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.

Antititin antibody in early- and late-onset myasthenia gravis.

OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against neuromuscular junction proteins, 85% of patients have antibodies against acetylcholine receptor (AChR-MG). Antititin antibodies are present in a subset of patients with MG. We aimed to determine the value of antititin antibodies as severity markers and thymoma predictors in early- and late-onset MG. MATERIALS & METHODS: Two-hundred and ninety-five consecutive MG patients (188 F and 107 M) aged 12-89 years (mean 50y) were included. 164 patients had early-onset (EOMG, ≤50 years of age), 131 had late-onset MG (LOMG). Twenty-six patients had thymoma. symptoms, severity graded with MGFA scale, thymus histology, medications, and treatment results were analyzed. RESULTS: Antititin antibodies were present in 81 (27%) of all patients: 54% of thymoma MG, 0.6% of non-thymomatous EOMG, and 55% of LOMG, with proportion of titin-positive patients increasing linearly from 40% in the 6th to 88% in the 9th decade of life. Titin-positive patients had more bulbar symptoms (P = 0.003). Severity of MG, need for immunosuppression, myasthenic crisis risk or treatment results were not related to its presence. Antititin antibodies had 56% sensitivity, 99% specificity, 90% positive predictive value (PPV), and 95% negative predictive value (NPV) for thymoma diagnosis in EOMG, and 50% sensitivity, 75% specificity, 71% PPV and 55% NPV in LOMG. CONCLUSIONS: Antititin antibodies have high PPV and NPV for thymoma in EOMG. In MG without thymoma, antititin antibodies can be considered as markers of LOMG, but not of a severe course in our MG cohort.

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.

How accurate is spirometry at predicting restrictive pulmonary impairment in children with myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction. Clinical symptoms are caused by weakness and increased fatigability of various muscle groups. Myasthenia may lead to significant respiratory dysfunction. The aim of our study was to estimate lung function in children with MG. We tested 23 non-smoking patients (18 girls and 5 boys) aged 7-18 years. Whole-body plethysmography and spirometry were performed in all patients. In 33% of the patients a decrease in VC <80% of predicted value was observed (VC = 89 +/-19%), but the analysis of TLC revealed restrictive pattern only in one patient (TLC = 102 +/-17%). In more than 75% of the children the value of RV above 120% of predicted value was found (RV = 146 +/-54%). Spirometric obstructive pattern measured by FEV1%VC <70% was not observed, although in 56% of the patients airway resistance was increased (Raw = 132 +/-44%). In 45% of the patients a decrease of PEF (76 +/-14%) was observed. In MG children true restrictive pulmonary impairment is rarely observed and a decrease in VC in these patents seems to result mainly from functional restriction provoked by an increase in RV. Spirometry is not an optimum method to assess functional changes in MG patients. The assessment of additional measures such as TLC, RV, and Raw is desirable.

Clinical, electrophysiological and immunological remissions after thymectomy in myasthenia gravis.

OBJECTIVES: Approximately 50% of patients treated with thymectomy have a chance for symptom-free life. However, immunological and neurophysiological abnormalities may be detected in patients with clinical remission. Although improvement usually parallels decrease in acetylcholine receptor antibody (AChRAb) levels and jitter values, there is a question what factors influence immunological and electrophysiological remission in a population of myasthenia gravis (MG) patients. METHODS: We analyzed retrospectively clinical data of 32 MG patients operated for generalized MG, followed-up at our department for 17.2 (4-31) years. They were in clinical remission for 12.8 (2-25) years. All of them had single fiber electromyograhy (SFEMG) of extensor digitorum communis muscle (EDC) muscle and estimation of AChRAb level at the end of follow-up. Their age at onset of MG was 17 years (6-48) and at thymectomy 19 (6.4-58) years. Tensilon test was positive in 30, repetitive nerve stimulation in 29 cases. RESULTS: Clinical remission was reached on average 4.2 years after thymectomy. SFEMG jitter value normalized in 60% of cases. AChRAb were negative only in 34% of patients. Jitter values correlated with AChRAb levels (P=0.006, r=0.5) but were not related to clinical factors. Only time to thymectomy correlated with time from thymectomy to clinical remission (P=0.001, r=0.5). CONCLUSIONS: Clinical remission is not always accompanied by normalization of SFEMG and AChRAb. Although normalization of neuromuscular transmission in patients with remission of MG is individual, short duration of MG before thymectomy increases the chance of early remission.

[Long-term prognosis in young adults after a cerebral ischemic episode]. / Rokowanie odlegle u mlodych chorych z przebytym incydentem niedokrwienia mózgu.

To asses long term prognosis in young adults with cerebral ischaemia a follow up study was performed. Eighty-four patients aged 18 to 45 years with the diagnosis of the first-ever ischaemic stroke or TIA were followed up. Four of them (4.8%) died within the first four weeks of cerebral ischaemia onset. Information about all but one patient (98.75%) who survived the first episode of cerebral ischaemia was obtained. The follow up time lasted 4 months till 8 years (mean 52 months +/- 20 months). Three of the patients died during the follow up (all--vascular deaths), twenty one others experienced second cerebral ischaemia one month to 80 months after the first one. Among the patients with first-ever ischaemic stroke the calculated incidence of vascular death or recurrent stroke in the patients who survived the first episode was 5.6% per year, and after 24 months--10.9%. Twenty-eight day mortality rate was in that group 5.6%. Twenty-eight day mortality rate, was in our group similar to the data from the literature, but recurrent stroke and vascular deaths appeared in our material twice as often as in the literature. It could be the effect of lifestyle and socioenvironmental determinants.

[Nocturnal paroxysmal hemoglobinuria--case report]. / Nocna napadowa hemoglobinuria--opis dwóch przypadków.

Paroxysmal nocturnal hemoglobinuria (PNH)-a case report. We present clinical and postmortem findings in patient with PNH who developed cerebral thrombosis. The pathogenesis of the PNH is discussed.

[Cerebral thrombosis in paroxysmal nocturnal hemoglobinuria: case report]. / Przypadek zakrzepicy naczyn mózgowych w przebiegu nocnej napadowej hemoglobinurii.

Clinical, radiological and postmortem findings in a 25-year old woman with paroxysmal nocturnal hemoglobinuria (PNH) who developed cerebral thrombosis are presented. The pathogenesis of the PNH is discussed.

Morphological picture in paroxysmal nocturnal hemoglobinuria. Case report.

25-year-old woman with paroxysmal nocturnal hemoglobinuria was admitted to the hospital because of headache, progressing right hemiparesis and speech disorders. Several days later patient lost consciousness. Cerebrospinal fluid was xanthochromic with increased pleocytosis and protein level. CT-scan revealed ischemic area with hemorrhagic focus within left cerebral hemisphere. Patient died 3 weeks after the admission. Brain section revealed hemorrhagic infarct in the cortex of the left parietal lobe, thrombosis of the superior sagittal sinus and "respiratory brain" changes. Microscopic examination revealed meningeal venous thrombosis, hemorrhagic infarct, vasculitis, abundant accumulation of bacteria within blood vessels, and other pathological changes such as petechiae, perivascular exudates and small, round areas composed of acellular fibrillary network. There were no macrophages and GFAP-positive astrocytes in any of these areas. Authors suggest that weak cell reactivity may be connected with alterations in cell membranes, mainly low phosphatidylinositol (GPI) content.