312

Imaging in Encephalitis
Arun Venkatesan, MD, PhD1 Balaji Jagdish, BS1

1 Division of Neuroimmunology and Neuroinfectious Diseases,
Department of Neurology, Johns Hopkins Encephalitis Center, Johns
Hopkins University School of Medicine, Baltimore, Maryland
Semin Neurol 2019;39:312–321.
Address for correspondence Arun Venkatesan, MD, PhD, Division of
Neuroimmunology and Neuroinfectious Diseases, Department of
Neurology, Johns Hopkins University School of Medicine, Baltimore,
MD 21287 (e-mail: avenkat2@jhmi.edu).

Abstract Despite recent advances in diagnostic and therapeutic modalities for infectious and
autoimmune encephalitis, the management of patients with suspected or confirmed
encephalitis poses a great challenge to physicians. Neuroimaging, including magnetic
resonance imaging (MRI) and positron emission tomography (PET) scanning, can play a
Keywords crucial role in substantiating the diagnosis of encephalitis and eliminating clinical
► autoimmune mimics of encephalitis from consideration. Moreover, characteristic neuroimaging
encephalitis patterns can aid in defining specific infectious and autoimmune etiologies. Volumetric

Downloaded by: Kent State University. Copyrighted material.

► infectious and functional MRI, in particular, are being increasingly used to characterize outcomes
encephalitis following encephalitis and can shed light on brain reorganization and function after the
► MRI acute phase of disease has resolved. Here, we discuss the uses of structural, functional,
► outcomes and PET neuroimaging in the clinical assessment of the acute and recovery phases of
► prognosis encephalitis.

Encephalitis refers to inflammation of the brain and can Neuroimaging in Diagnosis

present with an array of clinical symptoms including altered
level of consciousness, memory loss, psychiatric changes, sleep
disturbances, seizures, and weakness.1 While there are numer-
ous causes, etiologies can be classified into two broad cate-
gories: autoimmune and infectious. Autoimmune encephalitis
is a result of the generation of immune responses against
components of the host’s central nervous system (CNS). In
contrast, infectious encephalitis is often a result of viral or
bacterial infections, and thus may additionally manifest with
fever and other systemic infectious symptoms and signs.1,2
As many clinical manifestations are shared between auto-
immune and infectious encephalitis, various diagnostic mod-
alities are employed to help discern the specific etiology. While
electroencephalography (EEG) and cerebrospinal fluid (CSF)
analysis are used in attempting to confirm the diagnosis of
encephalitis and determining the specific cause, neuroimaging
plays an increasingly important role. This review will discuss
neuroimaging modalities that can be used to help establish the
diagnosis of encephalitis and suggest specific causes, which
may correlate with outcomes.
Arun Venkatesan's ORCID is https://orcid.org/0000-0002-9335-
7361.
Neuroimaging plays a critical role in the acute evaluation of
patients with suspected encephalitis, as it may support the
diagnosis of encephalitis, point to specific etiologies, or identify
alternate conditions that mimic encephalitis. While computed
tomography (CT) scanning employs X-rays to best define bony
structures, conventional magnetic resonance imaging (MRI)
uses nuclear magnetic resonance to detect hydrogen nuclei
and provides excellent contrast between soft tissues. In all cases
of encephalitis, MRI is preferred over CT given the greater
sensitivity and specificity of MRI.3–5 In some situations, such
as clinical instability or limited availability of MRI, a head CT
must be relied upon and can be particularly useful in excluding
acute intracranial hemorrhage and confirming brain shift. With
conventional MRI imaging, complementary sequences are
obtained, including T1-weighted imaging (T1W) which defines
structural abnormalities, T2-weighted imaging (T2W) and
fluid-attenuated inversion recovery (FLAIR) sequences which
may identify areas of edema or inflammation, and susceptibil-
ity-weighted imaging for identification of areas of hemorrhage.
Postgadolinium T1W imaging can identify regions where the
blood–brain barrier has been disrupted, as can occur in the
setting of active inflammation. Particularly useful in the

Issue Theme Neuroinfectious Disease, Copyright © 2019 by Thieme Medical DOI https://doi.org/
Part 1; Guest Editor, Anna M. Cervantes- Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1687838.
Arslanian, MD New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.

diagnosis of encephalitis is diffusion-weighted imaging (DWI),
which identifies areas where diffusion of water is restricted.
This sequence may be more sensitive than other conventional
sequences for detection of early abnormalities in encephalitis.6,7
These conventional MRI sequences can support the diag-
nosis of encephalitis by demonstrating new T2/FLAIR, DWI,
and/or gadolinium enhancing lesions,2,8 while importantly
excluding other causes of acute neurologic dysfunction such
as ischemic or hemorrhagic stroke, posterior reversible
encephalopathy syndrome, rapidly expanding brain tumors,
and anoxic injury. In addition, the pattern of MRI abnorm-
alities may suggest specific etiologies as described below.
Temporal Lobe Abnormalities
Conventional MRI imaging demonstrating T2-FLAIR hyper-
intense lesions that localize to the medial temporal lobes can
be indicative of many pathologies. The major infectious
etiologic consideration is herpes simplex virus (HSV), most
commonly HSV-1. Lesions may be present in one or both
lobes, and the involvement is typically asymmetric (►Fig. 1).
Additional lesions may be seen in associated limbic areas
such as the insula, cingulate gyri, and inferolateral frontal
cortices with characteristic sparing of the basal ganglia early
in the disease process.9–12 While hemorrhage in the medial
temporal lobes has previously been noted to be typical of
HSV encephalitis, it is now typically only seen as a late-stage
manifestation since patients are likely being diagnosed ear-
lier.12 Of note, in immunocompromised individuals the
radiologic pattern may differ markedly, often with more
widespread brain and/or meningeal involvement.13 Other
infectious etiologies that can present with temporal lobe
involvement include varicella zoster virus (VZV), syphilis,
and Mycobacterium tuberculosis.12,14
In up to two-thirds of cases, brain MRI is abnormal in
acute autoimmune limbic encephalitis and typically demon-
strates medial temporal lobe T2-FLAIR abnormalities with
variable enhancement on T1W imaging following gadoli-
Fig. 1 HSV-1 encephalitis. Right temporal lobe abnormalities are clearly seen on FLAIR (A), while DWI (B) also shows areas of restricted diffusion
in the right insula and cingulate gyri as well as left temporal lobe (arrows). DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion
recovery.
Imaging in Encephalitis Venkatesan, Jagdish 313
nium administration. In contrast with HSV encephalitis,
autoimmune causes tend to present with bilateral, sym-
metric temporal lobe involvement (►Fig. 2) and more often
demonstrate lesions that are outside the limbic region.12 The
character of extralimbic involvement may provide clues to
specific autoimmune syndromes; for example, anti-Hu ence-
phalitis may present with additional lesions in the cerebel-
lum and brainstem,15–17 anti-Ma encephalitis with T2-FLAIR
abnormalities in the brainstem and thalamus,15,18 and anti-
GAD encephalitis may be accompanied by signs of cerebellar
atrophy.19,20 Autoimmune encephalitis associated with anti-
bodies targeting neuronal cell surface proteins, including the
voltage-gated potassium complex antigens LGI1 and CASPR2,
NMDA-receptor (NMDAR), AMPA-receptor, and GABA B-
receptors, may also exhibit T2-FLAIR hyperintensities in
the medial temporal lobes.19,21
Deep Gray Matter Abnormalities
When MRI imaging shows T2-FLAIR hyperintensities involving
the deep gray matter of the brain (basal ganglia, thalamus),
Downloaded by: Kent State University. Copyrighted material.
arboviruses including Japanese encephalitis virus, West Nile
virus (WNV), and tick-borne encephalitis virus are prominent
considerations.22–25 These viruses, along with enteroviruses
and rabies, may also affect the anterior horn cells in the spinal
cord, resulting in acute flaccid paralysis.26–28 In Japanese
encephalitis (JE), T2-FLAIR hyperintensities can be present
throughout the subcortical gray matter, including the substan-
tia nigra, basal ganglia, cerebellum, thalamus, and in some
patients the hippocampus, where the body and tail tend to be
involved.10,29,30 In children, an additional consideration is the
respiratory virus group (i.e., influenza, parainfluenza, adeno-
virus, etc.), which has been found to be associated with sym-
metric, bithalamic T2-FLAIR hyperintensities and accompanied
in some cases by hemorrhage.25 Rarely, autoimmune encepha-
litis presents with prominent deep gray matter involvement.
Basal ganglia abnormalities have been reported in anti-CRMP5
encephalitis, while lesions in the caudate, putamen, globus
Seminars in Neurology Vol. 39 No. 3/2019
314 Imaging in Encephalitis Venkatesan, Jagdish
Fig. 2 Autoimmune limbic encephalitis. Bilateral mesial temporal lobe abnormalities seen on FLAIR (A) and more clearly on DWI (B). Note the
symmetric nature of the lesions. (C) FDG-PET imaging demonstrates hyperavidity in the left mesial temporal lobe. DWI, diffusion-weighted
imaging; FDG-PET, fluorodeoxyglucose-positron emission tomography; FLAIR, fluid-attenuated inversion recovery.
pallidus, and substantia nigra have been described in antido-
pamine D2 receptor encephalitis, most notably in children.19,31
Brainstem Abnormalities
A broad range of infectious and autoimmune etiologies can
result in brainstem encephalitis.32,33 Listeria monocytogenes is
infamous for causing encephalitis of the pons and medulla
(termed rhombencephalitis) predominantly in immunocom-
petent individuals, and is often accompanied by multiple rim-
enhancing lesions within the lower brainstem (►Fig. 3).34,35
Other infectious considerations include neurobrucellosis,
arboviruses, and enteroviruses. Of the latter, enterovirus-71
is associated with posteriorly located, often bilateral, brain-
stem abnormalities that are hyperintense on T2W imaging and
hypointense on T1W imaging.36 CNS Whipple’s disease can
Fig. 3 Listeria rhombencephalitis. Coronal T1 postgadolinium scan
shows multiple rim enhancing lesions in the brainstem.
Seminars in Neurology Vol. 39 No. 3/2019
Downloaded by: Kent State University. Copyrighted material.
also present with T2-FLAIR hyperintensities in the brainstem,
though the imaging manifestations are protean and in some
cases MRI is normal.37,38
Autoimmune causes of brainstem encephalitis predomi-
nate over infectious ones.33 Acute demyelinating disorders,
including acute disseminated encephalomyelitis (ADEM) and
neuromyelitis optica (NMO), often present with T2-FLAIR
hyperintensities in the brainstem and may additionally involve
the spinal cord or supratentorial areas. In one study of demye-
linating brainstem lesions, patients with ADEM more fre-
quently demonstrated midbrain and ventral lesions and
those with NMO more often had pontine or medullary and
dorsal lesions, while both groups had lesions with less well-
defined margins than individuals with multiple sclerosis.39
Behcet’s disease is a frequent cause of brainstem encephalitis,
particularly in the eastern rim of the Mediterranean and the
Middle East.9,35 Other autoimmune considerations include
Bickerstaff’s brainstem encephalitis, anti-Ri and antiglycine
receptor encephalitis, and CLIPPERS (chronic lymphocytic
inflammation with pontine perivascular enhancement
responsive to steroids). The latter is a syndrome with multiple
etiologies whose MRI features include small, homogenous
gadolinium enhancing nodules in the posterior fossa without
rim enhancement or mass effect (►Fig. 4).40
White Matter Abnormalities
Abnormalities of the white matter may arise in several
settings, including as a result of a small-vessel vasculopathy
with resultant hypoperfusion or infarction, or in the setting
of demyelination. VZV can cause a vasculopathy in both
immunocompetent and immunocompromised individuals,
though small-vessel vasculopathy with concomitant white
matter lesions is more common in the latter.41 T2-FLAIR and/
or DWI lesions may solely involve the white matter or may be
present at the gray–white junction. The punctate, innumer-
able deep white matter lesions that can occur in the acute
phase of pediatric Rocky Mountain spotted fever encephalitis
have been described as having a “starry sky” appearance on
 Imaging in Encephalitis Venkatesan, Jagdish 315

Fig. 4 CLIPPERS. Sagittal FLAIR (A) and axial T1 postgadolinium (B) images demonstrate scattered punctate abnormalities in the dorsal pons.
CLIPPERS, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; FLAIR, fluid-attenuated inversion
recovery.

T2-FLAIR or DWI42 and also likely represent a small-vessel

Downloaded by: Kent State University. Copyrighted material.

vasculopathy. In neuroborreliosis, multiple deep and peri-
ventricular white matter lesions can develop that are
thought to represent demyelination.43,44 Those who develop
progressive multifocal leukoencephalopathy as a result of
John Cunningham virus infection of myelin-producing oli-
godendrocytes, on the other hand, typically develop multi-
focal subcortical white matter lesions with involvement of
the subcortical U-fibers, and little or no mass effect or
gadolinium enhancement on MRI.45,46 Individuals with
acquired immunodeficiency syndrome or other severe
immunocompromised conditions are at risk for cytomega-
lovirus encephalitis, which can manifest with periventricu-
lar T2-FLAIR hyperintensities, termed an “owl’s eye”
appearance.9,10 Finally, lesions in the splenium of the corpus
callosum may occur in the setting of encephalitis (►Fig. 5).
Often found in association with influenza infection, this has
also been noted with Epstein–Barr virus, rotavirus, and
Mycoplasma pneumoniae.47 The reversible nature of these
lesions suggests the possibility of transient metabolic com-
promise, perhaps in association with excitotoxic injury.48
Notably, such lesions are not specific for infection but can
be seen in a wide variety of conditions including hypogly-
cemia, drug toxicity, and seizure.

Multifocal Abnormalities Fig. 5 Influenza-associated encephalitis. DWI demonstrates

As described above and in ►Table 1, several infectious and
autoimmune etiologies can present with multifocal CNS
involvement. In particular, ADEM, a syndrome characterized
by encephalopathy and focal neurologic signs often following
infection or vaccination, typically presents with multiple
areas of T2-FLAIR hyperintensity in the cerebral cortex,
brainstem, optic nerve, and spinal cord. The lesions may
involve white or gray matter, and enhancement is common;
when enhancement is observed, all of the lesions enhance to
a similar degree since they tend to arise synchronously.
While many infectious agents will result in complete rim
enhancement following gadolinium administration, in
ADEM the enhancement is typically characterized by incom-
restricted diffusion within the splenium of the corpus callosum; this
resolved on follow-up imaging 2 weeks later. DWI, diffusion-weighted
imaging.
plete “C-shaped” patterns of enhancement, likely as a result
of perivenous inflammation.49 Lesions often demonstrate
restriction of diffusion in a peripheral pattern on DWI
sequences, perhaps as a result of trapping of water within
layers of injured myelin or the presence of hypercellular
infiltrates at the leading edge of expanding lesions.50 Lesions
in anti-GABAa receptor encephalitis may be mistaken for
ADEM, as multifocal cortical and subcortical lesions are
typically seen. One point of distinction, however, is that
the lesions in anti-GABAa receptor encephalitis are often

Seminars in Neurology Vol. 39 No. 3/2019

316 Imaging in Encephalitis Venkatesan, Jagdish

Table 1 Selected causes of multifocal encephalitis

Pathogen Characteristic brain MRI findings

VZV Ischemic or hemorrhagic lesions in white matter or gray–white matter junction
Enteroviruses Abnormalities may involve deep gray matter (i.e., thalamus, basal ganglia),
brainstem, and spinal cord
Arboviruses Abnormalities may involve deep gray matter (i.e. thalamus, basal ganglia),
brainstem, and spinal cord
JC virus Multifocal subcortical white matter lesions
Measles Cerebral edema, multifocal lesions, can resemble ADEM in acute setting
Mumps Lesions in brainstem, hippocampus, splenium of corpus callosum
Nipah virus Widespread punctate subcortical and deep white matter lesions
Rabies virus Multifocal abnormalities throughout cortex, deep gray nuclei, brainstem, cerebral
white matter; gray matter is involved much more frequently than white matter
Borrelia spp. Multifocal lesions in subcortical and periventricular white matter, may mimic
multiple sclerosis
Rickettsia spp. Multiple punctate areas of restricted diffusion, “starry sky” pattern
Mycobacterium tuberculosis Multiple rim-enhancing and/or vascular lesions

Downloaded by: Kent State University. Copyrighted material.

Fungal infections Multiple rim-enhancing lesions
(Coccidioides, Histoplasma, Blastomyces)
Balamuthia mandrillaris Multifocal T2 hyperintensities with rim enhancement
Baylisascaris procyonis Multifocal or confluent white matter abnormalities with nodular enhancement
Autoimmune condition
ADEM Multifocal CNS involvement, white matter > gray matter, “C-shaped” rim of
enhancement, variable spinal cord involvement, lesions develop synchronously
MOG encephalomyelitis Multiple cortical or subcortical lesions, longitudinally extensive spinal cord lesions
Anti-GABAa receptor encephalitis Multiple asynchronous cortical and subcortical lesions

Abbreviations: ADEM, acute disseminated encephalomyelitis; CNS, central nervous system; JC, John Cunningham; MOG, myelin oligodendrocyte
glycoprotein; MRI, magnetic resonance imaging; VZV, varicella zoster virus.

asynchronous.51 Such lesions may be seen less frequently in
other autoimmune encephalitides (►Fig. 6).
Additional Neuroimaging Modalities
Particularly in cases of neuronal surface antibody-mediated
encephalitis, MRI may be normal. Indeed, a majority of
patients with anti-NMDAR encephalitis (50–77%) do not
present with any abnormalities upon standard MRI, nor do
up to one-third of patients with autoimmune limbic ence-
phalitis.15,52–54 As a result, there has been increased interest
in the evaluation of other neuroimaging modalities that may
contribute to the diagnosis of autoimmune encephalitis. In
this regard, fluorodeoxyglucose-positron emission tomogra-
phy (FDG-PET) may prove useful. Indeed, hyperavidity in the
mesial temporal lobes is frequently seen in autoimmune
limbic encephalitis, and current consensus includes this as
fulfilling radiographic criteria.2 Specific FDG-PET signatures
may be associated with subgroups of autoimmune encepha-
litis. In a study of eight patients with anti-NMDAR encepha-
litis who were evaluated within 12 weeks or less of symptom
onset, FDG-PET/CT showed cortical hypometabolism in
seven patients and significant medial occipital lobe hypo-
metabolism in six of the eight patients.55 These patients also
exhibited greater occipital hypometabolism when compared
with other patients with confirmed and probable autoim-
mune encephalitis. In anti-LGI1 encephalitis, where basal
ganglia T1 and T2 hyperintensities have been reported on
MRI, FDG-PET has shown evidence of basal ganglia hyper-
metabolism,56–58 though prospective studies are needed.
Neuroimaging Biomarkers and Outcomes
The mortality rate for acute encephalitis has been reported to
be between 5 and 15%. Half or more of survivors are left with
substantial neurological and cognitive deficits, which may
include lower intelligence quotients, behavioral impairments,
attention-deficit hyperactivity disorder, and residual motor
deficits.59 Mortality rates in autoimmune encephalitis tend to
be lower than infectious cases, although prolonged recovery
and the potential for immune relapses may contribute to long-
term morbidity. Notably, those patients with autoimmune
encephalitis associated with antibodies targeting intracellular
proteins, such as anti-Hu, anti-Ma/Ta, anti-GAD, and anti-CV2,
have a poorer prognosis than those with antibodies targeting
cell surface proteins.60 Several potentially modifiable factors
are predictive of a poor outcome in cohorts of all-cause
encephalitis; these include delays to treatment, raised intra-
cranial pressure and cerebral edema, lower body temperature,

Seminars in Neurology Vol. 39 No. 3/2019


Fig. 6 Anti-CASPR2 encephalitis. FLAIR imaging demonstrates an
atypical pattern of multiple T2 hyperintensities predominantly in the
subcortical white matter of the right hemisphere. FLAIR, fluid-atte-
nuated inversion recovery.
uncontrolled seizures, thrombocytopenia, and hospital-
acquired infections.61–63 An EEG has been found to have
some value, since normal EEG early in admission is associated
with positive outcomes.64 There has also been interest in the
development of blood and CSF-based biomarkers of prognosis,
including elevated levels of neural proteins or inflammatory
cytokines which may correlate with poor outcome.65–67 Over-
all, however, there exists a relative paucity of clinically useful
biomarkers for prognosis following encephalitis and thus there
is considerable interest in developing neuroimaging biomar-
kers. Below we will describe outcomes and neuroimaging
correlates for selected infectious and autoimmune causes of
encephalitis. While there are few established neuroimaging
biomarkers for prognosis, the discussion will focus on promis-
ing approaches and challenges.
The mortality rate for patients with HSV encephalitis is up
to 15% despite treatment with acyclovir, with the majority of
survivors experiencing severe neurologic and cognitive
sequelae.9,68,69 Clinical factors associated with poor prog-
nosis include delayed initiation of acyclovir, older age, a
lower Glasgow coma scale on admission, seizures, and devel-
opment of hospital-acquired infections.68–70 From a neuroi-
maging perspective, the extent and location of injury to the
temporal lobes have been shown to correlate with dysfunc-
tion. A study of long-term sequelae in 11 HSV encephalitic
individuals demonstrated that MRI findings of left-sided
amygdala damage and reduction in hippocampal and amyg-
dala volume71 and bilateral temporal lobe swelling were
Imaging in Encephalitis Venkatesan, Jagdish 317
associated with the severity of neuropsychological seque-
lae.72 More recently, restricted diffusion on MRI was found in
two-thirds of patients with herpes simplex encephalitis who
experienced poor outcome.73
WNV encephalitis carries a 10% mortality rate.59 Survivors
experience various neurocognitive deficits such as deficiencies
in language/social communication, memory impairment,
executive dysfunction, and defects in attention and concentra-
tion.74 A cross-sectional study of individuals who had suffered
from West Nile neuroinvasive disease showed significant
cortical thinning in both cerebral hemispheres on MRI, pri-
marily in the frontal and limbic cortices, as compared with age-
and gender-matched controls.75 Cortical thinning in the left
hemisphere correlated with neuropsychological impairment
as measured by the Repeatable Battery for the Assessment of
Neuropsychological Status (RBANS). Additionally, regional
atrophy was noted in the cerebellum, brain stem, thalamus,
putamen, and globus pallidus compared with controls. Thus,
despite the propensity for deep gray matter involvement in the
acute phase of WNV encephalitis,76 the resulting damage
Downloaded by: Kent State University. Copyrighted material.
appears to be more widespread and will need to be carefully
characterized in prospective studies.
JEV is responsible for numerous cases of encephalitis
worldwide, is associated with a high mortality rate (up to
30%), and the majority of surviving children suffer from
functional impairment, especially in behavior, language,
and limb use.77,78 In one series of over 100 children in
Malaysia, those with poor outcome at hospital discharge
were more likely to have experienced seizures before or at
hospital admission, to have a faster heart rate, to have
required intubation, to have a reduced Glasgow coma score,
and to have abnormal motor signs.79 Despite the prevalence
and severity of JE, however, neuroimaging biomarkers have
not been well characterized. Three patients with physical
and cognitive disability 3 years following onset of JE showed
continued abnormal signal intensities on MRI in the thala-
mus, basal ganglia, and brainstem, as might be expected
given the prominent deep gray abnormalities seen in the
acute setting.80 Overall, loss of clinical follow-up and lack of
ready access to MRI have likely contributed to the dearth of
neuroimaging data following JE.
While the mortality following anti-NMDAR encephalitis
patients is low if the disease is identified early and immu-
notherapy is instituted, many survivors suffer from memory
deficits and executive dysfunction.81–83 FDG-PET may shed
light on prognosis, as the time to normalization of occipital
hypometabolism may correlate with outcomes in some
patients with anti-NMDAR encephalitis.55,82 In addition, struc-
tural and functional neuroimaging correlates to neurocogni-
tive dysfunction following anti-NMDAR encephalitis are being
vigorously explored.52 In a structural MRI study of 40 anti-
NMDAR encephalitis patients who were clinically considered
to be past the acute phase of the disease, hippocampal
volumetry demonstrated atrophy of the entire left and right
hippocampus along with CA4/DG, subiculum, and presubicu-
lum.81 Atrophy of the CA1 and CA2/3 subfields of the right
hippocampus and reduction in fimbria volume of the left
hippocampus was also present. Additionally, hippocampal
Seminars in Neurology Vol. 39 No. 3/2019
318 Imaging in Encephalitis Venkatesan, Jagdish
microstructure integrity, as measured by mean diffusivity, was
abnormal. These data highlight the broad impact of anti-
NMDAR encephalitis on hippocampal input, output, and
microstructural integrity. Moreover, there were strong corre-
lations of hippocampal volume and mean diffusivity with
verbal and visuospatial memory performance, and thus these
measures have potential as radiological biomarkers of cogni-
tive function following anti-NMDAR encephalitis.81
Functional MRI (fMRI) measures have also been found to
correlate with neurocognitive dysfunction following anti-
NMDAR encephalitis. In a study of 24 individuals with post-
acute phase anti-NMDAR encephalitis, fMRI analysis showed
significantly reduced connectivity between the anterior
default mode network (comprised of the medial prefrontal
cortex, anterior cingulate cortex, parts of the posterior cingu-
late cortex, and parts of the medial temporal lobes) and the
anterior hippocampus bilaterally.52 This reduction of func-
tional connectivity strongly correlated with patients’ memory
performance.52 Within the same study, diffusion tensor ima-
ging showed alterations in white matter integrity especially in
the cingulum bundle, which has been associated with impair-
ments of working memory and executive function.52 More
recently, an observational study of 43 individuals past the
acute phase of anti-NMDAR encephalitis again demonstrated
altered functional connectivity. fMRI showed decoupling of
the medial temporal and the default-mode networks, impaired
frontotemporal connectivity, and reduced hippocampal func-
tional connectivity. Functional connectivity was also impaired
within distributed large-scale networks throughout the
brain.84 Memory impairment was shown to correlate with
hippocampal and medial temporal lobe network connectivity,
while schizophrenia-like symptoms (i.e., hallucinations, delu-
sions, mutism, catatonia) correlated with impairments in
functional connectivity in the frontoparietal networks.84
Longitudinal studies will be necessary to determine how these
network changes evolve over time.
The 2-year case fatality rate in those with LGI1 encepha-
litis is up to 19%, and immune-mediated relapses are com-
mon, occurring in up to one-third of cases.85,86 Survivors
report amnesia, spatial disorientation, and insomnia, and
have been found to have deficiencies in working memory and
visuospatial abilities.85–87 Clinical predictors of poor out-
come include absence of response to initial immunotherapy
and the development of clinical relapses.88 During the acute
stage of the disease, hippocampal T2/FLAIR hyperintense
signal abnormalities are observed in most patients and often
evolve into hippocampal atrophy with persistent cognitive
dysfunction.89–91 Global atrophy has also been noted follow-
ing the acute stage.92,93 In a study of nine patients in whom
multimodal MRI was performed, diffusion tensor imaging
demonstrated widespread increases in fractional anisotropy
throughout the brain, reflecting decreased white matter
integrity and corroborating the notion that LGI1 affects the
brain in a global fashion.93 Interestingly, better outcomes on
modified Rankin Scale were associated with higher cerebel-
lar gray matter volume, while increased cognitive capacity
was associated with higher putaminal volumes; the signifi-
cance of these findings is unclear and will need to be followed
Seminars in Neurology Vol. 39 No. 3/2019
up in larger studies. fMRI performed on 27 postacute stage
anti-LGl1 encephalitis individuals also demonstrated that
the disease affects a wider range of brain regions than the
limbic system.87 The principal findings were of increased
connectivity in the ventral and dorsal default mode network,
and decreased connectivity within the salience network, all
associated with better memory performance. The authors
hypothesized that these changes in functional connectivity
may arise as secondary or compensatory changes to focal
damage to the hippocampus or alternatively as a direct result
of more global effects of the LGI1 antibody. The latter is
supported by the finding that while LGI1 is predominantly
expressed in the hippocampus, it is also found to a lesser
extent in the inner layers of the cortex.94 Taken together,
these structural and functional studies support the notion
that LGI encephalitis causes widespread brain dysfunction
and reorganization and point the way toward radiological
measures that may serve as useful correlates for outcomes.
Conclusions
Downloaded by: Kent State University. Copyrighted material.
Despite recent advancements in diagnosis and treatment,
encephalitis continues to pose a substantial challenge for
clinicians. Neuroimaging can play an important role in con-
firming that a patient indeed has encephalitis and in defining
the specific etiology. While our knowledge of outcomes follow-
ing encephalitis is still quite rudimentary, correlations with
structural and functional neuroimaging parameters have
shown some promise. While conventional MRI has proven
useful to our understanding of causes and outcomes in ence-
phalitis, additional neuroimaging modalities such as PET ima-
ging and fMRI may prove complementary and are likely to
contribute to a mechanistic understanding of postencephalitis
brain reorganization and function. Larger cross-sectional stu-
dies, as well as longitudinal studies that correlate imaging with
long-term function, are needed to better define and improve
patient outcomes for this often devastating condition.
Conflict of Interest
None.
References
1 Vallabhaneni D, Naveed MA, Mangla R, Zidan A, Mehta RI. Perfu-
sion imaging in autoimmune encephalitis. Case Rep Radiol 2018;
2018:3538645
2 Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of
autoimmune encephalitis. Lancet Neurol 2016;15(04):391–404
3 Steiner I, Budka H, Chaudhuri A, et al. Viral encephalitis: a review of
diagnostic methods and guidelines for management. Eur J Neurol
2005;12(05):331–343
4 Schroth G, Kretzschmar K, Gawehn J, Voigt K. Advantage of
magnetic resonance imaging in the diagnosis of cerebral infec-
tions. Neuroradiology 1987;29(02):120–126
5 Marchbank ND, Howlett DC, Sallomi DF, Hughes DV. Magnetic
resonance imaging is preferred in diagnosing suspected cerebral
infections. BMJ 2000;320(7228):187–188
6 Kiroğlu Y, Calli C, Yunten N, et al. Diffusion-weighted MR imaging
of viral encephalitis. Neuroradiology 2006;48(12):875–880

7 Tsuchiya K, Katase S, Yoshino A, Hachiya J. Diffusion-weighted MR
imaging of encephalitis. AJR Am J Roentgenol 1999;173(04):
1097–1099
8 Venkatesan A, Tunkel AR, Bloch KC, et al; International Encepha-
litis Consortium Case definitions, diagnostic algorithms, and
priorities in encephalitis: consensus statement of the interna-
tional encephalitis consortium. Clin Infect Dis 2013;57(08):
1114–1128
9 Bertrand A, Leclercq D, Martinez-Almoyna L, Girard N, Stahl JP,
De-Broucker T. MR imaging of adult acute infectious encephalitis.
Med Mal Infect 2017;47(03):195–205
10 Rath TJ, Hughes M, Arabi M, Shah GV. Imaging of cerebritis,
encephalitis, and brain abscess. Neuroimaging Clin N Am 2012;
22(04):585–607
11 Defres S, Keller SS, Das K, et al; ENCEPH UK study group A
feasibility study of quantifying longitudinal brain changes in
herpes simplex virus (HSV) encephalitis using magnetic reso-
nance imaging (MRI) and stereology. PLoS One 2017;12(01):
e0170215
12 Chow FC, Glaser CA, Sheriff H, et al. Use of clinical and neuroima-
ging characteristics to distinguish temporal lobe herpes simplex
encephalitis from its mimics. Clin Infect Dis 2015;60(09):
1377–1383
13 Tan IL, McArthur JC, Venkatesan A, Nath A. Atypical manifesta-
tions and poor outcome of herpes simplex encephalitis in the
immunocompromised. Neurology 2012;79(21):2125–2132
14 Whitley RJ, Cobbs CG, Alford CA Jr, et al; NIAD Collaborative
Antiviral Study Group Diseases that mimic herpes simplex ence-
phalitis. Diagnosis, presentation, and outcome. JAMA 1989;262
(02):234–239
15 Kelley BP, Patel SC, Marin HL, Corrigan JJ, Mitsias PD, Griffith B.
Autoimmune encephalitis: pathophysiology and imaging review
of an overlooked diagnosis. AJNR Am J Neuroradiol 2017;38(06):
1070–1078
16 da Rocha AJ, Nunes RH, Maia AC Jr, do Amaral LL. Recognizing
autoimmune-mediated encephalitis in the differential diagnosis
of limbic disorders. AJNR Am J Neuroradiol 2015;36(12):
2196–2205
17 Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J.
Paraneoplastic limbic encephalitis: neurological symptoms,
immunological findings and tumour association in 50 patients.
Brain 2000;123(Pt 7):1481–1494
18 Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2-
associated encephalitis. Brain 2004;127(Pt 8):1831–1844
19 Heine J, Prüss H, Bartsch T, Ploner CJ, Paul F, Finke C. Imaging of
autoimmune encephalitis–relevance for clinical practice and
hippocampal function. Neuroscience 2015;309:68–83
20 Saiz A, Blanco Y, Sabater L, et al. Spectrum of neurological
syndromes associated with glutamic acid decarboxylase antibo-
dies: diagnostic clues for this association. Brain 2008;131(Pt
10):2553–2563
21 Höftberger R, Titulaer MJ, Sabater L, et al. Encephalitis and GABAB
receptor antibodies: novel findings in a new case series of 20
patients. Neurology 2013;81(17):1500–1506
22 Knox J, Cowan RU, Doyle JS, et al. Murray Valley encephalitis: a
review of clinical features, diagnosis and treatment. Med J Aust
2012;196(05):322–326
23 Wong SH, Smith DW, Fallon MJ, Kermode AG. Murray valley
encephalitis mimicking herpes simplex encephalitis. J Clin Neu-
rosci 2005;12(07):822–824
24 Deresiewicz RL, Thaler SJ, Hsu L, Zamani AA. Clinical and neuror-
adiographic manifestations of eastern equine encephalitis. N Engl
J Med 1997;336(26):1867–1874
25 Beattie GC, Glaser CA, Sheriff H, et al. Encephalitis with thalamic and
basal ganglia abnormalities: etiologies, neuroimaging, and poten-
tial role of respiratory viruses. Clin Infect Dis 2013;56(06):825–832
26 Solomon T, Kneen R, Dung NM, et al. Poliomyelitis-like illness due to
Japanese encephalitis virus. Lancet 1998;351(9109):1094–1097
Imaging in Encephalitis Venkatesan, Jagdish 319
27 Ooi MH, Wong SC, Lewthwaite P, Cardosa MJ, Solomon T. Clinical
features, diagnosis, and management of enterovirus 71. Lancet
Neurol 2010;9(11):1097–1105
28 Jain H, Deshpande A, Favaz AM, Rajagopal KV. MRI in rabies
encephalitis. BMJ Case Rep 2013;2013. doi: 10.1136/bcr-2013-
201825
29 Handique SK, Das RR, Barman K, et al. Temporal lobe involvement
in Japanese encephalitis: problems in differential diagnosis. AJNR
Am J Neuroradiol 2006;27(05):1027–1031
30 Basumatary LJ, Raja D, Bhuyan D, Das M, Goswami M, Kayal AK.
Clinical and radiological spectrum of Japanese encephalitis. J Neurol
Sci 2013;325(1–2):15–21
31 Dale RC, Merheb V, Pillai S, et al. Antibodies to surface dopamine-2
receptor in autoimmune movement and psychiatric disorders.
Brain 2012;135(Pt 11):3453–3468
32 Jubelt B, Mihai C, Li TM, Veerapaneni P. Rhombencephalitis/
brainstem encephalitis. Curr Neurol Neurosci Rep 2011;11(06):
543–552
33 Tan IL, Mowry EM, Steele SU, et al. Brainstem encephalitis:
etiologies, treatment, and predictors of outcome. J Neurol 2013;
260(09):2312–2319
34 Charlier C, Poirée S, Delavaud C, et al; MONALISA Study Group
Imaging of human neurolisteriosis: a prospective study of 71
Downloaded by: Kent State University. Copyrighted material.
cases. Clin Infect Dis 2018;67(09):1419–1426
35 Moragas M, Martínez-Yélamos S, Majós C, Fernández-Viladrich P,
Rubio F, Arbizu T. Rhombencephalitis: a series of 97 patients.
Medicine (Baltimore) 2011;90(04):256–261
36 Chen F, Liu T, Li J, Xing Z, Huang S, Wen G. MRI characteristics and
follow-up findings in patients with neurological complications of
enterovirus 71-related hand, foot, and mouth disease. Int J Clin
Exp Med 2014;7(09):2696–2704
37 Compain C, Sacre K, Puéchal X, et al. Central nervous system
involvement in Whipple disease: clinical study of 18 patients and
long-term follow-up. Medicine (Baltimore) 2013;92(06):324–330
38 Black DF, Aksamit AJ, Morris JM. MR imaging of central nervous
system Whipple disease: a 15-year review. AJNR Am J Neuroradiol
2010;31(08):1493–1497
39 Lu Z, Zhang B, Qiu W, et al. Comparative brain stem lesions on MRI
of acute disseminated encephalomyelitis, neuromyelitis optica,
and multiple sclerosis. PLoS One 2011;6(08):e22766
40 Tobin WO, Guo Y, Krecke KN, et al. Diagnostic criteria for chronic
lymphocytic inflammation with pontine perivascular enhance-
ment responsive to steroids (CLIPPERS). Brain 2017;140(09):
2415–2425
41 Gilden D, Cohrs RJ, Mahalingam R, Nagel MA. Varicella zoster virus
vasculopathies: diverse clinical manifestations, laboratory features,
pathogenesis, and treatment. Lancet Neurol 2009;8(08):731–740
42 Bradshaw MJ, Lalor KB, Vu N, Pruthi S, Bloch KC. Child neurology:
Rocky Mountain spotted fever encephalitis. Neurology 2017;88
(11):e92–e95
43 Agarwal R, Sze G. Neuro-lyme disease: MR imaging findings.
Radiology 2009;253(01):167–173
44 Agosta F, Rocca MA, Benedetti B, Capra R, Cordioli C, Filippi M. MR
imaging assessment of brain and cervical cord damage in patients
with neuroborreliosis. AJNR Am J Neuroradiol 2006;27(04):892–894
45 Sahraian MA, Radue EW, Eshaghi A, Besliu S, Minagar A. Progres-
sive multifocal leukoencephalopathy: a review of the neuroima-
ging features and differential diagnosis. Eur J Neurol 2012;19(08):
1060–1069
46 Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria:
consensus statement from the AAN Neuroinfectious Disease
Section. Neurology 2013;80(15):1430–1438
47 Bulakbasi N, Kocaoglu M, Tayfun C, Ucoz T. Transient splenial
lesion of the corpus callosum in clinically mild influenza-asso-
ciated encephalitis/encephalopathy. AJNR Am J Neuroradiol
2006;27(09):1983–1986
48 Gallucci M, Limbucci N, Paonessa A, Caranci F. Reversible focal
splenial lesions. Neuroradiology 2007;49(07):541–544
Seminars in Neurology Vol. 39 No. 3/2019
320 Imaging in Encephalitis Venkatesan, Jagdish
49 Young NP, Weinshenker BG, Parisi JE, et al. Perivenous demyelina-
tion: association with clinically defined acute disseminated
encephalomyelitis and comparison with pathologically con-
firmed multiple sclerosis. Brain 2010;133(Pt 2):333–348
50 Abou Zeid N, Pirko I, Erickson B, et al. Diffusion-weighted imaging
characteristics of biopsy-proven demyelinating brain lesions.
Neurology 2012;78(21):1655–1662
51 Spatola M, Petit-Pedrol M, Simabukuro MM, et al. Investigations in
GABAA receptor antibody-associated encephalitis. Neurology 2017;
88(11):1012–1020
52 Finke C, Kopp UA, Scheel M, et al. Functional and structural brain
changes in anti-N-methyl-D-aspartate receptor encephalitis. Ann
Neurol 2013;74(02):284–296
53 Wang R, Lai XH, Liu X, et al. Brain magnetic resonance-imaging
findings of anti-N-methyl-D-aspartate receptor encephalitis: a
cohort follow-up study in Chinese patients. J Neurol 2018;265(02):
362–369
54 Zhang T, Duan Y, Ye J, et al. Brain MRI characteristics of patients
with anti-N-methyl-D-aspartate receptor encephalitis and their
associations with 2-year clinical outcome. AJNR Am J Neuroradiol
2018;39(05):824–829
55 Probasco JC, Solnes L, Nalluri A, et al. Decreased occipital lobe
metabolism by FDG-PET/CT: an anti-NMDA receptor encephalitis
biomarker. Neurol Neuroimmunol Neuroinflamm 2017;5(01):e413
56 Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures
precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69
(05):892–900
57 Flanagan EP, Kotsenas AL, Britton JW, et al. Basal ganglia T1
hyperintensity in LGI1-autoantibody faciobrachial dystonic sei-
zures. Neurol Neuroimmunol Neuroinflamm 2015;2(06):e161
58 Dodich A, Cerami C, Iannaccone S, et al. Neuropsychological and
FDG-PET profiles in VGKC autoimmune limbic encephalitis. Brain
Cogn 2016;108:81–87
59 Venkatesan A. Epidemiology and outcomes of acute encephalitis.
Curr Opin Neurol 2015;28(03):277–282
60 Lancaster E. The diagnosis and treatment of autoimmune ence-
phalitis. J Clin Neurol 2016;12(01):1–13
61 Sonneville R, Gault N, de Montmollin E, et al. Clinical spectrum
and outcomes of patients with encephalitis requiring intensive
care. Eur J Neurol 2015;22(01):6–16, e1
62 Thakur KT, Motta M, Asemota AO, et al. Predictors of outcome in
acute encephalitis. Neurology 2013;81(09):793–800
63 Singh TD, Fugate JE, Rabinstein AA. The spectrum of acute
encephalitis: causes, management, and predictors of outcome.
Neurology 2015;84(04):359–366
64 Sutter R, Kaplan PW, Cervenka MC, et al. Electroencephalography
for diagnosis and prognosis of acute encephalitis. Clin Neurophy-
siol 2015;126(08):1524–1531
65 Tsukahara H, Fujii Y, Matsubara K, et al. Prognostic value of brain
injury biomarkers in acute encephalitis/encephalopathy. Pediatr
Int 2013;55(04):461–464
66 Sellner J, Davies NW, Howard RS, Petzold A. Neurofilament heavy
chain as a marker of neuroaxonal pathology and prognosis in
acute encephalitis. Eur J Neurol 2014;21(06):845–850
67 Michael BD, Griffiths MJ, Granerod J, et al. The interleukin-1
balance during encephalitis is associated with clinical severity,
blood-brain barrier permeability, neuroimaging changes, and
disease outcome. J Infect Dis 2016;213(10):1651–1660
68 Sili U, Kaya A, Mert A; HSV Encephalitis Study Group Herpes
simplex virus encephalitis: clinical manifestations, diagnosis
and outcome in 106 adult patients. J Clin Virol 2014;60(02):
112–118
69 Raschilas F, Wolff M, Delatour F, et al. Outcome of and prognostic
factors for herpes simplex encephalitis in adult patients: results of
a multicenter study. Clin Infect Dis 2002;35(03):254–260
70 Erdem H, Cag Y, Ozturk-Engin D, et al. Results of a multinational
study suggest the need for rapid diagnosis and early antiviral
Seminars in Neurology Vol. 39 No. 3/2019
treatment at the onset of herpetic meningoencephalitis. Anti-
microb Agents Chemother 2015;59(06):3084–3089
71 Caparros-Lefebvre D, Girard-Buttaz I, Reboul S, et al. Cognitive
and psychiatric impairment in herpes simplex virus encephalitis
suggest involvement of the amygdalo-frontal pathways. J Neurol
1996;243(03):248–256
72 Reed LJ, Lasserson D, Marsden P, Bright P, Stanhope N, Kopelman
MD. Correlations of regional cerebral metabolism with memory
performance and executive function in patients with herpes
encephalitis or frontal lobe lesions. Neuropsychology 2005;19
(05):555–565
73 Singh TD, Fugate JE, Hocker S, Wijdicks EFM, Aksamit AJ Jr,
Rabinstein AA. Predictors of outcome in HSV encephalitis.
J Neurol 2016;263(02):277–289
74 Davis LE, DeBiasi R, Goade DE, et al. West Nile virus neuroinvasive
disease. Ann Neurol 2006;60(03):286–300
75 Murray KO, Nolan MS, Ronca SE, et al. The neurocognitive and MRI
outcomes of West Nile virus infection: preliminary analysis using
an external control group. Front Neurol 2018;9:111
76 Sejvar JJ. Clinical manifestations and outcomes of West Nile virus
infection. Viruses 2014;6(02):606–623
77 Griffiths MJ, Lemon JV, Rayamajhi A, et al. The functional, social and
economic impact of acute encephalitis syndrome in Nepal–a long-
Downloaded by: Kent State University. Copyrighted material.
itudinal follow-up study. PLoS Negl Trop Dis 2013;7(09):e2383
78 Cao L, Fu S, Gao X, et al. Low protective efficacy of the current
Japanese encephalitis vaccine against the emerging genotype 5
Japanese encephalitis virus. PLoS Negl Trop Dis 2016;10(05):
e0004686
79 Ooi MH, Lewthwaite P, Lai BF, et al. The epidemiology, clinical
features, and long-term prognosis of Japanese encephalitis in
central sarawak, malaysia, 1997-2005. Clin Infect Dis 2008;47
(04):458–468
80 Shoji H, Murakami T, Murai I, et al. A follow-up study by CT and
MRI in 3 cases of Japanese encephalitis. Neuroradiology 1990;32
(03):215–219
81 Finke C, Kopp UA, Pajkert A, et al. Structural hippocampal damage
following anti-N-methyl-D-aspartate receptor encephalitis. Biol
Psychiatry 2016;79(09):727–734
82 Finke C, Kopp UA, Prüss H, Dalmau J, Wandinger KP, Ploner CJ.
Cognitive deficits following anti-NMDA receptor encephalitis.
J Neurol Neurosurg Psychiatry 2012;83(02):195–198
83 Yeshokumar AK, Gordon-Lipkin E, Arenivas A, et al. Neurobeha-
vioral outcomes in autoimmune encephalitis. J Neuroimmunol
2017;312:8–14
84 Peer M, Prüss H, Ben-Dayan I, Paul F, Arzy S, Finke C. Functional
connectivity of large-scale brain networks in patients with anti-
NMDA receptor encephalitis: an observational study. Lancet
Psychiatry 2017;4(10):768–774
85 Li W, Wu S, Meng Q, et al. Clinical characteristics and short-term
prognosis of LGI1 antibody encephalitis: a retrospective case
study. BMC Neurol 2018;18(01):96
86 van Sonderen A, Thijs RD, Coenders EC, et al. Anti-LGI1 encepha-
litis: clinical syndrome and long-term follow-up. Neurology
2016;87(14):1449–1456
87 Heine J, Prüss H, Kopp UA, et al. Beyond the limbic system:
disruption and functional compensation of large-scale brain
networks in patients with anti-LGI1 encephalitis. J Neurol Neu-
rosurg Psychiatry 2018;89(11):1191–1199
88 Ariño H, Armangué T, Petit-Pedrol M, et al. Anti-LGI1-associated
cognitive impairment: presentation and long-term outcome.
Neurology 2016;87(08):759–765
89 Finke C, Prüss H, Heine J, et al. Evaluation of cognitive deficits and
structural hippocampal damage in encephalitis with leucine-rich,
glioma-inactivated 1 antibodies. JAMA Neurol 2017;74(01):50–59
90 Navarro V, Kas A, Apartis E, et al; collaborators Motor cortex and
hippocampus are the two main cortical targets in LGI1-antibody
encephalitis. Brain 2016;139(Pt 4):1079–1093

91 Gadoth A, Pittock SJ, Dubey D, et al. Expanded phenotypes and
outcomes among 256 LGI1/CASPR2-IgG-positive patients. Ann
Neurol 2017;82(01):79–92
92 Irani SR, Stagg CJ, Schott JM, et al. Faciobrachial dystonic seizures:
the influence of immunotherapy on seizure control and preven-
tion of cognitive impairment in a broadening phenotype. Brain
2013;136(Pt 10):3151–3162
Imaging in Encephalitis Venkatesan, Jagdish 321
93 Szots M, Blaabjerg M, Orsi G, et al. Global brain atrophy and
metabolic dysfunction in LGI1 encephalitis: a prospective multi-
modal MRI study. J Neurol Sci 2017;376:159–165
94 Herranz-Pérez V, Olucha-Bordonau FE, Morante-Redolat JM,
Pérez-Tur J. Regional distribution of the leucine-rich glioma
inactivated (LGI) gene family transcripts in the adult mouse brain.
Brain Res 2010;1307:177–194
Downloaded by: Kent State University. Copyrighted material.
Seminars in Neurology Vol. 39 No. 3/2019