autoimmune mediated encephalitis

8/12/2019 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: [email protected]

W. Van Paesschen :R. Vandenberghe

Department of Neurology, University Hospitals K.U.Leuven,Herestraat 49,


K. Van Laere

Department of Nuclear Medicine,

University Hospitals K.U.Leuven,

Herestraat 49,


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

838 Neuroradiology (2011) 53:837851


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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

Neuroradiology (2011) 53:837851 839


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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)

http://www.pnseuronet.org/http://www.pnseuronet.org/


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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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