 2002). MRI demonstrates non-specific increased T2 and decreased T1 signal abnormalities in the white matter which may have a patchy or confluent distribution (Fig. 6.4) (Sze and Zimmerman, 1988). Nodular increased T2 signal abnormalities may also be noted within the brainstem, basal ganglia, cerebellum, and hippocampus, some of which may undergo hemorrhagic transformation, resulting in regions of hyperintense T1 signal abnormality (Maschke et al., 2002). Periventricular enhancement of the subependymal regions with gadolinium-infused imaging may also be demonstrated in the setting of ventriculitis (Maschke et al., 2002). Inflammation of the retina and spinal cord results in enlargement and abnormal enhancement of the aforementioned structures (Tien et al., 1991; Maschke et al., 2002). Occasionally, CMV infection may present as a ring-enhancing cerebral mass with marked edema mimicking an intracranial neoplasm (Dyer et al., 1995). Neuropathologic autopsy studies of premature infants with CMV have demonstrated the characteristic intracellular inclusion bodies with associated periventricular and cortical inflammatory changes resulting in necrosis and calcification (Perlman and Argyle, 1992). As a result, CT imaging in infants with congenital CMV infection classically shows intracranial calcifications in a periventricular distribution, although calcification of the brain parenchyma or vascular structures has been reported (Fig. 6.5) (Demmler, 1996; Boppana et al., 1997). Other neuroradiology findings include dilated

Fig. 6.5. In utero cytomegalovirus (CMV) infection. Axial non-contrast computed tomography scan of the head demonstrates massive hydrocephalus as well as bilateral periventricular calcifications in this infant with in utero CMV infection.

ventricles, hydrocephalus, cortical atrophy, subdural hematomas, or effusion and non-specific white-matter hypodensities (Demmler, 1996). CMV infection early in utero can also result in abnormal fetal brain development, with MRI better at demonstrating associated migrational or cortical gyral abnormalities as well as any evidence of delayed myelination or cerebellar hypoplasia (Fig. 6.6) (Demmler, 1996). Porencephalic cysts may occasionally be seen adjacent to the ventricular

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Fig. 6.6. In utero cytomegalovirus (CMV) infection. Coronal T2-weighted image demonstrates thickened and disordered cortex in the right frontal and temporal lobes (arrows) compatible with pachygyria in this infant with in utero CMV infection.

system, with MR disclosing cystic lesions which follow cerebrospinal fluid on all sequences (Moinuddin et al., 2003). Imaging findings in congenital CMV infection have an important prognostic purpose, as an abnormal CT scan of the head, especially one that demonstrates intracranial calcifications, is associated with an abnormal neurodevelopmental outcome (Boppana et al., 1997).

Human herpesvirus 6 (HHV-6) Reactivation of latent HHV-6 infection in immunocompromised patients, in particular those who have undergone allogenic stem cell transplantation, may result in an encephalitis, leptomeningitis, or neuritis (Sauter et al., 2009). The most common findings include symmetric or asymmetric high T2 signal within the uncus, amgydala, and hippocampal body with extension to the rhinal cortex and subiculum (Fig. 6.7) (Sauter et al., 2009). Extrahippocampal involvement has been documented in the olfactory cortex and cases of brainstem and basal ganglia inflammatory changes have been reported (Murakami et al., 2005; Crawford et al., 2007; Provenzale et al., 2008). DWI may show the earliest signs of the underlying inflammatory changes with patchy regions of restricted diffusion in the involved neural tissue (Sauter et al., 2009). CT findings are often unremarkable in the early stages of the disease (Sauter et al., 2009). A recent study by Noguchi et al. (2010) suggested that the underlying neuropathologic change of HHV-6 may

Fig. 6.7. Human herpesvirus-6 (HHV) infection. Axial fluid attenuated inversion recovery image of the brain demonstrates symmetric high signal abnormality within the limbic system in this patient who developed HHV-6 infection after a bone marrow transplant for treatment of lymphoma.

help in distinguishing the imaging findings from herpes simplex encephalitis (HSE). Pathologic specimens in HHV-6 have demonstrated reactive gliosis in the hippocampal gyrus and a demyelinating change with axonal deneration and reactive gliosis in the white matter as opposed to the hemorrhagic necrosis seen with HSE (Wainwright et al., 2001). The more aggressive pathophysiology in the latter may explain why inflammatory changes extend beyond the mesial temporal lobe in HSE and why signal abnormalities are detected earlier and last longer (Noguchi et al., 2010). This distinction is important as HHV-6 is resistant to acyclovir, the initial treatment of choice for HSE (Yoshida et al., 1998).

Human herpesvirus-8 (HHV-8) HHV-8 has been implicated in the development of both classic and human immunodeficiency virus (HIV)associated Kaposi’s sarcoma, as well as primary effusion lymphoma and multicentric Castleman’s disease (Restrepo et al., 2006). In the head and neck region, the diagnosis of Kaposi’s sarcoma may be suggested by the presence of hypervascular subcutaneous lesions and/or nodular enhancing masses with adenopathy and

NEUROIMAGING OF VIRAL INFECTIONS OF THE CENTRAL NERVOUS SYSTEM distortion of the valleculae and pyriform sinuses in the appropriate clinical setting (Restrepo et al., 2006). In the spine, Kaposi’s sarcoma may manifest as enhancing lesions within the vertebral bodies, which are isointense on T1 and hyperintense on T2-weighted images (Restrepo et al., 2006). Primary effusion lymphoma is a unique neoplastic process in that it presents as a pleural, pericardial, or peritoneal effusion without an associated mass, typically in patients with HIV (Chen et al., 2007). CNS involvement is rare, although the presence of HHV-8-associated primary effusion lymphoma has been reported in the subarachnoid space (Ely et al., 1999). Castleman’s disease is a lymphoproliferative disorder with rare CNS involvement (Matsumura et al., 2005). Case reports have described an extra-axial mass which is isointense on both T1- and T2-weighted images with surrounding edema slightly disproportionate to the size of the lesion (Matsumura et al., 2005). The mass demonstrates restricted diffusion and avidly enhances after intravenous gadolinium administration (Matsumura et al., 2005). The preoperative imaging findings are similar to a meningioma, with the definitive diagnosis established on histopathologic examination (Matsumura et al., 2005).

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to the CNS after multiplication at its inoculation site (Lury and Castillo, 2004). Thereafter, the virus induces diffuse brain necrosis, with polymorphonuclear infiltrates and fibrin deposition within the walls of the arteries, resulting in an acute vasculitis (Lury and Castillo, 2004). The earliest damage occurs in the deep gray matter, although involvement of the cervical spine may occur (Lury and Castillo, 2004). MRI is more sensitive than CT in depicting the regions of pathologic involvement, with the most common findings including high signal intensity on the T2-weighted images in the basal ganglia, thalami, and brainstem (Fig. 6.8) (Deresiewicz et al., 1997). Involvement of the cerebral cortex, leptomeningeal enhancement, and periventricular white-matter changes are less common (Deresiewicz et al., 1997). CT findings, when present, demonstrate non-specific regions of decreased attenuation most commonly in the deep gray matter (Deresiewicz et al., 1997). Clinically, EEE may mimic HSE, thus preferential involvement of the basal ganglia and thalami on MRI may be of clinical significance since this is not seen in HSE (Deresiewicz et al., 1997). The reason for this relative predilection of brain involvement has yet to be elucidated.

Herpesvirus simiae (B-virus) B-virus is an alpha-herpesvirus which causes a benign infection in its natural host, the Asiatic macaques (Estep et al., 2010). Transmission to humans occurs via exposure to the infected tissues or fluids of the monkeys, although there has been one reported case of a person-toperson transmission (Holmes et al., 1990). Symptoms are non-specific but may include ataxia, ascending flaccid paralysis, and fatal encephalitis, despite antiviral medication (Estep et al., 2010). B-virus is most often diffuse in its distribution and may cause transverse myelitis and a necrotizing retinitis (Nanda et al., 1990). Pathologic specimens have demonstrated similar findings to other herpesvirus encephalitides, with evidence of hemorrhagic foci, necrosis, and inflammatory changes (KleinschmidtDeMasters and Gilden, 2001). While no specific neuroimaging findings have been reported in the literature, the pathologic evidence would suggest similar imaging findings to other viral family members, namely hyperintense T2 signal abnormalities in a diffuse distribution, with hemorrhage and necrosis in more advanced disease.

ARBOVIRUS Eastern, Western, and Venezuelan equine encephalitis The Eastern equine encephalitis (EEE) virus is a mosquito-borne illness which spreads hematogenously

Fig. 6.8. Eastern equine encephalitis (EEE). Axial fluid attenuated inversion recovery image demonstrates increased signal intensity in the basal ganglia (white arrows) and thalami (black arrows) bilaterally as well as the right posterior parietal cortex. Serologies were positive for EEE.

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There is a paucity of radiology literature describing the imaging findings of both Western and Venezuelan equine encephalitis. Histologically, Western equine encephalitis (WEE) results in perivascular infiltration and multifocal necrosis, which occurs preferentially in the deep gray matter (Noran and Baker, 1945). The white matter, cerebral cortex, brainstem, and spinal cord show lesser degrees of involvement (Leech et al., 1981).

St. Louis encephalitis (SLE) SLE is transmitted through a mosquito-borne virus and has resulted in several epidemics in the eastern and central United States over the past few decades (Wasay et al., 2000). Histologic specimens have demonstrated evidence of perivascular inflammatory changes with neuronal degeneration and microglial proliferation, most prominent within the substantia nigra (Wasay et al., 2000). While there are limited data on the radiologic manifestations of this infection, MRI has demonstrated abnormally high T2-weighted signal intensity within the substantia nigra in patients with documented SLE (Fig. 6.9) (Cerna et al., 1999). Interestingly, disproportionate involvement of the substantia nigra may explain why tremulousness is an often characteristic clinical finding in patients with SLE (Cerna et al., 1999). The exact pathogenesis which leads to this distribution has yet to be described.

West Nile encephalitis West Nile encephalitis is an emerging infection with a rapid increase in incidence and geographic range (Centers for Disease Control and Prevention, 2002). Transmission is most often through a mosquito-infected vector, although transmission through breastfeeding,

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transplacental, organ transplantation, and transfusion of infected blood products has been reported (Iwamoto et al., 2003; Morse, 2003; Petropoulou et al., 2005). Histologic analysis of autopsied brains has demonstrated scattered microglial nodules in the gray and white matter, with a predilection for the brainstem and less frequent involvement of the cerebral cortex, thalamus, and cerebellum (Sampson et al., 2000). A perivascular inflammatory infiltrate is often present and underlying leptomeningitis and cranial nerve neuritis have also been described (Sampson et al., 2000). Necrosis and vasculitis are notably absent (Sampson et al., 2000). Limited pathologic data in the spine have demonstrated the presence of microglial nodules, with inflammatory changes most prominent within the anterior horn of the spinal cord (Kelley et al., 2003). Imaging findings in cases of West Nile encephalitis are non-specific, with a case series reporting increased T2 signal abnormality most often within the mesial temporal lobe and midbrain (Petropoulou et al., 2005). Meningeal, cerebellar, cortical, and white-matter imaging abnormalities are less commonly found (Fig. 6.10) (Ali et al., 2005; Petropoulou et al., 2005). Isolated restricted diffusion in the regions of neural involvement without associated T2 or FLAIR signal abnormalities has been associated with subsequent complete resolution of symptoms (Ali et al., 2005). Hyperintense T2 signal abnormality involving the anterior horns of the spinal cord may be noted in patients who present with flaccid paralysis (Kraushaar et al., 2005).

Japanese encephalitis Japanese encephalitis (JE) is the most frequent global cause of mosquito-borne encephalitis and is associated

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Fig. 6.9. St. Louis encephalitis. Axial T2-weighted images demonstrate symmetric increased signal intensity involving the insular cortex and thalami (arrows, A) as well as the substantia nigra, midbrain, and pons (arrows, B, C). (Reproduced from Solbrig et al., 2008.)

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Fig. 6.10. West Nile encephalitis. Axial fluid attenuated inversion recovery images (A, B) demonstrate increased signal in the thalami and corpus striatum. Increased signal intensity is also noted in the medial temporal lobes and cerebellum (curved arrow, B). Axial T1 postcontrast image (C) demonstrates enhancement in the thalami. (Reproduced from Arslanoglu et al., 2003.)

with significant morbidity and mortality (Weaver and Reisen, 2010). Imaging along with the appropriate clinical history plays a key role in suggesting the diagnosis and initiating the appropriate therapy (Prakash et al., 2004). The JE virus enters the nervous system hematogenously with subsequent spread through the dendritic axonal processes (Gourie-Debvi et al., 1995). Pathology studies have demonstrated diffuse inflammatory changes involving the basal ganglia, thalamus, cerebral cortex, brainstem, and cerebellum (Shankar et al., 1983). Histologic findings can be differentiated by three stages: acute (within 1 week), subacute, and chronic. In the acute setting, there is perivascular cuffing with small hemorrhages, thrombus formation, and parenchymal

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congestion (Miyake, 1964). Subsequently, the inflammatory response is less prominent while loss of neurons and glial proliferation become more pronounced (Miyake, 1964). After several weeks to months, there is ongoing degeneration of nervous tissue with fibrous thickening of the vascular walls and gliomesenchymal scarring (Miyake, 1964; Sawlani, 2009). Perivascular necrotic foci may also be present, particularly in the diencephalon and mesencephalon (Miyake, 1964). The most consistent finding on MRI is bilateral increased T2 signal abnormality in the thalami with or without hemorrhage (Fig. 6.11) (Kalita and Misra, 2000). Other regions of T2 or FLAIR signal abnormality include the basal ganglia, midbrain, cerebellum, pons,

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Fig. 6.11. Japanese encephalitis. Axial fluid attenuated inversion recovery images in two different patients with Japanese encephalitis demonstrate bilateral symmetric increased signal intensity (A) and asymmetric right thalamus signal abnormality (B) respectively. (Reproduced from Misra et al., 2010.)

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and cerebral cortex (Kalita and Misra, 2000). Like HSE, temporal lobe involvement may be seen with JE; however the pattern of disease may be slightly different, with preferential involvement of the body and tail of the hippocampus and relative sparing of the anterior temporal lobe and insula (Kalita and Misra, 2000; Handique et al., 2006). Furthermore, temporal lobe involvement is often seen with concomitant signal abnormalities in the basal ganglia and thalami, allowing differentiation from HSE (Kalita and Misra, 2000) since the basal ganglia and thalami are not involved in HSE. DWI with apparent diffusion coefficient (ADC) values may prove to play an important role in further differentiating HSE from JE, with a study by Sawlani (2009) suggesting that ADC values in acute HSE are lower than with acute JE, presumably reflecting the abundant cytotoxic edema in the former leading to early cell necrosis.

Tick-borne encephalitis Tick-borne encephalitis (TBE) spreads to humans following the bite of an infected tick, or less commonly, consumption of infected goat milk (Gritsun et al., 2003). Three subtypes of TBE virus exist, classified as follows: Far Eastern, Siberian, and Western European (Gritsun et al., 2003). Clinical severity is thought to differ among the subtypes, with the Far Eastern virus resulting in often fatal meningoencephalitis, while the Siberian and Eurpean subtypes produce milder encephalitis without significant neurologic sequelae (Gritsun et al., 2003). Histologic studies have demonstrated lymphocytic meningeal infiltration with neuronal necrosis and subsequent glial cell and phagocyte proliferation with associated perivascular infiltration involving the medulla, pons, cerebellum, basal ganglia, thalamus, and spinal cord (Kaiser, 1999). Limited imaging studies have consistently demonstrated nonenhancing high T2/FLAIR signal abnormality involving the thalami, with involvement of the brainstem, cerebellum, hypothalamus, penduncles, pons, and caudate nucleus being much less common (Kaiser, 1999; Marjelund et al., 2006). CT imaging may demonstrate non-specific regions of low attenuation with effacement of sulci and the basal cisterns corresponding to brain edema (Bender et al., 2005). Imaging of the spinal cord has demonstrated increased T2 signal abnormality within the anterior nerve roots of the spinal cord (Stich et al., 2007), with one case report demonstrating contrast enhancement of the cauda equina and corresponding nerve roots (Marjelund et al., 2006). While the pathogenesis of TBE is yet to be fully understood, the possibility of this infection should be considered in a patient with bilateral non-enhancing T2/FLAIR signal abnormalities in the thalami.

Dengue fever The pathogenesis of the neurologic manifestations of dengue fever (DF) is still being studied, with explanations ranging from metabolic derangements leading to encephalopathy and/or a viral-induced encephalitis (Wasay et al., 2008). Furthermore, other laboratory abnormalities associated with DF such as thrombocytopenia, prolonged prothrombin time, disseminated intravascular coagulation, and abnormal liver function tests may act synergistically to increase the propensity for intracranial hemorrhage, resulting in life-threatening dengue hemorrhagic fever (Cam et al., 2001). CT imaging is an excellent first-line imaging modality in this regard, with acute blood appearing as regions of high attenuation with or without midline shift. Given the rarity of neuronal involvement in DF, there is a paucity of literature on the expected imaging findings. Case reports and case series have demonstrated focal or generalized regions of non-specific increased T2 signal abnormality within the hippocampus, globus pallidus, thalamus, pons, and internal capsule (Fig. 6.12) (Lum et al., 1996; Cam et al., 2001). Involvement of the spinal cord is rare, but manifests as regions of hyperintense T2 signal (Wasay et al., 2008). Cases of acute disseminated encephalomyelitis (ADEM) following DF have also been reported in the literature (Yamamoto et al., 2002; Miranda de Sousa et al., 2006).

Chikungunya fever Chikungunya fever (CF) results from the bite of an infected mosquito, resulting in fever, arthralgias, and rash (Tyler, 2009). Neurologic sequelae are rare, but include encephalitis, myelopathy, and neuropathy (Tyler, 2009). Histologically, CF infection of the CNS results in a perivascular lymphocytic infiltrate with demyelinating foci (Ganesan et al., 2008). Imaging findings are often normal; however, reported findings include increased T2/FLAIR signal in the cingular gyrus and limbic cortex, as well as non-specific regions of restricted diffusion within the white matter (Fig. 6.13) (Robin et al., 2008). Enhancing nerve roots as well as region of hyperintense T2 signal in the cord have been reported in cases of neuropathy and myelopathy (Wadia, 2007; Ganesan et al., 2008).

Rift Valley fever There are limited case reports describing the epidemiologic, clinical, and imaging findings of Rift Valley fever encephalitis (RVFE). CNS manifestations range from 4.9% (Riou et al., 1989) to 18.1% (Balkhy and Memish, 2003), as reported in the Mauritania and Saudi Arabia outbreaks of 1987 and 2000–2001 respectively. While

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Fig. 6.12. Dengue fever. Axial fluid attenuated inversion recovery (A) and T2-weighted (B) images demonstrate bilateral symmetric increased signal within the hippocampi bilaterally in this patient with positive antidengue immunoglobulin G (IgG) and IgM cerebrospinal fluid serologies. (Reproduced from Gupta et al., 2008.)

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Fig. 6.13. Chikungunya fever. Axial T2 and T1 non-contrast images (A, B) demonstrate diffuse, symmetric area of increased T2 signal in the corpus callosum as well as the periventricular and subcortical white matter. Areas of hemorrhage are noted in both cerebral hemispheres, as manifested by area of dark T2 and bright T1-weighted signal intensity (arrows). (Reproduced from Das et al., 2010.)

the pathogenesis of RVFE remains unclear, histologic animal studies demonstrate evidence for active viral replication and necrotizing encephalitis with diffuse perivascular infiltrates of lymphocytes and macropahges within the cerebal parenchyma (Anderson et al., 1988). Imaging findings were reported in a single case of RVFE in an 18-year-old female in Saudi Arabia who presented with confusion, fever, and blurred vision (Alrajhi et al., 2004). While the CT findings were within normal limits, MRI demonstrated hypterintense T2 signal in the

frontoparietal regions bilaterally as well as evidence of subtle increased T2 signal in the right posterior thalamus (Alrajhi et al., 2004). DWI demonstrated bilateral regions of high signal within the cortex bilaterally (Alrajhi et al., 2004).

La Crosse encephalitis At CT, the most common imaging appearance of La Crosse viral encephalitis is a normal study. In their series

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of 127 patients with La Crosse encephalitis, McJunkin et al. (2001) report that in only 11 of the 92 patients who underwent CT were the imaging results abnormal. The most common positive finding, diffuse cerebral edema, was present in 8 patients. Multifocal edema was also seen, though less commonly. Severe cases resulted in effacement of the perimesencephalic cisterns and uncal herniation. MRI of La Crosse encephalitis also may be normal (Balkhy and Schreiber, 2000). Positive findings include focal signal abnormalities in hemispheric cortical and subcortical regions (Sokol et al., 2001; Khan et al., 2008), the insular cortex (Sokol et al., 2001; Khan et al., 2008), periventricular region (Garg and Kleiman, 1994), the putamen and caudate (Leber et al., 1995) and the medial temporal lobe, including the hippocampus and uncus (Fig. 6.14) (Sokol et al., 2001; Wurtz and Paleologos, 2000). The imaging findings at both CT and MR reflect the constant underlying pathologic process: inflammation. The radiographic findings likely reflect the severity of

Fig. 6.14. La Crosse encephalitis. Axial fluid attenuated inversion recovery image demonstrates multiple regions of increased signal intensity involving the frontotemporal lobes bilaterally, as well as the left insular cortex and medial left temporal lobe. The imaging findings are indistinguishable from herpes encephalitis; however, serologies confirmed the presence of La Crosse virus. (Reproduced from Sokol et al., 2001.)

involvement and the portion of the brain affected. The absence of pathognomonic features makes a specific diagnosis nearly impossible to render by imaging alone. Further, frequent involvement of the medial temporal lobe or lobes may falsely suggest HSE.

NIPAH AND HENDRA VIRUS The Nipah and Hendra viruses are closely related zoonotic viruses which are thought to be transmitted to humans via contact with pigs and horses respectively (Tyler, 2009). To date, four cases of human Hendra virus infection have been reported, two of which have been fatal (Hanna et al., 2006). Imaging findings in a single case report from Queensland, Australia, demonstrated multifocal high T2 signal abnormalities within the cortical gray matter bilaterally, which progressed over an 8-day period (Fig. 6.15) (O’Sullivan et al., 1997). Postmortem histologic analysis demonstrated evidence of leptomeningitis with lymphocyte and plasma cell infiltration (O’Sullivan et al., 1997). In addition, there were several discrete foci of necrosis involving the neocortex, basal ganglia, brainstem, and cerebellum (O’Sullivan et al., 1997). Nipah virus encephalitis (NPE) has been more readily demonstrated through data collected from recent outbreaks in Malaysia (Lim et al., 2000). In the acute phase of infection, MRI demonstrates small focal regions of hyperintense T2/FLAIR signal within the subcortical and deep white matter, and, to a lesser extent, gray matter, thalamus, and brainstem (Fig. 6.16) (Lim et al., 2000). These foci may or may not demonstrate enhancement with intravenous gadolinium administration, and some may demonstrate restricted diffusion (Lim et al., 2000). Of note, there is no significant mass effect or edema associated with these lesions, even with innumerably scattered foci (Lim et al., 2000). Approximately 1 month after the acute phase of infection, MRI may demonstrate transient punctate foci of hyperintense T1 signal intensity, which are of unknown etiology (Lim et al., 2002). The imaging findings of relapsing (usually after 8 months) or late-onset encephalitis are in distinction to the acute phase of illness, with MRI demonstrating larger, confluent, or patchy regions of high T2/ FLAIR signal within the cortex and subcortical white matter (Sejvar et al., 2007). Pathologic findings in NPE correlate well with acute and late-onset phase imaging findings. In the acute phase, viral antigen and viral inclusion were often seen in the cerebral vascular endothelial cells, resulting in a vasculitis with thrombosis and parenchymal necrosis, likely corresponding to the associated T2 signal abnormality (Wong et al., 2002). Histologic analysis of brain from patients with relapsing or late-onset encephalitis

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Fig. 6.15. Hendra virus encephalitis (A, B). Axial T2-weighted images (B performed 1 week after A) demonstrate rapid progression of hyperintense signal primarily involving the cortex of both cerebral hemipsheres bilaterally. (Reproduced from O’Sullivan et al., 1997.)

The above findings would suggest that, after entering the blood stream, Nipah virus induces a multifocal vasculitis with resulting thrombosis resulting in foci of high T2 signal intensity within the subcortical and deep white matter (Wong et al., 2002). Subsequent reactivation of directly infected neurons may then give rise to the relapsed or late-onset phase of disease (Tan et al., 2002).

ADENOVIRUS

Fig. 6.16. Nipah virus encephalitis. Axial fluid attenuated inversion recovery image demonstrates multiple bilateral punctate foci of increased signal intensity, predominantly involving the subcortical white matter. (Reproduced from Rumboldt, 2008.)

demonstrated more extensive neuronal injury (resulting in confluent T2 hyperintense lesions) with more prominent viral inclusions (Tan et al., 2002). Necrotic plaques and vasculitis were notably absent (Tan et al., 2002).

While adenoviruses are commonly encountered in the setting of upper respiratory tract infections and gastroenteritis, CNS involvement is rare (Rumboldt, 2008). Reported neurologic clinical syndromes include aseptic meningitis, myelitis, subacute focal encephalitis, and a Reye-like syndrome (Rumboldt, 2008). In immunocompetent patients, adenovirus-induced meningoencephalitis typically follows a benign and self-limited course with no significant imaging findings (Straussberg et al., 2001). In immunosuppressed patients, however, adenovirus may result in a more severe meningoencephalitis resulting in hemorrhagic degeneration in the inferomedial temporal cortex as well as the amygdalae, anterior hypothalamus, and inferior colliculi (Dubberke et al., 2006). These histologic findings are reflected by abnormally high T2 signal within the limbic system, as reported in a 31-year-old female with acute limbic encephalitis following type 2 adenovirus infection (Nagasawa et al., 2006). Other reported regions of involvement include the ependymal and subependymal cells (Anders et al., 1990), as well as the brainstem and cerebellum, where abnormal increased T2 signal intensity associated with patchy enhancement, mass effect,

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M. MATHUR ET AL. microcephaly and periventricular calcification. Other additional abnormalities included prominent gyral malformation, ventriculomegaly, hydrocephalus, porencephalic and periventricular cysts, encephalomalacia, and isolated cerebellar hypoplasia (Bonthius et al., 2007). The diversity in the abnormal findings is thought to be related to differences in the gestational age of infection (Bonthius et al., 2007).

HEPATITIS C

Fig. 6.17. Adenovirus encephalitis. Axial T2-weighted image demonstrates a focal, well-defined, hyperintense lesion involving the splenium of the corpus callosum. (Reproduced from Rumboldt, 2008.)

and hemorrhage is compatible with rhombencephalitis (Fig. 6.17) (Zagardo et al., 1998).

ARENAVIRUSES There is limited literature regarding both the clinical and radiological manifestations of the arenavirues that affect humans. Lassa fever (caused by Lassa virus) may give rise to sensorineural deafness during the convalescence phase and is unrelated to the severity of the acute illness. Postnatal lymphocytic choriomeningitis virus (LCMV) infection typically results in an aseptic meningitis, with symptoms lasting less than 3 weeks before the patient fully recovers (Foster et al., 2006). Occasionally, more severe disease may result in encephalitis, hydrocephalus, and transverse myelitis (Bonthius et al., 2007). In counterdistinction to postnatal disease, prenatal disease may result in devastating neuroteratogenic effects. In a study by Bonthius et al. (2007), who looked at the clinical and neuroradiologic findings of 20 children with serologically confirmed LCMV infection, the most common abnormalities included

CNS vasculitis related to mixed cryoglobulinemia (MC) in the setting of hepatitis C virus (HCV) infection is a rare but well-documented phenomenon (Petty et al., 1996). A study by Casato et al. (2005) looked at imaging data in 40 patients with MC vasculitis and HCV and reported that patients with HCV-MC had a higher mean number of total and periventricular white-matter hyperintense T2 signal abnormalities when compared with HCV and healthy controls. None of the HCV-MC patients demonstrated evidence of cerebral infarction related to arterial occlusive disease (Casato et al., 2005). The authors postulated that this difference may be related to underlying cerebral vasculitis, with the white matter being more vulnerable to ischemic changes owing to relatively widely spaced arterioles, few anastomoses, and sparse collateralization (Ginsberg et al., 1976; Casato et al., 2005). The exact mechanism of HCV-MC-related CNS vasculitis is not well understood (Casato et al., 2005).

HUMAN IMMUNODEFICIENCY VIRUS CNS imaging findings in patients infected with HIV can be categorized as related primarily to HIV infection, related to opportunistic infection, or resulting from neoplastic or vascular complication. We will focus only on the effects of the HIV virus itself. Brain MR images in HIV-infected patients may be normal or abnormal. Early changes of HIV encephalitis manifest as multifocal subcentimeter white-matter lesions appearing bright on T2-weighted images. These are generally symmetric and spare the subcortical U-fibers (Trotot and Gray, 1997; Bakshi, 2004). This pattern is seen in approximately 20% of cases (Bakshi, 2004). The chronic stage of HIV infection manifests as progressive white-matter signal abnormality in conjunction with brain atrophy. White-matter changes are hyperintense on T2-weighted images and typically slightly hypointense on T1-weighted images. These changes classically begin as “patchy” and “ill-defined” involvement of the deep white matter (Fig. 6.18). With progression of disease, however, these become confluent and may extend to involve the basal ganglia, cortex, cerebellum, brainstem, and spinal cord (Navia et al., 1986). Findings may be symmetric or asymmetric. There is little edema,

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Fig. 6.18. Human immunodeficiency virus encephalitis. Axial T2-weighted image (A) demonstrates bilateral symmetric regions of increased signal intensity in the periventricular and subcortical white matter. Repeat axial T2-weighted image after highly active antiretroviral therapy (HAART, B) demonstrates resolution of the previously seen white-matter abnormality.

which on imaging manifests as lack of mass effect. These lesions typically do not enhance (Jensen and Brant-Zawadzki, 1993). White-matter changes correspond to demyelination and vacuolation (Hawkins et al., 1993). While most patients demonstrate predominant findings in the white matter, in some the gray matter is more severely affected (Levy et al., 1985; Sze et al., 1987). Another chronic feature of HIV infection is progressive cerebral atrophy, which is most prominent centrally, resulting in ex vacuo ventricular dilatation out of proportion to sulcal prominence. With highly active antiretroviral therapy (HAART), T2 white-matter changes may diminish or stabilize, although cerebral atrophy may progress despite therapy (Thurnher et al., 2000). One study reimaged patients 2–4 years following a baseline MRI and found that, in neurologically asymptomatic patients, 20% had mildly abnormal MR results, which overall were stable over the study interval (Grant et al., 1987). Of those study patients with mild neurologic abnormality, 50% demonstrated mildly abnormal imaging findings. MR is more sensitive than CT for the detection of HIV-related brain changes. In particular, white-matter lesions are not well depicted by CT and, if seen, appear as non-specific white-matter hypodensities (Levy et al., 1985). MR spectroscopy provides a useful method of examining local brain metabolite concentrations. In the setting of HIV infection, there is a tendency towards relative decrease in NAA, and a tendency towards relative increase in choline and myoinositol (McConnell et al., 1994; Lopez-Villegas et al., 1997; Salvan et al., 1997; Banakar et al., 2008). The increment in choline and myoinositol levels can be seen relatively early in HIV infection; the increased choline levels persist as the disease progresses (Tracey et al., 1996); however, the myoinositol levels tend towards normalization (Lopez-Villegas et al., 1997). The decline in NAA levels

appears to correlate with the severity of neurologic deterioration (McConnell et al., 1994). MR spectroscopy particularly is useful in that it may demonstrate abnormalities in HIV-infected patients before clinical symptoms are present or before changes are present by conventional MR sequences. In addition, there is evidence that the degree of brain injury and response to HAART may be monitored by MRS (Chang et al., 1999). Primary spinal cord involvement with HIV may also occur. The predominant pathologic findings are vacuolation and demyelination (Sartoretti-Schefer et al., 1997; Berger and Sabet, 2002). The most common MR finding is cord atrophy, typically involving the thoracic cord (Chong et al., 1999). Intrinsic cord signal abnormality may also be seen, though less commonly. These lesions are typically hyperintense on T2-weighted images, slightly hypointense on T1-weighted images, and do not enhance (Sartoretti-Schefer et al., 1997; Chong et al., 1999). Focal cord lesions may be seen diffusely or may be limited to white-matter pathways, most typically the posterior columns (Gray et al., 1990; Sartoretti-Schefer et al., 1997; Chong et al., 1999).

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Progressive multifocal leukoencephalopathy (PML) is an uncommon opportunistic infection caused by the JC polyoma virus. The virus primarily affects oligodendrocytes, resulting in oligodendrocyte lysis and demyelination (Saribas et al., 2010). While PML is most commonly seen in the setting of underlying HIV-1 infection, it may also be seen in the context of hematologic malignancies and treatment with immunosuppressive medications (Cinque et al., 2009). MR is the current modality of choice for imaging patients with suspected PML. Lesions appear hyperintense on T2-weighted images and hypointense on

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Fig. 6.19. Progressive multifocal leukoencephalopathy. Axial fluid attenuated inversion recovery image (A) demonstrates marked increased signal in the subcortical and periventricular matter of the right cerebral hemisphere with mass effect upon the right lateral ventricle. Axial pre- (B) and postcontrast (C) images demonstrate enhancement along the edge of the T2 signal abnormality (arrow, C).

T1-weighted images. Lesions are most commonly found in the subcortical and periventricular white matter of the frontal and parieto-occipital lobes; they are also seen in the white matter of the cerebellar peduncles or hemispheres, and in the brainstem (Whiteman et al., 1993; Weber, 2008; Cinque et al., 2009). Early on, the lesions may be small but then progress to form larger areas of involvement, often with a scalloped border. The lesions are classically bilateral, asymmetric, multifocal, and lacking in mass effect. Only 9% of cases demonstrate enhancement, which is typically faint and peripheral (Fig. 6.19) (Whiteman et al., 1993). Spinal cord involvement is rare. In the setting of PML, MRI is more sensitive than CT and is better able to delineate areas of involvement (Whiteman et al., 1993). CT demonstrates regions of hypodensity in the white matter. The imaging distinction between HIV encephalitis and PML may be important if the clinical diagnosis is in doubt. As a guideline, HIV encephalitis is more symmetric, confluent, and has a greater tendency for involvement of the periventricular white matter. PML, on the other hand, is typically discrete and asymmetric. The correlation between imaging findings and clinical presentation is useful here. While PML patients often present with a focal neurologic deficit such as a sensory, motor, or visual deficit, HIV encephalitis often presents as dementia and global cognitive decline.

HUMAN T-LYMPHOTROPIC VIRUS TYPE I (HTLV-I) Adult T-cell leukemia/lymphoma (ATL) is the malignancy caused by HTLV-I. HTLV-I is also associated with

the development of HTLV-I-associated myelopathy/ tropical spastic paraparesis (HAM/TSP). The MRI appearance of ATL has been correlated with pathologic findings by Kitajima et al. (2002). Their study found that cortical masses, masses in the periventricular white matter, and masses in the deep gray matter were most common. These were seen variably with or without contrast enhancement. Leptomeningeal enhancement was also seen in some cases, indicative of meningeal involvement. Though less frequently, spinal nerve enhancement was observed. Pathologic findings consisted of clusters of tumor cells spread along perivascular channels as well as parenchymal infiltration by tumor. Secondary degeneration of neuronal tracts was observed. In instances of HAM/TSP, MRI typically reveals punctate regions of T2 hyperintensity affecting the deep and subcortical white matter with relative sparing of the immediate periventricular white matter (Kira et al., 1991). Lesions become more numerous and increasingly confluent with disease progression. Mass effect and contrast enhancement are typically absent (Kira et al., 1991).

ACUTE DISSEMINATED ENCEPHALOMYELITIS ADEM is thought to be an immune-mediated process typified pathologically by white-matter inflammation and demyelination. Gray matter also may be affected (Dale et al., 2000; Sonneville et al., 2008). In one study, CT was able to demonstrate abnormality in approximately one-third of affected patients, while MRI demonstrated abnormality in all patients (Sonneville et al.,

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Fig. 6.20. Acute disseminated encephalomyelitis. Axial T2-weighted (A) image of the brain demonstrates a non-specific region of high signal in the posterior left cerebrum involving the deep and subcortical white matter (arrow). Axial T1 pre- (B) and postcontrast (C) images demonstrate peripheral ring enhancement (arrow, C).

2008). The reported CT findings were hypodensities in the cerebral white matter and focal or diffuse cerebral edema. By MR, typical features include multiple asymmetric, poorly marginated hyperintense areas on T2-weighted images. Lesions typically involve the subcortical and deep white matter with relative sparing of the periventricular regions (Fig. 6.20). Gray-matter lesions frequently involve the cortex, thalamus, and basal ganglia. Lesions are typically isointense to slightly hypointense on T1-weighted images. Contrast enhancement is an uncommon feature, though when present, typically involves the majority of the lesions (Dale et al., 2000; Rossi, 2008). This enhancement pattern is intuitive because ADEM is usually a monophasic process with lesions presumably in a similar pathologic phase. Imaging features are often not pathognomonic and differential diagnoses often include multiple sclerosis and encephalitis.

SUBACUTE SCLEROSING PANENCEPHALITIS (SSPE) SSPE is a chronic and progressive encephalitis caused by a persistent infection of the brain by measles virus. MRI early in the course of SSPE may be normal (Brismar et al., 1996; Ozt€ urk et al., 2002). Early changes include bilateral, multifocal, asymmetric T2 hyperintense lesions of the periventricular and subcortical white matter (Anlar et al., 1996; Brismar et al., 1996). There is a predilection for involvement of the parietal and occipital lobes (Fig. 6.21). With time, these lesions may become larger, more numerous, and more confluent, and appear more symmetric. Late changes of SSPE include

Fig. 6.21. Subacute sclerosing panencephalitis (SSPE). Axial T2-weighted image demonstrates symmetric regions of increased signal intensity in the subcortical white matter, predominantly in the posterior cerebrum. Serology titers and electroencephalogram findings were compatible with SSPE. (Reproduced from Kubota et al., 2003.)

abnormal signal in the basal ganglia (typically the putamen), severe white-matter volume loss, and increased T2 signal in the gray matter (Anlar et al., 1996; Brismar et al., 1996; Ozt€ urk et al., 2002). In the late stage, thinning of the corpus callosum also may be seen (Brismar

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et al., 1996). Striatal necrosis, parenchymal hemorrhage, and parenchymal and leptomengingeal enhancement have also been reported as late findings (Lee et al., 2003).

imaging features of this infection are non-specific. Features described include increased T2 signal intensity in the cerebral white matter, basal ganglia, and thalami. Infratentorial involvement has been described in both the brainstem and the cerebellar hemispheres (Tarr et al., 1987; Unal et al., 2005). Several reports of MRI features in the spine describe long-segment areas of abnormality spanning multiple vertebral bodies with possible leptomeningeal contrast enhancement (Venketasubramanian, 1997; Unal et al., 2005).

RABIES ENCEPHALITIS Published reports detailing the imaging features of rabies are uncommon, resulting at least in part from the difficulty of imaging an agitated patient. CT imaging may be normal or show areas of diffuse or focal hypoattenuation involving the periventricular white matter and basal ganglia (Awasthi et al., 2001). Reports of the MR features of rabies encephalitis describe ill-defined mild areas of T2 hyperintensity in the brainstem, hippocampi, hypothalami, deep and subcortical white matter, and deep and cortical gray matter (Fig. 6.22) (Pleasure and Fischbein, 2000; Laothamatas et al., 2003; Solomon et al., 2005). Areas of mild enhancement have been reported (Pleasure and Fischbein, 2000), though this is not often seen and is likely a late-stage feature of the disease. No significant differences in imaging features were seen between patients with either clinical form of rabies (encephalitic versus paralytic) (Laothamatas et al., 2003). It is known that rabies travels retrograde via axoplasmic flow from the area of inoculation to the CNS. Interestingly, there is a reported case of enhancement along the brachial plexus of a patient who had been bitten in the arm (Laothamatas et al., 2003).

ENTEROVIRAL ENCEPHALITIS The enteroviruses include the coxsackieviruses, polioviruses, and echoviruses. Enteroviruses most often result in aseptic meningitis and aseptic meningitis is most often due to the enteroviruses (particularly the coxsackieviruses and echoviruses) (Kupila et al., 2006). Enteroviruses also are associated with ADEM. There are some reports detailing the imaging findings of enteroviral encephalitis. These are discussed below, in turn. The imaging features of encephalitis resulting from enterovirus 71 (EV71) have been described in a study of 20 patients identified during an EV71 outbreak (Shen et al., 1999). Five patients demonstrated normal MRI examinations. Of the 15 patients with positive studies, characteristic and constant findings were hyperintensity in the posterior portions of the medulla and pons; these changes were seen in all patients with MR abnormality (Fig. 6.23). The midbrain and dentate nuclei of the cerebellum were involved in approximately twothirds of study patients. Severe cases demonstrated involvement of the ventral horns of the spinal cord, basal ganglia, and thalami.

MUMPS ENCEPHALITIS There are not many published reports detailing the imaging appearance of mumps encephalitis. The reported

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Fig. 6.22. (A, B) Rabies encephalitis. Axial fluid attenuated inversion recovery image demonstrates increased signal in the caudate, lentiform nuclei, and bilateral thalami (A). Additional regions of increased signal intensity are noted in the left hippocampus and dorsal midbrain. (Reproduced from Rumboldt, 2008.)

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Echoviral encephalitis has a non-specific and inconstant appearance. Increased T2 and decreased T1 signal in the upper cervical cord, medulla, pons, midbrain, and posterior aspect of the putamen has been reported (Lum et al., 2002). A seemingly different pattern has been described: diffuse hyperintense signal in the white matter of both cerebral hemispheres, predominantly located in the periventricular and subcortical white matter, with extension of hyperintense signal into the cortical gray matter (Brunel et al., 2007). A third report describes T2 hyperintensities in the medial temporal lobes, caudate nuclei, insula, putamen, globus pallidus, and left frontal region, with involvement of both gray and white matter. These abnormalities were noted to worsen on follow-up imaging (Valcour et al., 2008). Contrast enhancement is variably present.

INFLUENZA

Fig. 6.23. Enteroviral encephalitis. Axial T2-weighted image demonstrates symmetric regions of increased signal intensity involving the posterior pons (arrows). (Reproduced from Rumboldt, 2008.)

There are several strains of poliovirus (types 1, 2, and 3) which may cause poliomyelitis, a historically important disease. Poliomyelitis is characterized by pathologic involvement of the motor neurons in the spinal cord and brainstem. The MR finding most characteristic of poliomyelitis is hyperintensity involving the region of the anterior horn cells on T2-weighted images (Kornreich et al., 1996; Rao and Bateman, 1997; Haq and Wasay, 2006; Choudhary et al., 2010). Contrast enhancement in the anterior spinal cord is inconstant, though it has also been described (Kornreich et al., 1996). In the posterior fossa, T2 signal abnormality has been described in the substantia nigra (Choudhary et al., 2010) and in the midbrain and medulla (Wasserstrom et al., 1992). Though it is less common in adults, Coxsackie B virus is thought to be responsible for the majority of cases of aseptic meningitis in children (Kaplan et al., 1983; Shaw and Cohen, 1993). There are additionally occasional reports of Coxsackie encephalitis. Berger et al. (2006) describe a patient who presented with normal CT imaging. MRI showed abnormal T2 and FLAIR signal in both medial temporal lobes without contrast enhancement. This finding showed near-complete resolution on subsequent MRI; however, a new abnormal focus developed in the left putamen.

Neurologic manifestations of influenza virus include Reye’s syndrome, febrile seizures, encephalitis, myelitis, and acute necrotizing encephalopathy (ANE). We will discuss only influenza encephalopathy and ANE. In the early stages of influenza encephalopathy, neuroimaging by CT or MRI may be normal. When present, imaging features include diffusely elevated T2 signal in the cerebral cortex, diffuse brain edema, and a reversible lesion in the splenium of the corpus collosum (Kimura et al., 1998; Yoshikawa et al., 2001). An additional imaging pattern reported is that of normal MRI findings in the acute phase followed by a diffuse low-density area as seen by CT, and finally evolution of mild brain atrophy (Yoshikawa et al., 2001). DWI may be more sensitive relative to conventional MR sequences for subtle lesions (Tokunaga et al., 2000). ANE is characterized by bilaterally symmetric necrotic brain lesions in the thalami, cerebral white matter, brainstem, and cerebellum (Mizuguchi, 1997). Eighteen percent of ANE cases are associated with influenza type A virus infection (Fig. 6.24) (Sugaya, 2000). Other infectious agents implicated with ANE include HHV-6 (Sugaya et al., 2002), measles (Ruggieri et al., 1998), and parainfluenza virus (Mastroyianni et al., 2003). The clinical symptoms of ANE closely resemble those of influenza encephalopathy and include impaired consciousness and convulsions, possibly leading to coma (Mizuguchi, 1997). CT may show hypodense or hyperdense lesions in the regions listed above (hyperdense areas are representative of hemorrhage). ANE has been well described in Asia, with the first report published in 1995 (Mizuguchi, 1997). More recently, ANE has been reported in the United States (Weitkamp et al., 2004).

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Fig. 6.24. Influenza A. Axial fluid attenuated inversion recovery (A) and T1 postcontrast image (B) demonstrate bilateral asymmetric non-enhancing regions of high signal intensity involving the thalami. A peripheral rim of restricted diffusion is demonstrated on the diffusion-weighted images (arrow, C). The imaging findings are consistent with acute necrotizing encephalopathy in this patient with serologic titers positive for underlying influenza A infection.

CONCLUSION This chapter has discussed CT and MRI findings in a variety of common, uncommon, and rare viral infectious diseases of the nervous system. Correlation between the underlying pathophysiologic mechanism of disease and imaging findings has been demonstrated where such correlations have been elucidated. While the role of CT may be limited to screening for devastating consequences of severe illness, such as hemorrhage or midline shift, MRI remains the modality of choice in demonstrating the early signs of infection/inflammation. Furthermore, image sequences such as DWI and MRS show promise in detecting disease earlier than conventional sequences and provide more specificity to the etiology of the signal abnormalities. Although not absolutely diagnostic, imaging findings greatly assist clinicians to narrow their differential diagnosis. Furthermore they point the way toward technologic advances in imaging and enhanced understanding of pathophysiologic mechanisms of disease.

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