Leucine-Rich Glioma-Inactivated 1 versus Contactin-Associated Protein-like 2 Antibody Neuropathic Pain: Clinical and Biological Comparisons.
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SUBMITTER: Ramanathan S
PROVIDER: S-EPMC8581990 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
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Leucine-Rich Glioma-Inactivated 1 versus Contactin-Associated Protein-like 2 Antibody Neuropathic Pain: Clinical and Biological Comparisons.
Ramanathan Sudarshini S Tseng Mandy M Davies Alexander J AJ Uy Christopher E CE Paneva Sofija S Mgbachi Victor C VC Michael Sophia S Varley James A JA Binks Sophie S Themistocleous Andreas C AC Fehmi Janev J Anziska Yaacov Y Soni Anushka A Hofer Monika M Waters Patrick P Brilot Fabienne F Dale Russell C RC Dawes John J Rinaldi Simon S Bennett David L DL Irani Sarosh R SR
Annals of neurology 20210830 4
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 s ...[more]
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Project description: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.
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Project description:ImportanceAlthough acquired autoimmune neuromyotonia (NMT) is associated with voltage-gated potassium channel (VGKC)-complex antibodies, to date there has been no systematic study of autoantibodies to the specific antigens leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein 2 (CASPR2), and contactin 2 together with the full clinical syndrome, particularly pain and autonomic and central nervous system involvement.ObjectivesTo study the full spectrum of clinical features and serum autoantibodies in patients with NMT, including the effects of pain on quality of life.Design, setting, and participantsA cohort study of clinical features and serologic testing in 38 patients with electrophysiologically-confirmed NMT, reviewed clinically between February 2007 and August 2009, in the Universities of Sydney and Kagoshima and followed up across 2 to 4 years. Association of NMT with quality of life was researched in an independent, patient-led, online pain survey conducted from April 2012 to May 2012. Serologic analyses were performed in 2012, and final data analysis was performed in 2016.Main outcomes and measuresClinical data and scores on the modified Rankin Scale (mRS), which measures disability on a range of 0 to 6, with 0 indicating normal and 6 indicating death, before and after treatments were combined with CASPR2, LGI1, and contactin 2 antibody status.ResultsAmong the 38-person NMT cohort, 25 (65.8%) were male and the median (range) age was 55 (12-85) years. Twenty-three (60.5%) were Japanese and 15 (39.5%) were of white race/ethnicity. Symptomatic treatments (mainly antiepileptic drugs) were used in most patients with mild disease (12 patients with mRS <3), whereas immunotherapies were successful in most patients with mRS scores greater than 2. Autoantibodies to VGKC-complex antigens (17 patients [45%]), bound to CASPR2 (5 [13%]), contactin 2 (5 patients, 1 with CASPR2 [13%]), LGI1 (2 [5%]), or both LGI1 and CASPR2 (6 [16%]). The last group of 6 patients had high mRS scores (mean [SD], 3.8 [1.7]), thymoma (4 patients), pain (5 patients), autonomic (6 patients) and sleep (5 patients) disturbance, suggesting Morvan syndrome. The 56 responders to the independent patient-led survey reported pain that could be severe, anatomically widespread, and that often resulted in unemployment, domestic problems, and poor quality of life.Conclusions and relevanceThe cohort study detailed underrecognized aspects of the clinical and serologic spectrum of NMT. The heterogeneity of clinical features and of specific antibodies limit associations, but the common existence of thymoma, pain, and autonomic and central nervous system features, often with both LGI1 and CASPR2 antibodies, should be better recognized to more completely address the range of comorbidities and consequences of the disease regarding quality of life.
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Project description:Patient-reported quality-of-life (QoL) and carer impacts are not reported after leucine-rich glioma-inactivated 1-antibody encephalitis (LGI1-Ab-E). From 60 patients, 85% (51 out of 60) showed one abnormal score across QoL assessments and 11 multimodal validated questionnaires. Compared to the premorbid state, QoL significantly deteriorated (p < 0.001) and, at a median of 41 months, fatigue was its most important predictor (p = 0.025). In total, 51% (26 out of 51) of carers reported significant burden. An abbreviated five-item battery explained most variance in QoL. Wide-ranging impacts post-LGI1-Ab-E include decreased QoL and high caregiver strain. We identify a rapid method to capture QoL in routine clinic or clinical trial settings.
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Project description:ImportanceThis observational study describes the efficacy and safety of rituximab in 5 patients with voltage-gated potassium channel (VGKC)-complex/leucine-rich, glioma-inactivated 1 (LGI1) antibody-associated encephalopathy. Rituximab is a monoclonal antibody that targets CD20 and is used to treat other neurologic and nonneurologic diseases.ObservationsThis case series reports sequential seizure frequencies, modified Rankin Scale scores, and VGKC-complex antibody titers in 5 adult patients (median age, 65 years; range, 48-73 years) treated with rituximab. Median time from symptom onset to rituximab initiation was 414 days (range, 312-851 days). One patient showed a rapid clinical improvement after treatment with rituximab alone and experienced a rituximab-responsive clinical relapse. Another showed possible improvement on neuropsychometric memory indexes after rituximab therapy. In contrast, all patients showed robust responses to treatment with glucocorticoids, intravenous immunoglobulins, and/or plasma exchange at some point in their illness. Treatment with glucocorticoids-less so with intravenous immunoglobulins and plasma exchange-was associated with the most marked reductions in VGKC-complex antibodies. The only patient who did not receive glucocorticoids showed the poorest clinical and serologic responses.Conclusions and relevanceRituximab was well tolerated in this predominantly older adult patient population and may be an effective option for some patients with LGI1 antibody-associated encephalopathy. Glucocorticoid therapy appears particularly efficacious. Earlier rituximab administration and randomized trials are required to formally assess efficacy.
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Project description: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.
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Project description:PurposeA general glucose metabolism pattern is observed in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis; however, it is unclear whether further subregional metabolic differences exist. Therefore, the present study aimed to conduct an in-depth exploration of the features of glucose metabolism within specific brain areas using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET).Materials and methodsThis retrospective study enrolled thirteen patients confirmed with LGI1 antibody encephalitis who were admitted to Beijing Tiantan Hospital from June 2021 to September 2022. All patients underwent 18F-FDG PET before initiating clinical treatment. Changes in glucose metabolism in specific brain areas were analyzed using Cortex ID software. The laterality of 18F-FDG uptake was assessed, and differences in specific brain areas were compared using paired t-tests.ResultsSignificant metabolic changes in at least one brain region in 11 out of 13 patients (84.6%) were revealed by semi-quantitative analysis (z-score > 2). A bilateral decrease in the 18F-FDG metabolic pattern was revealed in almost all brain regions of interest; in contrast, a hypermetabolic pattern was observed in the medial temporal region, with mean z-scores of 1.75 ± 3.27 and 2.36 ± 5.90 on the left and right sides, respectively (p = 0.497). In the prefrontal and temporal lobes, 18F-FDG metabolism was significantly lower in the lateral region than in the medial region on both sides. For the cingulate cortex, significant hypometabolism was also observed in the posterior part compared to the anterior counterpart on both the left (z-score: -1.20 ± 1.93 vs. -0.42 ± 1.18, respectively; p = 0.047) and right (z-score: -1.56 ± 1.96 vs. -0.33 ± 1.63, respectively; p = 0.001) sides. However, a significant difference in regional metabolism was observed only on the left side (p = 0.041).ConclusionAn asymmetric 18F-FDG metabolic pattern exists in patients with anti-LGI1 encephalitis. Meanwhile, varied regional metabolic differences were revealed bilaterally in specific cerebral areas, which could be associated with the clinical manifestations.
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