Clinical features of sleep apnea syndrome and cognitive impairment in multiple sclerosis.

BACKGROUND: Complications of obstructive sleep apnea (OSA) have been reported in patients with multiple sclerosis (MS). Patients with sleep apnea syndrome (SAS) due to OSA also show cognitive decline, with similar clinical characteristics to that manifested in MS. SAS due to OSA is a treatable condition, and the associated cognitive decline is expected to improve. This study investigates clinical features of SAS in people living with MS and contribute to improve cognitive dysfunction of MS. METHODS: A case-control study was conducted. Cognitive functions were evaluated by the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test 2 (PASAT-2) and 3 (PASAT-3). The Respiratory Event Index (REI) was measured using Out of Center Sleep Testing (OCST). We defined subjects with REI ≥ 5 as OSA and divided participants into two groups with or without SAS due to OSA. Cognitive and respiratory characteristics were statistically compared between patients with MS and healthy controls. RESULTS: We enrolled 67 people living with MS and 31 age- and sex-matched controls. OCST detected OSA in people living with MS and controls, and the prevalence rates were 28.4 % and 25.8 %, respectively. REI values (5.2 ± 7.9 vs 3.9 ± 5.2, p = 0.509) and number of participants with REI ≥ 5 (19 vs 8, p = 0.793) were similar between the MS and control group. The SDMT, PASAT-2, and PASAT-3 scores were significantly lower in the MS group than the control group (p < 0.001, p = 0.001, and p < 0.001, respectively). The interaction effect of MS and SAS on cognitive function was not significant in the SDMT (p = 0.078), but in the PASAT-2 (p = 0.043) and PASAT-3 (p = 0.020). CONCLUSION: This study revealed the prevalence rates of SAS in Japanese people living with MS and the usefulness of OCST for detection of SAS. This study also revealed that concomitant SAS can facilitate cognitive decline in people living with MS. These findings suggest that an appropriate intervention for OSA can be beneficial for people living with MS with cognitive decline.

Association between National Institutes of Health Stroke Scale and Functional Independence Measure scores in patients with ischemic stroke from convalescent rehabilitation outcomes.

We investigated the associations among neurological severity, activities of daily living (ADLs), and clinical factors in patients with ischemic stroke in convalescent rehabilitation outcome. The study sample included 723 patients with ischemic stroke (484 men and 239 women; mean age, 73.2 ± 8.5 years) for inpatient convalescent rehabilitation. National Institutes of Health Stroke Scale (NIHSS) was used to measure the neurological severity, and Functional Independence Measure (FIM) was used to assess ADLs at discharge. Leukoaraiosis was graded based on periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH) on magnetic resonance imaging. The correlations between NIHSS scores and total FIM scores were significant but relatively mild (r = -0.684, P < 0.001). Multiple regression analysis revealed that age and PVH grade significantly decreased their total FIM scores and affected the discrepancies between NIHSS scores at discharge (P < 0.001), but DWMH scores did not affect these results. Factors such as positive history of heart disease (P = 0.008) and bilateral infarction (P = 0.038) additionally decreased their total FIM scores and affected the discrepancies between NIHSS scores. These findings suggest that age, PVH, history of heart disease positive, and bilateral infarction in patients with ischemic stroke affected their performance of ADLs and the discrepancies between their neurological severities in convalescent rehabilitation outcomes, probably because the pathophysiological background of leukoaraiosis and these factors strongly decrease their ADL performance in post-phase ischemic stroke.

Investigation of inpatient convalescent rehabilitation outcomes in branch atheromatous disease.

PURPOSE: We investigated inpatient convalescent rehabilitation outcomes of Branch atheromatous disease (BAD). SUBJECTS AND METHODS: The subjects were 116 patients with lenticulostriate artery territory - BAD (LSA-BAD) and 29 with paramedian pontine artery territory - BAD (PPA-BAD). For all patients, the National Institutes of Health Stroke Scale (NIHSS), Functional Independence Measure (FIM) scores, and Brunnstrom recovery stages (BRS) of the upper limb, fingers, and lower limb were measured on admission and at discharge. RESULTS: There were no significant differences in clinical characteristics on admission between the LSA-BAD and PPA-BAD groups. The neurological severity of PPA-BAD, as measured by the NIHSS, was significantly milder compared with that of LSA-BAD upon admission (p = 0.015) and at discharge (p = 0.001). Patients with LSA-BAD had significantly less improvement in the BRS of the upper limb (p = 0.001), fingers (p < 0.001), and lower limb (p = 0.007) at discharge. Furthermore, they had significantly smaller changes in BRS between admission and discharge for the upper limb (p = 0.033) and fingers (p = 0.014) compared with patients with PPA-BAD. The improvement in BRS for patients with LSA-BAD tended to be limited to two stages; however, both patients with LSA-BAD and PPA-BAD saw sufficient gains in FIM at discharge. CONCLUSION: Rehabilitation outcomes following BAD in the convalescent period should be assessed in terms of improvements in pure-motor hemiparesis and activities of daily living. Furthermore, the disturbance patterns in the corticospinal tract by ischemic stroke lesions may be different between LSA-BAD and PPA-BAD.

Antenatal Glucocorticoid Administration Promotes Cardiac Structure and Energy Metabolism Maturation in Preterm Fetuses.

Although the rate of preterm birth has increased in recent decades, a number of preterm infants have escaped death due to improvements in perinatal and neonatal care. Antenatal glucocorticoid (GC) therapy has significantly contributed to progression in lung maturation; however, its potential effects on other organs remain controversial. Furthermore, the effects of antenatal GC therapy on the fetal heart show both pros and cons. Translational research in animal models indicates that constant fetal exposure to antenatal GC administration is sufficient for lung maturation. We have established a premature fetal rat model to investigate immature cardiopulmonary functions in the lungs and heart, including the effects of antenatal GC administration. In this review, we explain the mechanisms of antenatal GC actions on the heart in the fetus compared to those in the neonate. Antenatal GCs may contribute to premature heart maturation by accelerating cardiomyocyte proliferation, angiogenesis, energy production, and sarcoplasmic reticulum function. Additionally, this review specifically focuses on fetal heart growth with antenatal GC administration in experimental animal models. Moreover, knowledge regarding antenatal GC administration in experimental animal models can be coupled with that from developmental biology, with the potential for the generation of functional cells and tissues that could be used for regenerative medical purposes in the future.

Symbol digit modalities test predicts decline of off-road driving ability in Japanese patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic progressing neurological disease with exacerbations and remissions. Patients with MS can show a variety of neurological symptoms. Cognitive decline is noticed as one of them and is related with deterioration of daily life quality in a clinical practice. Driving a car is one of the common activities required in daily life and is also an important issue in MS patients. METHODS: To clarify the relationship between cognitive function and driving ability in MS patients, the symbol digit modalities test (SDMT) and a driving simulator were evaluated. We enrolled 24 patients with MS (5 males, 19 females, 39.04 ± 8.27 years old) and age- and sex-matched 24 healthy controls (5 males, 19 females, 40.54 ± 9.78 years old) in this study. They underwent the SDMT and also used a driving simulator to measure a total of 12 response values related to driving ability. In order to evaluate the relationship between SDMT and driving ability, MS patients were divided into two groups according to the median SDMT score: group A (SDMT 51 or more) and group B (SDMT less than 51). The data were statistically analyzed among control group, MS group A, and MS group B using Jonkheere-Terpstra trend test and Bonferroni's multiple comparison test. RESULTS: The group with higher scores on the SDMT tended to have significantly higher driving performance. Multiple comparison analysis among three groups showed that the reaction values for speed of response behavior were significantly higher in MS group B than control group. CONCLUSION: This study revealed a relationship between driving abilities and SDMT scores. Clinical evaluation using the SDMT may help to detect cognitive decline and to make a decision on driving a car in patients with MS.

Rare presentation of tuberculous hypertrophic pachymeningitis diagnosed by a biopsy of abdominal lymphadenopathy.

A 59-year-old man with medical history of diabetes mellitus and hypertension presented with a persistent fever of unknown origin and developed a headache. Laboratory tests, including polymerase chain reaction assays for Mycobacterium tuberculosis, showed no specific abnormal findings in blood or cerebrospinal fluid. Contrast-enhanced computed tomography revealed abdominal paraaortic lymphadenopathy. Abdominal lymph node biopsy showed caseous necrosis and suggested tuberculous lymphadenopathy. Intensive examinations revealed positive T-SPOT.TB test and multiple dural nodular hypertrophic lesions in brain magnetic resonance imaging. After antitubercular treatment, all clinical manifestations and dural nodular lesions improved. Finally, we diagnosed the patient with tuberculous hypertrophic pachymeningitis. To our knowledge, this is the first report of tuberculous hypertrophic pachymeningitis concomitant with abdominal tuberculous lymphadenopathy and no other dissemination. Systematic investigation of tuberculosis is important for pachymeningitis.

HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data.

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype-phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype-phenotype correlations are unclear in NMOSD.

Diffuse Large B-Cell Lymphoma of the Trachea in a Child With Symptoms of Bronchial Asthma.

Tracheal tumors are rare in children and manifest symptoms of airway obstruction. A 14-year-old boy with a 5-month history of dyspnea and wheezing was referred to our hospital. Although he had been initially diagnosed with bronchial asthma, computed tomography revealed tracheal tumors. Histologic examination showed only necrotic tissue. Thereafter, the systemic steroid treatment for bronchial asthma was tapered off. A second computed tomography scan revealed new lesions in the pancreas and lung. Biopsy of the pancreatic lesion revealed a diffuse large B-cell lymphoma. The patient was administered standard chemotherapy, following which he went into complete remission.

A successful treatment of tadalafil in incontinentia pigmenti with pulmonary hypertension.

We describe a female infant with incontinentia pigmenti complicated by severe pulmonary arterial hypertension that was markedly improved by tadalafil administration. The infant was referred to our institution because of neonatal seizures and generalized skin rash at the age of 1 day. She was diagnosed with incontinentia pigmenti on skin biopsy findings. In addition to incontinentia pigmenti, she had pulmonary arterial hypertension without structural heart disease. The pulmonary hypertension rapidly worsened at the age of 2 months and was confirmed by cardiac catheterization. The pulmonary artery pressure was equal to systemic pressure but it decreased in response to nitric oxide inhalation. We, therefore, initiated treatment with tadalafil of 1 mg/kg/day. The follow-up cardiac catheterization performed at 9 months revealed dramatic improvement in the pulmonary artery pressure. An IKBKG mutation with deletion of exons 4-10 was detected in the blood of both the patient and her mother. Our experience indicates that tadalafil may be beneficial in treating pulmonary arterial hypertension associated with incontinentia pigmenti.

Relationship between rheumatoid arthritis and locomotive syndrome: validation of the 25-question Geriatric Locomotive Function Scale in patients with rheumatoid arthritis.

This study aimed to understand the clinical state of locomotive syndrome (LS) in patients with rheumatoid arthritis (RA) and to validate the use of the 25-question Geriatric Locomotive Function Scale (GLFS-25) in patients with RA and compare it side-by-side with the Health Assessment Questionnaire-Disability Index (HAQ-DI). Subjects were 159 patients with RA (female, 112 (70.4%); mean age, 66.2 ± 12.0 years) who consecutively visited Yokkaichi Municipal Hospital between June and August 2017. Mean disease duration was 11.4 ± 9.3 years, mean HAQ-DI score was 0.5 ± 0.7 points, and mean GLFS-25 score was 17.8 ± 19.1 points. The correlation between GLFS-25 and HAQ-DI was analyzed using Spearman's rank correlation coefficient. The cut-off point of GLFS-25 corresponding to HAQ-DI≤0.5, which represents functional remission in patients with RA, was calculated by ROC analysis. GLFS-25 and HAQ-DI were positively and strongly correlated (correlation coefficient=0.798). The cut-off point of GLFS-25 corresponding to HAQ-DI≤0.5 was 20 points (sensitivity, 81%; specificity, 90%). Thus, the cut-off point of GLFS-25 corresponding to functional remission is higher than that for developing LS (i.e., 16 points). Moreover, the proportion of patients with LS among those with HAQ-DI ≤0.5 was 17.9%. In conclusion, our findings suggest that some patients with RA in remission may have LS, as well as the need to consider appropriate interventions for such patients.

Exposure of immature rat heart to antenatal glucocorticoid results in cardiac proliferation.

BACKGROUND: ATP synthesis and cardiac contraction-related protein production are accelerated in the immature fetal heart by antenatal glucocorticoids (GC). This study investigated the structural maturity of the myocardium and underlying signal pathway associated with cardiac growth in fetal rats that received antenatal GC. METHODS AND RESULTS: Dexamethasone (DEX) was given to pregnant rats for 2 days from day 17 or day 19 of gestation, and the hearts of 19 and 21 day fetuses and 1-day-old neonates were analyzed. Although irregular myofibril orientation was observed morphologically in 19 day fetal hearts, the myofibril components were organized in fetuses after DEX. The cross-sectional area of the myocardium and Ki-67-positive cells were significantly increased in fetal DEX groups, suggesting that cardiac enlargement resulted from myocyte proliferation. Glycogen synthase kinase-3ß (GSK-3ß) protein was significantly decreased in fetal DEX groups. ß-Catenin and vascular endothelial growth factor protein were also significantly increased. Furthermore, increased cardiomyocyte proliferation appeared to be mediated by GC receptors after culture with DEX in vitro. CONCLUSIONS: Antenatal DEX induces structural maturity accompanying cardiomyocyte proliferation in the premature fetal rat heart, and GSK-3ß and ß-catenin are thought to contribute to cardiac growth.

Usefulness of CT-based measurement of volar prominence for evaluation of risk of flexor tendon injury following fixation of a distal radius fracture.

BACKGROUND: Although some radiographic evaluations of the risk of flexor tendon injury following fixation of a distal radius fracture are useful, these radiographic measurements are limited because of their inability to obtain three-dimensional measurements. We hypothesized that CT-based measurements would be more sensitive indicators for risk estimation than radiography. METHODS: We retrospectively evaluated the relationship between plate positioning and the incidence of flexor tendon symptoms based on postoperative radiographic and CT-based measurements in 99 hands that were followed up for more than 12 months. We also compared the reproducibility, diagnostic accuracy, and ability to detect the plate-bone gap between radiographic and CT-based measurements. We also assessed the correlation between the volar prominence and plate-bone gap using CT. Multivariable analysis using stepwise logistic regression was performed to identify factors independently associated with tendon rupture or irritation. RESULTS: In single variable analysis, we found that the volar tilt was significantly smaller and the radiographic plate-to-critical line distance (PCL), CT-PCL, and CT-gap were significantly greater in the group with tendon irritation or rupture. Multivariable logistic regression analysis indicated that the CT-based measurement of the volar prominence is a significantly positive independent predictor of tendon rupture or irritation. CONCLUSION: CT-based measurement of the volar prominence may be one of the best radiographic predictors of the risk of flexor tendon injury following fixation of a distal radius fracture regardless of the plate type and distal prominence and the extent of rotation. This measurement may assist surgeons when deciding on the need for removal of hardware to decrease the long-term risk of flexor tendon rupture.

Fingolimod induces BAFF and expands circulating transitional B cells without activating memory B cells and plasma cells in multiple sclerosis.

Patients with multiple sclerosis (MS) who are treated with fingolimod have an increased proportion of transitional B cells in the circulation, but the underlying mechanism is not known. We hypothesized that B cell-activating factor of the tumor necrosis factor family (BAFF) is involved in the process. Compared with healthy controls and untreated MS patients, fingolimod-treated MS patients had significantly higher serum concentrations of BAFF, which positively correlated with the proportions and the absolute numbers of transitional B cells in blood. Despite the elevated concentrations of BAFF in fingolimod-treated MS patients, serum levels of soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor, and B cell maturation antigen were not elevated. Our results show that fingolimod induces BAFF in the circulation and expands transitional B cells, but does not activate memory B cells or plasma cells in MS, which is favorable for the treatment of this disease.

Fingolimod suppresses bone resorption in female patients with multiple sclerosis.

Fingolimod is a sphingosine-1-phosphate receptor agonist used to inhibit the inflammatory activity of multiple sclerosis (MS), and has been shown to suppress osteoporosis in mouse models. In this study, levels of bone turnover markers were quantified in serum and urine samples from MS patients treated with fingolimod. Compared with untreated MS patients and healthy controls, fingolimod-treated MS patients had a significantly lower level of the bone resorption marker type I collagen cross-linked N-telopeptide in urine. This finding was prominent in female but was not seen in male subjects. Our results suggest that fingolimod may have a beneficial effect on bone mass loss in female MS patients.

Diverse multi-organ histopathologic changes in a failed Fontan patient.

We report multi-organ histopathological changes in a patient with protein-losing enteropathy (PLE) over 12 years after Fontan operation. A 14-year-old boy with right isomerism heart and single ventricle had undergone Fontan procedure at 19 months of age, and PLE was diagnosed at 28 months. He had several episodes of intestinal bleeding and pre-renal failure with elevated creatine, and eventually died of pneumonia. The intrapulmonary small arteries showed medial and intimal thickening resembling pulmonary hypertension. No major ulcerative lesions were found in the small or large intestines. Dilated lymph ducts, one of the characteristic features of PLE, were not seen in mucosal and submucosal areas. Liver cirrhosis was obvious despite little increase in liver enzymes. Histological changes in bilateral kidneys were subtle despite repeated episodes of renal failure. Thus, there may be significant discrepancies between clinical manifestations and multi-organ histological changes in failed Fontan patients.

Displacement of the anterior leaflet of the tricuspid valve: Rare variant of Ebstein's anomaly.

In Ebstein's anomaly, the points of attachment, or hinges, of the septal and mural leaflets in the right ventricle are displaced away from the atrioventricular junction. In contrast, the junctional hinge of the anterior leaflet usually retains a normal position. Here, we report a case of giant right atrial aneurysm due to isolated displacement of the anterior leaflet of the tricuspid valve in an infant, a rare variant of Ebstein's anomaly. Enlargement of the right atrium, which was initially diagnosed during the fetal period, progressively and markedly dilated after birth and was successfully treated with surgical resection. Isolated displacement of the anterior leaflet should be recognized as a variant of Ebstein's anomaly.

Application of Cone Reconstruction for Neonatal Ebstein Anomaly or Tricuspid Valve Dysplasia.

BACKGROUND: Outcomes of surgical intervention for severe tricuspid regurgitation related to Ebstein anomaly or tricuspid valve dysplasia in the neonatal period, particularly when associated with pulmonary atresia, are extremely poor. However, owing to emerging innovative surgical techniques, such as cone reconstruction, outcomes of tricuspid valve plasty in the neonatal period have gradually improved. METHODS: The study retrospectively reviewed the medical records of 12 neonates who were diagnosed with severe tricuspid regurgitation and pulmonary atresia related to Ebstein anomaly (n = 9) or isolated tricuspid valve dysplasia (n = 3) between 2000 and 2013. RESULTS: The first 6 patients underwent palliative therapy in anticipation of future functional single-ventricle palliation (Starnes operation). Biventricular repair was performed in the 6 patients born after 2012. As tricuspid valve plasty, cone reconstruction has been applied since 2013. Five patients underwent a Starnes operation, and 5 patients underwent biventricular repair, including 4 cone reconstructions. Four of the 5 patients who underwent a Starnes operation died in-hospital; the remaining patient underwent a Fontan operation at age 2 years. Three of the 5 patients who underwent biventricular repair survived. On echocardiogram, the 3 survivors who were treated with biventricular repair had a preoperative tricuspid regurgitation flow velocity greater than 3.0 m/s. CONCLUSIONS: Biventricular repair with cone reconstruction can be applied for severe tricuspid regurgitation due to neonatal Ebstein anomaly or tricuspid valve dysplasia with associated pulmonary atresia. A tricuspid regurgitation flow velocity greater than 3.0 m/s may be an indicator of successful biventricular repair.

Prevalence and predictors of haemostatic complications in 412 Fontan patients: their relation to anticoagulation and haemodynamics.

OBJECTIVES: Our aim in the present study was to determine the prevalence of haemostatic events in our Fontan patients, to identify predictive factors and to determine their association with haemodynamics and anticoagulant therapy. METHODS: We retrospectively evaluated 424 Fontan patients and examined correlations between postoperative haemodynamics and anticoagulant regimens with haemostatic events. RESULTS: After exclusion of 12 patients with a mechanical valve at the time of Fontan operation, our 412 patients were sub-divided into 21 groups based on the therapeutic duration of warfarin and antiplatelet agent therapy. During the early 5- to 10-year postoperative period, patients receiving warfarin showed higher central venous pressure and lower arterial oxygen saturation (Sat) (P < 0.05-0.001). During a mean follow-up of 11.2 years, 29 (7.0%) haemostatic events occurred. With regard to haemorrhagic events, haemoptysis was most common (n = 13, 45%), followed by cerebral bleeds in 3 (10%). Of thrombo-embolic events, thrombosis in the Fontan pathway was the most common (n = 7, 24%), followed by cerebral infarction in 3. Early haemorrhagic events were associated with late Fontan operation and use of preoperative renin-angiotensin system blockers, while late events were related to heterotaxy syndrome, male gender and low Sat (P < 0.05-0.01). A low Sat was the only predictor of early postoperative thrombo-embolic events (P = 0.0192). Among the three subgroup analyses of fixed anticoagulant regimens, the most frequent haemorrhagic events were associated with long-term use of warfarin (P = 0.0033). None of the anticoagulant regimens that included warfarin and/or antiplatelet agents were independently associated with haemostatic events throughout the follow-up. CONCLUSIONS: Anticoagulant regimens in Fontan patients varied widely with a significant trend for warfarin use in patients with impaired haemodynamics. Low arterial oxygenation may predict haemostatic events. The relatively high prevalence of haemorrhagic complications indicates the need for individualized anticoagulant administration throughout the follow-up.

Experience of decortication for restrictive hemodynamics in adults with congenital heart disease.

We treated four postoperative adults with congenital heart disease with severe restrictive hemodynamics (RH), and performed decortication (DC) with the anticipation of some relief of the RH. The catheterizations before DC showed high central venous, and right and left ventricular end-diastolic pressures with "dip-and-plateau" pressure waveforms in the right and left ventricles. Upon myocardial histopathologic examination, moderate myocardial fibrotic change was demonstrated in two of three cases. DC led to decrease in type B natriuretic peptide levels in all cases, resulting in a decline in the central venous, right and left ventricular end-diastolic pressures in three cases. Successful DC-related relief of RH, dilatation of the ventricles with decline in central and end-diastolic pressures, was observed in only one case. Our limited DC-related hemodynamic improvement indicates a complexity of the severe RH, which may represent a unique intractable heart failure pathophysiology in intractable postoperative adult congenital heart disease.