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Infection, Inlammation, and Demyelinating Diseases

Section 3

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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

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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.

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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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Infection, Inflammation, and Demyelinating Diseases
330

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.)

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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

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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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Congenital, Acquired Pyogenic, and Acquired Viral Infections
333

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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Infection, Inflammation, and Demyelinating Diseases
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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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Congenital, Acquired Pyogenic, and Acquired Viral Infections
335

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).

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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Infection, Inflammation, and Demyelinating Diseases
336

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.

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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++.

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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

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(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

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Infection, Inflammation, and Demyelinating Diseases
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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.

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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.)

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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 ﬇.

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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

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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.)

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Infection, Inflammation, and Demyelinating Diseases
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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.

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Congenital, Acquired Pyogenic, and Acquired Viral Infections
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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.

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Infection, Inflammation, and Demyelinating Diseases
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(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
﬉.

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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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Infection, Inflammation, and Demyelinating Diseases
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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○

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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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Congenital, Acquired Pyogenic, and Acquired Viral Infections
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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.)

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(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.

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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,

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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

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(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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Infection, Inflammation, and Demyelinating Diseases
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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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Infection, Inflammation, and Demyelinating Diseases
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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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Congenital, Acquired Pyogenic, and Acquired Viral Infections
371

(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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Infection, Inflammation, and Demyelinating Diseases
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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

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(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.

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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•

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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.

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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

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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

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Infection, Inflammation, and Demyelinating Diseases
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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.)

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Tuberculosis and Fungal, Parasitic, and Other Infections
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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•

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Infection, Inflammation, and Demyelinating Diseases
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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.

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Tuberculosis and Fungal, Parasitic, and Other Infections
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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.

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Infection, Inflammation, and Demyelinating Diseases
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(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○

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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.)

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Infection, Inflammation, and Demyelinating Diseases
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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.

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Tuberculosis and Fungal, Parasitic, and Other Infections
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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

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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.

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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 ﬇.

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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.

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(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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Tuberculosis and Fungal, Parasitic, and Other Infections
393

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.)

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Infection, Inflammation, and Demyelinating Diseases
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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.

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Tuberculosis and Fungal, Parasitic, and Other Infections
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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.

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(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.

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(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).

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(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

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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.

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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.

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(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.

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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.

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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.

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(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

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Tuberculosis and Fungal, Parasitic, and Other Infections
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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 ﬈.

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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

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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

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Infection, Inflammation, and Demyelinating Diseases
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(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

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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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Infection, Inflammation, and Demyelinating Diseases
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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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Infection, Inflammation, and Demyelinating Diseases
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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.

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(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○

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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

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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.

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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.)

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Section 3:
Infection, Inflammation, and Demyelinating Diseases

Chapter 11.
Approach to Infection, Inflammation, and Demyelination
CNS Infections
HIV/AIDS
Demyelinating and
Inflammatory Diseases
Chapter 12.
Congenital, Acquired Pyogenic, and Acquired Viral Infections
Congenital Infections
Acquired Pyogenic
Infections
Acquired Viral Infections
Selected References
Chapter
13. Tuberculosis and Fungal, Parasitic, and Other Infections
Mycobacterial Infections
Fungal Infections
Miscellaneous and
Emerging CNS Infections
Selected References
Chapter 14.
HIV/AIDS
Overview
HIV Infection
Opportunistic Infections
Neoplasms in HIV/AIDS
Selected References
Chapter
15. Demyelinating and Inflammatory Diseases
Multiple Sclerosis and Variants

Congenital, Acquired Pyogenic, and Acquired Viral Infection:

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 empyema.

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

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 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.
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. Many 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 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 most 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 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., hypo intensity) (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

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