Association of Leucine-Rich Glioma Inactivated Protein 1, Contactin-Associated Protein 2, and Contactin 2 Antibodies With Clinical Features and Patient-Reported Pain in Acquired Neuromyotonia

Abstract

Importance: Although 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.

Objectives: To 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 participants: A 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 measures: Clinical 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.

Results: Among 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 relevance: The 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.

Figure 1.. Modified Rankin Scale (mRS) Scores in 28 Patients With Neuromyotonia (NMT) Before and After Treatment^a

A, Scores in male and female patients before treatment and at follow-up (FU). B, Scores before treatment and at FU according to treatment type. Further information on treatment responses is given in eTable 4 in the Supplement. C, Scores in patients with tumors (3 thymomas, 3 prostate tumors, and 1 acute lymphocytic leukemia after bone marrow transplant) and without tumors. In most cases, mRS scores were lower at FU (2-tailed paired t tests). The mRS measures disability on a range of 0 to 6, with 0 indicating normal and 6 indicating death. Solid horizontal lines indicate means. P values were determined by 2-tailed t test. AED indicates antiepileptic drugs and other symptomatic therapies; IT, immunotherapy. ^aP < .001 for the change in mRS score at FU. ^bP = .02 for the change in mRS score at FU. ^cP = .001 for the change in mRS score at FU.

Figure 2.. Antibodies in Patients With Neuromyotonia (NMT)

A, A serum sample positive for both contactin-associated protein 2 (CASPR2) and leucine-rich glioma inactivated protein 1 (LGI1) antibodies. The binding of the patient’s IgG antibodies (Abs) to human embryonic kidney cells (enhanced green fluorescent protein [EGFP] [green] label) was detected with Alexa fluor anti-human IgG (red). Binding was scored on a scale of 0 to 4, with 0 indicating negative; 1, positive; and 2 to 4, increasing positivity. This serum sample scored 2.5 and 2.0 as shown. Results of tests for contactin 2 Abs were negative (data not shown). This patient had mild disease (modified Rankin Scale [mRS] score, 2), unlike the other 5 patients with LGI1 and CASPR2 Abs (mRS scores, 3-5), and his disease responded to carbamazepine with immunotherapies (mRS score, 1). B, Voltage-gated potassium channel (VGKC)–complex antibody titers associated with the presence of specific Abs or none. The horizontal line indicates the cutoff for positivity, 1. Eleven serum samples were positive (>100pM) by radioimmunoprecipitation, but high titers were only found in those with LGI1 and CASPR2 Abs. C, The cell-based assay (CBA) scores in patients with either a single or 2 different Ab specificities. The horizontal line indicates the cutoff for positivity, 100pM. CASPR2 and LGI1 antibodies together gave the highest binding scores, but few reached the maximum score of 4. D, Modified Rankin Scale scores were not different between patients with or without detectable CBA Abs, but in both cases mRS scores decreased at follow-up (FU) (2-tailed paired t tests). ^aP = .003 for the change in mRS score at FU. ^bP = .002 for the change in mRS score at FU.

Figure 3.. Characteristics of Pain in 56 Patients With Neuromyotonia (NMT) or Related Diagnoses

A, Percentage of patients reporting pain in different anatomic regions. B, Percentage of patients reporting different types of pain. C, Pain scores at best, at worst, and after treatment. D, Influence of pain on quality of life. Patients responding to a patient-led online survey were asked to score their experiences of pain and its consequences on a scale of 0 to 10, with 0 indicating none or no effect and 10 indicating incapacitating or substantial effect. A summary of the questionnaire is in the Box, and the full questionnaire is provided in eTable 2 in the Supplement. Results in C and D are shown as median scores. Whiskers indicate interquartile range.