Effect of Chinese herbal medicines on the overall survival of patients with muscular dystrophies in Taiwan.

ETHNOPHARMACOLOGICAL RELEVANCE: Muscular dystrophies are a rare, severe, and genetically inherited group of disorders characterized by progressive loss of muscle fibers, leading to muscle weakness. The current treatment plan for muscular dystrophies includes the use of steroids to slow muscle deterioration by dampening the inflammatory response. AIM OF THE STUDY: Chinese herbal medicine (CHM) has been offered as an adjunctive therapy in Taiwan's medical healthcare plan, making it possible to track CHM usage in patients with muscular dystrophic disease. Therefore, we explored the long-term effects of CHM use on the overall mortality of patients with muscular dystrophies. MATERIALS AND METHODS: A total of 581 patients with muscular dystrophies were identified from the database of Registry for Catastrophic Illness Patients in Taiwan. Among them, 80 and 201 patients were CHM users and non-CHM users, respectively. Student's t-test, chi-squared test, Cox proportional hazard model, and Kaplan-Meier curve (log-rank test) were used for evaluation. Association rules and network analyses were performed to explore the combination of CHMs used in muscular dystrophies. RESULTS: Compared to non-CHM users, there were more female patients, more comorbidities, including chronic pulmonary disease and peptic ulcer disease in the CHM user group. Patients with prednisolone usage exhibited a lower risk of overall mortality than those who did not, after adjusting for age, sex, use of CHM, and comorbidities. CHM users showed a lower risk of overall mortality after adjusting for age, sex, prednisolone use, and comorbidities. The cumulative incidence of the overall survival was significantly higher in CHM users. Association rule and network analysis showed that one main CHM cluster was commonly used to treat patients with muscular dystrophies in Taiwan. The cluster includes Yin-Qiao-San, Ban-Xia-Bai-Zhu-Tian-Ma-Tang, Zhi-Ke (Citrus aurantium L.), Yu-Xing-Cao (Houttuynia cordata Thunb.), Che-Qian-Zi (Plantago asiatica L.), and Da-Huang (Rheum palmatum L.). CONCLUSIONS: Our data suggest that adjunctive therapy with CHM may help to reduce the overall mortality among patients with muscular dystrophies. The identification of the CHM cluster allows us to narrow down the key active compounds and may enable future therapeutic developments and clinical trial designs to improve overall survival in these patients.

Heart Transplantation in Muscular Dystrophy Patients: Is it a Viable Option?

BACKGROUND: Cardiomyopathy is a common complication among muscular dystrophy (MD) patients and often results in advanced heart failure and premature death. In spite of this, there is hesitancy to consider heart transplantation (HTx). This study describes the HTx outcomes in patients with MD in the United States. METHODS AND RESULTS: All HTx in the United Network for Organ Sharing database from October 1, 1987, to March 31, 2016, were identified. Two patient groups were created: MD cohort (n=81), and a cohort of all other cardiomyopathies, called cardiomyopathy-unmatched (n=41 317). Propensity score matching (ratio 1:2) was performed on transplant age, gender transplant year, renal function, and inotropic support at transplant to form a cardiomyopathy-matched cohort (n=162). Patient characteristics and posttransplant outcomes were compared. In the 81 patients with MD, Becker was the most common type (42%-52%). All the analyzed preoperative characteristics did not statistically differ between the MD and cardiomyopathy-matched cohorts except ventricular assist device use (16% versus 30%; P=0.017), ventilator support (0% versus 6%; P=0.031), and donor race mismatch (30% versus 55%; P<0.001). Median time on waitlist was not statistically different between the 2 groups (52 versus 59 days; P=0.12). Posttransplant survival of MD cohort was not statistically different compared with cardiomyopathy-matched cohort (P=0.18; hazard ratio [95% CI], 0.71 [0.42-1.18]) and was better than the cardiomyopathy-unmatched cohort (P=0.004; hazard ratio [95% CI], 0.53 [0.34-0.82]). Among the types of MD, no statistical difference was observed in posttransplant survival of Becker MD versus non-Becker MD (P=0.12; hazard ratio [95% CI], 2.17 [0.79-6.01]). CONCLUSIONS: Patients with MD undergoing HTx had similar long-term posttransplant survival compared with matched cardiomyopathy-related HTx recipients. HTx appears to be an effective treatment for a select group of muscular dystrophy patients with end-stage heart failure.

Differences in Race and Ethnicity in Muscular Dystrophy Mortality Rates for Males under 40 Years of Age, 2006-2015.

BACKGROUND/AIMS: Duchenne Muscular Dystrophy (DMD) has childhood onset, primarily affects males, and is usually fatal before the age of 40 years. Previous studies have indicated that this X-linked condition is more prevalent in whites than in blacks, but those were based on active surveillance, and limited to smaller populations and younger ages. METHODS: US death data were used to calculate mortality rates by race and ethnicity, with MD as either the underlying or multiple cause of death (MCD). Poisson approximation was used for confidence intervals; chi-square was used to compare rates. RESULTS: From 2006 to 2015, there were 3,256 deaths in males <40 years with MD as MCD, and 71% of these were aged 15-29 years. For whites, the average annual death rate was 0.43/100,000, which was significantly higher (p < 0.0001) that that of blacks (0.28), American Indian/Alaska Natives (0.20), and Asian/Pacific Islanders (0.21). The rate for non-Hispanic whites (0.46) was significantly higher (p < 0.0001) than the rates for Hispanic whites (0.31), Hispanic blacks (0.07), and non-Hispanic blacks (0.29). CONCLUSION: Since DMD is the primary cause of deaths in young males with MD, mortality rates are a reasonable proxy for the relative difference in racial prevalence. It appears that DMD is significantly more common in white males than in males of other races.

Outcomes of Hospitalised Muscular Dystrophy Patients.

BACKGROUND: In France, referral centres in teaching hospitals were created 10 years ago to provide MD patients with treatments and follow-up designed to prevent complications and improve outcomes. Respiratory failure is a major cause of death among subjects with MD, and its prevention and treatment can serve as a touchstone for assessing the effectiveness of MD care pathways. OBJECTIVE: We report data from a preliminary study of admissions of MD patients in France and of factors associated with mortality, with special emphasis on respiratory failure [RF]. METHODS: Retrospective analysis of the data from the French nationwide hospital database [Programme de M é dicalisation des syst é mes d'information, PMSI] for 2009 and 2010. RESULTS: 7187 admissions of patients with MD were included in the study. Most admissions were to teaching hospitals [5913/7187, 82.3%]. 302 [4.2%] patients were admitted for RF requiring invasive ventilation, 924 [12.9%] for RF requiring only NIV or high-flow oxygen therapy, and 5961 [82.9%] required no respiratory assistance. 494 [6.9%] admissions occurred on an emergency basis. 77/7187 [1.1%] patients died while hospitalised. Teaching-hospital admission was associated with lower frequencies of emergency admission [3.08% vs. 24.5%, p < 0.01] and in-hospital death [0.71% vs. 2.75%, p < 0.01]. CONCLUSIONS: Our data suggest that there is room for improvement in care pathways for MD patients requiring admission. Admission to referral centres may provide the best outcomes.Further studies are needed to assess associations between healthcare pathways and outcomes of MD subjects.

Long-term non-invasive ventilation in muscular dystrophy.

Long-term non-invasive ventilation (NIV) was introduced in the 1980s, initially mainly for patients with poliomyelitis, muscular dystrophy (MD) or scoliosis. The obesity-hypoventilation syndrome has since become the commonest reason for referral to most centres providing home-NIV. Patients with MD are numerically a much smaller part of the workload, but as their disease progresses the need for ventilatory support changes and they require regular comprehensive assessment of their condition. We have examined the trend in MD use of home-NIV in our unit over the last 25 years. The number of new referrals appears to be stabilizing at around 20-25 over a 5-year period, equivalent to approximately 0.5 per 100,000 of population per year. The mean age at commencement of home-NIV is now 37.5 years, with 5-year survival rates of 70-75%. Ten-year survival rates are just over 40%. The distance of usual place of residence from our unit is fairly stable, currently at a mean of 27 km. Excellent survival rates mean that patients with MD, while numerically small, are likely to remain an important part of the workload of centres providing home-NIV. Our data should prove useful in the planning of future services for this group of patients.

Highly efficient in vivo delivery of PMO into regenerating myotubes and rescue in laminin-α2 chain-null congenital muscular dystrophy mice.

Phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping is among the more promising approaches to the treatment of several neuromuscular disorders including Duchenne muscular dystrophy. The main weakness of this approach arises from the low efficiency and sporadic nature of the delivery of charge-neutral PMO into muscle fibers, the mechanism of which is unknown. In this study, to test our hypothesis that muscle fibers take up PMO more efficiently during myotube formation, we induced synchronous muscle regeneration by injection of cardiotoxin into the tibialis anterior muscle of Dmd exon 52-deficient mdx52 and wild-type mice. Interestingly, by in situ hybridization, we detected PMO mainly in embryonic myosin heavy chain-positive regenerating fibers. In addition, we showed that PMO or 2'-O-methyl phosphorothioate is taken up efficiently into C2C12 myotubes when transfected 24-72 h after the induction of differentiation but is poorly taken up into undifferentiated C2C12 myoblasts suggesting efficient uptake of PMO in the early stages of C2C12 myotube formation. Next, we tested the therapeutic potential of PMO for laminin-α2 chain-null dy(3K)/dy(3K) mice: a model of merosin-deficient congenital muscular dystrophy (MDC1A) with active muscle regeneration. We confirmed the recovery of laminin-α2 chain and slightly prolonged life span following skipping of the mutated exon 4 in dy(3K)/dy(3K) mice. These findings support the idea that PMO entry into fibers is dependent on a developmental stage in myogenesis rather than on dystrophinless muscle membranes and provide a platform for developing PMO-mediated therapies for a variety of muscular disorders, such as MDC1A, that involve active muscle regeneration.

Widening gap in age at muscular dystrophy-associated death between blacks and whites, 1986-2005.

BACKGROUND: Muscular dystrophies (MDs), characterized by progressive muscle wasting, are associated with 1 in 2,500 deaths in the United States. Although treatments slow the progression, these disorders lead to early death, usually due to cardiac or respiratory failure. METHODS: We analyzed death record data from 18,315 MD-associated deaths that occurred in the United States in 1986 through 2005 to assess trends in the age at death of people with MDs. RESULTS: From 1986 through 2005, the MD-associated mortality rate did not change among blacks, whites, males, or females. The median age at death among white females with MDs was 12 years higher than among black females. The frequency of reported cardiomyopathy increased among white but not black male decedents with MDs, although cardiomyopathy remained more commonly reported among black males. Among white males, the median age at death increased by 0.2 annually for those with and 1.3 for those without indications of cardiomyopathy. Among black males, the median age at death increased 0.3 years annually among those without reported cardiomyopathy. Among white males, the frequencies of pulmonary failure and pulmonary infection decreased significantly over time. CONCLUSIONS: Changes in age at death and reported clinical comorbidities reflect improvements in the treatment of MDs. White males with MDs have shown a greater increase in age at death over time than black males. Contributing factors to this difference might include differences in types of MDs, rates of genetic and environmental modifiers, natural history, socioeconomic factors, and access to and use of treatment options.

Aging with muscular dystrophy: pathophysiology and clinical management.

Major advances in the fields of medical science and physiology, molecular genetics, biomedical engineering, and computer science have provided individuals with muscular dystrophy (MD) with more functional equipment, allowing better strategies for improvement of quality of life. These advances have also allowed a significant number of these patients to live much longer. As progress continues to change management, it also changes patients' expectations. A comprehensive medical and rehabilitative approach to management of aging MD patients can often fulfill expectations and help them enjoy an enhanced quality of life.

Natural history of Ullrich congenital muscular dystrophy.

OBJECTIVE: To describe the course, complications, and prognosis of Ullrich congenital muscular dystrophy (UCMD), with special reference to life-changing events, including loss of ambulation, respiratory insufficiency, and death. METHODS: Review of the case notes of 13 patients with UCMD, aged 15 years or older at last visit, followed up at a tertiary neuromuscular centre, London, UK, from 1977 to 2007. Data collected were age at onset of symptoms, presenting symptoms, mobility, contractures, scoliosis, skin abnormalities, respiratory function, and feeding difficulties. RESULTS: The mean age at onset of symptoms was 12 months (SD 14 months). Eight patients (61.5%) acquired independent ambulation at a mean age of 1.7 years (SD 0.8 years). Nine patients (69.2%) became constant wheelchair users at a mean age of 11.1 years (SD 4.8 years). Three patients continued to ambulate indoors with assistance. Forced vital capacity (FVC) values were abnormal in all patients from age 6 years. The mean FVC (% predicted) declined at a mean rate of 2.6% (SD 4.1%) yearly. Nine patients (69.2%) started noninvasive ventilation at a mean age of 14.3 years (SD 5.0 years). Two patients died of respiratory insufficiency. CONCLUSION: In Ullrich congenital muscular dystrophy (UCMD), the decline in motor and respiratory functions is more rapid in the first decade of life. The deterioration is invariable, but not always correlated with age or severity at presentation. This information should be of help to better anticipate the difficulties encountered by patients with UCMD and in planning future therapeutic trials in this condition.

Reflections on the brainstem dysfunction in neurologically disabled children.

This article deals with the neurological basis of brainstem-related symptoms in disabled children. Synaptic interactions of respiratory and swallowing centers, which are briefly reviewed in this study, highlight the significance of the nucleus of solitary tract (NTS) in the stereotyped motor events. Coordination mechanisms between these two central pattern generators are also studied with a focus on the inhibitory action of decrementing expiratory neurons that terminate the inspiratory activity and become activated during swallowing. Dorsal brainstem lesions in hypoxic-ischemic encephalopathy (HIE) affect the area including NTS, and result in symptoms of apneusis, facial nerve paresis, dysphagia, gastroesophageal reflux, and laryngeal stridor. Leigh syndrome patients with similar distributions of medullary lesions show increased sighs, post-sigh apnea, hiccups, and vomiting in addition to the symptoms of HIE, suggesting pathologically augmented vagal reflex pathways. The present article also discusses the pathophysiology of laryngeal dystonia in xeroderma pigmentosum group A, self-mutilation in Lesch-Nyhan syndrome, and sudden unexpected death in Fukuyama congenital muscular dystrophy. Close observation and logical assessment of brainstem dysfunction symptoms should be encouraged in order to achieve better understanding and management of these symptoms in disabled children.

Trends and racial disparities in muscular dystrophy deaths in the United States, 1983-1998: an analysis of multiple cause mortality data.

To identify trends and patterns associated with muscular dystrophy (MD)-associated deaths, we analyzed population-based data from death certificates in the Multiple Cause Mortality Files compiled by the National Center for Health Statistics. From 1983 to 1998, 14,499 deaths in the United States were associated with ICD-9 codes for MD. The mortality rate for MD in the general U.S. population over this time period was 0.365 per 100,000 persons per year. Stratification by age at death revealed a trimodal distribution with peaks at 0, 17, and 62 years. The male-to-female ratio varied with age at death, a pattern consistent with a mixture of autosomal and X-linked MDs with different prognoses. Deaths related to MD appeared to be equally divided between presumed autosomal and X-linked MDs. The mortality rate was higher in Whites than in Blacks, for both autosomal and X-linked MDs. The median age at death was lower in Blacks than Whites for both males and females. Cardiac complications were more commonly noted among MD-associated deaths in Blacks (38.9%) than Whites (28.6%). Respiratory infections were noted in about 20% of MD-associated deaths and were more common in winter than summer months. Potential reasons for the racial differences include differences in prevalence rates, rates of diagnosis, and reporting on death certificates. Additional studies are needed to resolve these issues. Challenges in the interpretation of these data include the lack of ICD-9 codes specific for individual MDs and potential recording biases in underlying cause of death and contributing factors. We also present a method for estimating autosomal and X-linked contributions to the overall mortality rate of a genetically heterogeneous condition such as MD.

Trends in survival from muscular dystrophy in England and Wales and impact on respiratory services.

Respiratory failure is an important terminal event in muscular dystrophy, but increasingly is effectively treated by non-invasive ventilation. This study was designed to assess mortality statistics in this patient group in order to get an indication of future demand. Mortality data for all deaths from muscular dystrophy registered by death certification in England and Wales between 1993 and 1999 were analysed. In total, 817 deaths from muscular dystrophy were registered between 1993 and 1999. Annual number of deaths was unchanged over this period. Median age at death (interquartile range) for all cause muscular dystrophy increased from 20 (17-42.5) years in 1993, to 26 (17.5-63) years in 1999. Respiratory failure was the primary or contributory cause of death in 82% of cases. Two thirds of these deaths were during acute infection. We can expect 100 patients with muscular dystrophy to develop respiratory failure in England and Wales each year, so non-invasive ventilation services probably need to be able to provide for 0.2 new patients per 100,000 population annually. Respiratory services also need to provide adequate monitoring and early treatment of infection in these patients.

[Cardiac manifestations of muscular dystrophies]. / Kardiale Manifestationen bei Muskeldystrophien.

Muscular dystrophies (MD) are a clinically and genetically heterogeneous disease group. In the last few years, remarkable progress has been made in understanding the close und various relations between skeletal muscle disease and heart muscle disease. Cardiac involvement has been documented in a number of primary MDs and is even the dominant feature in some of them. The myocardium can be affected in the form of a dilated cardiomyopathy while the conduction system can be affected resulting in arrhythmias and conduction defects. Many patients with MD die because of cardiac complications like sudden cardiac death or congestive heart failure. Detailed clinical data about cardiac involvement are available for Duchenne/Becker MD, Emery-Dreifuss MD, myotonic dystrophy, and the different limb girdle MDs. Cardiac manifestations were also found in congenital MD, central core disease, proximal myotonic myopathy, and nemaline myopathy. No data about cardiac abnormalities are available in oculopharyngeal MD and rippling muscle disease. The heart of patients with primary MD should be carefully investigated because of the life-threatening events caused by cardiac complications. There is a strong need for a close collaboration between neurologists and cardiologists in order to provide optimal disease management for the affected patients.

Elimination of myostatin does not combat muscular dystrophy in dy mice but increases postnatal lethality.

Myostatin is a TGF-beta family member and a negative regulator of skeletal muscle growth. It has been proposed that reduction or elimination of myostatin could be a treatment for degenerative muscle diseases such as muscular dystrophy. Laminin-deficient congenital muscular dystrophy is one of the most severe forms of muscular dystrophy. To test the possibility of ameliorating the dystrophic phenotype in laminin deficiency by eliminating myostatin, we crossed dy(W) laminin alpha2-deficient and myostatin null mice. The resulting double-deficient dy(W)/dy(W);Mstn(-/-) mice had a severe clinical phenotype similar to that of dy(W)/dy(W) mice, even though muscle regeneration was increased. Degeneration and inflammation of muscle were not alleviated. The pre-weaning mortality of dy(W)/dy(W);Mstn(-/-) mice was increased compared to dy(W)/dy(W), most likely due to significantly less brown and white fat in the absence of myostatin, and postweaning mortality was not significantly improved. These results show that eliminating myostatin in laminin-deficiency promotes muscle formation, but at the expense of fat formation, and does not reduce muscle pathology. Any future therapy based on myostatin may have undesirable side effects.

Duchenne muscular dystrophy: prolongation of life by noninvasive ventilation and mechanically assisted coughing.

OBJECTIVE: To quantitate prolongation of survival for patients with Duchenne muscular dystrophy with the use of noninvasive intermittent positive-pressure ventilation (IPPV) with and without access to a protocol involving mechanically assisted coughing. DESIGN: In this retrospective review of all patients with Duchenne muscular dystrophy visiting a neuromuscular disease clinic, patients were trained to use mouth piece and nasal IPPV and mechanically assisted coughing to maintain oxyhemoglobin saturation >94% (protocol). Survival was considered prolonged when noninvasive IPPV was required full time. RESULTS: Ninety-one of 125 patients used noninvasive IPPV part time for 1.9 +/- 1.3 yr, and 51 went on to require it full time for 6.3 +/- 4.6 yr. Of the 31 noninvasive IPPV users who died without access to the protocol, 20 died from respiratory causes and seven died from cardiac causes. None of the 34 full-time noninvasive IPPV users with access to the protocol underwent tracheotomy or died from respiratory complications during a period of 5.4 +/- 4.0 yr, whereas three died from heart failure. Five patients with no breathing tolerance were extubated or decannulated to continuous noninvasive IPPV. CONCLUSIONS: Noninvasive respiratory aids can prolong survival and permit extubation or decannulation of patients with Duchenne muscular dystrophy with no breathing tolerance.

Nocturnal oxygenation and prognosis in Duchenne muscular dystrophy.

REM-related oxygen desaturation occurs in advanced Duchenne muscular dystrophy (DMD) and might be an independent predictor of disease progression. We have followed 18 patients for 10 yr after an initial respiratory sleep study or until death or onset of nasal ventilation. We measured baseline spirometry, blood gas tensions, maximal respiratory pressures, and body mass index. In 11 cases, VC was recorded serially. Median survival was 50 (range, 13 to 89) mo from initial study and unrelated to age at time of study, BMI, or mouth pressures but correlated with PaCO2 (r = -0.72, p < 0.005, n = 17), minimal nocturnal SaO2 (r = 0.62, p < 0.007, n = 18) and VC (r = 0. 65, p < 0.005, n = 17). Cox regression analysis showed a VC of less than 1 L at the time of study to be the best single predictor of subsequent survival. The only measure associated with age of death was the age at which the VC fell below 1 L (r = 0.79, p < 0.004). These data suggest measurement of PaCO2 or serial assessment of VC should be studied further as valid methods of assessing prognosis in DMD.

Cardioprotection for Duchenne's muscular dystrophy.

PURPOSE: To explore the use of neuroendocrine monitoring for more timely diagnosis of dilated cardiomyopathy (DCM) in Duchenne's muscular dystrophy (DMD) and to determine the effects of angiotensin-converting enzyme inhibitors (ACEI) and beta-blockers on neuroendocrine levels, left ventricular diastolic diameter (LVDd), ejection fraction, and mortality rate on DMD. METHODS: Eighty-five patients with DMD underwent yearly cardiac monitoring including neuroendocrine screening. Eleven patients had symptoms of DCM develop once plasma neuroendocrine levels increased. At this point the patients received ACEI for 9 to 62 months (35.8 +/- 18.4 months) and beta-blockers for 7 to 60 months (31.6 +/- 20.1 months). RESULTS: The combination of ACEI and beta-blockers relieved symptoms and signs of heart failure in all 11 patients and significantly reduced atrial natriuretic protein (ANP) levels from 197.5 +/- 152.1 pg/mL to 25.5 +/- 16.2 pg/mL ( P <.002) at 15.5 +/- 8.2 months, brain natriuretic protein from 523.8 +/- 434.8 pg/mL to 59.3 +/- 24. 2 pg/mL ( P <.05) at 12.2 +/- 3.1 months (data complete for 5 patients), norepinephrine levels from 1114 +/- 689 pg/mL to 360 +/- 257 pg/mL at 20.5 +/- 9.6 months for 11 patients (P =.001), and LVDd from 65.9 +/- 9.2 mm to 63.3 +/- 6.3 mm (P =.15) at 15.0 +/- 7.4 months for 10 patients, including 3 for whom the LVDd increased by 2 to 6 mm. The combination increased left ventricular ejection fraction (LVEF) from 25.1% +/- 9.2% to 36.5% +/- 5.8% (P <.001) at 17.1 +/- 11.0 months for 10 patients. For 9 of the patients ANP levels remained lower throughout the 36.8 +/- 20.1 month course of the follow-up. Two patients had sudden severe re-elevations of ANP levels just before death from congestive heart failure after 44 and 23 months of therapy, respectively. CONCLUSION: Neuroendocrine level monitoring can assist in the diagnosis of DCM in patients with DMD. Combination therapy with ACEI and beta-blockers can significantly decrease neuroendocrine activation and LVDd and reverse symptoms and signs of congestive heart failure for patients with DMD.