# 21 - 142 Encephalitis

### 142 Encephalitis

up to one-fourth infected. Persons who transmit infection or who have 
recently been infected and are still in the incubation period usually 
have no symptoms or only mild symptoms and seek medical attention 
only when notified of their exposure. Therefore, the clinician must 
encourage patients to participate in partner notification, must ensure 
that exposed persons are notified and treated, and must guarantee 
confidentiality to all involved. In the United States, local health departments often offer assistance in partner notification, treatment, and/
or counseling. It seems both feasible and most useful to notify those 
partners exposed within the patient’s likely period of infectiousness, 
which is often considered the preceding 1 month for gonorrhea, 1–2 
months for chlamydial infection, and up to 3 months for early syphilis.
Persons with a new-onset STI have a source contact who gave 
them the infection; in addition, they may have a secondary (spread or 
exposed) contact with whom they had sex after becoming infected. The 
identification and treatment of these two types of contacts have different objectives. Treatment of the source contact (often a casual contact) 
benefits the community by preventing further transmission and benefits the source contact; treatment of the recently exposed secondary 
contact (typically a spouse or another steady sexual partner) prevents 
the development of serious complications (such as PID) in the partner, 
reinfection of the index patient, and further spread of infection. A 
randomized trial compared patients’ delivery of therapy to partners 
exposed to gonorrhea or chlamydial infection with conventional notification and advice to partners to seek evaluation for STD; patients’ 
delivery of partners’ therapy, also known as expedited partner therapy 
(EPT), significantly reduced combined rates of reinfection of the index 
patient with N. gonorrhoeae or C. trachomatis. EPT, which is now commonly used by many practicing physicians, is currently permissible 
in 46 states and potentially allowable in the remaining four. (Updated 
information on the legal status of EPT is available at https://www 
.cdc.gov/sti/hcp/clinical-guidance/expedited-partner-therapy.html?CDC_
AAref_Val=https://www.cdc.gov/std/ept/.)
In summary, clinicians and public health agencies share responsibility for the prevention and control of STIs. In the current health care 
environment, the role of primary care clinicians has become increasingly important in STI prevention as well as in diagnosis and treatment, 
and the resurgence of bacterial STIs like congenital syphilis—particularly 
in the setting of HIV co-infection—emphasizes the need for risk 
assessment and routine screening.
Acknowledgment
The author wishes to acknowledge King K. Holmes, MD, PhD, for his 
valuable contributions to this chapter in prior editions.
■
■FURTHER READING
Cannon CA et al: On the horizon: Novel approaches to sexually transmitted infection prevention. Med Clin North Am 108:403, 2024.
Gottlieb SL et al: Advancing vaccine development for gonorrhoea 
and the Global STI Vaccine Roadmap. Sex Health 16:426, 2019.
Johnston C, Corey L: Current concepts for genital herpes simplex 
virus infection: Diagnostics and pathogenesis of genital tract shedding. Clin Microbiol Rev 29:149, 2016.
Kirkcaldy RD et al: Neisseria gonorrhoeae antimicrobial resistance 
among men who have sex with men and men who have sex exclusively with women: The Gonococcal Isolate Surveillance Project, 
2005–2010. Ann Intern Med 158:321, 2013.
Mlisana K et al: Symptomatic vaginal discharge is a poor predictor 
of sexually transmitted infections and genital tract inflammation in 
high-risk women in South Africa. J Infect Dis 206:6, 2012.
Price MJ et al: Risk of pelvic inflammatory disease following Chlamydia trachomatis infection: Analysis of prospective studies with a 
multistate model. Am J Epidemiol 178:484, 2013.
Tuddenham S et al: Diagnosis and treatment of sexually transmitted 
infections: A review. JAMA 327:161, 2022.
Unemo M et al: Sexually transmitted infections: Challenges ahead. 
Lancet Infect Dis 17:e235, 2017.
U.S. Preventive Services Task Force: Screening for chlamydia and 
gonorrhea: US Preventive Services Task Force Recommendation 
Statement. JAMA 326:949, 2021.

U.S. Preventive Services Task Force: Behavioral counseling inter-

ventions to prevent sexually transmitted infections. JAMA 324:674, 
2020.
Wiesenfeld HC et al: A randomized controlled trial of ceftriaxone 
and doxycycline, with or without metronidazole, for the treatment of 
acute pelvic inflammatory disease. Clin Infect Dis 13:ciaa101, 2020.
Workowski KA, Bachmann L: Sexually transmitted disease treatment 
guidelines, 2021. MMWR Recomm Rep 70:1, 2021.
Karen L. Roos, Michael R. Wilson,  
Kenneth L. Tyler

Encephalitis
■
■DEFINITION
Encephalitis is defined as an inflammation of the brain caused either 
by infection, usually with a virus, or from a primary autoimmune process. This chapter will focus on infectious causes of encephalitis. Many 
patients with encephalitis also have evidence of associated meningitis 
(meningoencephalitis) and, in some cases, involvement of the spinal 
cord or nerve roots (encephalomyelitis, encephalomyeloradiculitis).
CHAPTER 142
■
■CLINICAL MANIFESTATIONS
Similar to meningitis, encephalitis is typically an acute febrile illness. 
The patient with encephalitis commonly has an altered state of consciousness (confusion, behavioral abnormalities), or a depressed level 
of consciousness ranging from mild lethargy to coma, and evidence of 
either focal or diffuse neurologic signs and symptoms. Patients with 
encephalitis may have hallucinations, agitation, personality change, 
behavioral disorders, and, at times, a frankly psychotic state. Focal 
or generalized seizures occur in many patients with encephalitis. 
Virtually every possible type of focal neurologic disturbance has been 
reported in viral encephalitis; the signs and symptoms reflect the sites 
of infection and inflammation. The most commonly encountered focal 
findings are aphasia, ataxia, upper or lower motor neuron patterns of 
weakness, involuntary movements (e.g., myoclonic jerks, tremor), and 
cranial nerve deficits (e.g., ocular palsies, facial weakness). Involvement of the hypothalamic-pituitary axis may result in temperature 
dysregulation, diabetes insipidus, or the development of the syndrome 
of inappropriate secretion of antidiuretic hormone (SIADH). Even 
though neurotropic viruses typically cause injury in distinct regions of 
the central nervous system (CNS), variations in clinical presentations 
make it impossible to reliably establish the etiology of a specific case 
of encephalitis on clinical grounds alone (see “Differential Diagnosis,” 
below).
Encephalitis
■
■ETIOLOGY
In the United States, there are an estimated ~20,000 cases of encephalitis per year, although the actual number of cases is likely to be 
significantly higher. Despite comprehensive diagnostic efforts, most 
cases of acute encephalitis with a suspected viral etiology remain of 
unknown cause. Hundreds of viruses are capable of causing encephalitis, although only a limited subset is responsible for most cases in 
which a specific cause is identified (Table 142-1). The most commonly 
identified viruses causing sporadic cases of acute encephalitis in immunocompetent adults are herpesviruses (herpes simplex virus [HSV] 
[Chap. 197], varicella-zoster virus [VZV] [Chap. 198], and EpsteinBarr virus [EBV] [Chap. 199]). Epidemics of encephalitis are caused 
by arboviruses (Chap. 215), which belong to several different viral 
taxonomic groups including Alphaviruses (e.g., eastern equine encephalitis [EEE] virus and chikungunya virus), Flaviviruses (e.g., West Nile 
virus [WNV], St. Louis encephalitis virus, Japanese encephalitis virus,

TABLE 142-1  Viruses Causing Acute Encephalitis in North America
COMMON
LESS COMMON
Herpesviruses
  Cytomegalovirusa
Rabies
Eastern equine encephalitis virus
Powassan virus
Cytomegalovirusa
  Herpes simplex virus 1b
  Herpes simplex virus 2
  Human herpesvirus 6
  Varicella-zoster virus
  Epstein-Barr virus
Colorado tick fever virus
Mumps
Jamestown Canyon virus
Arthropod-borne viruses
  La Crosse virus
  West Nile virusc
  St. Louis encephalitis virus
  Zika
Enteroviruses
aImmunocompromised host. bThe most common cause of sporadic encephalitis. 
cThe most common cause of epidemic encephalitis.
Powassan virus, Zika virus, dengue virus, and tick-borne encephalitis 
virus), and Bunyaviruses (e.g., California encephalitis virus serogroup, 
La Crosse virus, Jamestown Canyon virus). Historically, the largest 
number of cases of arbovirus encephalitis in the United States has been 
due to St. Louis encephalitis virus and the California encephalitis virus 
serogroup. However, since 2002, WNV has been responsible for the 
majority of arbovirus meningitis and encephalitis cases in the United 
States. WNV caused 28,684 confirmed cases of neuroinvasive disease 
(encephalitis, meningitis, or myelitis) in the years 1999–2022 with 
2641 deaths. In 2023, there were 1599 reported cases of neuroinvasive 
disease (encephalitis, meningitis, acute flaccid paralysis). The majority 
of cases occur in August and September. It is important to recognize 
that WNV epidemics are unpredictable and that cases have occurred 
in every state in the continental United States. Since 2006, there have 
been increasing numbers of cases of the tick-borne Powassan virus 
primarily in the northeastern United States and Minnesota and Wis­
consin. New causes of viral CNS infections are constantly appearing, as 
evidenced by multiple outbreaks of cases of encephalitis in Southeast 
Asia caused by Nipah virus, a member of the Paramyxoviridae family; 
meningitis in Europe caused by Toscana virus, an arbovirus belonging 
to the Bunyavirus family; neurologic disorders associated with Zika 
virus, a flavivirus, in South America; and neurologic disorders associ­
ated with major epidemics of chikungunya virus, a togavirus, in Africa, 
India, and Southeast Asia. Dengue virus is common in >100 countries 
worldwide with cases on the rise in the Caribbean and Puerto Rico 
and rare cases reported in the United States in Florida and in south­
ern Texas. Parechoviruses including human parechovirus 3 (HPeV3), 
members of the Picornavirus family, have been reported as causes of 
fever, sepsis, and meningitis in infants (age <3 months) in the United 
States and abroad.
PART 5
Infectious Diseases
■
■LABORATORY DIAGNOSIS
CSF Examination 
Cerebrospinal fluid (CSF) examination should 
be performed in all patients with suspected viral encephalitis unless 
contraindicated by the presence of severely increased intracranial 
pressure (ICP). Ideally, at least 20 mL of the initial CSF sample should 
be collected, with 5–10 mL stored frozen for later studies, including 
additional direct detection tests like virus-specific polymerase chain 
reaction (PCR) or metagenomic next-generation sequencing, since 
many neuroinvasive viruses are only transiently present in the CSF. The 
characteristic CSF profile is indistinguishable from that of viral men­
ingitis (Chap. 143) and typically consists of a lymphocytic pleocytosis, 
a mildly elevated protein concentration, and a normal glucose concen­
tration. A CSF pleocytosis (>5 cells/μL) occurs in >95% of immuno­
competent patients with documented viral encephalitis. In rare cases, 
a pleocytosis may be absent on the initial lumbar puncture (LP) but 
present on subsequent LPs. Patients who are severely immunocompro­
mised by HIV infection, glucocorticoid or other immunosuppressant 

drugs, chemotherapy, or lymphoreticular malignancies may fail to 
mount a CSF inflammatory response. CSF cell counts exceed 500/μL 
in only about 10% of patients with encephalitis. Infections with certain 
arboviruses (e.g., EEE virus or California encephalitis virus), mumps, 
and lymphocytic choriomeningitis virus (LCMV) may occasionally 
result in cell counts >1000/μL, but this degree of pleocytosis should 
suggest the possibility of nonviral infections or other inflammatory 
processes. Atypical lymphocytes in the CSF may be seen in EBV infec­
tion and less commonly with other viruses, including cytomegalovirus 
(CMV), HSV, and enteroviruses. Increased numbers of plasmacy­
toid or Mollaret-like large mononuclear cells have been reported in 
WNV encephalitis. Polymorphonuclear pleocytosis occurs in ~45% of 
patients with WNV encephalitis and is also a common feature in CMV 
myeloradiculitis in immunocompromised patients. Large numbers of 
CSF polymorphonuclear leukocytes may be present in patients with 
encephalitis due to EEE virus, echovirus 9, and, more rarely, other 
enteroviruses. However, persisting CSF neutrophilia should prompt 
consideration of bacterial infection, leptospirosis, amebic infection, 
and noninfectious processes such as acute hemorrhagic leukoencepha­
litis (Chap. 456). About 20% of patients with encephalitis will have a 
significant number of red blood cells (>500/μL) in the CSF in a non­
traumatic tap. The pathologic correlate of this finding may be punctate 
microhemorrhages of the type seen with HSV; however, CSF red blood 
cells occur with similar frequency and in similar numbers in patients 
with nonherpetic focal encephalitides. A decreased CSF glucose con­
centration is distinctly unusual in viral encephalitis and should suggest 
the possibility of bacterial, fungal, tuberculous, parasitic, leptospiral, 
syphilitic, sarcoid, or neoplastic meningitis. Rare patients with mumps, 
LCMV, VZV, or advanced HSV encephalitis and many patients with 
CMV myeloradiculitis have low CSF glucose concentrations.
■
■CSF POLYMERASE CHAIN REACTION
CSF PCR has become the primary diagnostic test for CNS infections 
caused by HSV, CMV, EBV, HHV-6, and enteroviruses. In the case of 
VZV CNS infection, CSF PCR and detection of virus-specific IgM or 
intrathecal antibody synthesis both provide important aids to diag­
nosis. The sensitivity and specificity of CSF PCRs vary with the virus 
being tested. The sensitivity (~96%) and specificity (~99%) of HSV 
CSF PCR are equivalent to or exceed those of brain biopsy. It is impor­
tant to recognize that HSV CSF PCR results need to be interpreted 
after considering the likelihood of disease in the patient being tested, 
the timing of the test in relationship to onset of symptoms, and the 
prior use of antiviral therapy. A negative HSV CSF PCR test performed 
by a qualified laboratory at the appropriate time during illness in a 
patient with a high likelihood of HSV encephalitis based on clinical 
and laboratory abnormalities significantly reduces the likelihood of 
HSV encephalitis but does not exclude it. For example, in a patient 
with a pretest probability of 35% of having HSV encephalitis, a nega­
tive HSV CSF PCR reduces the posttest probability to ~2%, and for a 
patient with a pretest probability of 60%, a negative test reduces the 
posttest probability to ~6%. In both situations, a positive test makes the 
diagnosis almost certain (98–99%). There have been reports of initially 
negative HSV CSF PCR tests that were obtained early (≤72 h) follow­
ing symptom onset and that became positive when repeated 1–3 days 
later. The frequency of positive HSV CSF PCRs in patients with herpes 
encephalitis also decreases as a function of the duration of illness, with 
only ~20% of cases remaining positive after ≥14 days. PCR results are 
generally not affected by ≤1 week of antiviral therapy. In one study, 
98% of CSF specimens remained PCR positive during the first week 
of antiviral therapy, but the numbers fell to ~50% by 8–14 days and to 
~21% by >15 days after initiation of antiviral therapy.
The sensitivity and specificity of CSF PCR tests for viruses other 
than HSV have not been definitively characterized. Enteroviral (EV) 
CSF RT-PCR appears to have a sensitivity and specificity of >95%. EV 
RT-PCR sensitivity for EV-A71 may be considerably lower (~30% in 
some reports). Patients with EV-D68-associated acute flaccid myelitis 
(AFM) only rarely have a positive CSF RT-PCR (<3%) but may have a 
positive test on nasopharyngeal swab specimens. Parechoviruses are 
also not detected by standard EV RT-PCRs. The specificity of EBV

CSF PCR has not been established. Positive EBV CSF PCRs associ­
ated with positive tests for other pathogens have been reported and 
may reflect reactivation of EBV latent in lymphocytes that enter the 
CNS as a result of an unrelated infectious or inflammatory process. In 
patients with CNS infection due to VZV, CSF antibody and PCR stud­
ies should be considered complementary because patients may have 
evidence of intrathecal synthesis of VZV-specific antibodies and nega­
tive CSF PCRs. In the case of WNV infection, CSF PCR appears to be 
less sensitive than detection of WNV-specific CSF IgM, although PCR 
testing remains useful in immunocompromised patients who may not 
mount an effective anti-WNV antibody response. The recent pandemic 
due to SARS-CoV-2 (COVID-19) has been associated with cases of 
encephalopathy due to the indirect effects on the nervous system of 
multiorgan system failure and/or to a hyperinflammatory syndrome 
and disseminated intravascular coagulation, but also with rare cases of 
true encephalitis caused by viral CNS invasion. In both sets of patients, 
nasopharyngeal reverse transcriptase (RT)-PCR tests for SARS-CoV-2 
are positive, but only cases with encephalitis have a positive CSF RTPCR for SARS-CoV-2. Rare cases of neuroinvasion by SARS-CoV-2 
has also been detected by RT-PCR of brain tissue.
Unbiased metagenomic sequencing technologies capable of identi­
fying infectious genomes in CSF, brain, and other tissues have recently 
shown great promise for rapid diagnosis of obscure cases of encepha­
litis and other brain infections, especially in immunocompromised 
patients.
CSF Culture 
CSF culture is generally of limited utility in the diag­
nosis of acute viral encephalitis. Culture may be insensitive (e.g., >95% 
of patients with HSV encephalitis have negative CSF cultures, as do 
virtually all patients with EBV-associated CNS disease) and often takes 
too long to significantly affect immediate therapy.
Serologic Studies and Antigen Detection 
For many arbovi­
ruses including WNV, serologic studies remain important diagnostic 
tools. Serum antibody determination is less useful for viruses with 
high seroprevalence rates in the general population such as HSV, VZV, 
CMV, and EBV. For viruses with low seroprevalence rates, diagnosis 
of acute viral infection can be made by documenting seroconversion 
between acute-phase and convalescent sera (typically obtained after 
2–4 weeks) or by demonstrating the presence of virus-specific IgM 
antibodies. For viruses with high seroprevalence such as VZV and 
HSV, demonstration of synthesis of virus-specific antibodies in CSF, 
as shown by an increased IgG index or the presence of CSF IgM anti­
bodies, may be useful and can provide presumptive evidence of CNS 
infection. Unfortunately, the delay between onset of infection and the 
host’s generation of a virus-specific antibody response often means that 
serologic data are useful mainly for the retrospective establishment of a 
diagnosis, rather than in aiding acute diagnosis or management.
In patients with HSV encephalitis, antibodies to HSV-1 glycopro­
teins and HSV glycoprotein antigens have been detected in the CSF. 
Optimal detection of both HSV antibodies and antigen typically 
occurs after the first week of illness, limiting the utility of these tests 
in acute diagnosis. Nonetheless, HSV CSF antibody testing is of value 
in selected patients whose illness is >1 week in duration and who are 
CSF PCR negative for HSV. In the case of VZV infection, CSF IgM 
antibody tests may be positive when PCR fails to detect viral DNA, and 
both tests should be considered complementary rather than mutually 
exclusive.
Demonstration of CSF WNV IgM antibodies is diagnostic of WNV 
encephalitis because the high molecular weight of IgM antibodies 
restricts their passage from serum to CSF through the blood-brain 
barrier and their presence in CSF is therefore indicative of intrathecal 
synthesis. Timing of antibody testing may be important because the 
rate of CSF WNV IgM seropositivity increases during the first week 
after illness onset, reaching 80% or higher on day 7 after symptom 
onset. Although serum and CSF IgM antibodies generally persist for 
only a few months after acute infection, there are exceptions to this 
rule, and WNV serum IgM has been shown to persist in some patients 
for >1 year following acute infection.

MRI, CT, and EEG 
Patients with suspected encephalitis almost 
invariably undergo neuroimaging studies and often electroencephalo­
gram (EEG). These tests help identify or exclude alternative diagnoses 
and assist in the differentiation between a focal and a diffuse encepha­
litic process. Specific focal findings in a patient with encephalitis 
should always raise the possibility of HSV encephalitis. Examples of 
focal findings found in HSV encephalitis include: (1) areas of increased 
signal intensity in the frontotemporal, cingulate, or insular regions 
of the brain on T2-weighted, fluid-attenuated inversion recovery 
(FLAIR), or diffusion-weighted magnetic resonance imaging (MRI) 
(Fig. 142-1); (2) focal areas of low absorption, mass effect, and contrast 
enhancement in frontotemporal areas on computed tomography (CT); 
or (3) periodic focal temporal lobe spikes on a background of slow or 
low-amplitude (“flattened”) activity on EEG. Approximately 10% of 
patients with PCR-documented HSV encephalitis may have a normal 
MRI, although nearly 80% will have asymmetric abnormalities in the 
temporal lobe, and an additional 10% in extratemporal regions. The 
addition of FLAIR and diffusion-weighted images to the standard MRI 
sequences enhances sensitivity. Children with HSV encephalitis may 
have atypical patterns of MRI lesions and often show involvement of 
brain regions outside the frontotemporal areas. CT is less sensitive than 
MRI and is normal in up to 20–35% of patients. EEG abnormalities 
occur in >75% of PCR-documented cases of HSV encephalitis; they 
typically involve the temporal lobes but are often nonspecific. Some 
patients with HSV encephalitis have a distinctive EEG pattern consist­
ing of periodic, stereotyped, sharp-and-slow complexes originating in 
one or both temporal lobes and repeating at regular intervals of 2–3 s. 
The periodic complexes are typically noted between days 2 and 15 of 
the illness and are present in two-thirds of pathologically proven cases 
of HSV encephalitis.

CHAPTER 142
Significant MRI abnormalities are found in only approximately 
two-thirds of patients with WNV encephalitis, a frequency less than 
that found with HSV encephalitis. When present, abnormalities often 
involve deep brain structures, including the thalamus, basal ganglia, 
and brainstem, rather than the cortex, and may only be apparent on 
T2/FLAIR images. Similar MRI patterns can be observed in patients 
infected with other arboviruses, including other flaviviruses such as 
Japanese encephalitis virus and St. Louis encephalitis virus, as well the 
Alphavirus EEE virus. EEGs in patients with WNV encephalitis typi­
cally show generalized slowing that may be more anteriorly prominent 
rather than the temporally predominant pattern of sharp or periodic 
discharges more characteristic of HSV encephalitis. Patients with VZV 
encephalitis may show multifocal areas of hemorrhagic and ischemic 
infarction, reflecting the tendency of this virus to produce a CNS 
vasculopathy rather than a true encephalitis. Immunocompromised 
Encephalitis
FIGURE 142-1  Coronal fluid-attenuated inversion recovery (FLAIR) magnetic 
resonance image from a patient with herpes simplex encephalitis. Note the 
area of increased signal in the right temporal lobe (left side of image) confined 
predominantly to the gray matter. This patient had predominantly unilateral disease; 
bilateral lesions are more common but may be quite asymmetric in their intensity.

TABLE 142-2  Use of Diagnostic Tests in Encephalitis
The best test for WNV encephalitis is the CSF IgM antibody test. The prevalence 
of positive CSF IgM tests increases by about 10% per day after illness onset 
and reaches 70–80% by the end of the first week. Serum WNV IgM can provide 
evidence for recent WNV infection, but in the absence of other findings does not 
establish the diagnosis of neuroinvasive disease (meningitis, encephalitis, acute 
flaccid paralysis).
Approximately 80% of patients with proven HSV encephalitis have MRI 
abnormalities involving the temporal lobes. This percentage likely increases 
to >90% when FLAIR and diffusion-weighted MRI sequences are also used. 
The absence of temporal lobe lesions on MRI reduces the likelihood of HSV 
encephalitis and should prompt consideration of other diagnostic possibilities.
The CSF HSV PCR test may be negative in the first 72 h of symptoms of HSV 
encephalitis. A repeat study should be considered in patients with an initial early 
negative PCR in whom diagnostic suspicion of HSV encephalitis remains high 
and no alternative diagnosis has yet been established.
Detection of intrathecal synthesis (increased CSF/serum HSV antibody ratio 
corrected for breakdown of the blood-brain barrier) of HSV-specific antibody 
may be useful in diagnosis of HSV encephalitis in patients in whom only late (>1 
week after onset) CSF specimens are available and PCR studies are negative. 
Serum serology alone is of no value in diagnosis of HSV encephalitis due to the 
high seroprevalence rate in the general population.
Negative CSF viral cultures are of no value in excluding the diagnosis of HSV or 
EBV encephalitis.
VZV CSF IgM antibodies may be present in patients with a negative VZV CSF 
PCR. Both tests should be performed in patients with suspected VZV CNS 
disease.
The specificity of EBV CSF PCR for diagnosis of CNS infection is unknown. 
Positive tests may occur in patients with a CSF pleocytosis due to other causes. 
Detection of EBV CSF IgM or intrathecal synthesis of antibody to VCA supports 
the diagnosis of EBV encephalitis. Serologic studies consistent with acute EBV 
infection (e.g., IgM VCA, presence of antibodies against EA but not against 
EBNA) can help support the diagnosis.
In addition to broad-based PCR assays for bacterial and fungal infections, 
metagenomic next-generation sequencing (mNGS) allows for unbiased detection 
of nucleic acids from the whole range of infectious agents (except prions), which 
can then be confirmed by independent pathogen-specific techniques. Due to 
the sensitivity of this technology, there is a risk of false-positive results. As this 
technology becomes refined and the turnaround time faster, mNGS is likely to 
become a routine test on CSF for the diagnosis of encephalitis.
PART 5
Infectious Diseases
Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; DWI, 
diffusion-weighted imaging; EA, early antigen; EBNA, EBV-associated nuclear 
antigen; EBV, Epstein-Barr virus; FLAIR, fluid-attenuated inversion recovery; HSV, 
herpes simplex virus; IgM, immunoglobulin M; MRI, magnetic resonance imaging; 
PCR, polymerase chain reaction; VCA, viral capsid antibody; VZV, varicella-zoster 
virus; WNV, West Nile virus.
adult patients with CMV often have enlarged ventricles with areas of 
increased T2 signal on MRI outlining the ventricles and subependymal 
enhancement on T1-weighted postcontrast images. Prominent cerebel­
lar T2/FLAIR abnormalities have been observed with Powassan virus 
encephalitis and in children with herpesviruses like EBV and VZV. 
Table 142-2 highlights specific diagnostic test results in encephalitis 
that can be useful in clinical decision-making.
Brain Biopsy 
Brain biopsy is now generally reserved for patients in 
whom CSF PCR studies fail to lead to a specific diagnosis and who have 
focal abnormalities on MRI, no serologic evidence of autoimmune 
disease, and continue to show progressive clinical deterioration despite 
treatment with acyclovir and supportive therapy.
■
■DIFFERENTIAL DIAGNOSIS
Infection by a variety of other organisms can mimic viral encephalitis. 
In studies of biopsy-proven HSV encephalitis, common infectious 
mimics of focal viral encephalitis included mycobacteria, fungi, rick­
ettsiae, Listeria, Mycoplasma, and other bacteria (including Bartonella 
sp.) as well as neurosyphilis. There are an increasing number of anti­
bodies reported that cause autoimmune encephalitis and mimic those 
caused by viral infection, including those associated with antibodies 
against N-methyl-d-aspartate (NMDA) receptor, two components of 
the voltage-gated potassium channels/leucine-rich glioma inactivated 
protein-1 (LGI-1) and contracting-associated protein-like 2 (CASPR2), 

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), 
γ-aminobutyric acid (GABA) receptors, and glutamic acid decarboxyl­
ase (GAD 65) (Chap. 99). In most cases, diagnosis is made by detection 
of the specific autoantibodies in serum and/or CSF. NMDA receptor 
antibodies have been reported in up to 25% of patients who have recov­
ered from HSV encephalitis, and their presence should not exclude 
appropriate testing and treatment for HSV encephalitis. The develop­
ment of NMDA receptor antibodies in patients with HSV encephalitis 
may contribute to new or worsening symptoms in the weeks following 
recovery from HSV encephalitis. Autoimmune encephalitis may also 
be associated with specific cancers (paraneoplastic) and onconeuro­
nal antibodies (e.g., anti-Hu, Yo, Ma2, amphiphysin, CRMP5, CV2). 
Subacute or chronic forms of encephalitis may occur in association 
with autoantibodies against thyroglobulin and thyroperoxidase (Hashi­
moto’s encephalopathy) and with prion diseases.
Infection caused by the ameba Naegleria fowleri can also cause acute 
meningoencephalitis (primary amebic meningoencephalitis), whereas 
that caused by Acanthamoeba and Balamuthia more typically produces 
subacute or chronic granulomatous amebic meningoencephalitis. 
Naegleria thrive in warm, iron-rich pools of water, including those 
found in drains, canals, and both natural and human-made outdoor 
pools (Chap. 230). Infection has typically occurred in immunocompe­
tent children with a history of swimming in potentially infected water. 
The CSF, in contrast to the typical profile seen in viral encephalitis, 
often resembles that of bacterial meningitis with a neutrophilic pleocy­
tosis and hypoglycorrhachia. Motile trophozoites can be seen in a wet 
mount of warm, fresh CSF. There have been an increasing number of 
cases of Balamuthia mandrillaris amebic encephalitis in children and 
immunocompetent adults, mimicking acute viral encephalitis. This 
organism has also been associated with encephalitis in recipients of 
transplanted organs from a donor with unrecognized infection. No 
effective treatment has been approved, and mortality approaches 100%. 
There have been a few case reports of patients who recovered with 
nitroxoline therapy.
Encephalitis can be caused by the raccoon pinworm Baylisascaris 
procyonis. Clues to the diagnosis include a history of raccoon exposure, 
especially of playing in or eating dirt potentially contaminated with 
raccoon feces. Most patients are children, and many have an associated 
eosinophilia.
Once nonviral causes of encephalitis have been excluded, the major 
diagnostic challenge is to distinguish HSV from other viruses that 
cause encephalitis. This distinction is particularly important because 
in virtually every other instance the therapy is supportive, whereas 
specific and effective antiviral therapy is available for HSV, and its effi­
cacy is enhanced when it is instituted early in the course of infection. 
HSV encephalitis should be considered when clinical features suggest 
involvement of the inferomedial frontotemporal regions of the brain, 
including prominent olfactory or gustatory hallucinations, anosmia, 
unusual or bizarre behavior or personality alterations, or memory dis­
turbance. HSV encephalitis should always be suspected in patients with 
signs and symptoms consistent with acute encephalitis who have focal 
findings on clinical examination, neuroimaging studies, or EEG. The 
diagnostic procedure of choice in these patients is CSF PCR analysis for 
HSV. A positive CSF PCR establishes the diagnosis, and a negative test 
dramatically reduces the likelihood of HSV encephalitis (see above).
The anatomic distribution of lesions may provide an additional 
clue to diagnosis. Patients with rapidly progressive encephalitis and 
prominent brainstem signs, symptoms, or neuroimaging abnormali­
ties may be infected by flaviviruses (WNV, St. Louis encephalitis virus, 
Japanese encephalitis virus), HSV, enterovirus A71 (EV-A71), rabies, 
or Listeria monocytogenes. Significant involvement of deep gray matter 
structures, including the basal ganglia and thalamus, should also sug­
gest possible flavivirus infection. These patients may present clinically 
with prominent movement disorders (tremor, myoclonus) or other 
parkinsonian features. Patients with WNV infection can also present 
with a poliomyelitis-like AFM, as can patients infected with EV-A71, 
EV-D68, and less commonly, other enteroviruses. Acute flaccid paraly­
sis is characterized by the acute onset of a lower motor neuron type of 
weakness with flaccid tone, reduced or absent reflexes, and relatively

preserved sensation. Patients often have multisegmental increased 
FLAIR and T2 signal in the anterior horns of the spinal cord and a CSF 
lymphocytic pleocytosis.
Epidemiologic factors may provide important clues to the diagnosis 
of viral encephalitis. Particular attention should be paid to the season 
of the year; the geographic location and travel history; and possible 
exposure to animal bites or scratches, rodents, and ticks. Although 
transmission from the bite of an infected dog remains the most com­
mon cause of rabies (Chap. 214) worldwide, in the United States very 
few cases of dog rabies occur, and the most common risk factor is 
exposure to bats—although a clear history of a bite or scratch is often 
lacking. The classic clinical presentation of encephalitic (furious) rabies 
is fever, fluctuating consciousness, and autonomic hyperactivity. Pho­
bic spasms of the larynx, pharynx, neck muscles, and diaphragm can be 
triggered by attempts to swallow water (hydrophobia) or by inspiration 
(aerophobia). Patients may also present with paralytic (dumb) rabies 
characterized by acute ascending paralysis. Rabies due to the bite of a 
bat has a different clinical presentation than classic rabies due to a dog 
or wolf bite. Patients present with focal neurologic deficits, myoclonus, 
seizures, and hallucinations; phobic spasms are not a typical feature. 
Patients with rabies have a CSF lymphocytic pleocytosis and may show 
areas of increased T2 signal abnormality in the brainstem, hippocam­
pus, and hypothalamus. Diagnosis can be made by finding rabies virus 
antigen in brain tissue or in the neural innervation of hair follicles at 
the nape of the neck. PCR amplification of viral nucleic acid from CSF 
and saliva or tears may also enable diagnosis. Serology is frequently 
negative in both serum and CSF in the first week after onset of infec­
tion, which limits its acute diagnostic utility. No specific therapy is 
available, and cases are almost invariably fatal, with isolated survivors 
having devastating neurologic sequelae.
State public health authorities provide a valuable resource concern­
ing isolation of particular agents in individual regions. Regular updates 
concerning the number, type, and distribution of cases of arboviral 
encephalitis can be found on the Centers for Disease Control and Pre­
vention and U.S. Geological Survey (USGS) websites (http://www.cdc

.gov and http://diseasemaps.usgs.gov).
TREATMENT
Viral Encephalitis
Specific antiviral therapy should be initiated when appropriate. 
Vital functions, including respiration and blood pressure, should 
be monitored continuously and supported as required. In the initial 
stages of encephalitis, many patients will require care in an intensive 
care unit. Basic management and supportive therapy should include 
careful monitoring of ICP, fluid restriction, avoidance of hypotonic 
intravenous solutions, and suppression of fever. Seizures should be 
treated with standard anticonvulsant regimens, and prophylactic 
therapy should be considered in view of the high frequency of 
seizures in severe cases of encephalitis. As with all seriously ill, 
immobilized patients with altered levels of consciousness, encepha­
litis patients are at risk for aspiration pneumonia, stasis ulcers and 
decubiti, contractures, deep venous thrombosis and its complica­
tions, and infections of indwelling lines and catheters.
Acyclovir is of benefit in the treatment of HSV and should be 
started empirically in patients with suspected viral encephalitis, 
especially if focal features are present, while awaiting viral diagnos­
tic studies. Treatment should be discontinued in patients found not 
to have HSV encephalitis, with the possible exception of patients 
with severe encephalitis due to VZV or EBV. HSV, VZV, and EBV all 
encode an enzyme deoxypyrimidine (thymidine) kinase that phos­
phorylates acyclovir to produce acyclovir-5′-monophosphate. Host 
cell enzymes then phosphorylate this compound to form a triphos­
phate derivative. It is the triphosphate that acts as an antiviral agent 
by inhibiting viral DNA polymerase and by causing premature 
termination of nascent viral DNA chains. The specificity of action 
depends on the fact that uninfected cells do not phosphorylate 
significant amounts of acyclovir to acyclovir-5′-monophosphate. A 

second level of specificity is provided by the fact that the acyclovir 
triphosphate is a more potent inhibitor of viral DNA polymerase 
than of the analogous host cell enzymes.

Adults should receive a dose of 10 mg/kg of acyclovir intrave­
nously every 8 h (30 mg/kg per day total dose) for 21 days. Neonatal 
HSV CNS infection is less responsive to acyclovir therapy than HSV 
encephalitis in adults; it is recommended that neonates with HSV 
encephalitis receive 20 mg/kg of acyclovir every 8 h (60 mg/kg per 
day total dose) for a minimum of 21 days.
Prior to intravenous administration, acyclovir should be diluted 
to a concentration ≤7 mg/mL. (A 70-kg person would receive a dose 
of 700 mg, which would be diluted in a volume of 100 mL.) Each 
dose should be infused slowly over 1 h, rather than by rapid or bolus 
infusion, to minimize the risk of renal dysfunction. Care should 
be taken to avoid extravasation or intramuscular or subcutaneous 
administration. The alkaline pH of acyclovir can cause local inflam­
mation and phlebitis (9%). Dose adjustment is required in patients 
with impaired renal glomerular filtration. Penetration into CSF is 
excellent, with average drug levels ~50% of serum levels. Complica­
tions of therapy include elevations in blood urea nitrogen and creat­
inine levels (5%), thrombocytopenia (6%), gastrointestinal toxicity 
(nausea, vomiting, diarrhea) (7%), and neurotoxicity (lethargy or 
obtundation, disorientation, confusion, agitation, hallucinations, 
tremors, seizures) (1%). Acyclovir resistance may be mediated by 
changes in either the viral deoxypyrimidine kinase or DNA poly­
merase. To date, acyclovir-resistant isolates have not been a signifi­
cant clinical problem in immunocompetent individuals. It is now 
appreciated that some patients with worsening symptoms in the 
weeks following recovery from HSV encephalitis have developed 
NMDA receptor encephalitis requiring immunosuppression rather 
than having developed an acyclovir-resistant isolate. However, there 
have been reports of clinically virulent acyclovir-resistant HSV iso­
lates from sites outside the CNS in immunocompromised individu­
als, including those with AIDS.
CHAPTER 142
Encephalitis
Oral antiviral drugs with efficacy against HSV, VZV, and EBV, 
including acyclovir, famciclovir, and valacyclovir, have not been 
evaluated in the treatment of encephalitis as primary therapy. 
Additional oral valaciclovir following a 14- to 21-day course of 
intravenous acyclovir does not improve outcomes in adult patients 
with HSV encephalitis. The role of adjunctive intravenous gluco­
corticoids in treatment of HSV and VZV infection remains unclear. 
Experimental models and case reports of HSV encephalitis suggest 
that glucocorticoids may be efficacious, although no data from 
randomized controlled human trials are available. Ganciclovir and 
foscarnet, as combination therapy, are used in the treatment of 
CMV-related CNS infections. Cidofovir (see below) may provide 
an alternative in patients who fail to respond to ganciclovir and 
foscarnet, although data concerning its use in CMV CNS infections 
are extremely limited.
Ganciclovir is a synthetic nucleoside analogue of 2′-deoxyguano­
sine. The drug is preferentially phosphorylated by virus-induced 
cellular kinases. Ganciclovir triphosphate acts as a competitive 
inhibitor of the CMV DNA polymerase, and its incorporation into 
nascent viral DNA results in premature chain termination. Follow­
ing intravenous administration, CSF concentrations of ganciclovir 
are 25–70% of coincident plasma levels. The usual dose for treat­
ment of severe neurologic illnesses is 5 mg/kg every 12 h given 
intravenously at a constant rate over 1 h. Induction therapy is fol­
lowed by maintenance therapy of 5 mg/kg every day for an indefi­
nite period. Induction therapy should be continued until patients 
show a decline in CSF pleocytosis and a reduction in CSF CMV 
DNA copy number on quantitative PCR testing (where available). 
Doses should be adjusted in patients with renal insufficiency. Treat­
ment is often limited by the development of granulocytopenia and 
thrombocytopenia (20–25%), which may require reduction in or 
discontinuation of therapy. Gastrointestinal side effects, including 
nausea, vomiting, diarrhea, and abdominal pain, occur in ~20% of 
patients. Some patients treated with ganciclovir for CMV retinitis 
have developed retinal detachment, but the causal relationship to

ganciclovir treatment is unclear. Valganciclovir is an orally bioavail­
able prodrug that can generate high serum levels of ganciclovir, 
although studies of its efficacy in treating CMV CNS infections are 
limited.

Foscarnet is a pyrophosphate analogue that inhibits viral DNA 
polymerases by binding to the pyrophosphate-binding site. Fol­
lowing intravenous infusion, CSF concentrations range from 15 
to 100% of coincident plasma levels. The usual dose for serious 
CMV-related neurologic illness is 60 mg/kg every 8 h administered 
by constant infusion over 1 h. Induction therapy for 14–21 days is 
followed by maintenance therapy (60–120 mg/kg per day). Induc­
tion therapy may need to be extended in patients who fail to show a 
decline in CSF pleocytosis and a reduction in CSF CMV DNA copy 
number on quantitative PCR tests (where available). Approximately 
one-third of patients develop renal impairment during treatment, 
which is reversible following discontinuation of therapy in most, 
but not all, cases. This is often associated with elevations in serum 
creatinine and proteinuria and is less frequent in patients who are 
adequately hydrated. Many patients experience fatigue and nausea. 
Reductions in serum calcium, magnesium, and potassium occur in 
~15% of patients and may be associated with tetany, cardiac rhythm 
disturbances, or seizures.
Cidofovir is a nucleotide analogue that is effective in treating 
CMV retinitis and equivalent to or better than ganciclovir in some 
experimental models of murine CMV encephalitis, although data 
concerning its efficacy in human CMV CNS disease are limited. 
The usual dose is 5 mg/kg intravenously once weekly for 2 weeks, 
then biweekly for two or more additional doses, depending on clini­
cal response. Patients must be prehydrated with normal saline (e.g., 
1 L over 1–2 h) prior to each dose and treated with probenecid (e.g., 
1 g 3 h before cidofovir and 1 g 2 and 8 h after cidofovir). Nephro­
toxicity is common; the dose should be reduced if renal function 
deteriorates.
PART 5
Infectious Diseases
Intravenous ribavirin (15–25 mg/kg per day in divided doses 
given every 8 h) has been reported to be of benefit in isolated cases 
of severe encephalitis due to California encephalitis (La Crosse) 
virus. Ribavirin might be of benefit for the rare patients, typically 
infants or young children, with severe adenovirus or rotavirus 
encephalitis and in patients with encephalitis due to LCMV or other 
arenaviruses. However, clinical trials are lacking. Hemolysis, with 
resulting anemia, has been the major side effect limiting therapy.
No specific antiviral therapy of proven efficacy is currently 
available for treatment of WNV encephalitis. Patients have been 
treated with interferon-α, ribavirin, an Israeli IVIg preparation 
that contains high-titer anti-WNV antibody (Omr-IgG-am), and 
humanized monoclonal antibodies directed against the viral enve­
lope glycoprotein (www.clinicaltrials.gov, identifiers NCT00927953 
and 00515385). Omr-IgG-am did not improve outcomes in patients 
with WNV neuroinvasive disease, but the study design was poten­
tially flawed as some patients received drug up to a week after 
symptom onset, when expected benefit may have been minimal. Of 
the six West Nile virus human vaccines that advanced into phase I 
clinical trials, only two live attenuated virus vaccines have advanced 
to phase II clinical trials. There has been success with four equine 
vaccines, but all require multiple primary doses and annual boost­
ers. The ideal human WNV vaccine needs to provide complete 
and long-lasting protective immunity after the administration of a 
single dose. Effective vaccines are already in human use for preven­
tion of other flavivirus infections including Japanese encephalitis 
and yellow fever.
The Centers for Disease Control and Prevention (CDC) Clini­
cal Considerations for COVID-19 treatment in outpatients as of 
January 2024 state that the preferred treatment for mild to mod­
erate COVID-19 infection in adults is oral ritonavir-boosted nir­
matrelvir. This antiviral is U.S. Food and Drug Administration 
(FDA) approved in adults with mild-to-moderate COVID-19 with 
symptoms of <5 days in duration who are at high risk of developing 
severe COVID-19 due to older age (>50 years) or other risk fac­
tors. It has also been approved under emergency use authorization 

(EUA) for 12- to 17-year-olds. A 3-day course of intravenous 
remdesivir is the second preferred treatment option after ritonavirboosted nirmatrelvir for adults and pediatric patients as young as 
28 days. Immunocompromised patients may be treated with longer 
or additional courses. The FDA has issued an EUA for the use of 
COVID-19 convalescent plasma with high titers of anti–SARSCoV-2 antibodies for the treatment of COVID-19 in immunocom­
promised patients from disease or immunosuppressive therapy. 
The antiviral molnupiravir can be used for therapy according to 
the CDC but has been less effective in clinical trials than ritonavirboosted nirmatrelvir or remdesivir.
■
■SEQUELAE
There is considerable variation in the incidence and severity of sequelae 
in patients surviving viral encephalitis. In the case of EEE virus infec­
tion, nearly 80% of survivors have severe neurologic sequelae. At the 
other extreme are infections due to EBV, California encephalitis virus, 
and Venezuelan equine encephalitis virus, where severe sequelae are 
unusual. For example, ~5–15% of children infected with La Crosse 
virus have a residual seizure disorder, and 1% have persistent hemi­
paresis. Detailed information about sequelae in patients with HSV 
encephalitis treated with acyclovir is available from the NIAID-Collab­
orative Antiviral Study Group (CASG) trials. Of 32 acyclovir-treated 
patients, 26 survived (81%). Of the 26 survivors, 12 (46%) had no or 
only minor sequelae, 3 (12%) were moderately impaired (gainfully 
employed but not functioning at their previous level), and 11 (42%) 
were severely impaired (requiring continuous supportive care). The 
incidence and severity of sequelae were directly related to the age of 
the patient and the level of consciousness at the time of initiation of 
therapy. Patients with severe neurologic impairment (Glasgow Coma 
Scale score 6) at initiation of therapy either died or survived with severe 
sequelae. Young patients (<30 years) with good neurologic function 
at initiation of therapy did substantially better (100% survival, 62% 
with no or mild sequelae) compared with their older counterparts 
(>30 years; 64% survival, 57% no or mild sequelae). Many patients 
with WNV infection have sequelae, including cognitive impairment; 
weakness; and hyper- or hypokinetic movement disorders, including 
tremor, myoclonus, and parkinsonism. In a large longitudinal study 
of prognosis in 156 patients with WNV infection, the mean time 
to achieve recovery (defined as 95% of maximal predicted score on 
specific validated tests) was 112–148 days for fatigue, 121–175 days 
for physical function, 131–139 days for mood, and 302–455 days for 
mental function (the longer interval in each case representing patients 
with invasive CNS disease).
CHRONIC ENCEPHALITIS
■
■PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY
Clinical Features and Pathology 
Progressive multifocal leuko­
encephalopathy (PML) is characterized pathologically by multifocal 
areas of demyelination of varying size distributed throughout the brain 
but sparing the spinal cord and optic nerves. In addition to demyelin­
ation, there are characteristic cytologic alterations in both astrocytes 
and oligodendrocytes. Astrocytes are enlarged and contain hyper­
chromatic, deformed, and bizarre nuclei and frequent mitotic figures. 
Oligodendrocytes have enlarged, densely staining nuclei that contain 
viral inclusions formed by crystalline arrays of JC virus (JCV) particles. 
Patients often present with visual deficits (45%), typically a homony­
mous hemianopia; mental impairment (38%) (dementia, confusion, 
personality change); weakness, including hemi- or monoparesis; and 
ataxia. Seizures occur in ~20% of patients, predominantly in those with 
lesions abutting the cortex.
Almost all patients have an underlying immunosuppressive disor­
der or are receiving immunomodulatory therapy. The most common 
immunosuppressive disorder associated with PML is AIDS, followed 
by hematologic malignancies, solid organ and hematopoietic stem cell 
transplant, and chronic inflammatory diseases, including sarcoidosis. It

has been estimated that up to 5% of AIDS patients will develop PML. 
There has been considerable progress in the development of diseasemodifying therapies (DMTs) for multiple sclerosis and inflammatory 
bowel disease. Of the DMTs, the highest risk of PML is associated 
with natalizumab, a humanized monoclonal antibody that inhibits 
lymphocyte trafficking into CNS and bowel mucosa by binding to α4 
integrins. Overall risk in these patients has been estimated at ~4 PML 
cases per 1000 treated patients, but the risk depends on a variety of 
factors including anti-JCV antibody serostatus and the magnitude of 
the JCV antibody response, prior immunosuppressive therapy use, 
and duration of natalizumab therapy. Patients who lack detectable JCV 
antibody have a risk of developing PML of <0.1 case/1000 patients, 
whereas those who are JCV seropositive and have been exposed to 
prior immunosuppressive therapy and have received >24 months of 
natalizumab therapy have a risk of >1.3 cases/100 treated patients. 
Some recent studies suggest that extended dosing interval regimens 
of natalizumab (at 6- to 8-week intervals rather than the conventional 
4-week interval) may significantly reduce the risk of PML. Among 
JCV-seropositive individuals, those with higher JCV antibody index 
values, presumably due to the “immunizing” effects of more frequent 
JCV reactivations, appear to be at higher risk than those with low 
antibody indices. Alternative therapies are preferred in patients who 
are JCV seropositive. PML cases have also been reported in patients 
receiving other immunomodulatory agents including rituximab, ocrel­
izumab, fingolimod, and dimethyl fumarate, although the relative 
risks have not been clearly established, and many individual cases are 
complicated by previous exposure to other therapies including natali­
zumab. Prolonged lymphopenia, a side effect of dimethyl fumarate, 
is associated with an increased risk of PML. The basic clinical and 
diagnostic features appear to be similar in HIV-associated PML and 
PML associated with immunomodulatory drugs with the exception 
of an increased likelihood of MRI enhancement of PML lesions in 
immunomodulatory cases. In natalizumab-associated PML, patients 
will also almost invariably develop clinical and radiographic worsening 
of lesions with discontinuation of therapy, attributed to development of 
immune reconstitution inflammatory syndrome (IRIS).
Diagnostic Studies 
The diagnosis of PML is frequently suggested 
by MRI. MRI reveals multifocal asymmetric, coalescing white mat­
ter lesions located periventricularly, in the centrum semiovale, in the 
parietal-occipital region, and in the cerebellum. These lesions have 
increased signal on T2 and FLAIR images and decreased signal on 
T1-weighted images. HIV-PML lesions are classically nonenhancing 
(90%), but patients with immunomodulatory drug-associated PML 
may have peripheral ring enhancement. PML lesions are not typically 
associated with edema or mass effect. CT scans, which are less sensitive 
than MRI for the diagnosis of PML, often show hypodense nonenhanc­
ing white matter lesions. JCV infection may also induce rare cases of 
encephalitis and cerebellitis in immunocompromised patients that are 
distinct from PML and have differing neuroimaging features.
The CSF is typically normal, although mild elevation in protein and/
or IgG may be found. Pleocytosis occurs in <25% of cases, is predomi­
nantly mononuclear, and rarely exceeds 25 cells/μL. PCR amplification 
of JCV DNA from CSF has become an important diagnostic tool. The 
presence of a positive CSF PCR for JCV DNA in association with typi­
cal MRI lesions in the appropriate clinical setting is diagnostic of PML, 
reflecting the assay’s relatively high specificity (92–100%); however, 
sensitivity is variable, and a negative CSF PCR does not exclude the 
diagnosis. In HIV-negative patients and HIV-positive patients not 
receiving antiretroviral therapy (ART), sensitivity is likely 70–90%. In 
ART-treated patients, sensitivity may be closer to 60%, reflecting the 
lower JCV CSF viral load in this relatively more immunocompetent 
group. Patients with natalizumab-associated PML have highly variable 
amounts of JCV DNA in CSF. Some patients may have negative CSF 
PCRs performed in commercial laboratories, where assay detection 
thresholds are typically >100 JCV DNA copies/μL, but positive results 
in reference laboratories using supersensitive techniques (detection of 
10 JCV copies/μL or less). CSF studies with quantitative JCV PCR indi­
cate that patients with low JCV loads (<100 copies/μL) have a generally 

better prognosis than those with higher viral loads. Patients with nega­
tive CSF PCR studies may require brain biopsy for definitive diagnosis. 
In biopsy or necropsy specimens of brain, JCV antigen and nucleic 
acid can be detected by immunocytochemistry, in situ hybridization, 
or PCR amplification.

Serologic studies of JCV antibody are of modest value in diagno­
sis of PML due to the high basal seroprevalence level, although the 
absence of detectable JCV antibody may be useful in reducing the 
likelihood of PML in the differential diagnosis, as PML results from 
viral reactivation in previously infected individuals and virtually all 
confirmed cases have been JCV seropositive at diagnosis. Antibody 
testing may also be useful in risk stratification of patients receiving 
immunomodulatory therapies.
TREATMENT
Progressive Multifocal Leukoencephalopathy
No consistently effective therapy for PML is available. There are 
case reports of potential beneficial effects of the 5-HT2a receptor 
antagonist mirtazapine, which may inhibit binding of JCV to its 
receptor on oligodendrocytes. Retrospective noncontrolled studies 
have also suggested a possible beneficial effect of treatment with 
interferon-α. Neither of these agents has been tested in randomized 
controlled clinical trials. A prospective multicenter clinical trial to 
evaluate the efficacy of the antimalarial drug mefloquine failed to 
show benefit. Intravenous and/or intrathecal cytarabine were not 
shown to be of benefit in a randomized controlled trial in HIVassociated PML, although some experts suggest that cytarabine 
may have therapeutic efficacy in situations where breakdown of the 
blood-brain barrier allows sufficient CSF penetration. A random­
ized controlled trial of cidofovir in HIV-associated PML also failed 
to show significant benefit. Because PML almost invariably occurs 
in immunocompromised individuals, any therapeutic interventions 
designed to enhance or restore immunocompetence should be con­
sidered; a small series of patients treated with the PD-1 inhibitor 
pembrolizumab demonstrated clinical improvement and stabiliza­
tion. Positive results in small case series have also been reported in 
patients receiving infusions of BK or JC virus–specific cytotoxic T 
lymphocytes. Perhaps the most dramatic demonstration of the ben­
efit of restoring immune competence is disease stabilization and, 
in rare cases, improvement associated with an improved immune 
status of HIV-positive patients with AIDS following institution of 
ART. In HIV-positive PML patients treated with ART, 1-year sur­
vival is ~50%, although up to 80% of survivors may have significant 
neurologic sequelae. HIV-positive PML patients with higher CD4 
counts (>300/μL) and low or nondetectable HIV viral loads have 
a better prognosis than those with lower CD4 counts and higher 
viral loads. Although institution of ART enhances survival in HIVpositive PML patients, the associated immune reconstitution in 
patients with an underlying opportunistic infection such as PML 
may also result in a severe CNS inflammatory syndrome (IRIS) 
associated with clinical worsening, CSF pleocytosis, and the appear­
ance of new enhancing MRI lesions. Patients receiving natalizumab 
or other immunomodulatory therapies who are suspected of hav­
ing PML should have therapy immediately halted. Patients should 
be closely monitored for development of IRIS, which is generally 
treated with intravenous glucocorticoids, although controlled clini­
cal trials of efficacy remain lacking.
CHAPTER 142
Encephalitis
■
■SUBACUTE SCLEROSING PANENCEPHALITIS
Subacute sclerosing panencephalitis (SSPE) is a rare, chronic, progres­
sive demyelinating disease of the CNS associated with a chronic non­
permissive infection of brain tissue with measles virus. The frequency 
has been estimated at 1 in 100,000–500,000 measles cases. An average 
of five cases per year is reported in the United States. The incidence has 
declined dramatically since the introduction of a measles vaccine, but 
we may expect a rise in cases over the coming decades with increasing 
vaccine hesitancy and rising measles cases in the United States and