Dragana Lavrnic

The features of myasthenia gravis with autoantibodies to MuSK.

Objectives: To determine if myasthenia gravis (MG) with antibodies to MuSK is a distinct subgroup of seronegative MG. Methods: We assayed antibodies to muscle specific tyrosine kinase (MuSK) in 55 MG patients who had no antibodies to acetylcholine receptors and looked for the specific phenotype, comparing clinical features of anti-MuSK positive and anti-MuSK negative MG patients. Results: MG with anti-MuSK antibodies was characterised by a striking prevalence of female patients (15 women, two men). Age at onset ranged from 22 to 52 years, with 70.6% of patients presenting at <40 years of age. The majority of patients (82.4%) had prevalent involvement of facial and bulbar muscles. One third of them did not respond well to anticholinesterase drugs. Steroid immunosuppression was effective in eight patients (44.4%). Nine patients underwent thymectomy; six of these had no thymus pathology, while three had a hyperplastic thymus. At the end of the observation period, six (35.3%) patients were in remission, five (29.4%) improved, four (23.6%) did not change, and two (11.7%) had died. Conclusions: MG patients with antibodies to MuSK have characteristic clinical features that are different from features of the remaining seronegative MG patients. This emphasises the predictive value of anti-MuSK antibody analysis in seronegative MG patients.

A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis.

Double-seronegative myasthenia gravis (dSN-MG, without detectable AChR and MuSK antibodies) presents a serious gap in MG diagnosis and understanding. Recently, autoantibodies against the low-density lipoprotein receptor-related protein 4 (LRP4) have been identified in several dSN-MG sera, but with dramatic frequency variation (∼2-50%). We have developed a cell based assay (CBA) based on human LRP4 expressing HEK293 cells, for the reliable and efficient detection of LRP4 antibodies. We have screened about 800 MG patient sera from 10 countries for LRP4 antibodies. The overall frequency of LRP4-MG in the dSN-MG group (635 patients) was 18.7% but with variations among different populations (range 7-32.7%). Interestingly, we also identified double positive sera: 8/107 anti-AChR positive and 10/67 anti-MuSK positive sera also had detectable LRP4 antibodies, predominantly originating from only two of the participating groups. No LRP4 antibodies were identified in sera from 56 healthy controls tested, while 4/110 from patients with other neuroimmune diseases were positive. The clinical data, when available, for the LRP4-MG patients were then studied. At disease onset symptoms were mild (81% had MGFA grade I or II), with some identified thymic changes (32% hyperplasia, none with thymoma). On the other hand, double positive patients (AChR/LRP4-MG and MuSK/LRP4-MG) had more severe symptoms at onset compared with any single positive MG subgroup. Contrary to MuSK-MG, 27% of ocular dSN-MG patients were LRP4 antibody positive. Similarly, contrary to MuSK antibodies, which are predominantly of the IgG4 subtype, LRP4 antibodies were predominantly of the IgG1 and IgG2 subtypes. The prevalence was higher in women than in men (female/male ratio 2.5/1), with an average disease onset at ages 33.4 for females and 41.9 for males. Overall, the response of LRP4-MG patients to treatment was similar to published responses of AChR-MG rather than to MuSK-MG patients.

Epidemiological and clinical characteristics of myasthenia gravis in Belgrade, Yugoslavia (1983–1992)

This is the first epidemiological study of myasthenia gravis (MG) in the area of Belgrade. During the survey period (1983–1992), 124 incidental cases of MG were observed, producing an average annual incidence rate of 7.1 per million population (women, 8.3; men, 5.8). Age and sex specific incidence rates for females demonstrated a bimodal pattern, with the first peak in the age group between 20 and 40, and the second peak in the age group 70–80. The age‐specific rates for males showed unimodal pattern, reaching a maximum in the age group between 60 and 80. There was a tendency of more frequent disease appearance in the urban as opposed to the suburban districts. On the prevalence day, December 31, 1992, the point prevalence rate was 121.5 per million (women, 142.5; men, 98.8). Only for incidental cases, the point prevalence rate was 77.1 (women, 83.2; men, 70.4). The average annual mortality rate was 0.47 per million (females, 0.52; males, 0.42), while cumulative lethality was 5.6 (women, 5.6; men, 5.7). Most frequently initial symptoms were ocular, occurring in 58% patients. Through the period of investigation ocular symptoms were generalized in 68%, most frequently in the first 2 years (62.5%). Thymoma was confirmed in 11.3% of patients. In this group there was equal presence of both sexes, older median age at onset, and more severe clinical course of MG. Associated autoimmune disease was found in 17 out of 124 incidental cases (13.7%). The most common were thyroid diseases (7.3%). Family history of MG was recorded in 2 cases belonging to 1 family (1.6%).

Cyclosporine in the treatment of myasthenia gravis

Cyclosporine A (CsA) treatment was evaluated in 52 patients with severe generalized myasthenia gravis (MG) whose illness was not controlled by anticholinesterase drugs, thymectomy, corticosteroids, and azathioprine. The efficacy of CsA treatment was expressed by mean disability score quotient (MDSQ), which was obtained by comparing mean disability score (MDS) at the beginning of the treatment with the MDS at the end of the follow‐up period. For the entire group of patients MDSQ was 53.3%, indicating moderate improvement. Analyzing individual cases, eight patients (15%) did not improve, 17 (33%) showed moderate improvement, 20 (38%) showed remarkable improvement, and seven patients (14%) achieved complete remission. The most common side effects were rise of serum creatinine (seven), hypertension (two), gingival hyperplasia (two), hypertrichosis (six), myalgia (10), and ‘flu‐like’ symptoms (10 patients). The results of this study suggest that CsA is efficacious and safe treatment in severe and resistant forms of MG.

Impairment of cardiac autonomic control in patients with amyotrophic lateral sclerosis

Abstract The aim of this study was to investigate autonomic cardiac control in patients with amyotrophic lateral sclerosis (ALS). Fifty-five patients with sporadic ALS (28 female and 27 male; average age 56.00 ± 10.34 years) were compared to 30 healthy controls (17 female and 13 male; average age 42.87 ± 11.91 years). Patients with previous history of cardiac disease, diabetes mellitus, and impaired respiratory function were excluded from the study. Cardiovascular autonomic tests according to Ewing, power spectrum analysis of RR variability (low- and high-frequency bands – LF and HF, LF/HF index), real-time beat-to-beat ECG signal monitoring with heart rate variability analysis and baroreflex function analysis were carried out in all patients. Time-domain parameters of heart rate variability (mean RR interval, SDNN, SDANN, SDNN index, rMSSD and pNN50%) were obtained from 24-h ECG monitoring. ALS patients had a significantly higher score of sympathetic (p <0.01) and parasympathetic (p <0.001) dysfunction, as well as of the overall score of autonomic dysfunction (p <0.001). LF/HF index was significantly increased; baroreflex sensitivity and time-domain parameters of heart rate variability were highly significantly decreased in ALS patients (p <0.001). Our results demonstrated impaired cardiac autonomic control in ALS with marked parasympathetic dysfunction and sympathetic predominance.

Influence of multisystemic affection on health-related quality of life in patients with myotonic dystrophy type 1.

AIM To assess health-related quality of life (HRQoL) in patients with DM1, to identify muscular, multisystemic, central and social factors that may affect QoL and to define a DM1 patient in risk of poor QoL. PATIENTS AND METHOD This cross-sectional study comprised 120 DM1 consecutive patients. The following scales were used: Multidimensional Scale of Perceived Social Support (MSPSS), Muscular Impairment Rating Scale (MIRS), battery of neuropsychological tests, acceptance of illness scale (AIS), Hamilton rating scale for depression (Ham-D), Krupps Fatigue Severity Scale (FSS), Daytime Sleepiness Scale (DSS) and SF-36 questionnaire. RESULTS HRQoL was impaired in DM1 patients in both physical and mental domains (PCS was 41.8±23.5, MCS 47.0±24.3 and total SF-36 score 45.6±24.0). The most significant factors correlating with better SF-36 total score were younger age (β=-0.45, p<0.001), shorter duration of disease (β=-0.27, p=0.001), higher education (β=0.20, p=0.009), less severe muscular weakness (β=-0.52, p<0.001), normal swallowing (β=0.22, p=0.005), absence of fainting (β=0.31, p=0.002), absence of snoring (β=0.21, p=0.036), better acceptance of disease (β=-0.17, p=0.036), lower depressiveness (β=-0.46, p=0.001), lower fatigue (β=-0.32, p=0.001), absence of cataract (β=-0.21, p=0.034), absence of kyphosis (β=0.31, p=0.004) and absence of constipation (β=0.24, p=0.016). Second linear regression analysis revealed that depressed (β=-0.38, p<0.001) and elder patients (β=-0.27, p=0.007) and as well as those with poor acceptance of illness (β=-0.21, p=0.006) were in especially higher risk of having poor HRQoL (R(2)=0.68). CONCLUSION We identified different central, social, muscular, cardiorespiratory and other factors correlating with HRQoL. It is of great importance that most of these factors are amenable to treatment.

Is hyperlipidemia correlated with longer survival in patients with amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is the most serious form of degenerative motor neuron disease in adults, whose relentless course leads to death within 2–5 years, generally due to respiratory failure. Apart from the age and site of onset, no other factors have consistently demonstrated to be related to the ALS outcome. The aim of the study was to investigate the influence of fasting serum lipid levels (cholesterol and triglycerides) and the body mass index (BMI) at the time of diagnosis on survival in ALS patients. The study included 82 patients with ALS residing in the Belgrade area who were diagnosed with ALS over a time period of 4 years (2006–2009). Survival was assessed by the Kaplan–Meier method. In this retrospective study, 39 (47·56%) patients had normal values of lipids and 43 (52·43%) patients had hyperlipidemia. The mean survival time from the onset of symptoms for patients with normal lipidemia was 4·21±0·5 years, while the mean survival time from the onset of symptoms for patients with hyperlipidemia was 5·0±0·67 years (P = 0·36). We also did not register a significant difference in survival in relation to gender, the site or age of onset, even though we noticed a longer survival in patients with hyperlipidemia in all of the examined groups, especially in the group of younger patients, with the onset of the disease before the age of 45 years. If we take into account the fact that BMI is pathophysiologically associated with cholesterol and triglyceride serum levels, the results in our study complement each other showing that patients with a higher BMI, registered in 28·8% of the cases, do not live longer. Our findings show that hyperlipidemia, which we found in 52·43% of our ALS patients, at the time of diagnosis, is not related to significantly longer survival.

Titin antibodies in “seronegative” myasthenia gravis — A new role for an old antigen

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction of skeletal muscles. Triple-seronegative MG (tSN-MG, without detectable AChR, MuSK and LRP4 antibodies), which accounts for ~10% of MG patients, presents a serious gap in MG diagnosis and complicates differential diagnosis of similar disorders. Several AChR antibody positive patients (AChR-MG) also have antibodies against titin, usually detected by ELISA. We have developed a very sensitive radioimmunoprecipitation assay (RIPA) for titin antibodies, by which many previously negative samples were found positive, including several from tSN-MG patients. The validity of the RIPA results was confirmed by western blots. Using this RIPA we screened 667 MG sera from 13 countries; as expected, AChR-MG patients had the highest frequency of titin antibodies (40.9%), while MuSK-MG and LRP4-MG patients were positive in 14.6% and 16.4% respectively. Most importantly, 13.4% (50/372) of the tSN-MG patients were also titin antibody positive. None of the 121 healthy controls or the 90 myopathy patients, and only 3.6% (7/193) of other neurological disease patients were positive. We thus propose that the present titin antibody RIPA is a useful tool for serological MG diagnosis of tSN patients.

FAMILIAL OCCURRENCE OF AUTOIMMUNE MYASTHENIA GRAVIS WITH DIFFERENT ANTIBODY SPECIFICITY

Myasthenia gravis (MG) is an autoimmune disorder caused by autoimmune attack at the neuromuscular junction. Approximately 80–90% of patients have detectable serum anti-acetylcholine receptor antibodies (anti-AChR Ab)1 and 40–50% of anti-AChR Ab negative patients have antibodies to muscle specific kinase (MuSK).2 Most cases of familial MG are congenital and caused by hereditary defects in neuromuscular transmission. Familial cases of autoimmune MG with anti-AChR Ab are extremely rare.3 We report a case of familial autoimmune MG with different antibody specificity. ### Case 1. The mother, aged 45 years, was admitted to our hospital because of generalized weakness, difficulty in swallowing and speaking, double vision, and ptosis. Onset of the disease was 2 years previously. She had a history of mild sideropenic anemia. Neurologic examination and additional diagnostic tests (table) confirmed the diagnosis of MG. Serum anti-AChR Ab titer was elevated, while anti-MuSK Ab were negative. Treatment with pyridostigmine (180 mg/day) and prednisolone (60 mg on alternate day) resulted in improvement, and after several weeks thymectomy was performed. View this table: Table Clinical and laboratory findings in mother and daughter upon admission to the hospital Over the next 6 months she improved significantly (MGQS 6) and she is now in …

Amifampridine phosphate (Firdapse®) is effective and safe in a phase 3 clinical trial in LEMS

We evaluated the efficacy and safety of amifampridine phosphate (Firdapse®) for symptomatic treatment in Lambert‐Eaton myasthenic syndrome (LEMS).