Dilan Athauda

E De Pablo-Fernandez

Kurz

M Koide

R Arnautovíc

R S Delamont

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Case Report
High Grade Glioma Mimicking Voltage Gated Potassium
Channel Complex Associated Antibody Limbic Encephalitis
Dilan Athauda,1 R. S. Delamont,2 and E. De Pablo-Fernandez1
1 Neurology Department, Darent Valley Hospital, Darenth Wood Road, Dartford & Gravesham NHS Trust, Dartford DA2 8DA, UK
2Neurology Department, Kings College Hospital, London SE5 3RS, UK
Correspondence should be addressed to Dilan Athauda; dilanathauda@doctors.org.uk
Received 30 October 2013; Accepted 19 December 2013; Published 12 January 2014
Academic Editors: K. Arnautovı́c, R. Koide, and M. Kurz
Copyright © 2014 Dilan Athauda et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Though raised titres of voltage gated potassium channel (VGKC) complex antibodies have been occasionally associated with
extracranial tumours, mainly presenting asMorvan’s Syndrome or neuromyotonia, they have not yet been reported to be associated
with an intracranial malignancy. This is especially important as misdiagnosis of these conditions and delay of the appropriate
treatment can have important prognostic implications. We describe a patient with a high grade glioma presenting with clinical,
radiological, and serological features consistent with the diagnosis of VGKC antibody associated limbic encephalitis (LE). This is
the first association between a primary brain tumour and high titre of VGKC complex antibodies. Clinicoradiological progression
despite effective immunosuppressive treatment should prompt clinicians to look for alternative diagnoses. Further studies to
elucidate a possible association between VGKC complex and other surface antigen antibodies with primary brain tumours should
be carried out.
1. Introduction
VGKC complex antibody associated LE is considered a
nonparaneoplastic, immunoresponsive condition typically
presenting subacutely with memory loss, confusion, seizures,
and behavioural changes (though visual hallucinations and
psychosis have also been reported) [1]. Approximately 60%
of patients have high signal changes unilaterally or bilaterally
in the medial temporal lobes on FLAIR and T2 weighted
MR imaging [1]. Serum hyponatremia, another diagnosti-
cally useful feature, is present in around 60% of patients
[2]. The diagnosis is usually made with a combination of
clinicoradiological findings and the presence of high titre
VGKC complex antibodies (normal reference range is <100
picomolar (pM)). Though it is uncertain at what level a
titre of antibody becomes significant, previous studies have
suggested titres greater than 400 pM as “high” and levels
above this seem to be more associated with CNS disease
[1, 2]. Though the phenotype of VGKC complex antibody
associated LE is continually expanding, other important
conditions can often mimic the initial presentation and
alternative diagnoses should be considered in atypical cases.
Intracranialmalignancy is an important differential diagnosis
and can present with similar symptoms; however, there
have been no reports of elevated levels of VGKC complex
antibodies being found in association with an intracranial
malignancy. We report a case of a patient presenting initially
with characteristic features of VGKC complex associated
LE with elevated levels of VGKC antibodies in his serum
who, despite treatment with immunosuppression, clinically
deteriorated and was subsequently discovered to have a high
grade glioma.
2. Case Presentation
An 86-year-old man complaining of 1 week of lethargy and
irritability was found unconscious at home and taken to the
emergency department whereupon he had two generalised
tonic clonic (GTC) seizures. He had no past medical history
and was on no medication. There was no history of recent
illness, cognitive decline or travel.
On examination he had a temperature of 38∘C and had a
GCS of 10. Though his consciousness improved over the next
Hindawi Publishing Corporation
Case Reports in Neurological Medicine
Volume 2014, Article ID 458790, 4 pages
http://dx.doi.org/10.1155/2014/458790
2 Case Reports in Neurological Medicine
few hours he remained confused and verbally and physically
aggressive. Repeated neurological examination was normal.
He was started on ceftazidime, amoxicillin, and acyclovir for
a possible CNS infection.
Extensive blood tests including full blood count, elec-
trolytes, liver and thyroid function tests, CRP, ESR, ANA,
ANCA, anticardiolipin antibodies, vitamin B12, folate, ACE,
protein electrophoresis, Borrelia, and HIV serologies were
negative or normal. His initial brain CT scanwithout contrast
was normal and CSF analysis revealed a white cell count of 35
(30% lymphocytes), with normal protein and glucose, culture
and viral PCR. MRI brain showed high signal changes on T2
weighted images involving the right insula, parahippocampal
gyrus, hippocampus, and splenium of the corpus callosum
suggestive of limbic encephalitis (Figures 1(a) and 1(b)).
A paraneoplastic screen (for anti-Yo, anti-Hu, and anti-
Ri antibodies) was negative and CT chest, abdomen, and
pelvis did not identify any occult malignancy. His confusion
and behavioural abnormalities resolved a few days after
admission and he was discharged after completing 14 days of
treatment with intravenous acyclovir. An extended autoim-
mune screen was sent including voltage gated potassium
channel (VGKC) complex antibodies, N-methyl-D-aspartate
receptor (NMDAr), and glutamic acid decarboxylase (GAD)
antibodies.
Unfortunately, he was readmitted 15 days later with
fluctuating disorientation, aggressiveness, and complex visual
hallucinations. Neurological examination was unremarkable
including cognitive assessment (Mini-Mental State Examina-
tion score was 30/30). His extended immune screen returned
which was negative for NMDAr and GAD antibodies, but
he had a raised VGKC complex antibody titre of 437 pico-
molar (pM). Repeat MRI brain scan 5 weeks after initial
presentation showed persistent high T2 signal changes of the
right medial temporal lobe structures previously described
with new involvement of the right precuneus (Figures 1(c)
and 1(d)). A diagnosis of VGKC complex antibody limbic
encephalitis (LE) was made. The patient declined treatment
with plasmapheresis or intravenous immunoglobulins and
was started on oral prednisolone 40mg a day. He improved
and was discharged. Repeat serum testing sent for VGKC
antibodies 3 weeks after starting the steroids was now
undetectable.
He presented 25 days later with 3 generalised tonic
clonic seizures and gradual progressive cognitive decline.
On examination, he was disorientated, had mild left sided
hemiparesis, and was neglecting the left side. He underwent
a course of plasmapheresis for 5 days, but a repeat MRI
brain scan following the plasmapheresis showed aggressive
progression of the previous lesions, with new nodular foci
within the medial aspect of the right temporoparietal lobes
with mass effect, heterogeneous contrast enhancement, and
areas of necrosis more in keeping with a high grade glioma
than LE (Figures 1(e) and 1(f)).
Following review by a neurooncology multidisciplinary
team he was offered supportive care only. He subsequently
had a gradual deterioration of his condition with progressive
cognitive decline and general physical decline and occasional
generalized tonic seizures despite antiepileptic treatment.
3. Discussion
Our patient initially illustrated many of the classic clinical,
radiological, and serological features of VGKC antibody
complex LE: he had well-recognised symptoms of seizures,
amnesia, and personality change. He had unilateral high
signal changes in his medial temporal lobe on MRI T2
weighted imaging which is usually observed in such cases.
We also detected elevated levels of VGKC antibody in his
serum of 407 pM—usually undetectable. The suggested
treatment for VGKC complex associated LE is early
aggressive immunotherapies with a combination of high dose
steroids, plasma exchange, or intravenous immunoglobulins,
with a concurrent rapid fall of the antibody level with
effective therapy [3]. Typically prognosis is generally good
though radiological changes may take longer to improve,
with subsequent persistent temporomesial atrophy as
a common finding [1].
Despite the subsequent immunosuppressive therapies,
the patient developed progressive cognitive decline, visual
hallucinations, and left sided hemiparesis, with spreading
of the MRI changes involving new areas including the
medial parietal lobe and nodular enhancement—which is
atypical for VGKC associated LE. Though no histological
confirmation is available, repeat brainMRI 8months after the
initial presentation showed radiological findings in keeping
with an aggressive, high grade glioma.
The spectrum of conditions associated with VGKC com-
plex antibodies is in continuous expansion and raised titres
of VGKC complex antibodies have also been reported in
other clinical syndromes includingMorvan’s Syndrome, neu-
romyotonia, and faciobrachial dystonic seizures [1]. Though
neuromyotonia and Morvan’s Syndrome can be associated
with tumours, particularly thymomas, they are uncommon
in VGKC complex antibody LE and it is thought to be a
nonparaneoplastic condition.
A study to identify possible neurological and oncological
associations in patients with raised VGKC antibodies found
that 33% of patients identified with raised VGKC antibodies
had active tumours, mostly lung carcinomas, but also 3
haematological malignancies and 1 thymoma [4], though no
distinction between different clinical syndromes was made.
However, a more recent study that identified the clinical
phenotype and tumour association of 96 patients with VGKC
antibody titres >400 pM found that the majority—66%—
had LE, and of these, none were associated with underlying
tumours. Of the six patients identified in the studywith active
tumours all had either Morvan’s Syndrome or neuromy-
otonia, 5 had thymomas and one patient had endometrial
adenocarcinoma [5].
To our knowledge, no intracranial malignancy, either
primary or metastases, has been associated with raised
VGKC antibodies and this is the first case reporting this
association. This is extremely important as misdiagnosis of
these conditions and delay of the appropriate treatment could
have important prognostic implications.
It is impossible to ascertain that if an early diagnosis
in our case could have made an impact on his prognosis
though, as once the diagnosis was made, the patient was
Case Reports in Neurological Medicine 3
(a) (b)
(c) (d)
(e) (f)
Figure 1: (a, b) Coronal T2 weighted FLAIR brainMRI showing high signal changes involvingmedial temporal areas. (c, d) T1 weightedMRI
10 weeks later showing enhancement of the previous lesions after gadolinium administration with extension posterior to the occipital lobe.
(e, f) T1 weighted brain MRI showing rapid progression of the initial lesion with marked mass effect, areas of necrosis, and heterogeneous
contrast enhancement consistent with a high grade glioma.
only suitable for supportive care. This case illustrates that
clinicians treating patients with a presumed diagnosis of
VGKC complex antibody LE must maintain a high index of
suspicion, even in the presence of high levels of antibodies,
and should consider appropriate neuroimaging and alter-
native diagnoses if the patient fails to respond to effective
immunotherapy. It also highlights the difficulty of diagnosing
gliomas in the early stages despite MR imaging. Further
studies to investigate a possible association between VGKC
complex and other surface antigen antibodies with primary
brain tumours should be carried out in order to better
elucidate their role in these conditions.
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
4 Case Reports in Neurological Medicine
Acknowledgments
Many thanks are due to Angela Vincent who provided a
paper review and to the Nuffield Department of Clinical
Sciences, John Radcliffe Hospital, Oxford, for analysis of the
antibodies.
References
[1] L. Zuliani, F. Graus, B. Giometto, C. Bien, and A. Vincent,
“Central nervous system neuronal surface antibody associated
syndromes: Review and guidelines for recognition,” Journal of
Neurology, Neurosurgery and Psychiatry, vol. 83, no. 6, pp. 638–
645, 2012.
[2] A. Vincent, C. Buckley, J. M. Schott et al., “Potassium
channel antibody-associated encephalopathy: a potentially
immunotherapy-responsive form of limbic encephalitis,” Brain,
vol. 127, no. 3, pp. 701–712, 2004.
[3] S. A. B. Ahmad, H. A. Archer, C. M. Rice, S. Gerhand, M.
Bradley, and A.Wilkins, “Seronegative limbic encephalitis: case
report, literature review and proposed treatment algorithm,”
Practical Neurology, vol. 11, no. 6, pp. 355–361, 2011.
[4] K. M. Tan, V. A. Lennon, C. J. Klein, B. F. Boeve, and S. J.
Pittock, “Clinical spectrum of voltage-gated potassium channel
autoimmunity,” Neurology, vol. 70, no. 20, pp. 1883–1890, 2008.
[5] S. R. Irani, S. Alexander, P. Waters et al., “Antibodies to Kv1
potassium channel-complex proteins leucine-rich, glioma inac-
tivated 1 protein and contactin-associated protein-2 in limbic
encephalitis,Morvan’s syndrome and acquired neuromyotonia,”
Brain, vol. 133, no. 9, pp. 2734–2748, 2010.
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Case Report High Grade Glioma Mimicking Voltage Gated Potassium Channel Complex Associated Antibody Limbic Encephalitis

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Case Report High Grade Glioma Mimicking Voltage Gated Potassium Channel Complex Associated Antibody Limbic Encephalitis

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