Prospective measurement of quality of life in myotonic dystrophy type 1.

INTRODUCTION: Generic patient reported outcome measures have had varied success in tracking QoL in myotonic dystrophy type 1 (DM1). AIM: To analyze changes of Individualized Neuromuscular Quality of Life questionnaire (INQoL) scores in clinic patients with DM1 over a 6-year period. METHOD: Patients completed the INQoL at baseline and after a 6-year period through their attendance in a neurology outpatient clinic. Severity of muscular involvement in DM1 was analyzed using the Muscular Impairment Rating Scale (MIRS). RESULTS: Ninety-nine DM1 patients completed a baseline visit. Sixty-seven of these patients were retested at an interval time. The overall INQoL score improved in our sample of patients (P<.05) as did the following subscales: myotonia (P<.05), pain (P<.05), activities (P<.01), social relationships (P<.01), and body image (P<.05). No changes were observed for the independence and emotions scales. There were no differences in mean change of INQoL scores between patients with worsened MIRS and those with no change in MIRS scale after follow-up (P>.05). CONCLUSION: Individualized Neuromuscular Quality of Life questionnaire scores improved in our cohort of DM1 patients during a 6-year period. INQoL score did not correlate with progression of muscle weakness. This must be better understood before the selection of the instrument for use in trials to measure therapeutic benefit in DM1 patients.

Electrophysiological findings in patients with low density lipoprotein receptor related protein 4 positive myasthenia gravis.

BACKGROUND AND PURPOSE: The aim was to determine the electrophysiological profile of our cohort of low density lipoprotein receptor related protein 4 (LRP4) positive myasthenia gravis (MG) patients. METHODS: A repetitive nerve stimulation (RNS) test and jitter analysis using a concentric needle electrode were performed in 17 LRP4 positive MG patients. The results were compared to 31 muscle-specific tyrosine kinase (MuSK) positive and 28 acetylcholine receptor (AChR) positive MG patients. RESULTS: The RNS test was negative in almost all patients belonging to the LRP4/seronegative and LRP4/MuSK groups. It was positive most frequently in the AChR MG patients, especially those without anti-LRP4 antibodies. The presence of anti-LRP4 antibodies was connected to lower decrement values, whilst the independent presence of anti-AChR or anti-MuSK antibodies was connected to higher decrement values. Lowest jitter was recorded in patients with LRP4/seronegative MG. The highest percentage of pathological jitter analysis test results was present in MuSK and AChR MG patients. The isolate presence of anti-LRP4 antibodies did not influence the mean consecutive difference values, whilst mean consecutive difference values were higher in the presence of anti-AChR or anti-MuSK antibodies. CONCLUSIONS: Low density lipoprotein receptor related protein 4 positive patients make a distinct MG subgroup with rarely detected pathological electrophysiological test results. The lack of influence of anti-LRP4 antibodies on the different electrophysiological parameters brings into question the pathogenic role of anti-LRP4 antibodies in MG.

Five-year study of quality of life in myotonic dystrophy.

Background - Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. There is a complete lack of studies that assessed quality of life (QoL) trajectory during time in DM1 cohorts. Aim - To analyze changes of QoL in patients with DM1 during a 5-year follow-up period and to assess responsiveness of the SF-36 questionnaire. Patients and Method - At the baseline, this study comprised 84 DM1 patients, of whom 62 were retested after the mean period of 64.2 ± 3.9 months. Severity of muscular weakness was assessed using the Muscular Impairment Rating Scale (MIRS). Patients completed Serbian version of the SF-36 questionnaire as a measure of health-related QoL. Results - After 5 years, MIRS score of our DM1 patients showed significant progression of 0.5 grade (P < 0.01). All mental subdomains, role physical, and total SF-36 scores significantly improved after 5 years (P < 0.01). Unexpectedly, worsening of muscular weakness from mild to severe was in association with improvement of QoL. Conclusion - QoL improved in our cohort of DM1 patients during a 5-year period despite the progression of the disease. SF-36 should be used with caution as a patient-reported outcome measure in DM1 clinical trials.

High frequency of DQB1*05 and absolute absence of DRB1*13 in muscle-specific tyrosine kinase positive myasthenia gravis.

BACKGROUND AND PURPOSE: Myasthenia gravis (MG) is an autoimmune disease but certain genetic factors predispose its development. Since susceptibility to different forms of MG is linked to a number of allelic variants, the aim of this study was to explore the human leukocyte antigen (HLA) profile of our patients with muscle-specific tyrosine kinase (MuSK) MG. METHODS: Human leukocyte antigen (HLA) typing was performed in our cohort of 31 MuSK MG patients available for the study. The allele groups of DRB1* and DQB1* loci were typed with sequence-specific oligonucleotide probes and high resolution typing for DQB1* was performed using sequence-specific primers. HLA frequencies were compared with unrelated healthy bone marrow donors. RESULTS: Significant association of MuSK MG with alleles DRB1*14 [odds ratio (OR) 3.8], DRB1*16 (OR 3.3) (P < 0.01) and DQB1*05 (OR 2.2) (P < 0.05) was found. In our patients the most frequent DQB1* allele was DQB1*05:02. An absolute absence of DRB1*13 in our cohort of MuSK MG patients was also found, whilst this allele was present in 25% (495/1992) of control subjects (OR 0) (P < 0.01). The HLA DRB1*16-DQB1*05 (OR 2.9) haplotype was found to be associated with MuSK MG (P < 0.05). CONCLUSIONS: The strong association of MuSK MG with DQB1*05 alleles observed in patient series from other countries was confirmed. The novel finding in our cohort of MuSK MG patients was the absolute absence of DRB1*13 allele, which might have a protective role in the development of MuSK MG, at least in our population.

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.

Dependent and paranoid personality patterns in myotonic dystrophy type 1.

OBJECTIVES: To analyze frequency and type of personality pattern in patients with myotonic dystrophy type 1 (DM1), to correlate these findings with clinical data, and to assess its possible influence on quality of life (QoL). MATERIALS AND METHODS: This cross-sectional study comprised 62 patients with DM1. Following measures were used: Muscular Impairment Rating Scale, Raven's Standard Progressive Matrices (RSPM), Millon Multiaxial Clinical Inventory I (MMCI), SF-36, and Individualized Neuromuscular Quality of Life (INQoL) questionnaires. RESULTS: The presence of at least one pathological personality trait with score above 85 on MMCI was found in 47 (75.8%) patients. After clinical interview, 36 (58.1%) subjects had significant personality impairment. The most common personality trait in our cohort of patients was dependent found in 51.6% of patients, followed by paranoid (38.7%). Higher score on dependent personality scale correlated with lower education (rho = -0.251, P = 0.049). Dependent personality scores significantly differed between patients with physical and intellectual work (93.1 ± 8.9 vs 66.9 ± 31.7, P = 0.011). Paranoid score was higher in patients with lower education (rho = -0.293, P = 0.021), lower score on RSPM test (rho = -0.398, P = 0.004) and larger number of CTG repeats (rho = 0.254, P = 0.046). Presence of dependent personality was not in association with QoL scores (P > 0.05). On the other hand, patients with paranoid personality trait had worse QoL than those without it (P < 0.05). CONCLUSION: Almost 60% of our patients with DM1 had clinically significant personality impairment, with dependent and paranoid personality patterns being the most common. Paranoid personality may decrease QoL in these patients, which gives us new opportunities for symptomatic therapy in DM1.

Epidemiological study of adult-onset myasthenia gravis in the area of Belgrade (Serbia) in the period 1979-2008.

BACKGROUND: The aim of this study was to analyze the prevalence and incidence of adult-onset myasthenia gravis (MG) in the Belgrade population from 1979 to 2008. METHODS: Data on the number of MG patients and their basic demographic and clinical characteristics were collected from hospital records (1979-1992) and the Belgrade MG Registry (1993-2008). Incidence and prevalence were standardized by the direct method (using the world standard population). A time-trend analysis of MG incidence was performed using a linear regression model. RESULTS: During the study period 562 cases (316 women, 246 men) were registered. On December 31st, 2008, the standardized prevalence (according to the world standard population) was 188.3/1,000,000 (women: 237.8/1,000,000; men: 139.4/1,000,000). The average annual standardized incidence rate was 13.3/1,000,000 (women: 14.1/1,000,000; men: 12.2/1,000,000). The incidence rates tended to increase significantly in both sexes during the study period (y = 3.299 + 14.363x, p = 0.002). Age-specific incidence rates for women demonstrated a bimodal pattern, with the first peak in the 20- to 29-year age group and the second one in the ≥70-year group. For both genders, an increase in age-specific incidence rates was registered for all age groups, although this was significant (p = 0.001) only for an MG onset of ≥60 years of age. CONCLUSIONS: The study confirms an increase in the incidence of MG in the area of Belgrade during the study period, especially for those with MG onset after 60 years of age.

Altered serum levels of autophagy proteins Beclin-1 and mTOR in patients with exudative age-related macular degeneration.

Autophagy is a key process in the maintenance of cellular survival and homeostasis. Inhibition of autophagy results in degenerative changes resembling ageing. We wondered if autophagy can contribute to the pathogenesis of age-related macular degeneration (AMD). We aimed to investigate the serum concentrations of two key autophagy regulators, Beclin-1 and mechanistic target of rapamycin (mTOR), in patients with exudative AMD. This retrospective case-control study included 38 patients with exudative AMD and 36 sex- and age-matched controls selected among senile cataract patients. Circulating Beclin-1 and mTOR were assessed using an enzyme-linked immunosorbent assay. The proteins levels were correlated with age, sex, duration of ocular symptoms, as well as angiographic and optical coherence tomography findings. Serum Beclin-1 levels were much lower in patients with AMD than in controls (median, 0.100 ng/ml versus 1.123 ng/ml; p = 0.0033), while mTOR levels did not differ (median, 4.377 ng/ml versus 3.608 ng/ml; p = 0.4522). Participants of the study older than 70 years had lower Beclin-1 levels than younger ones (p = 0.0444). However, this difference was the most evident in patients with AMD (p = 0.0024). Serum mTOR levels increased with age. In patients with AMD, lower mTOR levels were associated with drusen, while higher levels were observed in those with a fibrous scar in the contralateral eye (p = 0.0212). Our findings suggest that circulating Beclin-1 decreases with age and that is downregulated in patients with AMD.

Effect of photodynamic therapy with verteporfin on tumor thickness and best corrected visual acuity in patients with circumscribed choroidal hemangioma: a single-center experience.

The management of circumscribed choroidal hemangioma (CCH) with photodynamic therapy (PDT) using verteporfin has resulted in significant functional and clinical improvement compared with the pre-PDT era. Literature data on factors influencing clinical outcomes and predictors of response to PDT in symptomatic CCH are inconsistent. The aim of this study was to investigate the efficacy of PDT with verteporfin in patients with CCH depending on symptom duration and tumor thickness at baseline. We analyzed the medical records of 37 patients with symptomatic CCH divided into 3 groups according to symptom duration (≤ 50 weeks, 51 - 100 weeks, and > 100 weeks) and into 2 groups according to tumor thickness (≤ 2.3 mm and > 2.3 mm). Patients were subjected to PDT with verteporfin at a concentration of 6 mg/m2 body surface area and a light dose of 50 J/cm2 at a wavelength of 689 nm. The mean number of treatment sessions was 1.57 (range, 1 - 3). Tumor thickness, the transverse and longitudinal diameters of the tumor base, and best corrected visual acuity (BCVA) were evaluated at baseline and at 12 - 15 months after treatment. After PDT, the mean tumor thickness in the whole study group decreased by 1.19 ± 0.66 mm (from 3.14 mm to 1.95 mm). Subgroup analyses revealed no significant differences between the 2 groups divided according to tumor thickness (p = 0.49). However, tumor thickness differed significantly between the 3 groups divided according to symptom duration (p < 0.05). BCVA increased in 22 patients (59.5%), remained unchanged in 12 patients (16.2%), and decreased in 3 patients (10.1%). Our study provides evidence for the efficacy of PDT with verteporfin in terms of improving or stabilizing visual function as well as reducing tumor thickness in patients with CCH, including those with long-lasting disease.

Leptin and the metabolic syndrome in patients with myotonic dystrophy type 1.

OBJECTIVES: To evaluate serum leptin concentration and its relation to metabolic syndrome (MSy) in non-diabetic patients with myotonic dystrophy type 1 (DM1). MATERIALS AND METHODS: This study included 34 DM1 patients, and the same number of healthy subjects matched for age, sex and body mass index (BMI). RESULTS: DM1 patients had increased BMI and insulin resistance, and increased leptin and insulin concentrations, but the other features of MSy such as diabetes, glucose intolerance and hypertension were not detected in DM1 patients. Serum leptin levels were higher in patients with DM1 than in healthy controls (8.5 +/- 6.6 ng/ml vs 3.6 +/- 2.9 ng/ml in men, and 13.9 +/- 10.0 ng/ml vs 10.9 +/- 6.9 ng/ml in women, respectively). In DM1 patients, leptin levels correlated with BMI, fasting insulin and insulin resistance (HOMA) (P < 0.01). CONCLUSIONS: The leptin overproduction correlated with insulin resistance in DM1 patients but the significance of this finding remains unclear.

Validation of Serbian version of the disease-specific myasthenia gravis questionnaire.

AIM: The aim of this study was to validate translated and cross-cultural adapted Italian version of myasthenia gravis-specific questionnaire (MGQ) in Serbian MG patients. MATERIALS AND METHODS: The questionnaire was validated in 140 consecutive MG patients from Belgrade. In each patient association between the total MGQ score and form and severity of the disease was determined. Also, correlation between regional domain scores of MGQ and main clinical findings according to Besinger's clinical score was analyzed. RESULTS: Patients' participation in the assessment was satisfactory with excellent internal consistency and reproducibility. Total MGQ score, as well as domain scores, correlated with highly significant inverse relationship with the disease severity and clinical status of patients at the moment of completing the questionnaire. Furthermore, the bulbar domain of the questionnaire appeared more specific and sensitive than clinical history and examination. CONCLUSION: We concluded that the Serbian version of the MGQ may be useful as a measure of clinical outcome in patients with MG.

Health-related quality of life in patients with myotonic dystrophy type 1 and amyotrophic lateral sclerosis.

The aim was to assess factors that might influence health-related quality of life (HRQoL) in patients with two different neuromuscular disorders - myotonic dystrophy type 1 (DM1) and amyotrophic lateral sclerosis (ALS). A cross-sectional study was performed on 79 patients with DM1 and 74 with ALS. The HRQoL was evaluated by SF-36, Serbian version. Depressive and anxiety symptoms were assessed using the Hamilton rating scale for depression and the Hamilton rating scale for anxiety respectively. Severity of muscular involvement in DM1 was measured with MRC scale and severity of ALS with ALSFRSr score. The mean total score as well as all domain scores of SF-36 were similar in DM1 and ALS patients (p > 0.05), except that ALS patients experienced less bodily pain (p < 0.05). Depressiveness was found in 51% and marked anxiety in 38% of DM1 patients. Emotional status and severity of muscular involvement emerged as significant independent contributing factors to the total SF-36 in DMI patients (p < 0.05). Only 3% of ALS patients showed depressiveness and 4% anxiety symptoms. The factors found to contribute to HRQoL in ALS patients were severity of disease and educational level ofpatients (p < 0.05). We found significant percentage of potentially treatable emotional disturbances which together with severity of disease significantly contributed to HRQoL in DM1 patients. On the other hand, in ALS patients depressiveness and anxious symptoms were uncommon and the factors found to contribute to HRQoL were severity of disease and educational level.

Prospective analysis of gait characteristics in chronic inflammatory demyelinating polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disorder that may lead to functional impairment, including gait abnormalities. Our aim was to analyze gait characteristics in patients with CIDP compared to healthy controls (HC). Moreover, we sought to determine changes of gait parameters after six-month follow-up period. Twenty-four patients with CIDP and 24 HCs performed basic walking task, dual-motor task, dual-mental task, and combined task using the same GAITRite system. Lower limb MRC-SS and lower limb INCAT disability score were assessed. Fourteen patients were retested after six months. Majority of gait parameters showed significant differences in all experimental conditions when compared between CIDP and HCs. The most consistent findings in CIDP were shorter stride length (SL), prolonged cycle time (CT) and double support time (DS), as well as increased variation of SL and of swing time (ST) (p < 0.05). During follow-up, INCAT improved in nine (64.3%) of 14 patients and MRC-SS improved in eight (57.1%) patients. Six-month changes of CT and its variation during combined task significantly differentiated patients with improved vs. non-improved INCAT (p < 0.05). In conclusion, patients with CIDP had slower gait with prolonged DS and with shorter SL compared to HCs. Increased variation of SL and of ST in CIDP may suggest a potential risk for instability and falls. Shorter CT duration and less CT variation during time correlated well with improvement in disability.

Involvement of serum anti-retinal antibodies in the pathophysiology of diabetic retinopathy: a pilot study.

The aim of this single-center cross-sectional study was to identify tissue targets for circulating anti-retinal antibodies (ARAs) in the serum of patients with diabetic retinopathy (DR). The study included 61 participants with DR (30 with nonproliferative diabetic retinopathy and 31 with proliferative diabetic retinopathy) and 30 healthy controls. An indirect immunofluorescence (IIF) test was used to detect serum ARAs and identify their targets in the tissue. Four types of ARAs were found in serum samples from DR patients: antibodies against the outer segments of the rods, antibodies against the outer segments of the cones, antibodies against the cytoplasmic components of retinal nuclear layer cells, and antibodies against retinal nerve fibers. A significant difference was noted between groups in the prevalence of antibodies against the outer segments of the rods (NPDR, 40%; PDR, 74.2%; and controls, 40%; P = 0.008) as well as antibodies against the outer segments of the cones (NPDR, 23.3%; PDR, 61.3%; and controls, 30%; P = 0.005). Interestingly, the distribution of immunofluorescence intensity for the outer segments of the rods and cones differed significantly between study groups (P ≢ 0.001 and P = 0.019, respectively). In conclusion, the results of our pilot study showed that in most patients with DR, the outer segments of photoreceptors tend to be the tissue target for serum ARAs. This may indicate their possible involvement in the pathogenesis of DR. However, further research is needed to fully elucidate whether these antibodies participate in photoreceptor damage in the course of DR.

Differences in anti-endothelial and anti-retinal antibody titers: implications for the pathohysiology of acute and chronic central serous chorioretinopathy.

The aim of the study was to evaluate the prevalence of serum anti-retinal (ARAs) and anti-endothelial cell antibodies (ACEAs) in patients with acute and chronic central serous chorioretinopathy (CSC). We enrolled 28 patients with acute CSC, 42 patients with chronic CSC, and 40 healthy controls. The presence of ARAs was determined by indirect immunofluorescence using monkey retina as an antigen substrate, while the presence of AECAs was determined using cultivated human umbilical vein endothelial cells (HUVECs) and primate skeletal muscle according to the manufacturer's instructions (Euroimmun AG). There were no differences in the prevalence of antibodies against rods, cones, cytoplasmic components of retinal nuclear layer cells, and retinal vessels between the acute and chronic CSC groups and the control group (P = 0.27, P = 0.16, P = 0.71, and P = 0.06, respectively). However, AECAs reactive with HUVECs were observed in 46% of patients with acute CSC, 45% of those with chronic CSC, and 22% of controls, whereas AECAs reactive with the skeletal muscle were present in 46%, 45%, and 15%, respectively (difference between groups: P = 0.045 for HUVECs and P = 0.005 for the skeletal muscle). Furthermore, AECA titers were higher in CSC patients than in controls (P = 0.004). This study provides evidence for the possible involvement of an autoimmune process directed against vessel antigens in the pathogenesis of CSC. AECAs may be more important than ARAs in this disease and may be involved in endothelial damage in the choroidal vessels and choriocapillaris, leading to hyperpermeability, which is central to the pathophysiology of CSC.

Non-responsiveness and tachyphylaxis to anti-vascular endothelial growth factor treatment in naive patients with exudative age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of central visual loss in people aged over 50 years in well developed countries. Although the anti-vascular endothelial growth factor (VEGF) therapy has become a standard treatment for exudative AMD, its effectiveness may be limited in some cases. We aimed to assess the prevalence of non-responsiveness and tachyphylaxis to anti-VEGF drugs in patients with exudative AMD. The study included 63 initially treatment-naive AMD patients who were analyzed for non-responsiveness and tachyphylaxis to intravitreal injections (IVI) of ranibizumab and aflibercept. The participants were enrolled in a National Healthcare Fund (NHF) Therapeutic Program for the Treatment of Exudative AMD. Best-corrected visual acuity (BCVA) and morphological features of a disease activity assessed in optical coherence tomography (OCT) were evaluated during a 12-month follow-up. The percentage of non-responders achieved 22.2% (14 eyes). No significant correlation was found between the type of VEGF inhibitor and a negative response to therapy. Eight patients (12.7%) developed early tachyphylaxis, which was more common in eyes treated with aflibercept (P = 0.04). The presence of serous pigment epithelium detachment (sPED) at baseline was associated with non-responsiveness as determined by both BCVA (OR 18.2, 95% CI 2.86 - 248; P = 0.021) and OCT features (OR 23.0, 95% CI 1.80 - 321; P = 0.030). Eyes treated with aflibercept showed statistically significant greater BCVA improvement (P = 0.0034) and central retinal thickness (CRT) reduction (P = 0.0129) as compared to ranibizumab group during a loading phase of therapy. In a maintain phase of treatment the differences in BCVA and CRT between these two groups were not statistically significant, however eyes treated with aflibercept still showed better functional and anatomical results. Anti-VEGF therapy is an effective method of treatment for exudative AMD, however some patients may show week or no positive reaction or may develop tachyphylaxis. Awareness of these possible negative effects is an important clinical problem in the long-term management of AMD patients with VEGF inhibitors.

Corticosteroids in chronic inflammatory demyelinating polyneuropathy : A retrospective, multicentre study, comparing efficacy and safety of daily prednisolone, pulsed dexamethasone, and pulsed intravenous methylprednisolone.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) can be treated with corticosteroids or intravenous immunoglobulins. Various corticosteroid regimens are currently used in CIDP, but it is unknown whether they are equally efficacious. In this retrospective study, we compared efficacy and safety of three corticosteroid regimens in CIDP patients. METHODS: We included treatment naïve patients that fulfilled the EFNS/PNS criteria for CIDP. Patients were treated with corticosteroids according to the local protocol of three CIDP expertise centres. Corticosteroid regimens consisted of daily oral prednisolone, pulsed oral dexamethasone, or pulsed intravenous methylprednisolone. Outcomes were number of responders to treatment, remission rate of treatment responders, overall probability of 5-year remission, and the occurrence of adverse events. RESULTS: A total of 125 patients were included. Sixty-seven (54%) patients received daily prednisone or prednisolone, 37 (30%) pulsed dexamethasone, and 21 (17%) pulsed intravenous methylprednisolone. Overall, 60% (95% CI 51-69%) responded to corticosteroids, with no significant difference between the three treatment regimens (p = 0.56). From the 75 responders, 61% (95% CI 50-73%) remained in remission, during a median follow-up of 55 months (range 1-197 months). The probability of responders reaching 5-year remission was 55% (95% Cl 44-70%), with no difference between the three groups. Adverse events leading to a change in treatment occurred in ten patients (8%). Two patients had a serious adverse event. CONCLUSION: Corticosteroids lead to improvement in 60% of patients and to remission in 61% of treatment responders. There were no differences between treatment modalities in terms of efficacy and safety.

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.

MuSK autoantibodies in myasthenia gravis detected by cell based assay--A multinational study.

Seronegative myasthenia gravis (MG) presents a serious gap in MG diagnosis and understanding. We applied a cell based assay (CBA) for the detection of muscle specific kinase (MuSK) antibodies undetectable by radioimmunoassay. We tested 633 triple-seronegative MG patients' sera from 13 countries, detecting 13% as positive. MuSK antibodies were found, at significantly lower frequencies, in 1.9% of healthy controls and 5.1% of other neuroimmune disease patients, including multiple sclerosis and neuromyelitis optica. The clinical data of the newly diagnosed MuSK-MG patients are presented. 27% of ocular seronegative patients were MuSK antibody positive. Moreover, 23% had thymic hyperplasia suggesting that thymic abnormalities are more common than believed.

Significant impact of behavioral and cognitive impairment on quality of life in patients with myotonic dystrophy type 1.

OBJECTIVE: To assess an impact of cognitive and behavioral impairment on QoL in a larger cohort of patients with DM1. METHODS: Sixty six genetically confirmed DM1 patients (22 with juvenile (jDM1) and 44 with adult form (aDM1) of the disease) were recruited. Following behavioral tests were used: Hamilton scales for depression and anxiety (HamD and HamA), Daytime Sleepiness Scale (DSS), and Krupp's Fatigue Severity Scale (FSS). Patients also underwent detailed classic neuropsychological investigation and Cambridge Neuropsychological Test Automated Battery (CANTAB). Individualized Neuromuscular Quality of Life questionnaire (INQoL) was used as a measure of QoL. RESULTS: Patients with jDM1 scored lower than aDM1 patients regarding total INQoL score and all INQoL subdomains, except for myotonia. Significant predictors of total INQoL score in patients with jDM1 were severity of fatigue (ß=+0.60, p<0.01) and percentage of correct responses on Spatial Recognition Memory test from CANTAB that measures visuospatial abilities (ß=-0.38, p<0.05). The most important predictors of total INQoL score in patients with aDM1 were severity of fatigue (ß=+0.36, p<0.05) and level of education (ß=-0.29, p<0.05). CONCLUSION: Our results showed clear influence of different central manifestations on QoL in patients with both aDM1 and jDM1.