Nationwide survey of Lambert-Eaton myasthenic syndrome in Japan

Introduction

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease that targets the P/Q-type voltage-gated calcium channel (VGCC) at the motor neuron terminal of the neuromuscular junction.1–3 The classical triad is proximal muscle weakness, decreased tendon reflexes and autonomic dysfunction.4 In addition, about 10% of patients show cerebellar signs almost exclusively related to small-cell lung carcinoma (SCLC).5 Historically, Drs Lambert and Eaton described patients having malignant tumours with unique electrophysiological findings.6 7 Myasthenia gravis (MG) also represents proximal muscle weakness; however, the targets of autoimmunity are molecules on the postsynaptic membrane.8 Electrophysiological testing is used to discriminate LEMS from MG.9 The anti-P/Q-type VGCC antibody is a diagnostic biomarker for LEMS and is positive in almost 90% of patients.10 Moreover, animal experiments found that patients’ IgG was pathogenic to mice’s skeletal muscle.11 12 Notably, SCLC is associated with LEMS with a frequency of 60%.13

An epidemiological study is a fundamental approach to understanding the aetiology of rare diseases. It also contributes to establishing healthcare policies for rare diseases of unknown aetiology. However, no nationwide survey has been performed for LEMS in Japan. Thus, we conducted a national study following a standard epidemiological protocol14 to estimate Japanese LEMS prevalence and clinical features.

Methods

Study design

We asked physicians at medical departments in Japan to fill survey sheets retrospectively based on the medical records. A task force of Validation of Evidence-based Diagnosis and Guidelines and Impact on Quality of Life in Patients with Neuroimmunological Diseases from the Ministry of Health, Labour and Welfare (MHLW) of Japan designed the diagnostic criteria of LEMS (online supplemental table S1). The Japanese Society of Neurology approved the diagnostic criteria in 2019. The study group followed the Survey Manual of Study on Epidemiological Data Collection and Intractable Diseases from the MHLW, third edition.14 In addition, this study was performed in parallel with a nationwide survey of MG in Japan funded by MHLW. We summarise the flow of the study in figure 1.

Request permission

Figure 1

Flowchart of the epidemiological study of LEMS 2018. The study comprises the first study and the second study. LEMS, Lambert-Eaton myasthenic syndrome.

Results

Second survey

We obtained 30 clinical records from medical departments (figure 1) consisting of 16 men and 14 women (men:women ratio=1:0.88). The mean (SD) of the onset age of total patients was 62.2 (11.1) years old. The mean (SD) onset age of the men was 63.3 (9.4) years old and that for the women was 60.9 (13.0) (p=0.5858, Student’s t test) (figure 2). The mean (SD) of onset age of patients with tumour was 67.1 (9.0) years old, and that for patients without tumour was 57.8 (11.2) years old (p=0.0103, Student’s t test) (figure 3).

Request permission

Figure 2

The onset age of patients. Complete analysis and the analyses by sex.

Request permission

Figure 3

The onset age of patients with or without cancer. Patients with cancer were significantly older than those without cancer (Student’s t-test, p = 0.0103).

We compared the P-LEMS and AI-LEMS (table 1). Men were predominant in P-LEMS; on the other hand, women were dominant in AI-LEMS (p=0.0136, Fisher’s exact test). Disease duration was significantly longer in AI-LEMS than in P-LEMS (figure 4). The median (IQR) for AI-LEMS was 7.5 (5–11.8) and for P-LEMS was 2 (1–6.3) (p=0.0134). The patients’ symptoms at the time of the study were not different from those of the initial symptoms (online supplemental table S4). Complications of other autoimmune diseases were not remarkable.

Request permission

Figure 4

Disease duration (years) of P-LEMS and AI-LEMS. Overlapping of the box, scatter and violin plots. The disease duration of AI-LEMS was significantly longer than P-LEMS (Wilcoxon/Kruskal-Wallis test, p=0.0134). LEMS, Lambert-Eaton myasthenic syndrome; P-LEMS, paraneoplastic LEMS; AI-LEMS, a primary autoimmune form of LEMS.

Table 1

View inline|View popup

Symptoms and background information of LEMS patients with or without tumour

SCLC was found in 71.4% of tumours (10/14). A family history of LEMS was absent. However, one patient had Hashimoto’s disease as a complication and a family history of Hashimoto’s disease in her sister and aunt.

A total of 21 (84%) patients were positive for anti-P/Q-type VGCC antibody (positive: 21/tested: 25) (table 2). There was no significant difference in the positivity ratio for this autoantibody between P-LEMS and AI-LEMS (table 2). The frequency of cerebellar signs was similar between the groups, almost identical to a previous report.15 The titres of the anti-P/Q-type VGCC antibody were not different between P-LEMS and AI-LEMS. Electrophysiological tests were also frequently positive in both groups. However, there was no difference in the positive percentile of laboratory tests between P-LEMS and AI-LEMS.

Table 2

View inline|View popup

Laboratory tests of LEMS patients with or without tumour

Table 3 shows the patients’ therapeutic status. AI-LEMS tended to receive 3,4-diaminopyridine (3,4-DAP) frequently. However, overall usage of 3,4-DAP was limited. Prednisolone (PSL) usage was lower in P-LEMS; however, the frequency was not significantly different. Four (25%) AI-LEMS received immunosuppressants (azathioprine, tacrolimus). The plasmapheresi was frequent adjunctive therapy. The length of hospital stay was not different between P-LEMS and AI-LEM (table 4). However, the modified Rankin scale was significantly higher in P-LEMS. No patients died of LEMS; however, four patients died of tumor-associated causes.

Table 3

View inline|View popup

Therapies of LEMS patients with or without tumour

Table 4

View inline|View popup

Prognosis of LEMS patients with or without tumours

Discussion

This study was the first nationwide epidemiological survey of LEMS in Japan using a survey manual. The prevalence of LEMS was similar to previous reports from other countries. An epidemiological study from the Netherlands in 2004 by Wirtz et al reported a prevalence of LEMS (95% CI) of 2.5 (1.8–3.4) in 1 000 000 population.16 Moreover, Abenroth et al reported a prevalence of 2.6 per 1 000 000 (confirmed cases) in the US Veterans Affairs population.17 The prognosis in SCLC is poor, and median survival without treatment has been reported as 2–4 months.18 Therefore, our methodology may have a lower prevalence estimation.

LEMS is classified into two categories: LEMS with tumour (paraneoplastic LEMS: P-LEMS) and LEMS without tumour (a primary autoimmune form of LEMS: AI-LEMS). Titulaer et al reported that 54% of patients with LEMS had SCLC.19 Moreover, studies reported that men were predominant in LEMS with SCLC.20–22 In the present study, we found SCLC in 10 out of 30 patients with LEMS (33.3%), and 80% of patients with SCLC were men. A previous study with a larger sample size (n=97 patients) by Titulaer et al5 reported that the median age at onset of P-LEMS (with SCLC) was 59.5 years old, and that of AI-LEMS was 54 years old. On the other hand, our study indicated a significantly younger onset age in AI-LEM. A previous study reported a significant predominance of males in P-LEMS, and that the men and women ratio was similar in AI-LEMS.5 However, the present study showed male predominance in P-LEMS and female predominance in AI-LEM. In Japan, overall smoking prevalence (25–64 years) decreased from 56.0% to 38.4% among men and 17.0% to 13.0% among women from 2001 to 2016.23 Therefore, the proportional changes in sex in P-LEMS and AI-LEMS might be attributed to the demographic change in the smoking population, a primary risk factor for SCLC. In addition, LEMS often manifested prior to SCLC diagnosis. Therefore, we have to follow AI-LEMS up for SCLC for years. LEMS is strongly associated with SCLC. We found four patients of LEMS had tumours other than SCLC (aggressive fibromatosis, oropharyngeal endocrine tumour, mixed tumour of lung (squamous cancer and mucinous adenocarcinoma), lung cancer suspected). We cannot exclude the possibility of coincidence of these tumours with LEMS.

Our diagnostic criteria for LEMS followed Titulaer et al,4 modifying the 60% increment rate of compound muscle action potentials (CMAPs) after maximum voluntary contraction or at high frequency (50 Hz), as Oh et al proposed a 60% increment of CMAP as the diagnostic criteria to include seronegative LEMS.24 Sixty per cent increment of CMAP includes false-positive diagnosis; however, a cut-off of 100% improves specificity at the expense of sensitivity. Therefore, we have to consider the appropriate cut-off for increment. The proximal muscle weakness in AI-LEMS was 81.3% in initial symptoms. However, we did not exclude 18.7% of patients from the diagnosis of LEMS. This diagnostic policy is because we could not see the patients nor check every patient’s medical record. Therefore, we admit that the diagnostic process allows individual biases of physicians. According to our diagnostic criteria, the definite LEMS was 16, and the probable LEMS was 4 out of 30 patients.

Our study did not find any differences between P-LEMS and AI-LEMS in frequencies of initial symptoms, current symptoms, cerebellar ataxia, anti-P/Q-type VGCC antibodies and electrophysiological findings. In the present study, the two groups shared similar clinical and laboratory findings; thus, our findings suggest the necessity of radiological examinations to identify tumours in patients with LEMS. On the other hand, the sex ratio and onset ages differed between P-LEMS and AI-LEMS; thus, there may be some aetiological differences between these two conditions.

There were no statistical differences in the selection of medicines between the LEMS with tumour and without tumour groups. However, overall usage of 3,4-DAP was limited compared with previous reports.25 In Japan, there is no available medicine for 3,4-DAP. Therefore, we must use a chemical reagent of 3,4-DAP to treat LEMS after a particular application and approval. The lack of commercially available medicine prevents physicians from subscribing to 3,4-DAP for patients with LEMS. Therefore, we have to change this situation. We also noticed that the use of PSL and immunosuppressant is few in P-LEMS. We think that was because of the reported improved survival of SCLC with LEMS compared with SCLC alone.26–28 As P-LEMS was more severe symptoms than AI-LEMS, we could treat P-LEMS more aggressively.

The limitation of this study was the relatively small number of recovery in the second survey after the first survey (30/348, 8.6%). In addition, this study is the first nationwide epidemiological study; therefore, we have no data to compare in Japan. Therefore, we should repeat the nationwide study periodically. Before this study, we established the diagnostic criteria and the classification of disease severity, contributing to this study’s reliability. Our survey is based on the patients with LEMS who visited the medical departments from 1 January 2017 to 31 December 2017. Therefore, there is a possibility that we missed deceased patients of P-LEMS in this study, and those affected our P-LEMS estimation with our methodology.

This study revealed the clinical features of LEMS in Japan. In addition, a nationwide periodical survey will contribute to understanding LEMS and help improve the treatment and welfare of patients.