VGKC-complex Antibodies Research Articles

When should we test for voltage-gated potassium channel complex antibodies? A retrospective case control study

Patients with voltage-gated potassium channel (VGKC)-complex antibodies are increasingly recognized as having central, peripheral or combined phenotypes. With increasing awareness, more patients are tested and the clinical spectrum is expanding. Consequently, clinicians may be uncertain as to which patients should or should not be tested. Previous studies have identified common clinical features, but none has looked at the usefulness of these in predicting seropositive disease. We conducted a case-control study of patients tested for VGKC-complex antibodies over 10years at a regional tertiary neurology centre determining which clinical/biochemical features were associated with antibody-positive disease. We found a marked increase in the numbers tested, although the percentage positive remained low. Antibody titre was highest in central disease (p<0.001). Time from presentation to testing was shorter in those with VGKC-disease (p=0.01). Seizures were present in 11 (69%) of those with VGKC-disease versus three (18%) without (odds ratio [OR] 10.3, 95% confidence interval [CI]: 2.0–52.7, p=0.005). There was an inverse correlation between the antibody titre and serum sodium. A multivariate model selected seizures and hyponatraemia as predictive of VGKC disease (sensitivity 75% and specificity 82%); faciobrachial dystonic movements were specific but insensitive. Interestingly serum alkaline phosphatase was higher in those with VGKC-disease (p=0.016) and highest in those with peripheral disease (p=0.015). An ALP>70u/L was strongly associated with antibody positivity (OR 4.11 95% CI: 1.43–11.8, p=0.007) with a sensitivity of 74.2%. The presence of seizures, faciobrachial movements, and hyponatraemia should raise suspicion of VGKC-disease; alkaline phosphatase may represent a novel biomarker, particularly in those with peripheral disease.

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

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. We conducted a single-center review of patients positive for VGKC-complex antibodies over an 8-year period. Among 114 patients positive for VGKC-complex antibody, 11 (9.6%) carrying the diagnosis of limbic encephalitis (n = 9) or neuromyotonia (n = 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. 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.

Neuronal autoantibodies in mesial temporal lobe epilepsy with hippocampal sclerosis

ObjectiveOur aim was to investigate the prevalence of neuronal autoantibodies (NAbs) in a large consecutive series with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) and to elucidate the clinical...

VGKC-Complex Antibody Encephalitis: Clinical Manifestations and Response to Immunotherapy (P2.251)

VGKC-Complex Antibody Encephalitis: Clinical Manifestations and Response to Immunotherapy (P2.251)

Autoantibodies to neuronal antigens in children with focal epilepsy and no prima facie signs of encephalitis.

There is increasing awareness of neuronal autoantibodies and their impact on the pathogenesis of epilepsy. We investigated children with focal epilepsy in order to provide an estimate of autoantibody frequency within a pediatric population without prima facie evidence of encephalitis using a broad panel of autoantibodies. This was done to assess the specificity of antibodies and to see whether antibodies might be of modifying influence on the course of focal epilepsies. We searched for autoantibodies in 124 patients with focal epilepsy (1-18 years; mean 10; 6 years). Sera were tested using a broad panel of surface and intracellular antigens. We found autoantibodies in 5/124 patients (4%): high-positive GAD65 antibodies (n=1), low-positive GAD65 antibodies (N=1), VGKC complex antibodies not reactive with LGI1 or CASPR2 (n=3). We did not find any distinctive features distinguishing antibody positive patients from those without antibodies. The antibodies found in this cohort are probably neither disease-specific nor pathogenic. This has been suggested before for these antigenic targets. Moreover, they do not seem to modify disease severity in the antibody-positive epilepsy patients.

Paediatric brainstem encephalitis associated with glial and neuronal autoantibodies.

Central nervous system (CNS) autoantibodies have been reported in a range of neuroimmune diseases, but there has not been a systematic evaluation of autoantibodies in paediatric patients with brainstem encephalitis. Serum samples from 57 children (40 male, 17 female, median age 12y, range 0.6-18y) with a diagnosis of brainstem encephalitis were tested retrospectively for antibodies to GQ1b, aquaporin-4 (AQP4), myelin oligodendrocyte glycoprotein (MOG), N-methyl-D-aspartate receptor, LGI1, CASPR2, glycine receptor (GlyR), DPPX, and the voltage gated potassium channel (VGKC)-complex. Disease localized to the brainstem was seen in 19 patients: Bickerstaff's brainstem encephalitis (n=14) and clinically isolated syndrome (n=5). Polyfocal presentation was seen in 38 children, with predominantly white matter disease in 18 patients and grey matter in 20 patients. CNS surface antibodies were found in 22/57 patients (two patients with double positivity): GQIb (n=6), NMDAR (n=7), GlyR (n=5), MOG (n=5), and one AQP4. Three patients were positive for VGKC-complex antibodies. All patients were negative for antibodies to DPPX and the VGKC-complex antigens LGI1, CASPR2, and contactin-2. Although there were some partial differences in the presentations, the clinical features and outcomes did not relate clearly to the presence or absence of specific antibodies. As determined retrospectively, 39% of patients had cell surface antibodies. The results did not suggest any relationship with treatment or outcomes obtained but it is possible that specific antibody detection could be a helpful guide to more intensive immunotherapies in some cases.

ID 309 – Clinical, electrophyisological and serological evaluation of patients with cramp-fasciculation syndrome

Objective Cramp-fasciculation syndrome (CFS) is a rare peripheral nerve hyperexcitability syndrome. There is little information on the clinical and serological profile of a CFS cohort followed by a single outpatient clinic. Method Clinical, electrophysiological and serological features of 6 CFS patients (5men/1woman, 27-61years-old) were investigated. Results All patients presented with cramps, fasciculations, muscle pain and autonomic symptoms, while two of them also reported numbness and burning sensation in the limbs which was reminiscent of neuropathic pain. Nerve conduction studies and RR interval variability tests revealed normal results. Sympathetic skin responses were increased in amplitude, and prolonged after-discharges were recorded from the foot muscles after tibial nerve stimulation in all the patients. Antibodies to voltage-gated potassium channel(VGKC)-complex proteins were found in 3patients, one of whom was also positive for contactin-associated protein-like2(CASPR2) antibody. Two patients with neuropathic pain displayed non-CASPR2 VGKC-complex antibodies. None of the patients had a malignancy. Five patients showed favorable response to carbamazepine or pregabalin treatment, whereas one VGKC-antibody positive patient was resistant to carbamazepine and immunosuppressant treatment. Conclusion Autonomic symptoms, neuropathic pain and VGKC-complex antibodies are commonly found in CFS patients. Key message VGKC-complex antibody positivity might be an indicator of neuropathic pain and resistance to treatment in CFS.

Distinct white matter integrity in glutamic acid decarboxylase and voltage-gated potassium channel-complex antibody-associated limbic encephalitis.

Autoantibodies against glutamic acid decarboxylase (GAD) and the voltage-gated potassium channel (VGKC) complex are associated with distinct subtypes of limbic encephalitis regarding clinical presentation, response to therapy, and outcome. The aim of this study was to investigate white matter changes in these two limbic encephalitis subtypes by means of diffusion tensor imaging (DTI). Diffusion data were obtained in 14 patients with GAD antibodies and 16 patients with VGKC-complex antibodies and compared with age- and gender-matched control groups. Voxelwise statistical analysis was carried out using tract-based spatial statistics. The results were furthermore compared with those of 15 patients with unilateral histologically confirmed hippocampal sclerosis and correlated with verbal and figural memory performance. We found widespread changes of fractional anisotropy and all diffusivity parameters in GAD-associated limbic encephalitis, whereas no changes were found in VGKC-complex-associated limbic encephalitis. The changes observed in the GAD group were even more extensive when compared against those of the hippocampal sclerosis group, although the disease duration was markedly shorter in patients with GAD antibodies. Correlation analysis revealed areas with a trend toward a negative correlation of diffusivity parameters with figural memory performance located mainly in the right temporal lobe in the GAD group as well. The present study provides further evidence that, depending on the associated antibody, limbic encephalitis features clearly distinct imaging characteristics by showing widespread white matter changes in GAD-associated limbic encephalitis and preserved white matter integrity in VGKC-complex-associated limbic encephalitis. Furthermore, our results contribute to a better understanding of the specific pathophysiologic properties in these two subforms of limbic encephalitis by revealing that patients with GAD antibodies show widespread affections of white matter across various regions of the brain. In contrast to this, the inflammatory process seems to be more localized in VGKC-complex-associated limbic encephalitis, primarily affecting mesiotemporal gray matter.

Antibodies to AMPA receptors in Rasmussen's encephalitis.

Rasmussen's encephalitis is a rare progressive childhood disorder characterized by frequent severe seizures, hemiparesis, encephalitis and mental deterioration, and associated with severe unilateral neuroinflammation. Autoantibodies, particularly to the GluA3 subtype of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propinonic acid receptor (AMPAR) were reported in the 1990s but not always confirmed. To explore further, sera from 52 patients with Rasmussen's encephalitis were tested by cell-based assays for antibodies to AMPAR GluA1/2/3, N-methyl-d-aspartate (NMDA NR1/2b), γ-aminobutyric acid type A and B (GABAAR α1/γ2/β2 and GABABR b1/b2) receptors, for potassium channel complex proteins, and for binding to live cortical and hippocampal neuronal cultures. Two patients' sera (3.8%) bound to HEK cells co-transfected with the GluA2 and GluA3 subunits. One additional patient had a low level of VGKC-complex antibodies. These three, and seven additional, sera bound to hippocampal cultures. No other antibodies were detected. Thus, despite the rarity of GluA2/3 antibodies, 10 patients (19.2%) had evidence of antibodies to neuronal antigens. Whether these antibodies play a primary role in RE, or appear secondary to the neuro-inflammatory damage in this highly destructive disease, requires further study.

Chapter 11 - Voltage-gated potassium channel–complex autoimmunity and associated clinical syndromes

Voltage-gated potassium channel (VGKC)-complex antibodies are defined by the radioimmunoprecipitation of Kv1 potassium channel subunits from brain tissue extracts and were initially discovered in patients with peripheral nerve hyperexcitability (PNH). Subsequently, they were found in patients with PNH plus psychosis, insomnia, and dysautonomia, collectively termed Morvan's syndrome (MoS), and in a limbic encephalopathy (LE) with prominent amnesia and frequent seizures. Most recently, they have been described in patients with pure epilepsies, especially in patients with the novel and distinctive semiology termed faciobrachial dystonic seizures (FBDS). In each of these conditions, there is a close correlation between clinical measures and antibody levels. The VGKC-complex is a group of proteins that are strongly associated in situ and after extraction in mild detergent. Two major targets of the autoantibodies are leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2). The patients with PNH or MoS are most likely to have CASPR2 antibodies, whereas LGI1 antibodies are found characteristically in patients with FBDS and LE. Crucially, each of these conditions has a good response to immunotherapies, often corticosteroids and plasma exchange, although optimal regimes require further study. VGKC-complex antibodies have also been described in neuropathic pain syndromes, chronic epilepsies, a polyradiculopathy in porcine abattoir workers, and some children with status epilepticus. Increasingly, however, the antigenic targets in these patients are not defined and in some cases the antibodies may be secondary rather than the primary cause. Future serologic studies should define all the antigenic components of the VGKC-complex, and further inform mechanisms of antibody pathogenicity and related inflammation.

Central nervous system antibody-mediated diseases with autonomic involvement – Focus on VGKC-complex (LGI1, CASPR2), NMDAR and GlyR antibodies

Central nervous system antibody-mediated diseases with autonomic involvement – Focus on VGKC-complex (LGI1, CASPR2), NMDAR and GlyR antibodies

The Spectrum of Neuromyotonia: Clinics, Therapy and Outcome

Neuromyotonia (NM), Isaacs-Zschoke-Mertens syndrome or continuous muscle fiber activity (CMFA), is a rare condition associated with VGKC-antibodies. Clinically, fasciculations, myokymias, muscle stiffness and a myotonic appearance of movements after contraction are typical findings. In addition, CNS-symptoms vary from moderate fatigue, poor concentration and autonomic symptoms to severe encephalopathy in Morvan's syndrome. In electromyography, spontaneous irregular discharges can be found frequently with typical di-, tri- or multiplet single motor unit discharges. In up to 60 %, serum antibodies against VGKC-complexes can be detected. Patients with neuromyotonia were evaluated for clinical symptoms, response to treatment and outcome over a five-year period of follow-up. For evaluation, we used video recording of clinical symptoms, electroneurography, electromyography and myosonography as well as immunological tests (VGKC-complex antibody including CASPR2 and IGL1). Furthermore, cerebral fluid and screening for neoplasias were done. Patients with evidence for neuropathy, myopathy or motor neuron disease, even if diagnosed in the follow-up, were excluded. In 3 of 5 patients, neuromyotonia was diagnosed by electromyography and positive VGKC antibodies. In two patients, diagnosis was based on typical clinical symptoms and electromyographical changes. Anticonvulsants (carbamazepine) for symptomatic treatment were moderately effective in four patients; treatment with i. v. immunoglobulins was highly successful in one patient with high positive VGKC-complex antibody titers. In one patient with low-titer VGKC antibodies, neither anticonvulsants nor i. v. immunoglobulins nor prednisone was a successful treatment. Neuromyotonia is a rare, treatable condition. However, due to the high variability of symptoms, response to therapy and outcome, neuromyotonia treatment needs to be highly individualized.

Paving the Way to Understand Autoantibody-Mediated Epilepsy on the Molecular Level.

Correct function of neuronal networks is enabled by a delicate interplay among neurons communicating with each other. One of the keys is the communication at chemical synapses where neurotransmitters like glutamate, GABA, and glycine enable signal transfer over the synaptic cleft. Thereby, the neurotransmitters are released from the presynapse and bind as ligands to specific receptors at the postsynaptic side to allow for modulation of the postsynaptic membrane potentials. The postsynaptic electrical signal, which is highly modulated by voltage-gated ion channels, spreads over the dendritic tree and is thus integrated to allow for generation of action potentials at the axon hillock. This concert of receptors and voltage-gated ion channels depends on correct function of all its components. Misfunction of receptors and/or voltage-gated potassium channels (VGKC) leads to diverse adverse effects in patients. Such malfunctions can be the result of inherited genetic alterations or pharmacological side effects by drugs. Recently, autoantibodies targeting receptor or channel complexes like NMDAR, AMPAR, GABA-receptors, glycine receptors, LGI1 or CASPR2 (previously termed as VGKC-complex antibodies) have been discovered. The presence of specific autoantibodies against these targets associates with severe forms of antibody-mediated encephalitis. Understanding the molecular details of autoantibody actions on receptor and VGKC complexes is highly desirable and may open the path to develop specific therapies to treat humoral autoimmune encephalitis. Here, we summarize the current knowledge and discuss technical approaches to fill the gap of knowledge. These techniques include electrophysiology, biochemical approaches for epitope mapping, and in silico modeling to simulate molecular interactions between autoantibody and its molecular target.

PP08.9 – 2594: Glycine receptor antibody mediated progressive encephalomyelitis with rigidity and myoclonus (PERM) presenting as an abnormal startle response in an adolescent girl

Objective To describe a young girl in whom stimulus sensitive spasms were a diagnostic clue to the underlying glycine receptor antibody mediated progressive encephalomyelitis with rigidity and myoclonus (PERM) which has been described mainly in adults. Methods We illustrate the clinical data from the case-notes with a video recording of stimulus-sensitive spasms. Results A previously well 15-year-old girl presented with a traumatic head injury after falling down the stairs. The noise from a doorbell had triggered a severe muscle spasm causing the fall. She sustained a complex skull fracture with coup-contrecoup brain injury. She had previously been evaluated over five months for stimulus-sensitive whole body spasms with axial hyperextension without impairment of consciousness. She also had daily stimulus-sensitive myoclonic jerks, headaches and subtle cognitive impairment over the preceding year. Whilst on the paediatric intensive care unit, she was noted to have spontaneous and stimulus-sensitive muscle spasms (EMG duration 360–680 ms with no EEG correlate). She also developed generalised tonic clonic seizures, which were treated with Levetiracetam. A diagnosis of PERM was considered and glycine receptor antibodies were found to be strongly positive in serum and CSF. VGKC-complex antibodies were also weakly positive but GAD and NMDAR antibodies were negative. Oligoclonal bands were positive in CSF but negative in serum. Paraneoplastic antibodies were negative. Brain MRI showed contusions in the right hemisphere. Body imaging did not identify any tumours. Glycine receptor gene analysis is awaited. Her spasms have improved with a residual mild startle response to touch or loud auditory stimuli. She has a residual left hemiparesis. She was not treated with immunomodulation but will be followed up, and immunotherapy considered if she does not continue to improve and antibodies persist. Conclusion Glycine receptor antibody-mediated progressive encephalomyelitis with rigidity and myoclonus can present in children as stimulus-sensitive muscle spasms.

Clinical relevance of VGKC-complex antibodies in children (P6.253)

Clinical relevance of VGKC-complex antibodies in children (P6.253)

An 11-year retrospective experience of antibodies against the voltage-gated potassium channel (VGKC) complex from a tertiary neurological centre.

Acquired diseases classically associated with VGKC-complex antibodies include peripheral nerve hyperexcitability (PNH), Morvan's syndrome, limbic encephalitis (LE), and epilepsy. However, not all such patients have VGKC-complex antibodies and antibodies have been reported in patients without a defined immune-mediated syndrome. To analyse the clinical relevance of positive VGKC-complex antibodies requested on the basis of initial clinical suspicion. We retrospectively analysed patients with positive VGKC-complex antibodies (>100 pM) referred to our institution between 2001 and 2011. 1,614 VGKC-complex assays were performed in 1,298 patients. Titres >100 pM were detected in 57/1,298 (4 %) patients. A classic VGKC-complex channelopathy (60 %) was associated with VGKC-complex antibody titres >400 pM (p = 0.0004). LGI1 or CASPR2 antibodies were only detected in classic VGKC-complex channelopathies (LE; n = 3/4 and PNH; n = 1/5). VGKC-complex antibody titres <400 pM were seen with PNH (n = 15/22; 68 %) but also a heterogeneous range of central and/or peripheral nervous system disorders. Electromyography was supportive of PNH in 65 % of cases and symptomatic treatment was beneficial in 46 % of patients. Irrespective of titre, the rate of malignancy in patients with VGKC-complex antibodies was higher than the age-matched national incidence of malignancy (OR 19.9, 95 % CI 8.97-44.0 p<0.0001). Clinical phenotyping and antibody titres >400 pM can help determine VGKC-complex antibody relevance. Antibody titres <400 pM are associated with PNH but also a more heterogeneous clinical spectrum. The antibody association in the latter is of doubtful clinical relevance. The rate of malignancy was significantly higher than the national incidence irrespective of titre.

Processing of MOG is affected by post-translational modification in virus infected non-human primate B cells

one had VGKC-complex antibodies (1767 pM). The remaining 19 patients all had N1 sequential sample available and hippocampal NSAb reactivity was seen in 17/19. 5/17 patients showedNSAbs in all their samples,which rose in intensity (n= 3) or remained at similar intensity (n= 2) over time. 6/17 patients had serum with negative, and subsequently, positive NSAb reactivity, 4/17 went from positive to negative reactivity and 2/17 went from negative to positive and then returned to negative reactivity, both over 3 months. Interestingly, patients with JEV showed that they showed large punctae along cell bodies and dendrites, comparedwith the fine speckled punctae seen with the known antigenic targets such as the NMDAR, LGI1 or CASPR2. NSAbs often coexisted with reactivity towards known antigenic targets including the VGKC-complex (n= 7), NMDAR (n= 4), CASPR2 (n= 4), LGI1 (n= 1) and GABAAR (n= 1). Antibodies against GAD, GABABR, AMPAR, D2R and NMDAR IgA/M/E were detected in 0/34 patients, and 0/16 available CSFs showed anyNSAbs. Interestingly, therewas a trend towards the poorest functional outcomes in the patients without any antibodies (p= 0.05). Conclusion: Patients with JEV commonly harbour NSAbs, many of which target unidentified antigens. This expands the described association of HSV with NSAbs, and generates questions about inflammatory mechanisms and the use of immunotherapies in patients with viral encephalitis.

B cell depletion alters T cell homing

one had VGKC-complex antibodies (1767 pM). The remaining 19 patients all had N1 sequential sample available and hippocampal NSAb reactivity was seen in 17/19. 5/17 patients showedNSAbs in all their samples,which rose in intensity (n= 3) or remained at similar intensity (n= 2) over time. 6/17 patients had serum with negative, and subsequently, positive NSAb reactivity, 4/17 went from positive to negative reactivity and 2/17 went from negative to positive and then returned to negative reactivity, both over 3 months. Interestingly, patients with JEV showed that they showed large punctae along cell bodies and dendrites, comparedwith the fine speckled punctae seen with the known antigenic targets such as the NMDAR, LGI1 or CASPR2. NSAbs often coexisted with reactivity towards known antigenic targets including the VGKC-complex (n= 7), NMDAR (n= 4), CASPR2 (n= 4), LGI1 (n= 1) and GABAAR (n= 1). Antibodies against GAD, GABABR, AMPAR, D2R and NMDAR IgA/M/E were detected in 0/34 patients, and 0/16 available CSFs showed anyNSAbs. Interestingly, therewas a trend towards the poorest functional outcomes in the patients without any antibodies (p= 0.05). Conclusion: Patients with JEV commonly harbour NSAbs, many of which target unidentified antigens. This expands the described association of HSV with NSAbs, and generates questions about inflammatory mechanisms and the use of immunotherapies in patients with viral encephalitis.

Neuronal antibodies in patients with suspected or confirmed sporadic Creutzfeldt-Jakob disease

ObjectivesThere have been reports of patients with antibodies to neuronal antigens misdiagnosed as sporadic Creutzfeldt-Jakob disease (sCJD). Conversely, low levels of antibodies to neuronal proteins have been reported in patients...

Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity.

In limbic encephalitis (LE) with antibodies (Abs) to the voltage-gated potassium channel complex (VGKC), the Abs are mainly directed to the VGKC-complex proteins, leucine-rich, glioma inactivated 1 protein (LGI1) or contactin-associated protein-like 2 (CASPR-2) or neither. Here, we relate the outcomes of VGKC-LE patients to the presence of Abs to LGI1, CASPR-2 or neither antigen (LGI1/CASPR-2-Ab(-)). Clinical, neuropsychology and MRI data were obtained from patient records for all LE patients from the Bonn Epilepsy Centre positive for VGKC-Abs by radioimmunoprecipitation assay between 2002 and 2011. Eighteen VGKC-LE patients were identified: nine patients (50%) had LGI1-Abs, three (16%) had CASPR-2-Abs; and six (33%) were negative for both LGI1- and CASPR-2-Abs. At first assessment, the groups did not differ clinically or radiologically, but faciobrachial dystonic seizures were only observed in two LGI1-Ab(+) patients. All patients received monthly intravenous methylprednisolone (MP) pulses. At the most recent follow up (median 26months), thirteen (72%) were seizure-free, and seizure-freedom rates did not differ between the Ab groups. Hippocampal atrophy had developed in 7/9 LGI1-Ab(+) patients, but in none of the CASPR-2-Ab(+) or LGI/CASPR-2-Ab(-) patients (p=0.003). While all subgroups improved, memory scores only normalized in six patients (33%) and LGI1-Ab(+) patients were left with significantly poorer memory than the other two subgroups. Most VGKC-LE patients become seizure-free with pulsed monthly MP, but memory outcome is less favourable. Hippocampal atrophy and poor memory recovery is common in patients with LGI1-Abs and suggests permanent functional damage. More intense immunotherapies could improve outcomes in LGI1-Ab(+)-LE.