Clinical Imaging 84 (2022) 1–30

Contents lists available at ScienceDirect

Clinical Imaging
journal homepage: www.elsevier.com/locate/clinimag

Neuroradiology

Brain on fire: an imaging-based review of autoimmune encephalitis☆

Christopher Ball, MD a, Ryan Fisicaro, MD a, Lee Morris III, MD a, Andrew White, DO a,
Thomas Pacicco, MD b, Karuna Raj, MD a, Amit Agarwal, MD a, Wan-Ching Lee, MD c,
Fang Frank Yu, MD a, *
a
Department of Radiology, University of Texas Southwestern, 5323 Harry Hines Blvd., Dallas, TX 75390, United States of America
b
University of Texas Southwestern, 5323 Harry Hines Blvd., Dallas, TX 75390, United States of America
c
Department of Emergency Medicine, University of Texas Southwestern, 5323 Harry Hines Blvd., Dallas, TX 75390, United States of America

A R T I C L E I N F O A B S T R A C T

Keywords: Autoimmune encephalitis represents an increasingly recognized group of immune-mediated disorders the affect
Autoimmune encephalitis the central nervous system. The purpose of this article is to highlight the characteristic MR imaging findings
Central nervous system associated with autoimmune encephalitis, describe the pathophysiology, review antibodies that have been
Limbic encephalitis
identified and their patterns of CNS involvement, and discuss approaches to management. Familiarity with the
MRI
imaging and clinical features of autoimmune encephalitis will prompt the radiologist to suggest the diagnosis
which can facilitate appropriate management.

1. Introduction and T cells.2,3,6 Examples of typical intracellular antigens include Hu,

Autoimmune encephalitis (AE) refers to a group of immune-
mediated disorders that involve the central nervous system (CNS).1 As
the pathophysiologic mechanism of AE is secondary to auto-antibodies
directed against various proteins within the CNS, the clinical and im­
aging manifestations may show considerable overlap.2 Similarly, given
that many of the clinical and imaging features are similar to more
common disease entities, AE remains a diagnosis of exclusion.3 None­
theless, the radiologist should be familiar with the imaging findings that
may be seen with AEs, so as to aid the referring clinician – particularly in
the setting of atypical clinical features and an otherwise negative
workup.4,5 In this review, we discuss the spectrum of imaging findings
associated with AE, the implicated auto-antibodies, as well as other
disease processes that can mimic the imaging features.
2. Pathophysiology
Antibody-associated disorders of the CNS are generally divided into
two groups, often termed “Group 1” and “Group 2”. The first group in­
cludes the classic paraneoplastic disorders in which there is a systemic
anti-tumoral immune response against intracellular antigens by both B
Yo, Ma, and CV2. The primary pathologic process in the CNS is thought
to be due to a T cell response which develops following sensitization to
antigens which are typically only found in the CNS but are produced
ectopically by the primary malignancy. The T cell response (directed
towards both the malignancy and neurons in the CNS that express these
intracellular antigens) that is ultimately responsible for the mechanism
of injury, all of which result in an irreversible loss of neurons.3,6–8 The
antibodies, which can be measured in the serum or CSF, may be useful
tumor markers but are not the primary cause of pathology in the CNS.
Due to neuronal loss, paraneoplastic AE with intracellular antigens is
associated with a monophasic disease course, fewer therapeutic options,
and an overall worse prognosis (Table 1).2,3,9
The second group is characterized by formation of auto-antibodies
which are primarily pathogenic. These antibodies target cell surface
proteins, ion channels, or receptors, and cause a change in the target's
structure, function, or location, depending on the antibody subtype.6,9,10
Current theories suggest that antibodies against cell surface antigens
may be formed as the antigens are released secondary to a viral infec­
tion, tumor, or other mechanisms. Examples of typical cell surface an­
tigens include NMDAr, VGKC, GABA, D2 and AMPAr. These may change
the behavior of the target and even result in tissue destruction over time;

The author(s) have no grants, conflicts of interest, or disclosures to divulge that are applicable to this submission.
☆

* Corresponding author.
E-mail addresses: ryan.fisicaro@utsouthwestern.edu (R. Fisicaro), Lee.Morris@utsouthwestern.edu (L. Morris), Andrew.White@UTSouthwestern.edu (A. White),
Karuna.Raj@utsouthwestern.edu (K. Raj), agarwal.amit@mayo.edu (A. Agarwal), annie.lee@utsouthwestern.edu (W.-C. Lee), frankf.yu@utsouthwestern.edu
(F.F. Yu).

https://doi.org/10.1016/j.clinimag.2021.12.011
Received 13 July 2021; Received in revised form 28 November 2021; Accepted 16 December 2021
Available online 31 December 2021
0899-7071/Published by Elsevier Inc.
C. Ball et al. Clinical Imaging 84 (2022) 1–30

Table 1
List of select antibodies and their intracellular targets.
Antibody Association with malignancy Clinical manifestation Image findings

Anti-Hu Small cell lung cancer Encephalomyelitis, sensory neuropathy, cerebellar T2 prolongation in limbic system, cerebellum and brainstem
(ANNA-1) degeneration
Anti-Ma Testicular, non-small cell lung and Brainstem dysfunction, ophthalmoplegia T2 prolongation in limbic system, thalamus and brainstem
breast cancers
Anti-GAD65 Stiff person syndrome, cerebellar ataxia, limbic T2 prolongation in the limbic system
encephalitis
Associated with Type 1 Diabetes
Anti-Yo Breast and ovarian cancer Ataxia, vertigo, nystagmus Cerebellar degeneration
Anti-CV2 Small cell lung cancer and thymomas Choreiform movements T2 prolongation in the striatum, longitudinal T2 prolongation
in the spinal cord
Anti-Ri Breast and small cell lung cancers Opsoclonus-myocolonus syndrome T2 prolongation in the brainstem, less commonly cerebellar
degeneration

Table 2
List of antibodies and their cell surface targets.
Antibody Association with malignancy Clinical manifestation Image findings

Anti-NMDAr Ovarian teratoma Viral prodrome, psychiatric symptoms, amnesia, Variable transient cortical T2 prolongation, often normal
seizures, encephalopathy
Anti-VGKC Epilepsy, limbic encephalitis T2 prolongation in mesial temporal lobes progressing to
(LGI1; mesial temporal sclerosis
Caspr2)
Anti-GABA A Rarely thymoma Epilepsy Extensive and multifocal extra-limbic T2 prolongation
Anti-GABA B Small cell lung or primary Limbic encephalitis T2 prolongation in the mesial temporal lobes
neuroendocrine cancers
Anti-AMPAr Breast, lung and thymic tumors Subacute psychiatric symptoms T2 prolongation in the hippocampi
Anti-VGCC Viral prodrome, neuropsychiatric symptoms, limbic T2 prolongation in the mesial temporal lobes, extra-limbic
dysfunction, seizures cortices and cerebellum
Anti-GluR3 Rasmussen's encephalitis, intractable epilepsy Homohemispheric atrophy and T2 prolongation
Anti-mGluR1 Lymphoma Ataxia Cerebellar atrophy
Anti-D2 Sydenham's chorea, Tourette's syndrome T2 prolongation of basal ganglia and substantia nigra
Anti-GlyR Upper motor neuron symptoms Variable transient cortical T2 prolongation, often normal

however, compared to AE with intracellular antigens, relatively little

neuronal cell death occurs. Removal of the antibody typically results in
recovery of receptor location or function; therefore, autoimmune en­
cephalitis with cell surface antigens has a significantly better prognosis.
Up to 80% of patients show significant improvement after therapy,
albeit often with a prolonged recovery course.2,3,6,10 Association with
malignancy in this group is variable, and a wider age range of patients,
including children and young adults, may be affected. In patients
without a known underlying malignancy, one should consider recent
infections or immunizations, as well as underlying systemic autoim­
mune disorders (Table 2).2,11
There is a third group which represents diseases caused by auto-
antibodies to intracellular synaptic proteins such as amphiphysin or
GAD65. These antigens are typically intracellular but may be expressed
on the cell surface during synaptic vesicle recycling. Both B cell (anti­
body) and T cell mechanisms may be involved in the pathogenesis of this
group.2,9 Fig. 1. Common antibodies grouped by typical sites of associated imaging
For each of the three groups, the involved antigens are expressed findings. Antibody names are bolded to indicate the most commonly re­
throughout the CNS, however there is thought to be enrichment of many ported location.
of these antigens within the hippocampus as well as occasionally the
cerebellum and brainstem. Therefore, in the majority of cases of auto­ 3. Imaging findings
immune encephalitis, both paraneoplastic and non-neoplastic, the
limbic system is involved, but involvement of other regions – such as the Magnetic resonance imaging (MRI) is the modality of choice for
striatum, cerebral cortex, brainstem, cerebellum and spinal cord – may characterization of autoimmune encephalitis and to distinguish from
occur. In fact, pathologic studies show that the inflammatory infiltrates other pathologies. Many patients will have a negative MRI, however
are usually not restricted to one location and often exceed the bound­ those with imaging findings typically show T2-prolongation in the
aries predicted on imaging and clinical exam (Fig. 1).3,10 affected area due to cortical edema.12 While less typical, ill-defined post-

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Fig. 2. Two patients with limbic AE: (A-C) 81 year-old male with a history of seizures and positive anti-LGI1 antibodies. (A) Axial FLAIR and (B) diffusion weighted
images demonstrate increased FLAIR signal and diffusion restriction in the right hippocampus. (C) Follow up axial FLAIR image obtained one year later at the level of
the hippocampi demonstrates decreased right hippocampal volume consistent with progression to mesial temporal sclerosis. (D–E) 71 year-old female with a history
of intractable seizures, small cell lung cancer and anti-Hu antibodies in the serum. (D) Axial T2/FLAIR demonstrates increased signal and atrophy of bilateral
hippocampi. (E) Axial T1W post contrast images demonstrate a small focus of enhancement in the right hippocampus.

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Fig. 2. (continued).

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Fig. 2. (continued).

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Fig. 2. (continued).

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Fig. 2. (continued).

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Fig. 3. HSV-1 encephalitis: 66 year-old male with recent onset of nausea, headache and seizures. Axial T2-FLAIR (A) and DWI (B) images demonstrate restricted
diffusion, cortical swelling, and edema within the right anterior and medial temporal lobe with extension to the right frontal lobe. Further workup including CSF
analysis led to the diagnosis of HSV-1 encephalitis.

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Fig. 3. (continued).

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Fig. 4. Temporal lobe glioma: 70 year-old male with history of scalp sarcoma and recent development of seizures. T2/FLAIR (A) and post contrast T1W images (B)
show an expansile T2 hyperintense, nonenhancing mass in the medial left temporal lobe. This mass was suspected to be a low grade glioma. During surveillance over
the following year, the lesion developed enhancing components and was eventually determined to be WHO grade IV glioblastoma at time of resection.
contrast enhancement and areas of restricted diffusion are possible and
can complicate the interpretation without a clear clinical picture.4,13,14
MRI findings, in conjunction with the clinical findings, can be useful to
distinguish AE from neoplasms, ischemic or hemorrhagic infarction, and
infections. In addition to MRI, fluorodeoxyglucose positron emission
tomography (FDG-PET) can be utilized to assess metabolic activity in the
affected brain parenchyma, which varies depending on disease chro­
nicity (Fig. 2).15 Herein, we describe will discuss the imaging findings
associated with specific clinical syndromes and the commonly impli­
cated auto-antibodies. This is intended to serve as a guide and it is
important to note that other antibodies could also present with these
clinical and imaging findings.
4. Limbic autoimmune encephalitis
Imaging features of limbic encephalitis (LE) on MRI include hyper­
intense signal within the mesial temporal lobes (amygdala and hippo­
campus) on T2-weighted and fluid attenuated inversion recovery
(FLAIR) sequences, although any structure within the limbic system may
be involved. Findings may be unilateral at first but can progress to
involve both temporal lobes. Associated parenchymal swelling can be
seen but eventually subsides and lead to atrophy (mesial temporal
sclerosis) over months to years.16 Other MRI findings can include
diffusion restriction and ill-defined enhancement which are often tran­
sient and usually occupy only a fraction of the region demonstrating T2/
FLAIR signal abnormality.4 FDG-PET shows increased FDG uptake
initially, followed by hypometabolism.17
Typical clinical features of limbic encephalitis are characterized by
the subacute onset of short-term memory loss, irritability, hallucina­
tions, and seizures.10 The AEs that typically result in limbic encephalitis
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Clinical Imaging 84 (2022) 1–30
include anti-Hu, anti-VGKC complex, anti-GAD65, anti-GABA-B and
anti-AMPAr.
4.1. Anti-Hu (ANNA-1) encephalitis
Anti-Hu encephalitis is a paraneoplastic AE targeting intracellular
antigens. It is the most common of the paraneoplastic encephalidites,
and approximately 75–86% of patients have an underlying small cell
carcinoma.9,18 While the limbic system is the most common site of
involvement, anti-Hu encephalitis is often multifocal with involvement
of the cerebellum, brainstem and spinal cord. Clinically, patients can
present with encephalitis or encephalomyelitis, subacute sensory neu­
ropathy, or cerebellar degeneration.12,18
4.2. Anti-VGKC complex encephalitis
Limbic encephalitis associated with voltage-gated potassium ion
channel (VGKC) complex antibodies is characterized by seizures which
can be attributed to the high concentration of potassium channels in
limbic structures.19–21 These antibodies target various proteins associ­
ated with the VGKC, including anti-leucine-rich glioma inactivated 1
(LGI1) and anti-contactin-associated protein-like 2 (Caspr2), instead of
the VGKC itself. Anti-VGKC complex antibodies have been reported in
6% percent of patients with long-standing epilepsy.22 Therefore, pa­
tients with medication-refractory epilepsy may have an immune-
mediated etiology and benefit from immunotherapy.4,21
Approximately 31% of cases do not demonstrate any abnormalities
on MR imaging.22 Progression to mesial temporal sclerosis characterized
by abnormal T2/FLAIR signal and hippocampal atrophy is more com­
mon in patients who initially demonstrate contrast enhancement and
C. Ball et al. Clinical Imaging 84 (2022) 1–30

Fig. 4. (continued).

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Fig. 5. Two patients with extra-limbic cortical AE: (A–B) 25 year-old female with recent history of seizures and impaired comprehension. The patient's serum was
positive for anti-NMDA receptor antibodies. Axial T2/FLAIR images demonstrate increased cortical signal in the left temporal lobe, left insula, and left insular cortex.
(C–D) Patient with Rasmussen's encephalitis. Confluent FLAIR hyperintense signal is noted involving the left cerebral cortex (A). Follow-up imaging obtained one
year later (B) shows interval parenchymal volume loss and increased confluent FLAIR hyperintensity within the entire left cerebral hemisphere, consistent with
evolution of the known Rasmussen's encephalitis.

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Fig. 5. (continued).
diffusion restriction.22 Abnormal findings outside of the limbic system
are uncommon in patients with anti-Caspr2 associated AE, while in
patients with anti-LGI1 associated AE there may be involvement of the
basal ganglia.17
Anti-LGI1 antibodies cause limbic encephalitis with characteristic
clinical features including hyponatremia, rapid eye movement sleep
disorders, and fasciobrachial dystonic or tonic seizures.9,23,24 In contrast
to LGI1 which is almost exclusively expressed in the CNS, Caspr2 is also
expressed in the peripheral nervous system. Therefore, Caspr2 anti­
bodies can cause limbic encephalitis as well as peripheral nervous sys­
tem hyperexcitability, known as Morvan disease.2,19,24
4.3. Anti-GAD65 encephalitis
Anti-glutamic acid decarboxylase 65 antibodies target the intracel­
lular enzyme necessary to synthesize gamma aminoburtyric acid
(GABA) which is an inhibitory neurotransmitter. Patients may present
with stiff man syndrome or cerebellar ataxia. Additional clinical pre­
sentations include temporal lobe epilepsy with cognitive behavioral
features and type I diabetes.9,25 MR imaging demonstrates signal ab­
normality and swelling in the amygdala and hippocampus typical of
limbic encephalitis.25 Multifocal CNS abnormalities are seen in a mi­
nority of cases.26
4.4. Anti-GABA B encephalitis
GABA-B are inhibitory neurotransmitters; disruption of these chan­
nels by auto-antibodies are associated with seizures.27 Imaging features
are similar to other limbic encephalitidies including T2/FLAIR hyper­
intense signal in the mesial temporal lobes. Anti-GABA B encephalitis
has a stronger association with underlying malignancy than other AEs
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Clinical Imaging 84 (2022) 1–30
with antibodies that target cell surface receptors, as small cell lung
cancer or primary neuroendocrine tumors are found in approximately
half of patients.2,5
4.5. Anti-AMPAr encephalitis
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid recep­
tor (AMPAr) encephalitis is caused by antibodies to the GluR1 and
GluR2 subunits of AMPAr.1 These patients classically present with
psychiatric symptoms. Anti-AMPAr encephalitis is more likely to occur
in women and is paraneoplastic in nearly 70% of cases, commonly
associated with thymic, breast, and lung tumors.1–3 MR imaging dem­
onstrates T2/FLAIR abnormalities isolated to the hippocampi.1,3
5. Imaging differential diagnosis of limbic encephalitis
Examples of limbic encephalitis mimics include herpes encephalitis,
primary CNS neoplasms, and ischemic infarcts. Herpes encephalitis most
often occurs as a result of herpes simplex virus (HSV) type 1 infection
and shares similar imaging findings with limbic encephalitis, demon­
strating signal abnormalities distributed within the temporal lobes,
insulae, and cingulate gyri.28 However, HSV encephalitis more
frequently demonstrates restricted diffusion and hemorrhage than
limbic encephalitis.13,29 Involvement of the basal ganglia on imaging
would favor AE over HSV encephalitis.4 Clinically, HSV encephalitis
presents with fever and a more rapid clinical deterioration (Fig. 3).28,30
Primary CNS neoplasms such as diffuse gliomas can appear similar to
limbic encephalitis with an infiltrative distribution of T2/FLAIR
hyperintense signal on MRI and hypermetabolism on PET imaging. If MR
spectroscopy is performed both lesions demonstrate decreased N-ace­
tylaspartate.31,32 Imaging differences include extension of T2/FLAIR
C. Ball et al. Clinical Imaging 84 (2022) 1–30

Fig. 5. (continued).

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Fig. 5. (continued).
hyperintense signal beyond the limbic system with CNS neoplasms.
Additionally, higher grade neoplasms are more likely to exhibit focal
mass-like necrotic changes with marked peripheral enhancement
(Fig. 4).
Ischemic infarcts can appear similar on imaging if the distribution of
signal abnormalities lie within the limbic system. Differentiation in
these cases relies on diffusion restriction in the acute setting or the
presence of a vessel cutoff on angiographic imaging.
6. Extra-limbic cortical autoimmune encephalitis
Imaging features of extra-limbic cortical autoimmune encephalitis
on MRI include multifocal areas of cortically-based T2/FLAIR hyper­
intensity with or without gyriform enhancement or subtle enhancement
of the overlying meninges. There should not be associated restricted
diffusion or hemorrhage.2,5 As the disease progresses, cortical laminar
necrosis may develop. AE's that more frequently result in extra-limbic
cortical encephalitis include anti-NMDAr, anti-VGCC, anti-GABA-A,
and anti-GluR3 (Fig. 5).
6.1. Anti-NMDAr encephalitis
Anti-NMDAr encephalitis is caused by antibodies to the GluN1 sub­
unit of the extracellular N-methyl-D-aspartate receptor (NMDAr).4
Clinically, anti-NMDAr encephalitis presents initially with a viral-like
prodrome followed by psychiatric symptoms, abnormal movements,
and memory impairment. The deficits are generally reversible at first but
can become permanent due to neuronal loss via NMDA-mediated
glutamate excitotoxicity in long-standing cases.5,7 The condition even­
tually progresses to encephalopathy, dyskinesia and dysautonomia.33
Anti-NMDAr encephalitis is associated with ovarian masses, particularly
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Clinical Imaging 84 (2022) 1–30
mature teratomas.3 One study of patients with NMDAr AE found that
52% of females aged 12 years or older had an underlying teratoma. Only
6% of males or females below the age of 12 in the same case series were
found to have a teratoma.33
It is reported that over half of anti-NMDAr encephalitis patients will
have normal MR imaging.4,5 When MRI abnormalities are present, the
location is highly variable. One study found that anti-NMDAr enceph­
alitis involved the extra-limbic cerebral cortices with or without
concomitant hippocampal involvement in 72% of abnormalities.34
Additionally, hippocampal involvement may be a sign of a worse
prognosis. Involvement of the cerebellum, basal ganglia, and brainstem
without hippocampal involvement is less common.34
6.2. Anti-VGCC encephalitis
Anti-voltage gated calcium channel (VGCC) encephalitis is a rare
subtype primarily reported in children and women. The natural history
begins as a viral prodrome followed by neuropsychiatric symptoms,
limbic dysfunction, and seizures.35
MR imaging usually demonstrates abnormal T2/FLAIR signal in the
mesial temporal lobes but can also involve the extra-limbic cortices and
cerebellum.35,36 Cortical involvement may demonstrate gyriform
enhancement that progresses to cortical laminar necrosis.5
6.3. Anti-GABA-A encephalitis
Patients with Anti-GABA-A antibodies may present clinically with
encephalopathy as well as a seizure disorder including refractory sei­
zures, status epilepticus, and epilepsia partialis continua. This may be
attributed to the fact that like GABA-B, GABA-A is an inhibitory
neurotransmitter.4,9 These patients tend to have extensive and
C. Ball et al. Clinical Imaging 84 (2022) 1–30

Fig. 6. NMDA encephalitis: 28 year old female with history of NMDA encephalitis presenting with worsening fatigues, slurred speech and multiple falls. T2/FLAIR
(A) images showed multiple areas of T2 hyperintensity in the bilateral basal ganglia as well as the insular regions. There was associated patchy post contrast
enhancement (B).

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Fig. 6. (continued).

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Fig. 7. Creutzfeldt-Jakob Disease: 53-year-old male with acute worsening of memory loss and ataxia. T2/FLAIR and DWI images (A–B) show T2-prolongation and
diffusion restriction within the bilateral basal ganglia and thalami. CSF analysis revealed elevated 14-3-3 protein.

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Fig. 8. Autoimmune cerebellitis: 63 year-old male presenting with ataxia. Axial T2-FLAIR (A) and T2w images (B) demonstrates hyperintense signal involving both
cerebellar hemispheres. The patient experienced marked symptomatic improvement following initiation of treatment with methylprednisolone.

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Fig. 9. Autoimmune rhomboencephalitis: 35 year-old female presenting with quadriplegia and respiratory failure. T2/FLAIR (A) and DWI (B) images show edema
and diffusion restriction primarily involving the pons and medulla.

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Fig. 9. (continued).

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Fig. 10. Behcet's disease: 34 year-old female with altered mental status, headache, and vision changes with subsequent history eliciting recurrent genital ulcers.
Coronal and axial T2-FLAIR images (A, B) show hyperintense signal within the midbrain, pons, and upper medulla with inclusion of the left thalamus and left medial
temporal lobe.
multifocal T2/FLAIR brain abnormalities outside of the limbic system.
Although usually not paraneoplastic, in the rare cases neoplasm is
found, thymoma is frequently the culprit.4,37
6.4. Anti-GluR3 (Rasmussen's) encephalitis
Rasmussen's Encephalitis has been associated with anti-glutamate
receptor 3 (GluR3) antibodies. This subset of encephalitis is most com­
mon in children and young adults who present with drug refractory focal
epilepsy, progressive hemiplegia, and cognitive decline.38
MR imaging will reveal holohemispheric atrophy and as well as
cortical or subcortical T2/FLAIR abnormalities (Fig. 5C–D). Atrophy and
signal changes are usually most prominent in the perisylvian region.
Unilateral atrophy of the caudate head can be an early finding.38
7. Imaging differential diagnosis of extra-limbic cortical
encephalitis
The differential considerations in extra-limbic cortical encephalitis
are similar to those in limbic encephalitis and include HSV, low-grade
gliomas, and metabolic derangements. HSV encephalitis may share
similar imaging findings to extra-limbic cortical encephalitis with signal
abnormalities distributed in the temporal and frontal lobes. However,
HSV is more likely to demonstrate petechial hemorrhage or patchy
enhancement, as well as more rapid clinical deterioration.28
Low-grade gliomas can also demonstrate cortically-based T2/FLAIR
signal changes that may or may not demonstrate post-contrast
enhancement. Findings favoring low-grade gliomas include
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Clinical Imaging 84 (2022) 1–30
unilaterality, a more pronounced component of mass effect with gyral
expansion as well as underlying white matter changes secondary to
vasogenic edema and non-enhancing tumor.39
Some metabolic derangements may result in cortical T2/FLAIR
hyperintensity similar to those seen in AE, such as hypoglycemic en­
cephalopathy and hyperammonemic encephalopathy. These cases often
show strongly restricted diffusion in the region of cortical signal ab­
normality, which is less typical for AE. Hyperammonemic encephalop­
athy classically affects the insular and cingulate cortices with relative
sparing of the occipital lobes and perirolandic regions. Hypoglycemic
encephalopathy commonly affects the parieto-occipital regions and the
temporal lobes. Basal ganglia involvement is common in both disease
entities. There are often accompanying metabolic derangements (e.g.,
elevated ammonia levels, markedly decreased serum glucose).40
8. Striatal autoimmune encephalitis
Imaging features of striatal autoimmune encephalitis on MRI include
hyperintense T2/FLAIR abnormalities in the basal ganglia, often bilat­
eral, with sparing of the mesial temporal lobes. Diffusion restriction is
usually absent which helps differentiate AE from the most common
differential diagnoses in this location.4–5 The AE's that typically result in
striatal encephalitis include anti-CV2 and anti-D2. Anti-NMDAr AE,
discussed above, may also show striatal involvement (Fig. 6).
8.1. Anti-CV2 encephalitis
CV2 is an intracellular antigen associated with paraneoplastic AE in
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Fig. 10. (continued).

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Fig. 11. Listeria monocytogenes infection: 43 year-old female with history of vertigo and nausea without improvement on treatment with steroids. The patient was
found to have listeria monocytogenes infection and improved with antibiotic therapy. Axial T2/FLAIR (A) and T1w postcontrast images (B) demonstrate a small focus
of edema and enhancement in the left dorsal medulla.
the setting of small cell carcinoma and malignant thymoma. These pa­
tients commonly present with bilateral striatal encephalitis character­
ized by choreiform movements.41 There is rarely involvement of the
limbic system on imaging.4 In addition to striatal encephalitis, anti-CV2
antibodies have been associated with longitudinal myelitis character­
ized on MRI as abnormal hyperintense T2/STIR signal affecting multiple
spinal cord levels.42
8.2. Anti-D2 encephalitis
Dopamine receptor-2 (D2) has high expression in the basal ganglia as
well as the substantia nigra and is involved in numerous neurological
processes including fine motor movements. Development of antibodies
to this receptor is a rare cause of striatal encephalitis which can present
clinically with Sydenham's chorea or Tourette's syndrome. MR imaging
demonstrates hyperintense T2/FLAIR signal in the basal ganglia and
substantia nigra.43
9. Imaging differential diagnosis of striatal encephalitis
The primary differential diagnoses of striatal encephalitis on imaging
include toxic-metabolic disorders such as hyperglycemia or carbon
monoxide poisoning, ischemia or infarction, and Creutzfeld-Jakob dis­
ease. All of these entities may result in increased T2/FLAIR signal in the
basal ganglia (Fig. 7).44 The absence of diffusion restriction helps to
differentiate this subset of autoimmune encephalitis from prion diseases
such as Creutzfeldt-Jakob as well as ischemic infarction.4,5,45 Lack of
abnormalities on the diffusion weighted images is less discriminatory
when considering toxic-metabolic etiologies, however the clinical his­
tory is usually revealing in these cases.
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Clinical Imaging 84 (2022) 1–30
10. Autoimmune cerebellitis
Imaging findings of autoimmune cerebellitis are similar to enceph­
alitis elsewhere in the CNS, ranging from a normal MRI to T2/FLAIR
hyperintensity involving the cerebellar hemispheres. While the MRI is
often normal at presentation, in cases of paraneoplastic cerebellar
degeneration (PCD), atrophy of the cerebellum may be seen on follow up
imaging studies months to years later.46,47 Typically, the disease is
characterized by ataxia, nystagmus, and difficulties with speech and
swallowing. PCD is usually progressive over a short time course and has
a poor prognosis. In general, cases in which the antibody is to a cell
surface receptor (anti-mGluR1), there is a better prognosis with treat­
ment of the underlying malignancy.13
The AEs that typically result in cerebellitis include: anti-Yo and anti-
mGluR1. Anti-Hu, anti-GAD65, and anti-VGCC AEs (discussed above)
may also show cerebellar involvement (Fig. 8).
10.1. Anti-Yo cerebellitis
Anti-Yo cerebellitis is associated with underlying breast and ovarian
malignancies in greater than 90% of the cases. Clinically, patients pre­
sent with PCD due to the interaction with cerebellar antigens. Anti-Yo
accounts for approximately half of all cases of PCD.47,48
10.2. Anti-mGluR1 cerebellitis
Anti-metabotropic glutamate receptor 1 is associated with Hodgkin's
lymphoma and presents with PCD.9
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Fig. 11. (continued).
11. Imaging differential diagnosis of cerebellitis
The differential for PCD includes alcohol or phenytoin-associated
degeneration, neurodegenerative disorders, metabolic deficiencies,
and sequelae of prior infection.49 In general, the clinical history is key to
differentiating between these possible causes.
12. Autoimmune brainstem encephalitis
Brainstem encephalitis or rhomboencephalitis, which refers to
inflammation of the brainstem with variable involvement of the cere­
bellum and cerebellar peduncles, can present with ataxia, speech diffi­
culties, sensorineural hearing loss, ophthalmoplegia, and even central
respiratory depression.13 The acute phase may be normal or show T2/
FLAIR hyperintensity within the brainstem, with or without cerebellar
involvement. Often, these disorders progress to show atrophy of the
25
Clinical Imaging 84 (2022) 1–30
brainstem and cerebellum on follow up imaging (Fig. 9).13,50
The AEs that typically result in brainstem involvement include: Anti-
Ma and anti-Ri. Anti-Hu and anti-Yo, discussed above, may also show
brainstem involvement.
12.1. Anti-Ma encephalitis
Anti-Ma antibodies (Ma1, Ma2 and Ma3) target intracellular antigens
and can be seen in the setting of testicular cancer, small cell lung cancer,
and breast cancer.4,51 There is a strong association of anti-Ma2 anti­
bodies with testicular germinal cell tumors, even when the tumor is
microscopic, and orchiectomy may lead to improvement or stabilization
of symptoms.52 MRI is abnormal in nearly three quarters of patients with
anti-Ma encephalitis. Imaging evidence of limbic system involvement is
present in nearly all cases, with hindbrain involvement in approximately
half of cases.2
C. Ball et al. Clinical Imaging 84 (2022) 1–30

Fig. 12. Differential considerations of autoimmune myelitis: (A and B- Subacute combined degeneration) 46 year-old female with history of chronic anemia and
gastric bypass presenting with 3-month history of weakness and ascending sensory loss. There is diffuse T2 prolongation along the dorsal columns in the cervical
spinal cord. There was symptomatic improvement after vitamin B12 supplementation. (C and D- Anti-MOG myelitis) 29 year-old male with headache, vision changes,
ataxia, and positive anti-MOG antibodies. Sagittal STIR and T1w-post contrast (C, D) of the cervical spine show patchy areas of T2 prolongation with associated
enhancement. There was also enhancement and edema in the optic nerves (not shown).

12.2. Anti-Ri encephalitis
Anti-Ri antibodies target intracellular antigens and are seen in the
setting of breast and small cell lung cancer. Anti-Ri associated rhom­
boencephalitis may present as brainstem involvement or, less
commonly, as PCD. These patients classically present clinically with
opsoclonus-myocolonus syndrome.2,53
rhomboencephalitis. Non-AE autoimmune etiologies may also demon­
strate T2 signal abnormalities within the brainstem; however, additional
characteristic imaging findings or clinical history may aid in differen­
tiation – such as callososeptal distribution with multiple sclerosis or a
history of oral and genital sores in Behçet's disease (Figs. 10 and 11).50,54
13.1. Autoimmune myelitis

13. Imaging differential diagnosis of autoimmune brainstem

MR imaging of autoimmune myelitis may demonstrate T2 hyper­
encephalitis
intensity and associated post-contrast enhancement within the spinal
cord. While many patients will have a normal MRI, in paraneoplastic
In the acute phase, brainstem encephalitis mimics include both in­
myelitis, nearly half of patients demonstrate longitudinally extensive,
fectious and viral etiologies, such as Listeria monocytogenes, Lyme dis­
symmetric T2 prolongation with patchy post contrast enhancement.55
ease, and Enterovirus, as well as non-AE autoimmune etiologies, such as
Antibodies to the glycine receptor (Anti-GlyR) are typically associated
multiple sclerosis and Behçet's disease.9,13,50 Once brainstem AE has
with autoimmune myelitis. Anti-Hu, anti-GAD65, and anti-CV2 AEs,
progressed to PCD the differential includes neurodegenerative disorders
which were discussed above, may also show spinal cord involvement.
such as multisystem atrophy.
The imaging similarities with infectious etiologies are that of T2
hyperintense signal within the brainstem; a clinical history of fevers or 13.2. Anti-GlyR myelitis
viral prodrome and CSF studies provide helpful differentiation from
Anti-glycine receptor antibodies target a primary inhibitory

26
C. Ball et al.
Fig. 12. (continued).
neurotransmitter in the spinal cord. These patients present clinically
with increased muscle tone, exaggerated startle response, and spasms.2
MR imaging of the spine is normal in most patients. In the subset of those
with imaging abnormalities, short or patchy lesions are most common.
Longitudinally extensive lesions are rarely seen in anti-GlyR associated
myelitis.56
14. Imaging differential diagnosis of autoimmune myelitis
A variety of diseases may mimic autoimmune myelitis such as neu­
romyelitis optica spectrum disorders (including anti-myelin oligoden­
drocyte glycoprotein MOG associated encephalomyelitis), Guillain-Barré
syndrome (GBS) and non-autoimmune entities similar in appearance to
GBS (e.g. viral meningitis, carcinomatous meningitis, and hereditary
neuropathies), and subacute combined degeneration. It is worth noting
that neuromyelitis optica spectrum disorders and GBS are sometimes
considered part of the autoimmune encephalitis continuum. Similarities
in imaging findings between autoimmune myelitis and its mimics are T2
prolongation within the spinal cord. A combination of additional im­
aging findings, clinical history, and laboratory data aids in
27
Clinical Imaging 84 (2022) 1–30
differentiation. In subacute combined degeneration, the location of
signal abnormalities in the dorsal columns of the spinal cord, lack of
post-contrast enhancement, and a clinical history (or risk factors) of
nutritional deficiency help to distinguish it from autoimmune myeliti­
s.57In neuromyelitis optica, imaging findings of optic neuritis, usually
within weeks if myelitis presents first, aid in differentiation. Serum
analysis demonstrates anti-aquaporin-4 antibody positivity. Individuals
with anti-MOG associated encephalomyelitis commonly have optic
neuritis and serum analysis demonstrating anti-MOG antibody positiv­
ity.58,59 GBS classically presents with enhancing cauda equina nerve
roots, preferentially affecting anterior motor neurons. Cancer metastatic
to the cord itself or to the leptomeninges typically demonstrates discrete
nodular enhancement, distinct from the contrast enhancement pattern
that can be seen with autoimmune myelitis (Fig. 12).
15. Conclusion
Autoimmune encephalidites are becoming increasingly recognized
as a cause of neurological syndromes. Patients can present with clinical
symptoms based primarily within the limbic system, brainstem,
C. Ball et al. Clinical Imaging 84 (2022) 1–30

Fig. 12. (continued).

28
C. Ball et al. Clinical Imaging 84 (2022) 1–30

Fig. 12. (continued).

29
C. Ball et al.
cerebellar, or spinal cord. Neuroimaging can be used alongside clinical
history, lumbar puncture for antibody testing, and electroencephalog­
raphy to support the diagnosis.
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