Trends in traumatic spinal cord injuries in Estonia from 1997 to 2018.

OBJECTIVE: To analyze time trends in incidence, causes and risk factors for traumatic spinal cord injuries (TSCI) in Estonia between 1997-2007 and 2008-2018. DESIGN: Retrospective, population-based cohort study. SETTING: Specialized trauma centres in Estonia. PARTICIPANTS: Medical records of patients with TSCI from 1997 to 2018. INTERVENTION: None. OUTCOME MEASURES: Demographical data, crude and age- and sex-adjusted incidence rates, causes of TSCI, level and extent of injury, associated injuries. RESULTS: A total of 940 new patients with TSCI were identified for the period of 1997-2018. The average annual incidence rate (standardized to the Estonian population by age and sex in 2011) decreased significantly from 37.8 (95% confidence interval (CI) 34.6-41.1) in the first period (1997-2008) to 28.2 per million population (95% CI 25.3-31.0) during the second period (2008-2018) (incidence rate ratio 0.74 (95% CI 0.65-0.85), P < 0.0001). The decrease in incidence was most significant among young men. The mean age at injury increased from 38.7 (±16.7) years to 46.6 (±19.9) years, P < 0.0001. Falls were the leading cause of injury during both periods followed by traffic accidents and sports injuries. Still, traffic accidents as a cause of TSCI decreased significantly (from 30.5% to 20.6%, P = 0.001) and falls increased (from 39.9% to 59.5%, P < 0.0001) during the second period. Alcohol consumption prior to injury also decreased significantly from 66.0% to 55.1% (P = 0.006). CONCLUSION: Estonia has become closer to other European countries regarding TSCI during the last decade; TSCI incidence has significantly decreased, the mean age at injury and the percentage of falls have increased.

Circulating miRNAs as Potential Biomarkers in Myasthenia Gravis: Tools for Personalized Medicine.

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies which attack receptors at the neuromuscular junction. One of the main difficulties in predicting the clinical course of MG is the heterogeneity of the disease, where disease progression differs greatly depending on the subgroup that the patient is classified into. MG subgroups are classified according to: age of onset [early-onset MG (EOMG; onset ≤ 50 years) versus late-onset MG (LOMG; onset > 50 years]; the presence of a thymoma (thymoma-associated MG); antibody subtype [acetylcholine receptor antibody seropositive (AChR+) and muscle-specific tyrosine kinase antibody seropositive (MuSK+)]; as well as clinical subtypes (ocular versus generalized MG). The diagnostic tests for MG, such as antibody titers, neurophysiological tests, and objective clinical fatigue score, do not necessarily reflect disease progression. Hence, there is a great need for reliable objective biomarkers in MG to follow the disease course as well as the individualized response to therapy toward personalized medicine. In this regard, circulating microRNAs (miRNAs) have emerged as promising potential biomarkers due to their accessibility in body fluids and unique profiles in different diseases, including autoimmune disorders. Several studies on circulating miRNAs in MG subtypes have revealed specific miRNA profiles in patients' sera. In generalized AChR+ EOMG, miR-150-5p and miR-21-5p are the most elevated miRNAs, with lower levels observed upon treatment with immunosuppression and thymectomy. In AChR+ generalized LOMG, the miR-150-5p, miR-21-5p, and miR-30e-5p levels are elevated and decrease in accordance with the clinical response after immunosuppression. In ocular MG, higher levels of miR-30e-5p discriminate patients who will later generalize from those remaining ocular. In contrast, in MuSK+ MG, the levels of the let-7 miRNA family members are elevated. Studies of circulating miRNA profiles in Lrp4 or agrin antibody-seropositive MG are still lacking. This review summarizes the present knowledge of circulating miRNAs in different subgroups of MG.

miR-30e-5p as predictor of generalization in ocular myasthenia gravis.

Objective: To determine a predictive factor for the risk of conversion from ocular myasthenia gravis (OMG) to generalized MG (GMG) in a prospective study. Methods: RNA was isolated from serum samples and detection of microRNA (miRNA) expression analyzed with qPCR. In the discovery set, 179 human miRNAs were assayed for profiling of five OMG patients and four age- and gender-matched healthy controls. Based on the specific accumulation pattern of 19 miRNAs from the discovery set, in addition to miRNAs previously found elevated in generalized MG (GMG; miR-150-5p and miR-30e-5p), 21 miRNAs were subsequently analyzed in a validation cohort of 83 OMG patients (82 immunosuppression treatment naive; 49 male) within 3 months of diagnosis and at a follow-up visit (median duration 28 months from first visit). Results: Thirteen patients generalized 14.8 ± 12.0 months after the diagnosis and the majority (85%) belonged to the late onset MG group. Two miRNAs were significantly higher in secondary GMG (SGMG) patients compared to OMG patients with late onset MG: miR-30e-5p (9.1 ± 0.5 vs. 6.3 ± 0.9; P < 0.0001) and miR-150-5p (7.4 ± 1.1 vs. 6.4 ± 1.1; P = 0.01). The sensitivity for miR-30e-5p in differentiating OMG and SGMG was 96% in all OMG patients and 100% in late onset OMG patients. Interpretation: This is the first study to describe a potential predictive factor associated with the risk of generalization for patients with OMG. Raised levels (>8) of miR-30e-5p at initial presentation in patients with ocular MG symptoms, give a predictive cut-off for subsequent generalization of 96-100%.

Cognitive dysfunction in mice with passively induced MuSK antibody seropositive myasthenia gravis.

Recent reports on cognitive dysfunction, in addition to skeletal muscle fatigue, in muscle-specific tyrosine kinase antibody seropositive (MuSK+) myasthenia gravis (MG) patients led us to study cognition in mice with MuSK+ passive transfer MG (PTMG). Twelve 7-week-old female wild-type C57BL/6J mice were passively immunized with IgG from MuSK+ MG patients and 12 control mice received intraperitoneal saline injections. Mice were evaluated with clinical, neurophysiological and behavioral tests (Barnes maze (BM) and novel object recognition (NOR)), and the muscles were immunostained to evaluate the neuromuscular junction in the end of the study. Two-thirds of the immunized mice developed clinically distinct MuSK+ PTMG. MuSK+ PTMG mice spent less time exploring the novel object in the NOR test (MuSK+ mice 36.4% ±â€¯14.0 vs controls 52.4% ±â€¯13.0, p = .02), unrelated to the muscle weakness and regardless of rodents' innate preference of novelty. In the BM test, control mice were more eager to use the direct strategy than the MuSK+ mice (MuSK+ 17.3% vs controls 29.5%, p = .02). Our findings shed new light on cognition dysfunction in human MuSK+ MG patients and indicate that recognition memory in the perirhinal cortex could be affected in MuSK+ MG.

Circulating microRNA plasma profile in MuSK+ myasthenia gravis.

Muscle-specific tyrosine kinase antibody positive myasthenia gravis (MuSK+ MG) is an immunological subtype with distinctive pathogenic mechanisms and clinical features. The aim of this study was to analyze the circulating plasma microRNA profile of patients with MuSK+ MG. From the discovery cohort miR-210-3p, miR-324-3p and miR-328-3p were further analyzed in the validation cohort. We found a distinct plasma profile of miR-210-3p and miR-324-3p that were significantly decreased in MuSK+ MG patients compared to healthy controls (4.1 ±â€¯1.4 vs 5.1 ±â€¯1.4, p = .006 and 4.7 ±â€¯1.0 vs 5.4 ±â€¯1.3, p = .02). These findings reveal a distinct plasma miRNA profile in MuSK+ MG.

Circulating microRNA miR-21-5p, miR-150-5p and miR-30e-5p correlate with clinical status in late onset myasthenia gravis.

There are no biomarkers for late onset myasthenia gravis (LOMG; onset >50 years). We evaluated circulating microRNA in a discovery cohort of 4 LOMG patients and 4 healthy controls and in a prospective diagnostic validation cohort of 73 LOMG patients (48 male) with longitudinal follow-up samples. In immunosuppression naïve patients, levels of miRNAs miR-150-5p, miR-21-5p and miR-30e-5p decreased in parallel with clinical improvement after initiation of immunosuppression and their levels positively correlated with the clinical MG composite score. Levels of miR-150-5p and miR-21-5p were lower in patients with ocular compared to generalized LOMG. Circulating miR-150-5p, miR-21-5p and miR-30e-5p correlate with the clinical course in LOMG.

Thymectomy lowers the myasthenia gravis biomarker miR-150-5p.

OBJECTIVE: The aim of the study was to analyze the effect of thymectomy on the proposed disease-specific microRNA (miRNA) biomarkers miR-150-5p and miR-21-5p in patients from the prospective randomized trial of thymectomy in myasthenia gravis (MGTX trial) and to evaluate the longitudinal changes in clinical patterns compared with these miRNA levels. METHODS: Serum samples were obtained from 80 patients with MG who were included in the MGTX trial. Thirty-eight patients were randomized to thymectomy plus prednisone treatment, and 42 patients were randomized to prednisone treatment. Serum samples were analyzed for the expression of miR-150-5p and miR-21-5p, with quantitative reverse transcriptase PCR at baseline and at 12, 24, and 36 months after randomization. The inclusion criteria for participation in the MGTX trial were age 18-65 years, generalized myasthenia gravis (Myasthenia Gravis Foundation of America Class II-IV), disease duration of less than 5 years, and seropositivity for acetylcholine receptor antibodies (AChR+). RESULTS: Patients treated with thymectomy had lower levels of miR-150-5p at 24 months, both compared with baseline values (p = 0.0011) and the prednisone group (p = 0.04). No change in miRNA levels was found in the prednisone group. Levels of miR-21-5p displayed a negative correlation with the prednisone dose within the prednisone-only group (p ≤ 0.001). CONCLUSIONS: Thymectomy lowers the levels of the proposed biomarker miR-150-5p, which strengthens its position as a potential disease-specific biomarker for AChR+ MG.

Diversity in mental fatigue and social profile of patients with myasthenia gravis in two different Northern European countries.

Self-estimated health can be used for comparison of different diseases between countries. It is important to elaborate on whether disparities in self-estimated health are due to disease-specific parameters or socioeconomic differences. In this study, we aimed at evaluating clinical and social similarities and differences in myasthenia gravis (MG) patients between comparable regions in two Baltic Sea countries, Estonia and Sweden. METHODS: This cross-sectional study included southern counties in Sweden and Estonia of comparable size. All patients with a confirmed MG diagnosis were asked to answer two questionnaires including demographic and disease-specific data, lifestyle issues, and mental fatigue (Fatigue Severity Scale [FSS]). Clinical fatigue was assessed objectively through the Quantitative Myasthenia Gravis Score (QMG). RESULTS: Thirty-six of 92 identified patients in Estonia and 40 of 70 identified MG patients in Sweden chose to participate in the study. The demographic characteristics and symptoms reported by the patients were similar. QMG score did not differ; however, the Estonian patients scored their current subjective disease severity significantly higher (5.6 ± 2.8) compared to the Swedish patients (3.4 ± 2.3, p = .0005). Estonian patients also had significantly higher FSS scores (5.0 ± 1.7) than Swedish patients (3.5 ± 1.6; p = .001). Swedish patients were more active and performed physical activity more regularly (29.1% in Estonia and 74.2% in Sweden, p = .004). CONCLUSIONS: Although, the patients had comparable clinical fatigue, Estonian patients evaluated their health state as being more severe and reported more mental fatigue than Swedish patients. These data indicate large regional differences in disease perception of MG, which is important to consider in international studies.

Neurosyphilis as a great imitator: a case report.

BACKGROUND: Neurosyphilis is defined as any involvement of the central nervous system by the bacterium Treponema pallidum. Movement disorders as manifestations of syphilis have been reported quite rarely. CASE PRESENTATION: We report a case of a 42-year-old Russian man living in Estonia with rapidly progressive dementia and movement disorders manifesting as myoclonus, cerebellar ataxia and parkinsonism. The mini mental state examination score was 12/30. After excluding different neurodegenerative causes, further diagnostic testing was consistent with neurosyphilis. Treatment with penicillin was started and 6 months later his mini mental state examination score was 25/30 and he had no myoclonus, parkinsonism or cerebellar dysfunction. CONCLUSION: Since syphilis is easily diagnosed and treatable, it should be considered and tested in patients with cognitive impairment and movement disorders.

3D Cinema and Headache: The First Evidential Relation and Analysis of Involved Factors.

BACKGROUND: A possible link between 3D movies and headache (HA) has never been a target of specific and systematic investigations. The aim of this study was to investigate the relationship between 3D cinema and HA and to evaluate possible risk factors of developing HA during or after watching a 3D movie. METHODS: This was a prospective, non-randomized, observational study. Six thousand specifically designed questionnaires were distributed to consecutive cinema visitors. Relative HA risks for 2D- vs. 3D-movie visitors and the effects of background variables were analyzed. RESULTS: The questionnaire was filled and returned by 1293 persons. The mean age of responders was 33.0 ± 11.3 years. Individuals who viewed 3D movies reported HA during or after the movie 1.61 times more often than 2D-movie viewers (11.1% in 3D vs. 7.2% in 2D movies, p = 0.017). The risk was higher in women: 2.65 times for 2D (p = 0.019) and 1.85 times for 3D movies (p = 0.06), and decreased with age by 4.6% with each year for 2D (p = 0.0035) and by 3.2% for 3D movies (p = 0.0098). Among 3D-movie visitors, those with previous HAs were 4.17 times more prone to get a cinema-induced HA (p = 0.02). The risk was the highest for persons with migraine (OR = 3.37, p = 0.001). CONCLUSION: For the first time, it was evidentially shown that 3D movies can provoke HA. Persons at risk are mostly younger women and/or migraineurs. Based on our results, for those belonging to the aforementioned risk groups, it can be mainly recommended to choose passive 3D technology and to view movies from the farthest possible distance.

A New Risk Factor for Traumatic Spinal Cord Injury.

Several behavioral factors such as violence, impulsivity, and alcohol-related problems are associated with traumatic spinal cord injury (TSCI). Such factors have been associated with inherently low neuronal serotonergic capacity that in turn is reflected in low activity of monoamine oxidase (MAO) as measured in platelets. The aim of the study was to characterize platelet MAO activity and impulsivity in persons with TSCI. Data were collected from 93 patients with TSCI and compared with 93 age- and gender-matched control subjects. Platelet MAO activity was measured radioenzymatically and expressed as nanomoles of beta-phenylethylamine oxidized per 10 to the tenth power platelets per minute. Facets of impulsivity were self-reported using Barratt Impulsiveness Scale (BIS-11). Most of the patients were men (87%). The mean time from TSCI was 4.3 ± 3.7 years. Twenty-one (24%) patients reported social problems associated with alcohol, and 30 (39%) patients had consumed alcohol before the trauma. Platelet MAO activity was significantly lower among the patients with TSCI (6.4 ± 3.2 vs.10.8 ± 5.2, p < 0.0001). This difference was not affected by consideration of their smoking status. The patients with TSCI had significantly higher BIS-11 impulsivity compared with the controls (62.8 ± 10.0 vs. 55.4 ± 8.6, p = 0.0001). The patients with TSCI have lower platelet MAO activity, and they are more impulsive compared with the healthy controls. Our results indicate that both low platelet MAO activity and high impulsivity are important risk factors for TSCI that can have predictive value and aid in undertaking preventive measures.

Headaches after traumatic spinal cord injury in Estonia.

BACKGROUND: Patients with traumatic spinal cord injury (TSCI) often suffer from different types of pain. However, headaches after TSCI have not been studied. AIM: The aim of this article is to examine the occurrence of headache among patients with TSCI. METHODS: This cross-sectional study included individuals with TSCI from 1997 to 2012 in Estonia. Patients with TSCI were interviewed via telephone. The interview was based on a questionnaire specifically designed to identify headache type using the International Classification of Headache Disorders, third edition (beta version). RESULTS: There were 73 patients with a mean age 37.1 ± 10.6 years. The mean time since TSCI was 7.5 ± 4.0 years. The most frequently mentioned pain was headache (71%), followed by back pain (60%) and pain in neck (44%).Headaches were more frequent after the trauma compared with the headaches before TSCI (71% vs 51%, ITALIC! p = 0.02). Headaches that arose after TSCI were not related to the concomitant brain injury ( ITALIC! p = 0.15). The occurrence of headache did not depend on the severity or the level of the TSCI.Eighty-five percent of patients had not contacted any physician and headache was not diagnosed. CONCLUSIONS: This is the first study that evidentially shows that headache is the most prevalent pain condition after TSCI. Despite this, the majority of patients never consult a physician, nor is their headache diagnosed or appropriately managed. This indicates that further studies are needed to provide evidence regarding the prevalence and causes of headache and its impact on quality of life.

Mortality and causes of death after traumatic spinal cord injury in Estonia.

STUDY DESIGN: Retrospective population-based study with mortality follow-up. OBJECTIVE: To study mortality, causes and risk factors for death in Estonian patients with traumatic spinal cord injury (TSCI). SETTING: All Estonian hospitals. METHODS: Medical records of patients with TSCI from all regional, central, general, and rehabilitation hospitals in Estonia from 1997 to 2007, were retrospectively reviewed. Mortality status was ascertained as of 31 December 2011. Causes of death were collected from the Estonian Causes of Death Registry. Standardized mortality ratios (SMRs) were calculated for the entire sample and for causes of death. A Cox proportional hazards modeling was used to identify the risk indicators for death. RESULTS: During the observation period (1997-2011) 162 patients of 595 died. Nearly half of the patients (n = 76) died during the first year after TSCI. The main causes of death were external causes (30%), cardiovascular disease (29%). and suicide (8%). The overall SMR was 2.81 (95% confidence interval 2.40-3.28) and SMR was higher for women than for men (3.80 vs. 2.70). Cause-specific SMRs were markedly elevated for sepsis and suicide. Mortality was significantly affected by the age at the time of injury, neurological level, and extent of the injury as well as the year of TSCI and complications. CONCLUSION: Life expectancy is significantly decreased in patients with TSCI in Estonia compared with the general population. Deaths during the first year after the injury have an important impact on statistics. Treatment of cardiovascular diseases, infections, and prevention of suicide are useful for reducing mortality in patients with TSCI.