A Simplified Approach to Encephalitis and Its Mimics

ARTICLE IN PRESS

A Simplified Approach to Encephalitis and Its Mimics: Key Clinical Decision Points in the Setting of Specific Imaging Abnormalities Colin D. McKnight, MD, Aine M. Kelly, MD, MS, MA, Myria Petrou, MA, MBChB, MS, Anna E. Nidecker, MD, Matthew T. Lorincz, MD, Duaa K. Altaee, BA, Stephen S. Gebarski, MD, Bradley Foerster, MD, PhD Rationale and Objectives: Infectious encephalitis is a relatively common cause of morbidity and mortality. Treatment of infectious encephalitis with antiviral medication can be highly effective when administered promptly. Clinical mimics of encephalitis arise from a broad range of pathologic processes, including toxic, metabolic, neoplastic, autoimmune, and cardiovascular etiologies. These mimics need to be rapidly differentiated from infectious encephalitis to appropriately manage the correct etiology; however, the many overlapping signs of these various entities present a challenge to accurate diagnosis. A systematic approach that considers both the clinical manifestations and the imaging findings of infectious encephalitis and its mimics can contribute to more accurate and timely diagnosis. Materials and Methods: Following an institutional review board approval, a health insurance portability and accountability act (HIPAA)compliant search of our institutional imaging database (teaching files) was conducted to generate a list of adult and pediatric patients who presented between January 1, 1995 and October 10, 2013 for imaging to evaluate possible cases of encephalitis. Pertinent medical records, including clinical notes as well as surgical and pathology reports, were reviewed and correlated with imaging findings. Clinical and imaging findings were combined to generate useful flowcharts designed to assist in distinguishing infectious encephalitis from its mimics. Key imaging features were reviewed and were placed in the context of the provided flowcharts. Results: Four flowcharts were presented based on the primary anatomic site of imaging abnormality: group 1: temporal lobe; group 2: cerebral cortex; group 3: deep gray matter; and group 4: white matter. An approach that combines features on clinical presentation was then detailed. Imaging examples were used to demonstrate similarities and key differences. Conclusions: Early recognition of infectious encephalitis is critical, but can be quite complex due to diverse pathologies and overlapping features. Synthesis of both the clinical and imaging features of infectious encephalitis and its mimics is critical to a timely and accurate diagnosis. The use of the flowcharts presented in this article can further enable both clinicians and radiologists to more confidently differentiate encephalitis from its mimics and improve patient care. Key Words: Encephalitis; magnetic resonance imaging. © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

INTRODUCTION

I

nfectious encephalitis is a relatively common cause of morbidity and mortality. Herpes simplex virus (HSV) alone results in an estimated 2000 deaths per year in the United

Acad Radiol 2017; ■:■■–■■ From the Department of Radiology, University of Michigan Medical Center, 1500 E. Medical Center Drive, UH B2-A209, Ann Arbor, MI 48109 (C.D.M., A.M.K., M.P., D.K.A., S.S.G., B.F.); Department of Radiology, University of California Davis Medical Center, Sacramento, California (A.E.N.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (M.T.L.). Received November 4, 2015; revised April 13, 2016; accepted April 15, 2016. Address correspondence to: C.D.M. e-mail: [email protected] © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.acra.2016.04.013

States (1). Treatment of infectious encephalitis with antiviral medication can be highly effective when administered promptly. This has been most clearly demonstrated in HSV encephalitis, with antiviral medication resulting in impressive reductions in mortality (2). Despite advances in treatment, the complexity of the imaging findings and clinical symptomatology associated with infectious encephalitis can result in delays in diagnosis and treatment, and consequently poor outcomes. Clinical mimics of encephalitis arise from a broad range of pathologic processes, including toxic, metabolic, neoplastic, autoimmune, and cardiovascular etiologies. These distinct entities need to be rapidly differentiated from infectious encephalitis to appropriately manage their separate root causes. When combined, the imaging findings and the clinical 1

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symptomatology of both infectious encephalitis and its associated noninfectious mimics are often unique. Thus, assessment of imaging and clinical findings together can frequently reveal the appropriate diagnosis, often before laboratory results are available. MATERIALS AND METHODS An institutional review board approval was obtained prior to initiating this health insurance portability and accountability act-compliant investigation. The requirement for subject or parent informed consent was waived by the institutional review board. A manual search of our institutional imaging database (teaching files) was conducted to generate a list of adult and pediatric patients who presented between January 1, 1995 (when the teaching file was created) and October 10, 2013 for imaging to evaluate possible cases of encephalitis and its mimics. Cases in the teaching file contain relevant clinical history such as age, sex, presenting symptoms and outcomes (surgical, pathology, or clinical follow up), and diagnostic imaging, but are otherwise de-identified. Radiology imaging, including computed tomography (CT) and magnetic resonance imaging (MRI), was reviewed. As this was a retrospective review of teaching files, not all imaging performed on patients was available, for the purposes of review, especially in some cases with normal initial CT. Where available, pertinent medical records, including clinical notes, and surgical and pathology reports, were reviewed and final diagnoses were correlated with the imaging findings. We included adult and pediatric patients who had a final clinical or pathologic diagnosis of encephalitis or its main mimics. The purpose of this article is to provide an intellectual framework to assess the crucial imaging and clinical decision points to facilitate the generation of an appropriate diagnosis in the setting of suspected encephalitis. Key imaging features are reviewed and are placed in the context of clinical flowcharts to simplify this often challenging diagnostic process. RESULTS AND DISCUSSION Group 1: Temporal Lobe Lesions

Herpes Encephalitis Herpes simplex virus encephalitis is a substantial cause of morbidity and mortality. Infection may occur in all ages. In the absence of antiviral therapy, mortality can exceed 70% in affected individuals (2). However, prompt recognition and treatment can significantly reduce mortality, with evidence demonstrating that the early administration of acyclovir can reduce mortality to 28% (2,3). Thus, clinical recognition, laboratory analysis, and rapid appropriate imaging are paramount to the early detection and treatment. In affected individuals, HSV-1 infection spreads via the lingual nerve to the trigeminal ganglion, where it is typically confined by the immune system, most frequently for long periods of time. Later in life, immunocompromise, stress, or 2

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trauma occasionally allow for viral reactivation. The virus overwhelms the host defense and spreads to adjacent brain structures. Headache, fever, behavioral changes, altered mental status, seizure, as well as focal or diffuse neurologic deficits may characterize the initial clinical presentation. This infectious process most frequently results in the characteristic pattern of asymmetric involvement of the bilateral limbic system, with most prominent involvement of the medial temporal lobes and less substantial involvement of the inferior aspect of the frontal lobes (4). Polymerase chain reaction analysis of cerebrospinal fluid may be negative in the first 72 hours (5). Thus, rapid imaging is essential to disease detection and the decision to initiate treatment. CT is a relatively insensitive method of detecting early herpes simplex virus encephalitis (6). MRI provides a much more sensitive and robust analysis of imaging changes secondary to HSV (6). The widely accepted most useful clues are T2 and fluid-attenuated inversion recovery (FLAIR) hyperintensity involving the medial temporal lobe and the inferior frontal lobe, with relative sparing of the adjacent white matter (6). In more progressed cases, cortical swelling with loss of the gray-white junction may be observed. Sparing of the deep gray nuclei is typical (7). If hemorrhagic changes have occurred, these are typically apparent as areas of susceptibility artifact on gradient echo imaging. Occasionally, meningeal postcontrast enhancement is seen. In addition, diffusion-weighted imaging may assist in earlier disease detection (8). Infarction Brain ischemia and infectious encephalitis can share a similar acute onset. This can lead to consideration of both entities in the setting of abrupt neurologic deficits. Ischemia can be related to both arterial and venous occlusion. Ischemia secondary to anterior cerebral artery occlusion can lead to clinical signs and imaging findings related to the cingulate gyri. Although this region can be involved in herpes encephalitis, it would be atypical to be involved in isolation, as would be the case with ischemia secondary to anterior cerebral artery occlusion. Middle cerebral artery distribution ischemia may lead to temporal lobe involvement; however, the hippocampus and limbic system are typically spared. Posterior cerebral artery ischemia can lead to signal abnormality and restricted diffusion often in the occipital lobes and inferior temporal lobes, which could also be seen in various other viral encephalpathies, although a wedge-like configuration can often point to an arterial etiology. Ischemia related to venous occlusion can also mimic viral encephalitis, although the pattern of brain involvement is often characterized by distinct venous territories. Additionally, other imaging findings such as susceptibility artifact and loss of flow voids often point to a venous etiology. Although some ischemic events such as embolism can lead to bilateral areas of ischemia, these processes infrequently involve the bilateral mesial temporal lobes and limbic system in contrast to herpes encephalitis. Although restricted diffusion can be seen in herpes encephalitis, well-defined diffusion restriction

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without substantial associated signal abnormalities may allow one to favor a diagnosis of acute ischemia. Additionally, an acute febrile illness or preceding flulike symptoms are characteristic of infectious encephalitis and are not a harbinger of acute ischemia. Primary Brain Tumors Occasionally a brain tumor, most commonly a low-grade diffuse astrocytoma, can mimic encephalitis. Both entities demonstrate increased T2 or FLAIR signal. Distinguishing these entities based on imaging findings can be difficult, although herpes encephalitis is typically limited to the limbic system and demonstrates asymmetric involvement of the temporal lobes. Diffuse low-grade astrocytomas are not typically multifocal. Key decision points include assessment of fever and acuity of onset. Patients with an astrocytoma are typically afebrile and onset is often subacute.

GROUP 1 Temporal Lobe Imaging Changes NO

Acute Symptoms?

Fever?

YES

YES

Encephalitis HSV Encephalitis

NO

Systemic Neoplasm?

YES

Infarction (Arterial or Venous)

NO

Limbic Encephalitis A small proportion of patients with cancer develop paraneoplastic symptoms related to their underlying neoplasm (9). By far the most common neoplasm to affect the central nervous system (CNS) in this manner is small cell lung cancer; however, other relatively commonly implicated neoplasms in descending order of occurrence include testicular tumors, breast cancer, Hodgkin lymphoma, teratomas, and thymomas (10). Numerous antibodies have been associated with limbic encephalitis, including the anti-Hu antibody, as well as the anti-Ma2, anti-CRMP5, and anti-amphiphysin antibodies (9). The most common clinical symptoms include severe impairment of short-term memory; however, other behavioral changes, including anxiety, depression, irritability, personality changes, and seizures, are recognized associated symptoms (11). This specific paraneoplastic syndrome is characterized by T1 hypointensity and T2 or FLAIR hyperintensity in the mesial temporal lobes and the limbic system (11–13). Patchy enhancement is common, although blood products should prompt consideration of alternative disease processes such as herpes encephalitis. There may be minimal associated mass effect. The similarity of imaging findings associated with paraneoplastic limbic encephalitis often leads to suspicion of infectious encephalitis. Key clinical decision points include assessment of fever and acuity of onset. Patients with paraneoplastic limbic encephalitis will characteristically be afebrile and have a subacute onset. Known extracranial neoplasm, particularly small cell carcinoma, should prompt consideration of this entity. Often, a history of neoplasm is not known, generating a search for a primary malignancy. Flowchart 1 demonstrates the key decision points in distinguishing encephalitis and its mimics in a patient presenting with imaging abnormalities centered on the temporal lobe. Figure 1 demonstrates representative temporal lobe imaging features of HSV encephalitis, paraneoplastic limbic encephalitis, arterial infarction, and dural venous thrombosis or infarction.

Glioma

Limbic Encephalitis

Group 2: Imaging Changes Centered on the Cerebral Cortex

Varicella Zoster Virus Encephalitis Varicella zoster virus, the agent responsible for chicken pox, is most commonly acquired during childhood (14). In symptomatic patients, the virus reactivates during times of decreased immune response. This most commonly manifests in the elderly as shingles, when the virus travels from the dorsal root ganglion to produce a rash in a sensory nerve distribution (15). Both immunocompetent and immunosuppressed individuals are affected. Age varies widely, in one study ranging from 1 to 88 years (15). The virus has a predilection for the media of both large and small vessels, which can result in ischemic infarction of the brain or spinal cord, as well as aneurysm, subarachnoid hemorrhage, cerebral hemorrhage, and carotid dissection. Headache, mental status change, aphasia, ataxia, and visual changes are frequent presenting symptoms (16). Angiography in affected patients frequently demonstrates segmental constriction often with poststenotic dilatation (17). In one review, abnormality on angiography was seen in 70% of patients (15). Large and small arteries were involved in 50% of patients, whereas only large arteries were involved in 37% of patients and only small arteries were involved in 13% of patients (15). On MRI, in addition to findings of stroke, hyperintense T2 lesions at the gray-white matter junction are a clue to diagnosis (16). Epstein-Barr Virus Encephalitis The Epstein-Barr virus (EBV) is a ubiquitous lymphotrophic herpes virus that is acquired through oral transmission. The virus is most commonly recognized as the etiology of infectious mononucleosis characterized by fever, atypical lymphocytes on peripheral blood smear, tonsillar and lymph node swelling, 3

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(a)

(b)

(d)

(c)

(e)

Figure 1. (a) Demonstrates findings typical of HSV encephalitis including FLAIR signal hyperintensity with associated local mass effect of the left mesial temporal lobe. This 79-year-old woman presented with fever and altered mental status and was later found to have CSFproven HSV encephalitis. (b) Demonstrates similar FLAIR signal hyperintensity in the left mesial temporal lobe in a 59-year-old man presenting with confusion and language deficits. The patient was subsequently diagnosed with paraneoplastic limbic encephalitis. (c) Demonstrates FLAIR signal hyperintensity in the anterior right temporal lobe in a 50-year-old man with a right MCA distribution infarction. (d) Demonstrates FLAIR signal hyperintensity in the left temporoparietal region in a 67-year-old woman presenting with altered mental status in the setting of deep venous thrombosis and pulmonary embolism. (e) Demonstrates filling defect in the left transverse and left sigmoid sinus in this same patient with dural venous thrombosis and venous infarction. CSF, cerebrospinal fluid; FLAIR, fluid-attenuated inversion recovery; HSV, Herpes simplex virus; MCA, middle cerebral artery.

and liver dysfunction (18). Additional disease processes related to EBV infection include Burkitt’s lymphoma, gastric carcinoma, and CNS lymphoma (19). The overall incidence of neurologic complication arising from EBV is reported to be <7%, with neurologic symptoms composed of seizures, polyradiculitis, transverse myelitis, encephalitis, and cranial nerve palsies (20). The virus shows limited selectivity in age and sex, with affected individuals demonstrating a mean age of 26 and an age range of 20–79 (21). Common presentations of EBV encephalitis include altered consciousness, seizure, visual hallucination, and acute psychotic reaction. MRI findings are typically present in a minority of patients. These can include T2 hyperintensity in both gray and white matter, including in the deep gray nuclei and splenium of the corpus callosum. Diffusion abnormality can also be seen. Periventricular leukomalacia and brain atrophy are also common (22). Signal abnormities have been shown to be fully reversible in some cases (20). 4

EBV encephalitis should be considered in the febrile patient with T2 or FLAIR signal hyperintensity in the cerebral cortex, deep gray matter, and splenium of the corpus callosum. Posterior Reversible Encephalopathy Syndrome Posterior reversible encephalopathy syndrome (PRES) is a relatively common process characterized by acute hypertension resulting in damage to vascular endothelium. This insult causes the cerebral vasculature to lose its ability to autoregulate blood flow, which in turn can result in hyperperfusion and vasogenic edema. In addition to pregnancy and eclampsia or preeclampsia, several additional clinical settings predispose the patient to PRES, including arterial hypertension, chemotherapy regimens and organ transplants that require the use of immunosuppressant medications, septicemia, chronic renal failure, and autoimmune diseases (23). The most common symptoms of PRES include seizure, headache, and visual disturbance; however, paralysis is recognized in a small minority

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of patients (24). Symptoms typically abate following resolution of hypertension or discontinuation of the offending agent. Imaging findings are best seen on MRI as cortical, subcortical, and deep lesions, with T2 and FLAIR hyperintensity predominantly located in the parieto-occipital distribution. A vast majority of cases demonstrate involvement of the parietal or occipital lobes; however, a significant portion of patients will demonstrate signal abnormality in the frontal and temporal lobes, as well as in the cerebellar hemispheres (25). Restrictive diffusion is not typical but can be seen (23). CT may demonstrate patchy hypo-attenuation in the affected distribution. The onset of PRES is often acute, similar to that of encephalitis. Key distinguishing features are a lack of fever and any of the predisposing clinical scenarios discussed earlier, particularly pregnancy or hypertension. As will be mentioned later, PRES should also be considered in predisposed patients with imaging changes centered on the deep gray nuclei. Seizure Recent seizures may demonstrate MRI changes that mimic other intracranial pathology, such as encephalitis. Direct effects of the seizure correspond to imaging features thought to reflect transient cerebral edema. Most typically, T2 hyperintensity is seen in the gray matter or the subcortical white matter (26). The hippocampus and splenium of the corpus callosum may also be involved (27). There may be mild mass effect. Diffusion restriction may be seen acutely, and contrast enhancement may occur (27). Differentiating clinical features include a lack of fever and a recent history of seizure. Imaging features typically resolve within days to weeks. Follow-up MRI demonstrating improvement or resolution of imaging findings may also assist in more definitive diagnosis. Creutzfeldt-Jakob Disease Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, fatal, potentially transmissible cause of dementia. The responsible agent, a prion, is an abnormal isoform of a normal host protein devoid of DNA and RNA (28). Most cases are seen in individuals greater than 50 years of age (28). CJD is most frequently the result of spontaneous conversion of a normal host protein to a prion protein, although familial forms of CJD also exist (28). The term iatrogenic CJD refers to a disease occurring from contact with prion-containing material, such as surgical instruments or transplants. A variant form of CJD referred to as bovine spongiform encephalopathy is acquired through infected beef. CJD infection often presents with rapidly progressive dementia with associated myoclonic jerks, akinetic mutism, and cerebellar dysfunction (29). Bovine spongiform encephalopathy may demonstrate more prominent psychiatric and sensory symptoms. There is no effective treatment (28). Death typically occurs within months of onset of clinical symptoms. CJD is best appreciated on MRI where progressive T2 hyperintensity of the basal ganglia, thalamus, and cerebral cortex are typical (30). The caudate and putamen are more involved than the globus pallidus. The frontal, parietal, or

temporal cortex may be involved. A Heidenhain variant of CJD demonstrates occipital cortex involvement (31). Variant CJD or CJD related to bovine spongiform encephalopathy often demonstrates prominent T2 hyperintensity of the pulvinar of the thalamus or the dorsomedial thalamic nuclei (32). In patients with cortical ribbon signal abnormality on MRI, a lack of fever or seizure should prompt consideration of CJD. Relatively specific MRI findings involving the basal ganglia and cortex can also prompt a high degree of clinical suspicion. Cerebral spinal fluid analysis is often suggestive, although definitive diagnosis is made by brain biopsy (33). Flowchart 2 demonstrates the key decision points in distinguishing encephalitis and its mimics when a patient presents with an imaging abnormality centered on the cerebral cortex. Figure 2 demonstrates imaging abnormality centered on the cerebral cortex typical of EBV encephalitis, CJD, PRES, Varicella zoster encephalitis, and seizure. GROUP 2 Cortical Imaging Changes NO

Pregnant or Hypertensive? On Chemotherapy or Immunosuppressants?

YES

NO

Seizure?

YES

Fever?

Encephalitis VZV Encephalitis EBV Encephalitis

PRES

Consider seizure secondary to other etiolosies

YES

NO Consider CJD & Anoxic/Hypoxic Injury

Post Seizure

Group 3: Imaging Changes Centered on the Deep Gray Nuclei

West Nile Virus Encephalitis West Nile virus is a flavivirus that has gained great attention since its introduction to the Western hemisphere. This virus first presented in the United States as an outbreak in the New York area in 1999 (34) and was subsequently recognized as the cause of a meningoencephalitis epidemic in 2002 (35). West Nile virus is the most common cause of epidemic meningoencephalitis in North America (35). Infection rates are geographically dependent, with the highest rates occurring in North and South Dakota, Nebraska, Wyoming, Colorado, Oklahoma, New Mexico, and Montana (36). Infection is overwhelmingly seasonal, with 90% infected from July to September (36). 5

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(a)

(b)

(c)

(d)

(e)

(f)

Figure 2. (a) Demonstrates FLAIR signal hyperintensity centered on the bilateral mesial temporal lobe cortex in a patient with EBV encephalitis. (b) Demonstrates restricted diffusion centered on the cerebral cortex in a 70-year-old man presenting with altered mental status and pathologically proven Creutzfeldt-Jackob disease. (c) Demonstrates FLAIR signal hyperintensity centered on the right parietooccipital lobe in an 11-yearold patient presenting with hypertensive urgency. Findings are typical for posterior reversible encephalopathy syndrome. (d) Demonstrates focal flow defect in the M1 segment of the right MCA on MR angiography in a patient with Varicella zoster encephalitis. (e) Demonstrates subtle areas of FLAIR signal hyperintensity in the right caudate head and in the bilateral gray-white interface in the same patient. (f) Demonstrates subtle FLAIR signal hyperintensity in the left insula and left anterior temporal lobe in a 27-year-old woman with eclampsia following seizure. EBV, Epstein-Barr virus; FLAIR, fluid-attenuated inversion recovery; MCA, middle cerebral artery; MR, magnetic resonance.

Birds are known to be the primary host. The virus is transmitted to humans through mosquito bites, typically from the Culex genus. Approximately 80% of infected individuals are asymptomatic (37). In the symptomatic 20%, fever, headache, fatigue, lymphadenopathy, and arthralgia are typical symptoms (37). Patients may also exhibit gastrointestinal symptoms and can demonstrate an occasional maculopapular rash (38). More severe neurologic symptoms such as seizure, extrapyramidal signs, and acute flaccid paralysis are also well documented, although these occur in less than 1% of infected patients (39). There is currently no effective immunization for West Nile virus (36). Treatment is supportive, including hydration, airway protection, and seizure management as needed. Classic MRI findings of West Nile virus meningoencephalitis include hyperintensity on FLAIR and T2-weighted sequences in the bilateral basal ganglia or thalami. Less commonly, there is signal abnormality involving the midbrain, mesial temporal lobes, 6

cerebellum, spinal cord, and cauda equina (40). Extremity weakness or flaccid paralysis has been shown to correspond to spinal cord or cauda equina involvement (41). In some cases, restricted diffusion is identified as the only imaging finding (42). Additional studies have demonstrated that T2 and FLAIR signal abnormality may correlate to worse prognosis than when diffusion alteration is the sole MRI finding (43). Contrast enhancement is atypical but can occasionally be present. Key distinguishing features in a patient with signal abnormality centered on the deep gray matter include fever and a recent mosquito bite occurring from July to September in a WNV-endemic region. Rabies Encephalitis Rabies encephalitis is typically caused by introduction of the rabies viron following a bite by an infected animal. Other less common modes of spread including airborne transmission and infection

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(a)

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Figure 3. (a) Demonstrates FLAIR signal hyperintensity with involvement in the right putamen in an 8-year-old girl presenting with animal bite, weakness, and altered mental status. This was later confirmed to reflect rabies encephalitis by serum antibody and tissue biopsy. (b) Demonstrates FLAIR signal hyperintensity in the left thalamus as well as in the right parieto-occipital cortex in an 11-year-old boy presenting with hypertensive urgency who was diagnosed with posterior reversible encephalopathy. FLAIR, fluid-attenuated inversion recovery.

(b)

following corneal transplant have been documented (44,45). Approximately 26,400 to 61,000 people are estimated to die from rabies yearly, with the vast majority of fatalities occurring in Africa and India (46). Between 1980 and 1996, 32 cases of human rabies were reported in 20 states in the United States. Bats, dogs, and skunks were the most frequent animals responsible for transmission (47). Following an animal bite, the virus then achieves access to the CNS via retrograde axoplasmic transmission (48). Antemortem pathologic diagnosis of rabies encephalitis can be difficult and depends on determination of anti-rabies antibodies in serum or cerebrospinal fluid samples, histologic demonstration of the virus in tissues, or viral recovery either by animal inoculation or by culture in vitro (48). In the CNS, there is a proclivity toward infection of the gray matter. Ill-defined T2 and FLAIR hyperintensity in the brainstem, hippocampi, thalami, and basal ganglia are typical imaging findings. This constellation of findings may differentiate rabies from other viral encephalitides. Gadolinium enhancement has been seen in the hypothalamus, brainstem nuclei, spinal cord gray matter, and intradural cervical nerve roots in comatose patients (49). T1 hyperintensity has been demonstrated in some involved regions, which has been attributed to methemoglobin (50). Key distinguishing features in a patient with signal abnormality centered on the deep gray matter include fever and a recent animal bite, particularly if the bite occurred in an endemic area. Toxic and Metabolic Abnormalities Numerous toxic and metabolic abnormalities result in signal abnormality involving the deep gray matter. Detailed discussion of the numerous toxic and metabolic disorders is beyond the scope of this article, although it is important to note that several infectious encephalopathies share similar deep gray matter imaging features with this group of diseases. For example, as detailed earlier, West Nile virus and rabies encephalitis and EBV encephalitis often present with T2 hyperintensity in the

basal ganglia and thalamus. Assessment of imaging findings alone without knowledge of the presenting clinical scenario may lead to incorrect diagnosis. Key clinical features that may steer the diagnosis away from toxic or metabolic derangements in the setting of deep gray matter imaging abnormality include fever, recent mosquito bite during endemic seasons of West Nile virus, recent animal bite, or a clinical scenario which would predispose the patient to the development of PRES. Flowchart 3 demonstrates the key decision points in distinguishing encephalitis and its mimics when a patient presents with an imaging abnormality centered on the deep gray matter. Figure 3 demonstrates imaging features involving the deep gray matter in patients with rabies encephalitis and PRES. GROUP 3 Deep Gray Matter Imaging Changes NO

Fever?

YES

Bite? Pregnant or Hypertensive? On Chemotherapy or Immunosuppressants?

YES NO

PRES

Consider Toxic/ Metabolic & Anoxic/ Hypoxic Injury

YES

NO

EBV Encephalitis

What type of bite?

DOG/ BAT/ SKUNK

Rabies Encephalitis

MOSQUITO

WNV Encephalitis

Group 4: Imaging Changes Centered on the White Matter

Human Immunodeficiency Virus Encephalitis The human immunodeficiency virus (HIV) is a retrovirus that attacks the body’s immune system, rendering patients at risk 7

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for a variety of opportunistic pathogens. Prior to the advent of HAART (highly active antiretroviral therapy), HIV first presented with neurologic manifestations in 10%–20% of patients (51). In contrast to other secondary opportunistic infections in HIV patients, the AIDS dementia complex is a direct result of HIV infection. Both cognitive and motor function deficits are observed. Diagnosis is based on clinical manifestations, including inattention, indifference, and psychomotor slowing, as well as other objective deficits based on standardized neuropsychological tests (52). Although the prevalence of HIV-associated dementia has significantly decreased since the increased use of HAART, HIV-associated dementia remains a major burden to the HIV population, affecting approximately 11.2% of HIV-infected patients (53). The imaging features of AIDS dementia complex are frequently referred to as HIV encephalitis. CT imaging findings include diffuse, symmetric cerebral atrophy, and abnormal decreased attenuation in the periventricular white matter. MR imaging most typically demonstrates areas of increased periventricular T2 signal, with sparing of the subcortical U-fibers. Mass effect and enhancement are not typical features and should prompt the radiologist to consider alternative diagnoses (52). HIV encephalitis should be considered in patients presenting with signal abnormality centered on the cerebral white matter and laboratory testing confirming infection with HIV. Acute Disseminated Encephalomyelitis Acute disseminated encephalomyelitis (ADEM) is an autoimmune mediated process that results in severe acute demyelination of the brain and spinal cord. A temporal, if not causative, relationship with preceding infection or vaccination is recognized (54,55). A recent upper respiratory tract infection is reported in 50% of patients (56). Symptoms most typically develop 1–2 weeks following an infection or vaccination, although can be seen as late as 5 weeks following antigen introduction. The incidence of ADEM is highest in children, although affected individuals are most typically older than 3 years of age (54). Headache, drowsiness, seizures, behavioral changes, motor deficits, and cranial nerve abnormalities may be seen. Findings are best seen on MRI and typically consist of bilateral but asymmetric T2 and FLAIR hyperintensity, most frequently in the cerebral subcortical white matter. Gadolinium contrast enhancement is often present and can improve recognition (57). Corresponding low attenuation on CT may be seen; however, CT is less sensitive (58). Multifocal enhancing lesions may be seen on contrast-enhanced CT. The basal ganglia, brainstem, and posterior fossa may be involved. Spinal involvement can also be seen in a minority of patients. Although multifocal enhancing signal abnormality is most prominent in the subcortical white matter, this is a relatively nonspecific finding. In the setting of encephalopathy, eliciting a history of preceding illness or immunization in the prior few weeks can be extremely helpful in establishing a diag8

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nosis of ADEM. Affected individuals are most typically children, which is not typical of most other infectious causes of encephalitis. A lack of current infectious symptoms may also help guide the diagnosis away from infectious encephalitis. Lymphoma CNS lymphoma most typically presents with enhancing lesions in the basal ganglia or the periventricular white matter. Lesions often involve the corpus callosum and frequently abut the ependymal surfaces. Lymphoma is characteristically hyperdense on CT. Diffusion-weighted imaging demonstrates low apparent diffusion coefficient values, which may help distinguish CNS lymphoma from glioblastoma multiforme (59). Hemorrhage or necrosis can be seen in immunocompetent patients. In a patient with signal abnormality centered on the cerebral white matter, key distinguishing clinical parameters include lack of recent fever or vaccination. Lymphoma should remain a consideration in the setting of HIV. Flowchart 4 demonstrates the key decision points in distinguishing encephalitis and its mimics when a patient presents with an imaging abnormality centered on the cerebral white matter. Figure 4 demonstrates imaging abnormality centered on the cerebral white matter in patients with HIV encephalitis, grade 2 astrocytoma, CNS lymphoma, and ADEM. GROUP 4 White Matter Imaging Changes NO

Recent Vaccination?

Fever?

YES

YES

EBV Encephalitis

NO

HIV?

YES

ADEM

NO

Consider Glioma & Lymphoma

Consider HIV Encephalitis & Lymphoma

CONCLUSION Infectious encephalitis is associated with a relatively high rate of morbidity and mortality. Synthesis of both the clinical symptoms and imaging findings is critical to early diagnosis and treatment, thus potentiating drastic improvement in clinical outcomes. The use of the flowcharts presented in this article, which combine both clinical and imaging decision points, can further enable clinicians and radiologists to more confidently

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(a)

(b)

(c)

(d)

(e)

(f)

Figure 4. (a) Demonstrates diffuse cerebral white matter FLAIR signal hyperintensity with sparring of the subcortical U-fibers in this patient with HIV encephalopathy. (b) Demonstrates ill-defined white matter FLAIR signal hyperintensity in the left temporoparietal white matter in a 65-year-old woman with a grade 2 astrocytoma. (c) Demonstrates a focal-enhancing lesion centered on the right cerebral hemisphere white matter in a 67-year-old man with CNS lymphoma. (d) Demonstrates extensive surrounding FLAIR signal hyperintensity surrounding this lesion in the right cerebral hemisphere and extending to the right basal ganglia. (e,f) Demonstrate asymmetric FLAIR signal hyperintensity centered on the splenium of the corpus callosum, posterior internal capsule, and left parietal white matter in a patient with ADEM who presented with recent viral illness and altered mental status. ADEM, acute disseminated encephalomyelitis; CNS, central nervous system; FLAIR, fluidattenuated inversion recovery.

differentiate encephalitis from its common mimics and improve patient care.

6.

ACKNOWLEDGMENT Flowcharts were provided by Danielle Dobbs, medical illustrator.

7.

8.

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