Current Treatment Options for Patients with Myotonic Dystrophy Type 2

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Purpose of the review</jats:title> <jats:p>Myotonic dystrophy types 1 and 2 are frequent forms of muscular dystrophies in adulthood. Their clinical differences need to be taken into account for the most appropriate treatment of patients. The aim of this article is to provide an overview on the current and upcoming therapeutic options for patients with myotonic dystrophy type 2 (DM2).</jats:p> </jats:sec><jats:sec> <jats:title>Recent findings</jats:title> <jats:p>At the moment, no disease-modifying therapies are available for DM2; next-generation therapies may however be available in the near future. In the meanwhile, the symptomatic management of patients has greatly improved, thank to the production of consensus-based standards of care and the growing evidence of efficacy of anti-myotonic drugs, promising employment of cannabinoids for symptom’s relief, regular monitoring, and early detection of treatable extra-muscular manifestations.</jats:p> </jats:sec><jats:sec> <jats:title>Summary</jats:title> <jats:p>The treatment of DM2 is currently symptomatic and relies on the coordinated intervention of a multidisciplinary team. It remains to be determined whether upcoming causal therapies for myotonic dystrophy type 1 will be applicable also in DM2.</jats:p> </jats:sec&gt

Die klinischen und diagnostischen Merkmale der Myotonen Dystrophie Typ 2

Die Myotone Dystrophie Typ 2 (DM2) ist eine viel jüngere und weniger bekannte Erkrankung im Vergleich zur Myotone Dystrophie Typ 1 (DM1). Aufgrund ihrer niedrigen Prävalenz weltweit resultiert die Beschreibung des DM2 klinischen Bildes seit 1994 hauptsächlich aus klinischen Studien, die mit kleinen Patientenkollektiven (i.d.R. < 50 Patienten) durchgeführt wurden. Ziel dieser Promotionsarbeit ist die Phänotypdarstellung der klinischen Zeichen und Symptome in einer großen Kohorte von DM2 Patienten deutscher Herkunft. Insbesondere sollte der Einfluss von Alter und Geschlecht auf den DM2 Phänotyp erforscht werden. 307 Patienten aus 249 Familien mit einer genetisch gesicherten DM2 wurden in die Studie eingeschlossen. Folgende Daten wurden erhoben: (1) Demographie (Alter, Geschlecht, regionale Herkunft); (2) klinische Zeichen (Symptombeginn, erste Symptome, muskuläre Beschwerden im Verlauf, multisystemische Beteiligung); (3) Diagnostik (serologische Tests, Elektromyographie, Muskelbiopsie). Soweit anwendbar wurden die folgenden statistischen Tests verwendet: Mann–Whitney U-test, Kruskal–Wallis Test, Chi-square oder Fisher’s exact Tests. Spezifische Regressionsanalyseverfahren wurden zur Evaluation des Zusammenhangs zwischen unabhängige Variablen (z.B. Alter und Geschlecht) und spezifischen Symptomen durchgeführt. Die untersuchte Kohorte besteht aus 186 Frauen (61%) und 121 Männer. Bei Erkrankungsbeginn war das führende klinische Leitsymptom eine proximale muskuläre Schwäche (55,4%), gefolgt von Myalgien (35,5%) und der Myotonie (25,4%). Die proximale Muskelschwäche trat häufiger bei Frauen als bei Männern auf (p=0.0006). Hingegen trat bei Männer öfters Myalgien auf (OR=2.94 [95%CI 1.53-5.67]; P = 0.0012). Die Patienten mit Muskelschwäche als Erstsymptom waren älter als solche mit Myalgie und/oder Myotonie (Median 49, vs. 39 und 30 Jahren, p<0.0001). Mit zunehmender Erkrankungsdauer sankt pro Jahr die Wahrscheinlichkeit eine Myotonie zu entwickeln um 10% [OR 0.9 (95% CI 0.87–0.93) p<0.0001] und Myalgien um 6% [OR 0.94 (95% CI 0.91–0.97), p<0.0001]. Die häufigsten multisystemischen Komorbiditäten waren: Katarakt (49%), Dyslipidämie (41%), Schilddrüsenerkrankungen (32%) und ein Diabetes Mellitus (30%). Katarakt und Schilddrüsenerkrankung traten häufiger bei Frauen (jeweils p = 0,002) als bei Männern auf. Der frühe Erkrankungsbeginn ist ein unabhängiger Risikofaktor für das Auftreten von multisystematischer Organbeteiligung [OR 0.94 (95% CI 0.90–0.98)]. Zusammenfassend konnte in dieser aktualisierten klinischen Phänotyp-Beschreibung der DM2 ein deutlicher Einfluss von Alter und Geschlecht auf den Phänotyp gezeigt werden. Bei Frauen und mit steigendem Lebensalter wird die Krankheitslast progredient größer. Diese alters- und geschlechtsspezifischen Unterschiede müssen bei der Diagnosestellung, beim Management und in zukünftigen klinischen Studien der DM2 berücksichtigt werden

Releasing Down and Swinging Up: Exploring External Expression through Internal Fall

The goal of my thesis was to investigate how to externalize onstage my inner experience with authenticity and integrity. Using the challenge of playing the role of Irina in Anton Chekhovs Three Sisters, a version of the play where she is Deaf, I investigated how to externally communicate an internal experience through the use of the fall. This paper begins with in-studio research of my personal artistic challenge of releasing in order to externalize. It documents my summer work on physicality and voice while researching and training in American Sign Language. My scholarly research explores the phenomena of the fall as distinct from collapse and release, the life of the playwright, the context of the play, and finally, character analysis of Irina. This paper concludes with my findings from the rehearsal process

Bayesian Psychiatry and the Social Focus of Delusions

A large and growing body of research in computational psychiatry draws on Bayesian modelling to illuminate the dysfunctions and aberrations that underlie psychiatric disorders. After identifying the chief attractions of this research programme, we argue that its typical focus on abstract, domain-general inferential processes is likely to obscure many of the distinctive ways in which the human mind can break down and malfunction. We illustrate this by appeal to psychosis and the social phenomenology of delusions

Impact of Hepatic Encephalopathy in Cirrhosis on Quality-of-Life Issues

Hepatic encephalopathy (HE) has a major impact on health-related quality of life (HRQOL) in patients, which has clinical and psychosocial consequences. HRQOL in cirrhosis has been measured by generic and liver-specific instruments, with most studies indicating a negative impact of HE. HRQOL abnormalities span daily functioning, sleep-wake cycle changes, and the ability to work. Of these, sleep-wake cycle changes have a major effect on HRQOL, which remains challenging to treat. The personal effect of HRQOL is modulated by the presence of HE, the etiology of cirrhosis, and cognitive reserve. Patients with higher cognitive reserve are able to tolerate HE and its impact on HRQOL better than those with a poor cognitive reserve. The impact of HRQOL impairment is felt by patients (higher mortality and poor daily functioning), as well as by caregivers and families. Caregivers of patients with HE bear a major financial and psychological burden, which may affect their personal health and longevity

Transcranial Direct Corrent stimulation (tDCS) of the anterior prefrontal cortex (aPFC) modulates reinforcement learning and decision-making under uncertainty: A doubleblind crossover study

Reinforcement learning refers to the ability to acquire information from the outcomes of prior choices (i.e. positive and negative) in order to make predictions on the effect of future decision and adapt the behaviour basing on past experiences. The anterior prefrontal cortex (aPFC) is considered to play a key role in the representation of event value, reinforcement learning and decision-making. However, a causal evidence of the involvement of this area in these processes has not been provided yet. The aim of the study was to test the role of the orbitofrontal cortex in feedback processing, reinforcement learning and decision-making under uncertainly. Eighteen healthy individuals underwent three sessions of tDCS over the prefrontal pole (anodal, cathodal, sham) during a probabilistic learning (PL) task. In the PL task, participants were invited to learn the covert probabilistic stimulusoutcome association from positive and negative feedbacks in order to choose the best option. Afterwards, a probabilistic selection (PS) task was delivered to assess decisions based on the stimulus-reward associations acquired in the PL task. During cathodal tDCS, accuracy in the PL task was reduced and participants were less prone to maintain their choice after positive feedback or to change it after a negative one (i.e., winstay and lose-shift behavior). In addition, anodal tDCS affected the subsequent PS task by reducing the ability to choose the best alternative during hard probabilistic decisions. In conclusion, the present study suggests a causal role of aPFC in feedback trial-by-trial behavioral adaptation and decision-making under uncertainty

Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure

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Non-dystrophic myotonias: clinical and mutation spectrum of 70 German patients

Introduction. Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in a large German cohort. Methods. We retrospectively identified all patients with genetically confirmed NDM diagnosed in our center. The following data were analyzed: demographics, family history, muscular features, cardiac involvement, CK, EMG, genotype, other tested genes, treatment perceived efficacy. Results. 70 patients (age 40.2 years ± 14.9; 52.8% males) were included in our study (48 NDM-CLCN1, 22 NDM-SCN4A). The most frequent presenting symptoms were myotonia (NDM-CLCN1 83.3%, NDM-SCN4A 72.2%) and myalgia (NDM-CLCN1 57.4%, NDM-SCN4A 52.6%). Besides a more prominent facial involvement in NDM-SCN4A and cold-sensitivity in NDM-CLCN1, no other significant differences were observed between groups. Cardiac arrhythmia or conduction defects were documented in sixNDM-CLCN1 patients (three of them requiring a pacemaker) and one patient with NDM-SCN4A. CK was normal in 40% of patients. Myotonic runs in EMG were detected in 89.1% of CLCN1 and 78.9% of SCN4A. 50% of NDM-CLCN1 patients had the classic c.2680C>T (p.Arg894*) mutation. 12 new genetic variants are reported. About 50% of patients were not taking any anti-myotonic drug at the last follow-up. The anti-myotonic drugs with the best patient’s perceived efficacy were mexiletine and lamotrigine. Conclusion. This study highlights the relevant clinical overlap between NDM-CLCN1 and NDM-SCN4A patients and warrants the use of early and broad genetic investigation for the precise identification of the NDM subtype. Besides the clinical and genetic heterogeneity, the limited response to current anti-myotonic drugs constitutes a continuing challenge