Potassium Channel Antibody–Associated Encephalopathy Presenting With a Frontotemporal Dementia–like Syndrome

Potassium Channel Antibody–Associated Encephalopathy Presenting With a Frontotemporal Dementia–like Syndrome

OBSERVATION
Potassium Channel Antibody–Associated
Encephalopathy Presenting With
a Frontotemporal Dementia–like Syndrome
Andrew McKeon, MB, MRCPI; Michael Marnane, MB, MRCPI; Martin O’Connell, FFR, RCSI;
John P. Stack, FFR, RCSI; Peter J. Kelly, MD, FRCPI; Timothy Lynch, MD, FRCPI
Objective: To describe a patient who presented with
features suggestive of frontotemporal dementia (FTD) but
with some atypical findings and antibodies to neuronal
voltage-gated potassium channels (VGKC-Abs).
Design: Case report.
Setting: Mater Misericordiae University Hospital, Dublin, Ireland.
Results: An 82-year-old man presented with progressive
changes in personality, social conduct, and executive function with preservation of memory, deteriorating from baseline to requiring acute hospitalization within 6 months.
Transient deterioration (episodic speech arrest) with spontaneous recovery, atypical for frontotemporal dementia, was
A
Author Affiliations:
Departments of Neurology
(Drs McKeon, Marnane, Kelly,
and Lynch) and Radiology
(Messrs O’Connell and Stack),
Mater Misericordiae University
Hospital, Dublin, Ireland.
observed. The patient had an elevated VGKC-Ab titer (2624
pM [normal range, ⬍100 pM]), elevated protein levels in
cerebrospinal fluid, and a negative evaluation for malignancy. Magnetic resonance imaging of brain was normal
but [18F]-fluorodeoxyglucose positron emission tomographic imaging revealed bifrontal hypometabolism. A
marked and sustained improvement with steroid therapy
was observed.
Conclusion: Workup for a potentially reversible autoimmune-mediated encephalopathy, including a VGKC-Ab
titer, should be considered in patients presenting with
rapidly progressive behavioral and cognitive decline.
Arch Neurol. 2007;64(10):1528-1530
NTIBODIES REACTIVE WITH
neuronal voltage-gated potassium channels (VGKCAbs) were initially described in acquired
neuromyotonia and other disorders characterized by peripheral nerve hyperexcitability.1,2 The VGKC-Abs have also
emerged as a serologic marker of potentially reversible autoimmune encephalopathies.3-5 To date, they have usually been
reported as a nonparaneoplastic disorder
indistinguishable from paraneoplastic limbic encephalitis, characterized by amnesia, delirium, and seizures, termed VGKCAb–associated encephalopathy. 3 These
patients usually have hyponatremia due to
syndrome of inappropriate secretion antidiuretic hormone (SIADH) and mesial
temporal signal changes on magnetic resonance imaging (MRI). The VGKC-Abs
have also been associated with Morvan
syndrome6 and rapid eye movement sleep
behavior disorder7 and, in some patients,
with epilepsy.8 However, progressive loss
of social comportment, language, and executive function has not been described in
association with autoimmune encephalopathies but is usually attributed to frontotemporal dementia (FTD), a neurode-
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1528
generative disease primarily affecting the
frontal and anterior temporal lobes. 9
Herein we describe a patient who presented with rapidly progressing behavioral changes and loss of executive function, but with a fluctuating course, who
was found to have high serum VGKC-Ab
titers and improvement of the syndrome
with immunotherapy.
REPORT OF A CASE
An 82-year-old man presented to the emergency department of our hospital with a
6-month history of progressive personality change characterized by increasing irritability, aggressive outbursts, poor selfcare, repetitive facial grimacing, and
diminished insight. Because of his rapid
decline from a normal cognitive baseline
to loss of functional independence, acute
hospitalization of the patient was arranged. Examination revealed disinhibition, intermittent speech arrest, and
stereotyped facial movements. The MiniMental State Examination (MMSE) score
was 27 of 30 (with mild deficits in orientation and calculation only and 3/3 on testing recall). His Frontal Assessment Bat-
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tery score (FAB) was 11 of 18 with deficits in mental
flexibility, motor programming, and inhibitory control.
The FAB is a bedside cognitive and behavioral battery
(maximum possible score, 18) consisting of 6 subtests
assessing conceptualization, mental flexibility, motor programming, resistance to interference, inhibitory control, and environmental autonomy; subjects without frontal lobe dysfunction typically score 17 or 18. 10 A
neurodegenerative process causing frontal lobe dysfunction was initially suspected. Magnetic resonance imaging
showed age-appropriate generalized atrophy only. Electroencephalography demonstrated continuous frontal
slow-wave activity but no epileptiform changes despite
ongoing facial movements. A facial electromyogram demonstrated no evidence of peripheral nerve hyperexcitability. Cerebrospinal fluid (CSF) was acellular but with
an elevated protein level of 1316 mg/L. Serum VGKC-Ab
titer was markedly elevated at 2624 pM (normal range,
⬍ 100 pM). Blood work revealed SIADH with a serum
sodium level of 123 mEq/L (the conversion to millimoles per liter is 1-to-1), and subsequent testing did not
reveal any alternative cause for this. Test results for paraneoplastic and thyroid autoantibodies and vasculitic markers were negative. An [18F]-fluorodeoxyglucose positron emission tomographic (FDG-PET) image of the brain
(Figure) demonstrated bilateral frontal hypometabolism. Whole-body FDG-PET was negative for malignancy. A diagnosis of VGKC-Ab–associated encephalopathy with a disinhibited, dysexecutive presentation was
made. Treatment consisted of prednisolone 70 mg (1 mg/
kg) daily and subsequent taper. A treatment benefit was
noted after 3 weeks, and within 6 weeks the behavioral
syndrome, aphasia, and facial grimacing had improved
to the extent that the patient was discharged to his own
home, where further improvements took place. After 6
months of treatment, the MMSE score was 29 of 30, FAB
score was 17 of 18, SIADH had resolved, and VGKC-Ab
titer had fallen into the normal range. At this point, the
patient was taking 20-mg prednisolone by mouth daily
and had resumed all his premorbid self-care, household
activities, and outdoors activities, including going to the
grocery store and to church.
COMMENT
Our findings broaden the phenotypic spectrum of central nervous system disease associated with VGKC-Abs
to include patients with deterioration in social conduct
and personality change (cardinal features of FTD9) along
with other features commonly seen in FTD, such as executive dysfunction, decline in self-care, stereotyped behavior, and altered speech output but with relative preservation of memory.11 The therapeutic implications of our
findings are important because the patient in this report
showed reversibility with immunosuppression.
The patient described had a disinhibited and dysexecutive state and repetitive stereotyped facial movements. Personality change was an important presenting
feature, and unlike in limbic encephalitis, memory was
preserved. The rapid progression from a normal baseline over months, rather than an insidious course over
Figure. [18F]-fluorodeoxyglucose high-resolution 3-dimensional positron
emission tomographic brain image. Axial brain image demonstrates bilateral
frontal hypometabolism.
years, and the fluctuating speech disorder were key clinical features atypical for FTD that supported testing for
an autoimmune etiology, which included VGKC-Abs. The
repetitive facial grimacing seen in our patient likely
represented a stereotypy. Such patterned repetitive, purposeless movements are often seen in disorders of frontal function such as FTD.12 Peripheral nerve hyperexcitability and seizures were also considered, but a facial
electromyogram did not demonstrate any neuromyotonic discharges, and the electroencephalograph, captured during these movements, was normal. Although
neuropsychometric testing pretreatment and posttreatment is not readily available at our institution, the MMSE
and FAB scores assisted in demonstrating the domains
of cognition affected and monitoring response to therapy,
although we do acknowledge that test-retest reliability
has not been established for the FAB.10 Eighty percent
of patients with VGKC-Ab–associated encephalopathy
have been reported to have SIADH, and it typically resolves in tandem with falling VGKC-Ab titers when immunotherapy is undertaken.3
Magnetic resonance imaging is typically abnormal in
VGKC-Ab–associated limbic encephalitis with high signal seen in mesial temporal cortices on T2 or fluidattenuated inversion recovery sequences.3-5,13 Our patient had a normal MRI scan but had abnormalities on
functional neuroimaging, demonstrating bifrontal abnormalities, in keeping with a disinhibited, dysexecutive state. A previous report described a patient with a
VGKC-Ab–associated limbic encephalitis and bitemporal hypermetabolic changes on FDG-PET14 occurring in
tandem with ongoing electrographic seizure activity. Simi-
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lar to that of our patient, FDG-PET also demonstrated
bilateral frontal and neocortical temporal hypometabolism, adding further weight to the idea that the effects of
VGKC-Ab–associated disorders are not just confined to
the mesial temporal cortex.
Protein level in CSF was elevated in this patient, although
other features of central nervous system autoimmunity (elevated white cell count and supernumerary oligoclonal
bands) were absent. Our patient had a negative evaluation
for malignancy in keeping with previous reports of VGKCAb–associated encephalopathy being usually a nonparaneoplastic disorder.3,4 However, lung cancers and other
solid tumors have been associated with elevated VGKCAb titers, and vigilance for an occult malignancy should
be maintained. It also should be borne in mind that only
a limited number of paraneoplastic antibodies were ordered
in this case, and more extensive autoimmune profiling (for
collapsin response-mediated protein 5 [CRMP-5] IgG and
other markers of paraneoplastic autoimmunity) is important where the remote effect of a cancer is suspected as the
cause. Testing for VGKC-Abs in CSF (not undertaken in
our patient) is of limited utility, tending only to be positive in those with high serum titers.4
Consistent with previous literature regarding treatment of VGKC-Ab–associated limbic encephalitis, this
patient had a beneficial response from steroids after a few
weeks, but further improvements occurred with several
months of therapy in tandem with a reduction in
VGKC-Ab titer. The benefit from plasma exchange and
intravenous immunoglobulin is less certain but may play
a role in the initial stages of therapy.3 The duration of
illness is likely important in predicting the treatment response, and in 1 report, patients with symptoms for more
than 9 months responded poorly.4
This case expands the spectrum of central nervous system disorders associated with VGKC-Abs. In the evaluation of patients presenting with rapidly progressive
changes in personality, social conduct, and executive function, testing should be considered for inflammatory CSF
and serological markers of autoimmune disease, including VGKC-Ab.
Accepted for Publication: April 6, 2007.
Correspondence: Andrew McKeon, MB, MRCPI, Department of Neurology, Gonda 8 S, Mayo Clinic, 200 1st
St SW, Rochester, MN 55905 (mckeon.andrew@mayo
.edu).
Author Contributions: Study concept and design: McKeon,
Marnane, and Lynch. Acquisition of data: McKeon,
Marnane, O’Connell, Stack, Kelly, and Lynch. Analysis
and interpretation of data: McKeon, Marnane, and
O’Connell. Drafting of the manuscript: McKeon, Marnane,
and Lynch. Critical revision of the manuscript for important intellectual content: O’Connell, Stack, Kelly, and
Lynch. Administrative, technical, and material support:
McKeon, Marnane, Stack, and Lynch. Study supervision:
Lynch.
Financial Disclosure: Dr Lynch has received unrestricted grants from Schering, Serono, and Orion Pharma.
Additional Contribution: Professor Angela Vincent, John
Radcliffe Hospital, Oxford, England, performed paraneoplastic autoantibody and VGKC-Ab serologies.
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