Lomax et al.

37 Pezaro C, Mukherji D, Tunariu N, 39 Gardner JR, Livingston PM, Fraser SF. cancer survivorship. Recent Results Cancer
Cassidy AM, Omlin A, Bianchini D et al. Effects of exercise on treatment-related Res 2011; 186: 217–36.
Sarcopenia and change in body adverse effects for patients with prostate 42 Livingston PM, Craike M, Salmon J,
composition following maximal cancer receiving androgen-deprivation Courneya K, Fraser S, Gaskin C et al.,
androgen suppression with abiraterone therapy: a systematic review. J Clin the ENGAGE Uro-Oncology Clinicians'
in men with castration-resistant Oncol 2014; 32: 335–46. Group. The efficacy of a clinician
prostate cancer. Br J Cancer 2013; 109: 40 Keogh JW, MacLeod RD. Body referral and 12 week physical activity
325–31. composition, physical fitness, functional program among men living with
38 Attard G, Reid AH, Auchus RJ, Hughes performance, quality of life, and fatigue prostate cancer: a multicentre cluster
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advanced prostate cancer. J Clin RU. Physical activity and genitourinary 2012; 367: 965–7.
Endocrinol Metab 2012; 97: 507–16.

CLINICAL PERSPECTIVES

Autoimmune encephalitis
M. P. Newman,1 S. Blum,2,3 R. C. W. Wong,1,4 J. G. Scott,5,6 K. Prain,4 R. J. Wilson4 and D. Gillis1,4
Departments of 1Immunology and 2Neurology, Princess Alexandra Hospital, 3Mater Centre for Neurosciences, 4Division of Immunology, Central
Laboratory, HSSA Pathology Queensland, 5Discipline of Psychiatry, The University of Queensland Centre for Clinical Research, and 6Metro North
Mental Health, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia

Key words Abstract

autoimmune encephalitis, limbic encephalitis,
neuronal surface antigen antibody, anti-NMDAR, Over the past decade, the clinical spectrum of autoimmune encephalitis has expanded
anti-VGKC. with the emergence of several new clinicopathological entities. In particular, autoim-
mune encephalitis has recently been described in association with antibodies to surface
Correspondence receptors and ion channels on neurological tissues. Greater clinician awareness has
Martin Newman, Department of Immunology, resulted in autoimmune encephalitis being increasingly recognised in patients with
Princess Alexandra Hospital, 199 Ipswich Road, unexplained neurological and psychiatric symptoms and signs. The clinical spectrum of
Woolloongabba, Qld 4102, Australia. presentations, as well as our understanding of disease mechanisms and treatment regi-
Email: [email protected] mens, is rapidly developing. An understanding of these conditions is important to all
subspecialties of Internal Medicine, including neurology and clinical immunology, psy-
Received 20 July 2015; accepted 19 chiatry, intensive care and rehabilitation medicine. This review provides a contempo-
November 2015. rary overview of the aetiology, investigations and treatment of the most recently
described autoimmune encephalitides.
doi:10.1111/imj.12974

Introduction malignancies and had poor prognoses.2 Paraneoplastic

antibodies were found to act against intracellular pro-
Limbic encephalitis was first described in 1968 as a con-
teins, the best characterised of which are anti-Hu/
stellation of symptoms affecting cognition and beha-
ANNA-1, anti-Ri/ANNA-2, anti-CV2/CRMP5 and anti-
viour, frequently associated with seizures.1 Originally,
Ma2/Ta.2
most limbic encephalitides reported were paraneoplastic,
More recently, autoantibodies against the neuronal
associated with lung, breast, ovarian or testicular
cell surface or synapse have been described (Table 1).
These antibodies are likely directly pathogenic, interfer-
ing with cell surface proteins. The most commonly
Funding: None.
Conflict of interest: None. encountered antibodies of this type are the anti-N-

148 © 2016 Royal Australasian College of Physicians

 Autoimmune encephalitis

Table 1 Autoimmune encephalitis syndromes associated with antibodies against the neuronal cell surface and synaptic antigens

Antigen Clinical features Age range Sex ratio Tumour associations and
(median) years (F:M) frequency

NMDA receptor (NR1 Prodromal syndrome 0.6–85 (21) 4:1 Age dependant, ovarian
subunit)3,6 Psychiatric manifestations, seizures, amnesia, teratoma, 10–50%
movement disorder, autonomic instability
LGI120,21 Limbic encephalitis, seizures 30–80 (60) 1:2 Thymoma, thyroid, lung, renal cell
reported
<10% for all tumours combined
CASPR220,28 Morvan’s syndrome, neuromyotonia, limbic 46–77 (60) 1:4 Thymoma, 0–40%
encephalitis (less common)
AMPA receptor (GluR Limbic encephalitis, psychiatric syndromes 38–87 (60) 9:1 Lung, breast, thymoma, thymic
1/2)32 carcinoma
Up to 70% for all tumours
combined
GABA(b) receptor30 Limbic encephalitis, seizures 16–77 (62) 2:3 SCLC
50% (predominantly older
patients)
GABA(a) receptor31 Refractory seizures, status epilepticus 3–63 (22) 1:5 Thymoma in one of six cases
Glycine receptor α141 PERM, limbic encephalitis, stiff person 1–75 (49) Adults 6:5 Thymoma (most commonly),
syndrome Children lymphoma, breast
4:0 Up to 10% for all tumours
combined
mGluR542,43 Limbic encephalitis (Ophelia syndrome), 15–46 1:1 Hodgkin lymphoma
myoclonus 3/3 cases reported
DPPX44,45 Encephalitis, CNS hyperexcitability, agitation, 15–76 1:2 No tumours described
hyperekplexia, movement disorders,
seizures, PERM
DR246 Basal ganglia encephalitis, movement 1.6–15 (5.5) 1:1 No tumours described
disorders, psychiatric manifestations

AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CASPR2, contactin-associated protein-like 2; CNS, central nervous system; DPPX,
dipeptidyl-peptidase-like protein-6; DR2, dopamine 2 receptor; F, female; GABA, gamma-aminobutyric acid; GluR1/2, glutamate receptors 1 and 2;
GlyαR, glycine α receptor; LGI1, leucine-rich, glioma-inactivated 1; M, male; mGluR5, metabotropic glutamate receptor 5; NMDA, N-methyl-D-aspartic
acid; PERM, progressive encephalomyelitis with rigidity and myoclonus; SCLC, small-cell lung cancer.

methyl-D-aspartic acid (anti-NMDA) receptor antibody did not exist, expert opinion based on our clinical and
and the anti-leucine-rich, glioma-inactivated 1 (anti- laboratory experience was utilised.
LGI1) (voltage-gated potassium channel (VGKC)) anti-
body. It is probable that many cases previously labelled
as ‘idiopathic’ limbic encephalitis or ‘steroid responsive’
limbic encephalitis were caused by one of these autoanti- Anti-NMDA receptor encephalitis
bodies. Unlike the classic paraneoplastic encephalitides, Dalmau and colleagues in 2007 described 12 women
autoimmune encephalitis is less likely to be associated with ovarian teratomas who developed prominent psy-
with malignancy and can affect patients of all ages.2,3 chiatric symptoms, amnesia, seizures, dyskinesia, auto-
These syndromes can be severe, but respond to immuno- nomic dysfunction and a decreased level of
suppressive treatments, often with marked recovery. consciousness.4 These women were shown to have auto-
This review aims to provide clinicians with a contempo- antibodies against the NMDA receptor (anti-NMDAR) in
rary overview of the autoimmune encephalitides. both serum and cerebrospinal fluid (CSF).4
Following this seminal publication, anti-NMDAR
encephalitis has been increasingly recognised with over
Methods
700 cases reported by 2014.5 Anti-NMDAR encephalitis
A literature search was performed using PubMed using is now considered to be the most frequently diagnosed
the search strategy in Appendix I. Where possible, large of the autoimmune encephalitides and is one of the
studies and review articles were used. Where evidence commonest causes of encephalitis.6

© 2016 Royal Australasian College of Physicians 149

Newman et al.

Presentation and clinical features memory loss and confusion, are always present and of
increasing severity over time.6,7,11 Problems with lan-
Anti-NMDAR encephalitis has now been defined in sev-
guage are commonly observed, ranging from reduced
eral large case series of both adults and children and can
verbal output to mutism. Many patients frequently expe-
present as a paraneoplastic (usually ovarian teratoma) or
rience fluctuations in mental status resembling delirium.
non-paraneoplastic syndrome.5,7–9 The typical presenta-
Focal or generalised seizures (and even status epilepti-
tion is with initial neuropsychiatric features, followed
cus) may occur early or later in the disease course.8,12
by a severe and prolonged encephalitis9,10 (Figure 1). A
Seizure activity may be refractory to treatment necessi-
total of 80% of patients with anti-NMDAR encephalitis
tating the use of multiple anti-epileptic agents.12 How-
are female with a median age of onset of 21 years (age
ever, the frequency and intensity of the seizures tend to
range: 8 months to 85 years).5 Within the age groups of
decrease as the disease evolves.6
less than 12 years or more than 45 years, an increased
Concurrently, a variety of abnormal movements may
proportion of male patients (up to 40%) has been
occur, including choreiform movements and stereoty-
reported.5
pies.13 Formal electroencephalogram (EEG) evaluation is
In approximately 70% of patients, there is a prodrome
very important to distinguish between seizure activity
of headache, fever, vomiting, diarrhoea and upper respi-
and movement disorders, to ensure appropriate
ratory tract symptoms.6,7 It is unclear whether a preced-
treatment.
ing viral infection precipitates the pathogenesis of the
In the later stages of illness, there is a rapid decrease in
disease or whether this prodrome represents an intrinsic
responsiveness, with alternating agitation and catatonia,
part of the syndrome.
and an inability to follow verbal commands.7,10 A range
Typically within 2 weeks from onset, prominent psy-
of abnormal movements may be manifest: commonly
chiatric symptoms and personality changes emerge.6,7,10
orolinguofacial dyskinesias; but also limb and trunk
Common manifestations include anxiety, insomnia, hal-
choreoathetosis, elaborate movements of the arms and
lucinations, delusions, agitation, mania and hypersexual-
legs, oculogyric crisis, dystonia, rigidity and opisthotonic
ity, but social withdrawal and stereotypical behaviours
postures.6
may develop.6,7 Consequently, the majority of patients
Autonomic dysregulation, including thermodysregula-
in this phase present for psychiatric care. Cognitive
tion, cardiac arrhythmias, blood pressure instability and
changes, particularly impaired attention, short term

Syndrome onset and development - not all features may be present; may not reach later stages with prompt treatment

1-2 weeks

Early Presenting Features Later Features - often associated with decreased responsiveness
Features

Prodromal Behaviour/Cognition Psychiatric Language Seizures Movement Autonomic

Symptoms Symptoms Disorders Instability
Confusion Word finding
Focal
Fever Paranoid difficulties Ataxia Temperature
Disorientation Generalised
thoughts Echolalia Dysregulation
Headaches Dyskinesia
Memory Deficits Status
Hallucinations Echopraxia Blood Pressure
Diarrhoea Epilepticus Rigidity
Labile mood Instability
URTI Delusions Mutism Bizarre
symptoms Sleep disturbance posturing Hypoventilation
Hypersexuality
Cardiac Arrhythmias

Recovery-often in reverse order of onset

Figure 1 Usual acute clinical presentation of anti-N-methyl-D-aspartic acid receptor (NMDAR) encephalitis through various stages of development.

150 © 2016 Royal Australasian College of Physicians

 Autoimmune encephalitis

hypersalivation, frequently develop often requiring testicular tumour (including teratoma), neuroblastoma,
management in the intensive care setting.6,10,11 Hypo- Hodgkin lymphoma and various tumours of the breast,
ventilation may occur as the patient becomes comatose.6 lung and thymus.5,10
While the above descriptions are the most typical and
Prognosis
frequently documented, atypical presentations are being
increasingly recognised. These include isolated psychiat- Death from anti-NMDAR encephalitis is uncommon if
ric manifestations, dystonia or epilepsy syndromes. Pure treatment is prompt and aggressive.5 The long-term out-
monosymptomatic syndromes are uncommon, repre- look of an individual patient is dependent on early diag-
senting less than 5% of patients.7 However, most of nosis, appropriate treatment and complete removal of
these patients appear to develop other symptoms of the the associated tumour in paraneoplastic cases.5,18
condition over time. Intriguingly, recovery may occur in a multistage proc-
Finally, there are patients with longstanding psychiat- ess which is often in the reverse order of symptom pres-
ric, cognitive and personality changes, but without the entation6 (Figure 1). Many patients require
typical presenting symptoms described above who have hospitalisation for prolonged periods, followed by
been found to be anti-NMDAR antibody positive.14 The months of physical and behavioural rehabilitation.5,6
variety of initial clinical presentations described above Recovery is usually slow and can take up to 18 months.5
may well lead to the concept of anti-NMDAR spectrum In a cohort of 360 patients, 75% experienced a complete
disorders. or near complete recovery (with modified Rankin Scale
(mRS) of 1–2).6 The remainder who survived had seque-
Demographics and tumour association
lae that severely affected their quality of life (mRS > 3).6
The incidence of anti-NMDAR encephalitis is unknown In those who obtained full or near full recovery, 85%
and likely underestimated in the existing literature due still had significant neuropsychiatric symptoms at time of
to under-recognition. For example, anti-NMDAR discharge, and in some cases, these deficits were persist-
encephalitis was somewhat surprisingly found to be the ent.7,19 These included memory deficits and impairment
leading cause of encephalitis in retrospectively tested in executive function, with behavioural, language and
sera that had been collected by the California Encephali- social skill deficits tending to be the last to resolve.7,19
tis Project. In this cohort of patients aged under 30 years, This highlights the importance of a multidisciplinary
anti-NMDAR encephalitis was four times more common approach to treatment and rehabilitation.
than encephalitis caused by herpes simplex type-1,
varicella-zoster virus or West Nile virus and was slightly
Encephalitis associated with antibodies to
more common than enterovirus-related encephalitis.15
the VGKC complex
However, the authors did raise the possibility that refer-
ral bias may have affected these findings, and the discus- Antibodies to the VGKC complex are the second most
sion did not clarify if other aetiologies had been common cause of autoimmune encephalitis and are
identified. associated with a range of clinical syndromes. These
In another retrospective study of encephalitis of include limbic encephalitis, neuromyotonia, Morvan
unknown origin, in patients aged 18–35 years at a single syndrome as well as epilepsy syndromes.
institution intensive care unit over a 5-year period, six Recently, two distinct major antigens have been iden-
out of seven otherwise unknown origin cases were tified that are closely related to, but not part of the
found to be positive for anti-NMDAR antibodies on VGKC: leucine-rich glioma-inactivated 1 (LGI1) and
stored serum/CSF.16 Anti-NMDAR encephalitis repre- contactin-associated protein-like 2 (CASPR2). The iden-
sented 1% of all presentations within this age group in tification of antibodies to these proteins was significant,
this institution’s intensive care unit.16 A United Kingdom because the majority of high-titre VGKC antibodies are
multi-centre population-based study of causes of not directed against the VGKC directly, but rather LGI1
encephalitis determined that 4% of patients had anti- or CASPR2 antigens, which result in two distinct clinical
NMDAR encephalitis, the second most common syndromes.20–22 Many of the cases reported before 2010
immune-mediated encephalitis after acute disseminated with limbic encephalitis and VGKC antibodies were
encephalomyelitis.17 likely related to LGI1 antibodies.22
Teratomas are found in up to one third of adult
patients, with females of reproductive age being most
Anti-LGI1-associated encephalitis
commonly affected. In contrast, teratomas are unlikely
to be found in children and males.4,7,8 Other associated High-titre anti-VGKC antibodies are most commonly
tumours are rare, but include extra-ovarian teratoma, directed against LGI1. Patients with anti-LGI1 antibodies

© 2016 Royal Australasian College of Physicians 151

Newman et al.

develop classic symptoms of limbic encephalitis including In a recent retrospective study, low positive anti-
memory disturbance, confusion, neuropsychiatric fea- VGKC values not associated with LGI1 or CASPR2 were
tures and seizures, including non-convulsive status epi- found in patients with neurodegenerative diseases and
lepticus.20,21,23 A significant proportion develop patients with neurological symptoms, such as myoclonus
hyponatraemia and experience rapid eye movement or dystonia. Low positive anti-VGKC antibodies are less
sleep disturbance.20 likely to be associated with the development of limbic
Prior to developing the classic symptoms of limbic encephalitis.23
encephalitis, many patients experience frequent but brief These findings may be due to the presence of antibo-
faciobrachial dystonic seizures usually affecting the arm dies directed against other antigens in the VGKC com-
and ipsilateral face.24 Only a proportion of these patients plex which may be secondary to other pathologies or
have classical epileptiform changes on EEG. The seizures alternatively part of a normal repertoire of autoantibo-
are often refractory to anti-epileptic drugs, but respond dies found in otherwise healthy individuals which rise to
to immunosuppressive/immunomodulatory therapies.25 detectable levels under certain circumstances. However,
Limbic encephalitis and temporal lobe seizures can a relatively high proportion of patients (10% of cases)
develop later in the disease course. Importantly, anti- with low-level antibodies have been found to have
LGI1-associated limbic encephalitis is usually non- tumours (breast and endometrial). It remains unclear
paraneoplastic.20,21 whether such low positive results necessitate screening
Case series indicate a male preponderance with an for associated malignancies.23
average age of 60 years.20,21 Anti-LGI1-associated limbic
encephalitis is reported to generally respond well to
Anti-GABAb receptor encephalitis
promptly administered immunosuppressive regimens,
but the long-term outlook is uncertain.3,20,21 Some Anti-gamma-aminobutyric acidb (anti-GABAb) receptor
authors report that while the response to treatment is antibodies have been reported in a small proportion
faster, long-term recovery is not as complete as in (5%) of patients with limbic encephalitis.29,30 Clinical
patients with anti-NMDAR encephalitis,26 although no features consist of memory and behavioural changes, in
direct comparison studies exist. addition to prominent seizures (including status epilepti-
cus).30 Additional presentations include ataxia and
opsoclonus-myoclonus.30
Anti-CASPR2-associated encephalitis
In terms of associated malignancies, 50% of patients
The clinical spectrum associated with anti-CASPR2 anti- in a small case series (20 patients) were found to have
bodies differs from that associated with anti-LGI1 antibo- small-cell lung cancer (SCLC) with a median age of
dies. Limbic encephalitis is less frequently observed, 67 years, whereas patients without SCLC were much
whereas peripheral nerve hyperexcitability syndromes, younger (median age 39 years).30 Males and females
such as Morvan syndrome are more common.20,27 Mor- appear to be equally affected.29 Anti-GABAb receptor
van syndrome is a complex disease which combines neu- encephalitis is responsive to immunotherapy, although
romyotonia with autonomic disturbance and long-term prognosis is considered to be dictated by any
encephalopathy.27 Neuromyotonia associated with anti- underlying malignancy.30
CASPR2 antibodies is frequently associated with a pain-
ful peripheral neuropathy, but has been rarely reported
Anti-GABAa receptor encephalitis
in isolation.28 Patients can present with bulbar weak-
ness.27,28 Muscle atrophy and fasciculations may occur, Anti-gamma-aminobutyric acida (anti-GABAa) receptor
making anti-CASPR2 an important treatable differential encephalitis was first reported in 2014 in six patients
diagnosis of motor neuron disease.28 (two male children, one female teenager and three male
adults).31 The encephalopathy was acute and progressive
with refractory seizures (including status epilepticus)
Positive anti-VGKC not associated with anti-
being the predominant factor.31 Some patients required
LGI1 or anti-CASPR2 antibodies
pharmacologically induced coma. Immunotherapy leads
A high titre of anti-VGKC antibodies detected by radio- to a partial or complete recovery in the majority of cases,
immunoassay is likely to be clinically relevant and although two patients died due to persistent status epi-
associated with LGI1 or CASPR2. However, a positive lepticus or sepsis.31 Interestingly, other autoimmune dis-
low-titre result not directed against LGI1 or CASPR2 eases or associated antibodies were detected, primarily
is frequently encountered and can cause a clinical anti-thyroid peroxidase antibodies and anti-glutamic
dilemma.23 acid decarboxylase 65 (anti-GAD65) antibodies (both

152 © 2016 Royal Australasian College of Physicians

 Autoimmune encephalitis

intracellular antigens which themselves have been asso- detection of antibodies against LGI1, CASPR2 and
ciated with encephalopathy).31 Three of these six GABAa receptor.26,36 Therefore, both serum and CSF
patients would have fulfilled the diagnostic criteria for should be sent for testing in patients with suspected
steroid-responsive encephalopathy related to autoim- autoimmune encephalitis.
mune thyroiditis (Hashimoto encephalopathy).31 The reliability of serum antibody titres as a biomarker
This highlights the importance of testing for anti-GABAa of disease activity remains controversial. In anti-NMDAR
receptor antibodies when considering a diagnosis encephalitis, antibody titres in CSF, and to a lesser extent
of Hashimoto encephalopathy or anti-GAD65 in serum, correlate with clinical outcome.35 CSF anti-
encephalitis. body titres associate better with the disease course and
relapses than serum titres.35 However, anti-NMDAR
antibody titres should not be used solely to guide treat-
Anti-AMPA receptor encephalitis ment decisions due to technical reproducibility of testing
Encephalitis due to the presence of α-amino-3-hydroxy- and long-term persistence of antibodies even after clini-
5-methyl-4-isoxazolepropionic acid (anti-AMPA) recep- cal recovery.26
tor antibodies was first described in 2009.32 These At Pathology Queensland, anti-NMDAR antibody
patients presented with symptoms typical of a rapidly titres are not routinely performed as the commercial
progressive limbic encephalitis,32,33 although acute psy- NMDAR NR1 subunit-transfected cell lines used by all
chosis has been reported.34 Patients were usually middle Australian diagnostic laboratories are not readily amena-
aged with a strong female preponderance.32,33 The ble for end-point titration.37 The alternative approach
majority of cases reported thus far have been found to developed in our laboratory involves estimation of fluo-
have an underlying tumour (including breast, lung and rescent intensity of staining using concurrent testing of
thymus).32,33 While the syndrome is responsive to the latest specimen and the original (positive) sample.
immunotherapy and may be totally reversible, it has The immunofluorescence intensity of the transfected
been reported to have a tendency to relapse, sometimes cells on both samples is then compared visually using
repeatedly, despite removal of the tumour.32 digital photographs on the same digital platform, any dis-
cernible changes in intensity are reported.37

Other autoimmune encephalitis

syndromes associated with antibodies
against neuronal cell surface and Suspected autoimmune encephalitis with no
synaptic antigens autoimmune encephalitis autoantibody
Several other autoantibodies associated with encephalitis detected
have been reported, although they remain rare (Table 1). In patients clinically suspected to have autoimmune
Testing for these antibodies remains largely at the encephalitis, but with no detectable autoantibody in
research level. serum or CSF, recollection and repeat testing of both
serum and CSF is recommended.38 This is especially
important if only serum was initially tested.22
Antibody testing in autoimmune encephalitis
It is important to note that treatment with intravenous
Notwithstanding the fact that there are no standardised, immunoglobulin (IVIG) prior to the collection of serum
consensus-agreed clinical criteria for anti-NMDAR can make the interpretation of anti-NMDAR transfected
encephalitis, all patients with anti-NMDAR encephalitis slides in the laboratory more difficult and potentially
have antibodies detectable in CSF, however, in 14% of lead to false negative results. However, the prior use of
patients antibodies in the serum are not found.26,35 In IVIG does not affect the interpretation of CSF specimens.
our laboratory, this percentage may be as high as 30% Therefore, liaison with the testing laboratory and super-
(unpublished data). This is likely due to the fact that CSF vising immunopathologist should be contacted regarding
is tested undiluted in most laboratories (including ours), interpretation of testing in this scenario.
compared with 1:10–1:40 dilution for serum specimens. Once other causes of encephalitis have been excluded,
Thus, it is critical that CSF analysis be carried out when and the clinical scenario remains suggestive of autoim-
anti-NMDAR encephalitis is suspected and no antibody mune encephalitis, a trial of immunosuppression with
can be detected in the serum. CSF testing is preferred for corticosteroids and IVIG +/− plasmapheresis should be
anti-AMPA and anti-GABAb receptor antibodies.26 On considered and the clinical response carefully
the other hand, serum is the specimen of choice for the observed.22

© 2016 Royal Australasian College of Physicians 153

Newman et al.

Treatment of autoimmune encephalopathies In a large multi-institutional observational cohort

study of 577 patients with anti-NMDAR encephalitis,
Treatment regimens used in autoimmune encephalitis
92% of patients received first-line immunotherapy
are based on the principles of treatment of other life-
including steroids, IVIG and/or plasma exchange, com-
threatening autoimmune diseases. Various therapies,
bined with tumour removal (when applicable).5
including corticosteroids, IVIG, plasma exchange,
Improvement occurred within 4 weeks in 53% of
rituximab and cyclophosphamide are currently used
patients. A total of 97% demonstrated a good outcome
(Figure 2). However, there is no clear consensus and no
at 24 months as defined by mRS 0-2.5 The remaining
controlled randomised clinical trial data regarding which
47% of patients who did not respond to first-line treat-
immunotherapies should be used, the order in which
ment, generally had a poorer prognosis.5 However, non-
they should be applied or the duration of therapy. Most
responders who subsequently received rituximab and/or
experience has been attained in the treatment of the two
cyclophosphamide had better outcomes than those who
most common diseases – anti-NMDR and anti-LGI1
continued on first-line treatments or did not receive any
encephalitis.
further immunotherapy.5

Suspected Autoimmune Encephalitis

Serum/CSF† Specimen

Analysis for Onconeuronal and

Neuronal Cell Surface Antibodies

Exclusion of Infective causes

essential

MRI + EEG

Neuronal Cell Surface Antibodies Onconeuronal Antibodies Positive No Neuronal Auto-antibody

Positive detected
Anti-Hu/Anti-Ri/Anti-CV2/Anti-
Anti-NMDAR/ Anti-VGKC (LGI1, Ampihysin/Anti-Ma2/ etc
CASPR2)/Anti-AMPA/Anti-
Gly/Anti-GABA a/b

Methylprednisolone followed by Imaging of Chest/Abdomen/Pelvis Trial of treatment as per Neuronal

oral corticosteroid + IVIG +/- Cell Surface Antibody Pathway
Plasma Exchange Methylprednisolone followed by
oral corticosteroid Repeat Serum/CSFAnalysis
Imaging of Chest/Abdomen/Pelvis
Treatment of associated tumour Store Serum/CSF
Tumour removal if applicable
Seek expert advice

Rituximab +/-Cyclophosphamide

Chronic immunosuppression (ie

ongoing rituximab based on
peripheral CD19+ B-cell
quantification) and/or
† CSF particularly important for anti-NMDAR, anti-AMPA and anti-GABAb
mycophenolate/azathioprine/
encephalitis diagnosis
methotrexate

Observation for relapse and

tumour surveillance Figure 2 Treatment algorithm for suspected
autoimmune encephalitis.

154 © 2016 Royal Australasian College of Physicians

 Autoimmune encephalitis

In several autoimmune encephalitides, including anti- Screening and surveillance for underlying
NMDAR encephalitis, there is evidence of intrathecal tumours
synthesis of antibody.10 Therefore, therapies which pri-
Some authors have recommended that all patients with
marily reduce the amount of antibody in the circulation,
autoimmune encephalitis should be screened for
rather than the CNS, such as IVIG or plasmapheresis,
tumours at the onset of disease, but others have argued
may have only limited efficacy.22
that tumour screening is less important in patients with
Relapses in anti-NMDAR encephalitis patients with
antibodies, such as anti-LGI1 and anti-GABAa, which
non-paraneoplastic-associated disease have been
have a low association with underlying tumours. If the
reported to occur in around 10–25% of patients.9,39
initial tumour screening is negative in patients with anti-
Relapses may be separated by periods of months to years
bodies, such as anti-NMDAR in young adult women,
and occur more frequently in patients who are under-
anti-CASPR2, anti-AMPA receptor and anti-GABAb
treated or not treated with immunotherapy during the
receptor with a high reported association with underly-
first episode of disease.9,39
ing tumours, repeat screening at 3–6 months followed
In the largest study to date, those treated with second-
by screening at 6 monthly intervals for 4 years is
line therapies, such as rituximab and/or cyclophospha-
recommended.40
mide, were less likely to relapse than those who only
The modality of screening will be determined by the
received first-line immunosuppressive treatment.5 The
age and sex of the patient as well as the particular auto-
prolonged use of other immunosuppressive drugs, such
antibody detected. For example, to screen for ovarian
as mycophenolate or azathioprine, may decrease the risk
teratoma, transvaginal ultrasound followed by computed
of recurrence.6 Relapses are rarer in paraneoplastic cases,
tomography scan or magnetic resonance imaging of the
where symptoms usually improve after complete tumour
pelvis is recommended, and the reader is referred else-
removal.5
where for discussion of strategies of screening for other
As anti-LGI1 encephalitis is less common than anti-
malignancies.40
NMDAR encephalitis, only smaller published series are
available. Patients with anti-LGI1 encephalitis often
respond more quickly to IVIG, corticosteroids and
plasma exchange than those with anti-NMDAR enceph-
Conclusion
alitis.26 This may be due to the greater production of
pathogenic anti-LGI1 antibodies outside of the CNS com- The autoimmune encephalitides associated with surface
pared with anti-NMDAR antibodies.26 A total of 80% of receptors are an important and rapidly emerging group
patients is reported to have a good outcome, but the of antibody-associated neurological diseases. Recognition
mortality rate is around 6%, and approximately 15% of of these conditions is crucial as with prompt diagnosis
cases will relapse.20,21 and treatment the majority have favourable outcomes.
In our experience, early treatment with rituximab Undoubtedly, additional autoantibodies will continue to
and/or cyclophosphamide is beneficial in both paraneo- be detected and the pathogenic mechanisms will con-
plastic and non-paraneoplastic anti-NMDAR antibody- tinue to be elucidated. Close liaison with the testing lab-
mediated encephalitis. Onset of action for some immu- oratory and immunopathologist is essential.
nosuppressive agents may take several weeks (such as Rapid treatment with immunotherapy and tumour
with rituximab which takes 2–3 weeks for peripheral B- removal, if applicable, remains crucial to prevent pro-
cell depletion to be complete) and therefore, valuable gressive neurological decline and leads to considerable
treatment time may be lost whilst waiting for response clinical improvement in most cases. Patients need to be
to first-line agents (corticosteroids, IVIG and/or plasma- followed closely after recovery for signs of relapse. Acute
pheresis). Clinical improvement, even after aggressive and long-term treatment regimens will continue to
therapy with rituximab or cyclophosphamide, is often evolve, with treatment regimens in the rarer syndromes
slow with average acute hospital admission duration likely to be guided by those developed for anti-NMDAR
reported to be around 3 months.26 encephalitis.

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Appendix I

Search strategy for literature on autoimmune encephalitis

Database: PubMed

Search Strategy: (((((encephalitis) OR encephalopath*) AND autoimmune) AND limbic) OR "receptor encephalitis")
AND english[Language] (653 references)

© 2016 Royal Australasian College of Physicians 157