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The diagnosis and treatment of limbic encephalitis

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Acta Neurol Scand 2012: 126: 365–375 DOI: 10.1111/j.1600-0404.2012.01691.x
Review Article
The diagnosis and treatment of limbic
encephalitis
Asztely F, Kumlien E. The Diagnosis and Treatment of Limbic
Encephalitis.
Acta Neurol Scand: 2012: 126: 365–375.
© 2012 John Wiley & Sons A/S.
The term limbic encephalitis (LE) was first introduced in 1968. While
this disease was initially considered rare and is often fatal with very
few treatment options, several reports published in the last decade
provide a better description of this condition as well as possible causes
and some cases of successful treatment. The clinical manifestation of
LE is primarily defined by the subacute onset of short-term memory
loss, seizures, confusion and psychiatric symptoms suggesting the
involvement of the limbic system. In addition, EEG often shows focal
or generalized slow wave or epileptiform activity, and MRI findings
reveal hyperintense signals of the medial temporal lobes in
T2-weighted or FLAIR images. The current literature suggests that
LE is not a single disorder but is comprised of a group of
autoimmune disorders predominantly affecting the limbic system.
Before the diagnosis of LE can be determined, other causes of
subacute encephalopathy must be excluded, especially those resulting
from infectious aetiologies. LE has previously been regarded as a
paraneoplastic phenomenon associated with the classical
onconeuronal antibodies that are primarily directed against
intracellular antigens. However, recent literature suggests that LE is
also associated with antibodies that are directed against cell surface
antigens, and these cases of LE display a much weaker association to
the neoplasm. The treatment options for LE largely depend on the
aetiology of the disease and involve the removal of the primary
neoplasm. Therefore, a search for the underlying tumour is
mandatory. In addition, immunotherapy has been successful in a
significant number of patients where LE is not associated with cancer.
Introduction
Corsellis and collaborators introduced the term
‘limbic encephalitis’ (LE) more than 40 years ago
(1, 2). In their reports, six patients were described
who presented with progressive memory defects,
confusion and in some cases epileptic seizures,
and tumours were found in four patients, includ-
ing three bronchial carcinomas. Post-mortem
investigations of these patients showed ‘both
inflammatory and degenerative changes concen-
trated mainly on the temporal parts of the limbic
gray matter’. In addition, other parts of the brain
(e.g. brainstem and cerebellum) were also affected
Ó 2012 John Wiley & Sons A/S
ACTA NEUROLOGICA
SCANDINAVICA
F. Asztely1, E. Kumlien2
1
Section of Clinical Neuroscience and Rehabilitation,
Institute of Neuroscience and Physiology, Sahlgrenska
Academy, Göteborg University, Göteborg, Sweden;
2
Department of Neuroscience, Neurology, Uppsala
University, Uppsala, Sweden
Key words: autoimmune limbic encephalitis; limbic
encephalitis; limbic system; paraneoplastic limbic
encephalitis; paraneoplastic syndromes
Fredrik Asztely, Section of Clinical Neuroscience and
Rehabilitation, Institute of Neuroscience and
Physiology, Sahlgrenska Academy, Göteborg University,
SE 413 45 Göteborg,
Sweden
e-mail: Fredrik.asztely@neuro.gu.se
Accepted for publication May 17, 2012
by LE. The authors indicated that ‘a connection
between carcinoma and “limbic encephalitis” is
now justified even if it cannot be explained’.
Roughly 20 years later, several studies demonstrated
that patients with neurological symptoms and
tumours localized outside the CNS also had
serum antibodies that reacted with both tumour
and brain tissue (3–6). To date, several such para-
neoplastic antibodies directed against intracellular
antigens have been characterized. Therefore, this
association between neurological syndromes and
cancer led to the concept of paraneoplastic neuro-
logical syndromes. Graus and co-workers (7) sug-
gested using only well-characterized onconeuronal
365
Asztely & Kumlien
antibodies (i.e. anti-Hu, anti-Yo, anti-CV2/
CRMP5, anti-Ri, anti-Ma2 and anti-amphiphy-
sin) when diagnosing paraneoplastic neurological
syndromes, including LE. In addition, there were
also reports suggesting that LE was more
frequently associated with specific onconeural
antibodies (frequent in the case of anti-Hu and
anti-Ma2, less frequent for anti-CV2/CRMP5 and
anti-amphiphysin, and extremely rare for anti-
Yo)(8–10). Because LE was associated with these
‘classical onconeural antibodies’, these findings
strongly suggest an underlying malignancy associ-
ated with poor therapeutic response (11–13).
Nonetheless, these different classical onconeural
antibodies may serve as useful markers for
detection of primary tumours related to LE (see
Table 1).
In the beginning of 2000, robust evidence had
established that many patients with LE did not
have any detectable ‘classical onconeural antibod-
ies’ directed against intracellular antigens and/or
a neoplasm (9, 14–16). In fact, the frequency of
an underlying tumour is variable and has never
been reported to be higher than 70% (17, 18). To
date, several reports describe LE that is associ-
ated with ‘new antibodies’ that are directed
against neuronal cell surface antigens and ion
channels including voltage-gated potassium
channels, VGKC, and ligand-gated ion chan-
nels (i.e. NMDA, AMPA and GABAB recep-
tor channels – see Table 2) (19–27). A direct
pathogenic role of these antibodies directed
against synaptic protein is suggested by the
response to immunotherapy and the correlation
between antibody titers and neurological outcome
(26, 28–30). However, a substantial proportion of
LE associated with antibodies to cell surface anti-
gens is also associated with an underlying tumour
(8, 31).
The detection of antibodies to cell surface
antigens has contributed to the aetiological
understanding of otherwise unexplained epilepsies
that were associated with LE. The most relevant
Table 1 Classical onconeuronal antibodies associated with limbic encephalitis
Antibody positive
patients without
Antibody Tumour
Hu (ANNA1) Small cell lung cancer (SCLC)
CV2 (CRMP5) SCLC, thymoma
Amphiphysin Breast, SCLC
Ri (ANNA2) Breast, SCLC
Yo (PCA1) Ovarian, breast
Ma2 (Ta) Testicular
Modified from Graus et al. 2004 (7).
366
antibodies are those targeting antigens that are
receptors and proteins that play a critical role in
synaptic transmission and nerve cell excitability
(32–34). For some immune responses, evidence
indicates that these antibodies alter the structure
and function of the antigen, suggesting a direct
pathogenic effect (28, 35–37). Syndromes result-
ing from these immune responses are sometimes
referred to as autoimmune synaptic encephalopa-
thies (32, 37). For instance, faciobrachial dystonic
seizure (FBDS), a newly described epileptic
syndrome, has been associated with voltage-gated
potassium channel or VGKC-complex/LgI
antibodies, and FBDS often precedes the onset of
LE (38). Therefore, the recognition and early
treatment of FBDS with immunotherapies may
prevent the development of some forms of LE
(38). Other antibody targets in patients with LE,
and severe seizures are the GABAB receptors (26)
and AMPA receptors (28). Recently reported by
Dalmau and colleagues, anti-NMDA-receptor
encephalitis is a severe, potentially lethal disorder
that is often treatment-responsive (24, 25). This
disorder is predominantly seen in women and is
associated with the development of sudden
behavioural and personality changes followed by
seizures. In addition, serum and CSF antibodies
from these patients react with brain antigens that
are predominantly expressed in limbic structures
(39).
Antibodies against GAD (glutamic acid decar-
boxylase), an intracellular protein, have also been
detected in serum or cerebrospinal fluid (CSF) in
patients with LE. While the pathogenic proper-
ties of GAD antibodies have been debated (30,
40, 41), GAD antibodies are associated with a
paraneoplastic form of LE that sometimes responds
to immunotherapy. In patients diagnosed with
seronegative LE, it is not possible to identify any
known antibody associated with LE (22, 42, 43).
However, it is likely that new antibodies are yet
to be discovered. In many cases, seronegative LE
is associated with an underlying tumour (44, 45).
Table 2 Antibodies to neuronal surface and synaptic antigens
NMDA-receptor
AMPA-receptor
cancer (%) GABAB-receptor
Glycine-receptor
2 LGI1/VGKC
4 Caspr2
5
3 NMDA, N-methyl-D-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropion-
2 ic acid receptor; GABA, c-aminobutyric acid; LGI1, leucine-rich-glioma-inactivated 1;
4 VGKC, voltage-gated potassium channel; Caspr2, contactin-associated protein-like
2.
Modified after Lancaster et al. 2011 (32).
 Limbic encephalitis

Taken together, LE can be broadly divided A

into three major groups (see also Fig. 2):
1. LE associated with ‘classical onconeural
antibodies’ (against intracellular neuronal
antigens). The majority of these cases are
associated with a neoplasm (i.e. paraneoplastic
LE).
2. LE associated with antibodies against
neuronal surface/synaptic antigens. In some
cases, LE is also associated with a neoplasm (i.e.
paraneoplastic LE), and no neoplasm is found B
in many cases.
3. LE associated with no known antibody (i.e.
seronegative LE). Many cases are associated
with a neoplasm.

Diagnosis
Patients with LE usually have a subacute onset
of disease with memory impairment, confusion,
disorientation, agitation and sleep disturbances
(2, 9, 46, 47). Epileptic seizures are common and
may precede the onset of cognitive deficits by
months. Some patients have a more insidious C
onset with depression or hallucinations, which
may be misdiagnosed as psychiatric illness (48).
These patients may develop mood and sleep dis-
turbances, seizures, hallucinations and short-term
memory loss that can progress to dementia. EEG
abnormalities with focal slowing or epileptiform
activity in the temporal lobes (both) are typical.
MRI studies reveal increased signal activity on
T2 or FLAIR-weighted sequences in the tempo-
ral lobes corresponding to inflammatory infil-
trate (Fig. 1A), and FDG-PET of the brain
shows focal hypermetabolism in one or both tem-
poral lobes (Fig. 1B) (15, 49). It is unclear
whether these focal imaging abnormalities repre-
sent seizure activity or the underlying inflam-
matory process (50). CSF analysis usually Figure 1. A 61-year-old women with subacute onset of con-
shows lymphocytic pleocytosis, increased protein fusion, short-term memory loss, focal seizures and depres-
sion. CSF contained 21 white blood cells/mm3 (19
concentration and the presence of oligoclonal monocytes) and an increased protein concentration with
bands by isoelectric focusing (9). The diagnostic some discrete oligoclonal bands. Onconeuronal antibodies in
criteria of LE are based on both clinical and serum and CSF were negative. EEG showed generalized slow
wave abnormalities. (A) MRI investigation showed hyperin-
investigational findings, and these findings sug- tense signal abnormalities in bilateral medial temporal struc-
gest the involvement or dysfunction of the limbic tures. Screening with CT-thorax, CT-pelvis/abdomen,
system (Table 3) (7). Many patients with LE may mammography, MRI breast and transvaginal ultra sound
also have symptoms suggesting involvement of was negative. (B,C) The integrated whole body FDG-PET/
CT showed hypermetabolism in the right medial temporal
other areas of the nervous system such as lobe and an increased signal in a regional paraaortic lymph
cerebellar and brainstem symptoms and basal node. Cytology showed low differentiated adenocarcinoma.
ganglion signs (Table 4). Indeed, both Gulte- (PET-centre, Uppsala University Hospital).
kin et al. (9) and Lawn et al. (47) reported that
42–60% of the patients with LE also had symp- Epileptic seizures are a prominent feature of
toms suggesting involvement of extra-limbic LE. Granerod et al. (2010) reported that a major-
structures. ity of patients with autoimmune encephalitis

367
Asztely & Kumlien
present with seizures (51). However, more than
50% of patients who had encephalitis because of
herpes simplex virus or unknown viral aetiology
also present with seizures. By contrast, it is
uncommon for seizures to occur in patients with
acute disseminated encephalomyelitis (ADEM).
For example, Glaser et al. (2008) reported that
no imaging findings compatible with ADEM were
found in patients with refractory status epilepti-
cus in suspected encephalitis (52).
Differential diagnoses
No pathognomonic symptoms are present in
autoimmune LE (see Table 4). The majority of
cases of acute encephalopathy with memory loss,
psychiatric symptoms and seizures are caused by
infections or autoimmune inflammation (18, 51).
However, other causes of an acute/sub-acute
encephalopathy with limbic dysfunction must be
excluded prior to the diagnosis. While the list of
differential diagnoses is extensive, many of these
diagnoses can be excluded or confirmed by a
detailed clinical history, CT and/or MRI brain
imaging, and routine blood and CSF evaluation
(Table 5). Infectious aetiology should always be
ruled out first, and treatment with acyclovir and
antibiotics must not be delayed if any doubt
exists regarding the diagnosis. Herpes simplex
virus is the most common infectious agent
Table 3 Diagnostic criteria for paraneoplastic limbic encephalitis
Subacute onset (days or up to 12 weeks) of short-term memory loss, seizures,
confusion, and psychiatric symptoms suggesting involvement of the limbic system
Neuropathological or neuroradiological evidence (MRI SPECT, PET) of involvement
of the limbic system
Demonstration of cancer within 5 years of the diagnostic neurological symptoms
or the detection of well-characterized antibodies
CSF evidence of inflammation is reported in 80% of limbic encephalitis and may
be used to support the clinical diagnosis
Exclusion of other possible aetiologies of limbic dysfunction
Adapted by the Paraneoplastic Neurological Syndrome Euronetwork (7).
Table 4 Clinical features/symptoms of limbic encephalitis
Gultkien et al.(9) Lawn et al.(47)
Loss of short-term memory 84% Cognitive dysfunction (including
memory impairment and confusion)
Acute confusional state 46% Epileptic seizures
Epileptic seizures 50% Psychiatric abnormalities
Psychiatric abnormalities 42% Signs of ‘extralimbic’ neurological
involvement
Signs of ‘extralimbic’ 60%
neurological involvement
Hypothalamic symptoms 22%
368
associated with encephalitis (51, 53); however,
other infections must also be taken into account
(54). Furthermore, patients with systemic
infections, especially the elderly, may present with
symptoms of an acute encephalopathy including
limbic dysfunction. LE has also been described in
post-transplanted patients possibly related to
human herpes virus-6 (55).
Several studies have reported other causes of
acute/subacute encephalopathies that involve
limbic dysfunction; however, many of these
reports are based on a limited number of cases.
Although acute disseminated encephalomyelitis
(ADEM) is predominantly a paediatric disease,
cases have also been reported in the adult
population (56–58). Neurodegenerative causes
such as Creutzfeldt-Jakob disease (CJD) may
have clinical features suggestive of LE (59). As
many patients with LE express 14-3-3 protein in
the CSF (60, 61), this test cannot be used to dis-
tinguish CJD from LE. In addition, Wernicke
encephalopathy (WE) is an important differential
diagnosis among the metabolic encephalopathies
and those induced by nutritional factors, toxins,
or drugs (62–67). Connective tissue disorders
Table 5 Differential diagnoses of limbic encephalitis
Infection
Herpes simplex type 1 and 2, Varicella zoster virus, Enterovirus, Neuroborreliosis,
Adenovirus, HIV, TB, Listeria
Cytomegalovirus, Human herpesvirus-6/7, JC virus, Epstein-Barr virus, fungal/
parasitic (in immunocompromised patients)
Arboviruses, Poliomyelitis, Rabies, West Nile virus (if patient travelled abroad)
Systemic
Neurosyphilis
Acute demyelinating encephalomyelitis (ADEM)
Degenerative diseases
Creutzfeldt-Jakob disease
Rapidly progressive Alzheimer’s disease or dementia with Lewy bodies
Nutritional/toxic/drug
Wernicke encephalopathy (Thiamine deficiency)
Alcohol, including alcohol withdrawal syndrome
Other recreational drugs
Chemotherapy (such as Methotrexate)
Lithium
Metabolic
Uremic encephalopathy
Hepatic encephalopathy
Electrolyte disturbances
Connective tissue disorders and vasculitis
92% Systemic lupus erythematosus (SLE)
Behçet’s disease
58% Sjogren’s syndrome
50% Primary CNS vasculitis/angiitis
42% Primary or secondary CNS malignancy
Gliomas
Cerebral metastasis
Primary CNS lymphoma
Intravascular lymphoma

including systemic lupus erythematosus (SLE),
Sjogren’s syndrome and Behçet’s disease can
cause symptoms involving limbic dysfunction (68
–72), and cerebral vasculitis/angiitis may also
have predominantly limbic symptoms (73–75).
Gliomas, cerebral metastasis and primary CNS
lymphomas can involve limbic structures and
cause an acute/sub-acute encephalopathy (76–79).
Hashimoto’s encephalopathy has been described
as an acute/subacute encephalopathy associated
with high serum thyroid (TPO) antibodies and
thyroglobulin (TG)-antibodies (80). These patients
are either hypothyroid or hyperthyroid and often
respond favourably to treatment with steroids.
However, the TPO- and TG-antibodies are not
specific to Hashimotos’s encephalopathy, and
these antibodies can also be found in patients
with LE with antibodies against neuronal surface
antigens (e.g. NMDAR and VGKC) (81). Fur-
thermore, TPO- and TG-antibodies are common
in patients with other autoimmune disorders
including myasthenia gravis, diabetes mellitus
type 1, and connective tissue diseases (82). In
addition, TPO- and TG-antibodies are found in
10–15% of the general population (83). There-
fore, these anti-thyroid antibodies in association
Antibodies to cell
surface/synaptic antigens
Non-paraneoplastic
limbic encephalitis
IV methylprednisolone
/IV immunoglobulins/PLEX
Consider rituximab or
cyclophospamide
Regular tumour screening,
repeated every 6 months
See table 5
Figure 2. Management algorithm for limbic encephalitis (modified from Tüzün&Dalmau, 2007(85) and Ahmad et al. 2011(42)).
Limbic encephalitis
with an acute/subacute encephalopathy are not
pathogenic by themselves; however, their presence
should prompt the clinician to investigate other
autoimmune aetiologies in these patients (83, 84).
Treatment
The algorithms for treatment of LE are based on
either case reports or small case series. Despite the
limited data and no randomized controlled trial
evidence, the current clinical experience suggests
the following three general principles: (1) removal
and/or treatment of tumour (if known), (2)
immunotherapy, and (3) the treatment(s) should
start as early as possible. A suggested treatment
algorithm is provided in Fig. 2 (42, 85). It is
important to point out that the treatment(s) is not
only aimed at recovery, but also for the
prevention of relapses and progression of LE.
Removal and/or treatment of tumour
The identification and removal of a tumour is
the most important measure to improve or stabi-
lize paraneoplastic LE (86–88). However, as many
as 30–40% of the patients with paraneoplastic
Subacute encephalopathy
including limbic dysfunction
CT/MRI/lumbar puncture/EEG
Exclude other causes
(see table 4),
Paraneoplastic antibodies
including antibodies to cell
surface/synaptic antigens
Start searching for possible
neoplasm
Antibodies to intracellular
l Negative antibodies
(’classical’) neuronal antigens
Paraneoplastic Seronegative
limbic encephalitis limbic encephalitis
Oncological treatment IV methylprednisolone
Immunotherapy/ T-cell /IV immunoglobulins/PLEX
suppression
Consider Regular tumour screening,
IV methylprednisolone repeated every 6 months
/IV immunoglobulins/PLEX See table 5
369
Asztely & Kumlien

LE do not have any detectable antibodies associ-
ated with a tumour (17, 18). Therefore, all
patients with LE should be screened for underly-
ing tumours. Screening techniques for tumours
can include the following: (1) physical examina-
tion, (2) computed tomography (CT) of the tho-
rax, abdomen and pelvis, (3) mammography of
women and (3) ultrasonography, b-HCG and
AFP to screen for testicular tumours in men.
Recently, the European Federation of Neurologi-
cal Societies (EFNS) published a report
suggesting an algorithm for screening for tumours
in patients with paraneoplastic syndromes,
including LE (see Table 6) (89). If a paraneoplas-
tic antibody has been identified, the type of
antibody should provide a guide for subsequent
screening for a tumour (see Table 1) (89, Table 1,
90). However, no paraneoplastic antibody that is
unique for a specific neoplasm or broad area
screening is recommended. To date, [18F]fluorode-
oxyglucose positron emission tomography
(FDG-PET) represents the most sensitive
technique for detecting even small neoplasms.
While this strategy improves the detection of
tumours, the specificity of FDG-PET is not
optimal (91, 92). Recently, a study found that
integrated FDG-PET/CT detected histologically
proven cancer in 18% of patients with paraneo-
plastic syndromes and negative standard evalua-
tions, including CT (92). Furthermore, several
reports suggest that early detection and treatment
of a tumour improves the outcome. For instance,
Dalmau et al. (2008)(39) showed that patients
with LE (NMDAR antibody) demonstrated a
better outcome when the tumour was diagnosed
and treated within 4 months of the development
of neurological symptoms.
First line treatment with immunotherapy
While steroids, immunoglobulins (IvIg) and
plasma exchange (PLEX) have been investigated
for all types of LE (93–96), no evidence clearly
indicates the efficacy of these respective
treatments. Furthermore, these treatments were
combined and/or repeated in many cases. The
most common steroids were methylprednisolone
(1000 mg; i.v. administered for five consecutive
days) and alternatively prednisone (1 mg/kg body-
weight per day given orally). Another alternative
for treatment was IvIg (0.4 g/kg body weight for
five consecutive days; a total dose of 2 g/kg body
weight). In addition, one report recommends a
5 day course of IvIg in combination with methyl-
prednisolone for treatment of anti-NMDAR
encephalitis (88). If the first two treatments are not
successful, PLEX is often administered; however,
PLEX is rarely the first choice of treatment. If one
treatment is successful, the treatment should be
repeated; however, no consensus exists regarding
the frequency or duration. Some authors recom-
mend repeating the treatment(s) with a 6–8 week
interval (93). Furthermore, no consensus exists
regarding how long (i.e. how many cycles) these
treatments should last. An alternative to repeated
methylprednisolone treatment (i.v.) is a maintenance
treatment with oral prednisone (1 mg/kg body
weight) (29).

Table 6 Screening for tumours in paraneoplastic syndromes

Determine the nature of the antibody, and to lesser extent the clinical syndrome to assess the risk and type of an underlying malignancy.
As most paraneoplastic syndromes (PNS) are not specifically related to one antibody, testing for several neoplastic antibodies simultaneously will improve the yield,
avoiding loss of time before a malignancy is detected.
Screen for small cell lung cancer by CT-thorax followed by FDG-PET or integrated FDG-PET/CT.
Screen for thymoma by CT-thorax followed by FDG-PET or integrated FDG-PET/CT.
Screen for breast cancer by mammography followed by MRI breast. If negative, screen by FDG-PET/CT.
Screen for ovarian teratoma by transvaginal US followed by CT/MRI-pelvis/abdomen. If negative, screen by CT-thorax.
Screen for ovarian carcinoma by transvaginal US and CA-125, followed by CT-pelvis/abdomen or integrated FDG-PET/CT.
Screen for testicular tumour by US, b-HCG and AFP followed by CT of the pelvic region. Biopsy is recommended in men under the age of 50 with classical PNS and
microcalcifications detected using US.
If tumour screening is negative and the neurological condition is worsening, exploratory surgery and eventually preventive removal of the ovaries is warranted in post-
menopausal women with an anti-Yo-associated PNS.
Additional laboratory investigations have extra value if the antibody and the associated PNS are related to both paraneoplastic and a non-paraneoplastic subtype (e.g.
Lambert-Eaton myasthenic syndrome and myasthenia gravis). While positive markers raise suspicion of a tumour, normal values do not exclude malignancy as the
sensitivity is low to moderate.
If no paraneoplastic antibodies are found, the patient exhibits a classical PNS, and the neurological condition is deteriorating, the most likely site should be screened
with conventional methods guided by the type of PNS. If negative, screening by total-body FDG-PET is recommended.
Screen all adults with dermatomyositis by CT-thorax/abdomen. Women should also be tested by US of the pelvic region and mammography. Male patients under
50 years old should have US of the testes. Patients over 50 years old should have a colonoscopy.
Following initial screening in a patient with PNS and paraneoplastic antibodies, screening should be repeated after 3–6 months, and followed by regular screening every
6 months for 4 years. In patients with LEMS, 2 years of screening is sufficient. X-ray and tumour markers are not reliable for this disorder

Adapted from report of an EFNS Task Force (89).

370

Second line treatment
Either rituximab or cyclophosamide (or both) may
be considered for patients who fail to respond to
steroids/IvIg/PLEX immunomodulatory treat-
ment. Some reports indicate that rituximab
(375 mg/m2) has shown some efficacy for the
treatment of anti-NMDAR encephalitis where the
initial treatment with PLEX was not successful
(97). For instance, Frechette et al. (2011) reported
a successful treatment of anti-NMDAR encephali-
tis where initial treatment with IvIg and methyl-
prednisolone were not effective. Their subsequent
treatment consisted of rituximab (375 mg/m2)
once a week for 6 weeks as well as monthly cycles
of cyclophosamide (750 mg/m2 and IvIg 2 g/kg
body weight (eight cycles)) (98). In patients with
LE associated with surface/synaptic antigens,
Rosenfeld and Dalmau (2011) suggest treatment
with cyclophosamide (monthly) and rutuximab
(weekly for 4 weeks starting with the first dose of
cyclophosamide) if there is no or limited response
to one cycle of first line (88). Therefore, the num-
ber of cycles is empiric and should be based on
clinical outcome.
The prognosis for LE associated with ‘classical
onconeural antibodies’ to intracellular antigens
(i.e. anti-Hu, anti-CV2/CRMP5, anti-Ma2 and
anti-amphiphysin) is often poor with a limited
response to immunosuppressive therapy (44, 99).
Studies suggest that these forms of LE are pre-
dominantly mediated by a cytotoxic T-cell driven
mechanism (11, 100–104), and less than 10% of
these patients have substantial or full recovery (32,
105). However, several reports indicate that some
patients with anti-Ma2 associated LE may
improve with steroids/IvIg/PLEX treatment (9,
106). Owing to the very limited clinical evi-
dence, the efficacy of therapies suppressing T-cell
activation and cytotoxic T-cell mechanisms has not
yet been established. However, cyclophosamide has
demonstrated positive effects in some patients (85,
107). In addition, Shams’ili et al. (2006) reported a
limited response to treatment with rituximab in
one patient with LE and anti-Hu antibodies (108).
In cases of LE with classical onconeuronal anti-
bodies, immunotherapy must be used in combina-
tion with oncology treatment.
Treatment(s) should start early
Irani et al. (2010) reported that early treatment
(  40 days) of patients with NMDAR antibody
form of LE displayed a much better outcome and
less relapses than those who had begun their
treatment later (109). In addition, one study
Limbic encephalitis
suggested that the development of hippocampal
atrophy seen in some patients with LE might be
prevented with early treatment (93). From a
clinical point of view, this finding indicates that
treatment with immunotherapy should start as
soon as other differential diagnoses have been
excluded, especially diagnoses with an infectious
aetiology (107). Furthermore, antibodies associ-
ated with LE may diminish with treatment (15,
23, 39); therefore, it is essential to sample both
serum and CSF for analysis of antibodies early in
the disease course before commencement of the
treatment.
Supplementary symptomatic treatment
Most patients will require symptomatic treatments
with anti-epileptic drugs (AED), and often high
doses and/or a combination of several AEDs are
required. Furthermore, many patients develop
pharmacoresistant epilepsy, and patients may also
need treatment with psychotropic drugs for psy-
chiatric symptoms. However, the effective treat-
ment of these patients using these various drugs
may be hampered because psychotropic drugs may
increase the risk of seizures (110) and possible
pharmacokinetic interactions can exist between
antiepileptic and psychotropic drugs (111, 112)
and immunotherapies (113).
Assessment of treatment outcome
At present, no consensus exists regarding a clear
assessment of treatment outcome. The modified
Rankin scale (114) is often used to assess outcome
(115). Dalmau and co-workers have recommended
the utilization of a combination of the modified
Rankin scale (MRS) and mini-mental state exami-
nation (MMSE) (116). Patients are described as
having full recovery if they return to their jobs
(MRS 0, MMSE 29-30), mild deficits if they
returned to most activities of daily living and
remain stable for at least 2 months (MRS 1-2,
MMSE > 25), and severe deficits for all other
cases (39, 44). Other studies have utilized an array
of different neuropsychological assessments (23).
In LE with antibodies to cell surface/synaptic anti-
gens, examination of serum and CSF antibodies
with persistent titres can be used to guide treat-
ment decisions to determine the continued need
for treatment (29, 88, 94)
Follow-up
Patients with ‘classical’ paraneoplastic syndromes
(PNS) are almost always diagnosed within
371
Asztely & Kumlien
5 years after the onset of the first symptoms of
the PNS (7). Vedeler et al. (2006) reported that in
the majority of cases, the symptoms of the LE
antedated the diagnosis of a tumour exhibiting a
mean of 3–5 months (105) and argued for a
repeated screening after 3-6 months. Therefore, if
the initial tumour screening in a patient with LE
and paraneoplastic antibodies is negative,
screening for tumours should be repeated after 3–
6 months, and followed by regular screening
every 6 months for 4 years (89).
Conclusion
Limbic encephalitis was once considered a rare
disorder with a very poor prognosis. While it was
thought that LE was always related to a neoplasm,
several reports have been published in recent years
describing different forms of LE that are associ-
ated with different antibodies. These forms of LE
are not always associated with ‘well-characterized
classical’ antibodies or a neoplasm. Current evi-
dence demonstrates that LE is an autoimmune dis-
order that consists of a spectrum of autoimmune
diseases. Therefore, LE may be unrelated to a neo-
plasm in many cases, and some cases of LE show
a good response to immunotherapy.
Acknowledgements
The authors have no acknowledgement to declare.
Conflict of interest
There are no conflicts of interest to be reported.
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