Paul W. Wirtz

Overlapping demyelinating syndromes and anti–N-methyl-D-aspartate receptor encephalitis.

To report the clinical, radiological, and immunological association of demyelinating disorders with anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis.

SOX Antibodies in Small-Cell Lung Cancer and Lambert-Eaton Myasthenic Syndrome: Frequency and Relation With Survival

PURPOSE SOX1 antibodies are common in small-cell lung carcinoma (SCLC) with and without paraneoplastic syndrome (PNS) and can serve as serological tumor marker. Addition of other antibodies might improve its diagnostic power. We validated an enzyme-linked immunosorbent assay (ELISA) to assess the diagnostic value of serum antibodies in SCLC and Lambert-Eaton myasthenic syndrome (LEMS). Clinical outcome with respect to SOX antibodies was evaluated, as the SOX-related antitumor immune response might help to control the tumor growth. PATIENTS AND METHODS We used recombinant SOX1, SOX2, SOX3, SOX21, HuC, HuD, or HelN1 proteins in an ELISA to titrate serum samples and validated the assay by western blot. We tested 136 consecutive SCLC patients, 86 LEMS patients (43 with SCLC), 14 patients with SCLC and PNS (paraneoplastic cerebellar degeneration or Hu syndrome), 62 polyneuropathy patients, and 18 healthy controls. RESULTS Our ELISA was equally reliable as western blot. Forty-three percent of SCLC patients and 67% of SCLC-LEMS patients had antibodies to one of the SOX or Hu proteins. SOX antibodies had a sensitivity of 67% and a specificity of 95% to discriminate between LEMS with SCLC and nontumor LEMS. No difference in survival was observed between SOX positive and SOX negative SCLC patients. CONCLUSION SOX antibodies are specific serological markers for SCLC. Our assay is suitable for high throughput screening, detecting 43% of SCLC. SOX antibodies have diagnostic value in discriminating SCLC-LEMS from nontumor LEMS, but have no relation to survival in patients with SCLC.

Differences in clinical features between the Lambert-Eaton myasthenic syndrome with and without cancer: an analysis of 227 published cases.

To compare the clinical features of patients with the Lambert-Eaton myasthenic syndrome (LEMS) associated with carcinoma, with patients having LEMS but no cancer, reports on LEMS patients were analyzed systematically. Cancer was detected (CD group) in 62% of the 227 included cases. This CD group showed a male predominance (70%). No sex difference was found in patients in whom no cancer was detected (NCD group). Median age at onset of LEMS in the CD group was higher than in the NCD group (58 and 49.5 years, P<0.01). Median interval between onset of symptoms and diagnosis of LEMS was longest in NCD cases (P<0.001). CD patients had additional immunological disorders less frequently than NCD cases (6 and 27%, P<0.001). Symptoms distinguishing the CD group from the NCD group were weight loss (P<0.001) and need for prolonged artificial ventilation after anaesthesia (P<0.05). This analysis shows significant differences between CD and NCD cases of LEMS. The male predominance and higher age at onset in patients with a tumor probably reflects the characteristics of patients with small cell lung cancer. The high frequency of additional immunological disorders in patients without malignancy, together with the younger age at onset suggests a similar etiology as other non-paraneoplastic autoimmune diseases.

Difference in distribution of muscle weakness between myasthenia gravis and the Lambert–Eaton myasthenic syndrome

Background: Myasthenia gravis and the Lambert–Eaton myasthenic syndrome (LEMS) may have a similar distribution of muscle weakness. Deciding on a diagnosis of myasthenia gravis or LEMS on clinical grounds may therefore be difficult. Objective: To compare the localisation of initial muscle weakness and the distribution of weakness at the time of maximum severity in patients with myasthenia gravis and LEMS. Subjects: 101 patients with myasthenia gravis and 38 patients with LEMS. Results: In myasthenia gravis, initial weakness involved extraocular muscles in 59%, bulbar muscles in 29%, and limb muscles in 12% of the patients. In LEMS no patient had ocular weakness, 5% had bulbar weakness, and 95% had weakness of the limbs as the first symptom (p < 0.001). At the point of maximum severity, weakness in myasthenia gravis was purely ocular in 25%, oculobulbar in 5%, restricted to the limbs in 2%, and present in both oculobulbar muscles and limbs in 68%. At this point, none of the LEMS patients had weakness restricted to extraocular or bulbar muscles (p = 0.002). The legs were affected in all LEMS patients, whereas in 12 patients with generalised myasthenia gravis limb weakness was restricted to the arms (p = 0.024). Conclusions: In a patient suspected to have a myasthenic syndrome whose first symptom is ocular weakness, LEMS is virtually excluded. Limb weakness confined to the arms is only found in generalised myasthenia gravis and not in LEMS. Muscle weakness in myasthenia gravis tends to develop in a craniocaudal direction, and in the opposite direction in LEMS.

The Lambert–Eaton myasthenic syndrome 1988–2008: A clinical picture in 97 patients

BACKGROUND 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-tumor 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), dysartria (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. CONCLUSION 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.

Clinical Dutch-English Lambert-Eaton Myasthenic Syndrome (LEMS) Tumor Association Prediction Score Accurately Predicts Small-Cell Lung Cancer in the LEMS

PURPOSE Approximately one half of patients with Lambert-Eaton myasthenic syndrome (LEMS) have small-cell lung carcinomas (SCLC), aggressive tumors with poor prognosis. In view of its profound impact on therapy and survival, we developed and validated a score to identify the presence of SCLC early in the course of LEMS. PATIENTS AND METHODS We derived a prediction score for SCLC in LEMS in a nationwide cohort of 107 Dutch patients, and validated it in a similar cohort of 112 British patients. A Dutch-English LEMS Tumor Association Prediction (DELTA-P) score was developed based on multivariate logistic regression. RESULTS Age at onset, smoking behavior, weight loss, Karnofsky performance status, bulbar involvement, male sexual impotence, and the presence of Sry-like high-mobility group box protein 1 serum antibodies were independent predictors for SCLC in LEMS. A DELTA-P score was derived allocating 1 point for the presence of each of the following items at or within 3 months from onset: age at onset ≥ 50 years, smoking at diagnosis, weight loss ≥ 5%, bulbar involvement, erectile dysfunction, and Karnofsky performance status lower than 70. The area under the curve of the receiver operating curve was 94.4% in the derivation cohort and 94.6% in the validation set. A DELTA-P score of 0 or 1 corresponded to a 0% to 2.6% chance of SCLC, whereas scores of 4, 5, and 6 corresponded to chances of SCLC of 93.5%, 96.6%, and 100%, respectively. CONCLUSION The simple clinical DELTA-P score discriminated patients with LEMS with and without SCLC with high accuracy early in the course of LEMS.

The epidemiology of myasthenia gravis, Lambert-Eaton myasthenic syndrome and their associated tumours in the northern part of the province of South Holland.

Abstract. We studied the epidemiology of myasthenia gravis (MG) and the Lambert-Eaton myasthenic syndrome (LEMS), and their association with small cell lung carcinoma (SCLC) and thymoma, in a well defined region of the Netherlands. Available data on all the patients with MG, LEMS, thymoma or SCLC living between 1 January 1990 and 31 December 1999 in the northern region of South Holland, with a population of 1.7 million inhabitants, were evaluated. A total of 202 patients with MG (20 with thymoma) and ten patients with LEMS (seven with SCLC) were identified. LEMS was 46 times less prevalent (2.32 × 10−6) than MG (106.1 × 10−6), whereas the annual incidence rate of LEMS was 14 times lower (0.48 × 10−6) than of MG (6.48 × 10−6), reflecting the poor survival of LEMS patients with SCLC. SCLC was diagnosed in 1593 patients, seven (0.44 %) of whom developed LEMS. Mean age at diagnosis of SCLC was significantly lower in SCLC patients with LEMS (p = 0.006). A thymoma was diagnosed in 32 patients, of whom the ten patients with MG (31 %) had a younger age at diagnosis of thymoma than the patients without MG (p = 0.27). This study confirms the increasing prevalence of MG over the last few decades as reported by others, and underscores the relative rarity of LEMS. The frequency of LEMS in our patients with SCLC was lower than reported in previous studies. In patients with a SCLC or thymoma, the tumour was diagnosed at younger age in those who had the associated myasthenic syndrome.

Screening for Small-Cell Lung Cancer: A Follow-Up Study of Patients With Lambert-Eaton Myasthenic Syndrome

PURPOSE A small-cell lung carcinoma (SCLC) is found in 50% of patients with Lambert-Eaton myasthenic syndrome (LEMS). We evaluated screening to optimize screening strategy for SCLC. It is important to detect these tumors early in newly diagnosed patients with LEMS to offer optimal patient treatment. PATIENTS AND METHODS A large nationwide cohort study of consecutive patients in the Netherlands, seen between 1990 and 2007, were screened for the presence of a tumor using chest x-ray, computed tomography of the thorax (CT-thorax), [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET), bronchoscopy, and/or mediastinoscopy. RESULTS SCLC was found in 54 patients, and in 46 patients, no tumor was found during a median follow-up of 8 years (range, 3 to 26 years). All patients with SCLC had a positive smoking history and 86% were still smoking at diagnosis. SCLC was found in 92% of these patients within 3 months and in 96% within a year. At first screening, CT-thorax detected an SCLC in 45 patients (83%), whereas chest x-ray found the tumor in only 23 patients (51%). An SCLC was found during secondary screening in another nine patients (median, 3 months; range, 1 to 41 months). In six patients, a lung tumor was found by CT-thorax or FDG-PET, and in three patients, extrapulmonary metastases were found, initially without identifiable tumor mass on CT-thorax. CONCLUSION In almost all patients (96%), the SCLC was found within 1 year of diagnosis. CT-thorax scans detected most of the tumors (93%) and was far more sensitive than chest x-ray (51%). FDG-PET may have additive value in selected cases. We propose a screening protocol based on CT-thorax and FDG-PET.

Clinical fluctuations in MuSK myasthenia gravis are related to antigen-specific IgG4 instead of IgG1

We studied the longitudinal relation between disease severity and titers of antigen-specific IgG subclasses in sera of patients with myasthenia gravis and antibodies to Muscle Specific Kinase (MuSK MG). Six patients were included of whom 55 samples had been collected during 2.5-13.4 years. Anti-MuSK antibodies were determined by ELISA and with a cell-based immunofluorescence assay. Disease severity was scored on a semi continuous scale. Only antigen-specific IgG4, and not IgG1, titers were significantly associated with disease severity in a linear mixed effect model (p = 0.036). Levels of IgG4 antibodies were above IgG1 in all samples except in one patient who went into clinical remission while switching from IgG4 to IgG1. The results support an important role for IgG4 in the pathogenesis of MuSK MG, in contrast to MG with anti-acetylcholine receptor antibodies.

Efficacy of 3,4‐Diaminopyridine and Pyridostigmine in the Treatment of Lambert–Eaton Myasthenic Syndrome: A Randomized, Double‐Blind, Placebo‐Controlled, Crossover Study

3,4‐Diaminopyridine and pyridostigmine are widely used to treat Lambert–Eaton myasthenic syndrome (LEMS), either alone or in combination. 3,4‐Diaminopyridine enhances the release of acetylcholine at the neuromuscular synapse, and pyridostigmine inhibits the degradation of this neurotransmitter. Although this could lead to a synergistic effect on neuromuscular transmission, no studies have compared the effects of these drugs in patients with LEMS. Therefore, we performed a placebo‐controlled, double‐dummy, double‐blind, randomized, crossover study in nine patients with LEMS.