syndrome
Titulaer, M.J.
Citation
Titulaer, M. J. (2010, November 24). Prediction of small cell lung cancer in the Lambert-Eaton myasthenic syndrome. Department of Neurology, Faculty of Medicine / Leiden University Medical Center (LUMC), Leiden University. Retrieved from https://hdl.handle.net/1887/16174
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CHAPTER 3
The Lambert-Eaton myasthenic syndrome 1988-2008 a clinical picture in 97 patients
MJ Titulaer 1, PW Wirtz 2, JBM Kuks 3, HJ Schelhaas 4, AJ van der Kooi 5, CG Faber 6, WL van der Pol 7, M de Visser 5, PAE Sillevis Smitt 8,
JJGM Verschuuren 1
1 Dep. of Neurology, Leiden University Medical Center, Leiden, the Netherlands
2 Dep. of Neurology, Haga Hospital, the Hague, the Netherlands
3 Dep. of Neurology, University Medical Center Groningen, the Netherlands
4 Dep. of Neurology, Radboud University Nijmegen Medical Centre, the Netherlands
5 Dep. of Neurology, Academical Medical Center, Amsterdam, the Netherlands
6 Dep. of Neurology, University Hospital Maastricht, the Netherlands
7 Dep. of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, the Netherlands
8 Dep. of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands
Published in a special issue of the Journal of Neuroimmunology, in memory of Prof. J.
Newsom-Davis.
Abstract
Introduction Neuromuscular symptoms in patients with Lambert-Eaton myasthenic syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in LEMS patients without a SCLC. We studied how this clinical information, which is readily available at the first consultation, can be used to predict the presence of SCLC.
Patients and methods In our study we included 52 LEMS patients with SCLC and 45 non-tumour patients (NT-LEMS). We interviewed patients using a structured checklist and reviewed their clinical records. We compared frequency and onset of symptoms during the course of LEMS.
Results In the first six months, over half the SCLC-LEMS patients had developed seven separate symptoms, while NT-LEMS patients developed only two symptoms. Proximal leg weakness and dry mouth were early symptoms in both groups. Rapid involvement of proximal arm muscles (p = 0.0001), distal arm muscles (p = 0.0037), distal leg muscles (p = 0.0002), dysarthria (p = 0.0091) and the presence of erectile dysfunction (p = 0.007) were found significantly more often in SCLC-LEMS patients in both cohorts. Cerebellar symptoms, although present in 9% of LEMS patients, were almost exclusively related to SCLC-LEMS.
Conclusions A rapidly progressive course of disease from onset in LEMS patients should raise a high suspicion of SCLC. Special attention should be paid to involvement of upper extremities, involvement of distal arm and distal leg muscles, to erectile dysfunction and probably ataxia in order to discriminate between SCLC- LEMS and NT-LEMS.
Introduction
In their 1988 landmark paper Newsom-Davis and colleagues described the clinical signs and symptoms of the Lambert-Eaton myasthenic syndrome (LEMS) as a disorder of neuromuscular transmission, characterized by proximal muscle weakness, areflexia and autonomic dysfunction.1 In half the patients a small cell lung carcinoma (SCLC) is found, mostly following the diagnosis of LEMS.1, 2 Despite several detailed publications there is still some debate about the symptoms typical for LEMS.3-6 When LEMS is diagnosed, a progressive clinical course of LEMS is associated with SCLC,6 although specific symptoms of LEMS do not distinguish between patients with SCLC and without.1, 2, 6 Smoking habits and the absence of HLA-B8 are factors associated with a higher risk of a SCLC.7 Clinical symptoms seem to be able to predict the presence of a SCLC as well, but our first series only described 38 patients.6 As all studies only described a small number of patients with this rare disease,3-6 we collected and studied a second, consecutive cohort of 59 patients.
Patients and methods
We included all Dutch LEMS patients with and without SCLC seen in our Neurology outpatient clinic between 1990 and 2007. Our clinic is a tertiary neuromuscular centre with special interest and expertise in disorders of the neuromuscular junction. Nationwide referral and inclusion started from July 1, 1998, as described before.8 Cohort I, included between 1998 and 2003, has been described before.6 The patients seen in our clinic between 2003 and 2007 are clustered in cohort II.
Diagnostic criteria for LEMS were characteristic clinical features and either the presence of VGCC antibodies or electromyographic features.6
After obtaining informed consent, we interviewed and examined all patients using a structured checklist. We recorded demographic and clinical features related to LEMS, including date of appearance of symptoms, date of diagnosis of LEMS and date of diagnosis of SCLC. Besides, clinical records were reviewed. In 19 patients, who could not visit our outpatient clinic, clinical records were studied and the responsible neurologist was interviewed. To diagnose a patient as LEMS without a tumour, a follow-up of at least three years after diagnosis of LEMS was necessary. Although for most patients a long follow-up was available, symptoms
SCLC-LEMS NT-LEMS p
number of patients 52 (54%) 45 (46%)
male: female 35:17 20:25 0.026 *
median age at onset, years (range) 59.5 (37-77) 54.0 (15-73) < 0.0005 § time to diagnosis LEMS, months (range) 4 (1-40) 19 (1-265) < 0.0005 § time to diagnosis SCLC, months (range) 4 (-1-54) n.a.
P/Q-type Ca channel antibodies 51 (98%) 39 (87%) 0.047 *
Table 1 Baseline characteristics LEMS patients with and without SCLC.
* Fisher´s exact test ; § Mann-Whitney U test ; n.a. not applicable
were scored for the first 24 months only. As most patients have been recognized as LEMS patients within the first two years, this is the period in which clinical differences can be useful as a diagnostic tool.
Median values for age and time from onset till diagnosis of LEMS were compared using the Mann-Whitney U test. Statistical comparisons between the patients with and without SCLC were analyzed using a Fisher’s exact test.
Although the clinical parameters are not independent factors, some correction for multiple comparisons seemed reasonable. A p-value of less than 0.01 was considered statistically significant.
Kaplan-Meier plots and log-rank tests were made for clinical symptoms. Log- rank tests are calculated for cohort I, cohort II and for both cohorts combined. A symptom was considered significantly different if the uncorrected p-value was <
0.05 for both cohorts combined and < 0.1 for both cohort I and cohort II separately.
Statistical analysis was performed using SPSS 12 (SPSS Inc., Chicago, IL).
SCLC-LEMS NT-LEMS
cohort I cohort II cohort I cohort II
number of patients 13 39 25 20
male: female 12:01 23:16 12:13 8:12
median age at onset, years (range) 57 (50-77) 60 (37-77) 54 (17-66) 54 (15-69) time to diagnosis LEMS, months (range) 4 (2-11) 4 (1-40) 19 (2-265) 20 (1-234) time to diagnosis SCLC, months (range) 4 (0-33) 4 (-1-54) n.a. n.a.
P/Q-type Ca channel antibodies 13 (100%) 38 (97%) 24 (96%) 15 (75%) Table 2 Baseline characteristics for the two different cohorts LEMS patients
Results
We studied 97 patients with LEMS. Initially 104 patients were seen in our clinic, but seven patients were excluded. In five patients follow-up was less than three years, in two clinical information was insufficient. Patient characteristics are summarized in Table 1. Fifty-two patients (54%) developed a SCLC. These patients were older and more frequently male. LEMS was diagnosed more quickly after onset of symptoms in patients with SCLC than in patients without (four versus nineteen months, p < 0.0005). Characteristics differentiated for the two cohorts are shown in Table 2. More patients in the first cohort have an idiopathic autoimmune LEMS, while in the second cohort the majority of LEMS patients had a SCLC.
symptoms with SCLC-LEMS NT-LEMS all Fisher's exact
onset within 24months (n=52) (n=45)
yes no % yes no % % p uncorrected
eye complaints 31 21 60% 24 21 53% 57% 0.55
ptosis 23 29 44% 22 23 49% 46% 0.69
diplopia 21 31 40% 16 29 36% 38% 0.68
bulbar complaints 39 12 76% 29 16 64% 71% 0.26
dysartrhia 36 16 69% 25 19 57% 64% 0.29
difficulty swallowing 23 29 44% 19 26 42% 43% 1
difficulty chewing 20 30 40% 10 35 22% 32% 0.079
neck weakness 20 28 42% 16 29 36% 39% 0.67
proximal weakness legs 52 0 100% 45 0 100% 100% 1
distal weakness legs 32 19 63% 12 33 27% 46% 0.0005
proximal weakness arms 47 5 90% 33 12 73% 82% 0.034
distal weakness arms 33 19 63% 19 26 42% 54% 0.043
wheelchair dependence 17 35 33% 9 36 20% 27% 0.18
dry eyes 12 28 30% 13 32 29% 29% 1
dry mouth 35 6 85% 32 13 71% 78% 0.13
male impotence 20 6 77% 10 10 50% 65% 0.07
constipation 13 33 28% 13 32 29% 29% 1
cerebellar ataxia 8 42 16% 1 44 2% 9% 0.033
Table 3 Proportion of patients with onset of separate symptoms at any time within first 24 months, cumulative. Statistically significant if p < 0.01 (bold)
Firstly, the frequencies of all symptoms appearing anytime during the first 24 months were analyzed (Table 3). Only weakness of the distal muscles in the legs appeared significantly more frequent in LEMS patients with SCLC than in patients without SCLC. Cerebellar ataxia, although not frequently present, was almost exclusively seen in SCLC-related LEMS patients, but did not reach statistical significance.
Secondly, the period of time between onset of disease and the moment half of the patients developed a certain symptom was calculated for all symptoms (Table 4). This median time of symptom onset was lower in LEMS patients with SCLC than in patients without SCLC for all symptoms. Kaplan-Meier curves showed that all symptoms developed more slowly in LEMS patients without a tumour (Figure 1). In the first six months the SCLC-LEMS patients had developed on average seven separate symptoms, while NT-LEMS patients developed only two symptoms. Proximal leg weakness and dry mouth were early symptoms in both groups. Log-rank tests showed that rapid involvement of proximal arm muscles, distal arm muscles, distal leg muscles, dysarthria and the presence of erectile dysfunction occurred significantly earlier during the disease course in SCLC-LEMS patients in both cohorts (Table 4).
Discussion
LEMS almost invariably starts with proximal weakness, especially of the legs (80%). Thereafter, all symptoms appear earlier during the course of disease in patients with a SCLC. Over half the patients with LEMS and SCLC developed seven symptoms within six months versus only two in NT-LEMS patients. This more profound and serious clinical picture suggests that the tumour-initiated immune response is more aggressive, also suggested by the diagnostic delay of only 4 months in SCLC-related LEMS, versus 19 months for non-tumour LEMS.
This confirms previous observations.1
Although almost all plots show that symptoms in patients with SCLC evolve earlier, only five of sixteen reach significance overall and in both cohorts separately. The differences are partly underestimated because of a treatment effect. Many LEMS patients were treated with chemotherapy or immunotherapy after a diagnosis had been made, which most likely prevented the development of additional symptoms. This phenomenon can be recognized in the plots in Figure 1.
The SCLC-related curves rise steeply in the first months and flatten thereafter to
become horizontally afterwards, while the curves related to the patients without SCLC rise more gradually for more months.
Most data are rather comparable between the two cohorts, although some differences are noteworthy. As the first cohort started in 1998, it is partly cross- sectional. As patients with a SCLC die mostly from their lung cancer, an over-
symptoms SCLC-LEMS NT-LEMS Kaplan Meier log-rank
median (months) all cohort I cohort II
p p P
eye complaints 6 18 0.18 0.0089 0.88
ptosis * * 0.91 0.46 0.54
diplopia * * 0.41 0.087 0.85
bulbar complaints 3 13 0.0091 0.0007 0.091
dysarthria 5 18 0.026 0.046 0.087
difficulty swallowing * * 0.48 0.34 0.71
difficulty chewing * * 0.038 0.06 0.14
neck weakness * * 0.55 0.99 0.6
proximal weakness legs 0 0 0.099 0.95 0.15
distal weakness legs 3 * 0.0002 0.055 0.018
proximal weakness arms 1 8 0.0001 0.0013 0.01
distal weakness arms 4 * 0.0037 0.026 0.064
wheelchair dependence * * 0.069 0.15 0.08
dry eyes * * 0.98 0.77 0.51
dry mouth 1 5 0.039 0.0031 0.26
male impotence 0 20 0.007 0.029 0.089
constipation * * 0.81 0.056 0.83
cerebellar ataxia * * 0.011 0.63 0.016
Table 4 Time till half of the patients has developed the specific symptom and log-rank test for appearance of symptoms for LEMS patients with and without a SCLC.
Eye complaints (ptosis and/or diplopia) and bulbar symptoms (dysarthria, difficulty swallowing, difficulty chewing and/ or neck weakness) are not regarded as separate symptoms as they are a symptom category.
* < 50% of patients have developed the specific symptom within 24 months.
Statistically significant if p < 0.05 for all patients combined and if p < 0.1 for both cohort I and cohort II, separately (bold). Uncorrected p-values are given.
representation of LEMS patients without a tumour is seen in cohort I. This could have led to recall bias in the LEMS patients with a long history of symptoms. As the interviewer was not blinded to the SCLC status, this could have been another bias.
No discrepancies with the clinical charts could be found confirming these possibilities. Selection bias could have occurred as patients with a very aggressive tumour were underrepresented in this first cohort. This would lead to under-
0 6 12 18 24
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Figure 1 Probability of appearance of clinical symptoms from onset of LEMS within the first two years (in months). The solid lines represent LEMS patients with SCLC and the dashed lines LEMS patients without SCLC. Cohort I and II are com- bined. Censored cases (deceased or end of follow-up) are indicated by crosses.
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Figure 1 (continued)
estimation of occurrence of symptoms in patients with SCLC. In our second cohort we had access to all patients tested positive for VGCC antibodies and all patients from the Dutch neuromuscular centres, so we expect this second cohort to be nearly complete. Unfortunately, part of these patients could not be interviewed in a structured way. This might have lead to underreporting of symptoms. Especially for autonomic symptoms, we strongly suspect the chart data to underestimate the real incidence of symptoms. Autonomic symptoms might be a decisive clue to diagnose LEMS in patients with proximal weakness of the legs, so we would like to emphasize their importance.
Eye complaints (ptosis and/ or diplopia) are seen regularly in patients with LEMS, but mostly not very short after onset of symptoms and only exceptionally
isolated.4, 5 The severity of ocular symptoms is rather mild, especially compared to the severity in myasthenia gravis. Weakness of the proximal legs is almost invariably amongst the first symptoms. Although it is an important clue for diagnosing LEMS, it is of no value in discriminating between tumour and non- tumour forms of LEMS. Cerebellar ataxia should raise severe suspicion of a SCLC and legitimates a repeated thorough investigation for a neoplasm, inside or outside the chest. Weakness of arms (proximal and/ or distal), distal legs, bulbar muscles and erectile dysfunction all seem useful for predicting the presence of an underlying SCLC. Aside from clinical signs and symptoms other patient characteristics, like smoking, smoking history, HLA- profile, presence of Sox- antibodies, age and sex might be useful to discriminate between SCLC-LEMS and non-tumour patients.7, 9
Although more sophisticated techniques to predict the presence of a tumour might become available in the near future, the value of the abovementioned easy available clinical clues should not be underestimated. Twenty years after the publication of the paper of O’Neill, Murray and Newsom-Davis we think it is still of major importance to take a detailed clinical history and perform a thorough physical examination as they are very helpful in finding clues for the presence of an underlying tumour in patients with LEMS.
References
1. O'Neill JH, Murray NMF, Newsom-Davis J: The Lambert-Eaton myasthenic syndrome - a review of 50 cases. Brain 111:577-596, 1988
2. Wirtz PW, Smallegange TM, Wintzen AR, et al.: Differences in clinical features between the Lambert-Eaton myasthenic syndrome with and without cancer: an analysis of 227 published cases. Clin Neur Neurosurg 104:359-363, 2002
3. Burns TM, Russell JA, LaChance DH, et al.: Oculobulbar involvement is typical with Lambert-Eaton myasthenic syndrome. Ann Neurology 53:270- 273, 2003
4. Rudnicki SA: Lambert-Eaton myasthenic syndrome with pure ocular weakness. Neurology 68:1863-1864, 2007
5. Titulaer MJ, Wirtz PW, Wintzen AR, et al.: Lambert-Eaton myasthenic syndrome with pure ocular weakness. Neurology 70:86, 2008
6. Wirtz PW, Wintzen AR, Verschuuren JJ: Lambert-Eaton myasthenic syndrome has a more progressive course in patients with lung cancer.
Muscle Nerve 32:226-229, 2005
7. Wirtz PW, Willcox N, van der Slik AR, et al.: HLA and smoking in prediction and prognosis of small cell lung cancer in autoimmune Lambert-Eaton myasthenic syndrome. J Neuroimmunol 159:230-237, 2005
8. Wirtz PW, van Dijk JG, van Doorn PA, et al.: The epidemiology of the Lambert-Eaton myasthenic syndrome in the Netherlands. Neurology 63:397-398, 2004
9. Titulaer MJ, Verschuuren JJ: Lambert-Eaton Myasthenic Syndrome: Tumor versus Nontumor Forms. Ann N Y Acad Sci 1132:129-134, 2008
