Clinical commentary
Epileptic Disord 2013; 15 (4): 455-60
Acute amnesia and seizures
in a young female
María Eugenia García García, Sergio Muñiz Castrillo,
Irene Garcia Morales, Daniela Di Capua Sacoto,
Alberto Marcos Dolado
Neurology Department, Hospital Clínico San Carlos, Madrid, Spain
Received February 14, 2013; Accepted August 28, 2013
ABSTRACT – Limbic encephalitis is a condition characterised by an acute or
sub-acute onset of memory disorder, associated with seizures and psychiatric manifestations. Investigations such as brain MRI usually reveal a high
intensity signal in the medial temporal lobe and cerebrospinal fluid analysis
shows mild pleocytosis and oligoclonal bands. It may occur in association
with cancer, infection, or as an isolated clinical condition, often accompanying autoimmune disorders. Immune-mediated limbic encephalitis is
now subclassified according to the presence and type of autoantibodies,
which has significant consequences regarding the effectiveness of treatment and prognosis. Glutamic acid decarboxylase (GAD) is an enzyme that
catalyses glutamic acid into gamma aminobutyric acid. Anti-GAD antibodies
are associated with different neurological and non-neurological disorders,
but only a few cases of limbic encephalitis associated with anti-GAD antibodies have been reported in the literature, most of them nonparaneoplastic. Here, we report the case of a young female patient
with a medical history of psoriasis who developed an acute onset and
chronic evolution of anterograde amnesia, associated with drug-resistant
epilepsy. Brain MRI showed hyperintensity in the medial temporal lobes and
the biochemical studies revealed intrathecal synthesis of anti-GAD antibodies. Screening tests for tumours were negative. Despite antiepileptic
drugs, intravenous immunoglobulins and immunosuppressive treatment,
the patient did not show clinical improvement and one year later, she continues to present refractory temporal epilepsy and cognitive deficits.
doi:10.1684/epd.2013.0607
Key words: limbic encephalitis, glutamic acid decarboxylase, paraneoplastic antibody, immunotherapy
Correspondence:
María Eugenia García García
Neurology Department,
Hospital Clínico San Carlos,
C/ Profesor Martín Lagos s/n,
28039 Madrid, Spain
<mariugarciagarcia@hotmail.com>
Epileptic Disord, Vol. 15, No. 4, December 2013
Limbic encephalitis (LE) is a clinicopathological entity characterised
by an acute to sub-acute onset
of seizures, short-term memory
deficits, and behavioural changes
or other psychiatric symptoms
(Vincent et al., 2011).
The pathogenesis of LE is related
to inflammation of the medial
temporal lobe and may be considered as infectious (herpes simplex virus [HSV] and human herpesvirus 6) paraneoplastic, or nonparaneoplastic, based on immunemediated processes (Matà et al.,
2008). Currently, the diagnosis of
most typical LEs may be obtained
through the information provided
455
M.E. García García, et al.
by the combination of clinical, EEG, MRI, and routine
CSF studies, and it is no longer necessary to demonstrate an inflammatory infiltrate in the temporal lobe
(Tüzün and Dalmau, 2007). Taking into account the type
of antibody found, autoimmune LE has been classified
into two broad categories. The first one, paraneoplastic LE, includes patients with antibodies (Abs) directed
against intracellular antigens such as Hu, Yo, CV2,
Ri, and Ma2. These Abs are associated with cytotoxic
T cell mechanisms, which are considered the main
pathogenic effectors. Due to these Abs being highly
specific to cancer, an exhaustive evaluation is necessary to exclude tumour.
The second category, non-paraneoplastic limbic
encephalitis (NPLE), includes patients with Abs
directed to cell membrane antigens such as
voltage-gated potassium channel (VGKC), N-MethylD-aspartate receptor (NMDAR), or the group referred
to as “novel neuropil Abs”. These patients have better
clinical and neuroimaging response to immunotherapy than patients with paraneoplastic LE, except
when the Abs are directed against intraneuronal
antigens, as is the case for anti-GAD Abs (Malter et al.,
2010). Association with other autoimmune diseases
(ocular myasthenia and psoriasis) is common (Bien
and Scheffer, 2011).
Anti-GAD Abs are a type of intracellular Ab directed
against GAD. They were initially described in a patient
affected by stiff-person syndrome (Solimena et al.,
1988) and subsequently they have been reported in
other diseases such as type 1 diabetes, chronic cerebellar ataxia, drug-resistant epilepsy, myoclonus, and
LE (Saiz et al., 2008). Anti-GAD Ab-associated LE is a
rare condition and no more than a few cases have
been reported in the literature (Marchiori et al., 2001;
Vincent et al., 2011).
We report a case of NPLE associated with anti-GAD Abs
with no response to immunotherapy and severe consequences, such as memory loss and refractory temporal
lobe epilepsy.
Case study
A 29-year-old female was admitted to the emergency
care unit with a three-hour history of disorientation
and short-term memory loss. Her medical history was
unremarkable except for mild cutaneous psoriasis.
Furthermore, her mother endured Hashimoto’s thyroiditis and vitiligo, while her brother and one of her
cousins presented with multiple sclerosis and another
cousin was epileptic.
On admission, the patient presented disorientation,
severe anterograde amnesia, and several episodes
of déjà-vu and déjà-connu feeling. No other abnor-
456
malities were found in the neurological or physical
examinations. The blood test and cranial CT were
normal. The CSF analysis showed mild pleocytosis
with normal levels of glucose and protein. Owing
to the main symptoms of the patient being partial
seizures and anterograde amnesia, a medial temporal
lobe involvement was suspected. At that time, intravenous acyclovir (600 mg/8 hours) was initiated to
treat a suspected case of herpetic encephalitis and
antiepileptic drugs for acute symptomatic seizures
(levetiracetam at 2,000 mg/day and carbamazepine at
600 mg/day).
One day later, and in spite of the treatment, the
patient continued to have partial seizures consisting
of abdominal aura, oral automatisms, and déjà-vu and
déjà-connu feeling, with or without impairment of
consciousness. These episodes lasted from several
seconds to 2-3 minutes. Several antiepileptic drugs
(levetiracetam at 3,500 mg/day, carbamazepine at
800 mg/day, and phenytoin at 300 mg/day) were
necessary in order to control the seizures.
Routine haematological and biochemical analyses
were normal. Serological testing for HIV, syphilis,
cytomegalovirus, HSV-1, and HSV-2 were negative.
A serological panel for autoimmune disorders was
negative including: anti-nuclear, anti-double-stranded
DNA, anti-SS-A, and anti-SS-B, anti-cardiolipin, antithyroglobulin, and anti-thyroid peroxidase antibodies.
The antibodies to intracellular antigens associated
with paraneoplastic encephalitis (anti-Hu, anti-Yo, antiamphipysin, anti-Ri, anti-Ma2, and anti-CV2) and those
against cell surface antigens (anti-NMDA, anti-AMPA,
anti-GABA, and anti-VGKC complex, including antiLGI 1 and CASPR2) were negative. The anti-GAD Abs
showed high levels, both in serum and CSF, with a
CSF/serum index of 7.8 indicating intrathecal synthesis.
Oligoclonal bands were positive.
Initial brain MRI was carried out 48 hours after the
onset of the symptoms and did not show any abnormalities. A second MRI investigation was performed 20
days later and axial T2 and fluid attenuation inversion
recovery (FLAIR) sequences revealed a hyperintense
signal in both of the mesial temporal lobes (milder in
the right temporal lobe), suggesting LE (figure 1). An
ovarian ultrasound, whole-body CT, and PET-FDG were
unremarkable. A 24-hour video-EEG showed interictal
epileptiform activity in both anterior temporal lobes,
but mainly in the left side. Several typical seizures were
recorded showing a left temporal ictal onset with subsequent propagation to the contralateral side several
seconds later (figure 2).
The neuropsychological assessment revealed temporal disorientation, a mild dysexecutive syndrome with
difficulties in planning and decision-making, and a
Mini Mental State Test score of 24/30. Digit span
Epileptic Disord, Vol. 15, No. 4, December 2013
Limbic encephalitis in a young female
Subsequent brain MRI revealed bilateral hippocampal
atrophy (figure 3) while control whole-body CT and
FDG-PET were normal.
Discussion
Figure 1. Axial FLAIR-weighted brain MRI showing a hyperintense signal in both medial temporal lobes.
forward was almost average and digit span backward
was deficient. Memory tests showed a severe anterograde memory deficit (immediate free recall after
distraction and delayed free recall) with no improvement after being given clues. The Rey Complex Figure
test also revealed a visual memory deficit.
The patient was treated with two cycles of intravenous
immunoglobulins (400 mg/kg/24 hours, five days per
cycle) resulting in a decrease in the seizure frequency.
Due to this improvement, we decided to continue with
immunoglobulins (one cycle) instead of using steroids
or plasmapheresis and to start immunosuppressive
treatment. The patient was discharged with intravenous rituximab (0.5 g/week), cyclophosphamide
(200 mg/day for five days), and AEDs (lacosamide
at 300 mg/day and levetiracetam at 3,500 mg/day).
Four days later, she returned to the emergency unit
with abdominal pain. Blood tests showed liver toxicity, therefore immunotherapy was discontinued, and
when the transaminases were normal, azathioprine
was initiated without any side effects. One year after
the onset of the clinical symptoms, and in spite of the
different treatments, the patient continues to present
with refractory epilepsy and cognitive deficits. The
neuropsychological reassessment showed only a slight
improvement in visual memory and executive dysfunction and no changes in verbal memory test results.
Epileptic Disord, Vol. 15, No. 4, December 2013
We present the case of a young female with anti-GAD
Ab-associated NPLE, which is a very uncommon type
of LE and only a few cases have been reported in the
literature.
LE is a well-recognised condition characterised by
subacute development of short-term memory loss,
behavioural change, and seizures involving the temporomedial lobes. The initial differential diagnosis
may be challenging due to the myriad of clinical
presentations and lack of symptom specificity. Viral
infections, autoimmune disorders, and paraneoplastic syndromes are some of the possible aetiologies.
As HSV encephalitis is a possible cause, most patients
with subacute LE are prescribed acyclovir. In the case
of herpetic encephalitis, the presence of fever, an
accelerated presentation of symptoms, a significant
mass effect on T2-weighted sequences, or evidence
of haemorrhagic encephalitis based on MRI or CSF are
more frequent (Gultekin et al., 2000).
Given that our patient was a young female and
after ruling out infectious aetiology, we considered
anti-NMDAR Ab-associated LE as the most probable
diagnosis. Nevertheless, immunological tests for Abs
directed against cell membrane antigens or against
intracellular antigens were negative except the antiGAD Abs, which showed high titres in both serum and
CSF. Because anti-GAD Abs in serum may be found in
other diseases (DM1 or other endocrine autoimmune
disorders), the demonstration of positive intrathecal
synthesis of these Abs could indicate that the GAD
autoimmunity is related to the neurological syndrome
(Liimatainen et al., 2010).
Although the pathogenic role is unclear, it has
been proposed that anti-GAD Abs could impair
GABAergic synaptic transmission by reducing GABA
synthesis and/or interfering with exocytosis of GABA,
leading to increased excitability and lower seizure
threshold (Vianello et al., 2002). However, the correlation between disease activity, serum Ab titres,
and immunotherapy in anti-GAD Ab-associated LE
is otherwise unknown. A reduction in Ab titre with
immunotherapy in some reported cases was paralleled
with disease stabilisation (Blanc et al., 2009) while in
others cases, the titres did not fall substantially (Malter
et al., 2010). Considering this, we decided not to determine levels of anti-GAD Abs again and guide treatment
based on the severity of the symptoms.
In 80% of the patients with LE, CSF studies show inflammatory changes with lymphocytic pleocytosis and
457
M.E. García García, et al.
Fp1 - AVG
F3 - AVG
C3 - AVG
P3 - AVG
O1 - AVG
F7 - AVG
T3 - AVG
T5 - AVG
Fp2 - AVG
F4 - AVG
C4 - AVG
P4 - AVG
O2 - AVG
F8 - AVG
T4 - AVG
T6 - AVG
Fpz - AVG
Fz - AVG
Cz - AVG
Pz - AVG
Oz - AVG
ECG2 - ECG1
200 uV
Fp1 - AVG
F3 - AVG
C3 - AVG
P3 - AVG
O1 - AVG
F7 - AVG
T3 - AVG
T5 - AVG
Fp2 - AVG
F4 - AVG
C4 - AVG
P4 - AVG
O2 - AVG
F8 - AVG
T4 - AVG
T6 - AVG
Fpz - AVG
Fz - AVG
Cz - AVG
Pz - AVG
Oz - AVG
ECG2 - ECG1
20 mm
Fp1 - AVG
F3 - AVG
C3 - AVG
P3 - AVG
O1 - AVG
F7 - AVG
T3 - AVG
T5 - AVG
Fp2 - AVG
F4 - AVG
C4 - AVG
P4 - AVG
O2 - AVG
F8 - AVG
T4 - AVG
T6 - AVG
Fpz - AVG
Fz - AVG
Cz - AVG
Pz - AVG
Oz - AVG
ECG2 - ECG1
20 mm
Figure 2. Ictal EEG recording showing a left temporal ictal onset, subsequently spreading to the contralateral side, concomitant with
abdominal aura, oral automatisms, and an impression of déjà-vu.
458
Epileptic Disord, Vol. 15, No. 4, December 2013
Limbic encephalitis in a young female
ciated with anti-VGKC Abs. The cause of therapeutic
failure is unclear and although one proposed hypothesis is the appearance of fixed morphological
changes on brain MRI, this is considered doubtful as
structural abnormalities on brain MRI have been found
in equal proportions in patients with either anti-GAD
Abs or anti-VGKC Abs (Malter et al., 2010).
Conclusion
Although anti-GAD Ab-associated LE is a rare condition, physicians should consider it in patients with
unexplained acute onset of seizures and amnesia in
the absence of data on infection and after ruling
out other more common autoimmune LE. Currently,
data suggest that it is a disease relatively resistant
to immunotherapy, with a chronic course and poor
outcome.
Disclosures.
This work was not supported by any grant and it has not been
previously presented or published in any form. The authors have
no conflicts of interest to declare.
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Figure 3. Coronal T2-weighted brain MRI (during follow-up)
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