STINGing away the pain: the role of interferon-stimulated genes.

Pain and inflammation are biologically intertwined responses that warn the body of potential danger. In this issue of the JCI, Defaye, Bradaia, and colleagues identified a functional link between inflammation and pain, demonstrating that inflammation-induced activation of stimulator of IFN genes (STING) in dorsal root ganglia nociceptors reduced pain-like behaviors in a rodent model of inflammatory pain. Utilizing mice with a gain-of-function STING mutation, Defaye, Bradaia, and colleagues identified type I IFN regulation of voltage-gated potassium channels as the mechanism of this pain relief. Further investigation into mechanisms by which proinflammatory pathways can reduce pain may reveal druggable targets and insights into new approaches for treating persistent pain.

Leucine-Rich Glioma-Inactivated 1 versus Contactin-Associated Protein-like 2 Antibody Neuropathic Pain: Clinical and Biological Comparisons.

Pain is a under-recognized association of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. Of 147 patients with these autoantibodies, pain was experienced by 17 of 33 (52%) with CASPR2- versus 20 of 108 (19%) with LGI1 antibodies (p = 0.0005), and identified as neuropathic in 89% versus 58% of these, respectively. Typically, in both cohorts, normal nerve conduction studies and reduced intraepidermal nerve fiber densities were observed in the sampled patient subsets. In LGI1 antibody patients, pain responded to immunotherapy (p = 0.008), often rapidly, with greater residual patient-rated impairment observed in CASPR2 antibody patients (p = 0.019). Serum CASPR2 antibodies, but not LGI1 antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences that may underlie our clinical observations. ANN NEUROL 2021;90:683-690.

Voltage-gated potassium channel limbic encephalitis presenting as functional cognitive impairment.

Limbic encephalitis is often reported to present as seizures and impaired cognition with little focus on psychiatric presentations. In this case report, we present a 49-year-old man who initially presented to the Psychiatric Liaison Service with a several month history of confusion with the additional emergence of visual hallucinations and delusions. Due to the inconsistent nature of the symptoms in the context of a major financial stressor, a provisional functional cognitive impairment diagnosis was made. Investigations later revealed a positive titre of voltage-gated potassium channel (VGKC) antibodies, subtype leucine-rich glioma inactivated 1 accounting for his symptoms which dramatically resolved with steroids and immunoglobulins. This case highlighted the need for maintaining broad differential diagnoses in a patient presenting with unusual psychiatric symptoms.

Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2.

Autoantibodies to leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein like-2 (CASPR2) are associated with clinically distinctive syndromes that are highly immunotherapy responsive, such as limbic encephalitis, faciobrachial dystonic seizures, Morvan's syndrome and neuromyotonia. These autoantibodies target surface-exposed domains of LGI1 or CASPR2, and appear to be directly pathogenic. In contrast, voltage-gated potassium channel (VGKC) antibodies that lack LGI1 or CASPR2 reactivities ('double-negative') are common in healthy controls and have no consistent associations with distinct syndromes. These antibodies target intracellular epitopes and lack pathogenic potential. Moreover, the clinically important LGI1 and CASPR2 antibodies comprise only ~15% of VGKC-positive results, meaning that most VGKC-antibody positive results mislead rather than help. Further, initial VGKC testing misses some cases that have LGI1 and CASPR2 antibodies. These collective observations confirm that laboratories should stop testing for VGKC antibodies and instead, test only for LGI1 and CASPR2 antibodies. This change in practice will lead to significant patient benefit.

Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome.

OBJECTIVE: To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions. METHODS: Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters. RESULTS: Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6-46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention. CONCLUSIONS: This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.

Therapeutic plasma exchange in neurological disorders: Experience from a tertiary neuroscience centre.

Therapeutic plasma exchange (TPE) involves the extracorporeal separation of plasma from the cellular components of blood with replacement fluid, such as human albumin or fresh frozen plasma. A number of studies across the world revealed that more than one third of TPE procedures were performed for neurological disorders. Myasthenia gravis (MG), Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) were the most frequently cited indications for TPE, followed by multiple sclerosis (MS). However, treatments of these conditions have evolved over the years and it is likely that this has impacted on clinical practice. Here we present our experience of using TPE to treat neurological disorders. We reviewed the medical records of all 63 patients who received 349 procedures over 70 therapeutic cycles between 2012 and 2015 in a tertiary neurology centre. In total only 2 patients with GBS and MG were treated with TPE. The commonest indication was voltage gated potassium channel (VGKC) complex antibody associated disorders followed by CIDP and MS. There were 11 patients with limbic encephalitis. Nine of them had antibodies against VGKC complex and two had N-methyl-D-aspartate (NMDA) receptor antibodies. Sixty four percent of patients with limbic encephalitis and overall 78% of patients responded to TPE. The complication rate associated with this procedure was 8.6 per 100 therapeutic cycle. There was no treatment related mortality. We observed a change in indications of TPE compared to historical studies. It was less frequently used to treated GBS and MG. It was found to be safe and effective.

Anti-Voltage-gated Potassium Channel Limbic Encephalitis with Psychiatric Features: a Case Report.

We report a case of anti-voltage-gated potassium channel (VGKC) limbic encephalitis in a 47-year-old man presenting with a 2-year history of psychiatric features. The patient had cognitive impairment, slurred speech, and a mildly unsteady gait but no other neurological deficits or seizures. Results of blood, urine, and cerebrospinal fluid tests and magnetic resonance imaging of the brain were normal. However, electroencephalography showed an epileptogenic focus in the bilateral temporal regions with mild to moderate diffuse encephalopathy. Autoimmune panel results confirmed the diagnosis of anti-VGKC limbic encephalitis, with a serum VGKC concentration of 6730 pmol/L. The patient was treated with Keppra and pulsed intravenous methylprednisolone for 3 days, and his behaviour improved.

Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case Series.

Objective Limbic encephalitis (LE) is an inflammatory condition of the limbic system that has an acute or subacute onset. Several types of antibodies are related to the onset of LE, including anti-N-methyl D-aspartate receptor (NMDAR) antibodies and voltage-gated potassium channel (VGKC)-complex antibodies. However, the characteristics and prevalence of LE remain unclear, especially in Asian cohorts, due to the rarity. We aimed to survey their characteristics. Materials and Methods Data of 30 cases clinically defined as "definite autoimmune LE" (based on the standard criteria) were retrospectively collected. These patients were categorized into four subtypes: NMDAR (+) (n=8), VGKC (+) (n=2), antibodies related to paraneoplastic syndrome (n=2), and an antibody-negative group (uncategorized) (n=18). Results LE is rare in Japan, and affected only 30 of 16,759 hospital patients (0.2%) over a ten-year period. The NMDAR (+) group showed distinctive symptoms, while the other three groups had similar indications. Brain MRI indicated significant medial temporal lobe atrophy at one year follow up after discharge. The prevalence of cognitive dysfunction as a complication was 64% (9/14). First-line immunotherapy resulted in a good outcome. A drastic improvement was seen from 4.0±1.1 to 1.1+ on the modified Rankin Scale. A good treatment outcome was observed in all groups (NMDAR, VGKC, and uncategorized), suggesting the importance of an early clinical diagnosis and the early initiation of treatment. Furthermore, we reviewed 26 cases that were clinically diagnosed as definitive autoimmune LE in previous case reports. Conclusion Our findings show that the establishment of a clinical diagnosis based on the clinical criteria of definitive autoimmune LE is important for the initiation of immunotherapy.

Potassium channels in omnipause neurons.

Potassium (K+) channels are major contributors to fast and precise action potential generation. The aim of this study was to establish the immunoreactivity profile of several potassium channels in omnipause neurons (OPNs), which play a central role in premotor saccadic circuitry. To accomplish this, we histochemically examined monkey and human brainstem sections using antibodies against the voltage gated K+-channels KV1.1, KV3.1b and K+-Cl- cotransporter (KCC2). We found that OPNs of both species were positive for all three K+-antibodies and that the staining patterns were similar for both species. In individual OPNs, KV3.1b was detected on the somatic membrane and proximal dendrites, while KV1.1 was mainly confined to soma. Further, KCC2 immunoreactivity was strong in distal dendrites, but was weak in the somatic membrane. Our findings allow the speculation that the alterations in K+-channel expression in OPNs could be the underlying mechanism for several saccadic disorders through neuronal and circuit-level malfunction.

Hippocampal network abnormalities explain amnesia after VGKCC-Ab related autoimmune limbic encephalitis.

OBJECTIVE: Limbic encephalitis associated with antibodies to components of the voltage-gated potassium channel complex (VGKCC-Ab-LE) often leads to hippocampal atrophy and persistent memory impairment. Its long-term impact on regions beyond the hippocampus, and the relationship between brain damage and cognitive outcome, are poorly understood. We investigated the nature of structural and functional brain abnormalities following VGKCC-Ab-LE and its role in residual memory impairment. METHOD: A cross-sectional group study was conducted. Twenty-four VGKCC-Ab-LE patients (20 male, 4 female; mean (SD) age 63.86 (11.31) years) were recruited post-acutely along with age- and sex-matched healthy controls for neuropsychological assessment, structural MRI and resting-state functional MRI (rs-fMRI). Structural abnormalities were determined using volumetry and voxel-based morphometry; rs-fMRI data were analysed to investigate hippocampal functional connectivity (FC). Associations of memory performance with neuroimaging measures were examined. RESULTS: Patients showed selective memory impairment. Structural analyses revealed focal hippocampal atrophy within the medial temporal lobes, correlative atrophy in the mediodorsal thalamus, and additional volume reduction in the posteromedial cortex. There was no association between regional volumes and memory performance. Instead, patients demonstrated reduced posteromedial cortico-hippocampal and inter-hippocampal FC, which correlated with memory scores (r = 0.553; r = 0.582, respectively). The latter declined as a function of time since the acute illness (r = -0.531). CONCLUSION: VGKCC-Ab-LE results in persistent isolated memory impairment. Patients have hippocampal atrophy with further reduced mediodorsal thalamic and posteromedial cortical volumes. Crucially, reduced FC of remaining hippocampal tissue correlates more closely with memory function than does regional atrophy.

A clinical TRIAD for early suspicion of autoimmune encephalitis as a possibility in patients presenting with progressive cognitive decline.

Patients with progressive cognitive decline mostly suffer from degenerative disease and carry a relatively poor prognosis. But small groups among these patients have a potentially treatable cause of illness and therefore every patient with dementia needs to be considered treatable unless proved otherwise. This group can be identified only by high degree of suspicion based on clinical clues. We have evaluated the validity of some simple clinical clues which we noticed in our patients with immune mediated dementias. The Panic score, Epsworth sleepiness score, catatonic symptoms and history of seizures were compared between 23 and 11 patients with serologically confirmed anti-NMDA antibody and anti-VGKC antibody associated encephalitis respectively. They were compared with 20 patients with probable behavioral variant of Frontotemporal dementia (bvFTD) and 20 patients with probable Alzheimer's disease (AD). Chi-square test was used to compare across the groups and there was significant difference (P < 0.05) across the 4 groups comprising anti NMDA encephalitis, anti VGKC encephalitis, FTD and AD among the four variables (Panic scores, Catatonic symptoms, Epsworth sleepiness score and seizures) studied. Our study revealed that panic and sleepiness is highly significant when tested across all groups and catatonia showed a trend towards NMDA and when compared with degenerative dementia versus immune mediated syndromes all the 4 parameters were highly significant This simple bedside TRIAD of panic, sleepiness with either of catatonia or seizures if found in patients it is appropriate to order antibody assessment before anything else is planned. This needs to be evaluated in a larger sample.

Post-malaria neurological syndrome: Imported case series and literature review to unscramble the auto-immune hypothesis.

Post-malaria neurological syndrome (PMNS) is a complication that occurs after recovery from a severe Plasmodium falciparum attack. Over the past two decades, the description of several imported cases has confirmed that this syndrome is a clearly distinct entity, different from other post malarial neurological disorders. However, the underlying mechanisms are not yet elucidated. Herein, we present five imported PMNS cases managed in Marseille, France. The detection of neuronal surface antibodies to an encephalitic syndrome of unknown origin allowed us to reveal positivity of anti Voltage-Gated-Potassium Channel antibodies (anti VGKC) in one of them. Using treatment options from other autoimmune encephalitis has to be explored in patients with PMNS.

LGI1 and CASPR2 neurological autoimmunity in children.

The clinical phenotype of leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated proteinlike 2 (CASPR2) autoimmunity is well defined in adults. Data for children are limited (<10 cases). Among 13,319 pediatric patients serologically tested for autoimmune neurological disorders (2010-2017), 264 were seropositive for voltage-gated potassium channel-complex-IgG (radioimmunoprecipitation). Only 13 (4.9%) were positive by transfected cell-binding assay for LGI1-IgG (n = 7), CASPR2-IgG (n = 3), or both (n = 3). This is significantly less than in adults. Encephalopathy, seizures, and peripheral nerve hyperexcitability were common, as was coexisting autoimmunity. No faciobrachial dystonic seizures or cancers were identified. Functional neurologic disorders were frequently the initial diagnosis, and immunotherapy appeared beneficial. Ann Neurol 2018;84:473-480.

Distinction between anti-VGKC-complex seropositive patients with and without anti-LGI1/CASPR2 antibodies.

BACKGROUND: To identify clinical and paraclinical differences between anti-voltage-gated potassium channel (VGKC)-complex seropositive patients with and without anti-leucine-rich glioma-inactivated protein 1 (LGI1)/contactin-associated protein-like 2 (CASPR2) antibodies (Abs). METHODS: We performed a retrospective analysis of 50 anti-VGKC-complex seropositive patients from January 2013 to September 2016, and tested them for anti-LGI1/CASPR2 Abs. Comparative analysis was performed between anti-LGI1/CASPR2 seropositive and 'double negative' patients. RESULTS: Seven patients had anti-LGI1/CASPR2 Abs while 43 patients were 'double negative' for these 2 Abs. Three 'double negative' patients had other neuronal surface Abs and were excluded from analysis. Compared to 'double negative' patients, a higher proportion of anti-LGI1/CASPR2 seropositive patients had complex partial seizures (5/7 vs 5/40; p = .003), limbic encephalitis (4/7 vs 2/40; p = .003), hippocampal imaging abnormalities (5/7 vs 3/39; p < .001), temporal epileptiform activity/electrographic seizures (4/6 vs 4/27; p = .020), tumours (3/7 vs 0/40; p = .002), and received acute immunotherapy (5/7 vs 6/40; p = .005) and maintenance immunotherapy (5/7 vs 4/40; p = .001). Anti-LGI1/CASPR2 seropositive patients had higher anti-VGKC-complex Abs levels (median 2857 pM [range 933-6730] vs 165 pM [104-1065]; p < .001). In contrast, a higher proportion of 'double negative' patients had non-specific behavioral disorders (20/40 vs 0/7; p = .015), and 13 of 40 (32.5%) had alternative organic diagnoses. CONCLUSION: In anti-VGKC-complex seropositive patients, we identified features in patients with anti-LGI1/CASPR2 Abs distinct from 'double negative' patients, and found that 'double negative' patients were associated with non-specific clinical features and had a high rate of alternative diagnosis. These findings demonstrate the limited utility of anti-VGKC-complex Abs testing in suspected neurological autoimmunity.

Analysis and discussion of the rare complication of autoimmune encephalitis: Two case reports.

RATIONALE: Autoimmune encephalitis related to many antibodies against neuronal cell surface or synaptic proteins, it is increasingly recognized as the cause of a variety of neuropsychiatric syndromes. PATIENT CONCERNS: The two pediatric cases were about autoimmune encephalitis with rare complication. One patient was a 11-year-old girl and was diagnosed with Voltage-Gated Potassium Channel complex (VGKC) antibody-mediated encephalitis with rhabdomyolysis; the other was also a 11-year-old girl and was diagnosed with anti- N-methyl-D-aspartate receptor (NMDAR) encephalitis. DIAGNOSES: Both patients were diagnosed as autoimmune encephalitis with rare complication. INTERVENTIONS: Intravenous methylprednisolone, oral prednisone and intravenous immunoglobulin was administered to both patients. OUTCOMES: One patient was discharged after a half month's hospitalization; the other was finally with intestinal function failure, gradually developed multiple organ failure, and eventually died. LESSONS: The pathogenic mechanism of autoimmune encephalitis associated with autoimmune disease is not fully understood, but may be related to a common immune pathological mechanism with variance in susceptibility caused by genetic or environmental factors.

Distinct HLA associations of LGI1 and CASPR2-antibody diseases.

The recent biochemical distinction between antibodies against leucine-rich, glioma-inactivated-1 (LGI1), contactin-associated protein-2 (CASPR2) and intracellular epitopes of voltage-gated potassium-channels (VGKCs) demands aetiological explanations. Given established associations between human leucocyte antigen (HLA) alleles and adverse drug reactions, and our clinical observation of frequent adverse drugs reactions in patients with LGI1 antibodies, we compared HLA alleles between healthy controls (n = 5553) and 111 Caucasian patients with VGKC-complex autoantibodies. In patients with LGI1 antibodies (n = 68), HLA-DRB1*07:01 was strongly represented [odds ratio = 27.6 (95% confidence interval 12.9-72.2), P = 4.1 × 10-26]. In contrast, patients with CASPR2 antibodies (n = 31) showed over-representation of HLA-DRB1*11:01 [odds ratio = 9.4 (95% confidence interval 4.6-19.3), P = 5.7 × 10-6]. Other allelic associations for patients with LGI1 antibodies reflected linkage, and significant haplotypic associations included HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02, by comparison to DRB1*11:01-DQA1*05:01-DQB1*03:01 in CASPR2-antibody patients. Conditional analysis in LGI1-antibody patients resolved further independent class I and II associations. By comparison, patients with both LGI1 and CASPR2 antibodies (n = 3) carried yet another complement of HLA variants, and patients with intracellular VGKC antibodies (n = 9) lacked significant HLA associations. Within LGI1- or CASPR2-antibody patients, HLA associations did not correlate with clinical features. In silico predictions identified unique CASPR2- and LGI1-derived peptides potentially presented by the respective over-represented HLA molecules. These highly significant HLA associations dichotomize the underlying immunology in patients with LGI1 or CASPR2 antibodies, and inform T cell specificities and cellular interactions at disease initiation.10.1093/brain/awy109_video1awy109media15796480660001.