Unusual association of diseases/symptoms

Stroke preceding autoimmune encephalitis with neuronal
potassium channel antibody
Patricia Simal, Ana Maria Garcia-García, Carmen Serna-Candel, Jose Antonio Egido
Neurology Department, Stroke Unit, Hospital Clínico San Carlos, Madrid, Spain
Correspondence to Dr Jose Antonio Egido, jegidoh@yahoo.com

Summary
Autoimmune encephalitis related to voltage-gated potassium channel (VGKC) antibodies can occur as a complication of cancer but, more
frequently, as a non-paraneoplastic disorder. The prompt recognition and treatment could mitigate the morbidity associated with this entity,
but the broad-spectrum of neurological manifestations often makes the diagnosis a challenge. The authors describe, here, a unique case
of autoimmune encephalitis related to VGKC antibodies preceded by an ischaemic stroke. Conditions associated with the stroke (infection,
seizures, metabolic disturbances) had delayed the diagnosis. The authors suggest that autoimmune encephalitis needs to be taken into
consideration as part of a differential diagnosis in patients with prolonged encephalopathy following an ischaemic stroke. Infection may
trigger an inflammatory response. In addition, the rupture of blood brain barrier that occurs in stroke may have a pathogenic role by allowing
antibodies to gain access to the central nervous system.

BACKGROUND
Autoimmune encephalitis related to voltage-gated potassium channel (VGKC) can occur as a complication of cancer but, more frequently, as a non-paraneoplastic disorder.1
To the best of our knowledge, this is the first case described
in the context of an acute ischaemic stroke. Pneumonia,
as other complications of stroke, may trigger the autoimmune response. In addition, we suggest that the rupture of
blood brain barrier in ischaemic stroke might have played
a pathogenic role. It is important to take into consideration
this clinical entity in the differential diagnosis of encephalopathy after ischaemic stroke, since a prompt treatment
could improve the prognosis.

CASE PRESENTATION
A male patient over the sixth decade was admitted to our
stroke unit because of left arm paresis, facial asymmetry
and speech disturbance; signs that his family noticed when
he awoke of a morning.
Of note in his medical history were arterial hypertension, hypercholesterolaemia and coronary disease. His current medications were 300 mg daily of acetylsalicylic acid,
10 mg daily of simvastatin and 50 mg daily of metoprolol.
He had never smoked and had not indulged in any recreational drug abuse. Neither his wife nor family members
had noticed any symptoms of cognitive decline, personality changes or mood disturbance.
Clinical examination on admission identified a left visualspatial neglect, left visual extinction and a mild left facial
and brachial paresis. Brain CT scan showed a dense right
middle cerebral artery (MCA) and hypodensity of the right
basal ganglia. Initial blood tests were normal. Intravenous
thrombolysis was not indicated, the patient having arrived
at hospital beyond the therapeutic window. Two days
after admission, atrial fibrillation was detected in the ECG
monitoring. The diagnosis of cardioembolic infarction in

BMJ Case Reports 2012; doi:10.1136/bcr.08.2011.4637

the right MCA territory was made, and he was started on
intravenous sodium heparin perfusion.
The day after admission, the patient developed a respiratory infection with bronchospasm. Chest x-ray showed
a right pulmonary basal infiltrate. He initially received
intravenous amoxicillin-clavulanic acid, but other antibiotic regimens were needed because of persistent
pneumonia.
One week later there was significant deterioration of the
level of consciousness with hyponatraemia and fever.

INVESTIGATIONS
All microbiological tests performed, including blood, urinary, sputum cultures, legionella and pneumococcal urinary antigen tests were negative. Marantic and infective
endocarditis was also ruled out with a transoesophageal
echocardiogram. Cerebrospinal fluid (CSF) examination
revealed 1 white cell/ul, 39 mg/dl protein, 101 mg/dl glucose. CSF cultures, including Mycobacteria, were sterile.
CSF and blood serological tests (syphilis, Lyme, rickettsia,
HIV and brucella) were negative. PCR was also negative
for Herpes viridae DNA. No malignant cells were seen.
Thoracic, abdominal and pelvic CT scans showed bilateral
basal infiltrates, splenic and kidney infarctions. A second
evaluation performed 1 month later, showed an improvement of the pulmonary infiltrates and no evidence of
tumour. Bronchoscopy was negative for malignant cells.
Tumour markers (including PSA) as well as paraneoplastic and autoautoantibody tests (anti-Hu, anti-Yo, anti-Ri,
antiamphiphysin, anti-CV2/CRMP5, anti-PNMA2, antinuclear, p-antineutrophil cytoplasmic antibodies (ANCA),
c-ANCA, anticentromere B, antismooth muscle, antimitochondrial, anti-LKM1, antireticulin, antithyroid, antimyeloperoxidase, antiproteinase 3m, antiglomerular basement
membrane, anti-Jo-1, anti Ro, anti-La, anticardiolipin and
rheumatoid factor) were negative

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OUTCOME AND FOLLOW-UP

DISCUSSION

Despite improvement in the respiratory symptoms and
sodium level correction with water restriction, the fever
and decreased level of consciousness persisted in addition
to multi-focal myoclonus. A brain MRI performed on the
9th day of admission did not add any new information to
the previous diagnosis (figure 1A,B). Serial EEGs showed
generalised slowing. Autoimmune encephalopathy was
suspected and methylprednisolone intravenously was
begun on the 20th day of admission (dose of 1 g per day
for 5 days, followed by oral prednisone).
The patient experienced a dramatic, but transient,
improvement after the second dose of methylprednisolone. However, a few days later, the level of consciousness decreased progressively with additional
postural tremor and worsening of myoclonus that
required levetiracetam and valproate treatment. During
the following 2 months he evolved to a state of akinetic
mutism with multi-focal myoclonus. Brain MRI (figure
1C,D) showed an important frontal atrophy compared
to the previous study conducted 50 days previously. In
addition, he developed severe autonomic disturbances:
a resistant syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH), recurrent episodes of
hypotension and alternating diarrhoea and constipation.
Suspicion of autoimmune or paraneoplastic encephalitis
was very high but all the autoantibody tests available in
our laboratory were negative. Neuronal potassium channel antibody test was solicited from another clinical centre, and five doses of intravenous immunoglobulin were
administered 3 months after admission. There was an
improvement in the level of consciousness, but akinetic
mutism, myoclonus and tremor persisted.
Titres of neuronal potassium channel antibody of 193
pM confirmed the diagnosis. The patient died 1 month
later as a result of broncho-aspiration. Autopsy was not
performed because the family did not provide consent.

We describe, to the best of our knowledge the first time
in the literature, a case of autoimmune encephalitis with
VGKC antibodies after ischaemic stroke. Recently, a
patient with a stroke-like presentation has been reported,
but in that case, the diffusion restriction in MRI did not
completely match a vascular territory, with typical temporal mesial hyperintensities, and was considered a strokemimic.2
Titres of neuronal potassium channel antibody, although
not very high (laboratory reference level <100), were
conclusive within the context of a subacute encephalitis
with myoclonus, frontal dysfunction, tremor, SIADH and
autonomic disturbances. Moreover, it should be noted
that levels could have been decreased following the corticosteroid administration.3 Although the most typical
abnormality in brain MRI is the T2/flair hyperintensity of
mesial temporal region, cerebral atrophy exceeding that
expected for age has also been reported.4 A paraneoplastic
origin for these symptoms was carefully considered but
thoracic, abdominal and pelvic CT scans, tumour markers
and bronchoscopy were negative. However, confirmation
was not possible because a thorough postmortem study
was not performed.
A pathogenic role for VGKC autoantibodies in autoimmune encephalitis has been supported by animal passive-transfer experiments4 5 and invitro suppression of
potassium currents.6 A humoral immunity hypothesis
is also supported by the response to immunotherapy,3
compared with other paraneoplastic encephalitis with
antibodies directed towards intraneural antigens. A recent
study has shown that the target antigen of antibodies in
patients with limbic encephalitis previously attributed to
VGKC is, in fact, leucine-rich glioma-inactivated 1 (LGI1)
protein; a neuronal secreted protein that appears to connect presynaptic and postsynaptic protein complexes for
finely-tuned synaptic transmission. It has been speculated that antibody-mediated disruption of LGI1 function
causes increased excitability, which results in seizures and
other symptoms of encephalopathy.7
The rupture of blood brain barrier that occurs in stroke
may have a pathogenic role by allowing antibodies to
gain access to the central nervous system. Infection is the
most frequent condition that precedes the development
of this syndrome, probably by triggering an inflammatory
response.8 In this sense, there is amounting evidence that
inflammation plays an important role in cerebral ischaemia.
Brain response to ischaemic injury is associated with an
acute, and prolonged, inflammatory process characterised
by the activation of glial cells, the production of inflammatory cytokines, as well as leucocyte and monocyte
infiltration in the brain.9 In our patient, pneumonia may
have triggered the autoimmune response. Furthermore,
we suggest that the breakdown of the blood- brain barrier
in ischaemic stroke might have been instrumental in the
pathogenesis. Postischaemic autoimmune-mediated brain
injury has been previously reported, and patients that
develop an infection after stroke, especially pneumonia,
are more likely to evidence a lymphocyte Th1 (+) response
to nervous system proteins, like myelin basic protein and
glial fibrillar acid protein.10
Although a good response to immunomodulatory therapies had been observed, the patient also experienced a

Figure 1 Brain MRI performed on the 9th day (A, B) shows right
insular infarction and after 50 days important frontal atrophy (C,D).
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BMJ Case Reports 2012; doi:10.1136/bcr.08.2011.4637

dramatic, but transient, improvement following corticosteroid therapy. The response was milder with intravenous immunoglobulin but, since its administration
had been delayed, an irreversible brain injury could have
been established already by the time treatment was initiated. In a case series recently published, the response
did not differ significantly between patients treated
within 6 months of the neurological symptoms onset
and those treated later.4 Cases with a poor response to
immunosuppressive treatments have also been reported.11
Nevertheless, most authors recommend early immunotherapy administration.8

Learning points
Autoimmune encephalitis should be considered in
cases of prolonged encephalopathy following an
ischaemic stroke.
▶ Many symptoms could be wrongly interpreted as
oedema, infection and metabolic complications of
stroke, delaying the diagnosis.
▶ The prompt recognition and treatment may pre-empt
the mortality associated with intractable seizures
and electrolyte disturbances and might decrease the
morbidity associated with cerebral atrophy.8
▶

Acknowledgements The authors thank Dr Angela Vincent (Neurosciences
Group, Department of Clinical Neurology, Weatherall Institute of Molecular
Medicine, University of Oxford, UK) for her helpful insights.
Competing interests None.
Patient consent Not obtained.

REFERENCES
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limbic encephalitis with neuronal potassium channel antibody. Neurology
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4. Tan KM, Lennon VA, Klein CJ, et al. Clinical spectrum of voltage-gated
potassium channel autoimmunity. Neurology 2008;70:1883–90.
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neuromyotonia (Isaacs’ syndrome). Lancet 1991;338:75–7.
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patients with peripheral nerve hyperexcitability. Brain 1999;122:2057–66.
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limbic encephalitis previously attributed to potassium channels: a case series.
Lancet Neurol 2010;9:776–85.
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9. Kriz J, Lalancette-Hébert M. Inflammation, plasticity and real-time imaging
after cerebral ischemia. Acta Neuropathol 2009;117:497–509.
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Patricia S, Garcia-García AM, Serna-Candel C, Egido JA Stroke preceding autoimmune encephalitis with neuronal potassium channel antibody.
BMJ Case Reports 2012;10.1136/bcr.08.2011.4637, Published XXX
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