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Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.

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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 Shelagh M. J. Smith, FRCP,8 and Angela Vincent, FRCPath1,9
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 2011;69:892–900
imbic 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 The Abs are now recognized 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 epilepsy5,6 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 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:
From the 1Department of Clinical Neurology, Oxford University, Oxford, UK; 2Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge
University, Cambridge, UK; 3Centre for Neurosciences, Imperial College, London, UK; 4Dementia Research Centre, National Hospital for Neurology and
Neurosurgery, Queen Square, London, UK; 5Institute of Neurological Sciences and Clinical School, Prince of Wales Hospital and University of New South
Wales, Sydney, Australia; 6Westmead Hospital, University of Sydney, Sydney, Australia; 7Comprehensive Epilepsy Service, Prince of Wales Hospital, Sydney,
Australia; 8Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; and 9Institute of
Neurology, University College London, London, UK.
Additional supporting information can be found in the online version of this article.
C 2011 American Neurological Association
892 V
Irani et al: Lgi1 Ab Limbic Encephalitis
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 LE23 or Mor-
May 2011
van syndrome,10 but their FBDS were not described in those
publications. Videos were available for review in 16 of the
VGKC-complex Abs were determined by routine immunoprecipitation by patient serum immunoglobulin G (IgG) of
VGKC complexes from 125I-adendrotoxin–labeled rabbit brain
extract (normal range <100pM, as in Vincent et al1). Cellbased assays for Lgi1, Caspr2, and contactin-2 Abs used human
embryonic kidney 293 cells transfected with cDNAs encoding
membrane-anchored Lgi1, Caspr2, or contactin-2, which were
incubated with sera (1:20-1:100). The cells were washed, fixed,
incubated with fluorescent secondary Abs, and visualized under
the fluorescence microscope (for methods see Irani et al3).
A Distinctive FBDS Semiology before and
during Lgi1 Ab Limbic Encephalitis
Twenty-nine patients were identified with FBDS either
during the prodromal stage or during LE. The age range
was from 36 to 83 years (median, 64 years), with a male:female ratio of around 2:1. The distinctive FBDS are
shown in 5 illustrative still images (Fig 1A–E) and
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TABLE 1: Clinical Features of All Patients with
FBDS and Results of Investigation at Times When
No Cognitive Impairment Was Apparent
Clinical features of FBDS
n ¼ 29
Age, median yr (range)
64 (36–83)
Sex, male:female
Number of faciobrachial
seizures per day,
median (range)
50 (6–360)
Alteration in consciousness
19 (66%)a
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%)
Normal brain MRI
9 of 9 (100%)b
VGKC-complex antibodies,
mean pM (range)
1,962 (639–5,409)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.
Altered awareness was observed in 66% of patients but not
seen during all seizures in any individual.
One of these MRIs was later judged to have subtle bilateral
high hippocampal signal by 2 neuroradiologists with an interest in limbic encephalitis.
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 <3 seconds) and very
frequent, occurring at a median of 50 per day at their peak
(Table 1). FBDS always involved the arm and commonly
also the ipsilateral face (76%) and leg (34%). The trunk
was involved in 28% (see Fig 1F). Hand involvement
caused many patients to drop items within their grasp. In
69% of patients, FBDS could involve either side but were
always unilateral on any occasion. Twenty-four percent
produced vocalizations at the start of the FBDS. Ictal loss
of awareness was noted in a minority of seizures by either
the patient or carer/relative in 66% of patients. In 28% of
patients, the FBDS could be triggered by auditory stimuli
or high emotion. In addition, unexplained drop attacks,
often with backward falls, were reported by 62% of subjects unrelated to leg ictal dystonia. Overnight recordings,
when performed, identified some FBDS during sleep. No
patient had a family history of similar episodes.
Fifteen of the 64 patients (23%) with LE and
VGKC-complex Abs in our recent study had FBDS.3
Investigations When FBDS Alone Were Present
During the period of FBDS without cognitive impairment (see Table 1), both serum sodium levels (13 of 13
patients) and brain magnetic resonance imaging (MRI)
were normal (9 of 9 patients). The FBDS were predictive
of VGKC-complex Abs in each of the 4 patients with
FBDS who were identified by the authors and tested at
this stage; Lgi1 was identified as the specific antigenic
target within the VGKC complex in 3 of these. Electroencephalography (EEG) demonstrated ictal epileptiform
abnormalities in 7 patients with a frontotemporal (n ¼
2, for example Fig 2), frontal (n ¼ 2), or temporal (n ¼
3) focus. Two patients also developed temporal lobe seizures as well as FBDS before the onset of the amnesia.
FBDS as a Clinically Identifiable Prodrome
to Limbic Encephalitis
Three patients (10%) never experienced FBDS. Twenty
of the other 26 (77%) patients developed FBDS before
the onset of amnesia and confusion, with a median lag
of 36 days (Table 2). There were no clinically identifiable
triggers for the apparent switch from a period of FBDS
alone to the development of (often dense) amnesia. In
the remaining 6 patients, the seizures were only recognized during LE, after the onset of amnesia.
The majority of patients had FBDS that increased
in frequency until they reached a maximum at around the
time of onset of LE (shown later in Fig 3A–C). During
the period of isolated seizures, most patients were able to
perform daily activities independently. At the onset of
memory impairment/confusion, clear functional disability
was evident (see modified Rankin Scale, Fig 3C).
The LE was similar to that described previously (see
Table 2),1,3,11 with amnesia (100%), confusion (88%), hallucinations (35%) and sleep disturbances (31%), including
rapid eye movement sleep behavior disorder, hypersomnolence, and insomnia. One case had persistent foot dystonia
(see Supporting Information Video D). Principally during
the period of LE, 18 of 26 (70%) patients also developed
other nondystonic seizure types, including generalized
tonic-clonic seizures (n ¼ 13), typical complex partial
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Irani et al: Lgi1 Ab Limbic Encephalitis
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 1 second.
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 al3). 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 (<135mmol) was seen in 23 (88%) patients.
Twenty-five patients had cerebrospinal fluid (CSF)
sampled. Analysis of white cells, protein, glucose, and
CSF unmatched oligoclonal bands were unremarkable
in 20 (80%). Five patients had a mild lymphocytosis (6–
11 cells/mm3), and/or modestly elevated protein (0.63–
1.1g/l). All patients were found to be negative for oncoMay 2011
neural Abs by immunoblotting (ravo kit, ravo Diagnostika, Freiburg, Germany).
Imaging during Limbic Encephalitis
During the period of LE, 12 of 26 patients had normal brain
MRI. Of the other 14 patients, 10 showed bilateral (an
example shown in Fig 4A-C) and 3 showed unilateral
medial temporal lobe high T2 signal change, and 1 showed
high signal in the right caudate/putamen. Four patients, all
with initial bilateral high signal, developed hippocampal atrophy (after median follow-up of 8 months [range, 6–10
months], as illustrated in Fig 4C and D), and the individual
with caudate high signal had caudate atrophy at 3 months.
Eight patients underwent fluorodeoxyglucose (FDG)positron emission tomography (PET), and 2 underwent single photon emission computed tomography (SPECT) (1 had
both investigations). Four of the PET/SPECTs were abnormal at times when the MRI was normal. PET in 6 of 8
patients showed altered glucose metabolism in the temporal
region (increased in 4 and decreased in 2, Fig 4E and F).
More surprisingly, 5 of 8 patients showed abnormal glucose
metabolism in the basal ganglia (4 hypermetabolic and 1
hypometabolic, see Fig 4H-J for examples). The 2 patients
who underwent SPECT showed hypometabolic and hyperperfusion in the temporal lobe (hypoperfusion shown in
Fig 4G). Whole body computed tomography and/or PET
were unremarkable in the 28 patients tested. To date, no
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TABLE 2: Timing of FBDS, TLS, and LE from the 26 Patients Who Developed LE
n ¼ 26a (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)
12.5 (15 to 455)
Features associated with LE
26 (100%)
23 (88%)
9 (35%)
Sleep disturbance
7 (31%)
5 (19%)
4 (15%)
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 <135mmol
Normal brain MRI
23 (88%)
12 (46%)
Three other patients never developed amnesia or confusion and had normal MRI throughout their illness.
Two patients tested >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,
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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Irani et al: Lgi1 Ab Limbic Encephalitis
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
<20% reduction over the first month of administration (see
Fig 3D). Usually, there was an excellent correlation between
seizure reduction and fall in VGKC-complex Abs, often after
unsuccessful AED therapies (see Fig 3A–C), although this
was not universal. Adverse events with immunotherapies
were uncommon, although a fatal infection and a steroidinduced psychosis occurred in 2 patients during their LE.
In 4 of 6 patients given IvIg before prednisolone, the IvIg
was considered ineffective. The 3 patients with FBDS who
did not develop amnesia were not administered immunotherapy earlier than those who did develop amnesia (data not
Relapses are not common in VGKC-complex
Ab-associated LE. However, 4 of these patients relapsed
May 2011
after weaning prednisolone from 50 to 60mg down to
30mg over 3 months (n ¼ 3) or after IvIg only (n ¼ 1).
The FBDS were highly responsive to reinstitution of
prednisolone (example in Fig 3B).
The distinctive adult-onset, high-frequency, very brief,
AED-resistant FBDS described in this international
cohort of patients have a very unusual seizure semiology,
but appear to be closely associated with raised serum
VGKC-complex Abs, almost always of the Lgi1 subtype,
and a high probability of development of nonparaneoplastic LE. Recognition of these brief seizures, and their association with VGKC-complex/Lgi1 Abs, should prompt consideration of immunotherapies and may prevent the onset
and long-term consequences of limbic encephalitis.
The semiology is distinctive and was predictive of
VGKC-complex Abs in the 4 patients recently seen
by the authors, 3 of whom were treated and did not
develop LE. However, most of the patients were identified
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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.
retrospectively 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) contra898
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
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 LE3 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
Volume 69, No. 5
Irani et al: Lgi1 Ab Limbic Encephalitis
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
exposed to purified IgG from a patient with LE and Lgi1
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
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.
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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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
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