Voltage-gated Potassium Channel Complex Antibodies Research Articles

Characteristics of after-discharges following compound muscle action potential or F-wave in primary peripheral nerve hyperexcitability syndrome.

F-wave testing frequently reveals after-discharges of varied morphologies in patients with primary peripheral nerve hyperexcitability syndrome (PNHS), although reports are scant. This study aimed to explore the morphological characteristics of the after-discharges during F-wave tests in PNHS, and to assess the association between after-discharges and the disease classification. We conducted a retrospective analysis of patients diagnosed with PNHS between 2014 and 2022. The morphological characteristic and duration of after-discharges during F-wave tests were analyzed. After-discharges in the Morvan syndrome group were compared with those in non-Morvan group, and between groups with positive or negative voltage-gated potassium channel (VGKC) complex antibodies. Twenty-nine patients were included in the study, of which 25 exhibited after-discharges. All after-discharges in Morvan patients occurred following compound muscle action potential (CMAP). In non-Morvan patients, after-discharges occurred following F-wave (32%) and CMAP (47%). The durations of after-discharges following CMAP were significantly prolonged in Morvan (54.2 ± 18.8 ms) compared to non-Morvan patients (34.5 ± 15.0 ms). The majority of antibody-positive patients (18/20) exhibited after-discharges following CMAP, whereas 67% of antibody-negative patients (6/9) showed after-discharges following F-wave. The varying presentations of after-discharges, including their location (after CMAP or F-wave) and the duration of after-discharge can assist in clinically classifying PNHS.

Anti-Kv1.4 Antibody-positive Nivolumab-induced Myasthenia Gravis and Myositis Presenting with Bilateral Ptosis and Demonstrating Different Pathophysiologies.

Nivolumab blocks inhibitors of T-cell activation and restores antitumor immunity but promotes T-cell activity in host tissues by blocking inhibition of the T-cell function, resulting in immune-related adverse effects. We herein report an 80-year-old man presenting with nivolumab-related myasthenia gravis with anti-muscular voltage-gated potassium channel-complex (Kv1.4) antibodies. On day 29 after nivolumab administration, he simultaneously developed rapidly progressing right ptosis and left facial paralysis. Nivolumab administration was discontinued. He subsequently presented with bulbar paralysis, dyspnea, and muscle weakness and received intravenous immunoglobulin, methylprednisolone, and plasma exchange. The severity of nivolumab-related myasthenia gravis with anti-Kv1.4 antibodies presented with diverse clinical findings.

Orofacial dyskinesia in a patient with autoimmune encephalitis and voltagegated potassium channel complex antibodies

Orofacial dyskinesia in a patient with autoimmune encephalitis and voltagegated potassium channel complex antibodies

Persistent hiccup as one of the initial symptoms of leucine-rich glioma-inactivated-1 encephalitis: a case report

BackgroundAnti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, an autoimmune disorder, is characterized by faciobrachial dystonic seizures, epilepsy, memory deficits and altered mental status while hiccup is not commonly found in patients.Case presentationA 62-year-old male was presented with slurred speech, abnormal gait, faciobrachial dystonic seizures and impaired cognition. Besides, the hiccup was one of the initial symptoms. His brain magnetic resonance images (MRI) revealed multiple lesions with left caudate nucleus, putamen, insula and left hippocampus involvement. Because a diagnosis of antibody-related limbic encephalitis was suspected, studies including an autoimmune profile were done by cell-based assays. After anti-LGI1 antibodies were detected in both cerebrospinal fluid and serology, pulse methylprednisolone and intravenous immunoglobulin were started and hence hiccups disappeared along with other symptoms.ConclusionsClinicians should be aware that persistent hiccups might be one of the initial manifestations of LGI1 subtype of voltage-gated potassium channel complex antibody associated autoimmune encephalitis.

Clinical features and outcomes of leucine-rich glioma-inactivated protein 1 and contactin protein-like 2 antibody-associated autoimmune encephalitis in a Chinese cohort

The present study aimed to investigate the clinical manifestations, epidemiological characteristics, and outcomes of Chinese patients with voltage-gated potassium channel complex (VGKC) antibody–associated encephalitis. Patients diagnosed with VGKC antibody-associated encephalitis at our institution between January 2016 and December 2020 were included in this study. We retrospectively evaluated their clinical features, auxiliary examination results, treatments details, long-term outcomes, and risk factors for poor outcome. Of the 91 included patients, 61 (67.78%) were men and 30 (32.97%) were women. The most common clinical symptoms were seizures (n = 63, 69.23%), memory deficits (n = 62, 68.13%), mental behavioral disorders (n = 29, 31.87%), and hyponatremia (n = 57, 62.64%). Although patients with anti- leucine-rich glioma-inactivated 1 (LGI1) (n = 76) and anti- contactin-associated protein-like 2 (CASPR2) encephalitis (n = 15) had similar clinical manifestations, the former were more diverse. In total, 86 (94.51%) patients were treated with immunotherapy. Over a median follow-up period of 25 months, there were no mortalities and 14 (15.38%) patients experienced a relapse. Univariate analysis indicated differences in sex, modified Rankin Scale scores at onset, movement disorders, central hypoventilation, and intensive care unit occupancy between the good- and poor- outcome groups. Patients with anti-LGI1 and anti-CASPR2 encephalitis showed similar clinical manifestations while presenting delineating characteristics. Those with VGKC antibody-associated diseases generally responded well to immunotherapy and demonstrated favorable clinical outcomes. Several factors affected the prognosis, and a long-term follow-up examination is necessary.

Isaacs\u2019 syndrome as the initial presentation of malignant thymoma and associated with double-positive voltage-gated potassium channel complex antibodies, a case report

BackgroundIsaacs’ syndrome is a peripheral nerve hyperexcitability (PNH) syndrome due to peripheral motor nerve instability. Acquired Isaacs’ syndrome is recognized as a paraneoplastic autoimmune disease with possible pathogenic voltage-gated potassium channel (VGKC) complex antibodies. However, the longitudinal correlation between clinical symptoms, VGKC antibodies level, and drug response is still unclear.Case presentationA 45-year-old man had progressive four limbs soreness, muscle twitching, cramps, and pain 4 months before admission. Electromyography (EMG) studies showed myokymic discharges, neuromyotonia, and an incremental response in the high-rate (50 Hz) repetitive nerve stimulation (RNS) test. Isaacs’ syndrome was diagnosed based on clinical presentations and EMG reports. Serum studies showed positive VGKC complex antibodies, including leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. The acetylcholine receptor antibody was negative. Whole-body computed tomography (CT) and positron emission tomography revealed a mediastinal tumor with the great vessels encasement, right pleura, and diaphragm seeding. Biopsy confirmed a World Health Organization type B2 thymoma, with Masaoka stage IVa. His symptoms gradually improved and both LGI1 and CASPR2 antibodies titer became undetectable after concurrent chemoradiotherapy (CCRT) and high dose steroid treatment. However, his Isaacs’ syndrome recurred after the steroid was reduced 5 months later. Follow-up chest CT showed probable thymoma progression. LGI1 antibody turned positive again while CASPR2 antibody remained undetectable.ConclusionsOur patient demonstrates that Isaacs’ syndrome could be the initial and only neuromuscular manifestation of malignant thymoma. His Isaacs’ syndrome is correlated well with the LGI1 antibody level. With an unresectable thymoma, long-term immunosuppressant therapy may be necessary for the management of Isaacs’ syndrome in addition to CCRT for thymoma.

Inpatient Management of Encephalopathy.

Unexplained encephalopathy is a common occurrence in tertiary care centers and neurologic disorders should be considered after ruling out the infectious, toxic and metabolic etiologies. Neuroimaging combined with a thorough history and examination is often helpful in ruling out stroke and fulminant demyelinating encephalopathies. Autoimmune encephalopathy should be suspected in any patient with unexplained acute or subacute onset encephalopathy or rapidly progressing dementia. Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis is the most studied form and Hashimoto encephalitis is the most controversial form of autoimmune encephalopathies. Obtaining a combined serum and Cerebrospinal fluid (CSF) autoantibody testing will increase the diagnostic yield of autoimmune and paraneoplastic encephalitis. When diagnosing NMDA receptor antibodies CSF is always more sensitive than serum and in contrast, voltage-gated potassium channel (VGKC) complex antibodies are more readily detectable in serum than in CSF. Neural-specific antibody tests frequently result after several weeks and treatment should be administered without a significant delay to prevent brain damage. Autoimmune encephalitis is often treatment responsive when immunotherapy (glucocorticoids, intravenous immune globulin, plasma exchange) is used in various combinations. The absence of inflammatory markers and autoantibodies in the serum or CSF may not rule out the possibility of paraneoplastic encephalopathies.

Recognizing New-Onset Sleep Disorders in Autoimmune Encephalitis Often Prompt Earlier Diagnosis.

Sleep/wake disorders are common in patients with autoimmune encephalitis, sometimes the most prominent or sole initial symptom, then delaying diagnosis. Sleep/wake disorders in autoimmune encephalitis vary and include severe sleeplessness, hypersomnia, central and/or obstructive sleep apnea, rapid eye movement sleep behavior disorder, indeterminate sleep/wake states, and loss of circadian sleep/wake rhythms. N-methyl- d aspartate receptor encephalitis (NMDAR) is often associated with insomnia, then hypersomnia and sleep-related central hypoventilation. Profound sleeplessness and rapid eye movement sleep behavior disorder are seen in patients with voltage-gated potassium channel-complex antibodies. Fragmented sleep and hypersomnia are common in paraneoplastic syndromes associated with anti-MA protein encephalitis; rapid eye movement sleep behavior disorder in those with antibodies against leucine-rich glioma inactivated protein (LGI1) or contactin-associated protein 2 (CASPR2) antibodies. Antibodies against a cell adhesion protein IGLON5 may result in obstructive sleep apnea, inspiratory stridor, disorganized nonrapid eye movement sleep, and excessive movements and parasomnias fragmenting nonrapid and rapid eye movement sleep. Recognizing a particular sleep/wake disorder is often a presenting or prominent feature in certain autoimmune encephalitis permit for earlier diagnosis. This is important because reduced morbidity and better short- and long-term outcomes are associated with earlier diagnosis and immunotherapies.

Sleep Disorders in Leucine-Rich Glioma-Inactivated Protein 1 and Contactin Protein-Like 2 Antibody-Associated Diseases.

Objective: Sleep disorders are common in voltage-gated potassium channel complex antibody (VGKC-Ab) diseases. The aim was to investigate the sleep disturbances and polysomnography (PSG) characteristics in patients with VGKC-Ab-associated diseases.Methods: Twenty-seven patients with leucine-rich glioma-inactivated protein 1 antibody (LGI1-Ab) encephalitis, seven patients with contactin protein-like 2 antibody (Caspr2-Ab)-associated diseases, and 14 healthy controls with at least one PSG or actigraphy recording were recruited at Peking Union Medical College Hospital from January 2014 to July 2019.Results: Sleep disorders including insomnia, hypersomnia, rapid eye movement (REM) sleep behavior disorder (RBD), periodic limb movements in sleep (PLMS), agrypnia excitata, and obstructive sleep apnea syndrome were observed. Twenty-one PSG recordings from patients with LGI1-Ab encephalitis demonstrated a decrease in total sleep time (TST) (median 365.5, range 184.5–495.5 min), sleep efficiency (70.0%, 47–92%), N3 sleep (9.7%, 0–32.9%), and REM sleep (9.9%, 0.4–27.9%). Of five patients with Caspr2-Ab-associated diseases, TST was found to be 329.5 (167.0–377.5 min), and sleep efficiency was found to be 61.7% (34.6–71.7%). The percentage for N3 and REM sleep was found to be 15.0% (0–34.6%) and 12.7% (0–22.2%), respectively. Both RBD and PLMS were observed more frequently in patients with LGI1-Ab encephalitis. We identified status dissociatus (SD) in five (23.8%) patients with LGI1-Ab encephalitis and two (40%) patients with Caspr2-Ab diseases. The former is more likely to have simple limb movements rather than complex movements, which mimic the contents of their dreams. Continuous insomnia was more common in patients with Caspr2-Ab diseases than patients with LGI1-Ab encephalitis. Patients reported clinical and PSG improvements following immunotherapy.Conclusion: Sleep disorders in patients with VGKC-Ab-associated diseases include decreased TST and poor sleep efficiency. Our studies provide evidence of SD in patients with LGI1-Ab encephalitis.

MORVAN SYNDROME: AN INTERESTING CASE OF A RARE DISEASE

Morvan syndrome is a rare disorder of peripheral nerve hyperexcitability, autonomic and central nervous system hyperactivity. It is considered autoimmune and paraneoplastic in nature. The most common associated antibodies are voltage-gated potassium channel (VGKC) complex antibodies which target leucine-rich glioma inactivated 1(LGI-1) and contactin-associated protein 2 (CASPR-2). It is characterized by myokymia, burning pain, cramps, stiffness, weakness, hyperhidrosis, weight loss, insomnia, and hallucinations. Thymectomy, long-term immunosuppression, plasmapheresis, intravenous immunoglobulin (IVIG), steroids are the treatment options. Carbamazepine, phenytoin, amitriptyline, and benzodiazepine are useful in relieving symptoms. We report a rare case ofthis disease from western Rajasthan who presented with bilateral diffuse burning pain, cramps, insomnia, weight loss, hyperhidrosis, visual hallucinations, and continuous muscle twitching and rippling activity over the lower back paraspinal muscles. His serum VGKC antibodies were positive. He was treated with IV methylprednisolone (MPS) and IVIG and had a good response to therapy. We should look for rippling muscle movement in a high index of suspicion and should not be missed.

THUR 153 Antibodies against the voltage-gated potassium channel complex

Voltage-gated potassium channel (VGKC) complex antibodies have been associated with a spectrum of presentations including peripheral nerve hyperexcitability (PNH), Morvan’s syndrome, autoimmune encephalopathy, epilepsy and recently psychosis.We retrospectively reviewed the medical records of 70 patients from the Greater Manchester Neuroscience Centre, who had tested positive for VGKC-complex antibodies between 2012 and 2015 to identify the clinical relevance of positive results.The majority were diagnosed with autoimmune encephalopathy(19) followed by epilepsy(14), psychosis(10) and PNH(6). The remaining fifteen had other neurological presentations and six had no primary neurological disorder. 39/70 patients who had antibody titres>400 pM, were diagnosed with autoimmune encephalopathy(19), epilepsy(9), psychosis(4), PNH(3) and other disorders(4). 24/39 patients, who received treatment with one or a combination of corticosteroids, intravenous immunoglobulins, cyclophosphamide, plasma exchange, azathioprine or rituximab, had a diagnosis of autoimmune encephalopathy(18), epilepsy(2), psychosis(2) and malignancy(2). 16/24 were treatment responsive. 3/31 patients with lower titres were also treated, but only one with the classic phenotype (PNH) responded to treatment.The classic phenotype often had a titre >400 pM. PNH may have a titre ≤400 pM. The patients without classic presentations typically had titres≤400 pM. Consistent with previous studies, clinical phenotyping and antibody titre helped to determine the relevance of VGKC-complex antibodies.

Current Perspective on Voltage-gated Potassium Channel Complex Antibody Associated Diseases

Voltage-gated potassium channel (VGKC) complex auto-antibodies were initially identified in Isaacs' syndrome (IS), which is characterized by muscle cramps and neuromyotonia. These antibodies were subsequently identified in patients with Morvan's syndrome (MoS), which includes IS in conjunction with psychosis, insomnia, and dysautonomia. The antibodies have also been detected in a patient with limbic encephalopathy (LE) presenting with prominent amnesia and frequent seizures. Typical cases of LE have adult-onset, with frequent, brief dystonic seizures that predominantly affect the arms and ipsilateral face, and has recently been termed faciobrachial dystonic seizures. Autoantibodies against the extracellular domains of VGKC complex proteins, leucine-rich glioma-inactivated 1 (LGI1), and contactin-associated protein-2 (Caspr2), occur in patients with IS, MoS, and LE. However, routine testing has detected VGKC complex antibodies without LGI1 or Caspr2 reactivities (double-negative) in patients with other diseases, such as Creutzfeldt-Jakob disease and amyotrophic lateral sclerosis. Furthermore, double-negative VGKC complex antibodies are often directed against cytosolic epitopes of Kv1 subunits. Therefore, these antibodies should no longer be classified as neuronal-surface antibodies and lacking pathogenic potential. Novel information has been generated regarding autoantibody disruption of the physiological functions of target proteins. LGI1 antibodies neutralize the interaction between LGI1 and ADAM22, thereby reducing the synaptic AMPA receptors. It may be that the main action is on inhibitory neurons, explaining why the loss of AMPA receptors causes amnesia, neuronal excitability and seizures.

Peripheral Nerve Hyperexcitability Syndromes.

This article provides a review of the clinical phenotypes and evaluation of peripheral nerve hyperexcitability syndromes. These rare diagnoses include cramp-fasciculation syndrome, Isaacs syndrome, and Morvan syndrome. Recent investigations have led to an understanding of the autoimmune underpinnings of these conditions and their specific associated antibodies. As the presentation of peripheral nerve hyperexcitability syndromes includes muscle stiffness, twitches, and spasms, which are also shared with certain central nervous system and myopathic conditions, the differential diagnosis of peripheral nerve hyperexcitability syndromes is reviewed. Peripheral nerve hyperexcitability syndromes share clinical and electrodiagnostic evidence of motor nerve instability; however, their clinical presentations are varied. Case reviews have helped us understand the spectrum of symptoms associated with the three peripheral nerve hyperexcitability syndromes reviewed here: cramp-fasciculation syndrome, Isaacs syndrome, and Morvan syndrome. More recently, research has focused on understanding the voltage-gated potassium channel complex antibodies as well as neoplasms associated with these conditions. The diagnosis of peripheral nerve hyperexcitability syndromes requires a high index of suspicion, support from the physical examination, familiarity with the spectrum of symptoms associated with peripheral nerve hyperexcitability syndromes, and recognition of diagnostic EMG features. Voltage-gated potassium channel complex antibodies are associated with these conditions. Optimum treatment and autoimmune pathogenesis remain areas of active research.

Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies: Evidence for relative pathogenicity

Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies: Evidence for relative pathogenicity

14 Neurobehavioural characteristics of limbic encephalitis associated with voltage-gated potassium channel complex antibodies

Objective Limbic encephalitis associated with antibodies to the voltage-gated potassium channel complex (VGKC-LE) often results in memory impairment with accompanying hippocampal damage thus potentially providing a robust human model of hippocampal amnesia. However, comprehensive characterisation of the neurobehavioural profile of VGKC-LE patients is currently lacking. We aim to provide a detailed description of the clinical outcome of these patients as well as determine whether they are indeed a useful model for hippocampal amnesia studies. Method A group of VGKC-LE patients (n=17) and matched controls underwent clinical interview and extensive neuropsychology testing covering multiple cognitive domains. Structural magnetic resonance imaging (MRI) and resting-state functional MRI (rs-fMRI) was acquired in all subjects. Investigation of atrophy profiles was completed via manual delineation of medial temporal lobes (MTL) structures and FreeSurfer cortical parcellation using non-parametric permutation testing. Rs-fMRI data were analysed using both independent component analysis (ICA) and seed-based connectivity analysis (SBCA) to investigate aberrant functional connectivity of the default mode network (DMN) and anterior and posterior memory networks. Associations between memory performance and structure and functional measures were investigated. Results The neuropsychological profile indicates memory function is preferentially affected whereas non-memory function is spared. Moreover, recall memory (recall composite; p Conclusions We have demonstrated that VGKC-LE patients present with persistent memory impairment in line with a previous retrospective study (Butler et al., 2014; JNNP). We also demonstrate that VGKC-LE patients have focal hippocampal atrophy supporting the use of patients with limbic encephalitis as a human model of hippocampal amnesia. However, the presence of hippocampal atrophy alone does not clearly explain the memory deficits. Instead, our data strongly suggest that a functional disturbance at rest is a contributory factor and could explain inconsistencies currently existing in the hippocampal amnesia literature.

18 Recall deficits with preserved recognition memory in limbic encephalitis

Objective Limbic Encephalitis (LE) is an inflammatory neurological disorder of the medial temporal lobe that causes a memory syndrome. LE with Voltage-Gated Potassium-Channel Complex (VGKC-LE) antibodies preferentially affects the hippocampus: neuro-imaging and post-mortem studies demonstrate hippocampal inflammation with relative sparing of the Para-hippocampal gyrus and other brain areas. Behaviourally, a syndrome is produced characterised by long-term memory impairment, seizures and behavioural disturbances. This patient group allows assessment of the specific role of the hippocampus in recall and recognition memory as well as in other aspects of cognition. Our aim was to characterise this in more detail than has been done before. Method We report a study of seven patients with immunologically proven VGKC-LE in which we have carried out a systematic study of cognition including verbal and visual delayed recall and recognition. Each patient was matched by age, gender and IQ with two controls. We assessed pre-morbid intelligence [WTAR], general intelligence [short-form WAIS III], semantic memory [Graded Naming Test], visual perception [VOSP], executive function [Letter and Category Fluency: Trails and Colour-Word interference from [DK-EFS; Hayling-Brixton], memory [AMIPB and Warrington Recognition Memory; Doors and People], autobiographical memory [AMI] and emotion [DASS-21]. Results We found consistent and significant deficits in delayed verbal and visual recall but not in recognition memory in patients with VGKC-LE. The autobiographical memory interview showed a dissociation between their personal semantic schedule (unimpaired) and autobiographical incident memory, which was impaired. Patients had low immediate and delayed story recall scores as compared to control participants. There were no other significant differences in neuropsychological testing. Conclusion This unique patient group can provide insights into the role of the hippocampus in various brain processes. Our work supports models based on a critical hippocampal role in recall but not recognition memory. Ongoing work is further characterising the memory phenotype and its correlation with structural changes in the medial temporal lobe.

A Likely Case of Limbic Encephalitis in a Patient With Voltage-Gated Potassium Channel Complex Antibody, Without a Known Antigenic Target: A Review of the Disease State and Value of Antibody Titers

A Likely Case of Limbic Encephalitis in a Patient With Voltage-Gated Potassium Channel Complex Antibody, Without a Known Antigenic Target: A Review of the Disease State and Value of Antibody Titers

Antiepileptic drug therapy in patients with autoimmune epilepsy.

Objective:We aimed to report the pattern of usage and efficacy of antiepileptic drugs (AEDs) in patients with autoimmune epilepsy (AE).Methods:We retrospectively studied the Mayo Clinic's electronic medical record of patients with AE in which seizures were the main presenting feature. Clinical data, including demographics, seizure characteristics, type of AED and immunotherapy used, presence of neural antibody, and treatment outcomes, were reviewed.Results:The medical records of 252 adult patients diagnosed with autoimmune encephalitis and paraneoplastic disorders were reviewed. Seizure was the initial presentation in 50 patients (20%). Serum and/or CSF autoantibodies were detected in 41 (82%) patients, and 38 (76%) patients had neural autoantibodies. The majority (n = 43, 86%) received at least 1 form of immunotherapy in combination with AEDs, while the remainder received AEDs alone. Twenty-seven patients (54%) became seizure free: 18 (36%) with immunotherapy, 5 (10%) with AEDs alone, and 4 (8%) with AEDs after immunotherapy failure. Levetiracetam was the most commonly used (42/50); however, it was associated with 0% seizure-free response. AED seizure-free responses occurred with carbamazepine (n = 3) [3/16, 18.8%], lacosamide (n = 3) [3/18, 16.6%] with phenytoin (n = 1) [1/8, 12.5%], or oxcarbazepine (n = 2) [2/11, 18.1%]. Regardless of the type of therapy, voltage-gated potassium channel-complex antibody–positive patients were more likely to become seizure free compared with glutamic acid decarboxylase 65 antibody–positive cases (12/17 vs 2/10, p = 0.0183).Conclusions:In select patients, AEDs alone were effective in controlling seizures. AEDs with sodium channel blocking properties resulted in seizure freedom in a few cases. Prospective studies are needed to clarify AED selection and to elucidate their immunomodulatory properties in AE.

Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies

ObjectivesAutoantibodies against the extracellular domains of the voltage-gated potassium channel (VGKC) complex proteins, leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-2 (CASPR2), are found in patients with limbic encephalitis, faciobrachial dystonic...

Autoimmune encephalitis with anti-leucine-rich glioma-inactivated 1 or anti-contactin-associated protein-like 2 antibodies (formerly called voltage-gated potassium channel-complex antibodies).

Twenty years since the discovery of voltage-gated potassium channel (VGKC)-related autoimmunity; it is currently known that the antibodies are not directed at the VGKC itself but to two closely associated proteins, anti-leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (Caspr2). Antibodies to LGI1 and Caspr2 give well-described clinical phenotypes. Anti-LGI1 encephalitis patients mostly have limbic symptoms, and anti-Caspr2 patients have variable syndromes with both central and peripheral symptoms. A large group of patients with heterogeneous symptoms are VGKC positive but do not have antibodies against LGI1 or Caspr2. The clinical relevance of VGKC positivity in these 'double-negative' patients is questionable. This review focusses on these three essentially different subgroups. The clinical phenotypes of anti-LGI1 encephalitis and anti-Caspr2 encephalitis have been described in more detail including data on treatment and long-term follow-up. A specific human leukocyte antigen (HLA) association was found in nontumor anti-LGI1 encephalitis, but not clearly in those with tumors. There has been increasing interest in the VGKC patients without LGI1/Caspr2 antibodies questioning its relevance in clinical practice. Anti-LGI1 encephalitis and anti-Caspr2 encephalitis are separate clinical entities. Early recognition and treatment is necessary and rewarding. The term VGKC-complex antibodies, lumping patients with anti-LGI1, anti-Caspr2 antibodies or lacking both, should be considered obsolete.