Faciobrachial dystonic seizures precede Lgi1 antibody limbic ...

ORIGINAL ARTICLE
Faciobrachial Dystonic Seizures Precede
Lgi1 Antibody Limbic Encephalitis
Sarosh R. Irani, DPhil, 1 Andrew W. Michell, PhD, 2 Bethan Lang, PhD, 1 Philippa Pettingill, BSc, 1
Patrick Waters, PhD, 1 Michael R. Johnson, PhD, 3 Jonathan M. Schott, MD, 4
Richard J. E. Armstrong, PhD, 1,4 Alessandro S. Zagami, MD, 5 Andrew Bleasel, PhD, 6
Ernest R. Somerville, FRCAP, 5,7 ShelaghM.J.Smith,FRCP, 8 and Angela Vincent, FRCPath 1,9
Objective: To describe a distinctive seizure semiology that closely associates with voltage-gated potassium channel
(VGKC)-complex/Lgi1 antibodies and commonly precedes the onset of limbic encephalitis (LE).
Methods: Twenty-nine patients were identified by the authors (n ¼ 15) or referring clinicians (n ¼ 14). The temporal
progression of clinical features and serum sodium, brain magnetic resonance imaging (MRI), positron emission
tomography/single photon emission computed tomography, and VGKC-complex antibodies was studied.
Results: Videos and still images showed a distinctive adult-onset, frequent, brief dystonic seizure semiology that
predominantly affected the arm and ipsilateral face. We have termed these faciobrachial dystonic seizures (FBDS).
All patients tested during their illness had antibodies to VGKC complexes; the specific antigenic target was Lgi1 in
89%. Whereas 3 patients never developed LE, 20 of the remaining 26 (77%) experienced FBDS prior to the
development of the amnesia and confusion that characterize LE. During the prodrome of FBDS alone, patients had
normal sodium and brain MRIs, but electroencephalography demonstrated ictal epileptiform activity in 7 patients
(24%). Following development of LE, the patients often developed other seizure semiologies, including typical mesial
temporal lobe seizures. At this stage, investigations commonly showed hyponatremia and MRI hippocampal high T2
signal; functional brain imaging showed evidence of basal ganglia involvement in 5/8. Antiepileptic drugs (AEDs)
were generally ineffective and in 41% were associated with cutaneous reactions that were often severe. By contrast,
immunotherapies produced a clear, and often dramatic, reduction in FBDS frequency.
Interpretation: Recognition of FBDS should prompt testing for VGKC-complex/Lgi1 antibodies. AEDs often produce
adverse effects; treatment with immunotherapies may prevent the development of LE with its potential for cerebral
atrophy and cognitive impairment.
ANN NEUROL 2010;000:000–000
Limbic encephalitis (LE) associated with antibodies (Abs)
to the voltage-gated potassium channels (VGKCs) is a
well-established immunotherapy-responsive condition, usually
without an associated tumor. 1–3 TheAbsarenowrecognized
to bind to different components of VGKC complexes
such as leucine-rich glioma inactivated-1 (Lgi1) 3,4 or
contactin-associated protein 2 (Caspr2), 3 and we will refer
to them as VGKC-complex Abs. Similar Abs have also
been identified in around 10% of unselected patients with
otherwise unexplained and drug-resistant epilepsy 5,6 and in
4 patients with late onset epilepsy with an unusual semiology.
7,8 These 4 patients presented with very frequent, brief,
dystonic, seizure-like episodes.
Here, we describe 29 adult patients with this distinctive
antiepileptic drug (AED)-refractory, but immunotherapy-responsive,
seizure semiology, which we refer to as
faciobrachial dystonic seizures (FBDS). The majority of
patients subsequently developed a typical VGKC-complex
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22307
Received Sep 3, 2010, and in revised form Sep 27, 2010. Accepted for publication Oct 15, 2010.
Address correspondence to Dr Vincent, Nuffield Department of Clinical Neurosciences, West Wing, Level 6, John Radcliffe Hospital, Oxford, OX3 9DU,
United Kingdom. E-mail: angela.vincent@imm.ox.ac.uk
From the 1 Department of Clinical Neurology, Oxford University, Oxford, UK; 2 Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge
University, Cambridge, UK; 3 Centre for Neurosciences, Imperial College, London, UK; 4 Dementia Research Centre, National Hospital for Neurology and
Neurosurgery, Queen Square, London, UK; 5 Institute of Neurological Sciences and Clinical School, Prince of Wales Hospital and University of New South
Wales, Sydney, Australia; 6 Westmead Hospital, University of Sydney, Sydney, Australia; 7 Comprehensive Epilepsy Service, Prince of Wales Hospital, Sydney,
Australia; 8 Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; and 9 Institute of
Neurology, University College London, London, UK.
Additional supporting information can be found in the online version of this article.
VC 2010 American Neurological Association 1

ANNALS of Neurology
FIGURE 1: Faciobrachial dystonic seizures (FBDS). (A–E) Ictal stills of 5 patients included in this series are shown. The
ipsilateral face grimacing and arm posturing are visible in all cases. Videos are available, with the patients’ consent, in the
online supplementary data. (F) Percentage of patients with dystonic posturing of specified body part(s) during FBDS (white
bars) and whether FBDS remained strictly unilateral or sometimes alternated in an individual patient (black bars).
Ab-positive nonparaneoplastic LE. Because early treatment
of the LE syndrome may limit the duration or severity of the
illness and the degree of cognitive disability, recognition of
these seizures should offer a window of opportunity for early
treatment and possible prevention of permanent disability.
Patients and Methods
In total, 29 patients with FBDS are described. Referring neurologists
communicated with the authors verbally, via questionnaires
(as part of Irani et al, 3 a study of patients with VGKC-complex
Abs >400pM) and/or clinic letters. In addition, 26 of 29
patients/relatives subsequently underwent retrospective telephone/
personal interviews. Emphasis was placed on the nature of
the seizures, their timing in relation to development of LE, and
the treatment responses. Overall, 17 patients were seen by the
authors (n ¼ 6), referring neurologists (n ¼ 6), or general practitioners
(n ¼ 5) while FBDS alone were present. In another 6
patients, timing of the FBDS was obtained from the relatives. In
the remaining 6 patients, FBDS were recognized by the authors
(n ¼ 3) or the referring neurologists (n ¼ 3) during the LE.
The FBDS in 3 of these patients were described previously.
7 Other patients were included in studies of LE 23 or Mor-
van syndrome, 10 but their FBDS were not described in those
publications. Videos were available for review in 16 of the
patients.
VGKC-complex Abs were determined by routine immunoprecipitation
by patient serum immunoglobulin G (IgG) of
VGKC complexes from 125 I-adendrotoxin–labeled rabbit brain
extract (normal range

TABLE 1: Clinical Features of All Patients with
FBDS and Results of Investigation at Times When
No Cognitive Impairment Was Apparent
Characteristic Value
Clinical features of FBDS n ¼ 29
Age, median yr (range) 64 (36–83)
Sex, male:female 19:10
Number of faciobrachial
seizures per day,
median (range)
50 (6–360)
Alteration in consciousness 19 (66%) a
Falls 18 (62%)
Stimulus-triggered seizures 8 (28%); auditory
in 6, high
emotion in 2
Ictal vocalizations 7 (24%)
Investigation results at time of FBDS without
cognitive impairment
Serum sodium level 13 of 13 (100%)
>135mmol
Normal brain MRI 9 of 9 (100%) b
VGKC-complex antibodies, 1,962 (639–5,409)
mean pM (range)
c
Lgi1 antibody positive 3 of 4 (75%)
Caspr2 antibody positive 0 of 4 (0%)
Contactin 2 antibody positive 0 of 4 (0%)
In 6 of 29 patients, FBDS were first recognized after onset
of amnesia/confusion.
a
Altered awareness was observed in 66% of patients but not
seen during all seizures in any individual.
b
One of these MRIs was later judged to have subtle bilateral
high hippocampal signal by 2 neuroradiologists with an interest
in limbic encephalitis.
c
VGKC-complex antibody testing was only requested on 4
samples during the period of FBDS alone. Three of these
patients were given immunotherapies and never developed
amnesia; only 1 progressed to develop amnesia/confusion
(this case is also included in Table 2).
FBDS ¼ faciobrachial dystonic seizures; MRI ¼ magnetic resonance
imaging; VGKC ¼ voltage-gated potassium channel.
corresponding videos (Supporting Information Videos A–
E). The FBDS were very brief (usually

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FIGURE 2: Electroencephalography. (A) Interictal and (B) ictal electroencephalograms (EEGs) were recorded during a
faciobrachial dystonic seizure in a 39-year-old woman. On this occasion, ictal 2 to 4Hz spike-wave activity was noted of maximal
amplitude over the left frontotemporal region. The interictal EEG was normal. Ictal epileptiform activity was seen in 7 of 29 cases.
Bar 5 1second.
medial temporal lobe seizures (n ¼ 12), and simple partial
seizures with piloerection (n ¼ 1), which have all previously
been reported in VGKC-complex Ab-associated LE. 1,3,12,13
Investigations during or after the Period
of Limbic Encephalitis (n ¼ 26)
All 24 patients with active LE had serum VGKC-complex
Abs by radioimmunoprecipitation (see Table 2 and
Supporting Information Fig). Lgi1 Abs were present in
22 (2 of these also had Abs against Caspr2, and 1 also
against contactin-2; for further information about these
antigens, see Irani et al 3 ). We were unable to identify the
specific target in 2 VGKC-complex Ab-positive patients.
Two patients who were tested >4 years after the illness
were negative for VGKC-complex Abs, but 1 of these
was positive for Lgi1 Abs by the cell-based assay.
Interictal EEG abnormalities included diffuse mild
slowing (n ¼ 9), bilateral frontotemporal slowing (n ¼ 6), or
temporal sharp waves (n ¼ 2). In 9 patients, no EEG abnormalities
were detected. At this stage in the illness, hyponatremia
(

TABLE 2: Timing of FBDS, TLS, and LE from the 26 Patients Who Developed LE
Characteristic Value
Timings n ¼ 26 a (unless otherwise stated)
Patients with FBDS prior to amnesia, No. 20 (77%)
Days from FBDS onset to amnesia/confusion, median (range) 36 ( 150 to 730) a
Additional seizure semiologies Total ¼18 (70%); generalized tonic
clonic ¼ 13; complex partial ¼ 12
(all MTLS); simple partial ¼ 1
Patients with onset of TLS after onset of FBDS, No. 10 of 12 (83%)
Days from onset of FBDS to onset of temporal
lobe seizures, median (range)
Features associated with LE
12.5 ( 15 to 455)
Amnesia 26 (100%)
Confusion 23 (88%)
Hallucinations 9 (35%)
Sleep disturbance 7 (31%)
Depression 5 (19%)
Dysautonomia 4 (15%)
Pain 4 (15%)
Cerebellar features 2 (8%)
Interictal limb dystonia 1 (4%)
Investigations during LE n ¼ 26
VGKC-complex antibodies, mean pM (range) 2,281 (0–8,800) b
Lgi1antibody positive 23 (88%) b
Lgi1 and Caspr2 or contactin 2 antibodies 3 (12%)
No VGKC-complex–specific target determined 3 (12%)
Serum sodium 4 years after their illness had negative VGKC-complex antibodies as assessed by the routine radioimmunoprecipitation
assay (Lgi1 antibodies were detected by cell-based assay in 1 of these patients); 1 patient administered intravenous
immunoglobulins 3 weeks before antibody testing had low positive VGKC-complex antibody levels (238pM).
FBDS ¼ faciobrachial dystonic seizures; TLS ¼ temporal lobe seizures; LE¼ limbic encephalitis; MTLS ¼ mesial temporal lobe seizures
as defined clinically or by electroencephalography; VGKC ¼ voltage-gated potassium channel; MRI ¼ magnetic resonance imaging.
patient has developed a tumor after a median follow-up of
2.75 years (range, 0.5–8 years).
Response to Treatments in All 29 Patients
For each patient, a mean of 2.6 AEDs were administered
(range, 1–6). The effect on FBDS frequency was generally
poor, and only 4 patients showed a good (20–50%) or
excellent (>50%) reduction in FBDS frequency within 1
month of treatment (see Fig 3D). Significant side effects
were seen in 12 patients (41%) (see Fig 3D), with a localized
rash in 8 patients (carbamazepine in 4, phenytoin in 2,
Irani et al: Lgi1 Ab Limbic Encephalitis
lamotrigine in 1, and levetiracetam in 1) and erythroderma
in 2 patients (both phenytoin). In addition, 2 patients
developed Stevens-Johnson syndrome after receiving carbamazepine;
1 required intensive care unit admission.
By contrast, the FBDS response to immunotherapy
was excellent (see Fig 3). Two patients were not offered
immunotherapies, because they were originally seen before
widespread knowledge of VGKC-complex Abs. They progressed
from FBDS only to develop amnesia/confusion
with hyponatremia. With AEDs, but without immunotherapy,
these 2 patients made some symptomatic recovery
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FIGURE 3: Clinical and serological responses to immunotherapies. (A–C) voltage-gated potassium channel (VGKC)-complex
antibody (Ab) titers, seizures per day, and modified Rankin Scores (mRS, green in C) are shown in individual cases. The purple
asterisk indicates the onset of amnesia/confusion. Pred 5 prednisolone; IvIg 5 intravenous immunoglobulins; Px 5 plasma
exchange; Aza 5 azathioprine; AEDs 5 antiepileptic drugs. (D) The responses of the patients to AEDs (n 5 29) and/or
immunotherapies (ITs, n 5 27) and the adverse events attributed to these medications (blue bar) are illustrated.
at 4-year follow-up, although 1 case still experiences daily
FBDS. Of the other 27 patients, steroid therapy (oral or
intravenous) was used in 24 of 27, 14 received intravenous
immunoglobulin (IvIg), 13 were given plasma exchange,
and 1 received rituximab. Fourteen patients (52%) showed a
>50% reduction in seizure frequency, 12 (44%) showed
a 20 to 50% reduction, and only 1 case (4%) had

etrospectively from those who had already developed LE
with high levels of VGKC Abs (>400pM), and it is not
yet clear whether FBDS are 100% predictive of VGKC
Abs and whether, if untreated, FBDS inevitably proceed
to LE. One patient sampled after recovery was negative
for VGKC Abs but positive for Lgi1 Abs; this indicates
that not all Lgi1 is associated with VGKCs and that Abs to
Lgi1, and by inference to other associated proteins such as
Caspr2, may be found in patients who are not positive for
VGKC-complex Abs by the immunoprecipitation assay;
but that also requires further study. For the time being, we
continue to screen sera initially with the radioimmunoprecipitation
assay for VGKC-complex Abs, but assays for
Lgi1 and Caspr2 Abs are being developed for wider use.
The description here significantly extends the original
report of 3 patients with these seizurelike episodes, 7
and argues against a paroxysmal movement disorder. The
epileptic nature of FBDS is supported by the associated
brief loss of awareness and the highly stereotyped semiology,
although a coincident epileptiform change on scalp
EEG was only demonstrated in the minority. The ictal
onset zone has not been determined, but the high frequency
of brief attacks with a startle component and
trunk turning are suggestive of frontal lobe involvement.
14 However, ictal head version and predominant
nocturnal episodes, also typical of frontal lobe seizures,
were not apparent. Furthermore, typical temporal lobe
seizures have a longer duration, occur less frequently, and
commonly show a sustained (often >10 seconds) contra-
Irani et al: Lgi1 Ab Limbic Encephalitis
FIGURE 4: Examples of brain imaging in faciobrachial dystonic seizures (FBDS). (A–C) Typical medial temporal lobe high signal
from magnetic resonance imaging (MRI) is shown during periods of amnesia in 3 patients. Hippocampal atrophy was seen in
some cases at follow-up MRI (eg, change from C to D). Fluorodeoxyglucose-positron emission tomography (PET) and single
photon emission computed tomography (SPECT) images in 7 patients showed basal ganglia and temporal lobe abnormalities,
which included (E) temporal lobe PET bilateral hypermetabolism, (F) right hypometabolism, or (G) SPECT left hypoperfusion.
Three examples of metabolic changes within the basal ganglia are shown in H and I (bilateral hypermetabolism) and J (left
hypermetabolism). These images were acquired during the limbic encephalitis phase, when the patients were also having many
brief FBDS per hour, and it was difficult to identify whether they were directly related to the FBDS.
lateral arm dystonia with automatisms and absence of
face involvement. 15,16 Irrespective of the location of the
ictal onset zone, it seems likely that the ictal dystonia in
these patients reflects basal ganglia involvement. This is
supported by the surprisingly frequent demonstration of
abnormal basal ganglia metabolism on FDG-PET, which
has previously been shown in typical temporal lobe seizures
associated with upper limb dystonia. 17,18 The few
previous VGKC-complex Ab LE studies using PET have
not detected basal ganglia abnormalities. 12,19,20 Thus,
this may be a relatively specific feature within the subset
of patients with FBDS and may be related to their ictal
dystonia.
These seizures are likely to have been seen by
others. Descriptions of very frequent brief twitches affecting
the shoulder and ipsilateral face appear in recent case
reports of patients with seizures and VGKC-complex
Abs. 8,10,21,22 Moreover, given that around 20% of our 64
patients with VGKC-complex Ab LE 3 had FBDS, it is
interesting that 2 surveys of VGKC Ab-positive patients
noted a 22% and 40% frequency of myoclonus. 4,20
It is now clear that VGKC-complex Abs, at least in
patients with high titers, 3 are rarely directed against Kv1potassium
channels themselves, but bind to other proteins
that are tightly complexed with Kv1 subunits in
situ and in detergent extracts. 3,4 Almost all patients
sampled during their illness, before immunotherapies
began, had Abs directed against Lgi1, which is a secreted
protein that modulates neuronal morphology and
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ANNALS of Neurology
synaptic excitability. 23 Abs to Lgi1 are likely to induce similar
complex effects depending on where and how they act
and will require detailed investigations. One study has
found epileptiform activity in mouse hippocampal slices
exposedtopurifiedIgGfromapatientwithLEandLgi1
Abs, likely as a result of the Abs enhancing neurotransmitter
release at mossy fiber/CA3 pyramidal cell synapses, and
consistent with a reduction of VGKC expression or function.
24 Of relevance, Lgi1 mutant mice show increased seizure
susceptibility, with prominent dystonic, myoclonic,
and generalized seizures, 25–27 and Lgi1 mutations have
been discovered in humans with autosomal dominant lateral
temporal lobe epilepsy. 28–30 However, by contrast to
the patients we describe, patients with Lgi1 mutations often
have an excellent response to AEDs and infrequent
seizures, although 1 family has been described with a high
frequency of drug-resistant seizures. 31
Recognition of the very brief adult-onset, frequent
faciobrachial dystonic seizures should prompt testing for
VGKC-complex or Lgi1 Abs. Our data suggest that this
syndrome is unlikely to be associated with an underlying
tumor, although this should still be excluded, and that
caution should be used with trials of multiple AEDs,
which are frequently ineffective and associated with an
unusually high risk of adverse reactions. As, when present,
the characteristic FBDS often predate the onset of
amnesia/confusion, their recognition may provide a therapeutic
window of opportunity during which time
immunotherapies may prevent the LE and possibly the
potential sequelae of cerebral atrophy and cognitive
impairment. 1,3,11,32
Acknowledgments
S.R.I. was supported by the National Institute for Health
Research (NIHR), Department of Health, UK. A. W. M.
receives support from the Cambridge NIHR Biomedical
Research Centre. J.M.S. is a UK Higher Education
Funding Council for England Clinical Senior Lecturer.
Some of this work was undertaken at University College
London Hospitals/University College London, which
received a proportion of funding from the Department
of Health’s NIHR Biomedical Research Centres funding
scheme. B.L. receives funding from Epilepsy Research
UK. P.P. is supported by a Medical Research Council
Clinician Scientist Fellowship to Dr C. Buckley. P.W.
and A.V. receive support from the Oxford NIHR Biomedical
Research Centre. The Dementia Research Centre
is an Alzheimer’s Research Trust Coordinating Centre.
We thank Medical Illustration (John Radcliffe Hospital)
for help with the video editing, and particularly the
patients, their relatives/carers, and the following neuro-
logists for the clinical details: Drs M. Bogdanovic, D.
Hilton-Jones, K. Nithi, J. Palace, T. Andrews, O. C.
Cockerell, C. Everett, M. Husain, P. Jarman, M. Lunn,
P. Rudge, P. Maddison, J. Bowen, M. Lawden, J. Stone,
N. Lawn, K. Fuller, and W. Huynh.
Authorship
S.R.I. and A.W.M. are first authors. E.R.S., S.M.J.S., and
A.V. are senior authors.
Potential Conflicts of Interest
A.V. and the Department of Clinical Neurology in Oxford
receive royalties and payments for Ab assays. A.V. is the
inventor on patent application WO/2010/046716 entitled
‘‘Neurological Autoimmune Disorders.’’ The patent has
been licensed to Euroimmun AG for the development of
assays for Lgi1 and other VGKC-complex Abs. A.V. has
done paid consultancy for Athena Diagnostics, and is
employed by Oxford University and University College
London. A.V.B.L. has a grant pending from Wellcome
Trust and received payment for a lecture from Euroimmune.
A.V., B.L., P.W., and S.R.I. may receive royalties
for testing of VGKC complex Abs.
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