autoimmune mediated encephalitis
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CONTINUING EDUCATION
Autoimmune-mediated encephalitis
Philippe Demaerel &Wim Van Dessel &Wim Van Paesschen &Rik Vandenberghe &
Koen Van Laere &Jennifer Linn
Received: 23 November 2010 /Accepted: 24 December 2010 /Published online: 27 January 2011# Springer-Verlag 2011
Abstract Autoimmune-mediated encephalitis may occur as
a paraneoplastic or as a non-paraneoplastic condition. Therole of neuroimaging in autoimmune-mediated encephalitis
has changed in the last decade partly due to improvements
in sequence optimisation and higher field strength and
partly due to the discovery of an increasing number of
antibodies to neuronal cell and cell membrane antigens.
Imaging is important since it can support the clinical
diagnosis particularly in the absence of antibodies. Struc-
tural imaging findings can be subtle and are usually best
seen on FLAIR images. A progressive as well as a
relapsingremitting course can be observed. Autoimmune-
mediated encephalitis is classically linked to involvement
of the hippocampus and amygdala, but extensive changes in
the temporal cortex, basal ganglia, hypothalamus, brain
stem, frontal and parietal cortex are not unusual. This report
is based on a review of the literature (except the literature in
Japanese) and own findings in patients with autoimmune-
mediated encephalitis.
Keywords Limbic . Paraneoplastic . Autoantibody .
MR imaging . Autoimmune
Background
Autoimmune-mediated encephalitis (AME) may occur as a
paraneoplastic or non-paraneoplastic condition and remains,
despite continuous advances in diagnosis and treatment,
incompletely understood. Limbic encephalitis (LE) is prob-
ably the best known AME, but other entities that will be
briefly included in this review are paraneoplastic cerebellar
degeneration and opsoclonus-myoclonus syndrome.
The term LE was introduced in 1968 in association with
cancer but can occur in the absence of malignancy too [1].
LE is a T-cell immune-mediated subacute neurological
disorder with antibodies against an intracellular or
membrane-bound antigen.
Recently, a classification has been proposed for AME on
the basis of the location of the antigen [2, 3]. AME better
describes these neuroimmunological diseases than LE,
although the latter term is still widely used. It is beyond
the scope of this report to list all antibody (Ab)-related
disorders but only those with frequently associated imaging
findings.
The commonly reported antigens inside the neuron
include Hu, CV2, amphiphysin, Ri, Yo and Ma2 and are
often referred to as onconeural antigens. The neoplasms
associated with these antigens are small cell lung cancer
(SCLC), testicular tumours, ovarian teratoma and breast
cancer, but the presence of these antigens is not necessarily
linked to a paraneoplastic encephalitis. Antibodies to Ma2
P. Demaerel (*) : W. Van Dessel
Department of Radiology, University Hospitals K.U.Leuven,
Herestraat 49,
3000 Leuven, Belgium
e-mail: philippe.demaerel@uzleuven.be
W. Van Paesschen :R. Vandenberghe
Department of Neurology, University Hospitals K.U.Leuven,Herestraat 49,
3000 Leuven, Belgium
K. Van Laere
Department of Nuclear Medicine,
University Hospitals K.U.Leuven,
Herestraat 49,
3000 Leuven, Belgium
J. Linn
Department of Neuroradiology, University Hospital Mnchen,
Munich, Germany
Neuroradiology (2011) 53:837851
DOI 10.1007/s00234-010-0832-0
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are mainly associated with testicular tumours and it is not
uncommon to find only a microscopic intratubular germ
cell tumour without evidence of cancer in these patients [4].
Antibodies to glutamic acid decarboxylase (GAD) have
been reported in stiff-person syndrome (characterized by
symmetrical muscle rigidity and stiffness) in a non-
paraneoplastic setting, often in association with other
autoimmune disorders, such as insulin-dependent diabetesmellitus [57]. This syndrome has also been reported in
association with thymoma and renal cell carcinoma [8,9].
Antigens in the cell membrane (neuropil antobodies) include
voltage-gated potassium channels (VGKC), and N-methyl-D-
aspartate (NMDA), AMPA, -aminobutyric acid (GABA)
and glycine receptors and can be associated with a neoplasm
(e.g. thymoma, SCLC, prostate adenocarcinoma) but are often
non-paraneoplastic. VGKC-Ab have been demonstrated in
acquired neuromyotonia and related disorders involving the
peripheral nervous system as well as in Morvans syndrome
(neuromyotonia and autonomic disorders) [10].
A separate group concerns patients with an ovarianteratoma and antigens that co-localize with EFA6A, a
hippocampal protein upregulated by NMDA receptors and
involved in the regulation of dendritic development of
hippocampal neurons [11]. Ances et al. have reported five
patients with until now unidentified neuropil Ab, different
from the VGKC [12]. The corresponding cell membrane
antigen co-localize with synaptophysin and spinophilin and
are more concentrated in the hippocampus and cerebellum,
but individual characterization has not yet been achieved.
Antibodies against the metabotropic glutamate receptor
type 1 (mGLuR1) have been reported in patients with
cerebellar ataxia and Hodgkins lymphoma [13]. Antineuro-
nal nuclear antibody type 2 (anti-Ri) has been decribed in
opsoclonus-myoclonus syndrome and breast carcinoma, but
can occasionally be observed in association with other
cancers [14].
Paraneoplastic cerebellar degeneration (PCD) has been
linked to nine different antibodies to neuronal antigens
including Yo, Ri, Ma, Hu and mGluR1 [15]. Ovarian, lung
and breast cancer and Hodgkins lymphoma have been
reported to be more often associated with PCD.
Rasmussen encephalitis is a T-cell-mediated inflamma-
tory disorder involving one cerebral hemisphere and
resulting in frequent intractable seizures. Autoimmune
antibodies may play a role in the pathogenesis, but there
is not sufficient evidence to confirm this [16]. Rasmussen
encephalitis will not be discussed here.
Diagnosis
The clinical presentation of AME may include partial
seizures, mood and behavioural changes and cognitive
impairment, e.g. amnestic syndrome [1719]. It has been
suggested that the most common etiology of de novo
temporal lobe epilepsy in adults is LE.Patients with CV2 antibodies can have chorea. Meso-
diencephalic encephalitis can be seen in patients with Ma2
antibodies. The antibodies that target neuronal antigens are
thought to cause the neurological symptoms.
The clinical features together with signs of brain
inflammation (mild cerebrospinal fluid (CSF) pleocytosis
and CSF oligoclonal bands) justify the diagnosis of non-
paraneoplastic AME confirmed by follow-up and absence
of evidence of cancer.
Adults with opsoclonus-myoclonus syndrome and an
underlying malignancy present with ataxia, horizontal gaze
paresis and often laryngospasm and jaw dystonia [14]. The
definite diagnosis of paraneoplastic LE requires the clinical
presentation and morphological evidence of involvement of
the limbic system and the presence of antibodies or a
Fig. 2 Bilateral involvement of the hippocampus and amygdala is
seen in a patient with paraneoplastic encephalitis and a colon
adenocarcinoma
Fig. 1 Coronal FLAIR image at 3 T shows subtle lesion in the left
amygdala in a patient with anti-GAD and anti-GABA antibodies
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Fig. 3 Progressive bilateral (right more than left) hippocampal atrophy over a time span of 15 months in a patient with autoantibody-mediated
encephalitis without detectable antibodies (ac)
Fig. 4 Demonstration of extra-
limbic lesions in non-
paraneoplastic encephalitis (a)
and in anti-GAD antibody en-
cephalitis with subsequent de-
tection of a thymoma (b)
Fig. 5 Axial FLAIR (a) and
gadolinium-enhanced T1-
weighted (b) images in a non-
paraneoplastic encephalitis
without detectable antibodies,
showing the irregular enhancing
lesions in the hippocampus and
anterior temporal lobe
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tumour within 5 years after the onset of the symptoms
(http://www.pnseuronet.org)[20].
Patients with PCD often present with ataxia, diplopia,
nystagmus and vertigo.
In up to 50% of the patients with clinical evidence of
LE, no antibodies can be identified [21]. On the other hand,
antibodies can be found in the absence of imaging and
clinical signs of LE too. In 60% of the patients, antibodiesare detected prior to the detection of cancer.
T he s pe ci fi ci ty f or t he p re se nc e o f a t um ou r
is almost 100% but the sensitivity is only 60% [22].
The search for antibodies is important and many
of the appropriate antibody tests are commercially avail-
able today.
Neuropathology shows a mononuclear inflammatory cell
infiltration, loss of neurons and proliferation of astrocytes.
This appearance does not allow a neuropathologicalconfirmation of the paraneoplastic etiology.
Fig. 6 Anti-VGKC antibody non-paraneoplastic encephalitis with normal MR imaging (a) but FDG-PET showed intense hypometabolism
covering temporoparietooccipital lobes bilaterally without evidence for focal hypermetabolism (b, c)
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Fig. 7 Paraneoplastic cerebellar degeneration with anti-Purkinje cell antibodies in a patient with B-cell non-Hodgkins lymphoma. PET/CT
demonstrated several enlarged para-aortic and retro-esophagal lymph nodes and the supraclavicular lymph node was biopsied
Table 1 Predilection sites of involvement in autoimmune-mediated encephalitis
Literature findings Authors own experience
AME with neuronal antigen (often
paraneoplastic)
GAD: hippocampus, amygdala, cerebral
cortex (can be thymoma related)
GAD: hippocampus, cerebral cortex (can be thymoma
related)
Ma2: hippocampus, amygdala,
hypothalamus, thalamus, midbrain
Ma2: hippocampus and anterior temporal cortex,
hypothalamus, mammillary bodies (testicular cancer)
CV2: CV2: hippocampus, amygdala, basal ganglia, insular cortex
(lung cancer)
Purkinje cell: Purkinje cell: cerebellum (B-cell lymphoma related)
Ri: Ri: brain stem (breast cancer related)
AME with cell membrane antigen
(often non-paraneoplastic)
VGKC: hippocampus, amygdala, basal
ganglia
VGKC: hippocampus, amygdala and anterior temporal
cortex
NMDA: hippocampus, cerebral cortex NMDA: hippocampus, cerebral cortex, basal ganglia,
thalamus
AME without detectable antibodies Paraneoplastic: hippocampus and parahippocampal area
(colon, prostate, testicular cancer)
Non-paraneoplastic: hippocampus, amygdala, thalamus,
anterior temporal cortex
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Fig. 9 Anti-Ma2 antibody encephalitis in a patient with testicular
cancer and behavioural disturbances and amnesia. Axial FLAIR
images show bilateral involvement of the amygdala and hippocampus
as well as pathological changes in the hypothalamus and optic chiasm
(a,b). Follow-up imaging 8 months later show progressive swelling of
the amygdalohippocampal region and extension into the adjacent
anterior temporal cortex on the right side (ce). Coronal T2-weighted
images 14 months (f) and 2 years (g) later show progressive
hippocampal atrophy
Fig. 8 Axial FLAIR images in anti-GAD antibody encephalitis with subsequent detection of a thymoma show bilateral cortical lesions in the
frontal, parietal and temporal lobes (ac)
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Imaging
Introduction and general findings
MR imaging is the modality of choice for demonstrating the
pathological changes associated with AME. It is accepted that
approximately 70% of patients who have LE get abnormal-
ities in the temporal lobes [23]. However, imaging can remain
normal in a subset of cases and changes can be extremely
subtle particularly at the early stage of the disease (Fig. 1).
AME typically involves the hippocampus and amygdala
on one or both sides and then corresponds to LE (Fig. 2).
Fig. 10 Anti-CV2 antibody encephalitis in a patient with a neuroendocrine tumour. Axial FLAIR images (ad) show involvement of the left
amygdala, hippocampus, the anterior temporal cortex and white matter and the right lentiform and caudate nucleus
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At presentation, a swelling of these structures is best seen
on FLAIR images and is associated with a variable degree
of increased signal [24]. In case reports, diffusion-weighted
imaging has shown high signal within the affected areas,
with or without decreased apparent diffusion coefficient
[25,26]. Follow-up will often show atrophy of the affected
area (Fig.3).
Extralimbic paraneoplastic brain lesions are increasinglybeing reported [18] (Fig. 4). Both focal and meningeal
contrast enhancement have been reported but are very
unusual [11,22,27,28] (Fig.5). In general, it is not possible
to differentiate paraneoplastic from non-paraneoplastic AME.
Functional imaging is extremely helpful and more often
demonstrates bilateral abnormalities that are complementa-
ry to structural imaging findings [29] (Fig. 6). Even in the
absence of structural MRI abnormalities, fluorodeoxyglu-
cose positron emission tomography (FDG-PET) may show
hypermetabolism in the medial temporal lobe [12, 3032].
PET proved to offer additional information compared with
MRI and may have potential for clinical course predictionand treatment follow-up [12]. In paraneoplastic cerebellar
degeneration, cerebellar hypometabolism is more often seen
than structural MRI changes [33].
Whole-body FDG-PET also plays a clear role for tumour
detection for patients with paraneoplastic antibodies and no
evidence of a tumour on structural imaging [34]. Ideally,
whole-body FDG-PET/CT is recommended and can replace
the combined chest and abdominal CT (Fig. 7)[35,36].
We reviewed 19 patients, 14 presented with antibodies
and 5 without antibodies. Seizures were the most common
clinical presentation, followed by behavioural and mood
changes. In nine patients, a tumour was found. Brain
imaging findings were normal in two patients: one patient
with Hodgkins lymphoma, anti-MGluR1 antibodies and a
PCD and one patient with anti-GABA and anti-GAD
antibodies in a non-paraneoplastic setting.
Eleven patients had involvement of the amygdalohippo-
campal region, four presented with initial bilateral lesions
and four with unilateral hippocampal abnormalities, and in
three patients, there was progression from a unilateral to a
bilateral involvement. Diffusion-weighted MRI was avail-
able in all patients and showed restricted diffusion in two
cases. The initial extent of involvement did not influence
outcome. Progressive atrophy occurred in most cases on
follow-up. The imaging findings are summarized in Table 1
and are discussed in detail below.
Imaging in AME with antigens inside the neuron
Antibodies against GAD have been associated with para-
neoplastic and non-paraneoplastic limbic encephalitis [6,
Fig. 11 Paraneoplastic cerebellar degeneration with anti-Purkinje cellantibodies in a patient with B-cell non-Hodgkins lymphoma. The first
examination was obtained because of dizziness and unsteady gait and
showed subtle lesions in the cerebellum on both sides (a). Follow-up
1 month later shows progression of the lesion in the left hemisphere
(b) and progressive atrophy after 2 months (c)
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37]. Bilateral involvement of the amygdala and hippocam-
pus has been described as well as extratemporal cortical
lesions. Vernino and Lennon have reported 12 patients with
thymoma-related encephalopathy, 9 of whom had limbic
abnormalities and 3 had extralimbic cortical lesions [8].
VGKC and GAD were amongst the detected antibodies.
We have seen one patient with anti-GAD antibody
positive encephalitis who presented with several corticallesions and in whom a thymoma was found (Fig. 8).
Following the resection of the thymoma, the patient
recovered completely.
In one patient with anti-GAD and GABA antibodies,
imaging showed subtle involvement of the hippocampal
region, and in another one, imaging was normal. In anti-
Ma2 encephalitis, MRI changes can be seen in the
amygdalohippocampal region but are frequently located in
the hypothalamus, thalamus and midbrain. Contrast en-
hancement has been reported [38].
In two patients with anti-Ma2 antibodies, we found
bilateral hippocampal lesions in both with extension in the
anterior temporal cortex and with abnormalities in the
hypothalamus and mammillary bodies in one (Fig. 9) [4].
The patient with anti-CV2 antibodies had initially relaps-ingremitting lesions in the caudate and lentiform nucleus
and later involvement of the amygdala and hippocampus
with extension in the insular cortex (Fig. 10).
There was bilateral but asymmetrical involvement of the
hippocampus with extension into the parahippocampal area in
the two other patients with AME and a tumour but without
detectable antibodies.
Fig. 12 Anti-Ri antibody encephalitis in a patient with a history of breast carcinoma and spastic tetraparesis and sensorimotor polyneuropathy.
Axial T2 (a, b) and FLAIR (c, d) images show the diffuse involvement of the medulla oblongata and pons
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Paraneoplastic cerebellar degeneration has been associ-
ated with at least nine antineuronal antibodies. In a large
series of 50 patients with PCD, there was no evidence of
intracranial lesions in the acute stage [15]. There have been
reports of cerebellar atrophy after several months. We
observed cerebellar lesions in one patient with anti-Purkinje
cell antibodies and a B-cell lymphoma (Fig. 11). Two
patients with anti-Ri antibodies had involvement of thebrain stem (Figs. 12 and13).
In a series of eight patients with opsoclonus-myoclonus
syndrome and cancer who underwent brain MR imaging,
MRI was normal in five cases, temporal lobe lesions shown
in two patients and dorsal brain stem lesions in one patient
[14]. We found focal lesions in the dorsal brain stem in our
patient (Fig. 13).
Imaging in AME with antigens in the cell membrane
(neuropil antobodies)
AME due to VGKC-Ab is usually non-paraneoplastic. In
3 series of 27 patients, bilateral medial temporal lobe
involvement was seen in 18 (66%) patients and unilateral
involvement in 7 patients [7,10,39]. Imaging was normal
in two patients. Involvement of the basal ganglia has been
reported. We found extension of the unilateral MR
changes beyond the hippocampus involving the amygdala
and anterior temporal cortex in two patients with VGKC
antibodies (Fig. 14). MR imaging was normal in the third
patient but FDG-PET of the brain showed extended and
intense hypometabolism covering temporoparietooccipital
lobes bilaterally without evidence for focal hypermetabo-lism. Extralimbic frontal involvement has been reported in
NMDA Ab-related encephalopathy [40], but MR imaging
often remains normal too. Our patient with anti-NMDA
had extensive lesions in the basal ganglia, thalamus,
hippocampus and cortex (Fig. 15). In the remaining three
patients, no Ab were found. Bilateral asymmetrical hippo-
campal involvement was seen in one patient, unilateral
hippocampal involvement in another patient and left amygda-
lohippocampal involvement with extension in the anterior
temporal cortex and thalamus in the third patient (Fig.16).
The patients with ovarian teratoma and antibodies to
antigens that co-localize with EFA6A were characterized by
the absence of limbic abnormalities in more than 60% of
the patients and medial temporal lobe lesions were absent.
Instead, a wide variation of cerebral and cerebellar cortical
lesions is seen as well as brain stem involvement. Normal
imaging findings have been reported too.
Differential diagnosis
Hashimoto encephalopathy has to be considered as a
differential diagnosis. It is found in patients with autoim-
mune thyroiditis which is associated with high levels of
anti-thyroid antibodies in serum and CSF. Non-specific MR
changes such as atrophy and white matter lesion occur in
50% of the patients. They often present with symptoms
similar to those in (non)paraneoplastic encephalitis. Hashi-
moto encephalopathy can be seen in association with
Sjgrens syndrome and systemic lupus erythematosus. A
common feature of these diseases is the steroid responsive-
ness, but involvement of the limbic system on MR imaging
Fig. 13 Anti-Ri antibody encephalitis in opsoclonus-myoclonus
without detectable neoplasm. Axial FLAIR (a, b) images show
involvement of the midbrain and medulla oblongata on the right side
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is lacking. Steroid responsive LE has been reported and
anti-white matter antibodies were detected [41].
Wernicke Korsakoff encephalopathy, Herpes simplex me-
ningoencephalitis and gliomatosis cerebri or low grade glioma
are to be considered amongst the differential diagnoses because
of predominant involvement of the temporal lobe and/or
thalamus. In the rare case with contrast enhancement, malignant
tumours should be included in the differential diagnosis.Acute non-herpetic LE has been reported in Japan. In
these cases, bilateral swelling of the medial temporal lobe
was seen on MRI. The neurological signs and laboratory
findings were similar to paraneoplastic LE but there is no
evidence of a tumour [42].
Postictal changes after prolonged seizures can also result
in MR changes involving the medial temporal lobe.
Clinically, it can be difficult to distinguish metabolic
encephalopathy, Alzheimers disease or primary psychiatric
disorders from (non)paraneoplastic encephalitis.
Occasionally, the imaging findings may resemble
po st er io r re ve rs ib le en ce ph al op at hy sy nd ro me , an
expression of neurotoxicity through a T-cell immune-
mediated response.
Treatment and prognosis
In paraneoplastic neurological disorders, the search for a
tumour and tumour treatment are mandatory and can
result in a rapid improvement of the neurological signs
and symptoms. Plasma exchange and long-term immu-
nomodulation with intravenous immunoglobulins, in
combination with high dose intravenous corticosteroids,
are the classical treatments of AME. Generally speaking,
therapy response is better in patients with antineural
antibodies against cell membrane antigens, e.g. in
Fig. 14 Anti-VGKC antibody non-paraneoplastic encephalitis with
unilateral involvement of the amygdala, hippocampus and adjacent
anterior medial temporal cortex on the left side (ad). Note the
swelling of the amygdala and hippocampus on initial presentation
with limited increase of signal intensity (a). FDG-PET at the same
time showed hypermetabolism in the left anterior temporal lobe (e).
Ictal perfusion imaging with 99mTc-ECD SPECT, co-registered with
MR images, clearly showed an ictal onset zone at this region (f)
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patients withVGKC antibodies an improvement can be
observed with immune therapy in 507 0% of t he
patients. Good therapeutic response has been reported
in patients with a history of a treated adenocarcinoma
and paraneoplastic encephalitis with anti-Hu antibodies
several years later [24].
Conclusion
AME is a complex immune-mediated disorder. Our insight
in its pathogenesis is improving, and although it is a rare
disorder, the disease is probably under-recognized. A wide
range of structural and functional imaging findings is being
Fig. 14 (continued)
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Fig. 15 Anti-NMDA antibody non-paraneoplastic encephalitis with extralimbic lesions in the caudate nucleus, the lentiform nucleus and
thalamus (a, b). Not the evidence of diffusion restriction on the apparent diffusion coefficient map ( c)
Fig. 16 Limbic encephalitis
without antibodies and without
detectable neoplasm. Involve-
ment of the hippocampus,
amygdala and adjacent anteriortemporal cortex is visible on the
initial examination (a, b). On
the follow-up scan 1 month lat-
er, the bilateral lesions are better
seen (c). Follow-up 2 weeks
later shows further extension of
the lesions in the temporal lobe
on the left side and a periven-
tricular lesion (d, e)
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reported. Temporal lobe changes are common but often
extension beyond the amygdala and hippocampus is seen,
involving extralimbic structures. MR imaging plays an
important role in the diagnosis because of the non-specific
clinical presentation.
Summary
Paraneoplastic encephalitis often precedes the clinical
manifestations of cancer with a delay of several
months.
Both limbic and/or extralimbic lesions can be observed
in paraneoplastic encephalitis and in non-paraneoplastic
(limbic) encephalitis. The imaging findings can be subtle
and are usually better seen on (coronal) FLAIR images.
A progressive as well as a relapsingremitting course can
be seen.
MRI can play an important role in reaching the correct
diagnosis in patients without Ab, which can be of
importance in the rapid initiation of a treatment. Structural and functional imaging play an important
role in the screening for associated tumours.
Conflict of interest We declare that we have no conflict of interest.
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