Clinical utility of seropositive voltage-gated potassium channel–complex antibody

Abstract

Background: Antibodies against voltage-gated potassium channel (VGKC)-complex are implicated in the pathogenesis of acquired neuromyotonia, limbic encephalitis, faciobrachial dystonic seizure, and Morvan syndrome. Outside these entities, the clinical value of VGKC-complex antibodies remains unclear. Methods: We conducted a single-center review of patients positive for VGKC-complex antibodies over an 8-year period. Results: Among 114 patients positive for VGKC-complex antibody, 11 (9.6%) carrying the diagnosis of limbic encephalitis (n 5 9) or neuromyotonia (n 5 2) constituted the classic group, and the remaining 103 cases of various neurologic and non-neurologic disorders comprised the nonclassic group. The median titer for the classic group was higher than the nonclassic group (p , 0.0001). A total of 90.9% of the patients in the classic and 21.4% in the nonclassic group possessed high (.0.25 nM) VGKC-complex antibody levels (p , 0.0001). A total of 75.0% of the patients in the high-level group had definite or probable autoimmune basis, while nonautoimmune disorders were seen in 75.6% of patients from the low-level group (p , 0.0001). A total of 26.3% of patients were found with active or remote solid organ or hematologic malignancy, but no antibody titer difference was observed among subgroups of absent, active, or remote malignancy. Compared to age-matched US national census, rates of active cancer in our cohort were higher in patients older than 45 years. Conclusions: High VGKC-complex antibody titers are more likely found in patients with classically associated syndromes and other autoimmune conditions. Low-level VGKC-complex antibodies can be detected in nonspecific and mostly nonautoimmune disorders. The presence of VGKC-complex antibody, rather than its level, may serve as a marker of malignancy. Neurol Clin Pract 2016;6:409-418 A ntibodies against voltage-gated potassium channel (VGKC)-complex were first identified in the peripheral nerve hyperexcitability disorder neuromyotonia, and subsequently in patients with Morvan syndrome, limbic encephalitis (LE), and faciobrachial dystonic seizure. 1-4 These diagnoses, constituting the classic Neurohospitalist Program (AJ),

Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management

“…These antibodies may or may not be relevant to the patient's presentation depending on the clinical picture, and their presence should not preclude thorough exclusion of other potential causes of the neurological presentation. [31][32][33] The antibody level (for some antibodies like GAD65antibody), clinical presentation, disease course, CSF findings and smoking or cancer history are factors that can be used to determine the clinical relevance of the positive antibody. [33][34][35] The NAAs confidence scale is one suggested tool to increase the confidence in the clinical relevance of these less specific antibodies (table 3).…”

Voltage-gated potassium channel blanket testing in first-episode psychosis: Diagnostic nihilism?

“…Retrospective review of low-positive VGKC cohorts has found that most cases were not associated with any encephalitic syndrome and those that were, had early prominent neurological symptoms (Hacohen et al, 2013;Huda et al, 2015;Jammoul et al, 2016;Paterson et al, 2014). Rather than being directly pathogenic, it is hypothesised that the antibodies in the low-positive VGKC cases may result from neuronal damage, such as in association with multiple sclerosis, amyotrophic lateral sclerosis or Creutzfeldt-Jakob disease, or may indicate non-neuronal autoimmunity (Fujita et al, 2012;Huda et al, 2015;Jammoul et al, 2016;Lang et al, 2017). In addition, VGKC antibodies may be an oncogenic marker, with higher than expected rates of malignancy seen, even in low-positive cases scanning (Jammoul et al, 2016;Klein et al, 2013;Paterson et al, 2014).…”

“…Rather than being directly pathogenic, it is hypothesised that the antibodies in the low-positive VGKC cases may result from neuronal damage, such as in association with multiple sclerosis, amyotrophic lateral sclerosis or Creutzfeldt-Jakob disease, or may indicate non-neuronal autoimmunity (Fujita et al, 2012;Huda et al, 2015;Jammoul et al, 2016;Lang et al, 2017). In addition, VGKC antibodies may be an oncogenic marker, with higher than expected rates of malignancy seen, even in low-positive cases scanning (Jammoul et al, 2016;Klein et al, 2013;Paterson et al, 2014). No low-positive VGKC case in this study had evidence of neurological illness or malignancy, although this cohort is significantly younger than other neurological VGKC cohorts described, but two cases did have a past history of non-neurological autoimmunity (Pozo-Rosich et al, 2003;Tan et al, 2008).…”

“…Cases were clustered, based on the manufacturer instructions (RSR) and literature review, into two groups for comparison: low-positive VGKC (VGKC titre 85-300 pM) and high-positive VGKC (VGKC titre >300 pM) (Huda et al, 2015;Jammoul et al, 2016;Paterson et al, 2014;Van Sonderen et al, 2016). Descriptive statistics were employed for analysis of the data.…”

“…VGKC syndromes may be paraneoplastic and are primarily associated with strongly positive VGKC titres (>300 pM) (Irani et al, 2010;Paterson et al, 2014). The significance of 'low-positive' titres in the 85-300 pM range is unclear (Huda et al, 2015;Jammoul et al, 2016;Paterson et al, 2014;Van Sonderen et al, 2016). In addition, it is now understood that classical syndromes associated with positive VGKC testing usually have specific antibodies directed to components of the VGKC complex (leucinerich glioma-inactivated protein 1 [LGi1] and contactinassociated protein 2 [CASPR2]) (Irani et al, 2010;Van Sonderen et al, 2016).…”