Anna Paola Batocchi

Course and treatment of myasthenia gravis during pregnancy

Objective: To evaluate the influence of myasthenia gravis (MG) on pregnancy and potential treatment risks for infants and mothers. Background: MG frequently affects young women in the second and third decades of life, overlapping with the childbearing years. Knowledge of the potential effects of 1) pregnancy on the course of MG and 2) the use of immunosuppressive drugs during pregnancy is limited, rendering decision-making difficult for both patient and physician. Methods: We studied 47 women who became pregnant after the onset of MG. Immunosuppressive drugs were administered when MG symptoms were not controlled with anticholinesterases. Sixty-four pregnancies resulted in 55 children and 10 abortions. Results: During pregnancy, MG relapsed in 4 of 23 (17%) asymptomatic patients who were not on therapy before conception; in patients taking therapy, MG symptoms improved in 12 of 31 pregnancies (39%), remained unchanged in 13 (42%), and deteriorated in 6 (19%). MG symptoms worsened after delivery in 15 of 54 (28%) pregnancies. Anti-acetylcholine receptor antibody (anti-AChR ab) was positive in 40 of 47 mothers and was assayed in 30 of 55 newborns; 13 were positive and 5 of 55 (9%) showed signs of neonatal MG (NMG). All affected babies were seropositive. Conclusions: Pregnancy does not worsen the long-term outcome of MG. The course of the disease is highly variable and unpredictable during gestation and can change in subsequent pregnancies. The occurrence of NMG does not correlate with either maternal disease severity or anti-AChR antibody titer. Immunosuppressive therapy, plasmapheresis, and IV human immunoglobulins can be administered safely if needed.

Acetylcholine receptor M3 domain: stereochemical and volume contributions to channel gating.

By defining the functional defect in a congenital myasthenic syndrome (CMS), we show that the third transmembrane domain (M3) of the muscle acetylcholine receptor governs the speed and efficiency of gating of its channel. The clinical phenotype of this CMS results from the mutation V285I in M3 of the α subunit, which attenuates endplate currents, accelerates their decay and causes abnormally brief acetylcholine-induced single-channel currents. Kinetic analysis of engineered αV285I receptors demonstrated a predominant effect on channel gating, with abnormally slow opening and rapid closing rates. Analysis of site-directed mutations revealed stereochemical and volume-dependent contributions of αV285 to channel gating. Thus, we demonstrate a functional role for the M3 domain as a key component of the nicotinic acetylcholine receptor channel-gating mechanism.By defining the functional defect in a congenital myasthenic syndrome (CMS), we show that the third transmembrane domain (M3) of the muscle acetylcholine receptor governs the speed and efficiency of gating of its channel. The clinical phenotype of this CMS results from the mutation V285I in M3 of the α subunit, which attenuates endplate currents, accelerates their decay and causes abnormally brief acetylcholine-induced single-channel currents. Kinetic analysis of engineered αV285I receptors demonstrated a predominant effect on channel gating, with abnormally slow opening and rapid closing rates. Analysis of site-directed mutations revealed stereochemical and volume-dependent contributions of αV285 to channel gating. Thus, we demonstrate a functional role for the M3 domain as a key component of the nicotinic acetylcholine receptor channel-gating mechanism.

pSTAT1, pSTAT3, and T-bet expression in peripheral blood mononuclear cells from relapsing-remitting multiple sclerosis patients correlates with disease activity.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, and it is considered to be a T helper 1 (Th1) cell‐mediated autoimmune disease. T‐bet has been identified as a key transcription factor for the development of Th1 cells and the induction of interferon (IFN)‐γ production. T‐bet is induced during T‐cell activation by the IFN‐γ signal transducer and activator of transcription (STAT)‐1 signalling pathway. In this study we found an up‐regulation of T‐bet and pSTAT1 in peripheral blood CD4+ and CD8+ T cells and monocytes from relapsing‐remitting MS patients in relapse compared with patients in remission and with healthy subjects. The increased expression of pSTAT1 strongly correlated with T‐bet expression in CD4+ and CD8+ cells and monocytes from patients in relapse and was associated with an increased production of IFN‐γ by peripheral blood mononuclear cells (PBMCs). pSTAT3 was also up‐regulated in CD4+ and CD8+ cells and monocytes from patients in relapse and was associated with an increased production of interleukin (IL)‐10 but not of IL‐6. pSTAT1, pSTAT3, and T‐bet expression strongly correlated with Gd‐DTPA‐enhanced lesions on brain and spinal cord magnetic resonance imaging. Our data show for the first time that there is an up‐regulation of type 1 immunity‐correlated transcription factors such as STAT1 and T‐bet in peripheral blood subpopulations of MS patients in the active phase of disease. The evaluation of T‐bet and pSTAT1 expression in peripheral blood CD4+, CD8+ T cells and monocytes could be used as a marker of disease activity in relapsing‐remitting MS.

Thymoma in patients with MG: Characteristics and long-term outcome

Objective: To examine the characteristics of thymoma when associated with MG and to evaluate those conditions that can complicate management and affect survival. Methods: The study includes 207 myasthenic patients who were operated on for thymoma, with at least 1-year follow-up from surgery. MG severity and response to treatment, the occurrence of paraneoplastic diseases and extrathymic malignancies, thymoma histologic types and stages, adjuvant therapy, tumor recurrences, and causes of death were recorded. Results: MG-associated thymoma was predominantly of B type and was invasive in the majority of patients. MG was generally severe, and most patients remained dependent on immunosuppressive therapy. Other paraneoplastic disorders and extrathymic malignancies were found in 9.66 and 11.11% of patients. Thymoma recurrences occurred in 18 of 115 patients with invasive tumors (15.65%) and were often associated with the onset/aggravation of autoimmune diseases. On completion of the study, MG and thymoma accounted for a similar mortality rate. Conclusions: Thymoma should be considered as a potentially malignant tumor requiring prolonged follow-up. The presence of myasthenic weakness can still complicate its management. Thymoma-related deaths are bound to outnumber those due to MG in the future.

Prognosis of myasthenia gravis: A multicenter follow-up study of 844 patients

The prognosis of myasthenia gravis (MG) was assessed retrospectively using life-table analysis in 844 patients followed up for a mean period of 5 years in 3 major Italian centers. The chance of achieving at least a 1-year remission after treatment withdrawal (complete remission) was assessed as a specific end-point in the whole population and in selected subgroups with reference to the principal prognostic variables. The cumulative probability of complete remission was 1% by 1 year, 8% by 3 years, 13% by 5 years, and 21% by 10 years. The only variables correlated to the chance of complete remission were younger age at onset of MG, lower severity of symptoms at onset and nadir, and shorter disease duration at diagnosis. In addition, thymectomy and early surgery seemed to influence the chance of remission. Other factors (including the presence of thymoma) did not significantly influence the outcome of the disease.

Leptin as a marker of multiple sclerosis activity in patients treated with interferon-beta

The role of leptin was investigated in relapsing-remitting multiple sclerosis (MS). Control and MS patients showed comparable baseline serum leptin levels. During the first year of IFNbeta-1a treatment, leptin significantly decreased since 2 months after starting therapy in 11 patients who had no relapses. A significant decrease in IL12/IL10 ratio was observed in this group of patients only after 1 year of treatment. An increase of leptin was observed before the first clinical exacerbation in 13 relapsing patients. Leptin may play a pathogenic role in MS and can be a useful marker of disease activity and response to therapy.

Cisplatin neuropathy: clinical course and neurophysiological findings

SummarySixteen patients treated with cisplatin (CDDP) 40 mg/m2 on days 1–5 every 4 weeks for three courses (cumulative dose 600 mg/m2) were clinically and neurophysiologically tested before, during and 1, 3, 6, 9 and 12 months after CDDP administration. The first symptoms of polyneuropathy occurred in 4 of 9 patients after the second course (cumulative dose 400 mg/m2). One month after treatment 1 of 9 patients was asymptomatic, 5 complained of symptoms and 3 showed clinical and neurophysiological signs of polyneuropathy. Three months after CDDP all patients were affected. Clinical and neurophysiological signs of severity progression were noted up to 6 months after treatment with CDDP.

A multicentre follow-up study of 1152 patients with myasthenia gravis in Italy

SummaryA multicentre retrospective study was carried out on the characteristics and course of myasthenia gravis (MG) in Italy. Data from 1152 patients, fairly representative of the myasthenic population seeking medical advice, were analysed for diagnostic criteria, clinical aspects and therapeutic approaches. Mean follow-up was 4.9 years. The disease was correctly diagnosed within 2 years of the onset in 80% of cases. Onset of symptoms peaked in the second and third decade in females and fell between 20 and 59 years in males. At first observation 87% of the patients had generalized MG. Maximal worsening was observed within 3 years in 77% of patients. At the last follow-up, 35% of cases were symptom-free (pharmacological remission 24%, remission without treatment 11%). The more severe the disease at the first observation and at the maximal worsening of symptoms, the lower was the proportion of remissions. Steroids were given in 54% and immunosuppressants in 18%. Thymectomy was performed in 72%, mostly in women, younger than age 40, and with generalized MG. Thymectomy seemed to improve the course of the disease, mostly in patients operated on shortly after diagnosis and those with generalized mild-to-moderate disease and with a normally involuted thymus. MG was lethal in 4% of patients, principally men, older than 40, in grade 3 or worse at first observation, with a short history of disease, and with thymona.

Juvenile myasthenia gravis with prepubertal onset

Juvenile myasthenia gravis (JMG) with prepubertal onset is an uncommon disease. We studied 19 patients with age at onset ranging from 1.5 to 9.2 years and compared their clinical characteristics and response to therapy with 114 cases with MG onset after the prepubertal age, up to 20 years. Neither sex prevalence nor autoimmune diseases other than MG were found in younger patients. Although ocular myasthenia was more frequent than in later-onset JMG, children with generalized symptoms were often severely affected and respiratory involvement was present in 8/19 patients. Anti-acetylcholine receptor antibodies were detected at a lower rate and, in contrast with results in older patients, seronegativity was more frequent among children with generalized disease. Three out of six patients with onset before the age of five showed spontaneous remission. Nine prepubertal patients underwent thymectomy and, as most of them also received immunosuppressive therapy, the influence of surgery on disease outcome remains unclear; in no case was thymoma found. This is in contrast to the good results after thymectomy and the presence of thymoma in the later-onset group. Eleven patients in the prepubertal series were treated with immunosuppressive therapy. At the end of follow-up, most patients were in good condition. The frequency of immunosuppressive therapy and the rate of good therapeutic results did not differ from those observed in older patients.

Correlations between peripheral blood mononuclear cell production of BDNF, TNF-alpha, IL-6, IL-10 and cognitive performances in multiple sclerosis patients.

The aim of this study was to investigate the role of Brain Derived Neurotrophic Factor (BDNF) and inflammatory factors in the development of cognitive dysfunctions in Multiple Sclerosis (MS). We correlated peripheral blood mononuclear cell (PBMC) production of BDNF, Tumor Necrosis Factor‐alpha (TNF‐α), Interleukin (IL)‐6 and IL‐10 with performances on specific neuropsychological tasks in a selected series of MS patients. We studied a sample of 30 patients with relapsing‐remitting (RR)MS, segregated by gender and matched for age, education, disease duration, type of immunomodulating therapy, degree of disability and overall cognitive status. We found that low BDNF levels were correlated with increased time of execution on a divided attention and visual scanning task whereas high levels of IL‐6 were correlated with low Mini Mental State Examination scores. We did not observe any significant correlations between IL‐10, TNF‐α levels and cognitive performances in our patients. In conclusion our study shows a correlation between low BDNF and high IL‐6 production by PBMCs and poorer performances in cognitive tasks in RRMS patients suggesting a possible role of these factors in cognitive impairment in MS.