REVIEW ARTICLE
Magnetic Resonance Imaging in Viral and Prion Diseases of the Central Nervous System Behroze Vachha, MD, PhD,* Rafael Rojas, MD,† Sanjay P. Prabhu, MD,‡ Rafeeque Bhadelia, MD,† and Gul Moonis, MD† Abstract: The early detection and specific diagnosis of viral infections of the central nervous system are important because many of these diseases are potentially treatable. However, clinical symptoms and physical examination are often nonspecific, and rapid diagnostic tests are available for some, but not all, viruses. Neuroimaging, in conjunction with clinical history and laboratory tests, plays an important role in narrowing the differential diagnoses. In this article, we review the clinical features, imaging characteristics, diagnosis, and treatment of the more common viral infections and prions that involve the central nervous system. Key Words: viral, CNS, MRI, CT, CMV, HSV, HIV, arbovirus (Top Magn Reson Imaging 2014;23: 293–302)
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he early detection and specific diagnosis of viral infections of the central nervous system (CNS) is important because many of these diseases are potentially treatable. The diagnosis of CNS viral infections, however, is challenging because the clinical symptoms and physical examination are often nonspecific, and rapid diagnostic tests are available for some but not all viruses.1 Diagnostic decision making includes a detailed history and laboratory tests, however, neuroimaging, particularly magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion weighted MRI (DWI), plays an important role in narrowing the differential diagnoses and is an important component of the diagnostic process. In this article, we review the clinical features, imaging characteristics, diagnosis, and treatment of the more common viral infections that involve the CNS. Because infections of the developing brain have different manifestations and neurological consequences compared to those that affect the adult brain, we divide viral infections commonly encountered in clinical practice into the following categories: congenital viral infections and acquired viral infections, including acute cerebellitis and prion diseases.
CONGENITAL VIRAL INFECTIONS
Approximately 90% of infants with congenital CMV infection are asymptomatic at birth but are at risk of developing hearing loss at approximately 18 months of age. Infants that manifest symptoms at birth (hyperactivity, petechiae, jaundice, hepatosplenomegaly, and hypotonia) are at increased risk of developing permanent disabilities. Greater than 50% of infected infants with systemic manifestations also present with CNS involvement including microcephaly, chorioretinitis, hearing impairment, cerebral palsy, epilepsy, and mental retardation.5,6 The gestational age of the child at the time of in utero infection predicts the pattern and severity of CNS involvement such that first and second trimester infections result in the most severe outcomes. Specifically, infection before 18 weeks result in lissencephaly, small cerebellum, and ventriculomegaly; infection at 18 to 24 weeks results in cortical gyral abnormalities, such as polymicrogyria (Fig. 1A); infection after 24 weeks results in myelin delay, ventriculomegaly, and periventricular calcifications; and perinatal infection results in focal white matter injury.7 T1-weighted MR images show subependymal hyperintense foci corresponding to periventricular calcifications (Fig. 1A) with susceptibility effect noted on susceptibility weighted images (Fig. 1B). T2-weighted (T2W) and fluid attenuated inversion recovery (FLAIR) images demonstrate myelin destruction. T2Whyperintense periventricular cysts may be seen particularly in the region of the anterior temporal lobe (Fig. 1C). Central nervous system toxoplasmosis can be distinguished from CMV by the presence of scattered parenchymal calcifications as compared to the periventricular/subependymal calcifications seen in CMV. Diagnosis of intrauterine infection involves detection of CMV-DNA from amniotic fluid or fetal blood by polymerase chain reaction (PCR) analysis.1 Postnatally, diagnosis is made by isolation of virus from the body fluid of infants within 3 weeks of birth.8,9 Ganciclovir and valganciclovir provide effective reduction in hearing loss and improvement in development of those infants treated at birth, however their use is limited by drug related toxicities.10–12
Cytomegalovirus Congenital cytomegalovirus (CMV), a ubiquitous DNA virus of the herpesviridae family, is the most common congenital infection in the United State occurring in approximately 1% of all live born infants.2,3 In utero infection may be caused by transplacental transmission of the virus. Postnatally, infants may be infected during parturition or by ingestion of breast milk.3,4 From the *Neuroradiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, †Neuroradiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, and ‡Boston Children's Hospital, Boston, MA. Reprints: Behroze Vachha, MD, PhD, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114 (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright ©2014 by Lippincott Williams & Wilkins
Herpes Simplex Virus Type 2 Herpes simplex virus (HSV) is a ubiquitous DNA virus belonging to the Herpesviridae family. Eighty percent of neonatal HSV infections are caused by HSV type 2 (HSV-2) and 20% of cases are caused by HSV type 1 (HSV-1).7 Infections are transmitted vertically from the mother to the infant; 85% of cases occur in the peripartum period, 5% occur in utero, and 10% occur postnatally through contact with oral or skin lesions.7 Neonatal HSV infection results in 3 distinct disease patterns with progressive increase in morbidity and mortality: (1) disease localized to the skin, eye or mouth; (2) encephalitis, with or without skin, eye or mouth involvement; (3) disseminated infection that involves multiple sites, including the CNS, lung, liver, adrenals, skin, eye, or mouth.6,7,13,14 Nonspecific clinical features,
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FIGURE 1. Congenital CMV. (A) Axial magnetization prepared rapid gradient echo image in a 13-year-old boy presenting with seizures for many years demonstrates polymicrogyria (arrow), ventriculomegaly and mineralization along the ventricular margins (arrowhead). (B) Susceptibility weighted image (SWI) in a 14-year-old male presenting with seizures demonstrates susceptibility foci consistent with periventricular calcifications. (C) Axial T2-weighted image in an 8-year-old boy with sensorineural hearing loss demonstrates a right temporal lobe cyst (arrow).
such as lethargy, poor feeding, fever, seizures, and bulging fontanelles, are common.13,14 Magnetic resonance imaging is the imaging modality of choice in suspected cases of neonatal HSV infections. Neonatal HSV infections produce more diffuse involvement of the cerebral white matter and involve the temporal and frontal lobes.7,14 Hypointensity on T1-weighted images and hyperintensity on T2W and FLAIR images within the cortex, subcortical white matter, and basal ganglia with contrast enhancement is typical. Hemorrhagic foci may develop in the later stage of the disease and are best seen on susceptibility weighted images. Areas of restricted diffusion on DWI may be the only positive imaging findings in early cases. Figure 2 illustrates MRI findings in a patient with HSV-2 encephalitis. Later in the disease, there may be volume loss with enlarged ventricles and cystic encephalomalacia (Fig. 3). Diagnosis of neonatal HSV infection requires a high index of suspicion particularly if the history of infection in the mother is not known. Herpes simplex virus infections should be suspected in infants with nonspecific symptoms, such as poor feeding, lethargy, or seizure in the first month of life. Diagnosis is made by cerebrospinal fluid (CSF) PCR or viral isolation from ulcerated vesicles or mucocutaneous lesions.1,13
Antiviral therapy with acyclovir is recommended in all infants pending culture results and has been shown to reduce morbidity.13
Rubella The incidence of congenital rubella syndrome in the United States has declined with the advent of the measles-mumpsrubella vaccination.15 The risk of congenital infection resulting in miscarriage, fetal death, and congenital malformations is highest during the first 12 weeks of gestation and decreases after the 12th week of gestation with defects rare after the 20th week of gestation.7,16 When infection occurs in the first and second trimesters, the common clinical manifestations include deafness, cataract, glaucoma, micropthalmos, chorioretinitis, cardiac anomalies, microcephaly, cerebral palsy, seizures, and psychomotor retardation.7 Imaging features are nonspecific and include periventricular white matter and basal ganglia calcifications best visualized on nonenhanced CT scans, ventriculomegaly, and microcephaly.7 Additionally, MRI demonstrates delayed myelination with oligogyria or macrogyria.7,17 T2 hyperintense signal in the periventricular and subcortical white matter has been reported both in children and adults with a diagnosis of congenital rubella (Fig. 4).17,18
FIGURE 2. HSV-2 encephalitis. (A) Diffusion-weighted image in an 18-day-old neonate presenting with seizures demonstrates restricted diffusion within the left greater than right cerebral hemispheres. (B) Coronal gadolinium enhanced T1-weighted image demonstrates patchy enhancement within the left and right cerebral hemispheres. In contrast to adult HSV infections, neonatal HSV infections produce more diffuse involvement of the cerebral white matter as in this case.
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FIGURE 3. HSV-2 encephalitis. (A) Diffusion-weighted image in a 7-month-old boy presenting with seizures demonstrates restricted diffusion within the left temporal lobe. Axial T1-weighted (B) and axial T2-weighted (C) images in the same child after a course of intravenous acyclovir demonstrate volume loss and cystic encephalomalacic changes in the left temporal lobe at the site of previous acute HSV encephalitis.
Congenital Human Immunodeficiency Virus Human immunodeficiency virus (HIV) is a neurotropic human RNA virus belonging to the retroviridae family, with the subtype HIV-1 being responsible for most of the cases of congenital HIV/AIDS.1,6,7,19 Approximately 90% of congenital HIV is transmitted vertically from the mother to the infant. Most infants are infected either during the third trimester or at birth, although occasionally older infants are infected during breast feeding.1,6,7,19–22 The child usually presents with developmental delay, progressive motor dysfunction, and failure to thrive. Opportunistic infections are less common in HIV-infected children compared to adults. Magnetic resonance imaging shows atrophy of predominantly the frontal lobes with T2/FLAIR hyperintensity in the periventricular white matter and centrum semiovale with relative sparing of the subcortical white matter and absence of restricted diffusion, mass effect, and contrast enhancement (Fig. 5A). Bilateral symmetric calcifications in children older than 2 months are highly suspicious for congenital HIV (Fig. 5B). Basal ganglia calcifications are best visualized on noncontrast-enhanced head CT scans or T2*GRE sequences on MRI. Ectasia and fusiform dilation of intracranial arteries has been described in 3% to 5% of cases.6,7,14 Early diagnosis of congenital HIV infection is crucial and should occur rapidly postnatally when mothers are known to be HIV-positive to allow rapid prophylactic management. Polymerase chain reaction of viral DNA is used to detect infection in neonates.23 Antiretroviral therapy for expectant mothers and for newborns with short courses of zidovudine or single-dose nevirapine have been shown to be effective in systematic reviews.24
by fever, headache, seizures, and altered mental status with rapid progression to death in 2 weeks without treatment. Magnetic resonance imaging is the imaging modality of choice with a characteristic pattern of bilateral but asymmetric T2/FLAIR hyperintense signal abnormality initially within the hippocampi and mesial temporal lobe structures, progressing to involve the insular cortices and frontal lobes with sparing of the basal ganglia (Fig. 6A). Patchy enhancement of the cortex and/or the white matter is seen after contrast administration. The DWI shows increased signal intensity in the affected areas early in the course of the disease often preceding the FLAIR abnormalities (Fig. 6B). In suspected HSE, the work-up must be initiated rapidly but should not delay empiric treatment with acyclovir. Focal neurologic deficits, CSF pleocytosis, and abnormalities on imaging may not always be present in the early stages of the disease. The diagnosis is confirmed by PCR or brain biopsy. The definitive treatment is acyclovir.
Human Herpes Virus-6 Human herpes virus-6 (HHV-6) is a ubiquitous DNA virus belonging to the roseolovirus genus of the betaherpesvirus
ACQUIRED VIRAL INFECTIONS Herpes Simplex Encephalopathy Herpes simplex virus-1 is the most common worldwide cause of nonepidemic viral encephalitis, and it is estimated that 10% of all cases of encephalitis in the United States are because of HSV-1 infection.6,14 The virus is acquired early in life and resides in a latent form in the trigeminal ganglia and the vagus nerve. Reactivation of latent HSV-1 infection can occur spontaneously or may be triggered by trauma, stress, and immunosuppression.6,14 Involvement of the CNS can result in herpes simplex encephalopathy (HSE) characterized ©2014 Lippincott Williams & Wilkins
FIGURE 4. Congenital rubella. Axial FLAIR image in a 3-year-old girl with developmental delay demonstrates periventricular and subcortical white matter signal abnormalities. www.topicsinmri.com
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FIGURE 5. Congenital HIV. (A) Axial FLAIR image in an 11-year-old woman presenting with expressive language delay demonstrates extensive, confluent T2 prolongation in the bilateral periventricular white matter with relative sparing of the subcortical U fibers. (B) Axial noncontrast-enhanced T1-weighted image in a 12-year-old female with memory and concentration problems demonstrate intrinsic T1 hyperintensity within bilateral basal ganglia consistent with mineralization. There is gyriform mineralization with laminar necrosis in the right posterior cerebral hemisphere.
subfamily.25,26 There are 2 known variants, HHV-6A and HHV-6B. Human herpes virus-6B causes the childhood illness roseola infantum or sixth disease.25 Primary infections with HHV-6 are acquired before the age of 2 years with the virus remaining latent and asymptomatic in immunocompetent adults. In contrast, HHV-6B reactivation is common in transplant recipients resulting in severe clinical manifestations, such as encephalitis, bone marrow suppression, and pneumonitis.27–29 Magnetic resonance imaging is the imaging modality of choice with imaging features similar to HSV encephalitis including bilateral but asymmetric T2/FLAIR hyperintense signal abnormality initially within the hippocampi, amygdala, parahippocampal gyri, insular regions, and inferior frontal lobes (Fig. 7).30 In contrast to HSV encephalitis, there is usually no enhancement after the administration of gadolinium in affected brain regions in HHV6 encephalitis. Clinically, CSF PCR is the most definitive test used in the evaluation of HHV6-associated encephalitis.29 Patients are usually treated with foscarnet or ganciclovir.31,32
Human Immunodeficiency Virus As in congenital HIV, the subtype HIV-1 is responsible for most of the cases of acquired HIV/AIDS although the imaging presentation is distinct from that seen in congenital HIV. The HIVinfected monocytes and lymphocytes migrate across the intact blood brain barrier within 24 to 48 hours after initial exposure, persisting in perivascular macrophages and microglia.14 Human immunodeficiency virus is neurovirulent with clinically relevant cognitive impairment noted in at least 50% of patients despite combination antiretroviral therapy.33–35 With the introduction of highly active antiretroviral therapies (HAART) the incidence of rapidly progressive dementia has declined, however, HIV-associated neurocognitive disorders remain frequent, although typically with milder symptoms.6 The HIV-associated neurocognitive disorder encompasses a hierarchy of progressively more severe patterns of neurological involvement. It can range from asymptomatic neurocognitive impairment to minor
FIGURE 6. HSV-1 encephalitis. (A) Axial FLAIR image in a 34-year-old man with altered mental status and fever demonstrates hyperintense signal within medial and lateral temporal lobes (right greater than left), the inferior frontal lobe and bilateral insula. (B) Diffusion weighted images demonstrate restricted diffusion in the same regions.
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FIGURE 7. HHV-6 encephalitis. Axial FLAIR image in a 53-year-old woman with acute myeloid leukemia status post-allogeneic stem cell transplant with new bilateral upper and lower extremity paresthesias shows hyperintense signal within bilateral (right greater than left) medial temporal lobes as well as in the left posterior temporal lobe (arrow).
neurocognitive disorder to more severe HIV-associated dementia also called AIDS dementia complex or HIV encephalopathy.36 The work-up for HIV encephalopathy includes lumbar puncture with CSF analysis, neuropsychological testing, and neuroimaging. Imaging studies often make the diagnoses of HIV dementia, myelopathy, or neuropathy with gadolinium-enhanced MRI being the imaging modality of choice. Magnetic resonance imaging findings include cerebral atrophy and white matter disease.7 Three patterns of brain atrophy are noted: (1) central atrophy which preferentially affects the basal ganglia and the deep white matter with associated ventriculomegaly; (2) global atrophy with predominant frontal lobe involvement; and (3) necrotizing encephalopathy.7 The disease is best seen on T2/FLAIR sequences as diffuse, bilateral symmetric white matter hyperintensity with relative sparing of subcortical U-fibers (Fig. 8; contrast from progressive multifocal leukoencephalopathy which involves subcortical U-fibers). There is no associated mass effect or enhancement except in the case of acute fulminant HIV encephalopathy where there may be perivenular enhancement. The MRS demonstrates decreased levels of n-acetyl aspartate (NAA) and elevated choline. Diffusion tensor imaging demonstrates elevated radial diffusivity in patients with HIV encephalopathy, suggesting demyelinating changes of the white matter play an important role in the disease process. Vacuolar myelopathy or AIDS-associated myelopathy seen in 20% to 55% of patients with AIDS demonstrates characteristic bilateral symmetric T2 hyperintensity in the dorsal columns of the spinal cord extending over multiple segments.37–39 The pattern is almost identical to that seen in subacute combined degeneration due to vitamin B12 deficiency and may reflect abnormal vitamin B12 metabolism in these patients. Highly active antiretroviral therapy is the treatment of choice for HIV-related cognitive disorders. Aggressive early treatment of patients with HIV disease with HAART does not prevent the onset of CNS manifestations of HIV but decreases the severity of HIV dementia.40
Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of a latent infection with a papovavirus called the ©2014 Lippincott Williams & Wilkins
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JC virus.41 The virus acquired in childhood remains latent until the host's immune status is compromised, such as in patients with cancer, patients on chemotherapy/steroid treatment, transplant patients on immunosuppressive drugs, in patients with HIV and in patients with multiple sclerosis treated with monoclonal antibody therapy (e.g., natalizumab).42–44 In contrast to HIV, dementia is a not a characteristic of PML. Patients usually present with altered mental status, progressive neurological symptoms, and lethargy.41 Magnetic resonance imaging is the imaging modality of choice to evaluate patients suspected of having PML. Progressive multifocal leukoencephalopathy is characterized by T2 hyperintense, multifocal lesions involving the subcortical, and periventricular white matter. The lesions are bilateral, asymmetric, demonstrate no contrast enhancement or mass effect and have a predilection for the parietoccipital region, thalamus, and basal ganglia. Imaging findings distinguishing PML from HIV include: (1) involvement of the subcortical U-fibers in PML which is typically spared in HIV encephalopathy (Fig. 9); (2) T1-hypointense PML lesion compared to HIV lesions which are nearly always isointense to the white matter; and (3) marked reduction of magnetization transfer in PML compared to HIV likely reflecting the destruction of macromolecules such as myelin lipids in PML. Two distinct patterns are noted with MRS. During the initial and active phase of the disease there is low NAA, elevated choline and occasionally elevated lactate, while in end-stage PML, all metabolites are low. Progressive multifocal leukoencephalopathy has a poor prognosis without treatment with overall survival of 6 to 12 months.45 Highly active antiretroviral therapy has been reported to improve survival in these patients.45 Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical deterioration in the patient’s clinical status attributed to recovery of the immune system after HAART.46 Progressive multifocal leukoencephalopathy-IRIS may occur in up to 23% of HIV-associated PML.44 Progressive multifocal leukoencephalopathyIRIS may also be seen in patients with multiple sclerosis who are on monoclonal antibody therapy.47 Progressive multifocal leukoencephalopathy-IRIS manifests as worsening of MRI findings with development of temporary contrast enhancing lesions that appear increased in size and more
FIGURE 8. HIV encephalopathy. Axial FLAIR image in a 40-year-old man presenting with slowly progressing cognitive decline demonstrates diffuse, bilateral relatively symmetric white matter hyperintensity with relative sparing of subcortical U-fibers. www.topicsinmri.com
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FIGURE 9. Progressive multifocal leukoencephalopathy. (A) Axial FLAIR image in a 51-year-old woman with known HIV presenting with new onset altered mental status and lethargy demonstrates hyperintense signal within the right cerebral hemisphere with involvement of subcortical U-fibers consistent with progressive multifocal leukoencephalopathy (c.f. HIV-encephalopathy described in Figure 8 where there is sparing of subcortical U-fibers). (B) Axial T1 post contrast enhanced image demonstrates very faint enhancement.
confluent with mass effect and edema which is noted a few weeks after starting treatment and which disappears at a later stage48 (Fig. 10). Use of pulsed corticosteroids has been suggested to rapidly decrease the symptoms of IRIS.49
Arboviruses Arthropod-borne viruses, that is, arboviruses, are transmitted to humans by arthropod vectors.50,51 Arboviruses that cause human encephalitis are members of Flaviviridae (e.g., West Nile virus, Japanese encephalitis virus, St. Louis encephalitis virus, Murray Valley encephalitis virus), Togaviridae (e.g., Eastern and Western Equine encephalitis virus), and Bunyaviridae (La Crosse encephalitis virus).1 The common arboviral encephalitides vary in epidemiology, morbidity, and mortality, and no specific treatment exists for these diseases; however, it is important to distinguish
these encephalitides from the more treatable herpes simplex and varicella zoster encephalitides. West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease in the United States.50 The characteristic imaging findings of WNV encephalitis include T2 hyperintense bilateral basal ganglia, thalamic and brainstem lesions which usually demonstrate restricted diffusion on DWI. West Nile virus involvement of the spinal cord results in edema and diffuse increase in signal intensity with variable patchy enhancement of a long segment of cord (Fig. 11). There is no specific treatment for this disease with the best course of management being prevention of mosquito bites. The imaging findings of encephalitides caused by other flaviviridae are similar to WNV encephalitis. Japanese encephalitis (JE) virus is the most important cause of arboviral encephalitis worldwide but is less common in the United States.50 T2 hyperintense thalamic and brainstem lesions (specifically involving the
FIGURE 10. PML-IRIS. (A) Axial FLAIR image in the same patient as in Figure 9, 3 weeks after starting anti-retroviral therapy, demonstrates more confluent white matter hyperintensities with associated mass effect on the adjacent right lateral ventricle. (B) Axial T1 post contrast enhanced image demonstrates more pronounced patchy enhancement.
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FIGURE 11. West Nile virus encephalitis. (A) Sagittal STIR image in a 40-year-old man presenting with sudden onset head ache and fever demonstrates edema and diffuse increase in signal intensity. (B) Sagittal T1 post-contrast with fat saturation image demonstrates variable patchy enhancement of a long segment of cord.
substantia nigra) are noted. The lesions are often hemorrhagic, and bilateral thalamic hemorrhages are highly characteristic for JE. Medial temporal lobe involvement similar to HSE is occasionally seen in JE; however unlike HSE, the insular cortex and anterior temporal lobes are usually spared in JE. Similarly, T2 hyperintense basal ganglia and thalamic lesions are noted in Eastern Equine encephalitis (Fig. 12) and Western Equine encephalitis.52
changes associated with neuronal loss. The causative agents of these diseases are called “prions” because they induce abnormal folding of specific normal cellular proteins in the brain called prion proteins with resultant brain damage. Human prion diseases include sporadic Creutzfeldt-Jakob disease (CJD), sporadic fatal insomnia, familial CJD, new variant CJD, iatrogenic CJD, kuru, Gerstmann-Straussler-Sheinker disease, and fatal insomnia. Approximately 90% of cases of human
Acute Cerebellitis Acute cerebellitis is characterized by an acute or subacute onset of cerebellar ataxia following an infection or vaccination and is more commonly seen in children.53 Most symptoms resolve completely over weeks to months; however, occasionally transtentorial herniation can lead to arterial infarction and death. Varicella is involved in over one fourth of cases in children younger than 15 years of age; however, numerous other infectious agents including many other viruses (e.g. measles, mumps, coxsackievirus, parvovirus B19, echovirus, enteroviruses, Epstein-Barr virus, hepatitis A, herpes simplex virus I, and human herpesvirus 6) and some bacteria have also been implicated.53–55 Magnetic resonance imaging findings included bilateral confluent T1 and T2 prolongation of the gray and white matter of the cerebellar hemispheres with restricted diffusion on diffusionweighted imaging (Fig. 13). Treatment of this condition is usually supportive with steroids and antiviral therapy indicated if a specific viral etiology has been identified.53
PRIONS Prion diseases or transmissible spongiform encephalopathies are rare progressive neurodegenerative disorders that affect both humans and animals and are characterized by characteristic spongiform ©2014 Lippincott Williams & Wilkins
FIGURE 12. Eastern Equine encephalitis. Axial FLAIR image in a 13-year-old boy with fever and mild altered mental status demonstrates hyperintense signal within the caudate nuclei, putamen and thalami bilaterally (right greater than left). www.topicsinmri.com
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FIGURE 13. Acute viral cerebellitis. (A) Axial T2-weighted image in a 5-year-old boy presenting with a 10-day history of worsening behavior, altered mental status and ataxia on examination with elevated Epstein-Barr virus (EBV) Ig M titers, demonstrates diffuse enlargement of bilateral cerebellar hemispheres with patchy abnormal T2 prolongation. (B) Axial post-contrast T1-weighted image demonstrates leptomeningeal enhancement.
prion disease are classified as sporadic CJD with an unknown origin or source of infection, 10% of cases are caused by hereditary CJD or caused by corneal transplantation, ingestion of prion-contaminated growth hormone and transplantation of cadaveric dura mater, and the remaining cases are represented by Gerstmann-Straussler-Sheinker disease.56 The most common clinical manifestation of CJD is rapidly progressive fatal dementia leading to death in a few weeks or months and myoclonus. In sporadic CJD, most patients develop characteristic periodic or pseudoperiodic paroxysms of sharp waves or spikes on a slow background on electroencephalogram (EEG). Patients with variant CJD do not show the typical EEG changes, and findings are often normal. Magnetic resonance imaging with DWI is the imaging modality of choice. Magnetic resonance imaging findings of sporadic CJD include progressive T2/FLAIR hyperintensity of the basal
ganglia (caudate and putamen involved more than globus pallidi), thalamus, and cerebral cortex.56 The DWI demonstrates characteristic-restricted diffusion of basal ganglia, thalami, and the cerebral cortex even in the absence of T2/FLAIR abnormalities (Fig. 14). These lesions show no evidence of contrast enhancement. In the end-stage of CJD, the DWI may return to normal. Cortical involvement in sporadic CJD consists of high signal intensity in the insula, the cingulate and superior frontal gyri, and in the cortical areas near the midline, best visualized on diffusion weighted imaging.57 The suspicion of sporadic CJD should be raised in patients with dementia who have the described cortical changes even without involvement of the deep gray matter.58 The MRS shows low NAA in all parts of the brain, but this is a nonspecific finding. There are 2 signs that are characteristic of variant CJD: the “pulvinar sign” which is symmetric T2 hyperintensity of the
FIGURE 14. Creutzfeldt-Jacob disease. Diffusion weighted imaging demonstrates restricted diffusion within the cortex (A) and within the left caudate head (B) in a 40-year-old man with initial presentation of rapid cognitive decline.
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7. Lo CP, Chen CY. Neuroimaging of viral infections in infants and young children. Neuroimaging Clin N Am. 2008;18:119–132; viii. 8. Boppana SB, Ross SA, Novak Z, et al. Dried blood spot real-time polymerase chain reaction assays to screen newborns for congenital cytomegalovirus infection. JAMA. 2010;303:1375–1382. 9. Ross SA, Boppana SB. Congenital cytomegalovirus infection: outcome and diagnosis. Semin Pediatr Infect Dis. 2005;16:44–49. 10. Oliver SE, Cloud GA, Sanchez PJ, et al. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system. J Clin Virol. 2009;46(Suppl 4):S22–S26. 11. Kimberlin DW, Lin CY, Sanchez PJ, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr. 2003;143:16–25. 12. Kimberlin DW. Antiviral therapy for cytomegalovirus infections in pediatric patients. Semin Pediatr Infect Dis. 2002;13:22–30. 13. Rudnick CM, Hoekzema GS. Neonatal herpes simplex virus infections. Am Fam Physician. 2002;65:1138–1142.
FIGURE 15. Variant Creutzfeldt-Jacob disease. Axial diffusion-weighted MRI in a 51-year-old woman with 2 to 3 months of rapid cognitive decline demonstrates hockey stick-like thalamic hyperintensities (arrows) as well as hyperintensities in the caudate and putamen bilaterally.
pulvinar of the thalami relative to the anterior putamen, and the “hockey stick sign” (Fig. 15) which represent symmetric pulvinar and dorsomedial thalamic nuclear T2 hyperintensity.59,60 Familial CJD has an earlier age of onset and longer duration than sporadic CJD but is similar to sporadic CJD in imaging findings. GerstmannStraussler-Sheinker disease is characterized by cerebral and cerebellar atrophies as well as signal changes in the basal ganglia.61–63 Fatal familial insomnia results in reduced activity in the thalami on positron emission tomography.63 Diagnosis of CJD is made by the clinical history of rapidly progressive dementia, EEG pattern of sharp and slow wave complexes, characteristic MRI findings and specific neuronal proteins (14-3-3 and Tau) in CSF.64 Unfortunately, there is no definite treatment for the disease, and the outcome is inexorably fatal.
SUMMARY Familiarity with the clinical course and imaging findings of various commonly encountered CNS viral infections is helpful in making the correct diagnosis and in guiding appropriate therapy. REFERENCES 1. Solbrig MV, Hasso AN, Jay CA. CNS viruses—diagnostic approach. Neuroimaging Clin N Am. 2008;18:1–18; vii. 2. Malm G, Engman ML. Congenital cytomegalovirus infections. Semin Fetal Neonatal Med. 2007;12:154–159. 3. Nassetta L, Kimberlin D, Whitley R. Treatment of congenital cytomegalovirus infection: implications for future therapeutic strategies. J Antimicrob Chemother. 2009;63:862–867.
14. Osborn A. Osborn's Brain: Imaging, Pathology, and Anatomy. Manitoba, Canada: Amirsys, Inc; 2013. 15. (CDC) CfDCaP. Progress toward elimination of rubella and congenital rubella syndrome—the Americas, 2003–2008. MMWR Morb Mortal Wkly Rep. 2008:57:1176. 16. Yoshimura M, Tohyama J, Maegaki Y, et al. Computed tomography and magnetic resonance imaging of the brain in congenital rubella syndrome. No To Hattatsu. 1996;28:385–390. 17. Sugita K, Ando M, Makino M, et al. Magnetic resonance imaging of the brain in congenital rubella virus and cytomegalovirus infections. Neuroradiology. 1991;33:239–242. 18. Lane B, Sullivan EV, Lim KO, et al. White matter MR hyperintensities in adult patients with congenital rubella. AJNR Am J Neuroradiol. 1996;17:99–103. 19. Rumboldt Z, Thurnher MM, Gupta RK. Central nervous system infections. Semin Roentgenol. 2007;42:62–91. 20. John GC, Richardson BA, Nduati RW, et al. Timing of breast milk HIV-1 transmission: a meta-analysis. East Afr Med J. 2001;78:75–79. 21. Kreiss J. Breastfeeding and vertical transmission of HIV-1. Acta Paediatr Suppl. 1997;421:113–117. 22. John GC, Kreiss J. Mother-to-child transmission of human immunodeficiency virus type 1. Epidemiol Rev. 1996;18:149–157. 23. Zaman MM, Recco RA, Haag R. Infection with non-B subtype HIV type 1 complicates management of established infection in adult patients and diagnosis of infection in newborn infants. Clin Infect Dis. 2002;34:417–418. 24. Brocklehurst P, Volmink J. Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection. Cochrane Database Syst Rev. 2002:CD003510. 25. Mori Y, Yamnishi K. HHV-6A, 6B, and 7: pathogenesis, host response, and clinical disease. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al., eds. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007.
4. Munro SC, Trincado D, Hall B, et al. Symptomatic infant characteristics of congenital cytomegalovirus disease in Australia. J Paediatr Child Health. 2005;41:449–452.
26. Wang F, Pellet PE. HHV-6A, 6B, and 7: immunobiology and host response. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al., eds. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007.
5. Barkovich AJ, Lindan CE. Congenital cytomegalovirus infection of the brain: imaging analysis and embryologic considerations. AJNR Am J Neuroradiol. 1994;15:703–715.
27. Nash PJ, Avery RK, Tang WH, et al. Encephalitis owing to human herpesvirus-6 after cardiac transplant. Am J Transplant. 2004;4: 1200–1203.
6. Castillo M, Thurnher M. Imaging viral and prion infections. Semin Roentgenol. 2004;39:482–494.
28. Wainwright MS, Martin PL, Morse RP, et al. Human herpesvirus 6 limbic encephalitis after stem cell transplantation. Ann Neurol. 2001;50:612–619.
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29. Vu T, Carrum G, Hutton G, et al. Human herpesvirus-6 encephalitis following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2007;39:705–709.
47. Tan IL, McArthur JC, Clifford DB, et al. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology. 2011; 77:1061–1067.
30. Gorniak RJ, Young GS, Wiese DE, et al. MR imaging of human herpesvirus-6-associated encephalitis in 4 patients with anterograde amnesia after allogeneic hematopoietic stem-cell transplantation. AJNR Am J Neuroradiol. 2006;27:887–891.
48. Elston JW, Thaker H. Immune reconstitution inflammatory syndrome. Int J STD AIDS. 2009;20:221–224.
31. De Bolle L, Manichanh C, Agut H, et al. Human herpesvirus 6 DNA polymerase: enzymatic parameters, sensitivity to ganciclovir and determination of the role of the A961V mutation in HHV-6 ganciclovir resistance. Antiviral Res. 2004;64:17–25. 32. De Clercq E, Naesens L, De Bolle L, et al. Antiviral agents active against human herpesviruses HHV-6, HHV-7 and HHV-8. Rev Med Virol. 2001;11: 381–395. 33. Clifford DB, Ances BM. HIV-associated neurocognitive disorder. Lancet Infect Dis. 2013;13:976–986. 34. Ances BM, Clifford DB. HIV-associated neurocognitive disorders and the impact of combination antiretroviral therapies. Curr Neurol Neurosci Rep. 2008;8:455–461. 35. Clifford DB. HIV-associated neurocognitive disease continues in the antiretroviral era. Top HIV Med. 2008;16:94–98. 36. Goodkin K, Aronow A, Baldwin G, et al., eds. HIV-1 associated neurocognitive disorders in the HAART era. The Spectrum of Neuro-AIDS Disorders. Washington, DC: ASM Press; 2008. 37. Rottnek M, Di Rocco A, Laudier D, et al. Axonal damage is a late component of vacuolar myelopathy. Neurology. 2002;58:479–481. 38. Chong J, Di Rocco A, Tagliati M, et al. MR findings in AIDS-associated myelopathy. AJNR Am J Neuroradiol. 1999;20:1412–1416. 39. Anneken K, Fischera M, Evers S, et al. Recurrent vacuolar myelopathy in HIV infection. J Infect. 2006;52:e181–e183. 40. Heaton RK, Franklin DR, Ellis RJ, et al. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol. 2011;17:3–16. 41. Johnson R. Acute disseminated encephalomyelitis and progressive multifocal leukoencephalopathy. In: Shapira A, ed. Neurology and clinical neuroscience. Philadelphia: Elsevier; 2007:1060–1062. 42. Mateen FJ, Muralidharan R, Carone M, et al. Progressive multifocal leukoencephalopathy in transplant recipients. Ann Neurol. 2011;70: 305–322. 43. Clifford DB, De Luca A, Simpson DM, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 2010;9:438–446. 44. Cinque P, Koralnik IJ, Gerevini S, et al. Progressive multifocal leukoencephalopathy in HIV-1 infection. Lancet Infect Dis. 2009;9: 625–636. 45. Rumboldt Z. Imaging of topographic viral CNS infections. Neuroimaging Clin N Am. 2008;18:85–92; viii. 46. Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore). 2002;81:213–227.
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49. Travis J, Varma A, duPlessis D, et al. Immune reconstitution associated with progressive multifocal leukoencephalopathy in human immunodeficiency virus: a case discussion and review of the literature. Neurologist. 2008;14:321–326. 50. Center for Disease Control and Prevention West Nile virus disease and other arboviral diseases—United States, 2011. MMWR Morb Mortal Wkly Rep. 2012;61:510–514. 51. Reimann CA, Hayes EB, DiGuiseppi C, et al. Epidemiology of neuroinvasive arboviral disease in the United States, 1999–2007. Am J Trop Med Hyg. 2008;79:974–979. 52. Brant W, Helms C. Fundamentals of diagnostic radiology. Philadelphia: Lippincott Williams and Wilkins; 2007. 53. De Bruecker Y, Claus F, Demaerel P, et al. MRI findings in acute cerebellitis. Eur Radiol. 2004;14:1478–1483. 54. Nussinovitch M, Prais D, Volovitz B, et al. Post-infectious acute cerebellar ataxia in children. Clin Pediatr (Phila). 2003;42:581–584. 55. Cohen HA, Ashkenazi A, Nussinovitch M, et al. Mumps-associated acute cerebellar ataxia. Am J Dis Child. 1992;146:930–931. 56. Ukisu R, Kushihashi T, Tanaka E, et al. Diffusion-weighted MR imaging of early-stage Creutzfeldt-Jakob disease: typical and atypical manifestations. Radiographics. 2006;26(Suppl 1):S191–S204. 57. Tschampa HJ, Kallenberg K, Kretzschmar HA, et al. Pattern of cortical changes in sporadic Creutzfeldt-Jakob disease. AJNR Am J Neuroradiol. 2007;28:1114–1118. 58. Tschampa HJ, Zerr I, Urbach H. Radiological assessment of Creutzfeldt-Jakob disease. Eur Radiol. 2007;17:1200–1211. 59. Collie DA, Summers DM, Sellar RJ, et al. Diagnosing variant Creutzfeldt-Jakob disease with the pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases. AJNR Am J Neuroradiol. 2003; 24:1560–1569. 60. Summers DM, Collie DA, Sellar RJ, et al. The pulvinar sign and diagnosis of Creutzfeldt-Jakob disease. Neurology. 2002;59:962; author reply 962. 61. Simpson M, Johanssen V, Boyd A, et al. Unusual clinical and molecular-pathological profile of Gerstmann-Straussler-Scheinker disease associated with a novel PRNP mutation (V176G). JAMA Neurol. 2013;70:1180–1185. 62. Collins S, McLean CA, Masters CL. Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, and kuru: a review of these less common human transmissible spongiform encephalopathies. J Clin Neurosci. 2001; 8:387–397. 63. Aralasmak A, Crain BJ, Zou WQ, et al. A prion disease—possible Gerstmann-Straussler-Scheinker disease: a case report. J Comput Assist Tomogr. 2006;30:135–139. 64. Sanchez-Juan P, Green A, Ladogana A, et al. CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology. 2006;67:637–643.
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Magnetic Resonance Imaging in Viral and Prion Diseases of the Central Nervous System Behroze Vachha, MD, PhD,* Rafael Rojas, MD,† Sanjay P. Prabhu, MD,‡ Rafeeque Bhadelia, MD,† and Gul Moonis, MD† Abstract: The early detection and specific diagnosis of viral infections of the central nervous system are important because many of these diseases are potentially treatable. However, clinical symptoms and physical examination are often nonspecific, and rapid diagnostic tests are available for some, but not all, viruses. Neuroimaging, in conjunction with clinical history and laboratory tests, plays an important role in narrowing the differential diagnoses. In this article, we review the clinical features, imaging characteristics, diagnosis, and treatment of the more common viral infections and prions that involve the central nervous system. Key Words: viral, CNS, MRI, CT, CMV, HSV, HIV, arbovirus (Top Magn Reson Imaging 2014;23: 293–302)
T
he early detection and specific diagnosis of viral infections of the central nervous system (CNS) is important because many of these diseases are potentially treatable. The diagnosis of CNS viral infections, however, is challenging because the clinical symptoms and physical examination are often nonspecific, and rapid diagnostic tests are available for some but not all viruses.1 Diagnostic decision making includes a detailed history and laboratory tests, however, neuroimaging, particularly magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion weighted MRI (DWI), plays an important role in narrowing the differential diagnoses and is an important component of the diagnostic process. In this article, we review the clinical features, imaging characteristics, diagnosis, and treatment of the more common viral infections that involve the CNS. Because infections of the developing brain have different manifestations and neurological consequences compared to those that affect the adult brain, we divide viral infections commonly encountered in clinical practice into the following categories: congenital viral infections and acquired viral infections, including acute cerebellitis and prion diseases.
CONGENITAL VIRAL INFECTIONS
Approximately 90% of infants with congenital CMV infection are asymptomatic at birth but are at risk of developing hearing loss at approximately 18 months of age. Infants that manifest symptoms at birth (hyperactivity, petechiae, jaundice, hepatosplenomegaly, and hypotonia) are at increased risk of developing permanent disabilities. Greater than 50% of infected infants with systemic manifestations also present with CNS involvement including microcephaly, chorioretinitis, hearing impairment, cerebral palsy, epilepsy, and mental retardation.5,6 The gestational age of the child at the time of in utero infection predicts the pattern and severity of CNS involvement such that first and second trimester infections result in the most severe outcomes. Specifically, infection before 18 weeks result in lissencephaly, small cerebellum, and ventriculomegaly; infection at 18 to 24 weeks results in cortical gyral abnormalities, such as polymicrogyria (Fig. 1A); infection after 24 weeks results in myelin delay, ventriculomegaly, and periventricular calcifications; and perinatal infection results in focal white matter injury.7 T1-weighted MR images show subependymal hyperintense foci corresponding to periventricular calcifications (Fig. 1A) with susceptibility effect noted on susceptibility weighted images (Fig. 1B). T2-weighted (T2W) and fluid attenuated inversion recovery (FLAIR) images demonstrate myelin destruction. T2Whyperintense periventricular cysts may be seen particularly in the region of the anterior temporal lobe (Fig. 1C). Central nervous system toxoplasmosis can be distinguished from CMV by the presence of scattered parenchymal calcifications as compared to the periventricular/subependymal calcifications seen in CMV. Diagnosis of intrauterine infection involves detection of CMV-DNA from amniotic fluid or fetal blood by polymerase chain reaction (PCR) analysis.1 Postnatally, diagnosis is made by isolation of virus from the body fluid of infants within 3 weeks of birth.8,9 Ganciclovir and valganciclovir provide effective reduction in hearing loss and improvement in development of those infants treated at birth, however their use is limited by drug related toxicities.10–12
Cytomegalovirus Congenital cytomegalovirus (CMV), a ubiquitous DNA virus of the herpesviridae family, is the most common congenital infection in the United State occurring in approximately 1% of all live born infants.2,3 In utero infection may be caused by transplacental transmission of the virus. Postnatally, infants may be infected during parturition or by ingestion of breast milk.3,4 From the *Neuroradiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, †Neuroradiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, and ‡Boston Children's Hospital, Boston, MA. Reprints: Behroze Vachha, MD, PhD, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114 (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright ©2014 by Lippincott Williams & Wilkins
Herpes Simplex Virus Type 2 Herpes simplex virus (HSV) is a ubiquitous DNA virus belonging to the Herpesviridae family. Eighty percent of neonatal HSV infections are caused by HSV type 2 (HSV-2) and 20% of cases are caused by HSV type 1 (HSV-1).7 Infections are transmitted vertically from the mother to the infant; 85% of cases occur in the peripartum period, 5% occur in utero, and 10% occur postnatally through contact with oral or skin lesions.7 Neonatal HSV infection results in 3 distinct disease patterns with progressive increase in morbidity and mortality: (1) disease localized to the skin, eye or mouth; (2) encephalitis, with or without skin, eye or mouth involvement; (3) disseminated infection that involves multiple sites, including the CNS, lung, liver, adrenals, skin, eye, or mouth.6,7,13,14 Nonspecific clinical features,
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FIGURE 1. Congenital CMV. (A) Axial magnetization prepared rapid gradient echo image in a 13-year-old boy presenting with seizures for many years demonstrates polymicrogyria (arrow), ventriculomegaly and mineralization along the ventricular margins (arrowhead). (B) Susceptibility weighted image (SWI) in a 14-year-old male presenting with seizures demonstrates susceptibility foci consistent with periventricular calcifications. (C) Axial T2-weighted image in an 8-year-old boy with sensorineural hearing loss demonstrates a right temporal lobe cyst (arrow).
such as lethargy, poor feeding, fever, seizures, and bulging fontanelles, are common.13,14 Magnetic resonance imaging is the imaging modality of choice in suspected cases of neonatal HSV infections. Neonatal HSV infections produce more diffuse involvement of the cerebral white matter and involve the temporal and frontal lobes.7,14 Hypointensity on T1-weighted images and hyperintensity on T2W and FLAIR images within the cortex, subcortical white matter, and basal ganglia with contrast enhancement is typical. Hemorrhagic foci may develop in the later stage of the disease and are best seen on susceptibility weighted images. Areas of restricted diffusion on DWI may be the only positive imaging findings in early cases. Figure 2 illustrates MRI findings in a patient with HSV-2 encephalitis. Later in the disease, there may be volume loss with enlarged ventricles and cystic encephalomalacia (Fig. 3). Diagnosis of neonatal HSV infection requires a high index of suspicion particularly if the history of infection in the mother is not known. Herpes simplex virus infections should be suspected in infants with nonspecific symptoms, such as poor feeding, lethargy, or seizure in the first month of life. Diagnosis is made by cerebrospinal fluid (CSF) PCR or viral isolation from ulcerated vesicles or mucocutaneous lesions.1,13
Antiviral therapy with acyclovir is recommended in all infants pending culture results and has been shown to reduce morbidity.13
Rubella The incidence of congenital rubella syndrome in the United States has declined with the advent of the measles-mumpsrubella vaccination.15 The risk of congenital infection resulting in miscarriage, fetal death, and congenital malformations is highest during the first 12 weeks of gestation and decreases after the 12th week of gestation with defects rare after the 20th week of gestation.7,16 When infection occurs in the first and second trimesters, the common clinical manifestations include deafness, cataract, glaucoma, micropthalmos, chorioretinitis, cardiac anomalies, microcephaly, cerebral palsy, seizures, and psychomotor retardation.7 Imaging features are nonspecific and include periventricular white matter and basal ganglia calcifications best visualized on nonenhanced CT scans, ventriculomegaly, and microcephaly.7 Additionally, MRI demonstrates delayed myelination with oligogyria or macrogyria.7,17 T2 hyperintense signal in the periventricular and subcortical white matter has been reported both in children and adults with a diagnosis of congenital rubella (Fig. 4).17,18
FIGURE 2. HSV-2 encephalitis. (A) Diffusion-weighted image in an 18-day-old neonate presenting with seizures demonstrates restricted diffusion within the left greater than right cerebral hemispheres. (B) Coronal gadolinium enhanced T1-weighted image demonstrates patchy enhancement within the left and right cerebral hemispheres. In contrast to adult HSV infections, neonatal HSV infections produce more diffuse involvement of the cerebral white matter as in this case.
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FIGURE 3. HSV-2 encephalitis. (A) Diffusion-weighted image in a 7-month-old boy presenting with seizures demonstrates restricted diffusion within the left temporal lobe. Axial T1-weighted (B) and axial T2-weighted (C) images in the same child after a course of intravenous acyclovir demonstrate volume loss and cystic encephalomalacic changes in the left temporal lobe at the site of previous acute HSV encephalitis.
Congenital Human Immunodeficiency Virus Human immunodeficiency virus (HIV) is a neurotropic human RNA virus belonging to the retroviridae family, with the subtype HIV-1 being responsible for most of the cases of congenital HIV/AIDS.1,6,7,19 Approximately 90% of congenital HIV is transmitted vertically from the mother to the infant. Most infants are infected either during the third trimester or at birth, although occasionally older infants are infected during breast feeding.1,6,7,19–22 The child usually presents with developmental delay, progressive motor dysfunction, and failure to thrive. Opportunistic infections are less common in HIV-infected children compared to adults. Magnetic resonance imaging shows atrophy of predominantly the frontal lobes with T2/FLAIR hyperintensity in the periventricular white matter and centrum semiovale with relative sparing of the subcortical white matter and absence of restricted diffusion, mass effect, and contrast enhancement (Fig. 5A). Bilateral symmetric calcifications in children older than 2 months are highly suspicious for congenital HIV (Fig. 5B). Basal ganglia calcifications are best visualized on noncontrast-enhanced head CT scans or T2*GRE sequences on MRI. Ectasia and fusiform dilation of intracranial arteries has been described in 3% to 5% of cases.6,7,14 Early diagnosis of congenital HIV infection is crucial and should occur rapidly postnatally when mothers are known to be HIV-positive to allow rapid prophylactic management. Polymerase chain reaction of viral DNA is used to detect infection in neonates.23 Antiretroviral therapy for expectant mothers and for newborns with short courses of zidovudine or single-dose nevirapine have been shown to be effective in systematic reviews.24
by fever, headache, seizures, and altered mental status with rapid progression to death in 2 weeks without treatment. Magnetic resonance imaging is the imaging modality of choice with a characteristic pattern of bilateral but asymmetric T2/FLAIR hyperintense signal abnormality initially within the hippocampi and mesial temporal lobe structures, progressing to involve the insular cortices and frontal lobes with sparing of the basal ganglia (Fig. 6A). Patchy enhancement of the cortex and/or the white matter is seen after contrast administration. The DWI shows increased signal intensity in the affected areas early in the course of the disease often preceding the FLAIR abnormalities (Fig. 6B). In suspected HSE, the work-up must be initiated rapidly but should not delay empiric treatment with acyclovir. Focal neurologic deficits, CSF pleocytosis, and abnormalities on imaging may not always be present in the early stages of the disease. The diagnosis is confirmed by PCR or brain biopsy. The definitive treatment is acyclovir.
Human Herpes Virus-6 Human herpes virus-6 (HHV-6) is a ubiquitous DNA virus belonging to the roseolovirus genus of the betaherpesvirus
ACQUIRED VIRAL INFECTIONS Herpes Simplex Encephalopathy Herpes simplex virus-1 is the most common worldwide cause of nonepidemic viral encephalitis, and it is estimated that 10% of all cases of encephalitis in the United States are because of HSV-1 infection.6,14 The virus is acquired early in life and resides in a latent form in the trigeminal ganglia and the vagus nerve. Reactivation of latent HSV-1 infection can occur spontaneously or may be triggered by trauma, stress, and immunosuppression.6,14 Involvement of the CNS can result in herpes simplex encephalopathy (HSE) characterized ©2014 Lippincott Williams & Wilkins
FIGURE 4. Congenital rubella. Axial FLAIR image in a 3-year-old girl with developmental delay demonstrates periventricular and subcortical white matter signal abnormalities. www.topicsinmri.com
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FIGURE 5. Congenital HIV. (A) Axial FLAIR image in an 11-year-old woman presenting with expressive language delay demonstrates extensive, confluent T2 prolongation in the bilateral periventricular white matter with relative sparing of the subcortical U fibers. (B) Axial noncontrast-enhanced T1-weighted image in a 12-year-old female with memory and concentration problems demonstrate intrinsic T1 hyperintensity within bilateral basal ganglia consistent with mineralization. There is gyriform mineralization with laminar necrosis in the right posterior cerebral hemisphere.
subfamily.25,26 There are 2 known variants, HHV-6A and HHV-6B. Human herpes virus-6B causes the childhood illness roseola infantum or sixth disease.25 Primary infections with HHV-6 are acquired before the age of 2 years with the virus remaining latent and asymptomatic in immunocompetent adults. In contrast, HHV-6B reactivation is common in transplant recipients resulting in severe clinical manifestations, such as encephalitis, bone marrow suppression, and pneumonitis.27–29 Magnetic resonance imaging is the imaging modality of choice with imaging features similar to HSV encephalitis including bilateral but asymmetric T2/FLAIR hyperintense signal abnormality initially within the hippocampi, amygdala, parahippocampal gyri, insular regions, and inferior frontal lobes (Fig. 7).30 In contrast to HSV encephalitis, there is usually no enhancement after the administration of gadolinium in affected brain regions in HHV6 encephalitis. Clinically, CSF PCR is the most definitive test used in the evaluation of HHV6-associated encephalitis.29 Patients are usually treated with foscarnet or ganciclovir.31,32
Human Immunodeficiency Virus As in congenital HIV, the subtype HIV-1 is responsible for most of the cases of acquired HIV/AIDS although the imaging presentation is distinct from that seen in congenital HIV. The HIVinfected monocytes and lymphocytes migrate across the intact blood brain barrier within 24 to 48 hours after initial exposure, persisting in perivascular macrophages and microglia.14 Human immunodeficiency virus is neurovirulent with clinically relevant cognitive impairment noted in at least 50% of patients despite combination antiretroviral therapy.33–35 With the introduction of highly active antiretroviral therapies (HAART) the incidence of rapidly progressive dementia has declined, however, HIV-associated neurocognitive disorders remain frequent, although typically with milder symptoms.6 The HIV-associated neurocognitive disorder encompasses a hierarchy of progressively more severe patterns of neurological involvement. It can range from asymptomatic neurocognitive impairment to minor
FIGURE 6. HSV-1 encephalitis. (A) Axial FLAIR image in a 34-year-old man with altered mental status and fever demonstrates hyperintense signal within medial and lateral temporal lobes (right greater than left), the inferior frontal lobe and bilateral insula. (B) Diffusion weighted images demonstrate restricted diffusion in the same regions.
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FIGURE 7. HHV-6 encephalitis. Axial FLAIR image in a 53-year-old woman with acute myeloid leukemia status post-allogeneic stem cell transplant with new bilateral upper and lower extremity paresthesias shows hyperintense signal within bilateral (right greater than left) medial temporal lobes as well as in the left posterior temporal lobe (arrow).
neurocognitive disorder to more severe HIV-associated dementia also called AIDS dementia complex or HIV encephalopathy.36 The work-up for HIV encephalopathy includes lumbar puncture with CSF analysis, neuropsychological testing, and neuroimaging. Imaging studies often make the diagnoses of HIV dementia, myelopathy, or neuropathy with gadolinium-enhanced MRI being the imaging modality of choice. Magnetic resonance imaging findings include cerebral atrophy and white matter disease.7 Three patterns of brain atrophy are noted: (1) central atrophy which preferentially affects the basal ganglia and the deep white matter with associated ventriculomegaly; (2) global atrophy with predominant frontal lobe involvement; and (3) necrotizing encephalopathy.7 The disease is best seen on T2/FLAIR sequences as diffuse, bilateral symmetric white matter hyperintensity with relative sparing of subcortical U-fibers (Fig. 8; contrast from progressive multifocal leukoencephalopathy which involves subcortical U-fibers). There is no associated mass effect or enhancement except in the case of acute fulminant HIV encephalopathy where there may be perivenular enhancement. The MRS demonstrates decreased levels of n-acetyl aspartate (NAA) and elevated choline. Diffusion tensor imaging demonstrates elevated radial diffusivity in patients with HIV encephalopathy, suggesting demyelinating changes of the white matter play an important role in the disease process. Vacuolar myelopathy or AIDS-associated myelopathy seen in 20% to 55% of patients with AIDS demonstrates characteristic bilateral symmetric T2 hyperintensity in the dorsal columns of the spinal cord extending over multiple segments.37–39 The pattern is almost identical to that seen in subacute combined degeneration due to vitamin B12 deficiency and may reflect abnormal vitamin B12 metabolism in these patients. Highly active antiretroviral therapy is the treatment of choice for HIV-related cognitive disorders. Aggressive early treatment of patients with HIV disease with HAART does not prevent the onset of CNS manifestations of HIV but decreases the severity of HIV dementia.40
Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of a latent infection with a papovavirus called the ©2014 Lippincott Williams & Wilkins
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JC virus.41 The virus acquired in childhood remains latent until the host's immune status is compromised, such as in patients with cancer, patients on chemotherapy/steroid treatment, transplant patients on immunosuppressive drugs, in patients with HIV and in patients with multiple sclerosis treated with monoclonal antibody therapy (e.g., natalizumab).42–44 In contrast to HIV, dementia is a not a characteristic of PML. Patients usually present with altered mental status, progressive neurological symptoms, and lethargy.41 Magnetic resonance imaging is the imaging modality of choice to evaluate patients suspected of having PML. Progressive multifocal leukoencephalopathy is characterized by T2 hyperintense, multifocal lesions involving the subcortical, and periventricular white matter. The lesions are bilateral, asymmetric, demonstrate no contrast enhancement or mass effect and have a predilection for the parietoccipital region, thalamus, and basal ganglia. Imaging findings distinguishing PML from HIV include: (1) involvement of the subcortical U-fibers in PML which is typically spared in HIV encephalopathy (Fig. 9); (2) T1-hypointense PML lesion compared to HIV lesions which are nearly always isointense to the white matter; and (3) marked reduction of magnetization transfer in PML compared to HIV likely reflecting the destruction of macromolecules such as myelin lipids in PML. Two distinct patterns are noted with MRS. During the initial and active phase of the disease there is low NAA, elevated choline and occasionally elevated lactate, while in end-stage PML, all metabolites are low. Progressive multifocal leukoencephalopathy has a poor prognosis without treatment with overall survival of 6 to 12 months.45 Highly active antiretroviral therapy has been reported to improve survival in these patients.45 Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical deterioration in the patient’s clinical status attributed to recovery of the immune system after HAART.46 Progressive multifocal leukoencephalopathy-IRIS may occur in up to 23% of HIV-associated PML.44 Progressive multifocal leukoencephalopathyIRIS may also be seen in patients with multiple sclerosis who are on monoclonal antibody therapy.47 Progressive multifocal leukoencephalopathy-IRIS manifests as worsening of MRI findings with development of temporary contrast enhancing lesions that appear increased in size and more
FIGURE 8. HIV encephalopathy. Axial FLAIR image in a 40-year-old man presenting with slowly progressing cognitive decline demonstrates diffuse, bilateral relatively symmetric white matter hyperintensity with relative sparing of subcortical U-fibers. www.topicsinmri.com
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FIGURE 9. Progressive multifocal leukoencephalopathy. (A) Axial FLAIR image in a 51-year-old woman with known HIV presenting with new onset altered mental status and lethargy demonstrates hyperintense signal within the right cerebral hemisphere with involvement of subcortical U-fibers consistent with progressive multifocal leukoencephalopathy (c.f. HIV-encephalopathy described in Figure 8 where there is sparing of subcortical U-fibers). (B) Axial T1 post contrast enhanced image demonstrates very faint enhancement.
confluent with mass effect and edema which is noted a few weeks after starting treatment and which disappears at a later stage48 (Fig. 10). Use of pulsed corticosteroids has been suggested to rapidly decrease the symptoms of IRIS.49
Arboviruses Arthropod-borne viruses, that is, arboviruses, are transmitted to humans by arthropod vectors.50,51 Arboviruses that cause human encephalitis are members of Flaviviridae (e.g., West Nile virus, Japanese encephalitis virus, St. Louis encephalitis virus, Murray Valley encephalitis virus), Togaviridae (e.g., Eastern and Western Equine encephalitis virus), and Bunyaviridae (La Crosse encephalitis virus).1 The common arboviral encephalitides vary in epidemiology, morbidity, and mortality, and no specific treatment exists for these diseases; however, it is important to distinguish
these encephalitides from the more treatable herpes simplex and varicella zoster encephalitides. West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease in the United States.50 The characteristic imaging findings of WNV encephalitis include T2 hyperintense bilateral basal ganglia, thalamic and brainstem lesions which usually demonstrate restricted diffusion on DWI. West Nile virus involvement of the spinal cord results in edema and diffuse increase in signal intensity with variable patchy enhancement of a long segment of cord (Fig. 11). There is no specific treatment for this disease with the best course of management being prevention of mosquito bites. The imaging findings of encephalitides caused by other flaviviridae are similar to WNV encephalitis. Japanese encephalitis (JE) virus is the most important cause of arboviral encephalitis worldwide but is less common in the United States.50 T2 hyperintense thalamic and brainstem lesions (specifically involving the
FIGURE 10. PML-IRIS. (A) Axial FLAIR image in the same patient as in Figure 9, 3 weeks after starting anti-retroviral therapy, demonstrates more confluent white matter hyperintensities with associated mass effect on the adjacent right lateral ventricle. (B) Axial T1 post contrast enhanced image demonstrates more pronounced patchy enhancement.
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MRI in Viral and Prion Diseases
FIGURE 11. West Nile virus encephalitis. (A) Sagittal STIR image in a 40-year-old man presenting with sudden onset head ache and fever demonstrates edema and diffuse increase in signal intensity. (B) Sagittal T1 post-contrast with fat saturation image demonstrates variable patchy enhancement of a long segment of cord.
substantia nigra) are noted. The lesions are often hemorrhagic, and bilateral thalamic hemorrhages are highly characteristic for JE. Medial temporal lobe involvement similar to HSE is occasionally seen in JE; however unlike HSE, the insular cortex and anterior temporal lobes are usually spared in JE. Similarly, T2 hyperintense basal ganglia and thalamic lesions are noted in Eastern Equine encephalitis (Fig. 12) and Western Equine encephalitis.52
changes associated with neuronal loss. The causative agents of these diseases are called “prions” because they induce abnormal folding of specific normal cellular proteins in the brain called prion proteins with resultant brain damage. Human prion diseases include sporadic Creutzfeldt-Jakob disease (CJD), sporadic fatal insomnia, familial CJD, new variant CJD, iatrogenic CJD, kuru, Gerstmann-Straussler-Sheinker disease, and fatal insomnia. Approximately 90% of cases of human
Acute Cerebellitis Acute cerebellitis is characterized by an acute or subacute onset of cerebellar ataxia following an infection or vaccination and is more commonly seen in children.53 Most symptoms resolve completely over weeks to months; however, occasionally transtentorial herniation can lead to arterial infarction and death. Varicella is involved in over one fourth of cases in children younger than 15 years of age; however, numerous other infectious agents including many other viruses (e.g. measles, mumps, coxsackievirus, parvovirus B19, echovirus, enteroviruses, Epstein-Barr virus, hepatitis A, herpes simplex virus I, and human herpesvirus 6) and some bacteria have also been implicated.53–55 Magnetic resonance imaging findings included bilateral confluent T1 and T2 prolongation of the gray and white matter of the cerebellar hemispheres with restricted diffusion on diffusionweighted imaging (Fig. 13). Treatment of this condition is usually supportive with steroids and antiviral therapy indicated if a specific viral etiology has been identified.53
PRIONS Prion diseases or transmissible spongiform encephalopathies are rare progressive neurodegenerative disorders that affect both humans and animals and are characterized by characteristic spongiform ©2014 Lippincott Williams & Wilkins
FIGURE 12. Eastern Equine encephalitis. Axial FLAIR image in a 13-year-old boy with fever and mild altered mental status demonstrates hyperintense signal within the caudate nuclei, putamen and thalami bilaterally (right greater than left). www.topicsinmri.com
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FIGURE 13. Acute viral cerebellitis. (A) Axial T2-weighted image in a 5-year-old boy presenting with a 10-day history of worsening behavior, altered mental status and ataxia on examination with elevated Epstein-Barr virus (EBV) Ig M titers, demonstrates diffuse enlargement of bilateral cerebellar hemispheres with patchy abnormal T2 prolongation. (B) Axial post-contrast T1-weighted image demonstrates leptomeningeal enhancement.
prion disease are classified as sporadic CJD with an unknown origin or source of infection, 10% of cases are caused by hereditary CJD or caused by corneal transplantation, ingestion of prion-contaminated growth hormone and transplantation of cadaveric dura mater, and the remaining cases are represented by Gerstmann-Straussler-Sheinker disease.56 The most common clinical manifestation of CJD is rapidly progressive fatal dementia leading to death in a few weeks or months and myoclonus. In sporadic CJD, most patients develop characteristic periodic or pseudoperiodic paroxysms of sharp waves or spikes on a slow background on electroencephalogram (EEG). Patients with variant CJD do not show the typical EEG changes, and findings are often normal. Magnetic resonance imaging with DWI is the imaging modality of choice. Magnetic resonance imaging findings of sporadic CJD include progressive T2/FLAIR hyperintensity of the basal
ganglia (caudate and putamen involved more than globus pallidi), thalamus, and cerebral cortex.56 The DWI demonstrates characteristic-restricted diffusion of basal ganglia, thalami, and the cerebral cortex even in the absence of T2/FLAIR abnormalities (Fig. 14). These lesions show no evidence of contrast enhancement. In the end-stage of CJD, the DWI may return to normal. Cortical involvement in sporadic CJD consists of high signal intensity in the insula, the cingulate and superior frontal gyri, and in the cortical areas near the midline, best visualized on diffusion weighted imaging.57 The suspicion of sporadic CJD should be raised in patients with dementia who have the described cortical changes even without involvement of the deep gray matter.58 The MRS shows low NAA in all parts of the brain, but this is a nonspecific finding. There are 2 signs that are characteristic of variant CJD: the “pulvinar sign” which is symmetric T2 hyperintensity of the
FIGURE 14. Creutzfeldt-Jacob disease. Diffusion weighted imaging demonstrates restricted diffusion within the cortex (A) and within the left caudate head (B) in a 40-year-old man with initial presentation of rapid cognitive decline.
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MRI in Viral and Prion Diseases
7. Lo CP, Chen CY. Neuroimaging of viral infections in infants and young children. Neuroimaging Clin N Am. 2008;18:119–132; viii. 8. Boppana SB, Ross SA, Novak Z, et al. Dried blood spot real-time polymerase chain reaction assays to screen newborns for congenital cytomegalovirus infection. JAMA. 2010;303:1375–1382. 9. Ross SA, Boppana SB. Congenital cytomegalovirus infection: outcome and diagnosis. Semin Pediatr Infect Dis. 2005;16:44–49. 10. Oliver SE, Cloud GA, Sanchez PJ, et al. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system. J Clin Virol. 2009;46(Suppl 4):S22–S26. 11. Kimberlin DW, Lin CY, Sanchez PJ, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr. 2003;143:16–25. 12. Kimberlin DW. Antiviral therapy for cytomegalovirus infections in pediatric patients. Semin Pediatr Infect Dis. 2002;13:22–30. 13. Rudnick CM, Hoekzema GS. Neonatal herpes simplex virus infections. Am Fam Physician. 2002;65:1138–1142.
FIGURE 15. Variant Creutzfeldt-Jacob disease. Axial diffusion-weighted MRI in a 51-year-old woman with 2 to 3 months of rapid cognitive decline demonstrates hockey stick-like thalamic hyperintensities (arrows) as well as hyperintensities in the caudate and putamen bilaterally.
pulvinar of the thalami relative to the anterior putamen, and the “hockey stick sign” (Fig. 15) which represent symmetric pulvinar and dorsomedial thalamic nuclear T2 hyperintensity.59,60 Familial CJD has an earlier age of onset and longer duration than sporadic CJD but is similar to sporadic CJD in imaging findings. GerstmannStraussler-Sheinker disease is characterized by cerebral and cerebellar atrophies as well as signal changes in the basal ganglia.61–63 Fatal familial insomnia results in reduced activity in the thalami on positron emission tomography.63 Diagnosis of CJD is made by the clinical history of rapidly progressive dementia, EEG pattern of sharp and slow wave complexes, characteristic MRI findings and specific neuronal proteins (14-3-3 and Tau) in CSF.64 Unfortunately, there is no definite treatment for the disease, and the outcome is inexorably fatal.
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