From VGKC to LGI1 and Caspr2 encephalitis: The evolution of a disease entity over time.

A wide variety of clinical syndromes has been associated with antibodies to voltage-gated potassium channels (VGKCs). Six years ago, it was discovered that patients do not truly have antibodies to potassium channels, but to associated proteins. This enabled the distinction of three VGKC-positive subgroups: anti-LGI1 patients, anti-Caspr2 patients and VGKC-positive patients lacking both antibodies. Patients with LGI1-antibodies have a limbic encephalitis, often with hyponatremia, and about half of the patients have typical faciobrachial dystonic seizures. Caspr2-antibodies cause a more variable syndrome of peripheral or central nervous system symptoms, almost exclusively affecting older males. Immunotherapy seems to be beneficial in patients with antibodies to LGI1 or Caspr2, stressing the need for early diagnosis. Half of the VGKC-positive patients lack antibodies to both LGI1 and Caspr2. This is a heterogeneous group of patients with a wide variety of clinical syndromes, raising the question whether VGKC-positivity is truly a marker of disease in these patients. Data regarding this issue are limited, but a recent study did not show any clinical relevance of VGKC-positivity in the absence of antibodies to LGI1 and Caspr2. The three VGKC-positive subgroups are essentially different, therefore, the lumping term 'VGKC-complex antibodies' should be abolished.

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.

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 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.

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.

HLA class I and II in Lambert-Eaton myasthenic syndrome without associated tumor.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder, in which antibodies against voltage-gated calcium channels located at nerve terminals cause muscle weakness and autonomic dysfunction. In approximately half of the patients the autoimmune process is initiated by a tumor. In the other half of patients no tumor is found and the etiology is unknown. The aims of this study were to investigate the strength of HLA-associations with nontumor LEMS (NT-LEMS) and to study the relation of HLA-haplotypes with age at onset of LEMS and other clinical features. Therefore, typing of HLA class I and II was performed in 19 patients with NT-LEMS, who were clinically evaluated. NT-LEMS was significantly associated with alleles of both HLA-class I (i.e. HLA-B8) as well as -class II (i.e. HLA-DR3 and -DQ2). HLA-B8+ patients had significantly younger age at onset of LEMS and tended to be female. This study shows that HLA-class I haplotype is associated with a distinct phenotype in NT-LEMS.

[Proximal muscle weakness, depressed tendon reflexes and autonomic dysfunction: the Lambert-Eaton myasthenic syndrome]. / Proximale spierzwakte, verlaagde peesreflexen en autonome disfunctie: Lambert-Eaton-myastheniesyndroom.

Three patients with Lambert-Eaton myasthenic syndrome (LEMS), two men aged 61 and 64 and a woman aged 55 years, all developed proximal weakness, depressed tendon reflexes and autonomic dysfunction. Although this clinical triad is highly suggestive for LEMS, the disorder had not been recognized initially. The woman had a small-cell bronchial carcinoma, treated successfully by chemotherapy, whereafter the LEMS symptoms gradually disappeared. The first man was treated with 3,4-diaminopyridine and azathioprine, whereupon his symptoms diminished. The other man had only slight complaints and refused drug treatment. The three cases illustrate that presentation and course of LEMS can vary between patients. Furthermore, clinical and electrophysiological features can suggest myasthenia gravis, myopathy or axonal polyneuropathy. Therapeutic options and the risk of underlying malignancy make early diagnosis important. In conclusion, in every patient presenting with unexplained proximal weakness, LEMS should be considered, especially if depressed tendon reflexes and autonomic dysfunction are found as well.

Paraparesis after lumbar puncture in a male with leukemia.

A diagnostic lumbar puncture was performed in a 12-year-old male with acute lymphoblastic leukemia. Because of thrombocytopenia (platelet count 42,000/mm(3)), a platelet transfusion was given immediately before the lumbar puncture. However, the platelet count was not re-examined. The patient developed progressive paraparesis shortly after the lumbar puncture. Magnetic resonance imaging revealed an extensive spinal subdural hematoma from the T2 to S2 level. This case report illustrates the sometimes dramatic consequences of lumbar puncture in patients with childhood leukemia. Guidelines for the examination of the platelet count and correction of thrombocytopenia before lumbar puncture are discussed.

Potential substance abuse. Detection among adolescent patients. Using the Drug and Alcohol Problem (DAP) Quick Screen, a 30-item questionnaire.

The authors administered an abbreviated revision of a previously field-tested, self-administered, brief screening test (the 30-item Drug and Alcohol Problem Quick Screen) to 355 consecutive middle-class adolescent patients seen at a five-pediatrician group practice setting. Ninety-six percent (341) of the subjects completed the 30-item screening questionnaire. Eighty-nine percent of the 341 responders wrote in their names in the space provided for that purpose. Fifty-two patients (approximately 15%) of the 341 responded "yes" to six or more items in the current study. Based on a previous study comparing scores from 200 adolescents from the same pediatric practice with answers from 100 identified adolescent drug abusers at a drug abuse treatment facility, those patients with a score of 6 or more were considered high risk for "red flag" behaviors, particularly drug or alcohol abuse. Forty (77%) of those patients who scored six or greater identified themselves by name. Four key items on the questionnaire accounted for 70 percent of the variation between those at high and those at low risk for drug or alcohol abuse. These four most important items encompassed 1) use of tobacco products; 2) accusation by others of having a drinking or drug problem; 3) school suspension; and 4) riding in a motor vehicle with a driver who drank too much. The DAP Quick Screen appears to be practical as a screening tool in physician's offices for detection of serious problems during adolescence.