Cognitive impairment in myotonic dystrophy type 1 (DM1)

OBJECTIVE: To characterize the progression of the cognitive involvement in patients affected by myotonic dystrophy type 1 (DM1) by a longitudinal neuropsychological follow-up study. METHODS: In a previous study we documented an ageing-related decline of frontal and temporal cognitive functions in juvenile/adult forms of DM1, irrespectively of the n(CTG) in leukocytes and the severity of muscle weakness. Here we present the results of a neuropsychological follow-up study performed in 34 out of 70 DM1 patients previously studied. Patients were divided into four groups according to their genotype (E1:50-150; E2:150-500; E3:500-1000; E4: >1000 CTG). The neuropsychological test battery included MMSE, memory, linguistic, level, praxis, attentional and frontal-executive tasks. Statistical analysis was performed by One way MANOVA with repeated measures analysis and by Wilcoxon match paired test. RESULTS: The whole group of patients showed a significant deterioration in linguistic functions, together with a tendency towards decline in executive abilities, confirming a predominant involvement of cognitive functions subserved by fronto-temporal areas. We found no significant correlation between the progression of cognitive decline and the n(CTG) in leukocytes. Moreover, we observed that patients belonging to E2 group, with the highest mean age, got scores lower than E3 patients, with particular regard both to linguistic and executive tasks. CONCLUSIONS: These data support our previous hypothesis that the cognitive damage is confined to frontotemporal functions in adult DM1 patients, with a tendency towards a decline with aging.     

Respiratory dysfunction in myotonic dystrophy type 1: A systematic review

Myotonic dystrophy type 1 (DM1) is one of the most common muscular dystrophies in adults. This review summarises the current literature regarding the natural history of respiratory dysfunction in DM1, the role of central respiratory drive and peripheral respiratory muscle involvement and its significance in respiratory function, and investigates the relationship between genetics (CTG repeat length) and respiratory dysfunction. The review included all articles that reported spirometry on 10 or more myotonic dystrophy patients. The final review included 55 articles between 1964 and 2017. The major conclusions of this review were (1) confirmation of the current consensus that respiratory dysfunction, predominantly a restrictive ventilatory pattern, is common in myotonic dystrophy and is associated with alveolar hypoventilation, chronic hypercapnia, and sleep disturbance in the form of sleep apnoea and sleep related disordered breathing; (2) contrary to commonly held belief, there is no consensus in the literature regarding the relationship between CTG repeat length and severity of respiratory dysfunction and a relationship has not been established; (3) the natural history and time-course of respiratory functional decline is very poorly understood in the current literature; (4) there is a consensus that there is a significant involvement of central respiratory drive in this alveolar hypoventilation however the current literature does not identify the mechanism for this.     

The prevalence of faecal incontinence in myotonic dystrophy type 1

Faecal incontinence is recognised as a feature of myotonic dystrophy along with other symptoms of bowel dysfunction, but its prevalence is poorly defined. We have surveyed 152 unselected myotonic dystrophy patients. We identified issues with bowel control in 104 (68% of the study population). Forty-eight (32%) reported faecal incontinence in the 4 weeks prior to completion of the questionnaire. Fifty-six patients (37%) reported having to change their lifestyle because of incontinence issues at some point in the prior 4 weeks. This study shows a high frequency of life-changing symptoms in a large unselected, cohort of patients with myotonic dystrophy type 1, and highlights lower gastrointestinal symptoms as an important issue for further research.     

帕金森病患者健康相关生活质量的影响因素研究

目的探讨影响帕金森病(PD)患者健康相关生活质量(HRQoL)的主要因素。方法选用39项PD问卷(PDQ-39)、PD统一评定量表(UPDRS)和相关非运动症状评定量表对99例PD患者进行调查,分析影响HRQoL的主要因素。结果相关分析显示,PDQ-39综合指数(PDQ-39SI)与病程、每日左旋多巴剂量、UPDRSⅡ、Ⅲ、Ⅳ评分、Hoehn-Yahr分期、17项汉密尔顿抑郁量表(HRSD-17)、汉密尔顿焦虑量表(HAMA)和爱泼沃斯嗜睡量表(ESS)评分呈正相关(r为0.42～0.80,P均小于0.01),与简易精神状态量表(MMSE)、帕金森病睡眠量表(PDSS)评分呈负相关(r为-0.47、-0.68,P均小于0.01),与PD分型呈正相关(r=0.23,P<0.05)。进一步的多元回归结果表明:UPDRSⅡ、HAMD-17、ESS评分是影响PDQ-39SI的主要因素,3因素相加对HRQoL的影响起决定作用的72.1%。结论非运动症状对PD患者HRQoL有着显著的影响,应重视对抑郁和日间过度嗜睡等非运动症状的治疗。     

Executive dysfunction and avoidant personality trait in myotonic dystrophy type 1 (DM-1) and in proximal myotonic myopathy (PROMM/DM-2)

A previous study in proximal myotonic myopathy (PROMM/DM-2) and myotonic dystrophy type 1 (DM-1) using brain positron emission tomography demonstrated a reduced cerebral blood flow in the frontal and temporal regions associated with cognitive impairment. The objective was to investigate further cognitive and behavioural aspects in a new series of patients with DM-1 and PROMM/DM-2. Nineteen patients with genetically determined PROMM/DM-2 and 21 patients with moderately severe DM-1 underwent neuropsychological testing and neuropsychiatric interviews. DM-1 and PROMM/DM-2 patients had significantly lower scores on tests of frontal lobe function compared to controls. Neuropsychiatric interviews demonstrated an avoidant trait personality disorder in both patient groups. Brain single photon emission computed tomography showed frontal and parieto-occipital hypoperfusion. The results suggest that there is a specific cognitive and behavioural profile in PROMM/DM-2 and in DM-1, and that this profile is associated with hypoperfusion in frontal and parieto-occipital regions of the brain.     

Myasthenia gravis and thymoma coexisting with myotonic dystrophy type 1

We describe a 34-year old man presenting with subacute generalized myasthenic symptoms. His clinical features and laboratory investigations demonstrated both myasthenia gravis and myotonic dystrophy type 1. The computerized tomography of chest revealed anterior mediastinal mass. The lymphocyte-rich thymoma was removed surgically and he received radiotherapy. Recent observations suggested that the patients with myotonic dystrophy may have an increased risk of benign and malignant tumours but its coexistence with thymoma is very rare. The risk of thymoma associated with myotonic dystrophy is unknown.     

Metabolic syndrome in patients with myotonic dystrophy type 1

Introduction: The aim of this study was to assess the frequency and features of metabolic syndrome (MetS) in myotonic dystrophy type 1 (DM1). Methods: We studied 66 DM1 patients (50% men, aged 41.9 ± 10.5 years, disease duration of 19.3 ± 8.6 years). New worldwide consensus criteria for MetS from 2009 were used. Results: Components of MetS were present at the following frequencies: hypertriglyceridemia 67%; low HDL cholesterol 35%; hypertension 18%; central obesity 14%; and hyperglycemia 9%. MetS was present in 11 (17%) patients. The presence of MetS was not associated with patients' gender, age, disease severity, disease duration, or CTG repeat length (P > 0.05). Patients with MetS had significantly lower total SF‐36 scores as a measure of quality of life in comparison to patients without MetS (P < 0.05). Conclusion: Although certain components of MetS were very frequent in patients with DM1, only 17% met the criteria for MetS. Muscle Nerve 52 : 273–277, 2015     

四例强直性肌营养不良1型患者认知功能及头颅MRI研究

目的 探讨强直性肌营养不良1型(DM1)患者的认知功能、智力和头颅MRI改变.方法 选择广州医学院第二附属医院神经内科自2011年9月至2011年12月间诊治的一家系4例DM1患者为研究对象,采用中国修订韦氏智力量表和韦氏记忆量表检测智力,采用蒙特利尔认知评估量表(MoCA)和神经行为认知状况测试(NCSE)检测认知功能,同时行颅脑MRI检查. 结果 1例患者智商(IQ)和记忆商数(MQ)正常,其余3例患者IQ和MQ有不同程度下降,其中IQ下降以言语智商(VIQ)下降较明显.3例患者MoCA和NCSE检测示其视空间/执行、计算、记忆和抽象能力损害较明显;另1例患者MoCA检测虽然总分正常,但语言分测试中句子复述和词语流畅性检查均失分.MRI检查示3例患者存在不同程度脑萎缩,并以额叶、颞叶萎缩较明显;4例患者均存在不同程度的脑白质病变和颅骨增厚. 结论 DMI患者存在多种认知功能障碍和脑部病变,值得进一步研究.     

Transcranial sonography in patients with myotonic dystrophy type 1

Introduction: In this study we analyzed transcranial sonography (TCS) in patients with myotonic dystrophy type 1 (DM1). Methods: This cross‐sectional study included 66 DM1 patients and 55 matched healthy controls (HCs). Echogenicity of the brainstem raphe (BR) and substantia nigra (SN) and third ventricle width (DTV) were assessed by TCS. Results: BR hypoechogenicity was more common in DM1 patients than in HCs (37.7% vs. 7.8%, P < 0.01). Patients with depression or fatigue were more likely to have BR hypoechogenicity (80.0% vs. 29.4%, P < 0.01 and 51.9% vs. 24.2%, P < 0.05, respectively). Both hypoechogenicity and hyperechogenicity of SN were more frequent in DM1 patients than in controls (26.2% vs. 10.9% and 13.1% vs. 1.8%, respectively, P < 0.01). DTV was increased in DM1 patients compared with HCs (6.0 ± 1.4 vs. 4.9 ± 0.9 mm, P < 0.01). Conclusion: TCS can offer new insight into structural changes of several cerebral areas in patients with DM1. Muscle Nerve 50:278–282, 2014     

Leptin and the metabolic syndrome in patients with myotonic dystrophy type 1

Rakocevic Stojanovic V, Peric S, Lavrnic D, Popovic S, Ille T, Stevic Z, Basta I, Apostolski S. Leptin and the metabolic syndrome in patients with myotonic dystrophy type 1.
Acta Neurol Scand: 2010: 121: 94–98.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – To evaluate serum leptin concentration and its relation to metabolic syndrome (MSy) in non‐diabetic patients with myotonic dystrophy type 1 (DM1). Materials and methods – This study included 34 DM1 patients, and the same number of healthy subjects matched for age, sex and body mass index (BMI). Results – DM1 patients had increased BMI and insulin resistance, and increased leptin and insulin concentrations, but the other features of MSy such as diabetes, glucose intolerance and hypertension were not detected in DM1 patients. Serum leptin levels were higher in patients with DM1 than in healthy controls (8.5 ± 6.6 ng/ml vs 3.6 ± 2.9 ng/ml in men, and 13.9 ± 10.0 ng/ml vs 10.9 ± 6.9 ng/ml in women, respectively). In DM1 patients, leptin levels correlated with BMI, fasting insulin and insulin resistance (HOMA) (P < 0.01). Conclusions – The leptin overproduction correlated with insulin resistance in DM1 patients but the significance of this finding remains unclear.     

Sleep-disordered breathing and effects of non-invasive ventilation on objective sleep and nocturnal respiration in patients with myotonic dystrophy type I

Patients with myotonic dystrophy type I (DM1) may develop nocturnal hypoventilation, requiring non-invasive ventilation. Data on long-term adherence to non-invasive ventilation, or sleep and ventilation outcomes are scarce. We retrospectively collected baseline polysomnography and capnometry results from 36 adult patients with sleep-related symptoms (42.9?±?12.5 years, 20 female), plus follow-up sleep study records from those treated with non-invasive ventilation. Sleep-disordered breathing was found in 33 patients (91.7%) including 8 (22.2%) with daytime hypercapnia. Twenty-six patients (72.2%) showed nocturnal hypoventilation on transcutaneous capnometry. The sensitivity of oximetry to detect nocturnal hypoventilation was only 0.38. Twenty-eight patients (77.8%) showed sleep apnea, which was predominantly obstructive (n?=?8), central (n?=?9), or “mixed” (n?=?11). Thirty-two patients were initiated on non-invasive ventilation which significantly improved ventilation and oxygenation in the first night of treatment. Follow-up revealed stable normoxia and normocapnia without deterioration of sleep outcomes for up to 52 months. Adherence to treatment was low to moderate, with substantial inter-individual variability.Sleep disordered breathing is highly prevalent in adult DM1 patients complaining of daytime sleepiness, and non-invasive ventilation significantly, rapidly and persistently improves nocturnal gas exchange. Capnometry is superior to oximetry for detection of nocturnal hypoventilation. Adherence to non-invasive ventilation remains a major issue in DM1, and long-term treatment benefits should be individually assessed.     

Longitudinal in vivo muscle function analysis of the DMSXL mouse model of myotonic dystrophy type 1

Myotonic dystrophy is the most common adult muscle dystrophy. In view of emerging therapies, which use animal models as a proof of principle, the development of reliable outcome measures for in vivo longitudinal study of mouse skeletal muscle function is becoming crucial. To satisfy this need, we have developed a device to measure ankle dorsi- and plantarflexion torque in rodents. We present an in vivo 8-month longitudinal study of the contractile properties of the skeletal muscles of the DMSXL mouse model of myotonic dystrophy type 1. Between 4 and 12 months of age, we observed a reduction in muscle strength in the ankle dorsi- and plantarflexors of DMSXL compared to control mice although the strength per muscle cross-section was normal. Mild steady myotonia but no abnormal muscle fatigue was also observed in the DMSXL mice. Magnetic resonance imaging and histological analysis performed at the end of the study showed respectively reduced muscle cross-section area and smaller muscle fibre diameter in DMSXL mice. In conclusion, our study demonstrates the feasibility of carrying out longitudinal in vivo studies of muscle function over several months in a mouse model of myotonic dystrophy confirming the feasibility of this method to test preclinical therapeutics.     

Swallowing assessment in myotonic dystrophy type 1 using fiberoptic endoscopic evaluation of swallowing (FEES)

This study describes the swallowing function of patients with myotonic dystrophy type 1 (DM1) and the effect of bolus consistency on swallowing in this group. The aim of the study is twofold: (a) to identify which (and to what extent) swallowing variables change for DM1 patients relative to healthy control subjects and (b) to examine whether the degree of oropharyngeal dysphagia is associated with disease severity. Forty-five consecutive DM1 patients and ten healthy subjects underwent a swallowing assessment, at Maastricht University medical Center in the Netherlands. The assessment included a standardized fiberoptic endoscopic evaluation of swallowing (FEES) protocol using different bolus consistencies. Clinical severity of the disease was assessed using the muscular impairment rating scale (MIRS). Significant differences were found between patients and controls for all FEES variables. The magnitude of these differences depended on the bolus consistency. The odds of a more pathological swallowing outcome increased significantly with higher MIRS levels. In conclusion, swallowing function is found to be significantly altered in DM1 patients. The results emphasize the importance of conducting a detailed swallowing assessment in all patients, even those with mild muscle weakness.     

Cognitive decline over time in adults with myotonic dystrophy type 1: A 9-year longitudinal study

Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disease with multisystemic involvement including the central nervous system. The evolution of the cognitive profile is a matter of debate, whether an eventual decline could be global or process-specific. Study aims are to describe, compare and document the clinical relevance of the progression of cognitive abilities in DM1 patients with adult and late-onset phenotypes. A total of 115 DM1 patients (90 adult; 25 late-onset) were assessed twice within a 9-year period on cognitive abilities (language, memory, visual attention, processing speed, visuoconstructive abilities and executive functions) and intellectual functioning (WAIS-R 7). A significant worsening over time was observed for verbal memory, visual attention, and processing speed. The progression in cognitive scores correlated with age and disease duration, but not with nCTG, muscular impairment nor education at baseline. Intellectual functioning remained stable. The rate of decline was higher among the late-onset phenotype than in the adult phenotype. Results showed that executive functions, language, and visual memory are impaired earlier in adult life, while verbal memory, visual attention, and processing speed decline later. Globally, results suggest an early and accelerated normal ageing process. This longitudinal study was based on the largest sample and the longest time period studied to date. These findings are highly relevant for clinical practice and genetic counselling.     

Treatment of myotonic dystrophy with acetazolamide

Summary This report describes a patient with myotonic dystrophy who had severe action and percussion myotonia. The patient was unresponsive to diphenylhydantoin therapy. Treatment with acetazolamide, 250 mg daily, decreased the myotonia markedly. A possible mechanism of the favorable effect of acetazolamide in myotonia is discussed.

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Zusammenfassung Es wird ein Patient mit Dystrophia Myotonica beschrieben, der eine sehr ausgeprägte Myotonie nach aktiver Muskelkontraktion und Muskelperkussion aufwies. Er reagierte nicht auf eine Diphenylhydantoinbehandlung. Eine Therapie mit Acetazolamide, 250 mg täglich, bewirkte eine deutliche Verminderung der myotonen Reaktion. Es wird der mögliche Wirkungsmechanismus des Acetazolamides bei der Myotonie diskutiert.