Voltage-Gated Potassium Channel Autoimmunity Mimicking Creutzfeldt-Jakob Disease

Neuroimmunology Laboratory, Hilton 3-78F, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Archives of neurology (Impact Factor: 7.42). 11/2008; 65(10):1341-6. DOI: 10.1001/archneur.65.10.1341
Source: PubMed


Rapidly progressive dementia has a variety of causes, including Creutzfeldt-Jakob disease (CJD) and neuronal voltage-gated potassium channel (VGKC) autoantibody-associated encephalopathy.
To describe patients thought initially to have CJD but found subsequently to have immunotherapy-responsive VGKC autoimmunity.
Observational, prospective case series.
Department of Neurology, Mayo Clinic, and the Memory and Aging Center, University of California, San Francisco. Patients A clinical serologic cohort of 15 patients referred for paraneoplastic autoantibody evaluation. Seven patients were evaluated clinically by at least one of us. Clinical information for the remaining patients was obtained by physician interview or medical record review.
Clinical features, magnetic resonance imaging abnormalities, electroencephalographic patterns, cerebrospinal fluid analyses, and responses to immunomodulatory therapy.
All the patients presented subacutely with neurologic manifestations, including rapidly progressive dementia, myoclonus, extrapyramidal dysfunction, visual hallucinations, psychiatric disturbance, and seizures; most (60%) satisfied World Health Organization diagnostic criteria for CJD. Magnetic resonance imaging abnormalities included cerebral cortical diffusion-weighted imaging hyperintensities. Electroencephalographic abnormalities included diffuse slowing, frontal intermittent rhythmic delta activity, and focal epileptogenic activity but not periodic sharp wave complexes. Cerebrospinal fluid 14-3-3 protein or neuron-specific enolase levels were elevated in 5 of 8 patients. Hyponatremia was common (60%). Neoplasia was confirmed histologically in 5 patients (33%) and was suspected in another 5. Most patients' conditions (92%) improved after immunomodulatory therapy.
Clinical, radiologic, electrophysiologic, and laboratory findings in VGKC autoantibody-associated encephalopathy may be confused with those of CJD. Serologic evaluation for markers of neurologic autoimmunity, including VGKC autoantibodies, may be warranted in suspected CJD cases.

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Available from: Michael D Geschwind, Jul 24, 2014
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    • "These events were commonly seen in the context of VGKC-complex limbic encephalitis and we proposed the term faciobrachial dystonic seizures to help clinicians recognize this distinctive and potentially treatable disorder (Irani et al., 2011). Faciobrachial dystonic seizures were consistently associated with antibodies against the LGI1 (leucine-rich, glioma inactivated 1 protein) component of the VGKC-complex and appeared to respond well to immunotherapy (Irani et al., 2008, 2011; Geschwind et al., 2008; Barajas et al., 2010; Andrade et al., 2011; Vincent et al., 2011; Quek et al., 2012). A recent multicentre study revealed that faciobrachial dystonic seizures often preceded the onset of limbic encephalitis , leading to the hypothesis that early immunotherapy for faciobrachial dystonic seizures might postpone or even prevent progression to the cognitive impairment that characterizes limbic encephalitis (Irani et al., 2011). "
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    ABSTRACT: Voltage-gated potassium channel complex antibodies, particularly those directed against leucine-rich glioma inactivated 1, are associated with a common form of limbic encephalitis that presents with cognitive impairment and seizures. Faciobrachial dystonic seizures have recently been reported as immunotherapy-responsive, brief, frequent events that often predate the cognitive impairment associated with this limbic encephalitis. However, these observations were made from a retrospective study without serial cognitive assessments. Here, we undertook the first prospective study of faciobrachial dystonic seizures with serial assessments of seizure frequencies, cognition and antibodies in 10 cases identified over 20 months. We hypothesized that (i) faciobrachial dystonic seizures would show a differential response to anti-epileptic drugs and immunotherapy; and that (ii) effective treatment of faciobrachial dystonic seizures would accelerate recovery and prevent the development of cognitive impairment. The 10 cases expand both the known age at onset (28 to 92 years, median 68) and clinical features, with events of longer duration, simultaneously bilateral events, prominent automatisms, sensory aura, and post-ictal fear and speech arrest. Ictal epileptiform electroencephalographic changes were present in three cases. All 10 cases were positive for voltage-gated potassium channel-complex antibodies (346-4515 pM): nine showed specificity for leucine-rich glioma inactivated 1. Seven cases had normal clinical magnetic resonance imaging, and the cerebrospinal fluid examination was unremarkable in all seven tested. Faciobrachial dystonic seizures were controlled more effectively with immunotherapy than anti-epileptic drugs (P = 0.006). Strikingly, in the nine cases who remained anti-epileptic drug refractory for a median of 30 days (range 11-200), the addition of corticosteroids was associated with cessation of faciobrachial dystonic seizures within 1 week in three and within 2 months in six cases. Voltage-gated potassium channel-complex antibodies persisted in the four cases with relapses of faciobrachial dystonic seizures during corticosteroid withdrawal. Time to recovery of baseline function was positively correlated with time to immunotherapy (r = 0.74; P = 0.03) but not time to anti-epileptic drug administration (r = 0.55; P = 0.10). Of 10 cases, the eight cases who received anti-epileptic drugs (n = 3) or no treatment (n = 5) all developed cognitive impairment. By contrast, the two who did not develop cognitive impairment received immunotherapy to treat their faciobrachial dystonic seizures (P = 0.02). In eight cases without clinical magnetic resonance imaging evidence of hippocampal signal change, cross-sectional volumetric magnetic resonance imaging post-recovery, after accounting for age and head size, revealed cases (n = 8) had smaller brain volumes than healthy controls (n = 13) (P < 0.001). In conclusion, faciobrachial dystonic seizures can be prospectively identified as a form of epilepsy with an expanding phenotype. Immunotherapy is associated with excellent control of the frequently anti-epileptic drug refractory seizures, hastens time to recovery, and may prevent the subsequent development of cognitive impairment observed in this study.
    Full-text · Article · Sep 2013 · Brain
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    • "The lesions present in non-herpetic limbic encephalitis are typically detected by magnetic resonance imaging (MRI) during the early phase. There are several case reports regarding MRI patterns of anti-N-methyl-D-aspartate receptor (NMDAR) and anti-voltage gated potassium channel (VGKC) antibody encephalitis.5,6 However, case reports regarding anti-GluR antibody-positive encephalitis MRI are uncommon, and the relationship between anti-GluR and anti-NMDAR remains unclear. "
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    ABSTRACT: We report two cases of anti-glutamic acid receptor (anti-GluR) antibody-positive encephalitis in males with symptoms such as Parkinsonism, urinary retention, and paralytic ileus. Although non-herpetic encephalitis typically shows magnetic resonance imaging (MRI) lesions in the limbic system during early stages, the present cases showed MRI lesions during later stages in the bilateral claustrum and pons. In both cases, anti-GluRɛ2 and δ2 antibodies were later shown to be positive in the cerebrospinal fluid but negative in the serum. Although early detection of anti-GluR antibodies is essential, early treatment may be significantly more important.
    Preview · Article · Jun 2013 · Clinical Medicine Insights: Case Reports
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    • "In addition to these syndromes, VGKC-antibodies have also been identified in some patients with idiopathic epilepsy (McKnight et al., 2005) and recently in a form of late-onset dystonic epilepsy (Irani et al., 2008; Barajas et al., 2009). In most cases these syndromes have a subacute onset and respond well to immunomodulatory therapies (Buckley et al., 2001; Thieben et al., 2004; Vincent et al., 2004; Geschwind et al., 2008; Irani et al., 2008), although neuromyotonia may require only symptomatic treatments . Both neuromyotonia and Morvan's syndrome can be associated with tumours, particularly thymomas, but tumours appear to be uncommon in typical VGKC-antibody associated limbic encephalitis or idiopathic epilepsy. "
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    ABSTRACT: Antibodies that immunoprecipitate (125)I-alpha-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan's syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with (125)I-alpha-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan's syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.
    Full-text · Article · Sep 2010 · Brain
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