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Infection, Inlammation, and Demyelinating Diseases

Section 3

Chapter 11 327

Approach to Infection, Inflammation, and Demyelination The plague (both literal and figurative) of infectious diseases has been a threat to humankind for millennia. Parasitic infestations have been identified in Egyptian mummies from the Old Kingdom and still affect people today. Our ancient enemies—tuberculosis and malaria—once seemed to be under relative control. But are they? Absolutely not. One in three people in the world has been infected with M. tuberculosis.

In the antibiotic era, once-dreaded infections may seem a distant memory. But are they truly relegated to the medical history scrap heap? Hardly.

I once heard Dr. Joshua Lederberg, who shared the 1958 Nobel Prize in Physiology or Medicine for his discoveries concerning recombination and organization of bacterial genes, make a very telling comment. He remarked, "We are in an 'evolutionary foot race' with our closest competitors, viruses and bacteria." Guess who's winning? One doesn't need to be a genius to guess just who is winning ... and it isn't us humans!

Widespread use of antibiotics had its inevitable result. Adaptive evolution has rendered some organisms resistant even to the "antibiotics of last resort." Outbreaks of diverse multidrug-resistant organisms, once rare, are reported with increasing frequency. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) have achieved significant rates of colonization and infection in most intensive care units. To date, interventions aimed at reducing transmission of resistant bacteria in such high-risk settings have been relatively ineffective.

Misuse or mismanagement of first-line drugs has also resulted in the development of multidrug-resistant TB (MDR TB). MDR TB and the recent emergence of extensively drug-resistant TB (XDR TB) jeopardize the major gains achieved by several decades of TB control. The significant progress made in reducing TB-related deaths in immunocompromised patients is also threatened by these developments.

Although any part of the human body can become inflamed or infected, the brain has long been considered an "immunologically protected" site because of the blood-brain barrier. Although CNS infections are considerably less common than their systemic counterparts, the brain is by no means invulnerable to onslaught from pathogenic organisms.

The role of medical imaging in the emergent evaluation of intracranial infection ideally should be supportive, not primary. But in many health care facilities worldwide, triage of acute CNS disease frequently uses brain imaging as an initial noninvasive "screening procedure." Therefore, the

CNS Infections 328

HIV/AIDS 329

Demyelinating and Inflammatory Diseases 329

Infection, Inflammation, and Demyelinating Diseases 328

(11-1) Note small, well-encapsulated frontal lobe abscess ﬈ with a larger, less well-defined lesion in the contralateral hemisphere. The large abscess ruptured into the ventricle ﬉, causing pyocephalus and death. (Courtesy R. Hewlett, MD.)

(11-2) Autopsy specimen shows the dura st reflected up to reveal a purulent-appearing collection in the underlying subdural space ﬊. Findings are typical for a pyogenic subdural empyema. (Courtesy R. Hewlett, MD.)

radiologist may be the first—not the last—to recognize the presence of possible CNS infection.

In this part, we devote chapters 12 and 13 to CNS infections. HIV/AIDS is covered in Chapter 14. The last chapter, Chapter 15, considers the surprisingly broad spectrum of noninfectious idiopathic inflammatory and demyelinating disorders that affect the CNS.

INFECTION, INFLAMMATION, AND DEMYELINATING DISORDERS

CNS Infections Overview and classification• Congenital, pyogenic, viral infections• TB, fungal, parasitic, emerging infections•

HIV/AIDS HIV infection• Opportunistic infections• AIDS-defining neoplasms•

Demyelinating and Inflammatory Diseases MS, variants and mimics• Postinfectious demyelination• Inflammatory-like disorders•

CNS Infections The concept that the brain was an "immune privileged" organ in which the blood-brain barrier (BBB) was a relative fortress that restricted pathogen entry and limited inflammation has recently undergone significant revision. Lymphocytes circulate through the normal healthy brain, immune responses can

occur without lasting consequence, and cross-talk between the brain and extra-CNS organs is both extensive and robust.

Evidence has also recently emerged that there is extensive CSF and interstitial fluid (ISF) exchange throughout the brain, a process now termed "glymphatics."

A pathway of waste removal from the CNS does exist and is facilitated by CSF entering the brain parenchyma and spinal cord via aquaporin 4 water channels on astrocytes that surround the brain vasculature. This wave of CSF entry drives ISF toward the perivenous space, where it collects and drains through lymphatic channels in the dural sinuses through foramina at the skull base to the deep cervical lymph nodes. The process flushes extracellular debris (including β-amyloid) from the parenchyma.

The presence of these drainage systems within the CNS is evidence that there is a constant flow and exchange of proteins within the brain and the blood. CD4+ central and effector memory T cells are found in healthy CSF. The brain is therefore not a "privileged organ" that is immunologically isolated from the rest of the body but rather is actively monitored by—and accessible to—blood-borne lymphocytes and their mediators.

A surprising large number of pathogens, including many neurotropic viruses, can infect the CNS. Well over 200 different organisms have been described as causing CNS infections of one type or another. Routes of entry include transsynaptic spread (e.g., herpes viruses), "hiding" within blood-borne lymphocytes that access the brain (e.g., HIV and JC viruses), and using the choroid plexus as a gateway into the CNS.

Approach to Infection, Inflammation, and Demyelination 329

(11-3) Autopsy case of tuberculous meningitis shows thick exudate filling the basal cisterns ﬇ and covering the pial surfaces of the frontal/temporal lobes and cerebellum ﬊. (Courtesy R. Hewlett, MD.)

(11-4) Axial cut section of autopsied brain in a patient with septicemia shows multifocal petechial hemorrhages, primarily in the cortex and gray-white matter interfaces. (Courtesy R. Hewlett, MD.)

Imaging plays an increasingly key role in the evaluation of potential CNS infections. However, imaging findings are often nonspecific, so a careful history and appropriate clinical- laboratory investigations are necessary for accurate diagnosis and appropriate treatment.

CNS infections can be classified in several ways. The most common method is to divide them into congenital/neonatal and acquired infections. Categorizing infections purely according to disease category, i.e., pyogenic, viral, granulomatous, parasitic, etc., is also very common. As imaging findings overlap considerably, this system is of little help to the radiologist.

In this text, we follow a combination of classifications. We first subdivide infections into congenital and acquired disorders. Congenital infections are discussed in Chapter 12. Because this is a relatively short discussion, we combine these with acquired pyogenic and viral infections.

Our discussion of pyogenic infections begins with the meninges (meningitis). We follow with a consideration of focal brain infections (cerebritis, abscess), the often lethal complication of ventriculitis (pyocephalus) (11-1), and pus collections in the extraaxial spaces (subdural/epidural empyemas) (11-2). We then focus on the CNS manifestations of acquired viral infections.

In Chapter 13, we consider the pathogenesis and imaging of tuberculosis, fungal infections, and parasitic and protozoal infestations. We conclude this second chapter on infections with a brief discussion of spirochetes and emerging CNS infections (e.g., the rare hemorrhagic viral fevers).

HIV/AIDS In the more than three decades since AIDS was first identified, the disease has become a worldwide epidemic. With the development of effective combination antiretroviral therapies, HIV/AIDS has evolved from a virtual death sentence to a chronic but manageable disease—if the treatment is (1) available and (2) affordable. As treated patients with HIV/AIDS now often survive for a decade or longer, the imaging spectrum of HIV/AIDS has also evolved.

Treated HIV/AIDS as a chronic disease looks very different from HIV/AIDS in so-called high-burden regions of the world. In such places, HIV in socioeconomically disadvantaged patients often behaves as an acute, fulminant infection. Comorbid diseases such as TB, malaria, or overwhelming bacterial sepsis are common complications and may dominate the imaging presentation.

Complications of HAART treatment have created their own set of recognized disorders, such as immune reconstitution inflammatory syndrome (IRIS). In Chapter 14, we consider the effect of HIV itself on the CNS (HIV encephalitis), as well as opportunistic infections, IRIS, miscellaneous manifestations of HIV/AIDS, and HIV-associated neoplasms.

Demyelinating and Inflammatory Diseases The final chapter in this part is devoted to demyelinating and noninfectious inflammatory diseases of the CNS.

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First, let us be clear on terminology. Infection is caused by microorganisms. Inflammation is not synonymous with infection. Inflammation (from the Latin meaning "to ignite" or "set alight") is the response of tissues to a variety of pathogens (which may or may not be infectious microorganisms). The inflammatory "cascade" is complex and multifactorial. It involves the vascular system, immune system, and cellular responses, such as microglial activation, the primary component of the brain's innate immune response.

The CNS functions as a unique microenvironment that responds differently than the body's other systems to infiltrating immune cells. The brain white matter is especially susceptible to inflammatory disease. Inflammation can be acute or chronic, manageable or life-threatening. Therefore, imaging plays a central role in the identification and follow-up of neuroinflammatory disorders.

The bulk of Chapter 15 is devoted to multiple sclerosis (11-5). Also included is a discussion of MS variants (11-6) and the

surprisingly broad spectrum of idiopathic (noninfectious) inflammatory demyelinating diseases (IIDDs), such as neuromyelitis optica. Susac syndrome is a retinocochleocerebral vasculopathy that is often mistaken for MS on imaging studies, so it too is discussed in the context of IIDDs.

Postinfection, postvaccination, autoimmune-mediated demyelinating disorders are considered next. Acute disseminated encephalomyelitis (ADEM) and its most fulminant variant, acute hemorrhagic leukoencephalitis (AHLE), are delineated in detail.

We close the chapter with a discussion of neurosarcoid and inflammatory pseudotumors, including the rapidly expanding category of IgG4-related disorders.

(11-7) Axial autopsied brain shows a solitary "horse-show" postinfectious tumefactive demyelinating lesion ﬈. (11-8) Coronal gross pathology in a case of severe multiple sclerosis shows confluent demyelination in the subcortical white matter ﬈. Note sparing of the subcortical U-fibers.

(11-5) H&E/Luxol fast blue stain emphasizes the sharp interface between lesion (pale-staining tissue ﬇) and normal parenchyma (blue-staining tissue ﬊) typical of most demyelinating plaques. (Courtesy B. K. DeMasters, MD.) (11-6) Gross autopsy with close-up view of "tumefactive" demyelinating disease ﬊ shows peripheral necrosis ﬈ with mass effect on the adjacent gyrus ﬇. (Courtesy B. K. DeMasters, MD.)

Chapter 12 331

Congenital, Acquired Pyogenic, and Acquired Viral Infections Infectious diseases can be conveniently divided into congenital/neonatal and acquired infections. There are unique infectious agents that affect the developing brain. The stage of fetal development at the time of infection is often more important than the causative organism. The clinical manifestations of fetal and neonatal infection and long-term neurologic consequences compared with infections that affect the more mature or fully developed brain will be emphasized below.

We then delineate the first major category of acquired infections, i.e., pyogenic infections. We start with meningitis, the most common of the pyogenic infections. Abscess, together with its earliest manifestations (cerebritis), is discussed next, followed by considerations of ventriculitis (a rare but potentially fatal complication of deep-seated brain abscesses) and intracranial empyemas.

We close the chapter with a discussion of the pathologic and imaging manifestations of acquired viral infections.

Congenital Infections Parenchymal calcifications are the hallmark of most congenital infections and have been reported with cytomegalovirus (CMV) (12-2A), toxoplasmosis (12-6A), congenital herpes simplex virus (HSV) infection (12- 8A), rubella (12-15), congenital varicella-zoster virus (12-17), Zika virus (12- 12B), and lymphocytic choriomeningitis virus (LCMV) (12-16).

Infections of the fetal brain result in a spectrum of injury and malformation that depends more on the timing of infection than the infectious agent itself. Infections early in fetal development (e.g., during the first trimester) usually result in miscarriage, severe brain destruction, and/or profound malformations such as anencephaly, agyria, and lissencephaly.

When infections occur later in pregnancy, encephaloclastic manifestations and myelination disturbance (e.g., demyelination, dysmyelination, and hypomyelination) predominate. Microcephaly with frank brain destruction and widespread encephalomalacia are common (12-11A).

With few exceptions (toxoplasmosis and syphilis), most congenital/perinatal infections are viral and are usually secondary to transplacental passage of the infectious agent. Zika virus is a relative newcomer to the list of viruses recognized as a cause of congenital CNS infection and is capable of causing profound brain destruction and resultant microcephaly. Zika virus infection

Congenital Infections 331 TORCH Infections 332 Congenital Cytomegalovirus 332 Congenital Toxoplasmosis 336 Herpes Simplex Virus: Congenital

and Neonatal Infections 337 Zika Virus Infection 340 Lymphocytic Choriomeningitis

Virus 341 Congenital (Perinatal) HIV 342 Other Congenital Infections 343

Acquired Pyogenic Infections 346 Meningitis 346 Abscess 353 Ventriculitis 358 Empyemas 359

Acquired Viral Infections 364 Herpes Simplex Encephalitis 364 HHV-6 Encephalopathy 368 Miscellaneous Acute Viral

Encephalitides 369 Chronic Encephalitides 372

Infection, Inflammation, and Demyelinating Diseases 332

(12-2B) T2WI in the same patient shows ventriculomegaly, periventricular Ca++ st, and simplified gyral pattern (polymicrogyria) ﬇.

(12-2A) NECT in a newborn with CMV shows broad sylvian fissures ﬇, periventricular Ca++ st, and cerebellar hypoplasia st.

(12-1) Congenital CMV is shown with periventricular parenchymal calcifications ﬉, damaged white matter ﬊, dysplastic cortex ﬈.

represents the first reported congenital CNS infection to be mostly transmitted by mosquitoes.

Six members of the herpesvirus family cause neurologic disease in children: HSV-1, HSV-2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), CMV, and human herpesvirus 6 (HHV-6).

Aside from CMV, HSV-2, Zika virus, and congenital HIV (vertically transmitted), congenital CNS infections have become less common due to immunization programs, prenatal screening, and global infection surveillance.

Here, an overview of the TORCH infections and important non-TORCH congenital/perinatal CNS infections is presented, beginning with the most globally common of the congenital infections, congenital CMV infection.

TORCH Infections

Terminology

Congenital infections are often grouped together and simply called TORCH infections—the acronym for toxoplasmosis, rubella, cytomegalovirus, and herpes. If congenital syphilis is included, the grouping is called TORCH(S) or (S)TORCH.

Etiology

In addition to the recognized "classic" TORCH(S) infections, a host of new organisms have been identified as causing congenital and perinatal infections. These include Zika virus, LCMV, human Parvovirus B19, human parechovirus, hepatitis B, VZV, tuberculosis, HIV, and the parasitic infection toxocariasis.

Imaging

CMV, toxoplasmosis, rubella, Zika virus, VZV, lymphocytic choriomeningitis virus, and HIV may all cause parenchymal calcifications. The location and distribution of the calcifications may strongly suggest the specific infectious agent. CMV causes periventricular calcifications, cysts, cortical clefts, polymicrogyria (PMG), schizencephaly, and white matter injury. Early CNS infection with Zika virus leads to severe microcephaly and calcifications at the gray matter-white matter junction. Rubella and HSV cause lobar destruction, cystic encephalomalacia, and nonpatterned calcifications. Congenital syphilis is relatively rare, causing basilar meningitis, arterial strokes, and scattered dystrophic calcifications. Congenital HIV is associated with basal ganglia calcification, atrophy, and aneurysmal arteriopathy.

TORCH(S), Zika virus, and LCMV infections should be considered in newborns and infants with microcephaly, parenchymal calcifications, chorioretinitis, and intrauterine growth restriction (12-1).

Congenital Cytomegalovirus CMV is the leading cause of nonhereditary deafness in children and is the most common cause of congenital brain infection in developed countries.

Terminology and Etiology

Congenital CMV infection is also called CMV encephalitis. CMV is a ubiquitous DNA virus that belongs to the human herpesvirus family.

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Pathology

The timing of the gestational infection determines the magnitude of brain insult. Early gestational CMV infection causes germinal zone necrosis with subependymal cysts and dystrophic calcifications. White matter volume loss occurs at all gestational ages and can be diffuse or multifocal. Malformations of cortical development are very common, with PMG having the greatest prevalence (12-2B).

Microscopic examination shows cytomegaly with viral inclusions in the nuclei and cytoplasm. Patchy and focal cellular necrosis, particularly of germinal matrix cells, is typical of first-trimester infection. Vascular inflammation and thrombosis are also common.

Clinical Issues

Epidemiology. CMV is the most common of all congenital infections. Between 0.25-1.00% of newborn infants shed CMV

in their urine or saliva at birth. This translates to nearly 35,000 viral-shedding newborns annually. Of these, 10% develop CNS or systemic symptoms and signs. Up to 4,000 newborns in the USA are annually confirmed to have symptomatic CMV infection (e.g., congenital CMV disease). This later category has significant long-term neurodevelopmental sequelae.

Presentation and Natural History. With advances in fetal imaging, particularly fetal MR, many of the CNS imaging manifestations of congenital CMV infection that have have been chronicled in the newborn and infant are elegantly depicted antenatally (e.g., PMG, germinolytic cysts, and cerebellar dysgenesis).

Symptomatic newborns and infants may exhibit microcephaly, jaundice, hepatosplenomegaly, chorioretinitis, and rash. Asymptomatic newborns with congenital CMV infection may show microcephaly and otherwise initially appear developmentally normal. Sensorineural hearing loss, seizures, and developmental delay are the major long-term risks.

(12-3C) T2WI in the same patient demonstrates diffuse PMG ﬈, GM heterotopia ﬉, and vertical hippocampi. Note the left tela choroidea germinolytic cyst ﬈. (12- 3D) T2WI in the same microcephalic infant shows GM heterotopia ﬉, PMG ﬈, and cerebellar hypoplasia ﬉. Note ventriculomegaly.

(12-3A) NECT in a microcephalic infant with confirmed congenital CMV infection and hearing loss (SNHL) shows caudostriatal ﬉ Ca++. (12-3B) T1WI in an infant with congenital CMV, shows broad sylvian fissures ﬇, diffuse polymicrogyria (PMG) ﬈, and gray matter (GM) heterotopia ﬉. Note T1 prolongation within frontal white matter.

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(12-4C) AXIAL T2 FLAIR image demonstrates bilateral temporal lobe cysts ﬈ and scattered WM hyperintensities ﬉.

(12-4B) T2WI showing diffuse, asymmetric white matter (WM) T2 prolongation. Bilateral diffuse polymicrogyria is present ﬈.

(12-4A) NECT shows a solitary calcification st, broad sylvian fissures ﬇, and simplified gyri (PMG) st in an infant with CMV.

Newborns with systemic manifestations (e.g., hepatosplenomegaly, petechiae, and jaundice) have a slightly worse overall prognosis. Greater than half of all neonates with systemic signs and symptoms also have CNS involvement. The vast majority of these newborns that demonstrate microcephaly, ventriculomegaly, cortical malformations (e.g., PMG), white matter abnormalities, and parenchymal calcifications have major neurodevelopmental sequelae (e.g., cerebral palsy, epilepsy, and mental retardation).

Treatment Options. Early (before gestational week 17) maternal hyperimmunoglobulin therapy improves the outcome of fetuses from women with primary CMV infection. The use of antiviral agents is also being explored for the treatment of symptomatic congenital CMV beyond the neonatal period. Antiviral agents that specifically target CMV are ganciclovir, valganciclovir (VGVC), foscarnet, and cidofovir. VGVC is well tolerated and may improve or help preserve auditory function in infected infants.

Imaging

General Features. Imaging features of congenital CMV are protean, including microcephaly, ventriculomegaly, germinolytic cysts, cortical malformations (e.g., PMG), Ca++, cerebellar and hippocampal dysgenesis, and white matter abnormalities. As a general rule, the earlier the fetal infection, the more severe the findings (12-1) (12-4).

CT Findings. NECT scans show intracranial calcifications and ventriculomegaly in the majority of symptomatic infants. Calcifications are predominantly periventricular, with a predilection for the germinal matrix zones, particularly the caudostriatal regions (12-2A). Calcifications vary from numerous bilateral thick calcifications to faint punctate unilateral foci (12- 2A) (12-3A) (12-4A). Calcification may be entirely absent (e.g., some NECT series of proven congenital CMV CNS disease report the prevalence of intracranial Ca++ at 66%). Therefore, the absence of intracranial Ca++ does not exclude diagnosis of congenital CMV. NECT may also demonstrate cortical clefting and other features reflecting underlying cortical malformation (e.g., PMG).

MR Findings. MR remains the most sensitive imaging tool and examination of choice to depict the magnitude of congenital CNS CMV findings. MR shows the broad range of CMV-induced CNS abnormalities. This includes microcephaly with ventriculomegaly, cortical migrational and organizational abnormalities (the most common of which is PMG), cysts (germinal zone and pretemporal), parenchymal calcifications, white matter abnormalities (dysplastic and demyelinating), hippocampal dysgenesis, and cerebellar dysgenesis. It bears reemphasizing that cortical migrational and organizational abnormalities are present in approximately 10-50% of congenital CMV cases and range from minor dysgenesis with focal cortical clefting, simplified gyral pattern and "open" lateral cerebral/sylvian fissures (e.g. PMG), to more severe manifestations including agyria, lissencephaly, and schizencephaly.

PMG in most congenital CMV infection imaging reviews remains the most common imaging abnormality that will be detected, more common than calcification.

T1WI shows microcephaly and enlarged ventricles and cysts with a predilection for the periventricular germinal zones and pretemporal white matter. Cortical abnormalities such as cerebellar and hippocampal dysgenesis are well depicted (12-3C) (12-3D). Also, subependymal hyperintense foci of T1 shortening caused by the periventricular calcifications may be seen. White matter hypointensities correspond to regions of demyelination and dysplasia. Sagittal midline T1WI shows a diminished cranial-to-facial ratio, indicating microcephaly. 3D T1WI

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techniques (e.g., 3D-SPGR) with isotropic axial and coronal reformations aide in detecting cortical, hippocampal, and cerebellar abnormalities (e.g., PMG) (12-3) (12-4).

T2WI and FLAIR images show myelin delay, white matter destruction, demyelination, and white matter volume loss with focal, patchy, or confluent hyperintensities at sites of white matter abnormality. Periventricular (e.g., germinal zone and anterior temporal lobe) cysts are common (12-4) (12-5). The pretemporal white matter cysts often begin as regions of T1 and T2 prolongation (12-4C) (12-5C). T2WI also demonstrates the indistinct gray matter/white matter interface characteristic of PMG and characterizes other patterns of cortical organizational and migrational disturbance (12-3C). Coronal T2WI and FLAIR demonstrate the patterns of vertically dysmorphic hippocampi and cerebellar dysgenesis (12-3). Calcifications appear as foci of T2 shortening (e.g., hypointensity) (12-1).

SWIs, including SWI-filtered phase maps, are able to distinguish paramagnetic substances (blood products as hypointense) from diamagnetic substances (calcification as hyperintense). Thus, SWI represents a valuable MR sequence in the imaging evaluation of suspected congenital CNS infections.

Fetal MR is more sensitive than US in the early detection of CMV-associated CNS abnormalities.

Ultrasound. Cranial sonography is useful for evaluation of the neonatal and infant brain (up to 6-8 months of age). In the setting of congenital CMV infection, cranial sonography may be technically challenging, as microcephaly (due to poor brain growth and brain destruction) is associated with overlapping sutures and diminished size of the anterior and posterior fontanelles, which represent the probe contact points for sonography. When an acoustic window is present, enlarged ventricles, periventricular hyperechogenic foci that correspond to the subependymal calcifications seen on NECT and MR (SWI), may be seen.

Other findings include germinal zone cysts (germinolytic), which may be present along the caudostriatal grooves in the periventricular zones and in the anterior temporal white matter. Lenticulostriate mineralizing vasculopathy appearing as linear and branching hyperechogenicities within the thalami and basal ganglia although not pathognomonic for CMV occurs in 25-30% of congenital CMV infections.

CONGENITAL CMV INFECTION SPECTRUM OF IMAGING ABNORMALITIES

Calcifications (caudostriatal and periventricular)• Cerebellar hypoplasia• Cerebral cortical abnormalities•

Polymicrogyria○ Cortical cleft dysplasia○ Schizencephaly○ Lissencephaly○ Pachygyria○ Hippocampal dysplasia○

Cysts (germinolytic and anterior temporal)• White matter abnormality•

Differential Diagnosis

The differential diagnosis of congenital CMV includes other TORCH and non- TORCH infections, including toxoplasmosis, Zika virus, and LCMV. Toxoplasmosis is much less common than CMV and typically causes scattered parenchymal calcifications, not the dominant subependymal

(12-5C) Sagittal T2 FLAIR shows multifocal WM hyperintensities st and anterior temporal lobe cysts ﬇.

(12-5B) Coronal T2WI in the same patient shows periventricular WM hyperintensities st, anterior temporal lobe cysts ﬇, and bilateral PMG st.

(12-5A) T2WI in a 3y girl with CMV shows WM hyperintensities st, germinolytic cyst ﬇, and malformations of cortical development st.

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pattern observed in CMV. Microcephaly and cortical dysplasia are also significantly less common in congenital toxoplasmosis. Up to 50% of toxoplasmosis patients have hydrocephalus. Zika and LCMV may display an array of imaging abnormalities that are precise mimics of congenital CMV disease.

Zika Virus Infection. Ca++ is universal, occurring at the at the GM/WM junctions. Additionally, ventriculomegaly, malformations of cortical development (e.g., PMG), occipital pseudocysts, callosal dysgenesis, myelination disturbance, and brainstem and cerebellar hypoplasia are frequently reported.

LCMV. CT and MR findings may mimic CMV. LCM may cause necrotizing ependymitis and aqueductal obstruction with resultant hydrocephalus and macrocephaly, like 50% of congenital toxoplasmosis cases (12-16).

Pseudo-TORCH Syndromes. Some genetic disorders mimic the imaging abnormalities of congenital infections. Adams-

Oliver, Baraitser-Reardon, Aicardi-Goutières syndrome, RNAse T2-deficient leukoencephalopathy, Coats plus syndrome, leukoencephalopathy, cerebral calcification, and cysts are rare, mostly autosomal-recessive demyelinating and degenerative disorders. Basal ganglia and brainstem calcifications are more common than the subependymal pattern characteristic of CMV, Zika, or LCMV.

Pseudo-TORCH syndromes, unlike congenital infections, show progressive decline in neurological status and advancing imaging abnormalities. Pseudo-TORCH syndromes typically lack malformations of the cortex (e.g. PMG) that are so common in many of the congenital infections.

Congenital Toxoplasmosis

Etiology and Pathology

Congenital toxoplasmosis is caused by intrauterine infection with Toxoplasma gondii, one of the world's most common

(12-6C) Axial NECT through cerebral convexities shows peripheral nature of the calcifications in this child with congenital toxoplasmosis. The linear "tram-track" calcification pattern described in some cases is nicely demonstrated here st. (12-6D) Axial T2WI in same girl shows normal hemispheric cortex without evidence of malformation, typically seen with CMV. Hydrocephalus is more common in toxoplasmosis.

(12-6A) Axial NECT image from a 12y developmentally delayed girl with known congenital toxoplasmosis shows that punctate and linear calcifications primarily involve the cerebral cortex and subcortical white matter st. A single periventricular calcification is present st, contrasting this case with CMV. (12-6B) Axial NECT from the same girl shows scattered calcifications. Cortical anomalies are uncommon in congenital toxoplasmosis.

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(12-7A) NECT shows 13d neonate with fever, lethargy, respiratory distress, hypoglycemia, and hepatomegaly, showing diffuse cerebral edema. Note the focal hyperattenuation (hemorrhage) within the cerebellar hemispheres st.

(12-7B) ADC map in the same neonate shows widespread symmetric diffusion restriction in the cortex ﬇, basal ganglia st, and thalami st. CSF PCR was positive for herpes simplex virus (HSV). This is disseminated congenital HSV infection.

obligate intracellular parasites. Infected domestic cats (e.g., the parasite's ultimate host) represent a major source of human infection, endemic in some developed countries (e.g., France). The infection in humans is usually acquired from the ingestion of contaminated water or undercooked food products (usually fresh fruit, vegetables, and meat) or by direct contact with the feces of an infected cat (e.g., gardening, litter box, or the child's sandbox).

Ependymitis leading to aqueductal obstruction and hydrocephalus with resultant macrocephaly is seen in approximately 50% of congenital toxoplasmosis. A diffuse inflammation of the meninges is present with large and small granulomatous lesions. Unlike CMV, malformations of cortical development are rare.

Clinical Issues

Toxoplasmosis is the second most common congenital infection. Approximately 5 in 1,000 pregnant women are infected with it. Estimates of the risk of fetal transmission vary from 10-100%.

Congenital toxoplasmosis causes severe chorioretinitis, jaundice, hepatosplenomegaly, growth retardation, and brain damage. Chorioretinitis is often severe. Infants with subclinical infection at birth are at risk for seizures, as well as delayed cognitive, motor, and visual defects.

Imaging and Differential Diagnosis

With some exceptions, imaging features of congenital toxoplasmosis resemble those of CMV, Zika, and LCMV. NECT scans show extensive parenchymal calcifications that often appear "scattered" throughout the brain parenchyma (12-6)

unlike the germinal zone calcifications of CMV or subcortical calcifications of Zika virus infection. MR scans may show multiple subcortical cysts, porencephaly, and ventriculomegaly (hydrocephalus) often due to inflammatory debris and aqueductal obstruction. There is a notable lack of cortical malformations in those affected with congenital toxoplasmosis (12-6D) in contradistinction to those afflicted with congenital CMV disease (12-2B).

Malformations of cortical development that are so common in Zika virus, congenital CMV, and LCMV infections are rare in toxoplasmosis.

Herpes Simplex Virus: Congenital and Neonatal Infections

Terminology

CNS involvement in HSV infection is called congenital or neonatal HSV when it involves neonates. In contradistinction, herpes simplex encephalitis (HSE) (HSE is also sometimes called herpes simplex virus encephalitis) describes encephalitis in individuals beyond the first postnatal month. In this section, we discuss neonatal HSV. HSE is discussed subsequently with other acquired viral infections.

Etiology

Herpes simplex viruses (HSV-1 and HSV-2) are double- stranded DNA viruses and members of the family Herpesviridae that infect humans. Approximately 2,000 infants in the USA annually are diagnosed with neonatal infections with either HSV-1 or HSV-2. The morbidity and mortality in

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(12-9) Autopsied brain from an infant with end- stage HSV shows markedly enlarged ventricles and extensive holohemispheric cystic encephalomalacia ﬊. (12- 10) Coronal FLAIR in a microcephalic infant with a history of peripartum HSV-2 shows extensive cerebral hemispheric cystic encephalomalacia ﬇ and gliosis st. Note the passive ventricular enlargement.

(12-8C) T2WI in the same infant, 1 month later shows extensive multicystic encephalomalacia with blood-fluid levels st. Note ribbon-like T2 shortening within the cortex ﬇ reflecting hemorrhage and or Ca++. (12-8D) T2WI through the convexity in the same patient illustrates holohemispheric cystic encephalomalacia ﬈ underlying regions of gyral T2 shortening ﬇. This case illustrates early and late changes of congenital HSV.

(12-8A) A 4-week-old infant born to an HSV-2- positive mother had several days of fever and lethargy. T1WI shows multiple bilateral cortical st and basal ganglia ﬇ foci of T1 shortening, suggestive of subacute hemorrhage. (12-8B) More cephalad scan in the same patient shows additional areas of cortical T1 shortening st. Susceptibility-weighted MR with filtered phase maps aids in differentiating hemorrhage from calcification.

Congenital, Acquired Pyogenic, and Acquired Viral Infections 339

neonatal HSV-2 encephalitis is significantly worse compared with HSV-1 encephalitis. These are lifelong viral infections.

Pathology

Neonatal HSV encephalitis is a diffuse disease, without the predilection for the temporal lobes and limbic system seen in older children and adults.

Early changes include meningoencephalitis with necrosis, hemorrhage, and microglial proliferation. Atrophy with gross cystic encephalomalacia and parenchymal calcifications is typical of late-stage HSV. Near-total loss of brain substance with hydranencephaly is seen in severe cases.

Clinical Issues

Epidemiology. HSV-2 is one of the most prevalent sexually transmitted infections worldwide. Approximately 2% of women acquire HSV-2 annually. The majority are asymptomatic, and most are completely unaware of the disease. Neonatal HSV infections are vertically transmitted, occurring in approximately 1 in 3,200 deliveries in the United States. Prevalence is higher in African Americans, low-income mothers, and mothers with multiple sexual partners.

The vast majority (85%) of neonatal HSV is acquired at parturition, and 10% is contracted postnatally. Only 5% of cases are due to in utero transmission. Those who have contracted their infection in utero may manifest the congenital infection syndrome, namely microcephaly, skin rash or scarring, and cataracts. The risk is increased with primary maternal infection during the third trimester and can be decreased by cesarean delivery.

Presentation. Neonatal HSV infection causes three clinicopathological disease patterns: (1) skin, eye, and mouth disease; (2) encephalitis; and (3) disseminated disease with or without CNS disease. Approximately 50% of all infants with neonatal HSV will have CNS involvement, either isolated or as part of disseminated disease.

Clinicians must have a high index of suspicion for neonatal HSV infection. Only two-thirds of the infected neonates with HSV encephalitis show a herpetic skin rash. This disseminated infection presents with lethargy, poor feeding, jaundice, hepatomegaly, seizures, and respiratory distress. The fontanelle may bulge. Onset of symptoms in perinatal HSV infection is 2-4 weeks following delivery (peak = 16 days). The definitive diagnosis is based on detecting HSV DNA in the serum or CSF (e.g., PCR). Note that as many as 25% of neonates with HSV encephalitis have negative PCR studies.

Natural History. Death by 1 year of age occurs in approximately 50% of untreated neonates with overt CNS disease and 85% with disseminated infection. Half of surviving infants have permanent deafness, vision loss, cerebral palsy, and/or epilepsy.

Treatment Options. Prompt administration of antiviral therapy with high-dose acyclovir significantly reduces morbidity, especially in infants with disseminated disease, and should be initiated whenever perinatal HSV encephalitis is

suspected even when the initial PCR is "negative." In such a case, empiric therapy with acyclovir should be initiated, lumbar puncture repeated, and PCR performed.

Imaging

Unlike childhood or adult HSE, neonatal HSV CNS infection is much more diffuse. Both gray and white matter are affected. HSV is known to damage many brain regions with necrosis, cellular debris, hemorrhage, macrophage and mononuclear inflammatory cellular infiltration, calcification, and hypertrophied astrocytes. Interestingly, the pial-glial membrane remains intact, and the ependyma and choroid plexuses are spared, in contrast to CMV (12-7).

ALERT: The radiologist should strongly consider neonatal HSV encephalitis when cranial imaging at 2-3 weeks of neonatal life shows unexplained diffuse cerebral edema, with leptomeningeal enhancement, without or with cerebral parenchymal hemorrhage. Early MR with diffusion is advised (12-7).

CT Findings. NECT may be normal early in the disease or show diffuse hypoattenuation involving both cortex and subcortical white matter reflecting cerebral edema (12-7A). Hemorrhages may present as multifocal punctate, patchy, and curvilinear regions of hyperattenuation in the basal ganglia, white matter, and cortex (12-7A).

MR Findings. MR without and with intravenous MR contrast (with a critical eye to DWI abnormalities) is the imaging procedure of choice in suspected cases of neonatal HSV, with recognition that the normal unmyelinated neonatal white matter presents a challenge in the early detection of HSV encephalitis.

HSV encephalitis is nonpatterned. In the acute and subacute stages of this disease, multifocal lesions (67%), deep gray matter involvement (58%), hemorrhage (66%), "watershed" pattern of injury (40%), and the occasional involvement of the brainstem and cerebellum have been reported.

DWI and ADC maps detect early cellular necrosis and are key, not only for the initial diagnosis of neonatal HSV encephalitis, but also to detect rare CNS relapses. In half of all patients, DWI demonstrates bilateral or significantly more extensive disease than seen on conventional MR (12-7B). Areas of restricted diffusion may be the only positive imaging findings in early cases. Late-stage disease shows severe volume loss with enlarged ventricles and multicystic encephalomalacia (12-9) (12-10).

In the early stages, diffuse cerebral edema may predominate. T1WI may be normal or show hypointensity (T1 prolongation) in affected areas. Proton density and FSE T2 sequences show hyperintensity in the cortex, white matter, and basal ganglia.

Warning: FLAIR sequences at less than 8 months of age underestimate parenchymal pathology, particularly within the hemispheric white matter. Hemorrhagic foci are common (66%) within 1 week of clinical diagnosis and best detected with T2* sequences (e.g., GRE, SWI), SWI being six times more sensitive to detect parenchymal Ca++.

Infection, Inflammation, and Demyelinating Diseases 340

Neurological Manifestations of Herpes Virus Infections Beyond 4 Weeks

Virus Immunocompetent Hosts Immunosuppressed Hosts CMV Meningoencephalitis Retinitis, microglial nodular encephalitis

EBV Meningoencephalitis, cerebellitis, optic neuritis, brainstem encephalitis

EBV, primary CNS lymphomas

HHV-6 Febrile seizures (< 2 years), hippocampi and amygdala, extratemporal involvement

Meningoencephalitis, leukoencephalitis, acute necrotizing encephalitis

HSV-1 Limbic structures involved, asymmetric bilateral, vascular territory involvement

Encephalitis

HSV-2 Aseptic meningitis May have myelitis

VZV Cerebellitis, vasculitis (stroke) (basal ganglia), multifocal leukoencephalopathy

Multifocal leukoencephalopathy

(Table 12-1) CMV = cytomegalovirus; EBV = Epstein-Barr virus; HHV = human herpesvirus; HSV = herpes simplex virus; VZV, varicella zoster virus.

Foci of patchy enhancement, typically a meningeal pattern of enhancement, are common on T1 C+ scans. In later stages, T1 shortening and T2 hypointensity with "blooming" on T2* GRE/SWI secondary to hemorrhagic foci may develop (12-8).

MRS early in HSV encephalitis shows elevated lactate, lipids, choline, and excitatory neurotransmitters. NAA is reduced.

Ultrasound. Acutely, ultrasound demonstrates diffuse edema ("salt and pepper" pattern). Less common are linear echoes in the basal ganglia, similar to CMV.

Differential Diagnosis

The major differential diagnoses for neonatal HSV are other TORCH and non-TORCH infections. Neonates with HSV are usually normal for the first few days after delivery. Brain scans are normal or minimally abnormal early in the disease course. Calcifications and migrational anomalies are absent.

Because the initial imaging features of acute and subacute HSV encephalitis are often so nonspecific and may manifest with generalized cerebral edema, metabolic, toxic, and hypoxic ischemic insults must also be considered in the differential diagnosis.

In some cases, HSV causes watershed distribution ischemic injury in areas remote from the primary herpetic lesions and may be difficult to distinguish from partial protracted or mild to moderate hypoxic-ischemic injury (HII). However, term infants with HII typically follow a different clinical course, becoming symptomatic in the immediate postnatal period. Profound HII preferentially affects the perirolandic cortex and sulcal depths, white matter, hippocampi, and deep gray nuclei, including the ventrolateral thalami. Hemorrhage with "blooming" on T2* GRE is uncommon in neonatal HII.

Zika Virus Infection

Etiology

Zika virus is a single-stranded RNA Flavivirus, closely related to Dengue fever, yellow fever, West Nile virus, and Chikungunya. The virus is mostly transmitted by infected female mosquito

vector bites, particularly Aedes aegypti mosquitos. It can also be transmitted through blood contamination perinatally and sexually. Zika virus has been directly linked to severe fetal microcephaly in infants born to infected mothers.

Pathology

Like CMV, Zika virus crosses the fetal-placental barrier and has been isolated from the brain and CSF of microcephalic newborns and the placental tissue and amniotic fluid. The virus leads to neurotoxicity and in experimental models impaired human neurosphere growth. Fetal germinal matrix tissue is a target for Zika virus. As with other congenital CNS infections, the timing of infection dictates the scope and magnitude of brain injury and malformation.

Clinical Issues

The diagnosis of Zika virus infection in the adult is complicated by the fact that up to 80% of infected individuals are asymptomatic. The symptoms when present are nonspecific and mild. Headache, rash, and fever may be reported. Conjunctivitis and Guillain-Barré syndrome are uncommon clinical manifestations of the infection.

Compared with congenital CMV disease, brain involvement with Zika virus infection tends to routinely cause severe brain damage, indicating a poor prognosis for neurologic outcome. The affected newborn shows microcephaly, a nonspecific term that refers to a smaller than expected head for normal gestational age. In Zika virus infection and other congenital infections, insults to the developing brain lead to microencephaly (small brain), which results in a small head (microcephaly). Also, associated overlapping sutures, closed fontanelles, and redundant scalp skin folds may be clinically observed. Seizures, poor feeding, hypotonia, and lethargy are nonspecific common clinical features among severely affected newborns.

Imaging

Cerebral parenchymal calcifications are universally present. The cerebral hemispheric GM-WM junction is the most

Congenital, Acquired Pyogenic, and Acquired Viral Infections 341

(12-11A) Sagittal T1WI shows diminished cranio-to-facial ratio secondary to microencephaly in congenital Zika viral infection. T1 shortening at GM-WM junction st reflects Ca++. (Courtesy L. Brandao, MD.)

(12-11B) T1WI shows T1 shortening at the GM-WM junctions st reflecting Ca++. Note the smooth brain surface, shallow sulci, and hazy GM-WM transitions consistent with PMG ﬇. (Courtesy L. Brandao, MD.)

common location (12-12). Other sites include the basal ganglia/thalami, brainstem, and cerebellum. Cerebral, cerebellar, and brain stem volume loss, ventriculomegaly, and resultant microencephaly are seen. Disorders of the corpus callosum and cortex are common. Polymicrogyria (PMG), lissencephaly, and pachygyria are also seen. PMG is reported in up to 65% of affected newborns. Other reported abnormalities include occipital periventricular cysts, demyelination, microphthalmia, and cataracts.

MR is the most comprehensive tool to depict parenchymal calcifications (e.g., SWI with filtered phase maps), cortical migration, organizational abnormalities, ventriculomegaly, white mater myelination, developmental anomalies of the corpus callosum, and orbital abnormalities (12-11). The US acoustical window is often limited by the small or closed fontanelles and sutural overlap seen in severe microcephaly. NECT, although sensitive for the detection of calcification, will underestimate presence and extent of cortical malformations and exposes the neonate to ionizing radiation.

Differential Diagnosis

Congenital CMV presents with microcephaly, PMG, and Ca++ at caudostriatal groove. Toxoplasmosis presents with macrocephaly, hydrocephalus, scattered Ca++, and lack of cortical malformations. LCMV presents with microcephaly and macrocephaly, scattered Ca++, PMG, and "negative" TORCH tests. Pseudo-TORCH presents with microcephaly, scattered Ca++ including brainstem and basal ganglia, which progresses, atrophy, and lack of cortical malformations.

Lymphocytic Choriomeningitis Virus

Etiology

Congenital lymphocytic choriomeningitis virus (LCMV) is an arenavirus and member of the Arenaviridae family of viruses. Rodents are the principal reservoir for this viral infection. The geographic range is broad with many cases reported from rural environments. The overall incidence of congenital LCMV is unknown.

Pathology

LCMV has a strong tropism for neuroblasts. Additionally, LCM causes necrotizing ependymitis similar to that seen in cases of congenital toxoplasmosis. The range of injury and malformation includes microencephaly (e.g., CMV-like), periventricular calcification, hydrocephalus, cortical dysplasia, and focal cerebral destruction. High rates of chorioretinitis and hydrocephalus are observed, thus often mimicking the imaging features of toxoplasmosis.

Clinical Issues

Unlike many other congenital CNS infections, hepatosplenomegaly, jaundice, and skin rash (e.g., petechial/purpuric) are absent in congenital LCMV. High rates of congenital hydrocephalus (likely secondary to the exudative ependymitis and aqueductal obstruction) and chorioretinitis are observed in LCMV.

Diagnosing LCMV requires the detection of LCMV-specific serologic responses (IgG and IgM). Detecting LCM viral- specific-IgG strongly suggests congenital infection. Such

Infection, Inflammation, and Demyelinating Diseases 342

testing is not routine in the TORCH(S) laboratory inquiry. Thus, confirming LCMV requires nuanced laboratory assessment.

Imaging

The imaging findings of congenital LCMV infection can mimic those of CMV or toxoplasmosis (12-16). Timing of the infection dictates the pattern of CNS injury. Unlike toxoplasmosis, malformations of cortical development do occur with LCMV. Hydrocephalus and calcifications can be shown with US, NECT, and MR. Malformations in cortical development are best displayed with MR. MR represents the imaging gold standard for the comprehensive characterization of injury and malformation for LCMV and all other congenital CNS infections.

Consider congenital LCMV infection when the imaging findings mimic CMV, Zika, or toxoplasmosis and the clinical and serologic evaluation is "normal."

Differential Diagnosis

Toxoplasmosis lacks cortical malformations, congenital CMV typically shows caudostriatal groove or periventricular Ca++ and PMG, Zika virus Ca++ is most common at the GM/WM junction, and psuedo-TORCH Ca++ involves the brainstem, basal ganglia, WM, and cortex and lacks cortical malformations.

Congenital (Perinatal) HIV The imaging presentation of congenital HIV infection is quite different from the findings in acquired HIV/AIDS. Congenital HIV resembles the other congenital viral infections and is therefore discussed here. Acquired HIV/AIDS is considered separately (see Chapter 14).

(12-12C) NECT shows numerous GM-WM junction calcifications st, diffuse polymicrogyria (PMG) causing simplified gyral pattern ﬇, enlarged primitive-appearing sylvian fissures ﬈, and ventriculomegaly. (12- 12D) Coronal NECT shows characteristic peripheral Ca++ st, ventriculomegaly, and holohemispheric polymicrogyria ﬇. (Courtesy A. Pessoa, MD.)

(12-12A) Axial NECT shows Zika-infected neonate. Peripheral Ca++ involves cortex and GM- WM junctions st. Broad sylvian fissures, simplified gyral pattern (PMG) ﬇, and ventriculomegaly are seen. Note the coronal sutural overlap st due to microencephaly. (12-12B) NECT shows another microencephalic newborn showing Ca++ at GM-WM junctions st. Diffuse PMG ﬇, ventriculomegaly, and rhombencephalosynapsis st are seen.

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SELECTED CONGENITAL AND PERINATAL INFECTIONS: NEUROIMAGING FINDINGS AND COMMON CAUSES

Cytomegalovirus Microcephaly, Ca++ at caudostriatal groove, polymicrogyria (PMG), cysts, WM abnormalities, cerebellar hypoplasia, vertical hippocampi

•

Toxoplasmosis Macrocephaly, hydrocephalus, scattered Ca++, lack of cortical malformations

•

Herpes Simplex Virus Early-diffuse cerebral edema, multifocal lesions, DWI abnormalities, hemorrhage, watershed infarctions, leptomeningeal enhancement, late cystic encephalomalacia

•

LCMV May precisely mimic features of CMV, negative routine TORCH testing

•

Zika Virus Microcephaly, ventriculomegaly, Ca++ at GM-WM junctions, cortical malformations

•

Rubella Microcephaly, Ca++ (basal ganglia, periventricular, and cortex) may cause lobar destruction

•

Varicella Zoster Necrosis of WM, deep GM nuclei, cerebellum ventriculomegaly, cerebellar aplasia, PMG

•

Syphilis Basilar meningitis, stroke, scattered Ca++•

HIV Atrophy, basal ganglia Ca++, fusiform arteriopathy•

Human Parechovirus Confluent periventricular WM abnormality mimic of perinatal periventricular leukomalacia

•

Human Parvovirus B19 WM, cortical, and BG injury in setting of severe fetal anemia

•

Etiology

The causative agent is the retrovirus human immunodeficiency virus type 1 (HIV). At least 90% of congenital HIV cases are vertically transmitted (mother-to- child transmission). A minority (approximately 10%) might be due to blood transfusions, other blood products given therapeutically, or organ/tissue transplantation. Most infants become infected at birth or during the third trimester. Occasionally older infants are infected during breast feeding.

Pathology

The most characteristic gross finding is generalized brain volume loss with symmetric enlargement of the ventricles and subarachnoid spaces. Multiple foci of microglia, macrophages, infiltration of microglial nodules, and multinucleated giant cells containing viral particles are typical. Patchy myelin pallor

and vacuolization are common. Mineralizing microangiopathy with basal ganglia calcifications and endothelial hypertrophy with gross cerebral vasculopathy are seen in some cases.

Clinical Issues

Epidemiology. Congenital HIV infection is diminishing as highly active antiretroviral therapy (HAART) becomes more widely available. Children account for just 2% of all HIV/AIDS patients in the USA and Europe but still represent 5-25% of cases worldwide. Congenital and acquired CMV infections are strong independent correlates of mother-to-child HIV transmission.

Presentation and Natural History. Symptoms generally begin around 3 months of life. Developmental delay, progressive motor dysfunction, and failure to thrive are the most common CNS symptoms. Hepatosplenomegaly, lymphadenopathy, and parotid lymphoepithelial cysts are common manifestations of congenital HIV.

Without antiretroviral therapy, infants and children with HIV encephalopathy show acquired microcephaly, progressive motor dysfunction, cognitive and developmental delay, apathy, dementia, hyperreflexia, ataxia, weakness, myoclonus, and/or seizures. Approximately 20% of infected infants die. Opportunistic infections are less common in HIV-infected children compared with adults; however, stroke is more common. Secondary CNS complications of congenital HIV include primary CNS lymphoma, stroke, opportunistic infection, and aneurysmal arteriopathy.

Imaging

The most striking and consistent finding is atrophy, particularly in the frontal lobes. Bilaterally symmetric basal ganglia calcifications are common (12-13). Calcifications can be identified in the hemispheric white matter and cerebellum.

Ectasia and fusiform enlargement of intracranial arteries are found in 3-5% of cases (12-14). Secondary VZV infectious vasculopathy has been implicated in the development of aneurysmal arteriopathy in HIV. Strokes with foci of restricted diffusion and subarachnoid hemorrhage may occur as complications of the underlying vasculopathy.

Differential Diagnosis

The differential diagnosis of congenital HIV is other TORCH infections. CMV is characterized by periventricular calcifications, microcephaly, and cortical dysplasia. Other than volume loss, the brain in congenital HIV appears normal. Toxoplasmosis is much less common than CMV and causes scattered parenchymal calcifications, not symmetric basal ganglia lesions. Pseudo-TORCH Ca++ involves cortex and WM, basal ganglia, brainstem, and cerebellum.

Other Congenital Infections

Rubella (German Measles)

Humans are the only reservoir for the rubella virus. Transmission is via virus-contaminated respiratory secretions.

Infection, Inflammation, and Demyelinating Diseases 344

Prior to widespread implementation of measles-mumps- rubella vaccine, epidemics of rubella occurred globally in 6- to 9-year intervals. With the advent of effective vaccination programs, the worldwide prevalence of congenital rubella syndrome (CRS) has declined dramatically. Approximately 100,000 infants are born with CRS, mostly in countries with low national vaccination rates.

Early in utero infection (e.g., particularly in the first trimester) results in miscarriage, fetal death, or congenital malformations in surviving infants. Late infection causes generalized brain volume loss, dystrophic calcifications, and regions of demyelination and/or gliosis.

The triad CRS includes ophthalmic (e.g., retinopathy, cataracts, microphthalmia), auditory (e.g., sensorineural deafness), and cardiac (e.g., patent ductus arteriosis, pulmonary artery stenosis) findings. Other clinical findings in CRS include craniofacial defects, microcephaly, and thrombocytopenic purpura.

Imaging findings are nonspecific, and, like other congenital infections, the timing of infection dictates the magnitude of destructive changes. Reported findings include microcephaly, parenchymal calcifications including cortical calcifications (12- 15), delayed myelination, periventricular and basal ganglia cysts, frontal-dominant white matter lesions (NECT hypoattenuating and MR T2 hyperintense), and atrophy, and, in severe cases, total brain destruction has been described.

Congenital Syphilis

Congenital syphilis (CS) is caused by transplacental passage of the Treponema pallidum spirochete from untreated mothers with syphilis. Infection occurs typically in the second and third trimesters.

Up to 60% of infants infected with CS are asymptomatic at birth. Symptoms typically develop later in infancy with early signs and symptoms including jaundice, hepatosplenomegaly, and rash. Later craniofacial signs and symptoms include saddle

(12-14A) Axial T2WI MR in an 11y child demonstrates late manifestations of congenital HIV. Note prominent ventricles and sulci as well as multifocal white matter hyperintensities ﬈. (12- 14B) Submentovertex view of an MRA obtained in the same patient shows striking multicentric fusiform arteriopathy in both middle cerebral arteries ﬇.

(12-13A) Axial NECT scan in a 5y child with congenital HIV shows bilateral symmetric calcifications in the basal ganglia st and the subcortical white matter ﬇. Prominent lateral cerebral fissures st reflect atrophy. (12-13B) Axial NECT scan in the same patient shows fairly symmetric punctate and curvilinear calcifications at the gray-white matter junctions ﬇ caused by mineralizing microangiopathy. (Courtesy V. Mathews, MD.)

Congenital, Acquired Pyogenic, and Acquired Viral Infections 345

nose deformity, frontal bossing, rhagades (scars around the mouth and nose), Hutchinson teeth, seizures, stroke, and signs of increased intracranial pressure. The most common imaging findings in CS are hydrocephalus and meningitis with leptomeningeal enhancement.

Imaging findings in CS include leptomeningeal enhancement, hydrocephalus, and cerebral infarction. Cisternal exudative meningitis can as a result of gumma formation lead to hypothalamic and pituitary dysfunction.

Congenital Varicella Zoster Virus Infection

In unimmunized populations, the rate of varicella infection (chickenpox) acquired through contact with respiratory secretions of infected children ranges between 1-3 per 1,000 pregnancies. Less than 2% of these pregnancies result in congenital varicella zoster syndrome. Neonates and infants with this congenital infection, like infants with congenital HSV and LCMV infections, generally lack the signs and symptoms of congenital infection, such as jaundice, hepatosplenomegaly, and skin rash (e.g., petechial/purpuric). Congenital varicella infection prior to 20 postconceptional weeks may lead to spontaneous abortion or embryopathic insults, including microcephaly secondary to cerebral destruction, chorioretinitis, limb and digit hypoplasia, and a distinctive pattern of skin scarring known as cicatrix.

Imaging findings in congenital varicella zoster infection include microcephaly, parenchymal calcifications, ventriculomegaly, polymicrogyria, and nonpatterned necrosis of white matter, lobar cortical and subcortical tissues, and deep gray nuclei. Similar necrotic lesions have been described in the cerebellum, leading to cerebellar atrophy (12-17). MR is the most sensitive imaging tool to fully appraise injury.

Congenital/Perinatal Human Parechovirus Infection

Parechovirus is a picornavirus that can cause encephalitis and permanent injury to the developing CNS. It shows tropism for the periventricular white matter (e.g., leukotropic). The neonate may present with a sepsis-like illness, rash, fever, irritability, and seizures. CSF pleocytosis is uncommon, unlike most cases of meningoencephalitis. At present, no specific antiviral therapy is available.

Imaging findings in perinatal parechovirus infection include detection of bilateral confluent white matter abnormalities. NECT shows low-attenuation regions, and MR acutely demonstrates restricted diffusion as well as T1 and T2 prolongation. These leukotropic changes have been mistaken for perinatal white matter hypoxic ischemic injury in the preterm newborn.

Congenital Human Parvovirus B19

Human Parvovirus B19 is one well-documented cause of severe fetal anemia and a known cause of fetal death. The virus is also known to affect patients with immunologic disorders such as sickle cell anemia. Human Parvovirus B19 is the only known Parvovirus that is pathogenic to humans. The risk of maternal to fetal transmission is greatest in the first and second trimesters.

Imaging findings as a result of severe fetal anemia and intracranial resistive indices (transcranial Doppler US) drop. Resultant cerebral injury (e.g., ischemia, infarction, or severe diffuse destruction) may occur.

(12-17) NECT shows extreme microcephaly, extensive subcortical calcifications, and undersulcated brain in congenital VZV infection.

(12-16) NECT in an infant with congenital lymphocytic choriomeningitis shows focal parenchymal st and periventricular Ca++ ﬇.

(12-15) NECT scan in an 18m boy with congenital rubella shows subtle subcortical st and basal ganglia calcifications ﬇.

Infection, Inflammation, and Demyelinating Diseases 346

Acquired Pyogenic Infections

Meningitis Meningitis is a worldwide disease that leaves up to half of all survivors with permanent neurologic sequelae. Despite advances in antimicrobial therapy and vaccine development, bacterial meningitis represents a significant cause of morbidity and mortality. Infants, children, and the elderly or immunocompromised patients are at special risk. In this section, we focus on the etiology, pathology, and imaging findings of this potentially devastating disease.

Terminology

Meningitis is an acute or chronic inflammatory infiltrate of meninges and CSF. Pachymeningitis involves the dura- arachnoid; leptomeningitis affects the pia and subarachnoid spaces.

Etiology

Meningitis can be acquired in several different ways. Hematogeneous spread from remote systemic infection is the most common route. Direct geographic extension from sinusitis, otitis, or mastoiditis is the second most common method of spread. Penetrating injuries and skull fractures (especially of the skull base) are rare but important causes of meningitis.

Regardless of origin, all bacteria have to breach the blood- brain barrier (BBB) and blood-CSF barrier to invade the CNS. Bacterial binding to brain endothelial cells is a prerequisite for successful penetration into the CSF. Once accomplished, this results in meningeal inflammation, increased BBB permeability, CSF pleocytosis, and infiltration of the nervous tissue itself.

Many different infectious agents can cause meningitis. Most cases are caused by acute pyogenic (bacterial) infection. Meningitis can also be acute lymphocytic (viral) or chronic (tubercular or granulomatous).

The most common responsible agent varies with age, geography, and immune status. Group Bβ-hemolytic streptococcal meningitis is the leading cause of newborn meningitis in developed countries, whereas enteric, gram- negative organisms (typically Escherichia coli, less commonly Enterobacter or Citrobacter) cause the majority of cases in developing countries.

Vaccination has significantly decreased the incidence of Haemophilus influenzae meningitis, so the most common cause of childhood bacterial meningitis is now Neisseria meningitidis.

Adult meningitis is typically caused by Streptococcus pneumoniae or N. meningitidis (meningococci). The tetravalent meningococcal vaccine used to vaccinate adolescents in the USA does not contain serotype B, the causative organism of

one-third of all cases of meningococcal disease in industrialized countries.

Listeria monocytogenes, S. pneumoniae, gram-negative bacilli, and N. meningitidis affect adults over the age of 55 as well as individuals with chronic illnesses.

Tuberculous meningitis is common in developing countries and in immunocompromised patients (e.g., HIV/AIDS patients and solid organ transplant recipients).

NEONATAL BACTERIAL MENINGITIS: COMMON CAUSES AND IMAGING

Group B Streptococcus Leptomeningeal enhancement, ischemic/infarctive injuries, white matter lesions (scattered or confluent)

•

Citrobacter species Rapidly cavitating lesions of the cerebral white matter, “squared” rim-enhancing abscesses

•

Enterobacter species Like Citrobacter shows tropism for cerebral white matter, large rim-enhancing cavitary lesions

•

Escherichia coli Basal meningitis, ventriculitis, cerebral abscess, and hydrocephalus

•

Listeria Monocytogenes Granulomatous involvement of meninges, choroid plexus, and subependymal regions

•

BACTERIAL MENINGITIS IN INFANTS: COMMON CAUSES

Infants Gram positive•

Group B streptococcus (Streptococcus agalactiae)○ Staphylococcus aureus○ Staphylococcus epidermidis○

Gram negative• Escherichia coli○ Citrobacter species○ Listeria monocytogenes○ Pseudomonas aeruginosis○

BACTERIAL MENINGITIS IN CHILDREN: COMMON CAUSES

Older Children and Adolescents Haemophilus influenzae type B• Non-type B or nontypable Haemophilus influenzae• Mycobacterium tuberculosis• Neisseria meningitides• Streptococcus pneumoniae•

Pathology

Location. The basal cisterns and subarachnoid spaces are the CSF spaces most commonly involved by meningitis, followed

Congenital, Acquired Pyogenic, and Acquired Viral Infections 347

by the cerebral convexity sulci (12-18) (12-19) (12-20) (12- 22).

Gross Pathology. Cloudy CSF initially fills the subarachnoid spaces, followed by development of a variably dense purulent exudate that covers the pial surfaces. Vessels within the exudate may show inflammatory changes and necrosis.

Microscopic Features. The meningeal exudate contains the inciting organisms, inflammatory cells, fibrin, and cellular debris. The underlying brain parenchyma is often edematous, with subpial astrocytic and microglial proliferation.

Meningoencephalitis shows inflammatory changes in the pia, and the perivascular spaces may act as a conduit for extension from the pia into the underlying brain parenchyma.

Clinical Issues

Epidemiology and Demographics. Bacterial infections of the CNS are neurologic emergencies. These include meningitis, brain abscess, empyemas, and suppurative dual sinus thrombophlebitis (see Chapter 9).

Pyogenic meningitis is the most common cause of acute febrile encephalopathy. The overall prevalence of meningitis is estimated at 3:100,000 in industrialized countries. In the United States, meningitis is diagnosed in 62:100,000 emergency department visits.

Presentation. Presentation depends on patient age. In adults, fever (≥ 38.5°C) and either headache, nuchal rigidity, or altered mental status are the most common symptoms. Although less than half of all patients present with the classic triad of fever, neck stiffness, and altered mental status, nearly 100% will have at least one of these symptoms. Vomiting is another common but underrecognized manifestation of CNS infection.

(12-19) Graphic of meningitis shows purulent exudate involving the leptomeninges and filling the basal cisterns and sulci ﬊. The underlying brain is mildly hyperemic ﬈. Venous and arterial spasm/occlusion may result in parenchymal infarction. (12-20) Axial autopsy section shows meningitis with exudate completely filling the suprasellar cistern ﬈ and sylvian fissures ﬊. (Courtesy R. Hewlett, MD.)

(12-18A) Autopsied brain shows typical changes of severe meningitis with dense purulent exudate covering the pons ﬈, coating the cranial nerves ﬉, and filling the basal cisterns ﬊. (12-18B) As seen in this autopsy photo, the exudate coats the medulla st and completely fills the cisterna magna ﬊. (Courtesy R. Hewlett, MD.)

Infection, Inflammation, and Demyelinating Diseases 348

Fever, lethargy, poor feeding, and irritability are common among infected infants. Children with N. meningitidis infection may develop a purpuric rash. Diffuse intravascular coagulopathy (DIC) may develop with meningococcal or H. Influenzae meningitis. Seizures occur in 30% of patients.

CSF shows leukocytosis (mainly polymorphonuclear cells), elevated protein, and decreased glucose. A normal C-reactive protein has a high negative predictive value in the diagnosis of bacterial meningitis.

Natural History. Despite rapid recognition and effective therapy, meningitis still has significant morbidity and mortality rates. Death rates from 15-25% have been reported in disadvantaged children with poor living conditions.

Complications are both common and numerous. Extraventricular obstructive hydrocephalus is one of the earliest and most common complications. The choroid plexus can become infected, causing choroid plexitis and then

ventriculitis. Infection can also extend from the pia along the perivascular spaces into the brain parenchyma itself, causing cerebritis and then abscess.

Sub- and epidural empyemas or sterile effusions may develop. Cerebrovascular complications of meningitis include vasculitis, thrombosis, and occlusion of both arteries and veins.

Treatment Options. Specific antibiotic therapy should be based on culture and sensitivity.

Imaging

General Features. The "gold standard" for the diagnosis of bacterial meningitis is CSF analysis. Remember: Imaging is neither sensitive nor specific for the detection of meningitis! Therefore, imaging should be used in conjunction with—and not as a substitute for—appropriate clinical and laboratory evaluation.

(12-21C) The patient returned 3 weeks later with increasing headaches and altered mental status. FLAIR shows the basal cisterns, and sulci are all hyperintense ﬈. Progressive hydrocephalus is noted, and transependymal interstitial edema is seen ﬊. (12-21D) T1 C+ FS in the same case shows diffuse linear and nodular sulcal-cisternal enhancement st. This is pyogenic meningitis and has led to associated hydrocephalus.

(12-21A) NECT in a 25y man with headache and fever shows mild enlargement of both temporal horns st. CSF in the suprasellar cistern ﬇ appears mildly hyperdense ("dirty"), and the sylvian fissures st appear effaced. (12-21B) More cephalad NECT shows that the lateral and third ventricles are slightly enlarged. Note poor visualization of the superficial sulci, leading to a somewhat "featureless" appearance. Scan was initially read as normal.

Congenital, Acquired Pyogenic, and Acquired Viral Infections 349

Imaging studies are best used to confirm the diagnosis and assess possible complications. Whereas CT is commonly employed as a screening examination in cases of headache and suspected meningitis, both the primary and acute manifestations of meningitis as well as secondary complications are best depicted on MR.

CT Findings. Initial NECT scans may be normal or show only mild ventricular enlargement (12-21B) (12-25A). "Blurred" ventricular margins indicate acute obstructive hydrocephalus with accumulation of extracellular fluid in the deep white matter. Bone CT should be carefully evaluated for sinusitis and otomastoiditis.

As the cellular inflammatory exudate develops, it replaces the normally clear CSF. Subtle effacement of surface landmarks may occur as sulcal-cisternal CSF becomes almost isodense with brain (12-21A). In rare cases, subtle hyperattenuation may be present in the basal subarachnoid spaces.

CECT may show intense enhancement of the inflammatory exudate as it covers the brain surfaces, extending into and filling the sulci.

MR Findings. The purulent exudates of acute meningitis are isointense with underlying brain on T1WI, giving the appearance of "dirty" CSF. The exudates are isointense with CSF on T2WI and do not suppress on FLAIR. Hyperintensity in the subarachnoid cisterns and superficial sulci on FLAIR is a typical but nonspecific finding of meningitis (12-21C).

DWI is especially helpful in meningitis, as the purulent subarachnoid space exudates usually show restriction (12- 23B). pMR may demonstrate multiple regions of increased cerebral blood flow.

Pia-subarachnoid space enhancement occurs in 50% of patients (12-21D). A curvilinear pattern that follows the gyri and sulci (the "pial-cisternal" pattern) is typical (12-23A) and is more common than dura-arachnoid enhancement.

(12-23B) DWI in the same patient shows that the viscous pus filling the convexity sulci restricts strongly st. This is streptococcal meningitis with secondary vasculitis. (12-23C) DWI in the same case shows multifocal acute basal ganglia st, thalamic ﬇, and deep parenchymal infarcts st.

(12-22) Autopsy case with close-up view shows typical changes of pyogenic meningitis. The convexity sulci are filled with purulent exudate ﬈. (Courtesy R. Hewlett, MD.) (12-23A) T1 C+ FS scan in a case of acute pyogenic meningitis shows that diffuse, intensely enhancing exudate fills the convexity sulci st. FLAIR imaging is also sensitive in detecting SAS pathology.

Infection, Inflammation, and Demyelinating Diseases 350

(12-24E) Enhanced T1WI in the same patient with E. coli meningitis shows retrocerebellar subdural empyemas st. Note the thick enhancing meningeal ﬈ and endosteal dura st. (12- 24F) Enhanced T1WI in the same patient shows a rim-enhancing occipital lobe abscess ﬇ and leptomeningeal enhancement st. Early hydrocephalus is also noted.

(12-24C) DWI in the same patient shows a focal hyperintensity within the right occipital lobe consistent with abscess ﬊. Note the lateral ventricular dilation (hydrocephalus). (12-24D) FLAIR in the same patient shows right occipital sulcal and cortical FLAIR hyperintensity ﬈ and expansion of the SASs with complex CSF signal st. Note early ventricular enlargement.

(12-24A) DWI in neonate with confirmed E. coli meningitis shows posterior fossa hyperintense subdural collections (empyemas) ﬈. (12-24B) DWI in the same patient shows viscous dependent ventricular debris (ventriculitis) ﬈. Note the vasogenic edema (increased diffusivity) within the occipital lobe ﬉.

Congenital, Acquired Pyogenic, and Acquired Viral Infections 351

(12-25E) SWI in the same patient shows numerous tubular hypointensities within the lateral cerebral fissures and adjacent to the temporal lobes consistent with slow venous flow or thrombosis ﬊. (12-25F) Enhanced T1WI in the same patient, with confirmed Group B Strep meningitis, shows regions of leptomeningeal enhancement st.

(12-25C) DWI in the same patient shows vermian ﬇ and left temporal lobe st hyperintensities confirmed on ADC maps as regions of ischemia/infarction. Note retrocerebellar subdural collections (empyemas) ﬈. DWI is useful in cases of suspected meningitis. (12-25D) FLAIR in the same patient shows expanded "dirty" CSF signal throughout the subarachnoid spaces st. Note the enlarged frontal horns with normal FLAIR CSF signal.

(12-25A) NECT shows a 3m infant with fever and focal seizure. Temporal horn dilation st and left temporal lobe hypoattenuation st are seen. (12-25B) NECT sagittal reformation shows superior vermian hypoattenuation (infarction) ﬉. Note the prominence of the third ventricle st and basal cisterns ﬇.

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(12-28) CT ventriculogram shows dilated 4th ventricle, obstructed outflow at foramina of Luschka ﬈. EVOH is secondary to meningitis.

(12-27) Sagittal T1WI shows basilar meningitis ﬊. Lateral, 3rd ventricles are enlarged; 4th ventricle st appears "ballooned" or obstructed.

(12-26) Autopsy of meningitis ﬇ with EVOH shows lateral ﬈, 3rd ﬊, 4th ventricular ﬉, aqueductal dilation. (Ellison, Neuropath, 3e.)

Postcontrast T2-weighted FLAIR and delayed postcontrast T1-weighted sequences may be helpful additions in detecting subtle cases.

Angiography. Irregular foci of constriction and dilatation characteristic of vasculitis can sometimes be identified on CTA or DSA.

Complications of Meningitis. Other than hydrocephalus, complications from meningitis are relatively uncommon. Postmeningitis reactive effusions—sterile CSF-like fluid pockets—develop in 5-10% of children treated for acute bacterial meningitis. Effusions are generally benign lesions that regress spontaneously over a few days and do not require treatment.

Effusions can occur either in the subdural (most common) or subarachnoid spaces. The frontal, parietal, and temporal convexities are the most common sites. NECT shows bilateral crescentic extraaxial collections that are iso- to slightly hyperdense compared with normal CSF.

Effusions are iso- to slightly hyperintense to CSF on T1WI and isointense on T2WI. They are often slightly hyperintense relative to CSF on FLAIR. Effusions usually do not enhance on T1 C+ but occasionally demonstrate enhancement along the medial (cerebral) surfaces of the lesions. Effusions do not restrict on DWI, differentiating them from subdural empyemas (12- 24).

Less common complications include pyocephalus (ventriculitis), empyema (12-46), cerebritis and/or abscess (12-24), venous occlusion, and ischemia (12-23C). All are discussed separately below.

Differential Diagnosis

The major differential diagnosis of infectious meningitis is noninfectious meningitis. Other causes of meningitis include noninfectious inflammatory disorders (e.g., rheumatoid or systemic lupus erythematosus-associated meningitis, IgG4-related disease, drug-related aseptic meningitis, and multiple sclerosis) and neoplastic or carcinomatous meningitis. All can appear identical on imaging, so correlation with clinical information and laboratory findings is essential. Remember: Sulcal/cisternal FLAIR hyperintensity is a nonspecific finding and can be seen with a number of different entities (see box below).

CAUSES OF HYPERINTENSE CSF ON FLAIR

Common Blood•

Subarachnoid hemorrhage○ Infection•

Meningitis○ Artifact•

Susceptibility; flow○ Tumor•

CSF metastases○

Less Common High inspired oxygen•

4-5x signal with 100% O₂○ Prominent vessels•

Stroke (pial collaterals); "ivy" sign (moyamoya); pial angioma (Sturge-Weber)

○

Rare But Important Fat (ruptured dermoid)• Gadolinium in CSF•

Renal failure; blood-brain barrier leakage○

Congenital, Acquired Pyogenic, and Acquired Viral Infections 353

Abscess

Terminology

A cerebral abscess is a localized infection of the brain parenchyma.

Etiology

Most abscesses are caused by hematogeneous spread from an extracranial location (e.g., lung or urinary tract infection and endocarditis). Abscesses may also result from penetrating injury or direct geographic extension from sinonasal and otomastoid infection. These typically begin as extraaxial infections such as empyema (see below) or meningitis (see above) and then spread into the brain itself.

Abscesses are most often bacterial, but they can also be fungal, parasitic, or (rarely) granulomatous. Although myriad organisms can cause abscess formation, the most common agents in immunocompetent adults are Streptococcus species,Staphylococcus aureus, and pneumococci. Enterobacter species like Citrobacter are a common cause of cerebral abscess in neonates. Streptococcus intermedius is emerging as an important cause of cerebral abscess in immunocompetent children and adolescents. In 20-30% of abscesses, cultures are sterile, and no specific organism is identified.

Proinflammatory molecules such as tumor necrosis factor-α and interleukin- 1β induce various cell adhesion molecules that facilitate extravasation of peripheral immune cells and promote abscess development.

Bacterial abscesses are relatively uncommon in immunocompromised patients. Klebsiella is common in diabetics, and fungal infections by Aspergillus and Nocardia are common in transplant recipients. In patients with HIV/AIDS, toxoplasmosis and tuberculosis are the most common opportunistic infections.

In children, predisposing factors for cerebral abscess formation include meningitis, uncorrected cyanotic heart disease, sepsis, suppurative pulmonary infection, paranasal sinus or otomastoid trauma or suppurative infections, endocarditis, and immunodeficiency or immunosuppression states.

Pathology

Four general stages are recognized in the evolution of a cerebral abscess: (1) focal suppurative encephalitis/early cerebritis, (2) focal suppurative encephalitis/late cerebritis, (3) early encapsulation, and (4) late encapsulation. Each has its own distinctive pathologic appearance, which in turn determines the imaging findings.

Focal Suppurative Encephalitis. Sometimes also called the "early cerebritis" stage of abscess formation, in this earliest stage, suppurative infection is focal but not yet localized (12-29). An unencapsulated, edematous, hyperemic mass of leukocytes and bacteria is present for 1-3 days after the initial infection (12-30).

Focal Suppurative Encephalitis With Confluent Central Necrosis. The next stage of abscess formation is also called "late cerebritis" and begins 2-3 days after the initial infection (12-31). This stage typically lasts between a week and 10 days.

Patchy necrotic foci within the suppurative mass form, enlarge, and then coalesce into a confluent necrotic mass. By days 5-7, a necrotic core is surrounded by a poorly organized, irregular rim of granulation tissue consisting of inflammatory cells, macrophages, and fibroblasts. The surrounding brain is edematous and contains swollen reactive astrocytes.

(12-31) Autopsied late cerebritis demonstrates coalescing lesion with some central necrosis ﬊, the beginnings of an ill-defined abscess rim ﬈.

(12-30) Autopsy specimen shows foci of early cerebritis, unencapsulated edema, and petechial hemorrhages ﬈. (Courtesy R. Hewlett, MD.)

(12-29) Graphic of early cerebritis shows focal unencapsulated mass of petechial hemorrhage, inflammatory cells, and edema ﬊.

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BRAIN ABSCESS: PATHOLOGY AND EVOLUTION

Stages Focal suppurative encephalitis (days 1-2)•

Edematous, suppurative mass○ No visible necrosis or capsule○

Focal suppurative encephalitis with confluent central necrosis (days 2-7)

•

Necrotic foci form, begin to coalesce○ Poorly organized irregular rim○

Early encapsulation (days 5-14)• Coalescent core○ Well-defined wall of fibroblasts, collagen○

Late encapsulation (> 2 weeks)• Wall thickens, then shrinks○ Inflammation; edema decreases/disappears○

Early Encapsulation. The "early capsule" stage starts around 1 week. Proliferating fibroblasts deposit reticulin around the outer rim of the abscess cavity. The abscess wall is now composed of an inner rim of granulation tissue at the edge of the necrotic center (12-34) and an outer rim of multiple concentric layers of fibroblasts and collagen (12-35). The necrotic core liquefies completely by 7-10 days, and newly formed capillaries around the mass become prominent.

Late Capsulation. The "late capsule" stage begins several weeks following infection and may last for several months.

With treatment, the central cavity gradually involutes and shrinks. Collagen deposition further thickens the wall, and the surrounding vasogenic edema disappears. The wall eventually contains densely packed reticulin and is lined by sparse macrophages. Eventually only a small gliotic nodule of collagen and fibroblasts remains.

(12-33A) (L) CECT shows faint, ill-defined left temporal lobe ring enhancing lesion with peripheral edema ﬇. (R) DWI MR shows strong diffusion restriction st in the center of the mass. (12-33B) (L) The mass exhibits a hyperintense center st, hypointense periphery ﬇ on T2WI. (R) Irregular, poorly defined enhancing rim st is seen on T1 C+ FS. This is the late cerebritis stage of abscess formation.

(12-32A) (L) NECT shows ill-defined hypoattenuation st and mass effect within the right temporal lobe. Arterial infarction was suspected. (R) T2WI shows a hyperintense right temporal lobe mass ﬇. (12-32B) (L) DWI shows restricted diffusion at the periphery st, center ﬇ of the lesion. (R) Coronal T1 C+ shows a faint rim of peripheral enhancement st. Early cerebritis stage of abscess formation.

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Clinical Issues

Demographics. Brain abscesses are rare. Only 2,500 cases are reported annually in the USA. Brain abscesses occur at all ages but are most common in patients between the third and fourth decades. Almost 25% occur in children under the age of 15 years. The M:F ratio is 2:1 in adults and 3:1 in children.

Presentation and Prognosis. Headache, seizure, and focal neurologic deficits are the typical presenting symptoms. Fever is common but not universal. CSF cultures may be normal early in the infection.

Brain abscesses are potentially fatal but treatable lesions. Rapid diagnosis, stereotactic surgery, and appropriate medical treatment have reduced mortality to 2-4%.

Imaging

General Features. Imaging findings evolve with time and are related to the stage of abscess development. MR is more sensitive than CT and is the procedure of choice.

Early Cerebritis. Very early cerebritis may be invisible on CT. A poorly marginated cortical/subcortical hypodense mass is the most common finding (12-32A). Early cerebritis often shows little or no enhancement on CECT.

Early cerebritis is hypo- to isointense on T1WI and hyperintense on T2/FLAIR. T2* GRE may show punctate "blooming" hemorrhagic foci. Patchy enhancement may or may not be present. DWI shows diffusion restriction (12-32B).

Late Cerebritis. A better-delineated central hypodense mass with surrounding edema is seen on NECT. CECT typically shows irregular rim enhancement (12-33A).

Late cerebritis has a hypointense center and an iso- to mildly hyperintense rim on T1WI. The central core of the cerebritis is hyperintense on T2WI, whereas the rim is relatively hypointense. Intense but somewhat irregular rim enhancement is present on T1 C+ images (12-33B).

Late cerebritis restricts strongly on DWI (12-33A). MRS shows cytosolic amino acids (0.9 ppm), lactate (1.3 ppm), and acetate (1.9 ppm) in the necrotic core (12-38). The abscess wall demonstrates low rCBV on pMR.

BRAIN ABSCESS IMAGING: CEREBRITIS STAGES

Early Cerebritis CT•

Ill-defined hypodense mass on NECT○ Usually no enhancement○

MR• T2/FLAIR heterogeneously hyperintense○ T2* ± petechial hemorrhage; DWI + (often mild)○ T1 C+ may show patchy enhancement○

Late Cerebritis CT•

Round/ovoid hypodense mass on NECT○ ± Thin, irregular ring on CECT○

MR• T2/FLAIR hyperintense center, hypointense irregular rim

○

T2* GRE hypointense rim; DWI ++○ Moderate/strong but irregular enhancing rim○

Early Capsule. Abscesses are now well-delineated round or ovoid masses with liquefied, hyperintense cores on T2/FLAIR. The rims of abscesses are usually thin, complete, smooth, and

(12-34) (L) Graphic shows edema ﬉ surrounding early capsule abscess. Well-defined double-layered wall ﬊ surrounds a central core of necrosis, inflammatory debris ﬈. (R) Micrograph shows double-layered abscess wall ﬇. (Ellison, Neuropath, 3e.)

(12-35) Abscess at early capsule stage is shown. Necrotic core st is surrounded by a double-layered, well-developed capsule ﬈. (Courtesy R. Hewlett, MD.)

Infection, Inflammation, and Demyelinating Diseases 356

(12-37C) DWI (L) and ADC map (R) in the same case show that necrotic contents of the abscess cavity restrict strongly, whereas the wall of the capsule itself does not. (12-38) MRS in another late cerebritis/early capsule abscess with TR 2,000 TE 35 shows amino acids (valine, leucine, isoleucine) at 0.9 ppm st, acetate at 1.9 ppm ﬇, lactate at 1.3 ppm st, and succinate at 2.4 ppm ﬈.

(12-37A) T2WI in early capsule stage of abscess development shows classic "double rim" sign with hypointense outer rim st and mildly hyperintense inner rim ﬊ surrounding very hyperintense necrotic core. Note peripheral edema st and mass effect (uncal herniation) ﬉. (12- 37B) T1 C+ FS in the same case shows intense enhancement st of the well-developed abscess capsule.

(12-36A) (L and R) NECT scans show large, well- defined lesion with hyperdense rim ﬇ and a hypodense center st. (12- 36B) Axial (L), coronal (R) CECT scans show complete, well-delineated rim enhancement ﬇. The abscess has progressed from late cerebritis to the early capsule stage. Note wall defect st with adjacent area of new cerebritis st.

Congenital, Acquired Pyogenic, and Acquired Viral Infections 357

hypointense on T2WI. A "double rim" sign demonstrating two concentric rims, the outer hypointense and the inner hyperintense relative to cavity contents, is seen in 75% of cases (12-37A).

The necrotic core of encapsulated abscesses restricts strongly on DWI. T1 C+ sequences show a strongly enhancing rim (12- 24) (12-37B) that is thinnest on its deepest (ventricular) side and "blooms" on T2*.

Late Capsule. With treatment, the abscess cavity gradually collapses while the capsule thickens even as the overall mass diminishes in size. The shrinking abscess often assumes a "crenulated" appearance, much like a deflated balloon (12- 39A).

Contrast enhancement in the resolving abscess may persist for months, long after clinical symptoms have resolved (12- 39).

BRAIN ABSCESS IMAGING: CAPSULE STAGES

Early Capsule Well-defined mass + strongly-enhancing rim• Core: T2/FLAIR hyperintense, DWI +++• Wall: "Double rim" sign (hyperintense inner, hypointense outer)

•

Late Capsule Wall thickens, cavity and edema reduce• Enhancing focus may persist for months•

Differential Diagnosis

The differential diagnosis of abscess varies with its stage of development. Early cerebritis is so poorly defined that it can be difficult to characterize and can mimic many lesions, including cerebral ischemia or neoplasm.

(12-39C) The patient was treated with intravenous antibiotics for 6 weeks. Follow-up scan at the end of treatment shows a small residual enhancing nodule st with almost complete resolution of the surrounding edema. (12- 39D) Follow-up T1 C+ FS scan 1 year later shows that only a small hypointense nonenhancing focus remains st.

(12-39A) Axial T1 C+ FS scan in a 65y man with a history of dental abscess, headaches for 2-3 weeks shows a left posterior frontal thick-walled ring- enhancing mass st. Findings are consistent with late capsule stage of abscess development. (12- 39B) Coronal T1 C+ FS scan in the same case shows the abscess wall st is thinnest on its deepest side ﬇, next to the lateral ventricle. Note edema and mass effect on the ventricle.

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(12-41B) DWI in the same patient shows that the abscess viscous contents st and ventricular purulent debris ﬇ restrict.

(12-41A) Axial T1 C+ FS scan shows meningitis and an abscess st with intraventricular rupture (ventriculitis) ﬇.

(12-40) Autopsy of IVRBA shows ependymal infection ﬈, choroid plexitis ﬉, pus adhering to ventricular walls ﬊. (Courtesy R. Hewlett, MD.)

Once a ring develops around the necrotic center, the differential diagnosis is basically that of a generic ring-enhancing mass. Although there are many ring-enhancing lesions in the CNS, the most common differential diagnosis is infection vs. neoplasm (glioblastoma or metastasis).

Tumors have increased rCBV in their "rind," usually do not restrict (or if they do, not as strongly as an abscess), and do not demonstrate cytosolic amino acids on MRS.

Less common entities that can appear as a ring-enhancing mass include demyelinating disease, in which the ring is usually incomplete and "open" toward the cortex. Resolving hematomas can exhibit a vascular, ring- enhancing pattern.

BRAIN ABSCESS: DIFFERENTIAL DIAGNOSIS

Early Cerebritis Encephalitis (may be indistinguishable)• Stroke•

Vascular distribution○ Usually involves both cortex, WM○

Neoplasm (e.g., diffusely infiltrating low-grade astrocytoma)• Usually doesn't enhance or restrict○

Late Cerebritis/Early Capsule Neoplasm•

Primary (glioblastoma)○ Metastasis○

Demyelinating disease• Incomplete ("horseshoe") enhancement○

Ventriculitis Primary intraventricular abscess is rare. A collection of purulent material in the ventricle is more likely due to intraventricular rupture of a brain abscess (IVRBA), a catastrophic complication. Ventriculitis also occurs as a complication of meningitis and neurosurgical procedures such as external ventricular drainage. Recognition and prompt intervention are necessary to treat this highly lethal condition.

Terminology

Ventriculitis is also called ependymitis, pyocephalus, and (less commonly) ventricular empyema.

Etiology

Infection of the ventricular ependyma most often occurs when a pyogenic abscess ruptures through its thin, medial capsule into the adjacent ventricle. Risk of IVRBA increases if an abscess is deep-seated, multiloculated, and/or close to the ventricular wall. A reduction of 1 mm between the ventricle and brain abscess increases the rupture rate by 10%.

Ventriculitis can also occur as a complication of meningitis, usually via spread of infection through the choroid plexus (choroid plexitis) into the CSF. In the pediatric population, ventriculitis is common in newborns with E. coli and group B streptococcus meningitis, and infants and young children with typable and non-typable Haemophilus species.

Nosocomial meningitis/ventriculitis is a rare but potentially devastating complication following neurosurgical interventions. Patients who require external ventricular drainage (EVD) are at special risk for development of device-related meningitis and ventriculitis. The infection rate of EVDs is high,

Congenital, Acquired Pyogenic, and Acquired Viral Infections 359

even with antibiotic-impregnated devices. Reported incidences range from 5-20%.

The most common pathogens causing ventriculitis are Staphylococcus, Streptococcus, and Enterobacter. Infections are often multidrug resistant and difficult to treat.

Pathology

Autopsy examination shows that the ependyma, subependymal region, and choroid plexus are congested and covered with pus (12-40). Hemorrhagic ependymitis may be present. Hydrocephalus with pus obstructing the aqueduct is common.

Clinical Issues

Epidemiology and Demographics. The incidence of IVRBA varies. Recent studies estimate that intraventricular rupture occurs in up to 35% of brain abscesses. Male patients are more commonly affected than female patients.

Presentation. Clinical features of IVRBA can be indistinguishable from those of brain abscesses without intraventricular rupture. In general, headaches are more severe and are accompanied by signs of meningeal irritation. Rapid deterioration of clinical status is typical.

Natural History and Treatment Options. Image-guided stereotactic aspiration is the simplest, safest method to obtain pus for culture and to decompress the abscess cavity. The combination of third-generation cephalosporins and metronidazole is the mainstay of initial empirical antimicrobial treatment. The choice of definitive antibiotics depends on culture results.

Despite aggressive medical and surgical management, many patients do poorly and succumb to the disease. Overall mortality is 25-85%. Only 40% of patients survive with good functional outcome.

Imaging

Ventriculomegaly with a debris level in the dependent part of the occipital horns together with periventricular hypodensity is the classic finding on NECT scans. The ventricular walls may enhance on CECT.

MR should be the first-line imaging modality in cases of suspected ventriculitis. Irregular ventricular debris that appears hyperintense to CSF on T1WI and hypointense on T2WI with layering in the dependent occipital horns is typical.

The most sensitive sequences are FLAIR and DWI. A "halo" of periventricular hyperintensity is usually present on both T2WI and FLAIR scans. DWI shows striking diffusion restriction of the layered debris (12-41B).

Ependymal enhancement is seen in only 60% of cases and varies from minimal to moderate (12-41A). When present, ependymal enhancement tends to be relatively smooth, thin and linear rather than thick and nodular.

Differential Diagnosis

The differential diagnosis of IVRBA is limited. Sudden deterioration of a patient with a known cerebral abscess together with intraventricular debris and pus on MR is almost certainly IVRBA.

Ependymal enhancement without intraventricular debris and pus is a nonspecific finding on imaging studies. Mild, thin, linear enhancement of the periventricular and ependymal veins is normal, especially around the frontal horns, septi pellucidi, and atria of the lateral ventricles.

Primary malignant CNS neoplasms such as glioblastoma multiforme and primary CNS lymphoma can spread along the ventricular ependyma, giving it a thick or nodular "lumpy- bumpy" appearance. Germinoma and metastasis from an extracranial primary neoplasm can both cause irregular ependymal thickening and enhancement.

Empyemas Extraaxial infections of the CNS are rare but potentially life- threatening conditions. Early diagnosis and prompt treatment are essential to maximize neurologic recovery.

Terminology

Empyemas are pus collections that can occur in either the subdural or epidural space.

Etiology

The pathophysiologic basis of empyemas varies with patient age. Empyemas in infants and young children are most commonly secondary to bacterial meningitis.

In older children and adults, over two-thirds of empyemas occur as extension of infection from paranasal sinus disease. Infection can erode directly through the thin posterior wall of the frontal sinus, which is half the thickness of the anterior wall (12-42). Infection may also spread indirectly in retrograde fashion through valveless bridging emissary veins.

Approximately 20% of empyemas in older children and adults are secondary to otomastoiditis. Rare causes of empyemas include penetrating head trauma, neurosurgical procedures, or hematogenous spread of pathogens from a distant extracranial site.

The most common organisms are staphylococci and streptococci.

Pathology

Location. Subdural empyemas (SDEs) are much more common than epidural empyemas (EDEs). The most common locations are the frontal and frontoparietal convexities. Peritentorial collections are rare but important locations for SDEs. In unusual cases, SDEs may be complicated by cerebritis or abscess in the adjacent brain.

Size and Number. Empyemas vary in size and extent. They range from small, focal epidural collections (12-42) to

Infection, Inflammation, and Demyelinating Diseases 360

(12-43B) T1 C+ scan shows the frontal sinusitis st, cellulitis st, and enhancing endosteal dura ﬇ displaced by the epidural empyema.

(12-43A) Sagittal T2WI is from a child with frontal sinusitis st causing scalp cellulitis st and epidural empyema ﬇.

(12-42) Purulent frontal sinusitis ﬇ with extension into epidural space causes epidural empyema ﬈ and frontal lobe cerebritis st.

extensive subdural infections that spread over most of the cerebral hemisphere and extend into the interhemispheric fissure.

Multiple lesions including mixed intra- and extradural collections are seen in 15-20% of cases. Loculated and/or multiple unilateral collections are more common than separate bilateral empyemas.

Gross and Microscopic Features. The most common gross appearance of an empyema is an encapsulated, thick, yellowish, purulent collection lying between the dura and the arachnoid. Early empyemas may be unencapsulated collections of cloudy, more fluid-like material.

Microscopic features are those of nonspecific inflammatory infiltrate with varying amounts of granulation tissue.

Clinical Issues

Epidemiology. SDEs and EDEs are rare in the developed world due to the early and judicious use of antibiotics. The incidence of extraaxial CNS infections is higher in patients with limited access to medical care.

Demographics. Extraaxial CNS infections can occur at any age but tend to occur at a significantly earlier age than brain abscesses. Male patients are more often affected than female patients. An adolescent boy with significant headache and fever should elicit a high index of suspicion for sinusitis complications and prompt immediate imaging evaluation.

Presentation. The most common clinical presentation is headache, followed by fever and altered sensorium. Preceding symptoms of sinusitis or otomastoiditis are common. Meningismus, seizures, and focal motor signs are also frequent.

"Pott puffy tumor"—a fluctuant ("doughy"), tender erythematous swelling of the frontal scalp—is considered a specific sign for frontal bone osteomyelitis with a subperiosteal abscess. Most occur in the setting of untreated frontal sinusitis. If the posterior table of the sinus is breached, an EDE may form. "Pott puffy tumor" is seen in up to one-third of patients with frontal EDE. Orbital cellulitis is a less common but significant sign of empyema.

Natural History and Treatment Options. The interval between initial infection (usually sinusitis) and onset of the empyema is typically 1-3 weeks. EDEs have a better prognosis than SDEs. Once established, untreated empyemas can spread quite rapidly, extending from the extraaxial spaces into the subjacent brain. Besides cerebritis and abscess formation, the other major complication of empyema is cortical vein thrombosis with venous ischemia.

Surgical drainage and rapid initiation of empiric intravenous antibiotic therapy (initially vancomycin and a third-generation cephalosporin) has been shown to reduce mortality. Mortality of treated empyemas is still significant, ranging from 10-15%.

Imaging

Imaging is essential to the early diagnosis of empyema. NECT scans may be normal or show a hypodense extraaxial collection (12-45A) that demonstrates peripheral enhancement on CECT (12-44A). Bone CT should be evaluated for signs of sinusitis and otomastoiditis (12-47A).

MR is the procedure of choice for evaluating potential empyemas. T1 scans show an extraaxial collection that is mildly hyperintense relative to CSF. SDEs are typically crescentic and lie over the cerebral hemisphere. The extracerebral space is widened, and the underlying sulci are compressed by

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the collection. SDEs often extend into the interhemispheric fissure but do not cross the midline.

EDEs are biconvex and usually more focal than SDEs. The inwardly displaced dura can sometimes be identified as a thin hypointense line between the epidural collection and the underlying brain (12-43). In contrast to SDEs, frontal EDEs may cross the midline, confirming their epidural location (12- 47B).

Empyemas are iso- to hyperintense compared with CSF on T2WI and are hyperintense on FLAIR (12-45B). Hyperintensity in the underlying brain parenchyma may be caused by cerebritis or ischemia (either venous or arterial).

SDEs typically demonstrate striking diffusion restriction on DWI (12-45D). EDEs are variable but usually have at least some restricting component (12- 44C).

Empyemas show variable enhancement depending on the amount of granulomatous tissue and inflammation present (12-24). The encapsulating membranes, especially on the outer margin, enhance moderately strongly (12-43B) (12-44B) (12-45C).

Differential Diagnosis

The major differential diagnosis of extraaxial empyema is a nonpurulent extraaxial collection such as subdural effusion, subdural hygroma, and chronic subdural hematoma.

A subdural effusion is usually postmeningitic, is typically bilateral, and does not restrict on DWI. Because of its increased proteinaceous contents, effusions are typically hyperintense to CSF on FLAIR.

A subdural hygroma is a sterile, nonenhancing, nonrestricting CSF collection that occurs with a tear in the arachnoid, allowing escape of CSF into the subdural space. Hygromas are usually posttraumatic or postsurgical and behave exactly like CSF on imaging studies.

A chronic subdural hematoma (cSDH) is hypodense on NECT. Signal intensity varies with chronicity. Early cSDHs are hyperintense compared with CSF on both T1WI and T2/FLAIR. They may show some residual blood that "blooms" on T2* (GRE, SWI). The encapsulating membranes enhance and may show diffusion restriction. In contrast to SDEs, the cSDH contents themselves typically do not restrict on DWI. Very longstanding cSDHs look similar to CSF and may show little or no residual evidence of prior hemorrhage.

EMPYEMAS

Pathology Subdural empyemas (SDEs) > > epidural empyemas (EDEs)• EDE focal (usually next to sinus, mastoid)• SDE spreads diffusely along hemispheres, tentorium/falx•

Imaging Bone CT: look for sinus, ear infection• EDE is focal, biconvex, can cross midline• SDE is crescentic, covers hemisphere, may extend into interhemispheric fissure

•

SDEs restrict strongly on DWI; EDEs variable•

Differential Diagnosis Chronic SDH, subdural hygroma, effusion• (12-44C) DWI shows a small hyperintense

crescent of epidural pus st that lies immediately outside the thick displaced dura ﬇.

(12-44B) Axial T1 C+ FS in the same patient shows displaced thickened endosteal dura st. Note reactive dural thickening ﬇.

(12-44A) CECT shows frontal sinusitis (small fluid level) ﬊ and biconvex lentiform epidural fluid collection with enhancing rim st.

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(12-46A) Axial T1 C+ scan in a child with pyogenic meningitis shows pia- subarachnoid space enhancement that follows the surfaces of the brain, extending into the sulci st. A small bifrontal fluid subdural collection (empyema) ﬇ is present. (12-46B) Coronal T1 C+ image shows that the meningitis extends over the convexal surfaces of the brain st. The subdural collections are encased by a thickened dura ﬇. Subdural empyemas restrict on DWI; effusions do not.

(12-45C) Axial T1 C+ SPGR for stereotactic aspiration shows outer endosteal dural enhancement ﬊. Leptomeningeal enhancement st is consistent with meningitis. (12-45D) Axial DWI shows that the subdural empyema st restricts strongly and uniformly. Interhemispheric extension ﬇ does not cross midline. Subdural empyema was drained at craniotomy, and S. pneumoniae was cultured.

(12-45A) NECT in a 51y man with acute sinusitis who developed severe headache and altered mental status shows a hypoattenuating subdural collection st that compresses underlying brain. Fluid is slightly hyperattenuating compared with sulcal CSF. (12-45B) FLAIR in the same patient shows that the fluid collection st does not suppress. The underlying sulci are hyperintense, suggesting meningitis. Cortical edema is also present ﬇.

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(12-48C) Axial DWI in the same case shows that the interhemispheric fluid collection restricts (confirmed on ADC map) and splays apart thickened dura ﬇. (12- 48D) T1 C+ MR in the same patient shows that the thickened, intensely enhancing dura st surrounds the nonenhancing epidural abscess.

(12-48A) Sagittal bone CT in a patient with frontal sinusitis st and chronic headaches shows diffuse thickening and sclerosis ﬇ of the frontal and anterior parietal bones. Findings suggest chronic osteomyelitis. (12-48B) Sagittal T2WI in the same patient shows a huge epidural fluid collection ﬇ connecting directly st to the infected frontal sinus st. DWI helps characterize pyogenic nature of sinus fluid.

(12-47A) A 66y man developed headaches and frontal scalp swelling several weeks after resection of an anterior fossa meningioma. Bone CT shows soft tissue scalp mass st and bone destruction ﬇ suspicious for osteomyelitis. (12- 47B) CECT shows a subperiosteal abscess st and large bifrontal epidural empyema ﬈. Note thin film of intradural fluid st between layers of periosteal and meningeal dura. It's frontal sinusitis with Pott puffy tumor.

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(12-50B) Axial section in the same case shows petechial hemorrhages in insular cortex of both temporal lobes ﬈. (Courtesy R. Hewlett, MD.)

(12-50A) Autopsy of HSE shows hemorrhagic lesions in the basal medial temporal lobes and subfrontal regions st. (Courtesy R. Hewlett, MD.)

(12-49) Graphic shows herpes encephalitis with bilateral, asymmetric involvement of temporal lobes ﬈, cingulate gyri ﬊, and insula ﬉.

Acquired Viral Infections A number of both familiar and and less well-known but emerging viruses can cause CNS infections. In this section, we focus on neurotropic herpes virus infections, which can promote acute fulminant CNS disease and become latent with the potential of reactivation that may last for decades.

Eight members of the herpes virus family are known to cause disease in humans. These are herpes simplex virus 1 (HSV-1) and HSV-2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes virus (HHV)-6, HHV-7, and HHV-8. Each has its own disease spectrum, clinical setting, and imaging findings.

HSV-1 typically involves the skin and facial mucosa, whereas HSV-2 is primarily associated with genital infection. HHV-6 and HHV-7 are increasingly recognized as major causes of morbidity and mortality in transplant recipients, whereas EBV and HHV-8 (also known as Kaposi sarcoma- associated herpesvirus) have proven oncogenic potential.

Congenital HSV-2 and CMV were both considered earlier, as their manifestations in newborn infants differ from those of acquired herpesvirus infections. HSV-1 and HHV-6 are discussed in this section. VZV and EBV are discussed later in the chapter under Miscellaneous Acute Viral Encephalitides.

In children, more than 100 viral species have either directly or indirectly been associated with CNS infection. In addition to viruses mentioned above, many other viruses have been implicated as important agents associated with pediatric encephalitis, including Influenzae A and B, adenovirus, respiratory syncytial virus (RSV), H1N1, parainfluenzae, and human metapneumovirus (HMPV)—a group collectively called the respiratory viruses. Most viruses reach the pediatric CNS hematogenously and enter the CNS via the choroid plexus or directly through the vascular endothelium.

Herpes Simplex Encephalitis

Terminology

CNS involvement in HSV infection is called congenital or neonatal HSV when it involves neonates but is designated herpes simplex encephalitis (HSE) in all individuals beyond the first postnatal month. HSE is also sometimes called HSV encephalitis.

Etiology

After the neonatal period, over 95% of HSE is caused by reactivation of HSV- 1, an obligate intracellular pathogen. The virus initially gains entry into cells in the nasopharyngeal mucosa, invades sensory lingual branches of the trigeminal nerve, then passes in retrograde fashion into the trigeminal ganglion. It establishes a lifelong latent infection within sensory neurons of the trigeminal ganglion, where it can remain dormant indefinitely.

Genetic errors in Toll-like receptor 3 (TLR3) have been linked to HSE infection susceptibility. "Relapsing HSE" is often an NMDA receptor encephalitis triggered by antecedent HSV infection.

Pathology

Location. HSE has a striking affinity for the limbic system (12-49). The anterior and medial temporal lobes, insular cortex, subfrontal area, and cingulate gyri are most frequently affected (12-50A). Bilateral but asymmetric disease is typical (12-50B). Extratemporal, extralimbic

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involvement occurs but is more common in children compared with adults. When it occurs, extralimbic HSE most often involves the parietal cortex. Brainstem-predominant infection is uncommon. The basal ganglia are usually spared.

Gross Pathology. HSE is a fulminant, hemorrhagic, necrotizing encephalitis. Massive tissue necrosis accompanied by numerous petechial hemorrhages and severe edema is typical. Inflammation and tissue destruction are predominantly cortical but may extend into the subcortical white matter. Advanced cases demonstrate gross temporal lobe rarefaction and cavitation.

Microscopic Features. Perivascular lymphocytic cuffing with diffuse neutrophil infiltration into the necrotic parenchyma is typical. Large "owl's- eye" viral inclusions in neurons, astrocytes, and oligodendrocytes are seen in the acute and subacute phases. Tissue destruction with neuronophagia and apoptosis is striking.

Clinical Issues

Epidemiology. HSV-1 is the most common worldwide cause of sporadic (i.e., nonepidemic) viral encephalitis. Overall prevalence is 1-3:1,000,000.

Demographics. HSE may occur at any age. It follows a bimodal age distribution, with one-third of all cases occurring between the ages of 6 months and 3 years and one-half seen in patients older than 50. There is no sex predilection.

Presentation. A viral prodrome followed by fever, headache, seizures, behavioral changes, and altered mental status is typical.

Natural History. HSE is a devastating infection with mortality rates ranging from 50-70%. Rapid clinical deterioration with coma and death is typical. Nearly two-thirds of survivors have significant neurologic deficits despite antiviral therapy.

Treatment Options. Antiviral therapy with intravenous acyclovir should be started immediately if HSE is suspected. Definitive diagnosis requires PCR confirmation. CSF PCR is 96-98% sensitive.

HERPES SIMPLEX ENCEPHALITIS (HSE)

Etiology > 95% caused by HSV-1•

Pathology Necrotizing, hemorrhagic encephalitis• Limbic system•

Anteromedial temporal lobes, insular cortex○ Subfrontal region, cingulate gyri○

Imaging Bilateral > unilateral; asymmetric > symmetric• FLAIR most sensitive• DWI shows restriction•

Imaging

CT Findings. NECT is often normal early in the disease course. Hypodensity with mild mass effect in one or both temporal lobes and the insula may be present (12-51A). CECT is usually negative, although patchy or gyriform enhancement may develop after 24-48 hours (12-51C).

MR Findings. MR is the imaging procedure of choice. T1 scans show gyral swelling with indistinct gray-white interfaces (12-52A). T2 scans

(12-51C) More cephalad CECT shows a hypoattenuating insular mass st with superficial gyriform enhancement ﬇.

(12-51B) CECT in the same case obtained 48 hours later shows a hypoattenuating temporal lobe mass st. Note uncal herniation ﬇.

(12-51A) NECT in 60y woman with altered mental status shows an ill-defined low attenuation temporal lobe mass st, but was called normal.

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demonstrate cortical/subcortical hyperintensity with relative sparing of the underlying white matter. FLAIR is the most sensitive sequence and may be positive before signal changes are apparent on either T1- or T2WI. Bilateral but asymmetric involvement of the temporal lobes and insula is characteristic of HSE but is not always present.

T2* (GRE, SWI) may demonstrate petechial hemorrhages after 24-48 hours (12-53). Gyriform T1 shortening, volume loss, and confluent curvilinear "blooming" foci on T2* are seen in the subacute and chronic phases of HSE.

HSE shows restricted diffusion early in the disease course (12- 52B), sometimes preceding visible FLAIR abnormalities. Enhancement varies from none (early) to intense gyriform enhancement several days later (12-52D).

Differential Diagnosis

The major differential diagnoses for HSE are neoplasm, acute cerebral ischemia, status epilepticus, other encephalitides (especially HHV-6), and paraneoplastic limbic encephalitis. Primary neoplasms such as diffusely infiltrating astrocytoma usually involve white matter or white matter plus cortex.

Acute cerebral ischemia-infarction occurs in a typical vascular distribution, involving both the cortex and white matter. Onset is typically sudden compared with HSE, and a history of fever or a viral prodrome with flu-like illness is lacking. Especially in immunocompromised patients, late acute/subacute HSE itself can have a "pseudo-ischemic" appearance caused by widespread dead or dying neurons.

Status epilepticus is usually unilateral and typically involves just the cortex. Postictal edema is transient but generally more widespread, often involving most or all of the hemispheric cortex.

(12-52C) T1 C+ FS shows gyriform enhancement in the left insula and low- attenuation edema. (12- 52D) Coronal T1 C+ shows gyriform cortical enhancement ﬇ but also pial (leptomeningeal) enhancement st. This is PCR-proven HSE meningoencephalitis. Note the ipsilateral ventricular compression and displacement.

(12-52A) MR in the same patient as on the prior page shows left temporal lobe hypointensity ﬉ on T1WI (L), hyperintensity st on FLAIR (R). (12-52B) DWI in the same case shows restricted diffusion st in the anterior temporal lobe cortex (L) and insular cortex (R).

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(12-53E) FLAIR performed 5 months later shows severe atrophy. Temporal lobe confluent hyperintensities ﬇ with patchy foci of marked hypointensity ﬈ are consistent with encephalomalacia and chronic hemorrhage. (12- 53F) T2* GRE shows marked confluent "blooming" in both anterior temporal lobes ﬈ from the old hemorrhages. Similar findings were present in the insular cortex and cingulate gyri (not shown).

(12-53C) More cephalad DWI in the same patient shows symmetric restricted diffusion in both cingulate gyri st. Because of the strong suspicion for HSE, the patient was placed on antiviral agents. PCR was positive for HSV-1. (12- 53D) Despite treatment, the patient did poorly. Repeat NECT scan 2 weeks later shows confluent hemorrhages in both anteromedial temporal lobes st.

(12-53A) A 68y man presented to the ED with viral prodrome and confusion. Initial NECT scan (not shown) was negative. FLAIR shows hyperintensity in both insular cortices st. (12- 53B) DWI shows marked diffusion restriction in both insular cortices st. Somewhat less striking hyperintensity is seen in both anterior temporal lobes ﬇.

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HHV-6 encephalitis usually involves just the medial temporal lobes, but, if extrahippocampal lesions are present, it may be difficult to distinguish from HSE solely on the basis of imaging findings.

Antibody-mediated CNS disorders such as limbic encephalitis and autoimmune encephalitis often have a more protracted, subacute onset and frequently present with altered mental status of unclear etiology. In some cases, imaging findings may be virtually indistinguishable from those of HSE.

HHV-6 Encephalopathy

Etiology

More than 90% of the general population is seropositive for HHV-6 by 2 years of age. Most primary infections are asymptomatic, after which the virus remains latent.

Clinical Issues

HHV-6 can become pathogenic in immunocompromised patients, especially those with hematopoietic stem cell or solid organ transplantation. The median interval between transplantation and onset of neurologic symptoms is 3 weeks. Patients typically present with altered mental status, short- term memory loss, and seizures.

Imaging

NECT scans are typically normal. MR shows predominant or exclusive involvement of one or both medial temporal lobes (hippocampus and amygdala) (12-54). Extrahippocampal disease is less common than with HSE. Transient hyperintensity of the mesial temporal lobes on T2WI and FLAIR with restriction on DWI is typical. T2* (GRE, SWI) scans show no evidence of hemorrhage.

(12-54C) DWI shows strong, symmetric diffusion restriction st in the hippocampi, medial temporal lobes, and amygdalae. (12-54D) DWI shows restricted diffusion in the hippocampal tails st and left insular cortex ﬇. There is also mild involvement of the right insular cortex st. This is variant HHV-6 encephalitis with extrahippocampal involvement.

(12-54A) Axial FLAIR in a 43y man with proven HHV-6 encephalitis shows bilaterally symmetrical hyperintensity in the hippocampi st and anteromedial temporal lobes st, including the amygdalae. (12-54B) More cephalad FLAIR shows involvement of the hippocampal tails st and left insular cortex ﬇.

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(12-55) T2WI in a 9y girl with a 2-week history of ear infection, headaches, confusion, and ataxia shows acute cerebellitis. Note edema and mass effect, seen as hyperintensity in both cerebellar hemispheres st. PCR was positive for VZV.

(12-56) VZV vasculitis with basal ganglia infarct in a 4y girl is shown. NECT and FLAIR scans show putaminal infarct st that restricts, as shown on DWI ﬇ and ADC st.

Differential Diagnosis

The major differential diagnosis is HSE. The disease course of HSE is more fulminant. Extratemporal involvement and hemorrhagic necrosis are common in HSE but rare in HHV-6 encephalopathy. In contrast to HSE, in HHV-6, MR abnormalities tend to resolve with time. Postictal hippocampal hyperemia is transient, and extrahippocampal involvement is absent.

HHV-6 ENCEPHALITIS

Clinical Issues Patients often immunocompromised•

Hematopoietic stem cell, solid organ transplants○

Imaging Findings Bilateral medial temporal lobes•

Symmetric > asymmetric involvement○ Extratemporal lesions less common than in HSE○

T2/FLAIR hyperintense• Restricts on DWI•

Differential Diagnosis HSE, limbic encephalitis• Postictal hyperemia•

Miscellaneous Acute Viral Encephalitides Viral encephalitis is a medical emergency. Prognosis depends on both the specific pathogen and host immunologic status. Timely, accurate diagnosis and prompt therapy can improve survival and reduce the likelihood of brain injury.

Many viruses can cause encephalitis. Over 100 different viruses in more than a dozen families have been implicated in CNS infection. HSV-1, EBV, mumps, measles, and enteroviruses are responsible for most cases of encephalitis in immunocompetent patients.

Viral infection of the CNS is almost always part of generalized systemic disease. Most viruses infect the brain via hematogeneous spread. Others—such as some of the herpesviruses and rabies virus—are neurotropic and spread directly from infected mucosa or conjunctiva along nerve roots into the CNS.

CSF or serum analysis with pathogen identification by PCR amplification establishes the definitive diagnosis. Nevertheless, imaging is essential to early diagnosis and treatment.

The most common nonepidemic viral encephalitis, herpes encephalitis, was discussed earlier. In this section, we consider additional examples of viral CNS infections. We begin with two other members of the herpesvirus family—VCV and EBV. We then turn our attention to selected sporadic and epidemic encephalitides.

Varicella-Zoster Encephalitis

The incidence of VZV infection has decreased significantly since the introduction of a live attenuated VZV vaccine in 1995. Yet despite widespread vaccination rates, VZV continues to cause CNS disease. VZV, which causes chickenpox (varicella) and shingles (zoster), also causes Bell palsy, Ramsay- Hunt syndrome, meningitis, encephalitis, myelitis, Reye syndrome, and postherpetic neuralgia.

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(12-57) FLAIR image in a 13y girl with fever and headache shows bilateral hyperintensities in the basal ganglia st. PCR was positive for EBV. EBV may affect the optic nerves and chiasm as well.

(12-58) FLAIR image of EBV encephalitis in a 29y man with headache, fever, diplopia, and somnolence shows sulcal hyperintensities st, focal lesion in CC splenium st, medulla ﬇. WM lesions don't enhance; splenium lesion restricts on DWI ﬉.

VZV may cause a vasculopathy of both intra- and extracerebral arteries. Ischemic or hemorrhagic strokes, aneurysms, subarachnoid and parenchymal hemorrhages, arterial ectasias, and dissections have all been described.

VZV encephalitis has a wide age range with a median age at diagnosis of 46 years. Between 25-30% of patients are under 18 years of age.

Symptoms generally begin 10 days after chickenpox rash or varicella vaccination. Note, however, that many patients with CNS VZV disease present without the characteristic accompanying zoster rash.

Meningitis is the most frequent overall manifestation (50% of cases) and the most common clinical presentation in immunocompetent patients (90%). Encephalitis is the second most common CNS presentation (42%) but the most common manifestation in immunodeficient patients (67%). The most common presentation in children is acute cerebellar ataxia. Acute disseminated encephalomyelitis (ADEM) is rare (8%).

Cerebellitis with diffuse cerebellar swelling and hyperintensity on T2/FLAIR scan is common (12-55). Children may develop multifocal leukoencephalopathy with patchy foci of T2/FLAIR hyperintensity. VZV vasculopathy with stroke causes multifocal cortical, basal ganglia, and deep white matter hyperintensities (12-56). Enhancement on T1 C+ FS scans is variable in VZV encephalitis, and, when it occurs, it is typically patchy and mild. Restriction on DWI is common.

Epstein-Barr Encephalitis

EBV causes infectious mononucleosis. Uncontrolled proliferation of EBV-infected B cells results in posttransplant lymphoproliferative disease (PTLD). EBV is found in more than

90% of PTLD cases occurring within the first posttransplant year.

Mononucleosis is usually a benign, self-limiting disease. Neurologic complications occur in less than 7% of cases, but occasionally CNS disease can be the sole manifestation of EBV infection. Seizures, polyradiculomyelitis, transverse myelitis, encephalitis, cerebellitis, meningitis, and cranial nerve palsies have all been described as complications of EBV.

EBV has a predilection for deep gray nuclei. Bilateral diffuse T2/FLAIR hyperintensities in the basal ganglia and thalami are common (12-57). Patchy white matter hyperintensities are seen in some cases. EBV can also cause a transient, reversible lesion of the corpus callosum splenium that demonstrates restriction on DWI (12-58).

The differential diagnosis of EBV includes ADEM and other viral infections, especially West Nile virus.

West Nile Virus Encephalitis

West Nile virus (WNV) is a mosquito-borne Flavivirus that causes periodic epidemics of febrile illness and sporadic encephalitis in Africa, the Mediterranean basin, Europe, and southwest Asia. The first outbreak in the Western hemisphere occurred in New York in 1999. Since then, WNV has spread across North America and into parts of Central and South America. WNV is now the most common cause of epidemic meningoencephalitis in North America.

WNV cycles between mosquito vectors and bird hosts; humans are incidental hosts. Transmission increases in warmer months; in the Northern hemispheres, peak activity is from July through October. Nearly 80% of human WNV infections are clinically silent. Mild, self-limited fever is seen in 20%. Less

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(12-59) Typical findings of West Nile virus (WNV) encephalitis include bilateral but asymmetric nonenhancing lesions in the basal ganglia and midbrain st. DWI may demonstrate restriction ﬇. WNV is also tropic for spinal cord GM.

(12-60) Sagittal T1 (L) and T2 (R) scans show findings of rabies encephalomyelitis. Note involvement of the medulla st and cervicothoracic spinal cord ﬇. (Courtesy R. Ramakantan, MD.)

than 1% of patients develop neuro-invasive disease. Immunosuppressed patients and the elderly are at higher risk.

WNV CNS infection can result in meningitis, encephalitis, and acute flaccid paralysis/poliomyelitis. The definitive diagnosis is made by PCR.

Bilateral hyperintensities on T2/FLAIR in the basal ganglia, thalami, and brainstem are typical (12-59). WNV may cause a transient corpus callosum splenium lesion. Lesions restrict on DWI but rarely enhance.

Rabies Encephalitis

Rabies encephalitis is caused by a neurotropic RNA virus of the Rhabdoviridae family and is a significant public health problem in developing countries.

Nearly 55,000 deaths due to rabies encephalitis occur annually, 99% of them in Asia and Africa. The dog is the major vector and viral reservoir, although other mammals (e.g., bats, wolves, raccoons, skunks, and mongooses) may act as major hosts. The virus is abundant in the saliva of the infected animal and is deposited in bite wounds.

The virus replicates in muscle tissues at the wound, then infects motor neurons, and accesses the CNS by retrograde axoplasmic flow.

Human rabies encephalitis is a rapidly fulminant disease that is invariably fatal once clinical symptoms become evident. The history and clinical presentation are highly suggestive, but the definitive diagnosis requires laboratory confirmation of rabies antigen or rabies antibodies or isolation of the virus from biologic samples.

Rabies virus has a predilection for the brainstem, thalami, and hippocampi. MR shows poorly delineated hyperintensities in the dorsal medulla and upper spinal cord (12-60), pontine tegmentum, periaqueductal gray matter, midbrain, medial thalami/hypothalami, and hippocampi. Hemorrhage and enhancement are generally absent, helping differentiate rabies from Japanese encephalitis and other viral encephalitides.

Influenza-Associated Encephalopathy

Influenza-associated encephalitis or encephalopathy (IAE) is characterized by high fever, convulsions, severe brain edema, and high mortality. It usually affects children younger than 5 years. Onset of neurologic deterioration occurs a few days to a week after the first signs of influenza infection. Many viruses have been reported as causing IAE, most recently H3N2 and influenza A (H1N1, also known as swine flu). The morbidity and mortality are particularly impressive among patients with trisomy 21 (12-68).

Imaging studies are abnormal in the majority of cases. Symmetric bilateral thalamic lesions (12-61), hemispheric edema, and reversible lesions in the corpus callosum splenium and WM are common. Findings resembling posterior reversible encephalopathy syndrome (PRES) have also been reported.

Acute Necrotizing Encephalopathy

Acute necrotizing encephalopathy (ANE) is a more severe, life- threatening form of IAE characterized by high fever, seizures, and rapid clinical deterioration within 2 or 3 days after symptom onset. The disease is often fatal. Most cases occur in children or young adults.

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(12-63) ANE in obtunded 4y girl w/ influenza A shows bithalamic T2WI hyperintense lesions st, hemorrhage on T2* ﬈, diffusion restriction ﬇.

(12-62) Autopsied case of ANE shows symmetric hemorrhagic necrosis in thalami ﬊, midbrain ﬈, and pons st. (Courtesy R. Hewlett, MD.)

(12-61) T2WI in a 2y girl with influenza- associated encephalopathy (IAE) shows bithalamic fluffy hyperintensities st.

ANE causes symmetric, often hemorrhagic, brain necrosis. The thalami, midbrain tegmentum, and pons are most severely affected (12-62). Periventricular white matter, cerebellar, and spinal cord involvement has been reported in some cases.

CT may be normal early in the disease course. Bilaterally symmetric hyperintensity in the thalami is seen on T2/FLAIR (12-63). The midbrain, pons, cerebellum, and deep cerebral white matter are frequently involved. T2* (GRE, SWI) shows "blooming" foci of petechial hemorrhage, most often in the thalami. Restriction on DWI has been described in some cases.

Miscellaneous Infectious Viral Encephalitides

A host of other viral encephalitides have been identified. Whereas some (such as rotavirus encephalitis) are widespread, others (e.g., Japanese encephalitis, LaCrosse encephalitis, Nipah virus encephalitis) currently have a more restricted geographic distribution.

Encephalitis caused by a member of the pediatric respiratory virus group (Table 12-2) often demonstrates basal ganglia and thalamic T2 prolongation and variable diffusivity changes on MR.

Arthropod-borne (ticks and mosquitoes) viruses represent an underappreciated cause of encephalitis in older pediatric patients and adults. Most of these viruses are from the Flaviviridae family. MR demonstrates T2 hyperintense lesions of the thalami, substantial nigra, basal ganglia, brainstem, cerebellum, and cerebral cortical and hemispheric WM.

Chronic Encephalitides Some viruses cause acute, fulminating CNS infection. Others have a more insidious onset, producing a "slow" chronic infection. Some—such as the measles virus—can cause both. In this section, we briefly consider two chronic encephalitides: the measles reactivation syndrome called subacute sclerosing panencephalitis and Rasmussen encephalitis.

Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a rare progressive encephalitis that occurs years after measles virus infection. A few cases in immunocompromised patients occur following immunization. The measles virus infects neurons and remains latent for years. Why and how reactivation occurs are not fully understood.

Measles virus disproportionately affects children in regions with low measles vaccination rates. Almost all patients are children or adolescents; adult-onset SSPE occurs but is rare. There is a 2:1 male predominance. SSPE is rare in developed countries where vaccination rates are high.

On average, clinical manifestations appear 6 years after measles virus infection. Symptom onset is often insidious, with behavioral and cognitive deterioration, myoclonic seizures, and progressive motor impairment. Elevated measles antibody titers in CSF establish the diagnosis.

SSPE shows relentless progression (12-64). More than 95% of patients die within 5 years, most within 1-6 months after symptom onset. To date, there is no effective treatment.

Imaging may be normal in the early stages of the disease, so normal MR does not exclude SSPE. Inflammatory infiltrates in cortical gray matter are the major pathologic findings in early SSPE; gray matter reduction in the frontotemporal cortex may occur before other lesions become apparent (12-65). Other abnormal findings eventually develop, with bilateral but asymmetric cortical and subcortical white matter and periventricular and

Congenital, Acquired Pyogenic, and Acquired Viral Infections 373

(12-67A) Axial FLAIR in a 23y patient with medically refractory epilepsy secondary to RE shows left frontotemporal lobe volume loss with left lateral ventricle, sulcal enlargement. Note hyperintensity in WM, BG, insular cortex st. (12- 67B) Coronal T2WI in the same patient shows fronto-temporal and insular atrophy ﬈ well. This is Rasmussen encephalitis. Note extensive WM hyperintensity, reflecting combination of edema and gliosis ﬉.

(12-66A) Axial T2WI in a 13y child with unexplained cognitive decline and progressive motor impairment shows bilateral asymmetric WM hyperintensities in both occipital lobes st. The frontal WM appears normal. The ventricles are mildly enlarged for the patient's age. (12-66B) T2WI in the same child 6 months later shows WM hyperintensities having spread to involve both the frontal and parietal lobes. CSF was positive for measles antibodies.

(12-64) Autopsy of SSPE shows grossly enlarged ventricles and sulci with striking volume loss in basal ganglia and cerebral WM. In the occipital poles, the WM is so thin the ventricles almost contact the cortical GM. (12-65) T1WI in a 16y boy with deteriorating school performance and behavioral change shows diffuse atrophy with bifrontal and bioccipital hypointensities st. CSF was positive for measles antibodies.

Infection, Inflammation, and Demyelinating Diseases 374

Imaging Features of Selected Causes of Acute Pediatric Encephalitis

Disorder Imaging Findings Bartonella henselae (cat scratch disease) May cause vasculitis and stroke, T2 hyperintense lesions in thalami,

basal ganglia, and WM

Epstein-Barr virus encephalitis Shows tropism for deep gray matter structures, nonspecific involvement of cortex and hemispheric WM, cause of optic neuritis

Arthropod-borne encephalitis Bilateral thalamic, symmetric or asymmetric T2 hyperintensities, without or with putamen and caudate involvement

HSV encephalitis, children and adolescence Limbic system involvement, asymmetric–bilateral hemorrhage, deep gray matter spared

Japanese encephalitis T2 prolongation of lesions involving thalami and hypothalami, minimal enhancement, reduced diffusion of lesions

Lyme disease Subcortical WM T2 hyperintense lesions, periventricular WM lesions that mimic MS, nerve root and meningeal enhancement

Measles encephalomyelitis Predominant involvement of thalami, corpus striatum, and cerebral cortex with T2 hyperintense lesions

Mycoplasma pneumoniae encephalitis Leptomeningeal infiltration, may resemble primary angiitis enhancement of nerve roots, subcortical WM T2 hyperintense lesions

Nonpolio enteroviruses Diverse, rhombencephalitis, leptomeningeal enhancement, cerebellar T2 hyperintense lesions

West Nile virus encephalitis Bilateral basal ganglia and thalamic T2 hyperintense lesions

(Table 12-2) WM = white matter.

basal ganglia hyperintensity on T2/FLAIR sequences (12-66). Diffuse atrophy with ventricular and sulcal enlargement ensues as the disease progresses. MRS shows decreased NAA and choline with elevated myoinositol and glutamine/glutamate.

Rasmussen Encephalitis

Rasmussen encephalitis (RE) is also called chronic focal (localized) encephalitis. RE is a rare progressive chronic encephalitis characterized by drug-resistant epilepsy, progressive hemiparesis, and mental impairment.

The exact etiology of RE is unknown. Viral infection or autoimmune disease such as NMDA receptor encephalitis following HSV infection have been suggested as possible etiologies. Biopsy findings are nonspecific, with leptomeningeal and perivascular lymphocytic infiltrates, microglial nodules, neuronal loss, and gliosis. Patients are clinically normal until seizures begin, usually between the ages of 14 months and 14 years. Peak onset is between 3 and 6 years. Neurologic deficits are progressive, and the seizures often become medically refractory. Treatment options have included immunomodulatory therapy, focal cortical resection, and functional hemispherectomy.

Initial imaging studies are usually normal. With time, hyperintensity on T2/FLAIR develops in the cortex and subcortical white matter of the affected hemisphere (12-67). The disease is characterized by unilateral progressive cortical atrophy. Basal ganglia atrophy is seen in the majority of cases. MRS findings are nonspecific with decreased NAA and increased Cho. Myoinositol may be mildly elevated.

CHRONIC ENCEPHALITIDES

Subacute Sclerosing Panencephalitis (SSPE) Measles virus reactivation• Occurs years after initial infection• Almost always fatal• WM hyperintensity• Progressive atrophy•

Rasmussen Encephalitis Etiology unknown (viral, autoimmune)• Medically refractory epilepsy• Unilateral• WM hyperintensity, volume loss•

Congenital, Acquired Pyogenic, and Acquired Viral Infections 375

MISCELLANEOUS NEUROTROPIC VIRUS INFECTIONS

Varicella-Zoster Encephalitis After chickenpox or vaccination• Cortex, GM-WM junction, deep gray nuclei• Cerebellitis, leukoencephalopathy, vasculopathy•

Epstein-Barr Virus Encephalitis Rare mononucleosis complication• Bilateral BG, midbrain, WM/splenium• Cranial nerves, myelitis, polyneuropathies•

West Nile Virus Encephalitis Most common epidemic meningoencephalitis in North America• Bilateral BG, thalami, brainstem• Cranial nerves, spinal cord/cauda equina•

Rabies Encephalitis Developing > > developed countries• Gray matter predominates• Brainstem, thalami, spinal cord; limbic system•

Influenza-Associated Encephalopathy (IAE) H1N1 (influenza A or "swine flu")• Bilateral thalami, corpus callosum splenium• Acute necrotizing encephalopathy•

More fulminant form of IAE (often fatal)○

Nipah Virus Multifocal T2/FLAIR hyperintensities• ± DWI restriction, enhancement•

Rotavirus Encephalitis Common GI pathogen in children• Cerebellitis, corpus callosum splenium•

Japanese Encephalitis Most common human endemic encephalitis•

Korea, Japan, India, Southeast Asia○ Bilateral thalami, BG, substantia nigra, hippocampi• High morbidity, mortality•

LaCrosse Encephalitis School-aged children (Midwest USA)• Mimics herpes simplex encephalitis but more benign•

Chikungunya Encephalitis CHIKV-associated CNS disease• Flavivirus related to dengue, West Nile, Japanese encephalitis• Usually < 1 year and > 65 years• 15-20% fatality• Multifocal T2/FLAIR WM hyperintensities, DWI restriction•

Zika Virus A. aegypti mosquito• A flavivirus similar to dengue, West Nile virus, etc.• Transmitted congenitally, sexually, blood products• Microcephaly in newborn• May cause Guillain-Barré syndrome, possibly other neurologic disorders

•

Dengue Virus Can cause dengue hemorrhagic fever, dengue shock syndrome• BG, thalami, temporal lobes, pons, cord•

(12-68C) T2*GRE shows extensive cerebral microbleeds ﬈, predominately in the white matter. This is PCR+ for H1N1 virus.

(12-68B) More cephalad T2WI shows bilateral hyperintensities in the globi pallidi st but otherwise appears normal.

(12-68A) Axial T2WI in a 15y comatose boy with trisomy 21 and flu-like symptoms shows pontine hyperintensity st resembling CPM.

Infection, Inflammation, and Demyelinating Diseases 376

Selected References Congenital Infections

Lee J: Malformations of cortical development: genetic mechanisms and diagnostic approach. Korean J Pediatr. 60(1):1-9, 2017

Kahle KT et al: Hydrocephalus in children. Lancet. 387(10020):788- 99, 2016

Arbelaez A et al: Congenital brain infections. Top Magn Reson Imaging. 23(3):165-72, 2014

Parmar H et al: Pediatric intracranial infections. Neuroimaging Clin N Am. 22(4):707-25, 2012

Congenital Cytomegalovirus

Kawasaki H et al: Pathogenesis of developmental anomalies of the central nervous system induced by congenital cytomegalovirus infection. Pathol Int. 67(2):72-82, 2017

Herpes Simplex Virus: Congenital and Neonatal Infections

Harris JB et al: Neonatal herpes simplex viral infections and acyclovir: an update. J Pediatr Pharmacol Ther. 22(2):88-93, 2017

Zika Virus Infection

Yun SI et al: Zika virus: an emerging flavivirus. J Microbiol. 55(3):204-219, 2017

Coyne CB et al: Zika virus - reigniting the TORCH. Nat Rev Microbiol. 14(11):707-715, 2016

Congenital (Perinatal) HIV

Muller WJ: Treatment of perinatal viral infections to improve neurologic outcomes. Pediatr Res. 81(1-2):162-169, 2017

Other Congenital Infections

Yazigi A et al: Fetal and neonatal abnormalities due to congenital rubella syndrome: a review of literature. J Matern Fetal Neonatal Med. 30(3):274-278, 2017

Acquired Pyogenic Infections

Meningitis

Dorsett M et al: Diagnosis and treatment of central nervous system infections in the emergency department. Emerg Med Clin North Am. 34(4):917-942, 2016

Wong AM et al: Arterial spin-labeling perfusion imaging of childhood meningitis: a case series. Childs Nerv Syst. 32(3):563-7, 2016

Shih RY et al: Bacterial, fungal, and parasitic infections of the central nervous system: radiologic-pathologic correlation and historical perspectives. Radiographics. 35(4):1141-69, 2015

Mohan S et al: Imaging of meningitis and ventriculitis. Neuroimaging Clin N Am. 22(4):557-83, 2012

Abscess

Brook I: Microbiology and treatment of brain abscess. J Clin Neurosci. 38:8-12, 2017

Sonneville R et al: An update on bacterial brain abscess in immunocompetent patients. Clin Microbiol Infect. ePub, 2017

Ventriculitis

Hazany S et al: Magnetic resonance imaging of infectious meningitis and ventriculitis in adults. Top Magn Reson Imaging. 23(5):315-25, 2014

Empyemas

Mattogno PP et al: Intracranial subdural empyema: diagnosis and treatment update. J Neurosurg Sci. ePub, 2017

Patel NA et al: Systematic review and case report: intracranial complications of pediatric sinusitis. Int J Pediatr Otorhinolaryngol. 86:200-12, 2016

Acquired Viral Infections

Boucher A et al: Epidemiology of infectious encephalitis causes in 2016. Med Mal Infect. 47(3):221-235, 2017

Koeller KK et al: Viral and prion infections of the central nervous system: radiologic-pathologic correlation: from the radiologic pathology archives. Radiographics. 37(1):199-233, 2017

Shives KD et al: Molecular mechanisms of neuroinflammation and injury during acute viral encephalitis. J Neuroimmunol. 308:102- 111, 2017

Herpes Simplex Encephalitis

Gnann JW Jr et al: Herpes simplex encephalitis: an update. Curr Infect Dis Rep. 19(3):13, 2017

Nosadini M et al: Herpes simplex virus-induced anti-N-methyl-D- aspartate receptor encephalitis: a systematic literature review with analysis of 43 cases. Dev Med Child Neurol. ePub, 2017

Kaewpoowat Q et al: Herpes simplex and varicella zoster CNS infections: clinical presentations, treatments and outcomes. Infection. 44(3):337-45, 2016

Soares BP et al: Imaging of herpesvirus infections of the CNS. AJR Am J Roentgenol. 206(1):39-48, 2016

Miscellaneous Acute Viral Encephalitides

Koeller KK et al: Viral and prion infections of the central nervous system: radiologic-pathologic correlation: from the radiologic pathology archives. Radiographics. 37(1):199-233, 2017

Lin D et al: Reversible splenial lesions presenting in conjunction with febrile illness: a case series and literature review. Emerg Radiol. ePub, 2017

Saxena V et al: West Nile virus. Clin Lab Med. 37(2):243-252, 2017

Shives KD et al: Molecular mechanisms of neuroinflammation and injury during acute viral encephalitis. J Neuroimmunol. 308:102- 111, 2017

Yun SI et al: Zika virus: an emerging flavivirus. J Microbiol. 55(3):204-219, 2017

Al-Qahtani AA et al: Zika virus: a new pandemic threat. J Infect Dev Ctries. 10(3):201-7, 2016

Billioux BJ et al: Neurological complications of Ebola virus infection. Neurotherapeutics. 13(3):461-70, 2016

Yoganathan S et al: Acute necrotising encephalopathy in a child with H1N1 influenza infection: a clinicoradiological diagnosis and follow-up. BMJ Case Rep. 2016:bcr2015213429, 2016

Chapter 13 377

Tuberculosis and Fungal, Parasitic, and Other Infections Overview

Infectious diseases are increasingly worldwide phenomena, with what once seemed exclusively local indigenous diseases rapidly spreading around the globe. New pathogens have emerged, as viruses such as HIV—almost unheard of 30 years ago—have become global health concerns. The rise in food and waterborne pathogens is unmistakable. Immigration and widespread travel have resulted in formerly exotic "tropical diseases" such as neurocysticercosis and other parasitic infections becoming commonplace.

In this chapter, we continue the delineation of acquired infections that we began in Chapter 12 with pyogenic and viral CNS infections. We first turn our attention to mycobacterial infections, focusing primarily on tuberculosis. We follow with an in-depth discussion of fungal and parasitic infections. We close the chapter with a brief consideration of miscellaneous and emerging CNS infections to remind us that the "hot zone" is right outside our windows, no matter where we live!

Mycobacterial Infections Mycobacteria are small, rod-shaped, acid-fast bacilli with more than 125 recognized species. They are divided into three main groups, each with a different signature disease: (1) Mycobacterium tuberculosis (tuberculosis), (2) nontuberculous mycobacteria ("atypical" mycobacterial spectrum infections), and (3) M. leprae (leprosy). Each group has different pathologic features, clinical manifestations, and imaging findings.

Of the three groups, the so-called M. tuberculosis complex is responsible for the vast majority of human mycobacterial infections. It causes more than 98% of CNS tuberculosis (TB) and is therefore the major focus of our discussion. We follow with a brief review of nontuberculous mycobacterial infection and its rare manifestations in the head and neck. Leprosy causes peripheral neuropathy but virtually never affects the CNS and is not considered further.

Tuberculosis

Etiology

Most TB is caused by M. tuberculosis. Less common species that are also considered part of the M. tuberculosis complex include M. africanum, M. microti, M. canetti, and M. bovis. Human-to-human transmission is typical. Animal-to-human transmission via M. bovis, a common pathogen in the past, is now rarely encountered. Neurotuberculosis is secondary to hematogeneous spread from extracranial infection, most frequently in the lungs.

CNS TB begins with the development of small TB ("Rich") foci in the subpial or subependymal surfaces of the brain and spinal cord. Rupture of a Rich

Mycobacterial Infections 377 Tuberculosis 377 Nontuberculous Mycobacterial

Infections 384

Fungal Infections 385

Parasitic Infections 390 Neurocysticercosis 390 Echinococcosis 398 Amebiasis 400 Malaria 402 Other Parasitic Infections 405

Miscellaneous and Emerging CNS Infections 407

Spirochete Infections of the CNS 407 Emerging CNS Infections 411

Infection, Inflammation, and Demyelinating Diseases 378

focus into the subarachnoid space causes meningitis, vasculitis, and occasionally encephalitis.

Pathology

CNS TB has several distinct pathologic manifestations. Acute/subacute TB meningitis (TBM) constitutes 70-80% of cases. An inflammatory reaction ("exudate") with a variable admixture of exudative, proliferative, and necrotizing components in the subarachnoid cisterns is the typical finding (13-1). Rarely, TBM presents as an isolated pachymeningitis with focal or diffuse dura-arachnoid thickening.

The second most common manifestation of neurotuberculosis is a focal parenchymal infection with central caseating necrosis (TB granuloma or tuberculoma).

The least common manifestation of CNS TB is "abscess," which contains macrophages and liquefied necrotic debris. (As it usually does not contain pus with neutrophils, most TB

"abscesses" are more correctly called pseudoabscesses.) TB pseudoabscesses are rare in immunocompetent patients but are found in 20% of patients coinfected with TB and HIV.

Location. TBM has a striking predilection for the basal cisterns although exudates in the superficial convexity sulci do occur.

Tuberculomas are space-occupying masses of granulomatous tissue. The majority occur in the cerebral hemispheres, especially the frontal and parietal lobes and basal ganglia. Occasionally, CNS TB presents as a focal dural (13-11), intraventricular (choroid plexus), or isolated calvarial lesion.

TB abscesses can be found anywhere in the brain, from the hemispheres to the midbrain to the cerebellum.

Size and Number. Tuberculomas vary in size. The majority are small (less than 2.5 cm), and the "miliary" nodules are often just a few millimeters in diameter. "Giant" tuberculomas can reach 4-6 cm.

(13-3) Axial section through the suprasellar cistern in another autopsied case of TBM shows thick exudate ﬈ filling the suprasellar cistern and coating the pons. Note the extremely small diameter of the supraclinoid internal carotid arteries ﬊ due to TB vasculitis. (Courtesy R. Hewlett, MD.) (13-4) Surgically resected TB gumma shows the solid "cheesy" appearance of a caseating granuloma. (Courtesy R. Hewlett, MD.)

(13-1) Coronal graphic shows basilar TB meningitis (TBM) ﬇ and tuberculomas ﬈, which often coexist. Note the vessel irregularity ﬉ and early basal ganglia ischemia related to arteritis. (13-2) Autopsy case shows typical findings of TBM with dense exudates extending throughout the basal cisterns ﬈. Gross appearance is indistinguishable from that of pyogenic meningitis. (Courtesy R. Hewlett, MD.)

Tuberculosis and Fungal, Parasitic, and Other Infections 379

Tuberculomas also vary in number, ranging from a solitary lesion to innumerable small "miliary" lesions.

Gross Pathology. TBM is seen as a dense, diffuse, glutinous exudate that accumulates in the basal cisterns, coating the brain surfaces and cranial nerves (13-2). The suprasellar/chiasmatic region, ambient cisterns, and interpeduncular fossa are most commonly involved (13-3).

Tuberculomas have a creamy, cheese-like, necrotic center surrounded by a grayish granulomatous rim (13-4).

Microscopic Features. Edema, perivascular infiltrates, and microglial reaction are common in brain tissue immediately under the tuberculous exudate.

The inflammatory exudate encases major vessels and their perforating branches, invading vessel walls and causing a true panarteritis (sometimes called "endarteritis obliterans"). Vessel occlusions with secondary infarcts are identified in 40% of autopsied cases of TBM, most commonly in the basal ganglia and internal capsule. Large territorial infarcts are less common.

Mature tuberculomas demonstrate central caseating necrosis with a surrounding capsule that contains fibroblasts, multinucleated giant cells (generally Langerhans type), epithelioid histiocytes, plasma cells, and lymphocytes. Acid- fast bacilli may be difficult to identify.

TB abscesses consist of vascular granulation tissue with acid- fast bacilli, liquefied necrotic debris, and macrophages.

Clinical Issues

Epidemiology. TB is endemic in many developing countries and is reemerging in developed countries because of widespread immigration and HIV/AIDS. Worldwide, 8-10 million new cases are reported each year. The highest prevalence is in Southeast Asia, which accounts for one-third of all cases.

CNS infections account for only 10% of all TB infections but are among the most devastating of its many manifestations. One of the most common "brain tumors" in endemic countries is tuberculoma, which accounts for 10-30% of all brain parenchymal masses.

CNS TB occurs in both immunocompetent and immunocompromised patients. Among people with latent TB infection, HIV is the strongest known risk factor for progression to active TB. In TB and HIV/AIDS coinfection, each disease also greatly amplifies the lethality of the other.

Demographics. CNS TB occurs at all ages, but 60-70% of cases occur during the first two decades. There is no sex predilection.

Presentation. The most common manifestation of active CNS TB is meningitis (TBM). Presentation varies from fever and headache with mild meningismus to confusion, lethargy, seizures, and coma. Symptoms of increased intracranial pressure are common.

Cranial neuropathies, especially involving CNs II, III, IV, VI, and VII, are common.

Diagnosis. CSF shows low glucose, elevated protein, and lymphocytic pleocytosis. Acid-fast bacilli can sometimes be identified visually in CSF smears. Positive ELISA (sensitive) or Western blot (specific) immunoconfirmation as well as PCR or growth and identification of M. tuberculosis in cultures are the most common methods for establishing a definitive diagnosis of TBM.

Natural History and Treatment. Prognosis is variable and depends on the patient's immune status as well as treatment. Untreated TB can be fatal in 4-8 weeks. Even with treatment, one-third of patients deteriorate within 6 weeks. Overall mortality is 25-30% and is even higher in drug-resistant TB.

Multidrug-resistant TB (MDR TB) is resistant to at least two of the first-line anti-TB drugs, isoniazid and rifampin. Extensively drug-resistant TB (XDR TB) is defined as TB that is resistant to isoniazid and rifampin, any fluoroquinolone, and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin).

Common complications of CNS TB include hydrocephalus (70%) and stroke (up to 40%). The majority of survivors have long-term morbidity with seizures, mental retardation, neurologic deficits, and even paralysis.

CNS TB: ETIOLOGY, PATHOLOGY, AND CLINICAL ISSUES

Etiology Mycobacterium tuberculosis complex•

Vast majority caused by M. tuberculosis○ Other mycobacteria (e.g., M. bovis) rare○

Human-to-human transmission• Hematogeneous spread from extracranial site•

Lung > GI, GU○ Other: bone, lymph nodes○

Pathology TB meningitis (70-80%)•

Exudative, proliferative, necrotizing inflammatory reaction

○

Basal cisterns > convexity sulci○ Tuberculoma (TB granuloma) (20-30%)•

Caseating necrosis○ Cerebral hemispheres, basal ganglia○

Pseudoabscess (rare)•

Epidemiology and Demographics 8-10 million new cases annually• All ages, but 60-70% in children < 20 years• CNS TB in 2-5% of cases• 10-30% of brain parenchymal masses in endemic areas•

Presentation and Diagnosis Fever, headache, meningismus, signs of ↑ intracranial pressure

•

PCR best, most rapid definitive diagnosis•

Prognosis Overall mortality (25-30%)• Worse with MDR or XDR TB•

Infection, Inflammation, and Demyelinating Diseases 380

Imaging

General Features. Early diagnosis and treatment are necessary to reduce the significant morbidity and mortality associated with CNS TB. As CT scans may be normal in the earliest stages of TBM, contrast-enhanced MR is the imaging procedure of choice.

CT Findings

TB meningitis. Nonspecific hydrocephalus is the most frequent finding on NECT. "Blurred" ventricular margins indicate extracellular fluid accumulation in the subependymal white matter. As the disease progresses, iso- to mildly hyperdense basilar and sulcal exudates replace and efface the normal hypodense CSF (13-5A). CECT usually shows intense enhancement of the basilar meninges and subarachnoid spaces (13-5B).

Patients who deteriorate during treatment often develop new hydrocephalus, infarcts, exudates, or tuberculomas.

Tuberculoma. NECT scans show one or more iso- to slightly hyperdense round, lobulated, or crenated masses with variable perilesional edema. Calcification can be seen in healed granulomas (13-6). CECT scans demonstrate punctate, solid, or ring-like enhancement (13-7).

Abscess. TB abscesses are hypodense on NECT with significant mass effect and surrounding edema. Ring enhancement is seen on CECT.

MR Findings

TB meningitis. Basilar exudates are isointense with brain on T1WI, giving the appearance of "dirty" CSF. FLAIR scans show increased signal intensity in the sulci and cisterns. Marked linear or nodular meningeal enhancement is seen on T1 C+ FS sequences (13-8). Focal or diffuse dura-arachnoid

(13-6) Two different axial images from an NECT scan in a patient with CNS TB shows two calcified healed granulomas st. There was no evidence of active TBM. (Courtesy R. Ramakantan, MD.) (13-7) CECT scan in a 6y immunocompetent boy shows multiple small punctate-enhancing tuberculomas st.

(13-5A) NECT in a 6m child with tuberculous meningitis shows acute obstructive hydrocephalus with dilated temporal horns st and effacement of the sylvian fissures with slightly hyperdense exudate st. (13-5B) CECT in the same case shows thick enhancing exudates throughout the basilar cisterns but most striking in the sylvian fissures st.

Tuberculosis and Fungal, Parasitic, and Other Infections 381

enhancement (pachymeningitis) with or without involvement of the underlying subarachnoid spaces may occur but is uncommon.

Tuberculous exudates often extend into the brain parenchyma along the perivascular spaces, causing a meningoencephalitis.

Vascular complications occur in 20-50% of cases. The "flow voids" of major arteries may appear irregular or reduced. Parenchyma adjacent to meningeal inflammation may demonstrate necrosis. Penetrating artery infarcts with enhancement and restricted diffusion are common.

Cranial nerve involvement is seen in 17-40% of cases. The optic nerve and CNs III, IV, and VII are most commonly affected. The affected cranial nerves appear thickened and enhance intensely on postcontrast images.

Tuberculoma. The most common parenchymal lesion in CNS TB is tuberculoma. Most TB granulomas are solid caseating, necrotizing lesions that appear hypo- or isointense with brain on T1WI and hypointense on T2WI (13-9A). Liquefied areas may be T2 hyperintense with a hypointense rim and resemble abscess (13-10A).

Enhancement is variable, ranging from small punctate foci to multiple rim- enhancing lesions. Mild to moderate round or lobulated ring-like enhancement around a nonenhancing center is the most typical pattern (13- 9B) (13-10B). pMR shows elevated relative cerebral blood volume in the cellular, hypervascular, enhancing rim. Solid caseating tuberculomas do not restrict on DWI although liquefied foci may restrict.

MRS can be very helpful in characterizing tuberculomas and distinguishing them from neoplasm or pyogenic abscess. A prominent decrease in NAA:Cr with a modest decrease in NAA:Cho is typical. A large lipid peak with absence of other metabolites such as amino acids and succinate is seen in 85-90% of cases (13-10C).

Cerebritis and Abscess. Focal TB cerebritis is very rare. TB abscesses are also uncommon and can be solitary or multiple. They are often multiloculated, are typically larger than granulomas ( > 3 cm), and can resemble neoplasm. TB abscesses are hypodense with peripheral edema and mass effect on NECT and show moderate ring enhancement on CECT.

Unlike tuberculomas, TB abscesses are usually hyperintense to brain on T2/FLAIR and restrict on DWI. A ring-enhancing multiloculated lesion or multiple separate lesions is the typical finding on T1 C+ images. MRS shows lipid and lactate peaks without evidence of cytosolic amino acids.

Differential Diagnosis

The major differential diagnosis of TBM is pyogenic or carcinomatous meningitis, as their imaging findings can be indistinguishable. Carcinomatous meningitis is usually seen in older patients with a known systemic or primary CNS neoplasm.

Neurosarcoidosis can also mimic TBM. Infiltration of the pituitary gland, infundibulum, and hypothalamus is common.

The major differential diagnosis of multiple parenchymal tuberculomas is neurocysticercosis (NCC). NCC usually shows multiple lesions in different stages of evolution. Tuberculomas can also resemble pyogenic abscesses or neoplasms (13-11) (13-12) (13-13). Abscesses restrict on DWI. Tuberculomas have a large lipid peak on MRS and lack the elevated Cho typical of neoplasm.

TB abscesses appear identical to pyogenic abscesses on standard imaging studies. Both show restricted diffusion. MRS of TB abscesses shows no evidence of cytosolic amino acids, the spectral hallmark of pyogenic lesions.

(13-9B) T1 C+ scan in the same case illustrates additional lesions with punctate st, ring enhancement ﬇. (Courtesy R. Ramakantan, MD.)

(13-9A) T2WI demonstrates multifocal tuberculomas as hypointense foci surrounded by edema st.

(13-8) T1 C+ FS scans show TBM with hydrocephalus, enhancing exudate throughout the basal cisterns and subarachnoid spaces.

Infection, Inflammation, and Demyelinating Diseases 382

(13-10C) MRS, with TE = 35 ms, demonstrates decreased NAA and prominent lipid lactate peak st.

(13-10B) T1 C+ FS scan demonstrates both solid st and thick rim enhancement.

(13-10A) Axial T2WI shows hypointense caseating tuberculomas ﬈ and edema ﬊. Central liquefaction is hyperintense st.

CNS TUBERCULOSIS: IMAGING AND DIFFERENTIAL DIAGNOSIS

General Features Best procedure = contrast-enhanced MR• Findings vary with pathology•

TB meningitis (TMB)○ Tuberculoma○ Abscess○

Combination of findings (usually TBM, tuberculoma)•

CT Findings TBM•

Can be normal in early stages!○ Nonspecific hydrocephalus common○ "Blurred" ventricular margins○ Effaced basilar cisterns, sulci○ Iso-/mildly hyperdense exudates○ Thick, intense pia-subarachnoid space enhancement○ Can cause pachymeningopathy with diffuse dura-arachnoid enhancement

○

Look for secondary parenchymal infarcts○ Tuberculoma•

Iso-/hyperdense parenchymal mass(es)○ Round, lobulated > irregular margins○ Variable edema○ Punctate, solid, or ring enhancement○ May cause focal enhancing dural mass○ Chronic; healed may calcify○

Abscess• Hypodense mass○ Perilesional edema usually marked○ Ring enhancement○

MR Findings TBM•

Can be normal○ "Dirty" CSF on T1WI○ Hyperintense on FLAIR○ Linear, nodular pia-subarachnoid space enhancement○ May extend via perivascular spaces into brain○ Vasculitis, secondary infarcts common○ Penetrating arteries > large territorial infarcts○

Tuberculoma• Hypo-/isointense with brain on T1WI○ Most are hypointense on T2WI○ Rim enhancement○ Rare = dural-based enhancing mass○ Large lipid peak on MRS○

Abscess• T2/FLAIR hyperintense○ Striking perilesional edema○ Rim, multiloculated enhancement○

Differential Diagnosis TBM•

Pyogenic, carcinomatous meningitis○ Neurosarcoid○

Tuberculoma• Neurocysticercosis○ Primary or metastatic neoplasm○ Pyogenic abscess○ Dural-based mass can mimic meningioma○

Tuberculosis and Fungal, Parasitic, and Other Infections 383

(13-13C) T1 C+ FS MR shows that the mass has multiple conglomerate foci of ring st and solid ﬇ enhancement surrounding nonenhancing areas ﬉. (13-13D) ADC map shows some foci of restricted diffusion ﬈. Pathology disclosed granulomas with large, multifocal areas of coalescing necrosis. Although the causative organism was never identified, the most likely diagnosis was considered to be TB granuloma.

(13-13A) Axial T1WI in a 21y postpartum woman with seizures shows a mixed hypo-, iso- , and hyperintense mass st in the corpus callosum and left parietooccipital lobe. (13-13B) Axial T2WI in the same case shows that the mixed signal intensity mass has several areas that appear strikingly hypointense st.

(13-11) Gross autopsy case shows TB as a focal dural mass st. Appearance is indistinguishable from that of meningioma. (13- 12) CECT scan in a case of proven dura-based TB inflammatory pseudotumor shows extensive en plaque enhancing right frontotemporal mass st. (Courtesy A. Sillag, MD.)

Infection, Inflammation, and Demyelinating Diseases 384

Nontuberculous Mycobacterial Infections Nontuberculous mycobacteria (NTM) are ubiquitous organisms that are widely distributed in water and soil. The most prevalent NTM capable of causing disease in humans is Mycobacterium avium complex. Human disease is usually caused by environmental exposure, not human-to-human spread.

Compared with M. tuberculosis, NTM infections are uncommon. Most are caused by two closely related "atypical" mycobacteria, M. avium and M. intracellulare, which are collectively called M. avium-intracellulare complex (MAIC). Less common NTM include M. abscessus, M. fortuitum, and M. kansasii.

The most common manifestation of MAIC infection is pulmonary disease, which usually occurs in adults with intact

systemic immunity. Disseminated systemic infections are primarily seen in immunocompromised patients.

Three disease patterns are seen in the head and neck: (1) chronic cervical lymphadenitis, (2) immune reconstitution inflammatory syndrome (IRIS), and (3) CNS disease (13-14).

Nontuberculous Cervical Lymphadenitis

Clinical Issues. Subacute or chronic neck infection is by far the most common manifestation of MAIC in the head and neck. Children younger than 5 years and immunocompromised adults are typically affected. Most patients are afebrile and present with a painless, slowly enlarging submandibular or preauricular mass. Chest radiographs show no evidence of pulmonary TB.

Imaging. NECT scans demonstrate one or more enlarged, isodense, solid, or cystic-appearing level I and II lymph node(s). Unilateral disease is more common than bilateral disease.

(13-16A) T2WI FS scan in a 2y boy with a 5-month history of cervical adenopathy shows enlarged level II lymph nodes st and an enlarged, heterogeneous, less hyperintense lymph node st lateral to the right submandibular gland ﬇. (13-16B) T1 C+ FS scan demonstrates peripheral enhancement and central necrosis in the nodal mass st. The enlarged level II nodes enhance homogeneously. This is non-TB mycobacterial adenitis.

(13-14) Biopsy specimen of a CNS mycobacterial spindle cell pseudotumor from a patient with AIDS shows large numbers of acid-fast bacilli ﬊ that fill epithelioid histiocytes. Granulomas, multinucleated giant cells are absent. (Courtesy B. K. DeMasters, MD.) (13-15) Axial CECT in a 2y girl with a painless left neck mass shows multiple ring- enhancing lymph nodes st with low-attenuation centers; non-TB mycobacterial adenitis.

Tuberculosis and Fungal, Parasitic, and Other Infections 385

Inflammatory changes in the surrounding tissues are minimal or absent.

Rim enhancement is common on CECT (13-15). Occasionally, fistulization to the skin occurs.

MR shows hyperintense, cystic-appearing lymph node(s) with minimal surrounding inflammation on fat-saturated T2WI (13- 16A). T1 C+ FS illustrates marked peripheral enhancement around the nonenhancing necrotic centers (13-16B).

Differential Diagnosis. The major differential diagnosis of nontuberculous cervical lymphadenitis is suppurative lymphadenopathy. Patients present with fever and painful mass(es). Cellulitis with stranding of fat and adjacent structures is common.

Tuberculosis causes 95% of cervical lymphadenitis cases in adults but only 8% in children. Half of all cases occur in immunocompromised patients. Imaging studies demonstrate multiple enlarged posterior triangle and internal jugular nodes. Bilateral lesions are typical. Coexisting pulmonary disease is common.

Less common mimics are cat scratch disease and second branchial cleft cysts. Cat scratch disease presents 1-2 weeks following the incident and is seen as reactive adenopathy in regional nodes draining the lesion. Second branchial cleft cyst can mimic a cystic lymph node but is located between the submandibular gland and sternocleidomastoid muscle.

MAIC-Associated IRIS

Atypical microbacterial IRIS outside the CNS is common, usually occurring as pulmonary disease and/or lymphadenitis, but MAIC-associated CNS IRIS is very rare. Reported findings are perivascular granulomatous inflammation with multiple enhancing parenchymal lesions on T1 C+ scans.

CNS Disease

MAIC is an important AIDS-defining opportunistic infection that commonly occurs in patients with CD4 lymphocyte counts < 50 cells/μL.

MAIC causes a localized mass-like inflammatory lesion called a mycobacterial spindle cell pseudotumor. The most common sites are the lymph nodes, lungs, and skin. Most reported cases in the head and neck are found in the nose and orbit.

At biopsy, mycobacterial pseudotumors contain sheets of epithelioid histiocytes with mixed inflammatory cell infiltrate and little necrosis. Innumerable acid-fast intracellular organisms can be demonstrated, but granulomas and multinucleated giant cells are absent (13-14).

Intracranial lesions are uncommon. Imaging studies usually show an enhancing, dural-based mass that mimics meningioma or neurosarcoidosis. Cases of MAIC meningitis and brain abscess have been reported but are exceptionally rare.

NONTUBERCULOUS MYCOBACTERIAL INFECTION

Etiology and Clinical Issues Non-TB mycobacteria (NTM)•

"Atypical" mycobacteria○ Most common = M. avium, M. intracellulare○ Collectively termed M. avium-intracellulare complex (MAIC)

○

Pulmonary disease (immunocompetent)• Disseminated systemic disease (immunocompromised)

•

Head and neck disease less common; CNS rare•

Nontuberculous Cervical Lymphadenitis Subacute/chronic lymphadenopathy• Immunocompetent children < 5 years• Typical presentation: Painless submandibular, preauricular mass

•

Imaging shows enlarged, ring-enhanced node(s)•

Immune Reconstitution Inflammatory Syndrome HIV(+) patient with disseminated MAIC placed on HAART

•

Usually involves lungs, lymph nodes• CNS disease very rare•

Disseminated enhancing parenchymal lesions○

CNS Disease Due to NTM Clinical issues•

CNS MAIC < < < CNS TB○ Immunocompromised adults○

Pathology• Mass-like (mycobacterial spindle cell pseudotumor)○ Histiocytes, inflammatory cells, intracytoplasmic acid-fast bacilli

○

Lymph nodes, lungs, skin > > nose and orbit > CNS○ Imaging•

Focal dural-based mass○ Can mimic meningioma, neurosarcoid○

Fungal Infections Fungi are ubiquitous organisms with worldwide distribution. Most CNS fungal infections are opportunistic, resulting from inhalation of fungal spores and pulmonary infection followed by hematogeneous dissemination. Once uncommon, their prevalence is rising as the number of immunocompromised patients increases worldwide.

Terminology

CNS fungal infections are also called cerebral mycosis. A focal "fungus ball" is also called a mycetoma or fungal granuloma.

Etiology

Fungal Pathogens. A number of fungal pathogens can cause CNS infections. The most common are Coccidioides immitis, Aspergillus fumigatus, Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, and Blastomyces dermatitidis.

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(13-18) Corona-like arrays of Aspergillus ﬈ penetrate the wall of a leptomeningeal blood vessel ﬊. (Courtesy B. K. DeMasters, MD.)

(13-17B) Axial section of cerebral hemisphere in the same case shows a hemorrhagic subcortical infarct ﬈. (Courtesy R. Hewlett, MD.)

(13-17A) Autopsy case demonstrates multiple hemorrhagic infarcts st typical of fungal infection.

Members of the Zygomycetes class (especially the Mucor genus) can also become pathogenic.

The specific agents vary with immune status. Candidiasis, mucormycosis, and cryptococcal infections are usually opportunistic infections. They occur in patients with predisposing factors such as diabetes, hematologic malignancies, and immunosuppression. Coccidioidomycosis and aspergillosis affect both immunocompetent (often elderly) and immunocompromised patients.

Environmental Exposure. Aside from C. albicans (a normal constituent of human gut flora), most fungal infections are initially acquired by inhaling fungal spores in contaminated dust and soil.

Coccidioidomycosis occurs in areas with low rainfall and high summer temperatures (e.g., Mexico, southwestern United States, some parts of South America), whereas histoplasmosis and blastomycosis occur in watershed areas with moist air and damp, rotting wood (e.g., Africa, around major lakes and river valleys in North America).

Systemic and CNS Infections. Sufficiently large numbers of inhaled spores can produce pulmonary infection. In immunocompetent patients, fungi such as Blastomycosis and Histoplasma are usually confined to the lungs, where they cause focal granulomatous disease.

Hematogeneous spread from the lungs to the CNS is the most common route of infection, and cryptococcal meningitis is the most common fungal disease of the CNS.

Fungal sinonasal infections may invade the skull base and cavernous sinus directly. Sinonasal disease with intracranial extension (rhinocerebral disease) is the most common pattern of Aspergillus and Mucor CNS infection.

Disseminated fungal disease usually occurs only in immunocompromised patients.

Pathology

CNS mycoses have four basic pathologic manifestations: diffuse meningeal disease (most common), solitary or multiple focal parenchymal lesions (common), disseminated nonfocal parenchymal disease (rare), and focal dura-based masses (rarest).

Location. The meninges are the most common site, followed by the brain parenchyma and spinal cord.

Size and Number. Parenchymal mycetomas vary in size from tiny (a few millimeters) to 1 or 2 cm. Large lesions are rare although multiple lesions are common.

Gross Pathology. The most common gross finding is basilar meningitis with congested meninges. Parenchymal fungal infections can be either focal or disseminated. Fungal abscesses are encapsulated lesions with a soft tan or thick mucoid-appearing center, an irregular reddish margin, and surrounding edema. Disseminated disease is less common and causes a fungal cerebritis with diffusely swollen brain.

Hemorrhagic infarcts, typically in the basal ganglia or at the gray-white matter junction, are common with angioinvasive fungi (13-17). On rare occasions, fungal infections can produce dura-based masses that closely resemble meningioma.

Microscopic Features. Microscopic features of CNS fungal infections vary with the specific agent (13-18). Blastomyces, Histoplasma, Cryptococcus, and Candida are yeasts. Aspergillus has branching septated hyphae, whereas

Tuberculosis and Fungal, Parasitic, and Other Infections 387

Mucor has broad nonseptated hyphae. Candida has pseudohyphae. Coccidioides has sporangia that contain endospores.

Fungal abscesses exhibit central coagulative necrosis with moderate amounts of acute (polymorphonuclear leukocytic) or chronic (lymphohistiocytic) inflammation mixed with variable numbers of fungal organisms. Abscesses are surrounded by a rim of granulation tissue, perivascular hemorrhage, and thrombosed vessels. Fungal granulomas are less common and are characterized by the presence of multinucleated giant cells. Extraaxial fungal infections are characterized predominantly by spindle cell proliferations.

Clinical Issues

Epidemiology. Epidemiology varies with the specific fungus. Many infections are both common and asymptomatic (e.g., approximately 25% of the entire population in the USA and Canada are infected with Histoplasma).

Candidiasis is the most common nosocomial fungal infection worldwide. Aspergillosis accounts for 20-30% of fungal brain abscesses and is the most common cerebral complication following bone marrow transplantation. Mucor is ubiquitous but generally infects only immunocompromised patients.

Demographics and Presentation. Immunocompetent patients have a bimodal age distribution with fungal infections disproportionately represented in children and older individuals. There is a slight male predominance. Immunocompromised patients of all ages and both sexes are at risk.

Nonspecific symptoms such as weight loss, fever, malaise, and fatigue are common. Many patients initially have symptoms of pulmonary infection. CNS involvement is presaged by headache, meningismus, mental status changes, and/or seizure.

CLINICAL FEATURES, COMMON AGENTS, TYPICAL PATHOLOGY OF FUNGAL INFECTIONS

Normal/Immunocompetent Blastomyces (meningitis, abscess)• Histoplasma (meningitis, abscess)• Coccidioides (meningitis, meningoencephalitis)•

HIV/AIDS, TNF Treatment Cryptococcus (meningoencephalitis, gelatinous pseudocysts)• Histoplasma (meningitis)•

Neutropenia Candida (meningitis, abscess)• Aspergillus (abscess, hemorrhagic infarcts)•

Hematopoietic Stem Cell Transplant/Steroids Aspergillus (abscess, hemorrhagic infarcts)• Mucor (sinus infection, abscess, infarcts ± hemorrhage)• Nocardia (abscess, meningitis)•

Solid Organ Transplant Candida (meningitis, abscess)• Aspergillus (abscess, hemorrhagic infarcts)• Cryptococcus (meningoencephalitis)• Nocardia (abscess, meningitis)•

Neurosurgery Candida (abscess)•

(13-21) CECT shows multiloculated ring- enhancing mass lesion st with edema. Nocardia abscess was found at surgery.

(13-20) CECT scan shows an irregular, crenulated enhancing lesion ﬇ with edema, ventriculitis st. This is a solitary aspergilloma.

(13-19) NECT scan shows multifocal hemorrhages. Angioinvasive aspergillosis was documented at surgery.

Infection, Inflammation, and Demyelinating Diseases 388

Imaging

General Features. Findings vary with the patient's immune status. Well-formed fungal abscesses are seen in immunocompetent patients. Imaging early in the course of a rapidly progressive infection in an immunocompromised patient may show diffuse cerebral edema more characteristic of encephalitis than fungal abscess.

CT Findings. Findings on NECT include hypodense parenchymal lesions caused by focal granulomas or ischemia. Hydrocephalus is common in patients with fungal meningitis. Patients with coccidioidal meningitis may demonstrate thickened, mildly hyperdense basal meninges.

Disseminated parenchymal infection causes diffuse cerebral edema. Multifocal parenchymal hemorrhages are common in patients with angioinvasive fungal species (13-19) (13-27).

Diffuse meningeal disease demonstrates pia-subarachnoid space enhancement on CECT. Multiple punctate or ring- enhancing parenchymal lesions are typical findings of parenchymal mycetomas (13-20) (13-21).

Mycetoma in the paranasal sinuses is usually seen as a single opacified hyperdense sinus that contains fine round to linear calcifications. Fungal sinusitis occasionally becomes invasive, crossing the mucosa to involve blood vessels, bone, orbit, cavernous sinuses, and intracranial cavities. Focal or widespread bone erosion with adjacent soft tissue infiltration can mimic neoplasm. Bone CT with reconstructions in all three standard planes is helpful to assess skull base involvement, and T1 C+ FS MR is the best modality to delineate disease spread beyond the nose and sinuses (13-28).

MR Findings. Fungal meningitis appears as "dirty" CSF on T1WI. Parenchymal lesions are typically hypointense on T1WI but demonstrate T1 shortening if subacute hemorrhage is

(13-23A) Axial T2WI in a patient with cocci meningitis shows hydrocephalus, multiple areas of cortical/subcortical hyperintensity st. Note focal hypointense central area ﬇ in one of the lesions. (13-23B) T1 C+ FS in the same case shows patchy areas of enhancement st. The hemorrhagic lesion seen on the T2WI shows a faint, incomplete rim of enhancement ﬇. This is cocci meningitis st with early cerebritis.

(13-22A) Sagittal T1 C+ scan in a 30y man with cocci meningitis/ventriculitis shows obstructive hydrocephalus with marked enlargement of 4th ventricle ﬇. Thick enhancing exudate st entirely fills suprasellar and prepontine cisterns and cisterna magna and extends inferiorly around the cervical spinal cord. (13-22B) Axial T1 C+ scan in the same patient shows extensive enhancement in the basal and ambient cisterns st. Note ependymitis ﬇.

Tuberculosis and Fungal, Parasitic, and Other Infections 389

present. Irregular walls with nonenhancing projections into the cavity are typical.

T2/FLAIR scans in patients with fungal cerebritis show bilateral but asymmetric cortical/subcortical white matter and basal ganglia hyperintensity (13-23A). Focal lesions (mycetomas) show high signal foci that typically have a peripheral hypointense rim, surrounded by vasogenic edema. T2* scans may show "blooming" foci caused by hemorrhages or calcification (13-26). Focal paranasal sinus and parenchymal mycetomas usually restrict on DWI (13-28D).

T1 C+ FS scans usually show diffuse, thick, enhancing basilar leptomeninges (13-22). Angioinvasive fungi may erode the skull base, cause plaque-like dural thickening, and occlude one or both carotid arteries (13-29) (13-30). Parenchymal lesions show punctate, ring-like, or irregular enhancement (13-23B) (13-25) (13-26).

MRS shows mildly elevated Cho and decreased NAA. A lactate peak is seen in 90% of cases, whereas lipid and amino acids are identified in approximately 50%. Multiple peaks resonating between 3.6 and 3.8 ppm are common and probably represent trehalose.

Differential Diagnosis

The major differential is pyogenic abscess(es) and tuberculoma. TB can appear similar to fungal abscesses on standard imaging studies. Gross hemorrhage is more common with fungal than either pyogenic or tubercular abscesses. Fungal abscesses have more irregularly shaped walls and internal nonenhancing projections. Resonance between 3.6 and 3.8 ppm on MRS is typical.

Other mimics of fungal abscesses are primary neoplasm (e.g., glioblastoma with central necrosis) or metastases.

(13-24C) T2* GRE shows multiple punctate "blooming" foci ﬈ within the mass, consistent with petechial hemorrhages. (13-24D) Axial T1 C+ shows the irregular, crenulated enhancing rim st that surrounds the central nonenhancing lesion core. Note extension into the lateral ventricle with diffuse ependymal enhancement ﬇. Aspergilloma was found at surgery and confirmed by histopathology.

(13-24A) Sagittal T1WI in the same case as Figure 13-20 shows hypointense edema surrounding a mildly hyperintense rim st. (13-24B) Axial T2WI shows that the lesion is mostly hypointense relative to cortex.

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(13-25) (Top) Autopsy case demonstrates multiple solid ﬈, necrotic ﬊ Nocardia abscesses in the cortex, gray-white matter junctions. (Bottom) T1 C+ FS shows multiple ring-enhancing st fungal abscesses.

(13-26) Aspergillus abscesses are in an immunosuppressed patient. Axial T1WI shows punctate and ring-like hyperintense foci st with "blooming" on T2* ﬈. Punctate ﬊ and rim enhancement is seen on T1 C+ FS ﬇. Lesions restrict on DWI st.

FUNGAL INFECTIONS: IMAGING AND DIFFERENTIAL DIAGNOSIS

CT Meningitis•

Iso-/hyperdense meninges○ Abscess•

Hypodense center○ Hyperdense rim○ Variable hemorrhage (angioinvasive infections)○

Sinonasal disease• Hyperdense (mycetoma)○ May demonstrate Ca++○ ± Bone destruction○ ± Intracranial extension○

MR Meningitis•

"Dirty" CSF○ Isointense with brain on T1WI○ Hyperintense on T2/FLAIR○

Abscess• Hypointense center, hyperintense rim on T1WI○ Hyperintense center, hypointense rim on T2WI○ Hemorrhagic "blooming" foci on T2* common○ Restriction on DWI○ Strong enhancement on T1 C+○ MRS lactate in 90%, lipids and amino acids in 50%; multiple peaks at 3.6-3.8 ppm

○

Differential Diagnosis Pyogenic, granulomatous meningitis• Pyogenic abscess• Neoplasm (primary, metastatic)•

Parasitic Infections Once considered endemic only in countries with poor sanitation and adverse economic conditions, parasitic diseases have become a global health concern, exacerbated by widespread travel and immigration.

With the exception of neurocysticercosis, CNS parasitic disease is rare. When they infest the brain, parasites can cause very bizarre-looking masses that can mimic neoplasm.

Neurocysticercosis Cysticercosis is the most common parasitic infection in the world, and CNS lesions eventually develop in 60-90% of patients with cysticercosis.

Terminology

When cysticercosis infects the CNS, it is termed neurocysticercosis (NCC). A "cysticercus" cyst in the brain is actually the secondary larval form of the parasite. The "scolex" is the head-like part of a tapeworm, bearing hooks and suckers. In the larval form, the scolex is invaginated into one end of the cyst, which is called the "bladder."

Etiology

Most NCC cases are caused by encysted larvae of the pork tapeworm Taenia solium and are acquired through fecal-oral contamination. Humans become infected by ingesting T. solium eggs. The eggs hatch and release their larvae that then disseminate via the bloodstream to virtually any organ in the body.

Tuberculosis and Fungal, Parasitic, and Other Infections 391

(13-28C) T1 C+ FS scan shows peripheral enhancement around the margins of the mass st. (13-28D) The mass shows diffusion restriction st.

(13-28A) Series of images demonstrates a focal sinonasal mycetoma. Axial T1WI shows an expansile, destructive isointense mass st in the nose and ethmoid sinus. The lesion invades the left orbit and extends posteriorly, obstructing the sphenoid sinus. (13-28B) The lesion is somewhat mixed signal intensity on T2WI FS but mostly appears profoundly hypointense st. Note obstructive changes in the sphenoid sinus ﬇.

(13-27A) NECT scan of angioinvasive aspergillosis shows hypodense infarcts in the cerebellum, midbrain, and frontal and temporal lobes. (13-27B) Axial NECT scan in the same patient shows that the basal ganglia infarcts exhibit some hemorrhagic transformation ﬇.

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(13-30D) T1 C+ FS scan through the top of the cavernous sinus shows the invaded enhancing left side st with absent flow void ﬇ (compare to the normal right side st). (13- 30E) Coronal T1 C+ FS shows the normal right cavernous ICA st, the occluded left ICA ﬇, and the cavernous sinus infiltration st. Invasive sinonasal mucormycosis in a diabetic patient is a potentially lethal lesion. This patient died from a massive left middle cerebral artery stroke shortly after the scan.

(13-30B) Axial T2WI FS shows normal right cavernous internal carotid artery "flow void" st with left cavernous sinus mass and occluded internal carotid artery st. (13- 30C) T1 C+ FS scan in the same patient shows the left cavernous sinus invasion st and occluded carotid artery ﬇.

(13-29) Close-up view shows autopsied cavernous sinus with invasive fungal sinusitis occluding the left cavernous internal carotid artery ﬇. (Courtesy R. Hewlett, MD.) (13-30A) Bone CT is of a patient with poorly controlled diabetes and invasive mucormycosis. Note bone invasion, destruction at orbital apex and sphenoid sinus ﬇.

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Pathology

Location. T. solium larvae are most common in the CNS, eyes, muscles, and subcutaneous tissue. The intracranial subarachnoid spaces are the most common CNS site, followed by the brain parenchyma and ventricles (fourth > third > lateral ventricles) (13-31). NCC cysts in the depths of sulci may incite an intense inflammatory response, effectively "sealing" the sulcus over the cysts and making them appear intraaxial.

Size and Number. Most parenchymal NCC cysts are small (a few millimeters to 1 cm). Occasionally, multiple large NCC cysts up to several centimeters can form in the subarachnoid space (the "racemose" form of NCC that resembles a bunch of grapes). Either solitary (20-50% of cases) or multiple small cysts may occur.

Gross Pathology. Four stages of NCC development and regression are recognized. Patients may have multiple lesions at different stages of evolution.

In the vesicular stage, viable larvae (the cysticerci) appear as translucent, thin-walled, fluid-filled cysts with an eccentrically located, whitish, invaginated scolex (13-32) (13-33).

In the colloidal vesicular stage, the larvae begin to degenerate. The cyst fluid becomes thick and turbid. A striking inflammatory response is incited and characterized by a collection of multinucleated giant cells, macrophages, and neutrophils. A fibrous capsule develops, and perilesional edema becomes prominent.

The granular nodular stage represents progressive involution with collapse and retraction of the cyst into a granulomatous nodule that will eventually calcify. Edema persists, but pericystic gliosis is the most common pathologic finding at this stage.

In the nodular calcified stage, the entire lesion becomes a fibrocalcified nodule (13-34). No host immune response is present.

(13-33) Low-power photomicrograph of cysticercus shows the invaginated scolex ﬈ lying within the thin- walled cyst ﬊, also known as the bladder. (Courtesy B. K. DeMasters, MD.) (13-34) Close-up view shows a nodular calcified NCC cyst ﬈. Note the lack of inflammation and lack of mass effect. (Courtesy R. Hewlett, MD.)

(13-31) This is NCC. Convexity cysts have scolex ﬉ and surrounding inflammation, which, around the largest cyst, "seals" the sulcus ﬈, makes it appear parenchymal. "Racemose" cysts ﬊ without scolices are seen in basal cisterns. (13-32) NCC in vesicular stage has a clear fluid- filled cyst ﬈ and white eccentrically positioned scolex ﬊. Note the 2nd granular nodular lesion ﬉. (Courtesy R. Hewlett, MD.)

Infection, Inflammation, and Demyelinating Diseases 394

NEUROCYSTICERCOSIS: GROSS PATHOLOGY

Location, Size, Number Subarachnoid > parenchyma > ventricles• Usually < 1 cm•

Subarachnoid ("racemose") cysts can be giant○ Multiple > solitary•

Can have multiple innumerable tiny ("miliary") cysts○

Development Stages Vesicular (quiescent, viable larva) = cyst + scolex• Colloidal vesicular (dying larva)•

Intense inflammation, edema○ Granular nodular (healing) = cyst involutes, edema ↓• Nodular calcified (healed)•

Quiescent, fibrocalcified nodule○ No edema○

Clinical Issues

Epidemiology. In countries where cysticercosis is endemic, calcified NCC granulomas are found in 10-20% of the entire population. Of these, approximately 5% (400,000 out of 75 million) will become symptomatic.

Demographics. NCC occurs at all ages, but peak symptomatic presentation is between 15 and 40 years. There is no sex or race predilection.

Presentation. NCC has a range of clinical manifestations. Signs and symptoms depend on number and location of larvae, developmental stage, infection duration, and presence or absence of host immune response.

Seizures/epilepsy are the most common symptoms (80%) and are a result of inflammation around degeneration cysts. Headache (35-40%) and focal neurologic deficit (15%) are also

(13-37A) Sagittal FLAIR in a 26y woman with headaches shows obstructive hydrocephalus with enlargement of the lateral, third, and fourth ventricles st as well as the aqueduct st. A solitary NCC cyst ﬇ is visible in the bottom of the 4th ventricle. (13-37B) Axial FLAIR shows cyst wall ﬇, scolex st, and interstitial fluid around the obstructed 4th ventricle. FLAIR hyperintensity st in the basal cisterns indicates meningitis.

(13-35) Disseminated NCC with many cysts, mostly in the subarachnoid space, shows cyst with scolex in the depth of frontal sulcus ﬈ surrounded by cortex ﬊, making a subarachnoid cyst appear intraparenchymal. (13-36) T2WI shows disseminated vesicular NCC with "salt and pepper." Innumerable tiny hyperintense cysticerci with scolices (seen as small black dots inside cysts) are present; perilesional edema is absent.

Tuberculosis and Fungal, Parasitic, and Other Infections 395

common. Between 10-12% of patients exhibit signs of elevated intracranial pressure.

NCC—particularly the subarachnoid forms—can also cause cerebral vascular diseases. These include cerebral infarction, TIAs, and cerebral hemorrhage.

Natural History. During the early stages of the disease, patients are frequently asymptomatic. Many patients remain asymptomatic for years. The average time from initial infestation until symptoms develop is 2-5 years. The time to progress through all four stages varies from 1-9 years with a mean of 5 years.

Treatment Options. Oral albendazole with or without steroids, excision/drainage of parenchymal lesions, and endoscopic resection of intraventricular lesions are treatment options.

Imaging

General Features. Imaging findings depend on several factors: (1) life cycle stage of T. solium at presentation, (2) host inflammatory response, (3) number and location of parasites, and (4) associated complications such as hydrocephalus and vascular disease.

Vesicular (quiescent) stage. NECT shows a smooth thin-walled cyst that is isodense to CSF. There is no surrounding edema and no enhancement on CECT.

MR shows that the cyst is isointense with CSF on T1 and T2/FLAIR. The scolex is discrete, nodular, and hyperintense ("target" or "dot in a hole" appearance) and may restrict on DWI. Enhancement is typically absent. Disseminated or "miliary" NCC has a striking "salt and pepper brain" appearance (13-35) (13-36) with notable lack of perilesional edema.

(13-38C) T2* GRE scan shows multiple "blooming black dots" characteristic of nodular calcified NCC. (13-38D) T1 C+ FS scan shows faint ring-like st and nodular st enhancement of healing granular nodular NCC cysts. "Shaggy" enhancement with adjacent edema ﬇ is characteristic of degenerating larvae in the colloidal vesicular stage. Multiple lesions in different stages of evolution are characteristic of NCC.

(13-38A) NECT scan in a patient with NCC shows multiple nodular calcified lesions st. A few demonstrate adjacent edema ﬇. (13-38B) FLAIR scan shows a few hypointense foci st caused by quiescent NCC in the nodular calcified stage. Several foci of perilesional edema are apparent around lesions in the colloidal vesicular stage ﬇, whereas minimal residual edema surrounds lesions in the granular nodular stage st.

Infection, Inflammation, and Demyelinating Diseases 396

(13-39E) (Top) Axial T1 C+ FS shows no enhancement of vesicular NCC cyst st, faint rim enhancement of granular nodular cyst wall st. (Bottom) More cephalad scan shows the granular nodular cyst has thick, intense rim enhancement ﬇. (13- 39F) Axial DWI (L) and ADC map (R) through the colloidal vesicular cyst show that the central viscous cavity of the cyst restricts strongly st. Mild restriction in the enhancing capsule ﬇ is present.

(13-39C) Axial FLAIR scan shows the vesicular NCC cyst with its scolex ﬇. The granular nodular cyst st has minimal residual edema. Group of FLAIR hyperintense sulci st represents leptomeningeal inflammation from the colloidal vesicular cyst above. (13-39D) More cephalad FLAIR MR shows that the colloidal vesicular cyst + nodule ﬇ has striking edema st and adjacent hyperintense sulci st.

(13-39A) Series of images in a 41y Hispanic man with seizures show NCC cysts in different stages. This axial T2WI demonstrates a vesicular (cyst + scolex, no edema) ﬇ and a cyst in the granular nodular stage st. (13-39B) More cephalad scan shows an intrasulcal NCC cyst in colloidal vesicular stage with a nodule (scolex) ﬈ and thick, mixed hypo- and hyperintense intense cyst wall ﬊. The surrounding edema st is striking.

Tuberculosis and Fungal, Parasitic, and Other Infections 397

(13-40) Solitary degenerating colloidal vesicular NCC cyst st with scolex ﬇ demonstrates perilesional edema ﬈, "shaggy" enhancement st.

(13-41) "Racemose" NCC shows numerous variable-sized cysts fill the ambient cistern st, sylvian fissure st. Note hydrocephalus, meningeal reaction with mild/moderate rim enhancement around the "bunch of grapes" cysts ﬇.

Colloidal vesicular stage (dying scolex). Cyst fluid is hyperdense relative to CSF on NECT and demonstrates a ring- enhancing capsule on CECT. Moderate to marked edema surrounds the degenerating dying larvae.

MR shows that the cyst fluid is mildly hyperintense to CSF on T1WI and that the scolex appears hyperintense on FLAIR (13- 37). Moderate to marked surrounding edema is present (13- 38B) and may even progress to a diffuse encephalitis.

Enhancement of the cyst wall is typically intense, ring-like, and often slightly "shaggy" (13-38D) (13-40). Restricted diffusion in the scolex and viscous degenerating cyst can be present (13-39).

Granular nodular (healing) stage. NECT shows mild residual edema. CECT demonstrates a progressively involuting, mildly to moderately enhancing nodule.

The cyst wall appears thickened and retracted, and the perilesional edema diminishes substantially, eventually disappearing. Nodular or faint ring-like enhancement is typical at this stage (13-38D).

Nodular calcified (inactive) stage. A small calcified nodule without surrounding edema or enhancement is seen on CT (13-38A). Shrunken, calcified lesions are seen as hypointensities on T1WI and T2WI. Perilesional edema is absent.

"Blooming" on T2* GRE is seen and may show multifocal "blooming black dots" if multiple calcified nodules are present (13-38C). Quiescent lesions do not enhance on T1 C+.

Special Features. "Racemose" NCC shows multilobulated, variably sized, grape-like lesions in the basal cisterns. Most

cysts lack an identifiable scolex. Arachnoiditis with fibrosis and scarring demonstrates rim enhancement around the cysts and along the brain surfaces. Obstructive hydrocephalus is common (13-41).

NCC-associated vasculitis with stroke is a rare but important complication of "racemose" NCC that can mimic tuberculosis. Most infarcts involve small perforating vessels although large territorial infarcts have been reported.

Intraventricular NCC is associated with poor prognosis. Intraventricular cysts may be difficult to detect on CT. FLAIR and CISS are the most sensitive sequences for detecting the cysts on MR. The fourth ventricle is the most common site (50- 55%) (13-37) followed by the third ventricle (25-30%), lateral ventricle (10-12%), and aqueduct (8-10%).

Differential Diagnosis

The differential diagnosis of NCC depends on lesion type and location. Subarachnoid/cisternal NCC can resemble TB meningitis. In contrast to NCC, the thick purulent basilar exudates typical of TB are solid and lack the cystic features of "racemose" NCC. Carcinomatous meningitis and neurosarcoid are also rarely cystic.

Abscess and multifocal septic emboli can resemble parenchymal NCC cysts but demonstrate a hypointense rim on T2WI and restrict strongly on DWI. A succinate peak on MRS helps distinguish a degenerating NCC cyst from abscess.

A giant parenchymal colloidal-vesicular NCC cyst with ring enhancement can mimic neoplasm, tuberculoma, or toxoplasmosis.

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(13-42A) T1 C+ scan in a 20y man with alveolar echinococcosis demonstrates cauliflower-like clusters of multiple small, irregular, ring-enhancing cysts st.

(13-42B) More cephalad T1 C+ scan shows additional collections of enhancing cysts st, edema ﬇. FLAIR scans (not shown) demonstrated edema around all of the clusters. (Courtesy M. Thurnher, MD.)

The differential diagnosis of intraventricular NCC cyst includes colloid cyst (solid), ependymal cyst (cystic but lacks a scolex), and choroid plexus cyst.

NEUROCYSTICERCOSIS: IMAGING AND DIFFERENTIAL DIAGNOSIS

Imaging Varies with stage•

Vesicular: Cyst with "dot" (scolex), no edema, no enhancement

○

Colloidal vesicular: Ring enhancement, edema striking

○

Granular nodular: Faint rim enhancement, edema decreased

○

Nodular calcified: CT Ca++, MR "black dots"○ Common to have lesions in different stages•

Differential Diagnosis Parenchymal (colloidal vesicular) cyst = neoplasm, toxoplasmosis, TB

•

"Racemose" (subarachnoid) NCC = pyogenic/TB meningitis

•

Intraventricular cyst = ependymal, choroid plexus cysts•

Echinococcosis

Terminology and Etiology

Infection by Echinococcus is called echinococcosis.

Two species of Echinococcus tapeworms, E. granulosis (EG) and E. multilocularis/alveolaris (EM/EA), are responsible for most human CNS infections. EG infestation is also called hydatid

disease or hydatid cyst (HC). Infection with EM/EA is also known as alveolar echinococcosis.

Epidemiology

After NCC, echinococcosis is the second most common parasitic infection that involves the CNS. Humans—most often children—become accidental intermediate hosts by ingesting eggs in soil contaminated by excrement from a definitive host. Approximately 1-2% of patients with EG and 3-5% of patients with EM/EA develop CNS disease.

EG usually affects children, whereas EM/EA is more common in adults.

Pathology

The gross appearances of EG and EM/EA differ. EG typically produces a well-delineated cyst (13-43). EM/EA has numerous irregular small cysts and appears as an infiltrative, invasive, neoplasm-like lesion in both liver and brain.

Hydatid cysts can be uni- or multilocular with "daughter cysts." The wall of a hydatid cyst has three layers: an outer dense fibrous pericyst, a middle laminated membranous ectocyst, and an inner germinal layer (the endocyst). It is the germinal layer that can produce "daughter cysts."

Imaging

The most common imaging appearance of HC is that of a large, unilocular, thin-walled cyst without calcification, edema, or enhancement on CT. Occasionally, a single large cyst will contain multiple "daughter cysts" (13-45).

Tuberculosis and Fungal, Parasitic, and Other Infections 399

(13-45) CECT scan shows a multiloculated hydatid cyst that contains multiple "daughter cysts." (Courtesy S. Nagi, MD.) (13-46) Series of axial MR scans with T1WI, FLAIR, DWI, and ADC (clockwise from top left corner) shows a hydatid cyst st with detached germinal membrane ﬇ and hydatid "sand" in the dependent part of the cyst st. Surrounding edema and mass effect are minimal.

(13-44A) Axial T1WI shows a unilocular hydatid cyst st. Mass effect relative to the overall cyst size is only moderate. (13-44B) T2WI in the same patient nicely demonstrates the typical three-layered cyst wall ﬊. (Courtesy R. Hewlett, MD.)

(13-43A) Autopsy case shows brain after the removal of a huge unilocular hydatid cyst. Note the well-demarcated border st between the cyst cavity and the brain. There is no surrounding edema, and the mass effect relative to the size of the cyst is minimal. (13- 43B) Photograph of the external cyst wall st with cut view of the cyst ﬇ shows the typical thin wall of a classic hydatid cyst. (Courtesy R. Hewlett, MD.)

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(13-47C) Histology shows meningitis ﬈, hemorrhage/inflammatory cells in Virchow-Robin spaces ﬊. (Courtesy B. K. DeMasters, MD.)

(13-47B) Coronal cut section in the same case demonstrates numerous focal parenchymal hemorrhages ﬈.

(13-47A) Gross pathology from a patient with amebic meningoencephalitis shows multiple basilar hemorrhagic exudates ﬈.

MR shows that cyst fluid is isointense with CSF on T1WI and T2WI (13-44). Sometimes a detached germinal membrane and hydatid "sand" can be seen in the dependent portion of the cyst (13-46).

EA consists of numerous irregular cysts that—unlike HC—are not sharply demarcated from surrounding brain and usually enhance following contrast administration. Irregular peripheral or ring-like, heterogeneous, nodular, and cauliflower-like patterns have been reported (13-42).

Differential Diagnosis

The differential diagnosis of a supratentorial intraaxial cystic mass is extensive and includes cystic neoplasms, abscess, parasitic cysts, and neuroglial cysts. Of these, the most difficult to distinguish from HCs are neuroglial cysts and porencephalic cysts. Neuroglial cysts are rarely as large as HCs. Porencephalic cysts are literally "holes in the brain" adjacent to—and usually connected with—an enlarged ventricle.

Amebiasis

Terminology and Etiology

Amebae are free-living organisms that are distributed worldwide. Species of the Acanthamoeba (Ac) genus are found in soil and dust, fresh or brackish water, and a variety of other locations ranging from hot tubs and hydrotherapy pools to air conditioning units, contact lens solutions, and dental irrigation units. Balamuthia mandrillaris is a soil-dwelling organism. Naegleria fowleri is found in both soil and fresh water. Entamoeba histolytica (EH) occurs in food or water contaminated with feces.

Up to 10% of the population worldwide is infected with EH, but CNS disease is rare.

Pathology

Two basic types of CNS amebic infection occur: primary amebic meningoencephalitis (PAM) and granulomatous amebic encephalitis (GAE). Amebic abscess occurs but is relatively uncommon in Western and industrialized countries.

Gross autopsies of PAM show a necrotizing, hemorrhagic meningitis and angiitis with focal lesions in the orbitofrontal (13-48) and temporal lobes, brainstem, and upper spinal cord (13-47). Numerous trophozoites are present, but no cysts are seen because of disease acuity.

GAE demonstrates granulomatous inflammation with multinucleated giant cells, trophozoites, and cysts. An amebic abscess has pus with trophozoites at the edge of the lesion.

Clinical Issues

PAM is an acute, rapidly progressive, necrotizing hemorrhagic meningoencephalitis caused by N. fowleri. Healthy children and immunocompetent young adults swimming in warm fresh water during the summer are the typical patients, presenting with fever, headache, and altered mental status. N. fowleri invades the olfactory mucosa and enters the brain along the olfactory nerves. PAM is almost always fatal. Death within 48- 72 hours is typical.

GAE is a subacute to chronic condition usually caused by one of six Acanthamoeba species or B. mandrillaris. GAE shows no seasonal predilection. GAE is generally associated with immunodeficiency (e.g., HIV/AIDS, organ transplantation) and chronic debilitating conditions such as malnutrition and diabetes. Presentation ranges from headache and chronic low-grade fever to

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(13-50C) Coronal T2WI shows hyperintensity in both thalami st, midbrain st, pons ﬇, and medulla ﬉. (13-50D) T1 C+ shows diffuse enhancement along the surface of the pons ﬇ and throughout the cerebral sulci st. Imaging diagnosis was meningoencephalitis of unknown etiology. The patient expired 5 days after admission. Autopsy disclosed primary amebic encephalitis.

(13-50A) A 60y man with URI and fever spiking to 103° developed altered mental status. He rapidly declined and became comatose with GCS 3. Axial FLAIR shows strikingly swollen, hyperintense pons st and diffuse sulcal hyperintensity ﬇. (13- 50B) T2WI in the same case shows swollen, hyperintense basal ganglia st and thalami st.

(13-48) Lateral view of an autopsied brain from a patient with amebic encephalitis shows focal parenchymal hemorrhage st. (13-49) (L) T2WI and (R) T2* GRE in another patient show multiple parenchymal hemorrhages ﬈ with "blooming." Biopsy disclosed amebic granuloma.

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(13-51) Sporozoites inoculated into blood infect the liver cells. When mature, they rupture the cells, releasing merozoites that infect RBCs. Merozoites develop into trophozoites or gametocytes, which are then ingested by uninfected mosquitoes.

(13-52) Classic "slate gray" edematous cortex of cerebral malaria (L) compared with normal brain (R). (Courtesy R. Hewlett, MD.)

fulminant infection (with B. mandrillaris). Focal symptoms are present for an average of 2 or 3 months.

Amebic abscess in the CNS is rare even in endemic areas and is usually caused by E. histolytica. Most patients have intestinal or liver infection. In contrast to GAE, amebic abscess is not related to immunodeficiency, and most infected patients are immunocompetent.

Symptoms are nonspecific and include headache, altered mental status, and meningeal symptoms.

Imaging

A broad spectrum of imaging findings in amebic meningoencephalitis has been described, including meningeal exudates, multifocal hemorrhagic parenchymal lesions (13- 49), and pseudotumoral lesions with necrosis.

PAM demonstrates findings of leptomeningitis with sulcal obliteration and enhancement, especially along the perimesencephalic cisterns (13-50D). Multifocal parenchymal lesions with involvement of posterior fossa structures, diencephalon, and thalamus are typical (13-50). Necrotizing angiitis with hemorrhages and frank infarction is seen in some cases.

GAE demonstrates a multifocal pattern with discrete lesions at the corticomedullary junction and/or a pseudotumoral pattern with a solitary mass-like lesion.

Amebic abscesses are usually located in the basal ganglia or at the gray-white matter junction. Solitary or multiple irregularly shaped ring-enhancing hemorrhagic lesions are the typical imaging finding.

Differential Diagnosis

The imaging features of amebiasis are nonspecific. Amebic abscesses and meningoencephalitis can mimic disease caused by other pyogenic, parasitic, and granulomatous infections. Multifocal parenchymal and pseudotumoral lesions can mimic neoplasm.

Malaria

Terminology and Etiology

Cerebral malaria (CM) is caused by infection with the protozoan parasite Plasmodium and is transmitted by infected Anopheles mosquitoes. Four species cause human disease: P. falciparum, P. vivax, P. ovale, and P. malariae. Of these, P. falciparum has the most severe morbidity and mortality and causes 95% of all CM cases.

The life cycle of a malaria parasite involves the female Anopheles mosquito and a human host. Sporozoites are inoculated into humans during the mosquitoes' "blood meal." The sporozoites invade and replicate asexually in liver cells, maturing into schizonts that rupture and release merozoites. The merozoites infect red blood cells (RBCs). Merozoites can develop into trophozoites, which undergo asexual reproduction in the blood, or into gametocytes, which reproduce sexually in deep tissue capillaries. Gametocytes are ingested by mosquitoes, and the cycle is repeated over and over again (13-51).

Pathology

Grossly the brain appears swollen, and its external surface is often a characteristic dusky dark red. Deposition of malaria

Tuberculosis and Fungal, Parasitic, and Other Infections 403

pigment can give the cortex a slate gray color (13-52). Petechial hemorrhages are often seen in the subcortical white matter, corpus callosum, cerebellum, and brainstem (13-55).

The major microscopic feature is sequestration of parasitized RBCs in the cerebral microvasculature (13-53). Perivascular ring and punctate microhemorrhages are common. Diagnostic black malarial pigment ("hemozoin bodies") within sequestered, hemoglobin-depleted "ghost" RBCs is common. Malaria parasites remain intravascular, so encephalitic inflammatory changes are absent.

Clinical Issues

Epidemiology and Demographics. Falciparum malaria is a leading cause of poor health, neurodisability, and death in tropical countries. Approximately 40% of the world's population is at risk. Between 250 and 500 million new cases of malaria develop every year, and more than half a million people die from the disease. The majority of cases occur in

sub-Saharan Africa, where children under 5 years of age are most affected. Peak prevalence is between 1 and 3 years.

Severe malaria develops in 1% of symptomatic malaria infections. Of these, CM is the most severe manifestation. The incidence of CM is 1,120 per 100,000 per year in endemic areas. Malaria causes approximately one million deaths each year.

Malaria is generally restricted to tropical and subtropical areas with altitudes under 1,500 meters and to travelers or immigrants coming from endemic areas. A few isolated cases of "airport malaria" have been reported. For such cases, falciparum malaria occurred in individuals who never traveled outside the country but became infected by imported anopheline mosquitoes at or around an international airport.

Presentation and Natural History. The incubation period from infection to symptom development is 1-3 weeks. Shaking chills followed by cyclical high fever and profuse

(13-55) Cerebral malaria shows innumerable petechial white matter hemorrhages ﬈ in the subcortical, deep white matter. (Courtesy L. Chimelli: A morphological approach to the diagnosis of protozoal infections of the CNS. Patholog Res Int. 2011.) (13-56) T2* SWI in a patient with cerebral malaria shows innumerable punctate "blooming" microhemorrhages throughout the white matter. (Courtesy K. Tong, MD.)

(13-53) In cerebral malaria, parasites convert metabolized hemoglobin to hemozoin ("malarial pigment"), seen here as tiny black "dots" in sequestered red blood cells ﬈. (Courtesy B. K. DeMasters, MD.) (13-54) Scans in a patient with malaria show T2 basal ganglia hyperintensities st that "bloom" on T2* GRE and restrict on DWI. (Courtesy R. Ramakantan, MD.)

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sweating are typical and correspond temporally to RBC lysis after schizonts mature. P. falciparum, P. ovale, and P. vivax are characterized by fever every 48 hours, whereas P. malariae cycles every 72 hours.

Prognosis is variable. Individuals with sickle cell trait generally have milder disease. In other cases, headache, altered sensorium, and seizures develop and can be followed within 1- 2 days by impaired consciousness, coma, and death. Mortality in CM is 15-20% even with appropriate therapy. Although many surviving patients recover completely, between 10-25% of affected children have long-term neurologic deficits.

P. falciparum relapse is rare. P. vivax and P. ovale can relapse, as dormant liver stages allow the parasite to survive during colder periods. Active forms can arise months to years later.

Imaging

Imaging findings on NECT vary from normal to striking. The most typical finding is focal infarcts in the cortex, basal ganglia, and thalami. Gross hemorrhage can occur but is rare. Diffuse cerebral edema is seen in severe CM and is especially prevalent in children.

MR shows focal hyperintensities in the basal ganglia, thalami, and white matter on T2/FLAIR (13-54). Confluent hyperintensities can occur in severe cases although large territorial infarcts are rare.

T2* scans demonstrate multifocal "blooming" petechial hemorrhages in the basal ganglia and cerebral white matter. These linear and punctate hypointensities are especially striking on susceptibility-weighted imaging (SWI) (13-55) (13- 56). Malarial lesions generally do not enhance on T1 C+.

(13-57C) Coronal T1 C+ shows patchy enhancement st around a central linear focus ﬇, suggesting an "arborization" pattern. (13-57D) Microscopic view from the biopsied lesion shows the encysted S. mansoni with the classic lateral spine ﬉. (Courtesy D. Kremens, MD, S. Galetta, MD.)

(13-57A) Axial T2WI in a 34y man with schistosomiasis shows a mixed hypo- and hyperintense lesion st involving the vermis and both cerebellar hemispheres. (13-57B) Axial T1 C+ scan shows a patchy "arborization" pattern of enhancement st.

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Differential Diagnosis

CM is a clinical diagnosis and should be considered in any patient with a febrile illness and impaired consciousness who lives in—or has recently traveled to—endemic malaria areas!

Differential diagnosis varies with patient age. The major imaging differential diagnosis of CM in adults is multiple cerebral emboli/infarction, which more commonly involves the gray-white matter junction or cortex. Multifocal white matter petechial hemorrhages on T2* are nonspecific and can be seen in fat emboli syndrome, acute hemorrhagic leukoencephalitis, diffuse vascular injury, and thrombotic microangiopathies such as disseminated intravascular coagulopathy.

The major differential diagnosis of CM in children is acute necrotizing encephalopathy and infantile bilateral striatal necrosis. These are generally influenza-associated diseases

and follow flu-like respiratory infection or rotavirus gastroenteritis.

Other Parasitic Infections Several parasites that affect humans invade the CNS, particularly if humans serve as intermediate or nonpermissive hosts. Schistosomiasis, paragonimiasis, sparganosis, trichinosis, and trypanosomiasis can occasionally involve the CNS. Although these parasitic infestations can occur at any age, they most commonly affect children and young adults.

Brain involvement is relatively uncommon. Common clinical features of CNS parasitoses include headache, epilepsy, and impaired consciousness. When CNS infestations occur, these parasites are associated with significant mortality and morbidity. Because imaging often resembles neoplasm, a history of travel to—or residence in—an endemic area is key to the diagnosis.

(13-59A) Axial T2WI in a patient with known sparganosis shows multiple ring-like hyperintensities st with central hypointense foci ﬇. (13-59B) Axial T1 C+ scan in the same patient shows nonspecific ring enhancement st. No "tunnel" sign was present. (Courtesy M. Castillo, MD.)

(13-58A) Axial T2WI in a young man from southeast Asia shows a heterogeneous right frontal lobe mass with intralesional hypointensities st, suggesting hemorrhage. Moderate perilesional edema ﬇ is present. (13- 58B) Coronal T1 C+ shows conglomerate ring- enhancing lesions st. Paragonimiasis granuloma was found at surgery.

Infection, Inflammation, and Demyelinating Diseases 406

Schistosomiasis

Schistosomiasis, also known as bilharziasis, is a trematode (fluke) infection that affects more than 200 million people worldwide.

Several Schistosoma species cause human disease. Schistosoma haematobium is endemic in Africa, especially the Nile River basin. S. mansoni is also endemic in Africa (the midcontinent and lake region), South America, and the Caribbean (13-57D). S. japonicum is endemic in China, and S. mekongi is endemic in Southeast Asia.

Schistosoma species have a complex life cycle. Ova in human urine and feces hatch in fresh water and enter snails as their intermediate host. Snails release motile larvae (cercariae) that infect humans wading or swimming in infested water. The larvae penetrate skin and migrate to the liver or lungs, where they mature. Adult worms migrate to venous plexuses in the

intestines (S. mansoni, S. japonicum) or bladder (S. hematobium).

The mature worms release eggs, which can be shed in urine or feces. Eggs can also disseminate to ectopic sites, including the brain. Focal meningeal and firm parenchymal masses are the typical gross pathologic findings. On microscopic examination, schistosome eggs show no spine (S. japonicum) or a terminal (S. haematobium) or lateral (S. mansoni) spine.

Typical imaging findings of neuroschistosomiasis are single or multiple conglomerated heterogeneous lesion(s) with edema and mass effect. A central linear enhancement surrounded by multiple punctate nodules (an "arborized" appearance) on T1 C+ MR (13-57C) has been described as characteristic.

Paragonimiasis

Paragonimiasis is another snail-borne trematode infection. Humans become infected by eating undercooked fresh water

(13-60C) Midline sagittal FLAIR in the same case shows punctate lesions in the subcortical white matter and corpus callosum st. A larger confluent lesion in the corpus callosum ﬇ is present just anterior to the splenium. (13-60D) More lateral FLAIR in the same case shows multiple punctate st and confluent ﬇ lesions in the subcortical white matter. Note sparing of the subcortical U fibers. This is documented Lyme disease.

(13-60A) Series of axial FLAIR images demonstrates the multifocal T2/FLAIR white matter hyperintensities persisting 1 year after complete clinical response to treatment. Lesions are present in both middle cerebellar peduncles st. (13-60B) More cephalad scan in the same case shows multifocal punctate st and patchy st and confluent ﬇ lesions in the subcortical and deep periventricular white matter.

Tuberculosis and Fungal, Parasitic, and Other Infections 407

(13-61) Axial (top), coronal (bottom) T1 C+ FS scans in a patient with Lyme disease demonstrate left CN VII st, bilateral CN V st, and left CN III ﬇ enhancement. (Courtesy P. Hildenbrand, MD.)

(13-62) T1 C+ FS scans in a patient with Lyme disease and multiple cranial nerve palsies show enhancement of the right fifth st and sixth st CNs as well as both oculomotor nerves ﬇. (Courtesy P. Hildenbrand, MD.)

crabs or crayfish contaminated by Paragonimus westermani, a lung fluke endemic in Asia and Central and South America. Worms penetrate the skull base foramina and meninges, then directly invade the brain, where they elicit a granulomatous inflammatory reaction. Adolescent boys are most commonly affected.

Imaging shows a heterogeneous mass with multiple conglomerated ring-enhancing lesions surrounded by edema (13-58). Intralesional hemorrhage is common.

Sparganosis

Sparganosis is a rare parasitic infection caused by the larval cestode of Spirometra mansoni. Nearly half of all reported cases are due to ingestion of raw or undercooked frogs or snakes. Sparganosis is endemic in Southeast Asia, China, Japan, and Korea.

Imaging studies show an irregularly shaped mass, usually in the cerebral white matter, surrounded by edema. The most common imaging finding is the "tunnel" sign, a hollow tube ("tunnel") several centimeters long created by the burrowing worm. The "tunnel" is surrounded by an enhancing rim of reactive inflammatory granulomatous tissue. The second most common feature of cerebral sparganosis is a conglomerate mass of ring- or bead-like enhancing lesions (13-59).

Sparganosis is typically characterized by the simultaneous presence of new and old lesions. Lesions in different stages of evolution from acute infection to cortical atrophy with white matter volume loss and calcifications around degenerated/dead worms are typical of this particular parasitic infestation.

Differential Diagnosis

Most parasitic infections share several common features. They usually present as mass-like lesions with edema and multiple "conglomerate" ring-enhancing foci. Metastasis and glioblastoma multiforme are two common neoplasms that can appear very similar to parasitic masses. Inflammatory granulomas (e.g., TB granulomas) can also mimic parasitic granulomas and are often endemic in the same geographic areas.

Miscellaneous and Emerging CNS Infections

Spirochete Infections of the CNS Two spirochete species can cause significant CNS disease: Borrelia (e.g., Lyme disease, relapsing fever borreliosis) and Treponema (neurosyphilis).

Lyme Disease

Terminology. Lyme disease (LD) is also known as Lyme borreliosis. LD with neurologic disease is called Lyme neuroborreliosis (LNB) or neuro-Lyme disease. Relapsing fever borreliosis is a multisystem disease that infects a variety of tissues including the CNS (rare).

Lyme disease is a multisystem inflammatory disease caused by B. burgdorferi in the United States and B. garinii or B. afzelii in Europe. LD is a zoonosis maintained in animals such as field mice and white-tailed deer.

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(13-63) (Upper L) T1 shows bilateral iso-/hypodense WM lesions ﬈. (Upper R) T2 shows bilateral "fluffy" hyperintense lesions st in the corona radiata. Sagittal (lower L) and coronal (lower R) show multifocal ring enhancement ﬇; rickettsial encephalitis.

(13-64) Sagittal T2WI (L) and T1 C+ FS scan (R) of the thoracic cord show hyperintense cord lesions st with patchy enhancement ﬇. This is documented Lyme disease. (Courtesy P Hildenbrand, MD.)

LD is transmitted to humans by bite of Ixodes ticks and requires at least 36 hours of tick attachment as the spirochete moves from the tick midgut to the salivary glands to be transmitted. Most cases result from the bite of an infected nymph (about the size of a poppy seed) and may easily go unnoticed.

Relapsing fever (RF) borreliosis is caused by arthropod-borne spirochetes of the genus Borrelia. The major agents vary worldwide. In North America, RF is generally caused by B. hermsii and B. turicatae and is transmitted by tick bites. Small mammals (principally rodents) and birds are the reservoir organisms.

Etiology. The precise mechanism of CNS involvement is unclear. Direct brain infection/invasion, antigen-driven autoimmune-mediated mechanisms, and vasculitis-like processes have been postulated.

Clinical Issues

Epidemiology and demographics. LD is now the most common tick-borne disease in the United States and Europe with 20,000 new cases reported each year.

Prevalence varies significantly with geography. Between 90- 95% of cases in the United States occur in the Mid-Atlantic states, the Northeast, and the upper Midwest (primarily Minnesota and Wisconsin). Occurrence peaks during the early summer, especially May and June.

LD occurs at all ages, but peak presentation is between 16 and 60 years. Thirty percent of cases occur in children.

Presentation. North American LD occurs in stages. Stage 1 occurs between 2 and 30 days after the initial tick bite and is

characterized by erythema migrans—a characteristic round, outwardly expanding, target-like ("bull's-eye") rash—and "summer flu" symptoms such as fever, headache, and malaise. Migrating myalgias and pain in large joints may develop ("Lyme arthritis").

Stage 2 occurs 1-4 months after infection and presents with neurologic and cardiac symptoms. Neurologic symptoms develop in approximately 10-15% of cases, whereas cardiac involvement occurs in 8%. Stage 3 can occur several years following the initial infection and manifests as arthritic and chronic neurologic symptoms.

The classic triad of North American LNB consists of aseptic meningitis, cranial neuritis, and radiculoneuritis. Uni- or bilateral facial palsy is common and helps differentiate LNB from other disorders. Erythema migrans, "Lyme arthritis," and carditis are also common.

The most common symptom in children is headache, followed by facial nerve palsy and meningismus.

The most common presentation of European LNB is the triad of Bannwarth syndrome: lymphocytic meningitis, cranial neuropathy, and painful radiculitis. Erythema migrans, "Lyme arthritis," and carditis are all uncommon manifestations of European LD.

Natural history. The diagnosis and treatment of chronic LD are controversial. To date, there is no systematic evidence that B. burgdorferi can be identified in patients with chronic symptoms following treated LD (posttreatment Lyme disease syndrome, or PTLDS). Multiple randomized prospective trials have demonstrated no durable or significant benefit in treating PTLDS patients with prolonged courses of antibiotics.

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(13-65) Close-up view of autopsied brain demonstrates the typical findings of meningovascular syphilis. Exudate covers the pons st. A syphilitic gumma ﬇ is also present. (Courtesy R. Hewlett, MD.)

(13-66) NECT scan in a patient with meningovascular syphilis shows left occipital st and thalamic infarcts ﬇. DSA (not shown) disclosed vasculitis-like findings. (Courtesy P. Hildenbrand, MD.)

Diagnosis. Both the American Academy of Neurology (AAN) and the European Federation of Neurological Societies have recommended criteria for the diagnosis of LMB. In addition to all of the criteria included in the AAN, the European Federation requires CSF pleocytosis, evidence for intrathecal B. burgdorferi antibody, and no other "obvious reasons" for the neurologic symptoms other than Lyme for the definite diagnosis of LD.

DIAGNOSIS OF LYME NEUROBORRELIOSIS

American Academy of Neurology Recommendations Possible exposure to Ixodes ticks in Lyme-endemic area• One or more of the following:•

Erythema migrans○ Immunologic evidence of exposure to Borrelia burgdorferi

○

Histopathologic, microbiologic, or PCR proof of B. burgdorferi infection

○

Occurrence of a clinical disorder within the realm of those associated with Lyme disease (no other apparent cause)

•

European Federation of Neurological Societies Definite neuroborreliosis = all of below:•

Neurologic symptoms suggestive of Lyme neuroborreliosis without other obvious reasons

○

CSF pleocytosis○ Intrathecal B. burgdorferi antibody production○

Possible neuroborreliosis = 2 of the above•

Pathology. Findings of meningitis and radiculitis predominate. Microscopic features include nonspecific perivascular T- lymphocytic cuffing and plasma cell infiltrates with axonal

degeneration. Lymphocytes and plasma cells accumulate in autonomic ganglia of the peripheral nervous system. Spirochetes can be identified in the leptomeninges, nerve roots, and dorsal root ganglia, but not in the CNS parenchyma.

Imaging. Approximately 12-15% of patients with untreated B. burgdorferi infection develop CNS involvement. NECT and CECT scans in these patients are usually normal. MR findings vary with clinical syndrome.

Cranial Neuropathy. The most common clinical presentation of early LNB in the USA is facial palsy and is commonly misdiagnosed as Bell palsy.

Cranial nerve involvement is especially common in North American LNB. CN VII is the most frequently involved (13-61), followed by CNs V and III. Involvement of other cranial nerves is less common.

Unilateral disease is more common than bilateral disease although multiple nerves can be affected (13-62). Uniform enhancement on T1 C+ FS is the typical finding.

Encephalopathy. The most common MR finding is multiple small (2-8 mm) subcortical and periventricular white matter hyperintensities on T2/FLAIR (13-60). These are identified in approximately half of all patients with LNB. Large "tumefactive" lesions are uncommon.

Enhancement of LNB white matter lesions varies from none to moderate (13-63). Occasionally "horseshoe" or incomplete ring enhancement occurs and can mimic demyelinating disease.

Myelitis and Radiculitis. Spinal cord involvement by B. burgdorferi is very rare but is more common in European LD.

Infection, Inflammation, and Demyelinating Diseases 410

Diffuse or multifocal hyperintense lesions on T2WI with patchy cord and linear nerve root enhancement are typical (13-64).

In European LNB, enhancement of cauda equina and lower spinal cord nerve roots is more common than cranial nerve enhancement.

Rare Manifestations. Rare reported manifestations of LNB include cerebral vasculitis with stroke, intracranial hypertension, chronic progressive encephalitis, and Borrelial lymphocytoma (predominately seen in Europe).

Differential Diagnosis. The major differential diagnosis of LNB is demyelinating disease. Multiple sclerosis (MS) frequently involves the periventricular white matter. Callososeptal involvement is more common in MS compared with LNB. Cranial nerve enhancement—especially CN VII—is less common than with LNB.

Susac syndrome typically involves the middle layers of the corpus callosum and is often accompanied by sensorineural hearing loss (rare in LNB) and visual symptoms.

Vasculitis involves the basal ganglia more than LNB does and rarely affects the cranial nerves.

Neurosyphilis

Terminology and Etiology. Syphilis is a chronic systemic infectious disease caused by the spirochete Treponema pallidum. Syphilis is usually transmitted via sexual contact although some cases of vertical transmission from mother to fetus have been reported. Neurosyphilis (NS) is also called neurolues. A focal syphilitic granuloma is called a gumma.

Epidemiology and Demographics. Once expected to be eradicated with the use of penicillin, syphilis has become dramatically more prevalent since 2000, primarily because of HIV/AIDS. Syphilis and HIV have emerged as important

(13-67C) More cephalad T1 C+ FS scan in the same patient shows intense enhancement in the pons and cerebellum st with extension into Meckel cave ﬇ and thickening of the adjacent dura. (13- 67D) Coronal T1 C+ scan demonstrates the syphilitic gumma st, adjacent dural thickening ﬇, and enhancement in both internal auditory canals st. The patient's CD4 count at the time of imaging was 200. This is biopsy-proven meningovascular syphilis.

(13-67A) Axial T2WI in a 47y HIV-positive man with trigeminal neuralgia shows a mixed iso- /hyperintense mass involving the pons, cerebellum, and trigeminal nerve st. (13- 67B) Axial T1 C+ FS demonstrates pial enhancement surrounding the medulla st and extending into the left internal auditory canal st.

Tuberculosis and Fungal, Parasitic, and Other Infections 411

copathogens with reciprocal augmentation in both transmission and disease progression. HIV-positive patients tend to experience more aggressive symptomatology and are at greater risk of developing neurologic disease.

The M:F ratio is 2:1. Most patients are between 18 and 64 years with a mean age of slightly over 50 years. Congenital syphilitic gummatous lesions are exceptionally rare.

Clinical Issues. Between 5-10% of patients with untreated syphilis develop NS. T. pallidum disseminates to the CNS within days after exposure, although symptomatic NS can occur up to 25 years after the initial chancre. Peak occurrence is 15 years after primary infection.

NS has been divided into five major but overlapping clinicopathologic categories, i.e., asymptomatic, meningeal, meningovascular, parenchymatous, and gummatous. Neuropsychiatric disturbances are the most common presentation. Clinical manifestations can occur during any stage of the infection.

Early NS generally presents as meningovascular disease. Late NS is associated with chronic syphilis in the brain and spinal cord but rarely presents with classic tabes dorsalis or general paresis. Neuropsychiatric disturbances, primarily cognitive impairment and personality change, are common.

CSF Venereal Disease Research Laboratory (VDRL) tests are specific but not especially sensitive tests for NS. CSF VDRL is positive in just over 60% of cases. T. pallidum hemagglutination assay is positive in 80-85%.

Pathology. Brain syphilitic gumma is a completely curable disease, so appropriate diagnosis is essential for patient treatment.

Syphilitic gummata consist of a dense inflammatory infiltrate with large numbers of lymphocytes and plasma cells surrounding a central caseous necrotic core. Vascular proliferation, endarteritis with intimal thickening, and perivascular inflammation are characteristic findings. The definitive histologic diagnosis is obtained using fluorescent isothiocyanate-labeled monoclonal antibodies or PCR.

Gummata probably arise from excessive response of the cell- mediated immune system. Nearly two-thirds are located along brain surfaces, especially over the cerebral convexities. Direct extension from syphilitic meningovascular pial inflammation into the adjacent brain along the penetrating perivascular spaces is the probable mechanism. Dural thickening and inflammation adjacent to cerebral gummata are common.

Imaging. Two neuroimaging patterns should alert the neuroradiologist to the possible diagnosis of cerebral gummas: dural-based lesions that can mimic meningiomas and medial temporal lobe abnormalities that can mimic herpes encephalitis.

Syphilitic gummata are hypodensity or mixed-density lesions on NECT that enhance intensely on CECT. A ring-like or diffuse enhancement pattern is typical.

MR shows the gummata are hypointense on T1 and heterogeneously hyperintense on T2WI. Marked enhancement on T1 C+ is seen, and a dural "tail" is present in one-third of cases (13-67).

Meningovascular syphilis may also cause a vasculopathy with lacunar or territorial infarcts that are indistinguishable from thromboembolic strokes (13-66).

Differential Diagnosis. Because of their relative rarity, syphilitic gummata are most commonly misdiagnosed as primary or metastatic neoplasms. HIV/AIDS patients who have positive blood/CSF syphilis titers and a cerebral mass lesion with characteristic imaging findings might warrant an empiric trial of intravenous penicillin G with follow-up imaging.

SPIROCHETE CNS INFECTIONS

Lyme Disease (Neuroborreliosis) 12-15% develop CNS infection• Cranial neuropathy•

CN VII > V, III; others less common○ Can affect multiple nerves○ Smooth, linear enhancement on T1 C+○

Encephalopathy• T2/FLAIR punctate/confluent subcortical/deep white matter hyperintensities in 50%

○

Less common = tumefactive lesions ("fluffy" lesions, ring or incomplete ring enhancement)

○

Myelitis/radiculopathy• Most common manifestation in European Lyme disease

○

Patchy cord enhancement○ Multiple nerve roots may enhance○

Neurosyphilis Increasing prevalence with AIDS epidemic•

75% men having sex with men○ 50% coinfected with HIV○ Can develop even with treated uncomplicated syphilis

○

Dural-based gummas (mimics meningioma)• Medial temporal lobe lesions (mimics herpes encephalitis)

•

Emerging CNS Infections Emerging infections are diseases that are literally emerging to infect humans. Some of these are zoonoses (i.e., diseases transmitted from animals to humans), whereas others are insect borne. Most rarely affect the CNS, but, when they do, the results can be disastrous. Examples of the latter include the hemorrhagic viral fevers such as Korean hemorrhagic fever, Rift Valley fever, hantavirus, dengue, and Ebola.

Listeriosis

Listeriosis is an emerging food-borne zoonotic infection caused by Listeria monocytogenes, a gram-positive facultative intracellular bacterium that dwells in soil, vegetation, or animal reservoirs. There are six species of Listeria, only one of which—L. monocytogenes—is pathogenic in humans.

Infection, Inflammation, and Demyelinating Diseases 412

(13-68) Listeriosis shows classic findings of midbrain abscess ﬈. T2WI (L), T1 C+ (R) a few days before death show focal hyperintense mass in left cerebral peduncle with hypointense rim st, perilesional edema, ring enhancement ﬊.

(13-69) FLAIR, T2WI, and DWI illustrate imaging findings of Dengue fever with bilateral, multifocal lesions in the basal ganglia and thalami st, medial temporal lobes st, midbrain and pons ﬉, and hypothalamus ﬇. (Courtesy D. Bertholdo, MD.)

Listeria causes gastroenteritis, mother-to-fetus infection, septicemia, and CNS infection in immunocompromised individuals, pregnant women, and newborns.

CNS listeriosis shows a specific tropism for the meninges and brainstem. Symptoms include fever, headache, cranial nerve palsies, vertigo, and somnolence. Once symptoms of CNS disease develop, the mortality rate is 25-30%.

Imaging findings are generally nonspecific. CNS listeriosis can occur as meningitis, encephalitis, cerebritis, or abscess. In the appropriate clinical setting, a solitary focal midbrain, pons, or medulla T2/FLAIR hyperintense, ring-enhancing mass with significant perilesional edema should suggest the possibility of L. monocytogenes abscess (13-68).

Multiple abscesses occur in approximately 20-25% of cases. They tend to be located in the same hemisphere and appear distributed along the white matter fiber tracts of the brain. This distinct pattern may allow for earlier diagnosis and possibly improve patient outcome.

Hemorrhagic Viral Fevers

The Centers for Disease Control and Prevention (CDC) has identified six biologic agents as "category A" (easily disseminated or transmitted from person to person, resulting in high mortality rate and potential for major public health risk): anthrax, smallpox, botulism, tularemia, viral hemorrhagic fever, and plague. Of these, the viral hemorrhagic fevers are the most likely to affect the CNS (13-70).

Filoviruses such as Ebola and Marburg are single-stranded RNA viruses that cause acute hemorrhagic fever with high mortality rates. Currently, there are no licensed vaccines or therapeutics to counter human Filovirus infections.

During the 2015 Ebola epidemic in West Africa, it became apparent that many patients likely died from acute fulminant meningoencephalitis, which was not initially recognized because of multiorgan involvement. Most are never imaged. The full range of neurologic sequelae in survivors is still being characterized in ongoing studies.

Hemorrhagic fevers with known CNS complications include dengue hemorrhagic fever/dengue shock syndrome and hantavirus with renal syndrome.

The flaviviruses—primarily dengue and Zika virus—are some of the most important emerging viral infections with high global disease incidence and the potential for rapid spread beyond nonendemic regions.

Dengue is increasingly common. Transmitted by Aedes mosquitoes, approximately 40% of the world's population is at risk of infection.

The clinical spectrum of dengue ranges from asymptomatic infection to life-threatening dengue hemorrhagic fever and dengue shock syndrome. Approximately 10% of patients with serologically confirmed dengue infection develop neurologic complications. In endemic areas, dengue has become the most frequent cause of encephalitis, surpassing even Herpes simplex virus.

Imaging studies may show multiple ischemic or hemorrhagic strokes (13-69). Meningitis, encephalitis, ADEM, Guillain-Barré syndrome, and pituitary apoplexy have been reported in some cases.

Zika virus (ZIKV) is related to dengue, Chikungunya, West Nile, yellow fever, and Japanese encephalitis viruses. Brazil is the epicenter of the current ZIKV epidemic, which is rapidly

Tuberculosis and Fungal, Parasitic, and Other Infections 413

spreading across the Americas. ZIKV is primarily a vector-borne disease carried by the Aedes mosquito. ZIKV can be transmitted congenitally, sexually, and through contaminated blood.

ZIKV causes severe microcephaly in infants born to infected mothers (congenital Zika syndrome). It has been reported to cause meningoencephalitis, myelitis, and Guillain-Barré syndrome in adults. To date, reported imaging findings are nonspecific.

Many patients with hantavirus or Korean hemorrhagic fever renal syndromes develop CNS symptoms such as acute psychiatric disorders, epilepsy, and meningismus. Autopsy studies demonstrate pituitary hemorrhage in 37%, pituitary necrosis in 5%, and brainstem hemorrhage in nearly 70%. In the few reported cases, MR showed pituitary hemorrhage and reversible splenium lesion in the corpus callosum.

MISCELLANEOUS/EMERGING CNS INFECTIONS

Listeriosis Predilection for meninges, midbrain/brainstem•

Hemorrhagic Viral, Tick-Borne Disorders Filovirus infections•

Ebola, Marburg, Rift Valley○ Flavivirus infections•

Dengue, Zika virus (ZIKV), Japanese encephalitis, West Nile fever

○

Dengue = multiple hemorrhagic foci, strokes, meningoencephalitis, pituitary apoplexy

○

ZIKV = microcephaly (infants); meningoencephalitis, myelitis, Guillain-Barré (adults)

○

Togavirus• Chikungunya = axonal spread from skin/nose to limbic system, subventricle zone

○

(13-70C) More cephalad T2*SWI MIP shows additional confluent hemorrhages ﬉ and scattered microbleeds ﬈. The basal ganglia are largely spared. (13-70D) More cephalad SWI shows numerous microhemorrhages. Fulminant hemorrhagic encephalitis is most likely viral. Inciting organism was not identified despite extensive laboratory investigation.

(13-70A) Axial FLAIR in a 38y man with altered mental status, progressive decline, and a seizure shows bilateral hyperintense lesions st in the white matter of both temporal lobes. (13-70B) SWI MIP obtained several days after the patient lapsed into a coma shows bilateral lobar hematomas ﬉ and numerous scattered petechial microhemorrhages ﬈.

Infection, Inflammation, and Demyelinating Diseases 414

Selected References Mycobacterial Infections

Tuberculosis

Chandra SR et al: Factors determining the clinical spectrum, course and response to treatment, and complications in seronegative patients with central nervous system tuberculosis. J Neurosci Rural Pract. 8(2):241-248, 2017

Chaudhary V et al: Central nervous system tuberculosis: an imaging perspective. Can Assoc Radiol J. 68(2):161-170, 2017

Erdem H et al: The burden and epidemiology of community- acquired central nervous system infections: a multinational study. Eur J Clin Microbiol Infect Dis. ePub, 2017

Li D et al: Magnetic resonance imaging characteristics and treatment aspects of ventricular tuberculosis in adult patients. Acta Radiol. 58(1):91-97, 2017

Synmon B et al: Clinical and radiological spectrum of intracranial tuberculosis: a hospital based study in Northeast India. Indian J Tuberc. 64(2):109-118, 2017

Xiao Y et al: A scoring system to effectively evaluate central nervous system tuberculosis in patients with military tuberculosis. PLoS One. 12(5):e0176651, 2017

Patil S et al: Immunoconfirmation of central nervous system tuberculosis by blotting: a study of 300 cases. Int J Mycobacteriol. 4(2):124-30, 2015

Sanei Taheri M et al: Central nervous system tuberculosis: an imaging-focused review of a reemerging disease. Radiol Res Pract. 2015:202806, 2015

Psimaras D et al: Solitary tuberculous brain lesions: 24 new cases and a review of the literature. Rev Neurol (Paris). 170(6-7):454-63, 2014

Nontuberculous Mycobacterial Infections

Sood G et al: Outbreaks of nontuberculous mycobacteria. Curr Opin Infect Dis. ePub, 2017

Vu A et al: Toll-like receptors in mycobacterial infection. Eur J Pharmacol. 808:1-7, 2017

Heraud D et al: Nontuberculous mycobacterial adenitis outside of the head and neck region in children: a case report and systematic review of the literature. Int J Mycobacteriol. 5(3):351-353, 2016

Wu UI et al: A genetic perspective on granulomatous diseases with an emphasis on mycobacterial infections. Semin Immunopathol. 38(2):199-212, 2016

Chowdhary M et al: Intracranial abscess due to Mycobacterium avium complex in an immunocompetent host: a case report. BMC Infect Dis. 15:281, 2015

Lee YC et al: Mycobacterium avium complex infection-related immune reconstitution inflammatory syndrome of the central nervous system in an HIV-infected patient: case report and review. J Microbiol Immunol Infect. 46(1):68-72, 2013

Fungal Infections

Aljuboori Z et al: Fungal brain abscess caused by "black mold" (Cladophialophora bantiana) - a case report of successful treatment with an emphasis on how fungal brain abscess may be different from bacterial brain abscess. Surg Neurol Int. 8:46, 2017

Baeesa SS et al: Invasive orbital apex aspergillosis with mycotic aneurysm formation and subarachnoid hemorrhage in immunocompetent patients. World Neurosurg. 102:42-48, 2017

Swinburne NC et al: Neuroimaging in central nervous system infections. Curr Neurol Neurosci Rep. 17(6):49, 2017

Ulett KB et al: Cerebral cryptococcoma mimicking glioblastoma. BMJ Case Rep. 2017, 2017

Bakhshaee M et al: Acute invasive fungal rhinosinusitis: our experience with 18 cases. Eur Arch Otorhinolaryngol. 273(12):4281-4287, 2016

Cadena J et al: Invasive aspergillosis: current strategies for diagnosis and management. Infect Dis Clin North Am. 30(1):125- 42, 2016

Farmakiotis D et al: Mucormycoses. Infect Dis Clin North Am. 30(1):143-63, 2016

Marzolf G et al: Magnetic resonance imaging of cerebral aspergillosis: imaging and pathological correlations. PLoS One. 11(4):e0152475, 2016

Shi M et al: Fungal infection in the brain: what we learned from intravital imaging. Front Immunol. 7:292, 2016

Vallabhaneni S et al: The global burden of fungal diseases. Infect Dis Clin North Am. 30(1):1-11, 2016

Panackal AA et al: Fungal infections of the central nervous dystem. Continuum (Minneap Minn). 21(6 Neuroinfectious Disease):1662- 78, 2015

Shih RY et al: Bacterial, fungal, and parasitic infections of the central nervous system: radiologic-pathologic correlation and historical perspectives. Radiographics. 35(4):1141-69, 2015

Parasitic Infections

Carrizosa Moog J et al: Epilepsy in the tropics: emerging etiologies. Seizure. 44:108-112, 2017

Finsterer J et al: Parasitoses of the human central nervous system. J Helminthol. 87(3):257-70, 2013

Neurocysticercosis

Meng Q et al: Disseminated cysticercosis. N Engl J Med. 375(26):e52, 2016

Ripp K et al: The masquerading cyst: extraparenchymal neurocysticercosis presenting as acute meningitis. Am J Med. 129(3):e1-3, 2016

Venkat B et al: A comprehensive review of imaging findings in human cysticercosis. Jpn J Radiol. 34(4):241-57, 2016

Mahale RR et al: Extraparenchymal (racemose) neurocysticercosis and its multitude manifestations: a comprehensive review. J Clin Neurol. 11(3):203-11, 2015

Santos GT et al: Reduced diffusion in neurocysticercosis: circumstances of appearance and possible natural history implications. AJNR Am J Neuroradiol. 34(2):310-6, 2013

Echinococcosis

Bali B et al: Preoperative diagnosis of cerebral hydatid cyst and its therapeutic implications. J Neurosurg Sci. 60(1):137-9, 2016

Taslakian B et al: Intracranial hydatid cyst: imaging findings of a rare disease. BMJ Case Rep. 2016:bcr2016216570, 2016

Stojkovic M et al: Cystic and alveolar echinococcosis. Handb Clin Neurol. 114:327-34, 2013

Amebiasis

Visvesvara GS: Infections with free-living amebae. Handb Clin Neurol. 114:153-68, 2013

Tuberculosis and Fungal, Parasitic, and Other Infections 415

Malaria

Carrizosa Moog J et al: Epilepsy in the tropics: emerging etiologies. Seizure. 44:108-112, 2017

Strangward P et al: A quantitative brain map of experimental cerebral malaria pathology. PLoS Pathog. 13(3):e1006267, 2017

Wassmer SC et al: Severe malaria: what's new on the pathogenesis front? Int J Parasitol. 47(2-3):145-152, 2017

Yusuf FH et al: Cerebral malaria: insight into pathogenesis, complications and molecular biomarkers. Infect Drug Resist. 10:57- 59, 2017

Hora R et al: Cerebral malaria - clinical manifestations and pathogenesis. Metab Brain Dis. 31(2):225-37, 2016

O'Brien MD et al: Lesson of the month 1: post-malaria neurological syndromes. Clin Med (Lond). 16(3):292-3, 2016

Other Parasitic Infections

Liao H et al: Imaging characteristics of cerebral sparganosis with live worms. J Neuroradiol. 43(6):378-383, 2016

Xia Y et al: Characteristic CT and MR imaging findings of cerebral paragonimiasis. J Neuroradiol. 43(3):200-6, 2016

Yu Y et al: Cerebral sparganosis in children: epidemiologic and radiologic characteristics and treatment outcomes: a report of 9 cases. World Neurosurg. 89:153-8, 2016

Lescano AG et al: Other cestodes: sparganosis, coenurosis and Taenia crassiceps cysticercosis. Handb Clin Neurol. 114:335-45, 2013

Pittella JE: Pathology of CNS parasitic infections. Handb Clin Neurol. 114:65-88, 2013

Miscellaneous and Emerging CNS Infections

Spirochete Infections of the CNS

Garkowski A et al: Cerebrovascular manifestations of Lyme neuroborreliosis-a systematic review of published cases. Front Neurol. 8:146, 2017

Ho EL et al: Neurosyphilis increases HIV-associated central nervous system inflammation but does not explain cognitive impairment in HIV-infected individuals with syphilis. Clin Infect Dis. ePub, 2017

Koedel U et al: Lyme neuroborreliosis. Curr Opin Infect Dis. 30(1):101-107, 2017

Zhong X et al: Neuropsychiatric features of neurosyphilis: frequency, relationship with the severity of cognitive impairment and comparison with Alzheimer disease. Dement Geriatr Cogn Disord. 43(5-6):308-319, 2017

Drago F et al: Neurosyphilis: from infection to autoinflammation? Int J STD AIDS. 27(4):327-8, 2016

Firlag-Burkacka E et al: High frequency of neurosyphilis in HIV- positive patients diagnosed with early syphilis. HIV Med. 17(5):323- 6, 2016

Ramgopal S et al: Lyme disease-related intracranial hypertension in children: clinical and imaging findings. J Neurol. 263(3):500-7, 2016

Sarbu N et al: White matter diseases with radiologic-pathologic correlation. Radiographics. 36(5):1426-47, 2016

Koedel U et al: Lyme neuroborreliosis-epidemiology, diagnosis and management. Nat Rev Neurol. 11(8):446-56, 2015

Marques AR: Lyme neuroborreliosis. Continuum (Minneap Minn). 21(6 Neuroinfectious Disease):1729-44, 2015

Marra CM: Neurosyphilis. Continuum (Minneap Minn). 21(6 Neuroinfectious Disease):1714-28, 2015

Hildenbrand P et al: Lyme neuroborreliosis: manifestations of a rapidly emerging zoonosis. AJNR Am J Neuroradiol. 30(6):1079-87, 2009

Emerging CNS Infections

Billioux BJ: Neurological complications and sequelae of Ebola virus disease. Curr Infect Dis Rep. 19(5):19, 2017

Décard BF et al: Listeria rhombencephalitis mimicking a demyelinating event in an immunocompetent young patient. Mult Scler. 23(1):123-125, 2017

El-Abassi R et al: Whipple's disease. J Neurol Sci. 377:197-206, 2017

Singh MV et al: Preventive and therapeutic challenges in combating Zika virus infection: are we getting any closer? J Neurovirol. 23(3):347-357, 2017

Brasil P et al: Guillain-Barré syndrome associated with Zika virus infection. Lancet. 387(10026):1482, 2016

Pal S et al: Clinico-radiological profile and outcome of dengue patients with central nervous system manifestations: a case series in an Eastern India tertiary care hospital. J Neurosci Rural Pract. 7(1):114-24, 2016

Williamson PR et al: CNS infections in 2015: emerging catastrophic infections and new insights into neuroimmunological host damage. Lancet Neurol. 15(1):17-9, 2016

Arslan F et al: The clinical features, diagnosis, treatment, and prognosis of neuroinvasive listeriosis: a multinational study. Eur J Clin Microbiol Infect Dis. 34(6):1213-21, 2015

Bojanowski MW et al: Spreading of multiple Listeria monocytogenes abscesses via central nervous system fiber tracts: case report. J Neurosurg. 123(6):1593-9, 2015

Peregrin J et al: Primary Whipple disease of the brain: case report with long-term clinical and MRI follow-up. Neuropsychiatr Dis Treat. 11:2461-9, 2015

Compain C et al: Central nervous system involvement in Whipple disease: clinical study of 18 patients and long-term follow-up. Medicine (Baltimore). 92(6):324-30, 2013

Denizot M et al: Encephalitis due to emerging viruses: CNS innate immunity and potential therapeutic targets. J Infect. 65(1):1-16, 2012

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Chapter 14 417

HIV/AIDS In this chapter, we explore the "many faces" of HIV/AIDS as it affects the central nervous system (CNS). We start by placing the disease in its epidemiologic and demographic context, then turn our attention to the pathology and imaging spectrum of CNS HIV/AIDS.

We next discuss the manifestation of HIV itself in the brain, i.e., HIV encephalitis. We follow with a consideration of unusual but important associated findings, such as HIV vasculopathy, HIV-associated bone marrow changes, and benign salivary gland lymphoepithelial lesions.

We then consider the broad spectrum of opportunistic infections that complicate HIV/AIDS and what happens when an HIV-positive patient is also coinfected with TB, another sexually transmitted disease, or malaria.

Long-term survivors with treated AIDS and the phenomenon of immune reconstitution inflammatory syndrome (IRIS) are then presented. We conclude the chapter by discussing neoplasms that occur in the setting of HIV/AIDS (the so-called AIDS-defining malignancies).

Overview

Introduction It has been more than 30 years since a new syndrome associated with profound suppression of cell-mediated immunity was first identified. The causative agent, a retrovirus, was given the appropriate name of human immunodeficiency virus (HIV), and the syndrome it caused was named acquired immunodeficiency syndrome (AIDS).

It required nearly a decade to develop highly active multidrug, multiclass treatment regimens for HIV/AIDS. Highly active antiretroviral therapy (HAART), also called combination antiretroviral therapy (cART), has resulted in a dramatic decline in mortality for treated patients. Overall AIDS-related deaths have dropped by nearly 20% in the last 10 years.

In wealthy, industrialized countries where widespread access to HAART is readily available, HIV/AIDS has evolved from a virtual death sentence to a chronic but manageable disease. Survival in these countries has increased from a mean of 10.5 years to 22.5 years in a single decade. That's the good news. The bad news? Progress is fragile and unevenly distributed. In many less-developed "high-burden" parts of the world, HIV incidence is still rising in epidemic numbers. The personal and socioeconomic consequences of the HIV/AIDS epidemic have been devastating.

Overview 417 Introduction 417 Epidemiology 418 Demographics 418

HIV Infection 418 HIV Encephalitis 419 Other Manifestations of HIV/AIDS 423

Opportunistic Infections 426 Toxoplasmosis 426 Cryptococcosis 430 Progressive Multifocal

Leukoencephalopathy 431 Other Opportunistic Infections 436 Immune Reconstitution

Inflammatory Syndrome 439

Neoplasms in HIV/AIDS 444 HIV-Associated Lymphomas 444 Kaposi Sarcoma 445

Infection, Inflammation, and Demyelinating Diseases 418

(14-1) Coronal autopsy of HIVE shows generalized volume loss with enlargement of the lateral ventricles, sylvian fissures. "Hazy," poorly defined abnormalities are present in WM ﬊ but spare the subcortical U-fibers. (Courtesy B. K. DeMasters, MD.)

(14-2) Axial NECT scan in a 38y man with longstanding HIV/AIDS shows gross cerebral atrophy and multifocal hypodensities st in the subcortical white matter.

Epidemiology Summaries of the global AIDS epidemic indicate that, in 2015 (the most recent year for which complete data are available), the number of people living with HIV totaled over 35 million.

The enormous investments in the HIV response over the past 15 years are paying huge dividends. In 2014, new HIV infections were estimated at 2 million, 40% lower than the peak in 1997. Approximately 1.2 million infected individuals die each year from HIV/AIDS and its complications, a decrease of 42% from the peak in 2004.

Despite the notable success of the global HIV program, over 22 million infected individuals are still not accessing antiretroviral therapy. Of these, nearly 70% are in sub-Saharan Africa, and 3.4 million are children under the age of 15 years. Women now account for almost 52% of adult cases globally, and adolescent girls and young women in sub-Saharan Africa are being infected at twice the rate as that of boys and men of the same age.

These disparities mean that socioeconomic determinants of health affect both the prevalence and manifestations of HIV/AIDS. The same disease can have vastly different consequences—and therefore imaging appearances—in different parts of the world.

Although AIDS deaths are declining with the expanding access to antiretroviral therapy, these gains are being challenged by increasing morbidity and mortality associated with coinfection and comorbidity from other diseases. Tuberculosis is still the leading cause of hospitalization of adults and children living with HIV and remains the leading cause of HIV-related deaths.

Demographics HIV is transmitted through unprotected sexual intercourse (anal or vaginal), transfusion of contaminated blood, and sharing of contaminated needles, as well as between mother and infant during pregnancy, childbirth, and breastfeeding.

HIV prevalence varies widely with geography, race/ethnicity, and sex. Sub-Saharan Africa accounts for nearly 70% of the global prevalence of HIV, disproportionately affecting women and young people. As a result of improved therapeutics and monitoring, HIV infections are also a growing concern in the elderly.

The most recently available data indicate that homosexual and bisexual men remain the population most heavily affected by HIV in the United States. New infection rates have been relatively stable since 2006 but are disproportionately higher in African American men compared with African American women, as well as higher in white men compared with white women.

Individuals with sexually transmitted diseases (including chlamydia, gonorrhea, syphilis, herpes, and human papillomavirus) are more likely than uninfected persons to acquire HIV infection. Approximately 10% of patients with hepatitis C are coinfected with HIV.

HIV Infection HIV is a neurovirulent infection that has both direct and indirect effects on the CNS. Neurologic complications can arise from the HIV infection itself, from opportunistic

HIV/AIDS 419

infections or neoplasms, and from treatment-related metabolic derangements.

In this section, we consider the effects of the HIV virus itself on the brain. Extracranial manifestations of HIV/AIDS may also be identified on brain imaging studies, so we discuss these as well.

HIV Encephalitis Between 75-90% of HIV/AIDS patients have demonstrable HIV-induced brain injury at autopsy (14-1). Although many patients remain asymptomatic for variable periods, brain infection is the initial presenting symptomatology in 5-10% of cases. Approximately 25% of treated HIV/AIDS patients develop moderate cognitive impairment despite good virologic response to therapy.

Terminology

HIV encephalitis (HIVE) and HIV leukoencephalopathy (HIVL) are the direct result of HIV infection of the brain. Opportunistic infections are absent early although coinfections or multiple infections are common later in the disease course.

HIV-associated neurocognitive disorders (HANDs) are the most frequent neurologic manifestations of HIVE and HIVL. The term "acquired immunodeficiency dementia complex" refers specifically to HIV-associated dementia.

Etiology

HIV is a pathogenic neurotropic human RNA retrovirus. HIV-1 is responsible for most cases of HIV/AIDS. HIV-2 infection is predominantly a disease of heterosexuals and is found primarily in West Africa. Unless otherwise noted in this discussion, "HIV" or "HIV infection" refers to HIV-1 infection.

(14-3C) Four years later, the same patient has developed severe HIV- associated dementia. Axial T2WI shows significantly increased volume loss, reflected by the enlarged lateral ventricles and sulci. Symmetric confluent hyperintensities have developed in the cerebral white matter st and corpus callosum splenium ﬇. (14-3D) FLAIR shows the dramatic interval WM changes of severe HIV encephalitis st. U-fibers are spared.

(14-3A) Axial T2WI in a 45y man with early dementia shows minimal enlargement of the lateral ventricles and sulci. (14- 3B) Axial FLAIR shows no evidence of white matter hyperintensities.

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HIV initially infects Langerhans (dendritic) cells in the skin and mucous membranes. Its envelope protein gp120 binds to CD4 receptors in these dendritic cells, which then migrate to lymphoid tissues and infect CD4-positive T cells. The virus proliferates in and then destroys the infected T cells. A burst of viremia develops within days and leads to widespread tissue dissemination.

The two major targets of viral infection are lymphoid tissue—especially T cells—and the CNS. HIV crosses the blood- brain barrier (BBB) both as cell-free virus and infected monocytes and T cells, which migrate across the intact BBB, penetrating the brain within 24-48 hours after initial exposure.

HIV infects astrocytes but does not directly infect neurons. However, once inside the brain, the HIV-infected monocytes and T cells produce proinflammatory cytokines such as TNF and IL-1β, which in turn further activate resident microglia and astrocytes.

The CNS-resident astroglia and microglia become activated, proliferate, and change to have an inflammatory expression signature. These activated cells, along with monocyte-derived perivascular macrophages, are the main contributors to neuroinflammation in HIV infection.

Neurons can be injured indirectly by viral proteins and neurotoxins. The activated cells also release neurotoxic factors such as excitatory amino acids and inflammatory mediators, resulting in neuronal dysfunction and cell death. However, neurons can be injured indirectly by viral proteins and neurotoxins. Some non-CNS peripheral reservoirs of virus also persist and may play an active role in ongoing brain injury, even with adequate treatment.

Pathology

Gross Pathology. Brain pathology in HIV/AIDS varies with patient age and disease acuity. In early stages, the brain appears grossly normal. Advanced HIVE results in generalized

(14-4C) Axial T1 C+ FS in the same patient shows no parenchymal or meningeal enhancement. (14-4D) Axial DWI shows no evidence of restricted diffusion. The slight hyperintensity in the hemispheric white matter is not true diffusion restriction; rather, it is secondary to T2 "shine- through."

(14-4A) T2WI in a 43y man with HIV/AIDS and mild early cognitive impairment shows diffuse, confluent, bilaterally symmetric hyperintensity in the cerebral white matter st. Note sparing of the subcortical U-fibers. (14-4B) FLAIR scan in the same patient shows the "hazy" confluent white matter hyperintensity st characteristic of HIVE. No atrophy is present, and—with the exception of a single focal left parietal lesion ﬇—the subcortical WM is spared.

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brain volume loss ("atrophy") with enlarged ventricles and subarachnoid spaces (14-1).

Microscopic Features. HIVE is characterized by gliosis, microglial clusters, perivascular macrophage accumulation, and multinucleated giant cells. The multinucleated giant cells contain viral antigens and are immunoreactive for the envelope protein gp120.

Immune activation (encephalitis) is often disproportionate to the amount of HIV virus present in the brain. Disseminated patchy foci of white and gray matter damage with myelin pallor and diffuse myelin loss are prominent features.

HIVL is characterized by ill-defined, diffuse myelin pallor with poorly demarcated areas of myelin loss. Lesions are most prominent in the deep periventricular white matter and corona radiata.

Clinical Issues

Epidemiology. Almost 60% of all AIDS patients eventually develop overt neurologic manifestations. Although combination antiretroviral therapy (cART) has significantly improved survival, approximately 15-25% of treated patients develop moderate cognitive impairment or full-blown AIDS dementia complex. In countries with widespread access to cART, AIDS dementia complex has become the most common neurologic complication of HIV infection.

Demographics. Both adult and pediatric HIV-positive patients can develop HIVE. From one-third to two-thirds of adult AIDS patients and 30-50% of pediatric cases are affected. The sex distribution of HIVE reflects that of HIV and varies with geographic region.

Age is consistently identified as a risk factor for HIV-related cognitive impairment. There is growing evidence that abnormal brain proteins accumulate in HIV-positive brains.

(14-5C) After 9 years on HAART, the patient discontinued his therapy and became acutely encephalopathic. FLAIR shows confluent WM hyperintensity extending throughout both hemispheres st with involvement of U-fibers st. (14-5D) T1 C+ FS shows linear enhancement along medullary veins st with patchy subcortical enhancing foci ﬇. PCR was negative for JCV, and biopsy disclosed fulminant acute on chronic HIV encephalitis.

(14-5A) Axial T2WI in an HIV/AIDS patient on HAART shows diffuse hazy deep and periventricular WM hyperintensity st. The subcortical U-fibers are spared. (14-5B) T1 C+ in the same case shows no abnormal enhancement. This is typical HIV encephalitis.

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Excess hyperphosphorylated tau, amyloid, and α-synuclein have all been identified and may contribute to the development of accelerated neurodegenerative syndromes and AIDS dementia complex.

Presentation. Some patients develop symptoms of an acute retroviral syndrome (ARVS) during the initial viremia. ARVS develops 2-4 weeks after infection and consists of sore throat, fever, lymphadenopathy, nausea, rashes, and variable neurologic changes.

HANDs develop as intermediate and long-term complications. Early brain infection with HIV is often asymptomatic, and cognitive and functional performances are both initially normal. Full-blown HIV-associated dementia causes advanced cognitive impairment and marked impact on daily function.

Natural History. Slowly progressive impairment of fine motor control, verbal fluency, and short-term memory is characteristic. Severe deterioration and subcortical dementia may develop in the final stages.

The latency period for HIV-2 infection is generally longer, and the viral loads are lower than with HIV-1. Immunodeficiency therefore evolves more slowly.

HIV ENCEPHALITIS: TERMS, ETIOLOGY, AND CLINICAL ISSUES

Terminology HIV encephalitis (HIVE)•

Direct results of HIV brain infection○ HIV-associated neurocognitive disorders (HANDs)○ Most serious is AIDS dementia complex○

Etiology HIV is neurotropic retrovirus•

Most human infections caused by HIV-1○ HIV-2 primarily in West Africa○

Cell-free virus, HIV-infected monocytes, T cells cross blood-brain barrier in 24-48 hours

•

HIV infects astrocytes and microglia, but not neurons• Activated astrocytes, microglia + perivascular macrophages → neuroinflammation

○

Neurons indirectly injured by viral proteins, cytokines, neurotoxins

○

Clinical Issues Epidemiology•

60% of AIDS patients develop neurologic disease○ 15-25% of highly active antiretroviral therapy (HAART)-treated patients develop AIDS dementia complex

○

Presentation• Acute retroviral syndrome rare○ More common = slow progressive impairment○

Treatment Options. cART has decreased HIV/AIDS morbidity and mortality. It does not prevent development of HIVE but does decrease its overall severity.

A further advance is the potentially game-changing potential of preexposure prophylaxis (using antiretroviral drugs to prevent HIV infection). Experts believe a strategic approach

using a combination of antiretroviral therapy with preexposure prophylaxis could almost eliminate HIV transmission to HIV-negative sexual and drug-using partners.

Imaging

General Features. HIVE does not cause mass effect. Even in the post-HAART era, the most common finding remains generalized progressive volume loss that is disproportionate to the patient's age. Cortical thinning and bilateral white matter lesions are the most common parenchymal abnormalities.

CT Findings. NECT scans may be normal in the early stages. Mild to moderate atrophy with patchy or confluent white matter hypodensity develops as the disease progresses (14- 2). HIVE does not enhance on CECT.

MR Findings. Generalized volume loss with enlarged ventricles and sulci is best appreciated on T1WI or thin-section inversion recovery sequences. Reduced gray matter volume in the medial and superior frontal gyri has been identified as a possible early imaging marker for HIVE. White matter signal intensity is generally normal or near normal on T1WI.

T2/FLAIR initially shows bilateral, patchy, relatively symmetric white matter hyperintensities. With time, confluent "hazy," ill- defined hyperintensity in the subcortical and deep cerebral white matter develops, and volume loss ensues (14-3). HIVE usually does not enhance on T1 C+ and usually shows no restriction on DWI (14-4). In fulminant cases, perivenular enhancement may indicate acute demyelination (14-5).

Advanced imaging modalities may show early changes of HIVE not readily apparent on standard MR. MRS demonstrates neuronal damage as decreased NAA. mI, a marker of glial activation, is often elevated. Other reported early changes in HIVE include increased choline-to-creatine (Cho:Cr) ratios bilaterally in the frontal gray and white matter, in the left parietal white matter, and in total Cho:Cr ratio.

DTI shows that patients with AIDS-related dementia exhibit significantly elevated mean and radial diffusivity in the parietal white matter compared with nondemented patients with HIVE. Radial diffusivity is affected to a much greater extent than axial diffusivity, suggesting that demyelination is the prominent disease process in white matter.

Differential Diagnosis

The major differential diagnosis of HIVE is progressive multifocal leukoencephalopathy (PML). PML has patchy white matter lesions that can be unilateral or bilateral and appear as strikingly asymmetric hyperintensities on T2/FLAIR. Both the hemispheric and posterior fossa white matter are commonly affected. PML often involves the subcortical U- fibers, which are usually spared in HIVE.

Coinfections with other infectious agents are common in HIVE and may complicate the imaging appearance. Cytomegalovirus (CMV) can also cause a diffuse white matter encephalitis and ependymitis. Toxoplasmosis causes multifocal punctate and "target" or ring-enhancing lesions

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(14-6) Autopsy case in a hemophiliac child with AIDS and HIV vasculopathy shows striking fusiform dilatation of both middle cerebral arteries st, as well as all components of the circle of Willis. (Courtesy L. Rourke, MD.)

(14-7) Axial T2WI in a 13y boy with congenital HIV/AIDS who presented acutely with bilateral upper and lower extremity weakness and a facial droop shows markedly enlarged "flow voids" of both middle cerebral arteries ﬈.

that are more prominent in the basal ganglia. Herpes encephalitis and human herpesvirus-6 (HHV-6) encephalitis both involve the temporal lobes, especially the cortex.

HIV ENCEPHALITIS: IMAGING AND DDx

NECT Normal or atrophy ± white matter (WM) hypodensity•

MR Volume loss with ↑ sulci, ventricles• T2/FLAIR "hazy" WM symmetric hyperintensity•

Spares subcortical U-fibers○ No mass effect• Usually no enhancement•

Possible exception = acute fulminant HIVE○

Differential Diagnosis Progressive multifocal leukoencephalopathy (PML)•

Coinfection with HIVE common○ Usually asymmetric○ Often involves U-fibers○

Opportunistic infections• Coinfection with HIVE common○ CMV causes encephalitis, ependymitis○ Toxoplasmosis: Multiple enhancing rings○ Herpes, HHV-6 usually involve temporal lobes○

Other Manifestations of HIV/AIDS

Vasculopathy

Cardiovascular disease has long been recognized as a consequence of HIV infection. While the etiology and pathogenesis of the cardiovascular disease are unknown, HIV

affects every aspect of the cardiac axis, causing a spectrum of disease ranging from cardiomyopathy and myocarditis to peripheral vascular disease. HIV-associated vasculopathy is an increasingly recognized clinical entity, causing high morbidity and increasing mortality.

Stroke is an uncommon but growing cause of mortality and morbidity in HIV/AIDS patients. Autopsy series have found a 4- 29% prevalence of cerebral infarction in patients with documented HIV/AIDS. Many of these strokes are due to non- HIV CNS coinfection, lymphoma, cardioembolic sources, or primary vasculitis. Approximately 5-6% are true HIV-associated vasculopathy with small vessel intimal thickening, mineralization, and perivascular inflammatory infiltrates.

HIV vasculopathy (HIV-V) and varicella-zoster virus (VZV) vasculitis are uncommon but increasingly important causes of stroke in the HIV/AIDS population.

HIV Vasculopathy. Striking nonatherosclerotic fusiform ectasias of the major intracranial arteries occur, usually in children with congenital HIV/AIDS (14-6) (14-7). HIV-V is generally associated with large hemispheric strokes.

VZV Vasculopathy. CNS VZV vasculopathy (VZV-V) affects both large and small cerebral vessels. Large vessel disease is most common in immunocompetent individuals, whereas small vessel disease usually develops in immunocompromised patients. Overt neurologic disease often occurs months after zoster and sometimes presents without any history of zoster rash. The diagnosis can be confirmed by finding anti-VZV antibody in CSF.

HIV/AIDS patients with VZV-V are generally younger than those with HIV-V. In contrast to those associated with HIV-V, most strokes associated with VZV-V are small, deep-seated,

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subcortical infarcts. Large cortical hemispheric strokes are relatively rare.

HIV/AIDS Bone Marrow Changes

The calvaria and skull base, as well as part of the facial bones and upper cervical spine, are visible on sagittal T1-weighted brain MRs (14-8). The cranium and mandible alone account for approximately 13% of active (red) marrow in adult humans. Add the cervical spine plus facial bones, and these structures together represent 15-20% of all bone marrow activity; therefore, carefully examining all the bones visible on brain MRs may provide important information regarding hematopoietic status.

Bone marrow abnormalities are common in HIV/AIDS patients and have been implicated in the brain injury underlying cognitive deterioration and dementia. Anemia before AIDS onset is strongly predictive of HIV-associated dementia (HAD). Escalation in monocyte trafficking from bone marrow into the

brain in late-stage infection may represent a critical determinant of HAD neuropathogenesis.

Pathology. Pathologic processes alter the composition of bone marrow, causing a relative increase in cellular hematopoietic tissue and a corresponding replacement of adipose tissue. Extracellular hemosiderin, hypercellularity, and increased numbers of monocytes and macrophages all contribute significantly to marrow hypercellularity.

The most common skeletal abnormalities in HIV/AIDS patients are myelodysplasia (69% of biopsy specimens), evidence of reticuloendothelial iron blockade (65%), hypercellularity (53%), megaloblastic hematopoiesis (38%), lymphocytic aggregates (36%), plasmacytosis (25%), fibrosis (20%), and granulomas (13%). Most of the marrow abnormalities associated with HIV infection are related directly to the infection itself or its complications, not to therapeutic intervention.

(14-9B) Axial T1WI in the same case shows that the upper nasopharynx is almost completely filled with enlarged adenoidal tissue st. (14-9C) Axial T1 C+ FS shows that the enlarged tonsils st enhance strongly and uniformly.

(14-8) Other H&N manifestations of HIV/AIDS include prominent lymphoid tissue (adenoids st, tonsils ﬈, Waldeyer ring ﬊) and reconversion of yellow to red (hematopoietic) marrow in the cervical spine and skull ﬇. (14- 9A) Sagittal T1WI in a 43y man with longstanding HIV/AIDS shows unusually prominent adenoids st.

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Imaging. Subtle changes in bone marrow may be difficult to detect on conventional MR images. Imaging findings that suggest marrow abnormalities are nonspecific. The prolonged T1 relaxation times alter signal intensity of hematopoietic bone marrow. Fatty T1 hyperintense "yellow" marrow is replaced with T1 hypointense tissue. The calvaria and clivus appear mottled or "gray." The affected vertebral bodies appear hypointense relative to the intervertebral discs (the "bright disc" sign).

Hypercellular bone marrow in HIV/AIDS patients may demonstrate reduced mean diffusivity on quantitative imaging before any grossly visible changes become apparent.

Benign Lymphoepithelial Lesions

Salivary gland disease is an important manifestation of HIV infection. Most lesions represent either benign nonneoplastic lymphoepithelial cysts or reactive lymphoid hyperplasia.

Benign lymphoepithelial lesions of the salivary glands include a spectrum of disorders ranging from the lymphoepithelial sialadenitis (LESA) of Sjögren syndrome to lymphoepithelial cysts (LEC) to both HIV-related and -unrelated cystic lymphoid hyperplasia (CLH).

LESA, LEC, and CLH share a common microscopic appearance characterized by epimyoepithelial islands and/or epithelium- lined cysts in a lymphoid stroma. However, they differ greatly regarding their etiology, clinical presentation, and management.

Benign lymphoepithelial lesions of HIV (BLL-HIV) are nonneoplastic cystic masses that enlarge salivary glands. Bilateral lesions are common. The parotid glands are most frequently affected (14-10).

NECT scans show multiple bilateral well-circumscribed cysts within enlarged parotid glands. A thin enhancing rim is present on CECT scans (14-11). The cysts are homogeneously

(14-12A) Axial T2WI in a 31y HIV-positive man shows hyperplastic Waldeyer ring st, prominent deep cervical lymph nodes st, and multiple variably sized cysts ﬇ in both parotid glands. (14-12B) Axial T1 C+ FS scan in the same patient shows rim- enhancing cysts in both parotid glands ﬇ and enlarged deep cervical lymph nodes st.

(14-10) Axial graphic shows typical lymphoid and lymphoepithelial lesions of HIV/AIDS. Note the hyperplastic tonsils ﬈ and multiple cysts in the superficial and deep lobes of both parotid glands ﬊. (14-11) Axial CECT scan in a 33y man with HIV/AIDS shows a large right parotid cyst with enhancing rim st and an enlarged Waldeyer ring ﬈.

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(14-13) Axial gross pathology from an HIV-positive patient shows ill-defined toxoplasmosis abscesses in both basal ganglia ﬈. Note hemorrhage ﬊ surrounding central necrosis in the right lesion. (Courtesy R. Hewlett, MD.)

(14-14) Hematoxylin and eosin photomicrograph of toxoplasmosis reveals multiple encysted organisms ﬈. (Courtesy B. K. DeMasters, MD.)

hyperintense on T2WI and demonstrate rim enhancement on T1 C+ (14-12A).

Lymphoid Hyperplasia

Lymphoid hyperplasia is common in patients with HIV/AIDS. Immunohistochemistry, fluorescent in situ hybridization, and transmission electron microscopy have all identified HIV in lymph nodes, tonsils, and adenoidal tissue. Histologic evaluation of adenoids and tonsils excised from HIV/AIDS patients demonstrates a spectrum of changes including florid follicular hyperplasia, follicle lysis, attenuated mantle zone, and the presence of multinucleated giant cells.

Affected patients can be asymptomatic or present with a nasopharyngeal mass, nasal stuffiness or bleeding, hearing loss, or cervical lymphadenopathy.

Lymphoid hyperplasia of Waldeyer ring is the most common finding observed on brain MR. Unusually prominent tonsils and adenoids in a patient over 25-30 years of age should raise suspicion of HIV infection (14-9).

The differential diagnosis of benign reactive lymphoid hyperplasia in HIV/AIDS patients is lymphoma.

Opportunistic Infections With the advent of highly active antiretroviral therapy (HAART), the prevalence of CNS opportunistic infections has decreased five- to tenfold. Nevertheless, these infections and HIV coinfections such as tuberculosis continue to create substantial morbidity.

Toxoplasmosis Toxoplasmosis (toxo) is the most common opportunistic infection and overall cause of a mass lesion in patients with HIV/AIDS.

Terminology and Etiology

Toxo is caused by the ubiquitous intracellular parasite Toxoplasma gondii. Between 20-70% of the population is seropositive for T. gondii, so infection in HIV/AIDS patients generally represents reactivation of latent infection.

T. gondii is an obligate intracellular parasite. Although any mammal can be a carrier and act as an intermediate host, cats are the definitive host. Humans become infected when the organism is accidentally ingested. The parasites rapidly multiply as tachyzoites. When the tachyzoites invade the CNS, they become bradyzoites and form parenchymal cysts.

Pathology

Location, Size, and Number. CNS toxo most commonly involves the basal ganglia, thalami, corticomedullary junctions, and cerebellum (14-13).

Multifocal lesions are more common than solitary ones. In contrast to lymphoma, only 15-20% of toxo lesions present as solitary masses. Although large lesions do occur, most lesions are small and average between 2-3 cm in diameter.

Gross and Microscopic Features. The macroscopic appearance of CNS toxo in patients with HIV/AIDS is that of poorly circumscribed necrotizing abscesses with a hyperemic border and soft yellowish contents (14-13).

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Microscopic features include coagulative necrosis, encysted toxo organisms, numerous free tachyzoites, and minimal host inflammatory response (14-14).

Clinical Issues

Demographics. Toxo prevalence varies widely. In countries in which HAART is widely available, its prevalence has diminished fourfold over the past decade, decreasing from 25% to 3-10%.

The overall prevalence of toxo in resource-poor regions is much higher. In Africa, 35-50% of all HIV/AIDS patients develop CNS toxoplasmosis. Immunocompromised patients are most likely to develop toxo when their CD4 counts fall below 200.

Presentation. Most HIV/AIDS patients with toxo present with focal neurologic findings superimposed on symptoms of global encephalopathy such as headache, confusion, and

lethargy. Mild hemiparesis is the most common focal abnormality. Chorea is relatively rare.

Natural History and Prognosis. CNS toxo is fatal if left untreated, yet early institution of therapy can be curative. Treated patients usually improve significantly within 2-4 weeks. In resource-poor socioeconomic environments, median survival is only 28 months.

Imaging

CT Findings. The most common finding on NECT scan is multiple ill-defined hypodense lesions in the basal ganglia or thalamus with moderate to marked peripheral edema (14- 15A).

Enhancement on CECT is closely correlated to CD4 count. In patients with counts under 50, enhancement is absent or faint. Enhancement becomes more pronounced as the CD4

(14-15C) T1 C+ FS scan in the same case demonstrates irregular ring-enhancing lesions ﬇. (14-15D) More cephalad T1 C+ demonstrates a classic "target" sign lesion with a peripheral rim of enhancement st surrounding a central enhancing nodule. This is toxoplasmosis.

(14-15A) NECT in a 33y HIV-positive man in the ER with altered mental status shows hypodense masses in the left basal ganglia st and frontal lobe st with marked peripheral edema. (14- 15B) T2WI in the same case shows three separate masses ﬇ that are surrounded by marked edema and appear very heterogeneous in signal intensity. Several small hyperintensities are also present in the right basal ganglia and thalamus st.

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(14-16E) More cephalad T1 C+ FS scan in the same patient demonstrates additional enhancing lesions st, including a "target" lesion in the left basal ganglia ﬇. (14-16F) pMR scan in the same patient shows that the "tumefactive" lesion has markedly reduced relative cerebral blood volume ﬇, consistent with toxoplasmosis rather than lymphoma.

(14-16C) More cephalad FLAIR scan in the same patient shows large, heterogeneously hyperintense lesions but numerous smaller foci scattered throughout the brain in the cortex and subcortical white matter st. (14-16D) T1 C+ FS scan shows that the "tumefactive" lesion enhances strongly but heterogeneously ﬇. Several other enhancing lesions are present st.

(14-16A) T2WI in an HIV- positive patient with toxoplasmosis shows multiple hyperintense lesions in both basal ganglia st, as well as a larger confluent lesion ﬇ around the occipital horn of the right lateral ventricle. (14-16B) FLAIR scan in the same patient shows multiple small, mostly hyperintense WM lesions st. A large "tumefactive" lesion ﬊ with a hypointense rim, hyperintense center, and striking peripheral edema is present.

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count rises. Multiple punctate and ring-enhancing masses are the most common finding.

MR Findings. T1WI shows a hypointense mass that occasionally demonstrates mild peripheral hyperintensity caused by coagulative necrosis or hemorrhage.

Alternating concentric zones of hyper- and hypointensity with marked perilesional edema are seen on T2WI (14-15B). The central T2 hyperintensity corresponds histologically to necrotizing abscess. As a toxo abscess organizes, intensity diminishes, and eventually the lesion becomes isointense relative to white matter. Perilesional hyperintensity represents edema with demyelination.

One or more nodular and ring-enhancing masses are typical on T1 C+ (14-15C). A ring-shaped zone of peripheral enhancement with a small eccentric mural nodule represents the "eccentric target" sign (14-15D). The enhancing nodule is a collection of concentrically thickened vessels, whereas the

rim enhancement is caused by an inflamed vascular zone that borders the necrotic abscess cavity.

Disseminated toxoplasmosis encephalitis, also called microglial nodule encephalitis, produces multifocal T2 hyperintensities in the basal ganglia and subcortical white matter. Enhancement may be absent or minimal despite fulminant disease.

MRS findings are nonspecific and often show a lipid-lactate peak. Toxo shows reduced relative cerebral blood volume (rCBV) on SPECT and pMR scans (14-16).

Differential Diagnosis

The major differential diagnosis is primary CNS lymphoma (PCNSL). CNS toxo typically presents with multifocal lesions. AIDS-related CNS toxo also has positive findings on serology in 80% of cases, and CSF PCR is definitive. Solitary toxo lesions

(14-19) Photomicrograph shows a branching vessel cut in longitudinal section ﬊ surrounded by enlarged perivascular spaces stuffed full of cryptococcal gelatinous pseudocysts ﬈. (Courtesy B. K. DeMasters, MD.) (14- 20) Axial NECT scan in an HIV-positive patient shows hypodense basal ganglia st. (Courtesy N. Omar, MD.)

(14-17) Coronal graphic shows multiple dilated perivascular spaces ﬈ filled with gelatinous mucoid-appearing material characteristic of cryptococcal infection in HIV/AIDS patients. (14-18) Coronal autopsied brain in HIV/AIDS shows innumerable tiny cryptococcal gelatinous pseudocysts in the basal ganglia ﬊. (Courtesy A. T. Yachnis, Neuropathology, 2014.)

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are uncommon. Approximately 70% of isolated CNS masses in HIV/AIDS patients are PCNSL.

Cryptococcosis Fungal infections can be life-threatening in immunocompromised patients, especially those with HIV/AIDS. Although many different fungi can cause CNS infection, the most common fungi to affect patients with HIV/AIDS are Candida albicans, Aspergillus species, and Cryptococcus neoformans (crypto). Cryptococcosis in immunocompetent patients was briefly discussed in Chapter 13. Here we focus on its appearance in immunocompromised patients.

Etiology and Epidemiology

Crypto is excreted in mammal and bird feces and is found in soil and dust. It is a ubiquitous fungus with worldwide distribution. The lungs are usually the primary infection site.

CNS infection occurs when organisms circulating in the blood are deposited in the subarachnoid cisterns and perivascular spaces.

Crypto is the third most common CNS infectious agent in HIV/AIDS patients, after HIV and T. gondii. Prior to HAART, crypto CNS infections occurred in 10% of HIV patients, but it is now relatively rare in developed countries. Crypto usually occurs when CD4 counts drop below 50-100 cells/μL.

Pathology

CNS cryptococcal infection takes three main forms: meningitis, gelatinous pseudocysts (14-17), and focal mass lesions called cryptococcomas. Cryptococcomas and meningitis are the most common forms in immunocompetent patients, whereas meningitis and gelatinous pseudocysts are the most common forms in HIV/AIDS patients (14-18).

(14-22B) Axial T2WI in the same patient shows multiple gelatinous pseudocysts in both lenticular nuclei st, as well as the head of the right caudate nucleus ﬇. (14-22C) FLAIR scan in the same patient shows that the pseudocysts suppress. Note "hazy" hyperintensity in the cerebral white matter st consistent with HIVE. (Courtesy T. Markel, MD.)

(14-21) T2WI in the same patient as Figure 14-20 shows that the lentiform nuclei and the heads of both caudate nuclei are grossly expanded by innumerable hyperintense cysts ﬇ characteristic of cryptococcal gelatinous pseudocysts. (Courtesy N. Omar, MD.) (14-22A) Axial T2WI in a 55y man with HIV/AIDS shows enlarged perivascular spaces in both cerebral peduncles st and in the left anterior perforated substance ﬇.

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(14-23) (L) Autopsy of advanced PML shows coalescent subcortical demyelinated foci st with multiple tiny cavities ﬊. (R) FLAIR of PML shows "spongy-appearing" hyperintense subcortical WM with multiple small hypointense cysts ﬇.

(14-24) Dark infected oligodendrocytes ﬈ are concentrated at the edge of the pink-appearing demyelinated foci ﬊ in this classic microscopic image of PML. (Both cases courtesy B. K. DeMasters, MD.)

In crypto meningitis or meningoencephalitis, the meninges become thickened and cloudy. Gelatinous mucoid-like cryptococcal capsular polysaccharides and budding yeast accumulate within dilated perivascular spaces (PVSs) (14-19). Multiple gelatinous pseudocysts occur in the basal ganglia, midbrain, dentate nuclei, and subcortical white matter.

Clinical Issues

Crypto in patients with HIV/AIDS typically presents as meningitis or meningoencephalitis. Common symptoms are headache, seizure, and blurred vision. Focal neurologic deficits are uncommon.

Imaging

NECT scans often show hypodensity in the basal ganglia (14- 20). Enhancement varies with immune status. CECT scans in immunocompromised patients typically show no enhancement.

Cryptococcal gelatinous pseudocysts are hypointense to brain on T1WI and very hyperintense on T2WI (14-21). The lesions generally follow CSF signal intensity and suppress on FLAIR (14-22). Perilesional edema is generally absent. Lack of enhancement on T1 C+ is typical although mild pial enhancement is sometimes observed.

Differential Diagnosis

Enlarged PVSs are a common normal finding in virtually all patients and are seen at all ages. They can occur in clusters and typically follow CSF signal intensity. Enlarged PVSs do not enhance. In HIV/AIDS patients with CD4 counts under 20,

symmetrically enlarged PVSs should be considered cryptococcal infection and treated as such.

Toxo usually has multifocal ring- or "target"-like enhancing lesions with significant surrounding edema. Tuberculosis usually demonstrates strong enhancement in the basal meninges. Tuberculomas are generally hypointense on T2WI. Primary CNS lymphoma in HIV/AIDS patients often shows hemorrhage, necrosis, and ring enhancement. Solitary lesions are more common than multifocal involvement.

Progressive Multifocal Leukoencephalopathy

Terminology

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC virus (JCV), a member of the Papovaviridae family. The virus was named "JC" after it was first isolated from autopsied brain tissue from a patient named John Cunningham.

Over the past two decades, the spectrum of JCV CNS infection has expanded beyond "classic" PML. Some investigators have suggested distinguishing between classic PML (cPML) and inflammatory PML (iPML). Other neurotropic forms of JCV infection include JCV encephalopathy (JCE), JC meningitis (JCM), and JCV infection of the cerebellar granular layer (JCV granule cell neuronopathy).

Etiology

JCV is a ubiquitous virus that circulates widely in the environment, primarily in sewage. More than 85% of the adult population worldwide has antibodies against JCV.

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(14-25) cPML in a 32y HIV-positive man is shown. Confluent left frontal T2 hyperintensity st spares cortex, does not enhance ﬇. NECT 6 weeks later shows the left frontal lesion has increased in size st, and a new right frontal hypodensity is present ﬊.

(14-26) MR in a clinically deteriorating 46y HIV-positive patient with a CD4 count < 10 cells/μL shows a confluent nonenhancing left occipital lesion st that crosses the corpus callosum ﬇. CSF was PCR-positive for JC virus.

Asymptomatic infection is probably acquired in childhood or adolescence and remains latent until the virus is reactivated.

In some immunocompromised patients, the reactivated JCV becomes neurotropic and infects oligodendrocytes, causing a progressive demyelinating encephalopathy, i.e., PML.

Three phases in the development of PML have been identified. The first phase is the primary but clinically inapparent infection. In the second phase, the virus persists as a latent peripheral infection, primarily in the kidneys, bone marrow, and lymphoid tissue. The third phase is that of reactivation and dissemination with hematogeneous spread to the CNS.

HIV-induced immunodeficiency is now the most common predisposing factor for symptomatic JCV infection and is responsible for 80% of all cases. PML also occurs in the setting of collagen vascular disease, immunosuppression for solid organ or bone marrow transplantation, chemotherapy with rituximab for hematologic malignancies, and treatment with the immunosuppressive agent natalizumab for multiple sclerosis or Crohn's disease.

The expanding spectrum of PML now also includes patients without severe depletion of cellular immunity. This generally occurs in conditions with less overt immunodeficiency such as idiopathic CD4 lymphocytopenia, systemic lupus erythematosus, cirrhosis, psoriasis, and even pregnancy. Cases of PML in the absence of any documented immunodeficiency have also been reported.

Pathology

Location. Activated JCV almost exclusively affects oligodendrocytes, causing multifocal asymmetric

demyelination with a predilection for the frontal and parietooccipital white matter.

Size and Number. Initial PML lesions are small, generally measuring a few millimeters in diameter. As the disease progresses, small foci coalesce into confluent lesions that can occupy large volumes of white matter.

Gross Pathology. Early lesions appear as small yellow-tan round to ovoid foci at the gray-white matter junction. The cortex remains normal. With lesion coalescence, large spongy- appearing depressions in the cerebral and cerebellar white matter appear (14-23). Unlike ischemic infarcts, PML lesions are rarely completely cavitated.

Microscopic Features. Demyelination ranges from myelin pallor to severe loss. Pale-staining demyelinating foci are bordered by large infected oligodendrocytes with violaceous nuclear inclusions (14-24). With the exception of cerebellar granular neurons, neuronal infection is rare.

Clinical Issues

Epidemiology. In the pre-HAART era, PML affected between 3-7% of HIV-positive patients and caused 18% of all CNS- related AIDS deaths. The increasingly widespread use of HAART has significantly reduced the prevalence of PML in patients with HIV/AIDS. The incidence has dropped from 0.7 to 0.07 per 100 person-years in the decade since the institution of HAART.

The incidence of natalizumab-associated PML is estimated at 1:1,000. Risk increases with duration of exposure.

Presentation and Natural History. Until recently, PML was the only known manifestation of CNS JCV infection. Newly

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(14-27E) DWI shows restricted diffusion in many new white matter lesions st, whereas the centers of several older lesions ﬇—including the ring-like area in the left frontal lobe—do not restrict. (14-27F) ADC shows restriction in the active margins of inflammation st. The patient's CSF PCR was positive for JC virus. With the mass effect and subtle enhancement, this was thought to represent the inflammatory PML variant.

(14-27C) Axial T1WI shows ill-defined white matter hypointensity st with effacement of the left superficial sulci ﬇ and a focal hypointense left frontal mass st. (14- 27D) T1 C+ FS shows faint but definite enhancement around the advancing margins of several lesions ﬇.

(14-27A) 54y woman on chemotherapy for acute myeloid leukemia developed headaches and visual problems. Axial NECT shows extensive hypodense lesion occupying most of the left hemisphere WM st. Note cortical swelling ﬇, mass effect on left lateral ventricle. (14-27B) FLAIR shows confluent WM hyperintensity crossing corpus callosum, sulcal obliteration, cortical hyperintensity ﬇. Note focal ring-like lesion st in the left frontal lobe.

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recognized presentations include PML-associated immune reconstitution inflammatory syndrome (IRIS, see below). Rare presentations include JCE, JCM, and an oligodendrocyte- sparing cerebellar syndrome associated with isolated infection of cerebellar granule cell neurons ("JCV granule cell neuronopathy").

The most common symptoms of PML are altered mental status, headache, lethargy, motor deficits, aphasia, and gait difficulties. In approximately 25% of patients, PML is the initial manifestation of AIDS and can appear early in the disease course while CD4 counts are above 200 cells/μL.

PML in untreated HIV/AIDS patients is often fatal with death in 6-8 months. HAART may stabilize the disease and improve overall survival, but PML is still the second most common cause of all AIDS-related deaths, second only to lymphoma.

PML in natalizumab-treated MS carries a high morbidity and mortality rate. Drug withdrawal and plasma exchange therapy

have been used with some success to increase survival in these patients.

PML: ETIOLOGY AND PATHOLOGY

Etiology Caused by JC virus (JCV)•

Ubiquitous; > 85% of adults have JCV antibodies○ Acquired in childhood, latent until reactivated○

Most common predisposing condition = HIV (80%)• Less common = collagen vascular disease, immunosuppression, MS treated with natalizumab (20%)

•

Rare = systemic lupus erythematosus, pregnancy•

Pathology Almost exclusively affects oligodendrocytes• Multifocal demyelination•

(14-28C) Axial T1 C+ FS scan shows very faint rim enhancement around the lesions st. (14-28D) DWI in the same patient shows lesions in three different stages. The right posterior cerebellar lesion st shows no restriction, the right middle cerebellar peduncle lesion st restricts strongly and uniformly, and the left cerebellar lesion shows restriction around the lesion's rim ﬇.

(14-28A) Axial T1WI MR in a 42y HIV-positive woman with cerebellar classic PML and gait difficulties shows several hypointense lesions in the cerebellum st. Note faint hyperintensity along the margins of the more anterior cerebellar lesions ﬇. (14-28B) Axial T2WI in the same patient shows the characteristic involvement of both middle cerebellar peduncles st.

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(14-29A) 27y HIV-positive man developed acute confusion, right- sided weakness. Axial T2WI shows confluent heterogeneous hyperintensity in left cerebral WM, basal ganglia st that crosses the corpus callosum ﬇ to involve the right frontal lobe st.

(14-29B) More superior image shows the inhomogeneously hyperintense nature of the lesion st. Tiny hyperintense microcysts are present in the right frontal white matter ﬇. This is acute inflammatory PML.

Imaging

General Features. Imaging plays a key role in the diagnosis and follow-up of JCV infections. cPML can appear as solitary or multifocal widespread lesions. Any area of the brain can be affected, although the supratentorial lobar white matter is the most commonly affected site. The posterior fossa white matter—especially the middle cerebellar peduncles—is the second most common location. In occasional cases, a solitary lesion in the subcortical U-fibers is present.

Extent varies from small scattered subcortical foci to large bilateral but asymmetric confluent white matter lesions. In the early acute stage of infection, some mass effect with focal gyral expansion can be present. At later stages, encephaloclastic changes with atrophy and volume loss predominate.

CT Findings. More than 90% of cPML cases show hypodense areas in the subcortical and deep periventricular white matter on NECT (14-25); 70% are multifocal. PML lesions generally do not enhance on CECT.

MR Findings

Classic PML. Multifocal, bilateral but asymmetric, irregularly shaped hypointensities on T1WI are typical. The lesions are heterogeneously hyperintense on T2WI (14-26) and typically extend into the subcortical U-fibers all the way to the undersurface of the cortex, which remains intact even in advanced disease (14-27). Smaller, almost microcyst-like, very hyperintense foci within and around the slightly less hyperintense confluent lesions represent the characteristic spongy lesions seen in more advanced PML (14-29).

PML generally does not enhance on T1 C+ scans, although faint peripheral rim-like enhancement occurs in 5% of all cases (14-28). The exception is hyperacute PML in the setting of IRIS (see below) and in MS patients on natalizumab. In these cases, striking foci with irregular rim enhancement are frequently—but not invariably—present. Corticosteroids significantly decrease the prevalence and intensity of enhancement.

Appearance on DWI varies according to disease stage. In newly active lesions, DWI restricts strongly. Slightly older lesions show a central core with low signal intensity and high mean diffusivity (MD) surrounded by a rim of higher signal intensity and lower MD. Chronic "burned out" lesions show increased diffusion due to disorganized cellular architecture (14-28).

DTI shows reduced fractional anisotropy consistent with disorganized white matter structure. As cPML lesions are comparatively avascular, pMR demonstrates reduced rCBV compared with unaffected white matter.

Findings on MRS are nonspecific, with decreased NAA reflecting neuronal loss. Increased choline, consistent with myelin destruction, and a lipid-lactate peak from necrosis are often present. Myoinositol is variable but may be elevated, consistent with inflammatory change.

Inflammatory PML. Imaging findings in iPML are identical to those of cPML except that the lesions demonstrate peripheral enhancement and/or mass effect (14-27) (14-29). Acute iPML may have relatively increased vascularity and rCBV caused by the inflammatory angiogenic effect. In some patients, lesions may demonstrate features of iPML early and then evolve to cPML later in the disease course.

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(14-30) CMV meningoencephalitis is shown in a 32y HIV-positive man. FLAIR shows hyperintensity in both parietal lobes, corresponding restriction on DWI st. T1 C+ scans show enhancement in the posterior fossa, convexity sulci ﬇.

(14-31) T1 C+ scan in a patient with HIV encephalitis shows generalized volume loss. Note striking ependymal enhancement ﬇, atypical for HIV encephalitis. This is CMV ventriculitis.

Miscellaneous JCV infections. JCV meningitis has no distinguishing features from other meningitides, demonstrating nonspecific sulcal-cisternal hyperintensity on FLAIR and enhancement on T1 C+ FS scans.

JCE initially affects the hemispheric gray matter, then extends into the subcortical white matter. JCV infection of the cerebellar granular layer is seen as cerebellar atrophy with T2 hyperintensity in the affected folia.

PML: CLINICAL FEATURES, IMAGING, AND DDx

Clinical Features PML pre-HAART = 3-7% of HIV(+); now sharply reduced

•

Major CNS JCV syndrome = classic PML• Others = iPML, JC encephalitis/meningitis•

Imaging Multifocal WM lesions•

Bilateral but asymmetric○ Involve subcortical U-fibers○ Spare cortex○

Usually no mass, no enhancement (unless iPML)•

Differential Diagnosis HIV encephalitis (doesn't involve U-fibers)• IRIS (PML-IRIS most common)• Other opportunistic infections (e.g., cytomegalovirus)•

Differential Diagnosis

The major differential diagnosis of cPML is HIV encephalitis (HIVE). HIVE demonstrates more symmetric WM disease while

sparing the subcortical U-fibers. IRIS is usually more acute and demonstrates strong but irregular ring-like enhancement.

Other Opportunistic Infections A number of other infectious/inflammatory processes can cause or exacerbate preexisting CNS disease in patients with HIV/AIDS. These include cytomegalovirus (CMV), sexually transmitted diseases (especially neurosyphilis), tuberculosis, fungal infections, malaria, and bacterial abscesses. In this section, we focus on acquired CMV infection (congenital CMV was discussed in Chapter 12), the "deadly intersection" between HIV/AIDS and TB coinfection, and the "triple collision" when HIV, TB, and malaria all overlap.

Cytomegalovirus

CMV is a member of the herpesvirus family. While it is a ubiquitous virus, CMV typically remains latent until reactivated. Several risk factors predispose patients to the development of overt CMV CNS disease: T-cell depletion syndromes, anti-thymocyte globulin, allogenic stem cell transplants, and HIV/AIDS. All cause severe, protracted T-cell immunodeficiency.

CNS CMV is a late-onset disease in immunocompromised patients. With increasing use of HAART, less than 2% of HIV/AIDS patients develop overt symptoms of CMV infection. Patients with CD4 counts under 50 cells/μL are most at risk.

Mortality in CNS CMV is high despite therapy with a combination of antiviral drugs. Ganciclovir-resistant CMV has developed, making prophylactic therapy difficult in high-risk patients.

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In contrast to congenital CMV in which the virus causes parenchymal calcifications, acquired CMV most commonly manifests as meningoencephalitis and ventriculitis/ependymitis. Although the imaging findings of meningoencephalitis resemble those of other infections (14- 30), enhancement along the ventricular ependyma in an immunocompromised patient is highly suggestive of CMV (14-31).

Retinitis and myelitis with radiculitis are the two most frequent extracranial presentations.

Tuberculosis

TB is one of the most devastating coinfections in immunocompromised patients and is the main cause of morbidity and mortality in HIV-infected patients worldwide. The emergence of multidrug-resistant and extensively drug- resistant TB (MDR TB and XDR TB) has occurred almost entirely in patients coinfected with HIV.

More than one-third of all HIV/AIDS patients worldwide are coinfected with TB, and this deadly combination is disproportionately prevalent in highly endemic, resource- limited regions such as sub-Saharan Africa.

HIV is the most powerful known risk factor for reactivation of latent TB to active disease. HIV patients who are coinfected with TB have a 100 times greater risk of developing active TB compared with non-HIV patients. Conversely, the host immune response to TB enhances HIV replication and accelerates disease progression.

In turn, TB coinfection exacerbates the severity and accelerates the progress of HIV. In such patients, AIDS can behave as an acute fulminating illness with meningitis, bacterial abscesses, sepsis, coma, and death (14-32). Mortality approaches 100%, and median survival is measured in days to a few weeks.

(14-32C) With his immune system severely weakened, the patient became septic and developed several acute pyogenic abscesses. Note that the abscess in the temporal lobe ﬉ is relatively poorly encapsulated. (14-32D) Two other abscesses are shown in the cerebellum ﬉. The ultimate cause of death was acute overwhelming sepsis. (Courtesy R. Hewlett, MD.)

(14-32A) Series of autopsy images, all from the same patient, shows the "cascade" of catastrophes caused by HIV-TB coinfection. Several of many multiple old healed granulomas ﬈ from prior CNS TB are shown in this axial section obtained through the temporal lobe. (14-32B) The patient became HIV positive, which reactivated his latent TB, causing severe tuberculous meningitis ﬊, as seen on this view of the basilar cisterns.

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(14-33A) An HIV-positive patient with CD4 count < 50 cells/μL had rapidly progressive left-sided weakness, decreased mental status. FLAIR shows several hypointense ﬈ and 1 hyperintense st lesion with marked mass effect, significant edema ﬇.

(14-33B) Axial T1 C+ scan in the same patient shows multiple rim-enhancing masses. This severely immunocompromised patient had both granulomas st and a pseudoabscess st in the setting of fulminant reactivated TB. (Courtesy S. Candy, MD.)

TB is treated first in HIV-related infection both to preserve the effectiveness of HAART and to prevent the development of TB-IRIS (see below).

The typical imaging findings in HIV-associated CNS TB may differ slightly from those in immunocompetent patients, looking like TB "gone wild" with multiple parenchymal granulomas and pseudoabscesses (14-33).

Immunocompromised patients with CD4 counts under 200 cells/μL mount a significantly attenuated immunologic response. Although meningitis is the most common manifestation of HIV-associated CNS TB, enhancement of meningeal inflammation, tuberculomas, and pseudoabscesses are often mild or absent even though greater numbers of acid-fast bacilli are present.

Malaria

The global burden of malaria remains high, and coinfection with multiple pathogenic organisms is common in endemic areas. HIV/AIDS and malaria have a bidirectional, synergistic interaction with each magnifying the deleterious effects of the other.

Seroprevalence of HIV-1 is high in patients with severe malaria. HIV-coinfected patients generally have a higher parasite burden, more complications, and a significantly higher case mortality rate.

In-hospital parasitemia, renal impairment, and clinical deterioration are common in these coinfected patients, so early identification of both infections is important for management.

HIV, TB, and malaria are three pandemics that overlap in resource-poor tropical countries. The least deadly condition is HIV infection without the other two comorbid disorders. The most deadly combinations are HIV-TB and HIV-TB-malaria.

MISCELLANEOUS OPPORTUNISTIC INFECTIONS

Cytomegalovirus (CMV) Herpesvirus family• Develops in 2% of HIV/AIDS patients• CD4 count usually < 50 cells/μL• Imaging•

Meningitis○ Ventriculitis/ependymitis○

Tuberculosis 1/3 of HIV/AIDS patients coinfected• HIV most powerful known risk factor for reactivating latent TB

•

100x risk than for non-AIDS patients○ TB enhances HIV replication, accelerates disease•

May present as acute, fulminant, fatal infection○ TB "gone wild"○

Malaria HIV coinfection worsens outcome• "Triple combination" of HIV-TB-malaria more deadly than HIV-malaria

•

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Immune Reconstitution Inflammatory Syndrome

Terminology

CNS immune reconstitution inflammatory syndrome (IRIS) is a T-cell-mediated encephalitis that occurs in the setting of treated HIV or autoimmune disease (e.g., multiple sclerosis). CNS IRIS is also called neuro-IRIS.

Etiology

Most investigators consider neuro-IRIS a dysregulated immune response and pathogen-driven disease whose clinical expression depends on host susceptibility, the intensity and quality of the immune response, and the specific characteristics of the "provoking pathogen" itself.

IRIS occurs when forced immune reconstitution causes an exaggerated response to infectious (or sometimes noninfectious antigens) with massive destruction of virus- infected cells. IRIS develops in two distinct scenarios, "unmasking" IRIS and "paradoxical" IRIS. Both differ in clinical expression, disease management, and prognosis although their imaging manifestations are similar.

"Unmasking" IRIS occurs when antiretroviral therapy reveals a subclinical, previously undiagnosed opportunistic infection. Immune restoration leads to an immune response against a living pathogen. Here brain parenchyma is damaged by both the replicating pathogen and the incited immune response.

"Paradoxical" IRIS occurs when a patient who has been successfully treated for a recent opportunistic infection unexpectedly deteriorates after initiation of antiretroviral therapy. Here there is no newly acquired or reactivated

(14-34C) The patient deteriorated 5 weeks after beginning cART. Repeat T2WI shows enlargement of the confluent left frontal lesion ﬇ with interval appearance of innumerable punctate hyperintensities st scattered throughout the subcortical and deep white matter of both hemispheres. (14-34D) T1 C+ FS shows that the confluent ﬇ and punctate lesions st enhance. CSF was positive for JC virus. This is PML- IRIS.

(14-34A) Baseline T2WI in a 40y man with untreated HIV/AIDS for 8 years shows diffuse volume loss and bifrontal hyperintense subcortical white matter lesions with both confluent ﬇ and round st, "punctate" lesions. (14-34B) Axial T1 C+ shows that none of the lesions enhance. The patient was placed on combination antiretroviral treatment (cART).

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(14-35E) T1 C+ FS shows enhancement ﬇ along the medial side of the lesion. (14-35F) More cephalad T1 C+ FS shows additional areas of strong contrast enhancement ﬇. CSF PCR was positive for JC virus, so the imaging diagnosis of PML-IRIS was confirmed.

(14-35C) DWI in the same case shows a central area of T2 "black out" st surrounded by an irregular area of restricted diffusion ﬇ along the periphery of the lesion. (14-35D) ADC shows T2 "shine-through" st in the center of the lesion with surrounding hypointensity ﬇, indicating true restricted diffusion.

(14-35A) Axial T2WI in a 56y man with HIV/AIDS who deteriorated 8 weeks after HAART shows patchy hyperintense lesions in the pons st and major cerebellar peduncles st. (14-35B) More cephalad T2WI through the corona radiata shows a confluent hyperintense lesion st surrounded by hazy, less hyperintensity ﬇ in the right cerebral hemisphere. Note involvement of the subcortical U-fibers st.

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(14-36E) Coronal T1 C+ scan shows multiple enhancing foci at the gray-white matter interfaces, as well as a large necrotic-looking left temporal lobe mass ﬇. (14-36F) T2* GRE scan shows multiple large and small hemorrhages. This is parasite-IRIS from reactivation of latent Chagas disease.

(14-36C) Multiple heterogeneously enhancing lesions are seen at the gray-white matter interfaces of both hemispheres. (14-36D) Axial T1 C+ FS scan through the vertex shows many more lesions.

(14-36A) A 38y HIV- positive man with a remote history of cardiac Chagas disease experienced acute worsening 2 weeks following initiation of HAART. T1 C+ FS scan shows multiple ring-like ﬇ and nodular enhancing lesions st and ventriculitis st. (14-36B) More cephalad scan shows additional lesions.

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(14-37C) Following plasmapheresis and immunoadsorption treatment, the disease stabilized.

(14-37B) Three months later, symptoms had progressed. Existing lesions have enlarged, and new lesions have appeared.

(14-37A) Baseline of natalizumab-associated PML-IRIS in MS shows posterior fossa lesions st with solitary focus of punctate enhancement st.

infection. The recovering immune response targets persistent pathogen- derived antigens or self-antigens and causes tissue damage.

Several different underlying pathogens have been identified with IRIS. The most common are JC virus (PML-IRIS), tuberculosis (TB-IRIS), and fungal infections, especially Cryptococcus (crypto-IRIS). Some parasitic infections—such as toxoplasmosis—are relatively common in HIV/AIDS patients but rarely associated with IRIS.

Not all neurotropic viruses cause IRIS. HIV itself rarely causes neuro-IRIS. Herpes viruses (e.g., herpes simplex virus, varicella-zoster virus, cytomegalovirus) are all rarely reported causes of neuro-IRIS.

An unusual type of IRIS occurs in MS patients treated with natalizumab who subsequently develop PML. Natalizumab-related PML is managed by discontinuation of the drug and instituting plasmapheresis/immunoadsorption (PLEX/IA) (14-37). Neurologic deficits and imaging studies in some patients worsen during subsequent immune reconstitution, causing natalizumab-associated PML-IRIS. Two types are recognized: patients with early PML-IRIS (IRIS develops before institution of PLEX/IA) and patients with late PML-IRIS (IRIS develops after treatment with PLEX/IA). Neurologic outcome is generally worse in early PML-IRIS with a mortality rate approaching 25%.

Pathology

There are no specific histologic features or biomarkers for neuro-IRIS; rather, the diagnosis is established on the basis of clinical manifestations, exclusion of other disorders, and imaging or histopathologic evidence of inflammatory reaction.

Clinical Issues

Epidemiology. Between 15-35% of AIDS patients beginning HAART develop IRIS. Of these, approximately 1% develop neuro-IRIS. The two most important risk factors are a low CD4 count and a short time interval between treatment of the underlying infection and the commencement of antiretroviral therapy. The highest risk is in patients with a count less than 50 cells/μL.

Epidemiology varies according to the specific "provoking pathogen." The most common cause of neuro-IRIS is JC virus. Latent virus is reactivated when patients become immunodeficient. The reactivated virus infects oligodendrocytes, causing the lytic demyelination characteristic of PML. Nearly one-third of patients with preexisting PML worsen after beginning HAART and are considered to have "unmasking" PML-IRIS.

TB-IRIS occurs in 15% of patients who are coinfected with TB if antiretroviral therapy is initiated before the TB is adequately treated. Inflammasome activation underlies the immunopathogenesis of TB-IRIS. Almost 20% of TB- IRIS patients develop neurologic involvement characterized by meningitis, tuberculomas, and radiculomyelopathies. TB-IRIS is associated with a mortality rate of up to 30%.

"Paradoxical" crypto-IRIS affects 20% of HIV-infected patients in whom antiretroviral therapy was initiated after treatment of neuromeningeal cryptococcosis. The major manifestation of crypto neuro-IRIS is aseptic recurrent meningitis. Parenchymal cryptococcomas are rare.

Despite the high prevalence of parasitic infestations in resource-poor countries, only a few cases of parasite-associated neuro-IRIS have been reported. All have been caused by T. gondii.

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(14-38A) A 36y woman with TB meningitis, newly diagnosed HIV was placed on anti-TB medications. Two months later cART was initiated. She acutely deteriorated in 4 weeks. Axial T1 C+ SPGR scan shows diffuse thick basilar cistern enhancement st.

(14-38B) Sagittal T1 C+ MR of the spine shows that the TB meningitis st also involves the spinal cord ﬇. This is an example of TB-IRIS. (Courtesy S. Candy, MD.)

Natalizumab-associated IRIS is rare. To date, approximately 50 cases have been reported. Most are PML-IRIS.

Presentation. Neuro-IRIS is a polymorphic condition with heterogeneous clinical manifestations. The most common presentation is clinical deterioration of a newly treated HIV- positive patient despite rising CD4 counts and diminishing viral loads.

Natural History and Treatment Options. Given that a low CD4 T-cell count is a major risk factor for developing IRIS, starting HAART at a count of > 350/μL will prevent most cases.

Systemic IRIS is usually mild and self-limited. Prognosis in neuro-IRIS is variable. Corticosteroids and cytokine neutralization therapy have been used for treatment of neuro-IRIS with mixed results and are controversial.

Patients with neuro-IRIS may die within days to weeks. Mortality from PML-IRIS exceeds 40%, whereas that of crypto- IRIS is about 20%. TB-IRIS mortality is slightly lower (13%).

Imaging

A widespread pattern of confluent and linear or "punctate" perivascular hyperintensities on T2/FLAIR is virtually pathognomonic of PML-IRIS. A "punctate" pattern of enhancement is typical in the acute stage (14-34).

Bizarre-looking parenchymal masses and progressively enlarging, enhancing lesions are also common in PML-IRIS and are seen in slightly less than half of all cases (14-35).

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)

Terminology and Etiology Neuro-IRIS•

"Unmasking" IRIS (HAART "unmasks" existing subclinical opportunistic infection)

○

"Paradoxical" IRIS (treated infection worsens after HAART)

○

Pathogens associated with neuro-IRIS• JC virus (PML-IRIS) most common○ Tuberculosis (TB-IRIS) next most common○ Fungi (crypto-IRIS)○ Drugs (natalizumab-associated PML-IRIS)○ Parasites (rare, except for toxo-IRIS)○ Neurotropic viruses (e.g., HIV, herpesviruses) rarely cause IRIS

○

Epidemiology 15-35% of AIDS patients starting HAART develop IRIS• Of these, 1% develop neuro-IRIS• CD4 count < 50 cells/μL = sharply increased risk of IRIS•

Imaging "Punctate" pattern of T2/FLAIR hyperintensities•

"Punctate" pattern of enhancement on T1 C+○ Confluent disease extending into subcortical U-fibers•

Variable mass-like enhancement, often bizarre and "wild"

○

Differential Diagnosis Non-IRIS-associated opportunistic infections• AIDS-defining malignancies•

Especially lymphoma○

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(14-39) Autopsy case of AIDS-related PCNSL shows a solitary mass in the basal ganglia with central necrosis and peripheral hemorrhage ﬊. (Courtesy R. Hewlett, MD.)

(14-40) Axial CECT scan in a different HIV-positive patient shows a solitary mass in the left basal ganglia with central necrosis ﬇ and mild rim enhancement st. Perilesional edema is marked. Biopsy disclosed PCNSL.

TB-IRIS patients can develop florid TB pseudoabscesses (TB "gone wild") and/or rapidly increasing enhancement in the basilar meninges (14-38). Less common types of IRIS include fungal-IRIS and parasite-IRIS (14-36).

Differential Diagnosis

The major imaging differential diagnosis of neuro-IRIS is non- IRIS-associated opportunistic infection. Contrast enhancement in combination with mass effect is more typical of IRIS but may be absent early in the disease course.

Neoplasms in HIV/AIDS In HIV-positive patients, both Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8; also known as Kaposi sarcoma- associated herpesvirus or KSHV) have been implicated in the development of a wide range of tumors.

EBV is associated with several malignancies including Hodgkin and non-Hodgkin lymphomas. EBV plays an especially prominent role in the development of lymphoma in patients with HIV or transplant-related immunosuppression.

KSHV-associated diseases include Kaposi sarcoma (KS), primary effusion lymphoma, and multicentric Castleman disease.

AIDS-defining malignancies (ADMs) include non-Hodgkin lymphomas, KS, and cervical cancer. The introduction of combination antiretroviral therapy (cART) has dramatically modified the natural history of HIV infection, causing a marked decline in the incidence of ADMs. In the United States and Europe, ADMs peaked in the mid-1990s and have since

declined substantially. Recent statistics from South Africa show that, if cART is started before advanced immunodeficiency develops, the cancer burden in HIV-positive patients (especially children) can be substantially reduced.

In this text, we briefly discuss the two AIDS-defining malignancies that can affect the scalp, skull, and brain: primary central nervous system lymphomas (PCNSLs) and KS.

HIV-Associated Lymphomas Compared with other cancers, cART has had a substantial but relatively smaller impact on the prevalence of lymphoma, which remains the most common ADM in the cART era.

HIV-associated PCNSLs are typically the diffuse large B-cell non-Hodgkin type. Malignancy risk is linked to the patient's immune status and increases with CD4 counts less than 50- 100 cells/μL.

PCNSLs are the second most common cerebral mass lesion in AIDS (exceeded only by toxoplasmosis) and develop in 2-6% of patients. PCNSLs cause approximately 70% of all solitary brain parenchymal lesions in HIV/AIDS patients.

PCNSLs present as single or (less commonly) multiple masses. More than 90% are supratentorial, with preferential location in the basal ganglia and deep white matter abutting the lateral ventricle. PCNSLs often cross the corpus callosum. Central necrosis and hemorrhage are common in AIDS-related lymphomas (14-39), which is reflected in the imaging findings (14-40) (14-41D).

The major differential diagnosis is toxoplasmosis. Toxoplasmosis is more commonly multiple, and lesions often exhibit the "eccentric target" sign, i.e., an eccentrically located

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nodule within a ring-enhancing mass. DSC-pMR is helpful in distinguishing PCNSL from toxoplasmosis; lymphoma typically has increased relative cerebral blood volume (rCBV), whereas toxoplasmosis does not. PET and SPECT are also helpful imaging adjuncts, as lymphoma is "hot" but toxo is "not."

Kaposi Sarcoma KS is the most common sarcoma in immunosuppressed patients. The next most frequent non-KS sarcoma is leiomyosarcoma, followed by angiosarcoma and fibrohistiocytic tumors.

KS develops from a combination of factors: HHV-8 infection (also known as KS-associated herpesvirus), altered immunity, and an inflammatory or angiogenic milieu. EBV infection is common in patients with HIV-associated leiomyosarcomas.

There has been a marked decline in the incidence of AIDS- related KS since the advent of antiretroviral therapy.

Transplant-related KS often resolves after reduction of immunosuppression, highlighting the role of cellular immune response in the control of HHV-8 infection.

KS is the most common neoplasm in untreated AIDS patients. Overall, the most common site is the skin (14-42), followed by mucous membranes, lymph nodes, and viscera. Classic KS is an indolent tumor with purplish or dark brown plaques and nodules, usually on the extremities. AIDS-associated KS is much more aggressive. Lesions most commonly occur on the face, genitals, and mucous membranes (14-43).

Cranial KS is unusual and much less common than CNS lymphoma. When it occurs, cranial KS is typically seen as a localized scalp thickening (14-44) or an infiltrating soft tissue mass in the skin of the face and neck. Calvarial invasion is unusual. KS is isointense with muscle on T1WI, hyperintense on T2WI, and enhances strongly on CECT or T1 C+ MR.

(14-41C) Axial T1 C+ FS scan shows an irregular rim of enhancement ﬇ around the central necrotic area and an eccentric enhancing nodule st within the necrotic mass. (14-41D) Because the coronal T1 C+ showed an "eccentric target" appearance st of the lesion, imaging diagnosis was toxoplasmosis (even though a solitary lesion is statistically more likely to be PCNSL). Anti-toxo therapy was ineffective. Biopsy showed diffuse large B-cell lymphoma.

(14-41A) Axial T2WI in an HIV/AIDS patient who developed right-sided weakness shows a solitary heterogeneous mass st at the junction of the left basal ganglia and deep white matter. (14-41B) The center of the lesion is isointense ﬇ with brain on FLAIR.

Infection, Inflammation, and Demyelinating Diseases 446

(14-44) CECT scan demonstrates KS of the scalp in this AIDS patient. Note infiltration of the skin and subcutaneous tissues st.

(14-43) AIDS-related KS can present in unusual anatomic sites, like this small reddish lesion ﬈ on the upper eyelid. (Courtesy T. Mentzel, MD.)

(14-42) Clinical photograph shows classic Kaposi sarcoma (KS) presenting with multiple nodular skin lesions. (Courtesy T. Mentzel, MD.)

AIDS-DEFINING MALIGNANCIES

HIV-Associated Lymphoma Etiology and pathology•

Often associated with EBV○ Most are diffuse large B-cell non-Hodgkin lymphoma type○

Clinical issues• Second most common mass lesion in AIDS○ Occurs in 2-6% of HIV/AIDS patients○ 70% of solitary CNS masses in HIV(+) patients○

Imaging• Hemorrhage, necrosis common○ Supratentorial (90%)○ Basal ganglia, deep WM (often crosses corpus callosum)○ Often ring-enhancing○ Increased rCBV○

Kaposi Sarcoma Etiology and pathology•

Associated with HHV-8○ Most common sarcoma in immunosuppressed○

Clinical issues• Antiretrovirals seriously reduce prevalence○ Skin, mucous membranes, lymph nodes, scalp○

Imaging• Localized scalp thickening○ Infiltrating soft tissue mass in skin of face or neck○

HIV/AIDS 447

Selected References HIV Infection

Hileman CO et al: Inflammation, immune activation, and antiretroviral therapy in HIV. Curr HIV/AIDS Rep. 14(3):93-100, 2017

Henderson D et al: Neurosurgery and human immunodeficiency virus in the era of combination antiretroviral therapy: a review. J Neurosurg. 1-11, 2016

Lee AM et al: Safety and diagnostic value of brain biopsy in HIV patients: a case series and meta-analysis of 1209 patients. J Neurol Neurosurg Psychiatry. 87(7):722-33, 2016

HIV Encephalitis

Boban J et al: Proton chemical shift imaging study of the combined antiretroviral therapy impact on neurometabolic parameters in chronic HIV infection. AJNR Am J Neuroradiol. 38(6):1122-1129, 2017

Boban J et al: HIV-associated neurodegeneration and neuroimmunity: multivoxel MR spectroscopy study in drug-naïve and treated patients. Eur Radiol. ePub, 2017

Caruana G et al: The burden of HIV-associated neurocognitive disorder (HAND) in post-HAART era: a multidisciplinary review of the literature. Eur Rev Med Pharmacol Sci. 21(9):2290-2301, 2017

Cysique LA et al: White matter measures are near normal in controlled HIV infection except in those with cognitive impairment and longer HIV duration. J Neurovirol. ePub, 2017

Eggers C et al: HIV-1-associated neurocognitive disorder: epidemiology, pathogenesis, diagnosis, and treatment. J Neurol. ePub, 2017

Tang Z et al: Identifying the white matter impairments among ART-naïve HIV patients: a multivariate pattern analysis of DTI data. Eur Radiol. ePub, 2017

Vera JH et al: PET brain imaging in HIV-associated neurocognitive disorders (HAND) in the era of combination antiretroviral therapy. Eur J Nucl Med Mol Imaging. 44(5):895-902, 2017

Other Manifestations of HIV/AIDS

Diaconu IA et al: Diagnosing HIV-associated cerebral diseases - the importance of Neuropathology in understanding HIV. Rom J Morphol Embryol. 57(2 Suppl):745-750, 2016

Opportunistic Infections

Low A et al: Incidence of opportunistic infections and the impact of antiretroviral therapy among HIV-infected adults in low- and middle-income countries: a systematic review and meta-analysis. Clin Infect Dis. 62(12):1595-603, 2016

Maziarz EK et al: Cryptococcosis. Infect Dis Clin North Am. 30(1):179-206, 2016

Offiah CE et al: Spectrum of imaging appearances of intracranial cryptococcal infection in HIV/AIDS patients in the anti-retroviral therapy era. Clin Radiol. 71(1):9-17, 2016

Progressive Multifocal Leukoencephalopathy

Hodel J et al: Punctate pattern: a promising imaging marker for the diagnosis of natalizumab-associated PML. Neurology. 86(16):1516-23, 2016

Other Opportunistic Infections

Bell LC et al: In vivo molecular dissection of the effects of HIV-1 in active tuberculosis. PLoS Pathog. 12(3):e1005469, 2016

Fehintola FA et al: Malaria and HIV/AIDS interaction in Ugandan children. Clin Infect Dis. 63(3):423-4, 2016

Immune Reconstitution Inflammatory Syndrome

Marais S et al: Inflammasome activation underlying central nervous system deterioration in HIV-associated tuberculosis. J Infect Dis. 215(5):677-686, 2017

Sainz-de-la-Maza S et al: Incidence and prognosis of immune reconstitution inflammatory syndrome in HIV-associated progressive multifocal leucoencephalopathy. Eur J Neurol. 23(5):919-25, 2016

Bauer J et al: Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome (IRIS). Acta Neuropathol. 130(6):751-64, 2015

Tanaka T et al: Central nervous system manifestations of tuberculosis-associated immune reconstitution inflammatory syndrome during adalimumab therapy: a case report and review of the literature. Intern Med. 54(7):847-51, 2015

Neoplasms in HIV/AIDS

McKenna C et al: TB or not to be? Kikuchi-Fujimoto disease: a rare but important differential for TB. BMJ Case Rep. 2017, 2017

Omer A et al: An integrated approach of network-based systems biology, molecular docking, and molecular dynamics approach to unravel the role of existing antiviral molecules against AIDS- associated cancer. J Biomol Struct Dyn. 35(7):1547-1558, 2017

Bohlius J et al: Incidence of AIDS-defining and other cancers in HIV- positive children in South Africa: Record Linkage Study. Pediatr Infect Dis J. 35(6):e164-70, 2016

Sugita Y et al: Primary central nervous system lymphomas and related diseases: pathological characteristics and discussion of the differential diagnosis. Neuropathology. 36(4):313-24, 2016

Brickman C et al: Cancer in the HIV-infected host: epidemiology and pathogenesis in the antiretroviral era. Curr HIV/AIDS Rep. 12(4):388-96, 2015

Pinzone MR et al: Epstein-barr virus- and Kaposi sarcoma- associated herpesvirus-related malignancies in the setting of human immunodeficiency virus infection. Semin Oncol. 42(2):258- 71, 2015

HIV-Associated Lymphomas

Karia SJ et al: AIDS-related primary CNS lymphoma. Lancet. 389(10085):2238, 2017

Lin TK et al: Primary CNS lymphomas of the brain: a retrospective analysis in a single institute. World Neurosurg. ePub, 2017

Kaposi Sarcoma

Auten M et al: Human herpesvirus 8-related diseases: histopathologic diagnosis and disease mechanisms. Semin Diagn Pathol. 34(4):371-376, 2017

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Chapter 15 449

Demyelinating and Inflammatory Diseases In the previous chapters, we discussed congenital and acquired infections. Here, we focus on the surprisingly broad spectrum of noninfectious inflammatory, autoimmune/autoantibody-mediated, and demyelinating disorders that can affect the CNS.

CNS inflammatory syndromes have been classified in numerous ways: by presentation (clinically isolated vs. polysymptomatic disease), pattern (monofocal or multifocal), geography (brain vs. spinal cord vs. peripheral nervous system), disease severity (from asymptomatic to severe), and disease course (monophasic, multiphasic, relapsing-remitting, progressive, etc.).

In this chapter, we follow a simplified approach, dividing our discussion into multiple sclerosis (MS) and its variants, postinfection/postvaccination inflammatory disorders, autoimmune/autoantibody-mediated disorders, and inflammatory-like disorders such as neurosarcoidosis and pseudotumors.

We begin with MS, delineating its etiology and pathology, epidemiology and clinical phenotypes, imaging appearance, and differential diagnosis. Following our detailed discussion of MS itself, we delineate several special variants such as Marburg and Schilder disease and Balo concentric sclerosis.

We then turn our attention to postinfection and postvaccination inflammatory syndromes. We focus on two particularly important entities: Acute disseminated encephalomyelitis (ADEM) and the fulminant, highly lethal acute hemorrhagic encephalomyelitis (AHEM).

The recent recognition of autoimmune encephalitis and autoantibody- mediated diseases as important disorders with overlapping neurological and imaging features is then addressed. Here we discuss neuromyelitis optica (also known as Devic disease or aquaporin-4 antibody disease) and nonparaneoplastic autoantibody-mediated CNS disorders such as anti-GAD limbic encephalitis. Susac syndrome—an immune-mediated microvascular endotheliopathy that can closely resemble MS—is also included here.

The chapter concludes by discussing three important inflammatory-like disorders of unknown or uncertain etiology: neurosarcoidosis, idiopathic inflammatory pseudotumors, and chronic inflammatory demyelinating polyneuropathy.

Multiple Sclerosis and Variants The growing recognition that multiple sclerosis (MS) is not a single entity but a clinical spectrum comprising different subtypes has led to shifting paradigms in understanding its pathogenesis and implementing personalized, patient-centered treatment strategies.

Multiple Sclerosis and Variants 449 Multiple Sclerosis 450 Multiple Sclerosis Variants 461

Postinfection and Postimmunization Demyelination 464

Acute Disseminated Encephalomyelitis 464

Acute Hemorrhagic Leukoencephalitis 469

Autoimmune Encephalitis 472 Autoimmune Encephalitis 472 Guillain-Barré Spectrum Disorders 474 Neuromyelitis Optica Spectrum

Disorder 474 Susac Syndrome 478 CLIPPERS 481

Inflammatory-Like Disorders 482 Neurosarcoidosis 482 Intracranial Inflammatory

Pseudotumors 486 IgG4-Related Disease 489 Chronic Inflammatory

Demyelinating Polyneuropathy 489

Infection, Inflammation, and Demyelinating Diseases 450

Multiple Sclerosis

Terminology

MS is a progressive neurodegenerative disorder characterized histopathologically by multiple inflammatory demyelinating foci called "plaques."

Etiology

General Concepts. MS is a multifactorial disease whose precise pathogenesis remains unknown. It is influenced by a complex interplay of genetic susceptibility and epigenetic and postgenomic events. Environmental factors with diverse, population-specific levels of prevalence-latitude gradient also play a prominent role.

Autoimmune-Mediated Demyelination. Immune dysregulation in MS involves "cross-talk" between the innate and adaptive immune systems. Dendritic cells (DCs) function

as antigen-presenting cells. Antigen binding to their surface activates the DCs, which then migrate across the BBB and communicate with naive CD4+ T cells. Proinflammatory cytokines and T-cell-mediated macrophage and resident microglia activation play a critical role in inflammatory demyelination, both in the initial and sustained immune responses to myelin antigens.

Environmental Factors. Epstein-Barr virus (EBV) exposure, chemicals, smoking, diet, and geographic variability all contribute to MS risk.

The risk of MS also varies across race and geographic regions. MS occurs less often in nonwhites compared with whites. MS frequency also increases with increasing latitude and is most common in temperate climates.

Genetics. MS is a partially heritable autoimmune disease. The strongest identified genetic risk factor is the human leukocyte antigen (HLA-A) gene with different HLA alleles in different

(15-3) Coronal autopsied brain shows periventricular patchy ﬈ and confluent ﬊ demyelinating plaques. Ovoid plaques ﬉ demonstrate the characteristic perpendicular orientation along medullary veins. Note atrophy with moderate ventricular and sulcal enlargement. (R. Hewlett, MD.) (15-4) Extensive confluent demyelinating plaques in the pons ﬈ are present in this autopsied MS case. (Courtesy R. Hewlett, MD.)

(15-1) Sagittal graphic illustrates multiple sclerosis plaques involving the corpus callosum, pons, and spinal cord. Note the characteristic perpendicular orientation of the lesions ﬈ at the callososeptal interface along penetrating venules. (15-2) Sagittal autopsied brain in a case with chronic multiple sclerosis (MS) shows a thinned corpus callosum with multiple lesions at the callososeptal interface.

Demyelinating and Inflammatory Diseases 451

subpopulations and ethnicities. Genome-wide association studies have pinpointed nearly 200 single nucleotide polymorphisms that contribute to MS pathogenesis. However, all the identified risk loci together account for only 50% of the inherited MS risk.

Epigenetic modifications represent the bridge between genetic and environmental factors, but their precise role in MS initiation, progression, and response to treatment remains to be elucidated.

Pathology

Location. Most MS plaques are supratentorial. Less than 10% occur in the posterior fossa although infratentorial lesions are relatively more common in children.

MS plaques in the deep cerebral white matter are linear, round, or ovoid lesions that are oriented perpendicular to the lateral ventricles (15-1) (15-5). Between 50-90% of all supratentorial lesions occur at or near the callososeptal interface and adjacent to the lateral ventricles (15-2) (15-3). Centripetal perivenular extension is common, causing the appearance of "Dawson fingers" radiating outward from the lateral ventricles.

Other commonly affected areas include the subcortical U- fibers, brachium pontis, brainstem (15-4), and spinal cord. Gray matter (cortex and basal ganglia) lesions are seen in 10% of cases.

Gross Pathology. Acute MS plaques are a tan-yellow color and have ill-defined margins with a granular texture. Chronic inactive plaques have more distinctly defined borders and are grayish in color with scarred and excavated, depressed centers (15-6).

MULTIPLE SCLEROSIS

Location Supratentorial (90%), infratentorial (10%) (higher in children)

•

Deep cerebral/periventricular white matter• Predilection for callososeptal interface• Perivenular extension (Dawson fingers)•

Size and Number Multiple > solitary• Mostly small (5-10 mm)• Giant "tumefactive" plaques can be several centimeters

•

30% of "tumefactive" MS lesions solitary○

Microscopic Features. Histopathologically, MS plaques typically demonstrate (1) relatively sharp borders, (2) macrophage infiltrates (both interstitial and perivascular), and (3) perivascular chronic inflammation (15-7) (15-8). Photomicrographs with Luxol fast blue stains contrast the "robin's-egg blue" of normally myelinated white matter (15-9) and the pale-staining, almost pinkish areas of myelin loss (15- 10).

Acute lesions are often hypercellular, with foamy macrophages and prominent perivascular T-cell lymphocytic cuffing. Normal-appearing white matter also frequently demonstrates changes, including microglial activation, T-cell infiltration, and perivascular lymphocytic cuffing.

Chronic plaques range from chronic active to chronic silent lesions. Chronic active lesions have continuing inflammation around their outer borders. Chronic silent ("burned out")

(15-5) Axial autopsy section shows typical ovoid, grayish MS plaques oriented perpendicularly and adjacent to the lateral ventricles ﬈, along medullary (deep white matter) veins ﬊. (Courtesy R. Hewlett, MD.)

(15-6) Close-up axial view of autopsied brain shows confluent periventricular demyelinating plaques ﬈. (Courtesy R. Hewlett, MD.)